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Hacker & Moore’s

E S S E N T I A L S O F

OBSTETRICS & GYNECOLOGY

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Hacker & Moore’s

E S S E N T I A L S O F

OBSTETRICS & GYNECOLOGY

Sixth Edition

Neville F. Hacker, MD Professor of Gynaecologic Oncology

Conjoint, University of New South Wales Director, Gynaecological Cancer Centre

Royal Hospital for Women Sydney, Australia

Joseph C. Gambone, DO, MPH, Executive Editor Professor Emeritus of Obstetrics and Gynecology

David Geffen School of Medicine at UCLA Attending Physician, Ronald Reagan UCLA Medical Center

Clinical Professor of Obstetrics and Gynecology Western University of Health Sciences

College of Osteopathic Medicine of the Pacific Private Infertility and Reproductive Endocrinology Practice, Durango, Colorado

Calvin J. Hobel, MD Miriam Jacobs Chair in Maternal-Fetal Medicine

Cedars-Sinai Medical Center Professor of Obstetrics and Gynecology

Professor of Pediatrics David Geffen School of Medicine at UCLA

Los Angeles, California

1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899

HACKER & MOORE’S ESSENTIALS OF OBSTETRICS & GYNECOLOGY, SIXTH EDITION

ISBN: 978-1-4557-7558-3

INTERNATIONAL EDITION ISBN: 978-0-323-34053-3

Copyright © 2016 by Elsevier, Inc. All rights reserved.

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This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.

With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions.

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Previous editions copyrighted 2010, 2004, 1998, 1992, and 1986.

Library of Congress Cataloging-in-Publication Data

Hacker & Moore’s essentials of obstetrics & gynecology / [edited by] Neville F. Hacker, Joseph C. Gambone, Calvin J. Hobel.—6th edition.

p. ; cm. Hacker and Moore’s essentials of obstetrics and gynecology Essentials of obstetrics and gynecology Preceded by Hacker and Moore’s essentials of obstetrics and gynecology / [edited by] Neville F. Hacker, Joseph

C. Gambone, Calvin J. Hobel. Includes bibliographical references and index. ISBN 978-1-4557-7558-3 (pbk. : alk. paper)–ISBN 978-0-323-34053-3 (international edition) I. Hacker, Neville F., editor. II. Gambone, Joseph C., editor. III. Hobel, Calvin J., editor. IV. Title: Hacker

and Moore’s essentials of obstetrics and gynecology. V. Title: Essentials of obstetrics and gynecology. [DNLM: 1. Obstetrics–methods. 2. Genital Diseases, Female. 3. Pregnancy Complications. WQ 100] RG101 618—dc23

2015035364

Acquisitions Editor: James Merritt Developmental Editor: Julia Rose Roberts Publishing Services Manager: Catherine Jackson Project Manager: Rhoda Howell Design Manager: Renee Duenow Illustrations Manager: Nichole Beard Marketing Manager: Melissa Darling

Printed in Canada

Last digit is the print number: 9 8 7 6 5 4 3 2 1

This edition is dedicated to our wives,

Estelle Hacker, Marge (Morris) Gambone, and Marsha Lynn Hobel.

Their understanding and support for the time and effort required

to complete this project was essential.

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vii

Contributors

Carolyn J. Alexander, MD Southern California Reproductive Center Beverly Hills, California; Clinical Associate Professor David Geffen School of Medicine at UCLA University of California, Los Angeles Los Angeles, California

Jonathan S. Berek, MD, MMS Laurie Kraus Lacob Professor Chair, Department of Obstetrics and Gynecology Stanford University School of Medicine Director, Stanford Women’s Cancer Center Director, Stanford Health Care Communication

Program Stanford, California

Lony C. Castro, MD, FACOG Specialist, Maternal-Fetal Medicine Professor and Chair, Department of Obstetrics and

Gynecology COMP/Western University of Health Sciences Pomona, California

Sara Churchill, MD Resident Physician Department of Obstetrics and Gynecology Cedars Sinai Medical Center Los Angeles, California

Daniel A. Dumesic, MD Professor, Department of Obstetrics and Gynecology Division Chief, Reproductive Endocrinology and

Infertility David Geffen School of Medicine at UCLA University of California, Los Angeles Los Angeles, California

Michael L. Friedlander, PhD, FRACP Conjoint Professor of Medicine Prince of Wales Clinical School University of New South Wales Sydney, Australia

Brian J. Koos, MD, DPhil Professor, Department of Obstetrics and Gynecology David Geffen School of Medicine at UCLA University of California, Los Angeles Los Angeles, California

Amy R. Lamb, PhD, CNM Nurse-Midwife and Researcher Obstetrics and Gynecology Cedars-Sinai Medical Center Los Angeles, California

Anita L. Nelson, MD Professor, Department of Obstetrics and Gynecology David Geffen School of Medicine at UCLA University of California, Los Angeles Los Angeles, California; Medical Director, Research Division California Family Health Council Los Angeles, California

William H. Parker, MD Health Sciences Clinical Professor Department of Obstetrics and Gynecology UCLA School of Medicine Santa Monica, California

Andrea J. Rapkin, MD Professor of Obstetrics and Gynecology David Geffen School of Medicine at UCLA University of California, Los Angeles Los Angeles, California

Bassam H. Rimawi, MD, FACOG Department of Gynecology and Obstetrics Division of Reproductive Infectious Diseases and

Maternal Fetal Medicine Emory University School of Medicine Atlanta, Georgia

viiiviii C O N T R I B U T O R S

Ingrid A. Rodi, MD Health Sciences Clinical Professor Director, Fertility Services UCLA Medical Center Santa Monica, California

Amy E. Rosenman, MD, FACOG, FPMRS Health Sciences Clinical Professor of Obstetrics and

Gynecology David Geffen School of Medicine at UCLA University of California, Los Angeles Los Angeles, California

David E. Soper, MD J. Marion Sims Professor Department of Obstetrics and Gynecology Medical University of South Carolina Charleston, South Carolina

John Williams III, MD Clinical Professor Department of Obstetrics and Gynecology David Geffen School of Medicine at UCLA University of California, Los Angeles Director of Reproductive Genetics Department of Obstetrics and Gynecology Cedars-Sinai Medical Center Los Angeles, California

Mark Zakowski, MD Associate Professor of Anesthesiology Adjunct, Charles Drew University of Medicine and

Science Chief, Obstetric Anesthesiology, Cedars-Sinai Medical

Center Los Angeles, California

ix

Preface

It has been thirty years since the first edition of Essen- tials of Obstetrics and Gynecology was published. As stated in the Preface to the First Edition, there was then, and continues to be today, a need for a textbook that covers the essential aspects of the specialty of Obstetrics and Gynecology, which is written primarily for the student and resident physician training in the field. The text has become known as ”Hacker and Moore” over the years, as a tribute to the pioneering work of the original editors. The late J. George “Jerry” Moore was the Professor and Chairman of Obstetrics and Gynecology at the University of California at Los Angeles (UCLA), and the concept for the book was his. Neville Hacker was then an Assistant Professor in the Department and was in charge of the Student Clerk- ship. He was co-opted by Jerry to co-edit the book, after the entire UCLA faculty had agreed to participate in its writing.

The first edition of any textbook contains the vision and forms the foundation of the intent of the work, as outlined in the original preface. The editors have always felt that a new edition should be published only when there was significant new clinical information to report. Based on that standard, we believe it is now time for the sixth and latest edition of “Hacker and Moore” to be published.

Medical education is continuously evolving, and has changed significantly since the first edition of this text- book was published in 1986. The internet with its world-wide web and other technologies have made information instantly available to students and resi- dents on a mobile phone or tablet during a clinical meeting. They are being taught to be life-long learners and information seekers. The classroom dynamics have been flipped in the past decade, in the sense that information transfer and gathering occurs before a

seminar, with classroom time now increasingly devoted to discussions and problem solving by teams of stu- dents supported by diverse faculty mentors. This is appropriate, because health care is increasingly being delivered by multidisciplinary teams of professionals rather than by individual practitioners. With the ever- increasing complexity of medical and surgical care, this trend is expected to continue.

Textbooks have the recognized disadvantage of not always containing the latest information on a topic and of having a limited “shelf life.” But just as newspapers and periodicals (printed or electronic) provide a “first and early draft” of human history and require frequent correction over time, medical texts should contain and document the time-tested facts of a discipline, along with newer information viewed through the prism of evidence-based and safe practice. It is our belief that textbooks will continue to provide the reliable essen- tials of all clinical practice, including the practice of obstetrics and gynecology.

All of the 42 chapters in this edition have been updated. Some chapters have been completely rewrit- ten. Others have been modified due to changes in clini- cal practice. As was the case in previous editions of this text, we have worked to include only the “essentials” of obstetrics and gynecology, making difficult choices about the breadth and depth of the material presented. Every attempt has been made to include material con- sistent with the learning objectives and goals proposed by the Association of Professors in Gynecology and Obstetrics (APGO), available on their website at www. apgo.org.

In addition to the authors and editors of this current edition, we wish to acknowledge and thank those who have contributed to all previous editions.* Their knowl- edge and wisdom contained in their words, some of

*Contributors from all previous editions: Juan J. Arce, Carol L. Archie, Ricardo Azziz, Martha J. Baird, Richard A. Bashore, A. David Barnes, Michael J. Bennett, Narender N. Bhatia, Jennifer Blake, Clifford Bochner, J. Robert Bragonier, Charles R. Brinkman III, Michael S. Broder, Philip G. Brooks, John E. Buster, Maria Bustillo, Richard P. Buyalos, Mary E. Carsten (deceased), Anita Bachus Chang, R. Jeffrey Chang, George Chapman, Ramen H. Chmait, Gautam Chaudhuri, Kenneth A. Conklin, Irvin M. Cushner (deceased), Alan H. DeCherney, Cath- erine Marin DeUgarte, William J. Dignam (deceased), John A. Eden, Bruce B. Ettinger, Ozlem Equils, Robin Farias-Eisner, Larry C. Ford (deceased), Michelle Fox, Janice I. French, Ann Garber, Anne D.M. Graham, Paul A. Gluck, William A. Growdon, John Gunning (deceased), Lewis A. Hamilton, Hunter A. Hammill, George S. Harris, Robert H. Hayashi, James M. Heaps, Howard L. Judd (deceased),

Continued

xx P R E FA C E

which remain in this edition, form the foundation of this work and will continue to enlighten future stu- dents of obstetrics and gynecology.

We greatly appreciate, and wish to acknowledge, the support and professionalism of James Merritt and his excellent production staff, particularly Rhoda Howell, Rachel McMullen, Amy Meros, and Julia Roberts at

Elsevier. We hope that the knowledge acquired from this book will encourage many to pursue a more in depth study of the specialty.

Joseph C. Gambone (Executive Editor) Neville F. Hacker

Calvin J. Hobel

Daniel A. Kahn, Samir Khalife, Ali Khraibi, Matthew Kim, Oscar A. Kletzky (deceased), Grace Elizabeth Kong, Larry R. Laufer, Thomas B. Lebherz (deceased), Joel B. Lench, Ronald S. Leuchter, John K.H. Lu, Michael C. Lu, Donald E. Marsden, John Marshall, Ruchi Mathur, James A. McGregor, Arnold L. Medearis deceased) David R. Meldrum, Robert Monoson, J. George Moore (deceased), Thomas R. Moore, John Morris (deceased), Suha H.N. Murad, Sathima Natarajan, Lauren Nathan, John Newnham, Tuan Nguyen, Bahij S. Nuwayhid, Gary Oakes, Dotun Ogunyemi, Aldo Palmieri, Groesbeck P. Parham, Ketan S. Patel, Margareta D. Pisarska, Gladys A. Ramos, Anthony E. Reading, Robert C. Reiter, Jean M. Ricci (Goodman), Michael G. Ross, Edward W. Savage, William D. Schlaff, Mousa Shamonki, James R. Shields, Klaus J. Staisch (deceased), Eric Surrey, Khalil Tabsh, Christopher M. Tarnay, Maryam Tarsa, Nancy Theroux, Paul J. Toot, Maclyn E. Wade (deceased), Nathan Wasserstrum, Barry G. Wren, and Linda Yielding.

2

1 CHAPTE R

CALVIN J. HOBEL • JOSEPH C. GAMBONE

A Life-Course Perspective for Women’s Health Care Safe, Ethical, Value-Based Practice with a Focus on Prevention

■  Clinical  practice  in  obstetrics  and  gynecology,  based  upon the principles of safe, ethical and value-based care,  is  facilitated  by  viewing  wellness  and  sickness  in  the  context  of  a  life-course perspective.  Effective  clinical  care  of  mother  and  child  must  begin  early,  even  before  conception, and continue throughout life.

■  Adaptive developmental plasticity and epigenetic modi- fication of genes during and after pregnancy can have a  significant impact on chronic diseases later in life.

■  Clinicians  should  incorporate  the  major  ethical  princi- ples  of  nonmaleficence,  beneficence,  autonomy,  and  justice  into  their  practices,  along  with  the  duties  

and  ideals  of  confidentiality  and  multidisciplinary  collaboration.

■  Regulatory, economic, and public pressure make assess- ment  and  improvement  of  safety  and  value  essential   in  the  delivery  of  women’s  health  care.  Optimal  health  outcomes  can  only  be  achieved  when  principles  from  continuous quality assessment and high reliability orga- nizations are combined with the systematic approach of  safety science and evidence-based medicine.

■  The  promising  area  of  clinical  preventive  services  in  obstetrics  and  gynecology,  as  in  all  heath  care,  is  trans- forming the practice of medicine in a very positive way.

CLINICAL KEYS FOR THIS CHAPTER

This chapter of Essentials of Obstetrics and Gynecology  is being revised at a time when the health and wellness  of the population of the United States and some other  developed  countries  of  the  world  are  being  evaluated  and  questioned.  A  recent  study  by  the  Harvard  Busi- ness  School  conducted  by  Professor  Michael  Porter  and his team ranked the United States only 70th in the  world in terms of overall health and wellness. Despite the fact that the United States spends far more on health care  (nearly  18%  of  gross  domestic  product  or  GDP) than any other nation, it continues to be ranked only about 37th out of 191 nations for health status and health system performance.  Further,  the  United  States  is  ranked  only  46th  for  average  life-expectancy  and  42nd  for  infant  mortality  by  the  World  Health  Organization  (WHO).  Clearly,  the  United  States  must  strive to improve its standing on these and other mea- sures of performance. This is especially important at a  time  when  the  health  care  delivery  system  enters  the  era  of  the  Affordable  Care  Act  (ACA),  and  efforts  to  provide  care  to  all  citizens  at  a  reasonable  cost  are  underway.

Obstetrics  and  gynecology  is  one  of  the  most   exciting  and  challenging  areas  of  health  care,  with  a 

number  of  significant  opportunities  for  improvement  such  as  infant  and  maternal  mortality.  The  specialty  provides  students  and  young  physicians  in  training  with  the  knowledge  and  skills  necessary  to  improve   the  health  of  women  and  their  children  very  early  in  their lives. In this first chapter of the book, some basic  principles and guidelines for improving health care are  provided, and several important factors that are influ- encing  the  health  of  women  and  their  children  are  suggested.

Principles of Practice There are four basic principles for practicing and improving health care. First, the safety of our patients must always be paramount.  In  recent  years  we  have  made  major  improvements  in  patient  safety,  in  large  part  by  emphasizing  teamwork  and  implementing  practices proven to be effective in the airline industry.  Second, we must be true to our personal pledge made when taking the Hippocratic Oath—to adhere to ethical practices. Third, we must transform to a value- based system of health care delivery.  Because  medi- cine  has  become  very  complex,  we  must  be  open  to  a 

C H A P T E R 1 A Life-Course Perspective for Women’s Health Care 3

structure  include  altered  DNA  methylation  by  both  histone acetylation and methylation.

Since the last edition of this text, investigators have  determined  that  alterations  in  the  in  utero  environ- ment during pregnancy may result in modifications to  the chromatin structure. These modifications may lead  to  persistent  changes  in  postnatal  gene  expression  which  may  render  the  child  more  susceptible  to   early onset adult disease. The conditions during preg- nancy that account for these epigenetic changes are preeclampsia, preterm birth, intrauterine growth restriction (IUGR), obesity, diabetes, poor nutrition, smoking, and some cancers.  Even  the  mothers  with  these  pregnancy  conditions  are  themselves  at  greater  risk for cardiovascular disease, hypertension, and dia- betes later in life. The onset for these conditions occurs  earlier  in  life  compared  to  those  women  who  have  normal pregnancies. Thus having a normal pregnancy may be protective of disease later in life.

It is now thought that the effect of harmful behav- iors and our environment on the expression of our genes may account for up to 40% of all premature deaths in the United States. Two of the top behavioral  factors related to this premature death rate are obesity  (and  its  usual  physical  inactivity)  and  smoking.  Envi- ronmental  exposures  to  metals,  solvents,  pesticides,  endocrine disruptors, and other reproductive toxicants  are also major concerns.

Second, in human biology, a phenomenon called adaptive developmental plasticity plays a very impor- tant role in helping to adjust behavior to meet any environmental challenge.  In  order  to  understand  human  development  over  time  (a life-course perspec- tive),  one  must  first  understand  what  is  normal  and  what  adverse  circumstances  may  challenge  and  then  change  normal  development  of  the  fetus.  These pro- tective modifications of growth and development which are programmed in utero to prevent fetal death, may become permanent.  The  price  the  fetus  may pay for short-term survival is later vulnerability to  conditions such as obesity, hypertension, insulin resis- tance, atherosclerosis, and even diabetes.

In relation to individual X and individual Y with the  same genomic makeup but different in utero environ- mental influences, metabolic changes that may be ini- tiated  in  utero  in  response  to  inadequate  nutritional  supplies (Figure 1-1) can lead to insulin resistance and  eventually  the  development  of  type  2  diabetes.  These  adaptive changes can even result in a reduced number  of nephrons in the kidneys as a stressed fetus conserves  limited nutritional resources for more important organ  systems in utero. This can then lead to a greater risk of  hypertension later in life.

This series of initially protective but eventually harmful developmental changes was first described in humans by David Barker, a British epidemiologist, who carefully assessed birth records of individuals

more cost-effective multidisciplinary approach to both  diagnostic  and  therapeutic  practice.  Performance  improvement efforts, practice management skills, and  effective communication are all necessary to efficiently  optimize  clinical  outcomes  and  value.  Fourth,  and  perhaps most importantly, we must focus on the pre- vention and early mitigation of disease, in addition to  our  continued  focus  on  its  treatment.  This  should  occur  in  a  patient-centered  manner,  meeting  their  needs and expectations.

For this reason, we emphasize an approach called a  life-course perspective for clinical practice, beginning  with  preconception  health,  continuing  throughout  pregnancy,  the  postpartum  period  (interconception  health),  and  then  giving  children  and  their  mothers  a  health perspective  for  adopting  and  maintaining  healthy living.

Before delving more deeply into these principles of  practice  (safety,  ethics,  value,  and  prevention),  some  newer concepts about the origins of disease are impor- tant to mention.

LIFE-COURSE PERSPECTIVE When does disease begin and lead to pathology and illness during the course of life?

First, although genetics is beginning to provide a much better understanding of the etiology of poor health, it probably accounts for only about one-third of the direct causes.  Imprinted  genes  from  both  the  mother and the father play an important role in passing  on  characteristics  to  the  offspring.  This  imprinting  process maintains the phenotype of the family in sub- sequent  generations.  However,  some  imprinted  and  nonimprinted genes can be upregulated or downregu- lated  by  subsequent  epigenetic  modifications,  due  to  environmental influences. For example, person X with  gene A has a disease but person Y with the same gene  does not. Clearly there is more to human development  and  disease  risk  than  genetic  makeup.  Currently  it  is  thought that factors such as poverty or abnormal health  behaviors  (poor  nutrition  and  smoking)  and/or  envi- ronmental  conditions  can  influence  the  expression  of  gene A without actually changing its genomic makeup.  This  may  occur  directly  or  these  factors  may  activate  another gene, A-2 downstream, which may then affect  gene A. This process whereby human cells can have the  same  genomic  makeup  but  different  characteristics  is  referred to as epigenetics (literally meaning “on top of genetics”), an exciting new frontier.

The developmental origins of adult disease hypoth- esis (Barker hypothesis) postulates that perturba- tions in the gestational environment may influence the development of adult diseases such as cardiovas- cular disease, obesity, diabetes, and stroke.  Current  evidence  suggests  that  this  occurs  through  the  repro- gramming of gene expression via epigenetic changes in  chromatin structure. Epigenetic changes in chromatin 

4 PA R T 1 Introduction

Normally,  as  soon  as  the  fight  or  flight  is  over,  the  stress  response  is  turned  off.  The body’s sympathetic response is counteracted by a parasympathetic response, which fires a signal via the vagal nerve to slow down the heart, and the HPA axis is shut off by cortisol via negative feedback mechanisms. Negative  feedback mechanisms are common to many biological  systems  and  work  very  much  like  a  thermostat. When  the  room  temperature  falls  below  a  preset  point,  the  thermostat turns on the heat. Once the preset tempera- ture is reached, the heat turns off the thermostat. Stress  turns  on  the  HPA  axis  to  produce  cortisol.  Cortisol,  in  turn, turns off the HPA axis to keep the stress response  in check.

This stress response works well for acute stress but it tends to break down under chronic stress.  In  the  face  of  chronic  and  repeated  stress,  the  body’s  stress  response  is  always  turned  on,  and  over  time  will  wear  out.  The  body  goes  from  being  “stressed”  to  being  “stressed  out”—from  a  state  of  allostasis  to  allostatic overload. This describes the cumulative wear and tear  on  the  body’s  adaptive  systems  from  chronic  stress.  Helpful  physiologic  mechanisms  that  initially  protect  may eventually be harmful.

The life-course perspective synthesizes both the developmental programming mechanisms of early life events and allostatic overload mechanisms of chronic life stress into a longitudinal model of health development. It is a way of looking at life not as discon- nected  stages,  but  as  an  integrated  continuum.  Thus   to promote a healthy first pregnancy, preconception health should be a priority. To promote preconception  health,  adolescent  health  must  be  provided  to  young  girls so that as women having children, they are free of  diseases  such  as  diabetes,  hypertension,  and  obesity  and  have  been  encouraged  to  eat  a  healthy  diet  and   to  abstain  from  using  tobacco  products.  Rather than episodic care that many women now receive, as a specialty we must strive toward disease prevention and health promotion over the continuum of a woman’s life.

IMPACT ON PUBLIC HEALTH The public health implications of the Barker hypoth- esis and other life-course events are significant. This  is  the  beginning  of  an  exciting  era  in  medicine  where  young  physicians  and  other  health  care  professionals  can  begin  to  take  charge  of  these  events  and  change  our health care delivery system in a very positive way.  Patients should be encouraged to take responsibility for improving their own health, particularly by prac- ticing healthy behaviors early in life. They should also  be  encouraged  to  improve  and  maintain  a  healthy  “green”  environment.  Currently  there  are  only  a  few  environmental  and  behavioral  factors  that  have  been  clearly  identified  as  part  of  the  Barker  hypothesis.  Many others are yet to be discovered.

and linked low birth weight (<2500 grams) to the development of hypertension, diabetes, atheroscle- rosis, and stroke later in life. The association between  poor fetal growth during intrauterine life, insulin resis- tance,  and  cardiovascular  disease  is  known  as  the  Barker hypothesis. The process whereby a stimulus or  insult, at a sensitive or critical period of fetal develop- ment,  induces  permanent  alterations  in  the  structure  and  functions  of  the  baby’s  vital  organs  is  now  com- monly referred to as developmental programming.

Third, another important concept in the life- course perspective is allostasis, which describes the body’s ability to maintain stability during physiologic change. A good example of allostasis is found in the body’s stress response.  When  the  body  is  under  stress (biological or psychological), it activates a stress  response. The sympathetic system kicks in and adren- alin flows to make the heart pump faster and harder  (with  the  end  result  of  delivering  more  blood  and  oxygen  to  vital  organs  including  the  brain).  The hypothalamic-pituitary-adrenal (HPA) axis is also activated  to  produce  more  cortisol,  which  has  many  actions to prepare the body for fight or flight.

FIGURE 1-1 The potential effects of intrauterine nutrition on sub- sequent adult health. There are genetic, nutritional, and environ- mental causes of poor fetal growth leading to a small phenotype. Having a large phenotype at birth has advantages. These data form the basis of the “developmental origins of adult disease” hypoth- esis (Barker hypothesis). Having a low birth weight increases the risk for diseases and conditions such as hypertension, atheroscle- rosis, stroke, and diabetes later in life. For example, a nutritionally deprived fetus in utero may develop insulin resistance as an adap- tation to preserve glucose supply to the brain rather than releasing it from the circulation to other less important tissues. Later in life, the insulin resistance that was protective in utero could increase the risk of diabetes as an adult. (From Bateson P, Barker D, Clutton- Brock T, et al: Developmental plasticity and human health. Nature 430:419-421, 2004. Adapted by permission from Macmillan Pub- lishers Ltd.)

HighLow

Good

Poor

A d

u lt

h e

a lth

Nutritional level

Large phenotype (Body size)

Small phenotype (Body size)

C H A P T E R 1 A Life-Course Perspective for Women’s Health Care 5

to  an  adverse  drug  reaction  (ADR).  The  latter  may  account for 1 out of 5 injuries or deaths for hospitalized  patients.  ADRs  commonly  occur  from  an  overdose,  a  side  effect,  or  an  interaction  among  several  concomi- tantly administered drugs. In order to minimize ADRs, health care providers should avoid the following actions: 1.  Prescribing unnecessary medications 2.  Treating mild side effects of one drug with a second,

more toxic drug 3.  Misinterpreting a drug’s side effect for a new

medical problem  and  prescribing  another  medication

4.  Prescribing a medication when there is any uncer- tainty about dosing

In the absence of automated systems, providers should  strive to write legibly and use only approved abbrevia- tions  and  dose  expressions.  Most  health  care  facilities  publish and circulate an acceptable list of appropriate  abbreviations,  as  a  means  of  reducing  medication  errors.

MEDICAL ERROR REPORTING According  to  the  U.S.  Agency  for  Healthcare  Research  & Quality (AHRQ), “Reporting is an important compo- nent  of  systems  to  improve  patient  safety.”  Incident  reporting  is  an  important  and  inexpensive  method  to  detect medical error and prevent future adverse events.  Unfortunately,  this  method  may  fail  to  impact  clinical  outcomes  effectively,  because  most  hospital  reporting  systems do not capture the majority of errors. Report- ing should be considered a quality improvement process (focused on system failures) rather than a performance evaluation method (blaming individual providers).

As  a  founding  member  of  the  National  Patient  Safety  Foundation  and  the  National  Patient  Safety  Partnership,  the  Joint  Commission  on  the  Accredita- tion  of  Healthcare  Organizations  ( JCAHO),  now  more  commonly known as The Joint Commission (TJC), has  formed  a  coalition  with  the  U.S.  Pharmacopoeia  (USP),  the  American  Medical  Association  (AMA),  and  the  American  Hospital  Association  (AHA)  to  create  patient  safety  reporting  principles.  Recognizing  that  fear  of  liability  discourages  error  reporting,  TJC  has  advised  the  U.S.  Congress  that  federal  statutory  pro- tection  must  be  afforded  to  those  who  report  medical  error.  An anonymous nonpunitive environment will encourage reporting.  Many  states  have  implemented  mandatory  reporting  systems  for  selected  medical  errors  to  improve  patient  safety  and  reduce  errors.  Others  consider  incident  reporting  and  analysis  as  peer  review  activities  immune  from  liability.  The IOM report recommends that health care providers be required to report errors that result in serious harm. Information collected should be made available to the public.  AHRQ  publishes  case  summaries  of 

Adaptive  developmental  plasticity  will  take  place  secondary  to  changes  in  genes  as  a  result  of  environ- mental and behavioral practices. Even the controversial  concept of climate change may play a role in this phe- nomenon.  Biological  processes  are  very  powerful  and  frequently unpredictable. Physicians must increasingly  strive for a safe, ethical, and value-based practice.

In order to facilitate the improvement of the health  and  wellness  of  women  and  children,  four  basic  prin- ciples  of  practice  should  guide  our  strategy:  patient safety, ethical practice, value,  and  the  need  for  a  patient-centered focus on prevention, as follows.

Patient Safety—The First Principle of Practice Safety  in  health  care  is  not  a  new  concept.  Facilities  have had safety programs in place since the early 1900s,  but  these  programs  have  traditionally  focused  on  emergency  preparedness,  environmental  safety,  secu- rity,  and  infection  control.  The  term  patient safety,  meaning  avoidance  of  medical  error,  was  first  coined  by  the  American  Society  of  Anesthesiologists  in  1984,  when  they  inaugurated  the  Anesthesia  Patient  Safety  Foundation  to  give  assurance  that  the  effects  of  anes- thesia would not harm patients.

Medical errors now rank as the fifth leading cause of death in the United States. The Institute of Medicine  (IOM)  published  an  alarming  report  in  1999  called  To Err Is Human: Building a Safer Health System.  This  report  estimated  that  between  44,000  and  98,000  Americans  die  each  year  as  a  result  of  medical  errors.  Error is defined as failure of a planned action to be completed as intended (e.g., failing to operate when obvious signs of appendicitis are present) or the use of a wrong plan to achieve an aim (e.g., wrong diag- nosis, wrong medication administered).  Medication  errors alone, occurring either in or out of the hospital,  are  estimated  to  account  for  over  7,000  deaths  annu- ally.  According  to  the  National  Council  on  Patient  Information and Education, “more than 2/3 of all phy- sician  visits  end  with  a  prescription.”  An  estimated  39-49%  of  all  medication  errors  occur  at  the  stage  of  drug  ordering.  Patient noncompliance also contrib- utes to medical errors.

The U.S. Pharmacopoeia (USP) MedMARx error tracking service estimates that as many as 100,000 medication errors occur annually.  Because  reporting  is voluntary and does not include all medical facilities  in the United States, the scope of the problem is likely  to  be  much  larger.  A  preventable  adverse  drug  event  (ADE)  is  one  type  of  medication  error.  Administering  the incorrect drug, an incorrect dose, wrong frequency,  or incorrect route may cause an ADE.

A drug that cures one patient’s condition may be the  one  that  causes  another  patient’s  injury  or  death  due 

6 PA R T 1 Introduction

ideals  and  the  concepts  derived  from  them  are  com- monly  accepted  and  taken  into  account.  Four  such  principles  or  ideals  are  nonmaleficence, beneficence, autonomy, and justice;  these  are generally accepted as the major ethical concepts that apply to health care.

NONMALEFICENCE The principle of primum non nocere or “first, do no harm” originates from the Hippocratic school, and although few would dispute the basic concept, in day- to-day medical practice, physicians and their patients may need to accept some harm from treatment (such as necessary surgical trauma) in order to achieve a desired outcome.  However,  there  is  an  ethical  obliga- tion  to  be  certain  that  recommended  medical  treat- ment,  surgery,  or  diagnostic  testing  is  not  likely  to  cause more harm than benefit.

BENEFICENCE The  duty  of  beneficence,  or  the  promotion  of  the  welfare of patients, is an important part of the Hippo- cratic Oath. Most would see its strict application as an  ideal rather than a duty, however. One could save many  suffering people in a Third World country by practicing  there or by giving a large portion of one’s income in aid,  but few would consider it a moral duty to do so. On the  other hand, when the concept of beneficence involves a specific patient encounter, the duty applies. A physi- cian prevented by conscience from participating in the  performance of an abortion, for example, would gener- ally be expected to provide lifesaving care for a woman  suffering  complications  after  such  a  procedure— putting her welfare first.

AUTONOMY The  right  of  self-determination  is  a  basic  concept  of  biomedical  ethics.  To exercise autonomy, an individ- ual must be capable of effective deliberation and be neither coerced into a particular course of action nor limited in her or his choices by external constraints.  Being  capable  of  effective  deliberation  implies  a  level  of  intellectual  capacity  and  the  ability  to  exercise  that  capacity. There  are  a  number  of  situations  in  which  it  may  be  reasonable  to  limit  autonomy:  (1)  to  prevent  harm to others, (2) to prevent self-harm, (3) to prevent  immoral acts, or (4) to benefit many others.

The concept of informed consent is derived directly  from  the  principle  of  autonomy,  and  from  a  desire  to  protect  patients  and  research  subjects  from  harm.  There is general agreement that consent must be gen- uinely voluntary and made after adequate disclosure of information.  As  a  minimum,  when  a  patient  con- sents to a procedure in health care, the patient should  be informed about the expectation of benefit as well as  the  other  reasonable  alternatives  and  possible  risks  that  are  known.  Table  1-1  provides  a  useful  checklist 

reported  medical  errors  and  near  misses  on  their   website.

DISCLOSURE OF MEDICAL ERROR The  National  Patient  Safety  Foundation  (NPSF)  was  one  of  the  first  organizations  to  address  the  issue  of  disclosure. Their position, finalized in November 2000,  states, “When a health care injury occurs, the patient and the family or representatives are entitled to a prompt explanation of how the injury occurred and its short- and long-term effects. When  an  error  con- tributed  to  the  injury,  the  patient  and  the  family  or  representatives should receive a truthful and compas- sionate  explanation  about  the  error  and  the  remedies  available to the patient. They should be informed that  the factors involved in the injury will be investigated so  that  steps  can  be  taken  to  reduce  the  likelihood  of  similar injury to other patients.”

The Joint Commission now requires hospitals to dis- close any serious harm caused by medical errors to the  harmed  parties.  Disclosing  an  error  can  be  very  diffi- cult  for  physicians  because  they  may  struggle  with  intense  feelings  of  incompetence,  betrayal  of  the  patient, and fear of litigation. Studies suggest that phy- sicians with good relationship skills are less likely to get sued. Furthermore, suits are settled more rapidly and for less money if errors are disclosed early. Simple rules for disclosing errors include: admit the mistake, acknowledge the listener’s anger, speak slowly, and stop frequently to allow the listener to talk.  Usually,  the  attending  physician  is  the  one  who  should  make  the disclosure and offer an apology.

Ethical Practice— The Second Principle Obstetrics  and  gynecology  encompasses  many  high- profile areas of ethical concern such as in vitro fertiliza- tion (IVF) and other assisted reproductive technologies  (ART),  abortion,  the  use  of  aborted  tissue  for  research  or treatment, surrogacy, contraception for minors, and  sterilization of persons with a mental illness. Neverthe- less, most ethical problems in the practice of medicine  arise in cases in which the medical condition or desired  procedure  itself  presents  no  moral  problem.  In the past, the main areas of ethical concern have related to the competence and beneficence of the physician. Current areas of ethical concern should include the goals, values, individual and appropriate cultural preferences of the patient, as well as those of the com- munity at large. Consideration of such issues enriches  the study of obstetrics and gynecology by emphasizing  that scientific knowledge and technical skills are most  meaningful in a social and moral context.

During  the  day-to-day  consideration  of  ethical  dilemmas  in  health  care,  a  number  of  principles  or 

C H A P T E R 1 A Life-Course Perspective for Women’s Health Care 7

considerations  of  autonomy  but  also  helps  promote  beneficence,  as  is  the  case  with  honesty.  In  obstetrics  and  gynecology,  conflicts  can  arise  as  in  the  case  of  a  woman  with  a  sexually  transmitted  infection  who  refuses to have a sexual partner informed, or a school- aged child seeking contraceptive advice or an abortion.

There are many other situations in which conflicting  responsibilities  make  confidentiality  a  difficult  issue.  The U.S. Health Insurance Portability and Accountabil- ity  Act  (HIPAA)  mandates  strict  rules  that  physician  practices  and  health  care  facilities  must  adhere  to  regarding  the  confidentiality  and  security  of  patient  health  care  records.  Some  are  concerned  that  these  regulations could restrict the flow of information about  patient care and may hinder efforts to improve overall  performance.

Caring  for  a  pregnant  woman  creates  a  unique  maternal-fetal relationship because the management  of the mother inevitably affects her baby. Until recently,  the only way by which an obstetrician could produce a  healthy  baby  was  by  maintaining  optimal  maternal  health,  but  as  the  fetus  becomes  more  accessible  to  diagnostic  and  therapeutic  interventions,  new  prob- lems emerge. Procedures performed on behalf of the fetus may violate the personal integrity and auton- omy of the mother.  The  obstetrician  with  a  dual  responsibility  to  mother  and  fetus  faces  a  potential  conflict of interest. Most conflicts will be resolved due to the willingness of most women to undergo consid- erable self-sacrifice to benefit their fetus.  When  a  woman  refuses  consent  for  a  procedure  that  presents  her  with  significant  risk,  her  autonomy  will  generally  be respected. However, there may be cases in which an  intervention that is likely to be efficacious carries little  risk  to  the  mother  and  can  reasonably  be  expected  to  prevent substantial harm to the fetus. These have occa- sionally ended in a court-ordered intervention.

Health care is a multidisciplinary activity and respectful and collegial relationships with other health professionals are very important. Although the  physician  has  traditionally  been  the  only  decision  maker, this situation has often caused concern among  other  health  care  professionals.  There is increasing

(PREPARED)  that  expands  on  the  minimum  informa- tion required.

The  exercise  of  autonomy  may  put  considerable  stress and conflict on those providing health care, as in  the case of a woman with a ruptured ectopic pregnancy  who refuses a lifesaving blood transfusion for religious  reasons and dies despite the best efforts of the medical  team. More complex questions may be raised by court- ordered cesarean deliveries for the benefit of the fetus.

JUSTICE Justice  relates  to  the  way  in  which  the  benefits  and  burdens of society are distributed. The general princi- ple that equals should be treated equally was espoused  by  Aristotle  and  is  widely  accepted  today,  but  it  does  require  that  one  be  able  to  define  the  relevant  differ- ences  between  individuals  and  groups.  Some  believe  all rational persons to have equal rights; others empha- size  need,  effort,  contribution,  and  merit;  still  others  seek  criteria  that  maximize  both  individual  and  social  utility.  In most Western societies, race, sex, and reli- gion are not considered morally legitimate criteria for the distribution of benefits, although they too may be taken into account in order to right what are per- ceived to be historic wrongs, in programs of affirma- tive action. When resources are scarce, issues of justice  become even more problematic. There are often com- peting claims from parties who appear equal by all rel- evant  criteria,  and  the  selection  criteria  themselves  become a moral issue. Most modern societies find the  rational rationing of health care resources to be appro- priate and acceptable (Figure 1-2).

OTHER DUTIES OF ETHICAL PRACTICE Confidentiality is a cornerstone of the relationship between physician and patient. This duty arises from 

TABLE 1-1

THE PREPARED SYSTEM: A CHECKLIST TO GUIDE PATIENT AND PROVIDER IN THE PROCESS OF INFORMED CONSENT

P lan The course of action being considered

R eason The indication or rationale

E xpectation The chances of benefit and failure

P references Patient-centered priorities (utilities) and cultural preferences affecting choice

A lternatives All other reasonable options

R isks The potential for harm from treatment

E xpenses All direct and indirect costs

D ecision Fully informed collaborative choice and consent

Modified from Reiter RC, Lench JB, Gambone JC: Consumer advocacy, elec- tive surgery, and the “golden era of medicine.” Obstet Gynecol 74:815–817, 1989.

FIGURE 1-2 Representation of arbitrary rationing commonly based on access or ability to pay versus planned clinical resource management based on measured value. Explicit rationing is objec- tionable to many despite the fact that implicit rationing still occurs.

Based on measured value

Explicit (planned)

Based on access or ability to pay

Implicit (arbitrary)

RationalIrrational

RATIONING

8 PA R T 1 Introduction

Value—The Third Principle of Practice The  mandate  from  payers  (government  and  employ- ers) and the public to measure and improve the effec- tiveness and efficiency (value) of health care services is  clear.  Unfortunately,  change  based  on  adoption  of  national standards derived from evidence-based prac- tice  and  randomized  controlled  trials  (RCTs)  alone   may  be  too  expensive  and  slow  to  meet  this  mandate.  Furthermore,  the  results  from  RCTs  may  not  always  establish  how  diagnostic  and  therapeutic  procedures  actually  work  in  clinical  practice.  For these reasons, health care organizations, including schools of public health and physician groups, must develop the tools to identify and adopt best practices and improve clin- ical outcomes locally.

Value in health care is defined as “clinical outcomes  considering  the  resources  used,”  or  results  divided  by  the  costs  of  care.  Figure  1-3  illustrates  a  collaborative  process that may be used to involve the patient in the  determination  of  value  when  decisions  about  treat- ments  are  being  made.  The  past  40  years  that  have  been  devoted  to  the  measurement  and  pursuit  of  quality improvement have not been successful in terms 

recognition that other clinicians involved in health care have a right to participate in any decision making. Physicians have not been as aware of the sen- sitivities  of  the  nursing  profession  and  other  allied  health  professionals  as  they  should  have  been.  For  example,  the  decision  to  either  operate  or  not  on  a  newborn  with  severe  spina  bifida  inevitably  leaves  nurses  with  responsibilities  to  the  infant,  the  parents,  and the doctor that may be in direct conflict with their  personal  values.  They  may  rightly  request  to  be  party  to the decision-making process, and although the exact  models  whereby  such  a  goal  may  be  achieved  are  debatable,  physicians  must  be  aware  of  the  legitimate  moral concerns of nurses and others involved.

Health  care  delivery  takes  place  in  a  very  complex  environment  and  relationships with other interested parties is becoming increasingly important. Hospi- tals, health insurance companies, and governments all claim an interest in what services are made avail- able or paid for,  and  this  may  prevent  individual  patients from receiving what their physician may con- sider optimal care. This poses moral problems not only  for  physicians  on  a  case-by-case  basis  but  also  for  insurance companies and society as a whole. An atmo- sphere of mutual trust should be sought, earned, and practiced in these relationships.

Finally,  and  very  importantly,  all  physicians  and  other  health  care  providers  should  be  mindful  of  a  potential  conflict of interest  that  may  occur  during  practice  or  during  performance  of  committee  work  at  the  local  or  national  level.  Even  the  appearance  of  a  conflict between a personal interest and the duty to put  patient  care  interest  first  can  undermine  the  confi- dence that patients and the public have in them.

MALPRACTICE AND MALOCCURRENCE Medical malpractice refers to care that is negligent and  below  the  accepted  standard.  When an undesired outcome occurs irrespective of the care that is given, it is referred to properly as medical maloccurrence.  The system of tort law that currently applies to medical  malpractice in the United States distorts the difference  between these two events in many cases. Clearly there  is  preventable  medical  error  resulting  from  negligent  care,  but  many  of  these  events  are  not  properly  addressed in our system. Too often medical maloccur- rence is judged to be malpractice.

The interface of medicine and the law raises major ethical issues because legality and morality are not always synonymous.  Professional  liability  insurance  premiums  for  obstetricians  are  testimony  to  the  rele- vance of legal issues to obstetric practice. Professional  liability  is  affecting  every  major  decision  that  is  made  by  the  practicing  obstetrician  and  gynecologist,  and  under these conditions, the “tunnel vision” that ensues  may obscure the ability to see clear answers to ethical  questions.

FIGURE 1-3 Involving the patient in the determination of value in decision making. Defining the Plan or Procedure along with its Reason or indication, its evidence-based Expectations, and the patient-centered Preferences for it helps to determine its effective- ness. Further defining of all other Alternatives, the associated Risks and complications along with all Expenses (Costs) determines its efficiency. Making a collaborative Decision based on this process helps to determine the Value of the treatment. (Modified from Gambone JC, Reiter RC, Hagey S: Clinical outcomes in gynecology: hysterectomy. Curr Probl Obstet Gynecol Fertil 16(4), 1993.)

P lan R eason E xpectations P references

A lternatives R isks E xpenses

D ecision

VALUE

EFFICIENCY

EFFECTIVENESS

C H A P T E R 1 A Life-Course Perspective for Women’s Health Care 9

making is replacing the older solo “captain of the ship”  principle  for  high-risk,  high-consequence  health  care  activities.  One  checklist  developed  for  health  care  for  use  in  the  operating  room  (Figure  1-4)  was  tested  worldwide by the WHO and resulted in a 47% reduction  in  surgical  mortality  and  a  36%  reduction  in  inpatient  complications.  The use of medical teams in health care has resulted in similar reductions in both mor- tality and morbidity.  Both  of  these  interventions  are  relatively inexpensive when compared to the gains and  both are highly effective.

Patient-Centered Prevention— The Fourth Principle of Practice The  prevention  and  mitigation  of  existing  disease   has  become  an  extremely  important  and  sometimes 

of  reducing  the  high  cost  of  care,  particularly  in  the  United  States. Transforming  health  care  organizations  into  high  reliability  organizations  (HROs)  that  deliver  patient-centered  value  has  become  the  main  focus  of  performance improvement today.

HIGH RELIABILITY IN HEALTH CARE Recent  progress  in  health  care  outcomes  has  been  attained by introducing the concepts and tools of HROs  into  health  care  delivery  facilities.  The  two  industries  that have led as HROs have been commercial aviation  and nuclear power plants. In aviation, the adoption of checklists and crew resource management (CRM) has improved commercial aviation safety significantly.  The  concepts  of  CRM  (called  medical  team  manage- ment  in  health  care)  are  now  being  adopted  for  high- risk procedures in trauma centers and operating rooms.  The development of high reliability teams for decision-

FIGURE 1-4 Surgical safety checklist. (Based on the WHO Surgical Safety Checklist: Available at http://whqlibdoc.who.int/publications/ 2009/9789241598590_eng_Checklist.pdf, © World Health Organization 2009. All rights reserved.)

SURGICAL SAFETY CHECKLIST

Before induction of anaesthesia Before skin incision Before patient leaves operating room

(with nurse, anaesthetist, and surgeon)(with nurse, anaesthetist, and surgeon)(with at least nurse and anaesthetist)

Has the patient confirmed his/her identity, site, procedure, and consent?

Is the site marked?

Is the anaesthesia machine and medication check complete?

Is the pulse oximeter on the patient and functioning?

Does the patient have a:

Known allergy?

Difficult airway or aspiration risk?

Risk of >500 ml blood loss (7 ml/kg in children)?

No Yes

Yes Not applicable

No Yes, and equipment/assistance available

No Yes, and two IVs/central access and fluids planned

Yes

Yes

Yes

This checklist is not intended to be comprehensive. Additions and modifications to fit local practice are encouraged.

Confirm all team members have introduced themselves by name and role.

Has antibiotic prophylaxis been given within the last 60 minutes?

Anticipated critical events To surgeon:

How long will the case take? What is the anticipated blood loss?

Yes Not applicable

Is essential imaging displayed? Yes Not applicable

What are the critical or non-critical steps?

To anaesthetist:

How long will the case take?

Are there any patient-specific concerns?

Confirm the patient’s name, procedure, and where the incision will be made.

To nursing team:

Are there equipment issues or concerns?

Has sterility (including indicator results) been confirmed?

Nurse verbally confirms: The name of the procedure Completion of instrument, sponge, and needle counts Specimen labeling (read specimen labels aloud, including patient name) Whether there are any equipment problems to be addressed

To surgeon, anaesthetist, and nurse: What are the key concerns for recovery and management of this patient?

10 PA R T 1 Introduction

overlooked  area  of  value-based  practice.  The  famous  American  humorist, Will  Rogers,  said  many  years  ago  that  people  should  only  pay  their  doctors  when  they  are well and not sick. This suggests a frustration that he  was  reflecting  publicly  that  medical  practice  had  neglected the promotion of wellness, resulting in a high  cost  of  sickness.  As  health  care  treatment  becomes  more expensive and complex, there is a greater incen- tive  for  government,  private  industry,  and  individuals  to invest in preventive services.

There are several good examples of effective preven- tive  interventions  that  are  now  available  in  obstetric  and  gynecologic  practice.  In obstetrics, the newer techniques for mitigating intrauterine fetal damage from chronic stress that may result in short- and long-term morbidity  (see  Chapters  7  and  9)  are increasingly successful.  And  in gynecology, the vac- cination against human papillomavirus (HPV ) infec- tion to prevent cervical cancer  (see  Chapters  22  and  38)  is  a  major  advance.  Box  1-1  contains  a  life- course  perspective  of  other  early,  effective  preventive  opportunities.

*For example, Kliegman R, Behrman R, Jenson H, et al: Nelson’s textbooks of pediatrics, ed 18, Philadelphia, 2007, Saunders.

BOX 1-1

LIFE-COURSE PERSPECTIVE OF EARLY PREVENTION OPPORTUNITIES

•  Preconception counseling (see Chapter 7) •  Antepartum  care  and  nutrition  counseling  (see  

Chapter 7) •  Intrapartum  care  and  surveillance  (see  Chapters  9  

and 10) •  Newborn  screening  (see  Chapter  8  and  pediatric  care 

textbooks*) •  Well-baby  visits,  breastfeeding  and  nutrition  counsel-

ing (see pediatric care textbooks*) •  Childhood  and  adolescent  screening  and  Immuniza-

tions (see pediatric care textbooks*) •  Adult preventive health screening (see Table 1-2)

TABLE 1-2

RECOMMENDED PREVENTIVE HEALTH SCREENING FOR WOMEN

Intervention/Procedure Risk(s)

Pap smear from age 21 irrespective of sexual activity: age 21-29, every 3 yr; age 30-65, every 3 yr with cytology only or every 5 yr with HPV testing added; age >65, only with history of significant CIN

After total hysterectomy (corpus and cervix) cytology not needed (see Chapter 38)

Cervical dysplasia/cancer

Annual breast exam ages >39 and every 1-3 yr age 20-39; high risk women should consider annual exam; screening mammography annually starting at age 40; USPSTF recommends starting at age 50; breast self-exam not universally recommended (see Chapter 29)

Breast cancer

Smoking cessation counseling, warning about second-hand smoke exposure

Lung cancer, heart disease, other health risks associated with smoking

Sigmoidoscopy or colonoscopy (preferred) every 3-5 yr after age 50 Colorectal cancer

Height and weight measurement for BMI calculation (see Box 2-2) Overweight and obesity

Regular blood pressure screening (every 2 yr) Hypertension and stroke

Cholesterol/lipid profile every 5 yr until age 65 Heart disease

Total skin inspection and selective biopsies Skin cancer (sun exposure)

Diet and exercise counseling; BMD testing for all women > age 64, or younger if at least one risk factor for osteoporosis (see Chapter 35)

Osteoporosis, fracture, and deformity

Blood sugar study with family history, obesity, or history of gestational diabetes

Diabetes mellitus; other comorbidities associated with obesity

Cervical sampling for Chlamydia, N. gonorrhoeae, syphilis, and HIV based on history of high-risk behavior (see Chapter 26)

Sexually transmitted infections

TSH starting at age 50 (see Chapter 35) Thyroid disease

PPD of tuberculin for high-risk women Tuberculosis

BMD, Bone mineral density; BMI, body mass index; CIN, cervical intraepithelial neoplasia; HIV, human immunodeficiency virus; HPV, human papillomavirus; Pap, Papanicolaou test; PPD, purified protein derivative; TSH, thyroid-stimulating hormone; USPSTF, United States Preventive Services Task Force.

C H A P T E R 1 A Life-Course Perspective for Women’s Health Care 11

IMMUNIZATIONS AND PREVENTIVE HEALTH SCREENING Because  public  health  recommendations  for  immuni- zations  may  change,  it  is  best  to  check  a  reliable   source  periodically  (e.g.,  www.cdc.gov)  for  the  latest  information  before  counseling  patients.  General  rec- ommendations  include  the  following  for  women  aged  19 to 49: measles, mumps and rubella (MMR), hepatitis  B, and varicella for women who are nonimmune. Addi- tionally,  vaccination  against  HPV  is  currently  recom- mended for girls and women aged 11 to 26, and a single  dose of tetanus-diphtheria-pertussis (Tdap) for adults  19  to  64  years  of  age  is  now  recommended  to  replace  the next booster dose of tetanus and diphtheria toxoids  (Td)  vaccine.  Influenza vaccine  annually  is  recom- mended  for  all  women  older  than  age  50  and  women  aged  19  to  49  who  are  health  care  workers,  who  have  chronic illnesses such as heart disease or diabetes mel-

litus, or who are pregnant or planning to become preg- nant  during  the  flu  season.  Pneumococcal vaccine  is  recommended  for  all  women  aged  65  and  older,  and  those  with  chronic  illnesses,  alcoholism,  or  who  are  immunosuppressed.  Meningococcal  and  hepatitis  A  vaccines  may  be  indicated  in  some  women  with  risk  factors. MMR, varicella, and HPV vaccines are contra- indicated during pregnancy.

Table 1-2 contains preventive screening recommen- dations  for  women.  These recommendations can change or be modified from time to time. The Ameri- can College of Obstetricians and Gynecologists (ACOG)  and  the  United  States  Preventive  Services  Task  Force  (USPSTF)  have  websites  that  keep  the  recommenda- tions  up  to  date.  The promising area of preventive services in obstetrics and gynecology, as in health care generally, is transforming the practice of medi- cine in a very positive way.

12

2  Clinical Approach to the Patient

C H

A P

T ER

JOSEPH C. GAMBONE

■  The  clinical  approach  to  obstetric  and  gynecologic  patients  requires  sensitivity  and  an  understanding  that  medical  issues  related  to  birth  and  reproductive  care  require a trusting relationship between a woman and her  obstetrician  and  gynecologist  as  well  as  all  health  care  professionals that she may encounter.

■  Recent  changes  in  the  acceptance  of  sexual  roles  in  society mean that a nonjudgmental approach is needed.  The  physician  should  be  careful  not  to  assume  that  a  casual and overly familiar approach is always acceptable  to all patients, especially older ones.

■  The  obstetric  history  and  physical  examination  should  be  complete  and  carefully  performed  with  the  goal  of 

providing care that results in the best clinical outcomes  for the mother and her child.

■  The  gynecologic  encounter  may  be  for  routine  preven- tive care or may be to address a specific clinical problem  that a woman may be having. Reproductive matters are  of  most  interest  during  the  early  adult  years.  Concerns  about chronic disorders typically arise later in life during  the pre- and postmenopausal years.

■  The physician and all health care professionals should be  aware that certain groups of women, such as the pediat- ric, geriatric, and disabled, have special needs and con- cerns.  Women  who  are  in  same-sex  relationships  and  transgender women may also have special needs.

CLINICAL KEYS FOR THIS CHAPTER

A  careful  history  and  physical  examination  should  form the basis for patient evaluation and clinical man- agement in obstetrics and gynecology, as in other clini- cal  disciplines.  This  chapter  outlines  the  essential  details  of  the  clinical  approach  to,  and  evaluation  of,  the  obstetric  and  gynecologic  patient.  The  clinical  approach to female patients has evolved in recent years  (see  Chapter  28).  It  is  important  for  the  clinician  who  cares  for  women  to  refrain  from  making  value  judg- ments  about  sexual  preferences  and  behavior,  unless  they are clearly unhealthy or dangerous. Some patients  may  have  special  needs  in  terms  of  their  clinical  care,  and an accepting and understanding attitude is impor- tant.  Pediatric  and  adolescent  patients,  the  geriatric  patient,  as  well  as  women  with  disabilities,  also  have  unique  gynecologic  and  reproductive  needs  and  this  chapter concludes with information about their evalu- ation and management.

Obstetric and Gynecologic Evaluation In  few  areas  of  medicine  is  it  necessary  to  be  more  sensitive  to  the  emotional  and  psychological  needs  of  the patient than in obstetrics and gynecology. By their  very nature, the history and physical examination may  cause embarrassment to some patients. The members  of  the  medical  care  team  are  individually  and  collec- tively  responsible  for  ensuring  that  each  patient’s  privacy and modesty are respected while providing the  highest level of medical care. Box 2-1 lists the appropri- ate steps for the clinical approach to the patient.

While a casual and familiar approach may be accept- able  to  many  younger  patients,  it  may  offend  others  and  be  quite  inappropriate  for  many  older  patients.  Different  circumstances  with  the  same  patient  may  dictate  different  levels  of  formality.  Entrance  to  the 

C H A P T E R 2 Clinical Approach to the Patient 13

the method of delivery in the present pregnancy. A  difficult forceps delivery or a cesarean delivery may  require a personal review of the labor and delivery  records.

5.  Duration of labor  (recorded  in  hours).  This  may  alert  the  physician  to  the  possibility  of  an  unusu- ally long or short labor.

6.  Type of anesthesia. Any complications of anesthe- sia should be noted.

7.  Maternal complications.  Urinary  tract  infections,  vaginal  bleeding,  hypertension,  and  postpartum  complications  may  be  repetitive;  such  knowledge  is helpful in anticipating and preventing problems  with the present pregnancy.

8.  Newborn weight (in grams or pounds and ounces).  This  information  may  give  indications  of  gesta- tional  diabetes,  fetal  growth  problems,  shoulder  dystocia, or cephalopelvic disproportion.

9.  Newborn gender.  This  may  provide  insight  into  patient  and  family  expectations  and  may  indicate  certain genetic risk factors.

10.  Fetal and neonatal complications.  Certain  ques- tions should be asked to elicit any problems and to  determine the need to obtain further information.  Inquiry should be made as to whether the baby had  any  problems  after  it  was  born,  whether  the  baby  breathed  and  cried  right  away,  and  whether  the  baby left the hospital with the mother.

MENSTRUAL HISTORY A  good  menstrual  history  is  essential  because  it  is  the  determinant for establishing the expected date of con- finement  (EDC).  A  modification  of  Nägele rule  for  establishing the EDC is to add 9 months and 7 days to  the first day of the last normal menstrual period (LMP).  For example:

LMP: July 20, 2015 EDC: April 27, 2016

This  calculation  assumes  a  normal  28-day  cycle,  and  adjustments must be made for longer or shorter cycles.  Any  bleeding  or  spotting  since  the  last  normal  men- strual  period  should  be  reviewed  in  detail  and  taken  into account when calculating an EDC.

CONTRACEPTIVE HISTORY This information is important for risk assessment. Hor- monal  contraceptives  taken  during  early  pregnancy  have  been  associated  with  birth  defects,  and  retained  intrauterine devices (IUDs) can cause early pregnancy  loss, infection, and premature delivery.

MEDICAL HISTORY The  importance  of  a  good  medical  history  cannot  be  overemphasized.  In  addition  to  common  disorders,  such  as  diabetes  mellitus,  hypertension,  and  renal  disease, which are known to affect pregnancy outcome,  all serious medical conditions should be recorded.

BOX 2-1

APPROACH TO THE PATIENT

The doctor should always: •  Knock before entering the patient’s room. •  Identify himself/herself. •  Meet  the  patient  initially  when  she  is  fully  dressed,  

if possible. •  Address the patient courteously and respectfully. •  Respect  the  patient’s  privacy  and  modesty  during  the 

interview and examination. •  Ensure cleanliness, good grooming, and good manners 

in all patient encounters. •  Beware  that  a  casual  and  familiar  approach  is  not 

acceptable  to  all  patients;  it  is  generally  best  to  avoid  addressing an adult patient by her first name.

•  Maintain the privacy of the patient’s medical informa- tion and records.

•  Be mindful and respectful of any cultural preferences.

patient’s  room  should  be  announced  by  a  knock  and  spoken identification. A personal introduction with the  stated  reason  for  the  visit  should  occur  before  any  questions  are  asked  or  an  examination  is  begun.  The  placement  of  the  examination  table  should  always  be  in a position that maximizes privacy for the patient as  other  health  care  professionals  enter  the  room.  Any  cultural beliefs and preferences for care and treatment  should be recognized and respected.

Obstetric History A complete history must be recorded at the time of the  prepregnancy  evaluation  or  at  the  initial  antenatal  visit. Several detailed standardized forms are available,  but  this  should  not  negate  the  need  for  a  detailed  chronologic  history  taken  personally  by  the  physician  who will be caring for the patient throughout her preg- nancy.  While  taking  the  history,  major  opportunities  will  usually  arise  to  provide  counseling  and  explana- tions  that  serve  to  establish  rapport  and  a  supportive  patient/physician encounter.

PREVIOUS PREGNANCIES Each  prior  pregnancy  should  be  reviewed  in  chrono- logic order and the following information recorded:

1.  Date of delivery (or pregnancy termination). 2.  Location of delivery (or pregnancy termination). 3.  Duration of gestation  (recorded  in  weeks). When 

correlated  with  birth  weight,  this  information  allows an assessment of fetal growth patterns. The  gestational  age  of  any  spontaneous  abortion  is  of  importance in any subsequent pregnancy.

4.  Type of delivery  (or  method  of  terminating  preg- nancy). This information is important for planning 

14 PA R T 1 Introduction

challenging  during  the  early  weeks  after  a  missed  menses. Urine pregnancy tests in the office are reliable  a few days after the first missed period, and office ultra- sonography is used increasingly as a routine.

SYMPTOMS OF PREGNANCY The  most  common  symptoms  in  the  early  months  of  pregnancy  are  missed  menses,  urinary  frequency,  breast  engorgement,  nausea,  tiredness,  and  easy  fati- gability. A missed or abnormal menses in a previously  normally menstruating, sexually active woman should  be considered to be caused by pregnancy until proven  otherwise.  Urinary  frequency  is  most  likely  caused  by  the pressure of the enlarged uterus on the bladder.

SIGNS OF PREGNANCY The signs of pregnancy may be divided into presump- tive, probable, and positive.

Presumptive Signs The  presumptive  signs  are  primarily  those  associated  with  skin  and  mucous  membrane  changes.  Discolor- ation and cyanosis of the vulva, vagina, and cervix are  related  to  the  generalized  engorgement  of  the  pelvic  organs and are, therefore, nonspecific. The dark discol- oration  of  the  vulva  and  vaginal  walls  is  known  as  Chadwick sign. Pigmentation of the skin and abdomi- nal  striae  are  nonspecific  and  unreliable  signs.  The  most  common  sites  for  pigmentation  are  the  midline  of  the  lower  abdomen  (linea  nigra),  over  the  bridge  of  the nose, and under the eyes. Pigmentation under the  eyes is called chloasma or the mask of pregnancy. Chlo- asma  is  also  an  occasional  side  effect  of  hormonal  contraceptives.

Probable Signs The  probable  signs  of  pregnancy  are  those  mainly  related to the detectable physical changes in the uterus.  During  early  pregnancy,  the  uterus  changes  in  size,  shape,  and  consistency.  Early  uterine  enlargement  tends to be in the anteroposterior diameter so that the  uterus becomes globular. In addition, because of asym- metric  implantation  of  the  ovum,  one  cornu  of  the  uterus  may  enlarge  slightly  (Piskaçek sign).  Uterine  consistency  becomes  softer,  and  it  may  be  possible   to  palpate  or  to  compress  the  connection  between   the  cervix  and  fundus.  This  change  is  referred  to  as  Hegar sign.  The  cervix  also  begins  to  soften  early  in  pregnancy.

Positive Signs The  positive  signs  of  pregnancy  include  the  detection  of  a  fetal  heartbeat  and  the  recognition  of  fetal  move- ments. Endovaginal ultrasound is capable of detecting  fetal  cardiac  activity  as  early  as  6  weeks  (from  last  menses) and fetal movement from about 7 to 8 weeks’  gestation.  Modern  Doppler  techniques  for  detecting 

SURGICAL HISTORY Each  surgical  procedure  should  be  recorded  chrono- logically,  including  date,  hospital,  surgeon,  and  com- plications. Trauma must also be listed (e.g., a fractured  pelvis may result in diminished pelvic capacity).

SOCIAL HISTORY Habits  such  as  smoking,  alcohol  use,  and  other  sub- stance  abuse  are  important  factors  that  must  be  recorded  and  managed  appropriately.  The  patient’s  contact or exposure to domesticated animals, particu- larly  cats  (which  carry  a  risk  of  toxoplasmosis),  is  important.

The  patient’s  type  of  work  and  lifestyle  may  affect  the pregnancy. Exposure to solvents (carbon tetrachlo- ride) or insulators (polychlorobromine compounds) in  the  workplace  may  lead  to  teratogenesis  or  hepatic  toxicity.

Obstetric Physical Examination GENERAL PHYSICAL EXAMINATION This  procedure  must  be  systematic  and  thorough  and  performed  as  early  as  possible  in  the  prenatal  period.  A complete physical examination provides an opportu- nity  to  detect  previously  unrecognized  abnormalities.  Normal  baseline  levels  must  also  be  established,  par- ticularly  those  of  weight,  blood  pressure,  funduscopic  (retina) appearance, and cardiac status.

PELVIC EXAMINATION The initial pelvic examination should be done early in  the  prenatal  period  and  should  include  the  following:  (1)  inspection  of  the  external  genitalia,  vagina,  and  cervix;  (2)  collection  of  cytologic  specimens  from  the  exocervix  (or  ectocervix)  and  superficial  endocervical  canal;  and  (3)  palpation  of  the  cervix,  uterus,  and  adnexa.  The  initial  estimate  of  gestational  age  by  uterine  size  becomes  less  accurate  as  pregnancy  pro- gresses. Rectal and rectovaginal examinations are also  important aspects of this initial pelvic evaluation.

CLINICAL PELVIMETRY This assessment, which is helpful for predicting poten- tial  problems  during  labor,  should  be  carried  out  fol- lowing the bimanual pelvic examination and before the  rectal examination. It is important that clinical pelvim- etry be carried out systematically. The details of clinical  pelvimetry are described in Chapter 8.

Diagnosis of Pregnancy The diagnosis of pregnancy and its location, based on  physical  signs  and  examination  alone,  may  be  quite 

C H A P T E R 2 Clinical Approach to the Patient 15

Abdominal Pain Many  gynecologic  problems  are  associated  with  abdominal  pain.  The  common  gynecologic  causes  of  acute  lower  abdominal  pain  are  salpingo-oophoritis  with peritoneal inflammation, torsion and infarction of  an ovarian cyst, endometriosis, or rupture of an ectopic  pregnancy.  Patterns  of  pain  radiation  should  be  recorded  and  may  provide  an  important  diagnostic  clue. Chronic lower abdominal pain is generally associ- ated  with  endometriosis,  chronic  pelvic  inflammatory  disease, or large pelvic tumors. It may also be the first  symptom of ovarian cancer.

Amenorrhea The  most  common  causes  of  amenorrhea  are  preg- nancy and the normal menopause. It is abnormal for a  young woman to reach the age of 16 without menstru- ating (primary amenorrhea). Pregnancy should be sus- pected in a woman between 15 and 45 years of age who  fails to menstruate within 35 days from the first day of  her  last  menstruation.  In  a  patient  with  amenorrhea  who  is  not  pregnant,  inquiry  should  be  made  about  menopausal  or  climacteric  symptoms  such  as  hot  flashes, vaginal dryness, or mild depression.

Other Symptoms Other  pertinent  symptoms  of  concern  include  dys- menorrhea,  premenstrual  tension,  fluid  retention,   leukorrhea, constipation, dyschezia, dyspareunia, and  abdominal distention. Lower back and sacral pain may  indicate uterine prolapse, enterocele, or rectocele.

MENSTRUAL HISTORY The menstrual history should include the age at men- arche  (average  is  12  to  13  years),  interval  between  periods (21 to 35 days with a median of 28 days), dura- tion of menses (average is 5 days), and character of the  flow (scant, normal, heavy, usually without clots). Any  intermenstrual  bleeding  (metrorrhagia)  should  be  noted. The date of onset of the LMP and the date of the  previous menstrual period should be recorded. Inquiry  should be made regarding menstrual cramps (dysmen- orrhea); if present, the age at onset, severity, and char- acter of the cramps should be recorded, together with  an  estimate  of  the  disability  incurred.  Midcycle  pain  (mittelschmerz)  and  a  midcycle  increase  in  vaginal  secretions are usually indicative of ovulatory cycles.

CONTRACEPTIVE HISTORY The  type  and  duration  of  each  contraceptive  method  must  be  recorded,  along  with  any  attendant  compli- cations.  These  may  include  amenorrhea  or  throm- boembolic  disease  with  hormonal  contraceptives;  dysmenorrhea, heavy bleeding (menorrhagia), or pelvic  infection with the intrauterine device; or contraceptive  failure with the diaphragm, or other barrier method.

the  fetal  heartbeat  may  be  successful  as  early  as  9  weeks and are nearly always positive by 12 weeks. Fetal  heart tones can usually be detected with a stethoscope  between  16  and  20  weeks.  The  multiparous  woman  generally recognizes fetal movements between 15 and  17  weeks,  whereas  the  primigravida  usually  does  not  recognize fetal movements until 18 to 20 weeks.

LABORATORY TESTS FOR PREGNANCY Pregnancy Tests Tests  to  detect  pregnancy  have  revolutionized  early  diagnosis.  Although  they  are  considered  a  probable  sign  of  pregnancy,  the  accuracy  of  these  tests  is  very  good.  All  commonly  used  methods  depend  on  the  detection  of  human  chorionic  gonadotropin  (hCG)  or  its β subunit in urine or serum. Depending on the spe- cific sensitivity of the test, pregnancy may be suspected  even prior to a missed menstrual period.

Diagnostic Ultrasonography The imaging technique of ultrasonography has made a  significant  contribution  to  the  diagnosis  and  evalua- tion of pregnancy. Using real-time ultrasonography, an  intrauterine gestational sac can be identified at 5 men- strual weeks (21st postovulatory day) and a fetal image  can  be  detected  by  5  to  6  weeks.  A  beating  heart  is  noted  at  7  weeks  or  even  sooner  with  the  latest  equipment.

Gynecologic History Gynecologic history-taking must be systematic to avoid  omissions, and it should be conducted with sensitivity  and without haste.

PRESENT ILLNESS The  patient  is  asked  to  state  her  main  complaint  and  to  relate  her  present  illness,  sequentially,  in  her  own  words.  Pertinent  negative  information  should  be  recorded,  and,  as  much  as  possible,  questions  should  be  reserved  until  after  the  patient  has  described  the  course  of  her  illness.  Generally,  the  history  provides  substantial clues to the diagnosis, so it is important to  evaluate  fully  the  more  common  symptoms  encoun- tered in gynecologic patients.

Abnormal Vaginal Bleeding Vaginal bleeding before the age of 9 years and after the  age of 52 years is cause for concern and requires inves- tigation.  These  are  the  general  limits  of  normal  men- struation,  and  although  the  occasional  woman  may  menstruate regularly and normally up to the age of 57  or  58  years,  it  is  important  to  ensure  that  she  is  not  bleeding from uterine cancer or from exogenous estro- gens. Prolongation of menses beyond 7 days or bleed- ing  between  menses  may  connote  abnormal  ovarian  function, uterine myomata, or endometriosis.

16 PA R T 1 Introduction

General Appearance The  patient’s  body  build,  posture,  state  of  nutrition,  demeanor, and state of well-being should be recorded.

Head and Neck Evidence  of  supraclavicular  lymphadenopathy,  oral  lesions, webbing of the neck, or goiter may be pertinent  to the gynecologic assessment.

Breasts The  breast  examination  is  particularly  important  in  gynecologic patients (see Chapters 30 and 32).

Heart and Lungs Examination  of  the  heart  and  lungs  is  of  importance,  particularly in a patient who requires surgery. The pres- ence  of  a  pleural  effusion  may  be  indicative  of  a  dis- seminated malignancy, particularly ovarian cancer.

Abdomen Examination  of  the  abdomen  is  critical  in  the  evalua- tion  of  the  gynecologic  patient. The  contour,  whether  flat,  scaphoid,  or  protuberant,  should  be  noted.  The  protuberant appearance may suggest ascites. The pres- ence  and  distribution  of  hair,  especially  in  the  area  of  the  escutcheon,  should  be  recorded,  as  should  the  presence of striae or operative scars.

Abdominal tenderness must be determined by placing one hand flat against the abdomen in the nonpainful areas initially,  then  gently  and  gradually  exerting  pressure  with  the  fingers  of  the  other  hand  (Figure 2-1). Rebound tenderness (a sign of peritoneal  irritation),  muscle  guarding,  and  abdominal  rigidity  should  be  gently  elicited,  again  first  in  the  nontender  areas.  A  “doughy”  abdomen,  in  which  the  guarding 

OBSTETRIC HISTORY Each  pregnancy,  delivery,  and  any  associated  compli- cations  should  be  listed  sequentially  with  relevant  details and dates.

SEXUAL HISTORY The  health  of,  and  current  relationship  with,  the  husband  or  partner(s)  may  provide  insight  into  the  present complaints. Inquiry should be made regarding  any pain (dyspareunia), bleeding, or dysuria associated  with  sexual  intercourse.  Sexual  satisfaction  should  be  discussed tactfully.

PAST HISTORY As in the obstetric history, any significant past medical  or  surgical  history  should  be  recorded,  as  should  the  patient’s family history. A list of current medications is  important.

SYSTEMIC REVIEW A  review  of  all  other  organ  systems  should  be  under- taken.  Habits  (tobacco,  alcohol,  other  substance  abuse), medications, usual weight with recent changes,  and loss of height (osteoporosis) are important parts of  the systemic review.

Gynecologic Physical Examination GENERAL PHYSICAL EXAMINATION A complete physical examination should be performed  on each new patient and repeated at least annually. The  initial examination should include the patient’s height,  weight, and arm span (in adolescent patients or those  with  endocrine  problems)  and  should  be  carried  out  with  the  patient  completely  disrobed  but  suitably  draped. A body mass index (BMI) should be calculated  (Box  2-2)  and  recorded.  The  examination  should  be  systematic and should include the following points.

Vital Signs Temperature,  pulse  rate,  respiratory  rate,  and  blood  pressure should be recorded.

FIGURE 2-1 The abdomen is palpated by placing the left palm flat against the abdominal wall and then gently exerting pressure with the fingers of the right hand. *Data from the National Heart, Lung, and Blood Institute.

BOX 2-2

CALCULATIONS AND DESIGNATIONS* OF BODY MASS INDEX

Body  mass  index  is  calculated  by  dividing  weight  in  kilo- grams  (kg)  by  height  in  meters  squared  or  weight  in  pounds by height in inches squared times 703.

Less than 18.5 = underweight 18.5 to 25 = normal weight 25 to 29.9 = overweight 30 to 34.9 = class one obesity 35 to 39.9 = class two obesity 40 or greater = extreme obesity

C H A P T E R 2 Clinical Approach to the Patient 17

cated with warm water only, so as not to interfere with  the  examination  of  cervical  cytology  or  any  vaginal  exudate. After gently spreading the labia to expose the  introitus,  the  speculum  should  be  inserted  with  the  blades entering the introitus transversely, then directed  posteriorly  in  the  axis  of  the  vagina  with  pressure  exerted  against  the  relatively  insensitive  perineum  to  avoid  contacting  the  sensitive  urethra.  As  the  anterior  blade  reaches  the  cervix,  the  speculum  is  opened  to  bring  the  cervix  into  view  (Figure  2-3).  As  the  vaginal  epithelium  is  inspected,  it  is  important  to  rotate  the  speculum  through  90  degrees,  so  that  lesions  on  the  anterior  or  posterior  walls  of  the  vagina  ordinarily  covered  by  the  blades  of  the  speculum  are  not  over- looked.  Vaginal  wall  relaxation  should  be  evaluated  using either a Sims speculum or the posterior blade of  a bivalve speculum. The patient is asked to bear down  ( Valsalva maneuver)  or  to  cough  to  demonstrate  any  stress incontinence. If the patient’s complaint involves  urinary stress or urgency, this portion of the examina- tion  should  be  carried  out  before  the  bladder  is  emptied.

The cervix should be inspected to determine its size,  shape, and color. The nulliparous patient generally has  a  conical,  unscarred  cervix  with  a  circular,  centrally  placed os; the multiparous cervix is generally bulbous 

increases  gradually  as  the  pressure  of  palpation  is  increased, is often seen with a hemoperitoneum.

It is important to palpate any abdominal mass. The  size should be specifically noted. Other characteristics  may be even more important in suggesting the diagno- sis, such as whether the mass is cystic or solid, smooth  or nodular, fixed or mobile, and whether it is associated  with ascites. In determining the reason for abdominal  distention  (tumor,  ascites,  or  distended  bowel),  it  is  important  to  percuss  carefully  the  areas  of  tympany  (gaseous distention) and dullness. A large tumor is gen- erally dull on top with loops of bowel displaced to the  flanks. Dullness that shifts as the patient turns onto her  side (shifting dullness) is suggestive of ascites.

Back Abnormal  curvature  of  the  vertebral  column  (dorsal  kyphosis  or  scoliosis)  is  an  important  observation   in  evaluating  osteoporosis  in  a  postmenopausal  woman.  Costovertebral  angle  tenderness  suggests  pyelonephritis, whereas psoas muscle spasm, which is  associated  with  flexion  of  the  hip,  may  occur  with  gynecologic infections, malignant infiltration, or acute  appendicitis.

Extremities The  presence  or  absence  of  varicosities,  edema,  pedal  pulsations, and cutaneous lesions may suggest patho- logic conditions within the pelvis. The height of pitting  edema  should  be  noted  (e.g.,  ankle,  shin,  to  the  knee,  or above).

PELVIC EXAMINATION The pelvic examination must be conducted systemati- cally and with careful sensitivity. The procedure should  be performed with smooth and gentle movements and  accompanied by reasonable explanations.

Vulva The  character  and  distribution  of  hair,  the  degree  of  development or atrophy of the labia, and the character  of the hymen (imperforate or cribriform) and introitus  (virginal, nulliparous, or multiparous) should be noted.  Any clitorimegaly should be noted, as should the pres- ence  of  cysts,  tumors,  or  inflammation  of  the  Bartho- lin gland.  The  urethra  and  Skene glands  should  be  inspected for any purulent exudates. The labia should  be inspected for any inflammatory, dystrophic, or neo- plastic lesions. Perineal relaxation and scarring should  be  noted  because  they  may  cause  dyspareunia  and  defects  in  anal  sphincter  tone.  The  urethra  should  be  “milked”  for  any  inflammatory  exudates,  which  if  found should be cultured for pathologic organisms.

Speculum Examination It is important to use an appropriately sized specu- lum  (Figure  2-2),  which  should  be  warmed  and  lubri-

FIGURE 2-2 A, Pediatric speculum. B, Pederson speculum. C, Graves speculum. The Pederson speculum has narrower blades and is more appropriate for examining a nulliparous patient. D, Parts of a speculum.

A B

D

Upper & lower blades

Thumb screw

Thumb hinge

Handle screw

HandleC

18 PA R T 1 Introduction

colaou, or Pap, smear), liquid-based sampling, or DNA  probe  for  human  papillomavirus  (HPV )  should  be  taken before the speculum is withdrawn. For the tradi- tional Pap smear the exocervix (or ectocervix) is gently  scraped  with  a  wooden  spatulum  or  plastic  broom,   and  the  endocervical  tissue  gently  sampled  with  a  cytobrush.

Bimanual Examination The  bimanual  pelvic  examination  provides  informa- tion about the uterus and adnexa (fallopian tubes and  ovaries).  During  this  portion  of  the  examination,  the  urinary bladder should be empty; if it is not, the inter- nal genitalia will be difficult to delineate, and the pro- cedure is more apt to be uncomfortable for the patient.  The  labia  are  separated,  and  the  gloved,  lubricated  index  finger  is  inserted  into  the  vagina,  avoiding  the  sensitive  urethral  meatus.  Pressure  is  exerted  posteri- orly  against  the  perineum  and  puborectalis  muscle,  which causes the introitus to gape somewhat, thereby  usually  allowing  the  middle  finger  to  be  inserted  as  well.  Intromission  of  the  two  fingers  into  the  depth  of  the vagina may be facilitated by having the patient bear  down slightly. If insertion of two fingers causes undue patient discomfort, examination with the index finger alone may give more information.

The cervix is palpated for consistency, contour, size,  and  tenderness  to  motion.  If the vaginal fornices are

and the os has a transverse configuration (Figure 2-4).  Any  purulent  cervical  discharge  should  be  cultured.  Plugged,  distended  cervical  glands  (nabothian folli- cles)  may  be  seen  on  the  exocervix  (or  ectocervix).  In  premenopausal  women,  the  squamocolumnar  junc- tion of the cervix is usually visible around the cervical  os,  particularly  in  patients  of  low  parity.  Postmeno- pausally, the junction is invariably retracted within the  endocervical canal. A cervical cytologic smear (Papani-

FIGURE 2-3 Proper insertion of the speculum so that the uterine cervix may be visualized.

FIGURE 2-4 Cervix of a nulliparous patient (A) and a multiparous patient (B). Note the circular os in the nulliparous cervix and the transverse os, resulting from lacerations at childbirth, in the mul- tiparous cervix.

A B MULTIPAROUS

Nabothian follicle

NULLIPAROUS

C H A P T E R 2 Clinical Approach to the Patient 19

FIGURE 2-5 Bimanual evaluation of the uterus by exerting gentle pressure on the uterus with the vaginal fingers against the abdominal hand.

FIGURE 2-6 Bimanual examination of the right adnexa. Note that fingers of the right hand are in the vagina.

absent, as may occur in postmenopausal women, it is not possible to appreciate the size of the cervix on bimanual examination. This can be determined only on rectovaginal or rectal examination.

The  uterus  is  evaluated  by  placing  the  abdominal  hand  flat  on  the  abdomen  with  the  fingers  pressing  gently just above the symphysis pubis. With the vaginal  fingers supinated in either the anterior or the posterior  vaginal  fornix,  the  uterine  corpus  is  pressed  gently  against the abdominal hand (Figure 2-5). As the uterus  is felt between the examining fingers of both hands, the  size,  configuration,  consistency,  and  mobility  of  the  organ are appreciated. If the muscles of the abdominal  wall  are  not  compliant  or  if  the  uterus  is  retroverted,  the  outline,  consistency,  and  mobility  must  be  deter- mined  by  ballottement  with  the  vaginal  fingers  in  the  fornices; in these circumstances, however, it is impos- sible to discern uterine size accurately.

By shifting the abdominal hand to either side of the  midline and gently elevating the lateral fornix up to the  abdominal  hand,  it  may  be  possible  to  outline  a  right  adnexal  mass  (Figure  2-6).  The  left  adnexa  are  best  appreciated  with  the  fingers  of  the  left  hand  in  the  vagina  (Figure  2-7).  The  examiner  should  stand  side- ways,  facing  the  patient’s  left,  with  the  left  hip  main- taining  pressure  against  the  left  elbow,  thereby 

20 PA R T 1 Introduction

adnexa. It is essential in evaluating the parametrium in patients with cervical cancer.  Rectal  examination  may also be essential in differentiating between a rec- tocele and an enterocele (Figure 2-8).

LABORATORY EVALUATION Appropriate  laboratory  tests  normally  include  a  uri- nalysis, complete blood count, erythrocyte sedimenta- tion  rate,  and  blood  chemistry  analyses.  Special  tests,  such  as  tumor  marker  and  hormone  assays,  are  per- formed when indicated.

ASSESSMENT A  reasonable  differential  diagnosis  should  be  possible  with the information gleaned from the history, physical  examination,  and  laboratory  tests.  The  plan  of  man- agement  should  aim  toward  a  chemical  or  histologic  confirmation  of  the  presumptive  diagnosis,  and  the  appropriate  therapeutic  options,  along  with  the  ratio- nale for each option, should be recorded.

Patients with Special Needs PEDIATRIC AND ADOLESCENT PATIENTS Girls  experience  fewer  gynecologic  problems  than   do  adult  women,  but  their  concerns  need  to  be  met  effectively and skillfully in a way that will allay anxiety  and  create  a  positive  attitude  toward  their  gyneco- logic  health.  Unique  complaints  fall  generally  into  a  handful  of  categories:  congenital  anomalies,  genital  injuries,  inflammation  of  the  nonestrogenized  genital  tract,  pubertal  problems,  and  psychosexual  concerns.  Genital ambiguity, trauma, and vaginal bleeding in the  prepubertal child are covered briefly in this chapter.

GENITAL AMBIGUITY Dealing with genital ambiguity in the newborn requires  a  coordinated  and  timely  response.  The family’s psy- chological well-being must be addressed because they must feel confident in the gender identity of their child. Ambiguity can result from masculinization  of a female child due to exogenous hormone ingestion  or  maternal  or  fetal  overproduction  of  androgen.  It  may  also  result  from  incomplete  virilization  of  a  male  infant,  hormonal  insensitivity,  gonadal  dysgenesis,  or  chromosomal  anomalies  (see  Chapters  18  and  20).  When assessing an infant with ambiguous genitalia, fluid and electrolyte balance should be monitored and blood drawn for 17-hydroxyprogesterone and cortisol to rule out 21-hydroxylase deficiency.  Life- threatening illness may be missed in children with the  salt-losing form of congenital adrenal hyperplasia (see  Chapter 33).

TRAUMA Straddle injuries are the most common cause of trauma  to the genitalia of a young girl, and the injuries have a 

providing better tactile sensation because of the relaxed  musculature  in  the  forearm  and  examining  hand. The  pouch of Douglas  is  also  carefully  assessed  for  nodu- larity or tenderness, as may occur with endometriosis,  pelvic inflammatory disease, or metastatic carcinoma.

It is usually impossible to feel the normal tube, and conditions must be optimal to appreciate the normal ovary. The  normal  ovary  has  the  size  and  consistency  of  a  shelled  oyster  and  may  be  felt  with  the  vaginal  fingers  as  they  are  passed  across  the  undersurface  of  the  abdominal  hand.  The  ovaries  are  very  tender  to  compression,  and  the  patient  is  uncomfortably  aware  of  any  ovarian  compression  or  movement  during  the  examination.

It may be impossible to differentiate between an ovarian or tubal mass or even a lateral uterine mass.  Generally,  left  adnexal  masses  are  more  difficult  to  evaluate than those on the right because of the position  of  the  sigmoid  colon  on  the  left  side  of  the  pelvis.  An  ultrasonic examination should be helpful for delineat- ing these features.

RECTAL EXAMINATION The anus should be inspected for lesions, hemorrhoids,  or  inflammation.  Rectal  sphincter  tone  should  be  recorded and any mucosal lesions noted. A guaiac test  should  be  performed  to  determine  the  presence  of  occult blood.

A rectovaginal examination is helpful in evaluating masses in the cul-de-sac, the rectovaginal septum, or

FIGURE 2-7 Bimanual examination of the left adnexa. Note that fingers of the left hand are in the vagina.

C H A P T E R 2 Clinical Approach to the Patient 21

withdrawal.  In  such  cases,  there  should  be  supportive  evidence of a hormonal effect, such as the presence of  breast  tissue  and  pale,  engorged  vaginal  epithelium.  Bleeding  disorders  are  uncommon  in  this  age  group  but should be considered. Vitamin K is routinely given  to  the  newborn,  but  some  parents  may  refuse  the  medication.

Precocious puberty  (see  Chapter  32)  may  present  with vaginal bleeding, although most commonly other  evidence of maturation will have preceded the bleeding  and will be evident on examination. At the very least, a  pale, estrogenized vaginal epithelium will be seen, and  cytology  from  the  vagina  will  confirm  the  hormonal  effect.  Transient  precocious  puberty  may  occur  in  response  to  a  functional ovarian cyst,  and  vaginal  bleeding may be triggered by the spontaneous resolu- tion of the cyst. Exogenous hormonal exposure should  be  considered,  because  children  have  been  known  to  ingest  birth  control  pills.  Ovarian tumors  resulting  in  pseudoprecocious puberty should be ruled out.

Vulvovaginitis  is  common  but  is  a  diagnosis  of  exclusion. When  bleeding  is  present,  it  is  necessary  to  assess  the  vagina  and  to  rule  out  a  foreign  body  or  vaginal tumor.

seasonal  peak  when  bicycles  come  out  in  the  spring.  The majority of these injuries are to the labia. Penetrat- ing  vaginal  injuries  can  cause  major  intraabdominal  damage with minimal external findings. Sexual assault must always be considered.  After  a  life-threatening  condition is ruled out, an ice pack, chilled bag of intra- venous  solution,  or  cool  compress  may  be  applied  to  the injured area and the child allowed to rest quietly for  20  minutes  before  being  assessed  further.  Extensive  injuries  usually  require  examination  under  anesthesia  and surgical repair.

In  any  case  of  trauma,  concurrent  damage  to  the  rectum or urinary tract should be considered. If there is any reason to suspect sexual or physical abuse, the child protection authorities must be notified, and the examination should include the collection of medico- legal evidence.

VAGINAL BLEEDING IN THE PREPUBERTAL CHILD Vaginal  bleeding  is  a  frequent  and  distressing  com- plaint  in  childhood.  Although  it  will  most  often  be  of  benign  etiology,  more  serious  pathology  must  always  be  ruled  out. Vaginal  bleeding  in  the  newborn  is  most  often  physiologic  as  a  result  of  maternal  estrogen 

FIGURE 2-8 Rectovaginal bimanual examination. During the Valsalva maneuver, an enterocele will separate the two fingers.

22 PA R T 1 Introduction

mentally or physically disabled individuals with obstet- ric  or  gynecologic  problems  or  attending  for  them  in  special  institutions  can  be  quite  challenging.  The  woman  with  a  disability  is  a  person  with  special  and  unique  needs,  and  communicating  to  her  a  sense  of  caring and respect is paramount.

Lesbian, Gay, Bisexual, and Transgender Patients This  group  of  patients  is  composed  of  lesbian,  gay,  bisexual,  and  transgender  women  and  men  and  is  known as LGBT.  There is now recognition that women  who are in a same-sex intimate relationship, as well as  those who are transgender, need special consideration  and understanding for the health issues that they may  encounter.  The  U.S.  Office  of  Prevention  and  Health  Promotion  points  out  that  LGBT  individuals,  possibly  because  of  the  discrimination  that  they  encounter,  have  higher  rates  of  psychiatric  disorders,  substance  abuse,  and  suicide. The  obstetrician  and  gynecologist  should be particularly sensitive to the needs that these  women may have regarding their reproductive health.  More information about the health disparities that the  LGBT  community  may  have  can  be  found  at  www. healthypeople.gov/LGBT.  For  more  detailed  informa- tion  about  the  specific  needs  that  lesbian  and  trans- gender  women  may  have,  the  American  College  of  Obstetricians  and  Gynecologists  Committee  Opinion  Number  525,  dated  May  2012  and  reaffirmed  in  2014,  can be consulted at www.ACOG.org. 

Vaginal tumors  are  the  most  serious  possibility  to  be  considered.  Sarcoma botryoides  classically  pres- ents with vaginal bleeding and grapelike vesicles. For- tunately, this is a rare tumor.

Geriatric Patients The gynecologic assessment of the elderly woman may  present  a  special  challenge.  Many  older  patients  tend  to  underreport  their  symptoms,  possibly  because  of  a  belief  that  any  new  physical  problems  are  due  to  the  normal aging process. Also, a fear of loss of their inde- pendence  may  contribute  to  this  denial  and  this  may  lead to a delay of diagnosis and perhaps a worse prog- nosis.  In  addition  to  the  routine  gynecologic  history  and  physical  examination,  these  patients  should  be  evaluated for any sensory impairments, such as visual  or  hearing  loss,  any  impaired  mobility,  malnutrition,  urinary incontinence, or confusion, which may be due  to polypharmacy. Appropriate referral, when improve- ment  can  be  reasonably  expected,  should  be  consid- ered for these problems once identified.

Gynecologic conditions such as atrophic vaginitis, uterine and vaginal prolapse, and genital tract malig- nancies are among the more common problems encountered in the geriatric patient.

Patients with Disabilities Women  with  developmental  or  acquired  disabilities  should  receive  the  same  high  quality  obstetric  and  gynecologic care as anyone else, with a goal of sustain- ing their best level of functioning. Assisting families of 

23

3  Female Reproductive Anatomy and Embryology

C H

A P

T ER

JOSEPH C. GAMBONE

■  The upper vagina, cervix, uterus, and fallopian tubes are  formed  from  the  paramesonephric  (müllerian)  ducts.  The absence of the Y chromosome leads to the develop- ment of the müllerian (female) system with virtual total  regression of the mesonephric (wolffian) or male system.  With  the Y  chromosome  present,  a  testis  is  formed  and  müllerian-inhibiting substance is produced, creating the  reverse situation.

■  The  vagina  is  a  flattened  tube  extending  from  the  hymenal  ring  at  the  vaginal  introitus  up  to  the  fornices  that surround the uterine cervix. The vaginal epithelium,  which is stratified squamous in type, and not mucosal, is  nonkeratinized  and  devoid  of  mucous  glands  and  hair  follicles.

■  The blood supply to the ovaries is provided by the ovarian  arteries, which arise from the abdominal aorta immedi- ately  below  the  renal  arteries.  The  venous  drainage  of  each  ovary  differs  in  that  the  right  ovary  drains  directly  into the inferior vena cava whereas the left ovary drains  into the left renal vein.

■  At  the  time  of  pelvic  examination  when  a  woman  is  in  the  dorsal-lithotomy  position,  the  uterus  may  be  pal- pated  to  be  tilted  forward  in  an  anterior  or  anteverted  position,  in  a  midline  position,  or  tilted  backward  in  a  posterior  or  retroverted  position.  The  top  or  corpus  of  the  uterus  may  also  be  folded  forward  (anteflexed)  or  backward (retroflexed). Most of the time this represents  normal anatomic variation.

■  Gynecologic surgeons use several types of skin incisions  for  the  performance  of “open”  surgical  procedures. The  most common is the low transverse or Pfannenstiel inci- sion.  When  more  exposure  is  needed  than  anticipated,  the skin incision can be extended and the rectus abdomi- nis  muscles  divided  with  diathermy.  This  is  called  a  Maylard  incision.  For  most  open  operations  for  cancer,  vertical  incisions  are  desirable,  because  they  can  be  readily extended to allow access to the upper abdomen.

CLINICAL KEYS FOR THIS CHAPTER

Other  chapters  in  this  book  deal  with  the  disruptive  deviations  from  normal  female  anatomy  and  physiol- ogy, whether they be congenital, functional, traumatic,  inflammatory,  neoplastic,  or  even  iatrogenic.  As  the  etiology  and  pathogenesis  of  clinical  problems  are   considered  in  these  other  chapters,  each  should  be  studied  in  the  context  of  normal  anatomy,  develop- ment,  and  physiology.  A  physician  cannot  practice  obstetrics  and  gynecology  effectively  without  under- standing  the  physiologic  processes  that  transpire  in  a  woman’s  life  as  she  passes  through  infancy,  adoles- cence,  reproductive  maturity,  and  the  climacteric.  As  the various clinical problems are addressed, it is impor- tant  to  consider  those  anatomic,  developmental,  and  physiologic  changes  that  normally  take  place  at  key  points in a woman’s life cycle.

This  chapter  presents  the  normal  anatomy  of  the  female  reproductive  tract  along  with  its  embryologic  development and the anatomy of some important sur- rounding structures. Applied anatomic issues, such as  the normal variation in uterine position and the types  of surgical incisions used by gynecologic surgeons, are  also covered.

Development of the External Genitalia Before the seventh week of development, the appear- ance of the external genital area is the same in males and females.  Elongation  of  the  genital  tubercle  into  a  phallus with a clearly defined terminal glans portion is 

24 PA R T 1 Introduction

muscles  and  inferiorly  by  the  skin  between  the  thighs  (Figure  3-2).  Anteriorly,  the  perineum  extends  to  the  symphysis pubis and the inferior borders of the pubic  bones.  Posteriorly,  it  is  limited  by  the  ischial  tuberosi- ties, the sacrotuberous ligaments, and the coccyx. The superficial and deep transverse perineal muscles cross the pelvic outlet between the two ischial tuber- osities and come together at the perineal body. They divide the space into the urogenital triangle anteri- orly and the anal triangle posteriorly.

The  urogenital  diaphragm  is  a  fibromuscular  sheet  that  stretches  across  the  pubic  arch.  It  is  pierced  by  the  vagina,  the  urethra,  the  artery  of  the  bulb,  the  internal  pudendal  vessels,  and  the  dorsal  nerve  of  the  clitoris.  Its  inferior  surface  is  covered  by  the  crura   of the clitoris, the vestibular bulbs, the greater vestibu- lar  (Bartholin)  glands,  and  the  superficial  perineal  muscles. The  Bartholin  glands  are  situated  just  poste- rior to the vestibular bulbs, and their ducts empty into  the  introitus  just  below  the  labia  minora.  They  are  often  the  site  of  gonococcal  infections  and  painful  abscesses.

noted in the 7th week, and gross inspection at this time  may  lead  to  faulty  sexual  identification. Ventrally  and  caudally,  the  urogenital  membrane,  made  up  of  both  endodermal  and  ectodermal  cells,  further  differenti- ates  into  the  genital  folds  laterally  and  the  urogenital  folds  medially.  The lateral genital folds develop into the labia majora, whereas the urogenital folds develop subsequently into the labia minora and prepuce of the clitoris.

The external genitalia of the fetus are readily distin- guishable as female at approximately 12 weeks (Figure  3-1).  In  the  male,  the  urethral  ostium  is  located  con- spicuously  on  the  elongated  phallus  by  this  time  and   is  smaller,  because  of  urogenital  fold  fusion  dorsally,  which  produces  a  prominent  raphe  from  the  anus  to  the urethral ostium. In the female, the hymen is usually  perforated by the time delivery occurs.

Anatomy of the External Genitalia The perineum represents the inferior boundary of the pelvis.  It  is  bounded  superiorly  by  the  levator  ani 

FIGURE 3-1 Development of the external female genitalia. A, Indifferent stage (approximately 7 weeks). B, Approximately 10 weeks. C, Approximately 12 weeks.

A

B C

Urogenital groove

Urogenital fold

Urogenital fold

Anus

Glans clitoridis

Genital swelling

Vestibule

Labium minora

Labium majora

Genital tubercle

C H A P T E R 3 Female Reproductive Anatomy and Embryology 25

The clitoris lies just in front of the urethra and con- sists of the glans, the body, and the crura.  Only  the  glans clitoris is visible externally. The body, composed  of a pair of corpora cavernosa, extends superiorly for a  distance  of  several  centimeters  and  divides  into  two  crura, which are attached to the undersurface of either  pubic  ramus.  Each  crus  is  covered  by  the  correspond- ing  ischiocavernosus  muscle.  Each  vestibular  bulb  (equivalent  to  the  corpus  spongiosum  of  the  penis)  extends posteriorly from the glans on either side of the  lower  vagina.  Each  bulb  is  attached  to  the  inferior  surface  of  the  perineal  membrane  and  covered  by  the  bulbocavernosus  muscle.  These  muscles  aid  in  con- stricting  the  venous  supply  to  the  erectile  vestibular  bulbs and also act as the sphincter vaginae.

As the labia minora are spread, the vaginal introitus,  guarded  by  the  hymenal  ring,  is  seen.  Usually,  the  hymen  is  represented  only  by  a  circle  of  carunculae  myrtiformes  around  the  vaginal  introitus. The  hymen 

VULVA The external genitalia are referred to collectively as the  vulva.  As  shown  in  Figure  3-3,  the vulva includes the mons veneris, labia majora, labia minora, clitoris, vulvovaginal (Bartholin) glands, fourchette, and perineum. The  most  prominent  features  of  the  vulva,  the  labia  majora,  are  large,  hair-covered  folds  of  skin  that  contain  sebaceous  glands  and  subcutaneous  fat  and lie on either side of the introitus. The labia minora  lie medially and contain no hair but have a rich supply  of  venous  sinuses,  sebaceous  glands,  and  nerves. The  labia minora may vary from scarcely noticeable struc- tures to leaf-like flaps measuring up to 3 cm in length.  Anteriorly, each splits into two folds. The posterior pair  of  folds  attach  to  the  inferior  surface  of  the  clitoris,  at  which point they unite to form the frenulum of the cli- toris. The anterior pair are united in a hoodlike configu- ration over the clitoris, forming the prepuce. Posteriorly,  the labia minora may extend almost to the fourchette.

FIGURE 3-2 The perineum, showing superficial structures on the left and deeper structures on the right.

Anal sphincter

Gluteus maximus m.

Levator ani m.

Ischial tuberosity

Bartholin gland

Inf. fascia of urogenital diaphragm

Vestibular bulb

Urethra

Coccyx

Crus of clitoris

Ischiocavernosus m.

Bulbocavernosus m.

Transverse perineal m.

26 PA R T 1 Introduction

of  the  mesonephric  system.  With  a  Y  chromosome  present,  a  testis  is  formed  and  müllerian-inhibiting  substance is produced, creating the reverse situation.

Mesonephric duct development occurs in each uro- genital ridge between weeks 2 and 4 and is thought to  influence the growth and development of the parame- sonephric  ducts.  The mesonephric ducts terminate caudally by opening into the urogenital sinus.  First  evidence  of  each  paramesonephric  duct  is  seen  at  6  weeks’ gestation as a groove in the coelomic epithelium  of  the  paired  urogenital  ridges,  lateral  to  the  cranial  pole of the mesonephric duct. Each paramesonephric duct opens into the coelomic cavity cranially  at  a  point  destined  to  become  a  tubal  ostium.  Coursing  caudally at first, parallel to the developing mesoneph- ric duct, the blind distal end of each paramesonephric  duct  eventually  crosses  dorsal  to  the  mesonephric  duct,  and  the  two  ducts  approximate  in  the  midline.  The two paramesonephric ducts fuse terminally at the urogenital septum, forming the uterovaginal primordium.  The  distal  point  of  fusion  is  known  as  the  müllerian tubercle (Müller tubercle)  and  can  be  seen  protruding  into  the  urogenital  sinus  dorsally  in  embryos at 9 to 10 weeks’ gestation (Figure 3-4). Later

may  take  many  forms,  however,  such  as  a  cribriform  plate with many small openings or a completely imper- forate diaphragm.

The  vestibule  of  the  vagina  is  that  portion  of  the  introitus  extending  inferiorly  from  the  hymenal  ring  between  the  labia  minora.  The  fourchette  represents  the  posterior  portion  of  the  vestibule  just  above  the  perineal  body.  Most of the vulva is innervated by the branches of the pudendal nerve. Anterior to the urethra, the vulva is innervated by the ilioinguinal and genitofemoral nerves.  This  area  is  not  anesthe- tized  adequately  by  a  pudendal  block,  and  repair  of  paraurethral  tears  should  be  supplemented  by  addi- tional subcutaneous anesthesia.

Internal Genital Development The upper vagina, cervix, uterus, and fallopian tubes are formed from the paramesonephric (müllerian) ducts.  Although  human  embryos,  whether  male  or  female,  possess  both  paired  paramesonephric  and  mesonephric  (wolffian)  ducts,  the absence of Y chro- mosomal influence leads to the development of the paramesonephric system with virtual total regression 

FIGURE 3-3 Female external genitalia.

Glans of clitoris

Mons veneris

Labium minus

Vaginal orifice

Bartholin duct

Perineum

Anterior commissure

Prepuce

Labium majus

Fourchette

Anus

External urinary meatus

C H A P T E R 3 Female Reproductive Anatomy and Embryology 27

dissolution of the septum between the fused parame- sonephric ducts leads to the development of a single uterine fundus, cervix, and, according to some inves- tigators, the upper vagina.

Degeneration  of  the  mesonephric  ducts  is  progres- sive from 10 to 16 weeks in the female fetus, although  vestigial  remnants  of  the  latter  may  be  noted  in  the  adult  (Gartner  duct  cyst,  paroöphoron,  epoöphoron)  (Figure 3-5). The myometrium and endometrial stroma  are derived from adjacent mesenchyme; the glandular  epithelium of the fallopian tubes, uterus, and cervix is  derived from the paramesonephric duct.

Solid vaginal plate formation and lengthening occur  from  the  12th  through  the  20th  weeks,  followed  by  caudad to cephalad canalization, which is usually com- pleted  in  utero.  Controversy  surrounds  the  relative  contribution  of  the  urogenital  sinus  and  parameso- nephric ducts to the development of the vagina, and it  is  uncertain  whether  the  whole  of  the  vaginal  plate  is  formed  secondary  to  growth  of  the  endoderm  of  the  urogenital sinus or whether the upper vagina is formed  from the paramesonephric ducts.

VAGINA The  vagina  is  a  flattened  tube  extending  posterosu- periorly  from  the  hymenal  ring  at  the  introitus  up   to  the  fornices  that  surround  the  cervix  (Figure  3-6).   Its epithelium, which is stratified squamous in type, is normally devoid of mucous glands and hair follicles and is nonkeratinized.  Gestational  exposure  to  diethylstilbestrol  (taken  by  the  mother)  may  result 

FIGURE 3-4 Early embryologic development of the genital tract (A-C) and vaginal plate (D). MD, Mesonephric duct; MT, müllerian tubercle; PD, paramesonephric duct; US, urogenital sinus; UVP, uterovaginal primordium; VP, vaginal plate. (Redrawn from Didusch JF, Koff AK: Development of the vagina in the human fetus. Contrib Embryol Carnegie Inst 24:61, 1933.)

MD

US

US

(8 wk) (10 wk) (11 wk)

A

B

C

D

PD

MT

MT

VP

Cervix

US

UVP

UVP

FIGURE 3-5 Remnants of the mesonephric (wolffian) ducts that may persist in the anterolateral vagina or adjacent to the uterus within the broad ligament or mesosalpinx.

.. ..

Gartner duct cyst

Gartner duct (vestigial remnant)

Ureter

Hydatid of Morgagni (paramesonephric

duct origin)

Paroophoron (distal tubules of the mesonephros)

Epoophoron (proximal tubules of the mesonephros)

28 PA R T 1 Introduction

FIGURE 3-6 Coronal section of the pelvis at the level of the uterine isthmus and ischial spines, showing the ligaments supporting the uterus.

Broad ligament

Uterus

Ovary

Infundibulopelvic ligament

Round ligament

Cut edge of peritoneum

Vaginal a.

Cervix

Ureter

Cardinal ligament

Crus of clitoris

Endopelvic fascia

Ischiocavernosus m.

Peroneal a.

Vestibular bulb Vestibule

Vagina HymenRound

ligament Labium minus Labium majus

Obturator internus m.

Uterine a.

Vaginal fornix

Levator ani m.

Ischiopubic ramus

Deep transverse perineal m. within

urogenital diaphragm

Colles fascia

in  columnar  glands  interspersed  with  the  squamous  epithelium  of  the  upper  two-thirds  of  the  vagina  (vaginal adenosis). Deep to the vaginal epithelium are  the  muscular  coats  of  the  vagina,  which  consist  of  an  inner circular and an outer longitudinal smooth muscle  layer. Remnants of the mesonephric ducts may some- times  be  demonstrated  along  the  vaginal  wall  in  the  subepithelial layers and may give rise to Gartner duct cysts. The adult vagina averages about 8 cm in length,  although  its  size  varies  considerably  with  age,  parity,  and  the  status  of  ovarian  function.  An  important  ana- tomic feature is the immediate proximity of the poste- rior fornix of the vagina to the pouch of Douglas, which  allows  easy  access  to  the  peritoneal  cavity  from  the  vagina, by either culdocentesis or colpotomy.

UTERUS The uterus consists of the cervix and the uterine corpus, which are joined by the isthmus. The uterine  isthmus  represents  a  transitional  area  wherein  the  endocervical  epithelium  gradually  changes  into  the  endometrial  lining.  In  late  pregnancy,  this  area  elon- gates and is referred to as the lower uterine segment.

The cervix is generally 2 to 3 cm in length. In infants  and children, the cervix is proportionately longer than  the  uterine  corpus  (Figure  3-7). The  portion  that  pro- trudes into the vagina and is surrounded by the fornices  is  covered  with  a  nonkeratinizing  squamous  epithe- lium. At about the external cervical os, the squamous epithelium covering the exocervix (or ectocervix) changes to simple columnar epithelium, the site of transition being referred to as the squamocolumnar junction. The cervical canal is lined by irregular, arbo- rized, simple columnar epithelium, which extends into  the stroma as cervical “glands” or crypts.

The  uterine  corpus  is  a  thick,  pear-shaped  organ,  somewhat  flattened  anteroposteriorly,  that  consists  of  largely interlacing smooth muscle fibers. The endome- trial  lining  of  the  uterine  corpus  may  vary  from  2  to  10 mm in thickness (which may be measured by ultra- sonic  imaging),  depending  on  the  stage  of  the  men- strual cycle. Most of the surface of the uterus is covered  by the peritoneal mesothelium.

Four paired sets of ligaments are attached to the uterus  (Figure  3-8).  Each  round  ligament  inserts  on  the  anterior  surface  of  the  uterus  just  in  front  of  the 

C H A P T E R 3 Female Reproductive Anatomy and Embryology 29

FIGURE 3-7 Changing proportion of the uterine cervix and corpus from infancy to adulthood. (Modified from Cunningham FG, Mac- Donald PC, Gant NF, et al, editors: Williams obstetrics, ed 20, East Norwalk, Conn, 1997, Appleton & Lange.)

Anterior peritoneal reflection

Isthmus

Internal os

Internal os

Internal os

INFANT YOUNG VIRGIN

MULTIPARAExternal os

Anterior peritoneal reflection

Corpus Cervix

2 3

1 3

2 3

1 3

1 2

1 2

Bladder

fallopian tube, passes to the pelvic side wall in a fold of  the  broad  ligament,  traverses  the  inguinal  canal,  and  ends in the labium majus. The round ligaments are of little supportive value in preventing uterine prolapse  but help to keep the uterus anteverted. The uterosacral ligaments  are  condensations  of  the  endopelvic  fascia  that arise from the sacral fascia and insert into the pos- teroinferior  portion  of  the  uterus  at  about  the  level  of  the isthmus. These ligaments contain sympathetic and  parasympathetic  nerve  fibers  that  supply  the  uterus.  They provide important support for the uterus and are  also  significant  in  precluding  the  development  of  an  enterocele.  The cardinal ligaments (Mackenrodt)  are  the other important supporting structures of the uterus  that  prevent  prolapse.  They  extend  from  the  pelvic  fascia  on  the  lateral  pelvic  walls  and  insert  into  the  lateral portion of the cervix and vagina, reaching supe- riorly to the level of the isthmus. The pubocervical liga- ments  pass  anteriorly  around  the  bladder  to  the  posterior surface of the pubic symphysis.

In addition, there are four peritoneal folds. Anteri- orly,  the vesicouterine fold  is  reflected  from  the  level  of the uterine isthmus onto the bladder. Posteriorly, the rectouterine fold passes from the posterior wall of the  uterus,  to  the  upper  fourth  of  the  vagina,  and  thence  onto  the  rectum.  The  pouch  between  the  cervix  and  vagina  anteriorly  and  rectum  posteriorly  forms  a  cul- de-sac, called the pouch of Douglas. Laterally, the two broad ligaments each pass from the side of the uterus  to the lateral wall of the pelvis. Between the two leaves  of  each  broad  ligament  are  contained  the  fallopian 

tube, the round ligament, and the ovarian ligament, in  addition to nerves, blood vessels, and lymphatics. The fold of broad ligament containing the fallopian tube is called the mesosalpinx. Between the end of the tube  and  ovary  and  the  pelvic  side  wall,  where  the  ureter  passes over the common iliac vessels, is the infundibu- lopelvic  ligament,  which  contains  the  vessels  and  nerves  for  the  ovary. The  ureter  may  be  injured  when  this ligament is ligated during a salpingo-oophorectomy  procedure if it is not clearly identified first.

The anatomic position of the uterus may vary within  the pelvic cavity as palpated during a pelvic examina- tion. With respect to the horizontal plane on the surface  of the examination table, the straight line axis extend- ing  from  the  cervix  to  the  fundal  end  of  the  uterine  corpus  may  be  in  one  of  three  positions.  The  uterus  may  tilt  in  a  forward  position  (anteverted),  it  may  be  only slightly forward and in mid-position, or it may tilt  in a backward direction (retroverted). Additionally, the  fundal  portion  of  the  uterus  may  fold  forward  (ante- flexed) or backward (retroflexed). Most of the time this  variation in position is normal and without clinical sig- nificance.  On  occasion  the  identification  of  this  ana- tomic  variation  is  important.  For  example,  extreme  flexion (ante or retro) may make insertion of an instru- ment  or  of  an  intrauterine  device  (IUD)  higher  risk.  A  retroverted and retroflexed uterus may also be a finding  in a woman with pelvic adhesions due to endometrio- sis or pelvic inflammation due to infection. Figure 3-9  illustrates  the  potential  positions  of  the  uterus  within  the pelvis.

30 PA R T 1 Introduction

quite mobile. The mobility of the fimbriated end of the  tube plays an important role in fertility. The ampullary  portion of the tube is the most common site of ectopic  pregnancies.

Normal Embryologic Development of the Ovary The earliest anatomic event in gonadogenesis is noted  at approximately 4 weeks’ gestational age (i.e., 4 weeks  from conception), when a thickening of the peritoneal,  or coelomic, epithelium on the ventromedial surface of  the  urogenital  ridge  occurs.  A  bulging  genital ridge  is  subsequently  produced  by  rapid  proliferation  of  the  coelomic epithelium in an area that is medial, but par- allel,  to  the  mesonephric  ridge.  Prior  to  the  5th  week,  this indifferent gonad consists of germinal epithelium 

FALLOPIAN TUBES The oviducts are bilateral muscular tubes (about 10 cm  in  length)  with  lumina  that  connect  the  uterine  cavity  with  the  peritoneal  cavity.  They  are  enclosed  in  the  medial  four-fifths  of  the  superior  aspect  of  the  broad  ligament.  The  tubes  are  lined  by  a  ciliated,  columnar  epithelium  that  is  thrown  into  branching  folds.  That  segment  of  the  tube  within  the  wall  of  the  uterus  is  referred  to  as  the  interstitial portion.  The  medial  portion of each tube is superior to the round ligament,  anterior to the ovarian ligament, and relatively fixed in  position.  This  nonmobile  portion  of  the  tube  has  a  fairly  narrow  lumen  and  is  referred  to  as  the  isthmus.  As  the  tube  proceeds  laterally,  it  is  located  anterior  to  the  ovary;  it  then  passes  around  the  lateral  portion  of  the ovary and down toward the cul-de-sac. The ampul- lary and fimbriated portions of the tube are suspended  from  the  broad  ligament  by  the  mesosalpinx  and  are 

FIGURE 3-8 View of the internal genital organs in the female pelvis. IVC, Inferior vena cava.

Round ligament

Ovarian ligament

Broad ligament

Fallopian tube

Ovary

Ovarian a. & v. (infundibulo- pelvic ligament)

Internal iliac a. & v.

Common iliac a. & v.

Sigmoid colon

Aorta IVC

Ureter

Uterosacral ligament

Uterine corpus

Full bladder

C H A P T E R 3 Female Reproductive Anatomy and Embryology 31

hindgut.  These  germ  cell  precursors  migrate  along  the hindgut dorsal mesentery (Figure 3-10) and are all  contained  in  the  mesenchyme  of  the  undifferentiated  urogenital ridge by 8 weeks’ gestation. Subsequent rep- lication  of  these  cells  by  mitotic  division  occurs,  with  maximal  mitotic  activity  noted  up  to  20  weeks’  gesta- tion  and  cessation  noted  by  term. These  oogonia,  the  end  result  of  this  germ  cell  proliferation,  are  incorpo- rated into the cortical sex cords of the genital ridge.

Histologically, the first evidence of follicles is seen at about 20 weeks, with germ cells surrounded by flattened cells derived from the cortical sex cords. These flattened cells are recognizable as granulosa

surrounding  the  internal  blastema,  a  primordial  mes- enchymal  cellular  mass  designated  to  become  the  ovarian  medulla.  After  5  weeks,  projections  from  the  germinal  epithelium  extend  like  spokes  into  the  mes- enchymal  blastema  to  form  primary sex cords.  Soon  thereafter  in  the  7th  week,  a  testis  can  be  identified  histologically if the embryo has a Y chromosome. In the  absence of a Y chromosome, definitive ovarian charac- teristics  do  not  appear  until  somewhere  between  the  12th and 16th weeks.

As early as 3 weeks’ gestation, relatively large pri- mordial germ cells appear intermixed with other cells in the endoderm of the yolk sac wall of the primitive

FIGURE 3-9 Uterine positions: A, Anteverted is the most common (normal) uterine position; B, anteverted and anteflexed when the uterine fundus is further forward toward the bladder; C, retroverted when the uterus is tilted backward toward the rectum. This position is not always abnormal but could indicate endometriosis affecting the uterosacral ligaments; and D, retroverted and retroflexed when there is an additional backward angle of the uterine fundus. A retroverted and retroflexed uterine position is more likely to be associated with endometriosis (see Chapter 25).

A B

DC

32 PA R T 1 Introduction

cells of coelomic epithelial origin and theca cells of mesenchymal origin.  The  oogonia  enter  the  pro- phase  of  the  first  meiotic  division  and  are  then  called  primary oocytes (see Chapter 4). It has been estimated  that  more  than  2  million  primary  oocytes,  or  their   precursors,  are  present  at  20  weeks’  gestation,  but   only  about  300,000  primordial  follicles  are  present  by   7 years of age.

Regression  of  the  primary  sex  cords  in  the  medulla  produces the rete ovarii, which are found histologically  in  the  hilus  of  the  ovary  along  with  another  testicular  analogue  called  Leydig cells,  which  are  thought  to  be  derived  from  mesenchyme.  Vestiges  of  the  rete  ovarii  and  of  the  degenerating  mesonephros  may  also  be  noted  at  times  in  the  mesovarium  or  mesosalpinx.  Structural homologues in males and females are shown  in Table 3-1.

Anatomy of the Ovaries The  ovaries  are  oval,  flattened,  compressible  organs,  approximately 3 × 2 × 2 cm in size. They are situated on  the superior surface of the broad ligament and are sus- pended between the ovarian ligament medially and the  suspensory ligament of the ovary or infundibulopelvic  ligament laterally and superiorly. Each occupies a posi- tion  in  the  ovarian  fossa  (of  Waldeyer),  which  is  a 

FIGURE 3-10 Migratory path of primordial germ cells from the yolk sac, along the hindgut mesentery, to the urogenital ridge at approximately 5 weeks.

Primordial germ cells

Hindgut

Allantois

Cloaca

Genital ridge

Mesonephric (medial) and paramesonephric

(lateral) ducts

TABLE 3-1

STRUCTURAL HOMOLOGUES IN MALES AND FEMALES

Primordia Female Male Major Determining Factors

Gonadal

Germ cells Oogonia Spermatogonia Sex chromosomes

Coelomic epithelium Granulosa cells Sertoli cells

Mesenchyme Theca cells Leydig cells

Mesonephros Rete ovarii Rete testis

Ductal

Paramesonephric (müllerian) duct

Fallopian tubes Uterus Superior 23 of vagina Gartner duct

Hydatid testis Absence of Y chromosome

Mesonephric (wolffian) duct Mesonephric tubules

Epoöphoron Paroöphoron

Vas deferens Seminal vesicles Epididymis Efferent ducts

Testosterone Müllerian inhibiting factor

External Genitalia

Urogenital sinus Vaginal contribution Skene glands Bartholin glands

Prostate Prostatic utricle Cowper glands Penis Corpora spongiosa Scrotum

Presence or absence of testosterone, dihydrotestosterone, and 5α-reductase enzyme

Genital tubercle Urogenital folds Genital folds

Clitoris Labia minora Labia majora

C H A P T E R 3 Female Reproductive Anatomy and Embryology 33

artery  through  the  uterine-ovarian  arterial  anastomo- sis.  The venous drainage from the right ovary is directly into the inferior vena cava, whereas that from the left ovary is into the left renal vein (Figure 3-11).

Anatomy of the Ureters The ureters extend 25 to 30 cm from the renal pelves to  their  insertion  into  the  bladder  at  the  trigone.  Each  descends immediately under the peritoneum, crossing  the  pelvic  brim  beneath  the  ovarian  vessels  just  ante- rior to the bifurcation of the common iliac artery. In the  true  pelvis,  the  ureter  initially  courses  inferiorly,  just  anterior  to  the  hypogastric  vessels,  and  stays  closely 

shallow  depression  on  the  lateral  pelvic  wall  just  pos- terior  to  the  external  iliac  vessels  and  anterior  to  the  ureter  and  hypogastric  vessels.  In  endometriosis  and  salpingo-oophoritis, the ovaries may be densely adher- ent to the ureter. Generally, the serosal covering and the  tunica albuginea of the ovary are quite thin, and devel- oping follicles and corpora lutea are readily visible.

The blood supply to the ovaries is provided by the long ovarian arteries, which arise from the abdomi- nal aorta immediately below the renal arteries. These  vessels  course  downward  and  cross  laterally  over  the  ureter at the level of the pelvic brim, passing branches  to  the  ureter  and  the  fallopian  tube.  The  ovary  also  receives  substantial  blood  supply  from  the  uterine 

FIGURE 3-11 Lymphatic drainage of the internal genital organs. IVC, Inferior vena cava.

L. adrenal gland

Superior mesenteric a.

L. ovarian a.

Para-aortic lymph nodes

Inferior mesenteric a.

L. common iliac v.

M. sacral v.

L. ovarian vessels

L. ureter

Fallopian tube

Ovary Round ligamentUterus

AortaIVC

RectumObturator node

External iliac nodes

Hypogastric a. and nodes

R. common iliac a. and

nodes

R. ovarian v.

M. sacral a.

R. ureter

34 PA R T 1 Introduction

lopian tubes, ovaries, and part of the rectum and anus.  The false (greater) pelvis is bounded by the lumbar ver- tebrae  posteriorly,  iliac  fossae  bilaterally,  and  the  abdominal wall anteriorly.

The  bony  pelvis  is  particularly  important  during  pregnancy and labor. It is clinically important to deter- mine  the  adequacy  of  the  pelvis  for  vaginal  birth  by  performing  pelvimetry.  This  may  be  done  during  a  pelvic  examination  or  using  computed  tomography,  which is more accurate (see Chapter 8).

Anatomy of the Lower Abdominal Wall Because  most  intraabdominal  gynecologic  operations  are performed through lower abdominal incisions, it is  important to review the anatomy of the lower abdomi- nal  wall  with  special  reference  to  the  muscles  and  fasciae.  After  transecting  the  skin,  subcutaneous  fat,  superficial  fascia  (Camper),  and  deep  fascia  (Scarpa)  the anterior rectus sheath is encountered (Figure 3-13).  The rectus sheath is a strong fibrous compartment formed by the aponeuroses of the three lateral abdominal wall muscles. The aponeuroses meet in the  midline  to  form  the  linea  alba  and  partially  encase   the two rectus abdominis muscles. The composition of  the  rectus  sheath  differs  in  its  upper  and  lower  por- tions. Above the midpoint between the umbilicus and  the  symphysis  pubis,  the  rectus  muscle  is  encased  anteriorly  by  the  aponeurosis  of  the  external  oblique  and  the  anterior  lamina  of  the  internal  oblique  apo- neurosis  and  posteriorly  by  the  aponeurosis  of  the  transversus  abdominis  and  the  posterior  lamina  of  

attached  to  the  peritoneum.  It  then  passes  forward  along  the  side  of  the  cervix  and  beneath  the  uterine  artery toward the trigone of the bladder.

Lymphatic Drainage The  lymphatic  drainage  of  the  vulva  and  lower  vagina  is  principally  to  the  inguinofemoral  lymph  nodes  and  then  to  the  external  iliac  chains  (see  Figure  3-11). The  lymphatic  drainage  of  the  cervix  takes  place  through  the parametria (cardinal ligaments) to the pelvic nodes  (the  hypogastric,  obturator,  and  external  iliac  groups)  and  then  to  the  common  iliac  and  para-aortic  chains.  The  lymphatic  drainage  from  the  endometrium  is  through  the  broad  ligament  and  infundibulopelvic  ligament to the pelvic and para-aortic chains. The lym- phatics  of  the  ovaries  pass  via  the  infundibulopelvic  ligaments  to  the  pelvic  and  para-aortic  nodes  (see  Figure 3-11).

Anatomy of the Bony Pelvis The  bony  pelvis  (Figure  3-12)  is  made  up  of  the  two paired innominate bones and the sacrum.  The  sym- physis pubis is formed anteriorly at the attachment of  both innominate bones. The sacrum has five to six ver- tebrae  that  are  fused  in  the  adult.  The sacrum articu- lates posteriorly with each innominate bone at the sacroiliac joints. The sacrum also articulates inferi- orly with the coccyx and superiorly with the fifth lumbar vertebra. The  true  (lesser)  pelvis  is  formed  by  the  sacrum  and  coccyx  posteriorly  and  by  the  pubis  anteriorly  and  ischium  laterally.  The  true  pelvis  con- tains the pelvic organs; the uterus, vagina, bladder, fal-

FIGURE 3-12 The bony pelvis.

Greater (false) pelvis Lesser (true) pelvis

Posterior superior iliac spine

Iliac crest

Iliac fossa

Sacrum

Acetabulum

Coccyx

Pubic symphysis

Ilium

Pubis

Ischium

Anterior superior

iliac spine

C H A P T E R 3 Female Reproductive Anatomy and Embryology 35

incision.  Each rectus muscle has a firm aponeurosis at its attachment to the symphysis pubis, and this tendinous aponeurosis can be transected if necessary to improve exposure, as in the Cherney incision,  and  resutured  securely  during  closure  of  the  abdomi- nal wall.

The inferior epigastric arteries arise from the exter- nal  iliac  arteries  and  proceed  superiorly  just  lateral  to  the rectus muscles between the transversalis fascia and  the  peritoneum.  They  enter  the  rectus  sheaths  at  the  level  of  the  semilunar  line  and  continue  their  course  superiorly  just  posterior  to  the  rectus  muscles.  In  a  transverse  rectus  muscle–cutting  (Maylard)  incision,  the  epigastric  arteries  can  be  retracted  laterally  or  ligated to allow a wide peritoneal incision.

the  internal  oblique  aponeurosis.  In the lower fourth of the abdomen, the posterior aponeurotic layer of the sheath terminates in a free crescentic margin, the semilunar fold of Douglas.

Each rectus abdominis muscle, encased in the rectus sheath on either side of the midline, extends from the superior aspect of the symphysis pubis to the anterior surface of the fifth, sixth, and seventh costal cartilages.  A  variable  number  of  tendinous  intersections  (three  to  five)  crosses  each  muscle  at  irregular  intervals,  and  any  transverse  rectus  surgical  incision  forms  a  new  fibrous  intersection  during  healing.  The  muscle  is  not  attached  to  the  posterior  sheath  and,  following  separation  from  the  anterior  sheath, can be retracted laterally, as in the Pfannenstiel 

FIGURE 3-13 Transverse section through the anterior abdominal wall just below the umbilicus (A) and just above the pubic symphysis (B). Note the absence of the posterior rectus sheath in B.

Anterior rectus sheath

Camper fascia

Scarpa fascia

Ext. oblique m.

Int. oblique m.

Transversus abdominis m.

Inferior epigastric vessels

Inferior epigastric vessels

Posterior rectus sheath

Linea alba

Transversalis fascia

Peritoneum

A

B

36 PA R T 1 Introduction

Abdominal Wall Incisions The most commonly used lower abdominal incision in gynecologic surgery is the Pfannenstiel incision  (Figure  3-14).  Although  it  does  not  always  give  suffi- cient exposure for extensive operations, it has cosmetic  advantages  in  that  it  is  generally  only  2 cm  above  the  symphysis  pubis,  and  the  scar  is  later  covered  by  the  pubic  hair.  Because  the  rectus  abdominis  muscles  are  not cut, eviscerations and wound hernias are extremely  uncommon.  For extensive pelvic procedures (e.g., radical hysterectomy and pelvic lymphadenectomy), a transverse muscle–cutting incision (Bardenheuer or Maylard) at a slightly higher level in the lower abdomen gives sufficient exposure.  In  addition,  the  skin incision falls within the lines of Langer, so a good  cosmetic result can be expected.

When it is anticipated that upper abdominal explo- ration  will  be  necessary,  such  as  in  a  patient  with   suspected  ovarian  cancer,  a  midline  incision  through  the  linea  alba  or  a  paramedian  vertical  incision  is  indicated.

FIGURE 3-14 Abdominal wall incisions: McBurney (A), lower midline (B), left lower paramedian (C), Pfannenstiel or Cherney (D), and transverse, Maylard or Bardenheuer (E).

A

B

C

D

E

37

4  Female Reproductive Physiology

C H

A P

T ER

JOSEPH C. GAMBONE

■  The female reproductive cycle (menstrual cycle) may be  viewed  as  four  separate  physiologic  cycles  (hypotha- lamic, pituitary, ovarian, and endometrial) but is actually  a  highly  complex  and  integrated  event. This  28  (±7)  day  cycle allows for the maturation and release of an oocyte  (usually  only  one)  that  if  fertilized  may  implant  in  a  receptive endometrium. If fertilization and implantation  do not occur, the end result is menstruation.

■  Communication  between  the  hypothalamus,  which  releases  gonadotropin-releasing  hormone  (GnRH)  in  pulses, and the pituitary gland is essential to permit the  pituitary  to  respond  to  changes  in  ovarian  hormones  (estradiol  and  progesterone)  and  other  factors.  This  essential  communication  results  in  both  negative  and  positive feedback for the release of the pituitary gonado- tropins, luteinizing hormone (LH) and follicle-stimulat- ing hormone (FSH). These gonadotropins, also released  in  pulses,  stimulate  follicular  growth  in  the  ovary  (FSH)  such  that  one  dominant  follicle  releases  an  oocyte  in  response to a midcycle surge in LH. Other growth factors  and  peptides  such  as  inhibin-A,  inhibin-B,  and  activin  act systemically and locally to control follicular growth.

■  After  oocyte  release,  the  dominant  (graafian)  follicle  becomes  the  corpus  luteum  and  secretes  both  estradiol  (E2) and progesterone (P4). The endometrium responds  to  E2  with  growth  or  proliferation  before  ovulation  and  to P4 and E2 after ovulation with maturation that allows  for  implantation  if  fertilization  occurs.  The  corpus  luteum continues to maintain the uterine lining, stimu- lated by human chorionic gonadotropin (hCG) from the  placental tissue if a pregnancy occurs.

■  Fertilization and implantation begin with normal sperm  function  and  penetration  of  the  oocyte  in  the  fallopian  tube.  Fertilization  restores  the  diploid  number  of  chro- mosomes and determines the sex of the zygote. The fer- tilized ovum reaches the endometrium about 3 days after  ovulation  and  after  another  several  days  the  blastocyst  implants.

■  As the blastocyst burrows into the endometrium, the tro- phoblastic strands branch to form the primitive villi. The  villi are first distinguished about the 12th day after fertil- ization  and  are  the  essential  structures  of  the  placenta.  The placenta is the life-support system for the develop- ing fetus for the rest of pregnancy.

CLINICAL KEYS FOR THIS CHAPTER

Reproductive Cycle Each  female  reproductive  cycle  (menstrual  cycle)   represents  a  complex  interaction  between  the  hypo- thalamus,  pituitary  gland,  ovaries,  and  endometrium.  Cyclic  changes  in  the  gonadotropins,  luteinizing  hormone (LH), and follicle-stimulating hormone (FSH)  and  sex  steroid  hormones,  mainly  estradiol  (E2)  and  progesterone  (P4),  induce  functional  as  well  as  mor- phologic  changes  in  the  ovary,  resulting  in  follicular  maturation,  ovulation,  and  corpus  luteum  formation.  Similar changes at the level of the endometrium allow  for successful implantation of the fertilized ovum or a  physiologic  shedding  of  the  menstrual  endometrium 

when  an  early  pregnancy  does  not  occur.  By  conven- tion,  the  normal  cycle  begins  on  the  first  day  of  men- strual  bleeding  and  ends  just  before  the  first  day  of   the  next  menses.  The  average  length  of  each  cycle  is   28 (±7) days.

The reproductive cycle can be viewed from the perspective of each of four physiologic com­ ponents  (Table  4-1).  The  cyclic  changes  within  the  hypothalamic-pituitary  axis,  ovary,  and  endometrium  are  sequentially  approached  in  this  chapter,  as  if  they  were  four  separate  cycles,  but  these  endocrine  events  occur in concert in a uniquely integrated fashion. The  chapter also includes a discussion of spermatogenesis,  fertilization, implantation, and placentation.

38 PA R T 1 Introduction

The  neurohypophysis  serves  primarily  to  transport  oxytocin and vasopressin (antidiuretic hormone) along  neuronal  projections  from  the  supraoptic  and  para- ventricular nuclei of the hypothalamus to their release  into the circulation.

The anterior pituitary contains different cell types that produce six protein hormones: follicle­ stimulating hormone (FSH), luteinizing hormone (LH), thyroid­stimulating hormone (TSH), prolactin, growth hormone (GH), and adrenocorticotropic hormone (ACTH).

The  gonadotropins,  FSH  and  LH,  are  synthesized  and stored in cells called gonadotrophs, whereas TSH  is produced by thyrotrophs. FSH, LH, and TSH are gly- coproteins, consisting of α and β subunits. The α sub- units  of  FSH,  LH,  and  TSH  are  identical.  The  same  α  subunit is also present in human chorionic gonadotro- pin  (hCG).  The  β  subunits  are  individual  for  each  hormone.  The  half-life  for  circulating  LH  is  about  30  minutes,  whereas  that  of  FSH  is  several  hours.  The   difference  in  half-lives  may  account,  at  least  in  part,   for  the  differential  secretion  patterns  of  these  two  gonadotropins.

Hypothalamic-Pituitary Axis PITUITARY GLAND The pituitary gland lies below the hypothalamus at the  base  of  the  brain  within  a  bony  cavity  (sella  turcica)  and is separated from the cranial cavity by a condensa- tion  of  dura  mater  overlying  the  sella  turcica  (dia- phragma sellae). The pituitary gland is divided into two  major  portions,  the  neurohypophysis  and  the  adeno- hypophysis (Figure 4-1). The neurohypophysis, which consists of the posterior lobe (pars nervosa), the neural stalk (infundibulum), and the median emi­ nence, is derived from neural tissue and is in direct continuity with the hypothalamus and central nervous system. The adenohypophysis, which con­ sists of the pars distalis (anterior lobe), pars inter­ media (intermediate lobe), and pars tuberalis, which surrounds the neural stalk, is derived from ectoderm.

The  arterial  blood  supply  to  the  median  eminence  and  the  neural  stalk  (pituitary  portal  system)  repre- sents  a  major  avenue  of  transport  for  hypothalamic  secretions to the anterior pituitary.

TABLE 4-1

ENDOCRINE COMPONENTS OF THE REPRODUCTIVE (MENSTRUAL) CYCLE

Component Activity Phases Comment(s)

Hypothalamic (arcuate nucleus)

Produces pulses of GnRH from the arcuate nucleus. GnRH has a very short half-life of 2-4 min. Action requires frequent pulses. GnRH is sometimes referred to as LH-RH because it generally causes a greater release of LH.

Frequency of pulses is variable among individuals. Pulses are more frequent and lower amplitude in follicular phase and less frequent but higher amplitude in luteal phase (see Figure 4-4). The hypothalamic component changes the least on a daily basis.

Permits the other components of the cycle to act and react. If pathology or medications (e.g., hormonal contraceptives or GnRH analogues) disrupt pulses, the entire cycle stops. When GnRH is given in a continuous infusion (no pulses) downregulation inhibits LH and FSH release.

Pituitary (anterior) Produces pulses of LH and FSH from the anterior portion of gland.

LH half-life is 30 min, FSH half-life is several hours.

Negative feedback initially with strong positive feedback resulting in LH surge and ovulation.

Surge of LH at midcycle triggers ovulation, maturing the oocyte and releasing it from the follicle.

Ovarian Theca cells produce androgens in response to LH. Granulosa cells aromatize androgens to estrogens in response to FSH (see Figure 4-3). Ovarian inhibins (A and B) inhibit and activin stimulates gonadotropins.

Follicular, ovulatory, and luteal phases. Average overall cycle length is 28 (±7) days. Luteal phase is generally constant at 12 to 14 days. Follicular phase may vary.

LH triggers ovulation at midcycle. LH then stimulates the corpus luteum to produce P4 and some E2. With pregnancy, placental hCG rescues the corpus luteum by mimicking LH.

Endometrial Estradiol (E2) from the ovary stimulates growth (proliferation) and progesterone (P4) from the corpus luteum converts endometrium to secretory and withdrawal of E2 and P4 leads to menstruation (see Figures 4-7 and 4-8).

Menstrual, proliferative, and secretory phases. The endometrial component changes the most on a daily basis. Histology may be used to “date” the endometrium and determine day of cycle.

Menstruation is the only visible component. Because it is visible, it is where the cycle is said to start but menstruation actually represents the end of the previous cycle.

FSH, Follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; LH, luteinizing hormone; LH-RH, luteinizing hormone–releasing hormone.

C H A P T E R 4 Female Reproductive Physiology 39

losa  cells  to  convert  these  androgens  into  estrogens  (androstenedione to estrone and testosterone to estra- diol) as depicted in Figure 4-3. Initially, at lower levels  of  estradiol,  there  is  a  negative  feedback  effect  on  the  release  of  LH  from  the  pool  of  gonadotropins  in  the  pituitary gonadotrophs. When estradiol levels rise later  in the follicular phase (>200 picograms for >50 hours),  there  is  a  positive  feedback  on  the  release  of  gonado- tropins,  resulting  in  the  LH  surge  and  ovulation.  The  latter occurs 36 to 44 hours after the onset of this mid- cycle  LH  surge. With  pharmacologic  doses  of  proges- tins contained in contraceptive pills, there is a profound  negative  feedback  effect  on  gonadotropin-releasing  hormone  (GnRH)  so  that  none  of  the  gonadotropin  pool  is  released.  Hence,  ovulation  is  blocked  (see  Chapter 27).

During the luteal phase, both LH and FSH are sig­ nificantly suppressed through the negative feedback effect of elevated circulating estradiol and progester­ one.  This  inhibition  persists  until  progesterone  and  estradiol levels decline near the end of the luteal phase  as  a  result  of  corpus  luteal  regression,  should  preg- nancy  fail  to  occur.  The  net  effect  is  a  slight  rise  in  serum  FSH,  which  initiates  new  follicular  growth  for  the  next  cycle.  The  duration  of  the  corpus  luteum’s  functional regression is such that menstruation gener- ally occurs 14 days after the LH surge in the absence of  pregnancy. When pregnancy occurs, the corpus luteum  is “rescued” by hCG which acts like LH and progester- one production continues.

Prolactin is secreted by lactotrophs. Unlike the case  with other peptide hormones produced by the adeno- hypophysis,  pituitary release of prolactin is under tonic inhibition by the hypothalamus.  The  half-life  for  circulating  prolactin  is  about  20  to  30  minutes.  In  addition to its lactogenic effect, prolactin may directly  or  indirectly  influence  hypothalamic,  pituitary,  and  ovarian  functions  in  relation  to  the  ovulatory  cycle,  particularly  in  the  pathologic  state  of  chronic  hyper- prolactinemia (see Chapter 33).

GONADOTROPIN SECRETORY PATTERNS A normal ovarian cycle can be divided into a follicular  and  a  luteal  phase  (Figure  4-2).  The  follicular  phase  begins with the onset of menses and culminates in the  preovulatory surge of LH. The luteal phase begins with  the  onset  of  the  preovulatory  LH  surge  and  ends  with  the first day of menses.

Decreasing levels of estradiol and progesterone from the regressing corpus luteum of the preceding cycle initiate a rise of FSH by a negative feedback mechanism, which stimulates follicular growth and estradiol secretion. A major characteristic of follicular  growth and estradiol secretion is explained by the two- gonadotropin (LH and FSH) two-cell (theca and granu- losa  cell)  theory  of  ovarian  follicular  development.  According  to  this  theory,  there  are  separate  cellular  functions in the ovarian follicle wherein LH stimulates  theca  cells  to  produce  androgens  (androstenedione  and testosterone) and FSH then stimulates the granu-

FIGURE 4-1 Hypothalamic-pituitary portal circulatory system. The pulses of gonadotropin-releasing hormone (GnRH) from the arcuate nucleus are transported to the anterior pituitary gland by way of this circulatory system. An interruption or significant alteration of GnRH pulses will cause the reproductive cycle to stop.

Pars nervosa of the

neurohypophysis

Median eminence

Pars tuberalis

Hypophyseal portal veins

Mamillary body

GnRH neuropeptides

Third ventricle

Adenohypophysis

Hypophyseal artery

Optic chiasm

40 PA R T 1 Introduction

factor (LRF). Both FSH and LH appear to be present in two different forms within the pituitary gonado­ trophs. One is a releasable form and the other a storage form. GnRH reaches the anterior pituitary via  the hypophyseal portal vessels and stimulates the syn- thesis  of  both  FSH  and  LH,  which  are  stored  within  gonadotrophs.  Subsequently,  GnRH  activates  and  transforms  these  molecules  into  releasable  forms.  GnRH  can  also  induce  immediate  release  of  both  LH  and FSH into the circulation. Receptors for GnRH have  been  found  in  other  tissues  including  the  ovary,  sug- gesting that GnRH may have a direct effect on ovarian  function as well.

GnRH is secreted in a pulsatile fashion throughout the menstrual cycle as depicted in  Figure 4­4.  The  frequency  of  GnRH  release,  as  assessed  indirectly  by 

HYPOTHALAMUS Five  different  small  peptides  or  biogenic  amines  that  affect  the  reproductive  cycle  have  been  isolated  from  the hypothalamus. All exert specific effects on the hor- monal  secretion  of  the  anterior  pituitary  gland.  They  are  GnRH, thyrotropin­releasing hormone (TRH), somatotropin release­inhibiting factor (SRIF) or somatostatin, corticotropin­releasing factor (CRF), and prolactin release­inhibiting factor (PIF).  Only  GnRH and PIF are discussed in this chapter.

GnRH is a decapeptide that is synthesized primarily  in the arcuate nucleus. It has a very short half-life of 2  to  4  minutes.  It  is  responsible  for  the  synthesis  and  release of both LH and FSH. Because it usually causes  the  release  of  more  LH  than  FSH,  it  is  less  commonly  called LH-releasing hormone (LH-RH) or LH-releasing 

FIGURE 4-2 Hormone activity and levels during a normal menstrual cycle. All four components of the cycle (hypothalamic, pituitary, ovarian, and endometrial) are represented in the figure. These components work in a highly integrated way in a cycle that represents one of the most complex endocrine/end organ systems in physiology. FSH, Follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone.

Ovulation

Menstrual phase

Proliferative phase

Secretory phase

Luteal phaseFollicular phase

Estradiol Progesterone

LH

FSH

0 4 8

Basalis

Functionalis

12 DAYS OF MENSTRUAL CYCLE

16 20 24 28

P IT

U IT

A R

Y G

O N

A D

O T

R O

P IN

S H

Y P

O T

H A

L A

M IC

G n

R H

O V

A R

IA N

S T

E R

O ID

S U

T E

R IN

E E

N D

O M

E T

R IU

M O

V A

R IA

N F

U N

C T

IO N

GnRH

Pulsatile Release Increasing frequency Less frequent

C H A P T E R 4 Female Reproductive Physiology 41

onto  the  median  eminence.  Serotonin  also  appears  to  inhibit  GnRH  pulsatile  release,  whereas  norepineph- rine stimulates it. Endogenous opioids suppress release  of GnRH from the hypothalamus in a manner that may  be partially regulated by ovarian steroids.

The hypothalamus produces PIF, which exerts chronic inhibition of prolactin release from the lac­ totrophs.  A  number  of  pharmacologic  agents  (e.g.,  chlorpromazine)  that  affect  dopaminergic  mecha- nisms also influence prolactin release. Dopamine itself  is secreted by hypothalamic neurons into the hypophy- seal portal vessels and inhibits prolactin release directly  within the adenohypophysis. Based on these observa- tions,  it  has  been  proposed  that  hypothalamic  dopa- mine may be the major PIF. In addition to the regulation  of prolactin release by PIF, the hypothalamus may also  produce  prolactin-releasing  factors  (PRF)  that  can  elicit  large  and  rapid  increases  in  prolactin  release  under  certain  conditions,  such  as  breast  stimulation  during  nursing.  Neither  PIF  nor  PRF  has  been  clearly  characterized  biochemically  as  of  2014.  TRH  serves   to  stimulate  prolactin  release  as  well.  This  phenome- non  may  explain  the  association  between  primary  hypothyroidism  (with  secondary  TRH  elevation)  and  hyperprolactinemia. The precursor protein for GnRH, called GnRH­associated peptide (GAP), has been

measurement of LH pulses, varies considerably among  individuals.  GnRH  pulses  in  the  follicular  phase  are  more frequent and of lower amplitude, whereas in the  luteal phase the pulses occur less frequently but are of  higher amplitude.

Intravenous  and  subcutaneous  administration  of  exogenous  pulsatile  GnRH  has  been  used  to  induce  ovulation in selected women who are not ovulating as  a  result  of  hypothalamic  dysfunction.  A continuous (nonpulsatile) infusion of GnRH results in a revers­ ible inhibition of gonadotropin secretion through a process of “downregulation” or desensitization of pituitary gonadotrophs.  This  represents  the  basic  mechanism  of  action  for  the  GnRH  analogues  (nona- peptides, containing only nine amino acids) that have  been  successfully  used  in  the  therapy  of  such  ovarian  hormone-dependent disorders as endometriosis, leio- myomas (fibroids), hirsutism, and precocious puberty.  There  are  both  agonistic  and  antagonistic  analogues   of GnRH.

Several mechanisms control the secretion of GnRH.  Estradiol appears to enhance hypothalamic release of GnRH and may help induce the midcycle LH surge by increasing GnRH release or by enhancing pituitary responsiveness to the decapeptide. Gonadotropins have an inhibitory effect on GnRH release. Catechol- amines may play a major regulatory role as well. Dopa- mine is synthesized in the arcuate and periventricular  nuclei and may have a direct inhibitory effect on GnRH  secretion via the tuberoinfundibular tract that projects 

FIGURE 4-3 The two-gonadotropin (LH and FSH), two-cell (theca cell on top and granulosa cell below) theory of follicular develop- ment. Each cell is theorized to perform separate functions; LH stimulates the production of androgens (androstenedione and tes- tosterone) in the theca cell and FSH stimulates the aromatization of these androgens to estrogens (estrone and estradiol) in the granulose cell. FSH, Follicle-stimulating hormone; LH, luteinizing hormone.

LH

FSH

+

+

Theca cell

Cholesterol

Androstenedione Testosterone

Androstenedione Testosterone

Estrone (E1) Estradiol (E2)

Granulosa cell

FIGURE 4-4 The pulsatile release of gonadotropin-releasing hormone (GnRH) during the normal menstrual cycle.

Higher amplitude Less frequent

Lower amplitude Increasing amplitude and frequency

GnRH pulses

Follicular Luteal

Ovulation

PHASES OF MENSTRUAL CYCLE

42 PA R T 1 Introduction

one comes from the peripheral conversion of adrenal pregnenolone and pregnenolone sulfate.  Just  before  ovulation, the unruptured but luteinizing graafian fol- licle  begins  to  produce  increasing  amounts  of  proges- terone.  At  about  this  time,  a  marked  increase  also  occurs  in  serum  17α-hydroxyprogesterone. The  eleva- tion of basal body temperature is temporally related to  the  central  effect  of  progesterone.  As  with  estradiol,  secretion of progestins by the corpus luteum reaches a  maximum  5  to  7  days  after  ovulation  and  returns  to  baseline  shortly  before  menstruation.  Should  preg- nancy  occur,  progesterone  levels,  and  therefore  basal  body temperature, remain elevated.

ANDROGENS Both the ovary and the adrenal glands secrete small amounts of testosterone, but most of the testosterone is derived from the metabolism of androstenedione, which is also secreted by both the ovary and the adrenal gland.  Near  midcycle,  an  increase  occurs  in  plasma  androstenedione,  which  reflects  enhanced  secretion  from  the  follicle.  During  the  luteal  phase,  a  second  rise  occurs  in  androstenedione,  which  reflects  enhanced secretion by the corpus luteum. The adrenal  gland  also  secretes  androstenedione  in  a  diurnal  pattern  similar  to  that  of  cortisol.  The  ovary  secretes  small amounts of the very potent dihydrotestosterone  (DHT), but the bulk of DHT is derived from the conver- sion of androstenedione and testosterone. The major- ity of dehydroepiandrosterone (DHEA) and virtually all  DHEA  sulfate  (DHEA-S),  which  are  weak  androgens,  are  secreted  by  the  adrenal  glands,  although  small  amounts of DHEA are secreted by the ovary.

identified to be both a potent inhibitor of prolactin secretion and an enhancer of gonadotropin release. These findings suggest that this GnRH­associated peptide may also be a physiologic PIF  and  could  explain the inverse relationship between gonadotropin  and  prolactin  secretions  seen  in  many  reproductive  states.

Ovarian Cycle ESTROGENS During  early  follicular  development,  circulating  estra- diol levels are relatively low. About 1 week before ovu- lation,  levels  begin  to  increase,  at  first  slowly,  then  rapidly. The  conversion  of  testosterone  to  estradiol  in  the  granulosa  cell  of  the  follicle  occurs  through  an  enzymatic process called aromatization and is depicted  in Figure 4-3. The levels generally reach a maximum 1  day  before  the  midcycle  LH  peak.  After  this  peak  and  before  ovulation,  there  is  a  marked  and  precipitous  fall.  During  the  luteal  phase,  estradiol  rises  to  a  maximum  5  to  7  days  after  ovulation  and  returns  to  baseline  shortly  before  menstruation.  Estrone  (E1,  a  weaker estrogen) secretion by the ovary is considerably  less  than  secretion  of  estradiol  but  follows  a  similar  pattern. Estrone is largely derived from the conversion  of  androstenedione  through  the  action  of  the  enzyme  aromatase (Figure 4-5).

PROGESTINS During follicular development, the ovary secretes only very small amounts of progesterone and 17α­hydroxyprogesterone. The bulk of the progester­

FIGURE 4-5 Steroidogenic pathways showing aromatization in red. Cmpd B, Corticosterone; Cmpd S, II-deoxycortisol; DHEA, dehydroepi- androsterone; DOC, desoxycorticosterone; OH, hydroxylase.

Aromatase

Aromatase

Androstenedione

Cholesterol Aldosterone

Cmpd BPregnenolone

17-OH Pregnenolone

∆5 PATHWAY

DHEA

Androstenediol

Progesterone

17-OH Progesterone

∆4 PATHWAY

Testosterone

DOC

Cmpd S Cortisol

Estrone (E1)

Estradiol (E2)

C H A P T E R 4 Female Reproductive Physiology 43

nous  material  surrounds  the  ovum,  forming  the  zona pellucida.  This  larger  unit  is  called  a  secondary follicle.

In  the  adult  ovary,  a graafian follicle  forms  as  the  innermost  three  or  four  layers  of  rapidly  multiplying  granulosa  cells  become  cuboidal  and  adherent  to  the  ovum  (cumulus oophorus).  In  addition,  a  fluid-filled  antrum forms among the granulosa cells. As the liquor  continues to accumulate, the antrum enlarges and the  centrally located primary oocyte migrates eccentrically  to the wall of the follicle. The innermost layer of granu- losa  cells  of  the  cumulus,  which  are  in  close  contact  with  the  zona  pellucida,  become  elongated  and  form  the corona radiata. The corona radiata is released with  the oocyte at ovulation. Covering the granulosa cells is  a thin basement membrane, outside of which connec- tive tissue cells organize themselves into two coats: the  theca interna and theca externa.

During each cycle, a cohort of follicles is recruited for development. Among the many developing folli­ cles, only one (the dominant follicle) usually contin­ ues differentiation and maturation into a follicle that ovulates.  The  remaining  follicles  undergo  atresia.  On  the basis of in vitro measurement of local steroid levels,  growing  follicles  can  be  classified  as  either  estrogen- predominant  or  androgen-predominant.  Follicles greater than 10 mm in diameter are usually estrogen­ predominant, whereas smaller follicles are usually androgen­predominant. Mature preovulatory follicles  reach  mean  diameters  of  approximately  18  to  25 mm.  Furthermore, in estrogen-predominant follicles, antral  FSH concentrations continue to rise while serum FSH  levels decline beginning at the mid-follicular phase. In  smaller,  androgen-predominant  follicles,  antral  fluid  FSH  values  decrease  while  serum  FSH  levels  decline;  thus,  the  intrafollicular  steroid  milieu  appears  to  play  an  important  role  in  determining  whether  a  follicle  undergoes  maturation  or  atresia.  Additional  follicles  may  be  “rescued”  from  atresia  by  administration  of  exogenous gonadotropins.

Follicular maturation is dependent on the local development of receptors for FSH and LH. FSH recep- tors are present on granulosa cells. Under FSH stimula- tion, granulosa cells proliferate and the number of FSH  receptors  per  follicle  increases  proportionately.  Thus,  the growing primary follicle is increasingly more sensi- tive  to  stimulation  by  FSH;  as  a  result,  estradiol  levels  increase. Estrogens, particularly estradiol, enhance the  induction of FSH receptors and act synergistically with  FSH to increase LH receptors.

During early stages of folliculogenesis, LH recep­ tors are present only on the theca interna layer.  LH  stimulation induces steroidogenesis and increases the  synthesis  of  androgens  by  thecal  cells.  In  nondomi- nant follicles, high local androgen levels may enhance  follicular  atresia.  However,  in  the  follicle  destined   to  reach  ovulation,  FSH  induces  the  formation  of  

SERUM-BINDING PROTEINS Circulating estrogens and androgens are mostly bound to specific sex hormone–binding globulins (SHBG) or to serum albumin. The remaining fraction  of sex hormones is unbound (free), and this is the bio- logically  active  fraction.  It  is  unclear  whether  steroids  bound to serum proteins (e.g., albumin) are accessible  for tissue uptake and utilization. The synthesis of SHBG  in  the  liver  is  increased  by  estrogens  and  thyroid  hor- mones but decreased by testosterone.

PROLACTIN Serum prolactin levels do not change strikingly during the normal menstrual cycle.  Both  the  serum  level  of  prolactin  and  prolactin  release  in  response  to  TRH  are  somewhat  more  elevated  during  the  luteal  phase than during the mid-follicular phase of the cycle.  This suggests that high amounts of circulating estradiol  and progesterone may enhance prolactin release. Pro­ lactin release varies throughout the day with the highest levels occurring during sleep.

Prolactin  may  participate  in  the  control  of  ovarian  steroidogenesis.  Prolactin  concentrations  in  follicular  fluid  change  markedly  during  follicular  growth.  The  highest prolactin concentrations are seen in small fol- licles  during  the  early  follicular  phase.  Prolactin  con- centrations  in  the  follicular  fluid  may  be  inversely  related to the production of progesterone. In addition,  hyperprolactinemia may alter gonadotropin secretion.  Despite these observations, the physiologic role of pro- lactin during the normal menstrual cycle has not been  clearly established.

FOLLICULAR DEVELOPMENT The  number  of  oocytes  is  maximal  in  the  fetus  at  6  to  7  million  at  20  weeks’  gestation.  Significant  atresia  (physiologic  loss)  of  oogonia  occurs  so  that  at  birth,  only  1  to  2  million  remain  in  both  ovaries.  At  puberty  (with  ongoing  atresia)  between  300,000  and  400,000  oocytes are available for ovulation with only 400 to 500  actually  ovulating.  After puberty, primordial follicles undergo sequential development, differentiation, and maturation until a mature graafian follicle is pro­ duced. The follicle then ruptures, releasing the ovum. Subsequent luteinization of the ruptured follicle pro­ duces the corpus luteum.

At approximately 8 to 10 weeks of fetal development,  oocytes  become  progressively  surrounded  by  precur- sor  granulosa  cells,  which  then  separate  themselves  from  the  underlying  stroma  by  a  basal  lamina.  This oocyte­granulosa cell complex is called a primordial follicle.  The  follicular  cells  become  cuboidal  and  the  stromal  cells  around  the  follicle  become  prominent.  This  process,  which  takes  place  in  the  fetal  ovary  at  between 20 and 24 weeks’ gestation, results in a primary follicle.  As  granulosa  cells  proliferate,  a  clear  gelati-

44 PA R T 1 Introduction

aromatase  enzyme  and  its  receptor  within  the  granu- losa cells. As a result, androgens produced in the theca  interna of the dominant follicle diffuse into the granu- losa cells and are aromatized into estrogens. FSH also enhances the induction of LH receptors on the gran­ ulosa cells of the follicle that is destined to ovulate.  These are essential for the appropriate response to the  LH  surge,  leading  to  the  final  stages  of  maturation,  ovulation,  and  the  luteal  phase  production  of  pro- gesterone.  Thus,  the presence of greater numbers of FSH receptors and granulosa cells and increased induction of aromatase enzyme and its receptors may differentiate between the follicle of the initial cohort that will eventually ovulate and those that will undergo atresia.

Growth  factors  such  as  insulin,  insulin-like  growth  factor (IGF), fibroblast growth factor (FGF), and epider- mal growth factor (EGF) may also play significant mito- genic  roles  in  folliculogenesis,  including  enhanced  responsiveness  to  FSH.  Ovarian  peptide  hormones,  inhibin-A, inhibin-B, and activin, have roles in gonado- tropin  regulation.  Both  forms  of  inhibin  act  to  inhibit  FSH,  whereas  activin  stimulates  FSH  release  and  potentiates  its  action  in  the  ovary.  Ovarian  granulosa  cells  also  produce  müllerian  inhibiting  hormone  (MIH),  levels  of  which  now  provide  a  more  accurate  assessment of ovarian reserve and potential female fer- tility (see Chapter 34).

OVULATION The  preovulatory  LH  surge  initiates  a  sequence  of  structural  and  biochemical  changes  that  culminate  in  ovulation.  Before ovulation, a general dissolution of the entire follicular wall occurs, particularly the portion that is on the surface of the ovary. Presumably  this  occurs  as a result of the action of proteolytic enzymes. With degeneration of the cells on the surface,  a stigma forms, and the follicular basement membrane  finally bulges through the stigma. When this ruptures,  the oocyte, together with the corona radiata and some  cells  of  the  cumulus  oophorus  are  expelled  into  the  peritoneal cavity, and ovulation takes place.

Ovulation is now known from ultrasonic studies to be a gradual phenomenon, with the collapse of the follicle taking from several minutes to as long as an hour or more. The oocyte adheres to the surface of the  ovary,  allowing  an  extended  period  during  which  the  muscular contractions of the fallopian tube may bring  it  in  contact  with  the  tubal  epithelium.  Probably  both  muscular  contractions  and  tubal  ciliary  movement  contribute  to  the  entry  of  the  oocyte  into,  and  the  transportation along, the fallopian tube. Ciliary activity  may  not  be  essential,  because  some  women  with  immotile cilia also become pregnant.

At birth, primary oocytes are in the prophase (dip­ lotene) stage of the first meiotic division.  They  con- tinue  in  this  phase  until  the  next  maturation  division 

occurs  (years  later)  in  conjunction  with  the  midcycle  LH surge. A few hours preceding ovulation, the chro­ matin is resolved into distinct chromosomes, and meiotic division takes place with unequal distribu­ tion of the cytoplasm to form a secondary oocyte and the first polar body. Each element contains 23 chro­ mosomes, each in the form of two monads.  The  second maturation spindle forms immediately and the  oocyte  remains  at  the  surface  of  the  ovary.  No  further  development takes place until after ovulation and fer- tilization  have  occurred.  At  that  time,  and  before  the  union of the male and female pronuclei, another divi- sion occurs to reduce the chromosomal component of  the egg pronucleus to 23 single chromosomes (22 plus  X  or Y),  each  composed  of  the  one  monad. The  ovum  and  a  second  polar  body  are  thus  formed.  The  first  polar body may also divide.

LUTEINIZATION AND CORPUS LUTEUM FUNCTION After  ovulation  and  under  the  influence  of  LH,  the  granulosa cells of the ruptured follicle undergo lutein- ization. These  luteinized  granulosa  cells,  plus  the  sur- rounding theca cells, capillaries, and connective tissue,  form  the  corpus  luteum,  which  produces  copious  amounts  of  progesterone  and  some  estradiol.  The normal functional life span of the corpus luteum is about 9 to 10 days.  After  this  time  it  regresses,  and  unless pregnancy occurs, menstruation ensues and the  corpus  luteum  is  gradually  replaced  by  an  avascular  scar  called  a  corpus albicans.  The  events  occurring  in  the  ovary  during  a  complete  cycle  are  shown  in  Figure 4-6.

Histophysiology of the Endometrium The endometrium is uniquely responsive to the circu- lating  progestins,  androgens,  and  estrogens.  It  is  this  responsiveness  that  gives  rise  to  menstruation  and  makes implantation and pregnancy possible.

Functionally,  the  endometrium  is  divided  into  two  zones:  (1)  the  outer portion,  or  functionalis,  which  undergoes cyclic changes in morphology and function  during the menstrual cycle and is sloughed off at men- struation; and (2) the inner portion, or basalis, which  remains  relatively  unchanged  during  each  menstrual  cycle  and,  after  menstruation,  provides  stem  cells  for  the  renewal  of  the  functionalis.  Basal arteries  are  regular  blood  vessels  found  in  the  basalis,  whereas  spiral arteries  are  specially  coiled  blood  vessels  seen  in the functionalis.

The  cyclic  changes  in  histophysiology  of  the  endo- metrium  can  be  divided  into  three  stages:  the  men- strual phase, the proliferative or estrogenic phase, and  the secretory or progestational phase.

C H A P T E R 4 Female Reproductive Physiology 45

luted,  and  the  endometrial  glands  are  straight,  with  narrow lumens containing some glycogen.

SECRETORY PHASE Following ovulation, progesterone secretion by the corpus luteum stimulates the glandular cells to secrete glycogen, mucus, and other substances. The glands become tortuous and the lumens are dilated

MENSTRUAL PHASE Because it is the only portion of the cycle that is visible  externally, the first day of menstruation is taken as day  1 of the menstrual cycle. The first 4 to 5 days of the cycle  are defined as the menstrual phase. During this phase, there is disruption and disintegration of the endome­ trial glands and stroma, leukocyte infiltration, and red blood cell extravasation. In addition to this slough- ing  of  the  functionalis,  there  is  a  compression  of  the  basalis  due  to  the  loss  of  ground  substances.  Despite  these degenerative changes, early evidence of renewed  tissue growth is usually present at this time within the  basalis of the endometrium.

PROLIFERATIVE PHASE The proliferative phase is characterized by endome­ trial proliferation or growth secondary to estrogenic stimulation.  Because  the  bases  of  the  endometrial  glands lie deep within the basalis, these epithelial cells  are not destroyed during menstruation.

During this phase of the cycle, the large increase in estrogen secretion causes marked cellular prolifera­ tion of the epithelial lining, the endometrial glands, and the connective tissue of the stroma  (Figure  4-7).  Numerous  mitoses  are  present  in  these  tissues  and  there is an increase in the length of the spiral arteries,  which traverse almost the entire thickness of the endo- metrium. By the end of the proliferative phase, cellular  proliferation  and  endometrial  growth  have  reached  a  maximum, the spiral arteries are elongated and convo-

FIGURE 4-6 Schematic representation of the sequence of events occurring in the ovary during a complete follicular cycle. (Adapted from Yen SC, Jaffe R, editors: Reproductive endocrinology, Philadelphia, 1978, Saunders.)

Primordial follicles

Developing follicles

Mature graafian follicle

Antrum

Theca cells

Follicular fluid

Granulosa cells

Cumulus oophorus

Primary oocyte

Ovulation Developing

corpus luteum

Corpus luteum

Corpus albicans

FIGURE 4-7 Early proliferative phase endometrium. Note the regular, tubular glands lined by pseudostratified columnar cells.

Enlarged gland

46 PA R T 1 Introduction

ized ovum continues to the uterus, where implantation  occurs and development of the conceptus continues.

Spermatogenesis requires about 74 days. Together with transportation, a total of about 3 months elapses before sperm are ejaculated. The sperm achieve motil- ity  during  their  passage  through  the  epididymis,  but  sperm  capacitation,  which  renders  them  capable  of  fertilization  in  vivo,  does  not  occur  until  they  are  removed  from  the  seminal  plasma  after  ejaculation.  Interestingly, sperm aspirated from the epididymis and  testis  can  be  used  to  achieve  fertilization  in  vitro  employing  intracytoplasmic  injection  techniques  directly into the ooplasm.

Estrogen  levels  are  high  at  the  time  of  ovulation,  resulting in an increased quantity, decreased viscosity,  and favorable electrolyte content of the cervical mucus.  These  are  the  ideal  characteristics  for  sperm  penetra- tion.  The average ejaculate contains 2 to 5 mL of semen; 40 to 300 million sperm may be deposited in the vagina, 50­90% of which are morphologically normal.  Fewer  than  200  sperm  achieve  proximity  to  the egg. Only one sperm fertilizes a single egg released  at ovulation.

The major loss of sperm occurs in the vagina follow- ing coitus, with expulsion of the semen from the introi- tus playing an important role. In addition, digestion of  sperm  by  vaginal  enzymes,  destruction  by  vaginal  acidity,  phagocytosis  of  sperm  along  the  reproductive  tract,  and  further  loss  from  passage  through  the  fallo- pian  tube  into  the  peritoneal  cavity  all  diminish  the  number of sperm capable of achieving fertilization.

Those sperm that do migrate from the alkaline envi- ronment  of  the  semen  to  the  alkaline  environment  of  the  cervical  mucus  exuding  from  the  cervical  os  are  directed  along  channels  of  lower-viscosity  mucus  into  the  cervical  crypts  where  they  are  stored  for  later  ascent. Two  waves  of  passage  to  the  tubes  may  occur.  Uterine contractions, probably facilitated by prosta­ glandin in the seminal plasma, propel sperm to the tubes within 5 minutes. Some evidence indicates that  these  sperm  may  not  be  as  capable  of  fertilization  as  those  that  arrive  later  largely  under  their  own  power.  Sperm  may  be  found  within  the  peritoneal  cavity  for  long  periods,  but  it  is  not  known  whether  they  are  capable  of  fertilization.  Ova are usually fertilized within 12 hours of ovulation.

Capacitation is the physiologic change that sperm must undergo in the female reproductive tract before fertilization.  Human  sperm  can  also  undergo  capaci- tation after a short incubation in defined culture media  without  residence  in  the  female  reproductive  tract,  which allows for in vitro fertilization (see Chapter 34).

The acrosome reaction is one of the principal com­ ponents of capacitation.  The  acrosome,  a  modified  lysosome, lies over the sperm head as a kind of “chemi- cal  drill-bit”  designed  to  enable  the  sperm  to  burrow  its  way  into  the  oocyte  (Figure  4-9).  The  overlying 

and filled with these substances. The stroma becomes  edematous.  Mitoses  are  rare.  The  spiral  arteries  con- tinue  to  extend  into  the  superficial  layer  of  the  endo- metrium and become convoluted (Figure 4-8).

The marked changes that occur in endometrial his- tology  during  the  secretory  phase  permit  relatively  precise timing (dating) of secretory endometrium.

If pregnancy does not occur by day 23, the corpus luteum begins to regress, secretion of progesterone and estradiol declines, and the endometrium under­ goes involution. About 1 day before the onset of men- struation,  marked  constriction  of  the  spiral  arterioles  takes  place,  causing  ischemia  of  the  endometrium   followed  by  leukocyte  infiltration  and  red  blood  cell  extravasation. It is thought that these events occur sec- ondary  to  prostaglandin  production  by  the  endome- trium.  The  resulting  necrosis  causes  menstruation  or  sloughing  of  the  endometrium.  Ironically,  menstrua- tion,  which  clinically  marks  the  beginning  of  the   menstrual  cycle,  is  actually  the  terminal  event  of  a  physiologic  process  that  enables  the  uterus  to  be  pre- pared  to  receive  another  conceptus. The  four  compo- nents of the “integrated” female reproductive cycle are  summarized in Table 4-1.

Spermatogenesis, Sperm Capacitation, and Fertilization Fertilization,  or  conception,  is  the  union  of  male  and  female  pronuclear  elements.  Conception  normally  takes place in the fallopian tube, after which the fertil-

FIGURE 4-8 Late secretory phase endometrium. Note the tortu- ous, saw-toothed appearance of the endometrial glands with secretions in the lumens. The stroma is edematous and necrotic during this stage, leading to sloughing of the endometrium at the time of menstruation.

Enlarged glands

C H A P T E R 4 Female Reproductive Physiology 47

tion restores the diploid number of chromosomes and determines the sex of the zygote. In couples with  infertility  resulting  from  severe  sperm  abnormalities,  fertilization  and  subsequent  pregnancy  can  be  suc- cessfully achieved after the injection of a single sperm,  with or without its tail, into the cytoplasm of the oocyte  (see Chapter 34).

Cleavage, Morula, Blastocyst Following fertilization, cleavage occurs. This consists of  a  rapid  succession  of  mitotic  divisions  that  produce  a  mulberry-like  mass  known  as  a  morula.  Fluid is secreted by the outer cells of the morula, and a single fluid­filled cavity develops, known as the blastocyst cavity.  An  inner-cell  mass  can  be  defined,  attached  eccentrically  to  the  outer  layer  of  flattened  cells;  the  latter  becomes  the  trophoblast.  The  embryo  at  this  stage  of  development  is  called  a  blastocyst,  and  the  zona pellucida disappears at about this time. A blasto- cyst cell can be removed and tested for genetic imper- fections  without  harming  further  development  of  the  conceptus.

Implantation The fertilized ovum reaches the endometrial cavity about 3 days after ovulation.

Hormones influence egg transportation.  Estrogen  causes “locking” of the egg in the tube, and progester- one  reverses  this  action.  Prostaglandins  have  diverse  effects.  Prostaglandin  E  relaxes  the  tubal  isthmus,  whereas prostaglandin F stimulates tubal motility. It is  unknown whether abnormalities of egg transportation  play a role in infertility, but in animal studies, accelera- tion of ovum transportation causes a failure of implan- tation.  Additional  cytokines  may  be  released  by  the  tubal  epithelium  and  embryo  to  enhance  embryo  transportation  and  development  and  to  signal  the  impending implantation in the endometrium.

Initial embryonic development primarily occurs in the ampullary portion of the fallopian tube  with  subsequent  rapid  transit  through  the  isthmus.  This  process  takes  approximately  3  days.  On reaching the uterine cavity, the embryo undergoes further devel­ opment for 2 to 3 days before implanting. The zona is  shed  and  the  blastocyst  adheres  to  the  endometrium,  a  process  that  is  probably  dependent  on  the  changes  in  the  surface  characteristics  of  the  embryo,  such  as  electrical charge and glycoprotein content. A variety of  proteolytic  enzymes  may  play  a  role  in  separating  the  endometrial cells and digesting the intercellular matrix.

Initially, the wall of the blastocyst facing the uterine  lumen  consists  of  a  single  layer  of  flattened  cells. The  thicker  opposite  wall  has  two  zones:  the  trophoblast  and  the  inner cell mass (embryonic disk).  The  latter  differentiates at 7.5 days into a thick plate of primitive

plasma  membrane  becomes  unstable  and  eventually  breaks  down,  releasing  hyaluronidase,  a  neuramini- dase, and corona­dispersing enzyme. Acrosin, bound  to the remaining inner acrosomal membrane, may play  a role in the final penetration of the zona pellucida. The  latter contains species-specific receptors for the plasma  membrane.  After  traversing  the  zona,  the  postacro- somal  region  of  the  sperm  head  fuses  with  the  oocyte  membrane, and the sperm nucleus is incorporated into  the  ooplasm. This  process  triggers  release  of  the  con- tents  of  the  cortical  granules  that  lie  at  the  periphery   of  the  oocyte. This  cortical  reaction  results  in  changes  in  the  oocyte  membrane  and  zona  pellucida  that  prevent the entrance of further sperm into the oocyte.

The process of capacitation may be inhibited by a factor in the semen, thus preserving maximum release of enzyme to allow effective penetration of the corona and zona pellucida surrounding the oocyte.  The  cellular  investments  of  the  oocyte  may  further  activate the sperm, thus facilitating penetration to the  oocyte  membrane.  The  corona  is  not  required  for  normal  fertilization  to  occur,  as  its  removal  has  no  effect on the rate or quality of fertilization in vitro. The  major  function  of  these  surrounding  granulosa  cells  and their intercellular matrix may be to serve as a sticky  mass that causes adherence to the ovarian surface and  to the mucosa of the tubal epithelium.

Following  penetration  of  the  oocyte,  the  sperm  nucleus  decondenses  to  form  the  male  pronucleus,  which  approaches  and  finally  fuses  with  the  female  pronucleus  at  syngamy  to  form  the  zygote.  Fertiliza­

FIGURE 4-9 The sperm head.

Inner acrosomal membrane

Outer acrosomal membrane

Nuclear envelope

Subacrosomal space

Acrosomal contents

Plasma membrane

Postacrosomal sheath

Nucleus

Equatorial segment

Posterior ring

Mitochondria

48 PA R T 1 Introduction

trophoblastic giant cells, which first appear as early as the time of implantation.  Minute  levels  of  hCG  appear  in  the  maternal  serum  at  this  time.  The  Nita­ buch layer  is  a  zone  of  fibrinoid  degeneration  where  the  trophoblast  meets  the  decidua. When  the  decidua  is  defective,  as  in  placenta  accreta,  the  Nitabuch  layer  is absent.

When the free blastocyst contacts the endometrium  after 4 to 6 days, the syncytiotrophoblast, a syncytium  of  cells,  differentiates  from  the  cytotrophoblast.  At about 9 days, lacunae, irregular fluid­filled spaces, appear within the thickened trophoblastic syncy­ tium.  This  is  soon  followed  by  the  appearance  of  maternal blood within the lacunae, as maternal tissue  is destroyed and the walls of the mother’s capillaries are  eroded.

Placenta As the blastocyst burrows deeper into the endome­ trium, the trophoblastic strands branch to form the solid, primitive villi traversing the lacunae. The  villi,  which  are  first  distinguished  about  the  12th  day  after  fertilization,  are  the  essential  structures  of  the  defini- tive placenta. Located originally over the entire surface  of  the  ovum,  the  villi  later  disappear  except  over  the  most  deeply  implanted  portion,  the  future  placental  site.

Embryonic mesenchyme  first  appears  as  isolated  cells within the cavity of the blastocyst. When the cavity  is  completely  lined  with  mesoderm,  it  is  termed  the  extraembryonic celom. Its membrane, the chorion, is  composed of trophoblast and mesenchyme. When the  solid  trophoblast  is  invaded  by  a  mesenchymal  core,  presumably  derived  from  cytotrophoblast,  secondary  villi are formed.

Maternal venous sinuses are tapped about 15 days after fertilization.  By  the  17th  day,  both  fetal  and  maternal blood vessels are functional, and a placental  circulation is established. The fetal circulation is com- pleted  when  the  blood  vessels  of  the  embryo  are  con- nected  with  chorionic  blood  vessels  that  are  formed  from  cytotrophoblast.  Proliferation  of  cellular  tropho- blasts at the tips of the villi produces cytotrophoblastic  columns that progressively extend through the periph- eral  syncytium.  Cytotrophoblastic  extensions  from  columns of adjacent villi join together to form the cyto- trophoblastic  shell,  which  attaches  the  villi  to  the  decidua. By the 19th day of development, the cytotro- phoblastic  shell  is  thick. Villi  contain  a  central  core  of  chorionic mesoderm, where blood vessels are develop- ing,  and  an  external  covering  of  syncytiotrophoblasts  or syncytium.

By three weeks, the relationship of the chorion to the decidua is evident. The greater part of the chorion,  denuded  of  villi,  is  designated  the  chorion laeve  (smooth  chorion).  Until  near  the  end  of  the  third 

“dorsal” ectoderm and an underlying layer of “ventral” endoderm. A group of small cells appears between the embryonic disk and trophoblast. A space develops within them, which becomes the amniotic cavity.

Under the influence of progesterone, decidual changes occur in the endometrium of the pregnant uterus.  The  endometrial  stromal  cells  enlarge  and  form  polygonal  or  round  decidual  cells.  The  nuclei  become  round  and  vesicular,  and  the  cytoplasm  becomes  clear,  slightly  basophilic,  and  surrounded  by  a  translucent  membrane.  During  pregnancy,  the  decidua thickens to a depth of 5 to 10 mm. The decidua basalis is the decidual layer directly beneath the site of  implantation. Integrins, a class of proteins involved in  cell-to-cell  adherence,  peak  within  the  endometrium  at the time of implantation and may play a significant  role.  Additional  growth  factors  act  in  a  synergistic  fashion  to  enhance  the  implantation  process.  The  decidua capsularis  is  the  layer  overlying  the  develop- ing ovum and separating it from the rest of the uterine  cavity.  The  decidua vera  (parietalis)  is  the  remaining  lining  of  the  uterine  cavity  (Figure  4-10).  The  space  between  the  decidua  capsularis  and  decidua  vera  is  obliterated by the 4th month with fusion of the capsu- laris and vera.

The decidua basalis enters into the formation of the basal plate of the placenta. The spongy zone of the  decidua basalis consists mainly of arteries and dilated  veins.  The decidua basalis is invaded extensively by

FIGURE 4-10 Early stage of implantation.

Ectoderm

Amniotic cavity

Decidua basalis

Extraembryonic celom

Vagina

Decidua vera (parietalis)

Yolk sac cavity

Uterine cavity

Cervical os

Uterine cavity

Decidua capsularis

Endoderm

C H A P T E R 4 Female Reproductive Physiology 49

Toward  mid-pregnancy  (20  weeks),  the  amniotic  fluid becomes increasingly important for fetal pulmo- nary  development.  The  latter  requires  a  fluid-filled  respiratory  tract  and  the  ability  of  the  fetus  to  “breathe”  in  utero,  moving  amniotic  fluid  into  and  out  of  the  lungs.  The absence of adequate amniotic fluid during mid­pregnancy is associated with pul­ monary hypoplasia at birth, which is often incom­ patible with life.

The amniotic fluid also has a protective role for the fetus. It contains antibacterial activity and acts to inhibit the growth of potentially pathogenic bacteria.  During labor and delivery, the amniotic fluid continues  to  serve  as  a  protective  medium  for  the  fetus,  aiding  dilation  of  the  cervix.  The  premature  infant,  with  its  fragile  head,  may  benefit  most  from  delivery  with  the  amniotic membranes intact (en caul). In addition, the  amniotic fluid may serve as a means of communication  for  the  fetus.  Fetal  maturity  and  readiness  for  delivery  may be signaled to the maternal uterus via fetal urinary  hormones excreted into the amniotic fluid.

month,  the  chorion  laeve  remains  separated  from  the  amnion by the extraembryonic celomic cavity. There- after, amnion and chorion are in intimate contact. The  villi adjacent to the decidua basalis enlarge and branch  (chorion frondosum)  and  progressively  assume  the  form  of  the  fully  developed  human  placenta  (Figure  4-11).  By 16 to 20 weeks, the chorion laeve contacts and fuses with the decidua vera, thus obliterating most of the uterine cavity.

Amniotic Fluid Throughout  normal  pregnancy,  the  amniotic  fluid  compartment allows the fetus room for growth, move- ment,  and  development.  Without  amniotic  fluid,  the  uterus  would  contract  and  compress  the  fetus.  In cases of leakage of amniotic fluid early in the first trimester, the fetus may develop structural abnor­ malities including facial distortion, limb reduction, and abdominal wall defects secondary to uterine compression.

FIGURE 4-11 Relationship of the chorion to the placenta.

Decidua vera

Villus

Embryo

Yolk sac cavity

Umbilical cord mesoderm

Chorion frondosum

Amniotic cavity

Decidua basalis

Decidua capsularis

Uterine cavity

Extraembryonic celom

Chorion laeve

Vagina Cervical os

52

5  Endocrinology of Pregnancy and Parturition

C H

A P

T ER

JOSEPH C. GAMBONE • CALVIN J. HOBEL

■  The  hormonal  and  nonhormonal  changes  that  occur  during pregnancy and parturition are regulated through  a physiological mechanism referred to as the fetoplacen- tal  unit.  A  series  of  hormones  and  transmitters  are  pro- duced by each of the components of this unit, and they  have  multiple  effects  within  and  between  the  fetus,  the  placenta and the mother.

■  The  fetal  component  of  the  fetoplacental  unit  plays  the  major  role  in  the  regulation  of  pregnancy  and  parturi- tion.  Most  of  the  activity  in  the  fetal  component  takes  place  in  the  fetal  adrenal  gland  which  is  larger  than  the  fetal kidney by mid-gestation. The fetal zone of the fetal  adrenal  gland  primarily  secretes  androgens  during  fetal  life  and  these  androgens  act  as  precursors  for  estrogen  production  in  the  placenta. The  overall  role  of  the  fetal  adrenal is not completely understood.

■  The placental trophoblasts are the source of human cho- rionic  gonadotropin  (hCG),  which  “rescues”  the  corpus  luteum  very  early  in  pregnancy.  The  placenta  also  pro- duces  large  amounts  of  steroid  and  peptide  hormones.  Because the placenta lacks the enzyme 17α-hydroxylase,  it cannot convert progesterone to estrogen. The placenta  instead uses androgens from the fetal adrenal as precur- sors  for  the  production  of  estrogens  that  are  needed  to  maintain  the  pregnancy.  In  addition  to  estrogens,  pro- gesterone and the corticosteroid, cortisol, are produced  in  the  placenta.  Peptide  hormones  include  human  pla- cental  lactogen  (hPL),  corticotropin-releasing  hormone  (CRH),  and  prolactin.  Other  important  hormones  and 

transmitters  include  oxytocin,  relaxin,  prostaglandins,  leukotrienes, and parathyroid hormone–related peptide.

■  Maternal  adaptation  and  regulation  of  pregnancy  and  parturition start with the secretion of 17-hydroxyproges- terone (17-OHP) from the ovarian corpus luteum. If the  maternal  ovary  is  deficient  in  progesterone  production,  the  pregnancy  is  likely  to  miscarry.  Placental  function  assures  adequate  amounts  of  estrogen  (mostly  estriol   or E3) to increase uterine blood flow for uterine growth,  and  progesterone  to  maintain  the  quiescent  state  of   the  uterus  throughout  most  of  the  gestational  period.  The  absence  of  myometrial  gap  junctions  facilitates  the  action of progesterone.

■  Labor (which initiates the parturition process) is a release  from  the  state  of  functional  uterine  quiescence  main- tained during pregnancy. This quiescence is due, in large  part, to the lack of gap junctions before the onset of labor  and the actions of progesterone. Three additional phases  of  parturition  follow  the  first  phase  of  quiescence,  as  follows. Phase 1: activation is initiated by uterine stretch  and fetal hypothalamic-pituitary-adrenal (HPA) activity.  Phase  2:  stimulation  most  likely  begins  with  placental  production  of  CRH.  This  phase  continues  with  cervical  ripening,  uterine  contractility,  and  decidual/fetal  mem- brane activation. Phase 3: involution involves expulsion  of the fetus with a dramatic increase in oxytocin release  and a decrease in parathyroid hormone–related peptide  (PTHrP)  expression.  This  phase  also  involves  placental  separation and continued uterine contractions.

CLINCAL KEYS FOR THIS CHAPTER

Women  undergo  major  endocrinologic  and  metabolic  changes  that  establish,  maintain,  and  end  pregnancy.  The  aim  of  these  changes  is  the  safe  delivery  of  an  infant that can survive outside of the uterus. The matu- ration of the fetus and the adaptation of the mother are  regulated  by  a  variety  of  hormones  and  transmitters  (Table  5-1).  This  chapter  deals  with  the  properties,  functions,  and  interactions  of  the  most  important  of 

these hormonal and nonhormonal substances as they  relate to pregnancy and parturition.

Fetoplacental Unit The  concept  of  the  fetoplacental  unit  is  based  on  observations of the interactions between hormones of  fetal, placental, and maternal origin. The fetoplacental

C H A P T E R 5 Endocrinology of Pregnancy and Parturition 53

TABLE 5-1

HORMONES AND TRANSMITTERS OF PREGNANCY AND PARTURITION

Hormone/Transmitter Source Function(s) Clinical Comments

Human chorionic gonadotropin (hCG)

Placental trophoblastic tissue

Prevents regression of (rescues) the corpus luteum of pregnancy; increases T-cells that affect immunity

A likely regulator of a process that provides immune tolerance for the fetus; other trophic activities

Human placental lactogen (hPL)

Placenta Antagonizes maternal glucose use so more is available for the fetus

Low values found in pregnancy loss; normal levels may increase risk of gestational diabetes

Corticotropin-releasing hormone (CRH)

Placenta Stimulates fetal adrenocorticotropic hormone (ACTH) secretion, which allows the fetal adrenal to secrete

DHEA-S for progesterone production; CRH may facilitate vasodilation

Fetal cortisol stimulates placental CRH release and fetal ACTH secretion; elevated levels may predict an increased risk of preterm birth

Prolactin Maternal and fetal (late pregnancy) anterior pituitary glands

Stimulation of postpartum milk production

May play a role in fetal adrenal growth, as well as fluid and electrolyte membrane transfer

Progesterone (P4) Placenta; precursors come from the maternal circulation

Prevents uterine contractions; suppresses gap junction formation

Maintains uterine quiescence

17-Hydroxyprogesterone (17-OHP)

Corpus luteum Supports early pregnancy until placental production of P4 begins

Corpus luteum function is essential in early pregnancy

Estrogens Estriol (E3), estrone (E1),

and estradiol (E2)

Placenta; conversion of androgens (DHEA, DHEA-S) from the fetal adrenal into estrogens

Estriol (E3) is the main estrogen of pregnancy; it increases uterine blood flow and prepares the breast for lactation

Placenta cannot convert progesterone to estrogen; lacks the enzyme 17α-hydroxylase; has role in lung surfactant production

Androgens Dehydroandrosterone

(DHEA) and its sulfate (DHEA-S)

Dihydrotestosterone (DHT)

During pregnancy, androgens originate mostly in the fetal adrenal cortex

DHEA production is favored, and is a precursor for placental estrogen production

Fetal testis produces testosterone, which is converted to DHT; this is needed for development of male external genitalia; hCG stimulates testosterone production

Cortisol Derived from circulating cholesterol

Plays a major role in the activation of labor by increasing placental release of CRH and prostaglandins

Late in pregnancy, cortisol promotes the production of lung surfactant

Oxytocin Maternal hypothalamus and posterior pituitary

Can cause uterine contractions; possible effects on emotion and well-being

Related to uterine contractions, but not the natural initiation of labor; facilitator of childbirth and breastfeeding

Relaxin Corpus luteum and placenta

Primary function is to promote implantation; also causes uterine relaxation

Too much relaxin can result in a shortened cervix and increased risk of premature labor; too little can interfere with implantation

Prostaglandins PGE2 PGF2α

Placental production from arachidonic acid

Thought to play a major role in the initiation of labor

Not true hormones; act at or close to the site of production; prostaglandin synthetase inhibitors can prolong labor

Leukotrienes Placental production from arachidonic acid

Initiate changes in the endometrium that allow for implantation

Not true hormones; act at or close to the site of production

Parathyroid hormone– related peptide (PTHrP)

Uterus and other organs

Relaxes the uterus and allows for stretch without contractions

Allows for fetal growth during pregnancy; gene that activates PTHrP is off during parturition

54 PA R T 2 Obstetrics

unit largely controls the endocrinologic events of the pregnancy.  Although  the  fetus,  the  placenta,  and  the  mother  all  provide  input,  the  fetus  appears  to  play   the  most  active  and  controlling  role  in  its  growth  and  maturation,  and  probably  also  in  the  events  that  lead  to parturition.

FETUS The adrenal gland is the major endocrine component of the fetus. In mid-pregnancy, it is larger than the fetal  kidney.  The  fetal  adrenal  cortex  consists  of  an  outer  definitive, or adult, zone and an inner, fetal, zone. The  definitive  zone  later  develops  into  the  three  compo- nents of the adult adrenal cortex: the zona fasciculata,  the zona glomerulosa, and the zona reticularis. During  fetal  life,  the  definitive  zone  secretes  primarily  gluco- corticoids  and  mineralocorticoids.  The fetal zone, at term, constitutes 80% of the fetal gland and primarily secretes androgens during fetal life.  It  involutes  fol- lowing delivery and completely disappears by the end  of  the  first  year  of  life. The  fetal  adrenal  medulla  syn- thesizes  and  stores  catecholamines,  which  play  an  important  role  in  maintaining  fetal  homeostasis.  The  overall role of the fetal adrenal during fetal growth and  maturation is not completely understood.

PLACENTA The  placenta,  which  functions  as  an  “extra  brain”  during pregnancy, is unique because it contains genes  from  both  the  mother  and  father.  In  addition,  it  is  the  source  of  a  brain  peptide,  corticotropin-releasing  hormone (CRH), which has a very important regulatory  role  in  pregnancy.  Thus,  the  placenta  produces  both  steroids  and  peptide  hormones  in  amounts  that  vary  with  gestational  age.  Precursors  for  progesterone  syn- thesis come from the maternal circulation. Because of the lack of the enzyme 17α-hydroxylase, the human placenta cannot directly convert progesterone to estrogen but must use androgens, largely from the fetal  adrenal  gland,  as  its  source  of  precursor  for  estrogen  production.

MOTHER The  mother  adapts  to  pregnancy  through  major   endocrinologic  and  metabolic  changes.  The ovarian corpus luteum produces progesterone (mostly 17- hydroxyprogesterone) in early pregnancy  until  its  production shifts to the placenta. The maternal hypo- thalamus and posterior pituitary produce and release oxytocin,  which  causes  uterine  contractions  and  milk  letdown.  The anterior pituitary produces prolactin,  which  stimulates  milk  production.  Several  important  changes in maternal metabolism are described later in  the chapter.

Hormones The fetoplacental unit produces a variety of hormones  to support the maturation of the fetus and the adapta- tion of the mother.

PEPTIDE HORMONES Human Chorionic Gonadotropin Human chorionic gonadotropin (hCG) is secreted by trophoblastic cells of the placenta and maintains pregnancy.  This  hormone  is  a  glycoprotein  with  a  molecular  weight  of  40,000  to  45,000  and  consists of two subunits: alpha (α) and beta (β). The α subunit is  shared  with  luteinizing  hormone  (LH)  and  thyroid- stimulating  hormone  (TSH).  The specificity of hCG is related to its β subunit (β-hCG), and a radioimmuno- assay  that  is  specific  for  the  β  subunit  allows  positive  identification  of  hCG.  Newer  immunoassays  for  hCG  are able to accurately measure low levels of hCG based  on  the  entire  molecule  and  not  just  the  beta  subunit.  The  presence  of  hCG  at  times  other  than  pregnancy  signals  the  presence  of  an  hCG-producing  tumor,  usually  a  hydatidiform  mole,  choriocarcinoma,  or  embryonal carcinoma (a germ cell tumor).

During pregnancy, hCG begins to rise 8 days after ovulation  (9  days  after  the  midcycle  LH  peak).  This  provides  the  basis  for  virtually  all  immunologic  or  chemical pregnancy tests. With continuing pregnancy,  hCG values peak at 60 to 90 days and then decline to a  moderate,  more  constant  level.  For the first 6 to 8 weeks of pregnancy, hCG maintains the corpus luteum and thereby ensures continued progesterone output until progesterone production shifts to the placenta.  Titers  of  hCG  may  be  abnormally  low  in  patients with an ectopic pregnancy or threatened abor- tion  and  abnormally  high  in  those  with  trophoblastic  disease (e.g., moles or choriocarcinoma). This hormone  may  also  regulate  steroid  biosynthesis  in  the  placenta  and the fetal adrenal gland, and stimulate testosterone  production in the fetal testicle. Early pregnancy is char- acterized  by  an  increase  in  regulatory  T  cells  (Tregs),  which  are  known  to  facilitate  maternal  immune  toler- ance  of  the  fetus.  Recent  animal  research  has  shown  that  hCG  acts  as  a  central  regulator  of  this  immune  tolerance during pregnancy.

Human Placental Lactogen Human placental lactogen (hPL) originates in the pla- centa. It is a single-chain polypeptide with a molecular  weight  of  22,300,  and  it  resembles  pituitary  growth  hormone  and  human  prolactin  in  structure.  Maternal  serum  concentrations  parallel  placental  weight,  rising  throughout  gestation  to  maximum  levels  in  the  last  4  weeks.  At  term,  hPL  accounts  for  10%  of  all  placental  protein production. Low values are found with threat- ened abortion and intrauterine fetal growth restriction. 

C H A P T E R 5 Endocrinology of Pregnancy and Parturition 55

Human placental lactogen antagonizes the cellular action of insulin and decreases maternal glucose uti- lization, which increases glucose availability to the fetus. This may play a role in the pathogenesis of ges- tational diabetes.

Corticotropin-Releasing Hormone During pregnancy the major source of CRH is the pla- centa  and  it  can  be  measured  as  early  as  12  weeks’  gestation,  when  it  passes  into  the  fetal  circulation.   This 41-amino acid peptide stimulates fetal adrenocor- ticotropic  hormone  (ACTH)  secretion,  which  in  turn  stimulates  the  fetal  adrenal  to  secrete  dehydroepi- androsterone  sulfate  (DHEA-S),  an  important  precur- sor  of  estrogen  production  by  the  placenta.  The  fetal  adrenal  gland  early  in  pregnancy  does  not  have  the  enzymes  to  produce  cortisol,  but  as  gestational  age  increases,  it  becomes  more  capable.  Fetal cortisol stimulates placental CRH release, which then stimu- lates fetal ACTH secretion, completing a positive feedback loop that plays an important role in the acti- vation and amplification of labor, both preterm and term.  Elevated  levels  of  CRH  in  mid-gestation  have  been  found  to  be  associated  with  an  increased  risk  of  subsequent spontaneous preterm labor.

Prolactin Prolactin  is  a  peptide  from  the  anterior  pituitary   with a molecular weight of about 20,000. Normal non- pregnant  levels  are  approximately  10 ng/mL.  During pregnancy, maternal prolactin levels rise in response to increasing maternal estrogen output that stimu- lates the anterior pituitary lactotrophs. The main effect of prolactin is stimulation of postpartum milk production. In the second half of pregnancy, prolactin  secreted  by  the  fetal  pituitary  may  be  an  important  stimulus  of  fetal  adrenal  growth.  Prolactin  may  also  play a role in fluid and electrolyte shifts across the fetal  membranes.

STEROID HORMONES Progesterone Progesterone  is  the  most  important  human  progesto- gen. In the luteal phase, it induces secretory changes in the endometrium and in pregnancy, higher levels induce decidual changes. Up to the sixth or seventh week of pregnancy, the major source of progesterone (as 17-hydroxyprogesterone) is the ovarian corpus luteum.  Thereafter,  the  placenta  begins  to  play  the  major  role.  If the corpus luteum of pregnancy is removed before 7 weeks and continuation of the preg- nancy is desired, progesterone should be given to prevent spontaneous abortion. Circulating progester- one  is  mostly  bound  to  carrier  proteins,  and  less  than  10% is free and physiologically active.

The  myometrium  receives  progesterone  directly  from  the  venous  blood  draining  the  placenta.  Proges-

terone prevents uterine contractions and may also be involved in establishing an immune tolerance for the products of conception. Progesterone also suppresses  gap junction formation, placental CRH expression, and  the  actions  of  estrogen,  cytokines,  and  prostaglandin.  This  steroid  hormone  therefore  plays  a  central  role  in  maintaining  uterine  quiescence  throughout  most  of  pregnancy.

The  fetus  inactivates  progesterone  by  transforma- tion to corticosteroids or by hydroxylation or conjuga- tion to inert excretory products. However, the placenta  can  convert  these  inert  materials  back  to  progester- one.  Steroid  biochemical  pathways  are  shown  in  Figure 5-1.

Estrogens Both fetus and placenta are involved in the biosynthe- sis of estrone, estradiol, and estriol. Cholesterol is con- verted to pregnenolone in the placenta. This precursor is converted into DHEA-S largely in the fetal, and to a lesser extent the maternal, adrenals.  The  DHEA-S  is  further  metabolized  by  the  placenta  to  estrone  (E1)  and, via testosterone, to estradiol (E2). Estriol (E3), the most abundant estrogen in human pregnancy, is syn- thesized in the placenta from 16α-hydroxy-DHEA-S, which is produced in the fetal liver from adrenal DHEA-S. Placental sulfatase is required to deconjugate  16α-hydroxy-DHEA-S  before  conversion  to  E3  (Figure  5-2).  Steroid  sulfatase  activity  in  the  placenta  is  high,  except in rare cases of sulfatase deficiency.

Estrogens have essential roles during pregnancy and  parturition.  They  increase  uterine  blood  flow  which  allows  for  necessary  uterine  growth.  They  help  to  prepare the breast tissue for lactation and they stimu- late  the  production  of  hormone-binding  globulins  in  the  liver.  They  also  play  a  role,  along  with  cortisol,  in  lung surfactant production.

A sudden decline of estriol in the maternal circula- tion may indicate fetal compromise in a neurologi- cally intact fetus.  Anencephalic  fetuses  lack  a  hypothalamus and have hypoplastic anterior pituitary  and  adrenal  glands;  thus,  estriol  production  is  only  about 10% of normal.

Androgens During pregnancy, androgens originate mainly in the fetal zone of the fetal adrenal cortex. Androgen secre- tion  is  stimulated  by  ACTH  and  hCG,  the  latter  being  effective  primarily  in  the  first  half  of  pregnancy,  when  it  is  present  in  high  concentration.  The  fetal  adrenal  favors  production  of  DHEA  over  testosterone  and  androstenedione. Fetal androgens enter the umbilical and placental circulation and serve as precursors for estrone, estradiol, and estriol (see Figure 5-1).

The fetal testis also secretes androgens, particularly  testosterone,  which  is  converted  within  target  cells  to  dihydrotestosterone  (DHT),  which  is  required  for  the 

56 PA R T 2 Obstetrics

plasma level of transcortin rises in pregnancy, probably  stimulated  by  estrogen,  and  the  plasma-free  cortisol  concentration doubles.

Both the fetal adrenal and the placenta participate in cortisol metabolism.  The  fetal  adrenal  is  stimu- lated  by  ACTH,  originating  from  the  fetal  pituitary,  to  produce  both  cortisol  and  DHEA-S.  In  contrast  to  DHEA-S,  which  is  produced  in  the  fetal  zone,  cortisol  originates in the definitive zone (see Figure 5-1). Toward  the  end  of  pregnancy  cortisol promotes differentia- tion of type II alveolar cells and the biosynthesis and release of surfactant into the alveoli.  Surfactant 

development  of  male  external  genitalia.  The  main  trophic stimulus appears to be hCG.

Glucocorticoids Cortisol is derived from circulating cholesterol  (see  Figure  5-1).  Maternal  plasma  cortisol  concentrations  rise throughout pregnancy and are the primary stimu- lus  for  CRH  production  by  the  placenta.  The  diurnal  rhythm of cortisol secretion persists during pregnancy  unless  the  patient  has  significant  psychosocial  stress,  which elevates the morning and late afternoon cortisol  level  at  which  time  the  diurnal  rhythm  is  lost.  The 

FIGURE 5-1 Main pathways of steroid hormone biosynthesis. Adrenal DHEA is largely transported as its sulfate, DHEA-S, which can also be formed from steroid sulfates starting with cholesterol sulfate. LDL, Low-density lipoprotein.

LDL cholesterol

CholesterolC-27

C-21

C-19

Pregnenolone

Dehydroepi- androsterone

(DHEA)

Dehydroepi- androsterone

sulfate (DHEA-S)

Fetal zone of adrenal cortex

17α-hydroxy- pregnenolone

Placenta Definitive zone of adrenal cortex

Progesterone

Androstenedione

Testosterone

17α-hydroxy- progesterone

11-deoxy- corticosterone

11-deoxy- cortisol

Cortico- sterone

Aldosterone

Cortisol

Estrone

C-18

17β-estradiol

FIGURE 5-2 Formation of estriol in the fetal-placental unit. DHEA-S, Dehydroepiandrosterone sulfate.

Cholesterol sulfate

Pregnenolone sulfate

DHEA-S DHEA-S

16α-hydroxyandrostenedione

16α-hydroxyestrone

Estriol

16α-OH-DHEA-S

16α-OH-DHEA-S

Pregnenolone

16α-OH-DHEA 16α-OH-DHEA-S

FETAL ADRENAL

FETAL LIVER

MATERNAL ADRENALPLACENTA

C H A P T E R 5 Endocrinology of Pregnancy and Parturition 57

taglandin F2α (PGF2α), prostacyclin, and thromboxane A2 are synthesized in the endometrium, myometrium, the fetal membranes, decidua, and placenta. PGE2 and PGF2α cause contraction of the uterus.  Their  receptors  in  the  myometrium  are  downregulated  during  pregnancy.  Prostaglandins  can  also  cause  con- traction of other smooth muscles, such as those of the  intestinal  tract.  Hence,  when  used  pharmacologically,  prostaglandins may give rise to undesirable side effects  such  as  nausea,  vomiting,  and  diarrhea. The  amniotic  fluid concentrations of PGE2 and PGF2α rise throughout  pregnancy  and  increase  further  during  spontaneous  labor. Levels are lower in women who require oxytocin  for induction of labor than in women going into spon- taneous  labor.  Administration  of  PGE2  or  PGF2α  by  various routes induces labor or abortion at any stage of  gestation.  Various synthetic prostaglandin deriva- tives are currently in use to terminate pregnancy at any stage and to induce labor at term.

Prostaglandins are thought to play a major role in the initiation and control of labor. Prostaglandin synthesis begins with the formation of arachidonic acid, an obligatory precursor of the prostaglandins of the “2” series (i.e., PGE2, PGF2α).  Arachidonic  acid  is  stored  in  esterified  form  as  glycerophospholipid  in   the  trophoblastic  membranes.  The  initial  step  is  the  hydrolysis of glycerophospholipids, which is catalyzed  by phospholipase A2 or C. Phospholipase A2 preferen- tially acts on chorionic phosphatidyl ethanolamine to release arachidonic acid  (Figure  5-3).  Free  arachi- donic  acid  does  not  accumulate.  Labor  appears  to  be  accompanied  by  a  cascade  of  events  in  the  chorion,  amnion,  and  decidua  that  release  arachidonic  acid  from  its  stored  form  and  convert  it  to  active  prosta- glandins.  17β-Estradiol  stimulates  several  enzymes  active  in  the  synthesis  of  prostaglandins  from  arachi- donic acid.

decreases the force required to inflate the lungs. Insuf- ficiency  of  surfactant  leads  to  respiratory  distress  in   the premature infant, which can cause death. Cortisol also plays an important role in the activation of labor,  increasing  the  release  of  placental  CRH  and  prostaglandins.

OTHER HORMONES AND TRANSMITTERS Oxytocin The  oxytocic  prohormone,  which  originates  in  the  supraoptic and paraventricular nuclei of the maternal  hypothalamus,  migrates  down  the  nerve  fibers,  and  oxytocin accumulates at the nerve endings in the pos- terior  pituitary.  Oxytocin  is  a  nonapeptide  which  is  released from the posterior pituitary by various stimuli,  such  as  distention  of  the  birth  canal  and  mammary  stimulation.  Oxytocin causes uterine contractions, but impairment of oxytocin production, as in diabe- tes insipidus, does not interfere with normal labor.  Fluctuations  in  circulating  oxytocin  levels  before  the  onset of labor do not correspond to changes in uterine  activity.  Maternal serum oxytocin levels rise only during the first stage of labor. Oxytocin can be admin- istered to induce labor, especially in term pregnancies,  or  to  increase  the  frequency  and  strength  of  contrac- tions during spontaneous labor.

Recently, oxytocin has been shown to affect regions  of  the  brain  involved  in  emotional,  cognitive,  and   social behaviors. The impact on “pro-social” behaviors  includes  positive  effects  on  relaxation,  trust,  and  psy- chological  stability.  If  confirmed,  these  effects  could  help during labor, childbirth, and aftercare.

Relaxin Relaxin is a peptide hormone that originates mostly from the ovarian corpus luteum.  The  placenta  also  produces relaxin and it reaches its peak concentration  in  the  maternal  circulation  at  the  10th  week  of  preg- nancy  and  then  declines.  Relaxin is associated with the softening of the cervix,  which  is  one  of  the  ana- tomical  signs  of  pregnancy.  Its primary function appears to be in promoting implantation of the embryo by facilitating angiogenesis.  During  hyper- stimulation  of  the  ovaries  of  women  undergoing  in  vitro  fertilization  (IVF),  the  ovaries  produce  excessive  levels of relaxin. This excess of relaxin has been shown  to  be  associated  with  shortening  of  the  cervix  and  an  increased risk of preterm labor.

Prostaglandins and Leukotrienes Prostaglandins  are  a  family  of  ubiquitous,  biologically  active lipids that are involved in a broad range of physi- ologic  and  pathophysiologic  responses.  They are not true hormones in that they are not synthesized in one  gland  and  transported  via  the  circulating  blood  to  a  target  organ.  Rather,  they  are  synthesized  at  or  near  their site of action. Prostaglandin E2 (PGE2) and pros-

FIGURE 5-3 Diagram of prostaglandin and leukotriene biosynthesis.

G ly

ce ro

l

Arachidonic acid Fatty acid

Phosphate

PHOSPHATIDYL ETHANOLAMINE

ARACHIDONIC ACID

PROSTAGLANDINS THROMBOXANES PROSTACYCLIN

LEUKOTRIENES

Ethanolamine

Phospholipase A2

LipoxygenaseCyclooxygenase

58 PA R T 2 Obstetrics

tion of potassium in the distal tubule of the kidney, thereby maintaining sodium and potassium balance.  The  concentration  of  renin-substrate  (a  plasma  protein), rises in pregnancy. It is thought that the high  concentrations  of  progesterone  and  estrogen  present  during pregnancy stimulate renin and renin-substrate  formation, thus giving rise to increased levels of angio- tensin II and greater aldosterone production. Aldoste- rone secretion rates decline in pregnancy-induced hypertension and, in some cases, may fall below non- pregnant levels.

CALCIUM METABOLISM Although calcium absorption is increased in preg- nancy, total maternal serum calcium declines. The fall in total calcium parallels that of serum albumin,  because  approximately  half  of  the  total  calcium  is  bound to albumin.  Ionic calcium, the physiologically important calcium fraction, remains essentially con- stant throughout pregnancy because of increased maternal production of parathyroid hormone. The latter facilitates the transfer of calcium across the placenta to the fetus for adequate bone development, and at the same time the mobilization of calcium from the mother’s skeleton to maintain adequate calcium homeostasis.  In  late  pregnancy,  coinciding  with  maximal  calcification  of  the  fetal  skeleton,  increased serum parathyroid hormone levels enhance  both  maternal  intestinal  absorption  of  calcium  and  bone resorption.

Calcium ions are actively transported across the placenta, and fetal serum levels of total as well as ionized calcium are higher than maternal levels in late pregnancy.  High  fetal  ionic  calcium  suppresses  fetal parathyroid hormone production and parathyroid  hormone  does  not  cross  the  placenta.  Furthermore,  calcitonin production is stimulated, thus providing the  fetus  with  ample  calcium  for  calcification  of  the  skel- eton.  In  the  first  24  to  48  hours  postpartum,  the  total  serum  calcium  concentration  in  the  neonate  usually  falls,  while  the  phosphorus  concentration  rises.  Both  adjust to adult levels within 1 week.

Parturition Parturition  means  childbirth,  and  labor  is  the  physio- logic  process  by  which  a  fetus  is  expelled  from  the  uterus to the outside world.

BIOCHEMICAL BASIS OF CONTRACTION Muscle  contraction  is  brought  about  by  the  sliding  of  actin  and  myosin  filaments  fueled  by  adenosine  tri- phosphate  (ATP)  and  calcium.  While skeletal muscle requires innervation, contraction of smooth muscles such as the myometrium is triggered primarily by hormonal stimuli.  Hormonal  receptors  have  been  found in the myometrial cell membrane.

There are two cyclooxygenase isoenzymes referred to as COX-1 or PGHS-1, and COX-2 or PGHS-2. These  isoenzymes  originate  from  separate  genes.  COX-1  is  expressed  in  quiescent  cells,  whereas  COX-2  is  induc- ible.  It  is  expressed  at  sites  of  inflammation  upon  cell  activation,  and  potentiates  the  inflammatory  process.  COX-1 mRNA expression is low in fetal membranes  and  does  not  change  with  gestational  age,  whereas  COX 2 mRNA expression in the amnion increases with gestational age.

Increased phospholipase A2 activity may lead to premature labor. Endocervical, intrauterine, or urinary tract infections are often associated with pre- mature labor. Many of the organisms producing these  infections have phospholipase A2 activity, which could  produce free arachidonic acid, followed by prostaglan- din synthesis, which could trigger labor.

Prostaglandin synthetase inhibitors can prolong gestation.  Nonsteroidal  antiinflammatory  drugs  (NSAIDs)  inhibit  phospholipase  A2,  whereas  aspirin- like drugs inhibit cyclooxygenase. Because PGE2 keeps  the  ductus  arteriosus  open,  premature  closure  of  the  ductus may occur after ingestion of NSAIDs or aspirin  in  large  amounts  or  for  a  prolonged  period  of  time,  resulting in fetal pulmonary hypertension and death.

An additional pathway for arachidonic acid metab- olism is the conversion of arachidonic acid to leuko- trienes  (see  Figure  5-3).  Both  prostaglandins  and  leukotrienes induce decidualization, which means that  they initiate changes in the endometrium during early  pregnancy  to  facilitate  implantation  of  the  fertilized  ovum.

Although PGF2α is more potent in producing uterine  contractile  activity,  PGE2 is the most potent prosta- glandin for ripening the cervix by inducing changes in  the  connective  tissue.  Hence,  PGE2  and  its  synthetic  derivatives  are  clinically  useful  for  cervical  ripening  before the induction of labor or abortion.

Changes in Maternal Metabolism Maternal  metabolism  adapts  to  pregnancy  through  endocrinologic regulation as described below.

ANGIOTENSIN-ALDOSTERONE Aldosterone is a mineralocorticoid synthesized in the zona glomerulosa of the adrenal cortex. The main source in pregnancy is the maternal adrenal. The fetal  adrenal  and  the  placenta  do  not  participate  signifi- cantly  in  aldosterone  production,  although  the  fetal  adrenal  is  capable  of  synthesizing  it.  Aldosterone secretion is regulated by the renin-angiotensin system. Increased renin formed in the kidney converts  angiotensinogen  (renin-substrate)  to  angiotensin  I,  which  is  further  metabolized  to  angiotensin  II,  which  in  turn  stimulates  aldosterone  secretion.  Aldosterone stimulates the absorption of sodium and the secre-

C H A P T E R 5 Endocrinology of Pregnancy and Parturition 59

mation  concerning  the  control  of  the  human  gesta- tional  length  or  the  mechanisms  that  control  the  initiation of labor.

Animal Models Most studies have been conducted in sheep, where the fetus appears to control the onset of labor.  The  fetal  hypothalamus  stimulates  the  fetal  pituitary  to  secrete  ACTH,  which  brings  about  a  surge  of  cortisol  from  the  fetal  adrenal.  The  cortisol  surge  induces  the  placental  enzyme  17α-hydroxylase  and  the  formation  of  androgens,  which  are  precursors  of  estrogen  (see  Figure  5-1),  while  simultaneously  decreasing  proges- terone  formation.  The  rise  in  the  estrogen-to- progesterone  ratio  leads  to  (1)  greater  secretion  of  prostaglandins; (2) formation of myometrial gap junc- tions, which provide areas of low resistance to current  flow and increase coordinated uterine contractions; (3)  cervical  ripening;  and  (4)  the  onset  of  labor.  Adminis- tered  ACTH,  glucocorticoids,  or  dexamethasone  can  also  initiate  parturition.  Removal  of  the  fetal  pituitary  or  adrenal,  both  of  which  are  required  for  the  cortisol  surge, will result in prolonged pregnancy.

In  a  breed  of  Guernsey  cows  with  a  genetic  defect  resulting  in  fetal  pituitary  and  adrenal  dysfunction,  pregnancy  is  prolonged,  and  normal  vaginal  delivery  does  not  occur.  In the rabbit, parturition directly follows a decline in progesterone production second- ary to a decline in corpus luteum function.  Abortion  can be prevented by administration of progesterone.

The Human Based  upon  animal  and  human  research,  the  process  of  normal  spontaneous  human  parturition  can  be  divided into four stages.

PHASE 0: QUIESCENCE. Throughout the majority of preg- nancy,  the  uterus  remains  relatively  quiescent.  Myo- metrial  activity  is  inhibited  during  pregnancy  by  various substances, but progesterone appears to play a central role in maintaining uterine quiescence.  Recently, it has been shown that various organs such as  the  lung,  heart,  bladder,  and  uterus  are  modulated  by  parathyroid  hormone–related  peptide  (PTHrP),  which  is  produced  in  each  of  these  organs.  This  peptide  hormone  is  stimulated  by  stretch,  and  during  preg- nancy  PTHrP  relaxes  the  uterus  to  facilitate  fetal  growth.  At  delivery,  the  gene  that  regulates  PTHrP  is  turned off, allowing the uterus to contract and to begin  the  involution  process.  This  reduces  the  risk  of  post- partum  hemorrhage.  Rare  uterine  contractions  that  occur during the quiescent phase are of low frequency  and  amplitude  and  are  poorly  coordinated;  these  are  commonly  referred  to  as  Braxton-Hicks contractions  in women. The poor coordination of these contractions  is  primarily  due  to  an  absence  of  gap  junctions  in  the  pregnant myometrium.

The binding of oxytocin and prostaglandins to their  respective receptors activates phospholipase C, which  hydrolyzes  phosphatidylinositol  bisphosphate,  a  lipid  present in the cell membrane, to inositol trisphosphate  and  diacylglycerol  (Figure  5-4).  Inositol  trisphosphate  induces  release  of  calcium  from  the  sarcoplasmic   reticulum,  an  intracellular  calcium  storage  area.  The  resulting high intracellular free calcium concentration  enables the myofibrils of the myometrium to contract.  Subsequently, the calcium is pumped back into the sar- coplasmic  reticulum  with  the  help  of  ATP,  and  more  calcium may enter from the extracellular fluid through  both voltage-operated and receptor-operated channels  that  open  briefly.  The maintenance of adequate maternal calcium levels is important because low maternal serum calcium levels have been observed in women at risk for cesarean delivery.

Unlike the heart, in which the bundle of His is present, no anatomic structures for synchronization of contractions have been found in the uterus; however, recently it has been observed that vitamin D deficiency during pregnancy is associated with myo- metrial dysfunction and a greater risk of cesarean delivery.  Uterine  contractions  spread  as  current  flows  from  cell  to  cell  through  areas  of  low  resistance.  Such  areas are associated with gap junctions, which become  especially  prominent  at  parturition.  Estradiol and prostaglandins promote the appearance of gap junc- tions,  whereas  progesterone  opposes  this  action  of  estradiol.

HORMONAL CONTROL OF GESTATIONAL LENGTH AND INITIATION OF LABOR Gestational length is under the hormonal control of the  fetus.  Each  species  has  not  only  a  unique  gestational  length,  but  also  unique  mechanisms  for  controlling  that  length.  Thus,  although  animal  models  provide  important  insights,  they  do  not  provide  specific  infor-

FIGURE 5-4 Diagram of inositol trisphosphate formation.

G ly

ce ro

l +

Arachidonic acid

Fatty acid

Phosphate

G ly

ce ro

l

Arachidonic acid

Fatty acid

PHOSPHATIDYLINOSITOL BIPHOSPHATE

DIACYLGLYCEROL INOSITOL TRISPHOSPHATE

Inositol

Phosphate

Phosphate

Phosphate Inositol

Phosphate

Phosphate

Phospholipase C

60 PA R T 2 Obstetrics

progesterone  action,  PRA inhibits progesterone action. The ratio of PRA to PRB in the myometrium in labor is increased, which in effect results in a pro- gesterone withdrawal.

Functional progesterone withdrawal results in functional estrogen predominance, in part as a result of the increase in placental production of estrogen.  The expression of estrogen receptor (ER) isoform, ERα,  is  normally  suppressed  by  progesterone  but  as  the  expression of PR-A increases relative to that of PR-B, so  does  the  expression  of  ERα  in  the  laboring  myome- trium. The rising expression of ERα facilitates increased  estrogen  action.  Increasing  levels  of  estrogen  also  enhance  expression  of  many  estrogen-dependent   contraction associated proteins (CAPs), including con- nexin  43  (gap  junctions),  oxytocin  receptor,  prosta- glandin  receptors,  cyclooxygenase-2  (COX-2,  which  results in prostaglandin production), and myosin light- chain  kinase  (MLCK,  which  stimulates  myometrial  contractility and labor).

The  progressive  cascade  of  biological  processes  leads  to  a  common  pathway  of  parturition,  involving  cervical  ripening,  uterine  contractility,  and  decidual/ fetal membrane activation. Cervical ripening is largely mediated by the actions of prostaglandins, uterine contractility by the actions of gap junctions and myosin light-chain kinase,  and  decidual/fetal mem- brane activation by the actions of enzymes such as metalloproteinases,  which  ultimately  lead  to  rupture  of the membranes.

PHASE 3: INVOLUTION. During expulsion of the fetus, there is a dramatic increase in the release of maternal oxytocin which facilitates the initiation of the final phase of labor. It is thought that some of the increase  in oxytocin comes from the fetal pituitary as a result of  compression of the fetal head as it passes through the  pelvis.  Within  a  short  time  after  the  expulsion  of  the  fetus  from  the  uterus  the  effect  of  PTHrP  decreases  which  facilitates  the  return  of  normal  nonpregnant  uterine  contractility.  This  decrease  accounts  for  the  increased sensitivity of the uterus to oxytocin. Phase 3 involves placental separation and continued uterine contractions.  Placental  separation  occurs  by  cleavage  along the plane of the decidua basalis. Uterine contrac- tion is essential to prevent bleeding from large venous  sinuses that are exposed after delivery of the placenta,  and  is  primarily  effected  by  oxytocin.  This  is  further  supported  by  oxytocin  let  down  during  early  breast  feeding.

PHASE 1: ACTIVATION. Normally, the signals for myo- metrial activation can come from uterine stretch as a result of fetal growth, or from activation of the fetal hypothalamic-pituitary-adrenal (HPA) axis as a result of fetal maturation.  Uterine  stretch  has  been  shown  in  animal  models  to  increase  gap  junctions  and  contraction-associated proteins in the myometrium. It  is  currently  thought  that  once  fetal  maturity  has  been  reached  (as  determined  by  as  yet  unknown  mecha- nisms),  the  fetal  hypothalamus  increases  CRH  secre- tion, which in turn stimulates ACTH expression by the  fetal pituitary and cortisol and androgen production by  the  fetal  adrenals.  Recent  data  from  pregnant  mice  suggest  that  the  fetus  signals  the  initiation  of  labor  by  secreting  a  major  lung  surfactant  protein,  SP-A,  into  the amniotic fluid.

These  data  support  a  critical  role  for  the  fetal  HPA  axis in the initiation of parturition, because surfactant  protein synthesis is stimulated by glucocorticoids. The  role of PTHrP may also be important in lung develop- ment  and  the  onset  of  parturition.  The concept of a role for the fetal lung in the initiation of parturition is particularly attractive because the fetal lung is the last major organ to mature.

PHASE 2: STIMULATION. Phase  2  involves  a  progressive  cascade  of  events  leading  to  a  common  pathway  of  parturition, and involving uterine contractility, cervical  ripening,  and  decidual/fetal  membrane  activation.  This cascade probably begins with placental produc- tion of CRH. Placental CRH synthesis is stimulated by  glucocorticoids,  in  contrast  to  the  inhibitory  effect  of  glucocorticoids  on  maternal  hypothalamic  CRH  syn- thesis.  Placental  CRH  enters  into  the  fetal  circulation  and, in turn, promotes fetal cortisol and DHEA-S pro- duction.  This  positive  feedback  loop  is  progressively  amplified,  thereby  driving  the  process  forward  from  fetal  HPA  activation  to  parturition  and  the  placental  production of estrogens.

For most of pregnancy, uterine quiescence is main- tained by the action of progesterone.  At  the  end  of  pregnancy  in  most  mammals,  maternal  progesterone  levels fall and estrogen levels rise. In human and non- human  primate  pregnancies,  the  concentrations  of  progesterone  and  estrogens  continue  to  rise  through- out  pregnancy  until  delivery  of  the  placenta.  A  func- tional  progesterone  withdrawal  may  occur  in  women  and  nonhuman  primates  by  alterations  in  proges- terone  receptor  (PR)  expression.  There are two pro- gesterone receptors (PRA and PRB) in the human myometrium.  In  contrast  to  PRB,  which  increases 

61

6  Maternal Physiologic and Immunologic Adaptation to Pregnancy

C H

A P

T ER

BRIAN J. KOOS • CALVIN J. HOBEL

■  The  hemodynamic  changes  associated  with  pregnancy  begin  at  6  weeks’  gestation  and  are  associated  with  sodium  and  water  retention. The  mechanisms  for  these  changes are secondary to elevations in the production of  aldosterone,  prostaglandins,  atrial  natriuretic  peptide,  and  nitric  oxide  that  reduce  arterial  vascular  tone.  This  is  followed  by  formation  of  arterial-venous  shunts,  due  to  invasion  of  the  trophoblasts  into  the  maternal  spiral  arteries. This invasion, completed at 22 weeks’ gestation,  allows maternal blood to flow easily into the intervillous  placental  space  and  to  supply  the  fetus  with  adequate  nutrition  and  with  exchanges  of  oxygen  and  carbon  dioxide.

■  After  complete  invasion  of  the  placenta  into  the  spiral  arteries,  both  the  systolic  and  diastolic  blood  pressure  fall  (diastolic  more  than  systolic).  Toward  the  end  of  pregnancy, both diastolic and systolic pressures begin to  increase.  The  gradual  increase  in  the  size  of  the  fetus  results  in  mechanical  changes  in  the  maternal  circula- tory and respiratory systems. For the respiratory system,  the  enlarging  fetus  and  uterus  increase  the  maternal  minute  ventilation  needed  to  support  the  increase  in  oxygen consumption of the fetus and placenta. Maternal  renal metabolic requirements are also increased.

■  Renal changes during pregnancy play an important role  in maintaining maternal-fetal homeostasis. The glomer- ular  filtration  rate  (GFR)  increases  early  in  pregnancy 

and  is  maintained  for  the  duration  of  the  pregnancy.  Renal function is important for the maintenance of intra  vascular volume, and the kidneys are able to decrease or  increase  sodium  tubular  reabsorption  to  maintain  sodium balance.

■  The placenta receives a significant amount of the cardiac  output  from  the  mother  and  the  fetus  returns  at  least  60% of its cardiac output to the placenta, suggesting that  the placenta plays a vital role in the metabolic regulation  of  fetal  homeostasis.  The  fetus  has  the  advantage  of  having  fetal  hemoglobin  that  is  capable  of  transferring  greater  amounts  of  oxygen  than  adult  hemoglobin. The  fetus, with a higher temperature and lower pH, can shift  the  oxygen-dissociation  curve  to  the  right,  while  the  lower  maternal  temperature  and  higher  maternal  pH  shifts the maternal curve to the left. This allows adequate  oxygen  transfer  from  the  mother  to  the  fetus  and  is  referred to as the double Bohr effect.

■  At  no  other  time  in  the  reproductive  life  of  a  woman  is  there  an  immune  challenge  as  robust  as  the  innate  immune system in pregnancy. This system is an inflam- matory response during early pregnancy followed by an  adaptive  immune  response,  T-lymphocyte  helper  cell-2  (Th-2),  in  mid-pregnancy  that  is  designed  to  prevent  rejection of the fetus. The mechanism by which tolerance  occurs is complex, and depends upon an organized regu- lation between Th-1 and Th-2 immunity.

CLINICAL KEYS FOR THIS CHAPTER

Maternal  physiologic  adjustments  to  pregnancy  are  designed to support the requirements of fetal homeo- stasis and growth, without unduly jeopardizing mater- nal  well-being.  This  is  accomplished  by  remodeling  maternal  cardiovascular,  respiratory,  renal,  and  endo- crinologic  systems  to  deliver  energy  and  growth  sub- strates to the fetus, while removing inappropriate heat  and waste products.

The uterus appears to be a privileged immunologic sanctuary for the fetus and placenta during preg­ nancy.  The  pregnant  mother’s  own  immunologic  defense  system  remains  intact,  while  allowing  an   antigenically  dissimilar  fetus  to  grow  and  thrive.  At   the  present  time,  it  is  not  completely  understood   how  this  maternal-fetal  immunologic  compatibility  is  regulated.

62 PA R T 2 Obstetrics

Normal Values in Pregnancy The normal values for several hematologic, biochemi- cal,  and  physiologic  indices  during  pregnancy  differ  markedly  from  those  in  the  nonpregnant  range  and  may also vary according to the duration of pregnancy.  These alterations are shown in Table 6-1.

Cardiovascular System CARDIAC OUTPUT The hemodynamic changes associated with pregnancy  are summarized in Table 6-2. Retention of sodium and

TABLE 6-1

COMMON LABORATORY VALUES IN PREGNANCY

Test Normal Range (Nonpregnant) Change in Pregnancy Timing

Serum Chemistries

Albumin 3.5-4.8 g/dL ↓ 1 g/dL Most by 20 wk, then gradual

Calcium (total) 9-10.3 mg/dL ↓ 10% Gradual fall

Chloride 95-105 mEq/L No significant change Gradual rise

Creatinine (female) 0.6-1.1 mg/dL ↓ 0.3 mg/dL Most by 20 wk

Fibrinogen 1.5-3.6 g/L ↑ 1-2 g/L Progressive

Glucose, fasting (plasma) 65-105 mg/dL ↓ 10% Gradual fall

Potassium (plasma) 3.5-4.5 mEq/L ↓ 0.2-0.3 mEq/L By 20 wk

Protein (total) 6.5-8.5 g/dL ↓ 1 g/dL By 20 wk, then stable

Sodium 135-145 mEq/L ↓ 2-4 mEq/L By 20 wk, then stable

Urea nitrogen 12-30 mg/dL ↓ 50% 1st trimester

Uric acid 3.5-8 mg/dL ↓ 33% 1st trimester, rise at term Urine Chemistries

Creatinine 15-25 mg/kg/day (1-1.4 g/day) No significant change

Protein Up to 150 mg/day Up to 250-300 mg/day By 20 wk

Creatinine clearance 90-130 mL/min/1.73 m2 ↓ 40-50% By 16 wk Serum Enzymatic Activities

Amylase 23-84 IU/L ↑ 50-100%

Transaminase Glutamic pyruvic (SGPT) 5-35 mU/mL No significant change Glutamic oxaloacetic (SGOT) 5-40 mU/mL No significant change

Hematocrit (female) 36-46% ↓ 4-7% Bottoms at 30-34 wk

Hemoglobin (female) 12-16 g/dL ↓ 1.5-2 g/dL Bottoms at 30-34 wk

Leukocyte count 4.8-10.8 × 103/mm3 ↑ 3.5 × 103/mm3 Gradual

Platelet count 150-400 × 103/mm3 Slight decrease Serum Hormone Values

Cortisol (plasma) 8-21 g/dL ↑ 20 g/dL

Prolactin (female) 25 ng/mL ↑ 50-400 ng/mL Gradual, peaks at term

Thyroxine (T4), total 5-11 g/dL ↑ 5 g/dL Early sustained

Triiodothyronine (T3), total 125-245 ng/dL ↑ 50% Early sustained

Data from Main DM, Main EK: Obstetrics and gynecology: a pocket reference, Chicago, 1984, Year Book, p 7.

water during pregnancy accounts for a total body water increase of 6 to 8 L, two-thirds of which is located  in the extravascular space. The total sodium accumu­ lation averages 500 to 900 mEq by the time of delivery.  The total blood volume increases by about 40% above nonpregnant levels, with wide individual variations.  The  plasma  volume  rises  as  early  as  the  sixth  week  of  pregnancy,  and  reaches  a  plateau  by  about  32  to  34  weeks’  gestation,  after  which  little  further  change  occurs.  The  increase  averages  50%  in  singleton  preg- nancies,  and  approaches  70%  with  a  twin  gestation.  The  red  blood  cell  mass  begins  to  increase  at  the   start  of  the  second  trimester,  and  continues  to  rise 

C H A P T E R 6 Maternal Physiologic and Immunologic Adaptation to Pregnancy 63

vasoconstrictor  tone,  and  with  it  blood  pressure,  nor- mally  increase.  The  normal,  modest  rise  of  arterial  pressure  as  term  approaches  should  be  distinguished  from  the  development  of  pregnancy-induced  hyper- tension  or  preeclampsia.  Pregnancy does not alter central venous pressures.

Blood  pressure,  as  measured  with  a  sphygmoma- nometer  cuff  around  the  brachial  artery,  varies  with  posture.  In  late  pregnancy,  arterial  pressure  is  higher  when the gravid woman is sitting compared with lying  supine.  When  elevations  in  blood  pressure  are  clini- cally  detected  during  pregnancy,  it  is  customary  to  repeat  the  measurement  with  the  patient  lying  on  her  left  side. This  practice  usually  introduces  a  systematic  error.  In  the  lateral  position,  the  blood  pressure  cuff  around the brachial artery is raised about 10 cm above  the  heart. This  leads  to  a  hydrostatic  fall  in  measured  pressure, yielding a reading about 7 mm Hg lower than  if  the  cuff  were  at  heart  level,  as  occurs  during  sitting  or supine measurements.

MECHANICAL CIRCULATORY EFFECTS OF THE GRAVID UTERUS As  pregnancy  progresses,  the  enlarging  uterus  dis- places  and  compresses  various  abdominal  structures,  including  the  iliac  veins  and  inferior  vena  cava  (and  probably  also  the  aorta),  with  marked  effects.  The supine position accentuates venous compression,  producing  a  fall  in  venous  return  and  hence  cardiac  output. In most gravid women, a compensatory rise in  peripheral resistance minimizes the fall in blood pres- sure.  In  up  to  10%  of  gravid  women,  a  significant  fall  occurs in blood pressure accompanied by symptoms of  nausea,  dizziness,  and  even  syncope.  This  supine hypotensive syndrome  is  relieved  by  changing  posi- tion to the left side (the venous return is greater when  the patient turns to the left side as compared with the  right  side).  The  expected  baroreflexive  tachycardia,  which normally occurs in response to other maneuvers  that  reduce  cardiac  output  and  blood  pressure,  does  not  accompany  caval  compression.  In  fact,  bradycar­ dia is often associated with the syndrome.

The venous compression by the gravid uterus in the supine position elevates pressure in veins that drain the legs and pelvic organs, thereby exacerbat­ ing varicose veins in the legs and vulva and causing hemorrhoids. The rise in venous pressure is the major  cause of the lower extremity edema that characterizes  pregnancy.  The  hypoalbuminemia  associated  with  pregnancy  also  shifts  the  balance  of  the  other  major  factor  in  the  Starling  equation  (colloid  osmotic  pres- sure)  in  favor  of  fluid  transfer  from  the  intravascular   to  the  extracellular  space.  Because of venous com­ pression, the rate of blood flow in the lower veins is also markedly reduced, causing a predisposition to thrombosis. The  various  effects  of  caval  compression  are  somewhat  mitigated  by  the  development  of  a 

throughout  pregnancy.  By  the  time  of  delivery,  it  is  20-35% above nonpregnant levels. The disproportion­ ate increase in plasma volume compared with the red cell volume results in hemodilution with a decreased hematocrit reading, sometimes referred to as physi­ ologic anemia of pregnancy.  If  iron  stores  are  ade- quate, the hematocrit tends to rise from the second to  the third trimester.

Cardiac output rises by the tenth week of gestation, reaching about 40% above nonpregnant levels by 20 to 24 weeks, after which there is little change. The rise  in  cardiac  output,  which  peaks  while  blood  volume  is  still  rising,  reflects  increases  mainly  in  stroke  volume  and,  to  a  lesser  extent,  in  heart  rate.  With  twin  and  triplet  pregnancies,  the  changes  in  cardiac  output  are  greater than those seen with singleton pregnancies.

The cardiovascular responses to exercise are altered  during  pregnancy.  For any given level of exercise, oxygen consumption is higher in pregnant than in nonpregnant women. Similarly, the cardiac output for  any level of exercise is increased during pregnancy, and  the maximum cardiac output is reached at lower levels  of  exercise.  It  is  not  clear  that  any  of  the  changes  in  hemodynamic responses to exercise are detrimental to  mother  or  fetus,  but  it  suggests  that  maternal  cardiac  reserves may be lower during pregnancy, and shunting  of  blood  away  from  the  uterus  may  occur  during  or  after exercise.

INTRAVASCULAR PRESSURES Systolic pressure falls only slightly during pregnancy, whereas diastolic pressure decreases more markedly; this reduction begins in the first trimester, reaches its  nadir in mid-pregnancy, and returns toward nonpreg- nant levels by term. These changes reflect the elevated  cardiac output and reduced peripheral resistance that  characterize  pregnancy. Toward  the  end  of  pregnancy, 

TABLE 6-2

CARDIOVASCULAR CHANGES IN PREGNANCY

Parameter Amount of Change Timing

Arterial blood pressures

Systolic ↓ 4-6 mm Hg All bottom at 20-24 wk, then rise gradually to prepregnancy values at term

Diastolic ↓ 8-15 mm Hg Mean ↓ 6-10 mm Hg

Heart rate ↑ 12-18 beats/min 1st, 2nd, 3rd trimesters

Stroke volume ↑ 10-30% 1st and 2nd trimesters, then stable until term

Cardiac output ↑ 33-45% Peaks in early 2nd trimester, then stable until term

Data from Main DM, Main EK: Obstetrics and gynecology: a pocket reference, Chicago, 1984, Year Book, p 18.

64 PA R T 2 Obstetrics

represented by the uteroplacental circulation. The ele- vations in cardiac output and uterine blood flow follow  different time courses in pregnancy, however, with the  former  reaching  its  maximum  in  the  second  trimester  and the latter increasing to term.

A unifying hypothesis suggests that the elevations in circulating steroid hormones in combination with increases in production of aldosterone and vasodila­ tors such as prostaglandins, atrial natriuretic peptide, nitric oxide, and probably others, reduce arterial tone and increase venous capacitance.  These  changes,  along  with  the  development  of  arteriovenous  shunts,  appear  responsible  for  the  increase  in  blood  volume  and the hyperdynamic circulation of pregnancy (high- flow,  low-resistance).  The  same  hormonal  changes  cause  relaxation  in  the  cytoskeleton  of  the  maternal  heart,  which  allows  the  end-diastolic  volume  (and  stroke volume) to increase.

OXYGEN-CARRYING CAPACITY OF BLOOD Plasma volume expands proportionately more than red blood cell volume, leading to a fall in hematocrit.  Optimal  pregnancy  outcomes  are  generally  achieved  with  a  maternal  hematocrit  of  33-35%.  Hematocrit  readings below 27%, or above 39%, are associated with  less  favorable  outcomes.  Despite the relatively low “optimal” hematocrit, the arteriovenous oxygen dif­ ference in pregnancy is below nonpregnant levels.  This  supports  the  concept  that  the  hemoglobin  con- centration in pregnancy is more than sufficient to meet  oxygen-carrying requirements.

Pregnancy requires about 1 g of elemental iron: 0.7 g for mother and 0.3 g for the placenta and fetus.  A  high  proportion  of  women  in  the  reproductive  age  group enter pregnancy without sufficient stores of iron  to meet the increased needs of pregnancy.

Respiratory System The  major  respiratory  changes  in  pregnancy  involve  three  factors:  the  mechanical  effects  of  the  enlarging  uterus, the increased total body oxygen consumption,  and the respiratory stimulant effects of progesterone.

RESPIRATORY MECHANICS IN PREGNANCY The changes in lung volume and capacities associated  with  pregnancy  are  detailed  in  Table  6-3.  The dia­ phragm at rest rises to a level of 4 cm above its usual resting position.  The  chest  enlarges  in  transverse  diameter by about 2.1 cm. Simultaneously, the subcos- tal  angle  increases  from  an  average  of  68.5  degrees  to  103.5  degrees  during  the  latter  part  of  gestation.  The  increase in uterine size cannot completely explain the  changes  in  chest  configuration,  as  these  mechanical  changes occur early in gestation.

As pregnancy progresses, the enlarging uterus elevates the resting position of the diaphragm.  This 

paravertebral  collateral  circulation  that  permits  blood  from  the  lower  body  to  bypass  the  occluded  inferior  vena cava.

During late pregnancy, the uterus can also par­ tially compress the aorta and its branches.  This  is  thought to account for the observation in some patients  of lower pressure in the femoral artery compared with  that in the brachial artery. This aortic compression can  be accentuated during a uterine contraction, and may  be  a  cause  of  fetal  distress  when  a  patient  is  in  the  supine  position.  This  phenomenon  has  been  referred  to as the Poseiro effect. Clinically, it can be suspected  when the femoral pulse is not palpable.

REGIONAL BLOOD FLOW Blood  flow  to  most  regions  of  the  body  increases  and  reaches a plateau relatively early in pregnancy. Notable  exceptions  occur  in  the  uterus,  kidney,  breasts,  and  skin, in each of which blood flow increases with gesta- tional  age.  Two of the major increases (those to the kidney and to the skin) serve purposes of elimination: the kidney of waste material and the skin of heat.  Both  processes  require  plasma  rather  than  whole  blood,  which  points  to  the  importance  of  the  dispro- portionate  increase  of  plasma  over  red  blood  cells  in  the blood volume expansion during pregnancy.

Early in pregnancy, renal blood flow increases to levels approximately 30% above nonpregnant levels  and  remains  unchanged  as  pregnancy  advances.  This  change accounts for the increased creatinine clearance  and  lower  serum  creatinine  level.  Engorgement  of  the  breasts begins early in gestation, with mammary blood  flow  increasing  two  to  three  times  in  later  pregnancy.  The skin blood flow increases slightly during the third  trimester, reaching 12% of cardiac output.

There  is  little  information  on  the  distribution  of  blood  flow  to  other  organ  systems  during  pregnancy.  The uterine blood flow increases from about 100 mL/ min in the nonpregnant state  (2%  of  cardiac  output)  to approximately 1200 mL/min  (17%  of  cardiac  output) at term. Uterine blood flow, and thus gas and  nutrient  transfer,  to  the  fetus  is  vulnerable.  When maternal cardiac output falls, blood flow to the brain, kidneys, and heart is supported by a redistribution of cardiac output, which shunts blood away from the uteroplacental circulation.  Similarly,  changes  in  per- fusion pressure can lead to decreases in uterine blood  flow. Because the uterine vessels are maximally dilated  during  pregnancy,  little  autoregulation  can  occur  to  improve uterine blood flow.

CONTROL OF CARDIOVASCULAR CHANGES The precise mechanisms accounting for the cardiovas- cular  changes  in  pregnancy  have  not  been  fully  eluci- dated. The rise in cardiac output and fall in peripheral  resistance during pregnancy may be explained in terms  of  the  circulatory  response  to  an  arteriovenous  shunt, 

C H A P T E R 6 Maternal Physiologic and Immunologic Adaptation to Pregnancy 65

tion,  the  arteriovenous  oxygen  difference  and  arterial  Pco2  both  fall.  The  fall  in  Pco2  (to  27-32 mm Hg),  by  definition, indicates hyperventilation.

The rise in minute ventilation reflects an approxi­ mately 40% increase in tidal volume at term; the respiratory rate does not change during pregnancy.  During exercise, pregnant subjects show a 38% increase  in  minute  ventilation  and  a  15%  increase  in  oxygen  consumption above comparable levels for postpartum  subjects. The mechanism is thought to be secondary to  the increase in minute ventilation secondary to increas- ing levels of progesterone and the increased metabolic  rate of both the mother and her fetus(es).

When  injected  into  normal  nonpregnant  subjects,  progesterone increases ventilation.  The  central  che- moreceptors  become  more  sensitive  to  CO2  (i.e.,  the  curve describing the ventilatory response to increasing  CO2 levels has a steeper slope). Such increased respira­ tory sensitivity to CO2 is characteristic of pregnancy and probably accounts for the hyperventilation of pregnancy.

In  summary,  both  at  rest  and  with  exercise,  minute  ventilation and, to a lesser extent, oxygen consumption  are increased during pregnancy. The respiratory stimu- lating effect of progesterone is probably responsible for  the  disproportionate  increase  in  minute  ventilation  over oxygen consumption.

ALVEOLAR-ARTERIAL GRADIENT AND ARTERIAL BLOOD GAS MEASUREMENTS The hyperventilation of pregnancy results in a respi­ ratory alkalosis.  Renal  compensatory  bicarbonate  excretion leads to a final maternal blood pH of between  7.40  and  7.45.  During  labor  (without  conduction 

results  in  less  negative  intrathoracic  pressure  and  a  decreased  resting  lung  volume,  that  is,  a  decrease  in  functional  residual  capacity  (FRC).  The  enlarging  uterus  produces  no  impairment  in  diaphragmatic  or  thoracic muscle motion. Hence, the vital capacity ( VC) remains unchanged. These characteristics—reduced FRC with unimpaired VC—are analogous to those seen in a pneumoperitoneum and contrast with those  seen  in  severe  obesity  or  abdominal  binding,  where   the  elevation  of  the  diaphragm  is  accompanied  by  decreased excursion of the respiratory muscles. Reduc- tions  in  both  the  expiratory  reserve  volume  and  the  residual volume contribute to the reduced FRC.

OXYGEN CONSUMPTION AND VENTILATION Total body oxygen consumption increases by about 15­20% in pregnancy.  Approximately  half  of  this  increase is accounted for by the uterus and its contents,  and  the  remainder  is  mainly  related  to  increased  maternal  renal  and  cardiac  work.  Smaller  increments  are a result of greater breast tissue mass and increased  work of the respiratory muscles.

In general, a rise in oxygen consumption is accom- panied  by  cardiorespiratory  responses  that  facilitate  oxygen delivery (i.e., by increases in cardiac output and  alveolar  ventilation).  To  the  extent  that  elevations  in  cardiac output and alveolar ventilation keep pace with  the  rise  in  oxygen  consumption,  the  arteriovenous  oxygen  difference  and  the  arterial  partial  pressure  of  carbon dioxide (Pco2), respectively, remain unchanged.  In pregnancy, the elevations in both cardiac output and alveolar ventilation are greater than those required to meet the increased oxygen consumption.  Hence, despite the rise in total body oxygen consump-

TABLE 6-3

LUNG VOLUMES AND CAPACITIES IN PREGNANCY

Test Definition Change in Pregnancy

Respiratory rate Breaths/minute No significant change

Tidal volume The volume of air inspired and expired at each breath

Progressive rise throughout pregnancy of 0.1-0.2 L

Expiratory reserve volume

The maximum volume of air that can be additionally expired after a normal expiration

Lowered by about 15% (0.55 L in late pregnancy compared with 0.65 L postpartum)

Residual volume The volume of air remaining in the lungs after a maximum expiration

Falls considerably (0.77 L in late pregnancy compared with 0.96 L postpartum)

Vital capacity The maximum volume of air that can be forcibly inspired after a maximum expiration

Unchanged, except for possibly a small terminal diminution

Inspiratory capacity The maximum volume of air that can be inspired from resting expiratory level

Increased by about 5%

Functional residual capacity

The volume of air in lungs at resting expiratory level

Lowered by about 18%

Minute ventilation The volume of air inspired or expired in 1 min Increased by about 40% as a result of the increased tidal volume and unchanged respiratory rate

Data from Main DM, Main EK: Obstetrics and gynecology: a pocket reference, Chicago, 1984, Year Book, p 14.

66 PA R T 2 Obstetrics

GFR is reflected in lower serum levels of creatinine and urea nitrogen, as noted in Table 6-1.

Pregnancy  is  associated  with  large  reductions  in  resistance in the afferent and efferent arterioles of the  renal arteries, which appears to involve vasorelaxation induced by relaxin, endothelin, and nitric oxide. The  resulting  rise  in  renal  plasma  flow  accounts  for  the  hyperfiltration.

RENAL TUBULAR FUNCTION Although 500 to 900 mEq of sodium is retained during  pregnancy, sodium balance is maintained with exqui­ site precision.  Despite  the  large  amounts  of  sodium  consumed  daily  (100  to  300 mEq),  only  20  to  30 mEq   of  sodium  is  retained  every  week.  Pregnant  women,  given high or low sodium diets, are able to decrease or  increase  their  sodium  tubular  reabsorption,  respec- tively, to maintain their sodium and fluid balance.

Pregnant  women  are  also  able  to  maintain  their  fluid  balance  with  no  change  in  the  concentrating   or  diluting  ability  of  the  kidney.  Plasma  osmolarity   is  reduced  by  approximately  10 mOsm/kg  of  water.  Potassium metabolism during pregnancy remains unchanged,  although  about  350 mEq  of  potassium  is  retained  during  pregnancy  for  fetoplacental  develop- ment and expansion of maternal red cell mass.

The hyperventilation (low partial pressure of CO2 in arterial blood [PaCO2]) of pregnancy results in respiratory alkalosis, which is compensated by renal excretion of bicarbonate.  As  a  result,  maternal  renal  buffering capacity is reduced.

FLUID VOLUMES The maternal extracellular volume, which consists of intravascular and interstitial components, increases throughout pregnancy, leading to a state of physio­ logic extracellular hypervolemia.  The  intravascular  volume, which consists of plasma and red cell compo- nents, increases approximately 50% during pregnancy.  Maternal interstitial volume shows its greatest increase  in the last trimester.

The  magnitude  of  the  rise  in  maternal  plasma  volume  correlates  with  the  size  of  the  fetus;  it  is  par- ticularly  marked  in  cases  of  multiple  gestation.  Mul- tiparous women with poor reproductive histories show  smaller  increments  in  plasma  volume  and  GFR  when  compared with those with a history of normal pregnan- cies and normal-sized babies.

RENIN-ANGIOTENSIN SYSTEM IN PREGNANCY Plasma  concentrations  of  renin,  renin  substrate,  and  angiotensin  I  and  II  are  increased  during  pregnancy.  Renin levels remain elevated throughout pregnancy,  with at least a portion of the renin circulating in a high- molecular-weight form.

The uterus and placenta,  like  the  kidney,  can produce renin,  and  extremely  high  concentrations  of 

anesthesia), the hyperventilation associated with each  contraction produces a further transient fall in Pco2. By  the end of the first stage of labor, when cervical dilation  is  complete,  a  decrease  in  arterial  Pco2  persists,  even  between contractions.

In  general,  when  alveolar  Pco2  falls  during  hyper- ventilation,  alveolar  partial  pressure  of  oxygen  (Po2)  shows a corresponding rise, leading to a rise in arterial  Po2. In the first trimester, the mean arterial Po2 may be  106 to108 mm Hg. There is a slight downward trend in arterial PO2 as pregnancy progresses. This  reflects,  at  least  in  part,  an  increased  alveolar-arterial  gradient,  possibly  resulting  from  the  decrease  in  functional  residual  capacity  or  FRC  discussed  previously,  which  leads to a ventilation-perfusion mismatch.

DYSPNEA OF PREGNANCY In  general,  airway  resistance  is  unchanged  or  even  decreased  in  pregnancy.  Despite the absence of obstructive or restrictive effects, dyspnea is a common symptom in pregnancy. Some studies have suggested that dyspnea may be experienced by as many as 60­70% of women at some time during pregnancy.  Although the mechanism has not been established, the  dyspnea  of  pregnancy  may  involve  the  increased  sen- sitivity to the lower levels of Pco2.

Renal Physiology ANATOMIC CHANGES IN THE URINARY TRACT The urinary collecting system, including the calyces, renal pelves, and ureters, undergoes marked dilation in pregnancy,  as  is  readily  seen  on  intravenous  uro- grams.  It  begins  in  the  first  trimester,  is  present  in   90% of women at term, and may persist until the 12th  to  16th  postpartum  week.  Progesterone  appears  to  produce  smooth  muscle  relaxation  in  various  organs,  including  the  ureter.  As the uterus enlarges, partial obstruction of the ureter occurs at the pelvic brim in both the supine and the upright positions. Because of  the relatively greater effect on the right side, some have  ascribed  a  role  to  the  dilated  ovarian  venous  plexus.  Ovarian venous drainage is asymmetric, with the right  vein  emptying  into  the  inferior  vena  cava  and  the  left  into the left renal vein.

RENAL BLOOD FLOW AND GLOMERULAR FILTRATION RATE Renal plasma flow and the glomerular filtration rate (GFR) increase early in pregnancy. Maximum plateau elevations of at least 40­50% above nonpregnant levels are reached by mid­gestation, and they remain unchanged to term.  As  with  cardiac  output,  renal  blood flow and GFR (clinically measured as the creati- nine  clearance)  reach  their  peak  relatively  early  in  pregnancy,  before  the  greatest  expansion  in  intravas- cular  and  extracellular  volume  occurs.  The elevated

C H A P T E R 6 Maternal Physiologic and Immunologic Adaptation to Pregnancy 67

renin occur in the amniotic fluid. The physiologic role  of uterine renin has not been established. Recently, the  renin-angiotensin  system  has  been  shown  to  partici- pate in the regulation of maternal-placental-fetal blood  flow  that  is  altered  by  various  disease  states  such  as  preeclampsia, obesity, and diabetes.

Homeostasis of Maternal Energy Substrates The metabolic regulation of energy substrates, includ- ing glucose, amino acids, fatty acids, and ketone bodies,  is complex and interrelated.

INSULIN EFFECTS AND GLUCOSE METABOLISM In pregnancy, the insulin response to glucose stimu­ lation is augmented. By the 10th week of normal preg- nancy  and  continuing  to  term,  fasting  concentrations  of  insulin  are  elevated  and  those  of  glucose  reduced.  Until  mid-gestation,  these  changes  are  accompanied  by  enhanced  intravenous  glucose  tolerance  (although  oral  glucose  tolerance  remains  unchanged).  Glycogen synthesis and storage by the liver increases, and gluconeogenesis is inhibited.  Thus,  during  the  first  half  of  pregnancy,  the  anabolic  actions  of  insulin  are  potentiated.

After early pregnancy, insulin resistance emerges, so glucose tolerance is impaired. The fall in serum glucose for a given dose of insulin is reduced com­ pared with the response in earlier pregnancy.  Eleva- tion  of  circulating  glucose  is  prolonged  after  meals,  although  fasting  glucose  remains  reduced,  as  in  early  pregnancy.

A variety of humoral factors derived from the pla­ centa have been suggested to account for the antiin­ sulin environment of the latter part of pregnancy. Perhaps the most important are cytokines and human placental lactogen (hPL),  which  antagonizes  the  peripheral  effects  of  insulin.  An  increase  in  levels  of  free cortisol and other hormones may also be involved  in the insulin resistance of pregnancy.

LIPID METABOLISM The potentiated anabolic effects of insulin that charac- terize early pregnancy lead to the inhibition of lipolysis.  During the second half of pregnancy, probably as a result of rising hPL levels, lipolysis is augmented, and fasting plasma concentrations of free fatty acids are elevated. Teleologically, the free fatty acids act as sub- strates  for  maternal  energy  metabolism,  whereas  glucose and amino acids cross the placenta to the fetus.  In  the  humoral  milieu  of  the  second  half  of  the  preg- nancy,  the  increased  free  fatty  acids  lead  to  ketone  body formation (β-hydroxybutyrate and acetoacetate).  Pregnancy is thus associated with an increased risk of ketoacidosis, especially after prolonged fasting.

In  the  context  of  maternal  lipid  metabolism,  the  most dramatic lipid change in pregnancy is the rise in  fasting triglyceride concentration.

Placental Transfer of Nutrients The  transfer  of  substances  across  the  placenta  occurs  by  several  mechanisms,  including  simple  diffusion,  facilitated diffusion, and active transport. Low molecu­ lar size and lipid solubility promote simple diffusion.  Substances  with  molecular  weights  greater  than  1000  Daltons,  such  as  polypeptides  and  proteins,  cross  the  placenta slowly, if at all.

Amino acids are actively transported across the pla- centa,  making  fetal  levels  higher  than  maternal  levels.  Glucose is transported by facilitated diffusion, leading  to  rapid  equilibrium  with  only  a  small  maternal-fetal  gradient. Glucose is the main energy substrate of the fetus,  although  amino  acids  and  lactate  may  contrib- ute up to 25% of fetal oxygen consumption. The degree  and mechanism of placental transfer of these and other  substances are summarized in Table 6-4.

Other Endocrine Changes THYROID The thyroid gland undergoes moderate enlargement during pregnancy. This  is  not  because  of  elevation  of  thyroid-stimulating  hormone  (TSH),  which  remains  unchanged. Placenta-derived human chorionic gonad- otropin  (hCG)  has  a  TSH-effect  on  the  thyroid  gland,  which can result in abnormally low levels of TSH in the  first trimester, when hCG concentrations are highest.

Circulating  thyroid  hormone  exists  in  two  primary  active  forms:  thyroxine  (T4)  and  triiodothyronine  (T3).  The former circulates in higher concentrations, is more  highly protein-bound, and is less metabolically potent  than T3,  for  which  it  may  serve  as  a  prohormone.  Cir- culating T4 is bound to carrier proteins, approximately  85%  to  thyroxine-binding  globulin  (TBG)  and  most  of  the  remainder  to  another  protein,  thyroxine-binding  prealbumin. It is believed that only the unbound frac- tion  of  the  circulating  hormone  is  biologically  active.  TBG is increased during pregnancy because the high estrogen levels induce increased hepatic synthesis.  The body responds by raising total circulating levels of  T4 and T3 and the net effect is that the free, biologically active concentration of each hormone is unchanged.  Therefore,  clinically,  the  free  T4  index,  which  corrects  the  total  circulating  T4  for  the  amount  of  binding  protein, is an appropriate measure of thyroid function,  with  the  same  normal  range  as  in  the  nonpregnant  state.

Only minimal amounts of thyroid hormone cross the placenta.  The  small  amount  of  thyroid  hormone 

68 PA R T 2 Obstetrics

TABLE 6-4

MATERNAL-FETAL TRANSFER DURING PREGNANCY

Function Substance Placental Transfer

Glucose homeostasis Glucose Excellent—”facilitated diffusion” Amino acids Excellent—active transport Free fatty acids Very limited—essential free fatty acids only Ketones Excellent—diffusion Insulin No transfer Glucagon No transfer

Thyroid function Thyroxine Very poor—diffusion Triiodothyronine Poor—diffusion Thyrotropin-releasing hormone Good Thyroid-stimulating immunoglobulin Good Thyroid-stimulating hormone Negligible transfer Propylthiouracil Excellent

Adrenal hormones Cortisol Excellent transfer and active placental conversion of cortisol to cortisone beginning at mid-pregnancy*

Adrenocorticotropic hormone No transfer

Parathyroid function Calcium Active transfer against gradient Magnesium Active transfer against gradient Phosphorus Active transfer against gradient Parathyroid hormone Not transferred

Immunoglobulins IgA Minimal passive transfer IgG Good—both passive and active transport from 7 wk gestation IgM No transfer

Data from Main DM, Main EK: Obstetrics and gynecology: a pocket reference, Chicago, 1984, Year Book, p 37. *At mid-gestation, placental 11β-hydroxysteroid dehydrogenase converts cortisol to cortisone.

that crosses the placenta is converted to reverse T3 (rT3)  which  is  metabolically  inactive.  The  fetus  does  not  require  thyroid  hormone  from  the  mother;  it  synthe- sizes  thyroid  hormone  from  its  own  thyroid  gland  to  meet  its  requirements.  The  fetus  does  not  require  thyroid  hormone  for  thermogenesis  in  utero  and  at  birth  it  releases  TSH  in  large  amounts  to  begin  the  release  of  thyroid  hormones  for  the  purpose  of  thermogenesis.

ADRENAL Adrenocorticotropic hormone (ACTH) and plasma cortisol levels are both elevated from 3 months’ gesta­ tion to delivery.  Circulating  cortisol  is  also  primarily  bound  to  a  specific  plasma  protein,  corticosteroid- binding globulin (CBG) or transcortin. Unlike the level of thyroid hormones, the mean unbound level of cor­ tisol is elevated in pregnancy;  there  is  also  some  loss  of  the  diurnal  variation  that  characterizes  its  concen- tration in nonpregnant women.

Weight Gain in Pregnancy The average weight gain in pregnancy uncomplicated by generalized edema is 12.5 kg (28 lb).  The  compo- nents of this weight gain are indicated in Table 6-5. The  products  of  conception  constitute  only  about  40%  of  the total maternal weight gain.

Placental Transfer of Oxygen and Carbon Dioxide FETAL OXYGENATION The placenta receives 60% of the combined ventricular  output,  whereas  the  postnatal  lung  receives  100%  of 

TABLE 6-5

ANALYSIS OF WEIGHT GAIN IN PREGNANCY

Tissues and Fluids

Increase in Weight (Grams) Up To:

10 wk 20 wk 30 wk 40 wk

Fetus 5 300 1500 3400

Placenta 20 170 430 650

Amniotic fluid 30 350 750 800

Uterus 140 320 600 970

Mammary gland 45 180 360 405

Blood 100 600 1300 1250

Interstitial fluid (no edema or leg edema)

0 30 80 1680

Maternal stores 310 2050 3480 3345

Total weight gained 650 4000 8500 12,500

Data from Hytten F, Chamberlain G, editors: Clinical physiology in obstetrics, Oxford, 1980, Blackwell Scientific, p 221.

C H A P T E R 6 Maternal Physiologic and Immunologic Adaptation to Pregnancy 69

depicted  in  Figure  6-1.  A  maternal shunt,  which  describes the fraction of blood shunted to the myoen- dometrium  and  is  estimated  to  constitute  20%  of  uterine blood flow, is depicted. Similarly, a fetal shunt,  which  supplies  blood  to  the  placenta  and  fetal  mem- branes  and  accounts  for  19%  of  umbilical  blood  flow,  is  shown.  The  maternal­to­fetal  Po2  and  Pco2  gradi- ents are calculated from measurements of gas tensions  in  the  uterine  and  umbilical  arteries  and  veins.  The umbilical vein of the fetus, like the pulmonary vein of the adult, carries the circulation’s most highly oxy­ genated blood.  The  umbilical  venous  Po2  of  about  28 mm Hg  is  relatively  low  by  adult  standards.  This  relatively  low  fetal  tension  is  essential  for  survival  in  utero,  because  a  high  Po2  initiates  physiologic  adjust- ments (e.g., closure of the ductus arteriosus and vaso- dilation of the pulmonary vessels) that normally occur  in the neonate but would be harmful in utero.

Although not involved in respiratory gas exchange, fetal breathing movements are critically involved in lung development and in the development of respira­ tory regulation. Fetal breathing differs from that in the  adult  in  that  it  is  episodic,  sensitive  to  fetal  glucose 

the  cardiac  output.  Unlike  the  lung,  which  consumes  little of the oxygen it transfers, a significant percentage of the oxygen derived from maternal blood at term is consumed by placental tissue.  The  degree  of  func- tional  shunting of  placental blood  past  exchange  sites  is  approximately  tenfold  greater  than  in  the  lung.  A  major  cause  of  this  functional  shunting  is  probably  a  mismatch between maternal and fetal blood flow at the  exchange sites, analogous to the ventilation-perfusion  inequalities that occur in the lung.

The uteroplacental circulation subserves fetal gas exchange.  Oxygen,  carbon  dioxide,  and  inert  gases  cross  the  placenta  by  simple  diffusion.  The  rate  of  transfer is proportional to the difference in gas tension  across  the  placenta  and  the  surface  area  of  the  pla- centa, and the transfer rate is inversely proportional to  diffusion  distance  between  maternal  and  fetal  blood.  The placenta normally does not pose a significant barrier to respiratory gas exchange, unless it becomes separated (abruption placenta) or edematous (severe hydrops fetalis).

The  anatomical  distribution  of  uterine  and  umbili- cal  blood  flow  and  O2  transfer  across  the  placenta  is 

FIGURE 6-1 Placental transfer of oxygen and carbon dioxide. BE, Base excess; Hb, hemoglobin. (Adapted from Bonica JJ: Obstetric analgesia and anesthesia, ed 2, Amsterdam, 1980, World Federation of Societies of Anesthesiologists, p 29.)

Uterine Artery

Uterine blood flow: 700-1200 mL/min Hb concentration: 12 g/dL Oxygen capacity: 16 mL/dL (Total QO2 through uterus: 3.5 mL/min)

PO2

PCO2

Umbilical blood flow: 350-500 mL/min Hb concentration: 15 g/dL Oxygen capacity: 22 mL/dL (Total QO2, 3.5 kg fetus: 2.0 mL/min)

= 100 mm Hg = 15.2 mL/dL = 95% = 32 mm Hg = 7.42 = – 3.0 mEq/L

PO2 CO2 SaO2 PCO2 pH BE

= 18 mm Hg = 8.0 mL/dL = 40% = 55 mm Hg = 7.21 = –9.0 mEq/L

PO2 CO2 SaO2 PCO2 pH BE

Umbilical Artery

Uterine Vein

PO2 = 33 mm Hg CO2 = 10.5 mL/dL SaO2 = 60% PCO2 = 40 mm Hg pH = 7.30 BE = − 6.0 mEq/L

Umbilical Vein

PO2 = 28 mm Hg CO2 = 15.0 mL/dL SaO2 = 70% PCO2 = 45 mm Hg pH = 7.32 BE = − 6.4 mEq/L

70 PA R T 2 Obstetrics

placenta, a double Bohr effect facilitates oxygen transfer from mother to fetus.  When  CO2  and  fixed  acids  are  transferred  from  fetus  to  mother,  the  associ- ated rise in fetal pH increases the fetal red blood cells’  affinity for oxygen uptake. The concomitant reduction  in  maternal  blood  pH  decreases  oxygen  affinity  and  promotes  its  unloading  of  oxygen  from  maternal  red  cells.

Fetal Circulation Several  anatomic  and  physiologic  factors  must  be  noted  in  considering  the  fetal  circulation  (Table  6-6  and Figure 6-3).

The normal adult circulation is a series circuit with  blood flowing through the right heart, the lungs, the left  heart,  the  systemic  circulation,  and  finally  the  right  heart.  In  the  fetus,  the  circulation  is  a  parallel  system  with  the  cardiac  outputs  from  the  right  and  left  ven- tricles directed primarily to different vascular beds. For  example,  the  right  ventricle,  which  contributes  about  65%  of  the  combined  output,  pumps  blood  primarily  through  the  pulmonary  artery,  ductus  arteriosus,  and  descending  aorta.  Only  a  small  fraction  of  right  ven- tricular  output  flows  through  the  pulmonary  circula- tion.  The  left  ventricle  supplies  blood  mainly  to  the  tissues  supplied  by  the  aortic  arch,  such  as  the  brain.  The fetal circulation is a parallel circuit characterized by channels (ductus venosus, foramen ovale, and

concentrations,  and  inhibited  by  hypoxia.  Because  of  its sensitivity to acute O2 deprivation, fetal breathing is  used clinically as an indicator of the adequacy of fetal  oxygenation.

FETAL AND MATERNAL HEMOGLOBIN DISSOCIATION CURVES Most  of  the  oxygen  in  blood  is  carried  by  hemoglobin  in  red  blood  cells.  The  maximum  amount  of  oxygen  carried  per  gram  of  hemoglobin,  that  is,  the  amount  carried  at  100%  saturation,  is  fixed  at  1.37 mL.  The  hemoglobin flow rates depend on blood flow rates and  hemoglobin  concentration.  The  uterine  blood  flow  at  term has been estimated at 700 to 1200 mL/min, with  about  75-88%  of  this  entering  the  intervillous  space.  The umbilical blood flow has been estimated at 350 to  500 mL/min, with more than 50% going to the placenta  (see Figure 6-1).

The  hemoglobin  concentration  of  the  blood  deter- mines its oxygen-carrying capacity, which is expressed  in milliliters of oxygen per 100 mL of blood. In the fetus  at or near term, the hemoglobin concentration is about  18 g/dL  and  oxygen-carrying  capacity  is  20  to  22 mL/ dL. The  maternal oxygen­carrying capacity of blood, which is generally proportional to the hemoglobin concentration, is lower than that of the fetus.

The  affinity  of  hemoglobin  for  oxygen,  which  is  reflected as the percentage saturation at a given oxygen  tension,  depends  on  chemical  conditions.  As  is  illus- trated in Figure 6-2, when compared with that in non­ pregnant adults, the binding of oxygen by hemoglobin is much greater in the fetus under standard condi­ tions of PCO2, pH, and temperature. In contrast, mater- nal  affinity  is  lower  under  these  conditions,  with  50%  of hemoglobin saturated with O2 at a Po2 of 26.5 mm Hg  (P50) for mother compared with 20 mm Hg for the fetus.

In vivo, the greater fetal temperature and lower pH shift the O2­dissociation curve to the right, while the lower maternal temperature and higher pH shift the maternal curve to the left.  As  a  result,  the  O2- dissociation curves for the fetal and maternal blood are  not  too  dissimilar  at  the  site  of  placental  transfer.  Maternal venous blood probably has an O2-saturation  of  about  73%  and  a  Po2  of  about  36 mm Hg,  and  the  corresponding  values  for  blood  in  the  umbilical  vein  are about 63% and 28 mm Hg, respectively. As the only source of O2 for the fetus, blood in the umbilical vein has a higher O2 saturation and PO2 than blood in the fetal circulation  (Figure  6-3).  In  the  presence  of  a  low  fetal  arterial  Po2,  fetal  oxygenation  is  maintained  by  a  high  rate  of  blood  flow  to  fetal  tissues,  which  is  sup- ported  by  a  very  high  cardiac  output.  This  feature,  along with the lower P50 of fetal blood, results in normal  O2 delivery to fetal organs.

The decrease in the affinity of hemoglobin for oxygen produced by a fall in pH is referred to as the Bohr effect. Because of the unique situation in the

FIGURE 6-2 The oxygen dissociation curve for fetal blood com- pared with maternal blood. The central continuous curve is for normal adult blood under standard conditions. A vertical line at an oxygen partial pressure of 30 mm Hg divides the curves. The fetal curve normally operates below that level and the maternal curve above it. (Adapted from Hytten F, Chamberlain G, editors: Clinical physiology in obstetrics, ed 2, Oxford, 1991, Blackwell, p 418.)

0 20 40 60 PO2 mm Hg

80

MOTHERFETUS

100

100

80

60

40

20

O X

Y G

E N

% S

A T

U R

A T

IO N

C H A P T E R 6 Maternal Physiologic and Immunologic Adaptation to Pregnancy 71

FIGURE 6-3 The fetal circulation. Numbers represent approximate values of percentage saturation of blood with oxygen in utero. IVC, Inferior vena cava. (Adapted from Parer JJ: Fetal circulation. In Sciarra JJ, editor: Obstetrics and gynecology, vol 3: maternal and fetal medicine, Hagerstown, Md, 1984, Harper & Row, p 2.)

L. ventricle

R. ventricle

Aorta

Renal v. & a.

Common iliac a.

Hypogastric a.

Umbilical a.

Umbilical cord

Umbilicus

Umbilical v.

Portal v.

Ductus venosus

Right atrium

Placenta

IVC

60

80

Left lung

Ductus arteriosus

Left atrium

Pulmonary a.

Foramen ovale

R. lung

Superior vena cava

65

25

25

55

55

70

60

65

Liver

72 PA R T 2 Obstetrics

to  the  umbilical  arteries,  which  carry  deoxygenated  blood to the placenta.

CHANGES IN THE ANATOMY OF THE CARDIOVASCULAR SYSTEM AFTER BIRTH The following changes occur after birth (see Table 6-6): 1.  Elimination of the placental circulation, with

interruption and eventual obliteration of the umbilical vessels

2.  Closure of the ductus venosus 3.  Closure of the foramen ovale 4.  Gradual constriction and eventual obliteration of

the ductus arteriosus 5.  Dilation of the pulmonary vessels and establish­

ment of the pulmonary circulation The elimination of the umbilical circulation, closure 

of  the  vascular  shunts,  and  establishment  of  the  pul- monary  circulation  will  change  the  vascular  circuitry   of  the  neonate  from  an  “in  parallel”  system  to  an  “in  series” system.

Immunology of Pregnancy Nearly  60  years  ago,  Peter  Medawar  recognized  the  apparent  paradox  of  the  immunologic  evasion  of  the  semiallogeneic fetus by the mother. He proposed three  hypotheses to explain this paradox: (1) anatomic sepa- ration of mother and fetus; (2) antigenic immaturity of  the fetus; or (3) immunologic “inertness” (tolerance) of  the  mother.  In  the  intervening  years,  it has become apparent that both the mother and her fetus are immunologically aware of each other, and yet toler­ ance exists for the most part.  Furthermore,  while  the  maternal immune response during pregnancy is quali- tatively  different,  pregnancy does not result in an overall maternal immunosuppression.

The  growth  and  development  of  a  semiallogeneic  conceptus  within  an  immunologically  competent  mother  depends  on  the  manner  in  which  pregnancy  alters  the  immune  regulatory  mechanisms.  Histori- cally,  attention  in  addressing  the  “Medawar  Paradox”  has  focused  exclusively  on  the  mother,  but  it  is  now  known  that  mammalian fetuses are capable of

ductus arteriosus) and preferential streaming, which function to maximize the delivery of more highly oxy­ genated blood to the upper body and brain, less highly oxygenated blood to the lower body, and very low blood flow to the nonfunctional lungs.

The umbilical vein, carrying oxygenated (80% sat­ urated) blood from the placenta to the fetal body, enters the portal system.  A  portion  of  this  umbilical- portal blood passes through the hepatic microcircula- tion,  where  oxygen  is  extracted,  and  thence  through  the  hepatic  veins  into  the  inferior  vena  cava.  The majority of the blood bypasses the liver through the ductus venosus, which directly enters the inferior vena cava, which also receives the unsaturated (25% saturated) venous return from the lower body. Blood  reaching  the  heart  via  the  inferior  vena  cava  has  an  oxygen  saturation  of  about  70%,  which  represents  the  most  highly  oxygenated  blood  in  the  heart.  Approxi- mately  one-third  of  blood  returning  to  the  heart  from  the inferior vena cava preferentially streams across the  foramen ovale into the left atrium, where it mixes with  the relatively meager pulmonary venous return. Blood  flows  from  the  left  atrium  into  the  left  ventricle,  and  then to the ascending aorta.

The proximal aorta, carrying the most highly satu­ rated blood leaving the heart (65%) gives off branches to supply the brain and upper body. Most of the blood  returning  via  the  inferior  vena  cava  enters  the  right  atrium,  where  it  mixes  with  the  unsaturated  blood  returning  via  the  superior  vena  cava  (25%  saturated).  Right ventricular outflow (O2 saturation of 55%) enters  the aorta via the ductus arteriosus, and the descending  aorta supplies the lower body with blood having less O2  saturation  (about  60%)  than  that  flowing  to  the  brain  and the upper body.

The  role  of  the  ductus  arteriosus  must  be  empha- sized. Right ventricular output enters the pulmonary trunk, from which its major portion, because of the high vascular resistance of the pulmonary circula­ tion, bypasses the lungs by flowing through the ductus arteriosus to the descending aorta.  Although  the  descending  aorta  supplies  branches  to  the  lower  fetal  body, the major portion of descending aortic flow goes 

TABLE 6-6

COMPONENTS OF THE FETAL CIRCULATION

Fetal Structure From/To Adult Remnant

Umbilical vein Umbilicus/ductus venosus Ligamentum teres hepatis

Ductus venosus Umbilical vein/inferior vena cava (bypasses liver) Ligamentum venosum

Foramen ovale Right atrium/left atrium Closed atrial wall

Ductus arteriosus Pulmonary artery/descending aorta Ligamentum arteriosum

Umbilical artery Common iliac artery/umbilicus Superior vesical arteries; lateral vesicoumbilical ligaments

Data from Main DM, Main EK: Obstetrics and gynecology: a pocket reference, Chicago, 1984, Year Book, p 34.

C H A P T E R 6 Maternal Physiologic and Immunologic Adaptation to Pregnancy 73

cells expressing viral antigens together with MHC I.  In  contrast  to  antigens  presented  in  the  context  of  MHC II, a portion of all cellular proteins are expressed on the cell surface of all normal cells in the context of MHC I.  By  this  mechanism,  the  immune  system  can  determine if a cell is producing “self” proteins or if the  cell has been altered (e.g., by virus) to produce foreign  proteins.

Once  CD4+ T  cells  are  activated,  they  can  direct  an  immune  response  by  secreting  proteins  (cytokines)  that activate surrounding cells. By secreting interferon-γ  and interleukin-2 (IL-2), a CD4+ T cell induces a cellular  immune response via CD8+ “killer” T cells. By secreting  IL-4 and IL-5, CD4+ T cells promote B cells to prolifer- ate  and  differentiate  for  immunoglobulin  (antibody)  production.  B cells exposed to antigen for the first time produce IgM. As the affinity of the immunoglobu- lin (antibody) increases, the B cell undergoes a genetic  rearrangement and may produce a variety of different  antibodies.  The  most  specific  are  usually  of  the  IgG  subtype. IgG crosses the placenta and will accumulate  in the fetus.

DEVELOPMENT OF FETAL IMMUNITY The innate immune effector cells first arise from hematopoietic progenitors noted in the blood islands of the yolk sac. By 8 embryonic weeks, the fetal liver becomes the source of these cells, and by 20 weeks, the fetal bone marrow takes over.

Macrophage like cells arise from the yolk sac around 4 weeks, and by 16 weeks, a fetus has the same  number of circulating macrophages as adults but they  are  less  functional.  The  fetus  has  fewer  tissue  macro- phages.  Immature granulocytes can be found in the fetal spleen and liver by 8 weeks. NK cells are detected in the liver by 8 to 13 weeks and complements 2 and 4 by 8 weeks. C1, 3, 5, 7, and 9 are found in the serum  by  18  weeks.  Maternal  complements  do  not  cross  the  placenta  into  the  fetus. The  complement  system  con- tinues  to  mature  after  parturition  and  adult  levels  are  reached  by  1  year  of  age.  Skin,  one  of  the  main  innate  barriers, completes its development 2 to 3 weeks after  birth.

The cellular component of the adaptive immunity, T cells, are also derived from hematopoietic progeni­ tors that are first seen in the blood islands of the yolk sac by 8 weeks. To differentiate into activated T cells, they must first migrate to the thymus gland. The thymus is a relatively large organ in the fetus, and its sole function appears to be to nurture and develop T cells.  After  maturation,  T  cells  develop  into  either  CD4  or  CD8  types  according  to  the  surface  receptor  expressed. By 16 weeks, the thymus contains T cells in  proportion to those found in the adult. In the newborn, the proportion of CD4 helper T cells and CD8 T cells is similar to that in the adult. However, interferon­γ production is less efficient in fetal CD4 helper T cells.

mounting immune responses in utero. The  interplay  between  the  fetal  and  maternal  immune  systems   is  complex  and  is  an  active  area  of  ongoing  investigation.

INNATE AND ADAPTIVE IMMUNITY Mammalian (including human) immune systems have  two fundamental responses: an early “innate” and a later more specific/robust adaptive response.

The innate immune response is the first line of defense, and includes surface barriers (mucosal immu- nity), saliva, tears, nasal secretions, perspiration, blood  and  tissue  monocytes/macrophages,  natural  killer  (NK)  cells,  endothelial  cells,  polymorphonuclear  neu- trophils,  the  complement  system,  dendritic  cells,  and  the  normal  microbial  flora.  The adaptive immune system is composed of cell mediated (T lymphocytes) and humoral responses (B lymphocytes­antibodies).  Activation  of  T  and  consequently  B  lymphocytes  is  critical  for  the  development  of  lifelong  immune  responses.

Through evolution,  innate  immune  cells  have  acquired mechanisms that recognize the foreign nature  of  the  inciting  antigen  and  mount  a  transient  protec- tion within hours. There is no need for major histocom- patibility  complex  (MHC)  molecules.  The epithelial cell interaction with the antigens induces the release of cytokines and chemokines; which attract the mac­ rophages, dendritic cells, and NK cells.  Macrophages  and  neutrophils  then  engulf  and  lyse  the  pathogens,  and  produce  cytokines.  NK  cells  play  the  key  role  in  destroying the virally infected cells. Damaged epithelial  cells  lead  to  the  activation  of  complements.  Comple- ments can directly kill the microbes by punching holes  in  their  membrane  and  indirectly  by  opsonizing  them  to  facilitate  their  phagocytosis.  Complements  also  promote the inflammatory cell recruitment. The cyto­ kines released from the immune cells activate the vascular endothelial cells, thereby increasing perme­ ability, and allowing immune effector cells to pene­ trate into the tissues.

The  critical  link  between  the  innate  immune  response and the adaptive immune response is antigen  presentation.  Foreign  proteins  that  are  phagocytosed  are processed intracellularly and then expressed on the  cell  surface  complexed  with  MHC  II.  Additionally,  the  presenting  cells  provide  critical  secondary  signals  (via  cell  surface  molecules)  that  are  permissive  for  appro- priate  T  cell  activation.  Among the most efficient antigen presenting cells are dendritic cells.

Dendritic cells play a key role in alerting the adap­ tive immune responses.  Immature  dendritic  cells  engulf  the  pathogens,  carry  them  to  the  lymph  nodes  and  present  them  to  CD4+  T-lymphocytes.  These  now  activated T  cells  develop  surface  receptors  for  specific  foreign  antigens  and  undergo  clonal  proliferation.  Cytotoxic (activated) T cells can directly kill target

74 PA R T 2 Obstetrics

placenta and promotes the release of antiinflamma­ tory cytokines such as IL­10.  The  soluble  forms  of  HLA-G  are  found  in  the  blood  of  pregnant  women.  HLA-G  is  thought  to  act  by  suppressing  the  activity  of  uterine NK cells, which normally destroy cells that lack  the expression of MHC I.

Understanding the mechanisms of immune regu­ lation is largely derived from the study of autoim­ mune diseases. Many disease-free individuals possess  potentially  autoreactive  T  cells.  A  variety  of  mecha- nisms regulate the response of CD4+ T cells so that they  do not react against self-antigens. Naive T helper cells  have the potential to become a variety of specialized T  cells. There are now four well-recognized possibilities,  each  with  a  unique  role  and  ability  to  cross  regulate.  TH1 cells  drive  cell-mediated  immunity  by  secreting  IL-2 and interferon-γ. TH2 cells drive humoral reactions  (antibody/B  cell)  by  secreting  IL-4.  Regulatory  T  cells  are regulatory subtypes that suppress ongoing cellular  immune  reactions  via  cell  contact.  Lastly,  there  is  a  newly described proinflammatory population of T cells  (TH17)  that  secrete  IL-17.  These TH17 cells, under normal circumstances, are important for the clear­ ance of parasites, bacteria, and fungi, but under pathologic conditions seem to play a crucial role in the development of autoimmune disease.  One  of  the hallmarks of T cell regulation is the ability of these  specialized  T  cell  populations  to  cross-regulate  each  other.

IMMUNOLOGIC RESPONSE DURING NORMAL PREGNANCY The mother’s immunologic defense system remains intact during pregnancy.  While  allowing  the  fetus  to  grow,  the  mother  must  still  be  able  to  protect  herself  and  her  fetus  from  infection  and  antigenically  foreign  substances.  The nonspecific (innate) mechanisms of the immunologic system (including phagocytosis and the inflammatory response) are not affected by preg­ nancy. The specific (adaptive) mechanisms of the immune response (humoral and cellular) are also not significantly affected. In fact, women with renal trans- plants do not experience any reduction in serious epi- sodes of acute rejection during pregnancy. No significant  change occurs in the leukocyte count. The percentage  of B or T lymphocytes is not appreciably altered, nor is  there  any  consistent  alteration  in  their  performance  during  pregnancy.  Immunoglobulin  levels  do  not  change  in  pregnancy  and  vaccine  responses  are  pre- served. The main question today, is what are the mech- anisms which provide this protection?

There are three reasons to suggest that vitamin D may be an important regulator of the immune system during pregnancy. First, it has been shown that vitamin  D  deficiency  in  women  who  have  renal  transplants  is  associated  with  an  increased  incidence  of  infections  and  an  increased  risk  of  kidney  rejection.  Vitamin  D 

Fetal B cells are first detected in the liver by 8 weeks  and  around  the  second  trimester,  B  cell  production  is  mostly from the bone marrow. Fetal B cells secrete IgG or IgA during the second trimester, but IgM antibod- ies are not secreted until the third trimester. Cord IgM  levels  greater  than  20 mg/dL  suggest  an  intrauterine  infection.  Maternal IgG crosses the placenta as early as the late first trimester, but the efficiency of the transport is poor until 30 weeks.  Significant  passive  immunity can be transferred to the fetus in this manner  and for this reason premature infants are not as well protected by maternal antibodies. IgM, because of its larger molecular size, is unable to cross the placenta.  The other immunoglobulins (IgA, IgD, and IgE) are also  confined  to  the  maternal  compartment,  but  the  fetus  can make its own IgA and IgM.

Physiologically, newborns have higher neutrophil and lymphocyte counts, and the proportion of lym­ phocytes and the absolute lymphocyte count are higher in neonates than in adults.

IMMUNOBIOLOGY OF THE MATERNAL-FETAL INTERACTION Pregnancy poses a special immunologic problem. The  embryo  must  implant  and  cause  a  portion  (placenta)  to  invade  the  uterine  lining  in  order  to  gain  access  to  the maternal circulation for nutrition and gas exchange.  The  maintenance  of  the  antigenically  dissimilar  fetus  in the uterus of the mother is of primary importance in  obstetrics.  The  total  picture  of  immune  regulation  at  the maternal-fetal interface is yet to be elucidated, but  the  following  is  a  synopsis  of  the  current  level  of  understanding.

The  primary  sites  of  modulation  of  the  maternal  response  are  the  decidua  of  the  uterus,  the  regional  lymphatics,  and  the  placenta.  In the uterus, NK cell– mediated inflammation is necessary for the appro­ priate attachment and penetration of the fertilized egg into the uterine wall and for early placental devel­ opment,  whereas  increased  suppressor  T  cells,  the  presence  of  molecules  that  inactivate  the  previously  activated  maternal  lymphocytes  (CTLA4),  and  the  absence  of  B  cells  provide  the  needed  immune  quies- cence to allow for successful pregnancy. The placenta,  decidua, and the membranes provide the key barrier in  protecting the growing fetus from microbial pathogens  and  toxins  circulating  in  the  mother’s  blood.  The syn­ cytiotrophoblast, that makes up the cell barrier between the fetal and maternal blood in the placenta, does not express classic self/nonself MHC I and II molecules.  Deeper  trophoblastic  cells  do  not  express  MHC II, but some express MHC I, which are not stimu- latory. This  allows  protection  from  invading  microbes  but  at  the  same  time  prevents  the  destruction  of  the  fetus.

Human leukocyte antigen G (HLA­G) suppresses the adaptive and innate immune responses in the

C H A P T E R 6 Maternal Physiologic and Immunologic Adaptation to Pregnancy 75

tory  profile  that  could  interfere  with  the  pregnancy,  shifting  it  to  the  adaptive  profile  that  supports  fetal  growth and normal pregnancy development.

Pregnant women are at higher risk of severe infec­ tion and death from certain pathogens such as viruses  (hepatitis, influenza, varicella, cytomegalovirus, polio),  bacteria  (listeria,  streptococcus,  gonorrhea,  salmo- nella, leprosy), and parasites (malaria, coccidioidomy- cosis) compared with nonpregnant women. Vitamin D  supplementation during pregnancy, therefore, may be  important  not  only  to  reduce  the  risk  of  immunologic  fetal rejection, but also to help prevent infection.

supplementation decreases this risk. It is likely that this  applies  to  pregnant  women  too.  Second,  both  the  decidua  surrounding  the  chorion  and  the  placenta  have been shown to produce the active form of vitamin  D, provided that the mother is not vitamin D deficient  of  the  circulating  form  of  vitamin  D  (25[OH]D). Thus,  the  decidua  and  placenta  provide  the  fetus  with  a  natural mechanism of immune surveillance controlled  by  the  availability  of  circulating  vitamin  from  the  mother. Third, recently it has also been shown that the  active  form  of  vitamin  D  stimulates  the  production  of  regulatory  T  cells  that  suppress  the  innate  inflamma-

76

7  Antepartum Care Preconception and Prenatal Care, Genetic Evaluation and Teratology, and Antenatal Fetal Assessment

C H

A P

T ER

CALVIN J. HOBEL • JOHN WILLIAMS III

■  Preconception counseling is an important component of  preventive  care  for  couples  that  are  considering  preg- nancy.  It  can  identify  risks  related  to  family  history,  maternal  medical  conditions,  and  fetal  and  maternal  chromosomal/genetic  disorders  that  may  result  in   congenital  abnormalities.  A  simple  screening  tool   called  Before Pregnancy  is  available  electronically  at  StudentConsult.com  to  facilitate  the  process  of  precon- ception assessment and counseling.

■  Adequate  prenatal  care,  including  nutritional  counsel- ing,  is  essential  for  obtaining  the  best  pregnancy  out- comes.  Early  pregnancy  complications,  secondary  to  factors  related  to  the  mother,  her  fetus,  or  the  placenta,  occur in some pregnancies. Early recognition and man- agement of these problems is vital for the success of the  pregnancy.  During  follow-up  visits,  it  is  important  to  reassure women that their pregnancy is progressing nor- mally or initiate appropriate testing when necessary.

■  Traditionally,  women  older  than  34  years  of  age  have  been  advised  to  have  prenatal  testing  because  they  are  at  increased  age-related  risk  for  having  offspring  with  chromosomal and genetic abnormalities and the risk of  the  more  invasive  techniques  is  less  than  the  risk  of  finding abnormalities. Recently, microarray comparative  genomic  hybridization  (microarray-CGH)  has  been  introduced into clinical practice. There are many submi- croscopic  chromosomal  abnormalities  that  can  now  be  detected  with  microarray-CGH  that  are  not  maternal  age-related.  Current  guidelines  therefore  recommend  that  prenatal  diagnostic  testing  with  amniocentesis  or 

chorionic villus sampling (CVS) be offered to all pregnant  women regardless of their age.

■  A number of noninvasive tests are available for screening  for  fetal  chromosomal  abnormalities.  These  include  second-trimester  maternal  serum  screening  (Quad- Screen), which offers a trisomy 21 detection rate of 81%;  first-trimester  serum  screening  combined  with  ultra- sonic  measurement  of  nuchal  translucency  and  visual- ization  of  nasal  bone,  which  has  a  Down  syndrome  detection  rate  of  93%,  and  integrated  first-  and  second- trimester  screening,  which  increases  the  detection  rate  to  95%.  Recently,  noninvasive  prenatal  testing  (NIPT)  using cell-free fetal DNA from maternal plasma has been  introduced. This less invasive type of prenatal testing has  been  reported  to  have  a  detection  rate  of  >99%  for  trisomy 21 and trisomy 18. False positive rates for these  screening tests have been reported and they should not  be  considered  diagnostic.  CVS  or  amniocentesis  is  required for confirmation (see Chapter 17).

■  Evaluation  of  fetal  well-being  during  pregnancy  starts  with  the  mother’s  “kick  count.”  When  <10  fetal  move- ments are detected in 1 hour on two separate occasions,  nonstress  testing  (NST)  and  ultrasonic  assessment  should  be  performed.  When  the  amniotic  fluid  index  (AFI),  determined  by  ultrasonic  measurement,  is  com- bined  with  fetal  movements,  an  NST,  and  evaluation  of  fetal tone, the assessment is referred to as a biophysical  profile. These techniques have largely replaced the con- traction stress test for antenatal fetal assessment.

CLINICAL KEYS FOR THIS CHAPTER

Pregnancy,  to  many  women,  is  one  of  the  greatest   experiences  of  their  lives.  Even  before  conceiving,   a  woman  may  contemplate  or  ask  whether  her  child  will be normal at birth and whether pregnancy will be  safe for her. Preconception and prenatal counseling by 

the  well-informed  health  care  professional  can  offer   a  sense  of  security  to  these  women  and  deliver  some   of  the  most  cost-effective  preventive  measures  in   all  of  health  care.  The  purpose  of  this  chapter  is  to  provide  the  reader  with  a  basic  understanding  of  the 

C H A P T E R 7 Antepartum Care 77

with obesity, diabetes, or hypertension), 6 months to 1 year before conception is attempted. A more ambi- tious  goal  is  for  all  women  to  participate,  because  not  all “at  risk”  women  will  be  identified  by  obvious  exist- ing comorbidities.

Prenatal Care The  three  basic  components  of  prenatal  care  are  (1)  early  and  continuing  risk  assessment,  (2)  health  pro- motion,  and  (3)  medical  and  psychosocial  interven- tions  and  follow-up.  Risk  assessment  includes  a  complete  history,  a  physical  examination,  laboratory  tests, and assessment of gestational age and well-being  of the mother and her fetus(es). Health promotion con- sists  of  providing  information  on  proposed  care,  enhancing  general  knowledge  of  pregnancy  and  par- enting,  and  promoting  and  supporting  healthful  behaviors. Interventions include the management and  treatment of any existing illness, provision of social and  financial resources if required, and referral to and con- sultation with other specialized providers.

THE FIRST PRENATAL VISIT The first prenatal visit provides an opportunity to review medical, reproductive, family, genetic, nutri- tional, and psychosocial histories.  Women  whose  health may be seriously jeopardized by the pregnancy,  such as those with Eisenmenger syndrome or a history  of  peripartum  cardiomyopathy,  should  be  counseled  about the option of terminating the pregnancy. Repro- ductive  histories  that  include  preterm  birth,  low  birth  weight, preeclampsia, stillbirth, congenital anomalies,  and  gestational  diabetes  are  important  to  record  because  of  the  substantial  risk  of  recurrence. Women  with prior cesarean delivery should be asked about the  circumstances  of  the  delivery,  and  discussion  about  options  for  the  mode  of  delivery  for  the  current  preg- nancy  should  be  initiated.  Additionally,  the impor- tance of screening women for domestic violence cannot be overemphasized. As many as 8-10% of preg- nant  women  are  physically  abused  during  pregnancy,  making  domestic  violence  more  common  than  pre- eclampsia, diabetes, IUGR, and preterm birth.

Standardized  forms  have  been  developed  to  facili- tate overall prenatal risk assessment, and this technol- ogy  has  been  incorporated  into  electronic  health  records  at  some  institutions.  A complete physical examination should be performed including assess- ment of the patient’s body mass index (BMI).  A  woman’s  BMI  can  increase  between  pregnancies  by  20-30%  because  of  excessive  weight  gain  in  the  first  pregnancy. Clinicians should be familiar with physical  findings  associated  with  normal  pregnancy,  such  as  systolic  murmurs,  exaggerated  splitting  and  S3  during  cardiac  auscultation,  or  spider  angiomata,  palmar   erythema,  linea  nigra,  and  striae  gravidarum  on  

appropriate  evaluation  and  the  optimal  care  that  should be provided when a woman is thinking of trying  to conceive, or has become pregnant.

Preconception Care Ideally, “prenatal care” should begin before preg- nancy.  Organogenesis  begins  early  in  pregnancy  and  placental development starts with implantation, about  7  days  after  conception.  Poor placental development has been linked to preeclampsia, preterm birth, and intrauterine growth restriction (IUGR), all of which are associated with low birth weight (<2500 grams), and may play a role in fetal programming of chronic diseases later in life.  This  is  known  as  the  Barker hypothesis  (see  Chapter  1).  In  addition,  obesity has become a world-wide problem associated with meta- bolic  dysregulation,  and  must  be  addressed  before  pregnancy if outcomes are to be improved.

By  the  time  most  pregnant  women  have  their  first  prenatal  visit,  it  is  too  late  to  address  the  risk  of  low  birth weight and obesity, and to reduce the risk of some  birth  defects.  The  growing  recognition  of  the  impor- tance  of  women’s  health  before  pregnancy  has  drawn  increasing attention to the need for more effective and  timely preconception care. Several models of precon- ception care have been developed.  According  to  one  model,  the  major  components  of  preconception  care  include  12  risk  assessments  and  6  health  promotions  and  these  are  summarized  in Table  7-1. To  cover  each  of  the  18  components  would  require  multiple  visits  to  a health care provider, and this is often not acceptable  to young women.

The  major  problem  associated  with  the  implemen- tation  of  preconception  care  is  a  lack  of  consensus   on  the  necessary  components  of  the  care.  For some, preconception care means a single prepregnancy check-up a few months before couples attempt to conceive. A single visit, however, may be inadequate to  address  some  problems  such  as  smoking  cessation  or  attaining and maintaining a healthy weight.

For others, preconception care should become an important part of comprehensive well-woman care, universally implemented from prepubescence to menopause.  In  practice,  however,  asking  providers  to  squeeze more into their already hurried visits may not  be  practical,  and  some  components  (e.g.,  genetic  screening  or  laboratory  testing)  may  not  be  indicated  for  every  woman.  Absence  of  any  preconception  care  will  miss  all  of  those  pregnancies  that  are  unintended  at the time of conception (50% in the United States) but  are continued despite a lack of planning.

In  order  to  address  these  issues,  Before Pregnancy is available electronically at StudentConsult.com and  may  be  used  to  evaluate  women  who  are  planning  a  pregnancy. This type of preconception care should be started, especially in high-risk women (e.g., women

78 PA R T 2 Obstetrics

TABLE 7-1

ELEMENTS OF PRECONCEPTION COUNSELING AND CARE

Major Components of Preconception Care Risk Assessment

Reproductive life plan Ask your patient if she plans to have any (more) children, and how long she plans to wait until she (next) becomes pregnant. Help her develop a plan to achieve those goals.

Past reproductive history Review prior adverse pregnancy outcomes, such as fetal loss, birth defects, low birthweight, and preterm birth, and assess ongoing biobehavioral risks that could lead to recurrence in a subsequent pregnancy.

Past medical history Ask about past medical history, such as rheumatic heart disease, thromboembolism, or autoimmune diseases that could affect future pregnancy. Screen for ongoing chronic conditions such as hypertension and diabetes.

Medications Review current medication use. Avoid category X drugs and most category D drugs unless potential maternal benefits outweigh fetal risks (see Box 7-3). Review use of over-the- counter medications, herbs and supplements.

Infections and immunizations Screen for periodontal, urogenital, and sexually transmitted infections as indicated. Discuss TORCH (toxoplasmosis, other, rubella, cytomegalovirus, and herpes) infections and update immunization for hepatitis B, rubella, varicella, Tdap (combined tetanus, diphtheria and pertussis), human papillomavirus, and influenza vaccines as needed.

Genetic screening and family history Assess risk of chromosomal or genetic disorders based on family history, ethnic background, and age. Offer cystic fibrosis screening. Discuss management of known genetic disorders (e.g., phenylketonuria, thrombophilia) before and during pregnancy.

Nutritional assessment Assess anthropometric (body mass index), biochemical (e.g., anemia), clinical, and dietary risks.

Substance abuse Ask about smoking, alcohol, drug use. Use T-ACE (tolerance, annoyed, cut down, eye opener) or CAGE (cut-down, annoyed, guilty, eye-opener) questions to screen for alcohol and substance abuse.

Toxins and teratogens Review exposures at home, neighborhood, and work. Review Material Safety Data Sheet and consult local Teratogen Information Service as needed.

Psychosocial concerns Screen for depression, anxiety, intimate-partner violence, and major psychosocial stressors.

Physical examination Focus on periodontal, thyroid, heart, breasts, and pelvic examination.

Laboratory tests Check complete blood count, urinalysis, blood type and antibody screen, rubella, syphilis, hepatitis B, HIV, cervical cytology; screen for gonorrhea, chlamydia, and diabetes in selected populations. Consider thyroid-stimulating hormone.

Major Components of Preconception Care Health Promotion

Family planning Promote family planning based on a woman’s reproductive life plan. For women who are not planning on getting pregnant, promote effective contraceptive use and discuss emergency contraception.

Healthy weight and nutrition Promote healthy prepregnancy weight through exercise and nutrition. Discuss macro- and micronutrients including 5-a-day and daily intake of multivitamin containing folic acid (see www.fns.usda.gov/5day).

Health behaviors Promote such health behaviors as nutrition, exercise, safe sex, effective use of contraception, dental flossing, and use of preventive health services. Discourage risk behaviors such as douching, nonseatbelt use, smoking, alcohol and substance abuse.

Stress resilience Promote healthy nutrition, exercise, sleep, and relaxation techniques; address ongoing stressors such as intimate partner violence; identify resources to help your patient develop problem-solving and conflict resolution skills, positive mental health, and relational resilience.

Healthy environments Discuss household, neighborhood, and occupational exposures to metals, organic solvents, pesticides, endocrine disruptors, and allergens. Give practical tips such as how to reduce exposures during commuting or picking up dry cleaning.

Interconception care Promote breastfeeding, back-to-sleep, positive parenting behaviors, and reduce ongoing biobehavioral risks.

C H A P T E R 7 Antepartum Care 79

seling  and  information  about  teratology,  and  provide  advice  on  alleviating  unpleasant  symptoms  during  pregnancy.  Information  about  nutrition,  behavioral  changes  to  expect,  and  the  benefits  of  breastfeeding  should be provided as prenatal care progresses. Clini- cal pelvimetry should be performed sometime before labor begins (see Chapter 8).

Confirming Pregnancy and Determining Viability About 30-40% of all pregnant women will have some bleeding during early pregnancy  (e.g.,  implantation bleeding), which may be mistaken for a period. There- fore,  a  pregnancy  test  should  be  performed  in  all  women  of  reproductive  age  who  present  with  abnor- mal vaginal bleeding.

The pregnancy test detects human chorionic gonadotropin (hCG) in the serum or the urine.  The  most  widely  used  standard  is  the  First  International  Reference  Preparation  (1st  IRP).  The  hCG  molecule  is  first  detectable  in  serum  6  to  8  days  after  ovulation.  A  titer  of  less  than  5 IU/L  is  considered  negative,  and  a  level above 25 IU/L is a positive result. Values between  6  and  24 IU/L  are  considered  equivocal,  and  the  test  should be repeated in 2 days. A concentration of about  100 IU/L is reached about the date of expected menses.  Most qualitative urine pregnancy tests can detect hCG  above 25 IU/L.

It  is  important  to  differentiate  a  normal  pregnancy  from  a  nonviable  or  ectopic  gestation.  In  the  first  30  days  of  a  normal  gestation,  the  level  of  hCG  doubles  every 2.2 days. In patients whose pregnancies are des- tined to abort, the level of hCG rises more slowly, pla- teaus, or declines.

The use of transvaginal ultrasonography has improved the accuracy of predicting viability in early pregnancies.  Using  transvaginal  ultrasonography,  the  gestational sac should be seen at 5 weeks’ gestation or  a  mean  hCG  level  of  about  1500 IU/L  (1st  IRP).  The  fetal  pole  should  be  seen  at  6  weeks  or  a  mean  hCG  level  of  about  5200 IU/L.  Fetal  cardiac  motion  should  be seen between 6 and 7 weeks or a mean hCG level of  about  17,500 IU/L.  The presence of a gestational sac of 8 mm (mean sac diameter) without a demonstra- ble yolk sac, 16 mm without a demonstrable embryo, or the absence of fetal cardiac motion in an embryo with a crown-rump length of greater than 5 mm indi- cates probable embryonic demise. When there is any  doubt  about  these  measurements,  it  is  best  to  repeat  the  evaluation  in  1  week  before  terminating  the  preg- nancy. Using pulse wave Doppler of the heart to deter- mine heart rate is not recommended.

INCIDENCE OF EARLY PREGNANCY LOSS Because  the  incidence  of  conception  is  unknown,   the  incidence  of  spontaneous  abortion  (miscarriage) 

inspection of the skin. During the breast examination,  clinicians  should initiate discussion about breast- feeding.  A  pelvic  examination  should  be  performed,  and  the  appearance  and  length  of  the  cervix  and  the  status of the last Papanicolaou (Pap) smear should be documented, or a new Pap smear obtained.

Prenatal laboratory testing should be undertaken as  outlined in Table 7-1 if not done during preconception  care.  Screening  for,  and  treatment  of  asymptomatic  bacteriuria  significantly  reduces  the  risk  of  pyelone- phritis and preterm delivery.

Women who are Rh negative should receive RhO(D) immune globulin (RhO-GAM) at 28 weeks’ gestation and postpartum, and at any point of care when sen- sitization may occur (e.g., threatened abortion or inva- sive  procedures  such  as  amniocentesis  and  chorionic  villus sampling [CVS]). Rubella vaccination is contra- indicated during pregnancy,  and  pregnant  women  who are found to be seronegative should be vaccinated  immediately postpartum.  Testing for syphilis is man- dated by law in virtually all states. Early diagnosis and  treatment  of  syphilis  can  reduce  perinatal  morbidity.  Women  who  test  negative  for  hepatitis B surface antigen  and  are  at  high  risk  for  hepatitis  B  infection  (e.g.,  health  care  workers)  are  candidates  for  vaccina- tion  before  and  during  pregnancy.  Infants  born  to  women who test positive for hepatitis B surface antigen  should  receive  both  hepatitis  B  immune  globulins  (HBIG) and hepatitis B vaccine within 12 hours of birth,  followed by two more injections of hepatitis B vaccine  in  the  first  6  months  of  life.  With  the  increasing  inci- dence of whooping cough (pertussis) and serious com- plications  in  young  children,  secondary  vaccination  with Tdap (tetanus, diphtheria and acellular pertussis)  vaccine  should  be  given,  ideally  between  27  and  36  weeks of pregnancy.

Voluntary  and  confidential  human immunodefi- ciency virus (HIV ) counseling and testing  should  be  offered  and  documented  in  the  medical  record.  Diag- nosis and treatment significantly reduce the risk of ver- tical  transmission.  Other  tests  such  as  screening  for  sexually  transmitted  infections  (STIs)  like  gonorrhea and chlamydia are generally considered routine.  All  pregnant  women  at  high  risk  for  tuberculosis  (TB)  should  be  screened  with  a  purified  protein  derivative  (PPD)  skin  test  when  they  begin  prenatal  care.  For  women  who  have  received  BCG  (bacillus  Calmette- Guérin) immunization (which can cause a positive test  in the absence of TB), a blood test is available called the  Interferon Gamma Release Assay (IGRA). A positive test  implies that the person has been infected with TB bac- teria.  HIV  and  other  perinatal  (TORCH)  infections  are  also discussed in Chapter 22.

Additionally, the clinician should use the first prena- tal visit to confirm pregnancy and determine viability,  estimate  gestational  age  and  due  date,  diagnose  and  deal  with  early  pregnancy  loss,  provide  genetic  coun-

80 PA R T 2 Obstetrics

Complete Abortion In complete abortion, after passage of all the products of conception,  the  uterine  contractions  and  bleeding  abate, the cervix closes, and the uterus is smaller than  the  period  of  amenorrhea  would  suggest.  Ultrasound  can be used to assess the presence of retained placental  tissue if excessive bleeding continues. In addition, the  symptoms of pregnancy are no longer present, and the  pregnancy test becomes negative.

Missed Abortion The  term  missed abortion  is  used  when  the fetus has died but is retained in the uterus,  usually  for  more  than  6  weeks.  Because  coagulation problems may develop,  fibrinogen  levels  should  be  checked  weekly  until  the  fetus  and  placenta  are  expelled  (spontane- ously) or removed surgically.

Recurrent Abortion Three successive spontaneous abortions usually occur before a patient is considered to be a recurrent aborter. Many clinicians feel that two successive first- trimester losses or a single second-trimester spontane- ous  abortion  is  justification  for  an  evaluation  of  a  couple  for  the  cause(s)  of  the  pregnancy  losses  (see  genetic evaluation section that follows).

ETIOLOGY OF RECURRENT ABORTION Although many factors may result in the loss of a single  pregnancy,  relatively  few  factors  are  present  consis- tently  in  couples  who  abort  recurrently.  Cause  and  effect relationships in individual patients are frequently  difficult to determine.

General Maternal Factors INFECTION. Mycoplasma, Listeria, or Toxoplasma should be specifically sought in women with recurrent  abortions  because  despite  being  found  infrequently,  they are all treatable with antibiotics (see Chapter 22).

SMOKING AND ALCOHOL. Maternal smoking and alcohol  consumption  are  associated  with  an  increased  inci- dence of chromosomally abnormal abortions. Women  who  smoke  20  or  more  cigarettes  daily  and  consume  more  than  seven  standard  alcoholic  drinks  per  week  have  a  fourfold  increase  in  their  risk  of  spontaneous  abortion. There is a doubling of the risk of spontaneous  abortion with as little as two drinks a week.

PSYCHOSOCIAL STRESS. Domestic  violence  and  other  forms  of  stress  are  associated  with  a  greater  risk  of  pregnancy  complications  such  as  spontaneous  abor- tion, preterm birth, and low birth weight.

MEDICAL DISORDERS. Diabetes mellitus, hypothyroid- ism, and systemic lupus erythematosus (SLE)  are 

cannot  be  determined  with  certainty.  Spontaneous abortion occurs in 10-15% of clinically recognizable pregnancies.  The  term  biochemical pregnancy  refers  to  the  presence  of  hCG  in  the  blood  of  a  woman  7  to   10  days  after  ovulation  but  in  whom  menstruation  occurs when expected. In other words, conception has  occurred,  but  spontaneous  loss  of  the  gestation  takes  place  without  prolongation  of  the  menstrual  cycle.  When  both  clinical  and  biochemical  pregnancies  are  considered,  evidence  would  suggest  that  more than 50% of all conceptions are lost, the majority in the 14 days following conception.

Real-time  ultrasonography  has  been  used  exten- sively  to  monitor  the  intrauterine  events  of  the  first  trimester of pregnancy. If a live, appropriately growing fetus is present at 8 weeks’ gestation, the fetal loss rate over the next 20 weeks (up to 28 weeks) is in the order of 3%.

TYPES OF SPONTANEOUS ABORTION The  terms  and  definitions  in  the  remainder  of   this  chapter  refer  only  to  clinically  recognizable  pregnancies.

Threatened Abortion The  term  threatened abortion is used when a preg- nancy is complicated by vaginal bleeding before the 20th week.  Pain  may  not  be  a  prominent  feature  of  threatened abortion, although a lower abdominal dull  ache  sometimes  accompanies  the  bleeding.  Vaginal  examination at this stage usually reveals a closed cervix.  Approximately  one-third  of  pregnant  women  have  some degree of vaginal bleeding during the first trimes- ter,  and  25-50% of threatened abortions eventually result in loss of the pregnancy.  Current  research  sug- gests that there is a continuum of risk between threat- ened  abortion  and  preterm  birth.  Thus,  the  use  of  ultrasound  to  assess  the  location  of  the  placenta  and  the length of the cervix may provide a baseline to help  assess changes after 20 weeks, and may help formulate  a  plan  of  management  to  prevent  early  preterm  birth  (see Chapter 12).

Inevitable Abortion In the case of inevitable abortion, a clinical pregnancy is complicated by both vaginal bleeding and cramp- like lower abdominal pain.  The  cervix  is  frequently  partially dilated, contributing to the inevitability of the  process.

Incomplete Abortion In  addition  to  vaginal  bleeding,  cramp-like  pain,  and  cervical  dilation,  an  incomplete  abortion  involves  the passage of some of the products of conception, often  described  by  the  woman  as  looking  like  pieces  of  skin  or liver.

C H A P T E R 7 Antepartum Care 81

ticularly  with  a  history  of  second  trimester  loss,  is   frequently  successful.  Complete  evaluation  of  the   congenitally  abnormal  uterus  usually  requires  laparo- scopic,  hysteroscopic,  and  hysterographic  examina- tion before any management plan can be made.

The  most  commonly  acquired  abnormalities  of  the  uterus  with  the  potential  to  affect  fecundity  are  sub- mucous fibroids.  Although  these  tend  to  occur  more  frequently  in  women  in  their  late  30s,  they  should  be  considered  when  investigating  pregnancy  loss  in  all  women. Removal of submucous fibroids and intramu- ral  fibroids  larger  than  6 cm  are  associated  with  improved fecundity, especially when there is distortion  of  the  endometrial  cavity.  Subserous  fibroids  do  not  appear to affect fecundity.

Intrauterine adhesions  result  from  trauma  to  the  basal layer of the endometrium from previous surgery  or infection. When most of the uterine cavity has been  obliterated (Asherman syndrome), amenorrhea results.  More  frequently,  fewer  intrauterine  adhesions  (syn- echiae)  are  present,  menses  are  reasonably  normal,  and  the  lesions  are  not  even  suspected  until  a  preg- nancy  is  attempted  and  lost.  Surgical  correction  of  these  intrauterine  adhesions  is  recommended  to  improve fecundity.

Fetal Factors The most common cause of spontaneous abortion is a significant genetic abnormality of the conceptus. In  spontaneous  first-trimester  abortions,  approximately  two-thirds  of  fetuses  have  significant  chromosomal  anomalies,  with  approximately  half  of  these  being  autosomal trisomies and the majority of the remainder  being  triploid,  tetraploid,  or  45,X  monosomies.  Fortu- nately,  the  majority  of  these  are  not  inherited  from  either  mother  or  father  and  are  single  nonrecurring  events.  When seen on ultrasonography before spon- taneous abortion, many such pregnancies appear to consist of an empty gestational sac.  When  a  fetus  is  present  in  many  late  first-trimester  and  early  second- trimester  abortions,  it  is  often  significantly  abnormal,  either  genetically  or  morphologically.  It  seems  that  nature has a way of identifying some of its major mis- takes and causing them to abort.

Placental Factors The  fetus  and  placenta  interact  in  terms  of  genetic   and neuroendocrine differences. For example, the pla- cental genetic structure is composed of genes from the  mother, the father, and even imprinted genes from the  parents of both the mother and father. How these inter- act and support normal development and specific dis- eases is the subject of intense investigation. For example  the placenta expresses an enzyme 11β-hydroxylase that converts cortisol to inactive corticosterone, which protects the fetus from excessive cortisol when

associated with recurrent pregnancy loss. The evidence  linking diabetes mellitus with spontaneous abortion is  not  conclusive,  and  severe  hypothyroidism  is  more  often associated with disordered ovulation than spon- taneous  abortion.  Up to 40% of clinical pregnancies are lost in women with SLE, and such patients have an  increased risk of pregnancy loss before developing the  clinical stigmata of the disease (see Chapter 16).

MATERNAL AGE. If a live fetus is demonstrated by ultra- sonography at 8 weeks’ gestational age, fewer than 2%  of  these  pregnancies  will  abort  spontaneously  when  the mother is younger than 30 years of age. If, however,  she is older than 40 years, the risk exceeds 10%, and it  may  be  as  high  as  50%  at  age  45  years.  The  probable  explanation is the increased incidence of chromosom- ally abnormal fetuses in older women.

Local Maternal Factors Uterine abnormalities,  including  cervical  incom- petence,  congenital  abnormalities  of  the  uterine  fundus  (as  may  result  from  gestational  exposure  to  diethylstilbestrol)  and  acquired  abnormalities  of  the  uterine fundus, are known to be associated with preg- nancy  loss.

Cervical incompetence  occurs  under  a  number  of  circumstances but is usually the result of trauma. This  occurs most frequently from mechanical dilation of the  cervix  at  the  time  of  termination  of  pregnancy,  but  it  may also occur at the time of diagnostic curettage. The diagnosis of cervical incompetence is usually made when a mid-trimester pregnancy is lost with a clinical picture of sudden unexpected rupture of the mem- branes, followed by painless expulsion of the prod- ucts of conception.

There continues to be controversy surrounding cer- vical incompetence, with some experts suggesting that  cervical  incompetence  is,  in  most  instances,  a  variant  of  preterm  delivery,  occurring  at  a  time  when  there  is  an associated finding of asymptomatic ascending infec- tion. The question today in terms of the etiology is what  comes first. Is it infection that causes the problem or is  it  some  form  of  metabolic  dysregulation  that  can  be  identified  early  and  treated  to  prevent  these  changes?  Chapter  12  covers  newer  concepts  of  the  cause(s)  of  early pregnancy loss and preterm birth.

When  cervical  incompetence  is  suspected  during  pregnancy  (e.g.,  history  of  cervical  incompetence  in  a  previous  pregnancy  or  of  cone  biopsy  of  the  cervix),  sequential  ultrasonography  of  the  cervix  indicating  funneling or shortness of the cervix or widening of the  lower uterine segment may identify the problem before  a pregnancy loss occurs.

A congenitally abnormal uterus may be associated  with  pregnancy  loss  in  both  the  first  and  the  second  trimesters. Surgical correction of the abnormality, par-

82 PA R T 2 Obstetrics

and stillbirth. The mechanism is thought to be related  to abnormal uterine muscle function (see Chapter 11).

Incomplete Abortion Until  bleeding  has  stopped  or  is  minimal,  it  is  best  to  insert an intravenous line and take blood for grouping  and cross-matching, as shock may occur from hemor- rhage or sepsis. Once the patient’s condition is stable, the remaining products of conception should be evacuated from the uterus using appropriate pain control.  These  tissues  should  be  sent  for  pathologic  evaluation.  An  incomplete  abortion  that  is  infected  must  be  managed  vigorously.  Delay  in  treatment  may  result  in  overwhelming  sepsis  that  may  lead  to  exces- sive  hemorrhage,  renal  and  hepatic  failure,  dissemi- nated  intravascular  coagulation  (DIC),  and  rarely,  death.

Missed Abortion Suspected  missed  abortion  should  be  confirmed  by  ultrasound to minimize the risk of sepsis and DIC, and  to  reduce  the  extent  of  hemorrhage  and  the  degree  of  pain  that  accompanies  the  spontaneous  expulsive  process. In some studies vitamin D deficiency has been  associated  with  early  pregnancy  loss.  A  proposed  mechanism  is  that  women  with  vitamin  D  deficiency  have  an  altered  immune  system.  Macrophages  do  not  make  the  antibacterial  peptide  cathelicidin,  which  is  important  in  reducing  the  risk  of  infection,  as  well  as  contributing to abnormal muscular function.

General Management Considerations When the patient is Rh negative and does not have Rh  (anti-D) antibodies, prophylactic RhO-GAM should be  administered  (see  Chapter  15).  All  couples  that  have  had  a  pregnancy  loss  should  be  seen  and  counseled  some weeks after the event. At that time, questions that  the couple may have can be answered, the findings of  any  pathologic  studies  discussed,  and  reassurance  given  about  their  chances  of  reproductive  success  in  the future.

Recurrent Abortion As  far  as  the  mother  is  concerned,  it  is  appropriate  to  rule out the presence of systemic disorders such as dia- betes mellitus, SLE, and thyroid disease, and it is also  necessary to test for the presence of a lupus anticoagu- lant. Paternal and maternal chromosomes should be evaluated, and hysteroscopy or hysterography should  be performed to evaluate the uterine cavity.

Over half of couples with recurrent losses will have normal findings during the standard evaluation. With  the information now available on the role of vitamin D  in the health of women, it is recommended that women  also be assessed for vitamin D deficiency.

When  a  specific  etiologic  factor  is  found,  appropri- ate  management  often  leads  to  reproductive  success. 

the mother is stressed. This  enzyme  is  not  turned  on  until 22 to 24 weeks, thus leaving the fetus at risk from  maternal stress before this gestational age. In addition,  genetic polymorphisms have been identified that limit  the  amount  of  this  enzyme  produced,  thus  rendering  the fetus at risk after 22 to 24 weeks.

Women with obesity during pregnancy have a greater risk of developing leptin (a placental peptide) resistance that leads to a greater risk of fetal IUGR,  which  in  turn  programs  the  fetus  for  obesity  during  childhood.  Thus,  it  is  important  for  the  student  to  develop  a  sound  understanding  of  the  role  of  the  pla- centa in fetal and maternal health.

Chromosomal Factors Occasionally,  fetal  chromosomal  abnormalities  occur  as a result of a chromosomal rearrangement (balanced  translocation  or  inversion)  in  either  or  both  parents.  Therefore, karyotyping is important for evaluation of couples suffering from recurrent abortion.

Immunologic Factors A successful pregnancy depends on a number of immu- nologic factors that allow the host (mother) to retain a  genetically  foreign  product  (fetus)  without  rejection  taking place (see Chapter 6). The precise mechanism of  this immunologic anomaly is not fully understood, but  the  immunologic  functioning  of  some  women  as  explained  in  more  detail  in  Chapter  6,  particularly  those  who  abort  recurrently  or  those  who  deliver  pre- maturely,  is  different  from  that  of  women  who  carry  pregnancies to term. Briefly the innate immune system  is  activated  in  early  pregnancy  with  the  production  of  specific  cytokines  that  prevent  early  rejection  of  the  fetus.  Subsequently  during  the  second  half  of  preg- nancy  the  adaptive  portion  of  the  immune  system  is  activated  to  downregulate  the  innate  immune  system  to support the developing fetus.

MANAGEMENT Threatened Abortion A threatened abortion is best managed by an ultrasonic  examination to determine the viability of the fetus. Of those in whom a live fetus is present, 94% will produce a live baby, although the incidence of preterm delivery  in  these  cases  may  be  somewhat  higher  than  in  those  who do not bleed in the first trimester. Once a live fetus has been demonstrated to the couple on ultrasonog- raphy, management consists essentially of reassur- ance;  however  they  should  be  encouraged  to  undergo  first-trimester  screening  for  chromosomal  abnormali- ties such as trisomy 13, 18, or 21. There is no need for  admission  to  hospital,  nor  is  there  any  evidence  that  bed  rest  improves  the  prognosis;  however,  psychoso- cial support is important. Recently, there has been evi- dence  that  women  with  vitamin  D  deficiency  are  at  increased  risk  of  spontaneous  abortion,  preterm  birth 

C H A P T E R 7 Antepartum Care 83

an  affected  child.  Women’s  concerns  and  preferences  vary  based  on  their  personal  beliefs.  Therefore,  the  decision  to  offer  prenatal  screening  and  diagnosis  should no longer be based on maternal age alone.

Additional  indications  for  genetic  counseling  and  prenatal diagnosis are listed in Box 7-1.

CONGENITAL AND HEREDITARY DISORDERS Chromosomal Disorders Chromosomal abnormalities occur in 0.5% of live births, but the incidence associated with spontane- ous abortions is much higher and is estimated to be approximately 50%. The most common chromosomal  abnormalities among live born infants are sex chromo- somal  aneuploidies  (e.g.,  Turner  syndrome  [45,X],  Klinefelter  syndrome  [47,XXY]),  balanced  Robertso- nian  translocations  (translocations  within  group  D  or  between  groups  D  and  G),  and  autosomal  trisomies  (e.g., Down syndrome; Figure 7-1).

Women older than 34 years are at increased risk of giving birth to children with autosomal trisomies (e.g., trisomy 21, 13, or 18) or sex chromosomal abnormalities (e.g., triple X syndrome, Klinefelter syndrome). The overall risk of Down syndrome (trisomy 21) is 1 per 800 live births.  It  increases  to  about 1 per 300 live births for women who are 35 to 39  years of age and to about 1 in 80 for those 40 to 45 years  of age. The incidence of Down syndrome diagnosed at  the  time  of  CVS  or  amniocentesis  is  considerably  higher. In women 35 to 39 years of age, the rate is about  1  in  125;  in  those  40  to  45,  it  is  about  1  in  20. The  dis- crepancy  between  the  rate  of  occurrence  at  delivery  and  that  at  prenatal  diagnosis  is  believed  to  be  due  in  part to fetal loss in the second and third trimester.

Ninety-five percent of cases of Down syndrome are due to meiotic nondisjunctional events leading to 47 chromosomes with an extra copy of chromosome number 21, whereas 4% are due to an unbalanced translocation.  Parents  of  a  child  with  translocation 

Many  of  the  congenital abnormalities of the uterus  can  now  be  diagnosed  using  pelvic  ultrasonography  and may no longer require laparotomy for repair. Cer- vical incompetence is managed by the placement of a  cervical suture (cerclage) at the level of the internal os;  this  suture  is  best  placed  in  the  first  trimester,  once  a  live  fetus  has  been  demonstrated  on  ultrasonography.  The effectiveness of prophylactic cervical cerclage in preventing recurrent loss from cervical incompe- tence has not been conclusively established  (see  Chapter 17).

Estimating Gestational Age and Date of Confinement Gestational age should be determined during the first prenatal visit.  Accurate  determination  of  gestational  age  may  become  important  later  in  pregnancy  for  the  management  of  obstetric  conditions  such  as  preterm  labor,  IUGR,  and  postdate  pregnancy.  Clinical  assess- ment to determine gestational age is usually appropri- ate for the woman with regular menstrual cycles and a  known last menstrual period that was confirmed by an  early  examination.  Estimated  date  of  confinement  (EDC)  or  “due  date”  may  be  determined  by  adding  9  months and 7 days to the first day of the last menstrual  period.

Ultrasonography may also be used to estimate ges- tational age. Measurement of fetal crown-rump length between 6 and 11 weeks’ gestation  can  define  gesta- tional  age  to  within  7  days.  At  12  to  20  weeks,  gesta- tional  age  can  be  determined  within  10  days  by  the  average  of  multiple  measurements  (e.g.,  biparietal  diameter,  femur  length,  abdominal  and  head  circum- ferences). Thereafter,  measurements  become  less  reli- able  with  advancing  gestation  (±3  weeks  in  the  third  trimester).

Patients Who Require Genetic Counseling Ideally, couples should receive preconception coun- seling before they decide to have children, so that genetic disease in the couple or their families may be identified.  Traditionally,  the  major  reason  couples  have  been  referred  for  prenatal  diagnosis  is  advanced  maternal  age.  However,  current clinical guidelines recommend that genetic counseling and invasive pre- natal diagnostic testing for chromosomal abnormali- ties be offered to all couples regardless of maternal age. A woman’s choice of whether to have a diagnostic  test or a screening test is based on many factors, includ- ing  the  risk  that  the  fetus  will  be  affected  with  a  chro- mosomal abnormality, the risk of miscarriage from an  invasive procedure, and the perceived burden of having 

BOX 7-1

INDICATIONS FOR GENETIC COUNSELING AND PRENATAL DIAGNOSIS OTHER THAN AGE

1.  A  previous  child  with  or  a  family  history  of  birth  defects, chromosomal abnormality, or known genetic  disorder

2.  A previous child with undiagnosed mental retardation 3.  A previous baby who died in the neonatal period 4.  Multiple fetal losses 5.  Abnormal serum marker screening results 6.  Consanguinity 7.  Maternal  conditions  predisposing  the  fetus  to  con-

genital abnormalities 8.  A current pregnancy history of teratogenic exposure 9.  A fetus with suspected abnormal ultrasonic findings

10.  A parent who is a known carrier of a genetic disorder

84 PA R T 2 Obstetrics

ously  be  detected  because  the  chromosomal  deletion  in these syndromes is beyond the resolution of banded  chromosomal  analysis.  Syndromes  that  can  be  identi- fied  by  FISH  analysis  include  Prader-Willi,  Angelman,  DiGeorge, and Williams syndromes. Trisomies can also  be identified in interphase cells with FISH probes.

Recently, microarray comparative genomic hybridization (microarray-CGH) has been intro- duced into clinical use. Microarray-CGH is a labora- tory technique that quickly scans through the entire genome.  With  this  technique,  the  patient’s  DNA  and  DNA  from  a  normal  control  are  labeled  with  fluores- cent dyes and applied to a microarray chip with oligo- nucleotide probes. A microarray scanner then measures  the fluorescent signals to detect a gain or loss of patient  DNA. Microarray-CGH can detect all unbalanced chro- mosomal  abnormalities,  including  trisomies  that  are  visible  with  light  microscopy,  as  well  as  minute  chro- mosomal alterations (micro deletions and micro dupli- cations), also known as copy number variants (CNV ) as  small as 200 kb. In comparison, deletions and duplica- tions smaller than 5 mb are not visible under standard  light  microscopy  used  in  karyotyping.  It  has  been  shown that 10-15% of children with normal karyotypes  who  have  intellectual  disability,  autism  spectrum  dis- order,  behavioral  disorders,  or  congenital  anomalies  also  have  a  significant  CNV.  In a recent blinded comparison between standard karyotyping and microarray-CGH in women undergoing prenatal diagnosis with CVS or amniocentesis, 1.7% of preg- nancies with a normal karyotype and normal ultra- sonic findings had a significant CNV.  In  the  future,  microarray-CGH  may  replace  standard  karyotype  in  prenatal diagnostic testing.

Single Gene Disorders Single gene disorders are relatively uncommon. They  follow  the  laws  of  mendelian  inheritance,  and  may  be  passed from generation to generation, as with autoso- mal dominant disorders, or affect siblings without any  family  history,  as  in  autosomal  recessive  disorders.  Males  may  be  affected  as  a  result  of  healthy  females  transmitting  the  abnormal  gene,  as  in  X-linked  reces- sive disorders.

Autosomal Dominant Disorders In autosomal dominant disorders, only one abnor- mal gene is necessary for disease manifestation. The affected individual has a 50% chance of passing the gene and the disorder on to offspring. The unaffected  offspring cannot pass on the gene or the disorder. The  occurrence and transmission of the genes are not influ- enced  by  gender.  A  spontaneous  mutation  of  genetic  material  in  the  germ  cells  of  clinically  normal  parents  can also result in an affected offspring.

The hallmark of autosomal dominant disease is the variable expressivity. It is important to determine  whether a child is affected by a spontaneous mutation 

Down  syndrome  have  rearrangements  between  chro- mosome  21  and  chromosomes  14,  15,  21,  or  22.  The  remaining 1% of individuals with Down syndrome have  the  mosaic  type,  which  consists  of  two  populations  of  cells, one with 46 and one with 47 chromosomes.

A couple who has previously had a child with trisomy  21  (Down  syndrome)  or  with  a  meiotic  nondisjunc- tional type of chromosomal abnormality is believed to  be  at  a  small  but  definite  increased  risk  (about  1%)  of  giving  birth  to  another  child  with  a  chromosomal  abnormality  and  should  be  referred  for  prenatal  diagnosis.

Approximately 1 in 500 individuals carries a bal- anced structural chromosomal rearrangement such as a translocation or inversion. Blood chromosomal studies should be performed on a couple after three or more spontaneous abortions because in approxi- mately 3-5% of such couples, one member is a carrier of a balanced rearrangement. The  recurrence  risk  for  spontaneous abortions, abnormal offspring, or both is  greatly  increased  among  translocation  carriers,  and  it  can be estimated according to the type of translocation  and  which  parent  carries  the  translocation.  For  example,  if  the  mother  carries  a  balanced  14;  21  Rob- ertsonian  translocation,  the  risk  for  a  child  with  an  unbalanced translocation resulting in Down syndrome  is 10-15%. However, if the father carries the transloca- tion,  the  risk  for  an  affected  child  is  2-3%.  These  couples should be alerted to the advisability of prena- tal diagnosis because of their increased risk for having  live  born  children  with  unbalanced  translocations.

Using  fluorescence  in  situ  hybridization  (FISH),  a  labeled  chromosome-specific  DNA  segment  or  probe  is  hybridized  to  metaphase,  prophase,  or  interphase  chromosomes and visualized with fluorescent micros- copy.  FISH  analysis  has  led  to  the  identification  of  a  number  of  genetic  syndromes  that  could  not  previ-

FIGURE 7-1 Karyotype of a patient with Down syndrome (47,XX + 21).

1 2 3 4 5

XX1211109876

1514 17 1816

22212019

13

C H A P T E R 7 Antepartum Care 85

technology, the CF gene has been mapped to chromo- some 7, and a gene deletion (AF508) has been found in  approximately  70%  of  carriers.  More  than  1500  muta- tions  have  been  identified  in  the  CF  gene.  Genetic  counseling is essential in offering CF carrier detection  because  15%  of  carriers  (and  maybe  more  depending  on  ethnic  group)  remain  undetected,  and  the  limita- tions of the testing must be explained. At present, it is  recommended that carrier detection for CF be offered  to all pregnant women. Individuals with a family history  of  CF,  partners  of  identified  CF  carriers,  parents  of  a  fetus  with  ultrasonic  findings  of  an  echogenic  bowel,  and those who donate sperm should be encouraged to  undergo carrier testing.

Sex-Linked Disorders Sex-linked disorders, caused by recessive genes located on the X chromosome, primarily affect males, whereas unaffected (or mildly affected) females carry the deleterious gene. There is no male-to-male trans- mission  of  X-linked  disorders.  Using  gene  mapping  technology,  many  sex-linked  disorders  such  as  Duch- enne muscular dystrophy (DMD) or fragile X syndrome  can  now  be  diagnosed  by  CVS  or  amniocentesis.  X-linked  disorders  can  occur  because  of  new  muta- tions  of  genetic  material  as  a  sporadic  event,  or  from  the inheritance of the X-linked recessive gene from the  carrier mother.

Fragile X syndrome is an X-linked disorder that is the second most common cause of developmental delay after Down syndrome, and the most common form of inherited cognitive delay. It has an incidence  of  1  per  1500  males  and  1  per  2500  females.  Mental  impairment  is  variable  in  heterozygous  females.  The  fragile  X  syndrome  is  caused  by  triplet  repeat  expan- sion  in  the  long  arm  of  the  X  chromosome.  Using  molecular  genetic  techniques,  the  number  of  triplet  repeats  can  be  measured  in  affected  individuals  to  confirm  a  suspected  diagnosis  of  fragile  X  or  fragile  X  carrier  status.  In  women  who  have  a  family  history  of  developmental  delay,  genetic  counseling  is  recom- mended  for  consideration  of  fragile  X  testing  in  the  patient or family member.

Multifactorial Disorders Many birth defects are inherited in a multifactorial fashion, which means that both genes and the environment play a role. Common multifactorial dis- orders include cleft lip or palate, neural tube defects (spina bifida or anencephaly), congenital heart defects, and pyloric stenosis.

Neural tube defects occur in about 1 per 1000 births in the United States. In Northern Ireland, Wales,  and Scotland, the incidence of neural tube defects is 6  to  8  per  1000  births.  Both  anencephaly  (congenital  absence of the forebrain) and spina bifida (open spine) 

or  is  the  product  of  a  parent  with  minimal  expression  of the same gene. A careful history and physical exami- nation of family members, in addition to biochemical,  radiologic,  or  histologic  testing,  may  be  necessary  to  determine the parents’ genetic status.

Some of the common autosomal dominant disor- ders include tuberous sclerosis, neurofibromatosis, achondroplasia, craniofacial synostosis, adult-onset polycystic kidney disease, and several types of mus- cular dystrophy.

Autosomal Recessive Disorders With autosomal recessive disorders, two affected genes must be present for manifestation of the disease. Usually there is no family history, but if a family history exists, siblings of either sex are equally likely to be affected. Consanguineous couples are at an  increased risk for having a child who is homozygous for  a deleterious recessive gene, with subsequent pregnan- cies being at 25% risk for producing a similarly affected  child.

The majority of autosomal recessive disorders (e.g., Tay-Sachs disease, sickle cell disorders, alpha- and beta-thalassemia, cystic fibrosis, and spinomus- cular atrophy, etc.) can be diagnosed prenatally by DNA analysis from amniocytes or chorionic villus cells.

GENETIC SCREENING FOR AUTOSOMAL RECESSIVE DISORDERS Carrier screening programs for autosomal recessive disorders have traditionally focused on high-risk populations, in which the frequency of heterozygotes is greater than in the general population. Screening for Tay-Sachs disease among Eastern European Jewish and French Canadian populations has proved to be particularly successful  in  the  recognition  of  couples  at  25%  risk  for  having  offspring  affected  with  this  fatal  disease.  Table  7-2  lists  selected  autosomal  recessive  disorders  for  which  genetic  screening  has  been initiated.

The most common gene carried by North Ameri- can whites is the cystic fibrosis (CF) gene (carrier fre- quency, 1/25).  With  the  use  of  recombinant  DNA 

TABLE 7-2

SELECTED AUTOSOMAL RECESSIVE DISEASES IN DEFINED ETHNIC GROUPS

Disease Ethnic Group Carrier Frequency

Sickle cell disease Blacks 1/10

Cystic fibrosis Whites 1/25

Tay-Sachs disease Jews, French Canadians

1/30

Thalassemia Mediterraneans, Southeast Asians

1/25

86 PA R T 2 Obstetrics

reduce the risk for Down syndrome, whereas nonvi- sualization (absence) has been associated with an increased risk. The addition of nasal bone assessment  to  nuchal  lucency  measurement  and  serum  biochem- istry  can  increase  the  Down  syndrome  detection  rate  to 93% with a screen positive rate of 5%.

SECOND-TRIMESTER SCREENING Traditionally, a woman was offered the serum triple screening test that measures α-fetoprotein (AFP), hCG, and unconjugated estriol (UE3) at 16 to 20 weeks’ gestation. Amniotic fluid AFP levels are frequently ele- vated  in  blood  samples  of  women  carrying  fetuses  affected  with  neural  tube  defects.  Approximately  80-85% of all open neural tube defects can be detected  by  maternal  serum  AFP  (MSAFP).  In  addition  to  open  neural  tube  defects,  ventral  wall  defects  (gastroschisis  or omphalocele) can cause elevations of MSAFP.

If the MSAFP level is elevated, an ultrasound should be done to rule out multiple gestation, fetal demise, or inaccurate gestational age  (all  of  which  can  give  false-positive  results).  If none of these factors are present, amniocentesis is recommended to deter- mine the amniotic fluid AFP level and to measure acetylcholinesterase (AChE). Acetylcholinesterase is a  protein  that  is  present  only  if  there  is  an  open  neural  tube defect.

An  association  between  low  maternal  serum  AFP  and Down syndrome has been noted. The combination  of low MSAFP, elevated hCG, and low UE3 levels (triple  screen)  has  a  detection  rate  for  Down  syndrome  of  approximately  70%,  with  a  positive  screen  result  in  approximately  5%  of  all  pregnancies.  Low  MSAFP,  low  hCG, and low UE3 levels can also be used to screen for  trisomy  18. With  the  addition  of  inhibin-A  (increased  with Down syndrome), the quadruple screen increases 

are believed to occur before 30 days’ gestation because  of  failure  of  the  neural  tube  to  close.  Newborns  with  anencephaly  are  stillborn  or  die  within  the  first  few  days of life. Newborns with spina bifida have a variable  course, depending on the site of the lesion and whether  it is a meningocele (herniation of the meninges through  an open spinal defect with cord remaining in its usual  position) or a myelocele (herniation of the spinal cord).  Folic  acid  has  been  shown  to  lower  the  risk  of  neural  tube defects, and women who have had an infant with  a neural tube defect should take vitamins plus 4 mg of folic acid daily before conception. Because neural tube closure is complete by 28 days post-conception, initiating folic acid after the first 28 days has no pro- phylactic value.

With multifactorial disorders in general and with neural tube defects in particular, a couple who has had one affected child has an increased risk of approx- imately 3% of having another similarly affected child.

Maternal Ultrasonic and Serum Marker Screening There  are  multiple  approaches  available  for  maternal  screening  for  fetal  aneuploidy.  Traditionally,  second- trimester  screening  has  been  the  standard  approach.  First-trimester  aneuploidy  screening  was  introduced  in  the  late  1990s.  First- and second-trimester screen- ing for aneuploidy using cell-free fetal DNA obtained from maternal plasma was introduced in 2012.

FIRST-TRIMESTER SCREENING A combination of maternal age, fetal nuchal translu- cency (NT) thickness and maternal serum-free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) are included in the first-trimester screen.  Maternal  age  alone has only a 30% detection rate. In the early 1990s  an  association  was  reported  between  fetal  chromo- somal abnormalities and the finding of an abnormally  increased nuchal translucency (an echo-free area at the  back  of  the  fetal  neck)  between  10  and  14  weeks’  ges- tational  age  (Figure  7-2).  Increased  nuchal  translu- cency  has  been  associated  with  both  chromosomal  abnormalities  and  other  congenital  anomalies.  Ele- vated levels of free β-hCG and low levels of plasma protein-A are associated with an increased risk for Down syndrome.  A  multicenter  study  in  the  United  States  reported  that  combining  first-trimester  mater- nal serum screening markers with nuchal translucency  and  maternal  age  showed  a  detection  rate  for  Down  syndrome of 79%, with a positive screening rate of 5%.  Anatomic  and  radiographic  studies  have  shown  absence  or  hypoplasia  of  the  nasal  bones  in  fetuses  with Down syndrome. Visualization of the nasal bone on first-trimester ultrasound has been shown to

FIGURE 7-2 Ultrasonic image of fetal head at 12 weeks and 0 days showing a lucent area at the posterior aspect of the fetal neck that can be measured. Normal values for this measurement and the risk associated with abnormal measurements are based on gestational age as determined by crown-rump length.

Nuchal fold measurement

C H A P T E R 7 Antepartum Care 87

ties  (45,X;  47,XXX;  47,XXY;  47,XYY).  There  are  many  other cytogenetic abnormalities that may be present in  addition  to  those  abnormalities  that  can  be  detected  with  NIPT.  False positive rates for NIPT have been reported  to  be  as  high  as  7%  for  trisomy  21,  36%  for  trisomy  18,  56%  for  trisomy  13,  and  60%  for  the  sex  chromosomal  abnormalities.  Thus, a positive NIPT result must be confirmed by a diagnostic test (amnio- centesis or CVS). Diagnostic tests provide a full karyo- type  analysis.  A  karyotype  is  a  genome-wide  test  that  evaluates  all  23  pairs  of  chromosomes  for  size,  shape,  and  banding  patterns,  to  detect  numerical  and  struc- tural  chromosomal  abnormalities.  The  karyotype  detects  a  much  broader  spectrum  of  chromosomal  abnormalities than a specific test for trisomy 21, 18, or  13. Although diagnostic tests are associated with a risk  for pregnancy loss, this risk is quite low in the hands of  experienced operators.

In  summary,  NIPT  screening  can  be  offered  to  women  who  are  at  risk  for  fetal  aneuploidy.  However,  it  should  only  be  offered  to  the  patient  after  pretest  counseling  that  includes  a  discussion  of  the  advan- tages  and  disadvantages  of  screening  and  diagnostic  tests.  In  addition,  a  family  history  should  be  obtained  to determine if the patient needs a prenatal diagnostic  test for an inherited genetic disorder.

Genetic counseling is an essential component of screening programs. It provides education and allevi- ates  anxiety  in  patients  with  abnormal  test  results.  Patients  must  be  informed  of  the  differences  between  screening results and diagnostic testing.

Diagnostic Procedures Recombinant DNA technology coupled with first- trimester fetal tissue sampling has enhanced the growth and development of prenatal diagnosis.  Obstetric procedures, such as ultrasonography, amnio- centesis, CVS, and cordocentesis (percutaneous umbil- ical blood sampling [PUBS]) are currently used during  prenatal  diagnosis.  These  procedures  are  described  and discussed in Chapter 17.

Teratology A teratogen is any agent or factor that can cause abnormalities of form or function (birth defects) in an exposed fetus.  Such  abnormalities  include  fetal  wastage  and  IUGR,  malformations  due  to  abnormal  growth  and  morphogenesis,  fetal  and  placental  endo- crine disruption, and abnormal central nervous system  performance.

It was not until the teratogenic effects of rubella infection were demonstrated in 1941 that any notable consideration was given to environmental factors and their potentially deleterious effects on human preg- nancy. In the succeeding decades, the susceptibility of 

the Down syndrome detection rate to 81% with a posi- tive screen result in 5% of pregnancies.

COMBINED FIRST- AND SECOND-TRIMESTER SCREENING In an attempt to improve the detection rate and mini- mize the screen positive rate and the number of inva- sive procedures, a few studies have been conducted to  evaluate  the  concept  of  combining  first-  and  second- trimester  screening.  The approaches that have been proposed include integrated screening and sequen- tial screening.

INTEGRATED SCREENING. With integrated screening, the  first- and second-trimester results are combined into a  single risk calculation, and are not reported until after  the  second-trimester  results  are  available.  This  approach has been found to have the highest sensitiv- ity and to be the most cost effective.

SEQUENTIAL SCREENING. This  involves  performance  of  both  first-  and  second-trimester  screening,  with   disclosure  of  the  first-trimester  results  for  clinical  management.

It is not uncommon for one or more of the bio- markers to be abnormal in the presence of a chromo- somally normal fetus.  An  elevated  level  of  β-hCG  or  AFP and low levels of PAPP-A or estriol (UE3) are asso- ciated with complications of pregnancy such as preterm  birth,  IUGR,  and  preeclampsia.  Thus,  these  pregnan- cies require close follow up.

Noninvasive prenatal testing (NIPT) using cell-free fetal DNA from maternal plasma: The quest to develop  an early definitive prenatal diagnostic test that is non- invasive  has  been  ongoing  for  more  than  40  years.  Initial  efforts  for  noninvasive  prenatal  diagnosis  were  directed at isolation of intact fetal cells from maternal  blood,  which  can  be  achieved  as  early  as  10  weeks’  gestational age. However, very few fetal cells are present  (1  fetal  cell  per  105  to  107  maternal  cells),  and  in  most  studies,  the  fetal  cell  yield  has  been  inconsistent.  Although  basic  work  has  demonstrated  the  biologic  availability of fetal cells for prenatal diagnosis, a practi- cal  technology  for  consistent  recovery  and  assay  has  not yet been developed.

The presence of cell-free fetal DNA (ffDNA) in maternal plasma was first reported in 1997.  The  source  of  ffDNA  is  from  apoptosis  of  trophoblast  cells  that  have  entered  the  maternal  circulation.  Detection of ffDNA in maternal plasma can be done as early as 9 to 10 weeks.  It  comprises  3-10%  of  total  maternal  plasma DNA at the end of the first trimester. A variety  of  methods  are  available  for  detection  of  fetal  trisomy  with  ffDNA.  Detection rates of 99.4%, 99.1%, and 91.7% have been reported for trisomy 21, trisomy 18, and trisomy 13, respectively. Detection rates of 96.2% have been reported for sex chromosome abnormali-

88 PA R T 2 Obstetrics

systems are affected.  Unfortunately,  most  women  do  not  realize  they  are  pregnant  until  this  critical  period  of  development  is  well  under  way.  From  about  the  fourth  month  of  pregnancy  to  the  end  of  gestation,  embryonic development consists primarily of increas- ing organ size. With the exception of a limited number  of  tissues  (brain  and  gonads),  teratogenic  exposure  after the fourth month usually causes decreased growth  without  malformation.  Very  little  attention  has  been  directed  toward  the  role  of  a  combination  of  factors  such  as  a  deficiency  in  folic  acid  along  with  the  pres- ence of a drug or chemical substance.

Nature of Teratogenic Agents Although  few  agents  are  known  to  cause  serious  mal- formations  in  a  large  proportion  of  exposed  individu- als,  there are probably hundreds of potentially teratogenic agents, given the right set of circum- stances (susceptible fetus, embryologically vulnerable  period,  large  teratogenic  dose).  Furthermore,  certain  drugs  combined  with  other  drugs  may  be  capable  of  producing  malformations,  although  neither  agent  would be teratogenic when taken alone.

TERATOGENIC AGENTS Teratogens may be assigned to three broad catego- ries: (1) drugs and chemical agents, (2) infectious agents, and (3) radiation.  The  list  that  follows  is  far  from exhaustive.

Alcohol The adverse effects of ethyl alcohol on fetal develop- ment were not fully realized until the 1970s. The fre- quency  of  the  fetal  alcohol  syndrome  runs  as  high  as  0.2%,  whereas  an  additional  0.4%  of  newborns  show  less severe features of the disorder (Box 7-2).

Antianxiety Agents Antianxiety  agents  are  currently  used  by  a  significant  number of pregnant women. Data regarding their tera- togenicity  are  conflicting,  although  exposure to mep- robamate or chlordiazepoxide has been associated with a greater than fourfold increase in severe con- genital anomalies. Fluoxetine is now the drug of choice  for  anxiety  and  depression  during  pregnancy  and  is  considered  safe  to  continue  even  in  women  who  breastfeed. The risk of recurrence of significant depres- sion during pregnancy is too great to routinely discon- tinue  treatment  during  pregnancy.  The  recent  data  suggesting that there is an association between vitamin  D  deficiency  and  the  risk  of  postpartum  depression  suggests that supplementation with vitamin D3 during  pregnancy may reduce the use of antianxiety agents.

Antineoplastic Agents Aminopterin and methotrexate, both of which are folic acid antagonists, have been clearly established

the  fetus  to  many  environmental  factors  has  been  appreciated.

Probably the best known teratogen is thalidomide,  which has been shown to cause phocomelia and other  malformations  in  the  offspring  of  mothers  who  had  been  given  the  drug  during  pregnancy.  It  is  the  only  example  of  a  teratogen  that,  when  introduced  to  the  pregnant  population,  led  to  a  dramatic  epidemic  of  a  specific malformation; withdrawal of the drug led to a  virtual disappearance of the malformation.

Although drugs are the most obvious source for tera- togenic  exposure,  chemical  waste  disposal,  alcohol,  tobacco,  cosmetics,  and  occupational  agents  contain  substances that individuals are exposed to, such as fer- tilizers  and  insecticides.  Some  of  these  agents  are  known  teratogens,  whereas  the  fetal  effects  of  others  are not known.

EXPOSURE Results  of  the  Collaborative  Perinatal  Project  indicate  that  more  than  900  different  drugs  are  taken  by  preg- nant  women  in  the  United  States  and  that  40%  of  women  take  medication  during  the  first  trimester,  when  organogenesis  is  occurring.  During  the  first  tri- mester  alone,  as  many  as  32%  of  pregnant  women   are  exposed  to  analgesics  (mostly  aspirin),  18%  to  immunizing agents, 16% to antimicrobial and antipar- asitic  agents,  and  6%  to  sedatives,  tranquilizers,  and  antidepressants.

PRINCIPLES OF TERATOLOGY Fetal Susceptibility The efficacy of a particular teratogen is, in part, depen- dent on the genetic makeup of both mother and fetus,  as well as on a number of factors related to the maternal- fetal  environment.  For  instance,  many  congenital  abnormalities,  such  as  oral  clefts,  congenital  heart  disease, and neural tube defects, are inherited through  multifactorial inheritance.

Dose Depending on the particular teratogen, there may be (1) no apparent effect at a low dose, (2) an organ- specific malformation at an intermediate dose, or (3) a spontaneous abortion at a high dose.  Additionally,  smaller  doses  administered  over  several  days  may  produce a different effect from a single large dose.

Timing Three stages of teratogenic susceptibility may be identified on the basis of gestational age. Before implantation (1 week postovulation in humans), there is no demonstrable teratogenic insult. The most vulnerable stage is between day 17 to day 56 postcon- ception or from approximately 4 weeks to 10 weeks by  gestational  age,  during  the  period  of  organogenesis.  The timing determines which organ system or

C H A P T E R 7 Antepartum Care 89

tion syndrome has been described, these abnormalities  may  be  more  closely  related  to  the  maternal  disease  necessitating the heparin use.

Anticonvulsants Approximately 1 in 200 pregnant women is epileptic.  Box 7-3 lists the etiologic factors that may play a role in  the  congenital  abnormalities  associated  with  in  utero  exposure to anticonvulsants. The complexity in provid- ing genetic counseling for pregnant epileptic women is  underscored  when  considering  the  interactive  effects  of  combined  anticonvulsant  treatment,  the  genetic  aspects of the disease itself, and the mother’s epilepsy.  The  goals  of  counseling  include  providing  the  patient  with the teratogenic risks of her medication, the risk of  seizures during pregnancy, and the effect of pregnancy  on  seizures.  From  a  medication  standpoint,  the  bene- fits  of  seizure  prevention  need  to  be  weighed  against  the teratogenicity of the drug.

DIPHENYLHYDANTOIN (DILANTIN). A specific syndrome, known as the fetal hydantoin syndrome, has been described,  the  clinical  features  of  which  include  craniofacial  abnormalities,  limb  reduction  defects,  prenatal-onset  growth  restriction,  mental  deficiency,  and  cardiovascular  anomalies.  Approximately  10%  of  exposed  fetuses  demonstrate  fetal  hydantoin  syn- drome,  whereas  an  additional  30%  may  have  isolated  features of the syndrome.

OXAZOLIDINEDIONE ANTICONVULSANTS. Trimethadi- one (Tridione) and paramethadione (Paradione), used to treat petit mal epilepsy, have been associated with a characteristic malformation syndrome in exposed fetuses.  The  clinical  features  include  cranio- facial abnormalities, prenatal-onset growth restriction,  an increased frequency of mental retardation, and car- diovascular abnormalities. Because of this serious tera- togenic potential and because petit mal epilepsy is rare  during reproductive years,  oxazolidinedione anticon- vulsants are contraindicated during pregnancy.

VALPROIC ACID. Valproic acid use during pregnancy is associated with a 1-2% risk of open spina bifida. 

as teratogens.  Exposure  before  40  days’  gestation  is  lethal  to  the  embryo;  later  exposure  during  the  first  trimester  produces  fetal  effects,  including  IUGR,  cra- niofacial anomalies, abnormal positioning of extremi- ties,  mental  retardation,  early  miscarriage,  stillbirth,  and neonatal death.

Alkylating agents,  including  busulfan,  chlorambu- cil,  cyclophosphamide,  and  nitrogen  mustard,  have been associated with fetal anomalies  such  as  severe  IUGR,  fetal  death,  cleft  palate,  microphthalmia,  limb  reduction  anomalies,  and  poorly  developed  external  genitalia.  During the first trimester, the teratogenic risks may be as high as 30%.

Anticoagulants COUMARIN DERIVATIVES. Use of warfarin (Coumadin) during the first trimester is associated with an increased risk of spontaneous abortion, IUGR, central nervous system defects (including mental retarda- tion), stillbirth, and a characteristic syndrome of craniofacial features known as the fetal warfarin syndrome.  Embryologically,  the  most  vulnerable  time  appears to be between 6 and 9 weeks after conception.  Warfarin  easily  crosses  the  placenta,  causing  bleeding  problems in the fetus, and is excreted in breast milk.

HEPARIN. Heparin has major advantages over Couma- din anticoagulants during pregnancy because it does not cross the placenta. Reported risks include prema- turity and fetal demise. Because no specific malforma-

BOX 7-3

ETIOLOGIC FACTORS THAT MAY PLAY A ROLE IN ANTICONVULSANT TERATOGENICITY

Antiepileptic Drugs Dose, serum levels, metabolism, teratogenicity, metabolic 

interactions

Genetic Predisposition Maternal, paternal, and fetal metabolism

Maternal Disease Teratogenicity, underlying disease, seizures

BOX 7-2

CLINICAL FEATURES OF FETAL ALCOHOL SYNDROME

Craniofacial Eyes: Short palpebral fissures, ptosis, strabismus, epican-

thic folds, myopia, microphthalmia Ears: Poorly formed concha, posterior rotation Nose: Short, hypoplastic philtrum Mouth:  Prominent  lateral  palatine  ridges,  micrognathia, 

cleft lip or palate, faulty enamel Maxilla: Hypoplastic

Cardiac Murmurs,  atrial  septal  defect,  ventricular  septal  defect, 

tetralogy of Fallot

Central Nervous System Mild-to-moderate mental retardation, microcephaly, poor 

coordination, hypotonia

Growth Prenatal-onset growth deficiency

Muscular Hernias of diaphragm, umbilicus, or groin

Skeletal Pectus  excavatum,  abnormal  palmar  creases,  nail  hypo-

plasia, scoliosis

90 PA R T 2 Obstetrics

effects are related to the extent of maternal exposure to  tobacco and include an increased risk for spontaneous  abortion, fetal death, neonatal death, and prematurity.  Pregnant  women  should  be  strongly  encouraged  to  avoid  smoking  (or  second-hand  smoke).  They  should  continue  to  abstain  after  delivery  because  second- hand  smoke  exposure  is  associated  with  an  increased  risk of respiratory diseases in infants and children.

ILLICIT DRUGS. Prenatal cocaine exposure, particu- larly among chronic abusers, has been associated with fetal malformations,  particularly  genitourinary  tract  anomalies,  and  behavioral  abnormalities  have  also been documented in such fetuses.

INFECTIOUS AGENTS. The exact frequency of significant  infection during pregnancy is not known, but it is prob- ably  between  15%  and  25%.  Viruses, bacteria, and parasites may have serious effects on the fetus, including fetal death, growth delay, congenital mal- formations, and mental deficiency.  In  more  recent  years, the AIDS epidemic has had a significant impact  on pregnancy management. With the now known asso- ciation between vitamin D deficiency and risk of infec- tions, vitamin D deficiency should be considered as an  associated factor in the risk of malformations.

RADIATION. Prenatal  ionizing  radiation  exposure  occurs frequently as a result of therapeutic or diagnos- tic medical and dental procedures. The medical effects of ionizing radiation are dose-dependent and include teratogenesis, mutagenesis, and carcinogenesis.  The  most  critical  period  appears  to  be  from  about  2  to  6  weeks after conception. Exposures before 2 weeks will  either produce a lethal effect or produce no effect at all.  Teratogenicity is still a possibility after 5 weeks, but the  risk  for  deleterious  consequences  is  relatively  small.  Diagnostic levels of radiation do not produce a tera- togenic risk in the developing fetus.

Advice during Pregnancy One  of  the  most  important  functions  of  prenatal  care  is  to  provide  information  and  support  to  the  woman   for  self-care.  The  Cochrane  pregnancy  and  childbirth  database (www.cochrane.org) has compiled systematic  reviews on the effectiveness of advice and interventions  during pregnancy and can be a useful source of infor- mation  for  prenatal  care  providers. The  following  sec- tions will examine advice given on alleviating unpleasant  symptoms, nutrition, lifestyle, and breastfeeding.

ALLEVIATING UNPLEASANT SYMPTOMS Nausea and vomiting complicate up to 70% of preg- nancies.  Eating  small,  frequent  meals,  and  avoiding  greasy  or  spicy  foods  may  help.  Also,  having  protein  snacks  at  night,  saltine  crackers  at  the  bedside,  and 

Other findings reported to be associated with valproic  acid exposure include cardiac defects, skeletal defects,  and craniofacial malformations.

CARBAMAZEPINE. As with valproic acid, carbamaze- pine (Tegretol) exposure during pregnancy is associ- ated with an increased risk for fetal spina bifida and is an indication for amniotic fluid AFP analysis. Some  studies have reported a specific malformation pattern  that  includes  minor  craniofacial  defects,  fingernail  hypoplasia,  and  developmental  delay,  which  are  fea- tures that would be unlikely to be detected prenatally.

PHENOBARBITAL. The  true  teratogenicity  of  phenobar- bital  is  difficult  to  assess  because  other  drugs  are  usually  taken  in  combination  with  this  agent,  but  the  risk appears to be very low. Potential complications of phenobarbital include neonatal withdrawal symp- toms and neonatal hemorrhage.

Hormones ESTROGEN/PROGESTIN COMBINATIONS. A  large  number  of  pregnant  women  are  exposed  to  progestins  or  progestin/estrogen  combinations  because  they  con- tinue  taking  birth  control  pills,  unaware  that  they  are  pregnant.  Recent  analyses  have  failed  to  confirm  any  teratogenicity,  and  the  United  States  Federal  Drug  Administration  (FDA)  has  removed  the  product  insert  warnings.  The main abnormality associated with the use of strongly androgenic progestins during preg- nancy is masculinization of the external genitalia in female fetuses, with a risk of up to 2%.

Miscellaneous Agents RETINOIDS. Isotretinoin  (Accutane)  is  prescribed  for  cystic acne or for acne that has not responded to other  forms  of  treatment.  Exposure during pregnancy is clearly associated with a specific malformation pattern that includes central nervous system, cardio- vascular, and craniofacial defects (especially ear abnormalities).  The  central  nervous  system  findings  include hydrocephaly, facial nerve palsies, and cortical  blindness.  Microcephaly,  with  severe  ear  anomalies,  microtia,  and  cleft  palate  are  common  findings.  The risk of spontaneous abortion or congenital malfor- mations is greater than 50% in patients who take isotretinoin throughout the first trimester.

Etretinate, used for severe psoriasis, has been simi- larly associated with a characteristic malformation pattern. However, unlike isotretinoin, which has a half- life  of  less  than  1  day,  etretinate  has  a  half-life  of  months,  leading  to  a  longer  risk  period  even  after  the  agent has been discontinued.

TOBACCO SMOKING. Maternal tobacco smoking inter- feres with prenatal growth, including birth weight, birth length, and head circumference. The teratogenic 

C H A P T E R 7 Antepartum Care 91

The appropriate weight gain range (based on pre- pregnancy BMI) during the second and third trimes- ters of pregnancy is listed in Table 7-3.

Inadequate weight gain has been associated with low birth weight.  Women  should  avoid  fasting  (>13  hours  without  food)  or  skipping  meals.  This  behavior  is associated with accelerated ketosis and a greater risk  of preterm delivery. They should eat five times per day  (breakfast, lunch, afternoon snack, dinner, and bedtime  snack).  Pregnant  women  should  never  skip  breakfast.  Excessive weight gain has been associated with fetal macrosomia.  Maternal  obesity  may  occur  over  time  between  pregnancies  because  of  the  difficulty  that  some  women  have  returning  to  prepregnancy  body  weight. This is especially true when a woman chooses  not to breastfeed her infant.

Although weight gain is an important consideration  during pregnancy, the clinician should emphasize the “right amount of nutrition” over the “right amount of weight gain.”  Normal  pregnancy  requires  an  increase  in daily caloric intake of 300 kcal.

LIFESTYLE ADVICE Women should be advised to rest when tired and reas- sured that the fatigue usually abates by the fourth month of pregnancy.  Normal  prepregnancy  activity  levels  are  usually  acceptable.  Advice  regarding  work  should be individualized to the nature of the work, the  health  status  of  the  woman,  and  the  condition  of  the  pregnancy.  Work  that  requires  prolonged  standing,  shift or night work, and high cumulative occupational  fatigue  has  been  associated  with  an  increased  risk  for  low birth weight and prematurity. Where working con- ditions involve occupational fatigue or stress, a change in work conditions during pregnancy should be recommended.

The increase in the use of mobile devices has allowed  women  to  network  and  access  mobile  applications  (APPs)  which  can  provide  information  about  preg- nancy.  In  addition,  establishing a network of friends  before  pregnancy  allows  women  to  share  information 

room-temperature  sodas  are  nonpharmacologic  approaches that may provide some relief. Where medi- cation is deemed necessary, antihistamines appear to be the drug of choice,  though  no  single  product  has  been  satisfactorily  tested  for  efficacy  and  safety.  Vitamin B6 (pyridoxine) and accupressure (“sea sick- ness arm bands”) may be effective. Patients with dehy- dration  and  electrolyte  abnormalities  from  vomiting  (hyperemesis  gravidarum)  should  be  evaluated  for  possible  secondary  causes,  and  they  may  need  hospi- talization for rehydration and antiemetic therapy.

Heartburn affects about two-thirds of women at some stage of pregnancy, resulting from progesterone- induced relaxation of the esophageal sphincter. Avoid- ing  lying  down  immediately  after  meals  and  elevating  the head of the bed may help reduce heartburn. When  these  simple  measures  fail,  antacids,  such  as  calcium  carbonate, should be used.

Constipation is a troublesome problem for many women in pregnancy, secondary to decreased colonic  motility.  Dietary  modification,  including  increased  fiber  and  water  intake,  can  help  lessen  this  problem.  Stool  softeners  may  be  used  in  combination  with  bulking agents. Irritant laxatives should be reserved for  short-term use in refractory cases.

Hemorrhoids  are  caused  by  increased  venous  pressure  in  the  rectum.  Increased  rest,  with  eleva- tion  of  the  legs,  and  avoidance  of  constipation  are  recommended.

Leg cramps are experienced by almost half of all pregnant women, particularly at night and in the later months of pregnancy.  Massage  and  stretching  may afford some relief during an attack. Both calcium  and  sodium  chloride  supplementation  appear  to  help  reduce  leg  cramps  in  pregnancy.  Recently,  vitamin  D  deficiency  in  both  men  and  women  has  been  associ- ated with leg cramps and muscle pain. Because recent  evidence suggests at least 40% of women during preg- nancy are vitamin D deficient, vitamin D supplementa- tion  at  1000  to  2000 IU/day  is  recommended.  Daily  requirements  are  400  to  600 IU/day,  which  is  the  amount of vitamin D in prenatal vitamins, so prenatal  vitamins will not correct the deficiency.

Backaches are common during pregnancy and are  lessened  by  avoiding  excessive  weight  gain.  Addition- ally,  exercise,  sensible  shoes,  and  specially  shaped  pillows  can  offer  relief.  In  cases  of  muscle  spasm  or  strain,  analgesics  (such  as  acetaminophen),  rest,  and  heat may lessen the symptoms.

NUTRITIONAL COUNSELING While  the  nutritional  care  plan  should  be  individual- ized, every woman can benefit from nutritional educa- tion  that  includes  counseling  on  weight  gain,  dietary  guidelines, physical activity, avoidance of harmful sub- stances  and  unsafe  foods,  and  the  importance  of  breastfeeding.

TABLE 7-3

APPROPRIATE WEIGHT GAIN IN PREGNANCY

BMI Recommended Weight Gain (lb)

Underweight <19 28-40

Normal 19-25 25-35

Overweight 25-29.5 15-25

Obese ≥30.0 11-20

Institute of Medicine of the National Academies of Science: Weight gain during pregnancy: reexamining the guidelines, May 28, 2009. Available at www.iom.nationalacademies.com/weightgainduringpregnancy. BMI, Body mass index.

92 PA R T 2 Obstetrics

FOLLOW-UP VISITS Prenatal visits should be scheduled every 4 weeks until 28 weeks’ gestation, every 2 to 3 weeks until 36 weeks, and then weekly until delivery. The schedule of  these  follow-up  visits,  however,  should  be  tailored  to  the  needs  of  individual  patients.  Women  should  be  screened  for  depression  early  in  pregnancy,  during   the  third  trimester  and  again  postpartum.  A  simple  self-administered 10 question screening tool, the “Edin- burgh Postnatal Depression Scale”  (EPDS),  is  avail- able  at  www.fresno.ucsf.edu/pediatrics/downloads/ edinburghscale.pdf.  The incidence of depression during pregnancy and the postpartum period is as high as 20%. Multiple studies have shown a signifi- cant relationship between vitamin D deficiency and depression.

During  each  regularly  scheduled  visit,  the  clinician  should  evaluate  blood  pressure,  weight,  urine  protein  and  glucose,  uterine  size  for  progressive  growth,  and  fetal  heart  rate.  After  the  woman  reports  quickening  (first  sensation  of  fetal  movement,  on  average  at  20  weeks’  gestation)  and  at  each  subsequent  visit,  she  should  be  asked  about  fetal  movement.  Between  24  and  34  weeks,  women  should  be  taught  the  warning  symptoms  of  preterm  labor  (uterine  contractions,  leakage  of  fluid,  vaginal  bleeding,  low  pelvic  pressure,  or  low  back  pain).  Patients  at  risk  may  require  addi- tional  visits  to  assess  signs  and  symptoms  of  preterm  labor.  Beginning  in  the  late  second  trimester,  they  should also be taught to recognize the warning symp- toms of preeclampsia (frontal headache, visual changes,  hand or facial swelling, epigastric or right upper quad- rant pain). Near term, they should be instructed on the  symptoms of labor.

Beginning at 28 weeks, systematic examination of the abdomen should be carried out at each prenatal visit to identify the lie (e.g., longitudinal, transverse, oblique), presentation (e.g., vertex, breech, shoulder), and position (e.g., flexion, extension, or rotation of the occiput) of the fetus. This can be accomplished by  the maneuvers of Leopold. The first maneuver involves  palpating  the  fundus  to  determine  which  part  of  the  fetus occupies the fundus. The head is round and hard,  whereas  the  breech  is  irregular  and  soft.  The  second maneuver  involves  palpating  either  side  of  the  abdomen  to  determine  on  which  side  the  fetal  back  lies.  The  fetal  back  is  linear  and  firm,  whereas  the  extremities  have  multiple  parts.  The  third maneuver  involves  grasping  the  presenting  part  between  the  thumb and third finger just above the pubic symphysis  to  determine  the  presenting  part. The  fourth maneu- ver involves palpating for the brow and the occiput of  the  fetus  to  determine  fetal  head  position  when  the  fetus  is  in  a  vertex  presentation.  This  is  best  accom- plished  with  the  examiner  facing  the  patient’s  feet   and  placing  both  hands  on  either  side  of  the  lower  abdomen  just  above  the  inlet.  By  exerting  pressure  in 

about pregnancy, and provide psychosocial support to  reduce pregnancy-specific stress.

Women should be advised to continue to exercise during pregnancy,  unless  there  is  hypertension,  preterm  labor,  rupture  of  the  membranes,  IUGR,  an  incompetent  cervix,  persistent  second-  or  third- trimester bleeding, or medical conditions that severely  restrict  physiologic  adaptations  to  exercise  during  pregnancy. They should avoid exercising in the supine  position after the first trimester, and should modify the  intensity of their exercise according to maternal symp- toms. Any type of exercise involving the potential for loss of balance or even mild abdominal trauma should be avoided.

Travel is acceptable under most circumstances.  Prolonged sitting increases the risk of thrombus forma- tion  and  thromboembolism.  Pregnant  women  should  be encouraged to ambulate periodically when taking a  long  flight  or  car  ride.  Support  stockings  may  help  reduce  lower  limb  edema  and  varicose  veins.  Interna- tional  travel  that  places  the  patient  at  a  high  risk  of  exposure  to  infectious  disease  should  be  avoided,  whenever  possible.  When  such  travel  cannot  be  avoided, appropriate vaccinations should be adminis- tered.  Specific  recommendations  are  available  at  www.cdc.gov;  select  “Traveler’s  Health.”  Live  attenu- ated  virus  vaccinations  are  generally  contraindicated  in  pregnancy,  but  inactivated  virus  vaccines  may  be  acceptable.

Increased, unchanged, and decreased levels of sexual activity can all be normal during pregnancy.  Abstinence or condom use may be advisable if there is  an  increased  risk  of  preterm  labor  or  repeated  preg- nancy  loss,  or  in  women  with  a  history  of  persistent  second- or third-trimester bleeding.

BREASTFEEDING Breastfeeding has been shown to significantly reduce morbidity and improve cognitive development during infancy and childhood.  Providers  should  initiate  dis- cussion  with  the  pregnant  woman  and  her  family  regarding breastfeeding during the first visit, including  possible  barriers  to  breastfeeding,  such  as  previous  poor  experiences,  misinformation,  or  nonsupportive  work  environment.  Clinicians  should  emphasize  that  weight gain during pregnancy is to support fetal growth  and for development of a nutritional reserve to support  effective  breastfeeding.  Breastfeeding for at least 6 months will facilitate complete loss of the required weight gain during pregnancy. This  behavior  reduces  the risk of postpartum weight retention and the risk of  developing  obesity.  Partners,  peers,  family  members  and  friends/support  groups  may  also  exert  an  impor- tant  influence  on  a  woman’s  decision  to  breastfeed.  Referral to a childbirth preparation class or a lactation  consultant  may  provide  additional  encouragement  to  initiate and support breastfeeding.

C H A P T E R 7 Antepartum Care 93

supine position, a continuous fetal heart rate tracing is  obtained  using  external  Doppler  equipment.  The  mother reports each fetal movement, and the effects of  the  fetal  movements  on  heart  rate  are  determined.  A normal fetus responds to fetal movement with accel- eration in fetal heart rate of 15 beats or more per minute above the baseline for at least 15 seconds  (Figure 7-3). If at least two such accelerations occur in  a  20-minute  interval,  the  fetus  is  regarded  as  being  healthy, and the test is said to be reactive. A nonreactive  NST is shown in Figure 7-4.

ULTRASONIC ASSESSMENT The next step in prenatal assessment is to determine the adequacy of amniotic fluid volume by real-time ultrasonography.  Reduced  fluid  (oligohydramnios)  suggests  fetal  compromise.  Oligohydramnios  can  be  defined  as  an  amniotic  fluid  index  (AFI)  of  less  than  5 cm.  The  AFI  represents  the  sum  of  the  linear  mea- surements (in centimeters) of the largest amniotic fluid  pockets  noted  on  ultrasonic  inspection  of  each  of  the  four  quadrants  of  the  gestational  sac.  When amniotic fluid is reduced, the fetus is more likely to become compromised as a result of umbilical cord compres- sion.  Excessive  amniotic  fluid  (polyhydramnios;  AFI >  23 cm) can be a sign of poor control in a diabetic preg- nancy  or  an  indication  that  the  fetus  may  have  an  anomaly.

Fetal breathing (chest wall movements) and fetal movements (stretching and rotational movements) are also used to assess the fetus.  A  fetus  that  has  at  least 30 breathing movements in 10 minutes or 3 body  movements  in  10  minutes  is  considered  healthy.  A  combination  of  a  reactive  NST,  adequate  amniotic  fluid,  adequate  fetal  breathing,  adequate  fetal  move- ments, and adequate tone is frequently referred to as a  normal biophysical profile. Each parameter is given a  score of 2. A normal profile equals 10. Table 7-4 lists the  recommended frequency for biophysical profile testing  based on high-risk conditions.

UMBILICAL ARTERY DOPPLER ASSESSMENT During the ultrasonic assessment, it is relatively easy to assess the fetal umbilical artery vascular resis- tance. A high systolic/diastolic ratio (S/D) (Figure 7-5)  suggests  abnormal  flow  because  of  increased  vascular  resistance within the fetal/placental circulation. When  the flow becomes very abnormal, diastolic flow ceases  and there can be a reversal of flow (Figure 7-6) from the  placenta  to  the  fetus. When  this  occurs  the  fetus  is  at  high risk and delivery is usually indicated.

PREVENTIVE HEALTH CARE Management before and during pregnancy presents an opportunity for patient education and the prac- tice of preventive medicine.  Childbirth  preparation  classes  for  both  the  patient  and  her  partner  are  very 

the direction of the pelvic inlet, the hand running along  the  back  will  bump  into  the  occiput  if  the  head  is  extended,  whereas  the  hand  on  the  same  side  of  the  small parts will bump into the brow if the head is flexed.  If there is a question about the presentation of the fetus a real time ultrasound may be performed.

Depending  on  the  practice  setting  and  population,  either  universal  or  selective  screening for gestational diabetes should be performed between 24 and 28 weeks’ gestation. Risk factors for selective screening include family history of diabetes; previous birth of a macrosomic, malformed, or stillborn baby; hyperten- sion; glycosuria; maternal age of 30 years or older; or previous gestational diabetes.  Repeat  measurements  of  hemoglobin  or  hematocrit  levels  early  in  the  third  trimester  have  been  recommended.  Tests  for  sexually  transmitted  infections  (e.g.,  syphilis)  may  also  be  repeated  at  32  to  36  weeks  if  the  woman  has  specific  risk factors for these diseases. The Centers for Disease  Control and Prevention recommend universal screen- ing for maternal colonization of group B streptococ- cus at 35 to 37 weeks’ gestation. The value of selective  ultrasound  for  specific  indications  has  been  clearly  established; the value of routine ultrasound in low-risk  pregnancies remains undetermined. Ultrasonic exami- nation during pregnancy is not harmful, but controlled trials have failed to demonstrate that routine ultra- sonic examinations for dating in early pregnancy, anatomic survey in mid-pregnancy, or assessment of fetal growth in late pregnancy improve perinatal outcome.

Assessment of Fetal Well-Being During  the  past  20  years,  electronic  monitoring  advances  have  made  the  fetus  more  accessible.  They  have allowed visualization of the fetus and recording of  intrauterine  fetal  activity.  A combination of maternal self-assessment, nonstress testing (NST), and real- time ultrasonic assessment is used to evaluate fetal well-being.

MATERNAL SELF-ASSESSMENT OF FETAL WELL-BEING A simple technique (kick counting) may be used to assess fetal well-being.  The  mother  assesses  fetal  movement  (kick  counts)  each  evening  while  lying  on  her  left  side.  She  should  recognize  10  movements  in  1  hour and if she does not, she should retest in 1 hour. If  she  still  does  not  have  10  fetal  movements  in  1  hour,  she  should  contact  her  doctor  or  present  herself  (usually  to  the  hospital)  for  an  NST  and  an  ultrasonic  assessment.

NONSTRESS TEST ASSESSMENT The first step in the assessment of fetal well-being is the NST.  With  the  mother  resting  in  the  left  lateral 

94 PA R T 2 Obstetrics

FIGURE 7-4 Nonreactive nonstress test. Note the lack of beat-to-beat variability and the lack of acceleration of the fetal heart rate (FHR) with fetal movements (arrows). bpm, Beats per minute.

26632 26633 FHR 240 BPM

210

180

150

120

90

60

30

26634 FHR 240 BPM

210

180

150

120

90

60

30

100

75

50

25

0 mm Hg

12

10

8

4

2

6

0 kP3

100

75

50

25

0UA mm Hg

100

75

50

25

0UA mm Hg

12

10

8

4

2

6

0 kP3

FIGURE 7-3 Reactive nonstress test. Note the fetal heart rate (FHR) accelerations with most fetal movements, denoted by spikes above 75 mm Hg in lower panel. bpm, Beats per minute.

FHR bpm 240

210

180

120

90

60

30

100

75

50

25

0

150

VARIABILITY INDEX

UA mm Hg

VARIABILITY %

UA mm Hg

UA mm Hg

VARIABILITY %

21

18

15

9

6

3

0

4

3

2

1

0

12

FHR bpm 240

210

180

120

90

60

30

100

75

50

25

0

4

3

2

1

0

100

75

50

25

0

150

VARIABILITY INDEX

21

18

15

9

6

3

0

12

FHR bpm 240

210

180

120

90

60

30

150

C H A P T E R 7 Antepartum Care 95

educational,  particularly  during  the  first  pregnancy.  These  classes  provide  an  important  opportunity  for  both  parents  to  enhance  bonding  to  the  infant  before  birth. The presence and encouragement of the baby’s father at these classes and during labor and delivery can be most helpful.

Although  preconception,  prenatal,  and  obstetric  information  is  of  primary  importance,  other topics that may have lifelong relevance can be introduced and emphasized during antepartum care. The preg- nancy itself is frequently a strong motivator for women to eliminate potentially harmful habits, such as smoking, or to change dietary patterns  that  are  associated  with  an  increased  incidence  of  obesity.  Therefore, a systematic approach to the dissemination  of preventive health care information is generally well  received by the pregnant woman.

TABLE 7-4

RECOMMENDED FREQUENCY FOR BIOPHYSICAL PROFILE TESTING

High-Risk Condition Frequency

Intrauterine Growth Restriction

Mild Weekly

Moderate* Twice weekly

Diabetes Mellitus

Class A Weekly, 37 to 40 wk

Twice weekly, beyond 40 wk

Class B and worse Twice weekly, beginning at 34 wk

Post-term pregnancy Twice weekly, beginning at 42 wk

Decreased fetal movements Weekly

Other high-risk conditions Weekly

Maternal or physician concern Weekly

*For severe intrauterine growth restriction, delivery is usually indicated.

FIGURE 7-5 Fetal umbilical artery Doppler assessment at 31 weeks and 3 days showing a series of Doppler waveforms with systolic (upper) peaks marked with X (+37 cm/sec) and lower X marking diastole (at +21 cm/sec). The systolic-to-diastolic ratio is calculated as 2.14 (upper right corner), and normal for this gestational age is <3.2.

Systolic

Diastolic

FIGURE 7-6 Fetal umbilical artery Doppler assessment at 26 weeks and 5 days in a case with reduced amniotic fluid (small lucent pocket left of midline with Doppler assessment of cord artery). The systolic-to-diastolic ratio cannot be calculated as in Figure 7-5 because of absent diastolic flow. Only systolic flow can be mea- sured (+30 cm/sec).

Absent diastolic flow

96

96

8  Normal Labor, Delivery, and Postpartum Care Anatomic Considerations, Obstetric Analgesia and Anesthesia, and Resuscitation of the Newborn

C H

A P

T ER

CALVIN J. HOBEL • MARK ZAKOWSKI

■  Knowledge  of  the  characteristics  of  the  fetal  head  and  maternal pelvis is necessary to understand the dynamic  relationship  between  these  two  anatomic  structures  during  labor.  The  fetal  head,  through  a  process  of  molding and flexion followed by internal rotation, passes  through the maternal pelvis during the first and second  stages  of  labor.  At  delivery  (expulsion),  there  is  external  rotation of the fetal head.

■  After  the  delivery  of  the  fetal  head  at  the  end  of  the  second  stage  of  labor,  attention  must  be  directed  to  the  management  of  the  third  and  fourth  stages  of  labor.   The  third  stage  of  labor  is  a  period  when  women  are   at  risk  for  postpartum  hemorrhage.  Hemorrhage  is  the  leading cause of maternal death worldwide and is among  the  top  three  causes  of  maternal  death  in  the  United  States. Uterine atony is the leading cause of postpartum  hemorrhage,  and  its  prevention  and/or  early  manage- ment are essential.

■  Women rate pain during labor as one of the most uncom- fortable  experiences  in  life.  Oxytocin  is  commonly  used  to  increase  the  frequency  and  strength  of  uterine  con- tractions,  which  also  increases  labor  pain.  Catechol- amine  release  and  maternal  hyperventilation  occur  during  labor.  The  resulting  vasoconstriction  of  the 

uterine arteries decreases uterine blood flow and oxygen  dissociation from hemoglobin, causing respiratory alka- losis. Whereas alternative methods offer some degree of  pain relief, the gold standard during labor and childbirth  is  epidural  (or  combined  spinal-epidural)  analgesia,  which  not  only  provides  near-complete  relief  but  also  improves  uterine  blood  flow,  fetal  oxygenation,  and  the  release  of  stress  hormones.  Fluid  administration  before  neuraxial analgesia helps prevent hypotension, which, if  it  does  occur,  may  be  treated  with  small  doses  of  vasopressors.

■  Approximately  one  in  three  women  have  a  cesarean  delivery in the United States. Although the use of general  anesthesia  for  cesarean  delivery  is  very  safe,  it  has  increased  maternal  and  neonatal  side  effects  as  well  as  maternal mortality. Most intravenous and inhaled anes- thetics cross the placenta. Regional anesthesia (spinal or  epidural)  is  preferable.  Some  neonatal  assistance  is  required  in  10%  of  births,  and  vigorous  resuscitation  is  required in 1%. Newborns are ventilated with lower con- centrations  of  oxygen  and  titrated  up  as  needed  to  achieve  their  normal  physiologic  oxygen  saturation  of  85-95% in the first minutes of life.

CLINICAL KEYS FOR THIS CHAPTER

Normal  labor  is  a  process  that  permits  a  series  of   extensive  physiologic  changes  in  the  mother  to  allow  for  the  delivery  of  her  fetus  through  the  birth  canal.  Labor is defined as progressive cervical effacement and dilation resulting from regular uterine contrac- tions that occur at least every 3 minutes and last 30 to 60 seconds each.

The role of the obstetrician and health care team is  to  anticipate  and  manage  abnormalities  that  may  occur during either the maternal or fetal birth process.  When a decision is made to intervene, it must be con- sidered carefully because each intervention carries not 

only  potential  benefits  but  also  potential  risks.  In  the  vast  majority  of  cases,  the  best  management  may  be  close  observation  and,  when  necessary,  cautious  intervention.

Anatomic Characteristics of the Fetal Head and Maternal Pelvis Successful  vaginal  delivery  requires  the  accommoda- tion,  by  molding  and  rotation,  of  the  descending  fetal  head to the maternal pelvis.

C H A P T E R 8 Normal Labor, Delivery, and Postpartum Care 97

laterally  and  serves  to  separate  the  occipital  from  the  parietal  bones.  The  coronal suture  extends  from  the  anterior  fontanelle  laterally  and  serves  to  separate   the  parietal  and  frontal  bones. The  frontal suture  lies  between the frontal bones and extends from the ante- rior fontanelle to the glabella (the prominence between  the eyebrows).

Fontanelles The membrane-filled spaces located at the point where the sutures intersect are known as fontanelles,  the  most  important  of  which  are  the  anterior and posterior fontanelles.  Clinically,  they  are  even  more  useful  than  the  sutures  for  determining  the  fetal  head  position.

The  posterior fontanelle  closes  at  6  to  8  weeks  of  life, whereas the anterior fontanelle does not become  ossified until approximately 18 months. This allows the  skull  to  accommodate  the  tremendous  growth  of  the  infant’s brain after birth.

The  anterior  fontanelle  (bregma)  is  found  at  the  intersection of the sagittal, frontal, and coronal sutures.  It  is  diamond-shaped,  measures  approximately  2  ×  3 cm, and is much larger than the posterior fontanelle.  The posterior fontanelle is Y- or T-shaped and is found  at the junction of the sagittal and lambdoid sutures.

Landmarks The  fetal  skull  is  characterized  by  a  number  of  land- marks.  From  front  to  back,  they  include  the  following  (Figure 8-2): 1.  Nasion: the root of the nose 2.  Glabella:  the  elevated  area  between  the  orbital 

ridges 3.  Sinciput (brow): the area between the anterior fon-

tanelle and the glabella 4.  Anterior fontanelle (bregma): diamond-shaped 5.  Vertex:  the  area  between  the  fontanelles  and 

bounded laterally by the parietal eminences 6.  Posterior fontanelle (lambda): Y- or T-shaped 7.  Occiput:  the  area  behind  and  inferior  to  the  poste-

rior fontanelle and lambdoid sutures

Diameters Several  diameters  of  the  fetal  skull  are  important  (see  Figures  8-1  and  8-2).  The  anteroposterior diameter  presenting  to  the  maternal  pelvis  depends  on  the  degree of flexion or extension of the head. It is impor- tant because the various diameters differ in length. The  following  measurements  are  considered  average  for  a  term fetus: 1.  Suboccipitobregmatic (9.5 cm):  the  presenting 

anteroposterior  diameter  when  the  head is well flexed,  as  in  an  occipitotransverse  or  occipitoante- rior position; it extends from the undersurface of the  occipital  bone  at  the  junction  with  the  neck  to  the  center of the anterior fontanelle.

FETAL HEAD The  head  is  the  largest  and  least  compressible  part  of  the  fetus.  Thus,  from  an  obstetric  viewpoint,  it  is  the  most  important  part,  whether  the  presentation  is  cephalic or breech.

The fetal skull consists of a base and a vault (the cranium).  The  base  of  the  skull  has  large,  ossified,  firmly united, and noncompressible bones. This serves  to  protect  the  vital  structures  contained  within  the  brain stem and its spinal connections.

The cranium consists of the occipital bone poste- riorly, two parietal bones bilaterally, and two frontal and temporal bones anteriorly.  The  cranial  bones  at  birth are thin, weakly ossified, easily compressible, and  interconnected  only  by  membranes.  These  features  allow  them  to  overlap  under  pressure  and  to  change  shape  to  conform  to  the  maternal  pelvis,  a  process  known as molding.

Sutures The membrane-occupied spaces between the cranial bones are known as sutures.  The  sagittal suture  lies  between  the  parietal  bones  and  extends  in  an  antero- posterior  direction  between  the  fontanelles,  dividing  the head into right and left sides (Figure 8-1). The lamb- doidal suture  extends  from  the  posterior  fontanelle 

FIGURE 8-1 Superior view of the fetal skull showing the sutures, fontanelles, and transverse diameters.

Posterior fontanelle

Occipital bone

Lambdoid suture

Biparietal diameter

Parietal eminence

Sagittal suture

Bitemporal diameter

Frontal boneFrontal

suture

Anterior fontanelle (bregma)

Coronal suture

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the  cavity  of  the  pelvis.  The  anterior  surface  of  the  sacrum is usually concave. It articulates with the ilium  at  its  upper  segment,  with  the  coccyx  at  its  lower  segment,  and  with  the  sacrospinous  and  sacrotuber- ous ligaments laterally.

The coccyx is composed of three to five rudimentary  vertebrae.  It  articulates  with  the  sacrum,  forming  a  joint, and occasionally the bones are fused.

The pelvis is divided into the false pelvis above and the true pelvis below the linea terminalis (the edge of the pelvic inlet).  The  false  pelvis  is  bordered  by  the  lumbar  vertebrae  posteriorly,  an  iliac  fossa  bilaterally,  and  the  abdominal  wall  anteriorly.  Its  only  obstetric  function is to support the pregnant uterus.

The true pelvis is a bony canal and is formed by the sacrum and coccyx posteriorly and by the ischium and pubis laterally and anteriorly. Its internal borders  are solid and relatively immobile. The posterior wall is  twice the length of the anterior wall. The true pelvis is  the  area  of  concern  to  the  obstetrician  because  its  dimensions  are  sometimes  not  adequate  to  permit  passage of the fetus.

Pelvic Planes The  pelvis  is  divided  into  the  following  four  planes   for  descriptive  purposes  (Table  8-1  and  Figures  8-3    and 8-4): 1.  The pelvic inlet 2.  The plane of greatest diameter 3.  The plane of least diameter 4.  The pelvic outlet

These  planes  are  imaginary,  flat  surfaces  that   extend  across  the  pelvis  at  different  levels.  Except  for 

2.  Occipitofrontal (11 cm): the presenting anteropos- terior  diameter  when  the  head  is  deflexed,  as  in  an  occipitoposterior  presentation;  it  extends  from  the  external occipital protuberance to the glabella.

3.  Supraoccipitomental (13.5 cm):  the  presenting  anteroposterior  diameter  in  a  brow  presentation  and  the  longest  anteroposterior  diameter  of  the  head; it extends from the vertex to the chin.

4.  Submentobregmatic (9.5 cm):  the  presenting  an - teroposterior  diameter  in  face  presentations;  it  extends from the junction of the neck and lower jaw  to the center of the anterior fontanelle. The transverse diameters  of  the  fetal  skull  are  as 

follows: 1.  Biparietal (9.5 cm): the largest transverse diameter; 

it extends between the parietal bones. 2.  Bitemporal (8 cm):  the  shortest  transverse  diame-

ter; it extends between the temporal bones. The  average  circumference  of  the  term  fetal  head, 

measured in the occipitofrontal plane, is 34.5 cm.

PELVIC ANATOMY Bony Pelvis The bony pelvis is made up of four bones: the sacrum, coccyx, and two innominates (composed of the ilium, ischium, and pubis).  These  are  held  together  by  the  sacroiliac  joints,  the  symphysis  pubis,  and  the  sacro- coccygeal joint. The union of the pelvis and the verte- bral  column  stabilizes  the  pelvis  and  allows  weight  to  be transmitted to the lower extremities.

The  sacrum  consists  of  five  fused  vertebrae.  The  anterior  superior  edge  of  the  first  sacral  vertebra  is  called  the  promontory,  which  protrudes  slightly  into 

FIGURE 8-2 Lateral view of the fetal skull showing the prominent landmarks and the anteroposterior diameters.

Anterior fontanelle (bregma)

Glabella

Nasion Posterior fontanelle

VERTEXSINCIPUT

Supraoccipitomental diameter

Submentobregmatic diameter

Suboccipitobregmatic diameter

Occipitofrontal diameter

OCCIPUT

C H A P T E R 8 Normal Labor, Delivery, and Postpartum Care 99

TABLE 8-1

AVERAGE LENGTH OF PELVIC PLANE DIAMETERS

Pelvic Plane Diameter Average Length (cm)

Inlet True conjugate 11.5 Obstetric conjugate 11 Transverse 13.5 Oblique 12.5 Posterior sagittal 4.5

Greatest diameter Anteroposterior 12.75 Transverse 12.5

Midplane Anteroposterior 12 Bispinous 10.5 Posterior sagittal 4.5-5

Outlet Anatomic anteroposterior

9.5

Obstetric anteroposterior

11.5

Bituberous 11 Posterior sagittal 7.5

FIGURE 8-3 Pelvic inlet and its diameters.

Posterior sagittal

R. obliqueL. oblique

Anteroposterior

Transverse

Diagonal conjugate

Anatomic conjugate

Obstetric conjugate

the  plane  of  greatest  diameter,  each  plane  is  clinically  significant.

The plane of the inlet is bordered by the pubic crest  anteriorly,  the  iliopectineal  line  of  the  innominate  bones laterally, and the promontory of the sacrum pos- teriorly.  The  fetal  head  enters  the  pelvis  through  this  plane in the transverse position.

The plane of greatest diameter is the largest part of  the  pelvic  cavity.  It  is  bordered  by  the  posterior  mid- point  of  the  pubis  anteriorly,  the  upper  part  of  the  obturator  foramina  laterally,  and  the  junction  of  the  second and third sacral vertebrae posteriorly. The fetal  head rotates to the anterior position in this plane.

The  plane of least diameter  is  the  most  important  from  a  clinical  standpoint  because  most  instances  of  arrest of descent occur at this level. It is bordered by the 

lower  edge  of  the  pubis  anteriorly,  the  ischial  spines  and  sacrospinous  ligaments  laterally,  and  the  lower  sacrum  posteriorly.  Low  transverse  arrests  generally  occur in this plane.

The plane of the pelvic outlet is formed by two tri- angular planes with a common base at the level of the  ischial tuberosities. The anterior triangle is bordered by  the subpubic angle at the apex, the pubic rami on the  sides,  and  the  bituberous  diameter  at  the  base.  The  posterior  triangle  is  bordered  by  the  sacrococcygeal  joint  at  its  apex,  the  sacrotuberous  ligaments  on  the  sides,  and  the  bituberous  diameter  at  the  base.  This  plane is the site of a low pelvic arrest.

Pelvic Diameters The  diameters  of  the  pelvic  planes  represent  the  amount of space available at each level. The key mea- surements  for  assessing  the  capacity  of  the  maternal  pelvis include the following: 1.  The obstetric conjugate of the inlet 2.  The bispinous diameter of the midplane 3.  The bituberous diameter of the outlet 4.  The anteroposterior sagittal diameter of the outlet

The average lengths of the diameters of each pelvic  plane are listed in Table 8-1.

Pelvic Inlet The  pelvic  inlet  has  five  important  diameters  (see  Figure 8-3). The anteroposterior diameter is described  by one of two measurements. The true conjugate (ana- tomic conjugate) is the anatomic diameter and extends  from the middle of the sacral promontory to the supe- rior surface of the pubic symphysis. The obstetric con- jugate represents the actual space available to the fetus  and extends from the middle of the sacral promontory  to the closest point on the convex posterior surface of  the symphysis pubis.

PA R T 2 Obstetrics100

PELVIC SHAPES Based on the general bony architecture, the pelvis may  be  classified  into  four  basic  types  (Figure  8-5):  gyne- coid, android, anthropoid, and platypelloid.

Gynecoid The gynecoid pelvis is the classic female type of pelvis  and  is  found  in  approximately  50% of women.  It  has  the following characteristics: 1.  Round at the inlet, with the widest transverse diam-

eter  only  slightly  greater  than  the  anteroposterior  diameter

2.  Sidewalls straight 3.  Ischial spines of average prominence 4.  Large sacrospinous notch (depicted in Figure 8-5) 5.  Well-curved sacrum 6.  Spacious  subpubic  arch  with  an  angle  of  approxi-

mately 90 degrees These features create a cylindrical shape that is spa-

cious throughout. The fetal head generally rotates into  the occipitoanterior position in this type of pelvis.

Android The android pelvis is the typical male type of pelvis. It  is  found  in  less than 30% of women  and  has  the  fol- lowing characteristics: 1.  Triangular  inlet  with  a  flat  posterior  segment  and 

the widest transverse diameter closer to the sacrum  than in the gynecoid type

2.  Convergent sidewalls with prominent spines 3.  Shallow sacral curve 4.  Long and narrow (small) sacrospinous notch (noted 

in Figure 8-5 in a gynecoid pelvis) 5.  Narrow subpubic arch

This type of pelvis has limited space at the inlet and  progressively  less  space  as  the  fetus  moves  down  the 

The  transverse diameter  is  the  widest  distance  between the iliopectineal lines. Each oblique diameter  extends  from  the  sacroiliac  joint  to  the  opposite  ilio- pectineal eminence.

The  posterior sagittal diameter  extends  from  the  anteroposterior  and  transverse  intersection  to  the  middle of the sacral promontory.

Plane of Greatest Diameter The  plane  of  greatest  diameter  has  two  noteworthy  diameters.  The  anteroposterior diameter  (see  Figure  8-4) extends from the midpoint of the posterior surface  of  the  pubis  to  the  junction  of  the  second  and  third  sacral vertebrae. The transverse diameter is the widest  distance between the lateral borders of the plane.

Plane of Least Diameter (Midplane) The plane of least diameter has three important diam- eters. The anteroposterior diameter extends from the  lower border of the pubis to the junction of the fourth  and  fifth  sacral  vertebrae.  The  transverse (bispinous) diameter extends between the ischial spines. The pos- terior sagittal diameter extends from the midpoint of  the  bispinous  diameter  to  the  junction  of  the  fourth  and fifth sacral vertebrae.

Pelvic Outlet The  pelvic  outlet  has  four  important  diameters  (see  Figure  8-4).  The  anatomic anteroposterior diameter  extends from the inferior margin of the pubis to the tip  of  the  coccyx,  whereas  the  obstetric anteroposterior diameter extends from the inferior margin of the pubis  to  the  sacrococcygeal  joint.  The  transverse (bituber- ous) diameter  extends  between  the  inner  surfaces  of  the  ischial  tuberosities,  and  the  posterior sagittal diameter  (not  listed)  extends  from  the  middle  of  the  transverse diameter to the sacrococcygeal joint.

FIGURE 8-4 Pelvic outlet and its diameters.

Transverse diameter

(bituberous)Ant. triangle

Sacrotuberous ligt.

Post. triangle Ant. sagittal Post. sagittal

Obstetric anteroposterior

diameter

C H A P T E R 8 Normal Labor, Delivery, and Postpartum Care 101

rior  position  because  there  is  more  space  in  the  posterior pelvis.

Platypelloid The platypelloid pelvis is best described as being a flat- tened gynecoid pelvis. It is found in only 3% of women,  and it has the following characteristics: 1.  A  short  anteroposterior  and  wide  transverse  diam-

eter, creating an oval-shaped inlet 2.  Straight or divergent sidewalls 3.  Posterior inclination of a flat sacrum 4.  A wide bispinous diameter 5.  Long but small sacrospinous notch 6.  A wide subpubic arch

The overall shape is that of a gentle curve through- out.  The  fetal  head  has  to  engage  in  the  transverse  diameter.

ENGAGEMENT Engagement occurs when the widest diameter of the fetal presenting part has passed through the pelvic inlet.  In  cephalic  presentations,  the  widest 

pelvis, because of the funneling effect of the sidewalls,  sacrum, and pubic rami. Thus, the amount of space is  restricted at all levels. The fetal head is forced to be in  the occipitoposterior position to conform to the narrow  anterior  pelvis.  Arrest  of  descent  is  common  at  the  midpelvis.

Anthropoid The  anthropoid  pelvis  resembles  that  of  the  anthro- poid ape. It is found in approximately 20% of women  and has the following characteristics: 1.  A  much  larger  anteroposterior  than  transverse 

diameter, creating a long, narrow oval at the inlet 2.  Sidewalls that do not converge 3.  Ischial  spines  that  are  not  prominent  but  are  close, 

because of the overall shape 4.  Variable,  but  usually  posterior,  inclination  of  the 

sacrum 5.  Small sacrospinous notch 6.  Narrow, outwardly shaped subpubic arch

The  fetal  head  can  engage  only  in  the  anteroposte- rior diameter and usually does so in the occipitoposte-

FIGURE 8-5 The four basic pelvic types. The dashed lines indicate the transverse diameter of the inlet. Note that the widest diameter of the inlet is posteriorly situated in an android or anthropoid pelvis. The gynecoid pelvis illustrates the location of the sacrospinous notch, present in all pelvic types.

Anthropoid

Gynecoid Android

Platypelloid

Sacrospinous notch

PA R T 2 Obstetrics102

The midpelvis cannot be measured accurately clin- ically in either the anteroposterior or transverse diam- eter. A reasonable estimate of the size of the midpelvis,  however,  can  be  obtained  as  follows.  The pelvic side- walls can be assessed to determine if they are conver- gent rather than having the normal, almost parallel, configuration. The ischial spines are palpated carefully  to  assess  their  prominence,  and  several  passes  are  made between the spines to approximate the bispinous  diameter.  The  length  of  the  sacrospinous  ligament  is  assessed by placing one finger on the ischial spine and  one  finger  on  the  sacrum  in  the  midline. The  average  length  is  three  fingerbreadths.  If  the  sacrospinous 

diameter  is  biparietal;  in  breech  presentations,  it  is  intertrochanteric.

The station of the presenting part in the pelvic canal is defined as its level above or below the plane of the ischial spines. The  level  of  the  ischial  spines  is  assigned  as “zero”  station,  and  each  centimeter  above  or below this level is given a minus or plus designation,  respectively.

In the majority of women, the bony presenting part is at the level of the ischial spines when the head has become engaged.  The  fetal  head  usually  engages  with its sagittal suture in the transverse diameter of the  pelvis. The  head  position  is  considered  to  be  synclitic  when  the  biparietal  diameter  is  parallel  to  the  pelvic  plane  and  the  sagittal  suture  is  midway  between  the  anterior  and  posterior  planes  of  the  pelvis. When  this  relationship is not present, the head is considered to be  asynclitic (Figure 8-6).

There  is  a  distinct  advantage  to  having  the  head  engage  in  asynclitism  in  certain  situations.  In  a  syn- clitic presentation, the biparietal diameter entering the  pelvis measures 9.5 cm; when the parietal bones enter  the  pelvis  in  an  asynclitic  manner,  however,  the  pre- senting  diameter  measures  8.75 cm.  Therefore,  asyn- clitism  permits  a  larger  head  to  enter  the  pelvis  than  would be possible in a synclitic presentation.

CLINICAL PELVIMETRY The  diameters  that  can  be  clinically  evaluated  can  be  assessed at the time of the first prenatal visit to screen  for  obvious  pelvic  contractions,  although  some  obste- tricians  believe  that  it  is  better  to  wait  until  later  in  pregnancy,  when  the  soft  tissues  are  more  distensible  and  the  examination  is  less  uncomfortable  and  possi- bly more accurate.

The  clinical  evaluation  is  started  by  assessing  the  pelvic inlet. The pelvic inlet can be evaluated clinically  for  its  anteroposterior  diameter.  The  obstetric  conju- gate  can  be  estimated  from  the  diagonal  conjugate,  which  is  obtained  during  clinical  examination  (see  Figure 8-3).

The diagonal conjugate is approximated by mea- suring from the lower border of the pubis to the sacral promontory, using the tip of the second finger and the point where the base of the index finger meets the pubis (Figure 8-7). The obstetric conjugate  is  then  estimated by subtracting 1.5 to 2 cm, depending on the  height  and  inclination  of  the  pubis.  Often  the  middle  finger  of  the  examining  hand  cannot  reach  the  sacral  promontory;  thus,  the  obstetric  conjugate  is  consid- ered adequate. If the diagonal conjugate is greater than  or  equal  to  11.5 cm,  the  anteroposterior  diameter  of  the inlet is considered to be adequate.

The anterior surface of the sacrum is then palpated  to  assess  its  curvature.  The  usual  shape  is  concave.  A  flat or convex shape may indicate anteroposterior con- striction throughout the pelvis.

FIGURE 8-6 Anterior asynclitism entering the pelvis (A) and syn- clitism in the pelvis (B). The curved arrow shows the direction to correct asynclitism, and the dashed lines show the axis that defines synclitism.

A

B

C H A P T E R 8 Normal Labor, Delivery, and Postpartum Care 103

It  should  always  be  questioned  whether  the  results  obtained  by  radiologic  assessment  will  have  sufficient  influence  on  the  patient’s  management  to  make  the  investigation worthwhile.

PREPARATION FOR LABOR Before  actual  labor  begins,  a  number  of  preparatory  physiologic events usually occur.

Lightening Two or more weeks before labor, the fetal head in most primigravid women settles into the brim of the pelvis. In multigravida, this often does not occur until  early in labor. Lightening may be noted by the mother  as a flattening of the upper abdomen and an increased  prominence of the lower abdomen.

False Labor During the last 4 to 8 weeks of pregnancy, the uterus undergoes irregular contractions that normally are painless. Such contractions appear unpredictably and  sporadically and can be rhythmic and of mild intensity.  In  the  last  month  of  pregnancy,  these  contractions   may  occur  more  frequently,  sometimes  every  10  to  20  minutes,  and  with  greater  intensity.  These Braxton Hicks contractions are considered false labor in that they are not associated with progressive cervical

notch that is located lateral to the ligament can accom- modate  two-and-one-half  fingers,  the  posterior  mid- pelvis  is  most  likely  of  adequate  dimensions.  A  short  ligament suggests a forward inclination of the sacrum  and a narrowed sacrospinous notch.

Finally, the pelvic outlet is assessed. This is done by  first  placing  a  fist  between  the  ischial  tuberosities.  An  8.5-cm distance is considered to indicate an adequate  transverse  diameter.  The  posterior  sagittal  measure- ment should also be greater than 8 cm. The infrapubic  angle is assessed by placing a thumb next to each infe- rior  pubic  ramus  and  then  estimating  the  angle  at  which  they  meet.  An  angle  of  less  than  90  degrees  is  associated with a contracted transverse diameter in the  midplane and outlet.

Radiologic Assessment of the Pelvis When  an  accurate  measurement  of  the  pelvis  is  indi- cated, nuclear magnetic resonance imaging (MRI) may  be used. The advantage of MRI over x-ray or computed  tomography  for  pelvic  assessment  is  the  lack  of  ioniz- ing radiation exposure.

Indications 1.  Clinical evidence or obstetric history suggestive of

pelvic abnormalities 2.  A history of pelvic trauma

FIGURE 8-7 Clinical estimation of the diagonal conjugate diameter of the pelvis.

PA R T 2 Obstetrics104

Manual separation of the chorioamnion from the lower  uterine  segment—referred  to  as  “stripping  the  mem- branes”—does  not  necessarily  speed  up  the  onset  of  labor. Artificial rupture of the membranes is not rec- ommended as a method to induce labor.

dilation or effacement. They  may  serve  a  physiologic  role in preparing the uterus and cervix for true labor.

Cervical Effacement Before the onset of parturition, the cervix is fre- quently noted to soften as a result of increased water content and collagen lysis. Simultaneous effacement, or thinning of the cervix, occurs as the internal os of the cervix is taken up into the lower uterine segment (Figure 8-8, B). Consequently, patients often present in  early labor with a cervix that is already partially effaced.  As  a  result  of  cervical  effacement,  the  mucous  plug  within the cervical canal may be released. The onset of  labor  may  thus  be  heralded  by  the  passage  of  a  small  amount  of  blood-tinged  mucus  from  the  vagina  (“bloody show”).

Induction and Augmentation of Labor Induction of labor is the process whereby labor is initi- ated  by  artificial  means  after  appropriate  assessment  of  the  mother  and  fetus  and  an  explanation  to  the  patient  of  the  indications  for  induction.  In  the  case  of  high-risk pregnancies, induction is necessary to reduce  the  risk  of  morbidity  to  the  mother  and  her  fetus.  In  general,  induction  of  labor  is  not  used  for  the  conve- nience  of  the  mother  or  her  family,  and  it  should  not  be done before 38 weeks’ gestation because of the pos- sibility  of  neonatal  morbidity.  Augmentation  is  the  artificial stimulation of labor that has begun spontane- ously (see Chapter 11).

Cervical  effacement  and  softening  (ripening)  occur  before the onset of spontaneous labor. Cervical ripen- ing  frequently  has  not  occurred  before  a  decision  to  induce labor, yet the success of induction is dependent  on these changes in the cervix.

Several mechanical and pharmacologic approaches may be used to promote cervical ripening before the actual induction of uterine contractions.  Currently  approved pharmacologic treatments include intravagi- nal  application  of  prostaglandin  E2  using  a  vaginal  insert  (on  a  string)  called  Cervidil,  which  can  be  removed quickly if the medication causes hyperstimu- lation. Cytotec, a synthetic prostaglandin E1 analogue,  has  also  been  approved  for  cervical  ripening.  One  25-µg  tablet  placed  intravaginally  effectively  initiates  cervical  ripening.  Although prostaglandin adminis- tration has been demonstrated to shorten the dura- tion of labor induction, the impact on cesarean delivery rates due to failed induction has been minimal.

Other methods of cervical ripening may include intrauterine placement of a Foley catheter into the cervix and inflation of the balloon with 10 cc of saline. 

FIGURE 8-8 A, The absence of cervical effacement before labor (X shows the location of the internal os in a normal cervix). B, Cervical os (X) being progressively taken up into the lower segment of the uterus (about 50% effaced). C, Cervical os (X) fully taken up (cervix is completely effaced).

A

X X

X X

X X

B

C

C H A P T E R 8 Normal Labor, Delivery, and Postpartum Care 105

In addition to cervical ripening, induction of labor requires the initiation of effective uterine contrac- tions. Oxytocin  is  identical  to  the  natural  pituitary  peptide, and it is the only drug approved for induction and augmentation of labor.  Pitocin  is  the  synthetic  preparation.

The physician must be fully aware of the indications  and contraindications for the use of induction and aug- mentation of labor (Table 8-2). The most common con- traindication  has  been  prior  uterine  surgery  in  which  there  has  been  complete  transection  of  the  uterine  wall. However, a previous lower transverse incision is no longer considered a contraindication to a trial of labor. This is referred to as vaginal birth after cesarean,  or VBAC.

TABLE 8-2

INDICATIONS AND CONTRAINDICATIONS FOR INDUCTION AND AUGMENTATION OF LABOR

Induction Augmentation

Indications

Maternal

Preeclampsia Abnormal labor (in the presence of inadequate uterine activity)

Diabetes mellitus Prolonged latent phase

Heart disease Prolonged active phase

Fetoplacental

Prolonged pregnancy

Intrauterine growth restriction

Abnormal fetal testing

Rhesus type incompatibility

Fetal abnormality

Premature rupture of membranes

Chorioamnionitis

Contraindications

Maternal

Absolute Same contraindications as for maternal and fetoplacental

Contracted pelvis

Relative Prior uterine surgery Classic cesarean delivery Complete transection of uterus

(myomectomy, reconstruction) Overdistended uterus

Fetoplacental

Preterm fetus without lung maturity

Acute fetal distress

Abnormal presentation

TABLE 8-3

BISHOP SCORE TO ASSESS LIKELIHOOD OF SUCCESSFUL INDUCTION OF LABOR

Physical Findings

Rating

0 1 2 3

Cervix

Position Posterior Mid Anterior —

Consistency Firm Medium Soft —

Effacement (%) 0-30 40-50 60-70 ≥80

Dilation (cm) 0 1-2 3-4 ≥5 Fetal Head

Station −3 −2 −1 +1

TECHNIQUE FOR INDUCTION AND AUGMENTATION OF LABOR A  hospital  obstetric  service  must  establish  guidelines  for  the  proper  use  of  oxytocin  for  induction  and  aug- mentation of labor. In general, an assessment and plan  of  management  should  be  outlined  in  the  patient’s  medical record. It is helpful to assess the likelihood of  success  by  a  careful  pelvic  examination  to  determine  the  Bishop score,  which  is  used  to  evaluate  the  status  of  the  cervix  and  the  station  of  the  fetal  head  (Table  8-3).  A  high  score  (9  to  13)  is  associated  with  a  high  likelihood  of  a  vaginal  delivery,  whereas  a  low  score  (<5) is associated with a decreased likelihood of success  (65-80%). Before induction is begun, the patient’s blood  must  be  typed  and  screened  for  antibodies.  A  blood  specimen  should  be  held  in  the  laboratory  in  case  crossmatching  becomes  necessary.  Continuous elec- tronic monitoring of the fetal heart rate and uterine activity is required during induction.  An  internal  uterine catheter for monitoring uterine pressure is sug- gested if intensity cannot be adequately assessed.

Oxytocin Infusion Several principles should be followed when oxytocin is  used to induce or augment labor: 1.  Oxytocin must be given intravenously to allow it to 

be  discontinued  quickly  if  a  complication  such  as  uterine  hypertonus  or  fetal  distress  develops.  Because oxytocin has a half-life of 3 to 5 minutes, its  physiologic effect will diminish quickly (within 15 to  30 minutes) after discontinuation.

2.  A dilute infusion must be used and “piggybacked” into the main intravenous (IV ) line so that it can be  stopped  quickly  if  necessary,  without  interrupting  the main IV route.

3.  The drug is best infused with a calibrated infusion pump  that  can  be  easily  adjusted  to  deliver  the  required infusion rate accurately.

PA R T 2 Obstetrics106

prolonged  infusion  of  oxytocin  can  result  in  uterine muscle fatigue (nonresponsiveness) and postdelivery uterine atony  (hypotonus),  which can increase the risk of postpartum hemorrhage.

STAGES OF LABOR There are four stages of labor,  each  of  which  is  considered  separately.  These  stages  in  actuality  are  definitions  of  progress  during  labor,  delivery,  and  the  puerperium  (Table  8-5).

The  first stage  lasts  from  the  onset  of  true  labor  to  complete dilation of the cervix. The second stage spans  from complete dilation of the cervix to the birth of the  baby. The third stage lasts from the birth of the baby to  delivery  of  the  placenta. The  fourth stage  spans  from  delivery of the placenta to stabilization of the patient’s  condition, usually at about 6 hours postpartum.

First Stage of Labor as Defined by the Friedman Labor Curve There is currently controversy about how to define the  progress  of  normal  labor.  Because  the  purpose  of  this  chapter is to define normal labor, we will use the stan- dard definitions provided by Friedman in 1978 (Figure  8-9).  The  Friedman  labor  curve,  as  well  as  a  recently  suggested modification, is covered in Chapter 11.

PHASES. The first stage of labor consists of two phases: a latent phase, during which cervical effacement and early dilation occur, and an active phase, during which more rapid cervical dilation occurs (see Figure  8-9). Although cervical softening and early effacement  may  occur  before  labor,  during  the  first  stage  of  labor  the entire cervical length (cervical os) is retracted into  the lower uterine segment (see Figure 8-8).

LENGTH. The length of the first stage may vary in rela- tion  to  parity;  primiparous  patients  generally  experi- ence  a  longer  first  stage  than  do  multiparous  patients  (see Table  8-5).  Because  the  latent  phase  may  overlap  considerably  with  the  preparatory  phase  of  labor,  its  duration is highly variable. It may also be influenced by  other  factors,  such  as  sedation  and  stress.  The  active  phase  begins  when  the  cervix  is  dilated  4 cm  in  the  presence  of  regularly  occurring  uterine  contractions.  The  recent  guidelines  proposed  by  Zhang  and  col- leagues regarding labor curves (see Chapter 11) suggest  that the active phase may not begin until 6-cm dilation.  The minimal dilation during the active phase of the first stage is nearly the same for normal primiparous and multiparous women: 1 and 1.2 cm/hr, respec- tively.  If  progress  is  slower  than  this,  evaluation  for  uterine  dysfunction,  fetal  malposition,  or  cephalopel- vic disproportion should be undertaken.

MEASUREMENT OF PROGRESS. During the first stage, the  progress of labor may be measured in terms of cervical 

4.  The induction of labor for a specific indication generally should not exceed 72 hours.  In  patients  with  a  low  Bishop  score,  it  is  not  unusual  for  an  induction to progress slowly. If the cervix effaces and  dilates,  it  is  recommended  that  the  membranes  be  ruptured on the third day. If adequate progress is not  made within 12 hours of rupturing the membranes,  a cesarean delivery may be performed.

5.  If adequate labor is established, the infusion rate and the concentration may be reduced,  especially  during  the  second  stage  of  labor.  Adherence  to  this  principle  avoids  the  risks  of  hyperstimulation  and  fetal distress, which frequently occur once labor has  been established. Substantial  variation  exists  regarding  the  initial 

dose,  incremental  dose,  and  time  interval  between  dose increments when oxytocin is used for labor induc- tion and augmentation. Well-performed clinical studies  have  supported  both  low-dose  (1  to  30 mU/min)  and  high-dose  (4  to  40 mU/min)  protocols,  as  shown  in  Table  8-4.  It  is  not  surprising  that  many  protocols  use  moderate  doses  of  oxytocin.  Generally,  intervals  between  dose  increments  should  be  no  less  than  20  minutes  to  permit  time  for  steady-state  plasma  levels  of oxytocin to be achieved and to prevent an increased  risk of uterine hyperstimulation.

COMPLICATIONS. The use of oxytocin for the induction  and augmentation of labor can cause three major com- plications.  First,  an  excessive  infusion  rate  can  cause  hyperstimulation and thereby cause fetal distress from  ischemia.  In  rare  situations,  a  tetanic  contraction  can  occur, which can lead to rupture of the uterus. Second,  because  oxytocin  has  a  structure  similar  to  that  of  antidiuretic  hormone,  it  has  an  intrinsic  antidiuretic effect  and  will  increase  water  reabsorption  from  the  glomerular  filtrate.  Severe water intoxication with convulsions and coma can occur rarely when oxytocin  is infused continuously for more than 24 hours. Third, 

TABLE 8-4

METHOD OF OXYTOCIN INFUSION FOR INDUCTION AND/OR AUGMENTATION OF LABOR

Low-Dose Protocol High-Dose Protocol

Starting dose 1 mU/min 4 mU/min

Increment 1 mU/min 4 mU/min

Interval 20 min 20 min

Limited by 5 contractions in 10 min

7 contractions in 15 min

Maximal dose 20-30 mU/min 40 mU/min

Solution: 10 U of oxytocin in 1000 mL of 5% dextrose or balanced salt solu- tion (10 mU/mL). Administration: Piggyback into main intravenous line; administer solution by infusion pump.

C H A P T E R 8 Normal Labor, Delivery, and Postpartum Care 107

FIGURE 8-9 Cervical dilation and descent of the fetal head during labor. The first descent curve represents a fetus with a floating present- ing part at the onset of labor, whereas the second represents a fetus with the presenting part fixed in the pelvis before labor. (Modified from Friedman EA: Labor: clinical evaluation and management, ed 2, East Norwalk, CT, 1978, Appleton-Century-Crofts, p 41.)

F E

T A

L

S T

A T

IO N

( cm

)

C E

R V

IC A

L D

IL A

T IO

N (

cm )

− 5

− 4

− 3

− 2

− 1

+ 1

+ 2

+ 3

+ 4

+ 5

0

10

Accel. Max. slope

Decel. 2nd stage

8

6

4

2

0

LATENT PHASE

Dilation

Descent #2

Descent #1

ACTIVE PHASE

TABLE 8-5

CHARACTERISTICS OF NORMAL LABOR

Characteristics Primipara Multipara

Duration of first stage 6-18 hr 2-10 hr

Rate of cervical dilation during active phase

1 cm/hr 1.2 cm/hr

Duration of second stage 30 min to 3 hr 5-30 min

Duration of third stage 0-30 min 0-30 min

effacement,  cervical  dilation,  and  descent  of  the  fetal  head.  The  clinical  pattern  of  the  uterine  contractions  alone  is  not  an  adequate  indication  of  progress.  After  completion of cervical dilation, the second stage com- mences. Thereafter, only the descent, flexion, and rota- tion  of  the  presenting  part  are  available  to  assess  the  progress of labor.

CLINICAL MANAGEMENT OF THE FIRST STAGE. Certain  steps  should  be  taken  in  the  clinical  management  of  the patient during the first stage of labor.

Maternal Position. The  mother  may  ambulate,  pro- vided  that  intermittent  monitoring  ensures  fetal  well- being  and  the  presenting  part  is  engaged  in  patients  with  ruptured  membranes.  If she is lying in bed, the lateral recumbent position should be encouraged  to 

ensure  adequate  perfusion  of  the  uteroplacental  unit.  When the patient is supine (on her back), the weight of  the uterus and fetus can compress the vessels supply- ing the uterus.

Administration of Fluids. Because of decreased gastric  emptying  during  labor,  oral fluids are best avoided.  However,  fasting  results  in  the  more  rapid  develop- ment  of  ketosis  in  pregnant  women.  Placement  of  a  16- to 18-gauge venous catheter is advisable during the  active phase of labor. It has been shown that giving at least 125 mL/hr of 10% dextrose (D) in normal saline (NS),  compared  with  5%  D/NS  or  just  NS,  results in significantly shorter labor. Thus,  the  IV  route  is  used  to  hydrate  the  patient  with  crystalloids  and  provide  calories  during  labor,  to  administer  oxytocin  after  the  delivery  of  the  placenta,  and  for  the  treatment  of  any  unanticipated emergencies.

Investigations. Every  woman  admitted  in  labor  should  have  a  hematocrit  or  hemoglobin  measure- ment  and  a  blood  clot  held  in  the  event  that  a  cross- match  is  needed.  Blood  group,  rhesus  (Rh)  type,  and  an  antibody  screen  should  be  done  if  these  are  not  known.  It  is  also  important  to  know  the  hepatitis  B  status of the mother so that a pediatrician can be noti- fied  if  the  mother  is  positive.  Additionally,  a  voided  urine specimen should be checked for the presence of  protein and glucose.

Maternal Monitoring. Maternal pulse rate, blood pres- sure,  respiratory  rate,  and  temperature  should  be 

PA R T 2 Obstetrics108

labor  and  preventing umbilical cord compression or cord prolapse if the presenting part is not engaged.

Second Stage of Labor At the beginning of the second stage, the mother usually has a desire to bear down with each contrac- tion.  This  abdominal  pressure,  together  with  the  uterine  contractile  force,  combines  to  expel  the  fetus.  During the second stage of labor (Figure 8-10, A), fetal descent must be monitored carefully  to  evaluate  the  progress  of  labor.  Descent  is  measured  in  terms  of  progress of the presenting part through the birth canal.

In  cephalic  presentations,  the  shape  of  the  fetal  head  may  be  altered  during  labor,  making  the  assess- ment  of  descent  more  difficult.  Molding  is  the  altera- tion  of  the  relationship  of  the  fetal  cranial  bones  to  each other as a result of the compressive forces exerted  by the bony maternal pelvis. Some molding is normal.  If  cephalopelvic  disproportion  is  present,  the  amount  of molding will be more pronounced. Caput is a local- ized,  edematous  swelling  of  the  scalp  caused  by  pres- sure of the cervix on the presenting portion of the fetal  head. The development of both molding and caput can  create a false impression of fetal descent.

The second stage generally takes from 30 minutes to 3 hours in primigravid women and from 5 to 30 minutes in multigravida.

MECHANISIM OF LABOR. Six  movements  of  the  baby  enable  it  to  adapt  to  the  maternal  pelvis:  descent,  flexion,  internal  rotation,  extension,  external  rotation,  and expulsion (see Figure 8-10). These movements are  discussed here for both an occipitoanterior and occipi- toposterior position at engagement. The mechanism of  labor for other than vertex presentations is covered in  Chapter 13.

Descent. Descent is brought about by the force of the  uterine  contractions,  maternal  bearing-down  (Val- salva) efforts, and, if the patient is upright, gravity.

Flexion. Partial flexion exists before labor as a result  of the natural muscle tone of the fetus. During descent,  resistance  from  the  cervix,  walls  of  the  pelvis,  and  pelvic floor causes further flexion of the cervical spine,  with  the  baby’s  chin  approaching  its  chest.  In the occipitoanterior position, the effect of flexion is to change the presenting diameter from the occipito- frontal to the smaller suboccipitobregmatic  (see  Figure 8-2). In the occipitoposterior position, complete  flexion  may  not  occur,  resulting  in  a  larger  presenting  diameter, which may contribute to a longer labor.

Internal Rotation. In  the  occipitoanterior  position,  the  fetal  head,  which  enters  the  pelvis  in  a  transverse  or  oblique  diameter,  rotates  so  that  the  occiput  turns  anteriorly  toward  the  symphysis  pubis.  Internal  rota- tion probably occurs as the fetal head meets the mus- cular sling of the pelvic floor. It is often not accomplished  until  the  presenting  part  has  reached  the  level  of  the 

recorded  every  1  to  2  hours  during  normal  labor  and  more frequently if indicated. Fluid balance, particularly  urine  output  and  fluid  intake,  should  be  monitored  carefully.

Analgesia. Adequate  analgesia  is  important  during  the first stage of labor (see later in this chapter).

Fetal Monitoring. The fetal heart rate should be eval- uated by auscultation with a DeLee stethoscope, by external monitoring with Doppler equipment, or by internal monitoring with a fetal scalp electrode.  In  uncomplicated  pregnancies,  continuous  electronic  fetal  monitoring  is  not  necessary,  as  several  studies  have  demonstrated  that  intermittent  auscultation  of  the  fetal  heart  rate,  when  performed  in  conjunction  with a 1 : 1 nurse-to-patient ratio, results in comparable  outcomes and may reduce the risk of cesarean delivery.  Continuous  fetal  heart  rate  monitoring  provides  a  record of the labor and may be preferred for documen- tation  and  medicolegal  reasons.  In patients with no significant obstetric risk factors, the fetal heart rate should be auscultated or the electronic monitor tracing evaluated at least every 30 minutes in the active phase of the first stage of labor and at least every 15 minutes in the second stage of labor. In patients with obstetric risk factors, the fetal heart rate should be auscultated or the electronic monitor- ing tracing evaluated at least every 15 minutes during the active phase of the first stage of labor (immedi- ately following a uterine contraction) and at least every 5 minutes during the second stage.

Uterine Activity. Uterine  contractions  should  be  monitored every 30 minutes by palpation for their fre- quency,  duration,  and  intensity.  For high-risk preg- nancies, uterine contractions should be monitored continuously along with the fetal heart rate. This can  be  achieved  electronically  using  either  an  external  tocodynamometer  or  an  internal  pressure  catheter  in  the  amniotic  cavity.  The  latter  is  particularly  of  value  when a patient’s labor is being augmented with oxyto- cin (Pitocin). When an internal catheter is not used, the  strength  of  uterine  contractions  should  be  monitored  by palpation every 15 minutes.

Vaginal Examination. During  the  latent  phase,  partic- ularly  when  the  membranes  are  ruptured,  vaginal  examinations should be done sparingly to decrease the  risk  of  an  intrauterine  infection.  In the active phase, the cervix should be assessed approximately every 2 hours to determine the progress of labor.  Cervical  effacement and dilation, the station and position of the  presenting part, and the presence of molding or caput  in vertex presentations should be recorded.

Amniotomy. The artificial rupture of fetal membranes  may  increase  uterine  activity  and  may  provide  infor- mation  on  the  volume  of  amniotic  fluid  and  the  pres- ence  or  absence  of  meconium;  however,  current  opinion  suggests  that  keeping  the  membranes  intact  may  be  of  value  in  supporting  the  normal  progress  of 

C H A P T E R 8 Normal Labor, Delivery, and Postpartum Care 109

FIGURE 8-10 Mechanism of labor for a vertex presentation in the left occipitotransverse position. A, Flexion and descent. B and C, Continued descent and commencement of internal rotation. D, Completion of internal rotation to the occipitoanterior position followed by delivery of the head by extension.

C

A

D

B

be more difficult to repair when they occur without an  episiotomy. The head is born by rapid extension as the  occiput, sinciput, nose, mouth, and chin pass over the  perineum.

In  the  occipitoposterior position,  the  head  is  born  by a combination of flexion and extension. At the time  of crowning, the posterior bony pelvis and the muscu- lar  sling  encourage  further  flexion. The  forehead,  sin- ciput, and occiput are born as the fetal chin approaches  the  chest.  Subsequently,  the  occiput  falls  back  as  the  head extends and the nose, mouth, and chin are born.

External Rotation. In  both  the  occipitoanterior  and  occipitoposterior  positions,  the  delivered  head  now  returns  to  its  original  position  at  the  time  of  engage- ment  to  align  itself  with  the  fetal  back  and  shoulders.  Further  head  rotation  may  occur  as  the  shoulders  undergo  an  internal  rotation  to  align  themselves  anteroposteriorly within the pelvis.

ischial  spines  (zero  station)  and  therefore  is  engaged.  In  the  occipitoposterior  positions,  the  fetal  head  may  rotate posteriorly so that the occiput turns toward the  hollow of the sacrum.

Extension. The  flexed  head  in  an  occipitoanterior  position  continues  to  descend  within  the  pelvis.  Because  the  vaginal  outlet  is  directed  upward  and  forward,  extension  must  occur  before  the  head  can  pass  through  it.  As  the  head  continues  its  descent,  there is bulging of the perineum followed by crowning  (see Figure 8-10, D). Crowning occurs when the largest  diameter  of  the  fetal  head  is  encircled  by  the  vulvar  ring.  At  this  time,  the  vertex  has  reached  station  +5.  When  indicated,  an  incision  in  the  perineum  (episi- otomy)  may  aid  in  reducing  perineal  resistance.  Current management is to allow the fetus to deliver without an episiotomy when possible.  Good  clinical  judgment is needed to avoid traumatic tears that may 

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Expulsion. Following  external  rotation  of  the  head,  the  anterior  shoulder  delivers  under  the  symphysis  pubis, followed by the posterior shoulder over the peri- neal body and the body of the child.

CLINICAL MANAGEMENT OF THE SECOND STAGE. As in the  first stage, certain steps should be taken in the clinical  management of the second stage of labor.

Maternal Position. With the exception of avoiding the  supine position, the mother may assume any comfort- able position for effective bearing down.

Bearing Down. With  each  contraction,  the  mother  should  be  encouraged  to  hold  her  breath  and  bear  down with expulsive efforts. This is particularly impor- tant for patients with regional anesthesia because their  reflex sensations may be impaired.

Fetal Monitoring. During  the  second  stage,  the  fetal  heart rate should be monitored continuously or evalu- ated  every  5  minutes  in  patients  with  obstetric  risk  factors.  Fetal  heart  rate  decelerations  (head  compres- sion or cord compression) with recovery following the  uterine  contraction  may  occur  normally  during  this  stage (see Chapter 9).

Vaginal Examination. Progress  should  be  recorded  approximately  every  30  minutes  during  the  second  stage. Particular attention should be paid to the descent  and flexion of the presenting part, the extent of internal  rotation,  and  the  development  of  molding  or  caput.  During the second stage of labor, the retracted cervix is  no longer palpable.

Delivery of the Fetus. When  delivery  is  imminent,  the  patient is usually placed in the lithotomy position, and  the  skin  over  the  lower  abdomen,  vulva,  anus,  and  upper  thighs  is  cleansed  with  an  antiseptic  solution.  Uncomplicated  deliveries,  particularly  in  multiparous  women,  may  be  carried  out  with  the  patient  in  the  supine position with the thighs flexed. The left lateral position  may  be  used  for  delivery  in  patients  who  desire  to  deliver  in  this  position,  for  those  with  hip  or  knee joint deformities that prevent adequate flexion, or  for  patients  with  a  superficial  or  deep  venous  throm- bosis in one of the lower extremities.

As the perineum becomes flattened by the crowning  head,  an  episiotomy  may  be  performed  to  prevent  perineal  lacerations.  Some  studies  show  that  the  per- formance  of  episiotomies  may  result  in  a  higher  pro- portion  of  lacerations  that  involve  the  anal  sphincter  (third degree) or anal mucosa (fourth degree).

To  facilitate  delivery  of  the  fetal  head,  a Ritgen maneuver is performed (Figure 8-11). The right hand,  draped  with  a  towel,  exerts  upward  pressure  through  the  distended  perineal  body,  first  to  the  supraorbital  ridges  and  then  to  the  chin.  This  upward  pressure,  which  increases  extension  of  the  head  and  prevents  it  from  slipping  back  between  contractions,  is  counter- acted by downward pressure on the occiput with the left 

hand. The downward pressure prevents rapid extension  of the head and allows a controlled delivery.

Once  the  head  is  delivered,  the  airway  is  cleared  of  blood  and  amniotic  fluid  using  a  bulb  suction  device.  The  oral  cavity  is  cleared  initially,  and  then  the  nares  are  cleared.  Suction  of  the  nares  is  not  performed  if  fetal  distress  or  meconium-stained  liquor  is  present,  because it may result in gasping and aspiration of pha- ryngeal contents. A second towel is used to wipe secre- tions from the face and head.

After the airway has been cleared, an index finger is  used to check whether the umbilical cord encircles the  neck.  If  so,  the  cord  can  usually  be  slipped  over  the  infant’s  head.  If  the  cord  is  too  tight,  it  can  be  cut  between two clamps.

Following  delivery  of  the  head,  the  shoulders  descend  and  rotate  into  the  anteroposterior  diameter  of  the  pelvis  and  are  delivered  (Figure  8-12).  Delivery of the anterior shoulder is aided by gentle downward traction on the externally rotated head. The brachial plexus may be injured if excessive force is used. The  posterior  shoulder  is  delivered  by  elevating  the  head.  Finally, the body is slowly extracted by traction on the  shoulders.

After  delivery,  blood  will  be  infused  from  the  pla- centa  into  the  newborn  if  the  baby  is  held  below  the  mother’s  introitus.  Delayed cord clamping is recom- mended for 1 to 2 minutes. For the preterm infant, in  particular, allowing 1 to 2 minutes provides important  benefits, such as improvement in circulatory and respi- ratory  function,  a  reduction  in  the  need  for  blood  transfusion, and reduced risk of intraventricular hem- orrhage.  After  the  cord  is  clamped,  the  newborn  is  given  to  the  mother  for  skin-to-skin  contact.  If  the  newborn is preterm and is stable after a brief period of  skin-to-skin  contact,  it  is  placed  under  an  infant  warmer to prevent hypothermia.

Third Stage of Labor Immediately after the baby’s delivery (the end of the second stage of labor), the cervix and vagina should be thoroughly inspected for lacerations, and surgical repair should be performed when necessary.  The  cervix,  vagina,  and  perineum  may  be  more  readily  examined before the separation of the placenta, as no  uterine  bleeding  should  be  present  to  obscure  visual- ization. Attention is directed to any: 1.  Perineal lacerations that continue to bleed and

need repair.  Lacerations,  with  or  without  episiot- omy, may be classified as follows: a.  First degree:  a  laceration  involving  the  vaginal 

epithelium or perineal skin b.  Second degree:  a  laceration  extending  into  the 

subepithelial  tissues  of  the  vagina  or  perineum  with or without involvement of the muscles of the  perineal body

C H A P T E R 8 Normal Labor, Delivery, and Postpartum Care 111

cord lengthens outside the vagina, (3) the fundus rises up,  and  (4)  the  uterus becomes firm and globular.  Only when these signs have appeared should the assis- tant attempt traction on the cord. With gentle traction  and  counterpressure  between  the  symphysis  and  fundus to prevent descent of the uterus into the pelvis,  the placenta is delivered.

The next appropriate step (after Pitocin infusion is started as mentioned above) is the application of uterine massage by either the physician or the nurse in attendance.  If  the  patient  is  at  risk  for  postpartum  hemorrhage  (e.g.,  because  of  anemia,  prolonged  oxy- tocic  augmentation  of  labor,  multiple  gestation,  mac- rosomia,  or  polyhydramnios),  manual  removal  of  the  placenta and manual exploration of the uterus may be  necessary.

Finally, the placenta should be examined to ensure its complete removal (no missing cotyledons) and to detect placental abnormalities. Dilation and curettage  may be necessary to evacuate retained placental tissue  that is causing hemorrhaging.

c.  Third degree:  a  laceration  involving  the  anal  sphincter

d.  Fourth degree:  a  laceration  involving  the  rectal  mucosa

2.  Cervical lacerations that are bleeding and need repair.

DELIVERY OF THE PLACENTA. Separation of the placenta  generally  occurs  within  2  to  10  minutes  of  the  end  of  the second stage of labor (delivery of the baby). Squeez- ing  the  fundus  to  hasten  placental  separation  is  not  recommended, because it may increase the likelihood  of  passage  of  fetal  cells  into  the  maternal  circulation.  The initial step in the management of the third stage of labor for prevention of postpartum hemorrhage is  to begin an IV infusion of 40 U of Pitocin in 500 mL of  saline at a rate of 10 mL/min for 5 minutes, followed by  1  to  2 mL/min  until  the  patient  is  transferred  to  the  postpartum unit.

Signs of placental separation  are  as  follows:  (1)  a fresh show of blood from the vagina, (2) the umbilical

FIGURE 8-11 Ritgen maneuver. The fingers of the right hand, pressing posterior to the rectum, are used to extend the head while coun- terpressure is applied to the occiput by the left hand to allow a controlled delivery of the fetal head.

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tion of the patient to prevent postpartum hemorrhage.  Blood pressure, pulse rate, and uterine blood loss must  be monitored closely, and it is important to instruct the  patient  on  massaging  the  uterus  to  maintain  uterine  tone.  It  is  during  this  time  that  serious  postpartum  hemorrhage most commonly occurs, but some women  may have frequent bleeding for up to 10 days postpar- tum,  usually  because  of  uterine  relaxation,  retained  placental  fragments,  or unrepaired lacerations.  An  increase  in  pulse  rate,  often  out  of  proportion  to  any  decrease in blood pressure, may indicate hypovolemia.

If an episiotomy has been performed (Figure 8-13),  it  should  be  repaired  as  illustrated  in  Figure  8-14.  Absorbable  sutures  (size  00)  should  be  used,  and  a  rectal  examination  should  be  done  to  ensure  that  the  sutures  have  not  inadvertently  transected  the  rectal  mucosa.  A  third-degree  tear  (Figure  8-15)  should  be  repaired as shown in Figure 8-16.

Fourth Stage of Labor The hour immediately following delivery and the first 4 hours postpartum require continued close observa-

FIGURE 8-12 Delivery of the shoulders. A, Gentle downward traction on the head is applied to deliver the anterior shoulder. B, Gentle upward traction is used to deliver the posterior shoulder.

A

B

C H A P T E R 8 Normal Labor, Delivery, and Postpartum Care 113

yellow-white  color  (lochia alba).  Foul-smelling  lochia  suggests endometritis.

Vagina Although  the  vagina  may  never  return  to  its  prepreg- nancy  state,  the  supportive  tissues  of  the  pelvic  floor  gradually regain their former tone. Women who deliver  vaginally should be taught and encouraged to perform  Kegel exercises (intermittent tightening of the perineal  muscles)  to  maintain  and  improve  the  supportive  tissues of the pelvic floor.

Cardiovascular System Immediately  following  delivery,  there  is  a  marked  increase  in  peripheral  vascular  resistance  because  of  the removal of the low-pressure uteroplacental circula- tory  shunt.  The  cardiac  output  and  plasma  volume  gradually  return  to  normal  during  the  first  2  weeks  of  the puerperium. As a result of the loss of plasma volume  and the diuresis of extracellular fluid, a marked weight  loss occurs in the first week.

Puerperium The puerperium consists of the period following delivery of the baby and placenta to approximately 6 weeks postpartum. During the puerperium, the repro- ductive  organs  and  maternal  physiology  return  to  the  prepregnancy  state,  although  menses  may  not  return  for much longer.

ANATOMIC AND PHYSIOLOGIC CHANGES Involution of the Uterus Through  a  process  of  tissue  catabolism,  the  uterus  rapidly decreases in weight from about 1000 g at deliv- ery to 100 to 200 g approximately 3 weeks postpartum.  The  cervix  similarly  loses  its  elasticity  and  regains  its  prepregnancy  firmness.  For  the  first  few  days  after  delivery,  the  uterine  discharge  (lochia)  appears  red  (lochia rubra),  because  of  the  presence  of  erythro- cytes. After 3 to 4 days, the lochia becomes paler (lochia serosa),  and  by  the  tenth  day,  it  assumes  a  white  or 

FIGURE 8-13 A, Mediolateral episiotomy. B, Midline episiotomy.

A B

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reported. If a patient has symptoms of depression, she  should  be  screened  using  the  Edinburgh  Postnatal  Depression  Scale. Vitamin  D  supplementation  is  safe,  and at least 2000 to 3000 IU/day can be started follow- ing assessment of the level of the vitamin (25[OH]D) in  the  patient’s  serum. With  understanding  and  reassur- ance  from  both  family  and  physician,  the  patient’s 

Psychosocial Changes It  is  fairly  common  for  women  to  exhibit  a  mild   degree of depression a few days following delivery. The  “postpartum blues”  are  probably  due  to  both  emo- tional  and  hormonal  factors.  Recently, a relationship between vitamin D deficiency (<20 ng/mL) or insuf- ficiency (20 to 29 ng/mL) and depression has been

FIGURE 8-14 A, Repair of a midline episiotomy. A taped sponge is placed in the upper vagina, and a continuous, locked 00 or 000 absorbable suture is used to close the vaginal epithelium from the apex to the hymeneal ring. B, Three interrupted sutures are used to close the deep perineal fascia (of Colles) and underlying levator ani muscles. The vaginal epithelial suture is brought below the skin into the subcutaneous tissue. C, The same continuous suture is used to close the superficial fascia down to the anal edge of the episiotomy. D, The same suture is used as a subcuticular stitch brought back to the hymeneal ring, where it is doubly tied. The sponge is then removed (which is very important).

A B

C D

C H A P T E R 8 Normal Labor, Delivery, and Postpartum Care 115

infant’s  gut  by  preventing  attachment  of  harmful  bac- teria  (e.g.,  Escherichia coli)  to  cells  on  the  mucosal  surface.  This  prevents  the  bacteria  from  penetrating  the  bowel  wall.  It  is  also  thought  that  maternal  lym- phocytes pass through the infant’s gut wall and initiate  immunologic  processes  that  are  not  yet  well  under- stood.  Breastfeeding thereby provides the newborn with passive immunity  against  certain  infectious  dis- eases until its own immune mechanisms become fully  functional  by  3  to  4  months.  Fourth, it is a way of transferring appropriate maternal bacteria to the infant’s gut.  This  also  occurs  as  the  infant  swallows  gut bacteria during its passage through the birth canal,  but  this  does  not  occur  if  the  baby  is  delivered  by  cesarean  delivery.  For  the  preterm  infant,  it  is  espe- cially  desirable  to  be  born  vaginally.  The  normal  bac- teria  obtained  assist  in  the  prevention  of  necrotizing  enterocolitis.

LACTATION Various  hormones,  such  as  estrogen,  progesterone,  human chorionic gonadotropin (hCG), cortisol, insulin, 

postpartum  blues  usually  resolve  without  conse- quence. Any prolonged episodes of depression during or after pregnancy should receive urgent attention.

Return of Menstruation and Ovulation In  women  who  do  not  nurse,  menstrual  flow  usually  returns by 6 to 8 weeks, although this is highly variable.  Although ovulation may not occur for several months,  particularly  in  nursing  mothers,  contraceptive  use  should be emphasized during the puerperium to avoid  an undesired pregnancy.

Breastfeeding There  are  many  advantages  to  breastfeeding.  First, breast milk is the ideal food for the newborn, is inexpensive, and is usually in good supply. Second, nursing accelerates the involution of the uterus  because  suckling  stimulates  the  release  of  oxytocin,  thereby causing increased uterine contractions. Third,  and probably most important, there are immunologic advantages for the baby from breastfeeding. Various  types of maternal antibodies are present in breast milk.  The predominant immunoglobulin is secretory immu- noglobulin  A  (IgA),  which  provides  protection  in  the 

FIGURE 8-15 Third-degree perineal tear extending into the rectum and avulsing the circular rectal sphincter.

FIGURE 8-16 Repair of a third-degree tear involves approximating the fascia surrounding the rectal sphincter muscle and reapproxi- mating the vaginal tears with locked continuous sutures. The process is then completed in the same way as with a midline episiotomy repair.

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and the mother should be started on a regimen of anti- biotics  immediately.  Because the majority of staphy- lococcal organisms are penicillinase-producing, a penicillinase-resistant antibiotic, such as dicloxa- cillin, should be used.  Breastfeeding  may  be  dis- continued  but  is  not  contraindicated.  An  appropriate  antibiotic  should  be  continued  for  7  to  10  days.  If  a  breast  abscess  ensues,  it  should  be  surgically  drained.  A breast pump can be used to maintain lactation until  the infection has cleared if nursing is discontinued.

Drug Passage to the Newborn Because  an  infant  may  ingest  up  to  500 mL  of  breast  milk per day, maternally administered drugs that pass  into  breast  milk  may  have  a  significant  effect  on  the  infant.  The  amount  of  drug  found  in  breast  milk  depends  on  the  maternal  dose,  the  rate  of  maternal  clearance, the physicochemical properties of the drug,  and the composition of the breast milk with respect to  fat  and  protein. The  gestational  age  of  the  infant  may  also be a determinant of the ultimate drug effect. Table  8-6  lists  selected  drugs  with  their  reported  newborn  effects.

Interconception Care Women  who  have  pregnancy  complications,  such  as  preterm birth, preeclampsia, intrauterine growth restriction, gestational diabetes, obesity, and perina- tal death,  are  at  greater  risk  of  having  the  same  prob- lems  with  subsequent  pregnancies.  Programs  now  offer  comprehensive  interconception care  to  address  conditions  that  have  been  shown  to  cause  poor  out- comes  by  providing  interventions  that  could  mitigate  or  eliminate  any  recurrence  and/or  improve  the  long- term  health  of  the  mother.  The  rationale  for  this  approach is to provide continuous obstetric care rather  than  episodic  care  triggered  by  another  pregnancy.  Studies  are  underway  to  determine  the  value  of  these  programs.

Obstetric Analgesia and Anesthesia The  goal  of  obstetric  analgesia  and  anesthesia  is  to  provide  effective  pain  relief  for  the  mother  during  the  course of labor and delivery that is safe for her and her  baby and that has minimal or no adverse effects on the  progress  and  outcome  of  labor.  Anesthetic  practices  have evolved to include an increased reliance on highly  effective and safe regional anesthetic techniques, using  low-concentration combinations of narcotics and local  anesthetics  to  minimize  the  adverse  effects  of  each.  Maternal  anesthetic  risk  has  also  declined  because  of  the increased safety of regional over general anesthesia  for cesarean deliveries. Maternal mortality because of anesthesia has decreased to less than 1 in 500,000 mothers.

prolactin,  and  placental  lactogen,  play  an  important  role  in  preparing  the  breasts  for  lactation.  At delivery, two events are instrumental in initiating lactation. The first is the drop in placental hormones, particu- larly estrogen.  Before  delivery,  these  hormones  inter- fere  with  the  lactogenic  action  of  prolactin.  Second, suckling stimulates the release of prolactin and oxy- tocin. The latter causes contraction of the myoepithe- lial  cells  in  the  alveoli  and  milk  ducts.  The  suckling  stimulus  is  thought  to  be  important  for  milk  produc- tion, as well as for the ejection of colostrum and milk.

On approximately the second day after delivery, colostrum is secreted. Its content is composed mostly  of  protein,  fat,  and  minerals.  It  is  the  colostrum  that  contains  secretory  IgA.  After about 3 to 6 days, the colostrum is replaced by mature milk. The content of  milk varies considerably, depending on the nutritional  status of the mother and the gestational age at the time  of delivery. In general, the major components of breast  milk  are  proteins,  lactose,  water,  and  fat.  The  major  proteins  synthesized  in  the  human  breast,  which  are  unique  and  are  not  found  in  cow’s  milk,  are  casein,  lactalbumin,  and  β-lactoglobulin.  Essential  amino  acids are delivered via the mother’s blood, and some of  the nonessential amino acids can be synthesized in the  breast. In addition, breast milk is a source of omega-3  fatty  acids,  which  are  important  for  early  brain  development.

LACTATION SUPPRESSION When the mother chooses not to breastfeed, lactation  suppression  is  indicated.  The simplest, and probably safest, method to accomplish this is to use a tight- fitting bra.  If  breast  distention  does  occur,  pumping  only  makes  the  situation  worse.  Ice  packs  should  be  applied and the discomfort managed with analgesics.

COMPLICATIONS OF BREASTFEEDING Cracked Nipples If  the  nipples  of  the  breast  become  fissured,  nursing  may become difficult. Because fissures are also a portal  of  entry  for  bacteria,  they  should  be  managed  aggres- sively  with  a  nipple  shield  and  an  appropriate  cream,  such as lanolin or Massé breast cream. Further breast- feeding  should  be  temporarily  stopped.  Milk  can  be  expressed  manually  until  the  nipples  heal,  at  which  time breastfeeding can be resumed.

Mastitis This  is  an  uncommon  complication  of  breastfeeding  and usually develops after 2 to 4 weeks. The first symp- toms  are  usually  slight  fever  and  chills.  These  are  fol- lowed  by  redness  of  a  segment  of  the  breast,  which  becomes  indurated  and  painful.  The etiologic agent is usually Staphylococcus aureus, which originates from the infant’s oral pharynx.  Milk  should  be  obtained  from  the  breast  for  culture  and  sensitivity, 

C H A P T E R 8 Normal Labor, Delivery, and Postpartum Care 117

hypotension  occurs  and  is  not  properly  and  promptly  treated.  Adequate  hydration  (e.g.,  1000 mL  of  lactated  Ringer solution) 30 to 60 minutes before regional anes- thesia helps to improve uterine blood flow and mitigate  the  risk  of  hypotension.  If  hypotension  does  occur  (>15%  below  baseline  or  <100 mm Hg  systolic  blood  pressure),  a  vasopressor  (e.g.,  10 mg  of  IV  ephedrine)  will  typically  restore  maternal  blood  pressure  and  uterine blood flow.

PAIN PATHWAYS The  pain  pathways  of  parturition  are  shown  in   Figure 8-17.

ADVERSE EFFECTS OF LABOR PAIN Maternal hyperventilation during contractions causes respiratory alkalosis that results in (1) a shift of the oxyhemoglobin dissociation curve to the left, (2) increased affinity of maternal hemoglobin for oxygen, and (3) decreased oxygen offloading to the fetus. The cyclic nature of contraction pain may cause  a hyperventilation-hypoventilation syndrome whereby  the mother blows off so much carbon dioxide during a 

TABLE 8-6

EFFECTS OF MATERNAL DRUG INGESTION ON BREASTFEEDING INFANTS

Drug Reported Infant Effects

Sedative-Hypnotics

Diazepam Sedation

Antipsychotics

Chlorpromazine No adverse effects reported

Haloperidol No adverse effects reported

Nonnarcotic Analgesics

Acetaminophen No adverse effects reported

Salicylates Theoretical risk of platelet dysfunction

Anticonvulsants

Phenobarbital Sedation

Phenytoin Sedation, decreased sucking

Narcotics

Heroin May cause addiction

Methadone Infant death reported

Meperidine No adverse effects reported

Antibiotics

Penicillin May modify bowel flora, cause allergy, or interfere with sepsis workup

Ampicillin Same as for penicillin

Erythromycin Same as for penicillin

Nitrofurantoin Theoretical risk of hemolytic anemia in infants with G6PD deficiency

Tetracycline Same as for penicillin; theoretical risk of discoloration of teeth and inhibition of bone growth

Digoxin No adverse effects reported

Thyroid Drugs

Thyroxine May interfere with screening for hypothyroidism

Propylthiouracil Nodular goiter

Antihypertensives

Methyldopa No adverse effects reported

Propranolol No adverse effects reported

Theophylline One case of infant irritability following maternal administration of a rapidly absorbed oral preparation

G6PD, Glucose-6-phosphate dehydrogenase.

UTERINE BLOOD FLOW Uterine blood flow at term accounts for 700 to 900 mL/ min (about 12% of maternal cardiac output) and is not  autoregulated.  Regional  analgesia  or  anesthesia  may  increase uterine blood flow, especially in patients with  preeclampsia,  by  relieving  pain  and  stress  and  reduc- ing  circulating  catecholamines.  Regional  analgesia  or  anesthesia  may  also  decrease  uterine  blood  flow  if 

FIGURE 8-17 Pain pathways of parturition: T10 to L1 supply inner- vation to the uterus, L1 to S4 supply pain pathways to the vagina and deep pelvic structures, and S2 to S4 supply nerve fibers to the pudendal nerve.

T10

T11

T12

L1

S2 S3

S4

PA R T 2 Obstetrics118

analgesia,  as  long  as  the  patient  is  having  regular,  painful  contractions.  Modern  epidural  management  includes  an  initial  bolus  of  local  anesthetic  bupiva- caine,  ropivacaine,  or  lidocaine,  as  well  as  narcotics  such as fentanyl or sufentanil to achieve a T10 sensory  level, followed by an infusion of a dilute solution of the  same agents until delivery. Pain during the first stage of  labor is conducted along the sympathetic fibers, enter- ing  the  spinal  cord  between  T10  and  L1.  Dilute  solu- tions  can  be  used  that  permit  ambulation,  referred  to  as  the “walking  epidural.”  The goal is to avoid motor block  to  minimize  any  adverse  effects  on  maternal  expulsive  efforts  in  the  second  stage  of  labor.  Com- bined spinal-epidural  is  a  technique  that  has  gained  popularity for both labor analgesia and repeat cesarean  deliveries.  It  provides  rapid  onset  of  analgesia  and/or  anesthesia  and  the  prolonged  administration  capabil- ity of an epidural catheter.

A pudendal nerve block anesthetizes somatic affer- ent nerve fibers entering the spinal cord at sacral seg- ments  S2  to  S4.  It  is usually effective at relieving the perineal pain of the second stage of labor,  as  well  as  the  pain  of  episiotomy  and  episiotomy  repair.  It  does  not affect the ongoing pain of uterine contractions.

ANESTHESIA FOR CESAREAN DELIVERY The type of anesthesia selected for cesarean delivery is  determined by the urgency of the surgery, the presence  or absence of a preexisting epidural catheter for labor,  the  patient’s  medical  condition,  pregnancy-related  complications,  and  the  presence  of  any  contraindica- tions to regional anesthesia. Absolute and relative con- traindications  to  regional  anesthesia  are  listed  in  Box  8-1.  All  patients  requiring  anesthesia  for  surgery  must  have an airway examination, regardless of how urgent  the  surgery  is.  A  brief  history  must  also  be  elicited.  If the history or the physical examination suggests that the intubation will be difficult (Box 8-2), then the patient must be given a regional anesthetic or have an awake intubation or the operation must be started with the patient under local anesthesia.

All  patients  should  be  premedicated  with  a  non- particulate  antacid.  Routine  monitors  are  placed, 

contraction that she hypoventilates between contrac- tions and may even become mildly hypoxemic between  contractions.  This  syndrome  is  exacerbated  by  sys- temic narcotics because they do not adequately relieve  the  pain  of  the  contraction  but  do  add  to  the  respira- tory  depression  between  contractions.  Hypoxemia between contractions may be attenuated by providing  supplemental  oxygen.  Finally,  labor pain results in increased levels of circulating catecholamines.  The  α-adrenergic effects of the catecholamines may reduce  uterine  blood  flow,  and  the  β2-adrenergic  effects  may  impair uterine contractility.

OPTIONS FOR LABOR PAIN RELIEF Nonpharmacologic methods  include  education  and  psychoprophylaxis  (Lamaze  method),  emotional  support,  back  massage,  hydrotherapy,  biofeedback,  transcutaneous  electrical  nerve  stimulation  (TENS),  acupuncture, and hypnosis (hypnobirthing). Scientific  assessment of these methods has yielded inconsistent  results. In most studies, acupuncture has been found to decrease pain. These  techniques  tend  to  work  best  early  in  the  first  stage  of  labor,  when  the  pain  is  least  intense,  and  may  decrease  pharmacologic  usage  at   that time.

Pharmacologic treatment options  include  paren- teral  narcotics,  regional  analgesia  (epidural,  spinal,  combined  spinal-epidural,  paracervical,  caudal,  and  pudendal  nerve  blocks)  and  inhalational  analgesics  (nitrous oxide).

Parenteral narcotics have very limited efficacy for the relief of labor pain. They work best in the early first  stage,  when  the  pain  is  primarily  visceral  and  less  intense. All opioids readily cross the placental barrier  and  may  cause  neonatal  respiratory  depression,  depending on the dose and timing relative to delivery.  They  may  also  cause  decreased  fetal  heart  rate  vari- ability  (due  to  narcotic  effect)  and  impaired  neonatal  breastfeeding.  Fentanyl  and  nalbuphine  are  the  most  commonly  used  and  have  short  neonatal  half-lives.  Remifentanil,  an  ultra-short-acting  narcotic,  may  be  used for IV patient-controlled analgesia when regional  anesthesia is contraindicated. In addition, remifentanil  has  been  used  for  routine  obstetric  analgesia  in  the  United  Kingdom,  with  several  case  reports  of  associ- ated respiratory arrest.

Neuraxial analgesia  (medication  injected  into  the  spinal column) is undoubtedly the most effective form  of  labor  pain  relief.  Lumbar epidural analgesia is the most common form of neuraxial analgesia,  and  its  use continues to increase nationally. It may be used to  provide  pain  relief  for  the  first  and  second  stages  of  labor and, by injecting a higher concentration of local  anesthetic, the block may be intensified and extended  to  provide  surgical  anesthesia  for  cesarean  delivery  or  postpartum  tubal  ligation.  There  is  no  fixed  cervical  dilation  at  which  it  is  appropriate  to  provide  epidural 

BOX 8-1

CONTRAINDICATIONS TO REGIONAL ANESTHESIA

Absolute Contraindications Patient refusal Coagulopathy Infection at needle insertion site Severe hypovolemia with ongoing blood loss

Relative Contraindications (Selected) Prior back surgery (including Harrington rod placement) Certain cardiac lesions, especially aortic stenosis Increased intracranial pressure

C H A P T E R 8 Normal Labor, Delivery, and Postpartum Care 119

BOX 8-2

FACTORS SUGGESTING DIFFICULT INTUBATION

Obesity and/or short neck Neck  flexion  and/or  extension  limitations  at  atlantooc-

cipital joint Short chin–hyoid distance (receding chin) Limited mouth opening Poor dentition and/or buck teeth Excess  oropharyngeal  tissues  (see  the  uvula  and  tonsillar 

pillars) Large tongue

TABLE 8-7

OBSTETRIC ANESTHESIA-RELATED MATERNAL COMPLICATIONS, UNITED STATES, 2004-2009

Complication Incidence

Arrest 1 : 128,400

Abscess/meningitis 1 : 6300

Death 0 : 257,000

Epidural hematoma 1 : 251,500

Failed intubation 1 : 533

High neuraxial block 1 : 4400

Neurologic Injury 1 : 36,000

Respiratory arrest 1 : 10,000

From D’Angelo R, Smiley RM, Riley ET, et al: Serious complications related to obstetric anesthesia. Anesthesiology 120:1505–1512, 2014.

TABLE 8-8

COMPARISON OF SPINAL AND EPIDURAL ANESTHESIA

Spinal Epidural

Advantages

Faster Can tailor duration to need

Technically easier Lower chance of postdural puncture headache

More reliable Slower onset Defined endpoint Beneficial in patients with cardiac

and hypertensive disorders Minimal chance of

patchy block Faster offset; discharge to room

sooner

Denser block

Lower drug exposure for mother and fetus

No chance of systemic toxicity

Disadvantages

Defined (limited) duration Slower onset

Higher chance of postdural puncture headache (limited by use of small-bore, pencil-point needles)

Higher risk of systemic toxicity because of accidental intravenous injection

Risk of high spinal from inadvertent intrathecal or subdural injection

Risk of “patchy block” from inadequate or asymmetrical dermatomal spread

including a noninvasive blood pressure monitor, elec- trocardiograph, and pulse oximeter, and adequate left  uterine  displacement  must  be  instituted.  Supplemen- tal oxygen is provided. A crystalloid preload bolus of 10  to  15 mL/kg  over  30  to  60  minutes  is  typically  given  before regional anesthesia.

For elective or urgent cesarean delivery (nonemer- gency), regional anesthesia is preferable because the airway is maintained. Complications involving loss of  the airway are the leading causes of anesthesia-related  maternal  mortality  and  are  usually  associated  with  general  anesthesia.  General  anesthesia  carries  a  1.7- fold higher risk of anesthesia-related maternal mortal- ity than regional anesthesia. Potential complications of  obstetric  anesthesia  are  listed  in Table  8-7. Women  in  labor  have  a  higher  risk  of  airway  complications  than  nonpregnant patients because they have (1) a twofold  higher chance of failed intubation; (2) a 60% increased  oxygen consumption; (3) a decreased functional resid- ual  capacity,  resulting  in  a  lower  oxygen  store;  and  (4)  a potentially increased risk of aspiration.

If no epidural is in place, a spinal block is fre- quently used.  A  comparison  of  the  characteristics  of  spinal and epidural anesthesia is shown in Table 8-8.

General anesthesia is employed for cesarean deliv- ery in three situations:  (1)  there  is  extreme  urgency  and no preexisting epidural catheter, (2) there is a con- traindication  to  regional  anesthesia,  or  (3)  regional  anesthesia has failed (1.7% incidence). When a relative  contraindication  to  regional  anesthesia  is  present,  the  benefits of regional anesthesia frequently outweigh the  risks in the pregnant patient.

The protocol for general anesthesia  for  cesarean  delivery  includes  oral administration of nonparticu- late antacid  (sodium  citrate),  routine  monitoring  and  left uterine displacement, preoxygenation for at least  four vital capacity breaths, and rapid sequence induc- tion of anesthesia with cricoid pressure  followed  by  intubation to prevent passive regurgitation and pul- monary aspiration of gastric contents.  Once  the  correct  position  of  the  endotracheal  tube  has  been  confirmed  by  end-tidal  CO2  and  auscultation  of  the  lungs, surgery may begin.

Induction agents used for general anesthesia include  propofol  (most  commonly),  thiopental  (not  currently  available  in  the  United  States),  etomidate  (when  car- diovascular stability is particularly desirable), and ket- amine (for patients with hypovolemia or asthma). The 

PA R T 2 Obstetrics120

nal fever may be due to (1) an alteration in the thermo- regulatory  threshold,  (2)  interference  with  peripheral  thermoreceptor  input  to  the  central  nervous  system,  (3) shifting heat calories from the core to the periphery  by  vasodilation,  (4)  an  imbalance  between  maternal  heat production and loss (decreased hyperventilation,  decreased  lower  body  sweating,  and  increased  shiver- ing),  or  (5)  preexisting  increased  interleukin-6  and  tumor  necrosis  factor-α  levels,  which  predispose  the  mother  to  maternal  fever  in  the  presence  of  regional  blocks. The average temperature increase is small, and  most  women  do  not  develop  fever;  however,  a  small  subset of women who are predisposed to develop fever  do so after epidural administration.

The risk of headache is about 1-2% with spinal anesthesia,  and  it  is  less  than  1%  with  an  epidural.  It  occurs  when  there  is  an  unintended  dural  puncture  (“wet  tap”).  Postdural puncture headaches are self- limited, usually resolving within 5 to 7 days. Cerebro- spinal fluid leaks through the hole in the dura, resulting  in  low  intracranial  pressure.  The hallmark is a severe positional headache:  little  or  no  headache  if  supine,  but  sudden  onset  of  severe  headache  when  sitting  upright or standing. The dural hole will heal in about 1  week, or it can be sealed with an epidural blood patch.  Symptomatic treatment includes narcotics, nonsteroi- dal  antiinflammatory  drugs,  caffeine,  sumatriptan,  and/or an abdominal binder.

There appears to be no association between new- onset, long-term back pain and labor epidural anal- gesia. The risk of new, chronic back pain in parturients  is high (up to 47%), regardless of whether they have had  an epidural. Pelvic girdle pain is common during preg- nancy and postpartum (>25%), with 26-82% of patients  having  MRI  evidence  of  levator  ani  tears  or  a  fracture  of the pubic bone.

Resuscitation of the Newborn Improved  surveillance  using  antenatal  and  intrapar- tum  fetal  heart  rate  monitoring,  real-time  ultrasonog- raphy,  amniocentesis,  and  umbilical  artery  Doppler  assessments has allowed the clinician to recognize the  fetus  at  risk  who  may  need  special  care  at  birth.  The  goals  of  an  organized  approach  to  neonatal  resuscita- tion  are  to  reverse  any  intrauterine  hypoxia  and  to  prevent postnatal asphyxia, which may result in acute  major organ damage and lifelong handicaps.

Preparation for Extrauterine Life Prematurity is the leading cause of poor neonatal outcome because the fetus has not yet progressed through complete stages of anatomic development and biochemical maturation. Even the fetus delivered  at  term  undergoes  changes  before  and  with  the  onset  of labor.

muscle  relaxant  used  to  facilitate  intubation  is  succi- nylcholine  (unless  contraindicated),  because  of  its  rapid onset and brief duration of action. If contraindi- cated, vecuronium or rocuronium may be used. Oxygen delivery is maintained at 50-100% until delivery if the baby is stressed.  Nitrous  oxide  may  be  added.  After  induction,  a  potent  inhalational  agent  is  admin- istered  at  a  modest  level  (0.5  minimum  alveolar   concentration)  to  minimize  myometrial  relaxation.  Narcotics may be administered after the delivery of the baby to reduce the need for inhalational anesthesia  and  provide  postoperative  pain  relief.  The patient must be extubated only when fully awake to mini- mize the risk of aspiration.

PATIENTS WHO BENEFIT FROM EARLY ANESTHETIC CONSULTATION General anesthesia can usually be avoided if an epidu- ral catheter is already in place, so it is helpful to identify  those  patients  who  are  at  increased  risk  of  requiring  surgery  (e.g.,  breech  presentation,  multiple  gestation,  prematurity, poor fetal heart rate tracing [Categories II  and  III;  see  Box  9-1],  severe  preeclampsia,  morbid  obesity)  and  those  patients  who  would  pose  an  espe- cially  high  anesthetic  risk.  Such  patients  should  be  advised  to  get  an  epidural  catheter  early  to  avoid  the  risks  of  a  crash  cesarean  under  general  anesthesia.  These  fetuses  may  also  benefit  from  the  improved  uterine blood flow and controlled delivery that epidu- ral analgesia allows.

Mothers  who  are  at  particularly  high  anesthetic   risk  should  receive  a  prelabor  consultation  for  known  significant  preexisting  medical  conditions  (e.g.,  diffi- cult  airway  [Box  8-2];  significant  respiratory,  cardiac,  hematologic  or  neurologic  disease;  spinal  surgery;   and  suspected  or  known  susceptibility  to  malignant  hyperthermia).

UNINTENDED CONSEQUENCES OF REGIONAL ANESTHESIA AND/OR ANALGESIA Patients who receive epidural analgesia for labor pain have a similar duration of the first stage of labor, but the second stage may be prolonged by 15 minutes on average.  Theoretically,  a  prolongation  of  the  second  stage could arise from effects on the release of endog- enous oxytocin, prostaglandin F2α, and other hormones  responsible for the propagation of labor. Prolongation  of  the  second  stage  could  also  be  due  to  impaired ability to push  (unlikely  as  long  as  motor  block  is  avoided  by  appropriate  adjustment  of  the  epidural  infusion)  or  to  decreased maternal urge to push  caused  by  sensory  blockade. The  latter  can  usually  be  overcome  by  appropriate  coaching  and  decreasing  or  halting the epidural infusion.

Other side effects and complications of regional anesthesia or analgesia include fever (0.5° C increase), headache, and backache. The association with mater-

C H A P T E R 8 Normal Labor, Delivery, and Postpartum Care 121

vagina, the physician should use a towel or gauze pad  to  remove  secretions  from  the  face.  In  addition,  bulb  suction  may  be  used  to  aspirate  secretions  from  the  oropharynx.  Initially, the mouth is suctioned before the nose so that no material is present to aspirate with the first breaths. Deep or vigorous suction should be avoided because posterior pharyngeal stimulation may cause bradycardia from a vagal reflex. If a moder- ate  amount  of  meconium  is  present,  placing  a  nasal  tracheal  catheter  into  the  oropharynx  and  applying  suction  before  delivering  the  body  are  thought  to  decrease  the  risk  of  meconium  aspiration.  If meco- nium is present and the baby is not vigorous (heart rate >100 beats/min, strong respiratory effort, and good muscular tone), intubation should be per- formed to suction the trachea after suction of the mouth.

2. Dry the Newborn An  important  part  of  neonatal  adaptation  is  the   initiation  of  nonshivering  thermogenesis.  Excessive  cooling  from  exposure  of  the  wet  skin  is  detrimental   to  all  preterm  infants  and  to  depressed  full-term  infants. The newborn should be placed in a preheated  environment and dried off with a towel before cutting  the  cord.  This  also  serves  to  stimulate  the  onset  of  respiration.

3. Clamp the Cord The  umbilical  arteries  usually  close  spontaneously  within 45 to 60 seconds after birth, whereas the umbili- cal  vein  remains  patent  for  3  to  5  minutes  or  longer.  Delayed cord clamping has been known for decades to  confer benefit to the fetus.

4. Ensure Onset of Respiration The  onset  of  respiration  normally  occurs  within  a   few  seconds  after  birth.  If respiration has not com- menced by 30 seconds, or if the heart rate is less than 100 beats/min, after delayed cord clamping, the infant should be passed off to the resuscitation team to manage the apnea and low heart rate with stimulation, and positive pressure ventilation should be started. If the baby is delivered at term, 21% oxygen  (room air) should be used initially and adjusted upward  as measured by pulse oximetry or clinically assessed in  terms  of  nonresponsiveness  to  resuscitation.  If the infant is preterm, 30-40% oxygen should be used initially  in  association  with  pulse  oximetry,  and  the  oxygen  concentration  should  be  adjusted  to  the   saturation expected relative to the number of minutes  after  birth  (Figure  8-18).  A  newborn  normally  starts  with an oxygen saturation of 60-65% at birth (by pulse  oximetry),  and  this  increases  to  85-95%  saturation   over  the  first  10  minutes  of  life.  Excessive oxygen delivery following hypoxia is associated with retinop- athy in about 5-15% of infants, and newborn lung

During  pregnancy,  fetal  thyroxine  (T4)  is  converted  to reverse triiodothyronine (T3), which is metabolically  inactive.  Several days before the onset of term labor, cortisol levels increase in the fetus and induce a change in thyroid hormone dynamics. Cortisol induces the enzyme system, allowing the conversion of T4 to triiodothyronine (T3), which is metabolically more active and necessary for neonatal thermogen- esis.  At  birth,  there  is  a  surge  of  thyroid-stimulating  hormone, and at no time during life does this hormone  reach such high levels as it does 30 minutes after birth.  This  is  followed  by  a  hyperthyroid  neonatal  state  for  several  days,  which  is  necessary  for  the  newborn  to  maintain its body temperature.

A second change that occurs with the onset of labor is a change in fetal breathing activity. Fetal breathing,  as  observed  by  real-time  ultrasonography,  is  rarely  observed  once  labor  is  established. This  is  thought  to  be  associated  with  a  decrease  in  pulmonary  fluid  dynamics that may be important for the onset of respi- ration  after  delivery,  as  well  as  with  the  retention  of  surfactant in the lungs.

Finally, labor is a stress to the fetus that stimulates the release of catecholamines. This  may  be  responsi- ble  for  the  mobilization  of  glucose,  lung  fluid  absorp- tion, alterations in the perfusion of organ systems, and,  possibly,  the  onset  of  respiration.  Only  at  times  of  severe  stress  later  in  life  are  catecholamine  levels  as  high as those at birth.

ETIOLOGY OF NEONATAL CARDIORESPIRATORY DEPRESSION At  term,  1%  of  infants  will  require  vigorous  resuscita- tion  (positive  pressure  ventilation  for  more  than  1  minute), with 10% requiring some assistance. At earlier  stages of gestation, almost all infants require some type  of supportive care.

FACILITATING NEONATAL ADAPTATION The  American  Congress  of  Obstetricians  and  Gyne- cologists  and  the  American  Society  of  Anesthesiolo- gists  have  made  joint  statements  that  a qualified provider other than the obstetrician or anesthesiolo- gist should be responsible for neonatal resuscitation.  All  nurses  working  in  the  delivery  room  should  be  trained  in  techniques  of  neonatal  assessment  and  resuscitation.  If  risk  factors  increase  the  likelihood  of  delivering an infant with cardiorespiratory depression,  a pediatrician trained in neonatal resuscitation should  be  present.

Following delivery of a normal newborn, the follow- ing important steps should occur:

1. Clear the Airway Descent through the birth canal causes compression of  the  chest  wall,  resulting  in  the  discharge  of  fluid  from  the mouth and nose. When the head emerges from the 

PA R T 2 Obstetrics122

respiratory distress syndrome.  Exogenous  surfactant  replacement varies from synthetic surfactant to modi- fied or unmodified extracts of natural surfactant. These  substances  can  be  given  by  tracheal  injection  at  birth  to  prevent  the  respiratory  distress  syndrome,  or  they  can  be  given  after  the  syndrome  has  developed  to  reduce its severity and to prevent mortality.

injury (bronchopulmonary dysplasia) may also be a problem. These injuries are especially likely to occur if  the infant is preterm.

5. Correct Surfactant Deficiency For the premature infant, surfactant deficiency is the basic defect responsible for the development of the

FIGURE 8-18 A time-based approach to the resuscitation of a normal and apneic or cyanotic newborn. BPM, Beats per minute; CPAP, continuous positive airway pressure; HR, heart rate; IV, intravenous; PPV, positive pressure ventilation; SPO2, peripheral arterial oxygen saturation. (American Academy of Pediatrics, American Heart Association: Textbook of neonatal resuscitation, ed 6, Elk Grove Village, IL, and Dallas, TX, 2011, American Academy of Pediatrics and American Heart Association.)

TERM GESTATION? BREATHING OR CRYING?

GOOD TONE?

WARM, CLEAR AIRWAY IF NECESSARY, DRY, STIMULATE

HR BELOW 100 BPM, GASPING, OR APNEA?

HR BELOW 100 BPM?

HR BELOW 60 BPM?

HR BELOW 60 BPM?

IV EPINEPHRINE

BIRTH

30 SEC

60 SEC

Targeted preductal SPO 2

after birth

1 min 60-65% 2 min 65-70% 3 min 70-75% 4 min 75-80% 5 min 80-85% 10 min 85-95%

CONSIDER INTUBATION CHEST COMPRESSION

COORDINATE WITH PPV

POST-RESUSCITATION CARE

TAKE STEPS TO CORRECT VENTILATION

PPV, SPO 2 MONITORING CLEAR AIRWAY

SPO 2 MONITORING

CONSIDER CPAP

LABORED BREATHING OR PERSISTENT CYANOSIS?

YES—STAY WITH MOTHER

NO

NO

NO

NO

NO

YES YES

YES

YES

YES

ROUTINE CARE • PROVIDE WARMTH • CLEAR AIRWAY IF NECESSARY • DRY • ONGOING EVALUATION

C H A P T E R 8 Normal Labor, Delivery, and Postpartum Care 123

2. Initiate Breathing The indications for positive pressure ventilation include apnea, gasping, and a heart rate less than 100 beats/min. With an established airway, either bag- mask  ventilation  or  ventilation  via  an  endotracheal  tube  should  be  initiated  at  a  rate  of  40  to  60 breaths/ min.  Usually,  the  heart  rate  increases  rapidly  after  the  apnea is corrected, and intermittent bag-mask ventila- tion  with  supplemental  oxygen  can  be  given  until  spontaneous  respiration  commences.  In  premature  infants  (<32  weeks),  oxygen  of  100%  or  less  should  be  commenced and titrated to an oxygen saturation in the  infant of 85-95%.

3. Ensure Cardiac Performance If  cardiac  performance  is  poor  (heart  rate  <60 beats/ min  after  30  seconds  of  positive  pressure  ventilation  with  oxygen  titrated  to  saturation),  external  cardiac  massage  should  be  initiated.  The best technique for cardiac massage in the newborn is to compress the lower third of the sternum with two thumbs with the hands around the chest. A compression should occur  every half-second, with an interposed ventilation after  every  third  compression  (3 : 1  ratio),  resulting  in  90  chest  compressions  and  30  ventilations  per  minute.  The sternum should be depressed to a depth of approx- imately  one-third  the  anteroposterior  diameter  of  the  chest, typically 2 to 2.5 cm in a full-term infant and 1.5  to  2.0 cm  in  a  preterm  neonate.  Cardiac  arrest  is  rare.  If cardiac massage and artificial ventilation are not successful in reestablishing cardiac function, an endotracheal or IV injection of a dilute solution of epinephrine must be given.  When  the  heart  rate  is  above  60 beats/min,  sternal  compression  may  be  dis- continued while ventilation is continued.

4. Correct Biochemical Abnormalities ACIDOSIS. In the case of a very sick newborn, an umbil- ical  arterial  catheter  should  be  placed  and  blood  gas  analyses performed to monitor the severity of the aci- dosis and the effectiveness of the resuscitation. Severe 

Apgar Score The  Apgar  score  is  an  excellent  tool  for  assessing  the  overall status of the newborn soon after birth (1 minute)  and after a 5-minute period of observation (Table 8-9).  A normal Apgar score is 7 or greater at 1 minute and 9  or 10 at 5 minutes.

Resuscitation of the Asphyxiated Infant During the past 15 years, increasing emphasis has been placed on transferring the mother with a high- risk pregnancy to a tertiary care regional center before labor  rather  than  transferring  the  sick  neonate  after delivery.

Ideally,  at  the  time  of  delivery,  a segment of cord should be doubly clamped to allow blood gas deter- minations  on  cord  arterial  and  venous  blood.  These  measurements serve as a baseline to assess the severity  of the neonatal hypoxia and acidosis.

SEQUENCE OF PROCEDURES A  stepwise  sequence  of  procedures  is  necessary  to  enable  a  smooth  transition  to  an  adult  circulation  pattern and a normal metabolic state (see Figure 8-18).

1. Establish an Airway After  placing  the  newborn  in  a  preheated  radiant  warmer,  the  airway  should  be  opened  by  slightly  extending  the  neck.  In any infant with a high likeli- hood of asphyxia, suctioning of the airway should be initiated after the delivery of the head.  The  asphyxi- ated  neonate  usually  has  meconium  present  in  the  upper  airway,  which  may  be  cleared  with  an  oral  suction  catheter  (DeLee  trap)  before  delivery  of  the  shoulders.  Immediately following the delivery, an endotracheal tube should be inserted to remove thick  mucus  or  meconium  from  the  trachea  and  upper  airway, unless the infant is vigorous (see above).

TABLE 8-9

APGAR SCORE FOR DETERMINING THE CONDITION OF A NEWBORN INFANT

Score

Sign 0 1 2

1. Heart rate Absent <100 beats/min >100 beats/min

2. Respiratory effort Absent Slow, weak cry Good, strong cry

3. Muscle tone Limp Some flexion of extremities Active motion

4. Reflex irritability (response to stimulation of sole of foot)

None Grimace Strong cry

5. Color Pale, blue Body, pink; extremities, blue Completely pink

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one  of  the  most  critical  aggravating  factors,  and  tem- perature  control  must  be  continuously  supported.  A  pneumothorax is not uncommon following a difficult  resuscitation.  It  must  be  recognized  promptly  and  decompressed with a chest tube. Also, a diaphragmatic hernia can result in the displacement of the stomach,  bowel,  or  both  into  the  thoracic  cavity.  Decreased  breath sounds and failure to improve pulmonary func- tion should alert the team to this possibility.

NEONATAL RESPIRATORY FAILURE Neonates in imminent danger of death from a narrow  range of conditions causing hypoxemia and respiratory  distress  not  responsive  to  conventional  forms  of  therapy  are  candidates  for  extracorporeal membrane oxygenation. The lives of infants with a congenital dia- phragmatic  hernia,  severe  meconium  aspiration,  or  other  forms  of  persistent  pulmonary  hypertension  have  been  saved  using  this  procedure  performed  in  selected  regional  centers.  Data  concerning  long-term  outcomes of infants treated with extracorporeal mem- brane oxygenation remain limited. Carotid artery and/ or jugular vein ligation, prolonged anticoagulation, and long-term circulatory bypass are necessary with this procedure, and concerns exist about their long- term consequences.

LONG-TERM OUTCOME Low birth weight (<2500 g), whether the result of pre- maturity or of intrauterine growth restriction, is an independent risk factor for cerebral palsy. By contrast,  for infants weighing more than 2500 g, Apgar scores less  than or equal to 3 at 5 minutes are generally not associ- ated  with  an  increased  risk  of  cerebral  palsy,  provided  that  there  is  no  associated  obstetric  complication.  If  both  a  low  Apgar  score  and  an  obstetric  complication  such  as  severe  fetal  distress  and/or  chorioamnionitis  are present, there is an increased risk of cerebral palsy.

TABLE 8-10

DRUGS USED TO RESUSCITATE THE NEONATE

Medication Concentration to Administer Preparation Dosage and Route Rate and Precautions

Epinephrine 1 : 10,000 1 mL 0.01-0.03 mg/kg 0.1-0.3 mL/kg IV or ET

Give rapidly May dilute with normal saline to

1-2 mL if given via ET May give up to 3 times IV dose if

given via ET

Volume expanders

PRBC Normal saline Ringer lactate

40 mL 10 mL/kg IV Give over 5-10 min Give by syringe or IV drip

Sodium bicarbonate

0.5 mEq/mL (4.2% solution)

20 mL or two 10 mL prefilled syringes

2 mEq/kg IV only (4 mL/kg)

Give slowly over at least 2 minutes Give only if infant is being

effectively ventilated

Naloxone hydrochloride

0.4 mg/mL 1 mL 0.1 mg/kg (0.25 mL/ kg) IV, ET, IM, SC

Giving rapidly is acceptable

ET, Endotracheal tube; IM, intramuscular; IV, intravenous; PRBC, packed red blood cells; SC, subcutaneous.

acidosis  can  be  corrected  by  the  infusion  of  sodium  bicarbonate if ventilation is adequate.

ANEMIA. On  rare  occasions,  the  newborn  may  have  abnormal perfusion secondary to blood loss (e.g., from  vasa  previa,  abruptio  placentae,  or  a  fetomaternal  transfusion),  which  can  be  corrected  only  by  immedi- ate  transfusion  with  blood  (packed  red  blood  cells).  A  solution  of  normal  saline  or  lactated  Ringer  solution  can be used to temporarily maintain an adequate vas- cular volume.

NARCOTIC DEPRESSION. Respiratory  depression  sec- ondary to medication is unusual with the increased use  of  conduction  anesthesia.  If  neonatal  respiratory  depression from excessive use of narcotics is suspected,  naloxone (Narcan) is an effective antidote. Intramuscu- lar  administration  is  just  as  effective  as,  and  easier  to  administer  than,  IV  dosing.  Table  8-10  lists  the  drugs  that  are  commonly  used  in  resuscitation  and  their  dosages.

HYPOGLYCEMIA. Hypoglycemia  can  also  contribute  to  unsuccessful  resuscitation,  especially  in  infants  with  intrauterine growth restriction or whose mothers have  diabetes. Glucose administration should be considered  after  the  other  issues  have  been  addressed.  The use of high concentrations of glucose (e.g., 25-50%) is contraindicated in asphyxiated newborns because the glucose is converted to lactic acid in the absence of oxygen, which may increase the likelihood of brain damage. Concentrated glucose solutions may also cause brain swelling. If glucose is required, its concen- tration should not exceed 10%.

OTHER FACTORS. Following  a  systematic  resuscitative  effort,  other  contributing  factors  must  be  identified  if  cardiorespiratory depression persists. Hypothermia is 

125

9 

Fetal Surveillance during Labor

C H

A P

T ER

CALVIN J. HOBEL • AMY R. LAMB

■  The most important principle of both fetal and maternal  surveillance  during  labor  is  that  childbirth  is  a  normal  process,  and  the  majority  of  laboring  women  and  their  fetuses  will  have  a  safe  journey.  Obstetricians  must  be  aware  of  each  patient’s  past  history  and  be  prepared  to  monitor  the  journey  based  upon  maternal  and  fetal  needs during the labor process.

■  Simple auscultation of the fetal heart rate in accordance  with specific guidelines is acceptable to assess the health  of  the  fetus.  Continuous  fetal  heart  rate  and  uterine  activity monitoring have the advantage of providing con- tinuous electronic records throughout the labor process  but may not always be necessary.

■  The  pathophysiology  of  abnormal  fetal  heart  rate  pat- terns is complex, and both clinical and research findings  suggest that hypoxia, acidosis, and inflammation form a 

triad of mixed metabolic dysregulation that may increase  the risk of early (during delivery) and late (during child- hood) physical and mental abnormalities.

■  To  improve  our  understanding  of  the  assessment  of  abnormal  and  potentially  pathologic  heart  rate  pat- terns, the National Institutes of Health (NIH) has devel- oped  a  three-tier  fetal  heart  rate  interpretation  system  (normal,  intermediate,  and  abnormal). This  is  designed  to  improve  the  recognition  of  risk  for  poor  fetal  out- comes  and  to  allow  implementation  of  strategies  for  effective intervention.

■  Abnormal  fetal  heart  rate  tracings  associated  with  hypoxia,  acidosis,  and  inflammation  have  five  charac- teristics:  (1)  absent  base  line  variability,  (2)  recurrent   late  decelerations,  (3)  recurrent  variable  decelerations,  (4) bradycardia, and (5) sinusoidal patterns.

CLINICAL KEYS FOR THIS CHAPTER

Effective  fetal  surveillance  during  labor  is  an  essential  element  of  good  obstetric  care.  On  the  basis  of  the  antepartum  maternal  history,  physical  examination,  and  laboratory  data,  20-30%  of  pregnancies  may  be  designated  high  risk,  and  50%  of  perinatal  morbidity  and mortality occurs in this group. The remaining 50% of morbidity and mortality occurs in pregnancies that are considered to be normal at the onset of labor.  Although fetal heart rate (FHR) monitoring by auscul- tation or continuous electronic fetal monitoring (EFM)  provides  useful  information  that  improves  the  man- agement of labor and reduces perinatal morbidity and  mortality,  evidence  about  its  complete  adequacy  for  fetal surveillance is conflicting.

The  pathogenesis  of  abnormal  FHR  patterns  is  complex  and  remains  poorly  understood.  In  the  past,  it was felt that hypoxia was the main cause of abnormal  FHR patterns and that continuous EFM and fetal scalp  sampling would reliably identify those fetuses at great- est  risk.  However,  a  decrease  in  the  incidence  of  cere- bral  palsy,  one  of  the  most  serious  complications 

associated  with  pregnancy  and  childbirth,  has  not  occurred with increased monitoring.

This chapter provides the current concepts and rec- ognized  standards  for  appropriate  fetal  surveillance  during labor.

Methods of Monitoring Fetal Heart Rate AUSCULTATION OF THE FETAL HEART RATE The  time-honored  technique  for  evaluating  the  fetus  during labor has been auscultation of the FHR. The first  step  in  deciding  on  the  optimal  method  (auscultation  or continuous EFM) is to determine whether a patient  has  any  risk  factors.  Auscultation of the fetal heart is performed by listening from the beginning of one contraction to the beginning of the next contraction.  For low-risk patients, a competent nurse should listen  every 30 minutes during the first stage of labor and at  least every 15 minutes in the second stage of labor. For 

PA R T 2 Obstetrics126

dysregulation  and  is  associated  with  a  complex  array   of  FHR  perturbations.  These  changes  in  heart  rate   are  difficult  to  interpret  without  better  ways  to  define  the most optimal biomarkers that identify the fetus at  highest  risk.  Important maternal and fetal biomark- ers of current research interest are inflammatory markers (such as C-reactive protein) and vitamin D deficiency.

EFM allows continuous reporting of the FHR, uterine  contractions,  maternal  heart  rate,  and  blood  pressure  (FHR-UC-MHR-MBP)  by  means  of  a  monitor  that  prints  results  on  a  two-channel  strip  chart  recorder  that  can  be  stored  as  part  of  an  electronic  record.  Uterine contractions result in a reduction in blood flow  to  the  placenta,  which  can  cause  an  interruption  in  fetal  oxygenation  and  lead  to  corresponding  altera- tions  in  the  FHR.  The “FHR-UC-MHR-MBP” record can be obtained using external transducers that are placed on the maternal abdomen and arm. It is impor- tant that external palpation of the uterus is carried out  to  determine  the  intensity  of  contractions  with  this  method. This technique is used in early labor.

Internal monitoring is carried out by placing a spiral electrode onto the fetal scalp to monitor heart rate and inserting a plastic catheter transcervically into the amniotic cavity to monitor uterine contrac- tions (Figure 9-1). To carry out this technique, the fetal  membranes  must  be  ruptured  and  the  cervix  must  be  dilated  to  at  least  2 cm.  Caution  must  be  exercised  when the decision to rupture the membranes is made, 

high-risk patients, the FHR should be assessed every 15  minutes  during  the  first  stage  of  labor  and  every  5  minutes  during  the  second  stage.  Some  studies  have  suggested  that  intermittent  auscultation  of  the  fetal  heart is comparable to continuous electronic monitor- ing, in terms of neonatal outcome, if performed at the  intervals stated above with a 1 : 1 patient-to-nurse ratio.

CONTINUOUS ELECTRONIC FETAL HEART RATE MONITORING EFM  during  labor  was  developed  to  detect  FHR  pat- terns frequently associated with delivery of infants in a  depressed condition. It was reasoned that early recog- nition  of  changes  in  FHR  patterns  that  are  associated  with  hypoxia  and  umbilical  cord  compression  would  serve  as  a  warning  that  would  enable  a  physician  to  intervene  and  prevent  fetal  death  or  irreversible  brain  injury.

Pathophysiology of Abnormal Fetal Heart Rate Patterns The  focus  of  EFM  has  been  on  the  recognition  that  hypoxia leads to a greater risk of acidosis, which can be  identified  by  fetal  scalp  blood  sampling  during  labor  and  cord  blood  gas  analysis  at  delivery.  Today, the cause of abnormal FHR patterns is thought to be more complex and probably related to a combination of hypoxia, acidosis, and inflammation  that  subjects  all  physiologic  systems  (brain,  heart,  placenta,  blood  vessels,  and  the  fetal  adrenal  gland)  to  multisystem 

FIGURE 9-1 Technique for internal continuous electronic monitoring of both fetal and maternal heart rates, as well as the pressure and frequency of uterine contractions. External monitoring of uterine contractions provides information only about the frequency of contractions.

Transcervical intrauterine

pressure catheter

Strain gauge

Fetal monitoring system

Fetal and

maternal heart rates

Scalp electrode

Intrauterine pressure

C H A P T E R 9 Fetal Surveillance during Labor 127

and  it  should  be  performed  only  when  more  exact  information  is  needed  to  monitor  a  mother  or  fetus   at risk.

Internal  monitoring  gives  better  FHR  tracings  because the rate is computed from the sharply defined  R-wave  peaks  of  the  fetal  electrocardiogram,  whereas  with the external technique, the rate is computed from  the  less  precisely  defined  first  heart  sound  obtained  with  an  ultrasonic  transducer.  However,  fetal  scalp  electrodes should be placed only when the benefit out- weighs the risk, and fetal scalp electrodes should always  be  placed  with  care.  For  example,  patients with spe- cific infections (HIV and hepatitis B) should not have a scalp electrode placed.  In  addition,  when  placing  a  scalp  electrode,  the  presenting  part  of  the  fetus  must  be  ascertained  to  avoid  placing  the  electrode  on  the  face  or  external  genitals  if  the  fetus  is  presenting  as  a  breech.

The  internal  uterine  catheter  allows  precise   measurement  of  the  intensity  of  the  contractions  in  millimeters  of  mercury,  whereas  the  external  tocody- namometer  measures  only  frequency  and  duration,  not  intensity.  The  strength  of  uterine  contractions,  however,  can  easily  be  assessed  by  abdominal  palpa- tion by a trained observer (a nurse or physician).

In  the  clinical  setting,  internal  and  external  tech- niques  are  often  combined  by  using  a  scalp  electrode  for  precise  heart  rate  recording  and  the  external   tocodynamometer  for  contractions.  This  approach  minimizes  possible  side  effects  from  invasive  internal  monitoring.

Etiology of Hypoxia, Acidosis, and Fetal Heart Rate Changes The  developing  fetus  presents  a  paradox.  Its  arterial  blood  oxygen  tension  is  only  25  ±  5 mm  Hg,  as  com- pared  with  adult  values  of  about  100 mm  Hg.  The   rate  of  oxygen  consumption,  however,  is  twice  that   of  the  adult  per  unit  weight,  and  its  oxygen  reserve  is  only  enough  to  meet  its  metabolic  needs  for  1  to  2  minutes.  Blood  flow  from  the  maternal  circulation,  which supplies the fetus with oxygen through placental  exchange  of  respiratory  gases,  is  momentarily  inter- rupted during a contraction. A normal fetus can with- stand the temporary reduction in blood flow to the placenta without developing hypoxia because suffi- cient oxygen exchange occurs during the interval between contractions.

Under normal circumstances, the FHR is deter- mined by the atrial pacemaker. Modulation of the rate  occurs physiologically through innervation of the heart  by  the  vagus  (decelerator)  and  sympathetic  (accelera- tor)  nerves.  A  fetus  whose  oxygen  supply  is  marginal  cannot  tolerate  the  stress  of  contractions  and  will  become  hypoxic.  Under hypoxic conditions, chemo-

receptors and baroreceptors in the peripheral arte- rial circulation of the fetus influence the FHR by giving rise to contraction-related or periodic FHR changes.  Hypoxia,  when  sufficiently  severe,  will  also  result  in  anaerobic  metabolism,  resulting  in  the  accu- mulation  of  pyruvic  and  lactic  acid  and  causing  fetal  acidosis. The degree of fetal acidosis can be measured by sampling blood from the presenting part. The normal fetal scalp blood pH varies between 7.25 and 7.30. Values below 7.20 are considered to be abnormal (fetal acidosis) but not necessarily indicative of fetal compromise.

The fetal oxygenation pathway can be interrupted at different locations within the uteroplacental-fetal circulatory loop.  For  example,  impairment  of  oxygen  transportation to the intervillous space may occur as a  result of maternal hypertension or anemia; oxygen dif- fusion  may  be  impaired  in  the  placenta  because  of  infarction  or  abruption;  or  the  oxygen  content  in  the  fetal  blood  may  be  impaired  because  of  hemolytic  anemia  in  rhesus  (Rh)-isoimmunization.  Figure  9-2  summarizes the clinical conditions that may be associ- ated with fetal distress during labor.

It is unrealistic to believe that hypoxia and acidosis  are  the  only  markers  that  determine  the  ultimate  outcome  of  the  fetus  and  neonate.  Other  markers   of  inflammation  and  the  immune  system  must  also  play  a  role.  Current research is focused on vitamin D deficiency and inflammatory markers such as interleukin-6 and C-reactive protein.

FETAL HEART RATE PATTERNS The assessment of the FHR depends on an evaluation of the baseline pattern and the periodic changes related to uterine contractions. Table 9-1 gives a com- prehensive  list  of  FHR  patterns  and  definitions  based  upon  a  workshop  sponsored  by  the  National  Institute  of Child Health and Human Development in 2008.

Baseline Assessment Baseline assessment of FHR requires the determina- tion of the rate (in beats/min) and the variability.  Normal  and  abnormal  rates  are  listed  in  Table  9-1.  Normal  FHR  baseline  is  from  110  to  160  beats/min;  tachycardia  is  a  baseline  greater  than  160  beats/min,  and  bradycardia  is  less  than  110  beats/min.  Baseline  variability  can  be  divided  into  short-  and  long-term  intervals. These are described in the subsections below. 1.  Short-term or beat-to-beat variability. This reflects 

the interval between either successive fetal electro- cardiographic  signals  or  mechanical  events  of  the  cardiac cycle. Normal short-term variability fluctu- ates between 6 and 25 beats/min. Variability below  5  beats/min  is  considered  to  be  potentially  abnor- mal. When associated with decelerations, a variabil- ity of less than 5 beats/min usually indicates severe  fetal distress.

PA R T 2 Obstetrics128

tions are abnormal and are categorized according to  a three-tier FHR interpretation system (Box 9-1).

Types of Patterns EARLY DECELERATION (HEAD COMPRESSION). This pattern  usually has an onset, maximum fall, and recovery that  is  coincident  with  the  onset,  peak,  and  end  of  the  uterine  contraction  (Figure  9-3).  The  nadir  of  the   FHR  coincides  with  the  peak  of  the  contraction.  This  pattern is seen when engagement of the fetal head has  occurred.  Early  decelerations  are  not  thought  to  be  associated with fetal distress. The pressure on the fetal  head leads to increased intracranial pressure that elicits  a  vagal  response  similar  to  the  Valsalva  maneuver  in  the  adult.  The  vagal  reflex  can  be  abolished  by  the  administration  of  atropine,  but  this  approach  is  not  used clinically.

LATE DECELERATION (UTEROPLACENTAL INSUFFICIENCY). This  pattern  has  an  onset,  maximal  decrease,  and  recovery  that  are  shifted  to  the  right  in  relation  to  the  contraction (Figure 9-4). Fetal hypoxia and acidosis are  usually  more  pronounced  with  severe  decelerations.  Severe,  repetitive  late  decelerations  usually  indicate  fetal metabolic acidosis, low arterial pH, and increased 

2.  Long-term variability.  These  fluctuations  may  be  described  in  terms  of  the  frequency  and  amplitude  of  change  in  the  baseline  rate.  The  normal  long- term  variability  is  3  to  10  cycles  per  minute.  Vari- ability  is  physiologically  decreased  during  the  state  of  quiet  sleep  of  the  fetus,  which  usually  lasts  for  about 25 minutes until transition occurs to another  state.  Changes  in  the  long-term  variability  in  pro- longed and difficult labors may be a sign of an accu- mulated risk of metabolic dysregulation.

3.  Decreased beat-to-beat variability. A prolonged flat  baseline is the result of fetal acidosis.

Periodic Fetal Heart Rate Changes Periodic  FHR  changes  are  changes  in  baseline  FHR  related  to  uterine  contractions.  The  responses  to  uterine contractions may be categorized as follows: 1.  No change. The FHR maintains the same character-

istics it had in the preceding baseline FHR. 2.  Acceleration.  The  FHR  increases  in  response  to 

uterine contractions. This is a normal response and  is reassuring that the fetal status is normal.

3.  Deceleration.  The  FHR  decreases  in  response  to  uterine  contractions.  Decelerations  may  be  early, late, variable, or mixed.  All  except  early  decelera-

FIGURE 9-2 Clinical conditions associated with fetal distress in labor.

Uterine conditions Tetanic contractions Hyperstimulation

Fetal conditions Anemia Infection Twin-twin transfusion

Maternal conditions

Hypertension Hypotension

Severe anemia Cardiac disease

Seizures Pulmonary disease

Placental conditions

Infarction Abruption

Postmature placenta

Leptin resistance Inflammation

Umbilical cord conditions One artery

Vasa previa Hematoma Short cord True knot

Nuchal cord prolapse

C H A P T E R 9 Fetal Surveillance during Labor 129

TABLE 9-1

ELECTRONIC FETAL MONITORING DEFINITIONS

Pattern Definition

Baseline The mean FHR rounded to increments of 5 excluding: Periodic or episodic changes Periods of marked FHR variability Segments of baseline that differ by more than 25 beats/min

The baseline must be for a minimum of 2 min in any 10-min segment, or the baseline for that time period is indeterminate; in this case, one may refer to the prior 10-min window for determination of baseline

Normal FHR baseline: 110-160 beats/min Tachycardia: FHR baseline is >160 beats/min Bradycardia: FHR baseline is <110 beats/min

Baseline variability Fluctuations in the baseline FHR that are irregular in amplitude and frequency Variability is visually quantitated as the amplitude or peak-to-trough in beats per minute

Absent: amplitude range undetectable Minimal: amplitude range detectable, but ≤5 beats/min Moderate (normal): amplitude range 6-25 beats/min Marked: amplitude range >25 beats/min

Acceleration A visually apparent abrupt increase (onset to peak in <30 sec) in the FHR At 32 weeks’ gestation and beyond, an acceleration has a peak ≥15 beats/min above baseline, with

a duration of 15 sec to 2 min from onset to return Before 32 weeks’ gestation, an acceleration has a peak ≥10 beats/min above baseline, with a

duration of ≥10 sec but <2 min from onset to return Prolonged acceleration lasts ≥2 min but <10 min in duration If an acceleration lasts ≥10 min, it is a baseline change

Early deceleration Visually apparent, usually symmetrical, gradual decrease and return of the FHR associated with a uterine contraction

A gradual FHR decrease is defined as from the onset to the FHR nadir or ≥30 sec The decrease in FHR is calculated from the onset to the nadir of the deceleration The nadir of the deceleration occurs at the same time as the peak of contraction In most cases, the onset, nadir, and recovery of the deceleration occur after the beginning, peak,

and ending of the contraction, respectively

Late deceleration Visually apparent, usually symmetrical, gradual decrease and return of the FHR associated with uterine contraction

A gradual FHR decrease is defined as one of ≥30 sec from the onset to the FHR nadir The decrease in FHR is calculated from the onset to the nadir of the deceleration The decrease is delayed in timing, with the nadir of the deceleration occurring after the peak of the

contraction In most cases, the onset, nadir, and recovery of the deceleration occur after the beginning, peak,

and ending of contraction, respectively

Variable deceleration Visually apparent abrupt decrease in FHR An abrupt FHR decrease is defined as one of <30 sec from the onset of the deceleration to the

beginning of the FHR nadir The decrease in FHR is calculated from the onset to the nadir of the deceleration The decrease in FHR is ≥15 beats/min, lasting ≥15 sec and <2 min in duration When variable decelerations are associated with uterine contractions, their onset, depth, and

duration commonly vary with successive uterine contractions

Prolonged deceleration Visually apparent decrease in the FHR below the baseline Decrease in the FHR from baseline that is ≥15 beats/min, lasting ≥2 min but <10 min in duration If a deceleration lasts ≥10 min, it is a baseline change

Sinusoidal pattern Visually apparent, smooth, sine wave–like, undulating pattern in FHR baseline with a cycle frequency of 3-5 per min that persists for ≥20 min

From Macones A, Hankins GDV, Spong CY, et al: The 2008 National Institute of Child Health and Human Development workshop report on electronic fetal monitoring: update on definitions, interpretation, and research guidelines. Obstet Gynecol 112:661–666, 2008. FHR, Fetal heart rate.

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FIGURE 9-3 Early deceleration. Note that the deceleration starts and ends with the uterine contraction. Good beat-to-beat variability is demonstrated.

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BOX 9-1

THREE-TIER FETAL HEART RATE INTERPRETATION SYSTEM

Category I (Normal) Category I FHR tracings include all of the following: •  Baseline rate: 110-160 beats/min •  Baseline FHR variability: moderate •  Late or variable decelerations: absent •  Early decelerations: present or absent •  Accelerations: present or absent

Category II (Intermediate/Possible Early Dysregulation) Category II FHR tracings include all FHR tracings not cate- gorized as Category I, or Category II tracings may represent  an  appreciable  fraction  of  those  encountered  in  clinical  care.  Examples  of  Category  II  FHR  tracings  include  any  of  the following four parameters: 1.  Baseline rate

•  Bradycardia  not  accompanied  by  absent  baseline  variability

•  Tachycardia 2.  Baseline FHR variability

•  Minimal baseline variability •  Absent  baseline  variability  not  accompanied  by 

recurrent decelerations •  Marked baseline variability

3.  Accelerations •  Absence  of  induced  accelerations  after  fetal 

stimulation 4.  Periodic or episodic decelerations

•  Recurrent  variable  decelerations  accompanied  by  minimal or moderate baseline variability

•  Prolonged deceleration >2 min but <10 min •  Recurrent  late  decelerations  with  moderate  baseline 

variability •  Variable  decelerations  with  other  characteristics, 

such  as  slow  return  to  baseline,  “overshoots,”  or  “shoulders”

Category III (Abnormal) Category III FHR tracings include either of the following: •  Absent  baseline  FHR  variability  and  any  of  the 

following: •  Recurrent late decelerations •  Recurrent variable decelerations •  Bradycardia

•  Sinusoidal pattern

C H A P T E R 9 Fetal Surveillance during Labor 131

FIGURE 9-4 Late decelerations on electronic fetal monitoring tracing as would be recorded with a severely distressed fetus. Note the fetal tachycardia, lack of beat-to-beat heart rate variability, and the late decelerations (upper trace). Uterine contractions are recorded in the lower trace.

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base  deficit  values.  The  partial  pressure  of  carbon  dioxide in the fetal blood is usually in the normal range,  and  the  fetal  blood  oxygen  partial  pressure  is  only  slightly  below  normal  because  of  the  Bohr  effect—the  shift to the left of the oxygen dissociation curve caused  by the acidosis.

VARIABLE DECELERATION (CORD COMPRESSION). This  pattern has a variable time of onset and a variable form  and may be nonrepetitive (Figure 9-5). Variable decel- erations  are  caused  by  umbilical  cord  compression.  Note that the decelerations have a more rapid drop and  more rapid return to normal. This is characteristic of a  reflex  change,  or  rapid  change,  compared  with  the  slower  change  in  both  early  and  late  decelerations.  Partial  or  complete  compression  of  the  cord  causes  a  sudden increase in blood pressure in the central circu- lation  of  the  fetus.  The  bradycardia  is  mediated  via  baroreceptors. This reflex can be abolished or amelio- rated  by  atropine  (e.g.,  chemical  vagotomy),  although  this  approach  is  not  used  clinically.  Fetal  blood  gases  indicate  respiratory  acidosis  with  a  low  pH  and  high  carbon dioxide. When cord compression has been pro- longed,  hypoxia  is  also  present,  showing  a  picture  of  combined  respiratory  and  metabolic  acidosis  in  fetal  blood gases.

The severity of variable decelerations is graded by their duration. When the FHR falls below 80 beats/min 

during the nadir of the deceleration, there is usually a  loss of the P-wave in the fetal electrocardiogram, indi- cating a nodal rhythm or a second-degree heart block.

NONPATTERN SIGNS OF FETAL DISTRESS Fetal Tachycardia As a baseline change, tachycardia is not a very reliable  sign  of  fetal  distress.  In general, fetal tachycardia occurs to improve placental circulation when the fetus is stressed. Brief periods of tachycardia (15 to 30  minutes) are usually associated with excessive oxytocic  augmentation  of  labor,  after  which  the  heart  rate  returns  to  baseline  when  the  augmentation  is  discon- tinued.  Prolonged periods of tachycardia are usually associated with elevated maternal temperature or an intrauterine infection, which should be ruled out. The  acid-base status is usually normal.

Meconium Early passage of meconium occurs any time before rupture of the membranes  and  is  classified  as  trace  (+1, +2, +3) and particulate based on its color and vis- cosity.  Trace  meconium  is  lightly  stained  yellow  or  greenish  amniotic  fluid.  Meconium  of +2  to +3  is  dark  green or black and is usually thick and tenacious with  a  pea  soup  appearance.  It  is  associated  with  lower  1-  and 5-minute Apgar scores and with the risk of meco- nium aspiration.

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egory includes changes in (1) baseline rate, (2) baseline  FHR  variability,  (3)  accelerations,  and  (4)  periodic  or  episodic  decelerations.  There  has  been  an  attempt  to  further  subdivide  Category  II  FHR  abnormalities  to  improve  the  recognition  of  changes  that  are  most  ominous. These subtypes are summarized in Box 9-2.

Strategies for Resuscitation Because Category II patterns are intermediate, resusci- tative measures always depend on the clinical circum- stances.  When abnormal patterns are seen, the first step should be a search for the underlying cause.  When  the  cause  is  identified,  such  as  maternal  hypo- tension, steps should be taken to correct the problem.  In general, a term-sized fetus tolerates Category II FHR  patterns better than a preterm fetus. A fetus with addi- tional  maternal  or  fetal  risk  factors,  such  as  preterm  labor,  intrauterine  growth  restriction,  preeclampsia, 

Late passage usually occurs during the second stage  of  labor,  after  clear  amniotic  fluid  has  been  noted  earlier.  Late  passage,  which  is  most  often  heavy,  is  usually  associated  with  some  event  (e.g.,  umbilical  cord compression or uterine hypertonus) late in labor  that causes fetal distress.

Strategies for Intervention In 2008, the National Institute of Child Health and Human Development reported on a series of work- shops on EFM with the goal of defining FHR charac- teristics more clearly  to  improve  the  predictive  value  of  monitoring  and  to  allow  evidence-based  clinical  management  of  intrapartum  fetal  compromise.  Table  9-1 lists the definitions for FHR characteristics, and Box  9-1 displays the three-tier FHR interpretation system.

CATEGORY I FHR (NORMAL) A normal FHR pattern is strongly predictive of normal  fetal  acid-base  status  at  the  time  of  observation.  The  characteristics  of  Category  I  tracings  are  a  normal  baseline rate, moderate FHR variability, and absence of  late or variable decelerations; early decelerations (head  compression) may be present or absent. The presence  of Category I FHR patterns requires no specific action.

CATEGORY II FHR (INTERMEDIATE/POSSIBLE EARLY DYSREGULATION) Category II FHR tracings are intermediate and are not  predictive of abnormal fetal acid-base status. This cat-

FIGURE 9-5 Umbilical cord compression pattern. Variable decelerations (cord compression) on electronic fetal monitoring traces (six panels [each panel = 60 seconds] beginning on the left side of each tracing) associated with maternal pushing in the second stage of labor. Note in both upper and lower traces the rapid drop in fetal heart rate with a nadir of 25 seconds, followed by a rapid return toward baseline. In the rightmost panels, the traces also show a decreased beat-to-beat variability with fetal tachycardia, which suggests some fetal distress (Category II-b tracing).

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From Parer JT, Ikeda T: A framework for standardized management of intra- partum fetal heart rate patterns. Am J Obstet Gynecol 197:26.e1–e6, 2007.

BOX 9-2

SUBTYPES OF CATEGORY II FHR TRACINGS

Category II-a:  Reduced  fetal  heart  rate  variability  but  without decelerations; risk of fetal acidosis is low

Category II-b:  Reduced  fetal  heart  rate  variability  with  mild decelerations; risk of fetal acidosis is moderate

Category II-c:  Absence  of  fetal  heart  rate  variability  and  deep decelerations; risk of fetal acidosis is high

C H A P T E R 9 Fetal Surveillance during Labor 133

by  most  obstetrical  services.  Until  new  biomarkers,  such as inflammatory markers, become available, reli- ance  must  be  placed  on  FHR  categories  to  determine  management.

A review of the five components of the classification  of Category III tracings is as follows: 1.  Absent baseline variability suggests a serious state 

of metabolic dysregulation. 2.  Recurrent late decelerations of the FHR have been 

associated  primarily  with  severely  reduced  utero- placental blood flow.

3.  Recurrent variable decelerations are characteristic  of  umbilical  cord  compression  and  are  associated  with  reduced  amniotic  fluid  volume.  They  may  be  related  to  the  loss  of  the  protective  effect  of  intact  membranes.

4.  Prolonged bradycardia is secondary to the failure of  the fetus to use its baroreceptive signaling to its car- diovascular centers to control heart rate because of  severe metabolic dysregulation.

5.  Sinusoidal patterns observed on admission suggest  the  possibility  of  severe  fetal  anemia  (of  unknown  cause),  and  the  occurrence  of  a  sinusoidal  pattern  during  labor  lasting  longer  than  20  minutes  is  sug- gestive of a severe, acute fetal bleed.

Strategies for Intervention The  simple  interventions  discussed  above  for  the  observations  of  Category  II  tracings  should  have  already  been  implemented,  except  maybe  amnioinfu- sion. There are four additional procedures that can be  used to assess the status of the fetus when Category III  FHR patterns are present: 1.  Fetal scalp blood sampling  for  pH  determination 

has  been  used  when  clinical  parameters  such  as  Category III FHR patterns and heavy meconium are  present,  but  it  is  no  longer  the  standard  of  practice  in  many  centers.  Fetal  scalp  pH  correctly  predicts  neonatal outcome in 82% of cases as determined by  the  Apgar  score.  The  false-positive  rate  is  approxi- mately  8%,  and  the  false-negative  rate  is  approxi- mately  10%.  Blood  is  obtained  from  the  fetus  by  placing  an  amnioscope  transvaginally  against  the  fetal  skull  (Figure  9-6).  Cervical  mucus  is  removed  with  cotton  swabs.  Silicone  grease  is  applied  to  the  skull for blood bead formation. A 2 × 2-mm lancet is  used for a stab incision, and a drop of blood is aspi- rated  into  a  long,  heparinized  capillary  tube  and  sent to the laboratory for pH and base deficit deter- minations. Table 9-2 lists the normal values for fetal  scalp blood samples.

2.  Ultrasonic Doppler velocimetry  for  blood  flow  measurements  in  umbilical  and  fetal  blood  vessels  and  percutaneous umbilical blood sampling  have  been  used  antepartum  in  some  centers,  but  they  are  generally  not  feasible  methods  for  labor  management.

diabetes,  or  intrauterine  infection  from  chorioamnio- nitis,  may  experience  metabolic  dysregulation  sooner  than a fetus in a normal parturient with Category I FHR  tracings.  The three simple interventions are to (1) change the woman’s position to the left lateral recum- bent,  or  if  she  is  already  on  her  side,  switch  positions  to  the  other  side;  (2) reduce the infusion rate of oxy- tocin  if  this  is  running;  and  (3) increase intravenous fluids  by  infusing  1 L  of  normal  saline  with  either  5%  or  10%  dextrose  to  ensure  adequate  vascular  volume  and  substrate  for  the  fetus  and  placenta.  Studies  have  shown that this intervention shortens labor in nullipa- rous women.

Amnioinfusion A  more  complex  intervention  for  repetitive  variable  decelerations  (cord  pattern)  is  amnioinfusion. This is the replacement of amniotic fluid with normal saline infused through a transcervical intrauterine pressure catheter, and it has been reported to decrease both the frequency and severity of variable decelerations.  The  use  of  a  double-lumen  uterine  catheter  is  recom- mended because it allows a continuous infusion while  measuring uterine tone to guard against overdistention  from  excessive  fluid  accumulation.  A  common  tech- nique  is  to  infuse  a  bolus  of  up  to  800 mL  of  normal  saline  at  a  rate  of  10  to  15 mL/min  over  a  period  of   50  to  80  minutes.  This  is  followed  by  a  maintenance  dose of 3 mL/min until delivery. Overdistention of the  uterine cavity can be avoided by maintaining the base- line  uterine  tone  in  the  normal  range  and  at  less  than  20 mm  Hg.  Amnioinfusion results in reduced cesar- ean deliveries for fetal distress and fewer low Apgar scores at birth without apparent maternal or fetal distress.

CATEGORY III FHR (ABNORMAL) Category  III  FHR  tracings  are  abnormal  and  require  prompt evaluation because each of the five character- istics  (listed  in  Box  9-1  under  Category  III  FHR  pat- terns)  is  predictive  of  abnormal  fetal  acid-base  status.  The  major  issue  is  to  determine  the  optimal  time  for  intervention,  either  by  vaginal  or  cesarean  delivery,  to  avoid serious perinatal morbidity and mortality. There  are  published  data  to  suggest  that,  in  the  presence  of  Category  III  FHR  patterns,  the  optimal  time  for  deliv- ery is within 30 minutes; thus, the delivery team must  act  quickly  to  decide  whether  there  is  sufficient  time  for  a  vaginal  delivery,  keeping  in  mind  that  it  takes  at  least 30 minutes to prepare for an emergency cesarean  delivery.  The  optimal  answer  is  somewhere  between  the  observations  of  Category  II  and  the  early  onset  of  Category  III,  so  it  is  sometimes  prudent  to  notify  the  surgical  team  that  a  cesarean  delivery  may  be  called  when Category II patterns are seen. The degree of fetal  acidosis, as determined by fetal scalp blood sampling,  to  identify  the  fetus  at  greatest  risk  is  no  longer  used 

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3.  If  cervical  dilation  and  station  permit,  the  safest  intervention  for  compression  of  the  umbilical  cord  is assisted vaginal delivery.

4.  Cesarean delivery is indicated for severe, repetitive  decelerations and a FHR tracing indicative of devel- oping  acidosis.  Another  circumstance  that  may  require  intervention  is  a  prolonged  deceleration.  This condition occurs when the FHR falls to 60 to 90  beats/min for more than 2 minutes.

Fetal Assessment at Birth to Document the Status of the Fetus at Risk for Birth Asphyxia APGAR SCORE The Apgar scoring system has classically been used to  assess  the  newborn’s  condition.  Over  time,  however,  the  Apgar  score  has  come  to  be  used  inappropriately   to  define  asphyxia.  This  is  a  misapplication  because  many  other  conditions  (e.g.,  prematurity,  maternal  drug  administration)  can  result  in  low  scores  that  are  not reflective of asphyxia. Asphyxia implies hypoxia of  sufficient degree to cause metabolic acidosis. Thus, the  Apgar  score  alone  cannot  be  used  to  define  asphyxia.  A  low  Apgar  score  of  less  than  5  helps  the  obstetric 

FIGURE 9-6 This technique of fetal scalp blood sampling via an amnioscope is still used in many centers. After making a small stab inci- sion in the fetal scalp, the blood is drawn off through a long, heparinized capillary tube.

Light source

TABLE 9-2

NORMAL RANGES FOR FETAL SCALP AND CORD BLOOD INDICES

Blood pH PCO2 (mm Hg)

PO2 (mm Hg)

Base Deficit (mEq/L)

Scalp Blood

Early labor

7.34-7.38 43-57 20-24 (−0.2)-(0.4)

Active phase

7.34-7.40 36-54 20-24 (−2.0)-(0.0)

Complete cervical dilation

7.26-7.42 36-60 20-24 (−3.3)-(−0.3)

Cord Blood

Artery 7.22-7.34 32-64 14-22 (−7.8)-(−2.2)

Vein 7.29-7.41 25-53 23-35 (−6.2)-(−1.8)

Data from Hobel CJ: Intrapartum clinical assessment of fetal distress. Am J Obstet Gynecol 110:336–342, 1971. PCO2, Partial pressure of carbon dioxide in fetal arterial blood; PO2, partial pressure of oxygen in fetal arterial blood.

C H A P T E R 9 Fetal Surveillance during Labor 135

there is significant but incomplete evidence of its effectiveness for improving long-term fetal outcome, particularly in preterm infants. Over the past 40 years,  more careful attention to monitoring of the fetus during  labor  has  led  to  a  reduction  in  the  incidence  of  post- term  fetal  complications  and  to  an  improvement  in  perinatal  mortality  rates.  The  incidence  of  hypoxic- ischemic  encephalopathy  in  term  infants  has  also  decreased. Preterm births (spontaneous and induced) continue to add to the pool of infants who develop cerebral palsy.

The improvements in outcome for term infants have  not been mirrored by improved prevention of cerebral  palsy  in  preterm  infants.  There  is  a  pressing  need  to  inform  the  public,  as  well  as  the  medical  profession,  that  cerebral palsy is probably not caused by events during labor such as asphyxia and acidosis.  These  intrapartum events appear to play only a small part in  the  overall  incidence  of  this  disorder.  Events  earlier   in  pregnancy  probably  play  the  major  role.  Newer methods must be used to determine the actual prena- tal events or unrecognized intrapartum events that increase the risk of preterm birth. These events could  include  the  subclinical  inflammation  associated  with  obesity.

team  to  focus  on  both  cardiovascular  and  respiratory  adaptation (see Table 8-9).

UMBILICAL CORD BLOOD SAMPLING A more appropriate tool for defining asphyxia is assess- ment of the fetal and neonatal acid-base status. Normal  ranges  for  these  indices  are  given  in  Table  9-2.  One  reasonable  protocol  for  umbilical  cord  blood  pH  and  blood gas analysis is as follows: 1.  Doubly clamp a segment of umbilical cord immedi-

ately after birth in all preterm deliveries and in term  deliveries where fetal distress is suspected, as well as  in  cases  where  the  1-  and/or  5-minute  Apgar  score  is low (<7).

2.  If a specimen cannot be obtained from the umbilical  artery of the cord, obtain a specimen from an artery  on the chorionic surface of the placenta.

Controversies about Fetal Monitoring for the Diagnosis and Treatment of Fetal Distress After more than 40 years of routine use of electronic monitoring for assessment of the FHR during labor,

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10  Obstetric Hemorrhage Antepartum, Intrapartum, and Postpartum

C H

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T ER

CALVIN J. HOBEL • AMY R. LAMB

■  Antepartum hemorrhage can be a very serious complica- tion  of  pregnancy.  Hemorrhage  may  be  painless  or  painful, and the source of the bleeding is usually mater- nal, but it can rarely be from the fetus. The initial evalu- ation  must  be  carefully  performed  to  first  stabilize  the  patient, assess the well-being of the fetus, and determine  the cause while establishing a plan of management.

■  The  causes  of  severe  antepartum/intrapartum  hemor- rhage are usually secondary to abnormal implantation of  the placenta. The incidence of placenta previa, the most  common  type  of  abnormal  placentation,  is  0.5%,  and  bleeding  from  a  placenta previa  accounts  for  approxi- mately 20% of all cases of antepartum hemorrhage. The  classic presentation of placenta previa is painless vaginal  bleeding  in  a  previously  normal  pregnancy.  Placenta accreta  is  a  condition  that  occurs  because  of  excessive  invasion  of  the  placental  trophoblasts  into  the  myome- trium,  resulting  in  failure  of  placental  separation.  This  usually leads to excessive bleeding when the placenta is  manually  removed  intrapartum.  Abruptio placentae  is  due to premature separation of the normally implanted  placenta. Placental abruption complicates 0.5-1.5% of all  pregnancies (1 in 120 births). Because the bleeding pen- etrates into the myometrium, it is associated with pain.

■  Fetal bleeding may be caused by an abnormal (velamen- tous) insertion of the umbilical cord between the amnion 

and chorion and away from the placenta. When the cord  insertion  and  placental  edge  are  close  to  the  cervical  opening, changes in the lower uterine segment that occur  before  labor  can  cause  stretching  and  bleeding  from   the  cord  vessels.  With  vaginal  ultrasound  and  a  simple  bedside  test  to  differentiate  maternal  blood  from  fetal  blood, the source of the bleeding can be diagnosed.

■  Postpartum hemorrhage is defined as blood loss in excess  of  500 mL  at  the  time  of  vaginal  delivery  or  in  excess  of  1000 mL  for  cesarean  delivery.  Postpartum  hemorrhage  is a leading cause of maternal mortality worldwide. The  prevalence of postpartum hemorrhage is approximately  6% of all deliveries and accounts for 25% of all maternal  deaths. Formulating a plan of management based on risk  factors  for  postpartum  hemorrhage  and  using  intrave- nous  oxytocin  and  manual  uterine  massage  after  the  delivery are key elements of an effective prevention plan  for postpartum hemorrhage.

■  When  postpartum  hemorrhage  occurs  after  the  patient  leaves  the  labor  and  delivery  area,  the  obstetric  team  must  reassess  the  patient  to  identify  the  less  common  causes of delayed postpartum hemorrhage. This requires  a careful search for retained products of conception and  clotting within the uterus that can keep it from contract- ing. Other rare causes, such as uterine rupture, must also  be considered.

CLINICAL KEYS FOR THIS CHAPTER

The most common causes of maternal death are hemorrhage, embolism, hypertensive disease, and infection. In this chapter, the causes of obstetric hem- orrhage  in  the  late  second  trimester  and  the  third  tri- mester  are  discussed. The  antepartum  causes  include  placenta previa and accreta, conditions that represent  abnormalities of placentation. Placental abruption and  fetal  causes  of  bleeding  may  also  present  before  labor  and may result in fetal death.

Postpartum hemorrhage (PPH) is the leading cause  of maternal mortality worldwide, and its prevention is 

an important part of labor management. Uterine atony,  genital  tract  birth  trauma,  and  placental  retention  are  the most common causes of PPH.

Antepartum Hemorrhage The incidence of bleeding in the late second trimester  and the third trimester is between 5% and 8%, because  bleeding before 20 weeks (time of potential viability) is  usually related to the risk of abortion and the manage- ment  is  less  emergent.  It  is  therefore  critical  for  the 

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obtaining a platelet count, serum fibrinogen level, pro- thrombin  time  (PT),  and  partial  thromboplastin  time.  Additionally,  the  patient  should  be  typed and cross- hatched for at least 4 units of blood  (packed  cells).  A  rapid but subjective method to test for coagulopathy is  to partially fill a “red-top” tube with blood. If a clot does  not  form,  or  once  formed  does  not  stay  clotted,  the  patient  most  likely  has  disseminated  intravascular  coagulation (DIC).

An important and accurate method of determin- ing the cause of bleeding in the late second trimester and the third trimester is ultrasonography. This eval- uation should include not only the location and extent  of  the  placenta  (initial  ultrasonic  assessment  to  rule  out  placenta  previa)  but  also  an  assessment  of  gesta- tional  age,  an  estimate  of  fetal  weight,  determination  of the fetal presentation, and screening for fetal anom- alies. Uterine activity and the fetal heart rate should be  assessed  with  a  monitored  strip  to  rule  out  labor  and  to establish fetal well-being (see Chapter 9).

Abnormal Placentation: Placenta Previa and Placenta Accreta PLACENTA PREVIA The incidence of placenta previa, the most common type of abnormal placentation, is 0.5%. Approxi- mately 20% of all cases of antepartum hemorrhage are due to placenta previa. Seventy percent of patients  with  placenta  previa  present  with  painless  vaginal  bleeding in the third trimester, 20% have contractions  associated  with  bleeding,  and  10%  have  the  diagnosis  made  incidentally  on  the  basis  of  ultrasonography  or  at term.

Predisposing Factors Factors that have been associated with a higher inci- dence of placenta previa include (1) multiparity,  which is associated with changes in the size and shape  of the uterus, providing more space in the lower uterine  segment for implantation; (2) increased maternal age; (3) prior placenta previa; (4) multiple gestation;  and  (5) cesarean delivery, which also changes the shape of  the  lower  uterine  segment.  Patients  with  a  prior  pla- centa previa have a 4-8% risk of having placenta previa  in a subsequent pregnancy.

Classification Placenta  previa  is  classified  according  to  the  relation- ship  of  the  placenta  to  the  internal  cervical  os  (Figure  10-1).  Complete placenta previa  implies  that  the  pla- centa  totally  covers  the  cervical  os.  A  complete  pla- centa  previa  may  be  central,  anterior,  or  posterior,  depending  on  where  the  center  of  the  placenta  is  located  relative  to  the  os.  Partial placenta previa  implies  that  the  placenta  partially  covers  the  internal 

well-being  of  both  the  mother  and  the  fetus  that  the  patient  who  presents  with  bleeding  in  the  late  second  trimester  and  the  third  trimester  be  evaluated  and  managed emergently.

INITIAL EVALUATION After  a  complete  history  has  been  taken,  physical  examination is performed, but a pelvic examination is  usually  postponed  until  an  abdominal  ultrasound  has  been  obtained  to  rule  out  placenta  previa. The  differ- ential  diagnosis  of  second-  and  third-trimester  bleed- ing is listed in Box 10-1.

The  vital  signs  and  amount  of  bleeding  should  be  checked  immediately,  as  should  the  patient’s  mental  status. The patient’s medical history should be checked  for  known  bleeding  disorders  or  liver  disease,  which  predispose the patient to coagulopathy. Once placenta  previa  has  been  excluded  by  abdominal  ultrasound,  a  sterile  speculum  examination  can  safely  be  done  to  rule  out  genital  tears  or  lesions  (e.g.,  cervical cancer)  that  may  be  responsible  for  the  bleeding.  If  none  are  identified,  a  digital  examination  or  pelvic  ultrasound  may be performed to determine whether cervical dila- tion is present.

If a patient is bleeding profusely, a team approach to the assessment and management should be insti- tuted to establish hemodynamic stability.  This  team  should  include  an  obstetrician,  an  anesthesiologist,  and nurses who are knowledgeable about the manage- ment  of  a  potentially  critically  ill  patient.  At  least  two  large-bore peripheral intravenous (IV ) lines should be  placed,  as  they  allow  the  most  rapid  replacement  of  fluid and blood volume. A central venous pressure line,  or preferably a pulmonary artery catheter, is helpful in  the management of hypovolemic shock.

A  complete blood count  should  be  obtained  and  compared  with  previous  evaluations  to  help  assess   the  amount  of  blood  loss,  although  acute  blood  loss  may  not  be  reflected  in  the  hemoglobin  level  until  homeostasis has been reestablished. An assessment of  the  patient’s  coagulation profile  should  be  done  by 

BOX 10-1

CAUSES OF ANTEPARTUM HEMORRHAGE (APH)

Common Placenta previa Preterm labor (marginal separation of placenta)

Uncommon Uterine rupture Fetal (chorionic) vessel rupture Cervical or vaginal lacerations Cervical or vaginal lesions, including cancer Congenital bleeding disorder Unknown (by exclusion of the above)

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lower  margin  of  the  placenta  may  be  obscured  and   the  diagnosis  of  placenta  previa  missed.  Transvaginal ultrasonography can accurately diagnose placenta previa in virtually 100% of cases.

Management Once  the  diagnosis  of  placenta  previa  is  established,  management decisions depend on the gestational age  of the fetus and the extent of the vaginal bleeding. With a preterm pregnancy, the goal is to attempt to obtain fetal maturation without compromising the mother’s health.  If  bleeding  is  excessive,  delivery  must  be  accomplished  by  cesarean,  regardless  of  gestational  age. When the bleeding episode is not profuse or repet- itive, the patient is managed expectantly in the hospital  on  bed  rest.  With  expectant  management,  70%  of  patients  will  have  recurrent  vaginal  bleeding  before  completion  of  36  weeks’  gestation  and  will  require  delivery.  If the patient reaches 36 weeks, fetal lung maturity should be determined by amniocentesis and the patient delivered by cesarean if the fetal lungs are mature.  Elective  delivery  is  preferable,  as  sponta- neous labor places the mother at greater risk for hem- orrhage  and  the  fetus  at  risk  for  hypovolemia  and  anemia.

LOW-LYING PLACENTA A  patient  with  a  low-lying  placenta  (placental  margin  within 2 cm of the endocervical os) may present in the  same  way  as  a  patient  with  placenta  previa.  It  may  be  difficult to distinguish a low-lying placenta from a mar- ginal  placenta  previa,  but  a  transvaginal  ultrasound  is  typically  diagnostic.  Vaginal delivery is not contrain- dicated, because during labor the fetal head com- presses the edge of the placenta, decreasing the risk of bleeding.  The  same  level  of  monitoring  should  be  maintained  for  maternal  hemodynamic  stability  and  fetal well-being.

MATERNAL-FETAL RISKS Maternal  mortality  from  placenta  previa  has  dropped  from  30%  to  less  than  1%  over  the  past  60  years. This  has  primarily  been  due  to  the  liberal  use  of  cesarean  delivery  and  careful  expectant  management.  The rare maternal death is generally associated with compli- cations of cesarean delivery or uncontrolled hemor- rhage from the placental site. The lower uterine segment does not contract well, especially after a lower uterine incision. DIC may also result if a massive  hemorrhage or an associated abruption occurs.

The risk of antepartum or intrapartum hemorrhage,  or both, is a constant threat to the patient with placenta  previa.  Bleeding  may  be  exacerbated  by  an  associated  placenta accreta or uterine atony. Placenta previa pre- disposes the patient to preterm delivery, which poses the greatest risk to the fetus. As a result of advances in  obstetric  and  neonatal  care,  the  perinatal  mortality  rate  (PMR)  for  patients  with  placenta  previa  has 

cervical os. A marginal placenta previa is one in which  the  edge  of  the  placenta  extends  to  the  margin  of  the  internal cervical os.

Diagnosis The classic presentation of placenta previa is painless vaginal bleeding in a previously normal pregnancy.  The  mean  gestational  age  at  onset  of  bleeding  is  30  weeks,  with  one-third  presenting  before  30  weeks.   Placenta  previa  is  almost  exclusively  diagnosed  on   the  basis  of  ultrasonography.  Between  4%  and  6%  of  patients have some degree of placenta previa on ultra- sonic examination before 20 weeks’ gestation. With the  development  of  the  lower  uterine  segment,  a  relative  upward  placental  migration  occurs,  with  90%  of  these  resolving  by  the  third  trimester.  Complete  placenta  previa  is  the  least  likely  to  resolve,  with  only  10%  of  cases  resolving  by  the  third  trimester.  When placenta previa is diagnosed in the second trimester, a repeat sonogram is indicated at 30 to 32 weeks for follow-up evaluation.

Transabdominal ultrasonography has an accuracy of 95% for placenta previa detection. If the placenta is  implanted  posteriorly  and  the  fetal  vertex  is  low,  the 

FIGURE 10-1 Types of placenta previa.

Partial placenta previa

Total placenta previa

Low implantation or low-lying placenta

Marginal placenta previa

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25% after two. The etiology may be the opposite of that  for  placenta  accreta.  Because  abruption  is  associated  with  maternal  hypertension  or  preeclampsia,  there  may be a failure of adequate placental implantation. Its  inciting  cause  is  unknown,  but  placental  separation  may be due to an inherent weakness or anomaly in the  spiral  arterioles.  Placental separation is initiated by hemorrhage into the decidua basalis with formation of a decidual hematoma.  The  resulting  separation  of  the decidua from the basal plate predisposes to further  separation and bleeding, as well as to compression and  destruction of placental tissue. Blood may either dissect  upward  toward  the  fundus,  resulting  in  a  concealed hemorrhage,  or  extend  downward  toward  the  cervix,  resulting in an external or revealed hemorrhage.

DIAGNOSIS AND MANAGEMENT Clinically, the diagnosis of a placental abruption is entertained if a patient presents with painful vaginal bleeding in association with uterine tenderness, hyperactivity, and increased tone.  The  signs  and  symptoms of placental abruption are variable, however.  The  most  common  finding  is  vaginal  bleeding,  which  is  seen  in  80%  of  cases.  Abdominal pain and uterine tenderness are present in 66% of cases, fetal distress in 60%, uterine hyperactivity and increased uterine tone in 34%, and fetal death in 15%.

The diagnosis of placental abruption is made clini- cally. Ultrasonography may detect only 2% of abrup- tions. Because placental abruption may coexist with a  placenta  previa,  the  reason  for  doing  an  initial  ultra- sonic examination is to exclude the previa.

Management  of  the  patient  with  an  abruption  includes  careful  maternal  hemodynamic  and  fetal  monitoring,  serial  evaluation  of  the  hematocrit  and  coagulation  profile,  and  delivery.  Intensive monitor- ing of both the mother and the fetus is essential  because  rapid  deterioration  of  the  condition  of  either  one can occur. Blood products for replacement should  always be available, and a large-bore (16- to 18-gauge)  IV  line  must  be  secured.  Red  blood  cells  should  be  given  liberally  if  indicated.  In the setting of placental abruption, the use of tocolytics or uterine relaxants is not advisable.  Uterine  tone  must  be  maintained  to  control bleeding following delivery, or at least to control  the  bleeding  sufficiently  to  allow  a  safe  hysterectomy  to be performed, if necessary.

MATERNAL-FETAL RISKS Abruption places the fetus at significant risk of hypoxia  and,  ultimately,  death.  The PMR due to placental abruption is 35%, and the condition accounts for 15%  of  third-trimester  stillbirths.  Fifteen  percent  of  live- born infants have significant neurologic impairment.

Placental abruption is the most common cause of DIC in pregnancy.  This  results  from  release  into  the  maternal  circulation  of  thromboplastin  from  the  dis- rupted  placenta  and  subplacental  decidua,  causing  a 

declined  over  the  past  decade.  The incidence of mal- presentation with placenta previa is 30%, presumably due to the mass effect of the placenta and distortion of the lower uterine segment.

PLACENTA ACCRETA Placenta accreta implies an abnormal attachment of the placenta through the uterine myometrium as a result of defective decidual formation (absent Nita- buch layer).  This  abnormal  myometrial  attachment  of  the  placental  villi  is  usually  superficial  (accreta),  but the villi may invade more deeply into the myome- trium (increta) or extend through to the uterine serosa  (percreta). Two-thirds of patients with this complica- tion require hysterectomy when an attempt to remove the placenta leads to severe hemorrhage intrapar- tum.  Patients  with  a  history  of  uterine  surgery  are  at  greatest  risk  of  developing  an  accreta.  In  fact,  those with prior cesarean delivery have a 10-50% risk of abnormal implantation.  If  ultrasonic  imaging  shows  accreta  prior  to  delivery,  elective  hysterectomy  may   be  performed to  prevent  hemorrhage.  The etiology of placenta accreta is complex, but recent evidence sug- gests  the  aggressive  invasion  of  the  placenta  into  the  spiral arteries is a process unique to primates that has  been  conserved  through  evolution.  It  ensures  that  invasion  of  the  uterine  arteries  is  complete  to  maxi- mize  fetal  access  to  the  maternal  circulation  for  maximal nutrition.

Abruptio Placentae Abruptio placentae, or premature separation of the normally implanted placenta, complicates 0.5-1.5% of all pregnancies (1 in 120 births).  Abruption  severe  enough  to  result  in  fetal  death  occurs  in  1  in  500  deliveries.

PREDISPOSING FACTORS AND PATHOPHYSIOLOGY Factors  associated  with  an  increased  incidence  of  abruption are noted in Box 10-2. The most common of  these  risk  factors  is  maternal hypertension,  either  chronic  or  as  a  result  of  preeclampsia.  The risk of recurrent abruption is 10% after one abruption and

BOX 10-2

RISK FACTORS FOR ABRUPTIO PLACENTAE

Maternal hypertension (chronic or pregnancy-induced) Placental abruption in a prior pregnancy Pregnancy after in vitro fertilization (IVF) Trauma Polyhydramnios with rapid decompression Premature rupture of membranes Short umbilical cord Folate deficiency Substance abuse (e.g., cocaine, amphetamines, tobacco)

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the  mother  is  hemorrhage  and  shock.  Although  the associated maternal mortality rate is now less than 1%, if the mother is left untreated, she will almost cer- tainly  die.  For  the  fetus,  rapid  intervention  will  mini- mize  morbidity  and  mortality.  The associated fetal mortality rate is still about 30%.

Fetal Bleeding Rupture  of  a  fetal  umbilical  vessel  complicates  0.1- 0.8% of pregnancies. This often results when the cord insertion is velamentous, implying that the vessels of  the cord insert between the amnion and chorion, away  from the placenta. The incidence of velamentous cord  insertion  varies  from  1%  in  singleton  pregnancies  to  10%  in  twins  and  50%  in  triplets.  If the unprotected vessels pass over the cervical os, this is termed a vasa previa. The incidence of vasa previa is 1 in 5000 preg- nancies. Velamentously inserted vessels need not pass  over the os to rupture.

The diagnosis of fetal bleeding is made by perform- ing an Apt test. After obtaining blood from the vagina  and putting it into a red-topped test tube, tap water or  distilled water is added. The water will lyse blood cells  and release hemoglobin into the solution. Adding 1 mL  of  KOH  results  in  a  brown  discoloration  when  the  hemoglobin  is  maternal.  If  the  blood  is  fetal  in  origin,  the color of the fluid will remain red because the fetal  hemoglobin will not be denatured by the KOH. Rupture  of  a  fetal  vessel  necessitates  immediate  abdominal  delivery.  Vasa previa alone carries a PMR of 50%, which increases to 75% if the membranes rupture.

Postpartum Hemorrhage Postpartum hemorrhage (PPH), the leading cause of maternal mortality, is defined as blood loss in excess of 500 mL at the time of vaginal delivery or blood loss in excess of 1000 mL following cesarean delivery. The  excessive  blood  loss  usually  occurs  in  the  immediate  postpartum period, but it can occur slowly over the first  24  hours.  Delayed PPH can occasionally occur, with the excessive bleeding commencing more than 24 hours after delivery. This is usually due to subinvolu- tion  of  the  uterus  and  disruption  of  the  placental  site  “scab” several weeks postpartum or to the retention of  placental  fragments  that  separate  several  days  after  delivery. The causes of PPH are listed in Box 10-3.

Since 1996, there has been a gradual increase in the  incidence of PPH in the United States and other devel- oped  countries.  This  increase  has  been  related  to  uterine  atony. The  cause  of  this  increase  is  not  known  and is currently under intense investigation.

UTERINE ATONY The majority of PPH cases (75-80%) are due to uterine atony. The factors predisposing to postpartum uterine 

consumptive  coagulopathy.  Clinically  significant  DIC  complicates 20% of cases and is most commonly seen  when  the  abruption  is  massive  or  fetal  death  has  occurred. Hypovolemic shock and acute renal failure as a result of massive hemorrhage may be seen with a severe abruption if hypovolemia is left uncorrected.  Sheehan syndrome (amenorrhea as a result of mater- nal  postpartum  pituitary  necrosis)  may be a delayed complication resulting from coagulation within the portal system of the pituitary stalk.  Assessment  of  pituitary function should be considered in the postpar- tum follow-up of women after a serious abruption with  a coagulation disorder.

Uterine Rupture Uterine  rupture  implies  complete  separation  of  the  uterine musculature through all of its layers, ultimately  with  all  or  a  part  of  the  fetus  being  extruded  from  the  uterine cavity. The overall incidence is 0.5%.

Uterine rupture may be spontaneous, traumatic, or  associated  with  a  prior  uterine  scar,  and  it  may  occur  during or before labor or at the time of delivery. A prior uterine scar is associated with 40% of cases.  With  a  prior  lower-segment  transverse  incision,  the  risk  for  rupture  is  less  than  1%,  whereas  the risk with a high vertical (classical) scar is 4-7%. Sixty percent of uterine  ruptures occur in previously unscarred uteri.

DIAGNOSIS AND MANAGEMENT The signs and symptoms of uterine rupture are highly  variable.  Typically, rupture is characterized by the sudden onset of intense abdominal pain. The patient  may or may not have vaginal bleeding, and if it occurs,  it  can  range  from  spotting  to  severe  hemorrhage.  Impending  rupture  may  be  heralded  by  hyperventila- tion, restlessness, agitation, and tachycardia. After the  rupture  has  occurred,  the  patient  may  be  free  of  pain  momentarily and then complain of diffuse pain there- after. The most consistent clinical finding is an abnor- mal  fetal  heart  rate  pattern.  The presenting part may be found to have retracted on pelvic examination, and fetal parts may be more easily palpable abdomi- nally.  Abnormal  contouring  of  the  abdomen  may  be  seen.  Fetal  distress  develops  commonly,  and  fetal death or long-term neurologic sequelae may occur in 10% of cases.

A  high  index  of  suspicion  is  required,  and  immedi- ate  laparotomy  is  essential.  In most cases, total abdominal hysterectomy is the treatment of choice,  although debridement of the rupture site and primary  closure may be considered in women of low parity who  desire more children.

MATERNAL-FETAL RISK Delay  in  management  of  uterine  rupture  places  both  mother  and  child  at  significant  risk. The  major  risk  to 

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to contract after placental separation (uterine atony) leads to excessive placental site bleeding.

During pregnancy, uterine relaxation is facilitated by progesterone and parathyroid hormone–related peptide (PTHrP). The latter plays an important role in  maintaining  uterine  relaxation  during  pregnancy  (see  Chapter  5);  however,  as  soon  as  the  uterus  is  emptied  (delivery  of  the  fetus  and  placenta),  the  gene  control- ling this hormone is turned off and the uterus is allowed  to contract more completely. If there is a failure of com- plete expulsion of the placenta or poor uterine contrac- tility  leading  to  excessive  bleeding,  the  uterus  will  fill  with blood. The distention is thought to reactivate the  expression  of  PTHrP  and  cause  uterine  relaxation,  thereby leading to excessive hemorrhage.

Management of Patients at Risk for Postpartum Hemorrhage Because  the  major  cause  of  PPH  is  uterine  atony,  the  initial  focus  should  be  on  prevention  of  uterine  atony  by considering the following steps: 1.  All  women  in  early  labor  who  have  risk  factors  for 

PPH  should  be  identified  (see  Box  10-4)  and  their  hemoglobin  checked.  For  medium-risk women,  their blood should be typed and screened for irregu- lar  antibodies  such  as  Rh  and  Kell.  For  high-risk women, 2 units of blood should be typed and cross- matched (refer to Stage 0 in Table 10-1).

2.  As soon as the fetus has been delivered, an infusion  of  oxytocin  (Pitocin)  10  to  40 U/L  IV  should  be  started  and  maintained  during  the  first  6  hours  postpartum.

3.  The  vagina  and  perineum  should  be  inspected  to  rule  out  any  lacerations  that  could  cause  excessive  bleeding.

4.  The  placenta  should  be  carefully  assessed  at  deliv- ery to make certain there are no missing cotyledons  (lobules of placenta).

5.  The  uterus  should  be  evaluated  by  abdominal  pal- pation during the first 1 to 2 hours before transfer to  the postpartum unit. The nurses on the postpartum  unit  should  frequently  assess  the  status  of  uterine  contractility, instructing the patient on how to assess  uterine firmness and reporting any excessive bleed- ing. For high-risk patients, continuation of the oxy- tocin IV infusion during the early postpartum hours  should be considered.

DIFFERENTIAL DIAGNOSIS: OTHER LESS COMMON CAUSES OF POSTPARTUM HEMORRHAGE If  the  cause  of  bleeding  has  not  been  identified,  the  management  of  PPH  requires  a  systematic  approach.  The  fundus  of  the  uterus  should  be  palpated  through  the  abdominal  wall  to  determine  the  presence  or 

atony  are  listed  in  Box  10-4.  Recently,  several  new  factors  have  been  identified  as  potential  causes  of  uterine  atony,  including  vitamin D deficiency and maternal and fetal genetic factors. Vitamin D is known  to  play  an  important  role  in  muscle  function,  and  muscle is a component of both the uterine and vascu- lar system. Studies have suggested that among patients  having a vaginal delivery, 18% of the variation in exces- sive postpartum bleeding may be attributable to mater- nal  genetic  factors,  11%  to  maternal  environmental  factors, and 11% to fetal genetic effects.

Most  of  the  blood  loss  due  to  uterine  atony  occurs  from  the  myometrial  spiral  arterioles  and  decidual  veins that previously supplied and drained the intervil- lous spaces of the placenta. As the contractions of the  partially  empty  uterus  cause  placental  separation,  bleeding  occurs  and  continues  until  the  uterine  mus- culature contracts around the blood vessels and acts as  a  physiologic-anatomic  ligature.  Failure of the uterus

†Medium-risk patients (one or more factors). *High-risk patients (one or more factors).

BOX 10-4

FACTORS PREDISPOSING TO POSTPARTUM UTERINE ATONY

History of postpartum hemorrhage* Prolonged labor* Grand multiparity (a parity of 5 or more)* Overdistention of the uterus†

Multiple gestations Polyhydramnios Fetal macrosomia

Oxytocic augmentation of labor†

Precipitous labor (one lasting <3 hr) Magnesium sulfate treatment of preeclampsia†

Chorioamnionitis†

Halogenated anesthetics Uterine leiomyomata†

Vitamin D deficiency Genetic and epigenetic factors (maternal, environmental, 

and fetal)

*Both of these conditions result in retained blood clots and placental frag- ments, causing uterine stretching and prevention of uterine contractions.

BOX 10-3

CAUSES OF POSTPARTUM HEMORRHAGE

Uterine atony* Retained placental tissue* Genital tract trauma Low placental implantation Uterine inversion Coagulation disorders Amniotic fluid embolism Retained dead fetus Inherited coagulopathy Abruptio placentae (usually ante- or intrapartum)

PA R T 2 Obstetrics142

RETAINED PLACENTAL TISSUE In about one-half of the patients with delayed PPH, placental fragments are present. The uterus is unable  to  maintain  a  contraction  and  involute  normally  around  a  retained  placental  tissue  mass.  If retained placental fragments are suspected, ultrasonic assess- ment of the uterus should be performed. If placental fragments are identified, manual exploration of the uterine cavity  should  be  performed,  with  the  patient  under  general  anesthesia  if  necessary. With  fingertips  together,  a  gloved  hand  may  be  slipped  through  the  open cervix and the hand inserted into the uterus. The  endometrial  surface  should  be  palpated  carefully  to  identify  any  retained  products  of  conception,  uterine  wall lacerations, or partial uterine inversion. If no cause  for  the  bleeding  is  found,  coagulopathy  must  be  considered.

LOW PLACENTAL IMPLANTATION Low  implantation  of  the  placenta  can  predispose  the  patient to PPH because the relative content of muscu- lature  decreases  in  the  lower  uterine  segment,  which  may result in insufficient muscular control of placental  site  bleeding.  Verifying  a  fully  drained  bladder  and   the  use  of  uterotonic  agents  such  as  oxytocin,  methy- lergonovine,  or  prostaglandin  is  usually  sufficient.  If 

absence  of  uterine atony.  Next,  a  quick  but  thorough  inspection  of  the  vagina  and  cervix  should  be  per- formed  to  ascertain  whether  any  lacerations  may  be  compounding  the  bleeding  problem.  Any  uterine inversion  or  pelvic hematoma  should  be  excluded  during  the  pelvic  examination.  (See Table  10-1,  Stages  1 and 2; begin hemorrhage protocol.)

GENITAL TRACT TRAUMA Trauma during delivery is the second most common cause of PPH.  During  vaginal  delivery,  lacerations  of  the  cervix  and  vagina  may  occur  spontaneously,  but  they are more common following the use of forceps or  a  vacuum  extractor.  The  vascular  beds  in  the  genital  tract are engorged during pregnancy, and bleeding can  be profuse. Lacerations are particularly prone to occur  over  the  perineal  body,  in  the  periurethral  area,  and  over the ischial spines along the posterolateral aspects  of the vagina. The cervix may lacerate at the two lateral  angles  while  rapidly  dilating  in  the  first  stage  of  labor.  Uterine rupture may occasionally occur.  At  the  time  of  delivery  by  low  transverse  cesarean,  an  inadvertent  lateral  extension  of  the  incision  can  damage  the  ascending  branches  of  the  uterine  arteries;  an  exten- sion inferiorly can damage the cervical branches of the  uterine artery.

TABLE 10-1

POSTPARTUM OBSTETRIC HEMORRHAGE CARE SUMMARY

Stage 0 Assess for Risk Factors (see Box 10-4) 1. Active management: IV infusion of oxytocin after delivery of the fetus and fundal

uterine massage after delivery of the placenta 2. Complete evaluation for missing placental cotyledons and examination of vagina

and cervix for lacerations with repair when needed to control bleeding 3. If high risk (history of postpartum hemorrhage plus 1 or more risk factors), consider

typing and crossmatching 2 U of PRBCs

All women in labor or giving birth

Stage 1 Begin Hemorrhage Protocol 1. Alert charge nurse and anesthesia staff 2. Type and crossmatch 2 U of PRBCs (if not already done) 3. Increase infusion rate of oxytocin, give methergine and repeat fundal massage 4. Measure blood loss

Blood loss >500 mL (vaginal delivery) >1000 mL (cesarean delivery)

Stage 2 Call for Help (Rapid Response Team) 1. Consider complete reexamination of vagina, cervix, and uterine cavity for source of

bleeding; if the patient is in the postpartum unit, consider moving her to labor and delivery or the operating room

2. Consider the next level of drugs (carboprost 250 µg IM or misoprostol 800 to 1000 µg per rectum) and request additional laboratory testing (e.g., a coagulation panel)

3. Consider blood transfusion (have 2 U of PRBCs plus 2 U of fresh frozen plasma at the bedside)

4. Consider placement of intrauterine balloon or involve interventional radiology when available for embolization

Total blood loss between 1000 and 1500 mL

Stage 3 Mobilize Surgical Team 1. Consider repeat laboratory tests, including coagulation studies and acid-base gas

assessment 2. Transfuse appropriately with PRBCs and platelets 3. Consider B-Lynch suture, uterine artery ligation, or hysterectomy

Total blood loss >1500 mL

Modified from the California Maternal Quality Care Collaborative. Available at www.CMQCC.org. Accessed May 10, 2015. IM, Intramuscular; IV, intravenous; PRBC, packed red blood cells.

C H A P T E R 10 Obstetric Hemorrhage 143

Obstetric Shock and External Bleeding Hypotension  without  significant  external  bleeding   may occasionally develop in an obstetric patient. This  condition  is  called  obstetric  shock.  The causes of obstetric shock include concealed hemorrhage within the uterus, uterine inversion, and amniotic fluid embolism.

An improperly sutured episiotomy can lead to a concealed PPH. If the first suture at the vaginal apex of  the  episiotomy  incision  does  not  incorporate  the  cut  and  retracted  arterioles,  these  can  continue  to  bleed,  creating a hematoma that can dissect cephalad into the  retroperitoneal  space.  This  may  cause  shock  without  external  evidence  of  blood  loss.  A soft tissue hema- toma, usually of the vulva, may occur following deliv- ery in the absence of any laceration. Uterine rupture  can  also  occur  secondary  to  blunt  abdominal  trauma  at the time of an automobile accident.

Management of Established Postpartum Hemorrhage and Obstetric Shock During  the  diagnostic  workup  of  an  established  hem- orrhage,  the  patient’s  vital  signs  must  be  monitored  closely. However, young healthy women may tolerate and mask hypovolemia well. The sensitivity and speci- ficity of the vital signs are not absolute. The estimated  blood loss is commonly underestimated, and it should  be  replaced  by  quantitated  blood  loss,  where  sponges  and pads are weighed and measured. Multiple units of  packed  red  blood  cells  must  be  typed  and  cross- matched,  and  IV  crystalloids  (such  as  normal  saline   or  lactated  Ringer  solution)  infused  to  restore  intra- vascular  volume.  Resuscitation with normal saline usually requires a volume of three times the esti- mated blood loss to replace the intravascular volume. During a massive hemorrhage, morbidity and/or mortality are reduced with an emphasis on early blood product replacement rather than crystalloid- based resuscitation.

UTERINE ATONY When uterine atony is determined to be the cause of the PPH, a rapid, continuous IV infusion of dilute oxy- tocin  (40  to  80 U  in  1 L  of  normal  saline)  should be given to increase uterine tone.  If  the  uterus  remains  atonic and the placental site bleeding continues, 0.2 mg  of  ergonovine maleate or methylergonovine  may  be  given  intramuscularly.  The  ergot  drugs  are  relatively  contraindicated in patients with hypertension because  the smooth muscle–constricting effects of these drugs  may  also  increase  vascular  tone  and  thus  increase  blood pressure to dangerous levels.

bleeding  continues,  surgical  management  must  be  considered.

COAGULATION DISORDERS Peripartum coagulation disorders are high-risk factors  for PPH, but fortunately they are quite rare.

Patients with thrombotic thrombocytopenia have a  rare  syndrome  of  unknown  etiology  characterized  by  thrombocytopenic  purpura,  microangiopathic  hemo- lytic  anemia,  transient  and  fluctuating  neurologic  signs, renal dysfunction, and a febrile course. In preg- nancy, the disease is usually fatal.

An amniotic fluid embolus is also rare and is associ- ated with an 80% mortality rate. This syndrome is char- acterized by a fulminating consumption coagulopathy,  intense  bronchospasm,  and  vasomotor  collapse.  It  is  triggered  by  an  intravascular  infusion  of  a  significant  quantity of amniotic fluid during a tumultuous or rapid  labor in the presence of ruptured membranes. During  the process of placental abruption, a small amount of  amniotic  fluid  may  leak  into  the  vascular  system,  and  the thromboplastin in the amniotic fluid may trigger a  consumption coagulopathy.

Patients  with  idiopathic thrombocytopenic pur- pura have platelets with abnormal function or a short- ened  lifespan.  This  causes  thrombocytopenia  and  a  tendency  to  bleed.  Circulating  antiplatelet  antibodies  of the immunoglobulin G type may occasionally cross  the placenta and result in fetal and neonatal thrombo- cytopenia as well.

von Willebrand disease  is  an  inherited  coagulopa- thy  characterized  by  a  prolonged  bleeding  time  due   to  factor  VIII  deficiency.  During  pregnancy,  these  patients are likely to have a decreased bleeding diathe- sis because pregnancy elevates factor VIII levels. In the  postpartum  period,  they  are  susceptible  to  delayed  bleeding as factor VIII levels fall.

UTERINE INVERSION Uterine  inversion  is  the  “turning  inside  out”  of  the  uterus in the third stage of labor. It is quite rare, occur- ring in only about 1 in 20,000 pregnancies. Just after the  second  stage  of  labor,  the  uterus  is  somewhat  atonic,  the cervix open, and the placenta attached.  Improper management of the third stage of labor can cause an iatrogenic uterine inversion.  If  the  inexperienced  physician  exerts  fundal  pressure  while  pulling  on  the  umbilical  cord  before  complete  placental  separation  (particularly  with  a  fundal  implantation  of  the  pla- centa),  uterine  inversion  may  occur.  As  the  fundus  of  the  uterus  moves  through  the  vagina,  the  inversion  exerts  traction  on  peritoneal  structures,  which  can  elicit  a  profound  vasovagal  response.  The  resulting  vasodilation increases bleeding and the risk of hypovo- lemic shock. If the placenta is completely or partially separated, the uterine atony may cause profuse bleeding, which compounds the vasovagal shock.

PA R T 2 Obstetrics144

An  intraoperative laceration of the ascending branch of the uterine artery during delivery through a  low transverse incision can easily be controlled by the  placement  of  a  large  suture  ligature  through  the  myo- metrium  and  broad  ligament  below  the  level  of  the  laceration. A uterine rupture usually necessitates sub- total  or  total  abdominal  hysterectomy,  although  small  defects may be repaired.

RETAINED PRODUCTS OF CONCEPTION When  the  placenta  cannot  be  delivered  in  the  usual  manner,  manual removal  is  necessary  (Figure  10-3).  This  should  be  performed  urgently  if  bleeding  is  profuse.  Otherwise,  it  is  reasonable  to  delay  for  30  minutes  to  await  spontaneous  separation.  General  anesthesia may be required. Following manual removal  of  the  placenta  or  placental  remnants,  the  uterus  should be scraped with a large curette.

UTERINE INVERSION The management of a uterine inversion requires quick  thinking.  The  patient  rapidly  goes  into  shock,  and  immediate intravascular volume expansion with IV crystalloids is required. An anesthesiologist should be  present. When the patient’s condition is stable, the par- tially separated placenta should be completely removed  and an attempt made to replace the uterus by placing  a  cupped  hand  into  the  inverted  fundus  from  below 

Analogues of prostaglandin F2α given intramuscu- larly are quite effective in controlling PPH caused by uterine atony.  The  15-methyl  analogue  carboprost  (Hemabate)  has  a  more  potent  uterotonic  effect  and  longer  duration  of  action  than  the  parent  compound.  The  expected  time  of  onset  of  the  uterotonic  effect  when the 15-methyl analogue is given intramuscularly  (0.25 mg) is 5 minutes, with a peak effect around 15 to  20  minutes.  When  injected  into  the  myometrium,  its  effect  may  be  more  rapid.  An  alternative  next-level  drug  is  misoprostol  800  to  1000  µg  per  rectum  (Table  10-1, Stage 2).

If  these  pharmacologic  treatments  fail,  a bimanual compression and massage of the uterine corpus may control the bleeding and cause the uterus to contract.  This  was  the  only  method  available  before  the  use  of  uterotonic drugs. Although packing the uterine cavity is no longer widely practiced,  it  may  occasionally  control PPH and obviate the need for surgical interven- tion.  Alternatively,  a large-volume balloon catheter  has  been  developed  that  performs  a  similar  function  while  maintaining  a  channel  into  the  uterine  cavity,  allowing  further  bleeding  to  be  monitored.  If  uterine  bleeding  persists  in  an  otherwise  stable  patient,  an  interventional  radiologist  may  be  able  to  place a per- cutaneous catheter into the uterine arteries for injec- tion of thrombogenic material to control blood flow and hemorrhaging (see Table 10-1, Stage 2).

Hysterectomy is a treatment of last resort.  If  the  patient has completed her childbearing, a supracervi- cal or total abdominal hysterectomy  is  the  definitive  therapy  for  intractable  PPH  caused  by  uterine  atony.  When  reproductive  potential  is  important  to  the  patient, ligation of the uterine arteries adjacent to the  uterus will lower the pulse pressure. This procedure is  more  successful  in  controlling  placental  site  hemor- rhage and is easier to perform than bilateral hypogas- tric artery ligation (see Table 10-1, Stage 3).

GENITAL TRACT TRAUMA When  PPH  is  related  to  genital  tract  trauma,  surgi- cal  intervention  is  necessary.  When  repairing  genital  tract  lacerations,  the first suture must be placed well above the apex of the laceration to incorporate any retracted bleeding arterioles into the ligature. Repair  of  vaginal  lacerations  requires  good  light  and  good  exposure,  and  the  tissues  should  be  approximated  without dead space. A running locked suture technique  provides  the  best  hemostasis  (Figure  10-2).  Cervical lacerations need not be sutured unless they are actively bleeding. Large, expanding hematomas of the  genital  tract  require  surgical  evacuation  of  clots  and  a  search  for  bleeding  vessels  that  can  be  ligated.  Stable hematomas can be observed and treated conserva- tively. A retroperitoneal hematoma generally begins in  the pelvis. If the bleeding cannot be controlled using a  vaginal approach, a laparotomy may be necessary.

FIGURE 10-2 Suturing a cervical laceration. The first suture must be placed above the apex of the laceration.

C H A P T E R 10 Obstetric Hemorrhage 145

lation;  rapid  volume  expansion  with  an  electrolyte  solution; positive inotropic cardiac support; placement  of a bladder catheter to monitor urine output; correc- tion  of  the  red  cell  deficit  by  transfusion  with  packed  red  blood  cells;  and  reversal  of  the  coagulopathy  with  the  use  of  platelets,  fibrinogen,  and  other  blood  components.

MANAGEMENT OF COAGULOPATHY When  PPH  is  associated  with  coagulopathy,  the  spe- cific defect should be corrected by the infusion of blood  products,  as  outlined  in  Box  10-5  and  Table  10-2.  Patients with thrombocytopenia require platelet con- centrate infusions; those with von Willebrand disease require factor VIII concentrate or cryoprecipitate.

A packed red cell infusion is given to a patient who  has  bled  sufficiently  to  compromise  the  delivery  of  oxygen  to  the  tissues.  Therefore,  institution  of  blood  transfusion  is  best  judged  by  symptoms  of  oxygen  deprivation rather than by some empirical hemoglobin 

and elevating it in the long axis of the vagina. If this is  unsuccessful, a further attempt should be made using  IV nitroglycerin  (100  µg)  or general anesthesia to relax the uterine muscle. Once replaced, a dilute infu- sion  of  oxytocin  should  be  started  to  cause  the  uterus  to  contract  before  removing  the  intrauterine  hand.  Rarely, the uterus cannot be replaced from below, and a surgical procedure may be required. At laparotomy,  a  vertical  incision  should  be  made  through  the  poste- rior portion of the cervix to incise the constriction ring  and allow the fundus to be replaced into the peritoneal  cavity. Suturing of the cervical incision completes this  procedure.

AMNIOTIC FLUID EMBOLUS The principal objectives of treatment for amniotic fluid embolism are to support the respiratory system, correct the shock, and replace the coagulation factors.  This  type  of  embolism  requires  immediate  cardiopul- monary  resuscitation,  usually  with  mechanical  venti-

FIGURE 10-3 Manual removal of the placenta. The abdominal hand provides counterpressure on the uterine fundus against the shearing force of the fingers in the uterus.

PA R T 2 Obstetrics146

In  the  setting  of  active  bleeding  greater  than  1000 mL,  the  hemorrhage  care  protocol  (see  Table  10-1) should be activated. Maternal mortality and mor- bidity  have  been  reduced  when  a  protocol  of  packed  red  blood  cells,  fresh  frozen  plasma,  and  platelets,  given  in  a  ratio  of  6 : 4 : 1,  is  implemented.  Treatment  should not be delayed while awaiting laboratory results  or blood product crossmatching.

level.  No  important  physiologic  impairment  has  been  noted at hemoglobin levels as low as 6 to 8 g/dL (hema- tocrit  of  18-24%).  In general, a 1-U transfusion of packed red blood cells will increase the hemoglobin level by 1 g/dL (and the hematocrit by 3-4%).

Massive blood replacement (when total blood volume is replaced in a 24-hour period) may be asso- ciated with thrombocytopenia, prolonged PT, and hypofibrinogenemia.  Thrombocytopenia  is  the  most  common abnormality, so platelet transfusion following  determination of a low platelet count is not an uncom- mon scenario. Fresh frozen plasma may be transfused  for prolonged PT or hypofibrinogenemia.

BOX 10-5

LABORATORY EVALUATION OF DISSEMINATED INTRAVASCULAR COAGULATION

Platelet count  (normal  range  150-450  ×  109/L):  1 U  of  platelets will raise the platelet count by 5-10 × 109/L

Plasma fibrinogen  (normal  range  175-600 mg/dL):  fresh  frozen plasma (FFP): 1 U = 1 g of fibrinogen; 4 U of FFP  will raise the plasma fibrinogen by 5-10 mg/dL

Cryoprecipitate:  1  bag  =  0.25 g  of  fibrinogen;  16  bags  raises the plasma fibrinogen by 5-10 mg/dL

Fibrin split products:  Normal  range:  <0.05  µg/mL  (D-dimer method)

TABLE 10-2

BLOOD PRODUCTS USED TO CORRECT COAGULATION DEFECTS

Blood Product Volume (mL) in 1 U* Effect of Transfusion

Platelet concentrate

30-40 Increases platelet count by about 5000-10,000

Cryoprecipitate 15-25 Supplies fibrinogen, factor VIII, von Willebrand factor, and fibronectin

Fresh frozen plasma

200 Supplies all factors except platelets (1 g of fibrinogen)

Packed red blood cells

200 Raises hematocrit 3-4%

*Quantity obtained from 1 U (500 mL) of fresh whole blood.

147

11  Uterine Contractility and Dystocia

C H

A P

T ER

CALVIN J. HOBEL • AMY R. LAMB

■  Normal  and  effective  spontaneous  labor  is  dependent  upon  normal  uterine  physiology  and  careful  watchful  waiting  without  overly  aggressive  obstetric  manage- ment.  Dystocia  is  dysfunctional  labor  that  often  has  complex origins, and may develop after the normal onset  of  labor  or  after  the  induction  of  labor  for  indicated  reasons.  Metabolic  dysregulation  before  pregnancy  or  during  pregnancy  secondary  to  the  mother’s  health  are  thought to contribute to the cause(s) of dystocia.

■  The  uterus  is  a  smooth  muscle  organ  that  undergoes  dramatic changes to accommodate the developing fetus.  Maternal, placental, and fetal hormones play important  roles  in  preparing  the  uterus  to  accept  a  growing  and  maturing  fetus,  permitting  labor  to  begin  naturally,  and  allowing  the  fetus  a  safe  passage  and  a  timely  delivery  into its new external environment.

■  The  Friedman  labor  curve  has  been  the  standard  used  for  plotting  the  progress  of  labor  as  defined  by  cervical  dilation  over  time.  More  recent  studies  suggest  that  the  age of women on becoming pregnant has increased and  their body mass index (BMI) before pregnancy is signifi- cantly higher. These factors, along with excessive weight  gain  during  pregnancy,  contribute  to  abnormalities  in 

the  progress  of  labor  during  the  latent  and  the  active  phases.  Thus,  more  attention  and  time  must  be  spent  observing  women  to  avoid  the  risk  of  cesarean  delivery.  Newer  parameters  for  defining  dystocia  have  been  pro- posed as a modification of the Friedman curve.

■  Recent  studies  of  the  pathogenesis  of  dystocia  have  focused on conditions that affect the metabolic dysregu- lation of normal myometrial function, such as infection  and  inflammation. These  conditions  are  more  common  in  overweight  and  obese  women.  Currently,  vitamin  D  deficiency is related to muscle dysfunction and a greater  risk of inflammation, and this deficiency may contribute  to the cause(s) of abnormal dystocia.

■  Oxytocin  for  myometrial  stimulation  in  patients  with  abnormal progress of labor should be used with caution.  Other risk factors such as abnormal presentation, exces- sive  size  of  the  fetus  (macrosomia),  developmental  abnormalities  of  the  fetus,  and  maternal  pelvic  abnor- malities that may increase the risk of dystocia should be  recognized  and  appropriate  management  initiated.  Current  evidence  indicates  that  conduction  anesthesia  does not increase the primary cesarean delivery rate.

CLINICAL KEYS FOR THIS CHAPTER

Although  the  definition  of  dystocia  is  “difficult child- birth,” the term is used interchangeably with dysfunc- tional labor  and  characterizes  labor  that  does  not  progress  normally.  Dystocia  may  be  caused  by  (1)  abnormalities  of  the  “Powers,”  such  as  ineffective  coordinated contractility and uterine expulsive forces;  (2) abnormalities of the “Passenger,” such as abnormal  fetal  lie,  fetal  macrosomia,  malpresentation,  malposi- tion,  or  fetal  anatomic  defects  or  (3)  abnormalities  of  the  “Passage,”  such  as  maternal  bony  pelvic  contrac- tures,  resulting  in  mechanical  interference  with  the  passage of the fetus through the birth canal.

The  cause  or  causes  of  abnormal  labor  should  be  determined  as  accurately  as  possible  so  that  an  effec-

tive and safe management plan can be developed. The  purpose  of  this  chapter  is  to  provide  the  student  with  specific metrics that have helped obstetricians under- stand normal and abnormal labor.

Physiologic Changes of Labor The  pregnant  uterus  is  a  large  smooth  muscle  organ  consisting  of  billions  of  smooth  muscle  cells.  Each  smooth  muscle  cell  becomes  a  contractile  element  when  the  intracellular  ionic  calcium  concentration  increases  to  trigger  an  enzymatic  process  that  results  in the formation of the actin-myosin element. Stimula- tion of oxytocin and/or prostaglandin receptors on the 

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aggregation.  Several hormones are known to affect cervical softening including prostaglandins (PGs) and relaxin. Prostaglandin E2 (PGE2) is considered the  major  hormone  causing  cervical  softening  and  an  increased  production  of  PGE2  coincides  with  reduc- tions  in  progesterone  levels  before  parturition.  The  increase in PGE2 also acts to increase uterine myome- trial contractions and uterine pressure and to stimulate  the cervix at the onset of labor.

Normal Labor Labor is diagnosed by regular, painful uterine con- tractions that increase in frequency and intensity with progressive cervical effacement or dilation.

In  early  latent  phase  labor,  the  cervix  softens  and  effaces  with  minimal  dilation.  This  is  followed  by  a  more  rapid  active  phase  of  dilation,  which  is  further subdivided into the acceleration (maximum slope) and deceleration phases. The descent of the fetal pre- senting  part  usually  begins  during  the  active  phase,  accelerating  toward  the  end  of  the  active  phase,  and  climaxing after the cervix is completely dilated. A useful  method for assessing the progress of labor and detect- ing abnormalities in a timely manner is to plot the rate  of cervical dilation and descent of the fetal presenting  part (Figure 11-1).

Normal cervical dilation and descent of the fetus take place in a progressive manner and occur within

plasma membrane of cells further activates the forma- tion of the actin-myosin element.

Contractions  occur  in  localized  areas  of  the  uterus  during  gestation,  but  during  parturition  the  entire  uterus contracts in an organized way to allow for birth.  These coordinated smooth muscle contractions occur  as  a  result  of  an  increase  in  number  and  action  of  special  gap  junction  structures.  Gap junctions are protein channels that form along the interface of two smooth muscle cell membranes and act by promot- ing the movement of action potentials throughout the myometrium.

During  labor,  two  distinct  segments  of  the  uterus   are  formed.  The  upper segment  actively  contracts  and  retracts  to  expel  the  fetus,  while  the  lower segment,  along  with  the  dilating  cervix,  becomes  thinner  and  passive  and  is  referred  to  as  the  lower  uterine segment (LUS).

The pregnant cervix contains collagen, small amounts of smooth muscle, and ground substance and must be structurally altered from a firm, intact sphincter to a soft, pliable, dilated structure through which the fetus can pass at the appropriate time. The  collagen fibers are helical strands of amino acids in an  intracellular  protein  matrix  of  glycosaminoglycan  branches  (GAGs). The  GAGs  determine  the  amount  of  aggregation  of  the  collagen  fibers.  Cervical  softening  involves  two  changes  in  the  intracellular  matrix:   a  reduction  in  the  number  of  collagen  fibers  and   an  increase  in  the  GAGs,  and  later  decreasing  fiber 

FIGURE 11-1 Graphic plot of cervical dilation (blue) and descent of the fetal presenting part (red) during labor. Red star 1 on the blue line indicates the beginning of the active phase of labor (as recommended by Cohen and Friedman) and red star 2 the beginning of the active phase of labor as recommended by Zhang et al. (Revised from Cohen WR, Friedman EA, editors: Management of labor, Gaithersburg, Md, 1983, Aspen Publishers, p 13; and Zhang J, Landy HJ, Branch DW, et al: Contemporary patterns of spontaneous labor with normal neonatal outcomes. Obstet Gynecol 116:1281–1287, 2010.)

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C H A P T E R 11 Uterine Contractility and Dystocia 149

a well-defined time period. Dysfunctional labor occurs when rates of dilation and descent exceed these time limits. The phase of labor and the configu- ration  of  the  abnormal  labor  curve  may  indicate  the  potential causes for the abnormal labor.

Abnormalities of the Latent Phase of Labor The normal limits of the latent phase of labor extend up to 18 hours for nulliparous patients and up to 10 hours for multiparous patients (see  Table 8-5).  A  latent  phase  that  exceeds  these  limits  is  considered  prolonged  and  may  be  caused  by  dysfunctional  labor,  premature  or  excessive  use  of  sedatives  or  analgesics,  fetal malposition, or abnormal fetal size. A long, closed,  firm cervix requires more time to efface and to undergo  early dilation than does a soft, partially effaced cervix,  but  it  is  doubtful  that  a  cervical  factor  alone  causes  a  prolongation  of  the  latent  phase.  Many patients who appear to be developing a prolonged latent phase are shown eventually to be in false labor or prelabor, with no progressive dilation of the cervix.

The  outcome  of  a  prolonged  latent  phase  is  gener- ally  favorable  for  both  the  mother  and  the  fetus,  pro- vided that no other abnormalities of labor subsequently  occur.

MANAGEMENT A prolonged latent phase caused by premature or excessive use of sedation or analgesia usually resolves spontaneously after the effects of the medication have worn off. Therapeutic rest with morphine sulfate  or an equivalent drug has been shown to be an effective  therapeutic  option  for  women  in  prolonged  latent  phase, with about 62% being subsequently admitted in  labor, particularly those at term with >50% effacement,  about 29% being discharged not in labor, and about 9%  being  admitted  for  category  II  fetal  heart  rate  tracings  for  continued  assessment. Thus,  women  in  true  labor  wake  up  in  active  labor,  while  those  in  prelabor  stop  contracting and can be discharged

If a definitive diagnosis of prolonged latent phase of labor has been made and there are medical reasons to expedite delivery, augmentation of labor by oxyto- cin may be performed.  This  is  accomplished  by  the  addition  of  20 U  of  oxytocin  to  1 L  of  lactated  Ringer  solution.  A  number  of  protocols  have  been  suggested  for  the  infusion  of  oxytocin.  Oxytocin  can  be  given  as  “low dose,” where the infusion is begun at a rate of 1.0  to  2.0 mU/min  and  is  increased  by  1  to  2 mU/min  increments  every  15  to  40  minutes  until  the  desired  frequency and intensity are obtained, or a maximum of  20  to  40 mU/min  has  been  reached.  The  “high  dose”  infusion  method  is  begun  at  a  rate  of  4  to  6 mU/min  with incremental increases of 4 to 6 mU/min every 15 

to 40 minutes until uterine contractions of the desired  frequency and intensity are obtained or a maximum of  40 mU/min has been reached.

Amniotomy  or  artificial  rupture  of  the  membranes  may  be  considered  as  part  of  the  management  of  the  latent  phase  of  labor;  however,  recent data suggest that amniotomy is associated with an increased risk of cesarean delivery.

Abnormalities of the Active Phase of Labor The beginning of the active phase of labor in terms of cervical dilation varies from 3 to 6 cm, depending on either a strict interpretation of the Friedman labor curve (3 cm) or an acceptance of recent evidence that the curve should be modified (up to 6 cm) in certain patients (primarily nulliparous women).  There  are  two clinical reasons for varying the interpretation of the  start  of  the  active  phase  of  labor.  First,  parity  plays  an  important  role,  and  anywhere  up  to  6 cm  is  generally  considered  to  be  reasonable  in  a  nulliparous  woman.  Second, recent population studies have demonstrated  that pregnant women are older and heavier now than earlier generations, so the progress of labor is expected to be slower today as a consequence. The  interpreta- tion of the start of the active phase of labor has conse- quences  in  terms  of  defining  dystocia,  particularly  in  the nulliparous patient. Thus, because of these factors  the onset of the active phase of labor may vary depend- ing  on  the  patient  population.  Note  the  differences  in  the onset of the active phases in Figures 11-1 and 11-2.

After  the  active  phase  of  labor  is  deemed  to  have  begun,  the  rate  of  dilation  progresses  more  rapidly  during  normal  labor.  Cervical dilation rates of less than 1.2 cm per hour in nulliparous women and 1.5 cm per hour in multiparous women constitute a protrac- tion disorder of the active phase of labor as depicted by the dashed blue line illustrated in Figure 11-2.

During  the  latter  part  of  the  active  phase,  the  fetal  presenting  part  also  descends  more  rapidly  through  the pelvis and continues to descend through the second  stage of labor as depicted by the red line in Figure 11-1.  A rate of descent of the presenting part of less than 1.0 cm per hour in nulliparous women and 2.0 cm per hour in multiparous women is considered to be a pro- traction disorder of descent as depicted by the red dashed line in Figure 11-2.

Figure  11-3  illustrates  differences  between  nullipa- rous  and  parous  women  in  terms  of  the  acceptable  length  of  the  active  phase  of  labor.  Note  the  marked  acceleration  in  multiparous  women,  whereas  nullipa- rous women do not accelerate but continue to demon- strate a slower rate of dilation. A correct interpretation of the beginning of the active phase of labor can have an impact on the frequency of cesarean deliveries for

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FIGURE 11-2 Normal dilation (blue) and descent (red) curves of normal labor and curves depicting protracted dilation and descent abnormalities of labor. Red star 1 on the blue line indicates the beginning of the active phase of labor (Friedman) and red star 2 the beginning of the active phase of labor as recommended by Zhang et al. (Revised from Friedman EA: Labor: clinical evaluation and man- agement, ed 2, New York, 1978, Appleton-Century-Crofts, p 65; and Zhang J, Landy HJ, Branch DW, et al: Contemporary patterns of spontaneous labor with normal neonatal outcomes. Obstet Gynecol 116:1281–1287, 2010.)

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active phase arrest of dilation.  By  not  accounting  for  a later but normal start of the active phase of labor and  not expecting a slower but normal progression of labor  in  certain  patients,  more  cesarean  deliveries  may  be  done unnecessarily.

MANAGEMENT The American College of Obstetricians and Gynecolo- gists (ACOG) recommends the use of oxytocin for all

protraction and arrest disorders.  Adequate  labor  is  defined  as  200  Montevideo  units  (which  is  the  sum  of  all the amplitudes of all the contractions in a 10 minute  window) as assessed by an intrauterine catheter for at  least  2  hours.  Arrest  of  labor  should  not  be  diagnosed  until  the  cervix  is  at  least  6 cm  dilated.  Therefore,   a  patient  having  four  contractions  in  10  minutes,   each  with  an  amplitude  of  50 mm Hg,  should  be  regarded as having adequate labor. Amniotomy should

C H A P T E R 11 Uterine Contractility and Dystocia 151

the  laboring  patient.  Disorders  of  the  dilation  and  descent phases of labor occur with increased frequency  in cases of abnormal presentation or position because  of the altered relationship between the presenting part  of the fetus and the maternal pelvis. Fetal malpresenta- tions are discussed further in Chapter 13.

Persistent Occipitotransverse Position The fetal head normally enters and engages in the maternal pelvis in an occipitotransverse (OT) posi- tion  and  then  rotates  to  an  occipitoanterior  (OA)  position or, in a small percentage of cases, to an occipi- toposterior (OP) position. This rotation occurs because  the head flexes as the leading part of the vertex encoun- ters  the  pelvic  floor  and  then  rotates  to  adjust  to  the  shape  of  the  gynecoid  pelvis.  In  a  small  number  of  cases,  the  head  fails  to  flex  and  rotate  and  persists  in  an OT position. This position may be caused by cepha- lopelvic  disproportion;  altered  pelvic  architecture,  such  as  in  a  patient  with  a  platypelloid  or  android  pelvis;  or  a  relaxed  pelvic  floor,  brought  about  by  epi- dural anesthesia or multiparity. The diagnosis of a per- sistent OT position may be difficult at times because of   the  obscuring  of  suture  lines  and  fontanelles  by  the  excessive  molding  and  caput  formation  that  often  accompany  this  abnormal  position.  If  the  position  remains  in  question,  an  ultrasonic  assessment  of  the  lower abdomen can determine whether or not the face  is pointing anterior or posterior, or if the head is flexed  or extended.

A persistent OT position with arrest of descent for a period of 1 hour or more is known as transverse arrest. Arrest occurs because of the deflexion that accompanies the persistent OT position, resulting in the larger occipitofrontal diameter (11 cm) becoming the presenting diameter.  Until  the  head  undergoes  flexion and rotation, further descent cannot take place.  Transverse  arrest  commonly  occurs  with  the  vertex  at  a +2 cm to +3 cm station (which is based on a 5-point  scale from zero at the level of the spines to 5 cm when  the vertex is beginning to crown before delivery).

The  management  of  transverse  arrest  at  a +2  to  +3  station  is  complex,  in  part,  because  at  these  stations,  the widest part of the fetal head is at or above the level  of the ischial spines. If the midpelvis is compromised,  cesarean delivery is indicated. If the pelvis is judged to  be  of  normal  size  and  the  fetus  is  not  macrosomic,  oxytocic  stimulation  of  labor  may  be  appropriate  if  uterine contractions are inadequate.

Manual rotation using the fingers of the examiner’s  hand or forceps rotation using Kielland forceps may be  indicated  if  the  pelvis  is  of  normal  size  and  shape.  Today, forceps rotations are rarely done because of limited training among younger physicians; vacuum extraction, if properly applied, may be attempted.  Forceps  rotation  and  delivery  of  a  persistent  OT  posi- tion  at  a  +2  to  +3  station  is  now  referred  to  as  a  low 

be considered if rupture of membranes has not occurred spontaneously.

Before  deciding  to  proceed  to  cesarean  delivery  in  the first stage of labor for abnormal labor progression,  it  should  be  ascertained  that  at  least  4  hours  of  ade- quate contractions, as defined by 200 Montevideo units  per 10 minutes, has occurred. In a nulliparous, single- ton  term  pregnancy,  continuing  labor  for  at  least  6  hours is still associated with a high likelihood of vaginal  delivery, provided that the fetal heart rate is reassuring  and  there  is  some  progress  in  labor.  A cesarean deliv- ery is indicated if cephalopelvic disproportion (CPD) is diagnosed.

ACTIVE MANAGEMENT OF LABOR Active management of labor has been proposed and utilized in the nulliparous patient as a safe method to lower the incidence of cesarean delivery for dystocia.  This  strategy  of  labor  management  is  based  on  the  assessment  of  the  active  phase  of  labor  as  presented  above.

The inclusion criteria and components of the active management of labor are as follows: (1) nullipa- rous patients should have spontaneous onset of labor and a singleton fetus in a cephalic presentation;  (2)  prenatal education classes  and  intrapartum  reassur- ances  to  set  realistic  patient  expectations  and  lower  patient anxiety; (3) constant supervision during labor,  usually  by  a  labor  nurse  specialist  or  midwife;  (4)  ret- rospective peer review of all cesarean deliveries;  (5)  no admittance to the labor unit without a clear diag- nosis of labor (this should be based not only on cervi- cal  dilation  but  also  on  the  quality  of  contractions,  which  should  be  regular  and  painful  with  at  least  one  of the following: complete cervical effacement, rupture  of  membranes,  or  bloody  show);  (6)  performance of regular examinations for progress of labor based on cervical dilation;  and  (7)  the use of medium to high dose oxytocin if the patient fails to demonstrate cervical dilation at a rate of 1 cm/hour or more in the first stage of labor or if there is no descent of the fetal head for 1 hour in the second stage. Most active  management  protocols  use  an  initial  infusion  rate   and increments of 4 to 6 mU/min of oxytocin with only  15  minutes  between  increments  to  a  maximum  of  40 mU/min. Performance of an amniotomy on admis- sion is no longer a requirement for the active manage- ment of labor.

Many programs using active management of labor have reported a reduction in cesarean delivery rate with no compromise of perinatal outcomes and no cases of uterine rupture.

DYSTOCIA CAUSED BY ABNORMAL PRESENTATION AND POSITION Presentations  other  than  vertex  and  positions  other  than occipitoanterior are considered to be abnormal in 

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tional  age  greater  than  40  weeks,  ethnicity,  maternal  birth  weight,  maternal  height,  and  maternal  age.  Maternal morbidities associated with macrosomia include labor dystocia, shoulder dystocia, and genital trauma,  and  there  is  a  corresponding  increase  in  the  cesarean delivery rate. There is also an increased inci- dence of postpartum hemorrhage and puerperal infection. Both of these conditions have recently been shown to be associated with maternal vitamin D defi- ciency during pregnancy. There is increased perinatal  morbidity  associated  with  dystocia  and  birth  trauma,  especially shoulder dystocia.

An accurate estimate of fetal weight is elusive. Errors in the estimation of macrosomia by ultrasound may be up to 50%.  Prospective  studies  have  shown  that  clinical estimates by physicians or patients are as inac- curate  as  ultrasonic  assessments.  Suspected  macro- somia alone is not an indication for caesarian delivery  or  induction  of  labor.  Induction  of  labor  has  not  been  shown to improve fetal or maternal outcome. Although  the mean duration of labor is prolonged for excessively  large fetuses, it is not unusual to encounter unexpected  shoulder  dystocia  after  a  labor  that  has  been  entirely  normal up to the moment of delivery.

Shoulder dystocia means difficult delivery of the shoulder. It has been defined as delivery of the shoul- der requiring the use of procedures in addition to gentle downward traction on the fetal head or a pro- longation of the head-to-body delivery interval to more than 60 seconds.

Shoulder dystocia depends on the size of the mater- nal pelvis in relation to the size of the fetus and occurs  from impaction of the shoulder on the pubic symphy- sis  anteriorly  or  the  sacral  promontory  posteriorly.   The  most  important  risk  factors  for  shoulder  dystocia  are  fetal  macrosomia  and  maternal  diabetes.  Others  include  obesity,  multiparity,  postterm  gestation,  short  stature, previous history of macrosomic birth, and pre- vious  history  of  shoulder  dystocia.  During  labor,  risk  factors  include  labor  induction,  epidural  analgesia,  prolonged labor, and operative vaginal delivery.

The major neonatal complication of shoulder dys- tocia is Erb palsy that can be caused by excessive trac- tion  on  the  brachial  plexus  by  the  delivery  attendant.  This  is  an  important  malpractice  risk  in  obstetrics.  When  Erb  palsy  occurs  on  the  posterior  shoulder,  the  damage could not have been caused by excessive trac- tion,  but  is  most  likely  due  to  abnormalities  of  the  sacral  promontory  applying  pressure  on  the  brachial  plexus  before  delivery.  Other  neonatal  complications  include  Klumpe palsy,  clavicular  fracture,  humeral  fracture,  hypoxia,  brain  injury,  and  death.  Maternal  complications  include  genital  tract  lacerations  and  postpartum hemorrhage.

Shoulder dystocia is recognized at delivery by retraction of the fetal head, which is called the “turtle sign.” Shoulder dystocia is not overcome by traction on 

forceps  procedure.  However,  because  of  the  marked  degree  of  molding  and  caput  formation  that  usually  occurs  in  this  circumstance,  the  bony  part  of  the  fetal  vertex may be at +1 station even though the scalp may  be visible at the introitus. Thus what appears to be an  uncomplicated  low  forceps  operation  may  actually  be  a more difficult midforceps procedure. One method for  avoiding this problem is to clinically evaluate the rela- tionship between the fetal head and the sacrum. If the  fetal head fills the hollow of the sacrum, the biparietal  diameter  is  usually  at  or  below  the  spines,  and  an  attempt at forceps delivery can be considered.

Persistent Occipitoposterior Position The  head  generally  rotates  from  OT  to  OA  during  the  descent  through  the  maternal  pelvis.  Even  if  the  head  initially  rotates  to  an  OP  position,  most  fetuses  will  eventually  rotate  spontaneously  during  labor  to  OA,  leaving  only  5-15%  of  fetuses  with  a  persistent  OP  position.

The course of labor in the presence of a persistent OP position is usually normal except for a tendency for the second stage to be prolonged (>2 hours). It is also associated with considerably more discomfort.  As with the persistent OT position, the fetal head may  become markedly molded with extensive caput forma- tion,  which  may  cause  difficulty  in  diagnosing  its  correct  station  and  position.  Observation of a pro- longed second stage of labor is appropriate, provided that labor continues to be progressive and the fetal heart rate is normal.

Delivery of the head may occur spontaneously in the  OP position, but if the perineum provides undue resis- tance  to  delivery,  a  low  forceps-assisted  delivery  may  be  required  (e.g.,  using  Simpson  forceps).  In  the  past,  a Kielland forceps rotation was usually performed, but  because of a lack of experience and training, fetuses in the OP position are usually now delivered without rotation. Use of a vacuum extractor with a cup designed for a safe and secure posterior application may be considered.  Sometimes  the  head  will  rotate,  but  it  will  usually  deliver  in  the  OP  position.  A  wide  mediolateral episiotomy may be required to lessen the  resistance of the outlet. Although routine episiotomies  are  no  longer  performed,  it  is  important  to  perform  them when indicated.

DYSTOCIA CAUSED BY ABNORMALITIES OF FETAL STRUCTURE Macrosomia and Shoulder Dystocia ACOG defines macrosomia as a fetus weighing 4500 g or more.  Large  for  gestational  age  is  defined  as  birth  weight  equal  to  or  above  the  90th  percentile  of  fetal  weight for a given gestational age. Macrosomia is asso- ciated  with  genetic  determinants,  maternal  diabetes,  prepregnancy  body  mass  index  (BMI),  weight  gain  during  pregnancy,  multiparity,  male  gender,  gesta-

C H A P T E R 11 Uterine Contractility and Dystocia 153

during  labor,  or  transabdominally  under  ultrasonic  guidance  before  or  during  labor.  Alternatively, the fetus may be delivered by cesarean to avoid the risk of  infection, which can result from transvaginal or trans- abdominal drainage. Intrauterine shunting of the fetal  ventricular  system  into  the  amniotic  fluid  compart- ment  is  still  an  experimental  procedure  that  has  not  been shown to have the long-term benefits required to  justify its performance.

The accumulation of ascites in the fetal abdomen or enlargement of fetal organs, such as the bladder or liver, may result in unexpected dystocia  (because  of  an  enlarged  fetal  abdomen)  after  the  fetal  head  has  been delivered. Ascites usually occurs as part of hydrops  (see  Chapter  16),  which  is  defined  as  fetal  fluid  reten- tion in two of the following sites: skin, abdomen, peri- cardial  cavity,  or  pleural  cavity.  Immune  hydrops  is  usually  caused  by  Rhesus  disease,  while  nonimmune  hydrops may be caused by congenital infections, chro- mosomal abnormalities, or fetal arrhythmias. If any of  the  above  conditions  are  present,  careful  ultrasonic  evaluation before or during labor should be performed  to identify excessive enlargement of the fetal abdomen.  Ascitic fluid or urine from a massively enlarged bladder   may  be  removed  by  transabdominal  drainage  with  a  needle  before  vaginal  delivery.  Cesarean  delivery  may  be indicated if the fetal abdomen cannot be sufficiently  decompressed.

A  defect  in  the  fetal  lumbosacral  vertebrae  may  result in the protrusion of a meningeal sac (meningo- cele)  or  a  sac  containing  a  portion  of  the  spinal  cord  (meningomyelocele).  These  defects  are  usually  detected  as  a  result  of  abnormal  serum  or  amniotic  fluid alpha-fetoprotein values or by ultrasonography. If  the  sac  is  large,  abdominal  delivery  is  advisable  to  avoid dystocia or rupture of the sac and potential infec- tion. When the sac is small and is covered by fetal skin,  as  reflected  by  a  normal  alpha-fetoprotein  value,  vaginal delivery is appropriate.

Other  potential  causes  of  fetal  dystocia  include  a  very  large  fetal  sacrococcygeal teratoma  and  con- joined twins.

DYSTOCIA CAUSED BY MATERNAL PELVIC ABNORMALITIES Cephalopelvic disproportion (CPD) exists if the maternal bony pelvis is not of sufficient size and of appropriate shape to allow the passage of the fetal head (see  Chapter 8  on pelvic anatomy and clinical pelvimetry).  This  problem  may  occur  as  a  result  of  contraction of one of the planes of the pelvis. Relative  CPD may exist with a normal pelvis, if the fetal head is  excessively  large  or  if  it  is  in  an  abnormal  position.  Contraction of the maternal pelvis usually occurs at the  level  of  the  inlet  or  midpelvis,  but  contraction of the outlet is extremely unusual unless it is found in asso- ciation with a midpelvic contraction.

the fetal head but, instead, by one or more maneuvers  designed to displace the anterior shoulder from behind  the symphysis pubis. An initial maneuver that can be attempted is suprapubic pressure,  which  involves  downward  or  lateral  pressure  with  the  hand  over  the  maternal  suprapubic  region  in  an  effort  to  guide  the  anterior  shoulder  under  or  away  from  the  symphysis  pubis. The McRoberts maneuver may also be employed  as  an  initial  or  second  procedure.  In  the  McRoberts  maneuver,  the  maternal  thighs  are  sharply  flexed  against  the  maternal  abdomen  to  reduce  the  angle  between  the  sacrum  and  spine,  thus  freeing  the  impacted  shoulder.  Additionally  the  “Gaskin” or “all- fours”  maneuver  may  be  attempted.  This  involves  having  the  mother  rotate  on  to  her  hands  and  knees.  This  position  may  help  to  dislodge  the  shoulder  by  reducing  the  angle  of  the  maternal  pelvis,  and  may  facilitate  easier  delivery  of  the  posterior  arm.  If  this  is  not  successful,  pressure  is  applied  with  the  operator’s  fingers against the scapula of the posterior shoulder in  an  attempt  to  rotate  (screw)  the  posterior  shoulder  upward  until  it  becomes  the  anterior  shoulder.  This   is  known  as  “Wood maneuver.”  If  this  maneuver does  not  correct  the  problem,  a  hand  is  inserted  into  the  vagina  and  the  posterior  arm  is  grasped  and  pulled  across  the  chest,  resulting  in  delivery  of  the  posterior  shoulder  and  displacement  of  the  anterior  shoulder  from  behind  the  symphysis  pubis.  Fracture  of  the  humerus may result from this maneuver, but the bone  heals quickly in the neonate. If none of these maneu- vers is successful, one or both clavicles must be frac- tured,  preferably  by  pressure  on  the  clavicle  directed  away  from  the  pleural  cavity  to  prevent  traumatic  puncture of the lungs.

A  maneuver  has  been  described,  attributed  to  Zavanelli, to manage shoulder dystocia when previous  methods  have  failed.  In  this  last-resort  procedure,  the  fetal  head  is  manually  returned  to  its  prerestitution  position, and then slowly replaced into the vagina and  then into the uterus by steady upward pressure against  the  head.  Delivery  is  then  accomplished  by  cesarean  delivery.  A  uterine  relaxant  may  be  required  to  carry  out this procedure.

Developmental Abnormalities Localized  abnormalities  of  fetal  anatomy  may  lead  to  dystocia.  Internal hydrocephalus  may  cause  enlarge- ment  of  the  fetal  head  to  the  extent  that  vaginal   delivery is not possible. The diagnosis is usually made  by  ultrasonography  performed  because  of  the  clinical  suspicion.  It  may  be  diagnosed  as  an  unexpected  finding  on  ultrasonography  performed  for  another  indication.

Several  options  are  available  for  the  delivery  of  the  fetus  with  hydrocephalus. Excessive cerebrospinal fluid may be removed  by  inserting  a  needle  directly  into  the  ventricular  space  through  the  dilated  cervix 

PA R T 2 Obstetrics154

arrest of descent, application of the head to the cervix  is poor, resulting in the loss of part of the force needed  for cervical dilation. Thus CPD may be associated with  a protracted rate of cervical dilation before an arrest of  descent is apparent.

DYSTOCIA CAUSED BY CONDUCTION ANESTHESIA The use of epidural anesthesia for pain control during  the  first  stage  of  labor  has  gained  wide  acceptance.  Refinement  of  the  epidural  technique  has  allowed  a  segmental  block  and  continuous  infusion  of  narcotics  and  local  anesthetics  that  can  be  titrated  for  better   pain  control,  with  less  interference  on  the  process  of  labor (see Chapter 8). Epidural anesthesia may reduce pelvic floor muscle tone and increase the incidence of malposition of the fetal head causing persistence of OP position. However, changes in the approach to epi- dural  anesthesia,  such  as  the  “walking  epidural”  may  reduce  the  risk  of  malpresentation.  Current  evidence  suggests  that  epidural  analgesia  does  not  increase  the  primary cesarean delivery rate.

CPD at the level of the pelvic inlet causes a failure of descent and engagement of the head.  The  finding  of  an  unengaged  head  in  a  nulliparous  patient  at   the  start  of  labor  indicates  an  increased  likelihood  of  CPD  at  the  pelvic  inlet,  but  an  unengaged  fetal  head   in  a  multiparous  patient  in  labor  is  not  an  unusual  occurrence.

The  management  of  a  nulliparous  patient  with  an  unengaged  fetal  head  in  labor  should  begin  with  a  careful clinical evaluation of the maternal pelvis. If the  pelvis  is  clinically  adequate,  expectant  management  with observation of the labor pattern is appropriate. If  uterine  contractions  are  ineffective,  oxytocic  stimula- tion of labor may be considered.

The occurrence of CPD at the level of the midpelvis occurs more frequently than inlet dystocia  because  the capacity of the midpelvis is smaller than that of the  inlet, and because deflection or positional abnormali- ties  of  the  fetal  head  are  more  likely  to  occur  at  that  level.  The  occurrence  of  bony  dystocia  at  the  level  of  the  midpelvis  is  usually  indicated  by  an  arrest  of  descent of the head at a +1 to +2 station. With CPD and 

155

12  Obstetric Complications Preterm Labor and Delivery, PROM, IUGR, Postterm Pregnancy, and IUFD

C H

A P

T ER

CALVIN J. HOBEL

■  Prematurity is the leading cause of infant morbidity and  mortality.  Preterm  birth  (PTB)  is  defined  as  deliveries  occurring  from  20  weeks  up  to  37  weeks  of  gestational  age. When preterm birth occurs either spontaneously or  in the presence of premature rupture of the membranes  (PROM),  it  must  be  appropriately  managed  to  prevent  early  delivery.  Premature  labor  and  delivery  is  best  pre- vented and managed by assessing and treating for infec- tions,  assuring  fetal  lung  maturity,  and  planning  a  safe  delivery as near to term as possible.

■  For the past 30 years, infection has been considered the  primary cause of premature labor and delivery. Treating  infections,  however,  has  not  prevented  preterm  birth,  but  has  decreased  the  morbidity  associated  with  it.  Today,  the  focus  for  prevention  of  preterm  labor  and  delivery  is  on  placental-uterine  vascular  dysregulation,  smoking,  and  psychosocial  and  workplace  stress. These  conditions  are  associated  with  the  risk  of  early  delivery  and  poor  fetal  growth.  Assisted  reproductive  technolo- gies (ARTs) implemented to treat infertility have led to a  greater  incidence  of  twinning  and  higher-order  multi- ples, which has increased the risk of preterm delivery.

■  Intrauterine growth restriction (IUGR) is defined as poor  fetal growth during pregnancy and reduced size at birth.  With  IUGR,  the  infant  birth  weight  is  less  than  the  10th  percentile  and  about  25%  of  preterm  infants  are  in  this  category.  The  causes  of  IUGR  are  maternal,  placental,  and fetal. The main maternal risk factors are poor nutri- tion, smoking, and metabolic diseases such as hyperten- sion and diabetes. Placental factors are mostly related to 

failure  of  proper  implantation  during  early  pregnancy.  More  recently,  metabolic  dysregulation  in  women  with  diabetes  has  been  shown  to  adversely  affect  placental  function  and  lead  to  poor  fetal  growth.  Fetal  factors  are  mostly  limited  to  chronic  fetal  infections  and  abnormal  development.

■  Postterm  delivery  occurs  when  there  is  a  failure  of  the  timely onset of labor and the fetus is not delivered at or  before  42  weeks’  gestation.  For  the  last  30  years,  practi- tioners have recognized that beginning at 41 weeks’ ges- tational  age,  the  risk  of  fetal  distress  increases  and  the  fetus  fails  to  continue  to  grow,  increasing  the  risk  of  morbidity  and  mortality.  Consequently,  fetal  assess- ment  techniques  have  been  developed  to  assess  fetal  well-being  when  labor  and  delivery  are  delayed.  When  signs  of  fetal  distress  are  identified,  labor  should  be  induced  to  rescue  the  fetus  from  a  potentially  hostile  environment.

■  Intrauterine  fetal  demise  (IUFD)  is  fetal  death  between  20 weeks’ gestation and the onset of labor. With improved  management  of  IUGR  and  postterm  pregnancies,  the  incidence  of  IUFD  has  decreased  dramatically.  The  remaining causes are often difficult to determine without  careful autopsy and genetic studies of the fetus. Manage- ment  should  address  the  risks  to  the  mother  of  waiting  for spontaneous onset of labor versus the risks of induc- tion  of  labor.  Psychosocial  support  for  the  family  after  delivery  is  important.  It  should  address  concerns  about  the cause of the fetal death, and how the risk of a similar  event can be reduced in the next pregnancy.

CLINICAL KEYS FOR THIS CHAPTER

About 30% of pregnant women are considered high risk for obstetric complications.  A  family  history  of  preterm birth, prior obstetric problems such as recur- rent early pregnancy loss, preterm birth or fetal demise,  and medical problems such as hypertension, diabetes,  and  obesity  are  considered  to  increase  the  risk  for  obstetric complications.

This  chapter  details  the  causes  and  treatments  for  preterm  labor  and  delivery,  premature  rupture  of  the  membranes  (PROM),  intrauterine  growth  restriction  (IUGR),  postterm  pregnancy,  and  intrauterine  fetal  demise  (IUFD).  Despite  years  of  study  and  research  into  these  problems,  their  causes  are  not  yet  fully  understood.

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labor, whereas black patients in public institutions have a higher proportion of deliveries due to preterm premature rupture of membranes (PPROM).

Attempts  have  been  made  to  define  further  the  spontaneous  preterm  labor  subgroups.  Some  experts  now  believe  this  may  be  caused  by  undiagnosed  con- ditions  of  poor  placental  implantation,  ascending  infections  via  the  vagina,  or  immunologic  rejection  of  uterine  and  cervical  origin.  Recently, genetic throm- bophilias have been shown to account for a signifi- cant proportion of the uteroplacental problems leading to IUGR and preeclampsia,  the  two  major  reasons  for  the  early  induction  of  labor  to  avoid  fetal  death.  In  the  past  10  years,  closer  surveillance  of  high  risk  pregnancies  has  led  to  earlier  delivery  and  an  increase in the rate of late preterm deliveries (between  34  and  37  weeks),  a  major  contribution  to  the  con- tinued  high  rate  of  preterm  birth.  The  decline  in  preterm birth rate over the past 7 years is thought to be  related  to  the  reduced  incidence  of  late  preterm  birth  deliveries.

More women are postponing childbirth as a lifestyle  choice, but this is associated with a greater risk of infer- tility. These women then require assisted reproductive  technologies  (ARTs)  to  become  pregnant.  These  tech- nologies are associated with the risk of multiple gesta- tions  and  the  associated  increased  risks  of  poor  fetal  growth and preterm birth. A variety of socioeconomic,  psychosocial, and medical conditions have been found  to carry an increased risk of preterm delivery in women  who postpone childbearing.

Socioeconomic Factors In the United States, the incidence of preterm deliver- ies in the black population is twice as high as that in the white population. This factor cannot be viewed as  a  single  entity  but  probably  encompasses  other  char- acteristics  of  the  population,  such  as  poor  access  to,  and procurement of, antenatal care, high stress levels,  poor  nutritional  status,  and  the  possibility  of  genetic  differences.  In  the  past  6  years  there  has  been  an  increase in the incidence of poverty and obesity, which  may  contribute  to  the  persistence  of  high  levels  of  preterm birth.

Obstetric, Medical, and Environmental Factors 1.  Recurrent preterm birth: When  one  preterm  birth 

has occurred, the relative risk of preterm delivery in  the  next  pregnancy  is  3.9,  which  increases  to  6.5  with two previous preterm deliveries.

2.  Second-trimester abortions: The  cause  of  second- trimester abortions when the fetus is normal is likely  to have the same cause as preterm labor (PTL) after  20  weeks.  Therefore,  these  early  pregnancy  losses  are associated with an increased risk for subsequent  preterm  delivery,  especially  if  a  previous  preterm  birth  has  also  occurred.  The  risk  associated  with 

Preterm Labor Worldwide,  preterm  labor  and  delivery  are  major  causes of perinatal morbidity and mortality. Although fewer than 12% of all infants born in the United States are preterm, their contribution to neonatal morbidity and mortality ranges from 50-70%.  The  medical  and  economic  impact  of  preterm  delivery  is  significant.  Major  goals  of  obstetric  care  should  be  to  reduce  the  incidence  of  the  condition  and  to  increase  the gestational age of infants whose preterm births are  unavoidable.

DEFINITION AND INCIDENCE Preterm birth (PTB) is usually defined as one occur- ring after 20 weeks and before 37 completed weeks of gestation. Labor that occurs between these gestational  ages  is  defined  as  preterm  labor.  Internationally,  the  lower boundary defining preterm birth varies between  20 and 24 weeks.

Preterm births in the United States increased from 9.8% in 1981 to 12.7% in 2005; however, in the past 6  years,  the  rate  has  declined  for  the  seventh  straight  year  to  11.4%.  Between  1988  and  2004,  the  mortality  rate  for  white  infants  declined  by  55%  to  5.7  infant  deaths  per  1000  live  births  and  the  mortality  rate  for  black  infants  declined  by  45%  to  13.6.  In  the  past  10  years the decline in infant mortality for both races has  been less than anticipated. Because prematurity is the leading cause of infant mortality, the prevention of prematurity has become a high priority.

ETIOLOGY AND RISK FACTORS The  causes  of  preterm  birth  and  their  estimated  fre- quencies are listed in Table 12-1. Private patients have a much higher proportion of spontaneous preterm

TABLE 12-1

PRIMARY CAUSES OF PRETERM BIRTH AND THEIR ESTIMATED FREQUENCY

Cause Frequency (%)

Spontaneous preterm labor 35-37

Multiple gestations* 12-15

Preterm premature rupture of membranes (PPROM)

12-15

Late preterm births 50-70

Pregnancy-associated hypertension 12-14

Cervical incompetence/uterine anomalies 12-14

Antepartum hemorrhage 5-6

Intrauterine growth restriction (IUGR) 4-6

*Increased proportion because of advancing maternal age and assisted reproductive technologies (ARTs). ART has increased the incidence of twin- ning by 50% with a very recent decline due to more elective single embryo transfers.

C H A P T E R 12 Obstetric Complications 157

branes.  When  the  fetal  membranes  are  disrupted,  as  with repetitive uterine activity, and/or in the presence  of infection, shortening of the cervix can occur. In the  presence of these changes, fibronectin (a protein sub- stance)  is  secreted  into  the  vagina  and  can  be  tested.   A positive fetal fibronectin test at 22 to 24 weeks pre- dicts more than half of the spontaneous preterm births that occur before 28 weeks.  A  positive  test  for  fetal fibronectin is significantly associated with a short  cervix, vaginal infections, and uterine activity. A nega- tive  test  is  the  best  predictor  of  a  low  risk  of  preterm  delivery.

Placental-Vascular Pathway The  placental-vascular  pathway  begins  early  in  preg- nancy  at  the  time  of  implantation,  when  there  are  important  changes  taking  place  at  the  placental/ decidual/myometrial  interface.  Initially,  there  are  important immunologic changes, with a switch from a  Th-1  (helper  cell)  type  of  immunity,  which  may  be  embryotoxic,  to  a  Th-2  antibody  profile,  in  which  blocking  antibody  production  is  thought  to  prevent  rejection. At the same time, the trophoblasts are invad- ing the spiral arteries of the decidua and myometrium,  assuring  that  a  low  resistance  vascular  connection  is  established.  All three conditions associated with preterm delivery (spontaneous, PROM, and IUGR) are associated with failure of the trophoblast to prop- erly invade the spinal arteries.  Poor  trophoblastic  invasion may be caused by placental factors or mater- nal abnormalities secondary to atherosclerosis. Altera- tions in both of these early changes are thought to play  an important role in the pathophysiology of poor fetal  growth,  an  important  component  of  preterm  birth  (indicated  and  spontaneous),  fetal  growth  restriction,  and preeclampsia.

The placenta is also an important source of proges- terone  production  that  plays  an  important  role  in  the  immune  system  and  in  the  maintenance  of  uterine  relaxation. The altered placental progesterone produc- tion in women at risk of preterm birth is thought to be  secondary  to  placental  hormonal  dysregulation.  Both  17-OH progesterone and vaginal progesterone play an  important role in the prevention of preterm birth.

Stress-Strain Pathway Both mental (cognitive) and work-related stress and strain are postulated to initiate a stress response that increases release of cortisol and catecholamines. The biochemical response to stress is important for the maintenance of metabolic regulation.  However,  cor- tisol  from  the  adrenal  gland  initiates  early  placental  corticotrophin-releasing hormone (CRH) gene expres- sion,  and  elevated  levels  of  CRH  are  known  to  initiate  labor  at  term.  Catecholamines  released  during  the  stress response not only affect blood flow to the utero- placental  unit,  but  also  cause  uterine  contractions 

induced  first-trimester  abortions  is  controversial,  because  they  are  more  likely  associated  with  mal- formed  fetuses  that  may  not  have  aborted  sponta- neously. However, if there are repeated first-trimester  spontaneous  abortions,  there  is  an  increased  risk   of  spontaneous  loss  of  a  normal  fetus  because  of  immunological  causes  that  are  poorly  understood.  Other  obstetric  factors  include  multiple  gestation  and polyhydramnios.

3.  Medical factors:  The  major  medical  factors  are  hypertension,  diabetes,  obesity,  and  genital  tract  infection. Other factors include bleeding in the first  trimester,  urinary  tract  infections,  uterine  anoma- lies, and incompetent cervix.

4.  Environmental and behavior factors:  Smoking  during  pregnancy  is  associated  with  an  increased  risk  of  preterm  birth.  Smoking  cessation  should  be  considered in any preventative program for preterm  birth.  Recently,  attention  has  been  directed  toward  maternal employment, physical activity, nutritional  status  stress,  and  anxiety  as  major  risk  factors  for  preterm birth. In addition, several papers have asso- ciated  vitamin  D  deficiency  with  a  greater  risk  of  preterm birth, preeclampsia, and IUGR.

PATHWAYS THOUGHT TO CAUSE PRETERM BIRTH: 1.  Infection (cervical-vaginal-urinary) 2.  Placental-vascular 3.  Psychosocial stress and work strain (fatigue) 4.  Uterine stretch (multiple gestations)

Infection-Cervical Pathway Bacterial  vaginosis  has  been  shown  to  be  associated  with  preterm  delivery,  independent  of  other  recog- nized risk factors. Treatment of bacterial vaginosis has reduced the incidence of preterm delivery. For many years, it has been known that treatment of asymp- tomatic and clinical cystitis is associated with a reduced incidence of PTB. In addition, treating women  in preterm labor with antibiotics significantly prolongs  the  time  from  the  onset  of  treatment  to  delivery,   compared  with  that  in  patients  who  do  not  receive  antibiotics.  Thus,  addressing  the  issue  of  these  rela- tively asymptomatic infections is an important strategy  for preventing preterm birth.

There  is  a  link  between  vaginal-cervical  infections  and progressive changes in the cervical length, as mea- sured  by  vaginal  ultrasonography.  The  relative  risk  of  preterm  birth  increases  significantly  from  2.4  for  a   cervical  length  of  3.5 cm  (50th  percentile)  to  6.2  for   a  length  of  2.5 cm  (10th  percentile).  Short cervices appear to be more common in women who have had prior preterm births and pregnancy terminations.

The most recent test to be developed is cervical and vaginal fetal fibronectin. This substance is a base- ment  membrane  protein  produced  by  the  fetal  mem-

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vaginal progesterone, 200 mg daily from 16 to 36 weeks  should be initiated.

DIAGNOSIS AND MANAGEMENT OF PRETERM LABOR The diagnosis of preterm labor  between  20  and  37  weeks  is  based  on  the  following  criteria  in  patients   with  ruptured  or  intact  membranes:  (1)  documented uterine contractions  (4  per  20  minutes  or  8  per  60  minutes) and (2) documented cervical change (cervi- cal  effacement  of  80%  or  cervical  dilation  of  2 cm  or  more). Uterine contractions are not a good predictor of  preterm labor, but cervical changes are.

Provided  that  membranes  are  not  ruptured  and  there  is  no  contraindication  to  a  vaginal  examination  (e.g.,  placenta  previa),  an initial assessment must be done to ascertain cervical length and dilation and the station and nature of the presenting part. The patient  should also be evaluated for the presence of any under- lying  correctable  problem,  such  as  a  urinary  tract  or  vaginal  infection.  She  should  be  placed  in  the  lateral  decubitus  position  to  take  the  uterine  weight  off  the  great  vessels,  monitored  for  the  presence  and  fre- quency  of  uterine  activity,  and  reexamined  for  evi- dence of cervical change after an appropriate interval,  unless  the  preceding  criteria  for  preterm  labor  have  already  been  met.  During the period of observation, either oral or parenteral hydration (5% dextrose) should be initiated.  Clear  liquids  of  caloric  value  should be considered. Fasting is not healthy during this  phase of management.

With adequate hydration and bed rest, uterine contractions cease in approximately 20% of patients.  These patients, however, remain at high risk for recur- rent preterm labor.

Because  of  the  role  of  cervical  colonization  and  vaginal  infection  in  the  etiology  of  preterm  labor  and  PROM, cultures should be taken for group B Strepto- coccus.  Other  organisms  that  may  be  important  are  Ureaplasma, Mycoplasma,  and  Gardnerella vaginalis.  The latter is associated with bacterial vaginosis, a diag- nosis that can be made by the presence of three of four  clinical signs (vaginal pH > 4.5, amine odor after addi- tion of a few drops of 10% potassium hydroxide [KOH]  on a glass slide, the presence of clue cells, and the pres- ence of a milky discharge).

Antibiotics should be administered to patients who are in preterm labor.  For  patients  who  are  not  allergic  to  penicillin,  a  7-day  course  of  ampicillin  and  erythromycin may be given. Those allergic to penicillin  may be given clindamycin.

Once the diagnosis of preterm labor has been made,  the  following  laboratory  tests  should  be  obtained:  complete  blood  cell  count,  random  blood  glucose  level,  serum  electrolyte  levels,  urinalysis,  and  urine  culture  and  sensitivity.  An ultrasonic examination of the fetus should be performed to assess fetal weight,

(norepinephrine). Poor nutrition in the form of reduced  calories  and/or  abnormal  patterns  of  intake  (fasting)  are  known  stressors  and  have  been  associated  with  a  significantly increased risk of preterm birth. In support of the stress pathway are the studies that have shown that the rate of change of CRH, a mediator of the stress response, increases significantly in the weeks before the onset of preterm labor. Thus, too much stress (chronic stress) is thought to be toxic and may cause preterm labor.  Stress  reduction  and  psychoso- cial  support  are  the  only  current  interventions  that   can  be  applied  to  this  pathway.  Meta-analyses  have  suggested  that  psychosocial  support  via  networking  between  women’s  social  groups  can  decrease  the  risk  of preterm birth.

Uterine Stretch Pathway Uterine stretch as a result of increasing volume during  normal  and  abnormal  gestations  is  an  important   physiological  mechanism  that  facilitates  the  process   of  emptying  the  uterus.  In  normal  pregnancy,  the  hormone  parathyroid-related protein (PTrP)  plays  an  important  role  in  relaxing  the  myometrial  tissues,  but  when  stretch  exceeds  certain  limits  (e.g.,  multiple  gestations,  fetal  macrosomia,  and  polyhydramnios),  PTrP fails to keep the uterus relaxed and labor begins.  This  pathway  is  common  in  patients  with  polyhy- dramnios and those with multiple gestations, both of  which have an increased risk of preterm birth.

PREVENTION OF PRETERM BIRTH The ideal time to assess risk factors for premature labor  and PTB is before conception. This allows time to iden- tify  problems  and  take  measures  to  mitigate  any  risk.  Unfortunately,  very  few  women  are  seen  before  preg- nancy for the type of counseling and intervention that  would be necessary (see Chapter 7) and it is usually at  the first prenatal visit that these measures are initiated.  The important risk factors for PTB are a history of previous PTB, a family history of PTB and child abuse, smoking (including second hand), a history of recur- rent early pregnancy losses, previous cervical surgery, obesity, substance abuse, and medical conditions such as hypertension and diabetes.

For  all  women,  but  particularly  those  who  are  at  high  risk  for  PTB,  medical  conditions  should  be  managed  and  appropriate  supplementation  of  folic  acid  (4 mg/day)  and  vitamin  D  (2000  to  3000 IU/day)  should  be  initiated  in  early  pregnancy,  in  addition  to  prenatal  vitamins.  A  probiotic  supplement  should  be  considered to improve the gut biome. The length of the  cervix  should  be  a  component  of  the  ultrasonic  study  at 18 to 20 weeks. Women with a short cervix (between 10 and 20 mm) should receive vaginal progesterone 200 mg daily from 19 to 20 weeks until 36 weeks. For  women  with  a  history  of  PTB,  250 mg  intramuscular  17OH progesterone caproate weekly, until 36 weeks, or 

C H A P T E R 12 Obstetric Complications 159

Although  magnesium  levels  required  for  tocolysis  have  not  been  critically  evaluated,  it  appears  that  the  levels  needed  may  be  higher  than  those  required  for  prevention of eclampsia. Levels from 5.5 to 7.0 mg/dL  appear to be appropriate. These can be achieved using  the  dosage  regimen  outlined  in  Box  12-1.  After the loading dose is given, a continuous infusion is main- tained, and plasma levels should be determined until therapeutic levels have been reached. The drug should  be  continued  at  therapeutic  levels  until  contractions  cease unless the labor progresses. Because magnesium  is excreted via the kidneys, adjustments must be made  in  patients  with  an  abnormal  creatinine  clearance.  Once successful tocolysis has been achieved, the infu- sion should be continued for at least 12 hours. The infusion rate may then be weaned over 2 to 4 hours and then discontinued.  In  very  high  risk  patients  (advanced  cervical  dilation  or  continued  labor  in  very  low birth weight cases), the infusion may be continued  until  the  fetus  has  been  exposed  to  glucocorticoids  to  enhance lung maturity.

A common minor side effect is a feeling of warmth and flushing on first administration. Respiratory depression is seen at magnesium levels of 12 to 15 mg/ dL,  and  cardiac conduction defects and arrest  are  seen at higher levels.

In  the  fetus,  plasma  magnesium  levels  approach  those  of  the  mother,  and  a  low  plasma  calcium  level  may  also  be  demonstrated.  The neonate may show some loss of muscle tone and drowsiness, resulting in a lower Apgar score. These effects are prolonged in the  preterm  neonate  because  of  the  decrease  in  renal  clearance.

Long-term parenteral magnesium therapy has been used for control of preterm labor in selected patients.  An  important  side  effect  seems  to  be  loss  of  calcium,  and  it  may  be  important  in  such  patients   to  institute  calcium  therapy  on  a  prophylactic  basis.  Because vitamin D deficiency has been associated with  the risk of premature labor, vitamin D supplementation  should be considered because vitamin D is required for  adequate mobilization of calcium from the skeleton.

Nifedipine Nifedipine as an oral agent is very effective in sup- pressing preterm labor with minimal maternal and fetal side effects. It works by inhibiting the slow, inward  current  of  calcium  ions  during  the  second  phase  of   the  action  potential  of  uterine  smooth  muscle  cells   and may gradually replace intravenous magnesium sulfate. The only side effects are headache, cutaneous  flushing, hypotension, and tachycardia. The latter two  side effects can be partially avoided by making certain  the  patient  is  well  hydrated  and  by  the  use  of  support  stockings, such as thromboembolism-deterrent (TED)  hose,  to  prevent  pooling  of  blood  in  the  lower  extremities.

document presentation, assess cervical length, and rule out the presence of any accompanying congeni- tal malformation. The test may also detect an underly- ing etiologic factor, such as twin pregnancy or uterine  anomaly.

If the patient does not respond to bed rest and hydration, tocolytic therapy should be instituted, provided that there are no contraindications.  Mea- sures implemented at 28 weeks should be more aggres- sive than those initiated at 35 weeks. Similarly, a patient  with advanced cervical dilation on admission requires  more aggressive management than one whose cervix is  closed and minimally effaced.

UTERINE TOCOLYTIC THERAPY It  is  assumed  that  physiologic  events  leading  to  the  initiation  of  labor  also  occur  in  preterm  labor.  The  pharmacologic  agents  presently  being  used  all  seem   to  inhibit  the  availability  of  calcium  ions,  but  they   may  also  exert  a  number  of  other  effects.  The  agents  currently  used  and  their  dosages  are  presented  in   Box 12-1.

Magnesium Sulfate In the United States, magnesium sulfate is frequently the drug of choice for initiating tocolytic therapy. Magnesium acts at the cellular level by competing with calcium for entry into the cell at the time of depolarization.  Successful  competition  results  in  an  effective decrease of intracellular calcium ions, result- ing in myometrial relaxation.

BOX 12-1

UTERINE TOCOLYTIC AGENTS

Magnesium Sulfate Solution:  Initial  solution  contains  6 g  (12 mL  of  50% 

MgSO4)  in  100 mL  of  5%  dextrose;  maintenance  solu- tion contains 10 g (20 mL of 50% MgSO4) in 500 mL of  5% dextrose

Initial dose: 6 g over 15 to 20 min, parenterally Titrating  dose:  2 g/hr  until  contractions  cease;  follow 

serum levels (5-7 mg/dL); maximal dose, 4 g/hr Maintenance dose: Maintain dose for 12 hr, then 1 g/hr for 

24 to 48 hr; consider switching to nifedipine (see below)

Nifedipine Preparation: Oral gelatin capsules of 10 or 20 mg Loading  dose:  30 mg;  if  contractions  persist  after  90 min, 

give  an  additional  20 mg  (second  dose);  if  labor  is   suppressed,  a  maintenance  dose  of  20 mg  is  given  orally  every  6 hr  for  24 hr  and  then  every  8 hr  for  another 24 hr

Failure:  If  contractions  persist  60 min  after  the  second  dose, treatment should be considered a failure

Prostaglandin Synthetase Inhibitors Short-term use only

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amniotic cavity is colonized with pathogens. It is rea- sonable to assume that a proportion of the remainder  will  have  occult  bacteria  in  the  decidual  cell  space  between  the  chorion  and  the  myometrium.  The use of prophylactic antibiotics in women with preterm labor may prevent progression from a subclinical infection to clinical amnionitis.

Contraindications to Tocolytic Therapy Contraindications include severe preeclampsia, severe bleeding from placenta previa or abruptio placentae, chorioamnionitis, IUGR, fetal anomalies incompati- ble with life, and fetal demise.  Because  of  the  low  success  rate,  advanced  cervical  dilation  may  also  pre- clude  tocolytic  therapy,  although  therapy  may  delay  delivery  sufficiently  for  glucocorticoid  administration  to  accelerate  fetal  lung  maturity.  Management  of  patients  should  be  individualized,  and  even  if  the  patient’s  cervix  is  dilated  to  6 cm  and  infrequent  con- tractions are occurring, it is advisable to employ toco- lytics and to administer glucocorticoid therapy.

USE OF GLUCOCORTICOIDS FOR FETAL PULMONARY MATURATION Antenatal corticosteroid therapy for fetal pulmonary maturation reduces mortality and the incidence of RDS and intraventricular hemorrhage (IVH) in preterm infants.  These  benefits  extend  to  a  broad  range  of  gestational  ages  (24  to  34  weeks)  and  are  not  limited  by  gender  or  race.  Treatment consists of 2 doses of 12 mg of betamethasone, given intramuscu- larly 24 hours apart, or 4 doses of 6 mg of dexametha- sone given intramuscularly 12 hours apart.  Optimal  benefit  begins  24  hours  after  initiation  of  therapy  and  lasts  7  days.  Treatment  with  corticosteroids  for  less  than 24 hours is still associated with significant reduc- tions  in  neonatal  mortality  secondary  to  respiratory  distress syndrome and intraventricular hemorrhage, so  they  should  be  given  unless  immediate  delivery  is  anticipated.

LABOR AND DELIVERY OF THE PRETERM INFANT A certain number of patients will not respond to toco- lytic  therapy.  The  goal  in  these  patients  should  be  to  conduct both labor and delivery in an optimal manner  so as not to contribute to the morbidity or mortality of  the preterm infant. All parameters for assessing gesta- tional  age  and  fetal  weight  must  be  considered.  With modern neonatal care, the lower limit of potential viability is 24 weeks or 500 g, although these limits vary with the expertise of the neonatal intensive care unit.

Fetal  heart  rate  patterns  characterized  as  Category  II  (Intermediate/possibly  Early  Dysregulation;  see  Boxes 9-1 and 9-2) that are relatively innocuous in the  term  fetus  may  indicate  a  more  ominous  outcome  for  the  preterm  fetus.  The  clinician  should  not  wait  until 

Prostaglandin Synthetase Inhibitors Prostaglandins  induce  myometrial  contractions  at  all  stages  of  gestation,  both  in  vivo  and  in  vitro.  Because  prostaglandins  are  locally  synthesized  and  possess  a  relatively  short  half-life,  prevention  of  their  synthesis  within the uterus could inhibit labor. These agents are used on a short-term basis  in  circumstances  where  prostaglandin production may be the inciting factor, as  may  occur  in  the  presence  of  uterine  fibroids.  In  the  United  States  indomethacin is the most commonly used prostaglandin inhibitor; it can be administered both orally and rectally, with some slight delay in absorption from rectal administration as compared with the oral route. Peak serum levels of indomethacin  occur 1.5 to 2 hours after oral administration. Excretion  of the intact drug occurs in maternal urine. It can result  in oligohydramnios and premature closure of the fetal  ductus arteriosus, which in turn may lead to neonatal  pulmonary  hypertension  and  cardiac  failure.  In  addi- tion,  indomethacin decreases fetal renal function, and indomethacin-exposed infants have a greater risk of necrotizing enterocolitis, intracranial hemor- rhage, and patent ductus arteriosus.  Short-term  use  may be acceptable, but if patients are given indometh- acin, the fetus should be evaluated with ultrasonogra- phy for ductus arteriosus flow.

Combined therapy with nifedipine and prostaglan- din  synthetase  inhibitors  is  currently  being  used  in  Australia, Canada, and Europe.

Oxytocin Receptor Antagonists Atosiban  was  the  first  oxytocin  receptor  antagonist  developed.  It  binds  to  receptors  in  the  myometrium  and other gestational tissues, preventing the oxytocin- induced  increase  in  inositol  triphosphate.  The  latter   is  the  messenger  that  increases  intracellular  calcium,  and causes myometrial contractions and up-regulation  of  prostaglandin  production.  These agents are not approved for use in the United States.

Efficacy of Tocolytic Therapy Although the advent of tocolytic agents has failed to decrease preterm births in large population studies, their use has improved neonatal survival, decreased respiratory distress syndrome (RDS), and increased the birth weight of infants. The benefit of measures to  postpone delivery beyond 34 weeks is under investiga- tion, with the thought that the longer the fetus remains  in utero the better the outcome.

Antibiotic Therapy A number of studies have advocated the use of antibi- otic  prophylaxis  in  patients  with  preterm  labor.  Such  patients  may  have  a  higher  incidence  of  subclinical chorioamnionitis than previously thought.

Diagnostic amniocentesis in patients with idio- pathic preterm labor has identified about 15% whose

C H A P T E R 12 Obstetric Complications 161

assess cervical dilation and length, and if the patient is  preterm, to obtain cervical cultures and amniotic fluid  samples for pulmonary maturation tests.

On  speculum  examination,  pooling  of  amniotic  fluid in the posterior vaginal fornix can usually be seen.  A  Valsalva  maneuver  or  slight  fundal  pressure  may  expel fluid from the cervical os, which is diagnostic of  PROM. Confirmation of the diagnosis can be made by (1) nitrazine paper test: amniotic fluid will turn blue in the presence of the alkaline amniotic fluid, (2) fern test: placing a sample of amniotic fluid on a micro- scopic slide left to air dry will show ferning, and (3) AmniSure test: a highly accurate test measuring placental alpha microglobulin-1 (PAMG-1), which is present in high levels in amniotic fluid. A fluid sample  is  obtained  with  a  vaginal  swab  and  placed  in  a  test  solution and the result read as positive or negative in 5  to 10 minutes. False-positive nitrazine test results occur  in  the  presence  of  alkaline  urine,  blood,  or  cervical  mucus. For the fern test, the presence of blood, which  is usually seen in patients in early labor, may make the  pattern  appear  to  be  skeletonized.  The  AmniSure  test  is not affected by the presence of blood or infection. As  in the case of preterm labor with intact membranes, a  complete ultrasonic examination should be carried out  to rule out fetal anomalies and to assess gestational age  and amniotic fluid volume.

MANAGEMENT General Considerations An intact amniotic sac serves as a mechanical barrier to infection,  but  in  addition,  amniotic  fluid  has  some  bacteriostatic  properties  that  may  play  a  role  in  pre- venting  chorioamnionitis  and  fetal  infections.  Intact membranes are not an absolute barrier to infection,  because bacterial colonization still occurs in the decid- ual  space/membrane  interface  in  10%  of  patients  in  term  labor  and  in  up  to  25%  of  patients  in  preterm  labor.

For  preterm  fetuses  with  PPROM,  the  risks  associ- ated  with  preterm  delivery  must  be  balanced  against  the  risks  of  infection  and  sepsis.  For  the  mother,  the  risks  include  not  only  the  development  of  chorioam- nionitis,  but  also  the  possibility  of  failed  induction  in  the presence of an unfavorable cervix, resulting in sub- sequent cesarean delivery.

Management is dictated to a large extent by the ges- tational age at the time of membrane rupture, although  the quantity of amniotic fluid remaining after PPROM may be as important as gestational age in determin- ing pregnancy outcome.

Ultrasonic  definition  of  oligohydramnios  has  been  standardized.  Objective  criteria  include  measurement  of  the  vertical  axis  of  amniotic  fluid  present  in  four  quadrants,  the  total  being  called  the  amniotic fluid index (AFI).  A  value  of  less  than  5 cm  is  considered  abnormal.

Category  III  (Abnormal)  patterns  are  observed.  In  Box  9-2 there are subtype patterns in Category II that may  help  the  clinician  to  consider  immediate  delivery  to  prevent  the  occurrence  of  Category  III  heart  rate  pat- terns. Continuous fetal heart monitoring and prompt attention to abnormal fetal heart rate patterns are extremely important.  Acidosis  at  birth  adversely  affects  respiratory  function  by  destroying  surfactant  and delaying its release.

With a vertex presentation, vaginal delivery is pre- ferred,  independent  of  gestational  age,  provided  that  fetal  acidosis  and  delivery  trauma  are  avoided.  Use of outlet forceps and an episiotomy to shorten the second stage are advocated. Some reports recommend  cesarean delivery for the very low birth weight baby.

Approximately 23% of infants present as a breech at  28  weeks,  compared  with  about  4%  at  term. This  pre- sentation carries an increased risk of cord prolapse or  compression.  In  addition,  cervical  entrapment  of  the  after-coming fetal head may occur at delivery because  before  term  the  head  is  proportionally  larger  than  the  buttocks.  For the breech fetus estimated at less than 1500 g, neonatal outcome is improved by cesarean delivery.

Premature Rupture of the Membranes DEFINITION AND INCIDENCE Premature rupture of the membranes (PROM) is defined as amniorrhexis (spontaneous rupture of the membranes as opposed to amniotomy) before the onset of labor at any stage of gestation. Preterm PROM  (PPROM) should be used to define those patients who  are preterm with ruptured membranes, whether or not  they have contractions.

ETIOLOGY AND RISK FACTORS The  etiology  of  PROM  remains  unclear,  but  a  variety   of  factors  are  purported  to  contribute  to  its  occur- rence, including vaginal and cervical infections, abnor- mal  membrane  physiology  (apoptosis  secondary  to  oxidative  stress),  incompetent  cervix,  and  nutritional  deficiencies.

DIAGNOSIS Diagnosis of PROM is based on the history of vaginal loss of fluid and confirmation of amniotic fluid in the vagina.  Episodic  urinary  incontinence,  leucorrhea,  or  loss  of  the  mucus  plug  must  be  ruled  out.  Because of the risk of introducing infection and the usually long latency period from the time of examination until delivery, the examiner’s hands should not be inserted into the vagina of a patient who is not in labor, whether preterm or term. A sterile vaginal speculum examina- tion should be performed to confirm the diagnosis, to 

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perform amniocentesis is based on the gestational age,  the  presence  of  early  signs  of  infection,  and  the  AFI   as  measured  by  real-time  ultrasonography.  Recently,  investigators have described elevation of inflammatory  cytokines in the amniotic fluid and in the fetal circula- tion  in  preterm  infants  who  have  subsequently  devel- oped chronic lung disease during the neonatal period.  A  similar  response  may  be  associated  with  a  greater  risk  of  damage  to  the  preterm  baby’s  brain,  thus  increasing  the  risk  of  cerebral  palsy.  Therefore,  the  management  of  patients  with  PROM  is  critical  for   the  prevention  of  neonatal  morbidity.  Some  centers  around the world do not conservatively manage PROM.

Ampicillin or erythromycin significantly prolongs the interval to delivery in patients with PPROM. The  neonates delivered from patients receiving prophylaxis  also have less morbidity.

Management of Chorioamnionitis Once chorioamnionitis has been diagnosed, antibi- otic therapy should be delayed only until appropriate cultures have been taken. Ampicillin and gentamycin  in combination are the drugs of choice. In the penicillin- sensitive  patient,  cephalosporins  may  be  indicated,  noting the 12% incidence of crossover sensitivity. Once  antibiotics have been started, labor should be induced.  If the condition of the cervix is unfavorable, and there is evidence of fetal involvement, it may be necessary to perform a cesarean delivery.

The presence of active genital herpes is an impor- tant concern in the presence of ruptured membranes.  Herpes  infection  at  a  site  remote  from  the  cervix  and  vagina  is  probably  not  associated  with  an  increased  risk of fetal infection, so the site of infection should be  taken into consideration before recommending imme- diate cesarean delivery.

Tocolytic Therapy The  use  of  tocolytics  to  control  preterm  labor  in  patients  with  PROM  is  controversial.  The  arguments  against  their  use  are  that  they  may  mask  evidence  of  maternal infection (e.g., tachycardia) and that contrac- tions  associated  with  the  membrane  rupture  may  be  indicative of uterine infection. Arguments for their use  are  that  PROM  is  sometimes  initially  associated  with  evidence of uterine contractions, and time is gained for  fetal pulmonary maturation. In the presence of infec- tion, tocolysis is usually unsuccessful.

Use of Corticosteroids There  is  a  “natural”  decreased  incidence  of  RDS  in  infants who are born with PPROM 16 to 72 hours after  membrane rupture, presumably because of the endog- enous  release  of  corticosteroids  from  the  stress  of  decreased  amniotic  fluid  volume  and  early  infection.  Perhaps  for  this  reason,  the  National  Institutes  of  Health  (NIH)  guidelines  for  glucocorticoid  therapy 

Oligohydramnios associated with PROM in the fetus at less than 24 weeks may lead to the develop- ment of pulmonary hypoplasia.  Factors  that  may  be  responsible include fetal crowding with thoracic com- pression,  restriction  of  fetal  breathing,  and  distur- bances  of  pulmonary  fluid  production  and  flow.  The  duration of membrane rupture is an important consid- eration.  Constraints  placed  on  fetal  movements  in  utero  can  also  result  in  a  variety  of  positional  skeletal  abnormalities, such as talipes equinovarus.

If PROM occurs at 36 weeks or later and the condi- tion of the cervix is favorable, labor should be induced after 6 to 12 hours if no spontaneous con- tractions occur.  In  the  presence  of  an  unfavorable  cervical  condition  with  no  evidence  of  infection,  it  is  reasonable  to  wait  24  hours  before  induction  of  labor  to  decrease  the  risk  of  failed  induction  and  maternal  febrile  morbidity.  The  following  discussion  applies  when  premature  membrane  rupture  occurs  before  36  weeks’  gestational  age.

Laboratory Tests In  addition  to  the  laboratory  tests  obtained  for  the  patient  in  preterm  labor,  sufficient  amniotic  fluid  can  usually  be  obtained  from  the  vaginal  pool  for  pulmo- nary maturation studies.  Because  of  the  higher  inci- dence  of  chorioamnionitis  in  association  with  PROM,  amniotic  fluid  should  also  be  examined  with  Gram stain and culture.

Conservative Expectant Management Conservative  management  applies  to  the  care  of  patients with PPROM who are observed with the expec- tation  of  prolonging  gestation.  Because the risk of infection appears to increase with the duration of membrane rupture, the goal of expectant manage- ment is to continue the pregnancy until the lung profile is mature.  Careful  surveillance  must  be  main- tained to diagnose chorioamnionitis at an early enough  stage to minimize fetal and maternal risks. In its fulmi- nant  state,  chorioamnionitis  is  associated  with  a  high  maternal  temperature  and  a  tender,  sometimes  irrita- ble, uterus.

In cases of subclinical infection, diagnosis and treatment may be delayed.  A  combination  of  factors  should  alert  the  clinician  to  the  possibility  of  chorio- amnionitis,  including  maternal  temperature  greater  than 100.4° F (38° C) in the absence of any other site of  infection, fetal tachycardia, a tender uterus, and uterine  irritability when noted on nonstress testing while mea- suring fetal heart rate and uterine activity.

The presence of bacteria by Gram stain or culture of amniotic fluid obtained at amniocentesis corre- lates with subsequent maternal infection in about 50% of cases and with neonatal sepsis in about 25%.  The  presence  of  white  blood  cells  alone  in  amniotic  fluid  is  less  predictive  of  infection.  The  decision  to 

C H A P T E R 12 Obstetric Complications 163

cant recycling seems to occur by resorption and secretion.

Initially, the important phospholipid was thought to be phosphatidylcholine (lecithin), but it is appar- ent that other components, such as phosphatidylino- sitol (PI) and phosphatidylglycerol (PG), are also important.  These  substances  are  produced  and  secreted in increasing amounts as gestation advances,  and  the  continued  egress  of  tracheal  fluid  into  the  amniotic fluid results in their increasing presence near  term.

Measurement  of  these  substances  in  the  amniotic  fluid  obtained  by  amniocentesis  allows  prediction  of  the  risk  of  development  of  RDS  in  the  neonate.  Leci- thin (L) levels increase rapidly after 35 weeks, whereas sphingomyelin (S) levels remain relatively constant  after this gestational age. The lecithin and sphingomy- elin  concentrations  are  measured  by  thin-layer  chro- matography  and  are  expressed  as  the  L/S ratio.  The  presence  of  blood  or  meconium  in  the  amniotic  fluid  will affect the L/S ratio; meconium will decrease it and  blood will normalize it to a value of 1.4.

LUNG PROFILE Using two-dimensional thin-layer chromatography, both PG and PI can be measured. Along with the L/S ratio, these make up the lung profile. RDS is rare when  the L/S ratio is greater than 2 and PG is present, whereas  when the L/S ratio is less than 2 and no PG is present,  more  than  90%  of  infants  will  develop  RDS.  If the L/S ratio indicates pulmonary immaturity (L/S < 2) but PG is present, fewer than 5% of infants develop RDS.  The lung profile offers a more reliable predictor of pul- monary  maturity,  especially  in  infants  of  diabetic  mothers.  Other  advantages  of  using  PG  are  that  con- tamination with vaginal secretions or blood, as occurs  in cases of ruptured membranes and vaginal pool sam- pling, does not interfere with its detection.

RAPID TESTS FOR FETAL LUNG MATURITY A  rapid  test  to  assess  fetal  lung  maturity,  which  could  then be followed up with the more standard tests, pro- vides  a  very  useful  clinical  tool.  One  such  test  is  the  lamellar body number density (LBND) assessment,  which  is  performed  using  an  electronic  cell  counter  (Coulter). This test can be completed within 2 hours by  any  hospital  clinical  laboratory.  Normal  ranges  have  been developed and depend on the individual labora- tory  (maturity  ≥  46,000 µL  LBND),  and  the  sensitivity  and predictive value are as good if not better than the  standard L/S ratio.

Surfactant Therapy RDS in preterm infants is caused by a lack of surfac- tant.  Surfactant  production  by  type  II  pneumocytes  may be induced by corticosteroids and thyroid-releasing 

recommend they be given to patients with PPROM only  up  to  32  weeks,  rather  than  up  to  34  weeks  as  recom- mended when the membranes are intact.

Outpatient Management Outpatient management is not recommended, unless  there is no evidence of infection and a normal AFI after  a period of inpatient observation for 2 to 3 days. In this  situation, the site of rupture may have closed by over- lapping  of  the  amnionic  and  chorionic  membranes.   To be eligible for such management, the patient should be reliable, fully informed regarding the risks involved, and prepared to participate in her own care.  The  fetus  should  be  presenting  as  a vertex,  and  the  cervix should be closed  to  minimize  the  chance  of  cord  prolapse.  At  home,  restricted  physical  activity  should be advised, no coital activity should occur, and  the  patient  should  monitor  her  temperature  at  least  four  times  per  day.  Instructions  should  be  given  to  return  immediately  if  the  temperature  exceeds  100°  F  (37.8° C).

The  patient  should  be  seen  weekly,  at  which  time  her  temperature  should  be  taken,  nonstress  testing  performed after 28 weeks, and the baseline fetal heart  rate  and  AFI  evaluated.  Ultrasonic  evaluation  of  fetal  growth  should  also  be  carried  out  every  2  weeks.  Any patient with oligohydramnios is not a candidate for outpatient management.

Labor and Delivery The  same  considerations  discussed  under  preterm  labor  apply  to  patients  with  PROM.  The  decrease  in  amniotic  fluid  that  is  sometimes  seen  can  result  in  early  cord  compression  and  the  presence  of  variable  fetal heart decelerations. This is true of both vertex and  breech presentations; therefore, there is a necessity for  abdominal delivery in a large number of cases.

Tests of Pulmonary Maturity By far the major determinant of successful extrauterine  existence is the ability of the neonate to maintain suc- cessful  oxygenation.  Pulmonary  maturation  involves  changes  in  pulmonary  anatomy  in  addition  to  altera- tions  of  physiologic  and  biochemical  parameters.  Beginning at about 24 weeks, the terminal bronchioles  divide into three or four respiratory bronchioles. Type II pneumocytes, which are important in surfactant synthesis, begin to proliferate during this phase.

Surfactant is required for successful lung function in the fetus and is a complex mixture of phospholipids,  neutral  lipids,  proteins,  carbohydrates,  and  salts.  It  is  important  in  decreasing  alveolar  surface  tension,  maintaining alveoli in an open position at a low inter- nal  alveolar  diameter,  and  decreasing  intraalveolar  lung  fluid.  Synthesis takes place in the type II pneu- mocytes by the incorporation of choline, and signifi-

PA R T 2 Obstetrics164

whose growth potential has been limited by pathologic  processes  in  utero,  with  resultant  increased  perinatal  morbidity  and  mortality  (Figure  12-1  defines  these  parameters).  Growth-restricted fetuses are particu- larly prone to problems such as meconium aspira- tion, asphyxia, polycythemia, hypoglycemia, and mental retardation. They are at greater risk for devel- oping adult onset conditions such as hypertension, diabetes, and atherosclerosis (see Barker hypothesis in Chapter 1).

ETIOLOGY The causes of IUGR can be grouped into  three  main  categories:  maternal, placental, and fetal.  Combina- tions of these are frequently found in pregnancies with  IUGR.

Maternal Maternal causes include poor nutritional intake, cigarette smoking, drug abuse, early cardiovascular

hormone,  but  many  premature  infants  still  develop  RDS.  Several  human  studies  using  instillation  of   surfactant  into  the  pulmonary  tree  immediately  post- delivery  have  shown  dramatic  improvements  in  lung  mechanics and infant survival. A wide variety of surfac- tant  preparations  are  now  available,  including  syn- thetic surfactants and surfactants derived from animal  sources.

Intrauterine Growth Restriction Intrauterine growth restriction (IUGR) by definition occurs when the birth weight of a newborn infant is below the 10th percentile for a given gestational age.  The  terms  small  for  gestational  age  (SGA),  low  birth  weight  (<2500  grams),  and  IUGR  should  not  be  used  synonymously.  The  term  SGA  merely  indicates  that  a  fetus  or  neonate  is  below  a  defined  reference  range  of  weight for a gestational age, whereas IUGR (<10th per- centile)  refers  to  a  small  group  of  fetuses  or  neonates 

FIGURE 12-1 The birth weight/gestational age growth curve showing three different parameters that describe the characteristics of the fetus at birth. First, the light pink color shows that any birth weight below <2500 grams is defined as underweight (low birth weight [LBW]). The medium pink color defines those pregnancies <10th percentile and defines fetuses that are classified as intrauterine growth restricted (IUGR). The dark pink color defines a new area that defines a fetus that is not LBW but is IUGR based upon the birth weight/ gestational aged growth curve. In addition it defines a group of fetuses who have had normal estimated fetal weight in early pregnancy, but because of complications during pregnancy (see case history in text) have poor fetal growth and become IUGR. This case is classic because it fits the criteria as defined by David Barker when he described the fetal origins for the risk of adult cardiovascular disease sec- ondary to fetal programming in utero. (The birth weight-gestational curve modified using Oken E, Kleinman KP, Rich-Edwards J, et al: A nearly continuous measure of birth weight for gestational age using a United States national reference. BMC Pediatr 3:6, 2003.)

X X

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Under 2500 grams (birth weight) <10% IUGR 10-25% Case study of fetal growth trajectory

C H A P T E R 12 Obstetric Complications 165

uterine blood flow, the fetal liver fails to store glycogen  because  of  inadequate  glucose  from  the  mother.  Changes in the liver are now thought to play an important role in programming the fetus for a greater risk of obesity and diabetes later in life. The fetal phe- notype  (small  size)  is  known  as  the  thrifty  phenotype,  but when born into an environment of plenty, there is  increased risk of developing obesity, diabetes, and car- diovascular disease in later life (see Chapter 1).

DIAGNOSIS Growth  restriction  may  go  undiagnosed  unless  the  obstetrician  establishes  the  correct  gestational  age  of  the  fetus  (Box  12-2),  identifies  high-risk  factors  from  the  obstetric  data  base,  and  serially  assesses  fetal  growth  by  fundal  height  or  ultrasonography.  Fetal or neonatal IUGR is usually defined as weight at or below the 10th percentile for gestational age.

Serial uterine fundal height measurements should serve as the primary screening tool for IUGR. A more  thorough  sonographic  assessment  should  be  under- taken when (1) the fundal height lags more than 3 cm  behind  expectations  or  (2)  the  mother  has  high-risk  conditions  such  as  preexisting  hypertension,  chronic  renal disease, advanced diabetes with vascular involve- ment,  preeclampsia,  viral  disease,  addiction  to  nico- tine,  alcohol,  or  hard  drugs,  or  the  presence  of  serum  lupus anticoagulant or antiphospholipid antibodies.

Recently,  interest  has  focused  on  the  prediction  of  patients  at  risk  for  IUGR  at  mid-pregnancy.  Patients  with  abnormal  triple  screens  (α-fetoprotein  [AFP],  human  chorionic  gonadotropin  [hCG],  and  unconju- gated estriol [UE3]) who do not have abnormal fetuses  by  ultrasonography  and  amniocentesis  may  be  at  increased  risk  for  IUGR.  In  addition,  elevations  of  umbilical  artery  and  uterine  artery  Doppler  assess- ments (increased resistance) as early as mid-pregnancy  have  been  associated  with  a  greater  risk  of  IUGR  as  pregnancy progresses.

At present, a number of sonographic parameters are used to diagnose IUGR: (1) biparietal diameter

disease, hypertension, diabetes, obesity (associated with leptin resistance), alcoholism, cyanotic heart disease, and pulmonary insufficiency. In recent years,  the  antiphospholipid syndrome  (autoantibody  pro- duction)  has  been  identified  as  a  cause  of  IUGR  in  some  women,  both  with  and  without  hypertension.  Antiphospholipid antibodies such as lupus-like antico- agulant  and  anticardiolipin  contribute  to  the  forma- tion of vascular lesions in both the uterine and placental  vasculature  that  may  result  in  impaired  fetal  growth  and  demise.  Recently,  several  hereditary thrombo- philias  have  been  identified,  which  have  been  associ- ated  with  a  greater  risk  for  IUGR,  abruption,  and  preeclampsia.  These  conditions  result  in  vascular  lesions  within  the  spinal  arteries  supplying  the  pla- centa.  Identification  and  treatment  with  low-dose  heparin  and  low-dose  aspirin  have  been  shown  to  reduce the risk of IUGR.

Placental This  category  is  representative  of  circumstances  in  which  there  is  inadequate  substrate  transfer  because   of  placental  insufficiency.  Conditions that lead to this state include essential hypertension, obesity (associated with leptin resistance which leads to placental dysfunction), chronic renal disease, and pregnancy-induced hypertension.  If  the  latter  occurs  late  in  pregnancy  and  is  not  accompanied  by  chronic  vascular  or  renal  disease,  significant  IUGR  is  unlikely  to occur. A small fraction of cases may be attributable  to  placental  or  cord  abnormalities  (e.g.,  velamentous  cord insertion).

Fetal Examples  of  fetal  causes  include  intrauterine infec- tion  (listeriosis  and  TORCH  [toxoplasmosis,  other  infections,  rubella,  cytomegalovirus  infection,  and  herpes  simplex]  agents)  and  congenital anomalies.  Chapter 22 reviews TORCH infections.

CLINICAL MANIFESTATIONS Two types of fetal growth restriction have been described: symmetric and asymmetric. In fetuses with  symmetric growth restriction, growth of both the head  and  the  body  is  inadequate.  The  head-to-abdominal  circumference  ratio  may  be  normal,  but  the  absolute  growth rate is decreased. Symmetric growth restriction  is  most  commonly  seen  in  association  with  intrauter- ine infections or congenital fetal anomalies.

When asymmetric growth restriction occurs, usually late in pregnancy, the brain is preferentially spared at the expense of abdominal viscera.  As  a  result,  the  head  size  is  proportionally  larger  than  the  abdominal size. The liver and fetal pancreas undergoes  the  most  dramatic  anatomical  and  biochemical  changes.  When  there  is  insufficient  nutrition  to  the  fetus, caused by either poor maternal nutrition or poor 

BOX 12-2

FACTORS TO BE EVALUATED IN DATING A PREGNANCY

Accuracy of the date of the last normal menstrual period. Evaluation  of  uterine  size  on  pelvic  examination  in  the 

first trimester. Evaluation  of  uterine  size  in  relation  to  gestational  age 

during  subsequent  antenatal  visits  (concordance  or  size-for-dates discrepancy).

Gestational age when fetal heart tones are first heard using  a Doppler ultrasonic device (usually at 12-14 weeks).

Date of quickening (usually 18-20 weeks in a primigravida  and 16-18 weeks in a multigravida).

Sonographic  measurement  of  fetal  length  (crown-rump)  in the first trimester is most accurate.

PA R T 2 Obstetrics166

ultrasonography. The accuracy depends on the quality  of the assessments, the criteria used for diagnosis, and  the effect of interventions applied when this diagnosis  is  made.  For  example,  an  improvement  may  be  observed  in  fetal  growth  after  interventions  such  as  work stoppage, bed rest, dietary modification, and cur- tailment of the use of tobacco, hard drugs, and alcohol.

It is worthwhile to plot out each serial measurement  on a standard growth curve. For example, a fetus mea- suring  near  the  10th  percentile  in  mid-gestation  may  continue to grow along that curve (SGA) or, conversely,  may fall well below the 10th percentile (IUGR) later in  pregnancy (see Figure 12-1).

MANAGEMENT Prepregnancy An  important  part  of  preventive  medicine  is  to  antici- pate the risk for women with a prior infant with IUGR,  and  to  consider  interventions  before  a  woman  plans  her  next  pregnancy.  Improving nutrition and stop- ping smoking are two approaches that should improve  fetal  growth.  The  patient  should  be  assessed  for  evi- dence of early cardiovascular disease as a cause of the  IUGR. The assessment should include measurement of  biomarkers  that  define  risk  for  cardiovascular  disease  such as hemoglobin A1c (HA1c), high-density lipopro- tein  (HDL),  and  C-reactive  protein  (CRP)  (risk  of  dia- betes,  hypertension,  and  inflammation).  For women with antiphospholipid antibodies and a past history of giving birth to an infant with IUGR, low-dose aspirin (81 mg/day) in early pregnancy may reduce the likelihood of recurrence.  For  patients  with  one  of  the  hereditary  thrombophilias,  low-dose  heparin  (5000 U  twice  daily),  with  or  without  low-dose  aspirin  (81 mg/day), has also been shown to reduce the risk of  recurrent IUGR.

Antepartum Once  a  fetus  has  been  identified  as  having  decreased  growth,  attention  should  be  directed  toward  modify- ing  any  associated  factors  that  can  be  changed.  Because  poor  nutrition  and  smoking  exert  their  main  effects  on  birth  weight  in  the  latter  half  of  pregnancy,  cessation of smoking and improved nutrition can have a positive impact.  The  working  woman  who  becomes  fatigued  is  more  likely  to  have  a  low-birth- weight  infant.  Work leave, or in some cases of mater- nal disease, hospitalization, will increase uterine blood flow and may improve the nutrition of the fetus  at  risk.

The objective of clinical management is to expe- dite delivery before the occurrence of fetal compro- mise, but after fetal lung maturation has been achieved. This requires regular fetal monitoring with a  twice-weekly  nonstress  test  (NST)  and  biophysical  profile.  Most  institutions  use  a  modified  biophysical  profile  that  includes  an  NST  and  AFI.  The  oxytocin 

(BPD), (2) head circumference, (3) abdominal cir- cumference, (4) femoral length, (5) amniotic fluid volume (6) calculated fetal weight, and (7) umbilical and uterine artery Doppler.  Of  these,  the abdominal circumference is the single most effective parameter for predicting fetal weight because it is reduced in both symmetric and asymmetric IUGR.  Most  formu- las for estimating fetal weight incorporate two or more  parameters to reduce the variance of measurements.

Clinical Example of Fetal Growth Restriction Using the standard fetal birth weight (vertical axis) and  gestational age (horizontal axis) the fetal growth profile  in a 34-year-old woman having her second pregnancy  is  illustrated  in  Figure  12-1.  In  this  case  the  patient’s  first  pregnancy  was  complicated  by  a  fetus  with  IUGR  at  term.  For  the  current  pregnancy,  her  weight  and  blood pressure were normal with a body mass index of  30.  At  20  weeks,  the  estimated  fetal  weight  by  ultra- sound  was  at  the  50th  percentile  and  genetic  markers  were  normal.  Follow-up  ultrasound  at  26  weeks  and  4  days showed a normal fetal weight at the 50th percen- tile,  but  by  29  weeks  and  5  days,  the  estimated  fetal  weight decreased to the 25th percentile, at which time  the maternal uterine artery vascular resistance was sig- nificantly  increased  and  the  fetal  umbilical  vascular  resistance  was  normal.  By  32  weeks,  the  fetal  weight  continued  to  decrease  and  both  maternal  uterine  artery and the umbilical artery vascular resistance were  abnormal,  suggesting  that  this  fetus  was  also  going  to  develop  IUGR.  Ultrasonic  measurements  at  34  weeks  and  3  days  showed  continued  poor  growth  and  by  37  weeks 3 days, the fetus was at the 10th percentile. Ante- natal  testing  revealed  an  abnormal  heart  rate  pattern  (loss  of  fetal  heart  rate  variability  and  a  nonreactive  fetal heart rate response to stimulation) and a reduced  amniotic fluid index. The fetus was delivered by cesar- ean  delivery  with  a  birth  weight  of  2652  grams.  Figure  12-1  illustrates  the  three  different  parameters  that  define  how  birth  weight  and  gestational  age  are  used  to detect abnormalities of fetal growth.

As  pregnancy  advances,  the  head  circumference  remains  greater  than  the  abdominal  circumference  until approximately 34 weeks, at which point the ratio  approaches  one  (see  Figure  12-1).  After 34 weeks, the normal pregnancy is associated with an abdominal circumference that is greater than the head circum- ference.  When  asymmetric  growth  restriction  occurs,  usually  in  the  third  trimester,  the  BPD  is  essentially  normal,  whereas  the  ratio  of  head  to  abdominal  cir- cumference  is  abnormal.  With symmetric growth restriction, the head-to-abdominal circumference ratio may be normal,  but  the  absolute  growth  rate  is  decreased,  and  estimated  fetal  weight  is  reduced  (see  Figure 12-1).

From 50-90% of infants with manifestations of IUGR at birth can be identified with serial prenatal

C H A P T E R 12 Obstetric Complications 167

levels is important, because the fetuses do not have adequate hepatic glycogen stores,  and  hypoglycemia  is  a  common  finding.  Furthermore,  hypothermia is not uncommon  in  these  infants.  Respiratory distress syndrome is more common in the presence of fetal distress, because fetal acidosis reduces surfactant syn- thesis and release.

PROGNOSIS The long-term prognosis for infants with IUGR must be  assessed  according  to  the  varied  etiologies  of  the  growth restriction. If infants with chromosomal abnor- malities,  autoimmune  disease,  congenital  anomalies,  and infection are excluded, the short-term outlook for these newborns is generally good. However, poor fetal  growth  in  utero  increases  the  risk  for  chronic  condi- tions  such  as  hypertension  and  diabetes  later  in  life  (see Chapter 1).

Postterm Pregnancy The prolonged or postterm pregnancy is one that per- sists beyond 42 weeks (294 days) from the onset of the  last  normal  menstrual  period.  Estimates of the inci- dence of postterm pregnancy range from 6-12% of all pregnancies.  The  incidence  of  postterm  pregnan- cies  has  been  reduced  significantly  in  the  past  10   years  because  induction  before  42  weeks  has  signifi- cantly reduced fetal morbidity secondary to prolonged  gestation.

Perinatal mortality is two to three times higher in these prolonged gestations. Much of the increased risk  to the fetus and neonate can be attributed to develop- ment  of  the  fetal postmaturity (dysmaturity) syn- drome, which occurs when a growth restricted fetus remains in utero beyond term. Occurring in 20-30% of  postterm pregnancies, this syndrome is related to the aging and infarction of the placenta,  with  resulting  placental insufficiency. Some of these fetuses meet the  criteria  for  having  IUGR  and  should  not  have  been  allowed to advance to term. If there is any evidence of  intrauterine  hypoxia  (such  as  meconium  staining  of  the  umbilical  cord,  fetal  membranes,  skin,  and  nails),  perinatal mortality is even further increased.

The fetus with postmaturity syndrome typically has  loss  of  subcutaneous  fat,  long  fingernails,  dry,  peeling  skin, and abundant hair. The 70-80% of postdate fetuses  not  affected  by  placental  insufficiency  continue  to  grow in utero, many to the point of macrosomia (birth weight greater than 4000 g). Macrosomia often results in abnormal labor, shoulder dystocia, birth trauma, and an increased incidence of cesarean delivery.

ETIOLOGY The cause of postterm pregnancy is unknown in most instances. Prolonged gestation is common in associa- tion with an anencephalic fetus.  This  is  probably 

challenge  test  (OCT)  is  rarely  used  because  its  false- positive rate approaches 50%.

Fetuses clinically suspected of IUGR could be approached as follows: 1.  For  cases  in  which  results  of  fetal  monitoring  are 

normal  and  ultrasonic  findings  strongly  suggest  normal  growth,  no clinical intervention  is  warranted.

2.  When ultrasonic findings strongly suggest IUGR, delivery is indicated at gestational ages of 34 weeks or later only if abnormal fetal surveillance indi- cates an increased risk of fetal death. Pulmonary maturity should normally be documented by amniocentesis.  In  the  presence  of  severe  oligohy- dramnios,  amniocentesis  may  not  be  feasible,  so  delivery  should  be  strongly  considered  without  assessment  of  lung  maturity.  These  fetuses  are   at  great  risk  of  asphyxia,  and  the  stress  associated  with  IUGR  usually  accelerates  fetal  pulmonary  maturity.

3.  For  those  cases  in  which  ultrasonic  findings  are  equivocal for IUGR, bed rest, fetal surveillance, and serial ultrasonic measurements at 3-weekly inter- vals are indicated to avoid preterm delivery Assessment of fetal movements  (kick  counts)  each 

evening  while  resting  comfortably  on  the  left  side  is  a  simple technique whereby a pregnant woman can help  in the assessment of fetal well-being. If 10 movements  are  not  perceived  in  1  hour,  a  biophysical  assessment  should  be  arranged.  Some  providers  instruct  their  patients,  irrespective  of  their  risk,  to  begin  a  fetal  kick  count chart at 28 weeks.

Doppler-derived umbilical artery systolic-to-dia- stolic ratios are abnormal in IUGR fetuses.  Fetuses  with growth restriction tend to have increased vascular  resistance  and  to  demonstrate  low,  absent,  or  reversal  of  diastolic  flow.  This  noninvasive  technique  can  be  used  to  evaluate  high-risk  patients,  and  may  help  in  the  timing  of  delivery  when  used  in  conjunction  with  the  modified  biophysical  profile  (see  Chapter  7  for  more  information  about  Doppler  assessment  of  fetal  well-being).

LABOR AND DELIVERY IUGR per se is not a contraindication to induction of labor,  but  there  should  be  a  low  threshold  to  perform  a cesarean delivery because of the poor capacity of the  IUGR  fetus  to  tolerate  asphyxia.  As  a  result,  during labor, these high-risk patients must be electronically monitored to detect the earliest evidence of fetal distress.

A  combined  obstetric-neonatal  team  approach  to  delivery  is  mandatory  because  of  the  likelihood  of   neonatal asphyxia.

After birth, the infant should be carefully examined  to rule out the possibility of congenital anomalies and  chronic  infections.  The monitoring of blood glucose

PA R T 2 Obstetrics168

Intrapartum Continuous  electronic  fetal  monitoring  must  be  employed  during  the  induction  of  labor.  The  patient  should  be  encouraged  to  lie  on  her  left  side  to  assure  adequate  perfusion  of  the  uterus  and  the fetal mem- branes should be ruptured as early as is feasible so that an internal fetal scalp electrode can be applied and the color of the amniotic fluid assessed. Cesarean  delivery  is  indicated  for  fetal  distress.  It  should  not  be  delayed because of the decreased capacity of the post- term  fetus  to  tolerate  asphyxia  and  the  increased  risk  of meconium aspiration. If meconium is present, neo- natal  asphyxia  should  be  anticipated,  and  a  neonatal  resuscitative team should be present at delivery.

Intrauterine Fetal Demise Intrauterine fetal demise (IUFD) is fetal death after 20 weeks’ gestation but before the onset of labor. It complicates about 1% of pregnancies. With the devel- opment  of  newer  diagnostic  and  therapeutic  modali- ties,  the  management  of  IUFD  has  shifted  from  watchful expectancy to more active intervention.

ETIOLOGY In more than 50% of cases, the etiology of antepartum fetal death is not known or cannot be determined.  Associated causes include IUGR, hypertensive diseases  of  pregnancy,  diabetes  mellitus,  erythroblastosis  fetalis,  umbilical  cord  accidents,  fetal  congenital  anomalies,  fetal  or  maternal  infections,  fetomaternal  hemorrhage, antiphospholipid antibodies, and heredi- tary thrombophilias.

DIAGNOSIS Clinically,  fetal  death  should  be  suspected  when  the  patient  reports  the  absence  of  fetal  movements,  par- ticularly  if  the  uterus  is  small  for  dates,  or  if  the  fetal  heart  tones  are  not  detected  using  a  Doppler  device.  Because the placenta may continue to produce hCG, a  positive pregnancy test does not exclude an IUFD.

Diagnostic confirmation has been greatly facilitated  since  the  advent  of  ultrasonography.  Real-time ultra- sonography confirms the lack of fetal movement and absence of fetal cardiac activity.

MANAGEMENT Fetal  demise  between  14  and  28  weeks  allows  for  two  different approaches: watchful expectancy and induc- tion of labor.

Watchful Expectancy About 80% of patients experience the spontaneous onset of labor within 2 to 3 weeks of fetal demise.  The  patient’s  feeling  of  personal  loss  and  guilt   may  create  significant  anxiety,  and  this  conservative  approach  may  prove  unacceptable.  Thus,  in  general, 

related  to  the  lack  of  a  fetal  labor-initiating  factor   from the fetal adrenals, which are hypoplastic in anen- cephalic  fetuses.  Rarely,  prolonged  gestation  may  be  associated  with  placental sulfatase deficiency  and  extrauterine pregnancy. Paternal genes, as expressed  by the fetus, play a role in the timing of birth.

DIAGNOSIS The diagnosis of postterm pregnancy is often difficult.  The  key  to  appropriate  classification  and  subsequent  successful perinatal management is the accurate dating  of  gestation.  It  is  estimated  that  uncertain dates are present in 20-30% of all pregnancies (see Box 12-2).

MANAGEMENT Antepartum The appropriate management revolves around identi- fying the low percentage of fetuses with postmaturity syndrome that are truly at risk of intrauterine hypoxia  and  fetal  demise. When  biophysical  tests  of  fetal  well- being  are  available,  the  timing  of  delivery  for  each  patient should be individualized. However, if the gesta- tional age is firmly established at 41 weeks, the fetal head is well fixed in the pelvis, and the condition of the cervix is favorable, labor usually should be induced.

The  two  clinical  problems  that  remain  are  (1)  patients with good dates at 42 weeks’ gestation with an  unripe  cervix  and  (2)  patients  with  uncertain  gesta- tional  age  seen  for  the  first  time  with  a  possible  or  probable diagnosis of prolonged pregnancy.

In  the  first  group  of  patients,  a  twice-weekly  NST  and  biophysical  profile  should  be  performed. The  AFI  is  an  important  ultrasonic  measurement  that  should  also be used in the management of these patients. The  AFI is the sum of the vertical dimensions (in centime- ters) of amniotic fluid pockets in each of the four quad- rants  of  the  gestational  sac.  Delivery is indicated if there is any indication of oligohydramnios (AFI < 5) or if spontaneous fetal heart rate decelerations are found on the NST. So long as these parameters of fetal  well-being  are  reassuring,  labor  need  not  be  induced  unless  the  cervical  condition  becomes  favorable,  the  fetus  is  judged  to  be  macrosomic,  or  there  are  other  obstetric indications for delivery.

Some  institutions  begin  weekly  testing  at  40  weeks  to avoid missing the few fetuses that are stressed before  41 weeks. At 41 weeks’ gestation with firm dates, deliv- ery should be initiated by the appropriate route, regardless of other factors,  in  view  of  the  increasing  potential for perinatal morbidity and mortality.

When the patient presents very late for initial assessment but the gestational age is in question and fetal assessment is normal, an expectant approach is often acceptable.  The  risk  of  intervention,  with  the  delivery  of  a  preterm  infant,  must  be  considered. The  woman  herself  can  participate  in  the  fetal  assessment  by doing fetal kick counts during the postterm period.

C H A P T E R 12 Obstetric Complications 169

period of expectant management, along with a hema- tocrit and platelet count.  If  the  fibrinogen  level  is  decreasing, even a “normal” fibrinogen level of 300 mg/ dL may be an early sign of consumptive coagulopathy  in cases of fetal demise. An elevated prothrombin and  partial thromboplastin time, the presence of fibrinogen- fibrin  degradation  products,  and  a  decreased  platelet  count may clarify the diagnosis.

If  laboratory  evidence  of  mild  disseminated   intravascular  coagulation  is  noted  in  the  absence  of  bleeding,  delivery  by  the  most  appropriate  means  is  recommended.  If  the  clotting  defect  is  more  severe  or  if there is evidence of bleeding, blood volume support  or  use  of  component  therapy  (fresh-frozen  plasma)  should be given before any intervention.

FOLLOW-UP A search should be undertaken to determine the cause  of  the  intrauterine  death.  TORCH and parvovirus studies and cultures for Listeria are indicated.  In  addition,  all women with a fetal demise should be tested for the presence of anticardiolipin antibodies. Testing for the hereditary thrombophilias should also be considered. If congenital abnormalities are detected, fetal chromosomal studies and total body radiographs should be done, in addition to a com- plete autopsy.  The  autopsy  report,  when  available,  must  be  discussed  in  detail  with  both  parents.  In  a  stillborn fetus, the best tissue for a chromosomal anal- ysis  is  the  fascia  lata,  obtained  from  the  lateral  aspect  of the thigh. The tissue can be stored in saline or Hanks  solution.  A significant number of cases of IUFD are the result of fetomaternal hemorrhage, which can be  detected  by  identifying  fetal  erythrocytes  in  maternal  blood (Kleihauer-Betke test).

The parents may experience feelings of guilt or anger,  which  may  be  magnified  when  there  is  an  abnormal fetus or genetic defect. Referral to a bereave- ment support group for counseling is advisable.

Subsequent pregnancies in a woman with a history  of IUFD must be managed as high-risk cases.

the  management  of  women  who  fail  to  go  into  labor  spontaneously  is  active  intervention  by  induction  of  labor or dilation and evacuation (D&E).

Induction of Labor Justifications  for  such  an  intervention  include  the  emotional burden  of  carrying  a  dead  fetus  on  the  patient, the slight possibility of chorioamnionitis, and  the  10% risk of disseminated intravascular coagula- tion  when  a  dead  fetus  is  retained  for  more  than  5  weeks in the second or third trimesters.

Vaginal suppositories of prostaglandin E2 (dino- prostone [Prostin E2]) can be used from the 12th to the 28th week of gestation.  Dinoprostone  is  an  effec- tive drug with an overall success rate approaching 97%.  Although  at  least  50%  of  patients  receiving  dinopros- tone experience nausea and vomiting or diarrhea with  temperature elevations, these side effects are transient  and  can  be  minimized  with  premedication  (i.e.,  pro- chlorperazine [Compazine]). There have been reported cases of uterine rupture and cervical lacerations,  but  with  properly  selected  patients,  the  drug  is  safe.  The  maximum  recommended  dose  is  a  20-mg  sup- pository  every  3  hours  until  delivery.  Dinoprostone usage in this range is contraindicated in patients with prior uterine incisions  (e.g.,  cesarean,  myomectomy)  because  of  the  unacceptable  risk  of  uterine  rupture.  Furthermore,  prostaglandins  are  contraindicated  in  patients  with  a  history  of  bronchial  asthma  or  active  pulmonary disease, although the E series act primarily  as  bronchodilators.  Misoprostol (Cytotec, a synthetic prostaglandin E1 analogue)  vaginal  tablets  have  been  found to be quite effective with little or no gastrointes- tinal  side  effects,  and  they  are  less  expensive  than  dinoprostone.

After 28 weeks’ gestation, if the condition of the cervix is favorable for induction and there are no con- traindications, Cytotec followed by oxytocin are the drugs of choice.

Monitoring of Coagulopathy Regardless  of  the  mode  of  therapy  chosen,  weekly fibrinogen levels should be monitored during the

170

13  Multifetal Gestation and Malpresentation

C H

A P

T ER

CALVIN J. HOBEL

■  In the United States and other developed countries, mul- tiple  gestations  have  increased,  and  currently  account  for at least 3.5% of live births. The two major reasons for  this increase have been the use of assisted reproductive  technologies (ARTs) to treat infertility, and the increasing  maternal age of women having children. Twins are twice  as  likely  in  women  over  the  age  of  35.  Complications  of  pregnancy  such  as  preeclampsia,  preterm  birth,  poor  fetal growth, and monochorionicity significantly increase  the risk of perinatal morbidity and mortality in multifetal  gestations.

■  The prognosis and the risk for morbidity are dependent  on zygosity (the genetic makeup of the zygote). Ultraso- nographic  evaluation  of  the  pregnancy  is  helpful  in  determining  zygosity.  Monozygotic  twins  (monochori- onic)  are  more  likely  to  involve  congenital  anomalies,  weight  discordance,  twin-twin  transfusion  syndrome  (TTTS),  and  other  morbidity.  Discordant  fetal  gender  confirms dizygotic (two chorions) gestations and visual- ization  of  a  thick  amnio-chorionic  septum  is  sugges- tive  of  dizygotic  twins.  Confirmation  of  the  zygosity   may  require  detailed  examination  of  the  placenta  at  delivery.

■  There  are  significant  physiologic  adaptations  that  must  occur  with  multiple  gestations.  In  a  normal  pregnancy, 

the  maternal  blood  volume  is  augmented  by  40%  (2 L)  over  the  nonpregnant  baseline,  while  in  multiple  gesta- tions  the  blood  volume  increases  by  3 L  or  more. These  changes  are  associated  with  a  significantly  increased   risk  of  iron  and  folate  deficiency,  and  an  increase  in   preeclampsia,  hypertension,  and  maternal  respiratory  problems such as shortness of breath (dyspnea).

■  Management  of  twin  gestations  during  pregnancy  and  delivery depends upon the type of problems that develop  during  pregnancy  such  as  preterm  labor,  poor  fetal  growth,  hypertensive  disorders,  and  how  the  fetuses  present  at  the  onset  of  labor.  The  key  is  to  establish  a  plan  of  management  that  assures  a  safe  delivery  at  or  near term. Generally, if the first twin (twin A) is in a vertex  position  and  the  delivery  is  by  the  vaginal  route,  it  is  appropriate  to  plan  to  deliver  twin  B  vaginally.  When  twin A is breech, the general consensus is that the birth  of both twins should be by cesarean delivery.

■  Common  malpresentations  include  breech  (the  most  common),  face,  and  brow.  Face  and  brow  presentations  occur in about 1 in 500 and 1 in 1400 deliveries, respec- tively.  Compound  and  shoulder  presentations  are  rare,  and usually are associated with premature births. Persis- tent brow presentations almost always require cesarean  delivery.

CLINICAL KEYS FOR THIS CHAPTER

Multiple  gestations  are  defined  as  any  pregnancy  in  which  two  or  more  embryos  or  fetuses  occupy  the  uterus  simultaneously.  It  is  of  utmost  importance  to  recognize  multiple  gestations  as  a  complication  of  pregnancy.  Because twins deliver at a mean gesta- tional age of about 36 weeks, the perinatal mortality and morbidity for multiple gestations dispropor- tionately exceed that of singleton pregnancies.  Maternal  morbidity  is  also  increased,  because  of  the  additional physiologic stresses associated with two (or  more)  fetuses  and  placentas  and  a  rapidly  enlarging  uterus.

The term malpresentation encompasses any fetal position other than vertex at delivery, and includes breech, face, brow, compound, and shoulder presen- tations.  Both  fetal  and  maternal  factors  contribute  to  the  occurrence  of  a  malpresentation.  The  most  common malpresentation is breech.

Multiple Gestations Multiple gestations include twins, identical and frater- nal, and high-order multiple gestations that consist of  three or more fetuses.

C H A P T E R 13 Multifetal Gestation and Malpresentation 171

Nigeria, twinning occurs in 1 of 22 gestations, whereas  in  the  Native  American  and  Inuit  populations,  twin- ning  is  less  than  one-fifth  of  that  rate. Twins  are  twice  as common in women over 35 as in women at 25 years  of age. Given these statistics, approximately two-thirds of spontaneously conceived twins are fraternal  and  one-third  are  identical  (monozygotic).  However,  in  recent  years,  the  incidence  of  multizygotic  multifetal  gestation has increased markedly with the more wide- spread use of ovulation induction agents and the prac- tice  of  transferring  multiple  embryos  after  in  vitro  fertilization.  The  incidence  of  multiple  gestations  fol- lowing the use of clomiphene is about 6-8% and about  20-30% following gonadotropin therapy.

DETERMINATION OF ZYGOSITY The  prognosis  and  expected  morbidity  of  twins  is  strongly  dependent  on  zygosity:  monozygotic twins are more likely to have congenital anomalies, weight discordance, twin-twin transfusion syndrome, neurologic morbidity, premature delivery, and fetal death.  Thus,  determination of zygosity is the most important next step after multifetal pregnancy has been first diagnosed.

Ultrasonographic evaluation of the pregnancy is frequently very helpful in determining zygosity.  Imaging of discordant fetal gender confirms a dizygotic  gestation.  Visualization  of  a  thick  amnion-chorionic  septum is suggestive of dizygotic twins, as is the pres- ence  of  a  “peak”  or  inverted  “V”  at  the  base  of  the  membrane  septum  (Figure  13-2,  A).  Conversely,  in  a  monochorionic  gestation,  the  dividing  membrane  is  fairly thin (see Figure 13-2, B). Because an early embry- onic split can infrequently result in dichorionic, diam- niotic twins with separate placentas, these findings are  not  definitive.  Similarly,  in  rare  cases  of  postzygotic  genetic  events,  monochorionic  twins  may  be  gender  discordant. Thus, definitive diagnosis of zygosity may require detailed examination of the placenta after delivery. Thirty percent of twins will be of different sex  and  are,  therefore,  dizygotic.  Twenty-three  percent  have  monochorionic  placentas  and  are,  therefore,  monozygotic.  Twenty-seven  percent  will  have  the  same  sex,  dichorionic  placentas,  but  different  blood  groupings,  and  must  be,  therefore,  dizygotic.  Twenty percent will have the same sex, dichorionic placentas, and identical blood groupings. For the latter group, further studies, such as human leukocyte antigen (HLA) typing or DNA analysis, will be required to allow determination of zygosity.

ABNORMALITIES OF THE TWINNING PROCESS Among  monozygotic  multiple  gestations,  abnormali- ties in the twinning process are relatively common and  include conjoined twins, interplacental vascular anas- tomoses, twin-twin transfusion syndrome (TTTS), fetal  malformations, and umbilical cord abnormalities.

ETIOLOGY AND CLASSIFICATION OF TWINNING Multiple  gestations  occur  either  as  the  result  of  the  splitting  of  an  embryo  (i.e.,  identical or monozygotic twinning) or the fertilization of two or more eggs pro- duced  in  a  single  menstrual  cycle  (i.e.,  fraternal or dizygotic twinning).  Because  dizygotic twins  arise  from separate eggs, they are structurally distinct preg- nancies coexisting in a single uterus, each with its own  amnion,  chorion,  and  placenta.  Monozygotic twins  arise from cleavage of a single fertilized egg at various  stages  during  embryogenesis,  and  thus  the  arrange- ment of the fetal membranes and placentas will depend  on the time at which the embryo divides (Table 13-1).  The  earlier  the  embryo  splits,  the  more  separate  the  membranes  and  placentas  will  be.  If  division  occurs  within the first 72 hours of fertilization, the membranes  will  be  diamniotic, dichorionic  with  a  thick,  four- layered intervening membrane. If division occurs after  4  to  8  days  of  development,  when  the  chorion  has  already formed, monochorionic, diamniotic twins will  evolve  with  a  thin,  two-layered  septum.  If  splitting  occurs  after  8  days,  when  both  amnion  and  chorion  have already formed, the result will be monochorionic, monoamniotic, twins  residing  in  a  single  sac  with  no  septum. Of all monozygotic twins, 30% are dichorionic,  diamniotic,  and  69%  are  monochorionic,  diamniotic.  Only  1%  of  twins  are  monoamnionic.  Because  twins  share  a  sac  in  this  type,  without  an  intervening  mem- brane, the risk of umbilical cord entanglement is high,  resulting in a net mortality in these twins of almost 50%  (Figure 13-1).

INCIDENCE AND EPIDEMIOLOGY Twins  account  for  approximately  3.5%  of  all  births  in  the United States. The frequency of monozygotic twin- ning,  which  depends  on  a  very  infrequent  biologic  event (embryo splitting), is constant in all populations  studied  at  about  1  in  250  births.  However,  the fre- quency of dizygotic twinning, which arises from mul- tiple ovulations in the mother, is strongly influenced by family history, ethnicity, and maternal age. A family  history  of  dizygotic  but  not  monozygotic  twins  in  the  maternal  pedigree  increases  the  likelihood  of  dizy- gotic  twinning  in  subsequent  generations.  In  western 

TABLE 13-1

THE RELATIONSHIP BETWEEN THE TIMING OF CLEAVAGE AND THE NATURE OF THE MEMBRANES IN TWIN GESTATIONS

Time of Cleavage* Nature of Membranes

0-72 hr Diamniotic, dichorionic

4-8 days Diamniotic, monochorionic

9-12 days Monoamniotic, monochorionic

*Time interval between ovulation and cleavage of the egg.

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more.  The  most  common  type  is  arterial-arterial,  fol- lowed  by  arterial-venous  and  then  venous-venous.  Vascular communications between the two fetuses via the placenta may give rise to a number of prob- lems, including abortion, hydramnios, TTTS, and fetal malformations.  Overall,  the  incidence  of  both  minor and major congenital malformations in twins is  twice  that  of  singletons,  with  the  greater  incidence  of  malformations occurring in monochorionic twins.

Twin-Twin Transfusion Syndrome The  presence  of  unbalanced  anastomoses  in  the  pla- centa  (typically  arterial-venous  connections)  leads  to  a  syndrome in which the circulation of one twin perfuses  that  of  the  other  (i.e.,  TTTS)  in  approximately  10% of monozygotic twins.  In  this  syndrome,  arterial  blood  from the “donor twin” enters the placenta (via the umbil- ical  artery)  and  is  taken  up  by  the  umbilical  venous  system belonging to the “recipient twin,” which results in  a net transfer of blood from the “donor” to the recipient 

Conjoined Twins If division of the embryo occurs very late (13 days, after  the  embryonic  disc  has  completely  formed),  cleavage  of  the  embryo  will  be  incomplete,  resulting  in  con- joined twins.  Fortunately,  this  is  a  very  rare  event,  occurring  once in 70,000 deliveries.  Conjoined  twins  are  classified  according  to  the  anatomic  location  of   the  incomplete  splitting:  thoracopagus  (anterior),  pygopagus  (posterior),  craniopagus  (cephalic),  or ischiopagus  (caudal).  The  majority  of  such  twins  are  thoracopagus.  Delivery  of  conjoined  twins  frequently  requires  cesarean  delivery,  but  postnatally,  these  ges- tations  have  a  surprisingly  optimistic  prognosis  in  many  cases.  More  advanced  contemporary  imaging  has allowed detailed mapping of the shared organs and  more successful surgical separations.

Interplacental Vascular Anastomoses Interplacental  vascular  anastomoses  occur  almost  exclusively in monochorionic twins at a rate of 90% or 

FIGURE 13-1 Diagrammatic representation of the major types of twin placentas found with monozygotic twins. (Redrawn from Benirschke K, Driscoll SG: Pathology of the human placenta, New York, 1974, Springer-Verlag, p 263.)

Diamniotic Dichorionic

(fused)

MONOCHORIONIC TWIN PLACENTATION DICHORIONIC TWIN PLACENTATION

Monoamniotic Monochorionic

(conjoined twins, with one cord)

Diamniotic Dichorionic

(separated )

Monoamniotic Monochorionic

(forked cord)

Diamniotic Monochorionic

Monoamniotic Monochorionic

C H A P T E R 13 Multifetal Gestation and Malpresentation 173

Given the poor prognosis of untreated TTTS (approx- imately  50%  survival  of  any  twin),  treatment with either serial amniocenteses with fluid reduction from the recipient twin’s sac, or laser photocoagulation of the anastomotic vessels on the surface of the placenta,  are performed in specialized centers.

Fetal Malformations Arterial-arterial  placental  anastomoses  can  result  in  fetal  structural  malformations.  In  this  situation,  the  arterial  blood  from  the  donor  twin  enters  the  arterial  circulation  of  the  recipient  twin,  and  the  reversed  blood flow may cause thrombosis within critical organs  or  atresias  due  to  trophoblastic  embolization.  The  recipient  twin,  being  perfused  in  a  reverse  direction  with relatively poorly oxygenated blood, fails to develop  normally.  This  so-called  acardiac twin  typically  has  aplastic  and/or  dysmorphic  anatomical  development  cephalad  of  the  abdomen,  but  often  has  fully  formed  lower extremities.

Umbilical Cord Abnormalities Abnormalities of the umbilical cord occur with a higher  frequency  in  twins  and  are  primarily  associated  with  monochorionic twins. Absence of one umbilical artery  occurs in about 3-4% of twins, as opposed to 0.5-1% of  singletons. The absence of one umbilical artery is sig- nificant because in 30% of such cases, it is associated with other congenital anomalies (e.g., renal agene- sis).  Marginal  and  velamentous  umbilical  cord  inser- tions  also  occur  more  frequently  in  twins  and  may  cause  growth  abnormalities,  particularly  in  the  third  trimester.

twin.  Fetal complications include hypovolemia, hypo- tension, anemia, oligohydramnios, and growth restric- tion in the donor twin, and hypervolemia, hydramnios, hyperviscosity, thrombosis, hypertension, cardiomeg- aly, polycythemia, edema, and congestive heart failure in the recipient twin.  Both  twins  are  at  risk  of  demise  from the circulatory derangement, and the pregnancy is  predisposed to preterm delivery due to overdistention of  the uterus with hydramnios.

Twin  to  twin  transfusion  is  diagnosed  using  ultra- sound.  Typically,  the  donor  twin  is  smaller  and  may  have  oligohydramnios,  absent  bladder,  and  anemia.  The  recipient  twin,  on  the  other  hand,  is  larger  with  possible polyhydramnios, cardiomegaly, and ascites or  hydrops (Figure 13-3).

FIGURE 13-2 A, Real-time ultrasound with a thick vertical amnion- chorion septum (membrane) separating one twin (left side) from the second twin on the right. The arrow (right) points to a “peak” or “inverted V” suggesting dizygotic twins. B, Ultrasound of a thin verti- cal membrane separating one twin on the left side from the second twin on the right suggesting a monochorionic gestational sack. ANT PLAC, Anterior placenta; TRV, transverse view of membrane.

B

ANT PLAC

A

Membrane TRV

FIGURE 13-3 Ultrasound of a twin-twin transfusion syndrome with one twin (upper left) in an amniotic cavity with a reduced fluid volume and a membrane separating this fetus from the second twin in an amniotic cavity with an excessive amount of fluid (right and lower half of scan image). ANT PLAC, Anterior placenta; MEMB, mem- brane (amnion); PCI, placental cord insertion; SAG, sagittal view.

ANT PLAC SAG PCI

MEMB PCI

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First and Second Trimesters Between  16  and  22  weeks,  the  patient  is  seen  every   2  weeks  for  ultrasonic  cervical  length  assessment,  because  incompetent cervix is more common with multiple gestations. A suture (cerclage) can be placed  in  the  cervix  if  marked  shortening  is  noted  in  the  absence of contractions, though the benefit of a cervi- cal cerclage has been under scrutiny recently and is the  subject  of  multiple  clinical  studies  with  conflicting  findings. Adequacy of maternal diet is assessed due to  the  increased  need  for  overall  calories,  iron,  vitamins,  and  folate.  The  Institute  of  Medicine  (IOM)  recom- mends women with twins gain a total of 16.0 to 20.5 kg  (35  to  45 lb)  during  the  pregnancy.  However,  optimal weight gain is somewhat dependent on prepregnancy maternal body mass index (BMI),  because  obese  women  (BMI  >  30)  have  better  outcomes  with  less  weight  gain  than  women  who  are  of  normal  weight  before pregnancy.

Third Trimester During the third trimester, prevention of prematurity is of utmost importance.  The  cervix  is  monitored  closely with ultrasonic measurements for early efface- ment  and  dilation  that  may  precede  frank  premature  labor.  A  cervical  length  less  than  25 mm  at  24  to  28  weeks  is  associated  with  a  doubling  of  the  risk  of  pre- mature  birth.  Interventions  to  prolong  the  length  of  twin pregnancy, such as bed rest, serial uterine activity  monitoring,  hospitalization,  and  prophylactic  vaginal  progesterone, have been carried out but have not been 

Retained Dead Fetus Syndrome It is not unusual for one twin to die in utero remote from term, whereas the remaining twin and the preg- nancy  continue  to  be  viable.  Over  time  (after  3  weeks  or  more  in  pregnancies  that  have  progressed  beyond  20  weeks),  the  retained dead fetus syndrome can develop, which involves disseminated intravascular coagulopathy in the mother as a result of the transfer  of  nonviable  fetal  material  with  thromboplastin-like  activity into the maternal circulation. In such cases, the  maternal  platelet  count  and  fibrinogen  levels  should  be  checked  once  a  week  to  identify  possible  coagula- tion  abnormalities. The  dead  fetus  will  be  reabsorbed  if the demise occurs before 12 weeks’ gestation. Beyond  this time, the fetus will shrink and become dehydrated  and flattened (fetus papyraceus).

ALTERED MATERNAL PHYSIOLOGIC ADAPTATION WITH MULTIPLE FETUSES A number of normal maternal physiologic responses to  pregnancy  are  exaggerated  with  multiple  gestations.  Whereas in normal pregnancy, maternal blood volume  is augmented by 40% (2 L over the nonpregnant base- line),  in  twins  this  increase  may  be  3 L  or  more.  The increased blood volume and demand for iron and folate increase the risk of anemia in the mother  and  make  the  patient  less  able  to  tolerate  the  stresses  of  infection,  labor,  and  premature  labor.  Preeclampsia and gestational hypertension are almost doubled in multifetal gestation. The increased uterine size associ- ated with multiple fetuses can cause maternal respira- tory embarrassment, orthostatic hypotension due to compression of the vena cava, and compromised renal function due to compression of the ureters.

DIAGNOSIS Historical  factors  such  as  a  maternal  family  history  of  dizygotic twinning, the use of fertility drugs, a maternal  sensation of feeling larger than with previous pregnan- cies, or a sensation of excessive fetal movements should  raise  the  suspicion  of  twins.  Physical  signs,  including  excessive weight gain, excessive uterine fundal growth,  and  auscultation  of  fetal  hearts  in  separate  quadrants  of  the  uterus  are  suggestive  but  not  diagnostic.  An  obstetric ultrasound should be performed when a mul- tiple gestation is suspected. The diagnosis of multiple gestations requires a sonographic examination dem- onstrating two separate fetuses and heart activities, and can be made as early as 6 weeks’ gestation.

ANTEPARTUM MANAGEMENT Because  of  the  high  risk  of  preterm  birth,  intensive  antepartum management schemes should be directed  at prolonging gestation and increasing birth weight, in  order  to  decrease  perinatal  morbidity  and  mortality.  The complications of multiple gestations are shown in  Box 13-1.

BOX 13-1

COMPLICATIONS OF MULTIPLE GESTATIONS

Maternal Anemia Hydramnios Hypertension Premature labor Postpartum uterine atony Postpartum hemorrhage Preeclampsia Cesarean delivery

Fetal Malpresentation Placenta previa Abruptio placentae Premature rupture of the membranes Prematurity Umbilical cord prolapse Intrauterine growth restriction Congenital anomalies Increased perinatal morbidity Increased perinatal mortality

C H A P T E R 13 Multifetal Gestation and Malpresentation 175

Vertex (twin A)-vertex (twin B) occurs 50% of the time,  followed  by  vertex-breech,  breech-vertex,  and  breech-breech.

Vertex-vertex twins are managed similarly to a singleton vertex presentation.  Both  fetal  heart  rates  should be monitored continuously during labor (Figure  13-4). Oxytocin (Pitocin) can be used to manage hypo- tonic  contractions.  After  delivery  of  the  first  twin,  the  cord is clamped (identified as twin A) and cut, but cord  blood samples are not obtained until the second fetus  has  been  delivered  to  prevent  potential  hemorrhage  from  the  undelivered  fetus  through  placental  vascular  anastomoses. A vaginal examination is then performed  to  assess  the  presentation  and  station  of  the  second  twin. If the second twin is still in a vertex presentation,  spontaneous delivery is expected. If necessary, forceps  or  vacuum  can  be  used  to  assist  delivery  of  a  vertex  second twin. Because the second twin is at increased risk of cord prolapse, abruptio placentae, and mal- presentation, careful attention to fetal heart moni- toring is necessary.

After  delivery  of  the  second  fetus,  the  cord  blood  samples  can  be  obtained  and  the  placenta  delivered.  Care  should  be  taken  not  to  disrupt  the  fetal  mem- branes,  as  these  will  often  reveal  the  zygosity  of  the  twins. Following delivery of the placenta, uterine tone  should be closely monitored, as the incidence of post- partum atony and hemorrhage is increased in multiple  gestations.  See  Chapter  10  for  the  prevention  of  post- partum hemorrhage.

consistently shown to prolong gestation. Nevertheless,  most  experts  utilize  a  combination  of  these  therapies,  individualized for the patient’s circumstances.

Discordant fetal growth,  which  is  signified  by  one  fetus flattening its growth rate, is a cause of morbidity  and mortality. Fetal growth is monitored by ultrasound  every  4  to  6  weeks  beginning  at  24  weeks,  with  addi- tional fetal surveillance (e.g., biophysical testing, non- stress  fetal  heart  rate  assessment)  when  fetal  growth  falls  below  the  normal  curve.  The patient should be monitored closely for signs of preeclampsia,  includ- ing the development of nondependent edema, urinary  protein, and rising arterial blood pressure.

Because  twins  experience  higher  rates  of  stillbirth  and growth restriction than singletons, fetal well-being should be confirmed at least weekly by nonstress testing (NST) or biophysical profile (BPP) assessment from 36 weeks onward, and earlier in the presence of  complications  such  as  intrauterine  growth  restriction  (IUGR),  discordant  growth,  hypertension,  or  polyhy- dramnios.  Umbilical  artery  Doppler  assessment  of  fetal well-being is helpful to help determine the timing  of delivery to prevent fetal demise if the fetus has IUGR  (see  Chapter  7).  The contraction stress test (CST) should not be used,  because  these  pregnancies  are  already predisposed to preterm labor.

Intrapartum Management TREATMENT OF PRETERM LABOR The treatment of preterm labor is discussed elsewhere  (see Chapter 12), but multiple gestations present special  challenges.  Relative contraindications to tocolysis in these pregnancies include a gestational age of 34 weeks or more, growth failure of one or more fetuses, concerning fetal status on biophysical moni- toring, and preeclampsia.  Aggressive  tocolysis  typi- cally involves use of agents with adverse cardiovascular  effects in the mother, such as β-mimetics, magnesium  sulfate,  and  calcium  channel  blockers.  These  agents,  particularly when combined with antenatal corticoste- roid  therapy,  have  been  associated  with  maternal  volume overload and congestive heart failure. Box 13-2  provides  a  list  of  necessary  prerequisites  for  the  man- agement  of  labor  in  pregnancies  complicated  by  mul- tiple gestations.

In the special case of monoamniotic twins, birth by cesarean delivery is usually accomplished by 34 to 36 weeks because of the increased risk of lethal cord entanglement. For diamniotic twin pregnancies,  delivery management is outlined below.

VERTEX-VERTEX PRESENTATIONS To  choose  the  safest  route  of  delivery  for  mother  and  babies, the presentations of the fetuses must be accu- rately  known.  By  convention,  the  presenting  twin  is  designated  as  twin  A  and  the  second  twin  as  twin  B. 

BOX 13-2

PREREQUISITES FOR THE INTRAPARTUM MANAGEMENT OF MULTIPLE GESTATIONS

A secondary or tertiary care center A  delivery  room  equipped  for  immediate  cesarean  deliv-

ery, if necessary A  well-functioning  large-bore  intravenous  line  (e.g., 

16-gauge) for rapid administration of fluids and blood Blood available for transfusion The  capability  to  continuously  monitor  the  fetal  heart 

rates simultaneously An  anesthesiologist  who  is  immediately  available  to 

administer  general  anesthesia  should  intrauterine  manipulation  or  cesarean  delivery  be  necessary  for  delivery of the second twin

Two  obstetricians  scrubbed  and  gowned  for  the  delivery,  one  of  whom  is  skilled  in  intrauterine  manipulation  and delivery of the second twin

Imaging techniques (i.e., sonography) for determining the  precise presentations of the twins

Two pediatricians, one of whom is skilled in the immedi- ate resuscitation of the newborn

An appropriate number of nurses to assist in the delivery  and care of the newborn infants

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BOX 13-3

CAUSES OF PERINATAL MORBIDITY AND MORTALITY IN TWINS

Respiratory distress syndrome Birth trauma Cerebral hemorrhage Birth asphyxia Birth anoxia Congenital anomalies Stillbirths Prematurity

FIGURE 13-4 A fetal heart rate (FHR) tracing of a twin gestation. One twin (dark tracing) has accelerations of FHR more marked than those of the second twin (lighter tracing). Both degrees of accelerations indicate a state of “fetal well-being” for both twins.

12 10 8 6 4 2 0 kPa

12 10 8 6 4 2 0 kPa

100

75

50

25

UA 0 mmHg

100

75

50

25

UA 0 mmHg

210

180

150

120

90

60

30

FHR 240 bpm

210

180

150

120

90

60

30

FHR 240 bpm

MANAGEMENT OF OTHER PRESENTATIONS Increased  risk  of  fetal  injury  exists  with  delivery  of  a  breech  fetus.  For  this  reason,  breech-breech and breech-vertex twins are usually delivered by cesarean delivery.  When  delivery  of  vertex-breech  or  vertex- transverse twins is contemplated, informed consent by  the  mother  and  the  skill  of  the  obstetrician  are  deter- mining  factors  in  choosing  between  cesarean  and  vaginal delivery. Although there is presently no scien- tific evidence that cesarean delivery is superior for the vertex-breech presentation, difficulty in extract- ing the breech second twin can result in umbilical cord prolapse, head entrapment, neck injury, and asphyxia.  Unless  the  obstetrician  is  comfortable  with  managing  these  problems,  planned  cesarean  is  the  only reasonable choice.

PERINATAL OUTCOME The high perinatal mortality rate in twin gestations  (30 to 50 per 1000 births), approximately five times that  in  singleton  gestations,  is largely attributable to pre- maturity and congenital anomalies  (Box  13-3).  Birth  asphyxia  is  also  a  significant  factor,  and  thus  it  is  not 

surprising  that  second  twins  have  twice  the  perinatal  mortality  of  first-born  twins.  Compared with single- tons, death from complications of birth trauma (with both cesarean and vaginal routes) is four times more frequent with second-born twins and twice as fre- quent with first-born twins.  Congenital  anomalies  and stillbirths account for about a third of the perinatal  mortality rate. Stillbirths occur twice as frequently in twins as in singletons. Cerebral hemorrhage, asphyxia,  and anoxia account for one-tenth of the overall perina- tal mortality rate.

Twin gestations experience a fourfold increase in cerebral palsy.  The  increased  morbidity  in  multiple  gestations is related to placental and anatomic abnor- malities, and trauma associated with the delivery. Low birth weight  (mean  birth  weight  in  twins  is  2395  vs.  3377 g  for  singletons),  prematurity, and IUGR may predispose to permanent brain injury. Postnatally, twins on average are shorter and lighter than single- tons of similar birth weight until 4 years of age.

MULTIPLE GESTATIONS WITH MORE THAN TWO FETUSES Although higher order multiple gestations (triplets and  higher) can result from embryo splitting and polyovu- lation,  the most frequent cause today is iatrogenic from the use of ovulation induction agents. The inci- dence  of  spontaneous  triplets  is  1  in  8000  and  that  of  spontaneous quadruplets 1 in 700,000 births. However,  because of the widespread use of assisted reproductive  technologies,  the  current  estimate  of  the  incidence  of  triplets  is  1  in  3000  births. This  rate  has  tripled  in  the  last  two  decades.  Recently advanced treatment for infertility, such as in vitro fertilization (IVF) has been focused on a reduction in multiple births. There  has  been  a  significant  decrease  in  twins  and  higher  order  multiple births from IVF as a result of embryo freezing 

C H A P T E R 13 Multifetal Gestation and Malpresentation 177

Etiology The major factor predisposing to breech presentation is prematurity.  Approximately  20-30%  of  all  singleton  breeches  are  of  low  birth  weight  (<2500 g).  However,  fetal  structural  anomalies  (e.g.,  hydrocephalus)  may  restrict the ability of the fetus to present as a vertex. In  breech  presentations,  the  incidence  of  structural  anomalies is greater than 6%, or two to three times that  of  a  vertex.  Other etiologic factors include uterine anomalies  (e.g.,  bicornuate  uterus),  multiple gesta- tion, placenta previa, hydramnios, contracted mater- nal pelvis, and pelvic tumors  that  obstruct  the  birth  canal.

Classification There  are  three  types  of  breech  presentation:  frank, complete, and incomplete or footling  (Figure  13-5).  Frank breech occurs when both fetal thighs are flexed  and  both  lower  extremities  are  extended  at  the  knees.  A complete breech  has  both  thighs  flexed  and  one  or  both  knees  flexed  (sitting  in  a  “squat”  position).  An incomplete (or footling) breech has one or both thighs  extended and one or both knees or feet lying below the  buttocks. At term, 65% of breech fetuses are frank, 25%  are complete, and 10% are incomplete.

Diagnosis The  diagnosis  of  breech  presentation  can  often  be  made by the Leopold examination (see Chapter 8), in  which  the  firm  fetal  head  is  palpated  in  the  fundal  region  and  the  softer,  smaller  breech  occupies  the  lower  uterine  segment  above  the  symphysis  pubis.  In  a frank breech in labor, the fetal buttocks, anus, sacrum,  and  ischial  tuberosities  can  be  palpated  on  vaginal 

at  the  blastocyst  stage  (day  5)  and  elective  single  embryo transfer.

Prematurity increases as the number of fetuses increases. The  average  length  of  gestation  is  33  weeks  for  triplets  but  only  29  weeks  for  quadruplets,  with  mean birth weights 1818 and 1395 g, respectively. The- oretically, delivery of higher order multiples can follow  the  principles  outlined  above  for  twins.  However,  in  contemporary practice, almost all high order multiples  are  delivered  by  cesarean  delivery  to  decrease  the  risk  of morbidity in these very premature pregnancies. The perinatal mortality rate for triplets and quadruplets is 50 to 100 per 1000 births, a rate that is twice that of twins.

Fetal Malpresentation Malpresentations of the fetus in utero include breech,  face,  and  brow  presentations,  with  breech  the  most  common and face and brow occurring in about 1 in 500  and  1  in  1400  deliveries,  respectively.  Compound  and  shoulder presentations are rare, and usually associated  with premature births.

BREECH PRESENTATION Breech presentation occurs when the fetal buttocks or  lower extremities present into the maternal pelvis. The incidence of breech presentation is 4% of all deliver- ies. Before 28 weeks, approximately 25% of fetuses are  presenting as a breech. As the fetus grows and occupies  more of the uterus, it tends to assume a vertex presen- tation to accommodate best to the confines and shape  of the uterus. By 34 weeks’ gestation, most fetuses have  assumed the vertex presentation position.

FIGURE 13-5 Types of breech presentation.

Complete Frank Footling

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Once  the  fetus  has  delivered  spontaneously  to  the  umbilicus (Figure 13-6, A), gentle downward traction is  exerted  until  the  scapulae  appear  at  the  introitus  (see  Figure  13-6,  B).  After  delivery  of  the  scapulae,  the  shoulders  are  delivered  by  sweeping  each  arm  in  turn  across the fetal chest until only the fetal head remains  undelivered  (see  Figure  13-6,  C).  Once  the  shoulders  have  been  delivered,  the  head  is  delivered  by  manual  flexion of the fetal head with one hand flexing the head  at the base of the skull while the operator’s other hand  is applied to the fetal maxilla for downward flexion (see  Figure  13-6,  D).  Some  obstetricians  use  Piper  forceps  routinely  because  this  method  has  been  shown  to  result in delivery of the head with the least amount of  trauma to the fetus (see Figure 13-6, E).

Cesarean Delivery During  the  process  of  breech  vaginal  delivery,  succes- sively  larger  parts  of  the  fetus  deliver,  with  the  largest  part, the fetal head, delivering last. In the very prema- ture  infant,  the  abdomen  is  much  smaller  than  the  head,  so  the  lower  extremities,  abdomen,  and  trunk  may  deliver  through  an  incompletely  dilated  cervix,  leaving  the  fetal  head  trapped. This  can  result  in  fetal  asphyxia and birth trauma. Premature breech fetuses are thus preferentially delivered by cesarean delivery because of the head-abdominal size disparity. Cesar- ean delivery is currently preferred for both preterm and  term  breech  infants,  although  significant  trauma  can  still occur if care is not taken with delivery of the arms  and head.

Complications and Outcome Even with optimal management, the perinatal mortal- ity  of  breech  fetuses  is  approximately  25  per  1000   live  births  versus  12  to  16  per  1000  for  nonbreech 

examination. With a complete breech, the feet, ankles,  and often the buttocks are palpable through the dilated  cervix.  Vaginal  examination  of  an  incomplete  breech  reveals  one  or  both  fetal  feet,  but  ultrasound  may  be  required for definitive diagnosis.

Pregnancy Management EXCLUDE FETAL AND UTERINE ANOMALIES. If breech pre- sentation  is  suspected  after  34  weeks,  the  prenatal  records  and  any  prior  ultrasonic  examinations  should  be  reviewed  for  the  presence  of  uterine  myomata,  a  müllerian  anomaly,  or  fetal  structural  abnormality.  If  suspicious,  a  thorough  ultrasonic  examination  should  be performed.

EXTERNAL CEPHALIC VERSION. External cephalic version  (ECV )  is  a  procedure  in  which  the  obstetrician  manu- ally  converts  the  breech  fetus  to  a  vertex  presentation  via  external  uterine  manipulation  under  ultrasonic  guidance. ECV may be considered in a breech presen- tation at term before the onset of labor. Version is not carried out before 36 to 37 weeks’ gestation  because  of the tendency for the premature fetus to revert spon- taneously  to  a  breech  presentation.  The  procedure  must  be  carried  out  in  a  hospital  that  is  equipped  to  perform  an  emergency  cesarean  delivery  because  of  the small risk of placental abruption or cord compres- sion.  The  patient  should  have  an  intravenous  access,  and should have nothing by mouth for 8 hours before  the  version  attempt  in  case  emergency  delivery  is   necessary.  Evidence of uteroplacental insufficiency, placenta previa, nonreassuring fetal monitoring, hypertension, intrauterine growth restriction, oligo- hydramnios, or a history of previous uterine surgery are contraindications to external cephalic version.  The  immediate  success  rate  of  external  version  is  35-76%. Though  ECV  has  been  shown  to  decrease  the  rate  of  cesarean  delivery,  perinatal  mortality  rate  has  not  been  affected  by  this  procedure.  Only  2%  of  suc- cessful term versions revert to breech.

Labor Management VAGINAL DELIVERY. Until  the  publication  of  random- ized  trials  demonstrating  that  vaginal  breech  delivery  was associated with increased perinatal mortality com- pared with planned cesarean, vaginal breech deliveries  were  performed  in  selected  centers  in  patients  who  met  strict  criteria.  These  criteria  are  summarized  in  Box 13-4. The standard of care now in most practices is to deliver all breeches by cesarean  to  avoid  the  potential morbidities of umbilical cord prolapse, head  entrapment, birth asphyxia, and birth trauma.

ASSISTED BREECH DELIVERY. Because the breech presen- tation can present in a setting in which cesarean deliv- ery  is  impossible  or  unsafe,  vaginal  delivery  of  the  breech continues to be an important practitioner skill. 

*Inlet: anteroposterior (AP) diameter ≥11.0 cm; transverse diameter ≥10.0 cm. Midpelvis: AP ≥11.5 cm, transverse diameter ≥10.0 cm.

BOX 13-4

CRITERIA FOR VAGINAL DELIVERY OF A BREECH PRESENTATION

Fetus  must  be  in  a  frank  or  complete  breech  presentation.

Gestational age should be at least 36 weeks. Estimated fetal weight should be between 2500 and 3800 g. Fetal head must be flexed. Maternal  pelvis  must  be  adequately  large,  as  assessed  by 

x-ray  pelvimetry*  or  tested  by  prior  delivery  of  a  rea- sonably large baby.

There  must  be  no  other  maternal  or  fetal  indication  for  cesarean delivery.

Anesthesiologist must be in attendance. Obstetrician must be experienced. Assistant must be scrubbed and prepared to guide the fetal 

head into the pelvis.

C H A P T E R 13 Multifetal Gestation and Malpresentation 179

A B

C

FIGURE 13-6 Partial breech extraction. A, After spontaneous deliv- ery to the umbilicus, traction is applied to the infant’s pelvis. When the scapulae are visible, rotation of the trunk allows delivery of the anterior shoulder. B, Delivery of the anterior shoulder by downward traction. C, Delivery of the posterior shoulder by upward traction. The posterior arm is freed digitally by splinting the fetal humerus (inset).

Continued

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FACE PRESENTATION Face presentation occurs when the fetal head is hyper- extended such that the fetal face, between the chin and  orbits, is the presenting part. The incidence is about 1 in 500 deliveries.

Etiology The  etiology  of  face  presentation  is  somewhat  enig- matic. During normal vertex delivery, the fetal head is  markedly  flexed,  with  the  fetal  occiput  as  the  leading  part.  Factors  that  permit  the  fetus  to  enter  the  pelvis 

fetuses. When prematurity and multiple gestations are  excluded,  the  perinatal  mortality  for  breech  fetuses  is  still significantly higher than for vertex fetuses. Factors that contribute to increased perinatal morbidity and mortality include lethal congenital anomalies, pre- maturity, birth trauma, and asphyxia.  Asphyxia  typi- cally results from umbilical cord prolapse during labor  or  entrapment  of  the  aftercoming  head.  Birth  trauma  can occur whenever forceful traction is exerted on the  fetus  and  can  involve  the  brachial  plexus  (Erb palsy),  pharynx, and liver.

D

E

D, Delivery of the after coming head using the Mauriceau-Smellie-Veit maneuver. Ab - dominal pressure is applied to main- tain flexion of the fetal head. E, Delivery of the after coming head using Piper forceps.

FIGURE 13-6, cont’d

C H A P T E R 13 Multifetal Gestation and Malpresentation 181

fetal head will be unable to extend farther to com- plete the expulsive process.  Thus,  mentum  posterior  cases  and  those  with  persistent  mentum  transverse  must  be  delivered  by  cesarean  delivery.  Because  final  rotation from mentum transverse may occur only after  a  significant  period  of  maternal  pushing,  patience  is  necessary.  Approximately  half  of  the  mentoposterior  and  mentotransverse  presentations  spontaneously  rotate to a mentoanterior position. When spontaneous  vaginal  delivery  (Figure  13-7)  or  low  forceps  delivery  occurs (Figure 13-8), perinatal morbidity and mortality  for  face  presentations  are  similar  to  those  for  vertex  presentations.

Other Presentations Brow presentation occurs when the presenting part of  the fetus is between the facial orbits and anterior fon- tanelle  (Figure  13-9).  This  type  of  presentation  arises   as the result of extension of the fetal head such that it  is  midway  between  flexion  (vertex  presentation)  and  hyperextension  (face  presentation).  The incidence is about 1 in 1400 deliveries. With a brow presentation, the presenting diameter is the supraoccipitomental diameter,  which  is  much  longer  than  the  presenting  diameter for a face or a vertex presentation.

The intrapartum management is expectant, because  the  brow  presentation  is  an  unstable  one.  Fifty  to  75  percent  will  convert  to  either  a  face  presentation,  through  extension,  or  a  vertex  presentation,  through 

FIGURE 13-7 Spontaneous delivery of a mentum anterior face presentation. Note the flexion of the head under the symphysis pubis. The chin appears first, followed by the nose, brow, vertex, and occiput.

with  a  markedly  extended  head  include  extreme  pre- maturity, high maternal parity, and congenital anoma- lies  such  as  fetal  goiter.  In  the  majority  of  cases,  no  etiologic factor is evident.

Diagnosis The  diagnosis  of  face  presentation  is  usually  made  at  the time of vaginal examination during labor, when the  soft tissues of the fetal mouth and nose are noted adja- cent  to  the  malar  bones  and  orbital  ridges.  Face  pre- sentation  is  then  confirmed  by  sonography.  Because  anencephalic  fetuses  uniformly  present  face  first,  anencephaly should be ruled out when face presenta- tion is suspected.

Mechanism of Labor The position of the presenting face is classified accord- ing to the location of the fetal chin (mentum). Approxi- mately 60% of face presentations are mentum anterior at the time of diagnosis,  whereas  15%  are  mentum  transverse  and  25%  mentum  posterior.  The  mechanism of labor with a face presentation is similar  to the vertex presentation in that the longest diameter  (mentum  to  brow)  enters  the  pelvis  transversely.  As  labor proceeds and the face descends to the midplane,  internal  rotation  occurs  into  the  vertical  axis.  If  the  mentum rotates anteriorly under the symphysis pubis,  vaginal  delivery  should  be  expected.  Forceps,  but  not  vacuum,  can  be  applied  to  assist  if  prerequisites  are  met.  However,  if the mentum rotates posteriorly, the

PA R T 2 Obstetrics182

flexion, and will subsequently deliver vaginally. With a persistent brow presentation, the large presenting diameter makes vaginal delivery impossible, unless the fetus is very small or the maternal pelvis is very large, and delivery must be accomplished by cesarean delivery. There  is  an  increased  incidence  of  both  pro- longed  labor  (30-50%)  and  dysfunctional  labor  (30%).  As  with  face  presentations,  midpelvic  delivery  and  methods  to  convert  the  brow  presentation  to  a  vertex  presentation  are  contraindicated.  Perinatal morbid- ity and mortality are similar to those for vertex presentations.

A  compound presentation  occurs  when  a  fetal  extremity  (usually  the  hand)  prolapses  alongside  the  presenting  part  (the  head)  and  both  parts  enter  the  maternal  pelvis  at  the  same  time.  This  presentation  occurs more frequently with premature gestations. The  incidence  of  a  hand  or  arm  prolapsing  alongside  the  presenting fetal head is 1 in 700 deliveries and manage- ment  is  expectant.  Usually  the  prolapsed  part  of  the  fetus does not interfere with labor. If the arm prolapses,  it is best to wait to see if it moves out of the way as the  head  descends.  If  it  does  not,  the  arm  may  be  gently  pushed  upward  while  the  head  is  simultaneously  pushed downward by fundal pressure. If the complete  extremity  prolapses  and  the  fetus  then  converts  to  a  shoulder presentation  (Figure  13-10),  birth  must  be  accomplished by cesarean delivery.

FIGURE 13-9 Brow presentation. Note the large presenting diameter (occipitomental).

FIGURE 13-10 Shoulder presentation. Note the transverse lie of the fetus with the back down, which cannot be delivered vaginally.

FIGURE 13-8 Simpson forceps applied to a mentum anterior face presentation.

183

14  Hypertensive Disorders of Pregnancy

C H

A P

T ER

LONY C. CASTRO • CALVIN J. HOBEL

■  Preeclampsia  (sometimes  called  toxemia of pregnancy)  is  a  multisystem  disorder  that  is  thought  to  arise  as  a  consequence  of  inadequate  cytotrophoblastic  invasion  of  the  spiral  uterine  arteries  and  failure  to  establish   the  normal  low  resistance  uteroplacental  circulation.  This  leads  to  placental  ischemia  and  the  presumptive  involvement  of  secondary  mediators  responsible  for  endothelial  dysfunction,  local  and  systemic  vasospasm,  and activation of the coagulation system. Clinical mani- festations  of  preeclampsia  reflect  this  pathophysiology,  and the disease begins to resolve with the delivery of the  placenta.

■  The diagnosis of preeclampsia is based on the presence  of  new-onset  hypertension  after  20  weeks’  gestation,  accompanied by new onset of proteinuria. When evalu- ating  a  pregnant  woman  with  new-onset  hypertension  without proteinuria, preeclampsia can also be diagnosed  if there is evidence of one or more of the following abnor- malities: thrombocytopenia or disseminated intravascu- lar  coagulation  (DIC),  elevated  transaminases  or  other  signs  of  hepatic  injury,  central  nervous  system  (CNS)  symptoms,  an  elevated  or  rising  serum  creatinine  level,  or pulmonary edema (Box 14-1).

■  Severe hypertension (systolic blood pressure ≥160 mm Hg  and/or  diastolic  blood  pressure  ≥110 mm Hg)  in  the  setting  of  preeclampsia  requires  rapid  blood  pressure 

control,  usually  with  parenteral  labetalol  or  hydralazine  to prevent CNS hemorrhage or stroke. When preeclamp- sia  is  accompanied  by  new-onset  grand  mal  seizures,   it  becomes  eclampsia.  Eclampsia  can  result  in  major  maternal  morbidity,  including  intracerebral  hemor- rhage,  placental  abruption,  and  preterm  birth  or  fetal  death.

■  The  diagnosis  of  chronic  hypertension  requires  at  least  either  known  hypertension  before  pregnancy  or  the  development  of  hypertension  before  20  weeks’  gesta- tion.  Chronic  hypertension  is  generally  not  treated  in  pregnancy unless the blood pressure is ≥160/105 mm Hg.  Superimposed  preeclampsia  is  diagnosed  by  the  detec- tion  of  new-onset  proteinuria  or  the  development  of  signs of severe preeclampsia after 20 weeks’ gestation in  a pregnant woman with chronic hypertension. Manage- ment  of  superimposed  preeclampsia  is  similar  to  that  outlined for preeclampsia.

■  Gestational hypertension  refers  to  the  development  of  elevated  blood  pressure  without  proteinuria  or  other  signs  of  preeclampsia  after  20  weeks’  gestation  or   within  72  hours  of  delivery  that  resolves  by  12  weeks  postpartum.  These  women  must  be  followed  closely,  because  a  significant  percentage  will  go  on  to  develop  preeclampsia  in  the  current  pregnancy  or  in  a  subse- quent pregnancy.

CLINICAL KEYS FOR THIS CHAPTER

The  hypertensive  disorders  of  pregnancy  (including  preeclampsia/eclampsia, chronic hypertension, super- imposed  preeclampsia,  and  gestational  hypertension)  are  important  contributors  to  maternal  and  perinatal  morbidity  and  mortality.  The  worldwide  incidence   of  these  disorders  is  reported  to  be  about  10%,  but  regional  estimates  vary,  depending  on  the  population  being  studied  and  on  the  criteria  used  for  diagnosis.  Preeclampsia  is  most  easily  recognized  in  pregnant  women  who  present  with  the  “classic  triad”  of  new-

onset  hypertension,  proteinuria,  and  edema  in  the  latter  half  of  pregnancy.  However,  this  is  only  one  of  the  ways  in  which  this  multisystem  disorder  can  present.  Both  the  mother  with  preeclampsia  and  the  fetus carried in an affected pregnancy can present with  significant multisystem disorders and complications.

The Centers for Disease Control and Prevention states that preeclampsia/eclampsia is one of the leading causes of maternal mortality in the United States. The mortality is primarily due to central

PA R T 2 Obstetrics184

first  and  second  trimesters  of  pregnancy  and  rises  to  prepregnancy levels in the third trimester.

The diagnosis of hypertension should be reserved for pregnant women with a systolic blood pressure ≥140 mm Hg and/or a diastolic blood pressure ≥90 mm Hg.  Blood  pressure  measurements  should  be  taken with the woman in the sitting position after she  has rested ≥10 minutes if she is ambulatory. In the hos- pitalized  patient,  either  sitting  or  lateral  decubitus  measurements  may  be  used;  however,  measurements  should be corrected to the level of the right atrium, and  consistency  of  measurement  is  advised. The  length  of  the  blood  pressure  cuff  should  be  ≥1.5  times  the  cir- cumference  of  the  upper  arm  and  the  fifth  Korotkoff  sound (disappearance) should be used for the determi- nation of diastolic pressure.

PREECLAMPSIA/ECLAMPSIA Preeclampsia is a multisystem disorder unique to pregnancy and has varying clinical presentations.  The  diagnosis  is  based  on  the  presence  of  new-onset  hypertension  in  the  latter  half  of  gestation,  accompa- nied  by  new-onset  proteinuria  and/or  other  evidence  of  organ  dysfunction.  When  evaluating  a  pregnant  woman  with  new-onset  hypertension  who  does  not  have  proteinuria,  preeclampsia  can  be  diagnosed  if  there is evidence of one or more of the following abnor- malities:  thrombocytopenia  or  disseminated  intravas- cular  coagulation  (DIC),  elevated  transaminases  or  other  signs  of  hepatic  injury,  CNS  symptoms,  an  ele- vated  or  rising  serum  creatinine  level,  or  pulmonary  edema.  Preeclampsia  is  classically  considered  to  be  a  disease affecting the first pregnancy, but it also occurs  in  multiparas,  especially  if  there  are  predisposing  risk  factors (see discussion of pathogenesis and risk factors  below). Box 14-1 lists the criteria for diagnosing severe  preeclampsia.

New-onset hypertension is defined as the devel- opment of hypertension  (systolic  blood  pressure  ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg on  two occasions 4 hours apart) in a woman whose blood pressure readings were previously normal, after the 20th week of pregnancy. New-onset proteinuria is defined as ≥0.3 g of protein in a timed 24-hour urine collection or a protein/creatinine ratio ≥0.3 after the 20th week of gestation.  This  usually  correlates  with  a  urinalysis  report  of ≥30 mg/dL  (1+  on  dipstick)  on  a  clean-catch urine sample. At each prenatal clinic visit,  a  pregnant  woman’s  blood  pressure,  weight,  and  dip- stick urinalysis should be recorded, and she should be  assessed for edema. Rising blood pressures should be of concern,  because  they  may  precede  the  develop- ment  of  the  full  preeclamptic  syndrome.  Similarly,   preeclampsia is often preceded by, or associated with, the development of generalized edema.  Dependent  edema (edema of the lower extremities) is very common  in  normal  pregnancies.  Hand  and  facial  edema  are 

nervous system (CNS) hemorrhage.  Because  of  this  concern, there is an increased emphasis on the use of  standardized  practice  guidelines  to  manage  patients  with  preeclampsia  and  other  hypertensive  disorders,  with the aim of decreasing the maternal and perinatal  morbidity and mortality that accompany them.

Classification and Definitions The  general  classification  of  hypertensive  disorders  recommended  in  2013  by  the  American  College  of  Obstetricians and Gynecologists (ACOG) Task Force on  Hypertension  in  Pregnancy  reaffirmed  the  previous  classification  of  hypertensive  disorders  used  in  the  Working Group Report on High Blood Pressure in Preg- nancy issued in 2000 (Box 14-2).

Blood pressure readings vary, depending on mater- nal  position  and  the  gestational  age  of  the  pregnancy.  Maternal  blood  pressure  tends  to  be  lower  in  the  left  lateral  decubitus  position  and  higher  in  the  sitting  position. In the supine position, some pregnant women  will  have  elevated  pressure,  whereas  others  will  have  supine  hypotension  due  to  compression  of  the  vena  cava by the uterus. In addition to positional variations,  arterial  blood  pressure  normally  declines  during  the 

Based on the American College of Obstetricians and Gynecologists Executive Summary: Hypertension in pregnancy, 2013.

BOX 14-2

GENERAL CLASSIFICATION OF HYPERTENSIVE DISORDERS OF PREGNANCY

•  Preeclampsia/eclampsia •  Chronic hypertension •  Chronic  hypertension  with  superimposed  pre-

eclampsia •  Gestational hypertension

BOX 14-1

CRITERIA FOR SEVERE PREECLAMPSIA

•  Severe  hypertension  (systolic  BP  ≥160 mm Hg  or  dia- stolic BP ≥110 mm Hg) at rest on two occasions at least  4 hr apart*

•  Renal  insufficiency  (serum  Cr >1.1 mg/dL  or  doubling  of baseline values)

•  Cerebral or visual disturbances •  Pulmonary edema •  Epigastric or right upper quadrant pain •  Elevated  liver  enzymes  (AST  or  ALT  at  least  two  times 

normal level) •  Thrombocytopenia (platelet count <100,000/µL)

Based on the American College of Obstetricians and Gynecologists Executive Summary: Hypertension in pregnancy, 2013. ALT, Serum alanine aminotransferase; AST, serum aspartate aminotransferase; BP, blood pressure; Cr, creatinine. *4-hr delay not required if antihypertensive therapy is initiated.

C H A P T E R 14 Hypertensive Disorders of Pregnancy 185

age will have secondary hypertension  that  has  renal,  vascular,  endocrinologic,  or  behavioral  causes  (e.g.,  methamphetamine  and  cocaine  use).  Most  of  these  conditions can be suspected on the basis of a thorough  history  and  physical  examination.  Certain  endocrino- logic  disorders,  in  particular  hyperthyroidism,  may  present for the first time during pregnancy. Depending  on  the  associated  symptoms,  signs,  and  response  to  medication, a workup to determine the etiology of the  hypertension  may  be  indicated.  It is not uncommon for the physiologic stress of pregnancy to cause sub- clinical vascular or renal disease to become manifest.  In these situations, it may be very difficult to differenti- ate  between  preeclampsia  and  an  aggravated  chronic  hypertensive  condition.  Sometimes  only  careful  post- partum follow-up will indicate the correct diagnosis.

CHRONIC HYPERTENSION WITH SUPERIMPOSED PREECLAMPSIA Preeclampsia  may  become  superimposed  on  chronic  hypertensive disease. Superimposed preeclampsia can  be  very  difficult  to  distinguish  from  poorly  controlled  chronic  hypertension,  especially  if  the  woman  is  not  seen until after the 20th week of gestation, but the two  conditions  are  managed  differently.  In  general,  super- imposed  preeclampsia  carries  a  worse  prognosis  than  either condition alone.

The diagnosis of superimposed preeclampsia should be reserved for those women with chronic hypertension who develop new-onset proteinuria (≥0.3 g in a 24-hour collection) after the 20th week of gestation. In pregnant women with preexisting hyper- tension and proteinuria, the diagnosis of superim- posed preeclampsia should be considered if they experience sudden significant increases in blood pressure or proteinuria or the new onset of any of the other signs and symptoms of severe preeclampsia  listed  in  Box  14-1,  including  thrombocytopenia  or  abnormally elevated liver enzymes.

GESTATIONAL HYPERTENSION The diagnosis of gestational hypertension is made if hypertension without proteinuria or other signs of organ dysfunction first appears after 20 weeks’ gesta- tion or within 48 to 72 hours of delivery and resolves by 12 weeks postpartum.  It  is  extremely  difficult  to  differentiate this condition from the early stages of pre- eclampsia.  These  women  must  be  followed  closely  because a significant percentage go on to develop pro- teinuria  and  the  full  preeclamptic  syndrome  at  a  later  stage in pregnancy. Others will have previously unrec- ognized chronic hypertension. The diagnosis of gesta- tional hypertension can only be made in retrospect, if the pregnancy has been completed without the development of proteinuria or other evidence of pre- eclampsia, and if the blood pressure has returned to normal before the 12th week postpartum.

more  likely  to  be  associated  with  preeclampsia,  but  they are not diagnostic of the preeclamptic syndrome.

Preeclampsia is often a progressive disease and may  have  severe  features,  depending  on  the  severity  of  the  hypertension  and  the  degree  to  which  other  organ  systems are affected. Box 14-1 lists specific criteria for the diagnosis of severe preeclampsia.  If  any  of  the  symptoms, signs, or laboratory abnormalities listed in  Box 14-1 are present in a woman with preeclampsia, it  is very likely that she has severe disease, which is asso- ciated  with  much  greater  maternal  and  perinatal  morbidity.

A variant of severe preeclampsia with particularly high morbidity is the HELLP syndrome. This syn- drome occurs in preeclamptic women with evidence of hemolysis, elevated liver enzymes, and low plate- lets (thrombocytopenia).  In  contrast  to  more  typical  presentations of preeclampsia, the patient with HELLP  syndrome is more likely to be multiparous, older than  25  years  of  age,  and  at  less  than  36  weeks’  gestation.  Hypertension  may  be  initially  absent  in  20%  of  the  patients,  whereas  30%  will  have  mild  elevations  in  blood pressure and 50% will have severe elevations.

ECLAMPSIA Eclampsia is the presence of new-onset grand mal seizures in a woman with preeclampsia that cannot be attributed to other causes. Patients with severe pre- eclampsia, especially those with CNS symptoms, are at  the  greatest  risk  of  developing  seizures,  but  the  sei- zures can occur in patients with preeclampsia without  other evidence of severe disease. There is a wide range in the reported frequency and timing of eclamptic seizures. Clinical practices, including the use of mag- nesium sulfate intrapartum and postpartum for seizure  prophylaxis  in  women  with  preeclampsia,  as  well  as  the  timely  recognition  and  delivery  of  women  with  severe  preeclampsia,  undoubtedly  influence these numbers. In one review of this subject, 38-53% of eclamptic seizures occurred before labor, 18-36% occurred during labor, and 11-44% occurred after delivery (usually within the first 24 to 48 hours). When  evaluating atypical cases of eclampsia (i.e., more than  48 hours postpartum or previous evidence of only mild  disease),  it  is  important  to  consider  other  causes  of  seizures,  such  as  underlying  seizure  disorder;  hyper- tensive  encephalopathy;  metabolic  abnormalities,  including  hypoglycemia  and  hyponatremia;  and  CNS  hemorrhage, thrombosis, tumor, or infection.

CHRONIC HYPERTENSION The diagnosis of chronic hypertension requires at least one of the following: known hypertension before pregnancy or the development of hypertension before 20 weeks’ gestation.

Most  pregnant  women  with  chronic  hypertension  will have essential hypertension, but  a small percent-

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proangiogenic  proteins  vascular  endothelial  growth  factor  and  placental  growth  factor  are  decreased,  whereas  levels  of  the  antiangiogenic  proteins  soluble  fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin  are markedly increased. In animal models, overexpres- sion of sFlt1 results in a preeclampsia-like syndrome.

Endothelial dysfunction leads to an imbalance between different classes of locally produced vaso- constrictors and vasodilators. Preeclampsia is associ- ated  with  a  disturbance  in  prostaglandin  production,  with a decrease in the ratio of the vasodilators prosta- glandin  E2  and  prostacyclin  to  the  vasoconstrictor  PGF2α  and  thromboxanes.  Endothelial changes also appear to involve a relative deficiency in the produc- tion of nitric oxide, a vasodilator and inhibitor of platelet aggregation, along with increased produc- tion of endothelin.  Endothelin  is  an  extremely  potent  vasoconstrictor  and  activator  of  platelets. This  shift  in  the production of locally acting vasoactive substances  could  enhance  vasoconstriction  in  response  to  circu- lating pressor hormones.

The net effect of the above-described processes would be widespread vasoconstriction leading to hypoxic/ischemic damage in different vascular beds,  systemic  hypertension,  activation  of  the  coagulation  system, and worsening placental ischemia. The relative  severity of the signs and symptoms of preeclampsia in  any given individual would vary on the basis of which  specific organ system was affected.

PATHOLOGY Three major pathologic lesions are classically associ- ated with preeclampsia and eclampsia: (1) lack of decidualization of the myometrial segments of the spiral arteries; (2) glomerular capillary endothelio- sis; and (3) ischemia, hemorrhage, and necrosis in many organs, presumably secondary to arteriolar constriction.

Under  normal  circumstances,  the  invasion  of  tro- phoblast  results  in  the  replacement  of  the  muscular  and  elastic  layers  of  the  spiral  arteries  by  fibrinoid   and  fibrous  tissue,  resulting  in  large,  tortuous,  low- resistance  channels  that  extend  through  the  myome- trium. In preeclampsia, this change is mostly limited to  the decidual segments of the vessels and may result in  a  60%  reduction  in  the  diameter  of  the  myometrial  segment  of  a  spiral  artery.  The extent of placental infarction is increased in almost all preeclamptic pregnancies.

The typical renal lesion of preeclampsia/eclampsia is “glomerular capillary endotheliosis,” which is best seen by electron microscopy.  This  disorder  is  mani- fested  by  marked  swelling  of  the  glomerular  capillary  endothelium  and  deposits  of  fibrinoid  material  in   and  beneath  the  endothelial  cells.  Arteriolar vaso- spasm of relatively short duration (1 hour) can cause hypoxia and necrosis of sensitive parenchymal cells.

Preeclampsia/Eclampsia PATHOGENESIS AND RISK FACTORS Preeclampsia is called a “disease of theories” because  genetic, immunologic, vascular, hormonal, nutritional,  and  behavioral  factors  have  all  been  proposed  as  causes.  No  single,  definitive  “cause”  has  been  identi- fied and the origins of the disease are considered to be  multifactorial.  Because of the resolution of the pre- eclampsia after delivery, most attention has been focused on the placenta and the uteroplacental-fetal interface.

Inadequate uteroplacental perfusion leading to placental ischemia, or hypoxia, appears to be central to the development of the disease.  This  has  been  attributed  to  failure  of  the  cytotrophoblasts  to  ade- quately invade the uterine spiral arteries and establish  the  low-resistance  uteroplacental  circulation  charac- teristic of normal pregnancy. Placental ischemia could  also  be  due  to  underlying  maternal  vascular  disease.  This could explain the well-documented maternal risk  factors  for  preeclampsia,  such  as  chronic  hyperten- sion,  advanced  maternal  age,  or  methamphetamine  use.  Immunologically  mediated  placental  vascular  damage  could  explain  the  higher  incidence  of  pre- eclampsia  in  primigravidas  and  in  pregnant  women  with autoimmune disorders such as the antiphospho- lipid syndrome. Alternatively, ischemia could be caused  by increased metabolic demand in the setting of a mul- tiple  gestation,  a  large  singleton  fetus,  or  gestational  trophoblastic  disease.  When preeclampsia arises in the early second trimester (14 to 20 weeks), a hyda- tidiform mole or choriocarcinoma should be consid- ered. Other as yet poorly defined genetic and environmental factors will likely be identified that explain the high risk of recurrence of preterm pre- eclampsia in subsequent pregnancies and the famil- ial association (i.e., increased risk in daughters of women with preeclampsia).

It is postulated that uteroplacental ischemia results in oxidative and inflammatory stress, with the involvement of secondary mediators leading to endo- thelial dysfunction, vasospasm, and activation of the coagulation system. The nature of these toxins has not  yet  been  identified,  but  it  may  involve  production  of  reactive oxygen and nitrogen species. This is supported  by  the  observation  that  preeclampsia  is  increased  in  pregnant  women  with  underlying  conditions,  such  as  obesity  and  diabetes,  that  are  associated  with  chronic  inflammation  and  dyslipidemia.  A  hypoxic  placenta  may  also  shed  microparticles  derived  from  apoptosis  of  syncytiotrophoblasts,  which  can  then  lead  to  wide- spread  endothelial  injury.  Antiangiogenic  factors  have  also been shown to cause systemic hypertension, vas- cular  injury,  and  activation  of  the  coagulation  system.  Preeclamptic women have an imbalance in angiogenic  and  antiangiogenic  proteins.  Circulating  levels  of  the 

C H A P T E R 14 Hypertensive Disorders of Pregnancy 187

with preeclampsia have an increase in total body fluid  volume  but  have  intravascular  volume  depletion.  The hematocrit may also increase, reflecting the relative hypovolemia and hemoconcentration. These “leaky” capillaries predispose women with preeclampsia to pulmonary edema if they are treated with aggressive volume loading. Diuretic therapy is generally not advised unless there is evidence of pulmonary edema.

Figure 14-1 shows a preeclamptic woman with fluid  retention  just  before  delivery  (see  Figure  14-1,  A)  and  at  her  postpartum  visit  6  weeks  after  delivery  (see  Figure 14-1, B).

Hypertension The elevation of blood pressure seen in preeclampsia (particularly the increase in diastolic pressure) is a result of generalized vasospasm and an increase in systemic vascular resistance.  The  blood  pressure  changes  may  occur  days  to  weeks  after  the  onset  of  pathologic fluid retention. Cardiac output in untreated  pregnant  patients  with  preeclampsia  is  not  signifi- cantly different from that of normal subjects in the last  trimester of pregnancy.

Renal Function Renal blood flow and glomerular filtration rate (GFR) are significantly lower than in patients with a normal 

Vasospasm of longer duration (3 hours) can lead to infarction of vital organs,  such  as  the  liver,  placenta,  and brain. In the liver, periportal necrosis and hemor- rhage  may  occur,  with  subcapsular  hematoma  and  hepatic rupture being rare complications. In the brain,  focal  areas  of  hemorrhage  and  necrosis  may  occur.  In  the  retina  (the  clinical  window  to  the  arterial  vascula- ture),  vasospasm  may  be  visualized  on  ophthalmo- scopic examination. Retinal hemorrhage is considered to be an extremely ominous sign because it may signal  similar phenomena in other vital organs.

CLINICAL AND LABORATORY MANIFESTATIONS Many  of  the  clinical  and  laboratory  manifestations  of  preeclampsia discussed below can be explained on the  basis of endothelial dysfunction, vasospasm, and acti- vation  of  the  coagulation  system.  This  unifying  prin- ciple may one day lead to the definitive explanation of  the causes of preeclampsia.

Weight Gain and Edema Abnormal weight gain and edema occur early with preeclampsia and reflect an expansion of the extra- vascular fluid compartment. This expansion is related  to  the  endothelial  injury  and  increased  capillary  per- meability  that  allow  fluid  to  diffuse  from  the  intravas- cular  to  the  extravascular  space.  Thus,  many  patients 

FIGURE 14-1 A postpartum patient after an eclamptic seizure and delivery secondary to severe preeclampsia (A). She experienced confu- sion, severe headache, and loss of vision before the eclamptic seizure. Note the marked facial edema. Because of the patient’s loss of vision, the diagnosis of posterior reversible encephalopathy syndrome was assessed by magnetic resonance imaging, which showed segmental vasoconstriction. The cause is related to loss of autoregulation of the cerebral circulation because of vascular endothelial damage and brain edema. The treatment includes prevention of recurrent seizures with magnesium sulfate, aggressive control of hypertension, and reduction of excessive vascular volume by rapid diuresis with furosemide. Note the patient’s status at 6 weeks postpartum (B). (From Sibai BM: Etiology and management of postpartum hypertension-preeclampsia. Am J Obstet Gynecol 206:470–475, 2012.)

A B

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hemorrhage, or abruption,  which  is  an  important  cause of perinatal morbidity and mortality.

Central Nervous System Effects Cerebral vascular resistance is high in patients with preeclampsia and eclampsia.  In  patients  with  hypertension without convulsions, cerebral blood flow  may  remain  within  normal  limits  as  a  result  of  auto- regulatory  phenomena.  In  patients  with  convulsions,  however, cerebral blood flow and oxygen consumption  are  significantly  lower.  Visual disturbances  such  as  blurred vision, spots, and scotomata represent degrees  of  retinal  vasospasm.  Sudden  loss  of  vision  (cortical  blindness)  is  due  to  occipital  lobe  ischemia.  If  the  mother  is  expeditiously  stabilized  and  delivered,  full  restoration  of  vision  is  likely  to  occur.  A new-onset headache and increased reflex irritability or hyper- reflexia are extremely concerning signs of CNS involvement and may predict imminent seizures.

Evaluation and Management of Preeclampsia There are three important questions the clinician must  ask when managing a woman with preeclampsia. First,  does the disease process have severe features? Second,  is  there  evidence  of  fetal  compromise  (i.e.,  IUGR,  oli- gohydramnios,  or  heart  rate  abnormalities)?  Third,  is  the  fetus  mature  enough  for  a  reasonably  uncompli- cated course after delivery?

Delivery is the only definitive cure for preeclamp- sia,  so  it  is  always  beneficial  for  the  mother;  however,  it may result in the delivery of a very preterm neonate.  The goal of management is to decrease or prevent the  maternal  complications  of  severe  preeclampsia  while  minimizing  the  neonatal  complications  arising  from  prematurity. A woman with preeclampsia, without evi- dence  of  fetal  compromise,  and  whose  disease  does  not  appear  to  be  severe  or  progressing  will  generally  not be delivered unless the gestational age is 37 weeks  or  older,  whereas  a woman with severe preeclampsia or eclampsia whose disease presents at or beyond 34 weeks’ gestation should usually be delivered after a brief period of stabilization. Severe preeclampsia pre- senting at less than 34 weeks’ gestation may in certain situations be stabilized, and with careful monitoring of the mother and fetus, delivery may be delayed until the pregnancy reaches 34 weeks.

The initial maternal assessment involves a complete  medical  history,  physical  examination,  and  laboratory  evaluation.  The  evaluation  should  focus  on  whether  there  is  any  past  history  of  elevated  blood  pressure  or  renal disease, either before pregnancy or during previ- ous  pregnancies.  The  patient  should  be  questioned  carefully  regarding  symptoms  of  severe  preeclamp- sia  or  its  complications,  including  headache,  visual 

pregnancy.  The  decrease  in  renal  blood  flow  results  from  constriction  of  the  afferent  arteriolar  system.   This afferent vasoconstriction may eventually lead to damage to the glomerular membranes, thereby increasing the permeability of these membranes to proteins and leading to proteinuria.  The  renal  vaso- constriction and decrease in GFR also account for ele- vations  in  serum  concentrations  of  creatinine,  blood  urea nitrogen, and uric acid.

In the antepartum period, proteinuria may occur days or weeks after the onset of hypertension.  If  the  disease first manifests during labor or in the immediate  postpartum  period,  this  progression  of  events  is  com- pressed  into  hours  and  sometimes  minutes.  Renal  involvement  may  progress  to  significant  oliguria  and  frank renal failure.

Coagulation System Activation of the coagulation system is often clinically  apparent  with  severe  disease.  Thrombocytopenia is the most common abnormality.  Although  platelet  counts  tend  to  decline  even  in  normal  pregnancies,  a  value  <100,000  cells/mm3  is  clearly  pathologic  and,  if  accompanied  by  other  signs  of  preeclampsia,  is  evi- dence  of  severe  disease.  DIC  may  occur,  especially  if  there  is  a  placental  abruption.  The specific combina- tion of hemolysis, elevated liver function tests, and low platelet levels (the HELLP syndrome)  can  occur  without  clinical  manifestations  of  DIC  and  is a sign of severe preeclampsia,  even  if  blood  pressures  are  normal  or  only  minimally  elevated. Women  with  pre- existing  thrombophilias,  either  acquired  or  inherited,  are at increased risk for developing preeclampsia.

Liver Function In the liver, vasospasm may result in focal hemor- rhages and infarctions leading to right upper quad- rant or epigastric pain and elevated serum enzyme levels (alanine aminotransferase and aspartate amino- transferase).  Hepatic  rupture  is  a  rare,  ominous  com- plication  of  preeclampsia  that  is  usually  associated  with the HELLP syndrome. When significant hemolysis  is present, bilirubin levels are often elevated. Elevated  alkaline  phosphatase  levels  are  frequently  seen  in  pregnancy  and  are  usually  not  of  clinical  significance,  as  they  are  mostly  due  to  placental  production  of  this  enzyme.

Placental Function Decreased uteroplacental perfusion and ischemia can lead to fetal compromise in the form of intrauter- ine growth restriction (IUGR), oligohydramnios, or fetal heart rate abnormalities. A commonly accepted  clinical  sign  of  inadequate  placental  perfusion  is  an  umbilical  artery  Doppler  study  revealing  absent  or  reversed umbilical artery end diastolic flow. Extensive placental infarctions can result in retroplacental

C H A P T E R 14 Hypertensive Disorders of Pregnancy 189

should be delivered by the time she reaches 37 weeks, or earlier if she develops signs or symptoms of worsening disease or if there is evidence of fetal compromise.

If the initial evaluation is consistent with the diag- nosis of severe preeclampsia, the patient should remain hospitalized for the remainder of the preg- nancy. After 34 weeks’ gestation, stabilization and deliv- ery are appropriate for most patients. For those patients  at  less  than  34  weeks’  gestation  who  have  severe  pre- eclampsia, the decision regarding delivery needs to be  individualized  after  carefully  considering  the  risks  to  the neonate of prematurity versus the potential mater- nal  and  fetal  risks  of  continuing  the  pregnancy.  Both  the mother and fetus require very close monitoring with  maternal  laboratory  parameters  and  fetal  assessment  testing  repeated  daily  or  more  often  if  necessary.  In some instances, initial stabilization of the patient with severe preterm preeclampsia with magnesium sulfate for seizure prophylaxis, along with medical control of severe hypertension and corticosteroids for fetal lung maturity, will moderate the disease process and allow delivery to be delayed in the hopes of advancing ges- tational age.  Either  a  deterioration  in  clinical  status  (e.g.,  uncontrollable  hypertension,  deteriorating  renal  function,  pulmonary  edema,  evidence  of  HELLP  syn- drome or coagulopathy, worsening liver function, CNS  symptoms,  abruption,  or  abnormal  fetal  testing)  or  attainment of a gestational age of 34 weeks is an indica- tion for delivery.

INTRAPARTUM MANAGEMENT OF PREECLAMPSIA Labor  should  be  induced,  and  vaginal  delivery  antici- pated,  in  the  absence  of  any  obstetric  indications  for  cesarean  delivery,  such  as  failure  to  progress  in  labor,  nonreassuring  fetal  status,  or  nonvertex  presentation.  The  mother  and  fetus  must  be  carefully  monitored  during labor and delivery. Two of the most important maternal issues to be dealt with are seizure prophy- laxis and control of hypertension.  Other  potential  maternal problems that may develop include oliguria,  pulmonary  edema,  and  thrombocytopenia  or  the  HELLP syndrome.

If the fetus is growth-restricted or if placental abruption occurs, the fetal heart rate tracing may show evidence of late decelerations, bradycardia, or other signs of fetal compromise necessitating cesarean delivery  (see  Chapter  9).  In  most  instances,  epidural anesthesia is the anesthetic of choice for oper- ative delivery or pain relief during labor, unless there is  evidence of coagulopathy.

SEIZURE PROPHYLAXIS Because  of  the  risk  of  seizures  and  their  attendant   morbidity and even mortality, attention must be given  to  the  level  of  CNS  irritability.  Peripheral  reflexes, 

changes,  nausea,  vomiting,  abdominal  or  epigastric  pain, and vaginal bleeding. Her medical record should  be  reviewed  to  determine  when  in  the  current  preg- nancy her blood pressure started to rise and when pro- teinuria developed.

The physical examination should be focused on the  assessment  of  blood  pressure,  weight  gain,  edema,  fundal  height,  and  reflexes,  as  well  as  on  a  qualitative  assessment of urinary protein excretion with a dipstick.  In addition, findings consistent with severe preeclamp- sia, such as epigastric or right upper quadrant tender- ness,  uterine  tenderness,  and  signs  of  pulmonary  edema,  should  be  sought.  If  there  is  severe  headache  or  visual  symptoms,  an  ophthalmic  examination  may  be  indicated.  The  initial  laboratory  studies  recom- mended are outlined in Box 14-3.

A careful fetal evaluation is also indicated.  This  should  begin  with  an  accurate  determination  of  fetal  gestational age based on clinical and sonographic data,  if  available.  Fetal  ultrasound  should  be  performed  to  evaluate  fetal  growth,  amniotic  fluid  index,  and  the  umbilical  artery  Doppler  resistance  index  or  systolic/  diastolic  ratio.  A nonstress test (NST) should also be done  to  determine  if  there  is  evidence  of  acute  fetal  compromise.

It is generally advisable to hospitalize patients with  a  presumed  diagnosis  of  preeclampsia  to  determine  the disease’s severity and the maternal and fetal status.  After  the  initial  evaluation,  if  there  is  no  evidence  of  severe  preeclampsia  or  fetal compromise, manage- ment consists of observation with careful monitoring of both the mother and fetus for progression of the disease. There is no evidence that bed rest is helpful,  although  some  activity  restriction  may  be  indicated.  Chronic  antihypertensive  therapy  or  diuretic  therapy  does not prevent the progression to severe disease and  is  not  recommended.  Depending  on  the  special  cir- cumstances  surrounding  each  case,  expectant  man- agement  can  be  carried  out  in  the  hospital  or  on  an  outpatient  basis.  The  mother  will  require  frequent  reassessment  of  symptoms  and  blood  pressure,  along  with weekly laboratory tests. The fetus needs to be fol- lowed with monitoring of fetal activity, heart rate reac- tivity  (NST),  and  amniotic  fluid  volume.  The patient

BOX 14-3

INITIAL LABORATORY EVALUATION FOR A PATIENT WITH PREECLAMPSIA

•  CBC, platelet count, LDH: if abnormal, order D-dimers,  coagulation panel, and smear

•  Renal studies: serum BUN creatinine and uric acid, uri- nalysis,  24-hr  urine  for  protein  and  creatinine,  or  protein/creatinine ratio

•  Liver function tests: AST, ALT, and bilirubin

ALT, Serum alanine aminotransferase; AST, serum aspartate aminotransferase; BUN, blood urea nitrogen; CBC, complete blood count; LDH, lactate dehydrogenase.

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output is essential.  A  magnesium  overdose  can  have  severe,  even  fatal,  consequences.  Magnesium  should  be  given  by  a  controlled  infusion  pump  with  a  fail-  safe  mechanism  to  prevent  errors  in  administration  (i.e., inadvertent bolus infusion). Serial assessments of urine output, deep tendon reflexes, and respirations are important for detecting signs of magnesium tox- icity.  These  clinical  assessments  should  be  supple- mented with serial measurements of serum magnesium  levels  every  6  hours  and  arterial  oxygen  saturation  via  pulse oximetry. In a patient who has oliguria or a serum  creatinine ≥1.1,  maintenance  infusion  rates  should  be  halved  and  serial  magnesium  levels  measured  every  2  hours. Magnesium toxicity can occur even in a patient with apparently normal renal function.  Magnesium  toxicity  is  treated  by  stopping  the  infusion  and,  when  severe,  administering  IV  calcium  gluconate,  10 mL  of   a  10%  solution,  along  with  resuscitative  measures  if  necessary.

ANTIHYPERTENSIVE THERAPY Arterial blood pressure ≥160 mm Hg systolic or ≥110 mm Hg diastolic must be treated promptly.  In  the  setting  of  severe  preeclampsia,  blood  pressures  reaching  these  levels  represent  a  hypertensive  emer- gency. In some women with preeclampsia, even eleva- tions of systolic blood pressure in the 150 to 159 mm Hg  range  require  urgent  treatment,  especially  in  those  women  whose  previous  systolic  blood  pressures  have  been in the 90 to 100 mm Hg range and who now have  HELLP syndrome or eclampsia.

The  goal  of  antihypertensive  therapy  in  severe  pre- eclampsia is to stabilize the mother by lowering blood  pressure  carefully  to  prevent  CNS  hemorrhage.  In  general,  the  blood  pressure  should  not  be  lowered  to  normal levels or to <130/80 mm Hg.  Caution must be exercised not to lower the arterial pressure too much or too rapidly, for either may result in a decreased uteroplacental blood flow and fetal distress, which may necessitate an emergency cesarean delivery in an unstable mother.

The safest, most efficacious drugs for the acute control of severe hypertension complicating pre- eclampsia are labetalol and hydralazine.  Although  hydralazine  has  theoretical  advantages  over  labetalol  in  that  it  is  a  direct  vasodilator  and  does  not  induce  bronchospasm,  rapid  bolus  infusions  are  potentially  more  likely  to  induce  precipitous  hypotension.  In  general,  either  is  acceptable,  and  use  of  one  or  the  other  will  be  determined  by  the  individual  circum- stances.  Table  14-3  details  the  dosages,  durations  of  action, and potential complications of these two drugs.

Oral nifedipine has been used successfully,  start- ing  at  a  dose  of  10 mg  orally  and  repeated  in  20  to   30  minutes  if  necessary  to  a  maximum  dose  of   30 mg. Nifedipine should be used cautiously to avoid hypotension,  particularly  when  used  in  conjunction 

particularly of the patella and ankle, are generally used  as  determinants  of  heightened  instability.  In patients with preeclampsia, severe headaches, visual changes, sustained clonus, or a positive Chvostek sign can be prodromal symptoms or signs of eclampsia.

Seizure prophylaxis with magnesium sulfate should  be  instituted  in  patients  with  severe  preeclampsia  during  the  initial  period  of  stabilization  and  again  during  the  intrapartum  period,  and  it  should  be   continued  for  24  hours  postpartum  or  until  there  is  evidence  of  resolution  of  the  disease.  Randomized controlled trials have confirmed that magnesium sulfate is the agent of choice for the prevention and treatment of eclamptic seizures. It is both efficacious for seizure control and associated with low neonatal morbidity.  Both  intramuscular  (IM)  and  intravenous  (IV )  routes  are  effective  for  prophylaxis;  however,  the  IM injections can be very painful, and only the IV route  is recommended in the United States.

Table  14-1  outlines  the  protocols  for  magnesium  administration,  and  Table  14-2  reviews  the  relation- ship between serum magnesium concentrations, clini- cal  response,  and  signs  of  toxicity,  including  loss  of  patellar  reflex,  warmth  and  flushing,  somnolence  and  slurred  speech,  and,  most  significantly,  paralysis  and  cardiac arrest. Therapeutic levels are generally accepted  to  be  in  the  range  of  4.8  to  9.6 mg/dL,  but,  to  avoid  toxicity, levels should not be allowed to rise above 7 to  8 mg/dL.  The magnesium ion is excreted exclusively through the kidneys, so careful monitoring of urine

TABLE 14-1

ANTICONVULSIVE MAGNESIUM SULFATE THERAPY

Type of Treatment IV* IM

Loading dose in 100 mL of fluid

4-6 g over 15-20 min

5 g in each buttock

Maintenance dose 1-2 g/hr controlled IV

5 g/4 hr infusion

IM, Intramuscular; IV, intravenous. *Only the IV route is recommended in the United States.

TABLE 14-2

CLINICAL CORRELATES OF SERUM MAGNESIUM SULFATE LEVELS

Clinical Response Serum Levels* (mg/dL)

Loss of patellar reflex 8-12

Warmth and flushing 9-12

Somnolence 10-12

Slurred speech 10-12

Paralysis and respiratory difficulty 15-17

Cardiac arrest 30-35

*Therapeutic range: 4.8-9.6 mg/dL.

C H A P T E R 14 Hypertensive Disorders of Pregnancy 191

be  prepared  to  recognize  an  eclamptic  seizure  and  begin  initial  resuscitative/stabilization  efforts.  The  management of these patients should be carried out by  a team of physicians and well-trained nurses in an iso- lated  labor  room,  with  minimal  noise  and  not  too  much  light.  As  with  any  seizure  condition,  the  initial  requirement is to protect the patient from injury, clear  the  airway,  and  give  oxygen  by  face  mask  to  relieve  hypoxia. Blood pressure and pulse oximetry should be  recorded  every  10  minutes  with  the  patient  in  the  lateral  position.  A  16-  to  18-gauge  IV  line  should  be  placed for drawing blood and administering drugs and  fluids.  An  indwelling  catheter  should  be  placed  in  the  bladder,  and  laboratory  tests  should  be  performed  as  outlined in Box 14-3.

Pharmacologic stabilization consists of preventing recurrent convulsions and controlling hypertension. Randomized controlled trials have confirmed that magnesium sulfate is the most efficacious drug for preventing recurrent eclamptic seizures and has the best safety profile for the mother and fetus.  The  administration  of  IV  magnesium  sulfate  for  the  treat- ment of eclamptic seizures is similar to its prophylactic  use  as  outlined  in  Table  14-1,  except  that  the  loading  dose  is  generally  increased  from  4  to  6 g. The  mainte- nance  dose  remains  2 g/hr  if  renal  function  appears  normal.  If  diazepam  (Valium)  is  used  in  addition  to  magnesium  sulfate,  personnel  skilled  in  intubation  should be readily available in case maternal respiratory 

with magnesium sulfate. Because of the potential for a  precipitous  drop  in  blood  pressure,  short-acting  nife- dipine is generally not advised in this setting.

MANAGEMENT OF FLUID BALANCE Accurately  recorded  intake  and  output  data  must  be  kept to calculate fluid requirements. Patients with pre- eclampsia experience vasoconstriction, have intersti- tial edema, and often demonstrate some degree of reduced intravascular volume, which may reduce urinary output.  In  addition,  they  may  be  receiving  several different therapeutic infusions, such as magne- sium sulfate and oxytocin, which have a direct or indi- rect effect on urinary output.

The most common errors that occur in the man- agement of these patients are fluid volume overload, resulting in pulmonary edema, and excessive volume restriction. Water intoxication is rare with current management. The conservative approach is to replace  documented output plus insensible loss with an appro- priate  electrolyte-containing  fluid.  Because  of  the   multifaceted  pathophysiology  of  this  disease,  central  hemodynamic  monitoring  using  a  pulmonary  artery  catheter  may  aid  in  the  management  of  refractory  cases of oliguria or pulmonary edema.

MANAGEMENT OF ECLAMPSIA Eclampsia is a true obstetric emergency, and all phy- sicians involved in the care of pregnant women should 

TABLE 14-3

EMERGENCY PARENTERAL THERAPY FOR SEVERE HYPERTENSION DURING PREGNANCY

Agent Action Dose Side Effects Comments

Hydralazine Direct vasodilator 5 mg IV over 1-2 min, then 5-10 mg IV every 20-40 min until blood pressure is 130-150/80-100 mm Hg. If no response after 20-25 mg, switch to another drug.

Alternatively, give continuous IV infusion of 0.5-10 mg/hr.

Headache, tachycardia, flushing, vomiting

Increases cardiac output and probably uterine renal blood flow; has historically been drug of choice for short-term control.

Labetalol hydrochloride

Nonselective α1-blocker β1-blocker

Start with 10-20 mg IV bolus. If response is inadequate after 10 min, give 20-80 mg IV every 20-30 min if needed to lower blood pressure to 130-150/80-100 mm Hg. Total dose not to exceed 300 mg.

Alternatively, give a continuous IV infusion of 1-2 mg/min.

Nausea, vomiting, heart block, bronchoconstriction, dizziness

Current drug of choice in many centers. Avoid if evidence of asthma or acute heart failure.

Nifedipine Calcium channel blocker

10-20 mg orally; repeat in 30 min if inadequate response, then 10-20 mg every 2-6 hours if needed to lower blood pressure to 130-150/80-100 mm Hg.

Reflex tachycardia and headaches

Modification of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII), 2004, Tables 21 and 23. IV, Intravenous.

PA R T 2 Obstetrics192

tolic blood pressure is ≥160 mm Hg or the diastolic blood pressure is ≥105 mm Hg. There is little evidence that lowering blood pressure below the 140/90 mm Hg range benefits the pregnancy.  In  fact,  lowering  the  blood  pressure  too  much  may  result  in  decreased  uterine perfusion pressure and iatrogenic fetal growth  restriction.  In many women, blood pressures will decrease to normal in the second trimester, and no antihypertensive medication will be needed.

As a general rule, the safest antihypertensive medi- cation  should  be  used  at  the  lowest  possible  dose  needed to keep blood pressure at about 130/80 mm Hg  to 140/90 mm Hg. Methyldopa is considered to be the  safest  antihypertensive  medication  in  pregnancy,  but  calcium channel blockers and  labetalol are also con- sidered  to  be  safe.  Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, renin inhibitors, and mineralocorticoid blockers should be avoided at all stages of pregnancy because of poten- tial fetal toxicity.  Beta  blockers  should  be  used  with  caution  because  they  may  cause  fetal  growth  restric- tion and may affect the interpretation of the NST. The  risks  and  benefits  of  moderate  exercise  (e.g.,  walking)  or increased periods of rest in the left lateral decubitus  position have not been well defined, although they are  often recommended.

Because these pregnancies have a high incidence of IUGR, both early and serial ultrasonic examina- tions are indicated.  The  early  ultrasound  (before  12  weeks)  is  primarily  for  dating,  and  the  18-  to  22-week  ultrasound  is  for  the  assessment  of  fetal  anomalies.  Serial ultrasonic examinations (every 3 to 4 weeks after  26  to  28  weeks)  are  of  great  assistance  in  detecting  IUGR.  Depending  on  the  clinical  circumstances,  peri- odic  fetal  monitoring  with  NSTs  and  amniotic  fluid  assessment, supplemented by umbilical artery Doppler  studies  if  there  is  evidence  of  IUGR  or  preeclampsia,  may be initiated as early as 26 to 28 weeks and should  be  commenced  by  32  to  34  weeks  in  all  patients  with  hypertension.  Maternal detection of daily fetal kick counts by the mother in the third trimester or earlier  is an important method of assessing fetal well-being.

A significant increase in hypertension or the devel- opment of proteinuria in a previously nonproteinuric patient with chronic hypertension is a likely sign of superimposed preeclampsia.  The  incidence  of  superimposed preeclampsia varies from 15-25%. These  patients should undergo repeat laboratory evaluation,  as  outlined  in  Box  14-3.  Management  should  follow  that outlined for severe preeclampsia.

The  timing  of  delivery  in  the  patient  with  chronic  hypertension  depends  on  the  clinical  circumstances.  For patients without evidence of fetal growth restric- tion or superimposed preeclampsia, in whom blood pressure is well controlled and who have no other indications for delivery, pregnancy may be allowed to progress until at least 38 weeks’ gestation, provided

depression  occurs.  In  general,  it  is  desirable  to  avoid  polypharmacy.

Eclamptic seizures often induce a fetal bradycar- dia that usually resolves after maternal stabilization and correction of hypoxia, unless there is a placental abruption. It is very important to stabilize the mother  before any attempt is made to deliver the infant. Induc- tion of labor or performing a cesarean delivery during  the  acute  phase  may  aggravate  the  course  of  the  disease.  Once hypoxia has been corrected, convul- sions controlled, and the diastolic blood pressures brought down to the 90 to 100 mm Hg range, delivery should be expedited, preferably by the vaginal route.

Currently, there is no scientifically proven method for the prevention of preeclampsia  that  is  applicable  to  the  general  population  of  pregnant  women.  Low- dose aspirin (60 to 80 mg/day beginning at the end of  the first trimester) has been studied extensively in over  30,000 women. Its use is currently advised by the ACOG   Task  Force  for  women  with  a  history  of  recurrent   preeclampsia or severe preterm preeclampsia, but the  risk reduction is likely to be small. Although nutritional  interventions have a sound theoretical and experimen- tal  basis,  it  is  likely  that  dietary  modifications  and  weight  reduction  will  have  to  be  implemented  before  conception in order to be successful. The current goal is to identify the disease early, monitor its effects on the mother and fetus, stabilize the patient if the disease is severe, and deliver the baby before there is major disease-induced maternal or fetal morbidity.

MANAGEMENT OF CHRONIC HYPERTENSION The primary goals of management of chronic hyper- tension are to control hypertension and detect the development of superimposed preeclampsia in the mother and IUGR in the fetus.  In  the  patient  with  uncomplicated  hypertension  whose  blood  pressures  are  well  controlled  and  who  does  not  show  signs  of  superimposed preeclampsia or IUGR, the outcome for  both the mother and fetus should be good.

When  a  woman  with  chronic  hypertension  is   first  seen  during  her  pregnancy,  it  is  important  to  review previous records to determine whether she has  essential  hypertension  or  a  secondary  cause  of  high  blood  pressure.  If  no  previous  evaluations  have  been  done,  it  may  be  appropriate  to  rule  out  some  of  the  more  common  endocrinologic,  renal,  or  cardiovascu- lar  causes  of  hypertension.  Baseline  laboratory  tests  similar to those outlined in Box 14-3, with the addition  of  an  electrocardiogram,  may  be  useful.  The  purpose  of  these  tests  is  to  establish  a  baseline  should  the  patient  later  develop  superimposed  preeclampsia,  as  well as to look for evidence of end organ dysfunction.

It is important to review the antihypertensive medi- cations  being  taken  and  to  discontinue  any  that  are  potentially  teratogenic.  The ACOG Task Force recom- mends starting antihypertensive therapy if the sys-

C H A P T E R 14 Hypertensive Disorders of Pregnancy 193

chronic hypertension later in life. The female offspring of women with preeclampsia experience an increased risk of preeclampsia in their own pregnancies, provid- ing evidence of a genetic basis for the disease.

Some  of  the  more  serious  complications  of  pre- eclampsia,  such  as  cerebrovascular  accidents  and   renal  failure,  may  have  long-term  maternal  sequelae.  Overall, the mortality rate of women with hypertensive  disease of pregnancy varies according to the severity of  the  disease,  socioeconomic  level,  and  quality  of  care  received. Although at present there is no proven way of  preventing preeclampsia, accessible, high-quality pre- natal  care  should  prevent  the  majority  of  severe  com- plications associated with the disease.

Fetal and neonatal sequelae are more difficult to determine, because some of the morbidity and mor- tality associated with these hypertensive syndromes are related to IUGR, prematurity, and acute and chronic fetal distress. All of these may have long-term CNS and cardiovascular effects.

that fetal well-being is normal.  Any  progression  beyond the 40th week should be very carefully consid- ered  and  probably  avoided.  The  presence  of  IUGR,  blood pressure deterioration, or the advent of protein- uria may dictate earlier delivery. The route of delivery should be vaginal in the absence of other obstetric reasons for cesarean delivery.

Sequelae and Outcomes Women with a history of severe preterm preeclampsia are at high risk for recurrent preeclampsia (up to 40%) in a subsequent pregnancy and are the ones most likely to benefit from prepregnancy lifestyle interventions or antepartum use of low-dose aspirin. There is increasing evidence that a history of pre- eclampsia raises a woman’s risk for cardiovascular disease in later life as compared with women who do not experience preeclampsia. Women with gestational  hypertension  also  seem  to  have  a  higher  incidence  of 

194

15 

Rhesus Alloimmunization

C H

A P

T ER

LONY C. CASTRO • CALVIN J. HOBEL

■  In this chapter, the term hydrops fetalis refers to immune  (or  rhesus  [Rh]  antibody-mediated)  hydrops  fetalis  and  is  synonymous  with  the  older  term  erythroblastosis fetalis. Hydrops fetalis is a form of in utero heart failure.  In the setting of Rh alloimmunization, it is characterized  by  the  presence  of  fetal  ascites,  pericardial  effusion,  pleural  effusion,  subcutaneous  edema  (best  seen  as  scalp  edema),  and  polyhydramnios.  The  Rh  complex  is  made up of a number of antigens, including C, D, E, c, d,   and e. The vast majority of cases of Rh alloimmunization  are due to antibodies to the D antigen.

■  Identifying  the  pregnancy  at  risk  for  RhD-mediated  hydrops  fetalis  involves  two  steps:  (1)  identifying  all  RhD-negative  pregnant  women  who  have  a  positive  anti-D  antibody  screen  and  (2)  determining  the  RhD  status  of  the  fetus,  either  by  inference  if  the  father  is  homozygous for the RhD antigen or by direct assessment  of the fetal RhD antigen status through fetal DNA testing.  Only  pregnancies  involving  an  RhD-negative  mother  sensitized  to  the  D  antigen  carrying  an  RhD-positive  fetus  are  at  risk  for  RhD  antibody-mediated  hydrops  fetalis.

■  Once  a  pregnancy  is  identified  as  being  at  risk  for  RhD antibody-mediated hydrops fetalis, serial maternal 

anti-D  antibody  titers  should  be  obtained.  Once  titers  reach a critical threshold (≥1 : 16), or if the mother has a  history of a previously affected fetus, serial fetal ultraso- nography  should  be  performed  to  detect  fetal  anemia.  These  include  Doppler  studies  of  the  middle  cerebral  artery (MCA) and fetal imaging for evidence of placento- megaly, hepatomegaly, and hydrops fetalis.

■  Treatment and management of an affected fetus involves  percutaneous umbilical cord blood sampling (PUBS) for  measurement of fetal hemoglobin, intrauterine transfu- sions,  betamethasone  to  enhance  fetal  lung  maturity,  antepartum testing, and assessment of the need for early  delivery.  These  fetuses  often  require  additional  treat- ment  for  hyperbilirubinemia  or  anemia  in  the  neonatal  period.

■  RhD isoimmunization is the only form of isoimmuniza- tion  that  can  be  prevented  with  passive  immunization.  This  is  done  by  routinely  administering  Rh  immune  globulin  to  all  RhD-negative  women  who  are  anti-D– negative  at  28  weeks’  gestation  and  within  72  hours  of  delivery  of  an  RhD-positive  fetus.  Rh  immune  globulin  should  also  be  given  to  these  women  after  any  episode  of antepartum bleeding or trauma.

CLINICAL KEYS FOR THIS CHAPTER

Rhesus (Rh) alloimmunization is an immunologic dis- order  that  occurs  in  a  pregnant,  Rh-negative  woman  who is carrying an Rh-positive fetus. The immunologic  system  in  the  mother  is  stimulated  by  fetal  cells  that  cross  the  placental  barrier  into  the  maternal  circula- tion  to  produce  antibodies  to  the  Rh  antigen,  which  then  cross  the  placenta  into  the  fetal  circulation  and  opsonize  fetal  Rh-positive  red  cells,  resulting  in  their  destruction in the spleen.

One  of  the  earliest  signs  of  fetal  anemia  caused  by  Rh  alloimmunization  is  an  elevated  fetal  middle  cere- bral artery (MCA) Doppler peak systolic velocity. Other  early  ultrasonic  signs  are  an  increase  in  the  size  and 

thickness of the placenta and fetal hepatomegaly. If the  hemolysis is allowed to progress untreated, it will result  in severe extramedullary hematopoiesis, portal hyper- tension, hypoalbuminemia, and the progressive devel- opment  of  in  utero  heart  failure  or  hydrops  fetalis.  Figure 15-1 shows a fetus severely affected by erythro- blastosis  fetalis,  which  should  now  be  completely  preventable.

Pathophysiology The  Rh  complex  is  made  up  of  a  number  of  antigens,  including C, D, E, c, d, e, and other variants, such as

C H A P T E R 15 Rhesus Alloimmunization 195

the  maternal  circulation  (fetomaternal  hemorrhage)  during  pregnancy. The  fetal  and  maternal  circulations  are  normally  separated  by  the  placental  barrier.  Small  hemorrhages occur in either direction across the intact  placenta throughout pregnancy. With advancing gesta- tional age, the incidence and size of these transplacen- tal  (fetomaternal)  hemorrhages  increase,  with  the  largest hemorrhages usually occurring at delivery. Most immunizations occur at the time of delivery, and antibodies appear either during the postpartum period or following exposure to the antigen in the next pregnancy.

Sensitization  can  also  occur  if  an  RhD-negative  woman  is  exposed  to  RhD-positive  blood  via  mis- matched transfusion or hematopoietic stem cell trans- plantation or by injection with contaminated needles.  In  rare  cases,  the  “grandmother”  theory  has  been  invoked.  This  theory  suggests  that  an  RhD-negative  woman may have been sensitized from birth by receiv- ing enough RhD-positive cells from her mother during  her own delivery (i.e., a maternal-fetal hemorrhage) to  produce an antibody response.

In general, two exposures to the RhD antigen are required to produce any significant sensitization,  unless the first exposure is massive. The first exposure  leads  to  primary  sensitization,  whereas  the  second  causes  an  anamnestic  response  leading  to  the  rapid  production  of  immunoglobulins.  The initial response to exposure to the RhD antigen is the production of immunoglobulin M (IgM) antibodies (which cannot cross the placenta) for a short period of time, followed by the production of IgG antibodies that are capable of crossing the placenta. If the fetus has the RhD antigen, these antibodies will coat the fetal red blood cells,  causing  them  to  be  destroyed,  or  hemolyzed,  in  the spleen. If the hemolysis is mild, the fetus can com- pensate by increasing the rate of erythropoiesis. If the  hemolysis  is  severe,  it  can  lead  to  profound  fetal  anemia,  resulting  in  extramedullary  hematopoiesis,  portal hypertension, hypoalbuminemia, hyperbilirubi- nemia,  and  heart  failure  (hydrops  fetalis),  as  well  as  intrauterine  fetal  death.  High  bilirubin  levels  can  damage the central nervous system and lead to neona- tal encephalopathy and kernicterus. Before the wide- spread use of RhD immune globulin for prevention of  RhD  isoimmunization,  kernicterus  was  one  of  the  leading  causes  of  cerebral  palsy  and  sensorineural  deafness.

If a pattern of mild, moderate, or severe disease has  been  established  with  two  or  more  previous  pregnan- cies, the disease tends either to be of the same severity  or  to  become  progressively  more  severe  with  subse- quent  pregnancies.  If a woman has a history of fetal hydrops with a previous pregnancy, the risk of hydrops with a subsequent pregnancy is about 90%.  Hydrops usually develops at the same time as or earlier  than in the previous pregnancy.

partial D antigens. More than 90% of cases of Rh allo- immunization  are  due  to  antibodies  to  the  D  antigen,  and  this  is  the  only  form  of  alloimmunization  that   can  be  prevented  with  Rh  immune  globulin  prophy- laxis. Therefore,  this  chapter  is  limited  to  a  discussion  of  the  D  antigen,  although  the  same  principles  apply   to  other  antigen-antibody  combinations.  A  person   who  lacks  the  D  antigen  on  the  surface  of  the  red   blood  cells  is  regarded  as  being  “RhD-negative,”  and   an  individual  with  the  D  antigen  is  considered  to  be  “RhD-positive.”

About  8%  of  African  Americans  are  RhD-negative,  whereas  about  15%  of  white  Americans  are  RhD- negative.  Only 1-2% of Asian and 1-2% of Native Americans are RhD-negative. When RhD-negative patients are exposed to the RhD antigen, they may become sensitized.  Most  cases  of  sensitization  are  caused  by  a  placental  leak  of  fetal  red  blood  cells  into 

FIGURE 15-1 Fetal hydrops is the most serious condition associ- ated with severe rhesus (Rh) incompatibility (erythroblastosis fetalis) between the mother and fetus. The fetal anemia caused by the blood incompatibility can lead to extramedullary hemato- poiesis, portal hypertension, heart failure, and excessive fluid leakage into the extracellular space of the fetus. This can lead to subcutaneous edema, hepatomegaly, ascites, pericardial effusion, and pleural effusion. Note the increased abdominal circumference of the infant in this photograph. The placenta is also enlarged (not pictured) in this condition, and increased fetal renal output (in response to the edema) leads to an increase in amniotic fluid (polyhydramnios). Fetal death is common. This condition should be very rare with preventive measures and modern management of Rh incompatibility.

PA R T 2 Obstetrics196

hemoglobin.  The  maternal  blood  is  fixed  on  a  slide  with  ethanol  (80%)  and  treated  with  a  citrate  phos- phate  buffer  to  remove  the  adult  hemoglobin.  After  staining with hematoxylin and eosin, the fetal cells can  readily  be  distinguished  from  the  maternal  cells.  All  cells  are  then  counted.  The  percentage  of  fetal  cells  present on the slide is determined and can be used to  estimate  the  extent  of  the  fetomaternal  hemorrhage  (measured in milliliters of whole blood) on the basis of  the following equation:

Percentage of fetal cells estimated maternal blood vo

× 5000 ( llume in milliliters)

As an example, if the Kleihauer-Betke is reported as  0.2%,  then  the  estimated  volume  of  fetal  blood  in  the  maternal  circulation  would  be  0.002 ×  5000,  or  10 mL  of  fetal  whole  blood.  There  are  a  number  of  different  formulas  available  for  estimating  the  degree  of  feto- maternal  hemorrhage,  and  all  should  be  viewed  as   estimates  based  on  their  underlying  assumptions  regarding  maternal  and  fetal  blood  volume.  However,  they  are  of  value  in  determining  the  amount  of  Rh  immune  globulin  to  administer  to  prevent  sensitiza- tion  of  an  RhD-negative  woman  who  is  suspected  of  having  a  fetomaternal  hemorrhage  (refer  to  the  “Pre- vention of RhD Alloimmunization” section later in this  chapter).

Recognition of the At-Risk Pregnancy A blood sample from every pregnant woman should be  sent  at  the  first  prenatal  visit  for  determination  of  the  blood group and RhD type and for antibody screening.  In RhD-negative patients whose anti-D antibody titers are positive (i.e., those who are RhD-sensitized), the RhD status of the father of the baby should be determined.

PATERNAL RHD GENOTYPING If the father is RhD-negative, the fetus will be RhD- negative and hemolytic disease will not occur, so further monitoring is unnecessary. If the father is RhD-positive, his Rh genotype should be determined using quantitative polymerase chain reaction.  If  he  is  homozygous  for  the  D  antigen,  the  fetus  will  be  RhD-positive and potentially affected. In this case, the  pregnancy  must  be  monitored  closely  for  hemolytic  disease.  If  the  father  is  heterozygous,  the  fetus  has  a  50% chance of being RhD-positive, indicating the need  for  fetal  RhD  genotyping.  Approximately  56%  of  RhD- positive  whites  are  heterozygous  for  the  RhD  antigen.  If  it  is  not  possible  to  test  the  D  antigen  status  and  zygosity  of  the  father,  it  must  be  assumed  that  he  is  D  antigen–positive.

Incidence Although fetomaternal hemorrhage is very common, the incidence of RhD immunization within 6 months of the delivery of the first RhD-positive, ABO- compatible infant is only about 8%. In addition, the incidence of sensitization with the development of a secondary immune response before the next RhD- positive pregnancy is 8%. Therefore, the overall risk of  immunization  for  the  second  full-term,  RhD-positive,  ABO-compatible  pregnancy  is  about  one  in  six  preg- nancies.  The  risk  of  RhD  sensitization  following  an  ABO-incompatible,  RhD-positive  pregnancy  is  only  about  2%.  The  protection  against  immunization  in  ABO-incompatible  pregnancies  is  due  to  the  destruc- tion of the ABO-incompatible cells in the maternal cir- culation and the removal of the red blood cell debris by  the liver.

Fetomaternal hemorrhage may also occur before delivery.  Establishment  of  the  fetal  circulation  occurs  at approximately 4 weeks’ gestation, and the presence  of the RhD antigen has been demonstrated as early as  38 days following conception. Consequently, RhD iso- immunization can occur at any time during pregnancy,  from  the  early  first  trimester  onward.  In  the  first  tri- mester,  the  most  common  causes  of  fetomaternal  hemorrhage  are  spontaneous  or  induced  abortions.  The incidence of immunization following spontane- ous abortion is 3.5%, whereas that following induced abortion is 5.5%. The risk is low in the first 8 weeks, but  it rises to significant levels by 12 weeks’ gestation. The risk of immunization following ectopic pregnancy is about 1%. Fetomaternal hemorrhage can also occur in the setting of second- or third-trimester vaginal bleeding, after invasive procedures such as amnio- centesis or chorionic villus sampling, after abdomi- nal trauma, or after external cephalic version.  If  necessary,  the  amount  of  fetal  blood  entering  the  maternal  circulation  after  an  episode  associated  with  fetomaternal  hemorrhage  can  be  estimated  using  the  Kleihauer-Betke  test  (described  in  the  next  section  of  this chapter). All pregnant RhD-negative women who are not sensitized to the D antigen should routinely receive prophylactic Rh immune globulin at 28 weeks’ gestation, within 72 hours of delivery of an RhD- positive fetus, and at the time of recognition of any of the problems cited above that are associated with fetomaternal hemorrhage.

Detecting Fetomaternal Hemorrhage The Kleihauer-Betke test is dependent on the fact that adult hemoglobin is more readily eluted through the cell membrane in the presence of acid than is fetal

C H A P T E R 15 Rhesus Alloimmunization 197

below 1 : 16.  In  patients  with  a  positive  titer  less  than  1 : 16,  repeat  titers  should  be  obtained  every  2  to  4  weeks.  If  the  titer  rises  to  1 : 16  or  greater,  a  detailed  ultrasound  to  detect  hydrops  and  Doppler  studies  of  the  MCA  are  indicated. Titers  are  not  generally  useful  for  following  a  patient  with  a  history  of  a  previous   fetus or neonate with hemolytic disease. In this setting,  even  if  the  titers  are  below  the  critical  threshold,  the  patient should be followed and evaluated as if her titers  were high.

ULTRASONIC DETECTION OF FETAL HEMOLYTIC DISEASE Ultrasonic examinations of a woman with a fetus at risk  for  hemolytic  disease  include  MCA  Doppler  studies  and  a  detailed  examination  looking  for  the  advent   of  fetal  hydrops.  Serial Doppler assessments of peak systolic velocity in the fetal MCA have proven to be the most valuable tools for detecting fetal anemia. In  at-risk  pregnancies,  this  test  should  be  performed  every  1  to  2  weeks  from  18  to  35  weeks’  gestation.  A   fetal  MCA  peak  systolic  velocity  value  above  1.5  mul- tiples of the median for gestational age is predictive of  moderate  to  severe  fetal  anemia  and  is  an  indication  for percutaneous umbilical blood sampling for precise  determination  of  fetal  hemoglobin  concentration.  Intrauterine  fetal  transfusion  should  follow  if  indi- cated. After 35 weeks’ gestation, this test may produce a higher false-positive rate (Figures 15-2 and 15-3).

TECHNIQUES FOR EVALUATING FETAL RHD STATUS Fetal  RhD  status  should  be  determined  in  RhD- sensitized pregnancies when the father is heterozygous  for  the  RhD  antigen  or  his  RhD  antigen  status  is  unknown.  This  can  be  done  noninvasively  by  testing  cell-free  fetal  DNA  in  maternal  plasma  as  early  as  the  end  of  the  first  trimester.  If  this  testing  is  inconclu- sive,  amniocentesis  can  be  performed  in  the  second  trimester and fetal RhD genotyping can be done using  amniocytes. A risk of amniocentesis, as noted earlier, is  fetomaternal hemorrhage and worsening of the hemo- lytic disease. Chorionic villus sampling carries an even  greater risk of worsening hemolytic disease if the fetus  is  RhD-positive,  and  its  use  for  determining  fetal  RhD  status is discouraged.

MATERNAL RHD ANTIBODY TITER Maternal anti-D antibody titers are used as a screen- ing tool to estimate the severity of fetal hemolysis in Rh disease. At many centers, anti-D antibody titers are  used  to  help  guide  decision  making  regarding  the  ini- tiation of testing procedures (e.g., MCA Doppler studies  and  percutaneous  umbilical  blood  sampling).  The American College of Obstetricians and Gynecologists and independent researchers have stated that a fetus in the first immunized pregnancy is not in serious jeopardy when the anti-D antibody titer remains

FIGURE 15-2 Middle cerebral artery (MCA) Doppler peak velocities based on gestational age. MoM, Multiples of the median. (Data from Moise KJ Jr: Management of rhesus alloimmunization in pregnancy. Obstet Gynecol 100:600–611, 2002.)

80 A zone—mild anemia

Median

1.5 MoM

1.29 MoM A

B B zone—moderate to severe anemia

70

60

50

40

30

20

353020 25

GESTATIONAL AGE (wk)

M C

A P

E A

K V

E L

O C

IT Y

( cm

/s e

c)

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tive zones for mild, moderate, and severe disease. The great drawback of using amniotic fluid spectropho- tometry to determine the severity of fetal hemolytic disease is that amniocentesis, especially if transpla- cental, can increase the severity of fetomaternal transfusion and worsen the severity of the disease. For this reason and others, amniotic fluid spectro- photometry has been replaced by serial Doppler assessments of MCA peak systolic velocities and is discussed for historical purposes only.

PERCUTANEOUS UMBILICAL BLOOD SAMPLING If there is ultrasonic evidence of fetal hydrops, or if the  MCA peak systolic velocity is greater than 1.5 multiples  of  the  median  for  gestational  age  (see  Figure  15-2),  moderate  to  severe  fetal  anemia  may  be  present  and  there  is  an  indication  for  fetal  blood  sampling  if  the  fetus  is  at  less  than  35  weeks’  gestation.  Advances  in  fetal  interventional  techniques  and  high-resolution  ultrasonography  have  made  direct  fetal  blood  sam- pling  the  most  accurate  method  for  the  diagnosis  of  fetal hemolytic disease. Percutaneous umbilical blood sampling (PUBS) can allow measurement of fetal hemoglobin, hematocrit, blood gases, pH, and biliru- bin levels.  If  the  fetal  hematocrit  is  less  than  30,  or  more than two standard deviations below the mean for  gestational age, intrauterine transfusion is indicated.

The ultrasonic examination should include a detailed  fetal  assessment  for  anatomy,  growth,  estimated  fetal  weight, and (if viable) biophysical profile, plus a deter- mination  of  placental  size  and  thickness  and  hepatic  size. Both the placenta and the fetal liver are enlarged with hydrops fetalis. Fetal hydrops is easily diagnosed on ultrasound by the characteristic appearance of two or more of the following: ascites, pleural effusion, pericardial effusion, skin edema, or polyhydramnios.  Appearance of any of these factors during an ultrasonic  examination  necessitates  therapeutic  intervention,  depending  on  the  fetal  gestational age.

AMNIOTIC FLUID SPECTROPHOTOMETRY Before  widespread  use  of  MCA  Doppler  studies,  spec- trophotometric  analysis  of  amniotic  fluid  bilirubin  concentration was the most frequently used method of  gauging  the  severity  of  fetal  hemolysis.  The  optical  density deviation (ΔOD) at 450 µ from a baseline drawn  between the OD values at 365 and 550 µ measures the  amniotic  fluid  unconjugated  bilirubin  level,  which  in  turn correlates with the cord blood hemoglobin of the  newborn at birth.

Liley  devised  a  graph  based  on  the  correlation  of  cord blood hemoglobin concentrations at birth and the  amniotic fluid ΔOD at 450 µ. Using this method, he was  able  to  establish  the  Liley  graph  or  curve  with  predic-

FIGURE 15-3 Obtaining a middle cerebral artery Doppler peak systolic velocity.

C H A P T E R 15 Rhesus Alloimmunization 199

is  lower  than  after  intravascular  transfusion.  Because  of  this,  intravascular  transfusion  is  the  method  of  choice for correcting fetal anemia, and intraperitoneal  transfusion is reserved for cases in which intravascular  transfusion is not possible, such as gestational age less  than 20 weeks.

Intravascular Transfusion In most cases, intravascular transfusion is the preferred  method.  Fetal  survival  is  better  with  this  technique  than  after  intraperitoneal  transfusions,  especially  if  there  is  ascites  or  other  evidence  of  hydrops.  In  addi- tion, transfusion into the peritoneal cavity can result in  fetal bradycardia or a pseudosinusoidal fetal heart rate  pattern  following  the  procedure  because  of  compres- sion at the site of insertion of the umbilical cord.

Under ultrasonic guidance, and using sterile tech- nique, a 22-gauge spinal needle is inserted into the umbilical vein near the placental insertion. An initial  fetal hematocrit is determined, and a paralyzing agent  is  injected.  The  volume  of  blood  to  be  transfused  is  based  on  the  estimated  fetal  body  weight,  as  deter- mined by ultrasonography, the initial fetal hematocrit,  the  target  fetal  hematocrit,  and  the  hematocrit  of  the  packed red cells to be transfused.

OTHER MODES OF THERAPY Maternal plasmapheresis combined with administra- tion of intravenous immunoglobulin may be helpful in  cases  of  severe  erythroblastosis  when  intrauterine  transfusions  have  not  been  successful,  but  further  research must be done before this can be recommended.  Phenobarbital  has  been  used  to  induce  fetal  hepatic  enzyme  maturation,  thereby  increasing  uptake  and  excretion of bilirubin by the liver. Treatment with phe- nobarbital is initiated at least 1 week before delivery.

TIMING OF DELIVERY IN THE RH-SENSITIZED FETUS In  addition  to  serial  MCA  Doppler  studies  and  detec- tion  of  hydrops,  these  fetuses  should  be  evaluated  twice  weekly  from  at  least  32  weeks  until  delivery  for  fetal  well-being  (nonstress  tests,  modified  biophysical  profile)  and  every  3  weeks  for  fetal  growth.  Although the goal is a term delivery, the risks of intrauterine demise, including that caused by procedure-related losses, must be balanced against the risks of prema- turity.  There  is  no  absolute  gestational  age  cutoff  for  intrauterine transfusions, but after 35 weeks the risk of  an  intrauterine  loss  may  be  greater  than  the  risk  of  a  neonatal  death.  It  may  be  prudent  in  this  setting   to  deliver  the  fetus  and  transfuse  the  neonate,  if   necessary.  If delivery is expected to occur before 34 weeks’ gestation (or if amniocentesis suggests an immature lung profile), betamethasone should be given at least 48 hours before delivery to enhance fetal pulmonary maturation.

The technique for fetal blood sampling is similar to  that  described  for  fetal  intravenous  transfusion.  One  drawback is that it requires expertise above and beyond  that required for amniocentesis. The major risk is fetal exsanguination from tears in placental vessels,  so  in  most  cases  blood  will  have  been  ordered  before  the  procedure and will be on hand in case an intrauterine  transfusion  is  needed  (see  below).  If  the  procedure  is  performed  by  an  experienced  practitioner,  the  risk   of  this  complication  and  fetal  death  is  no  more  than  1-2%. However, there is a greater risk of fetomaternal hemorrhage.  Percutaneous  umbilical  blood  sampling  should  not  be  a  first-line  method  of  assessing  fetal  status unless clearly indicated.

Management of the At-Risk Pregnancy INTRAUTERINE TRANSFUSION Intrauterine transfusion, initially introduced in 1963 as  an  intraperitoneal  transfusion  and  currently  usually  administered as an intravascular transfusion, has mark- edly changed the prognosis for severely affected fetuses.  The goal is to transfuse fresh group O, Rh-negative packed red blood cells.  In  addition  to  routine  blood  bank  screening  for  viruses  such  as  hepatitis  and  HIV,  the  blood  for  transfusion  is  irradiated,  washed,  pro- cessed through a leukocyte-poor filter, and screened for  cytomegalovirus.  Transfusions  are  done  under  ultra- sonic guidance using sterile technique, either in or near  the  operating  room  if  the  fetus  is  potentially  viable  so  that delivery can be accomplished expeditiously should  the fetal status deteriorate irreversibly.

Transfusions usually cannot be done until 18 to 20 weeks’ gestation, because fetal size limits vascular access. Repeat transfusions are generally scheduled at  1- to 3-week intervals, and the final transfusion is typi- cally performed at 32 to 35 weeks’ gestation. In general,  the fetus is delivered when the lungs are mature, when  it reaches 37 weeks, or if antepartum testing indicates  severe fetal compromise.

The overall survival rate following intrauterine transfusion is about 90%, but it is significantly lower for fetuses with hydrops before the transfusion.  Approximately  90%  of  survivors  are  reported  to  have  normal neurologic outcomes.

Fetal Intraperitoneal Transfusion Red blood cells are absorbed via the subdiaphragmatic  lymphatics  and  proceed  via  the  right  lymphatic  duct  into the fetal intravascular compartment. After transfu- sion,  the  absorption  of  blood  may  be  monitored  with  serial transverse ultrasonic scans of the fetal abdomen.  In nonhydropic fetuses, the blood should be absorbed within 7 to 9 days. In the presence of hydrops, absorp- tion is variable and the survival rate of hydropic fetuses 

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For  this  reason,  any  positive  antibody  screen  in  preg- nancy,  even  in  an  RhD-positive  woman,  should  be   followed  up  with  an  antibody  identification  and  titer.   If  the  antibody  screen  is  positive  for  one  or  more   antibodies  associated  with  hemolytic  disease  of  the  newborn,  the  pregnancy  should  be  followed  in  a  fashion  similar  to  that  advised  for  the  RhD-sensitized  pregnancy.

A  potential  exception  to  this  is  Kell  sensitization.  Antibody  titers  are  not  as  reliable  for  the  detection  of  fetal  anemia  in  this  situation,  probably  because  the  anemia  is  due  more  to  suppression  of  hematopoiesis  than  to  hemolysis.  The  MCA  peak  systolic  velocity  remains an excellent predictor of anemia in this setting.  It is extremely important to test the Kell antigen status  of  the  father  before  any  invasive  testing,  because  90%  of the population is Kell-negative.

Prevention of RhD Alloimmunization Because RhD immunization occurs in response to exposure of an RhD-negative mother to the RhD antigen, the mainstay for prevention is the avoidance of maternal exposure to the antigen.  Rh  immune  globulin diminishes the availability of the RhD antigen  to  the  maternal  immune  system,  although  the  exact  mechanism  by  which  it  prevents  RhD  alloimmuniza- tion is not well understood.

Rh  immune  globulin  is  prepared  from  fractionated  human plasma obtained from hyperreactive sensitized  donors. The plasma is screened for hepatitis B surface  antigen  and  anti-HIV-1.  The  globulin  is  available  in  several  dosages  for  intramuscular  injection.  Since the advent of its use in 1967, Rh immune globulin has dramatically reduced the incidence of Rh isoimmuni- zation. Three hundred micrograms (or 1 U) of Rh immune globulin can neutralize 30 mL of fetal RhD- positive blood in the maternal circulation.

Because the greatest risk for fetomaternal hemor- rhage occurs during labor and delivery, Rh immune globulin was initially administered only during the immediate postpartum period. This resulted in a 1-2%  failure rate, which is thought to be caused by exposure  of  the  mother  to  fetal  red  blood  cells  during  the  ante- partum  period.  The indications for the use of Rh immune globulin have therefore been broadened to include any antepartum event (such as amniocente- sis) that may increase the risk of transplacental hem- orrhage. The routine prophylactic administration of Rh immune globulin at 28 weeks’ gestation is now the standard of care.  Despite  adherence  to  this  sug- gested Rh immune globulin protocol, 0.27% of primip- arous  RhD-negative  patients  still  become  sensitized.  Although this is a low rate, it is still unacceptable, given  that it is preventable.

It is the responsibility of every health care practi- tioner who is involved in the care of pregnant women to prevent RhD alloimmunization by the appropriate administration of Rh immune globulin. Box 15-1 lists the indications and dosing for Rh immune globulin.

IRREGULAR ANTIBODIES Although RhD alloimmunization is the most common  cause of hemolytic disease in the newborn, other anti- gens in the Rh system (C, c, E, e) and other blood group systems, such as Kell, Duffy, or Kidd, can also cause fetal hemolytic disease. Kell antigen can elicit a  strong IgG response similar to RhD alloimmunization. 

BOX 15-1

INDICATIONS AND DOSING FOR RH IMMUNE GLOBULIN

•  Blood  type  and  antibody  screen  are  performed  for  all  pregnant women at their first prenatal visit.

•  Women  who  are  RhD-negative  with  a  negative  initial  screen should have a repeat screen at 28 weeks.

•  Those  women  with  a  negative  screen  at  28  weeks  should  receive  300 µg  of  Rh  immune  globulin  (prophylactically).

•  Those women with a positive screen should have their  antibodies identified. If RhD-negative, they should also  receive 300 µg of Rh immune globulin.

•  All  pregnant  women  who  are  RhD-negative  and  who  are  not  sensitized  (anti-D–negative)  and  who  experi- ence (1) spontaneous or induced abortion, (2) ectopic  pregnancy,  (3)  significant  vaginal  bleeding,  (4)  amnio- centesis, (5) abdominal trauma, or (6) cephalic version  should receive 50-100 µg of Rh immune globulin before  12 weeks’ gestation and be administered 300 µg if later  than 12 weeks.

•  Rh  immune  globulin  is  not  necessary  for  complete  molar pregnancies, but it is necessary for partial molar  pregnancies, where fetal tissue may be present. Because  this is not always clear at the time of evacuation, 300 µg  of the immune globulin should be given.

•  The  greatest  risk  of  fetomaternal  hemorrhage  is  at  the  time  of  delivery.  Rh  immune  globulin  (300 µg)  should  be  given  routinely  within  72  hours  of  delivery  to  all  Rh-negative,  anti-D–negative  women  who  deliver  an  Rh-positive child.

•  Additional  Rh  immune  globulin  is  indicated  if  the  delivery  is  complicated  by  excessive  hemorrhage  (>30 mL  of  fetal  blood  suspected  or  documented  by  Kleihauer-Betke testing).

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16  Common Medical and Surgical Conditions Complicating Pregnancy

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LONY C. CASTRO • JOSEPH C. GAMBONE

■  Diabetes  and  thyroid  disorders  are  among  the  most  common  and  consequential  medical  conditions  that  occur  during  pregnancy,  labor,  and  the  postpartum  period.  Diabetes  may  precede  pregnancy  or  may  occur  because of pregnancy, with a return to the prepregnancy  state  after  delivery.  Gestational diabetes mellitus  (GDM)  is  defined  as  glucose  intolerance  with  onset  or  first  rec- ognition during pregnancy. Pregestational diabetes mel- litus may be type 1 (insulin-dependent) or type 2. Thyroid  abnormalities occur in about 2% of pregnancies, and the  presentation  and  course  of  the  disease  may  be  affected  by the pregnancy.

■  Other important medical conditions include heart, auto- immune, renal, gastrointestinal (GI), lung, and thrombo- embolic  disorders.  Preexisting  cardiovascular  disease  and  conditions  such  as  asthma  and  cystic  fibrosis  are  encountered  more  commonly  because  of  modern  medical  management  that  has  allowed  more  women  than in the past to consider pregnancy. As a general rule,  most  pregnancies  complicated  by  these  medical  condi- tions  are  considered  “high  risk”  for  maternal  and  fetal  morbidity  and  mortality.  Good  outcomes  often  require  frequent  maternal  and  fetal  assessment  and  the  ability  to respond in a timely fashion to changes in the clinical  status of either the mother or her fetus.

■  Elective  delivery  for  medical  and  surgical  conditions  is  indicated  when  deteriorating  maternal  or  fetal  status  occurs  in  the  presence  of  a  term  fetus  or  when  there  is  evidence of fetal lung maturity. When a preterm delivery 

before  34  weeks’  gestation  is  necessary,  steroids  (beta- methasone) should be given to enhance fetal lung matu- rity and improve fetal outcomes. In some cases, cesarean  delivery is indicated.

■  Obstetricians  and  other  providers  should  focus  on  the  mitigation of the effects and prevention of medical con- ditions  that  may  complicate  pregnancy.  The  increased  prevalence  of  obesity  in  pregnant  women  in  the  United  States and elsewhere has resulted in metabolic dysregu- lation  (metabolic  syndrome)  that  increases  inflamma- tion  and  insulin  resistance.  The  risk  of  some  medical  disorders,  such  as  diabetes,  hypertension,  and  heart  disease, is increased due to excessive body weight during  pregnancy. Women should be encouraged to lose weight  before  pregnancy  and  to  limit  weight  gain  during  preg- nancy.  Physical  activity  and  a  healthy  diet  are  very  important before, during, and after pregnancy.

■  Surgical  conditions  that  may  complicate  pregnancy  include  appendicitis,  cholecystitis  and  cholelithiasis,  acute pancreatitis, bowel obstruction, abdominal trauma,  or  torsion  of  an  adnexal  structure  such  as  an  ovarian  tumor.  When  trauma  is  evaluated  during  pregnancy,   the  possibility  of  intimate  partner  abuse  must  be  ruled  out,  as  in  women  who  are  not  pregnant.  Strongly  indi- cated but nonemergent surgery is most safely performed  in the second trimester. Laparoscopy is becoming more  common  during  pregnancy,  and  guidelines  have  been  published  that  should  increase  the  safety  for  both  the  pregnant woman and her fetus.

CLINICAL KEYS FOR THIS CHAPTER

Most of the conditions discussed in this chapter are not  unique  to  pregnancy  and  understanding  the  causes,  diagnosis,  and  management  of  them  is  based  on  the  same  principles  that  would  apply  in  the  nonpregnant  woman.  Important issues  for  the  management  of  medical  and  surgical  problems  during  pregnancy  include  how the physiologic changes of pregnancy may affect the diagnosis and clinical course  of  the  disease, as well as how the disease may affect the preg- nancy, with particular attention to the fetus.

The  most  common  medical  and  surgical  disorders  that  may  complicate  pregnancy  are  covered  in  this  chapter. Common and important infectious diseases of  both nonpregnant and pregnant women are covered in  Chapter  22,  including  perinatal  infections  (toxoplas- mosis, others [syphilis, varicella zoster, parvovirus B19],  rubella,  cytomegalovirus  [CMV],  and  herpes,  referred  to  together  as  TORCH infections),  human  immunode- ficiency  virus  (HIV )  infection,  and  acquired  immuno- deficiency syndrome (AIDS).

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Complications Maternal and fetal complications of diabetes are listed  in Table  16-2.  Diabetes often coexists with the meta- bolic syndrome. This syndrome consists of a group of  risk  factors  for  diabetes,  coronary  heart  disease,  and  stroke  that  occur  together  (central  obesity,  insulin  resistance, and hyperlipidemia). Most fetal and neona- tal effects are attributed to the consequences of mater- nal hyperglycemia or, in the more advanced classes, to  maternal  vascular  disease.  Glucose crosses the pla- centa easily by facilitated diffusion, causing fetal hyperglycemia that stimulates pancreatic β-cells, and results in fetal hyperinsulinism. Fetal hyperglycemia during the period of embryogenesis is teratogenic.  There  is  a  direct  correlation  between  birth  defects  in  diabetic  pregnancies  and  increasing  glycosylated  hemoglobin  A1C  (HbA1C)  levels  in  the  first  trimester.  Fetal hyperglycemia and hyperinsulinemia later in pregnancy, especially in the third trimester, cause fetal overgrowth and macrosomia that predispose to birth trauma, including shoulder dystocia and Erb palsy. Fetal demise is most likely due to acidosis, hypotension from osmotic diuresis, or hypoxia from increased metabolism, coupled with inadequate pla- cental oxygen transfer.

Pregestational  diabetes  is  generally  associated  with  a  higher  rate  of  maternal  and  fetal  complications   due  to  the  greater  difficulty  in  achieving  glycemic  control,  the  higher  rate  of  congenital  malformations,  and the higher likelihood of vascular disease. Maternal  complications  include  worsening  nephropathy  and  retinopathy, a greater incidence of preterm preeclamp- sia,  and  a  higher  likelihood  of  diabetic  ketoacidosis.  Hypoglycemia is also much more common  because  of  the  need  for  insulin  therapy  and  stricter  glycemic  control  attempted  during  pregnancy.  Fetal compli- cations include an increased rate of abortions, anatomic birth defects, fetal growth restriction, and prematurity.

Diagnosis of Gestational Diabetes Mellitus The American College of Obstetricians and Gynecolo- gists (ACOG) recommends a two-step method to test for GDM. The first step involves universal screening for gestational diabetes between 24 and 28 weeks’ gestation with a 50-g, 1-hour oral glucose challenge test (OGCT), given without regard to most recent oral intake.  This  timing  recognizes  the  progressive  nature  of  insulin  resistance  in  pregnancy  due  to  rising  levels  of  hormones  such  as  human  placental  lactogen,  and  the test will identify most women with gestational dia- betes  while  allowing  for  several  weeks  of  therapy  to  reduce  potentially  adverse  consequences.  Screening is advised at the first prenatal visit in women with risk factors  such  as  a  previous  pregnancy  with  GDM,  a  history  of  polycystic  ovarian  disease,  or  obesity.  If  overt signs and symptoms of diabetes are present, the 

TABLE 16-1

WHITE CLASSIFICATION OF DIABETES IN PREGNANCY

Class Description

A1 Gestational diabetes; diagnosed in pregnancy and controlled with diet alone

A2 Gestational diabetes; diagnosed in pregnancy and controlled with diet and glyburide or insulin

B Pregestational diabetes developing after age 20 yr and duration <10 yr; controlled with diet and insulin

C Pregestational diabetes developing between ages 10 and 19 yr or duration 10-19 yr and controlled with diet and insulin

D Pregestational diabetes developing before age 10 yr or duration 20 yr or more or background retinopathy; controlled with diet and insulin

F Pregestational diabetes at any age or duration with nephropathy; controlled with diet and insulin

R Pregestational diabetes at any age or duration with proliferative retinopathy; controlled with diet and insulin

H Pregestational diabetes at any age or duration with arteriosclerotic heart disease; controlled with diet and insulin

Endocrine Disorders Diabetes  mellitus  and  thyroid  disease  are  the  two   most  common  endocrine  disorders  complicating  pregnancy.

DIABETES MELLITUS Incidence and Classification The prevalence of diabetes mellitus has greatly increased in the last 20 years.  In  the  United  States,  rates  appear  to  range  from  6-12%,  depending  on  the  population  studied  and  the  diagnostic  criteria  used.  Overall, 80-90% of diabetes in pregnant women is gestational, and about 10% is pregestational.

Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset or first recognition during pregnancy.  Rising  levels  of  human placental lactogen, progesterone, prolactin, and cortisol in pregnancy are some of the primary factors associated with progressive insulin resistance during pregnancy.  Studies  suggest  that  women  who  develop  GDM  have  chronic  insulin  resistance  and  that  GDM  is  a  “stress  test” for the development of diabetes later in life.

Pregestational diabetes mellitus  refers  to  diabetes  present  before  pregnancy  and  may  be  either  type  1   or  type  2  diabetes.  Most  obstetricians  use  the  White classification of diabetes during pregnancy to further refine the categories for GDM and pregestational diabetes.  This  classification  is  helpful  for  assessing  disease  severity  and  the  likelihood  of  complications  (Table 16-1).

C H A P T E R 16 Common Medical and Surgical Conditions Complicating Pregnancy 203

TABLE 16-2

MATERNAL AND FETAL COMPLICATIONS OF DIABETES MELLITUS

Entity Monitoring

Maternal Complications

Obstetric Complications

Polyhydramnios Close prenatal surveillance: blood glucose monitoring, ultrasonography

Preeclampsia Evaluation for signs and symptoms

Infections (e.g., UTI and candidiasis) Urine culture, wet mount, and appropriate therapy

Cesarean delivery Blood glucose monitoring, insulin and dietary adjustment to prevent fetal overgrowth

Genital trauma Ultrasonography to detect macrosomia, cesarean delivery for macrosomia

Diabetic Emergencies

Hypoglycemia Teach signs and symptoms; blood glucose monitoring; insulin and dietary adjustment

Diabetic coma Urgent medical management required

Ketoacidosis Check for ketones if glucose >200 mg/dL Vascular and End-Organ Involvement or Deterioration (in patients with pregestational diabetes mellitus)

Cardiac Electrocardiogram, first visit and as needed

Renal Renal function studies, first visit and as needed

Ophthalmic Funduscopic evaluation, first visit and as needed

Peripheral vascular Check for ulcers, foot sores; noninvasive Doppler studies as needed

Gastrointestinal disturbance Symptomatic treatment as needed

Neurologic

Peripheral neuropathy Neurologic and gastrointestinal consultations as needed

After Pregnancy

Type 2 diabetes Postpartum glucose testing of GDM, lifestyle changes (diet and exercise)

Metabolic syndrome Lifestyle changes (diet and exercise)

Obesity Lifestyle changes (diet and exercise)

Cardiovascular disease Annual check-up by physician, lifestyle changes (diet and exercise)

Fetal and Neonatal Complications*

Macrosomia with traumatic delivery Ultrasonography for estimated fetal weight before delivery (shoulder dystocia, Erb palsy), offer cesarean delivery if EFW >4500 g

Delayed organ maturity (pulmonary, hepatic, neurologic)

Avoid delivery before 39 weeks in GDM in the absence of maternal-fetal respiratory distress syndrome indications, unless amniocentesis indicates lung maturity

Neonatal hypocalcemia, neonatal hypoglycemia

Maintain maternal euglycemia especially intrapartum

Congenital Defects

Cardiovascular anomalies Preconception counseling and glucose control

Neural tube defects Maternal serum α-fetoprotein screening; fetal ultrasonography and fetal echocardiogram

Caudal regression syndrome

Other defects (e.g., renal)

Fetal Compromise

Intrauterine growth restriction Serial ultrasonography for fetal growth and estimated fetal weight, serial fetal antepartum surveillance; avoid postterm pregnancy

Intrauterine fetal death Doppler

Abnormal FHR patterns NST

EFW, Estimated fetal weight; FHR, fetal heart rate; GDM, gestational diabetes mellitus; NST, nonstress test; UTI, urinary tract infection. *Maintenance of maternal euglycemia (normal glucose levels) will decrease most of these complications.

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patients  less  than  80%  of  ideal  body  weight,  and  24 kcal/kg for gravidas who are 120-150% of ideal body  weight. The  diet  is  composed  of  about  45-50%  carbo- hydrate,  20-25%  protein,  and  20-25%  fat.  The  diet  should also contain a generous amount of fiber. Caloric  intake  is  divided  into  20%  at  breakfast,  30%  at  lunch,  30% at dinner, and 20% at a bedtime snack.

EXERCISE. Patients with diabetes should be encouraged  to  engage  in  mild  to  moderate  aerobic  exercise  (e.g.,  brisk walking) for about half an hour after meals.

PHARMACOLOGIC THERAPY. Patients  with  GDM  are  usually  managed  with  diet  and  exercise  alone,  but  if  euglycemia cannot be achieved, an oral hypoglycemic  agent  (glyburide)  or  insulin  should  be  added.  Glybu- ride  does  not  appear  to  enter  the  fetal  circulation  in  appreciable  quantities,  and  it  has  been  used  success- fully  to  treat  gestational  diabetes  after  the  first  trimester.

Insulin  is  the  medication  of  choice  to  maintain  eu- glycemia  in  pregnancy  and  is  the  recommended  therapy  in  women  with  pregestational  diabetes.  The  peak action of insulin lispro occurs between 30 and 90  minutes  after  injection,  that  of  regular  insulin  occurs  between  2  and  3  hours  after  injection,  and  that  of  neutral  protamine  Hagedorn (NPH)  insulin  occurs  between 6 and 10 hours after injection. A combination  of  rapid-  or  short-acting  (lispro  or  regular)  and  intermediate-acting  (NPH)  insulin  is  usually  given  in  split morning and evening doses or more frequently to  achieve  euglycemia.  A  method  for  calculating  insulin  dosage is shown in Box 16-1.

Antepartum Obstetric Management Aside  from  achieving  euglycemia,  adequate  surveil- lance should be maintained during pregnancy to detect  and  possibly  mitigate  maternal  and  fetal  complica- tions. In addition to routine prenatal screening tests for 

patient’s fasting blood sugar should be checked first. If a first-trimester screen is done and is found to be negative, it should be repeated at 24 to 28 weeks. Glucose values above 130 to 140 mg/dL on an OGCT are considered abnormal  and  have  an  80-90%  sensi- tivity in detecting GDM.

The second step involves performing a diagnostic 3-hour, 100-g oral glucose tolerance test (OGTT) if the screening test is abnormal. This involves checking the  patient’s  fasting  blood  glucose  after  an  overnight  fast,  having the patient consume a 100-g glucose drink, and  checking her glucose levels hourly for 3 hours. If there are two or more abnormal values on the 3-hour OGTT, the patient is diagnosed with GDM (Table 16-3). If the 1-hour screening (50 g of oral glucose) plasma glucose exceeds 200 mg/dL, an OGTT is not required and may dangerously elevate blood glucose values.

Management TEAM APPROACH. Management of gestational and pre- gestational  diabetes  requires  a  team  approach  involv- ing patient education and counseling, medical-nursing  assessments  and  interventions,  strategies  to  achieve  maternal euglycemia, and avoidance of fetal-neonatal  compromise.  Ideally,  this  team  should  include  the  patient, obstetrician, maternal-fetal medicine special- ist, clinical nurse specialist, nutritionist, social worker,  and neonatologist. The patient is included as an active  participant in formulating management strategies.

ACHIEVING EUGLYCEMIA. The importance of strict met- abolic control before and during pregnancy to decrease  the incidence of congenital anomalies, perinatal mor- bidity, and perinatal mortality has been established. To  achieve an optimal outcome, the patient’s fasting blood  glucose  level  should  be  less  than  95 mg/dL,  with  the  1-hour postprandial glucose level less than 140 mg/dL  and  the  2-hour  postprandial  glucose  level  less  than  120 mg/dL.

DIET. Caloric  requirements  are  calculated  on  the  basis  of  ideal  body  weight:  30 kcal/kg  for  those  patients  80-120% of ideal body weight, 35 to 40 kcal/kg for those 

TABLE 16-3

THREE-HOUR ORAL GLUCOSE TOLERANCE TEST

Test Maximal Normal Blood Glucose (mg/dL)

Fasting 95

1 hr 180

2 hr 155

3 hr 140

From Berggren EK, Boggess KA, Stuebe AM, et al: National Diabetes Data Group vs Carpenter-Coustan criteria to diagnose gestational diabetes. Am J Obstet Gynecol 205:253.e1-e7, 2011.

BOX 16-1

METHOD FOR CALCULATING THE STARTING DOSE OF INSULIN

Insulin Units = Body Weight (kg) ×0.6 (first trimester) ×0.7 (second trimester) ×0.8 (third trimester) Dosage Schedule: Give Two-Thirds in AM and One-Third in PM Before  breakfast:  two-thirds  NPH,  one-third  regular  or 

lispro Before dinner: one-half NPH, one-half regular or lispro (if 

on  lispro,  administer  additional  dose  before  bedtime  snack)

NPH, Neutral protamine Hagedorn.

C H A P T E R 16 Common Medical and Surgical Conditions Complicating Pregnancy 205

Women with GDM should undergo a 75-g OGTT at 6 to 12 weeks postpartum.

Patients should be counseled about changes in diet.  The American Diabetes Association diet with the same  distribution of carbohydrates, proteins, and fat should  be  maintained.  If  the  mother  is  breastfeeding,  500  calories/day should be added to the prepregnancy diet.

Contraception  counseling  should  involve  advising  the  patient  that  estrogen-containing  oral  contracep- tives are not recommended for women with advanced- stage diabetes with vascular disease.

THYROID DISEASES Thyroid  diseases  are  relatively  common  disorders  in  pregnancy,  complicating  up  to  2%  of  pregnancies.  Pregnancy  can  alter  the  presentation,  diagnosis,  and  course of thyroid disease. If inadequately treated, these  disorders can lead to major maternal, fetal, and neona- tal morbidity.

Normal Thyroid Physiology during Pregnancy With  the  increase  in  glomerular  filtration  rate  that  occurs during pregnancy, the renal excretion of iodine  increases and plasma inorganic iodine levels are nearly  halved.  Goiters  caused  by  iodine  deficiency  are  not  likely if plasma inorganic iodine levels are greater than  0.08  µg/dL  but  they  do  occur  (Figure  16-1).  An  inor- ganic iodine intake of 250 µg/day is sufficient to prevent  goiter  formation  during  pregnancy.  Prenatal  vitamins  typically contain 150 µg of iodine.

THYROID FUNCTION TESTS. The  estrogen-mediated  increase in thyroid-binding globulin during pregnancy  results  in  a  pronounced  rise  in  serum  total  thyroxine  (T4) and total triiodothyronine (T3) levels. Total T4 levels  in a pregnant woman can be up to 50% greater than the 

women with pregestational diabetes, a detailed obstet- ric ultrasonic study, fetal echocardiogram, and mater- nal serum α-fetoprotein should be obtained in the second trimester to check for congenital malforma- tions. This is especially important if the first trimester HbA1C is significantly elevated (>8.5%).  Maternal  renal,  cardiac,  and  ocular  function  must  be  closely  monitored. In women with GDM as well as those with class B or C pregestational diabetes, fetal macroso- mia is common and should be investigated,  whereas  for women with classes D, F, or R pregestational diabe- tes,  fetal  growth  restriction  occurs  more  commonly.  Abnormalities  of  fetal  growth  are  most  likely  to  be  present in the third trimester and can be confirmed by  ultrasound.

Serial antepartum testing should be performed in the third trimester. This testing can usually be delayed  until at or after 36 weeks, or later in women with well- controlled GDM. In patients with pregestational diabe- tes, fetal testing should be initiated between 32 and 34  weeks, or sooner if complications develop.

The timing of delivery depends on fetal and mater- nal status and the degree of glucose control. In general, in the setting of well-controlled GDM without other complications, spontaneous onset of labor at term may be awaited. Earlier intervention is indicated  if these conditions are not met. For macrosomic babies,  increased birth trauma to both mother and fetus should  be avoided. Cesarean delivery may be elected for large fetuses (>4500 g).

Intrapartum Management Intrapartum management of a patient with diabetes requires the establishment of maternal euglycemia during labor.  Plasma  glucose  levels  are  measured  fre- quently,  and,  if  elevated,  a  continuous  infusion  of  regular  insulin  is  given.  Insulin dosage is adjusted as needed to maintain a plasma glucose level between 80 and 120 mg/dL.  Many  insulin-dependent  patients  will  not  require  exogenous  insulin  during  labor.  Con- tinuous  electronic  fetal heart rate monitoring is recommended for all patients with diabetes.

Postpartum Period After delivery of the fetus and placenta, insulin requirements drop sharply because the placenta, which is the source of many insulin antagonists, has been removed. Many patients with insulin-dependent  diabetes may not require exogenous insulin for the first  48  to  72  hours  after  delivery.  Plasma glucose levels should be monitored and lispro or regular insulin given when plasma glucose levels are elevated. Women  with  pregestational  diabetes  can  be  restarted  on  two- thirds of the prepregnancy insulin dosage, with adjust- ments  made  as  necessary.  Women  with  GDM  treated  with  insulin  or  oral  hypoglycemic  agents  during  preg- nancy  frequently  do  not  need  treatment  postpartum. 

FIGURE 16-1 A goiter caused by iodine deficiency in a pregnant woman (circle). Although iodine deficiency is rare during preg- nancy, it can occur in areas where preconception and prenatal care are inadequate. (From Lemmi FO, Lemmi CAE: Physical assessment findings [CD-ROM], Philadelphia, 2009, Saunders.)

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cause  of  hyperthyroidism.  Other  causes  of  hyperthy- roidism  in  pregnancy  include  hCG-mediated  hyper- thyroidism,  such  as  that  seen  in  association  with  a  hydatidiform  mole,  and  toxic  nodular  goiter.  Patients  with  Graves  disease  tend  to  have  a  remission  during  the  third  trimester  of  pregnancy  and  an  exacerbation  during the postpartum period. The increased immuno- logic tolerance during pregnancy may lead to a decrease  in  thyroid  antibodies,  which  may  account  for  the  remission.

CLINICAL FEATURES. The clinical diagnosis of hyper- thyroidism in pregnancy is difficult, because many of  the signs and symptoms of the hyperdynamic circula- tion  associated  with  hyperthyroidism  are  present  in  a  normal  euthyroid  pregnant  woman.  A  resting  pulse  rate  greater  than  100  beats  per  minute,  a  wide  pulse  pressure,  tremor,  eye  changes  (exophthalmos),  failure  to gain weight despite normal or increased food intake,  and  heat  intolerance,  when  present,  are  all  helpful  in  making the clinical diagnosis.

INVESTIGATIONS. An elevated serum free T4 level and a  suppressed TSH level establish the diagnosis of hyper- thyroidism. Infrequently, a free T3 determination might  be needed to diagnose T3 thyrotoxicosis. In cases where  there  is  significant  discordance  between  the  clinical  findings and TSH and free thyroid hormone levels, it is  appropriate to measure the total T4 level, accepting as  normal up to 1.5 times the upper range in nonpregnant  women.

THERAPY. Because radioactive iodine treatment is contraindicated during pregnancy, medical treat- ment is generally given.  When  there  is  significant  maternal  tachycardia,  β-blockers  such  as  atenolol  or  propranolol  may  be  used  for  short-term  treatment,  with longer-term treatment increasing the risk of fetal  growth  restriction.  Thioamides are the mainstay of antithyroid therapy. They block the synthesis, but not  the  release,  of  thyroid  hormone.  PTU and methima- zole (Tapazole) are both effective, but they have differ- ent  safety  profiles.  Both  cross  the  placenta,  and  methimazole  has  been  associated  with  aplasia  cutis  congenita  (absence  of  a  portion  of  skin  at  birth)  and  fetal  gastrointestinal  (GI)  defects  to  a  greater  degree  than PTU. For the mother, methimazole appears safer  because  there  is  less  risk  of  liver  toxicity.  These drugs readily cross the placenta, and a concern during maternal treatment is the development of fetal goiter and hypothyroidism.  Although  there  is  no  conclusive  evidence  that  PTU  treatment  leads  to  cretinism  or  abnormalities in physical or intellectual development,  1-5% of children exposed in utero will develop a goiter  (Figure  16-2).  For  these  reasons, PTU should be used to treat overt hyperthyroidism in the first trimester, and methimazole should be used in the second and

upper limit of normal for nonpregnant women. Serum free thyroxine (free T4) and free triiodothyronine (free T3) levels usually remain in the normal range. Human chorionic gonadotropin (hCG) levels peak in the first trimester and can cause transient, subclinical hyper- thyroidism. In the setting of a molar pregnancy, the extremely high hCG levels can result in thyrotoxico- sis.  When  interpreting  serum  levels  of  thyroid- stimulating hormone (TSH) and free T4 and T3, it is best  to  use  a  laboratory  that  has  trimester-specific  values.  Generally  accepted  TSH  ranges  for  nonpregnant  and  pregnant women by trimester are shown in Table 16-4.

FETAL THYROID FUNCTION. Before  10  weeks’  gestation,  no organic iodine is present in the fetal thyroid. By the  end  of  the  first  trimester  (11  to  12  weeks),  the  fetal  thyroid  is  able  to  produce  iodothyronines  and T4,  and  by 12 to 14 weeks, it is able to concentrate iodine. Levels  of  these  hormones  remain  low  even  at  term,  but  they  increase  rapidly  in  the  neonate  within  48  hours  of  birth.

PLACENTAL TRANSFER OF THYROID HORMONE. Iodide  freely crosses the placenta, but TSH does not. Limited  transfer  of  T4  occurs  across  the  placenta  and  appears  to be important for fetal neural development in the first  trimester before fetal thyroid function begins. Thyroid hormone analogues such as methimazole and pro- pylthiouracil (PTU), with smaller molecular weights, cross the placental barrier and can potentially cause fetal hypothyroidism. Thyroid-releasing hormone can  cross  the  placental  barrier,  but  there  is  no  significant  placental  transfer  because  of  circulating  low  levels.  Thyroid-stimulating  antibodies  (TSH  receptor  anti- bodies)  also  cross  the  placenta  and  can  potentially  cause fetal and neonatal thyroid dysfunction.

Maternal Hyperthyroidism The incidence of maternal thyrotoxicosis is about 1 per 500 pregnancies. It is accompanied by an increased incidence of prematurity, intrauterine growth restriction (IUGR), superimposed preeclamp- sia, stillbirth, and neonatal morbidity and mortality.  Graves  disease  is  an  autoimmune  disorder  caused  by  thyroid-stimulating antibodies. It is the most common 

TABLE 16-4

MEDIAN VALUES OF THYROID-STIMULATING HORMONE

Pregnancy Stage Median Value*

Nonpregnant 0.3-4.2 U/mL

First trimester 0.5-5.0 U/mL

Second trimester 0.5-3.5 U/mL

Third trimester 0.5-4.0 U/mL

*Rounded to the nearest 0.5.

C H A P T E R 16 Common Medical and Surgical Conditions Complicating Pregnancy 207

potassium iodide 1 to 2 hours after starting PTU to block secretion of thyroid hormone, (4) additional blocking of the deamination of T4 to T3 with glucocor- ticoids (dexamethasone), (5) replacing fluid losses, and (6) rapidly lowering the patient’s body tempera- ture with hypothermic techniques. Management also  involves  intensive  maternal  and  fetal  monitoring  and  correction  of  precipitating  factors.  It  is  important  to  stabilize  the  patient  before  attempting  delivery  if  that  is being considered. Once the patient is stabilized and  no  longer  acutely  ill,  methimazole  should  be  substi- tuted for PTU to avoid hepatotoxicity.

Neonatal Thyrotoxicosis About 5% of pregnant women with a history of Graves disease give birth to children with thyrotoxicosis due to transplacental transfer of TSH receptor anti- bodies. It is transient and lasts less than 2 to 3 months,  but  if  clinically  significant  and  untreated,  it  is  associ- ated with neonatal morbidity and mortality. Fetal thy- rotoxicosis can be suspected if the baseline fetal heart  rate consistently exceeds 160 beats per minute. A fetal  goiter  can  often  be  identified  by  ultrasonography  in  such cases, and fetal growth restriction may be present.  This situation is associated with an increase in perina- tal morbidity and mortality and should be treated pre-  and postnatally.

Hypothyroidism Hypothyroidism (overt or subclinical) complicates up to 3% of pregnancies. The value of universal screen- ing  is  still  being  debated,  and  ACOG  is  currently  not  recommending  routine  screening.  However,  pregnant  women  with  symptoms  consistent  with  low  thyroid  hormone levels (fatigue, intolerance to cold, excessive  weight  gain)  or  with  risk  factors  (e.g.,  obesity,  type  1  diabetes  or  history  of  thyroid  disease)  should  be  screened.

The most important laboratory finding of hypo- thyroidism is an elevated TSH level. If the TSH level is  elevated, the diagnosis of overt vs. subclinical hypothy- roidism  can  be  made  based  on  whether  free  T4  levels  are  decreased.  Once  diagnosed,  therapy  such  as  levo- thyroxine  should  be  started,  and  serum  TSH  levels  should be measured monthly with appropriate adjust- ments  in  levothyroxine  dosage.  Pregnant  women  on  appropriate thyroid replacement therapy can expect a  normal  pregnancy  outcome,  but  untreated maternal hypothyroidism has been associated with an increased risk of spontaneous abortion, preeclampsia, abrup- tion, low-birth-weight or stillborn infants, and lower cognitive function in offspring.

CONGENITAL HYPOTHYROIDISM. Thyroid hormone defi- ciency during the fetal and early neonatal periods leads to generalized cognitive impairment. The sever- ity of symptoms depends on the time of onset and the 

third trimesters. Importantly, antithyroid drugs should  be  reduced  to  the  lowest  dose  that  results  in  free  T4  levels within the upper range of normal. Free T4 levels  should  be  checked  at  least  every  4  weeks.  Antithyroid  therapy  can  often  be  discontinued  after  30  weeks’   gestation, but the patient should be followed for recur- rent disease postpartum.

Methimazole and PTU are excreted in breast milk,  but  no  changes  occur  in  the  thyroid  function  tests  of  breastfed neonates. Methimazole is preferred over PTU  in  breastfeeding  mothers  because  of  the  lower  risk  of  liver toxicity.

Surgical management of a pregnant patient with hyperthyroidism during the second trimester is rec- ommended only when medical treatment fails.

Thyroid Storm The major risk for a pregnant patient with thyrotoxi- cosis is the development of a thyroid storm. Precipi- tating factors include infection, labor, cesarean delivery, or noncompliance with the medication regimen.  It  is  not  uncommon  to  mistakenly  attribute  the  signs  and  symptoms  of  severe  hyperthyroidism  to  preeclampsia.  In  the  former,  significant  proteinuria  is  usually  absent,  but  both  may  be  present  in  the  same  patient. Thyroid storm in a pregnant woman is a life- threatening medical emergency and should be treated in an intensive care setting. The signs and symptoms associated with a thyroid storm include hyperther- mia, marked maternal tachycardia, perspiration, and high-output renal failure or severe dehydration. Fetal  tachycardia can also be present.

Specific treatment involves (1) blocking β-adrenergic activity and controlling maternal heart rate with pro- pranolol, (2) blocking synthesis of thyroid hormone and conversion of T4 to T3 with PTU, (3) administering

FIGURE 16-2 Ultrasonic study of a fetus with a goiter caused by maternal treatment with propylthiouracil for hyperthyroidism. (From Polak M, Luton D: Fetal thyroïdology. Best Pract Res Clin Endocrinol Metab 28:161-173, 2014.)

A case of fetal goiter

PA R T 2 Obstetrics208

cardiac output in patients with mitral stenosis depends  on an adequate diastolic filling time.

CONGENITAL HEART DISEASE Congenital heart disease includes atrial or ventricu- lar septal defects, valvular defects, primary pulmo- nary hypertension (Eisenmenger syndrome), and cyanotic heart diseases such as tetralogy of Fallot and transposition of the great arteries.  If  the  anatomic  defect  has  been  corrected  during  childhood  with  no  residual damage, the patient is expected to go through  pregnancy without complications. Patients with persis- tent  atrial  or  ventricular  septal  defects  and  those  with  tetralogy  of  Fallot  with  complete  surgical  correction  generally  tolerate  pregnancy  well.  However,  patients with primary pulmonary hypertension or cyanotic heart disease with residual pulmonary hypertension are in danger of experiencing decompensation during pregnancy. Pulmonary hypertension from any cause is  associated with an increased risk of maternal mortality  during  pregnancy  or  in  the  immediate  postpartum  period. In all of these patients, care should be taken to  avoid  overloading  the  circulation  and  precipitating  pulmonary  congestion,  heart  failure,  or  hypotension,  all of which may lead to hypoxia and sudden death. In general, significant pulmonary hypertension with Eisenmenger syndrome is a contraindication to preg- nancy due to the high maternal mortality that accom- panies this condition.

CARDIAC ARRHYTHMIAS Palpitations  are  common  in  pregnancy  and  are  a  fre- quent indication for an electrocardiogram (ECG). If an arrhythmia is detected, an echocardiogram should be obtained to determine if there is underlying structural heart disease. Atrial premature beats are common, but usually benign and do not require therapy  other  than  elimination  of  exogenous  stimu- lants such as caffeine and cigarettes. The management of supraventricular tachyarrhythmias (SVTs) with carotid massage or the Valsalva maneuver, antiar- rhythmic therapy, or direct current cardioversion is based on the patient’s hemodynamic status. Atrial fibrillation and atrial flutter, though much less common than SVTs, are more serious and are usually associated with underlying maternal cardiac disease.  Tests  of  thyroid  function  should  also  be  done.  Treat- ment is similar to that in nonpregnant adults, although  antiarrhythmic agents cross the placenta and the fetal  risks are largely unknown. Heparin (or low-molecular- weight  heparin)  should  be  used  instead  of  warfarin  when anticoagulation is indicated.

ISCHEMIC HEART DISEASE It  is  anticipated  that  the  number  of  pregnant  women  with  coronary  artery  disease  or  other  causes  of  isch- emic  heart  disease  will  increase  as  the  number  of 

severity of the deprivation. The incidence of congeni- tal hypothyroidism is about 1 in 2000 to 4000 births.  The etiologic factors include thyroid dysgenesis, inborn  errors  of  thyroid  function,  and  iodine  deficiency.  Maternal and neonatal exposure to excess iodine (e.g.,  amiodorone, iodine-containing contrast dyes or disin- fectants, and supplements) is another potentially pre- ventable  cause.  Newborn screening programs can identify many cases of congenital hypothyroidism, and with early administration of thyroid hormone replacement, the impairment can be minimized.

Heart Disease Less than 5% of pregnancies in the United States are complicated by maternal cardiac disease, but it is an  important cause of maternal mortality. The cardiovas- cular adaptations to pregnancy, delivery, and the early  puerperium  can  trigger  acute  cardiovascular  decom- pensation in women with high-risk lesions. The physi- ologic  changes  discussed  in  Chapter  6,  including  the  rise  in  preload,  decrease  in  afterload,  and  increase  in  cardiac  output,  begin  in  the  first  trimester  and  peak  toward  the  end  of  the  second  or  early  third  trimester.  The  corresponding  physical  findings  of  a  new  systolic  flow murmur, an S3 gallop, an increase in resting heart  rate, a decline in diastolic blood pressure, and depen- dent edema can further complicate the clinical diagno- sis and management of these pregnancies.

The categories of heart disease in pregnancy include  rheumatic and congenital cardiac disease  as  well  as  arrhythmias, cardiomyopathies,  and  other  forms  of  acquired heart disease, such as coronary artery disease.  Better  treatment  of  rheumatic  fever  and  improvements in medical and surgical management of  congenital heart disease have meant that in a modern  tertiary  referral  center,  about 80% of patients with cardiac disease in pregnancy now have congenital heart disease.

RHEUMATIC HEART DISEASE The most common lesion associated with rheumatic heart disease is mitral stenosis,  followed  by  mitral  regurgitation.  Patients  with  mitral  stenosis,  especially  those  with  a  valve  area  less  than  1.5 cm2,  are at high risk of developing heart failure, subacute bacterial endocarditis, and thromboembolic disease. They also  have a higher rate of fetal wastage.

During  pregnancy,  the  mechanical  obstruction  associated  with  mitral  stenosis  worsens  as  cardiac  output increases. Asymptomatic patients may develop symptoms of cardiac decompensation or pulmonary edema as pregnancy progresses.  Atrial  fibrillation  is  more common in patients with severe mitral stenosis,  and  nearly all women who develop atrial fibrillation during pregnancy experience congestive heart failure.  Tachycardia  can  result  in  decompensation  because 

C H A P T E R 16 Common Medical and Surgical Conditions Complicating Pregnancy 209

class I or II disease are small, whereas they are greatly increased in patients with class III or IV disease or if they have cyanosis.  However,  the  type  and  severity  of  the defect is important as well. In general, mitral (valve  area <2  cm2)  and  aortic  stenosis  (valve  area <1.5  cm2)  carry  a  much  higher  risk  of  decompensation  than  do  mitral  or  aortic  regurgitation,  because  the  pregnancy- induced  decrease  in  systemic  vascular  resistance  improves  cardiac  output  in  the  setting  of  lesions  causing  regurgitation.  Other patients at high risk of morbidity and mortality include those with signifi- cant pulmonary hypertension, a LVEF less than 40%, Marfan syndrome, a mechanical valve, a previous history of a cardiac event or arrhythmia, or signifi- cant comorbidities.

Prenatal Management As  a  general  principle,  all pregnant cardiac patients should be managed with the help of a cardiologist, a maternal-fetal medicine specialist, and an anesthesi- ologist.  A  careful  history  and  physical  examination  should be performed, and an ECG and echocardiogram  should be obtained. This evaluation will assist in coun- seling  the  patient  about  risks  associated  with  preg- nancy,  and  all  available  options  (including  pregnancy  termination)  should  be  presented.  Frequent  prenatal  visits  are  indicated,  and  frequent  hospital  admissions  may be needed, especially for patients with class III or  IV cardiac disease.

AVOIDANCE OF EXCESSIVE WEIGHT GAIN AND EDEMA. There is no strong evidence to support sodium restric- tion  in  the  absence  of  heart  failure,  but  excessive   salt  intake  should  be  avoided.  Women  should  be  encouraged to rest in the left lateral decubitus position  (which  avoids  compression  of  the  vena  cava)  for  at  least  1  hour  every  day.  Adequate  sleep  should  be  encouraged.  If  there  is  evidence  of  chronic  left  ven- tricular  failure  not  adequately  treated  with  sodium  restriction,  a  loop  diuretic  and  β-blockers  should  be  added.  Aldosterone antagonists should be avoided because of their potential antiandrogenic effects on the fetus.

AVOIDANCE OF STRENUOUS ACTIVITY. Individuals  with  significant heart disease have decreased cardiac reserve  and are unable to increase their cardiac output to meet  the metabolic needs of exercise to the same extent that  healthy individuals are.

AVOIDANCE OF ANEMIA. With  anemia,  the  oxygen- carrying capacity of the blood decreases. Oxygen deliv- ery  to  tissues  is  generally  maintained  by  increased  cardiac  output.  An  increase  in  heart  rate,  especially  with mitral stenosis, leads to a decrease in left ventricu- lar filling time, resulting in pulmonary congestion and  edema.

pregnant women with comorbidities, such as age over  40  years,  obesity,  chronic  hypertension,  and  diabetes,  continues to rise. Stress testing and angiography should  be done before pregnancy. Use of lipid-lowering agents  or  angiotensin-converting  enzyme  (ACE)  inhibitors  should  be  avoided  during  pregnancy  because  these  drugs are currently labeled class X because of concerns  regarding fetal toxicity. Certain antiplatelet agents may  be safe for the fetus, but they should be stopped before  delivery to avoid bleeding complications.

PERIPARTUM CARDIOMYOPATHY The  occurrence  of  peripartum  cardiomyopathy  is  reported to have wide regional variation. Patients with  this condition have no underlying cardiac disease, and  symptoms  of  cardiac  decompensation  appear  during  the  last  weeks  of  pregnancy  or  within  6  months  post- partum. Pregnant women particularly at risk of devel- oping cardiomyopathy are those with a history of preeclampsia or hypertension and those who are poorly nourished.  It  appears  to  be  a  dilatational  car- diomyopathy with a decreased left ventricular ejection  fraction  (LVEF  <  45%).  Hypertensive  or  drug-induced  cardiomyopathy, ischemic heart disease, viral myocar- ditis,  and  valvular  heart  disease  must  be  excluded  in  these patients before the diagnosis can be made. With  prompt  diagnosis  and  skilled  management  (including  delivery if the disease presents antepartum), maternal  mortality rates have been declining but are still at least  10%.  These  women  have  a  30-50%  risk  of  persistent  cardiac  dysfunction  and  a  20-50%  recurrence  rate  in  subsequent pregnancies.

MANAGEMENT OF CARDIAC DISEASE DURING PREGNANCY The  New York  Heart  Association  functional  classifica- tion  of  heart  disease  is  of  value  in  assessing  the  risk  of  pregnancy  for  a  patient  with  acquired  cardiac  disease  and  in  determining  the  optimal  management  during  pregnancy,  labor,  and  delivery  (Table  16-5).  In  general, the maternal and fetal risks for patients with 

TABLE 16-5

NEW YORK HEART ASSOCIATION FUNCTIONAL CLASSIFICATION OF HEART DISEASE

Class Description

Class I No signs or symptoms of cardiac decompensation

Class II No symptoms at rest, but minor limitation of physical activity

Class III No symptoms at rest, but marked limitation of physical activity

Class IV Symptoms present at rest, discomfort increased with any kind of physical activity

PA R T 2 Obstetrics210

pletely repaired congenital heart disease, or a previous  history of bacterial endocarditis.

Acute cardiac decompensation with congestive heart failure should be managed as a medical emer- gency,  and  the  immediate  postpartum  period  poses  the  greatest  risk.  Medical  management  is  directed  at  correcting  the  precipitating  factors  and  may  include  administration  of  morphine  sulfate,  supplemental  oxygen  with  ventilatory  support  if  needed,  and  an  intravenous  loop  diuretic  (e.g.,  furosemide)  to  reduce  fluid  retention  and  preload. β-Blockers  should  not  be  used  in  the  setting  of  acute  heart  failure. Vasodilators  such  as  hydralazine,  nitroglycerin,  and,  rarely,  nitro- prusside are used to improve cardiac output by decreas- ing  afterload.  Some patients may require inotropic support  with  dopamine  or  dobutamine.  The  use  of  digitalis  is  controversial.  ACE inhibitors and similar drugs should be avoided. Very frequent monitoring of  vital  signs,  urine  output,  and  pulse  oximetry,  along  with  continuous  electrocardiographic  monitoring,  is  advised. Routine use of pulmonary artery catheteriza- tion is discouraged, and it may even be contraindicated  if the patient has cyanotic heart disease.

Autoimmune Disease in Pregnancy An autoimmune disease is one in which antibodies are  developed  against  the  host’s  own  tissues.  A  summary  of  the  interactions  of  primary  immunologic  disorders  and pregnancy is provided in Table 16-6.

IMMUNE THROMBOCYTOPENIA With immune thrombocytopenia (ITP), the low platelet  count  occurs  when  peripheral  platelet  destruction  exceeds bone marrow production. ITP is considered to  be  an  autoantibody  disorder  in  which  immunoglobu- lins  attach  to  maternal  platelets,  leading  to  platelet  sequestration  in  the  reticuloendothelial  system.  ITP  maybe  be  confused  with  gestational  thrombocytope- nia.  Gestational thrombocytopenia  is  unlikely  to  present with a platelet count less than 70,000/µL, is not associated with bleeding complications,  does  not  require therapy, occurs late in pregnancy, and resolves  after delivery.

Treatment In the absence of bleeding, therapy for ITP is usually not initiated unless platelet counts are less than 50,000/µL.  Oral  prednisone  at  a  dose  of  1 mg/kg  per  day is given initially, and once platelet counts improve,  it  is  tapered  off  over  several  weeks.  Severe  ITP  can  be  more  rapidly  treated  with  intravenous  immunoglobu- lin  (IVIG).  In patients with life-threatening hemor- rhage, platelet transfusions combined with high-dose steroids and IVIG may be required. Splenectomy is a last resort for patients who do not respond to medical  therapy. Maternal hemorrhage is unlikely if the platelet 

AVOIDANCE OF INFECTION. This  is  accomplished  by  routine  screening  for  sexually  transmitted  infections  and urinary tract infections, the timely administration  of  appropriate  immunizations,  and  vigilance  in  the  evaluation and treatment of any concerning symptoms  or signs of infection. Cesarean delivery should only be  performed  for  clear  obstetrical  indications,  in  part  because  of  the  increased  risk  of  endometritis  and  wound infections.

ANTICOAGULATION. Women  with  mechanical  valves  and  those  with  atrial  fibrillation  require  full  anti- coagulation  with  heparin  or  low-molecular-weight  heparin  in  pregnancy.  Warfarin  may  be  restarted  postpartum.

FETAL ECHOCARDIOGRAPHY. Women  with  congenital  heart  disease  have  an  increased  risk  of  having  chil- dren  with  heart  disease.  Early  detection  with  fetal  echocardiography  can  help  with  plans  for  neonatal  management.

Management of Delivery and the Immediate Postpartum Period Cardiac patients should be delivered vaginally unless obstetric indications for cesarean delivery are present. They should be allowed to labor in the lateral decubitus position  with  frequent  assessment  of  vital  signs, urine output, and pulse oximetry. Adequate pain  relief is important. Pushing should be avoided during the second stage of labor  because  the  associated  increase in intraabdominal pressure can lead to cardiac  decompensation.  The  second  stage  of  labor  can  be  assisted by performing an outlet forceps delivery or by  the use of a vacuum extractor.

The immediate postpartum period presents special  risks  to  the  cardiac  patient.  After  delivery  of  the  pla- centa, the uterus contracts and about 500 mL of blood  are  added  to  the  effective  blood  volume.  Cardiac output increases up to 80% above prelabor values in the first few hours after a vaginal delivery and up to 50% after cesarean delivery. To  minimize  the  risks  of  volume overload or depletion, careful attention should  be  paid  to  fluid  balance  (avoiding  overload)  and  pre- vention of uterine atony (avoiding depletion from blood loss) with oxytocin and uterine massage. When these measures are unsuccessful, prostaglandin F2α can be administered if pulmonary hypertension and reactive airway disease are not concerns. Methergine should be avoided  due  to  its  pronounced  vasocon- strictor effects.

A particular concern is the risk of endocarditis.  The  2008  American  Heart  Association  guidelines  state  that, in most cases, delivery does not increase the risk  of  infectious  endocarditis.  Antibiotic prophylaxis is recommended only for high-risk patients,  such  as  those  with  prosthetic  valves,  unrepaired  or  incom-

C H A P T E R 16 Common Medical and Surgical Conditions Complicating Pregnancy 211

bination of clinical and laboratory criteria. The criteria  proposed  by  the  American  College  of  Rheumatology  are  given  in  Table  16-7.  The  diagnosis  of  SLE  can  be  made  if  four  or  more  of  the  11  criteria  listed  in  Table  16-7 are present, serially or simultaneously.

SLE can flare up during any trimester or in the postpartum period. There is good evidence that the best pregnancy outcomes occur if the disease has been quiescent or under good control for at least 6 months before conception and there is no evidence of active lupus nephritis. A lupus flare, if it occurs, can be  life-threatening, but it is often difficult to differentiate  from  superimposed  preeclampsia,  and  both  may  coexist.  Complement  component  3  levels  are  usually  low  in  a  flare,  but  they  are  often  elevated  in  patients  with  preeclampsia.  Often  only  a  trial  of  therapy  will  enable  the  two  to  be  distinguished.  Flares  and  active  disease  are  generally  managed  with  steroids  and  hydroxychloroquine, drugs that have less fetal toxicity  than other immunosuppressive agents. The addition of  heparin  or  low-molecular-weight  heparin  in  prophy- lactic or therapeutic doses is dependent on the patient’s  medical and obstetric history and risk factors.

In  addition  to  flares,  worsening  nephritis,  and  pre- eclampsia, SLE is associated with a relatively high rate  of  other  pregnancy  complications.  These include an increased rate of miscarriage and intrauterine fetal death, especially when associated with antiphospho- lipid antibodies, as well as preterm delivery and fetal

count is greater than 40,000/µL at the time of delivery,  but concerns about the possibility of an epidural hema- toma  may  preclude  the  use  of  epidural  anesthesia.  Advanced consultation with anesthesia staff is advised.  The neonate should be monitored for thrombocy- topenia, because placental transfer of maternal antiplatelet antibodies can occur.  Rarely,  neonatal  intracranial hemorrhage may occur once the neonatal  platelet count has reached its nadir after the first 2 to 3  days of life. There is no correlation between fetal plate- let  counts  and  neonatal  outcome;  thus,  monitoring  fetal platelet counts is not done in pregnancy. Vaginal delivery is generally preferred,  because  there  is  little  evidence  that  the  fetal  outcome  is  improved  by  cesar- ean  delivery  and  surgery  carries  additional  maternal  risks.

SYSTEMIC LUPUS ERYTHEMATOSUS Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with multiple organ system involvement in which patients are subject to acute exacerbations or flares. Associated antibodies include  antinuclear,  anti-ribonucleoprotein  (anti-RNP),  and  anti-Smith (anti-Sm) antibodies. Anti-double-stranded  DNA (anti-dsDNA) antibody is associated with nephri- tis and lupus activity. Anti-Ro/SSA and anti-La/SSB are  present  in  Sjögren  syndrome  and  neonatal  lupus  with  heart block. Antihistone antibody is common in drug- induced SLE. The diagnosis of SLE is based on a com-

TABLE 16-6

AUTOIMMUNE DISEASE IN PREGNANCY

Disease

Effect of Disease on Pregnancy Effect of Pregnancy on Disease

Antibodies That Cross PlacentaMother Fetus

Rheumatoid arthritis

No significant effect No significant effect Teratogenic effects of

medication

Usually improved None

Idiopathic thrombocytopenic purpura

Antepartum, intrapartum, and postpartum hemorrhage

None (causes neonatal intracranial bleeding)

None Platelet antibodies

Graves disease No significant effect (avoid magnesium sulfate)

Intrauterine growth restriction (IUGR)

Neonatal thyrotoxicosis

Improved during pregnancy

Exacerbation postpartum

Thyroid-stimulating immunoglobulins

Myasthenia gravis No significant effect Transient neonatal myasthenia gravis

Variable during pregnancy

Moderate exacerbation postpartum

Antiacetylcholinesterase

Systemic lupus erythematosus

Increased incidence of uterine infection

Increased incidence of preeclampsia

Abortion (spontaneous) Preterm preeclampsia IUGR Stillbirth Congenital heart block Endomyocardial fibrosis

Exacerbation of disease Deterioration of renal

condition Anemia, leukopenia,

and thrombocytopenia

Anti-Ro/SSA, anti-La/ SSB

PA R T 2 Obstetrics212

include  an  unexplained  fetal  demise  after  10  weeks’  gestation, a history of preterm delivery before 34 weeks’  gestation  due  to  severe  preeclampsia  or  placental  insufficiency,  or  three  or  more  unexplained  miscar- riages before 10 weeks’ gestation. Lupus anticoagulant  can be screened for with an activated partial prothrom- bin time (aPTT) or with the dilute Russell viper venom  test,  a  sensitive  and  specific  radioimmunoassay  that   is  available  for  the  detection  of  anticardiolipin.  In   pregnancy,  a history of antiphospholipid syndrome is treated with prophylactic low-molecular-weight heparin and low-dose aspirin (81 mg), unless there is a history of thrombosis, in which case a full dosage of anticoagulants is indicated.

Renal Disorders ACUTE RENAL FAILURE Acute renal failure during pregnancy or in the postpar- tum  period  may  be  caused  by  deterioration  of  renal  function secondary to a preexisting renal disease or by  a  pregnancy-associated  disorder.  The  causes  can  be  classified  as  prerenal,  renal,  or  postrenal.  With prere- nal causes, a history of blood or fluid loss, such as that which occurs with obstetric hemorrhage or severe hyperemesis gravidarum, is usually apparent or can be elicited. Treatment is aimed at correcting the hypo- volemia and underlying disease process.

Renal causes are usually suspected in patients with a history of preexisting renal disease, such as lupus nephritis.  Acute  tubular  necrosis  (ATN)  can  compli- cate a septic abortion and pyelonephritis in pregnancy.  ATN can also be due to thrombotic microangiopa- thies  such  as  thrombotic  thrombocytopenic  purpura  and  hemolytic  uremic  syndrome,  preeclampsia  with  hemolysis,  elevated  liver  enzymes,  and  low  platelet  count  (HELLP)  syndrome  (see  Chapter  14),  or  acute  fatty liver of pregnancy with disseminated intravascu- lar  coagulopathy  (DIC).  Prolonged hypotension with DIC, such as that which occurs in the setting of massive abruption, retained dead fetus, or amniotic fluid embolus, can lead to acute cortical necrosis, which may present with the triad of anuria, gross hematuria, and flank pain. Treatment is directed at the underlying causes and delivery of the fetus if the patient is still pregnant.  Whereas  the  majority  of  patients  with  ATN  recover,  acute  cortical  necrosis  has  a  much  poorer  prognosis  and  many  of  these  patients  will require dialysis.

Postrenal causes of acute renal failure are less common, but they should be suspected in situations in which urologic obstructive lesions are present  or  in  which  there  is  a  history  of  kidney  stones.  In   many instances, simple measures, such as turning the  patient  on  the  left  side  to  displace  the  gravid  uterus  away  from  the  ureters  or  inserting  a  Foley  catheter   into the bladder to overcome urethral obstruction, will 

growth restriction.  These  pregnancies  require  close  monitoring  with  serial  assessment  of  renal  function,  blood counts, and immune markers of disease activity  (complement  levels  and  anti-dsDNA).  In  the  third  tri- mester, weekly maternal visits may be indicated, along  with  serial  ultrasonic  monitoring  of  fetal  growth  and  twice-weekly  antepartum  testing.  Neonatal lupus is associated with passive transmission of anti-Ro/SSA or anti-La/SSB antibodies  and  is  one  of  the  main  causes of congenital heart block.

ANTIPHOSPHOLIPID SYNDROME Antiphospholipid antibodies  are  circulating  antibod- ies  to  negatively  charged  phospholipids. They  include  lupus  anticoagulant,  anticardiolipin  immunoglobulin  G (IgG) or IgM antibodies, and β2-glycoprotein-1 anti- bodies.  They  may occur alone or in association with SLE. The antiphospholipid syndrome is defined as the presence of at least one of these antibodies in associa- tion with arterial or venous thrombosis and/or one or more obstetric complications.  These  complications 

TABLE 16-7

1997 REVISED CRITERIA OF THE AMERICAN RHEUMATISM ASSOCIATION FOR THE DIAGNOSIS OF SYSTEMIC LUPUS ERYTHEMATOSUS

Criteria* Comments

Malar rash Malar erythema

Discoid rash Erythematous patches, scaling, follicular plugging

Photosensitivity

Oral ulcers Usually painless

Arthritis Nonerosive involving two or more peripheral joints

Serositis Pleuritis or pericarditis

Renal disorder Proteinuria greater than 0.5 g/day or >3+ dipstick, or cellular casts

Neurological disorders

Seizures or psychosis without other cause

Hematological disorders

Hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia

Immunological disorders

Anti-dsDNA or anti-Sm antibodies, or false-positive VDRL, IgM or IgG anticardiolipin antibodies, or lupus anticoagulant

Antinuclear antibodies

Abnormal titer of ANAs

From Hochberg MC: Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725, 1997. Copyright 1997 American College of Rheumatology. Reprinted with permission of John Wiley & Sons, Inc. ANA, Antinuclear antibody; dsDNA, double-stranded DNA; Ig, immuno- globulin; Sm, Smith; VDRL, Venereal Disease Research Laboratory. *If four criteria are present at any time during the course of the disease, systemic lupus erythematosus can be diagnosed with 98% specificity and 97% sensitivity.

C H A P T E R 16 Common Medical and Surgical Conditions Complicating Pregnancy 213

Gastrointestinal Disorders NAUSEA AND VOMITING DURING PREGNANCY About 50-80% of pregnant women complain of nausea  and vomiting during the first trimester. The symptoms  are  usually  mild  and  disappear  during  the  early  part   of  the  second  trimester.  The underlying causes of nausea and vomiting during pregnancy are not well understood.

Treatment is usually symptomatic.  Patients  are  instructed  to  avoid  known  triggers  of  nausea  (e.g.,  coffee, strong odors, fatty foods); to eat frequent, small,  protein-rich  meals  or  snacks;  to  avoid  the  recumbent  position,  especially  after  meals;  and  to  use  an  extra  pillow to elevate the head when sleeping. Many patients  respond  to  pyridoxine  (vitamin  B6),  whereas  others  may require ginger, acupressure, or first-line antiemet- ics such as doxylamine.

HYPEREMESIS GRAVIDARUM Hyperemesis gravidarum is generally defined as per- sistent nausea and vomiting in pregnancy that is associated with ketosis and loss of more than 5% of prepregnancy body weight.  Even  though  the  exact  cause  is  unknown,  proposed  theories  include  psy- chological  abnormalities,  hormonal  changes  such  as  high  hCG  and  estradiol  levels,  gastric  dysrhythmias,  hyperacuity  of  the  olfactory  system,  subclinical  ves- tibular  disorders,  and  impairment  of  mitochondrial  fatty  acid  oxidation.  The overall incidence is about 1-2%. The disorder appears more frequently with first pregnancies, multiple pregnancies, and those with trophoblastic disease, but it tends to recur with subse- quent  pregnancies.  Pregnancy outcome is usually good if the disorder is treated and there is catch-up weight gain.

A history of intractable vomiting, beginning in the first trimester, is usually elicited.  Physical  findings  of  weight loss, dry and coated tongue, and decreased skin  turgor are very suggestive. Significant abdominal pain and tenderness are generally absent.  Laboratory  workup  includes  urine  tests  for  ketonuria  and  blood  tests for electrolytes and acetone, blood urea nitrogen  (BUN),  creatinine,  amylase,  lipase,  and  liver  function.  Electrolyte  disturbances  may  include  hypokalemia,  hyponatremia,  and  hypochloremic  alkalosis.  Liver  function  tests  and  amylase  and  lipase  levels  may  be  elevated.  Many  of  these  women  have  laboratory  evi- dence of mild hyperthyroidism, which resolves without  therapy as the pregnancy progresses.

Treatment is symptomatic  and  includes  the  inter- ventions  advised  for  the  more  benign  nausea  and   vomiting  of  pregnancy  noted  above.  If outpatient management fails, patients must be admitted for intravenous administration of fluids, electrolytes, glucose, vitamins, and medical therapy. Medical man- agement involves a stepwise approach beginning with 

resolve  the  problem.  In  situations  in  which  a  ureteral  or  renal  pelvic  obstruction  is  present  (e.g.,  stones),   surgical  intervention  may  be  indicated  to  relieve  the  obstruction.

CHRONIC RENAL DISEASE The outcome of pregnancies complicated by chronic renal disease is less favorable than that associated with acute renal failure.  Good  pregnancy  outcomes  may  be  expected  in  mild  renal  disease.  The  risk  of  adverse fetal outcomes and loss of maternal renal func- tion  increases  with  the  severity  of  the  renal  insuffi- ciency. In general, a serum creatinine greater than 1.5 to 2.0 mg/dL, especially if accompanied by hyperten- sion and/or nephrotic syndrome, greatly worsens the prognosis for the mother and fetus.  Management  principles  include  serial  monitoring  of  renal  function  by  24-hour  urinary  creatinine  clearance  and  protein  excretion,  as  well  as  screening  and  treating  the  pa - tient  for asymptomatic bacteriuria. Diastolic pressure  should  be  maintained  at  90 mm  Hg  or  less  to  prevent  further  renal  damage.  Superimposed preeclampsia is more difficult to diagnose because hypertension and proteinuria are already present.  Fetal  surveillance  is  important for assessing fetal growth and well-being.

PREGNANCY FOLLOWING RENAL TRANSPLANTATION Pregnancy  after  renal  transplantation  should  not  be  considered  before  thorough  counseling  about  mater- nal,  fetal,  and  neonatal  risks  takes  place.  Maternal  complications  of  pregnancy  include  high  rates  of  hypertension  and  preeclampsia  and  a  significant  risk  of  graft  rejection  and  failure.  Fetal complications include steroid-induced adrenal and hepatic insuffi- ciency, prematurity, and IUGR. In addition, the infant  may inherit the primary disease of the mother or other  family members. The mother and fetus or neonate are  both at increased risk of infection because of immuno- suppressive therapy. Before a patient attempts to con- ceive,  fetotoxic  medications  such  as  sirolimus  should  be  replaced  with  immunosuppressants  that  are  safer  for  the  fetus,  and  fetotoxic  infections  such  as  CMV  must be ruled out.

Patients who are good candidates for pregnancy are those who are 1 to 2 years posttransplant, have stable renal function (serum creatinine <1.5 mg/dL and proteinuria <500 mg/day), are not significantly hypertensive, and are taking low doses of prednisone and stable doses of cyclosporine.  These  medications  do  not  appear  to  have  significant  teratogenic  effects,  but long-term consequences on growth, immune func- tion,  and  neurocognitive  development  are  unknown.  Cyclosporin may have adverse maternal consequences,  including  a  blood  pressure  increase,  renal  function  decline,  hyperkalemia,  hyperuricemia,  and,  less  fre- quently, a hemolytic uremic syndrome.

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and  spicy  foods  and  administering  antacids  (see   safety issues under “Gastroesophageal Reflux Disease”  above),  H2  receptor  antagonists,  or  proton  pump  inhibitors.  Any  nonsteroidal  antiinflammatory  drugs  should  be  discontinued.  Antibiotic  therapy  should  be  considered  for  patients  with  Helicobacter pylori  infec- tion,  but  it  is  generally  not  given  until  the  patient  is  postpartum.

ACID ASPIRATION SYNDROME (MENDELSON SYNDROME) The pregnant patient in labor is at an increased risk of regurgitation and acid aspiration of gastric contents because of delayed gastric emptying and increased intraabdominal and intragastric pressures.  This  is  made  worse  when  associated  with  the  use  of  sedatives,  narcotics,  or  general  anesthesia.  Damage   to  the  pulmonary  tissue  is  greatest  when  the  pH  of   the  aspirated  fluid  is  less  than  2.5  or  the  volume  of   the  aspirate  is  greater  than  25 mL.  Acute gastric aspiration is a cause of acute respiratory distress syndrome (ARDS) in adults.  Treatment  consists  of  supplemental oxygen, measures to maintain the airway,  provision  of  ventilatory  support  if  needed,  and  addi- tional therapy for acute respiratory failure. Antibiotics  are  indicated  if  there  is  any  suggestion  of  infectious  pneumonitis.

Preventive efforts are directed at decreasing the acid secretion by the stomach and protecting the airway. Toward this end, women are usually not fed during labor.  They  should  have  no  food  intake  for  at  least  6  hours  before  elective  cesarean  delivery  and  no  liquid  intake  for  2  hours  before  surgery.  If  the  patient  is  to  undergo  any  surgical  procedure  that  requires  general  anesthesia,  acid  secretion  can  be  decreased  with  preoperative administration of an H2 receptor antagonist and sodium citrate.  In  this  setting,  a  “full  stomach”  should  be  presumed,  and  preoxygenation  followed by rapid sequence intubation performed.

CHRONIC INFLAMMATORY BOWEL DISEASE The  two  entities  described  under  chronic  inflamma- tory  bowel  disease  (IBD)  are  Crohn disease (regional enteritis) and ulcerative colitis. In general, pregnancy  appears  to  be  associated  with  greater  disease  activity  in  patients  with  ulcerative  colitis  than  in  those  with  Crohn disease.

Preconception care and counseling (see Chapter 7) that prepares a woman with IBD can improve preg- nancy outcome.  Patients  with  IBD  should  be  coun- seled on inheritance risks, and nutritional status should  be optimized. Use of supplemental folic acid is advised,  and if deficiencies are present, supplemental iron and  vitamin B12 should be prescribed. The best pregnancy outcomes occur in those patients who are in remis- sion at the time of conception and whose disease activity can be controlled with medication that has

vitamin  B6  (pyridoxine)  and  antihistamines  such  as  doxylamine  or  diphenhydramine.  If  vomiting  persists,  antiemetics of the phenothiazine class and promotility  agents  such  as  metoclopramide  may  be  needed.   Phenothiazines  such  as  promethazine  and  metoclo- pramide should be stopped immediately if they induce  any  signs  of  tardive  dyskinesia  (involuntary  move- ments, usually of the face). The addition of antacids or  H2 receptor antagonists (see “Gastroesophageal Reflux  Disease”  section  below)  may  also  prove  beneficial.   The few patients who do not respond to medical therapy may require nasogastric feeding or paren- teral nutrition.

GASTROESOPHAGEAL REFLUX DISEASE Some  amount  of  gastroesophageal  reflux  disease  (GERD) occurs in about 70% of pregnant women. The  main  symptoms  include  substernal  discomfort  aggra- vated by meals and the recumbent position. Hemateme- sis occasionally occurs. An unusual symptom peculiar  to  reflux  esophagitis  is  water  brash,  which  is  best  described as the sudden filling of the mouth with clear,  watery  material  that  has  a  salty  taste  and  produces  nausea.

Treatment Treatment is usually symptomatic.  Upper  GI  endos- copy is usually not necessary, unless there is significant  GI bleeding. Patients are instructed to eliminate dietary  triggers; refrain from eating large and late meals; avoid  the recumbent position, especially after meals; and use  an extra pillow to elevate the head when sleeping. Ant- acids  can  be  helpful  and  should  be  taken  1  to  3  hours  after meals and at bedtime. Those containing bismuth  or  bicarbonate  should  be  avoided  because  of  possible  fetal  toxicity.  Sucralfate  (aluminum  sucrose  sulfate)   is  a  surface-binding  agent  useful  in  pregnancy  for  symptom  relief  because  it  is  poorly  absorbed  and  has  no  apparent  fetal  toxicity.  An  H2  receptor  antagonist  (cimetidine) or a proton pump inhibitor (omepra- zole) is indicated if there is no response to the above- described measures. Both appear to be safe for the fetus, but proton pump inhibitors are not advised in breastfeeding women, because of lack of safety data.

PEPTIC ULCER Pregnancy conveys relative protection against the development of peptic ulceration and may ameliorate  an  already-present  ulcer.  Gastric  acid  secretion  is  probably not altered during pregnancy, although some  studies  suggest  modest  suppression.  The diagnosis of peptic ulcer disease is based mainly on symptomatic improvement in response to conservative treatment. Endoscopy is reserved for those patients who do not respond to treatment, have more severe GI symptoms, or manifest significant GI hemorrhage.  Treatment involves avoiding caffeine, alcohol, tobacco, 

C H A P T E R 16 Common Medical and Surgical Conditions Complicating Pregnancy 215

women in Connecticut to nearly 6% in a Latina popula- tion in Los Angeles. Rates are higher in Latin America,  with  the  highest  reported  rates  being  in  Chile  in  the  winter months. The etiology of ICP is most likely mul- tifactorial. A mutation in the MDR3 gene may be asso- ciated with up to 15% of cases.  In  addition,  a  strong  association  between  ICP  and  natural  progesterone  therapy  for  prevention  of  preterm  birth  has  recently  been reported.

The main symptom of ICP is itching (most intense on the palms and soles), without abdominal pain or a rash, which may occur as early as 20 weeks’ gestation.  Jaundice  is  rarely  observed.  Laboratory tests show elevated levels of serum bile acids.  Serum  levels  of  bilirubin and liver enzymes (e.g., aspartate and alanine  transaminase)  are  usually  normal,  but  they  may  be  mildly elevated. If liver enzymes and bilirubin levels are  significantly  elevated,  abdominal  ultrasonography  should  be  performed  to  exclude  gallbladder  obstruc- tion. A hepatitis screen to exclude viral hepatitis and an autoantibody screen for primary biliary cirrhosis should be performed.

Treatment and Follow-up Symptomatic  treatment  with  cold  baths,  emollients,  and  antihistamines  such  as  hydroxyzine  may  be  of  some  help.  The best results have been obtained with ursodeoxycholic acid. It significantly ameliorates  the  pruritus  and  reduces  serum  levels  of  bile  acids,  aminotransferases,  and  bilirubin.  The reason for the increased rate of fetal demise is unclear. Most happen  after  37  weeks’  gestation  and  may  be  secondary  to  pathology  induced  by  the  elevated  bile  acids  that  can  cross  the  placenta.  There  is  no  consensus  regarding  timing  of  delivery.  Serial fetal surveillance should be performed in the third trimester, with delivery at term if testing remains reassuring. Postpartum, maternal symptoms and bile acids usually normalize quickly.  Patients  should  be  screened  for  hepatitis  C,  and  liver  function  tests  should  be  followed  until  they  return to normal because a few patients may go on to  develop  cholecystitis,  fibrosis,  or  other  types  of  liver  disease.

ACUTE FATTY LIVER OF PREGNANCY Acute fatty liver of pregnancy is a rare but extremely serious complication that can occur in the third tri- mester of pregnancy. It is associated with diffuse microvesicular fatty infiltration of the liver, resulting in hepatic failure. The incidence is about 1 per 14,000  pregnancies. Although the cause is unknown, it may in  some instances result from an inborn error of metabo- lism, possibly a deficiency of long-chain 3-hydroxyacyl- coenzyme A dehydrogenase (LCHAD). Its presentation is variable, with abdominal pain, nausea and vomit- ing, jaundice, and increased irritability. Extreme poly- dipsia  or  pseudodiabetes  insipidus  may  be  present. 

minimal fetal toxicity. Major teratogens such as methotrexate must be discontinued before concep- tion. Overall, pregnancy in women with IBD is compli- cated by higher rates of preterm birth and IUGR, and  the frequency of these complications increases if there  are acute disease exacerbations during pregnancy.

Treatment The  principles  of  therapy  for  acute  exacerbations  of  IBD are similar for pregnant and nonpregnant patients,  but care must be taken to balance medication risks to  the  fetus  against  the  risks  of  active  disease.  Ionizing  radiation  should  be  avoided,  and  magnetic  resonance  enterography or flexible sigmoidoscopy should be per- formed,  when  there  is  a  clear  need  for  diagnostic  studies.  The  least  fetotoxic  antiinflammatory  and  immunosuppressant  medications  that  can  control  disease activity should be used. Sulfasalazine does not appear to be associated with fetal toxicity. Prednisone is metabolized by placental enzymes and relatively little crosses the placenta. However, first trimester use  has been associated with cleft lip and palate, and high  doses  can  inhibit  fetal  growth  and  cause  adrenal  sup- pression.  Use  of  azathioprine  in  pregnancy  has  been  reported  in  some  studies  to  be  associated  with  an  increased  risk  of  fetal  anomalies  and  preterm  birth.  If diarrhea is the main complaint, dietary restriction of lactose, fruits, and vegetables is necessary. If a lactose- free  diet  is  used,  calcium  supplementation  is  needed.  Daily  constipating agents, such as psyllium hydro- philic mucilloid (Metamucil), are quite effective. The  use of diphenoxylate-atropine (Lomotil) or loperamide  (Imodium)  should  be  restricted  to  patients  who  are  past the first trimester and in whom conservative man- agement fails. Surgery is indicated only for very severe complications, such as bowel perforation or abscess formation.  In  the  absence  of  compelling  obstetric  indications,  cesarean delivery is not recommended, unless there are perineal or rectal manifestations of Crohn disease.

Hepatic Disorders during Pregnancy INTRAHEPATIC CHOLESTASIS OF PREGNANCY Although  the  pathogenesis  of  intrahepatic  cholestasis  of pregnancy (ICP) is not known, some distinctive fea- tures  are  (1)  cholestasis and pruritus in the second half of pregnancy  without  other  major  liver  dysfunc- tion,  (2)  a tendency for recurrence  with  each  preg- nancy, (3) an association with oral contraceptives and multiple gestations,  (4)  a benign course  in  that  there  are  usually  no  maternal  hepatic  sequelae,  and  (5)  an increased rate of meconium-stained amniotic fluid and fetal demise. The reported prevalence of ICP in the  United  States  ranges  from  less  than  1%  of  pregnant 

PA R T 2 Obstetrics216

delivery, can cause endothelial injury to uteroplacental  and  pelvic  vessels.  Thus,  all  three  elements  of  the  Virchow  triad  (stasis,  endothelial  injury,  and  hyperco- agulability)  are  present  and  predispose  the  pregnant  woman  to VTE.  Additional important risk factors are previous history of a DVT or PE, acquired or inherited thrombophilias, smoking, and prolonged immobility  as  a  result  of  prescribed  bed  rest  for  certain  obstetric  complications.

DEEP VEIN THROMBOSIS Clinical Features The clinical diagnosis of DVT is difficult. Fifty percent of cases are asymptomatic. Pain in the calf in associa- tion  with  dorsiflexion  of  the  foot  (positive Homans sign)  is  a  clinical  sign  of  thrombosis  in  the  calf  veins.  Dull ache, tingling, tightness, or pain in the calf or leg,  especially when walking, may be present. Acute swell- ing and pain in the thigh area, as well as tenderness in  the  femoral  triangle,  are  suggestive  of  iliofemoral  thrombosis.  DVT in pregnancy is usually in the left leg.  In  a  patient  complaining  of  left  lower-extremity  pain  and  swelling,  the  finding  of  a  2-cm  difference  in  calf  circumference  is  one  of  the  more  reliable  clinical  signs of a DVT in pregnancy.

Investigations Compression ultrasonography  is  a  noninvasive  tech- nique  that  has  high  sensitivity  and  specificity  and  is currently the primary mode of diagnosis  used  for  DVT. Magnetic resonance imaging  (MRI)  has  been  used  to  evaluate  patients  suspected  of  having  pelvic  thrombosis  who  have  a  negative  Doppler  ultrasonic  examination.  D-Dimers  are  not  a  reliable  screening  tool for VTE in pregnancy.

Therapy Treatment of proven DVT during pregnancy should be initiated with either intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin (enoxaparin sodium) to achieve full antico- agulation. The unfractionated heparin dose is adjusted  to  1.5  to  2.5  times  the  control  aPTT.  Intravenous  anti- coagulation  should  be  maintained  for  at  least  5  to  7  days, after which treatment is converted to subcutane- ous heparin that must be continued for the duration of  the pregnancy and for up to 6 weeks postpartum, with  weekly  monitoring  of  the  aPTT.  Alternatively, enoxa- parin can be administered at a dose of 1 mg/kg sub- cutaneously every 12 hours. The dose can be adjusted  to  achieve  anti–factor  X  levels  of  0.6  to  1 U/mL.  Both forms of heparin are safe for the fetus and do not cross the placenta. Unfractionated heparin is associ- ated with a higher risk of maternal thrombocytope- nia and osteoporosis than is low-molecular-weight heparin.  Supplemental  calcium  and  vitamin  D3  (2000 IU/day)  should  be  advised,  along  with  periodic 

Hypoglycemia is frequently present and can be severe.  Hypertension and proteinuria are present in approxi- mately 50% of patients, raising the issue of coexisting preeclampsia. Patients can develop coagulopathy with intraabdominal hemorrhage, hepatic coma, and renal failure.

Diagnosis and Investigations Liver biopsy is diagnostic, but this is usually not done,  because  of  the  morbidity  associated  with  the  proce- dure. The  diagnosis  is  usually  based  on  the  character- istic clinical findings and laboratory tests. Other causes of liver failure should be ruled out, especially pre- eclampsia with HELLP syndrome. Laboratory findings  include  an  increase  in  prothrombin  time  and  partial  thromboplastin  time,  hyperbilirubinemia,  hyperam- monemia, hyperuricemia, and a moderate elevation of  the transaminase levels. BUN and creatinine levels are  elevated,  reflecting  the  degree  of  renal  failure,  and  hypoglycemia is present. Hematemesis and spontane- ous bleeding become manifest as DIC develops. Liver  failure is indicated by elevated blood ammonia levels.

Treatment Prompt delivery and intensive supportive care are indicated after diagnosis. Treatment is directed mainly at providing supportive measures, such as administration of intravenous fluids with 10% glucose to prevent dehydration and severe hypoglycemia. For the coagulopathy of hepatic failure, vitamin K supple- mentation is not effective, and fresh-frozen plasma or cryoprecipitate should be given  along  with  platelets  and packed red blood cells if there is DIC.

The disease can recur in subsequent pregnancies.  It is recommended that the woman and her neonate be  tested  for  an  LCHAD  defect.  Early  detection  of  such  a  defect  in  the  neonate  could  prevent  life-threatening  complications.  With  early  recognition,  immediate  delivery,  and  advances  in  critical  care  management,  mortality  is  about  7-18%,  and  fetal  mortality  about  9-23%.  In those who survive, recovery is complete, with no signs of chronic liver disease.

Venous Thromboembolic Disorders Pregnancy is a hypercoagulable state  with  up  to  a  fivefold  increased  risk  of  deep  vein  thrombosis  (DVT)  and  pulmonary  embolism  (PE).  The greatest risk of a venous thromboembolism ( VTE) is during the first few weeks postpartum, especially following a cesarean  delivery.  Pregnancy-induced  changes  in  coagulation  factors that favor clotting include a decrease in protein  S and increases in fibrinogen; factors VI, VII, and X; and  von Willebrand factor. Venous stasis results from com- pression of the pelvic veins by the gravid uterus, as well  as endocrine-mediated venodilation, often aggravated  by decreased mobility. Delivery, especially an operative 

C H A P T E R 16 Common Medical and Surgical Conditions Complicating Pregnancy 217

X-ray or in patients with asthma or chronic obstructive  pulmonary  disease.  (3) Computed tomographic pul- monary angiography:  This  technique  has  the  advan- tage  of  noninvasive  visualization  of  a  thrombus.  The  radiation  dose  to  the  fetus  is  considered  acceptably  low, but there is concern about the radiation exposure  to maternal breast tissue.

The  acute  treatment  of  PE  and  follow-up  during  pregnancy,  labor,  delivery,  and  the  postpartum  period  are the same as for DVT.

Thrombophilia Evaluation A  thrombophilia  workup  should  be  considered  for  patients with a PE or DVT, especially those with recur- rent thromboses, a positive family history, or an obstet- ric  history  suggestive  of  antiphospholipid  syndrome.  Tests to order include those for acquired thrombophil- ias (e.g., lupus anticoagulant, anticardiolipin antibody)  and inherited thrombophilias (factor V Leiden and the  prothrombin G20210A mutations, as well as proteins C  and S and antithrombin III titers).

Prophylactic Anticoagulant Therapy In pregnant patients with a past history of a PE or DVT,  prophylactic doses of heparin or low-molecular-weight  heparin should be given during pregnancy and contin- ued for 6 weeks postpartum. Subcutaneous injections of a prophylactic dose of heparin (5000 to 10,000 U every 12 hours) or enoxaparin sodium (40 mg once daily) provide sufficient prophylaxis for most patients,  although  some  pregnant  women  may  require  full   anticoagulation.  All  pregnant  women  having  cesarean  delivery  should  have  pneumatic  compression  stock- ings placed for thromboprophylaxis.

SUPERFICIAL THROMBOPHLEBITIS Superficial  thrombophlebitis  is  more  common  in  patients  with  varicose  veins,  obesity,  limited  physical  activity, or a previous history of superficial thrombosis.  In most patients, superficial thrombophlebitis is limited to the calf area, and symptoms include swell- ing and tenderness of the involved extremity. Physical  examination  reveals  erythema,  tenderness,  warmth,  and  a  palpable  cord  over  the  course  of  the  involved  superficial veins. Superficial thrombophlebitis usually does not progress to DVT or lead to PE, but lower-limb  ultrasound  is  indicated  if  there  is  concern  that  the  thrombosis may extend into the deep veins.

Treatment Treatment  of  superficial  thrombophlebitis  involves  elevation  of  the  leg,  pain  medications,  and  local   application of heat. There is usually no need for anti- coagulants, but antiinflammatory agents may be considered.  Ambulation  is  encouraged,  and  patients  should  be  instructed to wear support stockings  to  help avoid a repeat episode.

platelet  counts.  Because  of  its  longer  half-life  and  the  increased  risk  of  spinal  hematomas  with  neuraxial  anesthesia,  low-molecular-weight heparin should be stopped about 24 hours before delivery in the case of a planned induction or cesarean delivery. Alterna- tively, the patient can be switched to unfractionated heparin that can be stopped 6 hours before delivery.  If  the  aPTT  is  normal,  neuraxial  anesthesia  can  safely  be  administered.  If  there  are  no  signs  of  hemorrhage  postpartum,  low-molecular-weight  or  unfractionated  heparin  can  be  restarted  12  to  24  hours  postdelivery  and  the  patient  can  then  be  transitioned  to  warfarin,  which  should  be  continued  for  at  least  6  weeks   postpartum.  Warfarin is a vitamin K antagonist that crosses the placenta, carries risks of fetal hemorrhage and teratogenesis, and, with few exceptions, should be used only in the postpartum period. The  interna- tional  normalized  ratio  (INR)  is  commonly  used  to  measure  the  effects  of  warfarin,  and  the  target  INR  is  2.5 (range: 2.0 to 3.0). Breastfeeding is not a contrain- dication to the use of warfarin, low-molecular-weight heparin, or unfractionated heparin.

PULMONARY EMBOLISM PE is one of the most common causes of pregnancy- related death in the United States. The maternal mor- tality is less than 1% if treated early and greater than 80% if left untreated. In about 70% of cases, DVT is the  instigating  factor.  Early  detection  and  treatment  of  DVT  and  widespread  recognition  of  conditions  or  cir- cumstances requiring DVT prophylaxis are expected to  decrease the incidence of PE in pregnancy.

Clinical Features Suggestive  symptoms  of  PE  include  pleuritic  chest  pain,  shortness  of  breath,  air  hunger,  palpitations,  hemoptysis, and syncopal episodes. Suggestive signs of  PE  include  tachypnea,  tachycardia,  low-grade  fever,  a  pleural  friction  rub,  chest  splinting,  pulmonary  rales,  an  accentuated  pulmonic  valve  second  heart  sound,  and  even  right  ventricular  failure.  In most obstetric patients, the signs and symptoms of a PE are subtle.

Investigations An  ECG  can  show  sinus  tachycardia  with  or  without  premature  heartbeats  or  right  ventricular  axis  devia- tion.  On  a  chest  film,  atelectasis,  pleural  effusion,   obliteration  of  arterial  shadows,  and  elevation  of   the  diaphragm  may  be  present.  Arterial  blood  gases  obtained  on  room  air  may  show  an  oxygen  tension  below  80 mm  Hg.  PE is ultimately a radiologic diag- nosis. Three algorithms may be used. (1) Bilateral compression ultrasonography of the lower extremi- ties: If positive for DVT, a PE may be assumed in a symptomatic patient. (2) A ventilation-perfusion scan: This method poses minimal risk to the fetus, but  it  cannot  be  used  in  patients  with  an  abnormal  chest 

PA R T 2 Obstetrics218

and  palate,  IUGR,  and  adrenal  suppression.  Alterna- tive therapies include inhaled cromolyn sodium, leu- kotriene receptor antagonists, or sustained-release theophylline. Acute severe exacerbations must be treated aggressively with oxygen therapy, intravenous  fluids,  systemic  glucocorticoids,  administration  of  short-acting β2-agonists and ipratropium by nebulized  aerosol, and antibiotics if there is evidence of bacterial  infection.  Intravenous  magnesium  sulfate  or  subcuta- neous  terbutaline  can  be  added  if  needed. To  prevent  fetal  hypoxia,  pulse  oximetry  should  be  used  and  oxygen  saturation  should  be  maintained  at  95%  or  greater. Because of the hyperventilation and compen- sated  respiratory  alkalosis  present  in  normal  preg- nancy,  an arterial blood gas with a PaO2 less than 70 mm Hg and/or a PaCO2 greater than 35 mm Hg are indicative of severe respiratory compromise.  Some  patients  may  require  endotracheal  intubation  and  mechanical ventilation to maintain an adequate oxygen  supply.

Serial fetal monitoring and ultrasonic assessment of fetal growth should be implemented. The timing of  delivery is dependent on the status of both the mother  and  the  fetus.  When  pregnancy  is  progressing  well,  there is no need for early delivery, and it is advisable to  await  the  spontaneous  onset  of  labor.  Early delivery can be considered for fetal growth restriction or maternal deterioration.

Management of Labor and Delivery Labor  and  delivery  are  usually  not  triggers  of  acute  asthma  attacks.  Glucocorticoid  therapy,  including  inhaled  or  high-potency  topical  use  for  more  than  3  weeks, may suppress the hypothalamic-pituitary-adre- nal axis, and administration of stress doses of medica- tion during labor or delivery should be considered. An  epidural  block  during  labor  reduces  pain,  anxiety,  hyperventilation,  and  respiratory  effort,  all  of  which  are  known  to  aggravate  the  disease.  Vaginal delivery should be anticipated. Cesarean delivery is performed only for obstetric reasons.  Oxytocin  is  the  preferred  drug for the initial management of postpartum hemor- rhage.  Prostaglandins should not be used, because they are likely to trigger acute bronchoconstriction.

CYSTIC FIBROSIS Cystic fibrosis is due to mutations in the cystic fibrosis  transmembrane  conductance  regulator  gene,  CFTR,  which is the gene that regulates epithelial cell chloride  channel function. Because of improvements in diagno- sis and treatment, the majority of females with cystic fibrosis now survive to adulthood. It is the most severe form of obstructive lung disease observed during pregnancy, but there is no evidence that pregnancy increases the maternal risk, unless there is severe disease with pulmonary hypertension.  Preconcep- tion  care  and  counseling  should  involve  optimizing 

Pulmonary Diseases ASTHMA Asthma is a chronic inflammatory disorder charac- terized by bronchial hyperreactivity, and it is the most common pulmonary disease in pregnancy, affecting between 3% and 9% of pregnant women.  Asthma  in  pregnancy  is  currently  classified  according  to severity as (1) mild intermittent, (2) mild persistent,  (3)  moderate  persistent,  and  (4)  severe  persistent.  During  pregnancy,  condition  improves  in  about  one- third  of  patients  and  deteriorates  in  about  one-third,  and about one-third have no significant change.  Most exacerbations occur before the third trimester. Status  asthmaticus, the most severe form of asthma, compli- cates  about  0.2%  of  pregnancies.  Severe asthma is associated with an increased rate of miscarriage, preeclampsia, intrauterine fetal death, fetal growth restriction, and preterm birth.  These  complications  may occur as a result of intrauterine hypoxia.

Obstetric Management Pregnancy  does  not  induce  any  significant  changes  in  peak flow (PF), forced vital capacity (FVC), forced expi- ratory  volume  in  1  second  (FEV1),  or  the  FVC/FEV1  ratio. Most patients with asthma have been diagnosed  before pregnancy, and pregnancy does not change the  criteria for diagnosis (characteristic clinical symptoms  combined with abnormal spirometry [decreased FVC/ FEV1  and  decreased  PF  with  improvement  after  acute  bronchodilator therapy]).

Pregnant  women  with  asthma  should  be  followed  closely  and  educated  in  the  use  of  a  PF  meter.  The  avoidance  of  dehydration,  early  and  aggressive  treat- ment  of  respiratory  infections,  and  the  avoidance  of  hyperventilation, excessive physical activity, and aller- gens are important. Daily measurement of PF rates can  provide  useful  information  on  respiratory  status.  The  Working Group on Asthma in Pregnancy recommends  the  following  treatment guidelines: For those with mild intermittent asthma, a short-acting inhaled β2- agonist (albuterol) can be used as needed. Patients with mild persistent asthma should be treated with a daily low-dose inhaled glucocorticoid (budesonide). The preferred treatment for moderate persistent asthma is either a daily medium-dose inhaled gluco- corticoid or a combination of a daily low-dose inhaled glucocorticoid and a long-acting β2-agonist (salme- terol). Those with severe persistent asthma should be treated with a daily high-dose inhaled glucocorticoid combined with a long-acting β2-agonist. They may require the addition of a systemic glucocorticoid.  With  the  exception  of  systemic  glucocorticoids,  the  above-described  therapies  have  not  been  associated  with any significant fetal complications. Systemic com- bination  glucocorticoids  have  been  associated  with  fetal and/or neonatal complications, including cleft lip 

C H A P T E R 16 Common Medical and Surgical Conditions Complicating Pregnancy 219

other  AEDs.  The  neural  tube  closes  approximately  4  weeks  postconception,  before  many  women  realize  they  are  pregnant.  For  this  reason,  women of repro- ductive age who are taking AEDs are advised to take at least 0.4 to 0.8 mg of folic acid daily to protect against neural tube defects should they become preg- nant. This should be continued throughout pregnancy.  Those taking valproic acid or carbamazepine should be  prescribed  4 mg/day  of  folic  acid  for  1  to  3  months  preconception and through the first trimester.

If seizures are well controlled during pregnancy, no  change in therapy should be attempted. The AED that  is  effective  should  be  used,  and  serum  levels  of  the  unbound drug should be followed. The maternal serum  AFP should be measured at 15 to 19 weeks’ gestation to  screen  for  open  neural  tube  defects,  and  an  obstetric  ultrasound  should  be  done  at  18  to  22  weeks  to  look   for  fetal  anatomic  anomalies,  especially  neural  tube  defects,  cardiac  anomalies,  cleft  lip,  and  cleft  palate.  Because some AEDs increase the rate of vitamin K deg- radation, supplemental vitamin K (10 to 20 mg/day) is  usually  advised  after  35  weeks’  gestation  to  prevent  neonatal  hemorrhage.  Antacids  and  antihistamines  should  be  avoided  in  patients  receiving  phenytoin,  because  they  lower  plasma  levels  of  phenytoin  and  may precipitate a seizure attack.

For the treatment of status epilepticus, immediate hospitalization is required. Management is similar to  that  in  the  nonpregnant  adult.  Patency  of  the  airway  and  adequate  oxygenation  should  be  ensured.  After  blood  is  drawn  for  plasma  levels  of  anticonvulsants,  intravenous lorazepam should be given slowly, fol- lowed by a loading dose of phenytoin with continuous cardiac monitoring.

The management of labor and delivery follows obstetric indications. During labor and in the imme- diate postpartum period, anticonvulsant drugs must be continued.  The  dose  of  the  anticonvulsant  drug  may be lowered postpartum, provided that a therapeu- tic  level  is  maintained.  Although anticonvulsants are excreted in breast milk in small amounts, breastfeed- ing is not contraindicated.

Complications Pregnant patients with epilepsy have a twofold increase in maternal complications such as pre- eclampsia, abruption, hyperemesis, and premature labor. Fetal hypoxia is a potential consequence of maternal seizures, and there is a high incidence of intrauterine fetal demise. In the neonate, higher rates  of coagulopathy, drug withdrawal symptoms, and mor- bidity and mortality are reported. Congenital anoma- lies are more common in neonates exposed to AEDs in utero  than  among  offspring  of  untreated  women  with epilepsy and women without epilepsy. The overall risk of major malformations is 4-6%.  Small  retro- spective studies have raised the possibility of impaired 

nutrition  and  pulmonary  function,  as  well  as  testing  the father’s carrier status and counseling about inheri- tance  risks  to  the  fetus.  Women with pulmonary hypertension should be counseled about the greater risk that pregnancy poses for an adverse maternal, fetal, or neonatal outcome. Exocrine pancreatic insuf- ficiency is present in about 90% of patients, and screen- ing  for  diabetes  (if  not  already  diagnosed)  should  be  undertaken  early  in  pregnancy.  Women  with  malab- sorption  symptoms  might  become  more  emaciated  during pregnancy, and there are risks of superimposed  infections. In addition to either having cystic fibrosis or being a carrier of it, the fetus is at increased risk of IUGR and premature delivery.  Options  for  prenatal  diagnosis should be reviewed, and antepartum testing  should be instituted in the third trimester.

For labor and delivery, epidural analgesia is rec- ommended.  Outlet  forceps  or  vacuum-assisted  deliv- ery should also be considered. The Valsalva maneuver  should  be  avoided  because  of  the  associated  increase  in maternal oxygen requirements. Breastfeeding is rec- ommended  unless  the  mother’s  condition  does  not  allow it.

Central Nervous System Disease In  the  majority  of  cases,  seizure  frequency  does  not  change  in  pregnancy.  Some  factors  during  pregnancy  that  may  contribute  to  increased  seizure  frequency  include nausea and vomiting leading to missed doses,  decreased  GI  motility,  expanded  intravascular  volume  lowering  serum  drug  levels,  induction  of  enzymes  increasing drug metabolism, and increased glomerular  filtration hastening drug clearance.

Treatment Preconception  counseling  and  care  are  important.  Antiepileptic  drugs  (AEDs)  that  induce  cytochrome  P450 and related enzymes can decrease the efficacy of  hormonal contraception. In patients who have had no seizure activity for at least 2 years, AED therapy can be discontinued before conception.  First-generation  AEDs  include  phenytoin,  phenobarbital,  trimethadi- one,  clonazepam,  valproic  acid,  and  carbamazepine.  Second-generation  AEDs  include  lamotrigine,  topira- mate, and levetiracetam.

There  is  no  ideal  anticonvulsant  for  use  in  women  intending  to  become  pregnant  or  during  pregnancy,  and  all AEDs should be considered potential terato- gens.  In  general,  monotherapy should be attempted, using the lowest dose of the AED that most effectively controls the woman’s seizures.  Valproic  acid  is  an  exception. Valproic acid should probably not be used in a woman planning a pregnancy, unless other drugs  have  proven  ineffective.  Its  teratogenicity,  especially  the high risk of neural tube defects and neurodevelop- mental disorders, is unacceptably high compared with 

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bidity, and even mortality, for both the fetus and the mother.

GENERAL PRINCIPLES Elective surgery should be avoided in pregnancy. When surgery must be done, but not emergently (e.g.,  an  ovarian  neoplasm),  the second trimester is the safest time. During this period, the risks of teratogen- esis  and  miscarriage  are  much  lower  than  in  the  first  trimester, and the risk of preterm labor is lower than in  the  third  trimester.  Regional  analgesia  is  preferred  because it is associated with lower mortality and mor- bidity  than  general  anesthesia. There  is  little  evidence  of  teratogenicity  of  commonly  used  anesthetics.  Pul- monary aspiration is more common.  All  pregnant  women should be treated as if they have a full stomach  and premedicated with citrate and histamine H2 recep- tor  blockers.  Precautions must be taken to avoid maternal hypotension and hypoxia that have adverse effects on uteroplacental blood flow. When  possible,  the patient should be in the left lateral decubitus posi- tion. Pre- and postoperative fetal and uterine monitor- ing  are  indicated  in  the  third  trimester.  If  significant  blood loss is anticipated and the patient is anemic, it is  advisable to transfuse the patient preoperatively.

ACUTE CONDITIONS The general approach to acute surgical emergencies during pregnancy is to manage the problem, regard- less of the pregnancy.  Acute  nonobstetric  surgical  emergencies occur in all three trimesters of pregnancy.  The  overall  incidence  is  approximately  1  in  500  preg- nancies. The  more  common  acute  conditions  are  dis- cussed below.

Appendicitis Appendectomy for presumed acute appendicitis is the most common surgical emergency during preg- nancy.  The  incidence  of  acute  appendicitis  in  preg- nancy  is  approximately  0.05-0.1%,  and  it  is  constant  throughout  the  three  trimesters. The  usual  symptoms  of  acute  appendicitis,  such  as  epigastric  pain,  nausea,  vomiting,  and  lower  abdominal  pain,  may  be  less  apparent  during  pregnancy,  although  right lower- quadrant pain is still the most common presentation. The differential diagnosis may be especially confus- ing  (Box  16-2).  The  enlarging  uterus  displaces  the  appendix  superiorly  and  laterally  as  pregnancy  pro- gresses  (as  shown  in  Figure  16-3).  Tenderness and guarding are elicited more laterally than expected.  The  increased  white  blood  cell  count  seen  in  normal  pregnancy  further  confuses  the  issue.  Surgery  may  be  delayed, resulting in an increased rate of rupture, pre- mature  labor,  infant  morbidity,  and,  rarely,  maternal  death.

Imaging studies can increase the accuracy of the diagnosis of appendicitis but should never replace

cognitive  and  neurologic  function  in  the  offspring   that  may  manifest  later  in  life.  The  risk  of  a  seizure  disorder is greater among the children of mothers with  epilepsy.

Reducing the Morbidity of Medical Conditions during Pregnancy Metabolic dysregulation (metabolic syndrome) begins  in women who are obese and/or gain excessive weight  during pregnancy. Obesity is associated with a marked  increase in inflammation in fat cells, leading to insulin  resistance.  Because  of  the  current,  dramatic  increase  in  the  incidence  of  obesity  in  the  United  States  and  elsewhere,  weight  loss  beginning  before  pregnancy  and  prevention  of  excessive  weight  gain  during  preg- nancy  should  be  strongly  recommended.  Increased  physical  activity,  known  to  reduce  the  risk  of  obesity,  should be encouraged. Coupled with physical activity,  counseling  for  behavioral  changes  to  reduce  psycho- social stress, known to be a factor in the development  of  cardiovascular  disease,  should  also  be  recom- mended  for  women  at  risk.  Finally,  there  should  be  a  focus  on  the  gut-brain  connection,  a  new  theory  that  links  gut  dysregulation  (by  abnormal  bacteria)  with  brain  dysregulation  leading  to  insulin  resistance  and  inflammation.  Poor  diet  alters  the  gut  microbiome,  leading  to  gut  inflammation  and  alterations  in  appe- tite. Dietary changes such as the “Mediterranean diet”  plus  probiotics  can  alter  the  gut  biome,  resulting  in  improvement  in  metabolism  and  weight  loss.  Con- suming  smaller  portions  while  avoiding  calorie-dense  foods,  particularly  sugars  and  other  carbohydrates,  is  very important.

Recently, it has been shown that changes in the gut  biome  and  supplementation  with  vitamin  D  reduces  weight  gain,  improves  insulin  sensitivity,  and  reduces  hypertension. In order to improve the health of women  and their children, reducing the impact of medical dis- orders in pregnancy should have a high priority. Obste- tricians and other health care providers must focus on  the prevention and mitigation of the effects of medical  conditions that may complicate pregnancy.

Surgical Conditions during Pregnancy Pregnancy  substantially  enhances  the  problems  asso- ciated with surgery. Physiologic changes and the altered  immunologic responses of pregnancy change the diag- nostic  parameters  of  surgical  diseases.  Surgery  (espe- cially abdominal surgery) can increase the rate of fetal  loss.  Reluctance to operate on a pregnant woman with an acute surgical condition or a suspicious pelvic mass may add to critical delays and increase the mor-

C H A P T E R 16 Common Medical and Surgical Conditions Complicating Pregnancy 221

should  be  suspected  when  right  lower-quadrant  inflammation, an enlarged nonfilling tubular structure,  and/or  a  fecalith  are  noted. The  estimated  fetal  radia- tion  exposure  is  about  0.025  Gy.  Exposure  to  less  than  0.05  Gy  has  not  been  associated  with  an  increase  in  fetal anomalies or pregnancy loss. Table 16-8 shows the  dose of ionizing radiation to the fetus during common  diagnostic  radiologic  procedures.  MRI is now widely used for diagnostic assistance when appendicitis is suspected.

When acute appendicitis is diagnosed, laparotomy with appendectomy may be carried out. A McBurney,  transverse, or Rockey-Davis incision can be performed.  Laparoscopic appendectomy may also be considered.  A  potential  concern  with  laparoscopy  is  that  carbon dioxide used for insufflation can be absorbed across the peritoneum into the maternal blood stream and cross the placenta, leading to fetal respiratory acido- sis and hypercapnia. As gestation progresses, the like- lihood  increases  that  the  pneumoperitoneum  will  decrease venous return, cardiac output, and uteropla- cental blood flow. Guidelines to mitigate these harmful  fetal  effects  and  increase  the  overall  safety  of  laparos- copy  during  pregnancy  have  been  published  by  the  Society  of  American  Gastrointestinal  and  Endoscopic  Surgeons.  Laparoscopic appendectomy, as well as other laparoscopic procedures, may be considered during pregnancy in accordance with the guidelines listed in Box 16-3.

Acute Cholecystitis and Cholelithiasis An increase in serum cholesterol and lipid levels in pregnancy, along with biliary stasis, leads to a higher

initial physical evaluation.  The  American  College  of  Radiology  recommends  nonionizing  radiation  tech- niques such as ultrasonography and MRI in pregnant  women.  On  ultrasound,  the  abnormal  appendix  can   be  visualized  as  a  noncompressible  tubular  structure  measuring 6 mm or greater in the region of the patient’s  pain. Helical computed tomographic scanning has the  disadvantage  of  radiation  exposure,  but  appendicitis 

FIGURE 16-3 The changing position of the right colon and appen- dix as pregnancy progresses and the uterus enlarges upward and laterally.

8 mo

7 mo

6 mo

5 mo

4 mo

3 mo

TABLE 16-8

ESTIMATED FETAL EXPOSURE FROM SOME COMMON RADIOLOGIC PROCEDURES

Procedure Fetal Exposure (Gy)

Chest radiograph (two views) 0.000002-0.00007

Abdominal film (single view) 0.001

Intravenous pyelography >0.01*

Hip film (single view) 0.002

Mammography 0.0007-0.002

Barium enema or small bowel series 0.02-0.04

CT scan of head or chest <0.01

CT scan of abdomen and lumbar spine

0.035

CT pelvimetry 0.0025

Data from American College of Obstetricians and Gynecologists: Guidelines for diagnostic imaging during pregnancy. American College of Obstetricians and Gynecologists Committee opinion No. 299. Obset Gynecol 104:649, 2004. CT, Computed tomography. *Exposure depends on the number of films.

BOX 16-2

DIFFERENTIAL DIAGNOSIS OF ACUTE APPENDICITIS IN PREGNANCY

Ruptured corpus luteum Torsion of an adnexal mass Pyelonephritis Nephrolithiasis Ectopic pregnancy Hyperemesis gravidarum Acute mesenteric lymphadenitis Inflammatory bowel disease Tuboovarian abscess Acute mesenteric thrombosis Cholecystitis/cholelithiasis Concealed abruption

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*The American College of Obstetricians and Gynecologists recommends continuous fetal monitoring based upon the preoperative monitoring assessment and gestational age.

Data from www.sages.org/publications/guidelines/guidelines-for-diagnosis-treatment-and-use-of-laparoscopy-for-surgical-problems-during-pregnancy/. Accessed May 19, 2015. An explanation of the method for the assessment of evidence along with references is provided on this website.

BOX 16-3

SOCIETY OF AMERICAN GASTROINTESTINAL AND ENDOSCOPIC SURGEONS GUIDELINES FOR DIAGNOSIS, TREATMENT, AND USE OF LAPAROSCOPY FOR SURGICAL PROBLEMS DURING PREGNANCY (EVIDENCE RATING)

Diagnostic  laparoscopy  is  safe  and  effective  when  used  selectively in the workup and treatment of acute abdominal  processes in pregnancy (Moderate; Strong).

Laparoscopic treatment of acute abdominal diseases has  the same indications in pregnant and nonpregnant patients  (Moderate; Strong).

Laparoscopy can be performed safely during any trimes- ter of pregnancy (Moderate; Strong).

Gravid patients should be placed in the left lateral decu- bitus  position  to  minimize  compression  of  the  vena  cava  (Moderate; Strong).

Initial  abdominal  access  can  be  accomplished  safely  with an open (Hasson) technique, Veress needle, or optical  trocar if the location is adjusted according to fundal height  and previous incisions (Moderate; Strong).

CO2  insufflation  of  10-15 mm  Hg  can  be  safely  used  for  laparoscopy in the pregnant patient (Moderate; Strong).

Intraoperative  CO2  monitoring  by  capnography  should  be used during laparoscopy in the pregnant patient (Moder- ate; Strong).

Intraoperative  and  postoperative  pneumatic  compres- sion devices and early postoperative ambulation are recom- mended  as  prophylaxis  for  deep  vein  thrombosis  in  the  gravid patient (Moderate; Strong).

Laparoscopic cholecystectomy is the treatment of choice  in the pregnant patient with gallbladder disease, regardless  of trimester (Moderate; Strong).

Choledocholithiasis during pregnancy may be managed  with preoperative endoscopic retrograde cholangiopancre-

atography (ERCP) with sphincterotomy, followed by laparo- scopic  cholecystectomy,  laparoscopic  common  bile  duct  exploration, or postoperative ERCP (Moderate; Strong).

Laparoscopic appendectomy may be performed safely in  pregnant patients with appendicitis (Moderate; Strong)

Laparoscopic  adrenalectomy,  nephrectomy,  and  sple- nectomy  are  safe  procedures  in  pregnant  patients  (Low;  Weak).

Laparoscopy  is  a  safe  and  effective  treatment  in  gravid  patients  with  symptomatic  cystic  masses.  Observation  is  acceptable  for  all  other  cystic  lesions,  provided  ultrasound  findings  are  not  concerning  for  malignancy  and  tumor  markers  are  normal.  Initial  observation  is  warranted  for  most cystic lesions.

Laparoscopy  is  recommended  for  both  diagnosis  and  treatment  of  adnexal  torsion,  unless  clinical  severity  war- rants laparotomy (Low; Strong).

Fetal heart monitoring should occur preoperatively and  postoperatively  in  the  setting  of  urgent  abdominal  surgery  during pregnancy* (Moderate; Strong).

Obstetric consultation can be obtained pre- and/or post- operatively  based  on  the  severity  of  the  patient’s  disease,  gestational  age,  and  availability  of  the  consultant  (Moder- ate; Strong).

Tocolytics  should  not  be  used  prophylactically  in  preg- nant  women  undergoing  surgery,  but  they  should  be  con- sidered  perioperatively  when  signs  of  preterm  labor  are  present (High; Strong).

incidence of cholelithiasis, biliary obstruction, and cholecystitis.  High  levels  of  estrogens  in  pregnancy  increase the saturation of cholesterol in the bile. Virtu- ally all of the gallstones associated with pregnancy are  composed of crystallized cholesterol. Ultrasonography  has revealed a fairly high incidence of cholelithiasis in  pregnancy  (4%).  The  incidence  of  hospitalization  for  cholecystitis  in  pregnancy  is  1-2%,  but  only  1  in  2000  pregnant women require cholecystectomy.

Nausea and vomiting, along with right upper- quadrant tenderness and guarding, generally suggest biliary tract disease.  An  increasing  white  blood  cell  count with elevated alkaline phosphatase and bilirubin  levels, jaundice in the presence of stones, or increased  thickness  of  the  gallbladder  wall  on  ultrasonography  serves  to  authenticate  the  diagnosis.  Viral hepatitis must be considered in the differential diagnosis.  Markedly elevated aspartate transaminase and alanine  transaminase levels (>200 U/L), especially without leu- kocytosis, should suggest viral hepatitis.

Generally, cholecystitis can be managed medically in pregnancy. Parenteral fluids, gastric decompression,  and  dietary  measures  should  comprise  the  primary  approach.  Endoscopic  retrograde  cholangiopancrea- tography (ERCP) can be performed safely in pregnancy  with  little  ionizing  radiation  exposure  to  the  fetus  if   the  patient  has  cholangitis  or  pancreatitis  caused  by   a  common  bile  duct  stone.  If  symptoms  and  signs  persist  with  progressive  peritonitis  despite  medical  management  or  ERCP,  cholecystectomy  is  indicated.  Laparoscopic cholecystectomy has been performed in  pregnancy and is considered to be both indicated and  safe (see Box 16-3).

Acute Pancreatitis Generally, pancreatitis is associated with cholecysti- tis, cholelithiasis, or alcoholism.  It  has  also  been  associated with viral infections and drugs such as thia- zide  diuretics,  furosemide,  acetaminophen,  clonidine,  isoniazid,  rifampin,  tetracycline,  propoxyphene,  and 

C H A P T E R 16 Common Medical and Surgical Conditions Complicating Pregnancy 223

steroids. It is less common in pregnancy, and the inci- dence  in  pregnancy  varies  from  1 : 1000  to  1 : 4000,  increasing  somewhat  in  the  third  trimester.  However,  the mortality rate associated with pancreatitis is sig- nificantly higher in pregnancy.

The prime symptom of pancreatitis is severe, non- colicky epigastric pain radiating to the high back, which is relieved somewhat by leaning forward.  Nausea  and  vomiting  generally  are  present.  Upper  abdominal  guarding  may  be  difficult  to  assess  in  late  pregnancy.  An elevated serum amylase  (>200 U/dL)  and lipase generally confirm the diagnosis,  although  cholecystitis,  peptic  ulcer,  diabetic  ketoacidosis,  and  hyperemesis  gravidarum  may  also  be  associated  with  elevations of serum amylase.

Generally, the disease is self-limiting and responds within 1 to 10 days to bed rest, parenteral fluids, pain relief, and nasogastric suction.  Occasionally,  the  disease becomes severe and protracted, with extensive  pancreatic  edema  and  autodigestion,  massive  ascites,  hemoperitoneum,  fever,  and  paralytic  ileus.  In  such  cases, maternal and fetal mortality are high, and peri- toneal  lavage,  operative  drainage,  partial  pancreatic  resection,  or  some  combination  of  these  procedures  may be required.

Bowel Obstruction Bowel obstruction in pregnancy is usually associated with postoperative adhesions, although volvulus and intussusception are rare causes. It generally occurs in  late pregnancy and is associated with traction on adhe- sions as the uterus enlarges. An erect abdominal x-ray showing characteristic dilated loops of bowel and air- fluid levels serves to confirm the obstruction.

Management  does  not  differ  from  that  in  the   nonpregnant  patient.  Nasogastric  suction  should  be  instituted  and  fluid  and  electrolyte  balance  carefully  monitored.  When the obstruction does not resolve after 48 to 96 hours, an exploratory laparotomy should be carried out through an appropriate vertical incision. If uterine contractions occur postoperatively,  tocolytics may be employed.

Adnexal Torsion Torsion of the uterine adnexa occurs somewhat more  commonly  in  pregnancy,  possibly  because  the  sup- porting ligaments elongate as the gestation progresses.  Ovarian  tumors  (e.g.,  cystic  teratomas,  corpus  luteal  cysts)  may  become  ischemic  if  their  vascular  pedicles  undergo  torsion.  Such  ischemic  events  are  usually   heralded  by  the  sudden  onset  of  severe,  intermittent  abdominal  pain,  which  may  radiate  to  the  flank  and  down the anterior thigh.

During the first and early second trimesters, a mass is usually felt on pelvic examination or is visualized by ultrasonography. Later in the pregnancy, it may be

impossible to palpate a mass clinically.  Low-grade  fever and leukocytosis may be present, and serum cre- atine  phosphokinase  levels  may  be  elevated,  depend- ing on the extent of the infarction. In the first trimester,  the  differential  diagnosis  includes  ectopic  pregnancy  and hemorrhagic corpus luteum; later in pregnancy, a  degenerating fibroid should be considered.

Although the pain may diminish somewhat after 24 hours, removal of the infarcted organ is indicated. If the excised ovary contains the corpus luteum, pro- gesterone supplementation is generally necessary before 10 weeks’ gestation.

Abdominal Trauma By far the most common abdominal trauma in preg- nancy occurs in automobile accidents. Placental abruption, uterine contusions, and fetal skull frac- tures may result.  Placental  abruptions  are  treated  expectantly unless fetal monitoring indicates fetal dis- tress,  in  which  case  immediate  abdominal  delivery  is  in  order  if  the  fetus  is  at  a  gestational  age  that  is  con- sidered  “viable”  (23  to  24  weeks  or  later).  Abdominal  exploration  may  be  necessary  to  stop  bleeding  and  repair  uterine  lacerations.  Lap-and-shoulder  harness  seat belts, rather than lap belts, are advisable for preg- nant women after 12 weeks’ gestation.

Gunshot wounds of the abdomen are treated the same as they are in nonpregnant patients, with mea- sures taken to stop bleeding and repair visceral or uterine injuries. As long as the pregnancy is intact, the  uterus should not be disturbed. Careful monitoring of  fetal well-being should be maintained before and after  the operation.

Any  time  that  a  pregnant  woman  is  evaluated  for  trauma and the cause is not clearly apparent, the pos- sibility of domestic violence should be considered.  Chapter  29  covers  the  incidence  of  domestic  violence  and  the  approach  to  a  patient  who  may  be  the  victim  of  intimate  partner  abuse  or  other  types  of  domestic  violence.

Ovarian Tumors Adnexal  masses  are  not  uncommon  and  are  usually  identified  by  pelvic  examination  or  ultrasonography  early in the pregnancy. Paraovarian cysts, corpus luteal  cysts,  and  mature  teratomas  are  the  most  common.  Approximately 50-70% are functional cysts (e.g., corpus  luteal cysts) and spontaneously resolve as the gonado- tropin  levels  fall  during  the  second  trimester. The  risk  of finding a malignant ovarian tumor during pregnancy  is  approximately  3-7%,  with  germ  cell  and  epithelial  tumors  both  potentially  occurring.  Abdominal  and  transvaginal ultrasonography should be used for initial  diagnosis,  and  any  complex  mass  that  persists  or  any  simple  cyst  that  continues  to  enlarge  should  be  removed in the second trimester.

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17 

Obstetric Procedures

C H

A P

T ER

CALVIN J. HOBEL

■  Real-time  (two-dimensional  [2D])  ultrasonic  imaging  of  the  uterus,  placenta,  fetus,  and  cervix  has  become  important  for  assessment  of  almost  all  pregnancies  in  the United States. Early in pregnancy, ultrasonic imaging  is important for pregnancy dating and for ruling out mul- tiple  pregnancies.  During  mid-gestation,  measurement  of the biparietal diameter of the fetal head, the abdomi- nal circumference, and the femoral length can determine  normal or abnormal fetal growth, and later in pregnancy  changes  in  these  parameters  can  be  used  to  assess  the  progress of fetal growth and well-being.

■  Amniocentesis  was  the  first  invasive  procedure  devel- oped  to  access  amniotic  fluid.  Real-time  2D  ultrasound  has  significantly  reduced  complications  related  to  amniocentesis.  Access  to  amniotic  fluid  has  made  bio- chemical testing possible for assessment of fetal genetic  and metabolic parameters.

■  Placental  tissue  and  fetal  cells  can  be  obtained  safely  from  the  amnion  for  the  assessment  of  fetal  genetics.  Amniotic  fluid  obtained  by  amniocentesis  provides  access to cells shed from the amnion that can be used for 

genetic studies. Placental tissue obtained by either cho- rionic villus sampling (CVS) via the cervical route (trans- vaginal catheter) or by transabdominal needle aspiration  may also be used for genetic analysis of the fetus.

■  The cervix is an important barrier that protects the fetus  from  early  delivery. The  normal  length  of  the  cervix  is  4  to 5 cm, but, in approximately 5% of pregnancies, it can  silently  undergo  shortening.  If  identified  after  mid- pregnancy  (20  to  22  weeks),  a  cerclage  can  be  placed  around the cervix to keep it from further shortening and  dilating,  which  would  increase  the  risk  of  early  preterm  delivery.

■  Forceps  application  or  the  use  of  a  vacuum  extractor  (VE)  is  sometimes  warranted  to  safely  deliver  the  fetus.  When a woman experiences prolonged labor after com- plete cervical dilation and the fetus has descended to the  point where the head is at a station of at least +2 (using  a  0  to  5 cm  scale),  the  second  stage  of  labor  can  be  reduced  by  the  use  of  forceps  or  a VE.  When forceps or VE fails, a cesarean delivery should be performed.

CLINICAL KEYS FOR THIS CHAPTER

As  the  fetus  has  become  more  accessible  for  monitor- ing as a result of technological advances, the desire to  intervene on behalf of the fetus has led to the develop- ment  of  a  number  of  obstetric  diagnostic  and  thera- peutic  procedures.  Any  procedure  performed  during  pregnancy carries risks to both mother and fetus, so it  is  important  to  counsel  the  mother  regarding  the  potential  benefits  and  risks  of  all  options  before  embarking on any obstetric intervention.

The  diagnostic  indications  for  ultrasonic  imaging,  amniocentesis,  chorionic  villus  sampling  (CVS),  and  cordocentesis are covered in this chapter, as well as the  therapeutic  indications  for  cervical  cerclage,  obstetric  forceps, vacuum extraction, and cesarean delivery. The 

techniques used in these obstetric procedures are also  described.

Ultrasound Two-dimensional  (2D)  ultrasound  has  been  the  stan- dard  in  sonography  for  the  past  30  years.  Obstetric  transvaginal  and  transabdominal  sonography  play  a  pivotal role in contemporary obstetric care, with ultra- sonic  imaging  being  done  in  approximately  90%  of  pregnancies  in  the  United  States  today.  Human  data  have shown no adverse fetal effects of ultrasound. Box  17-1  lists  common  abnormalities  that  may  be  identi- fied prenatally with ultrasound.

C H A P T E R 17 Obstetric Procedures 225

malities.  It  is  performed  between  11  and  14  weeks’   gestation,  most  commonly  by  a  transabdominal  approach,  but  also  by  a  transvaginal  approach.  First- trimester  vaginal  ultrasound  can  also  identify  struc- tural malformations.

Transvaginal sonographic measurement of cervi- cal length in the mid-trimester can be used to identify patients at risk for preterm delivery.  The  median  length of the cervix at 24 to 28 weeks is 3.5 cm. Patients  with a cervical length less than 2.0 cm are at a three- to  fivefold increased risk of preterm birth.

Transvaginal ultrasonic imaging of the lower uterine segment in the second or third trimester allows for very precise identification of placental location in relation to the internal cervical os.  In  a  patient  with  vaginal  bleeding,  exclusion  of  placenta  previa is important in overall obstetric management.

TRANSABDOMINAL ULTRASOUND After 16 weeks’ gestation, transabdominal ultrasonic machines (second-trimester screening) are used to evaluate the fetus for structural abnormalities, provide a baseline assessment of fetal growth, and obtain information regarding fetal well-being  (see  Chapter  7).  The  ability  of  a  second-trimester  scan  to  identify  a  fetus  with  an  anomaly  ranges  from  17-74%.  This  wide-ranging  variation  in  sensitivity  is  probably  caused by differences in patient population and opera- tor  skill.  The  specificity—the  ability  of  ultrasound  to  correctly identify a normal fetus—approaches 100% in  all studies. Thus, ultrasound is useful in ruling out fetal anomalies, but it is not as reliable in detecting them.

In the third trimester, transabdominal ultrasound is useful for assessing fetal growth.  Serial  biometric  measurements  of  the  fetal  head,  abdomen,  and  limbs  provide  longitudinal  information  regarding  the  fetal  growth  trajectory.  Software  packages  integral  to  ultra- sound machines allow calculation of a fetal weight esti- mate from these measurements. This estimate is often  used  clinically.  However,  these  estimates  may  have  an  error of ±15% (a variation of ±1 lb or 450 g in a 7-lb or  3400-g  estimate),  which  limits  the  utility  of  ultrasonic  fetal weight estimates, especially in larger fetuses (>8 lb  or 4000 g).

Ultrasonic visualization of aspects of fetal behav- ior (e.g., body movement, fetal breathing) provide highly predictive information regarding fetal oxygen- ation and well-being. These  aspects  are  combined  to  determine the biophysical profile (Box 17-2). The risk  of  fetal  death  within  the  week  following  a  biophysical  profile score of 8 or more is less than 1%.

THREE-DIMENSIONAL SONOGRAPHY Three-dimensional (3D) ultrasonography provides the ability to acquire an entire volume of ultrasound- based information and then display any plane.  It  offers a huge number of display possibilities compared 

BOX 17-1

EXAMPLES OF FETAL ABNORMALITIES DETECTED BY PRENATAL ULTRASOUND

Central Nervous System •  Hydrocephalus •  Anencephaly •  Arachnoid cyst •  Porencephaly •  Agenesis of corpus callosum •  Spina bifida

Face •  Cleft lip and/or palate •  Hypoplasia of the nose

Neck •  Cystic hygroma •  Goiter •  Nuchal skin thickening

Heart •  Atrial septal defect •  Ventricular septal defect •  Tetralogy of Fallot •  Transposition of the great vessels •  Arrhythmias

Lungs •  Congenital cystic adenomatoid malformation •  Lung sequestration •  Diaphragmatic hernia

Abdominal Wall •  Gastroschisis •  Omphalocele

Gastrointestinal Tract •  Bowel atresia or obstruction •  Echogenic bowel

Urinary System •  Renal agenesis •  Polycystic kidney disease •  Hydronephrosis •  Posterior urethral valves

Skeletal Dysplasia

TRANSVAGINAL ULTRASOUND Transvaginal  ultrasound  is  useful  in  the  first  trimester  of pregnancy because the close proximity of the intra- vaginal ultrasonic transducer allows for high-frequency  scanning and better resolution of the pelvic organs and  developing  pregnancy  than  are  possible  with  transab- dominal  imaging.  Transvaginal ultrasound is com- monly used in the first trimester to determine accurate dating of the pregnancy, as well as fetal loca- tion and number (see Chapter 7). The nuchal translu- cency measurement (first-trimester screening),  a  sonographically derived assessment of the subcutane- ous  fluid  collection  at  the  level  of  the  fetal  neck,  is  a  screening  test  for  chromosomal  and  structural  abnor-

PA R T 2 Obstetrics226

Doppler  studies  of  the  fetal  middle  cerebral  artery   are used as a noninvasive estimate of fetal hematocrit.  This is useful in the management of severe fetal anemia  in  pregnancies  complicated  by  isoimmunization  (see  Chapter 15).

Finally,  ultrasound is used to assist in performing invasive obstetric procedures.  Amniocentesis,  CVS,  and  percutaneous  umbilical  blood  sampling  (cordo- centesis) are examples of procedures that require con- tinuous ultrasonic guidance.

Amniocentesis Amniocentesis,  which  involves  removing  a  sample  of  fluid  from  the  amniotic  cavity,  is  the  most  common  invasive  prenatal  diagnostic  procedure.  With  direct  ultrasonic  guidance,  a  22-gauge  needle  is  advanced  into a clear pocket of amniotic fluid under sterile con- ditions,  with  care  taken  to  avoid  maternal  bowel  and  blood  vessels,  as  well  as  the  placenta  if  possible.  Approximately  20 mL  of  amniotic  fluid  is  withdrawn  for  genetic  studies.  Rh immune globulin (RhoGAM) must be given to the Rh-negative gravida  because  of  the small risk of procedure-related isoimmunization.

GENETIC DIAGNOSIS Amniocentesis for prenatal diagnosis of chromosomal  anomalies  is  performed  at  16 to 20 weeks’ gestation.  The  procedure-related  risks are an approximately 0.3% pregnancy loss rate and a 1% postprocedure measurable amniotic fluid leakage rate. Early amnio- centesis done before the 15th week of gestation is asso- ciated  with  a  higher  miscarriage  rate  (3-4%),  a  higher  postprocedure  leakage  rate  (3%),  and  an  additional   risk  of  limb  deformities,  including  clubfoot  (1%).  Amniotic cells require 1 to 2 weeks of culture before final chromosomal analysis is possible, although fluo- rescence  in  situ  hybridization  can  be  used  with  chromosome-specific probes to diagnose certain chro- mosomal  disorders  (e.g.,  trisomy  21,  18,  and  13). This  gives preliminary results in 3 days.

Single gene defects that have been characterized at  the molecular level are amenable to prenatal diagnosis  via  amniocentesis.  By polymerase chain reaction, fetal DNA in the amniocytes can be amplified rapidly to allow for direct or indirect molecular analysis of genetic disorders.  Examples  of  common  prenatally  diagnosed  genetic  disorders  include  cystic  fibrosis,  Tay-Sachs disease, sickle cell disease, and fragile X syn- drome (see Chapter 7).

BIOCHEMICAL TESTING An  example  of  biochemical  testing  that  can  be  per- formed  on  amniotic  fluid  is  the  determination of the level of α-fetoprotein (AFP).  AFP  is  a  fetal  serum  protein  that  should,  under  normal  circumstances,  be  detectable in the amniotic fluid in only trace amounts. 

with  2D  ultrasound.  3D  volume  imaging  is  not  new,  because  computed  tomographic  and  magnetic  reso- nance  imaging  have  been  developed  for  subsequent  2D reconstruction. The main advantage of 3D over 2D  ultrasound  is  the  improved imaging of the fetus with malformations.  The  types  of  anomalies  in  which  3D  imaging  is  helpful  include  facial  defects  (Figure  17-1),  limb abnormalities, and neural tube defects. The most  important  advantage  of  3D  ultrasound  is  that  more  data  can  be  gathered  and  reviewed  over  a  shorter  period of time than is possible with 2D ultrasound.

DOPPLER SONOGRAPHY Pulse  color  flow  Doppler  can  precisely  measure  the  velocity  profile  of  blood  flowing  through  fetal  vessels,  which  then  allows for characterization of vascular impedance (resistance).  The  umbilical  artery,  which  normally  has  high-velocity  flow  during  cardiac  dias- tole,  may  have  low,  absent,  or  even  reversed  diastolic  flow in a compromised fetus with high-resistance pla- cental  vasculature.  Similarly,  because  the  peak  flow  velocity  through  a  blood  vessel  is  inversely  propor- tional  to  the  viscosity  of  the  liquid  flowing  through  it, 

FIGURE 17-1 Three-dimensional ultrasonic image of a fetal face showing normal facial anatomy.

*Two points for each time these events are documented on a real-time ultrasound during a 30-minute nonstress test, and two points for a reactive nonstress test.

BOX 17-2

BIOPHYSICAL PROFILE*

Fetal breathing—30 seconds of rhythmic movement of the  fetal thorax

Fetal movement—At  least  three  movements  of  the  fetal  body or limb

Fetal tone—One extension and flexion of a limb joint Amniotic fluid—Single deepest vertical pocket of amniotic 

fluid >2 cm

C H A P T E R 17 Obstetric Procedures 227

Chorionic Villus Sampling Another  method  used  to  access  fetal  cells  for  prenatal  genetic  diagnosis  is  CVS  of  the  placenta.  The  indica- tions for CVS are similar to amniocentesis. The advan- tage of CVS is that it can be performed earlier than amniocentesis (typically between the 10th and 12th weeks of gestation), allowing for earlier prenatal diag- nosis.  Although  technically  feasible,  CVS  is  not  per- formed  before  the  9th  week,  as  it  has  been  associated  with  an  increased  risk  of  oromandibular/limb  dystro- phy, presumably from a vascular insult.

CVS must be performed under sterile conditions either transcervically or transabdominally.  In  trans- cervical  CVS,  the  distal  3  to  5 cm  of  a  catheter  is   inserted  through  the  cervix  and  into  the  placenta   under  sonographic  guidance.  A  20-mL  syringe  with  nutrient  medium  is  attached,  and  negative  pressure   is  applied  to  obtain  fragments  of  placental  villi.  In  transabdominal  CVS,  an  18-  to  20-gauge  needle  is  inserted  into  the  placenta  transabdominally.  With  either  approach,  RhoGAM  should  be  administered  to  Rh-negative patients. The procedure-related fetal loss is less than 1%.

Direct  visual  inspection  of  dividing  villous  cells  obtained by CVS allows for detection of chromosomal  abnormalities  within  3  days,  and  tissue  culture  yields  cytogenetic results in 6 to 8 days. The diagnostic preci- sion of CVS is somewhat less than that achieved with amniocentesis because of a 1% risk of chromo- somal mosaicism, which is often due to confined pla- cental mosaicism.  A  disadvantage  of  CVS  is  that  amniotic  fluid  AFP  levels  cannot  be  assessed,  and   thus  patients  at  risk  for  neural  tube  defects  must  wait  until  amniocentesis  can  be  performed  in  the  second  trimester.

Cordocentesis Cordocentesis (percutaneous umbilical blood sam- pling) is a procedure in which fetal blood is obtained directly from the umbilical vein at the placental cord insertion site under direct ultrasonic guidance. Confir- mation  of  the  fetal  origin  of  the  blood  is  obtained  by  measuring the fetal mean corpuscular volume (MCV ),  which is typically greater than 120 fL (maternal MCV is  usually <100 fL).

Historically, the most common indication for cor- docentesis has been to determine fetal hematocrit in the hemolytic disease known as Rh isoimmunization.  With  the  recent  advent  of  assessment  of  fetal  anemia  by  Doppler  of  the  fetal  middle  cerebral  artery,  cordo- centesis is becoming less frequent. Today, cordocente- sis is often performed for rapid evaluation of the fetal karyotype. Unlike amniocytes, fetal leukocytes may be  cultured  rapidly,  and  results  are  typically  available  in   3 days.

If the fetal dorsal or ventral wall is open (e.g., neural tube defect or gastroschisis), amniotic fluid AFP will be elevated, allowing detection of these defects even if  ultrasonic  imaging  in  both  two  and  three  dimensions  is equivocal or not diagnostic.

DIAGNOSIS OF PERINATAL INFECTIONS In the United States, the most commonly encountered prenatal infections with potential sequelae for the fetus include cytomegalovirus, parvovirus B19, vari- cella zoster virus, and toxoplasmosis. Often these are  accompanied  by  findings  on  mid-trimester  ultraso- nography, including abdominal, liver, and intracranial  calcifications; fetal hydrops; echogenic bowel; ventric- ulomegaly;  and  intrauterine  growth  restriction.  These  findings can prompt amniotic fluid analysis via culture  or polymerase chain reaction to identify the pathogen.  In addition, amniotic fluid Gram stain, white blood cell count, glucose level, interleukin-6 level, and culture have been used to diagnose preterm chorio- amnionitis, which is associated with premature labor  (see Chapter 22).

OTHER DIAGNOSTIC TESTING Amniocentesis is commonly used in the third trimes- ter to determine the risk of neonatal lung immaturity  in  the  case  of  impending  premature  birth  or  before  elective  delivery.  This  is  performed  by  measuring  the  pulmonary phospholipids or lamellar bodies,  which  enter  the  amniotic  fluid  from  the  fetal  lungs.  The presence of phosphatidylglycerol and a lecithin-to- sphingomyelin ratio greater than 2.0 are associated with minimal risk of respiratory distress in the neonate.  In  a  case  of  suspected  premature  rupture  of  the  membranes,  when  the  diagnosis  is  unclear  using  standard  tests,  infusion  of  2  to  3 mL  of  dye  into  the  amniotic  fluid  may  be  performed.  If  the  dye  is  then  noted  on  a  vaginally  placed  tampon,  rupture  of  the  membranes is confirmed.

THERAPEUTIC AMNIOCENTESIS The primary role of a therapeutic amniocentesis has been in the management of polyhydramnios and twin-twin transfusion syndrome.  Polyhydramnios,  typically  defined  as  a  single  deepest  vertical  pocket  of  amniotic  fluid  greater  than  8 cm  on  ultrasound,  can  cause  maternal  respiratory  embarrassment  or  prema- ture  labor.  Excessive  amniotic  fluid  volume  may  arise  from  lack  of  fetal  swallowing  or  from  excessive  fetal  urination. The latter condition occurs in the twin-twin  transfusion  syndrome  (see  Chapter  13).  Serial  amnio- centeses to remove large volumes of excessive amniotic  fluid from the sac of the recipient twin have been asso- ciated  with  improved  perinatal  outcome;  however,  recent data suggest that laser ablation of placental vas- cular  connections  between  the  twin  placentas  with  twin-twin transfusion syndrome is significantly better.

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FIGURE 17-2 McDonald-type cervical cerclage. Although suture techniques may vary somewhat, four stiches (10, 7, 5, and 2 o’clock) are usually placed high into the cervix, using a nonabsorbable material such as Mersilene (A) and then tied (12 o’clock), providing additional support at the level of the internal cervical os (B). This suture is cut for labor. (From Gabbe SG, Simpson JL, Niebyl JR, et al: Obstetrics: normal and problem pregnancies, ed 5, Philadelphia, 2007, Churchill Livingstone.)

A B

The fetal loss rate is about 1% per procedure. In the  case  of  a  hydropic  fetus,  the  risk  of  fetal  loss  may  approach 7%. The cause of pregnancy loss may be cho- rioamnionitis,  rupture  of  membranes,  bleeding  from  the  puncture  site,  bradycardia,  or  thrombosis  of  the  umbilical vessel.

Cervical Cerclage Cervical insufficiency or incompetence is defined as the inability of the uterine cervix to retain a preg- nancy in the absence of contractions or labor  (see  Chapter 12). Cervical cerclage, a circumferential suture  placed into the cervix, has been proposed as a surgical  treatment for this condition. More recently, it has been  used in combination with vaginal progesterone for the  prevention  of  preterm  birth.  The cerclage is usually placed at 13 to 16 weeks’ gestation,  but  it  can  be  placed  at  22  to  24  weeks  when  cervical  shortening   is  observed  by  physical  examination  or  by  vaginal  ultrasonography.

The  most  common  procedure,  the  McDonald cer- clage,  involves  placement  of  a  simple  purse-string  monofilament suture near the cervicovaginal junction  (Figure 17-2). The Shirodkar cerclage differs in that the  stitch  is  placed  as  close  to  the  internal  os  as  possible.  The  bladder  and  rectum  are  dissected  off  the  cervix,  and the woven, tapelike suture is tied and placed under  the  vaginal  epithelium.  Transabdominal  cervicoisth- mic cerclage is rarely indicated; it is reserved for select  patients  with  previously  failed  vaginal  cerclage,  cervi- cal  hypoplasia,  or  a  cervix  severely  scarred  from  prior  lacerations or surgery. This type of cerclage entails dis- section of the bladder from the lower uterine segment  through an abdominal incision.

For transvaginal cerclage, the suture is typically removed before the onset of labor. For abdominal cer- clage, cesarean delivery is performed.  Patients  must  be counseled thoroughly regarding the risks associated  with cerclage, which include bleeding, infection, iatro- genic rupture of amniotic membranes, and damage to  adjacent organs (bladder and bowel).

Operative Delivery The  incidence  of  operative  obstetric  delivery  in  the  United States today is approximately 35-40%, of which  10-15%  are  operative  vaginal  deliveries  using  either  a  forceps or a vacuum device. Approximately 25-30% of all deliveries are cesarean deliveries.  Each  operative  procedure has inherent benefits and risks.

OBSTETRIC FORCEPS Forceps  are  instruments  designed  to  provide  traction  and/or  rotation  of  the  fetal  head  when  the  expulsive  efforts  of  the  mother  are  insufficient  to  accomplish  safe  delivery  of  the  fetus.  Commonly  used  forceps  are  shown  in  Figure  17-3.  There  are  two  classes  of  obstetric  forceps:  classical  forceps  and  specialized  forceps.  Forceps  selection  depends  on  the  obstetric  indication.

Classic or standard forceps are used to facilitate delivery by applying traction to the fetal skull.  The  components  of  each  blade  are  illustrated  in  Figure  17-4.  The  blades  have  a  cephalic curve  designed  to  conform  to  the  curvature  of  the  fetal  head.  Simpson  forceps  (an  example  of  classic  or  standard  forceps)  have a tapered cephalic curve that is designed to fit on  a molded fetal head. The pelvic curve of classic forceps  approximates the shape of the birth canal.

C H A P T E R 17 Obstetric Procedures 229

4.  To shorten the second stage of labor for maternal benefit. Maternal conditions such as hypertension,  cardiac  disorders,  or  pulmonary  disease,  in  which  strenuous  pushing  in  the  second  stage  of  labor   is  considered  hazardous,  may  be  indications  for  forceps  delivery.  Epidural  analgesia,  which  also  decreases  strenuous  pushing  during  the  second  stage  of  labor,  may  also  be  recommended  for  this  purpose.

Types of Forceps Operations Forceps  application  is  classified  according  to  the  station and position of the presenting part at the time  the forceps are applied. The American College of Obste- tricians and Gynecologists has proposed the following  classifications: 1.  Outlet forceps:  The  scalp  is  visible  at  the  introitus 

without separating the labia, fetal head at perineum,  fetal  skull  at  pelvic  floor,  sagittal  suture  in  antero- posterior  or  right/left  occipitoanterior  or  posterior  position, and rotation of the fetal head not exceed- ing 45 degrees.

2.  Low forceps: The leading part of the fetal skull is at  station  +2 cm  or  more  (using  the  5-point  scale  of  0 cm,  +1,  +2,  +3,  +4,  and  +5.  Low  forceps  have  two  subdivisions: rotation of 45 degrees or less and rota- tion of more than 45 degrees.

3.  Mid forceps:  The  fetal  head  is  engaged,  but  the  leading point of the skull is above station +2 cm. Before performing a forceps-assisted vaginal deliv-

ery, appropriate consent from the patient regarding potential risks and benefits should be obtained. The  indication for the procedure should be clearly outlined  to  the  patient  and  in  the  medical  record.  The cervix

Indications In general, there are four indications for an operative  vaginal delivery: 1.  Prolonged second stage of labor.  In  nulliparous 

women,  this  is  defined  as  lack  of  continuing  prog- ress  for  2  hours  without  regional  anesthesia  or  3  hours  with  regional  anesthesia.  In  multiparous  women,  it  is  defined  as  lack  of  continuing  progress  for  1  hour  without  regional  anesthesia  or  2  hours  with regional anesthesia.

2.  Suspicion of immediate or impending fetal com- promise as defined by Category III fetal heart rate patterns.

3.  To stabilize the after-coming head during a breech delivery (Figure 17-5).

FIGURE 17-3 Types of obstetric forceps in use. Simpson forceps are an example of classic or standard forceps. Kielland forceps (for mid forceps rotation) are an example of specialized forceps and are used infrequently.

Simpson

Kielland

Piper

Simpson

Kielland

Piper

FIGURE 17-4 Components of classic forceps.

Toe Blade

Cephalic curve

Shank

Pelvic curve

Lock Handle

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the procedure should be abandoned (failed forceps) in favor of a cesarean delivery.

VACUUM EXTRACTION The  vacuum  extractor  (VE)  is  an  instrument  that  uses  a suction cup that is applied to the fetal head. Because of the relative ease of using VEs compared with using forceps, the frequency of VE delivery has increased in the United States.  After  confirming  that  no  maternal  tissue  is  trapped  between  the  cup  and  the  fetal  head,  the  vacuum  seal  is  obtained  using  a  suction  pump.  Traction  is  then  applied  using  principles  similar  to  those described above for a forceps delivery. Flexion of the fetal head must be maintained to provide the smallest diameter to the maternal pelvis by placing the posterior edge of the suction cup 3 cm from the anterior fontanel squarely over the sagittal suture.  This is illustrated in Figure 17-6. With the aid of mater- nal  pushing  efforts,  traction  is  applied  parallel  to  the  axis of the birth canal. Detachment of the suction cup  from  the  fetal  head  during  traction  is  termed  a  “pop- off.”  If  progress  down  the  birth  canal  is  not  obtained  with  appropriate  traction,  or  if  two  “pop-offs”  occur,  the  procedure  should  be  discontinued  in  favor  of  a  cesarean  delivery.  The indications for vacuum deliv- ery are the same as for forceps delivery.

The prerequisites for use of the VE are also the same  as for forceps, with a few exceptions. The VE is contra- indicated in preterm delivery  because  the  preterm  fetal head and scalp are more prone to injury from the 

must be fully dilated, membranes ruptured, and the fetal head engaged into the pelvis (0 station). Clinical  assessment  to  determine  the  level  of  the  presenting  part, an estimate of the fetal size, and the adequacy of  the  maternal  pelvis  is  mandatory.  There must be no doubt regarding the position of the fetal head.  This  evaluation  is  performed  by  palpation  of  the  sutures  and  fontanels  in  comparison  to  the  maternal  pelvis.  Anesthesia must be adequate  via  either  pudendal  nerve  block  with  local  infiltration  (for  outlet  forceps  only)  or  regional  anesthesia.  The bladder should be emptied  to  prevent  damage  to  that  structure  and  to  provide more room to facilitate delivery.

Forceps Technique The  forceps  blades  are  inserted  sequentially  into  the  vagina such that the sagittal suture of the fetal head is  directly  between  and  perpendicular  to  the  shanks.  Damage  to  maternal  tissues  may  be  avoided  by  the  operator  placing  one  hand  into  the  vagina  to  guide   the  toe  of  the  blade  along  the  natural  pelvic  curve   of  the  birth  canal.  With  the  next  maternal  pushing  effort,  the  forceps  are  locked  and  traction  is  applied.  The  direction  of  pull  should  be  parallel  to  the  axis  of  the birth canal at that level, such that typically there is  downward traction initially, followed by ever-increasing  upward  traction  as  delivery  of  the  fetal  head  occurs.  With  complete  delivery  of  the  head,  the  shanks  are  nearly  perpendicular  to  the  floor.  If progress of the fetal head is not obtained with appropriate traction,

FIGURE 17-5 Delivery of the after-coming head using Piper forceps.

C H A P T E R 17 Obstetric Procedures 231

CESAREAN DELIVERY Cesarean  delivery  is  delivery  of  the  fetus  through  an  incision  in  the  maternal  abdomen  and  uterus.  Hospi- tals offering obstetric services must have the personnel  and equipment needed to perform an emergent cesar- ean  delivery  within  30  minutes. This  is  especially  true  for vaginal births after a prior cesarean delivery (VBAC),  where the risk of uterine rupture is higher than in those  women who have not had a prior cesarean delivery.

Cesarean delivery is the most common major opera- tion performed in the United States today. The rate of cesarean deliveries has increased over fivefold, from 5% of births in 1970 to at least 25-30% of births cur- rently. The  dramatic  increase  in  the  cesarean  delivery  rate  has  been  attributed  to  many  factors,  including  assumed benefit for the fetus; the fact that women are  postponing childbirth until a later age, when the risk is  higher; relatively low maternal risk in general; societal  preference; and fear of litigation.

The  perinatal  benefits  of  cesarean  delivery  are  largely  based  on  unquantified  and  scanty  evidence.  There has been over a 10-fold decrease in perinatal mortality in the United States over the last 40 years  concurrent  with  advances  in  prenatal,  intrapartum,  and neonatal care. How much of this improvement has  been  due  to  the  increased  use  of  cesarean  delivery  is  debatable,  with  the  exception  of  management  of  the  term  breech  delivery. With  the  latter  delivery  method,  perinatal and neonatal mortality and significant neo- natal morbidity have been shown to improve from 5.0% for those delivered vaginally to 1.6% for those delivered by cesarean.

suction  cup. The VE  is  suitable  for  all  vertex  presenta- tions,  but  unlike  forceps,  it must never be used for delivery of fetuses presenting by the face or breech.

COMPARISON OF FORCEPS AND VACUUM DELIVERY Understanding the potential advantages and disadvan- tages  of  each  operative  vaginal  delivery  instrument  allows  the  operator  to  counsel  the  mother  appropri- ately and to choose the device that is best suited for the  particular clinical situation.

Forceps have a higher overall success rate for vaginal  delivery.  The failure rate for forceps is 7%, whereas the failure rate for vacuum extraction is 12%. In general, forceps deliveries cause higher rates of maternal injury, and vacuum extraction causes higher rates of fetal morbidity.  Forceps  have  an  increased risk of trauma to vaginal and perineal tissues  and  damage  to  the  maternal  anal  sphincter.  In  con- trast, neonates delivered by vacuum have more cepha- lohematomas  (accumulation  of  blood  beneath  the  periosteum)  and  exclusively  have  subgaleal hemato- mas (blood in the space above the periosteum that has  a large potential space and can allow significant blood  loss)  and  retinal  hemorrhages.  Sequential use of one instrument followed by the other has been associated with a disproportionately high fetal morbidity rate  and  should  be  approached  with  extreme  caution.  Long-term  retrospective  studies  of  adolescents  who  were  delivered  by  normal  vaginal  delivery,  forceps,  vacuum extractions, and cesarean delivery have shown  little difference in physical or cognitive outcomes.

FIGURE 17-6 Application of the vacuum extractor. A, Incorrect application, which deflexes the fetal head, thereby increasing the present- ing diameter. B, Correct application over the posterior fontanel, which flexes the fetal head when traction is applied.

A B

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of  the  scar  in  a  subsequent  pregnancy  and  a  reduced  risk  of  bleeding,  peritonitis,  paralytic  ileus,  and  bowel  adhesions.

For the classical cesarean delivery,  a  vertical  inci- sion is made in the upper segment of the uterus through  the myometrium. A vertical incision may also be made  in  the  lower  segment,  in  which  case  the  procedure  is  referred  to  as  a  low vertical cesarean,  although  the  incision  invariably  extends  into  the  upper  segment.  The common indications for a classical cesarean delivery include preterm breech in a woman with an undeveloped lower uterine segment, transverse back- down fetal position, poor access to the lower segment because of myomas or adhesions, or a planned cesar- ean hysterectomy. The presence of cervical cancer is a rare indication.

The type of uterine incision has important implica- tions  regarding  risk  of  uterine  rupture  in  future  preg- nancies.  Uterine rupture,  defined  as  separation  of  the  uterine incision, may cause significant maternal com- plications  caused  by  massive  hemorrhage  and  fetal  damage or death. A LTCD incision is associated with a less than 1% risk of symptomatic uterine rupture in the subsequent pregnancy,  although  this  risk  may  be  higher  if  labor  induction  or  augmentation  is  carried  out. A classic cesarean delivery carries a 4-7% risk of uterine rupture. Patients with a classical uterine inci- sion  are  thus  destined  to  have  repeat  cesareans  for  all  subsequent deliveries.

Prevention Two clinical interventions have been shown to reduce  cesarean delivery rates: external cephalic version (ECV )  and VBAC.

EXTERNAL CEPHALIC VERSION. ECV converts a breech fetus to the vertex position  to  avoid  a  cesarean  deliv- ery  for  breech  presentation.  This  procedure  is  per- formed  under  ultrasonic  guidance  in  the  labor  and  delivery  suite  after  the  36th  or  37th  week  of  gestation.  A  tocolytic  may  be  given  to  decrease  uterine  tone.  Using external manipulation, the fetus is gently guided  to the vertex presentation. Fetal risk due to umbilical cord entanglement and placental abruption is low (<1%).

The success rate of ECV is about 60%. Parity, gesta- tional  age,  placental  location,  cervical  dilation,  and  fetal  station  affect  the  success  rate.  An  ECV  program  can decrease the rate of cesarean delivery in this group  of patients by more than half, and an obstetric service’s  overall cesarean delivery rate by approximately 2%.

VAGINAL BIRTH AFTER CESAREAN DELIVERY. A  prior  cesarean  is  the  second  most  common  overall  cause   of  cesarean  delivery  (25-30%).  In  fact,  about  10-15%   of  pregnant  women  have  had  a  previous  cesarean  delivery.

The overall maternal mortality rate from cesarean delivery is currently less than 1 in 1000,  but  this  is  about five times greater than the rate for vaginal deliv- ery.  However,  recent studies have shown that the maternal mortality rate for an elective cesarean deliv- ery approximates that of vaginal delivery. This is due  to  advances  in  surgical  techniques,  anesthetic  care,  blood transfusions, and antibiotics.

The maternal morbidity associated with cesarean delivery is increased compared with vaginal delivery because of increased postpartum infections, hemor- rhage, and thromboembolism.

Indications Four  indications  account  for  90%  of  the  marked  increase  in  cesarean  deliveries  over  the  past  40  years:  dystocia  (30%),  repeat  cesarean  (25-30%),  breech  pre- sentation  (10-15%),  and  fetal  distress  (10-15%).  An absolute indication for a cesarean delivery is a previ- ous full-thickness, nontransverse incision through the myometrium. This occurs in all classical cesarean  deliveries  and  some  myomectomy  surgeries.  All preg- nancies complicated by placenta previa should also be delivered by cesarean delivery.

Types of Cesarean Delivery Cesarean  deliveries  are  classified  by  the  uterine  inci- sion  (Figure  17-7),  not  by  the  skin  incision.  In the low transverse cesarean delivery (LTCD), the uterine incision is made transversely in the lower uterine segment after a bladder flap is established. The advan- tages of this approach include decreased rate of rupture 

FIGURE 17-7 Types of cesarean delivery incisions.

Classical

Low vertical

Low transverse

C H A P T E R 17 Obstetric Procedures 233

(malpresentation), depending on the indication for the  previous  cesarean  delivery.  Compared  with  repeat  cesarean  delivery,  a  successful  vaginal  delivery  is   associated  with  less  maternal  morbidity  without  any  increase in perinatal morbidity. If uterine rupture does  occur, there may be a 10-fold increase in perinatal mor- tality and substantial maternal morbidity as well.

A trial of labor may be offered if one or two previ- ous LTCDs have been performed, the uterine incision did not extend into the cervix or upper segment, and there is no history of prior uterine rupture. Adequate maternal pelvic dimensions should be noted by clini- cal examination. Personnel and equipment should be  immediately  available  in  case  an  emergent  cesarean  delivery is required within 30 minutes.

The overall success rate of VBAC is approximately 70%,  although  it  ranges  from  60%  (dystocia)  to  90% 

236

18  Benign Conditions and Congenital Anomalies of the Vulva and Vagina

C H

A P

T ER

ANITA L. NELSON • JOSEPH C. GAMBONE

■  Benign vulvovaginal problems are among the ten leading  disorders  encountered  by  primary  care  clinicians  in   the  United  States.  Women  with  these  disorders  com- monly present with irritation and pruritus (itching), but  many  conditions  are  asymptomatic  and  just  visually  troubling.

■  There  is  significant  variation  in  the  normal  appearance  of  the  female  vulva,  with  clitoral  and  labial  size  differ- ences.  Epithelial  lesions  in  this  area  are  often  described  on  the  basis  of  their  appearance  as  white,  red,  or  pig- mented;  other  lesions  include  ulcerations,  fissures,  as  well as solid and cystic masses.

■  Biopsy may be needed in some cases to confirm a diag- nosis and rule out premalignancy or malignancy before 

treatment. Corticosteroid and sex-steroid creams are fre- quently used, but surgery is indicated in some cases.

■  Benign vaginal problems include ulcerations and fistulas  as well as solid or cystic masses. Traumatic injury to the  vagina can occur at the time of obstetric delivery, surgi- cal procedures, or sexual assault.

■  Congenital abnormalities of the vulva frequently involve  ambiguous  genitalia  that  can  present  a  problem  with  gender assignment at birth. Agenesis is the most extreme  and significant congenital anomaly of the vagina. Other  structural  anomalies  include  canalization  defects  such  as  imperforate  hymen,  longitudinal  and  transverse  vaginal  septa,  partial  vaginal  development,  and  double  vagina.

CLINICAL KEYS FOR THIS CHAPTER

Vulvovaginal  problems  are  quite  common  in  gyneco- logic  practice.  Definitive  diagnosis  may  require  time  because complaints of pruritus (itching) and irritation  are  nonspecific  and  can  be  caused  by  a  wide  range  of  conditions.

This chapter describes a wide array of benign lesions  of  the  vulva  and  vagina.  Infectious  conditions  of  the  vulva  and  vagina  are  discussed  in  Chapter  22  and  premalignant/malignant  conditions  are  covered  in  Chapter 40. Although the diagnosis of many conditions  can  be  made  clinically,  biopsy  and  other  tests  may  be  needed  to  establish  an  accurate  diagnosis. The  differ- ential  diagnosis  for  many  of  these  conditions  can  be  extensive.  It is important to establish an accurate diagnosis before initiating therapy. Congenital anom- alies  of  the  vulva  and  vagina  are  also  covered  in  this  chapter.

Vulva There is considerable variation in the appearance of normal external female genitalia.  In  particular,  the 

distance  between  the  clitoral  base  and  the  urethra   and the distance between the posterior fourchette and  the  anus  (perineal  body)  vary  greatly  from  woman  to  woman.  Labia  minora  may  be  so  small  that  they  are  completely  covered  by  the  labia  majora  or  they   may  protrude  by  over  a  centimeter  beyond  the  limits  of  the  labia  majora.  The  labia  minora  may  not  be  symmetrical—at times, one may be considerably larger  than  the  other.  Clitoral  size  also  differs  greatly  from  woman to woman.

BENIGN CONDITIONS OF THE VULVA Epithelial Changes The epithelium of the vulva is susceptible to the same skin pathologies seen on other parts of the body.  Often the appearance of those processes may be altered  by  the  moisture  and  warmth  of  the  genital  tissue.  In  addition, there are epithelial problems that are unique  to  the  vulva  or  more  commonly  detected  in  this  area.  Other changes reflect the impact that systemic or other  diseases can have on the vulvar tissue. Most vulvar epi- thelial  lesions  present  with  symptoms  of  pruritus  or 

C H A P T E R 18 Benign Conditions and Congenital Anomalies of the Vulva and Vagina 237

WHITE LESIONS. Conditions that cause whitening of the  vulvar  epithelium  range  from  processes  that  result  from simple loss of pigment (vitiligo) to those that can  profoundly change the architecture of the vulva (lichen  sclerosus).

Vitiligo  affects  1-2%  of  the  population  and  is  often  associated with autoimmune conditions. Its initial pre- sentation  can  be  on  the  vulva,  but  it  often  involves  pigment loss on other parts of the body. The diagnosis  is  made  clinically;  rarely  is  biopsy  needed.  A  notable 

pain, but a significant minority of lesions are detected  only  on  examination.  Conservative  management  is  often  appropriate,  but  frequently  topical  corticoste- roids  and  systemic  pain  medications  may  be  needed.  Although  the  appearance  of  superficial  vulvar  lesions  varies  with  the  pigment  of  the  woman’s  skin,  they  are  generally  categorized  by  the  color  most  commonly  associated with them—white, red or pigmented. Table  18-1  lists  benign  conditions  of  the  vulva  along  with  their clinical features and treatment.

TABLE 18-1

BENIGN CONDITIONS OF THE VULVA

Epithelial Changes Clinical Features and Comments Treatment

White Lesions

Vitiligo Loss of pigment; associated with autoimmune conditions; clinical diagnosis with biopsy rarely needed

Observation

Lichen sclerosus Intense pruritus and dyspareunia; anogenital area of midlife women; biopsy shows loss of rete ridges with thin epidermis; recurrence is common; future squamous cell carcinoma risk increased

High potency topical corticosteroids

Lichen planus Inflammatory autoimmune process; intense epithelial changes in the vulva, vagina, and mouth; white “Wickham striae”; scarring possible; may appear as a red lesion initially

Topical corticosteroids

Lichen simplex chronicus

Histology shows squamous hyperplasia; thickening of the epithelium; itching results in rubbing and scratching; can mimic psoriasis so biopsy is indicated

Intermediate potency topical corticosteroids

Vulvovaginal atrophy

Occurs in many postmenopausal women; underlying fat of the labia decreased with thinning of the epithelium; appears white and vaginal opening may constrict

Estrogen creams or moisturizers; lubricants may be needed for coitus

Red Lesions

Eczema Term that defines a dermatitis with itching, swelling, and crusting; most common on the vulva is an allergic contact dermatitis

Depends on etiology; for contact dermatitis, identify irritant(s) and discontinue use

Seborrheic dermatitis

Affects skin folds of genital area; skin has red-glazed shiny appearance; may also find dry, greasy areas of the scalp too

Topical corticosteroids

Psoriasis Immune-mediated skin disease; red plaques with clear borders; biopsy; itching common; pustular form confused with candida

Topical corticosteroid is initial therapy

Pigmented Lesions

Genital melanosis Occurs in 10-15% of women; dark pigment on mucous membranes; smaller area may be lentigo; biopsy of dark, changing areas mandatory

Expectant management

Acanthosis nigricans

Increasingly common; pigmented areas on vulva, axilla, and neck; related to obesity and insulin resistance

None except weight loss and glucose control

Ulcerations and Fissures

Aphthous ulcers Painful lesions similar to “canker sores” in the mouth; may be small or as large as 2 cm wide and 1 cm deep

Usually symptomatic therapies

Behçet disease Genital and oral ulceration with uveitis; may be associated with other disease processes such as inflammatory bowel disease or antiviral therapy

Depends on etiology and underlying cause

Crohn disease Vulvar involvement of granulomatous intestinal tract inflammatory process due to fistulization

Treatment of underlying bowel disease

Traumatic ulceration

Iatrogenic or self-inflicted trauma due to scratching, overcleaning, or neglect

Counseling; suspect underlying psychiatric disorder

Continued

PA R T 3 Gynecology238

Epithelial Changes Clinical Features and Comments Treatment

Solid or Cystic Masses

Epidermal cysts Most common type of genital cyst; may form in obstructed hair follicles; usually asymptomatic but can be visually troubling

Counseling about body hair care and/or deflation by expressing contents

Vulvar vestibular papillomatosis

Soft, slightly elongated papules Reassurance

Genital warts Caused by human papillomavirus See Chapter 22

Fox-Fordyce disease

Chronic inflammation of apocrine glands causing intense itching; affects axillary area in addition to vulva

Systemic antipruritic therapy

Hidradenitis suppurativa

Painful, recurrent condition of the apocrine glands; results in red papules that have chronic purulent drainage; increased risk with obesity and smoking

Corticosteroid injection in the lesions; antibiotics only if cellulitis present; incision and drainage for comfort only; suppression with oral contraceptives reduces recurrences

Vascular lesions Tortuous varicosities; cherry angiomas and hematomas Evaluation, compression; possible evacuation of expanding hematoma

Urethral caruncle Solitary red papule at the urethral meatus; usually <1 cm diameter; appears as a collar around urethral opening

Observation and biopsy as needed; estrogen creams; surgery rarely indicated

FIGURE 18-1 Vulva with lichen sclerosus (circles). (From Moreland A, Kohl P: Genital and dermatologic examination. In Morse SA, Ballard RC, Holmes KK, et al, editors: Atlas of sexually transmitted diseases and AIDS, ed 4, Philadelphia, 2010, Elsevier, pp 1–23.)

TABLE 18-1

BENIGN CONDITIONS OF THE VULVA—cont’d

characteristic  is  the  brightness  of  the  depigmented  areas  amplified  by  increased  pigment  in  the  adjacent  unaffected areas.

Lichen sclerosus may affect men and women of any  age, and may involve the skin on any part of the body,  but is most commonly found in the anogenital area of  midlife women. It often presents with intense pruritus,  dyspareunia  and  burning  pain,  but  can  also  be  an  asymptomatic  finding.  Anal  involvement  can  cause  constipation.  The  skin  is  white,  thin,  and  inelastic,   with  a  crinkled  cigarette-paper  appearance  on  gentle  stretch.  Widespread  excoriation  is  common.  It  starts  with  isolated  pearly  white  papules  and  plaques  that  coalesce over time and form scars. The result is a “figure  of 8” field of scarring from the area encircling the labia,  constricting  down  around  the  perineal  body  and  bal- looning  out  again  around  the  perineal  area  into  the  gluteal cleft. The clitoral hood scars, burying the clitoris  (Figure  18-1).  There  is  shrinkage  or  loss  of  the  labia  minora,  contraction  of  the  tissue  in  the  vestibule  and  introitus, and scarring around the anus. Painful, bleed- ing fissures are common, especially in areas where the  inelastic epithelium is put under tension, such as with  attempted coitus (introital trauma) or defecation (peri- anal  trauma).  Biopsy  demonstrates  characteristic  loss  of  rete  ridges,  a  thin  epidermis,  and  a  mixed  lympho- cytic  infiltrate  lining  the  basement  membrane.  The  process  can  be  arrested  by  treatment  with  higher  potency corticosteroids, but recurrence is not uncom-

mon  and  up  to  10%  of  untreated  and  3%  of  treated  women  eventually  develop  squamous  cell  carcinoma  of the vulva. The histologic features of lichen sclerosus  are illustrated in Figure 18-2, A.

Lichen planus  is  an  inflammatory,  autoimmune  process  that  involves  epithelial  changes  on  the  vulva,  or  in  the  vagina  and  the  mouth.  Symptoms  include  severe burning, irritation, and dyspareunia. It induces 

C H A P T E R 18 Benign Conditions and Congenital Anomalies of the Vulva and Vagina 239

Vulvovaginal atrophy  occurs  in  many  postmeno- pausal  women  with  the  loss  of  ovarian  production  of  estradiol (E2). The subcutaneous fat in the labia majora  is  diminished  and  the  labia  minora  also  shrink.  The  epithelium thins, appears white, and is less elastic. The  vaginal introitus can constrict, creating an almost pre- pubertal  caliber,  which  may  make  coitus  uncomfort- able. Estrogen creams are usually effective. Moisturizers  can help women who are not candidates for hormonal  therapies.  Lubricants  can  be  used  for  intercourse,  if  needed.

RED LESIONS. Many  of  the  epithelial  lesions  on  the  vulva  can  be  accompanied  by  erythema,  and  many  infectious  processes,  such  as  candidal infections,  can  appear  red.  However,  the  lesions  included  in  this   category  represent  benign  underlying  dermatologic  changes  that  present  primarily  as  red  lesions.  These  include eczema, seborrheic dermatitis, and psoriasis. 

an intense erythema and erosions on the vulva, which  is often surrounded by reticulate white striae (Wickham  striae)  that  appear  as  classic  fernlike  or  lacy  patterns.  These  same  findings  are  commonly  found  on  the  mucous membranes of the mouth. Scarring, especially  in the vaginal vault, is common.

Lichen simplex chronicus (referred to as squa- mous hyperplasia histologically), represents thicken- ing  of  the  epithelium,  which  usually  results  from  rubbing or scratching in the absence of an underlying  dermatosis. It generally appears on keratinized skin as  white  plaques  or  darker  red  areas;  the  surface  is  often  marked  with  excoriations.  It  can  often  mimic  other  processes,  such  as  psoriasis,  lichen  planus  or  lichen  sclerosus, so biopsy is indicated. Histologically, the rete  ridges  deepen  with  hyperkeratosis  of  the  superficial  layer  of  the  epidermis  (see  Figure  18-2,  B).  Intermedi- ate potency topical corticosteroids are the cornerstone  of treatment.

FIGURE 18-2 A, Lichen sclerosus. Histology shows hyperkeratosis but the epidermis is thinner than normal. The most striking feature of lichen sclerosus is the presence of a hyaline zone in the superficial dermis. This is the result of edema and degeneration of the collagen and elastic fibers of the dermis. B, Squamous cell hyperplasia. Microscopy shows marked hyperkeratosis and parakeratosis with a promi- nent granular layer. Acanthosis, with prolongation of rete ridges, is also seen and there is a dense infiltrate of chronic inflammatory cells, mainly lymphocytes, in the superficial dermis.

Flaky keratin layer

Thin epidermis

Hyaline zone

Granular layer

Elongated rete ridges

Chronic inflammatory

infiltrate

Thick keratin layer (hyperkeratosis

and parakeratosis)

A

B

PA R T 3 Gynecology240

In  the  genitalia,  the  characteristics  of  many  of  these  processes  are  altered  by  the  moisture  and  heat  in  the  area, friction from clothing or scratching, and second- ary  infection  or  irritation  from  sweat,  urine,  stool,  or  overcleansing.  Fecal  or  urinary  incontinence  may  cause irritation and can accelerate skin breakdown due  to other etiologies.

Eczema  is  a  term  that  is  broadly  applied  to  a  wide  range  of  chronic  skin  conditions  characterized  by  rashes with dryness, swelling, itching, as well as crust- ing, flaking, cracking, blistering, oozing, or frank bleed- ing. The  reddish  appearance  of  eczema  in  the  vulva  is  profoundly  influenced  by  rubbing  and  scratching,  which  produce  thickening  and  excoriation,  respec- tively.  The  history  of  pruritus,  relieved  by  scratching,  and  the  shape  of  the  lesions  help  with  the  diagnosis,  but other etiologies must be ruled out first. One of the  most  common  subtypes  of  eczema  on  the  vulva  is  contact  dermatitis.  Contact dermatitis  (either  irritant  or allergic) is increasing in frequency on the vulva with  the use of a wide range of products on the genital tissue.  Common irritants include overwashing, female hygiene  products,  and  topical  medications. These  same  medi- cations, as well as chemicals found in sanitary protec- tion products, can induce allergic reactions on the vulva  with widespread erythema and even edema.

Seborrheic dermatitis  causes  a  dry  or  greasy  peeling,  reminiscent  of  dandruff  in  the  scalp,  face,  or  eyebrows.  In  the  genital  area,  the  lesions  tend  to  con- centrate  in  the  skin  folds,  with  less  prominent  lesion  borders  or  scaling.  The  skin  has  a  red  glazed,  shiny  texture,  occasionally  with  scaling  plaques,  in  the  absence  of  candida  or  psoriasis.  A  diagnosis  of  sebor- rheic dermatitis is strongly supported by finding char- acteristic lesions elsewhere.

Psoriasis  is  a  common  chronic  relapsing  immune- mediated  skin  disease  affecting  2-3%  of  the  popula- tion.  Psoriasis  may  involve  the  entire  genital  area,  including the gluteal cleft, but there may be less exten- sive  involvement.  Both  the  skin  fold  and  hair-bearing  areas may be involved. Red plaques with clear borders  are  the  hallmark  of  classic  genital  psoriasis,  but  the  silvery-white scales are generally less prominent on the  genitalia. Itching is a frequent complaint. Involvement  of knees, elbows, and nails helps to make the diagnosis.  Pustular  psoriasis  can  be  confused  with  candidal  infection.

PIGMENTED LESIONS. Pigmented lesions raise the great- est  concerns  for  malignancy,  but  there  are  several  benign lesions that are darkened. The concentration of  melanocytes  is  higher  in  the  vulva  than  other  body  tissue,  but  their  distribution  may  not  be  even,  which  can result in physiologic hyperpigmentation.

Genital melanosis is a relatively common finding; it  occurs in 10-15% of women. It consists of flat patches  and macules (0.5 to 2 cm) of dark pigment on mucous 

membrane  (labia  minora)  as  well  as  keratinized  skin  (labia  majora).  The  smaller  lesions  may  be  lentigo  (freckles) if they meet criteria on biopsy. There can be  concerning variation of color within the lesion and the  borders can be irregular, which raises differential diag- nosis  of  melanoma,  unless  the  lesion  has  been  stable  over  time.  Pigmentation  can  also  increase  following  tissue trauma or inflammation.

Acanthosis nigricans  is  increasingly  common  with  the  rising  prevalence  of  obesity  and  insulin  resistance  in  the  general  population.  It  presents  with  poorly  demarcated,  brown,  thickened,  ridged  lesions  in  the  superficial  layers  of  the  skin  on  the  vulva,  axilla,  and  neck.  The  histology  of  acanthosis  is  shown  in  Figure  18-2, B, and the clinical features of acanthosis nigricans  are shown in Figure 33-4.

Recent social trends have created new appearances  of  the  vulva  in  some  women,  and  made  treatment  of  medical  conditions  potentially  challenging.  Tattooing  and  body  piercing  practices,  as  well  as  all  techniques  used to remove pubic hair, are examples of such trends.

Ulcerations and Fissures Vulvar ulcerations may be the presenting complaint for  many  infectious  conditions  (herpes  simplex,  syphilis,  chancroid, Epstein-Barr) and malignancies (squamous  cell carcinoma); these conditions must always be ruled  out  before  a  benign  diagnosis  is  made.  The  most  common  noninfectious,  benign  conditions  causing  ulcerations  and  fissures  are  aphthous ulcers, Behçet disease and Crohn disease.

Aphthous ulcers  are  extremely  painful  lesions,  similar to the “canker sores” found in the mouth. They  can be small (<1 cm) and eventually heal without scar- ring,  or  they  can  be  larger  (>2 cm  diameter  and  1 cm  deep) and cause permanent scarring. Recurrence rates  are  as  high  as  35%.  Often  genital  aphthous  ulcers  are  associated with similar lesions elsewhere, as in Behçet  disease, which has genital and oral ulcerations as well  as  uveitis.  Genital  ulceration  can  be  associated  with  other  disease  processes,  such  as  inflammatory  bowel  disease, or induced by medications (e.g., antiretroviral  therapy).

Decubitus ulcers  are  most  likely  to  develop  when  chronic pressure is applied to tissue over bony promi- nences.  Tissue  made  moist  by  urinary  incontinence  may be more susceptible to breakdown.

Other ulceration  may  also  be  iatrogenic,  such  as  from  caustic  or  destructive  treatments  for  external  genital  warts  or  vulvar  intraepithelial  neoplasia.  Women  can  traumatize  the  area  mechanically  (direct  scratching, overcleansing, or neglect), either as a result  of  a  deeply  held  perception  that  the  area  is  dirty  or  as  part of a deeper psychiatric illness.

Crohn disease  is  a  granulomatous  inflammatory  process in the intestinal tract that can extend via fistu- lization  to  or  separately  appear  on  the  genital  area, 

C H A P T E R 18 Benign Conditions and Congenital Anomalies of the Vulva and Vagina 241

resulting in widespread, painful deep linear “knifelike”  ulceration  or  fissuring  in  the  skin  folds. These  fissures  may  be  accompanied  by  perianal  tags,  edema,  or  abscesses.  More  superficial  fissures  can  result  from  stretching of skin affected by lichen sclerosus.

Another more intense chronic inflammatory condi- tion  of  the  apocrine  glands  is  hidradenitis suppura- tiva.  This  is  a  painful,  recurrent,  progressive,  and  disfiguring  condition  in  which  painful  red  papules  from  beneath  the  skin  expand  and  eventually  rupture  and  create  ulceration  and  chronic,  purulent  draining  sinuses. The ulcers heal with thick contracting scarring.  Hidradenitis  suppurativa  can  involve  all  genital  areas.  The extragenital areas most affected include the axilla  and breast, along the “milk line.” Obesity and smoking  are risk factors. Medical and even surgical treatment is  often suboptimal.

Solid or Cystic Masses of the Vulva Epidermal cysts are the most common type of genital  cyst,  peaking  in  incidence  in  women  in  their  40s   and  50s  and  located  primarily  in  the  labia  majora,   labia  minora,  and  inguinal  areas.  Epidermal  cysts  develop  when  the  hair  follicles  become  obstructed;   the  deeper  portion  of  the  follicle  swells  to  accommo- date  the  desquamated  cells.  These  cysts  are  generally  dome-shaped, clear white to skin colored lesions rising  above the surrounding epithelium. Epidermal cysts are  usually  asymptomatic,  but  can  trouble  the  woman  from a cosmetic perspective.

Vulvar vestibular papillomatosis is a normal variant  very  analogous  to  pearly  penile  papules  in  men.  The  papillae  are  the  same  color  as  the  surrounding  tissue  from  which  they  protrude.  They  are  soft,  slightly   elongated  papules  generally  measuring  1  to  2 mm  in  height and diameter arranged in a linear pattern, with  one  single  protrusion  emanating  from  each  base,  as  opposed  to  external  genital warts  that  usually  have  multiple protrusions from the base.

Fordyce spots  are  sebaceous  glands  that  appear  as  small,  slightly  raised  dome-shaped  papules  along  the  Hart line on the labia minora. On the other hand, Fox- Fordyce disease represents a chronic inflammation of  apocrine glands that causes intense pruritus, mainly in  the axilla and labia majora and minora.

Vascular lesions  can  be  prominent  on  the  vulva.  Tortuous  varicosities  can  involve  the  labia  majora,  especially in pregnancy. Large varicose veins are usually  a  characteristic  blue  color,  but  smaller  veins  appear  darker  red.  The  lesions  disappear  temporarily  with  compression.  Cherry angiomas  and  angiokeratomas  are  clustered/superficial  capillaries  or  small  blood  vessels  that  appear  as  dark  red  to  purple  dots  on  the  vulva.  Hematomas  are  loculated  collections  of  blood  that  collect  following  trauma  such  as  accidental  inju- ries (bike accidents), incidental injuries (birth trauma),  or  sexual  assault.  The  soft  tissues  of  the  labia  can 

accommodate  substantial  amounts  of  blood,  but  dis- section  into  the  perivaginal  and  retroperitoneal  space  occurs commonly; significant blood loss can occur into  these  spaces.  Complete  evaluation  of  all  the  affected  tissues,  including  periurethral  and  perivaginal  areas,  must  be  done  to  insure  that  there  is  no  continued  active bleeding or tissue injury requiring urgent surgery.

Other Vulvar Masses Nevi  can  be  flat  or  elevated  pigmented  lesions  that  must be distinguished from melanoma. Acrochordons  are called skin tags when they are larger. Skin tags are  more commonly found in obese people and those with  insulin resistance. They are mainly found in the axilla,  neck, and skin folds of the genital area. Lipomas, neu- rofibromas, and endometriomas can also be found on  the  vulva.  Femoral hernias  can  dissect  into  the  labia  majora.  Swelling  of  the  labia  can  be  generalized  or  focal,  depending  on  the  etiology.  Galactoceles  in  the  vulva  are  rare,  but  are  milk-filled  cysts  that  may  form  in the milk line.

Two  particular  masses  involve  the  urethral  meatus.  A  urethral caruncle  is  a  solitary  red  papule  at  the  meatus. It generally measures less than 1 cm in diam- eter  and  is  pedunculated  or  dome-shaped  (Figure  18-3,  A).  It  must  be  distinguished  from  an  overt ure- thral prolapse, which occurs at the two age extremes.  It  appears  as  a  swollen  red  cuff  that  surrounds  the  meatus circumferentially, much as a collar around the  opening. The histology of a urethral caruncle is shown  in Figure 18-3, B.

CONGENITAL ANOMALIES OF THE VULVA The most significant of the vulvar anomalies are those that pose challenges to the assignment of gender at birth.  Caution,  sensitivity,  complete  evidence  collec- tion,  and  clear  communication  with  often  anxious  family members are all required. A thorough evaluation  may include careful physical examination, pelvic ultra- sonography  or  magnetic  resonance  imaging  (MRI),  hormonal  assays,  karyotyping,  and  often  consultation  with  specialists  before  a  recommendation  is  made  to  the  family  about  which  gender  would  be  better  for  rearing the newborn. In general, if there is suboptimal  development of penile or scrotal structures, the infant  should be assigned the female gender, because recon- structive surgery for females is much more likely to be  successful.

Ambiguous genitalia  can  present  with  clitoromeg- aly,  bifid  clitoris,  or  midline  fusion  of  the  labioscrotal  folds.  Clitoromegaly  in  adult  women  is  defined  as  being  present  when  the  product  of  the  length  of  the  clitoris  and  the  width  of  its  base  exceeds  35 mm2,  or  when  the  clitoral  base  exceeds  1 cm  in  diameter.  At  birth,  clitoromegaly  is  determined  by  the  relative  size  of the clitoris in relation to the other vulvar structures.  Clitoral agenesis  may  result  from  the  failure  of  the 

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female  external  genitalia  and,  later  in  life,  secondary  sexual characteristics. The syndrome may be complete  or  partial  (Figure  18-4).  In  utero,  müllerian-inhibiting  hormone (MIH) is produced, which results in absence  of the uterus and fallopian tubes. The vaginal depth is  variable  but  seldom  normal.  The  testes  are  usually  located  in  the  inguinal  canals,  labia,  or  abdomen  (usually  along  the  pelvic  sidewalls)  and  should  be  removed  after  the  young  woman  has  experienced  breast  development,  but  before  any  malignant  trans- formation  of  her  gonads  takes  place. The  higher  body  temperature  in  the  areas  where  the  male  gonads  are  located is thought to play a role in this transformation.  Surgical  removal  of  gonadal  tissue  is  recommended  just after puberty in these women.

True hermaphroditism  is  rare.  The  affected  child  has some degree of both female and male development  externally  and  internally;  dual  gonadal  development  occurs  with  either  a  combined  ovotestes  or  separate  gonads. The extent of masculinization depends on the  relative  amount  of  functioning  testicular  tissue  and  testosterone levels.

genital  tubercle  to  develop.  Incomplete  development  of the genitalia can result in a cloaca with no separation  of  the  bladder  and  the  vagina.  Many  of  these  defects  are  associated  with  other  problems,  such  as  bladder  exstrophy.

Female pseudohermaphroditism  is  caused  by  in  utero masculinization due to androgens from maternal  or  fetal  congenital  adrenal  hyperplasia,  androgen- producing  tumors  of  the  mother’s  ovary  or  adrenal  glands,  or  the  mother’s  use  of  exogenous  androgens.  Often the infant will present with ambiguous genitalia.  The  enlarged  clitoris  is  the  most  conspicuous  abnor- mality.  Fusion  of  the  labioscrotal  folds  can  produce  a  hypospadiac  urethral  meatus  and  a  malpositioned  introitus, but the internal genital organs will be normal.  Male pseudohermaphroditism,  which  most  com- monly results from mosaicism, may occur with varying  degrees of virilization and müllerian development.

Androgen insensitivity syndrome  (a  form  of  male  pseudohermaphroditism  and  formerly  called  testicu- lar  feminization)  is  a  genetic  deficiency  of  androgen  receptors  that  results  in  a  46,XY  infant  developing 

FIGURE 18-3 Urethral caruncle (arrow). A, This lesion usually presents as a small, painful, red lump at the urethral meatus. B, In this histologic example, transitional epithelium can be recognized and there is a papillomatous pattern involving small, neighboring glands. A little chronic inflammation is seen. (A, From Lemmi FO, Lemmi CAE: Physical assessment findings [CD-ROM], Philadelphia, 2009, Saunders.)

A

Squamous epithelium

Transitional epithelium

Chronic inflammation B

C H A P T E R 18 Benign Conditions and Congenital Anomalies of the Vulva and Vagina 243

thelium  is  very  sensitive  to  estrogen.  In  well- estrogenized  women,  the  epithelium  is  pink,  moist,  thickened, and folded into distensible rugae. Occasion- ally  papillomatosis  may  occur  in  the  vagina,  appear- ing  much  like  an  extensive  human  papillomavirus  (HPV )  infection.  In  prepubescent  girls,  postmeno- pausal  women,  and  estrogen-deficient  reproductive  aged women, the epithelium of the vagina is pale, flat,  smooth, dry, and fragile. Such atrophy can be uncom- fortable  for  women  who  attempt  coitus,  as  well  as  for  those  who  are  not  sexually  active;  for  the  latter,  the  thin, raw, dry characteristics of the atrophic epithelium  can cause symptoms of burning or irritation. It can be  particularly  painful  when  a  woman  recommences  sexual  intercourse  after  a  long  period  of  abstinence.  Lack  of  sexual  intercourse  will  have  altered  the  lining  of the vagina and constricted its diameter. Acute trau- matic  injury  can  ensue.  Such  a  woman  will  benefit  greatly  from  prior  topical  estrogen  therapy  and  use  of  a water-based lubricant during intercourse.

The  epithelium  of  the  vagina  is  also  subject  to  chemical irritants and contact dermatitis with the use  of various solutions for douching, allergic reactions to  vaginal antibiotic or antimycotic creams, spermicides,  or  latex  contraceptives.  Table  18-2  lists  the  important  vaginal  conditions,  along  with  clinical  features  and  treatment options for them.

Ulceration and Fistulas Most  ulceration  in  the  vagina  is  associated  with  acute  infections,  such  as  herpes simplex  or  cytomegalovi- rus. Vaginal lichen planus initially presents with small  ulcerations  and  generalized,  intense  erythema,  with  densely  packed  leukocytes  in  the  vaginal  discharge.  If  left  untreated,  the  vault  can  agglutinate  and  literally  scar  the  vagina  closed.  The  vaginal  secretions  irritate  the  vulva  and  cause  an  intense  burning  irritation  in  that area also.

Fistulas  from  the  bladder  into  the  vagina  can  form  as  a  result  of  surgical  complications,  prolonged 

IATROGENIC ANATOMICAL CHANGES Anatomical changes due to medical procedures  are  frequently  encountered  on  the  vulva.  The  most  common  relate  to  childbearing  scars  from  episioto- mies or obstetric lacerations, which can radiate poste- riorly from the introitus to the rectum, anteriorly to the  urethral meatus, or laterally into the labia. Other iatro- genic  changes  may  be  culturally  dependent.  Female genital mutilation (previously called female circumci- sion)  has  been  performed  on  more  than  130  million  women  worldwide  and  continues  to  be  a  common  practice in many societies where the role of women is  limited  and  an  explicit  demonstration  of  virginity  is  required  for  marriage.  This  practice  is  generally  con- demned  in  Western  societies.  Box  18-1  contains  the  World Health Organization (WHO) classification of the  different types of female genital mutilation, in increas- ing severity.

Vagina BENIGN CONDITIONS OF THE VAGINA Epithelial Changes The appearance of the vaginal walls varies greatly from  one woman to another. In part, this is because the epi-

FIGURE 18-4 Ambiguous genitalia in a child with an XY karyotype and partial androgen insensitivity. (From McKay M: Vulvar mani- festations of skin disorders. In Black M, McKay M, Braude P, et al, editors: Obstetric and gynecologic dermatology, ed 2, Edinburgh, 2003, Mosby, p 121.)

BOX 18-1

WORLD HEALTH ORGANIZATION (WHO) CLASSIFICATION OF FEMALE GENITAL MUTILATION

Type I—Partial  or  total  removal  of  the  clitoris  and/or  prepuce (clitoridectomy)

Type II—Partial  or  total  removal  of  the  clitoris  and  labia  minora, with or without the excision of the labia majora  (excision)

Type III—Narrowing of the vaginal orifice with creation of  a  covering  seal  by  cutting  and  appositioning  the  labia  minora  and/or  the  labia  majora,  with  or  without  exci- sion of the clitoris (infibulation)

Type IV—All other harmful procedures to the female geni- talia  for  nonmedical  purposes;  for  example,  pricking,  piercing, incising, scraping, and cauterizing

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TABLE 18-2

BENIGN CONDITIONS OF THE VAGINA

Epithelial Changes Clinical Features and Comments Treatment

Papillomatosis Appears like human papillomavirus infection Reassurance

Contact dermatitis Chemical irritation due to the use of douching solutions; allergic reactions to antimicrobial creams, spermicides, or latex condoms

Identify irritant and discontinue

Ulcerations and Fistulas

Ulcers Most ulceration of the vagina is associated with acute infection due to herpes simplex or cytomegalovirus; vaginal lichen planus may present as ulcers

See Chapter 22 for diagnosis and treatment of infectious causes; topical steroids

Fistulas Fistulas from the bladder or rectum into the vagina may occur due to surgical complication, infection, or malignancy

Surgical repair if conservative management unsuccessful unless due to advanced cancer

Cystic Masses

Bartholin cyst Cystic mass below hymenal ring at 4 or 8 o’clock; must rule out underlying malignancy in older women

If asymptomatic, no treatment; if symptomatic, consider drainage with Word catheter placement or marsupialization

Gartner duct cyst Thick walled, soft cystic structures formed from remnants of the Wolffian duct; usually asymptomatic

Treatment is usually not needed; surgical removal if symptomatic or increasing in size

Other

Traumatic injury Vaginal injury during obstetric delivery, surgery, or sexual assault; attention to any hematoma progression

Surgical repair; sexual assault reporting protocol (see Chapter 29)

Dermatologic Vaginal atrophy secondary to lower estrogen effect during pregnancy or after menopause; condyloma due to the papillomavirus; herpes simplex infection

Vaginal estrogen cream or systemic estrogen patch (menopause); removal or destruction of condyloma; antivirals for herpes simplex (see Chapters 22 and 35)

Vaginismus Involuntary contraction of the muscles surrounding the vaginal introitus

Psychological cause takes extensive counseling; treat any underlying physical cause

Foreign objects Objects placed and forgotten in the vagina; most common in young girls and older women who may have forgotten a pessary; vaginal bleeding and/or odor usually present

Removal; awareness of possible toxic shock syndrome (see Chapter 22)

pressure  applied  during  labor,  or  malignancies.  Fistu- las  from  the  bowel  into  the  vagina  can  result  from  incomplete healing of fourth degree lacerations, surgi- cal  complications,  malignancies,  or  granulomatous  processes, such as tuberculosis or Crohn disease.

One  unique  lesion  involves  an  acute  and  chronic  inflammation  of  the  vestibular  glands  found  near  the  introitus, scattered around the hymen or hymenal tags.  The  lesion  appears  as  a  1-  to  3-mm  red  dot,  which  is  extremely  tender. This  lesion  is  found  in  women  with  focal  provoked  vulvodynia  (vestibulodynia).  Careful  inspection  is  often  needed  to  locate  these  lesions.  Gentle  touch  with  a  cotton  tip  swab  will  elicit  signifi- cant  pain,  which  confirms  the  diagnosis.  The  tender- ness  of  this  lesion  may  prevent  not  only  intromission  and  any  sexual  intercourse,  but  also  any  speculum  or  digital examination.

Cystic Masses As  a  thin  epithelial  structure,  the  vagina  only  infre- quently  develops  significant  benign  masses.  Thick- walled,  soft  cysts  resulting  from  embryonic  remnants  can  present  in  the  vagina.  Gartner duct cysts  are  the  most  common  of  these.  They  arise  from  the  remnant  of  the Wolffian  duct  (mesonephros). They  vary  in  size  from 1 to 5 cm and are found on the anterolateral walls  in the upper half of the vagina and more laterally in the  lower  half.  Most  are  asymptomatic  and  require  no  treatment.  They  may  be  surgically  removed  when  symptomatic.

Bartholin cysts start with occlusion of the Bartholin  duct  at  the  4  and  8  o’clock  positions  of  the  vaginal  introitus.  The  trapped  mucinous  secretions  from  the  Bartholin gland accumulate and develop into a smooth,  skin colored cystic structure ranging from 1 to 5 cm in 

C H A P T E R 18 Benign Conditions and Congenital Anomalies of the Vulva and Vagina 245

bleeding.  Red,  raised,  friable  granulation  tissue  can  sometimes be seen along recent surgical scars, particu- larly at the apex of the vault following hysterectomy or  along episiotomy scars postpartum.

Other Benign Abnormalities of the Vagina Some  dermatologic  changes  may  occur  due  to  the  effect  of  lower  estrogen  levels  on  the  vaginal  epithe- lium  during  pregnancy  or  after  the  menopause.  The  resulting atrophic vaginitis may be treated with estro- gen  cream.  Infectious  lesions  such  as  vaginal warts  from  HPV  or  herpes simplex blisters  can  affect  the  vaginal epithelium.

Vaginismus  is  an  involuntary  contraction  of  the  muscles surrounding the introitus. It may have psycho- logical  and/or  physical  causes,  but  the  contraction  makes any vaginal penetration either extremely painful  or  impossible.  Many  women  with  vaginismus  report  prior  sexual  abuse,  but  others  may  deny  any  such 

diameter. Often they represent remnants of old Bartho- lin  abscesses.  Occasionally  they  may  develop  bilater- ally.  Digital  examination  of  the  duct  underlying  the  cystic  structure  is  important  to  rule  out  a  malignant  mass,  particularly  in  an  older  woman  who  presents  with  a  new  Bartholin  cyst.  Treatment  of  these  benign  cysts  is  needed  only  if  the  woman  is  symptomatic  (experiences  pressure-like  discomfort)  or  if  there  is  a  rapid change in the size or character of the cyst. Treat- ment can be with a Word catheter or by marsupializa- tion (Figure 18-5). Cystectomy is rarely indicated.

Trauma Injury  to  the  vagina  can  occur  at  the  time  of  delivery,  during  surgery,  or  more  generally  as  a  result  of  sexual  assault.  Large  hematomas  that  dissect  into  the  broad  ligament or retroperitoneal space can contain liters of  blood  and  cause  profound  anemia  and  even  shock.  Thorough  examination  is  needed  to  rule  out  ongoing 

FIGURE 18-5 Bartholin cysts are rarely removed, because of excessive bleeding that may occur. More commonly, they are drained by inserting a Word catheter or by marsupialization by first incising over the cyst (A) and then externalizing an opening to allow for drainage (B). The cyst lining is sutured to the vaginal epithelium to create a drainage opening for cyst fluid.

Enlarged surgically exposed Bartholin cyst

A B

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CONGENITAL ABNORMALITIES OF THE VAGINA Vaginal agenesis represents the most extreme instance  of  a  vaginal  anomaly,  with  total  absence  of  the  vagina  except for the most distal portion that is derived from  the urogenital sinus, which may appear as a dimple on  the vulva. If the uterus is absent but the fallopian tubes  are  spared,  the  defect  is  müllerian agenesis  or  Roki- tansky-Küster-Hauser syndrome.  Isolated  vaginal  agenesis with normal uterine and fallopian tube devel- opment  is  rare,  and  is  thought  to  be  the  end  result  of  isolated vaginal plate malformation. The more common  structural anomalies of the vagina include canalization  defects  such  as  imperforate hymen,  transverse and longitudinal vaginal septa, partial vaginal develop- ment, and double vagina.

Imperforate hymen represents the mildest form of  these  canalization  abnormalities.  It  occurs  at  the  site  where  the  vaginal  plate  contacts  the  urogenital  sinus.  After birth, a bulging, membrane-like structure may be  noticed  in  the  vestibule,  usually  blocking  egress  of  mucus. If not detected until after menarche, an imper- forate  hymen  may  be  seen  as  a  thin,  dark  bluish  or  thicker, clear membrane blocking menstrual flow at the  introitus (Figure 18-6, A and B). A similar anomaly, the  transverse vaginal septum,  is  most  commonly  found 

trauma.  It  is  important  that  the  health  care  profes- sional  understands  that  vaginismus  is  an  involuntary  reaction much like the reflex to shut the eyelid when a  foreign  object  is  seen  to  be  approaching.  Voluntary  control  can  be  learned,  but  it  takes  much  counseling  and patience.

Foreign bodies  can  be  forgotten  in  the  vagina.  Little  girls  may  place  small  beads  or  paper  into  that  pocket when they discover it. Older women may neglect  to  remove  tampons,  contraceptive  devices,  or  pessa- ries.  Generally,  a  strong  odor  and  copious  vaginal  dis- charge  compels  them  to  seek  professional  help.  Toxic  shock  syndrome  must  be  ruled  out.  Removal  of  the  foreign body, if necessary under general anesthesia, is  the  first  step  in  therapy.  Examination  of  the  tissue  for  any abrasions, then vaginal irrigation can help shorten  the recovery time.

Implants  of  endometriosis  can  occasionally  be  found  arising  from  the  vaginal  walls.  They  may  cause  pain  or  they  may  be  asymptomatic.  These  implants  may respond to cyclic hormones (see Chapter 25). The  anatomic  changes  associated  with  pelvic  relaxation,  including  anterior  vaginal  wall  prolapse  (cystocele),  posterior  vaginal  prolapse  (rectocele),  and  herniation  of  bowel  (enterocele),  are  discussed  in  detail  in  Chapter  23.

FIGURE 18-6 A, Vaginal bulge of an imperforate hymen in a 13-year-old who presented with pelvic pain, now constant but cyclical in the past. B, Old blood (hematocolpos) and some mucous (mucocolpos) is released after a stab incision is made through the hymen. (From McKay M: Vulvar manifestations of skin disorders. In Black M, McKay M, Braude P, et al, editors: Obstetric and gynecologic dermatol- ogy, ed 2, Edinburgh, 2003, Mosby, p 122.)

BA

C H A P T E R 18 Benign Conditions and Congenital Anomalies of the Vulva and Vagina 247

at  the  junction  of  the  upper  and  middle  thirds  of  the  vagina  (Figure  18-7).  Patients  with  an  imperforate  hymen  or  transverse  vaginal  septum  usually  have  normal development of the upper reproductive tract.

A midline longitudinal septum may be present, cre- ating a double vagina. The longitudinal septum may be  only partially present at various levels in the upper and  middle vagina, either in the midline or deviated to one  side. In addition, a longitudinal septum may attach to  the lateral vaginal wall, creating a blind vaginal pouch,  with  or  without  a  communicating  sinus  tract.  These  septa  are  usually  associated  with  a  double cervix  and  one of the various duplication anomalies of the uterine  fundus,  although  the  upper  tract  is  often  entirely  normal.

Adenosis  of  the  vaginal  wall  consists  of  islands  of  columnar epithelium in the normal squamous epithe- lium. It is often located in the upper third of the vagina.  The incidence of this finding is much higher in women  exposed to diethylstilbestrol in utero.

Urethral diverticula are small (0.3 to 3 cm), sac-like  projections  that  can  be  found  along  the  posterior  urethra  in  the  midline  of  the  anterior  vaginal  wall.  They  may  or  may  not  communicate  with  the  urethra,  and  they  may  cause  dyspareunia.  Urethral  diverticula  can  cause  recurrent  urinary  tract  infections  (see  Chapter 22).

FIGURE 18-7 Illustration of a transverse vaginal septum.

Transverse vaginal septum

248

19  Benign Conditions and Congenital Anomalies of the Uterine Corpus and Cervix

C H

A P

T ER

WILLIAM H. PARKER • JOSEPH C. GAMBONE

■  Uterine  fibroids  (also  called  leiomyomas)  are  benign  smooth  muscle  tumors,  and  about  80%  are  asymptom- atic.  They  are  very  common,  with  an  estimated  preva- lence  of  70%  by  the  sixth  decade  of  life.  Uterine  tumors  presenting as fibroids are rarely malignant, with less than  1 in 1000 leiomyosarcomas found at the time of surgical  removal. Fibroids may cause abnormal uterine bleeding,  pelvic discomfort, and pressure when they enlarge. They  can  cause  pain  (sometimes  severe)  if  degeneration  and  infarction occur.

■  Fibroids  arise  within  the  myometrium  (intramural)  but  may  grow  near  the  serosal  surface  (subserosal)  or  near  the  endometrium  (submucosal).  Some  fibroids  are  pedunculated. About 40% of fibroids enlarge during the  first trimester of pregnancy, but rarely thereafter.

■  Medical  treatment  with  progestins,  gonadotropin- releasing  hormone  (GnRH)  analogues,  or  other  hor- mones may be indicated initially for uterine bleeding and 

fibroid  enlargement.  Uterine  artery  embolization  (UAE)  and  magnetic  resonance  directed  ultrasound  may  be  used as alternatives to surgery. Surgical treatment ranges  from  myomectomy  (removal  of  one  or  several  fibroids)  for women who desire fertility or uterine preservation to  hysterectomy when less invasive treatments fail.

■  Endometrial  and  cervical  polyps  may  cause  uterine  bleeding  and  must  be  biopsied  to  rule  out  cancer.  Complex atypical endometrial hyperplasia progresses to  endometrial  cancer  in  about  20-30%  of  cases.  Simple  hyperplasia may be treated medically.

■  Congenital  anomalies  of  the  uterus  and  cervix  are  most  often due to incomplete fusion of the paramesonephric  (müllerian) ducts, incomplete dissolution of the midline  fusion of those ducts, or formation failures. Diagnosis of  uterine defects can be made by hysterosalpingogram or  magnetic resonance imaging. Some defects may be diag- nosed and treated by hysteroscopy.

CLINICAL KEYS FOR THIS CHAPTER

Congenital anomalies of the uterus and cervix are most  often  caused  by  incomplete  fusion  of  the  parameso- nephric  (müllerian)  ducts,  incomplete  dissolution  of  the midline fusion of those ducts, or formation failures.  Diagnosis  of  uterine  defects  can  be  made  by  hystero- salpingogram  (HSG)  or  magnetic  resonance  imaging  (MRI). Some defects may be diagnosed and treated by  hysteroscopy.

Benign  conditions  of  the  uterine  corpus  and  cervix  are  commonly  encountered  in  gynecologic  practice,  because  they  may  adversely  affect  a  woman’s  fertility,  cause abnormal uterine bleeding, or cause pelvic pain.  In  this  chapter,  benign  neoplasms,  epithelial  changes,  functional disorders of the uterus (corpus and cervix),  and  congenital  anomalies  are  discussed  along  with  both  conventional  and  emerging  therapies.  Cervical  dysplasia  along  with  cervical  cancer  is  covered  in  Chapter 38.

Benign Neoplastic Conditions UTERINE FIBROIDS (LEIOMYOMAS) Uterine  fibroids  are  benign  tumors  derived  from  the  smooth muscle cells of the myometrium. They are also  referred to as leiomyomas or myomas, but “fibroid” is  most often used today. Fibroids are the most common  neoplasm  of  the  uterus.  Estimates  are  that  more  than  70% of women have fibroids by the age of fifty, but most  are  asymptomatic.  However,  fibroids may be associ- ated with heavy menstrual bleeding or infertility, pelvic pressure related to uterine bulk and, rarely, pain secondary to degeneration.  Fibroids  are  the  primary  indication  for  as  many  as  one-third  of  the  500,000  hysterectomies  performed  in  the  United   States  each  year.  Although  fibroids  have  the  potential  to  grow  to  be  large,  they rarely become malignant.  Leiomyosarcomas occur in less than 1 per 1000 women 

C H A P T E R 19 Benign Conditions and Congenital Anomalies of the Uterine Corpus and Cervix 249

operated on for presumed fibroids. Rapid growth is not  always a reliable sign of leiomyosarcoma.

Risk  factors  associated  with  developing  fibroids  include  increasing  age  during  the  reproductive  years,  ethnicity,  nulliparity,  and  family  history.  African   American  women  have  a  2-  to  3-fold  increased  risk  of  developing fibroids compared with white women, and  they  may  develop  more  numerous  fibroids  and  at  a  younger age. Some studies have suggested that higher  body mass index (BMI) may be associated with a greater  risk of developing fibroids. In other studies, oral contra- ceptive pills have been associated with a reduced risk.

Pathogenesis of Fibroids Factors  that  initiate  fibroids  are  not  known.  These benign growths are monoclonal, and about 40% are chromosomally abnormal.  The  remaining  60%  may  have  as  yet  undetected  mutations  or  epigenetic  changes.  Genetic  differences  between  fibroids  and  leiomyosarcomas  indicate  that  leiomyosarcomas  do  not  result  from  malignant  degeneration  of  fibroids.  Ovarian sex steroids, both estrogen and progesterone,  are important for the growth of fibroids. Fibroids rarely  develop  before  menarche  and  seldom  develop  or  enlarge  after  menopause,  unless  stimulated  by  exoge- nous  hormones.  Approximately 40% of fibroids enlarge during pregnancy.  Most  of  the  growth  occurs  in the first trimester and they seldom interfere with the  course of the pregnancy.

Fibroids  have  increased  levels  of  estrogen  and  pro- gesterone  receptors  compared  with  other  smooth  muscle  cells.  Estrogen  stimulates  the  proliferation  of  smooth  muscle  cells,  whereas  progesterone  increases  the  production  of  proteins  that  interfere  with  pro- grammed  cell  death  (apoptosis).  Many  growth  factors  are  over-expressed  in  fibroids,  including  those  that  stimulate  the  production  of  fibronectin  and  collagen,  both  of  which  are  major  components  of  the  extracel- lular  matrix  that  characterizes  fibroids.  Other  growth  factors include those that increase smooth muscle pro- liferation  and  DNA  synthesis,  as  well  as  those  that  promote mitogenesis and angiogenesis.

Characteristics of Fibroids Fibroids  are  usually  elliptical  or  spherical,  well- circumscribed,  white,  firm  lesions  with  a  whorled  appearance  on  cut  section.  Although  the  fibroid  appears discrete, it does not have a true cellular capsule.  Compressed  smooth  muscle  cells  on  the  tumor’s  periphery provide the false impression of a true capsule.  This pseudocapsule contains a rich network of blood vessels, but few blood vessels and lymphatics actually traverse the pseudocapsule into the fibroid.

Fibroids  can  undergo  degenerative  changes,  most commonly hyaline acellularity,  in  which  the  fibrous  and muscular tissues are replaced with hyaline tissue.  If  the  hyaline  substance  breaks  down  from  a  further 

reduction in blood supply, cystic (fluid) degeneration may occur. Calcification may occur in degenerated fibroids,  particularly  after  the  menopause.  Fatty degeneration may also occur  but  is  rare.  During pregnancy, 5-10% of women with fibroids undergo a painful red or carneous degeneration  caused  by  hemorrhage into the tumor.

Fibroids  always  arise  within  the  myometrium  (intramural) but may develop near the serosal surface  (subserosal)  or  the  endometrium  (submucosal),  as  depicted in Figure 19-1. Fibroids very near the serosal  or  endometrial  surfaces  may  develop  pedicles.  The  submucosal  fibroids  can  be  propelled  by  uterine   contractions until they extend through the endocervi- cal  canal  and  deliver  through  the  cervical  os.  This  process  can  be  associated  with  significant  bleeding  and  cramping  pain.  A  subserosal  fibroid  on  a  long 

FIGURE 19-1 Uterine leiomyomas (fibroids) in various anatomic locations.

Pedunculated subserosal fibroid

Intramural fibroid

Submucosal fibroid

Parasitic fibroid attached to bowel

mesentery

Pedunculated submucosal fibroid

Cervical fibroid

Subserosal fibroid

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enlarged uterus with smoothly rounded or bosse- lated protrusions may be felt if the fibroids are subserosal or intramural.  The  tumors  are  usually  nontender,  although  degenerating  fibroids  can  be  tender  to  palpation. Their  consistency  may  vary  from  rock hard, as in the case of a calcified postmenopausal  leiomyoma,  to  soft  or  even  cystic,  as  in  the  case  of  cystic degeneration. In general, the fibroid uterus is in  the  midline,  but  sometimes  a  large  portion  of  the  fibroid  lies  in  the  lateral  aspect  of  the  pelvis  and  may  be indistinguishable from an adnexal mass. If the mass moves with the cervix, it is suggestive of a fibroid.  Often the presence of a fibroid precludes a proper eval- uation  of  the  adnexa,  but  ultrasonic  imaging,  as  seen  in Figure 19-2, can help to distinguish adnexal masses  from laterally placed fibroids.

Differential Diagnosis for Fibroids Fibroids  present  as  pelvic  masses  and  thus  the  differ- ential diagnosis is extensive and includes other uterine  pathology.  This  includes  adenomyosis  (see  Chapter   25),  uterine  sarcoma  (rarely),  and  other  pelvic  pro- cesses,  such  as  an ovarian neoplasm, a tubo-ovarian inflammatory mass, a pelvic kidney, a diverticular or inflammatory bowel mass, or cancer of the colon.  Ultrasonography may be helpful to visualize the fibroids  and  identify  normal  ovaries  apart  from  the  fibroids.  MRI  is  the  most  accurate  way  to  diagnose  uterine  fibroids if the diagnosis is uncertain. Figure 19-3 shows  the gross appearance of an irregularly enlarged uterus  with  multiple  fibroids  and  Figure  19-4  is  an  MRI  of  a  similarly deformed uterus preoperatively.

pedicle can present as a mass that feels separate from  the  uterus.  MRI  is  often  helpful  to  differentiate  a  pedunculated  fibroid  from  other  types  of  pelvic  masses.  Very  rarely,  pedunculated  subserosal  fibroids  attach  to  the  blood  supply  of  the  omentum  or  bowel  mesentery  and  lose  their  uterine  connections  to  become  parasitic growths.  Fibroids  can  also  arise  in  the  cervix,  between  the  leaves  of  the  broad  ligament  (intraligamentous), and very rarely in the various sup- porting ligaments (round or uterosacral) of the uterus.

Symptoms of Fibroids The majority of uterine fibroids (approximately 80%) cause no symptoms.  Occasionally,  a  woman  may  be  able  to  feel  a  lower  abdominal  mass  when  the  fibroid  protrudes  above  the  pelvis.  For  women  with  fibroids  that  are  asymptomatic  or  mildly  to  moderately  symp- tomatic, “watchful waiting” may allow treatment to be  deferred,  perhaps  indefinitely.  Symptomatic  women  may complain of pelvic pressure, congestion, bloat- ing, or a feeling of heaviness in the lower abdomen. Rarely, lower back pain may be associated with fibroids. If the fibroid presses upon the bladder, it may  cause frequency of urination or nocturia. A large fibroid  in  the  lower  uterine  segment  or  near  the  cervix  may  compress  the  vesicourethral  junction  and  lead  to  urinary  retention.  Compression  of  the  ureters  with  resultant hydronephrosis is very rare and, if suspected,  can be ruled out with a renal ultrasound.

Prolonged or heavy menstrual bleeding may be associated with submucosal fibroids.  Growth  factors  secreted  by  fibroids  interfere  with  the  blood-clotting  cascade.  Intermenstrual  bleeding  is  not  characteristic  of these tumors but may occasionally occur with sub- mucosal  fibroids  ulcerating  through  the  endometrial  lining. Excessive bleeding may result in anemia, weak- ness, and even dyspnea.

Fibroids do not usually cause pain, but severe pain may occur when degeneration (acute infarction) occurs within a fibroid.  Dyspareunia  can  occur  with  posterior fibroids near the vaginal cul-de-sac. There is  an increased incidence of secondary dysmenorrhea in  women  with  uterine  fibroids,  generally  caused  by  heavy  menstrual  bleeding.  Although  many  women  with uterine fibroids become pregnant and carry their  pregnancies  to  term,  submucosal fibroids  may be associated with an increased incidence of infertility,  possibly due  to  growth  factor  secretion  by  the  fibroid  that may interfere with implantation.

Signs of Fibroids Fibroids  smaller  than  a  12-  to  14-week  gestation  are  usually  confined  to  the  pelvis,  but  larger  fibroids  can  be  palpated  abdominally.  Before  examination,  the  bladder should be emptied because a full bladder will  alter  the  examiner’s  impression  of  uterine  size.  On bimanual pelvic examination, a firm, irregularly

FIGURE 19-2 Ultrasonic image of a uterus enlarged and irregularly distorted by multiple fibroids (arrows). Such studies are useful to help rule out ovarian enlargement too. B, Bladder; Cx, cervix; Ut, uterus; V, vagina. (From Mettler FA: Essentials of radiology, ed 2, Philadelphia, 2005, Saunders.)

V

Cx

B

Ut

+

x

C H A P T E R 19 Benign Conditions and Congenital Anomalies of the Uterine Corpus and Cervix 251

of  these  agents  can  be  administered.  Usually  their   use  is  confined  to  decreasing  uterine  size  and/or  increasing hemoglobin levels for women preparing for  surgical  treatments,  such  as  endometrial  ablation,  myomectomy, or hysterectomy.

Surgical Management Options When  uterine  fibroids  are  not  amenable  to  the  less  invasive  medical  therapies,  surgery  or  embolization  should  be  considered  (Table  19-1).  Even  after  child- bearing  is  complete,  many  women  desire  uterine   preserving  treatment  for  symptoms  of  fibroids.  Myo- mectomy should be considered as a safe alternative to hysterectomy.  Case-controlled  studies  suggest  that  there  may  be  less  risk  of  intraoperative  injury  to  the  bladder,  bowel,  and  ureters  with  myomectomy  when  compared with hysterectomy.

The surgical approach depends on the size, number,  and  location  of  the  various  fibroids.  MRIs  are  the  best  way to localize and estimate the volume of each fibroid,  and  to  determine  its  position  relative  to  the  endome- trium  and  other  anatomical  structures  in  the  pelvis.  Submucosal fibroids less than 5 cm may be resected at  the  time  of  hysteroscopy.  Pedunculated,  subserosal,  and many intramural fibroids may be removed laparo- scopically  or  with  robotic  assistance.  Laparotomy  is  generally reserved for larger or more numerous tumors.  If  the  endometrial  cavity  is  entered  during  myomec- tomy, future births are usually recommended to be by  cesarean  delivery  even  though  the  risk  of  rupture  is  reported to be very low. In skilled hands, myomectomy  may often avoid hysterectomy.

Although new fibroids may form following myomec- tomy, only 11% of women with three or fewer fibroids  and  about  25%  of  women  with  four  or  more  fibroids  will  require  a  subsequent  operation  because  of  new  fibroid growth. Less invasive techniques using laparos- copy  and  hysteroscopy  for  the  removal  of  fibroids,  including morcellation, have significantly reduced the  hospital stay necessary for myomectomy as well as the  morbidity  associated  with  larger  incisions  and  longer  operating times. Although this may be of great benefit  to  the  large  majority  of  appropriate  patients,  any  fast  growing fibroid in a premenopausal woman or enlarg- ing  fibroid  in  a  postmenopausal  woman  should  be  removed  at  open  operation.  At  least,  women  in  these  two circumstances should be warned about the possi- bility  of  a  sarcoma  and  the  potential  lethal  dangers  of  spread caused by open morcellation.

For  women  desiring  uterine  preservation  but  not  future fertility, surgical management of excessive bleed- ing  is  possible  using  procedures  that  ablate  the  endo- metrium.  With endometrial ablation, over 70% of women have a significant and satisfactory decrease in menstrual blood loss after one treatment, while others require repeat ablation or undergo hys- terectomy. Uterine artery embolization (UAE) is a

FIGURE 19-3 Gross appearance of an irregularly enlarged uterus with multiple fibroids. (From Voet RL: Color atlas of obstetric and gynecologic pathology, St Louis, 1997, Mosby.)

Management of Fibroids In  general,  when  asymptomatic  fibroids  are  detected,  treatment  is  not  necessary.  If  the  fibroid  uterus  is  causing  bothersome  symptoms  or  is  implicated  as  a  cause of infertility in a woman seeking pregnancy, then  some treatment is indicated. Traditionally, rapid growth  has been listed as an indication for removal but recent  studies show that rapid growth is not a reliable predic- tor of uterine sarcoma.

Medical Management Heavy or prolonged menstruation presumed to be caused by fibroids can initially be managed hormon- ally in some cases.  Many  women  with  symptomatic  fibroids  are  in  the  age  group  of  women  who  may   also  have  anovulation  as  the  cause  of  the  bleeding.  Progestin-only therapies  (oral  or  injected  medroxy- progesterone  acetate,  progestin-only  oral  contracep- tive  pills,  or  levonorgestrel-releasing  intrauterine  devices)  or combination hormonal contraceptive methods  (oral  contraceptive  pills,  vaginal  rings,  or  patches) are usually the first therapeutic option. The  goal  is  to  reduce  monthly  menstrual  blood  loss  with  cyclic  hormonal  methods  or  to  eliminate  menses   with  extended  or  continuous  use  of  these  methods.  Dysmenorrhea  is  also  markedly  reduced  by  these  measures.

Gonadotropin-releasing hormone (GnRH) ana- logues (agonists and antagonists)  block  ovarian  steroidogenesis,  which  reduces  the  volume  of  the   myometrium and fibroids and stops menstrual bleed- ing. However, because of the intense vasomotor symp- toms  and  the  deleterious  effect  the  GnRH-analogues  may have on bone mineral density, only short courses 

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TABLE 19-1

INTERVENTION FOR PATIENTS WITH FIBROIDS NOT AMENABLE TO MEDICAL THERAPY*

Clinical Presentation Nonmedical Options Comments

Desired fertility or uterine preservation Myomectomy or uterine artery embolization (UAE)†

Usually used for a limited number of fibroids

Poor surgical risk Endometrial ablation or UAE UAE only for a limited number of fibroids

No desired fertility or uterine preservation Endometrial ablation or hysterectomy Hysterectomy is definitive therapy

Rapidly growing uterus (double in size in 6 months)

Exploratory laparotomy, abdominal hysterectomy

More extensive surgery if malignancy discovered

*Generally failed medical therapy or large (>12 to 14 weeks’ gestational size) uterus. †Pregnancies after UAE are at higher risk.

FIGURE 19-4 Two magnetic resonance imaging views of two uterine fibroids F1 (A and C) and F2 (B and D). Significant uterine deformity due to fibroids can result in symptoms such as abnormal uterine bleeding when the fibroids are submucosal (entering the uterine cavity) or pelvic pressure and a feeling of fullness. Large fibroids may put pressure on the bladder (BL) resulting in urinary frequency. Fibroids rarely cause pain except when they undergo degeneration (infarction). (From Bouwsma EV, Gorny KR, Hesley GK, et al: Magnetic resonance-guided focused ultrasound surgery for leiomyoma-associated infertility. Fertil Steril 96:e9-e12, 2011, Figure 1.)

F2

A B

C D

F1

BL BL

F1

F2

BL BL

C H A P T E R 19 Benign Conditions and Congenital Anomalies of the Uterine Corpus and Cervix 253

NORMAL CERVIX At  birth,  a  pale  pink  squamous  epithelium  covers   the  outer  rim  of  the  cervix.  The  inner  region  of  the  exocervix  (or  ectocervix)  is  covered  with  the  taller  columnar cells. The junction between the two is called  the  original  squamocolumnar  junction,  as  seen  in  Figure  19-5. The  columnar  epithelium  appears  redder  because of the closer proximity of its underlying blood  vessels to the surface. With acidification of the vagina at menarche, the exocervix (or ectocervix) undergoes an accelerated rate of squamous metaplasia in a radial pattern, from the squamocolumnar junction inward, which produces the transformation zone.  A  new  squamocolumnar  junction  is  formed  that  moves  progressively  up  the  endocervical  canal  (see  Figure  38-1). Younger women are often found to have a reddish  ring  of  tissue  surrounding  the  os,  which  is  sometimes  called a cervical ectropion, but in reality, this is an area  of  columnar  epithelium  that  has  not  yet  undergone  normal squamous metaplasia.

Under the influence of estrogen (birth control pills,  pregnancy),  the  columnar  epithelium  of  more  mature  women  may  evert  and  present  as  an  ectropion  that  appears  similar.  The  columnar  cells  produce  mucus  and are more vulnerable to trauma and infection with  chlamydia.  Therefore,  women with a cervical ectro- pion may notice more vaginal secretions and, occa- sionally, postcoital spotting.  Once  other  etiologies  have  been  ruled  out,  no  treatment  is  needed  for  the  friable tissue.

Nabothian cysts  on  the  cervix  are  so  common  that  they are considered a normal variant. They result from 

procedure performed under conscious sedation using microspheres or small coils introduced into the uterine artery via a transcutaneous femoral approach. These coils and/or particles occlude the artery feeding the fibroid, leading to necrosis of the myoma. Fibroids often shrink in volume, and bleeding is successfully reduced in 90% of women.  After  UAE  is  performed,  pregnancy may still be possible, but there is a higher risk  of placental complications (accreta), postpartum hem- orrhage, premature delivery, and malpresentation.

Hysterectomy provides definitive therapy for uterine fibroids.  Approximately  200,000  hysterecto- mies  are  done  annually  in  the  United  States  to  treat  fibroids. If the uterus is very large or bulky, laparotomy  is  generally  the  preferred  approach. Vaginal  hysterec- tomy  or  total  laparoscopic  hysterectomy  are  both  excellent  options  for  women  with  smaller  uteri.  If  a  woman  desires  a  supracervical  hysterectomy,  the  vaginal  approach  is  not  possible  but  laparoscopic  supracervical  hysterectomy  may  be  used.  Usually  ovarian preservation is encouraged unless the woman  is over age 60, or has risk factors for ovarian carcinoma  (see Chapters 20 and 39).

Other technologies have been developed recently to  offer  newer  treatment  options.  Magnetic resonance- guided focused ultrasonography  (seldom  used)  pro- duces  energy  that  penetrates  through  soft  tissue  to  produce regions of protein denaturation and necrosis,  with minimal (20%) reduction of fibroid volume. Radio frequency ablation  through  a  laparoscope,  aided  by  intraoperative ultrasonic guidance, can also be used to  treat individual fibroids.

ENDOMETRIAL POLYPS Endometrial  polyps  (named  for  their  shape  and  not  their  histology)  form  from  the  endometrium  to  create  abnormal  protrusions  of  friable  tissue  into  the  endo- metrial  cavity.  They  can  cause  irregular  menstrual  bleeding during the reproductive years and postmeno- pausal  bleeding  after  menopause.  On  ultrasound,  endometrial  polyps  may  appear  as  a  focal  thickening  of  the  endometrial  stripe.  They can be more clearly recognized on saline infusion sonography (SIS)  or  visualized directly by hysteroscopy  (see  Figure  34-1).  Endometrial  polyps  may  evade  detection  by  endome- trial aspiration or dilation and curettage (D&C) because  they are too large to be aspirated through the sampling  orifice  and  are  very  flexible  and  can  be  pushed  out  of  the  path  of  the  sharp  curette.  Histologic  evaluation  of  the  polyp  is  imperative,  because  although  most  are  benign,  endometrial  hyperplasia,  endometrial  carci- noma,  and  carcinosarcomas  may  also  present  as  polyps.  Malignant  or  hyperplastic  polyps  are  signifi- cantly  more  common  in  postmenopausal  compared  with premenopausal women (5% versus 2%), and more  common in women with abnormal bleeding compared  to those without bleeding (4% versus 2%).

FIGURE 19-5 Squamocolumnar junction. In the “ideal” cervix, the original squamous epithelium abuts the columnar epithelium. The squamocolumnar junction thus formed may be situated at the external cervical os, but in most women of childbearing age, the original squamocolumnar junction is located on the vaginal portion of the cervix.

Squamocolumnar junction

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Similarly,  most  trauma  to  the  cervix  occurs  during  vaginal delivery. The cervix can tear if the infant deliv- ers  through  an  incompletely  dilated  cervical  os.  Lac- erations  can  also  occur  when  instruments  such  as  forceps  are  used  for  delivery  or  during  gynecologic  operations,  such  as  cervical  conization,  hysteroscopy,  or abortion. Trauma to the cervix can occur with sexual  assault.

Epithelial Conditions of the Uterus ENDOMETRIAL HYPERPLASIA Endometrial  hyperplasia  represents  an  overabundant  growth of the endometrium generally caused by persis- tent  levels  of  estrogen  unopposed  by  progesterone.  Hyperplasia is most frequently seen at the extremes of a woman’s reproductive years when ovulation is infrequent.  It  also  occurs  in  association  with  unop- posed estrogenic stimulation, such as the following: 1.  Polycystic ovarian syndrome (PCOS) and

anovulation 2.  Estrogen-producing  tumors  such  as  granulosa-

theca cell tumors 3.  Obesity because of peripheral conversion of andro-

gens to estrogen in adipose cells 4.  Prolonged  use  of  exogenous estrogens  without 

progesterone or progestins 5.  Use of tamoxifen

A spectrum of histologic variations exists. There are two categories (simple hyperplasia and complex hyperplasia) and two subcategories (with and without atypia). Complex atypical hyperplasia has the greatest  malignant  potential;  about  20-30%  of  cases  progress   to  endometrial  carcinoma,  if  untreated.  Figure  19-7  shows photomicrographs of normal proliferative endo- metrium,  simple  hyperplasia  (without  atypia),  and  complex hyperplasia with atypia.

Diagnosis Endometrial  hyperplasia  should  be  suspected  when  women  develop  intermenstrual  bleeding,  or  when  high-risk  women  develop  unexplained  heavy  or  pro- longed  bleeding.  In  premenopausal  women,  endo- metrial  sampling  is  necessary  to  obtain  a  histologic  diagnosis,  especially  for  women  at  high  risk  of  hyper- plasia (chronic anovulation, obesity, diabetes mellitus).  Office endometrial biopsy is easy to perform, but frac- tional D&C or hysteroscopically directed biopsy may be  needed to rule out carcinoma or other pathology. Post- menopausal women who have bleeding can be evalu- ated with transvaginal ultrasound and a thin (<4 mm) endometrial stripe is reassuring. Those whose endo- metrial stripe is thicker should be sampled.

Treatment Treatment  of  simple  hyperplasia  in  reproductive  aged  women  without  atypia  generally  consists  of  a  thor-

the process of squamous metaplasia. A layer of super- ficial squamous epithelium entraps an invagination of  columnar  cells  beneath  its  surface.  The  underlying  columnar  cells  continue  to  secrete  mucus,  and  a  mucous  retention  cyst  is  created.  Nabothian  cysts  are  opaque, with a yellowish or bluish hue. They vary gen- erally  in  size  from  0.3  to  3 cm  (Figure  19-6),  although  larger nabothian cysts have been reported.

CERVICAL POLYPS Ectocervical and endocervical polyps are the most common benign neoplastic growths of the cervix.  A  polyp is a localized proliferation of cells (usually colum- nar)  located  in  the  endocervix.  Endocervical  polyps  tend to the more beefy red in color and arise from the  endocervical canal on a long, pedunculated stalk. Ecto- cervical  polyps  are  less  common,  are  generally  pale,  and arise from the exocervix (or ectocervix) to create a  broad-based  protrusion.  Cervical  polyps  may  be  iso- lated or multiple and vary in diameter from a few mil- limeters  to  several  centimeters.  If symptomatic, they most commonly cause coital bleeding or menorrha- gia. Narrow-based polyps are removed by twisting the  polyp  off  at  its  base.  Broader-based  polyps  may  be  better  removed  with  cautery  or  other  modalities  that  can control bleeding after removal. Although the inci- dence of malignancy is very low (1% or less), both squamous cell carcinomas and adenocarcinomas can present as polyps.  All  specimens  must  be  sent  for  pathologic examination.

Trauma of the Uterine Corpus and Cervix Most trauma to the uterus has an obstetric basis, such  as  uterine  rupture  from  prolonged  labor,  caused  by  a  Bandl  ring,  or  rupture  along  a  previous  uterine  scar.  However,  uterine  perforation  is  also  possible  with  operative  procedures  such  as  D&C,  endometrial  aspi- ration, or intrauterine contraceptive (IUC) placement. 

FIGURE 19-6 Cervix of a multiparous woman with nabothian cysts.

Nabothian cysts

C H A P T E R 19 Benign Conditions and Congenital Anomalies of the Uterine Corpus and Cervix 255

FIGURE 19-7 Endometrial biopsies of normal proliferative endometrium (A), simple endometrial hyperplasia without atypia (B), and complex endometrial hyperplasia with cellular atypia (C). (From Espindola D, Kennedy KA, Fischer EG: Management of abnormal uterine bleeding and the pathology of endometrial hyperplasia. Obstet Gynecol Clin North Am 34:717-737, 2007.)

A B C

ough,  coordinated  sloughing  of  the  hyperplastic   endometrium  and  therapies  directed  at  preventing  recurrence. Simple hyperplasia without atypia should be treated initially with a progestin, such as 10 days each month for 3 months,  then  biopsy  should  be  repeated  to  confirm  normalization  of  the  endome- trium. Complex hyperplasia must be evaluated with a fractional D&C and should be initially treated with daily progestin therapy for 3 to 6 months. The levo- norgestrel intrauterine system may also be successful in reversing hyperplasia. Test of cure with another biopsy is then needed.  In  the  longer  run,  a  source  of  progestin  must  be  supplied.  Complex hyperplasia with atypia is best treated by hysterectomy once car- cinoma  has  been  excluded.  Endometrial ablation is absolutely contraindicated in any of these situations until the endometrium normalizes.

ASHERMAN SYNDROME Asherman syndrome is a condition where the endome- trium  is  denuded  and  the  endometrial  cavity  is  filled  with  adhesions.  Most  commonly,  the  scarring  results  from  curettage  in  high-risk  settings,  such  as  postpar- tum hemorrhage or septic abortion, although vigorous  scraping under any circumstances can result in the loss  of  the  endometrium  and  consequent  adhesion  of  opposing  myometrial  surfaces.  Endometrial  ablation  procedures  are  designed  to  deliberately  destroy  the  endometrium  and  create  such  scarring.  Subsequent  bleeding disorders can range from irregular bleeding to  amenorrhea depending on the amount of intrauterine  scarring.

Functional Conditions of the Uterine Corpus and Cervix Noncongenital cervical stenosis usually arises after trauma  (endocervical  curettage,  conization)  or 

hypoestrogenism  (menopause,  prolonged  depot  medroxyprogesterone  acetate  [MPA]  use).  Problems  arise  if  blood  from  the  endometrium  cannot  escape  into  the  vagina,  in  which  case  the  uterus  becomes  grossly  distended  (hematometra).  Similarly,  sperm  may be less likely to enter the upper genital tract. Cer- vical stenosis may also compromise cervical sampling  for microscopic evaluation.

Cervical incompetence  is  a  condition  in  which  the  cervix  is  unable  to  maintain  closure  under  the  pres- sure  of  a  progressively  enlarging  pregnant  uterus  and  painlessly  dilates,  resulting  in  pregnancy  loss,  most  commonly  in  the  second  trimester  (see  Chapter  12).  Cervical incompetence may be intrinsic  (caused  by  poor  ground  substance  in  the  cervix),  or  the result of cervical surgery  (especially  loop  electrosurgical  exci- sion  procedure  [LEEP]  and  cold  knife  conization)  for  cervical dysplasia.

Congenital Anomalies of the Uterine Corpus and Cervix The upper vagina, cervix, uterine corpus, and fallopian  tubes  are  formed  from  the  paramesonephric  (mülle- rian)  ducts.  The absence of a Y chromosome and the resultant absence of müllerian inhibiting substance lead to the development of the paramesonephric system, with the regression of the mesonephric system.  The  paramesonephric  ducts  first  arise  at  6  weeks  lateral  to  the  cranial  pole  of  the  mesonephric  duct  and  expand  caudally.  By  9  to  10  weeks,  they  fuse  in  the  midline  at  the  urogenital  septum  to  form  the  uterovaginal  primordium.  Later,  dissolution  of  the  septum  between  the  fused  paramesonephric  ducts  leads to the development of a single uterus and cervix.

The most common anomalies of the uterus result from either incomplete fusion of the paramesoneph- ric ducts, incomplete dissolution of the midline

PA R T 3 Gynecology256

FIGURE 19-8 Variations in uterine development. The dotted lines within circles represent potential sites of communication or obstruction.

Bicornuate uterus Rudimentary horn

Uterus didelphys Septate vagina

Cervical atresia

Bicornuate uterus

Normal uterus Subseptate uterus Arcuate uterus

Unicornuate uterusBicornuate uterus Double cervix

fusion of those ducts, or formation failures.  Figure  19-8 shows variations of the uterine and cervical devel- opment  and  demonstrates  that  communication  between  the  dual  systems  can  exist  at  several  levels.  Failure  of  fusion  is  most  evident  in  uterus didelphys,  which presents with two separate uterine bodies, each  with  its  own  cervix  and  attached  fallopian  tube  and  vagina. A bicornuate uterus with a rudimentary horn  also  represents  a  fusion  failure.  Less  complete  fusion  failure is seen in the bicornuate uterus with or without double cervices. Incomplete dissolution of the midline  fusion  of  the  paramesonephria  explains  the  septate uterus. Failure of formation can be seen in the unicor- nuate uterus. In müllerian agenesis, there is complete lack of development of the paramesonephric system.  The  affected  woman  generally  has  an  incomplete  development of the fallopian tubes associated with the  absence  of  the  uterus  and  most  of  the  vagina.  All  of  these conditions occur in normal karyotypic and phe- notypic females, but can be associated with important 

anomalies of the urinary system such as a horseshoe or  pelvic kidney.

The most common congenital cervical anomalies are the result of malfusion of the paramesonephric (müllerian) ducts with varying degrees of separation, as seen in the didelphys cervix or septate cervix.

These  different  anatomies  may  have  a  significant  effect  on  a  woman’s  risk  of  infertility  and  early  preg- nancy loss, and may also cause dysmenorrhea and dys- pareunia. Women  with  fusion  anomalies  may  present  with menstrual blood trapped in a noncommunicating  uterine horn or vagina.

In addition to these macroscopic differences, subtle  anomalies may exist within the uterine vascular system,  such  as  an  arteriovenous malformation,  rupture  of  which may cause life-threatening hemorrhage.

Although all of these anomalies can occur spontane- ously, they may also be caused by early maternal expo- sure to certain drugs. Historically, the most notable of  these drugs is diethylstilbestrol (DES), which increases 

C H A P T E R 19 Benign Conditions and Congenital Anomalies of the Uterine Corpus and Cervix 257

symptoms. The diagnosis of intrauterine defects can be  made by imaging studies such as HSG or MRI, and may  be  suspected  at  the  time  of  laparoscopy  because  of  visualized  uterine  distortion.  Hysteroscopy  may  be  performed  to  both  diagnose  and  treat  defects  such  as  the resection of a uterine septum. A bicornuate uterus  can  be  repaired  laparoscopically  by  performing  a  metroplasty,  thereby  creating  one  functional  uterine  cavity (see Chapter 31).

the risk of a small T-shaped endometrial cavity or cervi- cal deformity.

DIAGNOSIS AND TREATMENT OF CONGENITAL ANOMALIES Certain  congenital  anomalies  of  the  uterus  may  need  to be treated, especially if they are thought to be inter- fering  with  normal  function,  fertility,  or  causing  other 

258

20  Benign Conditions and Congenital Anomalies of the Ovaries and Fallopian Tubes

C H

A P

T ER

WILLIAM H. PARKER • JOSEPH C. GAMBONE

■  The  adnexa  are  composed  of  the  ovaries  and  fallopian  tubes, along with the blood vessels, ligaments, and con- nective  tissues  located  along  both  sides  of  the  uterus.  Benign  ovarian  masses  may  be  classified  as  functional,  inflammatory,  metaplastic,  or  neoplastic.  Functional  cysts  are  the  most  common  masses  and  almost  always  resolve  spontaneously.  Differentiating  between  benign  and  malignant  ovarian  masses  is  extremely  important  and can be challenging.

■  A  risk  assessment  tool,  the  Risk  of  Malignancy  Index  (RMI), may be used to help determine the likelihood that  ovarian masses are malignant. Nonmalignant masses are  generally  unilateral,  cystic  (without  solid  components),  mobile, and without ascites. CA-125 tumor marker levels  are usually normal but false positives may occur. Benign  ovarian neoplasms are divided into three cell types: epi- thelial, stromal, and germ-cell.

■  The  most  common  ovarian  neoplasm  in  the  premeno- pausal woman is the benign cystic teratoma or dermoid  cyst  which  is  a  germ-cell  type  of  tumor.  In  postmeno-

pausal  women  serous  cyst  adenomas  are  the  most  common.  Management  of  ovarian  masses  ranges  from  observation  and  ultrasonographic  follow-up  for  pre- sumed  functional  cysts,  to  surgical  removal.  Laparo- scopic  cystectomy  is  appropriate  for  cystic  masses  that  are considered very low risk for malignancy after appro- priate evaluation.

■  Recent evidence suggests that some ovarian cancers may  actually  originate  in  the  fallopian  tubes.  Benign  neo- plasms  of  the  tubes  include  epithelial  adenomas  and  polyps,  myomas  from  the  tubal  musculature,  inclusion  cysts,  and  angiomas.  Paraovarian  cysts  are  usually  located within the broad ligament.

■  Congenital  anomalies  of  the  ovaries  are  uncommon.  Absence,  duplication,  and  ectopic  location  of  ovarian  tissue,  as  well  as  supernumerary  ovaries  may  occur.  Rarely, an ovatestis (ovarian and testicular tissue) may be  present, resulting in intersex problems. Turner syndrome  (45 XO) is characterized by rudimentary streak gonads.

CLINICAL KEYS FOR THIS CHAPTER

The  ovaries  and  fallopian  tubes,  along  with  the  blood  vessels,  ligaments,  and  connective  tissues  located  along  both  sides  of  the  uterus,  are  referred  to  as  the  adnexa.  In  this  chapter,  after  presenting  the  recom- mended  workup  and  management  of  benign  adnexal  masses,  the  abnormal  development  and  congenital  anomalies  of  the  ovaries  and  fallopian  tubes  are  discussed.

Benign Conditions of the Ovaries The human ovary is prone to develop a wide variety of  tumors,  the  majority  of  which  are  benign.  Ovarian cysts are common, with a reported clinical prevalence of 15% in premenopausal and 8% in postmenopausal women.  Most  of  these  cysts  resolve  over  time  without  treatment.  As  indicated  in  Table  20-1,  ovarian  masses 

may be functional, inflammatory, metaplastic, or neo- plastic. During the childbearing years, 70% of nonin- flammatory benign ovarian tumors are functional.  The remainder are either neoplastic (20%) or metaplas- tic (endometriomas, accounting for 10%).

The  management  of  ovarian  tumors,  whether   functional,  benign,  or  malignant,  involves  difficult  decisions  that  may  affect  a  woman’s  hormonal  status  or  her  future  fertility.  Although  only  functional  cysts  and benign ovarian neoplasms are considered in detail  in  this  chapter,  diagnostic  methods  to  differentiate  benign masses from malignant ones are discussed.

FUNCTIONAL OVARIAN CYSTS AND TUMORS Dozens of ovarian follicles form the “cohort of follicles”  of  each  menstrual  cycle.  It  is  from  this  cohort  that  usually only one dominant follicle will fully develop to 

C H A P T E R 20 Benign Conditions and Congenital Anomalies of the Ovaries and Fallopian Tubes 259

appear  as  brown  to  reddish-brown  nodules  that  may  be cystic or solid. A luteoma of pregnancy (Figure 20-1)  may  be  associated  with  multifetal  pregnancies  or  hydramnios.  They can cause maternal virilization in 30% of women and, less often, ambiguous genitalia in  a  female  fetus.  Although  ovarian  enlargement  may  be  impressive, surgical resection is not indicated, because  luteomas regress spontaneously postpartum.

Polycystic ovarian syndrome, a functional disorder  generally  associated  with  chronic  anovulation,  hyper- androgenism, and insulin resistance, can also produce  enlarged  ovaries  with  multiple  simple  follicles  (Figure  20-2).  The  hormonal  aspects  and  treatment  of  this   syndrome are discussed further in Chapter 33.

Clinical Features An ovarian follicular cyst is usually asymptomatic,  but  a  patient  may  present  with  delayed  menses,  

TABLE 20-1

DIFFERENTIAL DIAGNOSIS OF OVARIAN MASSES

Pathogenesis Specific Type

Functional Follicular cysts Corpus luteal cysts Theca-luteal cysts Polycystic ovaries (multiple follicular cysts)

Inflammatory Salpingo-oophoritis Pyogenic oophoritis—puerperal, abortal, or

intrauterine device–related Granulomatous oophoritis

Metaplastic Endometriomas

Neoplastic Premenarchal years—10% are malignant Menstruating years—15% are malignant Postmenopausal years—50% are malignant

FIGURE 20-1 Gross appearance of a luteoma of pregnancy. Note the multiple brown nodules. (From Voet RL: Color atlas of obstetric and gynecologic pathology, St Louis, 1997, Mosby.)

FIGURE 20-2 Ovary with multiple cysts lining the capsule consis- tent with polycystic ovarian syndrome. (Courtesy Dr. Sathima Natarajan, Ronald Reagan—UCLA Medical Center.)

about 2 cm in size in each cycle (see Chapter 4). If ovu- lation  occurs,  the  remaining  follicle  becomes  the  corpus  luteum.  Functional  cysts,  including  follicular  and corpus luteal cysts, may appear from time to time  as part of the normal function of the ovary. To be clas- sified a “functional cyst,” the follicle must reach a diameter of at least 3 cm. Functional cysts may cause  a dull sensation or heaviness in the pelvis or, occasion- ally, pelvic pain.

A follicular cyst, lined by one or more layers of gran- ulosa  cells,  develops  when  an  ovarian  follicle  fails  to  rupture.  Similarly,  a corpus luteal cyst  may  develop  if  the  corpus  luteum  grows  to  over  3 cm  and  fails  to  regress  normally  after  14  days.  Hemorrhagic cysts  form when invasion of ovarian vessels into the corpus  luteal  cyst  2  to  3  days  after  ovulation  causes  bleeding  within  the  cyst.  Hemorrhagic  corpus  luteal  cysts  are  more  likely  to  cause  symptoms  and,  on  occasion,  rupture.

Other  specific  types  of  lutein  cysts  may  occur  in  association  with  abnormally  high  serum  levels  of  human  chorionic  gonadotropin  (hCG)  or  increased  ovarian  sensitivity  to  gonadotropins.  Theca-luteal cysts may develop in association with the high levels of hCG present in patients with a hydatidiform mole or choriocarcinoma. Patients undergoing ovulation induction with gonadotropins, clomiphene, or letro- zole may also develop theca-lutein cysts. Theca-lutein  cysts  are  usually  bilateral,  may  become  quite  large  (>30 cm), and characteristically regress slowly after the  gonadotropin level falls. Rarely, when follicles are stim- ulated  with  gonadotropins,  theca-lutein  cysts  can  become  so  extensive  as  to  cause  massive  ascites  and  dangerous  problems  with  systemic  fluid  imbalance.  This condition is referred to as ovarian hyperstimula- tion syndrome or OHSS (see Chapter 34).

A  luteoma of pregnancy  is  a  related  condition  in  which  there  is  a  hyperplasic  reaction  of  ovarian  theca  cells,  presumably  from  prolonged  hCG  stimulation  during  pregnancy.  The  luteomas  characteristically 

PA R T 3 Gynecology260

tivity  and  specificity  as  calculated  by  the  U.S.  Agency  for  Healthcare  Research  and  Quality  (AHRQ).  None  of  these  modalities  is  accurate  enough  to  be  used  alone  for diagnosis.

A pelvic ultrasound will confirm the cystic nature of  the  mass,  but  it  cannot  differentiate  with  certainty  between  a  functional  and  a  neoplastic  tumor.  Table  20-3 contains a risk assessment tool that can be useful  for  evaluating  suspicious  adnexal  masses  in  pre-  and  postmenopausal women. It is called the Risk of Malig- nancy Index  or  RMI.  CA-125  levels  may  be  “falsely”  elevated  in  some  premenopausal  women  with  endo- metriosis or fibroids as well as other benign conditions,  and  assay  numbers  for  CA-125  may  vary  among   laboratories.  For  these  reasons  the RMI should be interpreted carefully, particularly in premenopausal patients.

A follow-up ultrasound should be performed 6 weeks after the initial ultrasound. A cyst that enlarges  and increases in complexity should be considered sus- picious. Based upon a recent large study of over 30,000  women,  cysts  that  do  not  enlarge  or  increase  in  com- plexity  may  be  followed  with  ultrasound  every  few  months  until  stability  is  documented,  and  then  fre- quent  follow-up  imaging  may  be  safely  discontinued.  According  to  the  study  findings,  care  for  clinical  judg- ment must occur because the adverse consequences of  delayed diagnosis of ovarian cancer is significant.

Management If the RMI is low and the cyst is considered to be func- tional,  it  is  appropriate  to  wait and reexamine the patient after her next menses.  Low-dose  contracep- tive  agents  may  be  given  to  suppress  gonadotropin 

abnormal  uterine  bleeding,  or  pelvic  pain.  Occasion- ally, a functional cyst may undergo torsion (see below)  or  it  may  rupture,  which  may  produce  acute  lower  abdominal  pain  and  tenderness  and  the  differential  diagnosis  must  include  ectopic  pregnancy,  pelvic  abscess,  or  adnexal  torsion  of  an  ovarian  neoplasm.  Occasionally,  a  significant  hemoperitoneum  may  be  present.

Most  follicular  cysts  are  unilocular  (“simple”),  and  rarely can be as large as 15 cm in diameter. Regression  usually occurs during the subsequent menstrual cycles.  In general, a corpus luteal cyst is apt to be smaller but  more  firm  or  even  solid  in  consistency,  and  is more likely to cause pain or signs of peritoneal irritation.  Because it may continue to produce progesterone, it is  also more likely to cause delayed menses.

Diagnosis The presumptive diagnosis of a functional ovarian cyst  is usually made when a 5- to 8-cm cystic adnexal mass  is  noted  on  bimanual  examination  and  imaged  with  transvaginal ultrasonography; it is confirmed when the  lesion  regresses  over  the  course  of  the  next  several  cycles.  In general, a functional cyst is mobile, unilat- eral, and not associated with ascites.  On  rare  occa- sions,  the  mass  may  exceed  8 cm  and  be  quite  tender  to  palpation.  Occasionally,  hemorrhagic  corpus  luteal  cysts may have a solid rather than a cystic consistency,  and can be confused with ovarian cancer.

Masses that are suspicious for malignancy are more  solid,  fixed,  and  irregular,  and  they  may  be  bilateral.  Any  adnexal  mass  found  in  the  presence  of  ascites  or  an upper abdominal mass should be considered malig- nant  until  proven  otherwise,  unless  the  patient  has  hyperstimulation syndrome.

Table 20-2 lists the current modalities that are avail- able  to  evaluate  adnexal  masses  along  with  the  sensi-

TABLE 20-2

MODALITIES FOR THE EVALUATION OF ADNEXAL MASSES

Modality Sensitivity (%) Specificity (%)

Gray-scale transvaginal ultrasonography (UTX)

0.82-0.91 0.68-0.81

Doppler UTX 0.86 0.91

Computed tomography 0.90 0.75

Magnetic resonance imaging

0.91 0.88

Positron emission tomography

0.67 0.79

CA-125 level measurement

0.78 0.78

Data from Agency for Healthcare Research and Quality (AHRQ): Manage- ment of adnexal mass, AHRQ Publication No. 06-E004, Rockville, MD, 2006, AHRQ.

TABLE 20-3

CALCULATION OF THE RISK OF MALIGNANCY INDEX FOR AN OVARIAN MASS

Criteria Scoring System

A. Menopausal Status

Premenopausal 1

Postmenopausal 3

B. Ultrasonic Features

Multiloculated 1 feature = 1

Solid areas 2 or more features = 3Bilaterality

Ascites

C. Serum CA-125 titer Absolute value (normal = <35 U/mL)

Data from Jacobs I, Oram D, Fairbanks J, et al: A risk of malignancy index incorporating CA 125, ultrasound and menopausal status for the accurate preoperative diagnosis of ovarian cancer. Br J Obstet Gynaecol 97:922, 1990. Risk of Malignancy Index = A × B × C. A Risk of Malignancy Index (RMI) score of >200 will discriminate a benign from a malignant mass with a sensitivity of 87% and a specificity of 97%.

C H A P T E R 20 Benign Conditions and Congenital Anomalies of the Ovaries and Fallopian Tubes 261

Each  of  the  epithelial  ovarian  neoplasms  has  char- acteristic  clinical  and  histologic  features.  The  serous  tumors are bilateral in about 10% of cases. Of all serous tumors, about 70% are benign, 5-10% have border- line malignant potential, and 20-25% are malignant,  depending  largely  on  the  patient’s  age.  Larger  serous  cystadenomas tend to be multilocular, although small  unilocular  serous  cystomas  also  occur.  Histologically,  serous  tumors  characteristically  form  psammoma bodies  (from  the  Greek  psammos,  meaning  sand),  which are calcific, concentric concretions. Psammoma  bodies occur occasionally in benign serous neoplasms  and  frequently  in  serous  cystadenocarcinomas.  Papil- lary patterns are also common.

The mucinous neoplasms of the ovary can attain a huge size, often filling the entire pelvis and abdomen.  They  are  often  multilocular,  and  benign  mucinous  tumors  are  bilateral  in  less  than  10%  of  cases.  About 85% of mucinous tumors are benign.  Mucinous  tumors  are  often  associated  with  a  mucocele  of  the  appendix.  Rarely, a benign mucinous tumor may be complicated by pseudomyxoma peritonei,  a  condi- tion in which a great many benign implants are seeded  onto the surface of the bowel and other peritoneal sur- faces and produce large quantities of mucus.

The Brenner tumor is a small, smooth solid ovarian  neoplasm, usually benign, with a large fibrotic compo- nent that encases epithelioid cells that resemble tran- sitional cells of the bladder (Figure 20-4). In about 33%  of cases, Brenner tumors are associated with mucinous  epithelial elements.

Sex Cord–Stromal Ovarian Neoplasms These  tumors  include  thecomas,  granulosa-theca  cell  tumors, Sertoli-Leydig cell tumors, and fibromas. Com- binations  of  granulosa-theca  cell  and  Sertoli-Leydig  cell tumors are termed gynandroblastomas.

levels  and  to  prevent  development  of  another  cyst  which may confuse the evaluation.

If  the  lesion  does  not  fulfill  the  requirements  for  observation because it is solid, painful, fixed, or has an  elevated RMI, surgical exploration and/or referral to a  gynecologic  oncologist  is  indicated.  In  a  premeno- pausal woman laparoscopic cystectomy to allow histo- logic evaluation may be needed to differentiate between  a  functional  and  a  neoplastic  ovarian  cyst.  Aspiration of the fluid as a diagnostic tool is inappropriate because the false-negative rate for the cytologic examination is high and slow leakage of the fluid will disseminate cancer if the cyst is malignant.

BENIGN NEOPLASTIC OVARIAN TUMORS Ovarian  neoplasms  may  be  divided  generally  by  cell  type  of  origin  into  three  main  groups:  epithelial,  stromal, and germ-cell. Taken as a group, the epithelial  tumors  are  by  far  the  most  common,  although  the single most common benign ovarian neoplasm in a premenopausal woman is the benign cystic teratoma (dermoid cyst),  which  is  a  germ-cell  tumor.  Interest- ingly,  the  aggressive  form  of  serous  “ovarian”  cancer  has  been  shown  to  originate  frequently  from  the  fal- lopian tubes (see Chapter 39).

Epithelial Ovarian Neoplasms These  tumors  are  believed  to  be  derived  from  the  mesothelial  cells  lining  the  surface  of  the  ovary  and  also  lining  the  peritoneal  cavity.  A  mucinous  ovarian  neoplasm  cytologically  resembles  the  endocervical  epithelium,  an  endometrioid  neoplasm  resembles  the  endometrium,  and  serous  tumors  resemble  the  lining  of  the  fallopian  tubes.  The  most  common  epithelial  ovarian tumors are serous cystadenomas. Figure 20-3,  A and B shows the gross appearance of a mucinous (A)  and serous (B) cystadenoma.

FIGURE 20-3 Gross appearance of a mucinous (A) and serous (B) cystadenoma of the ovary. The mucinous type is generally multilocu- lated and can be quite large. (A, From Voet RL: Color atlas of obstetric and gynecologic pathology, St Louis, 1997, Mosby, Figure 6-31; B, from Voet RL: Color atlas of obstetric and gynecologic pathology, St Louis, 1997, Mosby, Figure 6-20.)

A BBA

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The  ovarian fibroma,  another  ovarian  stromal  tumor,  forms  a  solid,  encapsulated  smooth-surfaced  tumor made up of interlacing bundles of fibrocytes. It  is  not  hormonally  active.  The  fibroma  represents  a  stromal  cell  neoplasm  developing  from  mature  fibro- blasts  in  the  ovarian  stroma.  Figure  20-5  illustrates  a  gross  surgical  specimen  of  bilateral  ovarian  fibromas.  On  occasion,  this  tumor  is  associated  with  ascites  caused  by  the  transudation  of  fluid  from  the  ovarian  tissue. The  flow  of  this  ascitic  fluid  through  the  trans- diaphragmatic lymphatics into the right pleural cavity  may  result  in  Meigs syndrome  (ascites  and  hydrotho- rax in association with an ovarian fibroma). These effu- sions will spontaneously resolve when the fibroma has  been removed. The ovarian fibroma may be associated  with theca-cell elements called a fibrothecoma.

Germ-Cell Tumors Germ-cell neoplasms can occur at any age. They make  up  about  60%  of  ovarian  neoplasms  occurring  in  infants and children.

The most common ovarian neoplasm in the pre- menopausal woman is the benign cystic teratoma,  a  germ-cell  tumor  that  can  take  on  a  great  variety  of  forms with virtually all adult tissues being represented  within the mass (Figure 20-6). Ten to 15% of teratomas  are  bilateral.  The  benign  cystic  teratoma,  commonly  referred to as a dermoid cyst, is composed primarily of  ectodermal tissue (such as sweat and sebaceous glands,  hair  follicles,  and  teeth),  with  some  mesodermal  and  rarely endodermal elements.

These are slow-growing tumors and half the tumors  are  diagnosed  in  women  between  25  and  50  years  of  age.  Most  are  less  than  10 cm  in  diameter.  Because  of  the oily secretion of the sebaceous glands, the desqua- mated  squamous  cells,  the  presence  of  hair,  and  the 

The  tumors  in  this  category  derive  from  the  sex  cords and specialized stroma of the developing gonad.  The  embryologic  origins  of  granulosa  and  theca  cells  as  well  as  their  counterparts  in  the  testes,  the  Sertoli  and Leydig cells, arise from cells that make up this spe- cialized gonadal stroma. If the ultimate differentiation  of  cell  types  occurring  in  the  tumor  is  feminine,  the  neoplasm  becomes  a  granulosa-cell tumor,  a  theca- cell tumor,  or  in  many  instances,  a  mixed granulosa- theca cell tumor. Neoplasms containing cells that take  on  a  masculine  differentiation  become  Sertoli-Leydig cell tumors. This is far less common.

The granulosa-theca cell neoplasms as well as their androgenic counterparts are generally referred to as functioning (not functional) ovarian tumors.  They  occur  in  any  age  group,  from  birth  on,  but  more  commonly  in  the  postmenopausal  years.  Their  func- tioning  characteristics  are  responsible  for  a  variety  of  associated  presenting  signs  and  symptoms.  The granulosa-theca cell tumors promote feminizing signs and symptoms,  such  as  precocious  menarche,  precocious  thelarche,  or  premenarchal  uterine  bleed- ing during infancy and childhood. In the reproductive  years,  menorrhagia  (with  alternating  amenorrhea),  endometrial  hyperplasia,  and,  not  infrequently,  endo- metrial  cancer,  breast  tenderness,  and  fluid  retention  occur.  Postmenopausal  bleeding  may  occur  in  older  women with granulosa theca cell tumors.

In  contrast,  the less frequent Sertoli-Leydig cell tumors are responsible for virilizing effects,  such  as  hirsutism,  temporal  baldness,  deepening  of  the  voice,  clitoromegaly,  and  a  defeminizing  change  in  body  habitus  to  a  muscular  build.  Fifteen  percent  of  these  tumors  produce  no  obvious  endocrinologic  effects.  Except for the pure thecoma or fibroma, all of these tumors have low malignant potential  and  are  dis- cussed further in Chapter 39.

FIGURE 20-4 Gross appearance of a cut-open Brenner tumor. (Courtesy Dr. Sathima Natarajan, Ronald Reagan—UCLA Medical Center.) FIGURE 20-5 Bilateral ovarian fibromas in a surgical specimen with

the uterus (corpus and cervix) in the middle. (Courtesy Dr. Neville Hacker.)

C H A P T E R 20 Benign Conditions and Congenital Anomalies of the Ovaries and Fallopian Tubes 263

usually  enlarge  very  slowly,  so  that  an  increase  in  abdominal  girth  or  pressure  on  surrounding  organs  is  not perceived until the later stages of growth.

Any pelvic pain is generally mild and intermittent, unless the tumor twists on its pedicle (torsion), when  infarction may induce severe pain and tenderness. On  rare  occasions,  an ovarian cyst may rupture sponta- neously from internal hemorrhage or intracystic pressure, resulting in pain and peritoneal irritation. A  cyst may also rupture occasionally during or following  a  bimanual  pelvic  examination  or  with  intercourse.  Depending  on  the  cystic  contents,  pain  of  varying  degrees of severity can result. The escape of thin serous  fluid without hemorrhage may evoke some pain or ten- derness, but the oily contents of a dermoid cyst or the  thick  mucinous  fluid  of  a  mucinous  cystadenoma  are  irritating  to  both  the  parietal  and  the  visceral  perito- neum, and can lead to chemical peritonitis and severe  pain.  Without  surgical  treatment  and  irrigation  and  suctioning  of  the  fluid,  the  peritonitis  can  lead  to  the  subsequent formation of pelvic adhesions.

Bimanual  pelvic  examination  generally  indicates  the presence of the mass in the pelvis, but it may be too  small to be palpated. On the other hand, if the mass is  large enough, it may be detected by abdominal palpa- tion. Examination may suggest a cystic mass or a solid  tumor. Movement of the mass separate from the uterus  supports the suspicion of an adnexal mass instead of a  uterine fibroid. Percussion of the abdomen in a patient  with a large ovarian cyst may reveal dullness anteriorly  with  tympany  in  the  flanks  as  the  bowel  is  displaced  laterally by the tumor.

If the tumor has undergone torsion and infarction or rupture, signs of peritoneal irritation may be present.  If  complete  infarction  has  occurred,  there  may be abdominal rigidity. Paralytic ileus may also be  present.

Pelvic  ultrasonography,  particularly  transvaginal ultrasonography,  with  or  without  color  Doppler,  may  help  to  identify  the  size,  consistency,  and  location  of  the mass. It is particularly helpful in the diagnosis of a  dermoid cyst.

In  postmenopausal  patients  in  particular,  tumor  markers, such as serum CA 125, as part of the RMI (see  above and Table 20-2) may help to distinguish between  a benign and a malignant mass. When clinical evalua- tion,  pelvic  ultrasonography,  and  tumor  markers  all  indicate malignancy, the patient should be referred to a  gynecologic oncologist for evaluation and treatment.

MANAGEMENT OF OVARIAN NEOPLASMS Most benign-appearing ovarian cysts may be observed  and  followed  with  ultrasonography.  If  they  are  symp- tomatic  or  enlarging,  laparoscopic  management  is  usually  appropriate.  If  the  patient  is  premenopausal,  the  ovarian  neoplasm  is  unilocular,  and  there  are  no  excrescences  within  the  cyst,  an  ovarian  cystectomy 

presence of a dermoid tubercle (of Rokitansky), which  often contains a hard, well-formed tooth, the dermoid  cyst  has  a  characteristic  gross  and  histologic  appear- ance (see Figure 20-6). These tissues also have a char- acteristic appearance on ultrasonography,  usually  allowing a preoperative diagnosis. Other tissue compo- nents  commonly  found  in  benign  cystic  teratomas  include  mature  brain,  bronchus,  thyroid,  cartilage,  intestine,  bone,  and  carcinoid  cells.  As  opposed  to  similar  tissues  found  in  a  malignant  immature  tera- toma,  the  tissues  making  up  the  benign  (mature)   teratoma are all of an adult, well-differentiated form.

Mixed Ovarian Neoplasms The  most  common  ovarian  tumor  in  which  the  neo- plastic  elements  are  composed  of  more  than  one  cell  type  is  the  cystadenofibroma,  or  the  fibrocystade- noma.  These  tumors  generally  take  their  characteris- tics  from  the  epithelial  component,  although  they   tend  to  be  more  solid  than  the  epithelial  ovarian  neoplasms.

The  gonadoblastoma  is  a  tumor  composed  of  cells  resembling  those  of  a  dysgerminoma  and  others  resembling  granulosa  and  Sertoli  cells.  Characteristi- cally,  calcific  concretions  are  a  prominent  feature  of  this neoplasm. Almost all patients with a gonadoblas- toma have dysgenetic gonads, and a Y chromosome has been detected in more than 90% of cases. Although  the  gonadoblastoma  is  initially  benign,  about  half  of  these  tumors  may  predispose  to  the  development  of  dysgerminomas or other malignant germ-cell tumors.

Diagnosis of Benign Ovarian Tumors The  clinical  features  of  benign  ovarian  tumors  are   often  nonspecific.  Except  for  the  functioning  ovarian  neoplasms,  most benign ovarian tumors are asymp- tomatic unless they are larger than 6 to 8 cm.  They 

FIGURE 20-6 Gross appearance of a cut-open dermoid cyst. Note the presence of hair-bearing skin. (From Voet RL: Color atlas of obstetric and gynecologic pathology, St Louis, 1997, Mosby.)

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gonadal  development,  as  evidenced  by  the  rudimen- tary streaked ovaries that are a hallmark of the disorder.  Women with Turner syndrome usually progress through puberty and develop secondary sexual char- acteristics, but enter menopause shortly thereafter.  This  provides  evidence  that  two  X  chromosomes  are  required  for  normal  ovarian  development.  Testicular  predominance  occurs  with  the  addition  of  a  single  Y  chromosome,  even  in  the  face  of  multiple  X  chromo- somes. Such predominance is seen in Klinefelter syn- drome (47 XXY),  in  which  testicular  development  occurs  embryologically.  In  complete androgen insen- sitivity syndrome (46 XY), which is also known as tes- ticular feminization,  the  lack  of  androgen  receptors  produces  a  phenotypic  female  in  the  face  of  a Y  chro- mosome.  The  gonads  in  these  women  (functioning  testes)  should  be  removed  (usually  after  puberty)  because of their significant malignant potential.

Benign Conditions of the Fallopian Tubes Most  benign  “tumors”  of  the  fallopian  tubes  are  inflammatory/infectious enlargements such as a fluid- filled  tube  from  previous  infection  (hydrosalpinx)  and  a  pyosalpinx  (pus-filled  tube)  from  a  more  recent  and  active infection (Figure 20-7). When the fallopian tube  and  ovary  are  involved  the  infectious  mass  is  called  a  tubo-ovarian abscess or TOA (see Chapter 22).

Benign neoplasms of the oviducts are rare. Although  the  tubes,  uterine  corpus,  and  uterine  cervix  are   from  the  same  müllerian  anlage  (primordial  tissue), 

with  preservation  of  the  ovary  can  be  performed.  In postmenopausal women, at least unilateral salpingo- oophorectomy would be appropriate.  The  contralat- eral  ovary  should  be  carefully  inspected  to  exclude  a  bilateral lesion. Because of the possible coexistence of  an  appendiceal  mucocele  with  a  mucinous  cystade- noma, appendectomy should also be performed.

Laparotomy is usually indicated if the mass is suspicious for malignancy.  Any  ascitic  fluid  should  be collected on opening the peritoneal cavity and sent  for cytologic examination. A frozen-section histologic diagnosis should be obtained intraoperatively  to  exclude  malignancy.  The  definitive  treatment  will  depend on the type of neoplasm, the patient’s age, and  her desire for future childbearing.

Stromal-cell neoplasms of the ovary are generally treated by unilateral salpingo-oophorectomy when future pregnancies are a consideration.

Cystic teratomas (“dermoids”) can be treated by ovarian cystectomy. Because 15-20% are bilateral, the  contralateral  ovary  should  be  carefully  evaluated  and  any cysts resected.

In a patient with a gonadoblastoma, dysgenetic ovaries are usually present, necessitating bilateral salpingo-oophorectomy,  particularly  in  the  presence  of  a  Y  chromosome.  With  embryo  transfer  now  avail- able to these patients, the uterus should be left in situ  if future fertility is desired.

OVARIAN REMNANT SYNDROME Ovarian remnant syndrome may be the cause of cyclic  pelvic pain and deep dyspareunia in women who have  previously  undergone  hysterectomy  with  salpingo- oophorectomy. A residual part of the ovary may be left  inadvertently and adhere to the vaginal cuff or the ret- roperitoneal  space  near  a  ureter.  Surgical  excision  of  the small mass is required to relieve the pain.

The  ovarian  remnant  syndrome  must  be  distin- guished  from  the  residual ovary syndrome.  In  the  latter,  an  ovary  is  intentionally  left  at  the  time  of  hys- terectomy  but  subsequently  causes  deep  dyspareunia  if it becomes adherent to the vaginal cuff.

Congenital Anomalies of the Ovaries Abnormal  embryologic  development  of  the  ovaries  is  uncommon.  Congenital  duplication  or  absence  of  ovarian  tissue  may  occur,  as  may  ectopic  ovarian   tissue  and  supernumerary  ovaries.  Although  rare,  the  sexual  bipotentiality  noted  in  embryologic  develop- ment can progress without the usual regression of one  system,  producing  an  ovotestis  and  subsequent  inter- sex problems.

Genetic  chromosomal  disorders,  such  as  Turner syndrome (45 XO), are associated with a lack of normal 

FIGURE 20-7 Laparoscopic photograph of a right hydrosalpinx (arrow) with the ultrasonic image (inset) of this clear fluid-filled fallopian tube that represents previous infection and inflammation. (From Hornemann A, von Koschitzky H, Bohlman MK, et al: Iso- lated pyosalpinx in a 13-year-old virgin. Fertil Steril 91:2732.e9– e10, 2009, Figure 1.)

C H A P T E R 20 Benign Conditions and Congenital Anomalies of the Ovaries and Fallopian Tubes 265

the  mass  and  can  cause  hemorrhage  into  the  mass.  With  more  prolonged  and  extensive  torsion,  the  arte- rial supply is occluded and the mass necroses.

The diagnosis may be confusing because the patient  may also have fever, nausea, vomiting, and leukocyto- sis  suggestive  of  appendicitis.  Ultrasonic  studies,  including  Doppler  color  flow  studies,  can  help  pin- point the diagnosis preoperatively, but prompt surgical  intervention is required. If the mass has not undergone  significant  necrosis,  it  may  be  untwisted.  In  some  cases, the ovary may be sutured to the pelvic side wall  to  make  recurrence  less  likely.  If  the  tube  has  under- gone significant necrosis, a unilateral salpingectomy or  salpingo-oophorectomy may be necessary.

Congenital Anomalies of the Fallopian Tubes Isolated anomalies of the fallopian tubes, the end result  of  abnormal  development  of  the  proximal  unfused  portions  of  the  paramesonephric  ducts,  are  rare.  Aplasia or atresia,  usually  of  the  distal  ampullary  segment of the fallopian tube, is most commonly uni- lateral  in  the  presence  of  otherwise  normal  develop- ment. Bilateral aplasia is noted in some cases of uterine  and vaginal agenesis. Complete duplication of the fal- lopian  tubes  is  rarely  seen,  but  distal  duplication  and  accessory ostia are relatively common.

In  addition,  women  exposed  in  utero  to  certain  drugs,  such  as  diethylstilbestrol  (DES),  may  have  abnormalities in the architecture of the fallopian tubes;  with DES exposure, the tubes may be shortened, dis- torted, or clubbed.

the  tubes  have  been  thought  to  have  less  of  a  ten- dency  toward  neoplastic  transformation.  Recent evi- dence, however, suggests that some serous “ovarian” cancers may actually arise in the fallopian tubes (see  Chapter 39).

Benign tubal neoplasms that do occur are epithelial adenomas and polyps, myomas  from  the  tubal  mus- culature,  inclusion cysts  from  the  mesothelium,  or  angiomas  from  the  tubal  vasculature.  It  is  usually  difficult  to  differentiate  a  tubal  neoplasm  from  other  adnexal masses on examination, although ultrasonog- raphy  may  identify  the  ovary  separate  from  the  mass  and  determine  its  tubal  origin.  Salpingectomy  repre- sents the definitive treatment.

As the name paraovarian (beside the ovary) implies,  paraovarian neoplasms are generally located within the broad ligament  between  the  tube  and  the  ovary.  These  tumors  are  generally  small  compared  with  ovarian  cysts,  measuring  less  than  8 cm  in  diameter.  Histologically, most appear to be derived from parame- sonephric  (müllerian)  structures  or  occasionally  from  mesonephric (wolffian) remnants. Although the malig- nancy rate is less than 10%, it is necessary to resect the  cystic mass to obtain a pathologic assessment.

Torsion either of the ovary alone or of both the ovary and fallopian tube (adnexal torsion) represents an acute surgical emergency.  Torsion  is  a  complica- tion  of  benign  ovarian  tumors,  paraovarian  cysts,  and  tubal ligation remnants. Adnexal torsion causes severe  acute,  unilateral  lower  abdominal  pain,  which  starts  often  as  less  severe  pain  alternating  with  a  dull  sore- ness.  This  pattern  results  from  intermittent  twisting  and  untwisting  of  the  mass. With  torsion,  the  venous  blood  supply  is  occluded,  which  increases  pressure  in 

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21  Pelvic Pain Acute, Cyclic (Dysmenorrhea), and Chronic

C H

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ANDREA J. RAPKIN • JOSEPH C. GAMBONE

■  Acute pelvic pain of sudden onset can be caused by both  gynecologic  and  nongynecologic  disorders.  Adnexal  accidents  such  as  rupture  or  torsion  of  ovarian  cysts,  pelvic  infections,  tubal  rupture  of  ectopic  pregnancies,  and  aborting  intrauterine  pregnancies  are  the  more  common  gynecologic  causes.  Gastrointestinal  condi- tions,  such  as  appendicitis  and  bowel  obstruction,  and  genitourinary  problems,  such  as  cystitis  and  ureteral  stones  are  the  significant  nongynecologic  causes.  Early  diagnosis  and  expeditious  treatment,  often  surgical,  are  important for safe and effective clinical management of  acute pelvic pain.

■  The most common type of cyclic pelvic pain is recurrent  painful  menstruation  or  dysmenorrhea.  Dysmenorrhea  may be primary, when caused by excessive production of  prostaglandins (PGs), mainly PGF2α, or secondary, when  an underlying condition for the pain such as adenomyo- sis  or  endometriosis  is  diagnosed.  Primary  dysmenor- rhea  occurs  in  ovulatory  cycles  and  in  younger  women  (17  to  22  years).  Other  causes  of  secondary  menstrual  and perimenstrual recurrent pain include chronic pelvic  infection,  degenerating  fibroids,  and  pelvic  congestion.  Secondary  dysmenorrhea  is  not  limited  to  pain  only  during  menses  and  typically  occurs  in  older  women   (>30 years of age).

■  Treatment  of  primary  dysmenorrhea  involves  provision  of an explanation for the cause of the pain, and reassur-

ance,  along  with  nonsteroidal  antiinflammatory  drugs  (NSAIDs),  hormonal  contraceptives  to  block  ovulation,  and  other  nonpharmaceutical  interventions  such  as  transcutaneous  nerve  stimulation  and  acupuncture.  Treatment  of  secondary  dysmenorrhea  depends  on  the  underlying cause of the pain, with NSAIDs the preferred  initial choice.

■  Chronic pelvic pain (CPP) is noncyclic pain that lasts for  more than 6 months. Like other forms of pelvic pain, CPP  has  both  gynecologic  and  nongynecologic  causes.  Chronic  pain,  including  CPP,  differs  from  acute  pain  in  several  important  and  measurable  ways.  With  acute  pain,  the  pain  perception,  suffering,  and  behavior  are  usually commensurate with the degree of sensory input.  With chronic pain, such as CPP, the suffering and behav- ioral  responses  may  be  quite  exaggerated,  and  may  persist even after the pain stimulus has remitted.

■  The  appropriate  evaluation  and  treatment  of  CPP  is  challenging.  The  most  effective  treatment  occurs  when   a  multidisciplinary  team  manages  the  patient  with  ongoing, as opposed to episodic care. Psychiatric referral  for  psychopharmacologic  therapy  may  be  needed.  This  aspect  of  therapy  is  crucial,  because  many  of  these  patients  may  be  severely  depressed  and  they  may  be  withdrawn interpersonally, sexually, and occupationally.

CLINICAL KEYS FOR THIS CHAPTER

Pelvic  pain  is  a  frequent  complaint  in  gynecology.  It  may  be  acute,  cyclic,  and  associated  with  menstrua- tion, or chronic, lasting for more than 6 months. Acute pelvic pain is sudden in onset and is usually associated  with  significant  neuroautonomic  reflexes  such  as  nausea  and  vomiting,  diaphoresis,  and  apprehension.  There are several important gynecologic and nongyne- cologic causes of acute pain.

Half of all menstruating women are affected by painful menstruation or dysmenorrhea making it the  most common type of pelvic pain. Ten percent of these  women  have  severe  symptoms  necessitating  time  off  from  work  or  school.  Chronic pelvic pain (CPP) includes reproductive and nonreproductive organ– related pelvic pain  that  is  primarily  acyclic  and  that  lasts for 6 months or more.

C H A P T E R 21 Pelvic Pain 267

or  inflammatory  enlargement  predisposes  to  these  adnexal  accidents. The  pain  of  adnexal  torsion  can  be  intermittent  or  constant,  is  often  associated  with  nausea,  and  has  been  described  as  reverse  renal  colic  because  it  originates  in  the  pelvis  and  radiates  to  the  loin. An enlarging pelvic mass is found on examination  and ultrasound, with decreased or absent blood flow to  the adnexa on Doppler-ultrasonic studies. The need for  surgical intervention is common and urgent.

Functional ovarian cysts  (e.g.,  corpus  luteal  or  fol- licular  cysts)  may rupture  causing  leakage  of  fluid  or  blood that causes acute pain from peritoneal irritation.  When there is significant associated bleeding, the pain  may be followed by a hemoperitoneum and hypovole- mia. Surgical intervention is mandatory in this setting,  after adequate resuscitation with packed red cells and  intravenous fluids.

Reproductive organ infections such as endometri- tis or salpingo-oophoritis  (commonly  referred  to  as  pelvic  inflammatory  disease  or  PID)  can present acutely. Rupture of a tubo-ovarian abscess is a surgical  emergency  that  can  progress  to  hypotension  and  oli- guria  after  initially  presenting  with  diffuse  lower  abdominal  pain.  Pelvic  infection  is  covered  in  greater  detail in Chapter 22.

Several complications of early pregnancy, such as ectopic gestation  (see  Chapter  24)  and threatened or incomplete abortion, can cause acute pelvic pain and  are  generally  associated  with  abnormal  bleeding.  Ectopic  tubal  pregnancies  produce  pain  as  the  fallo- pian  tube  dilates  and  ruptures  into  the  abdominal  cavity, and can be life-threatening when not diagnosed  expeditiously.

Nongynecologic  causes  of  acute  lower  abdominal  pain  (see  Box  21-1)  are  frequently  in  the  differential  diagnosis  when  a  woman  presents  with  pelvic  pain.  Appendicitis  is  a  common  gastrointestinal  cause  of  acute lower abdominal pain that eventually localizes to  the  right  lower  quadrant  of  the  abdomen  (McBurney  point). The unilateral intensity of the pain usually dif- ferentiates  it  from  salpingo-oophoritis.  Rupture  of  an  infected appendix into the pelvic cavity can have a sig- nificant adverse effect on female fertility and may be a  diagnostic  challenge  during  pregnancy  (see  Chapter  16).  Diverticular abscess  is  also  not  uncommon  but  usually occurs in postmenopausal women.

Acute cystitis  (see  Chapter  22)  and  ureteral stone formation  (lithiasis)  and  passage  are  both  frequently  painful.  Urethral syndrome  can  present  acutely  and  become  chronic  over  time  when  not  recognized  and  treated.  Painful  pelvic  floor  disorders  are  covered  in  more detail in Chapter 23.

Cyclic Pelvic Pain: Dysmenorrhea Dysmenorrhea  is  painful  menstruation  with  absence  of  pain,  generally,  between  menstrual  periods.  It  may 

FIGURE 21-1 Torsion of an ovarian cyst and adnexal blood vessels. Note the large clot that has formed in the adnexal area (arrow) due to obstruction of venous outflow from a left ovarian cyst. (From Clement PB, Young RH: Atlas of gynecologic surgical pathol- ogy, Philadelphia, 2000, Saunders.)

BOX 21-1

CAUSES OF ACUTE PELVIC PAIN

Gynecologic Adnexal  accidents,  e.g.,  ovarian  cyst  torsion,  rupture,  or 

hemorrhage Acute infections, e.g., endometritis or pelvic inflammatory 

disease Pregnancy  complications,  e.g.,  ectopic  gestation  or 

abortion

Nongynecologic Gastrointestinal,  e.g.,  appendicitis,  enteritis,  or  intestinal 

obstruction Genitourinary,  e.g.,  cystitis,  ureteral  stones,  or  urethral 

syndrome Other,  e.g.,  pelvic  thrombophlebitis,  vascular  aneurysm, 

or porphyria

Acute Pelvic Pain It is important for the gynecologist to be aware of both  the  gynecologic  and  nongynecologic  causes  of  acute  pelvic  pain  (Box  21-1).  Delayed  diagnosis  and  treat- ment  of  acute  pelvic  pain  may  increase  the  morbidity  and even the mortality.

Adnexal  accidents,  including  torsion or rupture of an ovarian or fallopian tube cyst  (Figure  21-1),  can  cause  severe  lower  abdominal  pain.  Normal  ovaries  and  fallopian  tubes  rarely  undergo  torsion,  but  cystic 

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normal  levels  of  prostaglandins  (especially  PGF2α  and  PGE2), and these levels can be reduced to below normal  with  nonsteroidal  antiinflammatory  drugs  (NSAIDs),  which  are  effective  treatments.  Infusions  of  PGF2α  or  PGE2 reproduce the discomfort and many of the associ- ated  symptoms  such  as  nausea,  vomiting,  and  head- ache.  Secretory  endometrium  contains  much  more  prostaglandin than proliferative endometrium. Women  with  primary  dysmenorrhea  have  upregulated  cyclo- oxygenase  (COX)  enzyme  activity  as  a  major  cause  of  their  pain.  Anovulatory endometrium (without pro- gesterone) contains little prostaglandin, and these menses are usually painless. The thin endometrium in women using hormonal contraceptives also exhib- its decreased prostaglandin synthesis.

Figure  21-2  summarizes  the  relationships  among  endometrial  cell  wall  breakdown,  prostaglandin  syn- thesis, uterine contractions, ischemia, and pain.

Clinical Features The  clinical  features  of  primary  dysmenorrhea  are  summarized  in  Box  21-2.  Cramping  usually  begins  a  few hours before the onset of bleeding and may persist  for hours or days. It is localized to the lower abdomen 

be primary when there is no readily identifiable cause,  or secondary to organic pelvic disease. The typical age  range  of  occurrence  for  primary  dysmenorrhea  is  between 17 and 22 years, whereas secondary dysmen- orrhea  is  more  common  in  older  women  (>30  years  of age).

PRIMARY DYSMENORRHEA Pathophysiology Primary dysmenorrhea occurs during ovulatory cycles and usually appears within 6 to 12 months of the menarche. The etiology of primary dysmenorrhea  has  been  attributed  to  uterine  contractions  with   ischemia  and  production  of  prostaglandins.  Women  with  dysmenorrhea  have  increased  uterine  activity,  which results in increased resting tone, increased con- tractility,  and  increased  frequency  of  contractions.  During menstruation, prostaglandins are released as a  consequence  of  endometrial  cell  lysis,  with  instability  of lysosomes and release of enzymes which break down  cell membranes.

The evidence that prostaglandins are involved in primary dysmenorrhea is convincing.  Menstrual  fluid  from  women  with  this  disorder  has  higher  than 

FIGURE 21-2 Postulated mechanism of pain generation in primary dysmenorrhea. Nonsteroidal antiinflammatory drugs inhibit cyclooxy- genase, the enzyme that catalyzes the formation of prostaglandins from arachidonic acid. Hormonal contraceptives that block ovulation significantly reduce the formation of prostaglandins. Both drugs can mitigate this mechanism of pain and are effective treatment for primary dysmenorrhea. (Modified from Dawood MY: Hormones, prostaglandins and dysmenorrhea. In Dawood MY, editor: Dysmenorrhea, Baltimore, 1981, Williams & Wilkins.)

Corpus luteum

(regression)

1 Progesterone

2

(Menstrual flow)

↑ Prostaglandins +

Endoperoxides +

Metabolite

3 Increased myometrial contractions

5 PAIN (a)↑Uterine activity (b) Uterine ischemia (c) Sensitization of nerve terminals to prostaglandins and endoperoxides

4

Reduced blood flow (ischemia)

C H A P T E R 21 Pelvic Pain 269

and are also effective therapy for primary dysmen- orrhea.  Extended  cycle  use  of  OCs  or  the  use  of  long-acting  injectable  or  implantable  hormonal   contraceptives  or  progestin-containing  intrauterine  devices minimizes the number of withdrawal bleeding  episodes  that  users  have.  Some  patients  may  benefit  from using both hormonal contraception and NSAIDs.

Resistant  cases  may  respond  to  high  dose  continu- ous daily progestogens (especially medroxyprogester- one acetate  or  dydrogesterone).  Nonpharmacologic  pain management, particularly acupuncture or trans- cutaneous electrical stimulation (TENS) may be useful, as is psychotherapy, hypnosis, and heat patches.  Surgical  procedures  such  as  presacral neu- rectomy and uterosacral ligament section have been largely abandoned.

If a patient fails to respond to hormonal contracep- tion and NSAID therapy, the diagnosis of primary dys- menorrhea  should  be  questioned,  and  consideration  given  to  a  secondary  cause.  Ultrasonic  imaging,  lapa- roscopy,  and  possibly  hysteroscopy  should  be  per- formed to exclude pelvic disease.

SECONDARY DYSMENORRHEA Pathophysiology The  mechanism  of  pain  in  secondary  dysmenorrhea  depends  on  the  underlying  (secondary)  cause  and  in  most cases is not well understood. Prostaglandins may  also be involved in this type of dysmenorrhea, although  NSAIDs and hormonal contraceptives that do not sup- press menses altogether are less likely to provide satis- factory pain relief.

Clinical Features The clinical features of some of the underlying causes  of  secondary  dysmenorrhea  are  summarized  in  Box  21-4. In general, secondary dysmenorrhea is not limited  to  the  menses,  and  can  occur  up  to  2  weeks  before  as  well as up to a week after the menses. In addition, sec- ondary dysmenorrhea is less related to the first day of  flow, develops in older women (in their 30s or 40s), and  is usually associated with other symptoms such as dys- pareunia, infertility, or abnormal uterine bleeding.

Treatment Management consists of the treatment of the underly- ing disease. The treatments used for primary dysmen- orrhea are often helpful. Other specific treatments are  discussed  in  the  chapters  dealing  with  the  underlying  causes.

Chronic Pelvic Pain CPP refers to pelvic pain of more than 6 months’ duration that has a significant effect on daily function and quality of life.  CPP  includes  reproductive  and  nonreproductive  organ–related  pain.  Although  CPP  is 

and may radiate to the thighs and lower back. The pain  may  be  associated  with  altered  bowel  habits,  nausea,  fatigue, dizziness, and headache.

Treatment NSAIDs, which act as COX inhibitors, are highly effective in the treatment of primary dysmenorrhea  (Box 21-3). Typical examples include ibuprofen (400 to  600 mg  every  6  to  8  hours),  naproxen sodium  (250  to  500 mg  every  8  hours),  and  mefenamic acid  (500 mg  every  8  hours).  Decreasing  prostaglandin  production  by  enzyme  inhibition  is  the  basis  of  all  NSAIDs.  Pain  relief  is  better  if  NSAIDs  are  started  2  to  3  days  before  menstrual flow. Hormonal contraceptives, such as oral contraceptive pills (OCs), patches, or transvaginal rings, reduce menstrual flow and inhibit ovulation

BOX 21-3

TREATMENT OF PRIMARY DYSMENORRHEA

General Measures Reassurance and explanation

Medical Measures Nonsteroidal antiinflammatory drugs Hormonal  contraceptives  (including  hormone-releasing 

intrauterine devices and vaginal rings) Progestins Analgesics

Other Measures Transcutaneous nerve stimulation Acupuncture Psychotherapy Hypnotherapy

BOX 21-2

FEATURES OF PRIMARY DYSMENORRHEA

Initial Onset 90%  experience  symptoms  within  2  years  of  menarche 

(i.e., when ovulation begins).

Duration and Type of Pain Dysmenorrhea begins a few hours before or just after the 

onset of menstruation and usually lasts 48-72 hours. Pain  is  described  as  cramp-like  and  is  usually  strongest 

over  the  lower  abdomen,  but  may  radiate  to  the  back  or inner thighs.

Associated Symptoms Nausea and vomiting Fatigue Diarrhea Lower backache Headache

Pelvic Examination Normal findings

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TABLE 21-1

NERVES CARRYING PAINFUL IMPULSES FROM THE PELVIC ORGANS

Organ Spinal Segments Nerves

Perineum, vulva, lower vagina S2-4 Pudendal, inguinal, genitofemoral, posterofemoral cutaneous

Upper vagina, cervix, lower uterine segment, posterior urethra, bladder trigone, uterosacral and cardinal ligaments, rectosigmoid, lower ureters

S2-4 Pelvic parasympathetics

Uterine fundus, proximal fallopian tubes, broad ligament, upper bladder, cecum, appendix, terminal large bowel

T11-12, L1 Sympathetics via hypogastric plexus

Outer two-thirds of fallopian tubes, upper ureter T9-10 Sympathetics via aortic and superior mesenteric plexus

Ovaries T9-10 Sympathetics via renal and aortic plexus and celiac and mesenteric ganglia

Abdominal wall T12-L1 Sympathetics via renal and aortic plexus and celiac and mesenteric ganglia

T12-L1 Iliohypogastric T12-L1 Ilioinguinal L1-2 Genitofemoral

BOX 21-4

CHARACTERISTICS OF SOME CAUSES OF SECONDARY DYSMENORRHEA

Endometriosis Pain  extends  to  premenstrual  or  postmenstrual  phase  or  may be continuous; may also have deep dyspareunia, pre- menstrual spotting, a fixed retroverted uterus, and tender  pelvic  nodules  (especially  on  the  uterosacral  ligaments);  onset  is  usually  in  the  20s  and  30s  but  may  start  in  the  teens.

Pelvic Inflammation Initially pain may be menstrual, but often with each cycle  it  extends  into  the  premenstrual  phase;  may  have  inter- menstrual bleeding, dyspareunia, and pelvic tenderness.

Adenomyosis, Fibroid Tumors Uterus  is  generally  symmetrically  enlarged  and  may  be  mildly  tender;  dysmenorrhea  is  associated  with  a  dull  pelvic  dragging  sensation;  hypermenorrhea  and  dyspa- reunia may be present.

Ovarian Cysts (Especially Endometriosis and Luteal Cysts) Should be clinically evident.

Pelvic Congestion A dull, ill-defined pelvic ache, usually worse premenstru- ally, relieved by menses; not all investigators agree that this  is a cause of chronic pelvic pain.

an  enigmatic  disorder,  it  is  one  of  the  most  common  presenting  complaints  in  a  gynecologic  practice.  As a public health problem, it results in great cost to society in terms of hospital services, loss of produc- tivity, and human misery.

Obviously,  not  all  lower  abdominal  and  low  back  pains  are  of  gynecologic  origin.  Careful evaluation is needed to distinguish gynecologic pain from that of orthopedic, gastrointestinal, urologic, neurologic, and psychosomatic origin.  The  relationship  between  pelvic  pain  and  the  underlying  gynecologic  pathology  is often inexplicable, and frequently the pain is thought  to be psychosomatic.

Anatomy and Physiology The  innervations  of  the  pelvic  organs  that  convey  information  related  to  pain  are  shown  in  Table  21-1.  Painful  impulses  that  originate  in  the  skin,  muscles,  bones, joints, and parietal peritoneum travel in somatic  nerve  fibers,  whereas  those  originating  in  the  internal  organs travel in visceral nerves.

Visceral pain is more diffusely spread than somatic pain because of a phenomenon called viscerosomatic convergence, and the lack of a well-defined projection area in the sensory cortex for its identification.  Vis- cerosomatic  convergence  occurs  in  all  second-order  neurons  in  the  dorsal  horn  of  the  spinal  cord  that  receive visceral input. No second-order neurons in the  dorsal horn receive only visceral input. The visceroso- matic neurons have larger receptive fields than do the  somatic  second-order  neurons. Visceral  pain  is  there- fore  usually  referred  to  the  skin,  which  is  supplied  by  the corresponding spinal cord segment (referred pain).  For example, the initial pain of appendicitis is referred  to  the  epigastric  area  because  the  affected  structures  are  innervated  by  the  thoracic  cord  segments  T8,  T9,  and T10.

The  structures  of  the  female  genital  tract  vary   in  their  sensitivity  to  pain.  The  skin  of  the  external  

C H A P T E R 21 Pelvic Pain 271

The abdominal wall should be examined for evidence of myofascial trigger points and for iliohy- pogastric (T12, L1), ilioinguinal (T12, L1), or genito- femoral (L1, L2) nerve entrapment. Each dermatome  of  the  abdominal  wall  and  back  should  be  palpated  with  a  fingertip  and  points  of  severe  tenderness  or  “jump signs” should be marked with a pen. The patient  should  be  asked  to  tense  the  abdominal  muscles  by  performing  a  straight-leg  raising  maneuver  (both  legs  raised  at  least  6  inches  with  both  knees  straight)  or  a  partial sit-up. Points that are more tender or that repro- duce  the  patient’s  pain  suggest  nerve  entrapment,  impingement,  or  a  muscular  trigger  point  pain. These  points should be injected with 2 to 3 mL of 0.25% bupi- vacaine.  Chronic  abdominal  wall  pain  is  confirmed  if  the  pain  level  is  reduced  by  at  least  50%  and  outlasts  the duration of the local anesthetic.

A thorough pelvic examination should be per- formed, with an attempt made to reproduce and localize the patient’s pain. The examination should be performed gently  so  as  to  prevent  involuntary  guard- ing, which may obstruct the findings. The examination  may  be  suggestive  of  specific  pelvic  pathology.  For  example, patients with endometriosis may have a fixed  retroverted  uterus  with  tender  uterosacral  nodularity.  An adnexal mass may suggest ovarian pathology. Bilat- eral,  tender,  irregularly  enlarged  adnexal  structures  may  suggest  prior  salpingitis  with  subsequent  forma- tion  of  adhesions  and  bilateral  hydrosalpinges.  A  pro- lapsed uterus may account for pelvic pressure, pain, or  low backache.

FURTHER INVESTIGATIONS Psychological  evaluation  should  be  requested  if  an  obviously traumatic event has occurred with the onset  of pain; if there is obvious depression, anxiety, catastro- phizing,  psychosis,  or  secondary  gain;  or  to  aid  in  the  planning  of  pain  management  sessions.  The  latter   may  involve  cognitive  behavioral  and  stress  reduction  therapy.

Laboratory studies are of limited value in the diag- nosis of CPP, although a complete blood count, eryth- rocyte  sedimentation  rate  (ESR),  and  urinalysis  are  indicated. The ESR is nonspecific and will be increased  in  any  type  of  inflammatory  condition,  such  as  sub- acute  salpingo-oophoritis,  tuberculosis,  or  inflamma- tory bowel disease. Patients who are engaging in sexual  intercourse should have a pregnancy test if they have a  uterus  and  are  not  postmenopausal.  Pelvic ultraso- nography  should  be  performed  because  the  pelvic  examination may miss an adnexal mass, particularly in  obese  patients  or  in  those  who  are  unable  to  relax.  Routine urine analysis and studies to rule out sexually  transmitted infections are indicated depending on the  patient’s symptoms and risk factors. If bowel or urinary  symptoms are present, an abdominal and pelvic com- puted  tomographic  (CT)  scan,  endoscopy,  cystoscopy, 

genitalia is exquisitely sensitive. Pain sensation is vari- able  in  the  vagina,  and  the  upper  vagina  is  somewhat  less  sensitive  than  the  lower.  The cervix is relatively insensitive to small biopsies but is sensitive to deep incision or to dilation.  The  uterus  is  quite  sensitive.  The  ovaries  are  insensitive  to  many  stimuli,  but  they  are sensitive to rapid distention of the ovarian capsule  or compression during physical examination.

Patient Evaluation HISTORY A pain history should be obtained during the first visit.  Characteristics  of  the  pain  should  be  determined,  including  its  location,  radiation,  severity,  alleviating  and  aggravating  factors,  as  well  as  the  effects  of  men- struation,  level  of  stress,  work,  exercise,  and  inter- course.  Symptoms  related  to  the  gastrointestinal,  genitourinary, musculoskeletal, and neurologic systems  should  be  ascertained. This  process  can  be  guided  by  the Pain History Mnemonic outlined in Box 21-5.

PHYSICAL EXAMINATION The abdomen should be examined initially, and the patient should be asked to point to the exact location of the pain  and  its  radiation.  An  attempt  should  be  made to duplicate the pain by palpating each abdomi- nal quadrant. The severity of the pain should be quan- tified on a 0 to 10 scale (0 = no pain, 10 = hitting thumb  with a hammer).

Modified from Rapkin AJ, Howe CN: Chronic pelvic pain: a review. In Family practice recertification, Monroe Township, NJ, 2006, Medical World Communications, 28:59-67.

BOX 21-5

PAIN HISTORY MNEMONIC (OLD CAARTS)

Onset: When  and  how  did  the  pain  start?  Does  it  change  over time?

Location:  Localize  specifically—can  the  woman  put  a  finger on it?

Duration: How long does it last? Characteristics: e.g., cramping, aching, stabbing, itching Alleviating/aggravating factors:  What  makes  it  better 

(e.g., change of position, medication, stress reduction)  or  worse  (e.g.,  menstrual  cycle,  stress,  specific  activity)?

Associated symptoms: Gynecologic (e.g., dyspareunia, dysmenorrhea, abnor-

mal bleeding, discharge) Gastrointestinal (e.g., constipation, diarrhea, bloating, 

gas, rectal bleeding) Genitourinary  (e.g.,  urinary  frequency,  dysuria, 

urgency, incontinence) Neurological (specific nerve distribution of the pain)

Radiation: Does the pain move to other areas of the body? Temporal: Time of day and relationship to daily activities Severity:  On  a  scale  of  0  to  10  (from  no  pain  to  the  most 

severe imaginable)

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from  the  acute  infection.  It  is  also  thought  that  prior  PID  may  lead  to “upregulation”  of  sensory  processing  from  the  previously  inflamed  tissue.  Persistent  active  infection  is  called  acute  PID,  even  if  fever  and  perito- neal  signs  are  absent.  Recurrent  active  infections  that  require antibiotic therapy must be ruled out. PID is also  discussed in Chapter 22.

Before ascribing symptoms to adhesions, one must have specifically noted adhesions in the area of pain localization,  because  most  patients  with  extensive  pelvic adhesions discovered incidentally during surgery  for other reasons are asymptomatic.

Ovarian Pain Ovarian  cysts  are  usually  asymptomatic,  but  episodic  pain  may  occur  secondary  to  rapid  distention  of  the  ovarian capsule or rupture or leakage of irritating fluid  into  the  peritoneal  cavity.  An ovary or an ovarian remnant may occasionally become retroperitoneal secondary to inflammation or previous surgery, and cyst formation in these circumstances may be painful.  Some women, for unknown reasons, may develop mul- tiple  recurrent  functional  hemorrhagic  ovarian  cysts  that seem to cause pelvic pain and dyspareunia on an  intermittent basis.

Hormonal  suppression  of  ovulation  is  usually  an  effective treatment for painful functional cysts. The dif- ferential  diagnosis  of  ovarian  masses  is  covered  in  Chapter  20.  An  ovarian  cyst  may  also  be  an  endome- trioma, and if an endometrioma is suspected based on  history,  physical  examination,  and  ultrasonography,  surgical excision is usually indicated. Other benign and  malignant  ovarian  neoplasms  can  contribute  to  CPP,  but  are  often  asymptomatic.  A  benign  cystic  teratoma  (dermoid)  for  example  can  intermittently  twist  and  untwist, causing repeated episodes of subacute pain.

Uterine Pain Adenomyosis  (or  endometriosis  interna)  can  cause  dysmenorrhea,  dyspareunia,  and  menorrhagia,  but  rarely does it cause chronic daily intermenstrual pain.  Uterine myomas usually do not cause pelvic pain unless they are degenerating, undergoing torsion (twisting on their pedicles), or compressing pelvic nerves. A completely submucous leiomyoma can attempt to deliver via the cervix, which may cause considerable crampy uterine pain akin to childbirth.  This  is  generally  associated  with  heavy  vaginal  bleed- ing. During pregnancy, uterine myomas can cause pain  from rapid growth or infarction.

Pelvic pain is not likely to be caused by variations in  uterine position, but deep dyspareunia may occasion- ally be associated with uterine retroversion,  espe- cially when the uterus is fixed in place by adhesions or  endometriosis. The pain has been ascribed to irritation  of  pelvic  nerves  by  the  stretching  of  the  uterosacral  ligaments  as  well  as  to  congestion  of  pelvic  veins 

or CT urogram may be useful. Similarly, if there is clini- cal evidence of musculoskeletal disease, a lumbosacral  x-ray film, CT scan, magnetic resonance imaging (MRI)  scan, or orthopedic consultation may be in order.

Diagnostic laparoscopy is the ultimate method of diagnosis for patients with CPP of undetermined eti- ology. Laparoscopic examination and bimanual exam- ination  may  differ  in  20-30%  of  cases.  Laparoscopy  should  only  be  performed  if  no  etiology  for  the  pain  can  be  identified,  or  when  indicated  to  treat  specific  pathology.

Differential Diagnosis CAUSES OF CHRONIC PELVIC PAIN Of  women  with  CPP  who  are  subjected  to  diagnostic  laparoscopy,  approximately  a  third  have  no  apparent  pathology,  a  third  have  endometriosis,  somewhat  less  than the remaining third have adhesions or stigmata of  past  pelvic  inflammatory  disease  (PID),  and  the  small  remainder have other causes (Box 21-6).

Endometriosis Endometriosis  may  be  missed  visually  at  the  time  of  diagnostic laparoscopy in as many as 20-30% of women  who  have  histologically  proven  disease,  so  it  is  justifi- able  to  initiate  hormonal  treatment  based  on  a  pre- sumptive diagnosis of the disease once other etiologies  have  been  ruled  out.  Current  hormonal  therapies   are  often  very  effective  and  may  preclude  the  need   to  undergo  a  costly  surgical  procedure  that  is  not  without risk.

The size and location of the endometriotic implants do not appear to correlate with the presence of pain,  and  the  reasons  for  the  pain  are  not  fully  understood,  although prostaglandins, cytokines, and innervation of  lesions  have  been  hypothesized.  Endometriosis  is  covered more extensively in Chapter 25.

Chronic Pelvic Inflammatory Disease Chronic PID may cause pain because of anatomic dis- tortions  (hydrosalpinges  and  adhesions  between  the  tubes,  ovaries,  and  intestinal  structures)  that  result 

BOX 21-6

GYNECOLOGIC CAUSES OF CHRONIC PELVIC PAIN

Endometriosis Salpingo-oophoritis (pelvic inflammatory disease) Ovarian remnant syndrome Pelvic congestion syndrome Cyclic pelvic (uterine) pain Myomata uteri (degenerating) Adenomyosis Adhesions

C H A P T E R 21 Pelvic Pain 273

syndrome.  Red  flags  for  a  possible  gastrointestinal  malignancy  include  onset  of  pain  over  age  50,  family  history  of  bowel  cancer,  blood  in  the  stool,  nocturnal  pain, and alteration of stool caliber.

Neuromuscular Pain Pain of neuromuscular origin, which is experienced as  low back pain or abdominal wall pain, usually increases  with  activity  and  stress. Trigger  points  and  myalgia  of  the abdominal wall and pelvic floor muscles can cause  pelvic pain, vulvodynia, and dyspareunia. Chronic low back pain without lower abdominal pain is seldom of gynecologic origin. Fibromyalgia, or generalized myo- fascial pain syndrome can also cause pelvic pain. Occa- sionally,  neuromuscular  symptoms  are  accompanied  by a pelvic mass on examination or diagnostic imaging,  and  surgical  exploration  may  reveal  a  neuroma,  sarcoma,  or  bony  tumor.  Entrapped  or  compressed  nerves  in  the  abdominal  wall  (iliohypogastric  and   ilioinguinal  nerves  most  commonly)  or  pelvic  floor  (pudendal  nerve)  are  often  unrecognized  sources  of  pain. The nerves may become entrapped after surgery,  physical  trauma,  pregnancy  and  delivery,  or  occupa- tional injury.

PSYCHOLOGIC FACTORS A  pathologic  diagnosis  may  not  be  made  in  approxi- mately  one  third  of  patients  with  CPP,  even  after   laparoscopy.  This  has  led  to  the  postulation  that   psychological factors  may  be  primary.  When sub- jected to the Minnesota Multiphasic Personality Inventory (MMPI), these patients have shown a greater degree of anxiety, hypochondriasis, and hys- teria than control subjects. The profiles are similar, however, in patients who have chronic pain with organic pathology, indicating that chronic pain per se engenders a complex, debilitating, psychological response.  Patients  with  chronic  pain,  with  or  without  anatomic  pathology,  tend  to  feel  depressed,  anxious,  fearful,  helpless,  and  passive.  They  withdraw  from  social and sexual activity and are overwhelmed by pain  and  suffering.  Many  have  post-traumatic  stress  disor- der (PTSD) from emotional, physical, or sexual trauma.  Women with CPP are also at risk of developing chronic fatigue syndrome. Women with depression, anxiety, or  PTSD  must  be  treated  with  psychological  and/or  psy- chopharmacological therapy as part of the multidisci- plinary management of their CPP.

Pain Perception Factors Chronic  pain  is  characterized  by  neurophysiological,  emotional, and behavioral responses that are different  from those of acute pain. Both acute and chronic pain  involve  a  stimulus  and  a  psychic  response;  for  acute  pain,  these  responses  may  be  adaptive  and  appropri- ate, whereas for chronic pain this may not be the case.  The response to chronic pain may be greatly affected

secondary to retroversion. The dyspareunia is typically  worse  during  intercourse  in  the  missionary  position  and  is  improved  in  the  female  superior  position.  A  tender  uterus  that  is  in  a  fixed  retroverted  position  usually  signifies  other  intraperitoneal  pathology,  such  as  endometriosis  or  PID,  and  diagnosis  rests  on  lapa- roscopic findings.

Pelvic Congestion Syndrome The  concept  of  a  pelvic  congestion  syndrome  still  has  many  proponents.  This entity has been described in multiparous women who have pelvic vein varicosities and congested pelvic organs. The pelvic pain is worse  premenstrually  and  is  increased  by  fatigue,  standing,  and sexual intercourse. Many women with this condi- tion are noted to have a mobile, retroverted, soft, boggy,  and slightly enlarged uterus. There may be associated menorrhagia and urinary frequency.  Dilated  veins  may be seen on pelvic MRI with contrast. Factors other  than venous congestion may be involved in the genesis  of  pain,  because  most  women  with  pelvic  varicosities  have  no  pain.  Surgery  for  this  condition,  consisting  of  hysterectomy and oophorectomy, may be beneficial for women who have completed their families,  as  is  ovarian  hormonal  suppression  (decreased  blood  flow  to the pelvic organs) and cognitive behavioral therapy.  A few uncontrolled studies have suggested that embo- lization of involved veins by an interventional radiolo- gist may be helpful.

Genitourinary Pelvic Pain A variety of genitourinary problems may result in CPP.  Urethral syndrome, trigonitis, and interstitial cystitis/ painful bladder syndrome are prime examples. Urinary urgency, frequency, nocturia, and midline pelvic pain may suggest interstitial cystitis/painful bladder syndrome.  A  thorough  genitourinary  evalua- tion  is  an  important  part  of  the  workup  for  CPP  when  the  above  symptoms  are  reported.  As  many  as  one  in  five  women  have  interstitial  cystitis/painful  bladder  syndrome (see Chapter 23).

Gastrointestinal Pain Gastrointestinal sources of CPP include penetrating neoplasms of the gastrointestinal tract, irritable bowel syndrome, functional abdominal pain syn- drome (FAPS), celiac disease, partial bowel obstruc- tion, inflammatory bowel disease, diverticulitis, and hernia formation.  Because  the  innervation  of  the  lower  intestinal  tract  is  the  same  as  that  of  the  uterus  and fallopian tubes, pelvic pain may be confused with  pain of gynecologic origin. Irritable bowel syndrome is  the most common gastrointestinal cause of pelvic pain.  Pain  that  is  present  at  times  of  alteration  of  form  or  frequency  of  bowel  movements,  increased  before  and  improved  after  a  bowel  movement,  and  especially  if  worse  with  stress  and  eating,  may  be  irritable  bowel 

PA R T 3 Gynecology274

mechanisms of pain production (including central nervous system factors), symptomatic therapy should be undertaken. The symptoms of pain should be approached with the seriousness and direction afforded to any other condition.

THE MULTIDISCIPLINARY TEAM The most productive strategy for the management of patients with CPP is a multidisciplinary approach.  The  personnel  should  include  a  gynecologist,  a  psy- chologist who also has expertise in chronic pain, sexual  and  marital  counseling,  a  physical therapist  with  pelvic  floor  muscle  expertise,  and  for  more  complex  cases requiring diagnostic or therapeutic nerve blocks,  an  anesthesiologist.  An  acupuncturist  may  also  be  a  useful  referral.  It  is  the  role  of  the  psychologist  to  provide  cognitive  behavioral  pain  management  and  stress  reduction,  assertiveness  training,  and  adaptive  coping  strategies,  as  well  as  marital  and  sexual  coun- seling.  Psychiatric  referral  for  psychopharmacologic  therapy  may  be  needed.  This  aspect  of  therapy  is  crucial,  because  many  of  these  patients  have  become  severely  depressed  and  often  withdrawn  interperson- ally,  sexually,  and  occupationally.  Depression  may  be  secondary to pain, but without treatment of the depres- sion,  the  pain  may  persist.  Relaxation, cognitive and behavioral therapies are employed to replace the pain behavior and its secondary gain with effective behavioral responses. Multidisciplinary manage- ment has been shown to be more effective than tradi- tional gynecologic management.

MEDICAL AND SURGICAL MANAGEMENT The  gynecologist  continues  to  assess  progress,  coor- dinate  care,  and  provide  periodic  gynecologic  exami- nations.  In the initial stages of therapy, a trial of ovulation and or menstrual suppression with combined hormonal contraception (pills, patches, rings; cyclic or continuous), high-dose or intrauter- ine progestins or a gonadotropin-releasing hormone analogue (GnRH-a) may be helpful. Ovulation and/or  menstrual suppression is especially helpful in patients  who  have  midcycle,  premenstrual,  or  menstrual   exacerbation  of  pain,  or  in  those  who  have  ovarian  pathology,  such  as  periovarian  adhesions  or  recurrent  functional  cyst  formation.  NSAIDs are also useful.  Pharmacologic  approaches  to  increase  inhibitory   neuromodulators  such  as  norepinephrine,  serotonin  (5-HT),  and  GABA  or  sodium  channel  blockers  are   frequently  used  in  the  form  of  tricyclic  antidepres- sants,  selective  serotonin  reuptake  inhibitors  (SSRIs),  anticonvulsants  or  other  GABA-ergic  agents,  and  topical  or  injectable  local  anesthetics.

Surgical procedures that have not proved to be effective for CPP without pathology include unilat- eral adnexectomy for unilateral pain or total abdomi- nal hysterectomy, presacral neurectomy, or uterine

by operant conditioning. The patient’s reaction to pain and the reaction of significant others to the patient and her pain may be so reinforcing that the behavior may persist even after the painful stimulus has resolved. With acute pain, the pain perception, suf- fering,  and  behavior  are  usually  commensurate  with  the  degree  of  sensory  input.  In chronic pain, the suf- fering and behavioral responses to a given sensory input may be quite exaggerated and may persist even after the stimulus has remitted.

Modulation of Sensation Pain impulses are subjected to a large amount of mod- ulation  en  route  to,  and  within,  the  central  nervous  system.  The first synapse in the dorsal horn is an important focus of enhancement, inhibition, or facil- itation. Modulation of sensations may also occur within the spinothalamic system, the descending inhibitory neurosystems, the frontal cortex, and other brain regions.  Various  neurotransmitters  and  neuromodulators are present in the dorsal horn and at  higher levels of the neuraxis. Some excitatory modula- tors include substance P, glutamate, aspartate, calcito- nin  gene–related  peptide  (CGRP),  and  vasoactive  intestinal  peptide  (VIP).  Inhibitory  neuromediators  include endogenous opioid peptides, norepinephrine,  serotonin,  and  γ-aminobutyric  acid  (GABA).  Nerve  axons  that  have  been  compromised  after  inflamma- tion,  stretch,  or  crush  injury  can  develop  abnormal  sodium  channels.  These  changes  play  an  important  role in the development of allodynia (pain with gentle  touch) and hyperalgesia (pain with stimuli that are not  normally painful) in many women with CPP.

Within this context, anxiety, loss of self-efficacy, fear of pain, depression, and other psychological states are also considered to be facilitators or inhibi- tors of neurologic transmission.  It  is  possible  that  many  forms  of  CPP  may  result  from  modulation  of  afferent  impulses  (upregulation)  or  abnormality  of  descending  inhibition  in  the  dorsal  horn,  spinal  cord,  or brain.

Management When treating patients with CPP, a therapeutic, sup- portive, and sympathetic (but structured) physician- patient relationship should be established.  The  patient  should  be  given  regular  follow-up  appoint- ments,  and  should  not  be  told  to  call  only  if  the  pain  persists.  This  reinforces  pain  behavior  as  a  means  of  procuring sympathy and medical attention.

A  negative  evaluation  or  pathological  findings  not  amenable  to  therapy  (e.g.,  dense  pelvic  adhesions)  does  not  mean  that  the  patient  should  be  discharged  from  care  without  therapy  directed  toward  her  symp- toms. After initial reassurance that there is no serious underlying pathology and education as to the likely

C H A P T E R 21 Pelvic Pain 275

either  in  the  lower  abdominal  wall,  lower  back,  or  the  vagina.  A significant percentage of patients with pelvic pain have abdominal wall trigger points or nerve entrapments that respond to weekly or biweekly injections of a local anesthetic (usually up to five injections is sufficient) combined with alterations of activity or modification of behaviors that affect the area of pain. Injection of local anesthetic into myofas- cial  trigger  points  (Figure  21-3)  may  abolish  pain  by  lowering  the  impulses  from  the  area  of  referred  pain,  thereby diminishing the afferent impulses reaching the  dorsal  horn  to  a  level  below  the  threshold  for  pain  transmission (but the exact mechanism is not known).  Repeated  local  anesthetic  nerve  blocks  of  areas  of  nerve  impingement/entrapment  combined  with  instructions  to  patients  about  alteration  in  physical  activity  and  or  physical  therapy  can  be  helpful.  Along  with nerve threshold altering medications, these inter- ventions  can  down  regulate  neural  hypersensitivity  and permanently decrease or eliminate pain.

suspension for generalized pelvic pain.  Lysis  of  adhesions is also usually nonproductive, with the pos- sible exception of the situations where the site of adhe- sions,  as  visualized  by  the  laparoscope,  specifically  coincides with the localization of pain. However, pelvic  adhesions often recur following surgical lysis. Without proof of organic pathology or a reasonable functional explanation for the pelvic pain, a thorough psychoso- matic evaluation should be carried out before any surgical procedure is considered.

INJECTION THERAPIES Acupuncture, nerve blocks, and trigger-point injec- tions of local anesthetics may provide prolonged pain relief. Acupuncture has been used successfully for dys- menorrhea,  and  trigger-point  injections  and  nerve  blocks  with  local  anesthetics  have  been  used  success- fully  for  neuropathic  and  musculoskeletal  pain.  Acu- puncture  probably  increases  spinal  cord  endorphins.  In  women  with  CPP,  trigger  points  are  typically  found 

FIGURE 21-3 Trigger point injection technique for the abdominal wall for a patient with chronic pelvic pain. (From Auerbach PS: Wilder- ness medicine, ed 5, Philadelphia, 2007, Mosby.)

Skin surface view

Trigger point

Trigger point surface location

Skin

Subcutaneous tissue

Muscle

Lateral view

Syringe/needle

4-QUADRANT INJECTION TECHNIQUE

276

22  Infectious Diseases of the Female Reproductive and Urinary Tract

C H

A P

T ER

BASSAM H. RIMAWI • DAVID E. SOPER

■  Bacterial  vaginosis  (BV )  is  caused  by  an  alteration  of  normal  vaginal  bacterial  flora  that  results  in  the  loss   of  hydrogen  peroxide-producing  lactobacilli,  thereby  allowing  an  overgrowth  of  predominantly  anaerobic   bacteria.  Women  with  BV  are  at  increased  risk  for   pelvic  inflammatory  disease  (PID)  and  postabortal  and  postoperative  infection.  Trichomonas  vaginitis,  caused  by a flagellated parasite, is another sexually transmitted  infection  (STI)  that  often  accompanies  BV.  Both  are  treated with metronidazole.

■  PID is caused by microorganisms that colonize the endo- cervix  and  ascend  into  the  uterine  lining  and  fallopian  tubes.  Sexually  transmitted  Neisseria gonorrhoeae  and  Chlamydia trachomatis  are  the  two  most  common  causes  of  PID.  Traditionally,  the  diagnosis  of  PID  has  been  based  on  the  triad  of  symptoms  and  signs:  pelvic  pain,  cervical  and  adnexal  tenderness,  and  fever.  Many  women  have  more  subtle  and  mild  symptoms  that  may  delay  the  diagnosis.  Treatment  of  PID  is  with  broad- spectrum  antibiotics  on  an  outpatient  basis.  Any   sexual partner(s) should be evaluated and treated. A pos- sible  end-stage  development  of  PID  is  tubo-ovarian  abscess(es) that requires hospitalization.

■  Genital  ulcer  disease  is  usually  caused  by  herpes  simplex virus (HSV ) or syphilis, with chancroid, lympho- granuloma  venereum  (LGV ),  and  granuloma  inguinale  as  rare  causes.  Genital  warts,  caused  by  the  sexually  transmitted human papillomavirus (HPV ), are common  and  treated  by  removal/destruction.  Infection  with   HPV  types  6,  11,  16,  and  18  can  be  prevented  by  vaccination.

■  Cystitis  and  pyelonephritis  are  infections  of  the  urinary  tract, with Escherichia coli the causative bacteria 80% of  the  time.  Pyelonephritis  during  pregnancy  is  associated  with premature labor and delivery when not treated in a  timely manner.

■  Infections  during  pregnancy  include  chorioamnionitis  (also  called  intraamniotic  infection  syndrome  or  IAIS),  postpartum endometritis, and postabortal sepsis. IAIS is  an ascending infection caused by highly virulent organ- isms  such  as  Group-B  streptococcus.  IAIS  can  interfere  with  labor  and  should  be  treated  before  delivery.  Hepa- titis, human immunodeficiency virus (HIV ), and perina- tal  infections  can  complicate  the  management  of  pregnancy for the fetus and mother.

CLINICAL KEYS FOR THIS CHAPTER

Infectious  diseases  of  the  reproductive  and  urinary  tracts  are  interesting  and  challenging  disorders  in  gynecology.  Some  are  difficult  to  treat,  with  frequent  recurrences.  Some  occur  during  pregnancy  and  have  an impact on its course and outcome.

Infections  of  the  vulva,  vagina,  and  cervix  (lower  reproductive  tract)  and  the  uterine  corpus,  fallopian  tubes,  and  ovaries  (upper  reproductive  tract)  are  the  most  common  gynecologic  problems.  Many  are  sexu- ally  transmitted  infections  (STIs)  that  require  screen- ing,  early  recognition,  and  treatment.  The  diagnosis  and management of common reproductive and urinary  tract  infections  in  both  nonpregnant  and  pregnant  women are discussed in this chapter. Also covered are  the important perinatal infections that may impact the  mother and/or her fetus.

The Normal Female Reproductive Tract Normal  vaginal  secretions  are  composed  of  vulvar  secretions from sebaceous, sweat, Bartholin, and Skene  glands;  transudate  from  the  vaginal  wall;  exfoliated  vaginal and cervical cells; cervical mucus; endometrial  and  oviductal  fluids;  and  microorganisms  and  their  metabolic products. The normal vaginal flora is mostly aerobic, with an average of six different species of bacteria, the most common of which is the hydrogen peroxide–producing lactobacillus.  The  microbiology  of  the  vagina  is  determined  by  factors  that  affect  the  ability  of  bacteria  to  survive.  These  factors  include  vaginal pH and the availability of glucose for bacterial  metabolism.  The pH of the normal vagina is lower

C H A P T E R 22 Infectious Diseases of the Female Reproductive and Urinary Tract 277

Lactobacilli are usually absent. Women with BV are at increased risk for pelvic inflammatory disease (PID), postabortal PID, postoperative cuff infections after hysterectomy, and abnormal cervical cytology.  Preg- nant women with BV are at risk for premature rupture  of the membranes, preterm labor and delivery, chorio- amnionitis, and postcesarean endometritis.

Office-based  testing  is  required  to  diagnose  BV.  Figure  22-1  reveals  a  microscopy  of  a  clue  cell.  The  addition  of  potassium  hydroxide  to  the  vaginal  secre- tions  (the “whiff ” test)  releases  a  fishy,  amine-like  odor. Clinicians who are unable to perform microscopy  can  use  alternative  diagnostic  tests  such  as  a  pH  and  amines  test  card,  detection  of  G. vaginalis  ribosomal  RNA,  or  Gram  stain.  Culture  of  G. vaginalis  is  not  rec- ommended  as  a  diagnostic  tool  because  of  its  lack  of  specificity.

Ideally,  treatment  of  BV  should  inhibit  anaerobes  but  not  vaginal  lactobacilli.  Metronidazole,  an  antibi- otic with excellent activity against anaerobes but poor  activity  against  lactobacilli,  is the drug of choice for the treatment of BV.  Clindamycin  is  an  alternative  agent.  Table  22-1  illustrates  the  2015  Centers  for  Disease  Control  and  Prevention  (CDC)  guidelines  for  the  treatment  of  bacterial  vaginosis.  Table  22-2  lists  alternative  regimens  for  the  treatment  of  bacterial  vaginosis.  Many  clinicians  prefer  intravaginal  treat- ment  to  avoid  systemic  side  effects  such  as  mild   to  moderate  gastrointestinal  upset  and  an  unpleasant  taste.  Treatment of the male sexual partner does not improve therapeutic response and therefore is not recommended.

TRICHOMONAS VAGINITIS Trichomonas  vaginitis  is  caused  by  the  sexually  trans- mitted,  flagellated  parasite,  Trichomonas vaginalis. 

than 4.5, which is maintained by the production of lactic acid. Estrogen-stimulated vaginal epithelial cells  are rich in glycogen. Vaginal epithelial cells break down  glycogen to monosaccharides, which can be converted  by  the  cells  themselves,  and  by  lactobacilli  to  lactic  acid. Normal vaginal secretions are floccular in consis- tency, white in color, and usually located in the depen- dent portion of the vagina (posterior fornix).

Vaginal secretions can be analyzed by a wet-mount preparation.  A  sample  of  vaginal  secretions  is  sus- pended  in  0.5 mL  of  normal  saline  in  a  tube,  trans- ferred  to  a  slide,  covered  with  a  slip,  and  assessed  by  microscopy.  Microscopy  of  normal  vaginal  secretions  reveals  many  superficial  epithelial  cells,  few  white  blood  cells  (less  than  1  per  epithelial  cell),  and  few,  if  any,  clue  cells.  Clue cells are superficial vaginal epi- thelial cells with adherent bacteria, usually Gardner- ella vaginalis,  which  obliterate  the  crisp  cell  border  when  visualized  microscopically  (Figure  22-1).  Potas- sium  hydroxide  (KOH)  10%  may  be  added  to  the  slide  or a separate preparation can be made to examine the  secretions for evidence of fungal elements. Gram stain reveals normal superficial epithelial cells and a pre- dominance of gram-positive rods (lactobacilli).

Vaginal Infections BACTERIAL VAGINOSIS Bacterial  vaginosis  (BV )  is  an  alteration  of  normal  vaginal bacterial flora that results in the loss of hydro- gen peroxide–producing lactobacilli and an overgrowth  of predominantly anaerobic bacteria. Anaerobic bacte- ria can be found in less than 1% of the flora of normal  women.  In women with BV, the concentration of anaerobes, and G. vaginalis and Mycoplasma hominis, is 100 to 1000 times higher than in normal women. 

FIGURE 22-1 Wet mount microscopy of vaginal secretions from a patient with bacterial vaginosis. Note the presence of a clue cell, which is an epithelial cell with “serrated” edges caused by bacteria (arrows).

40µ TABLE 22-1

2015 CENTERS FOR DISEASE CONTROL (CDC) RECOMMENDED FIRST-LINE REGIMEN FOR BACTERIAL VAGINOSIS

Metronidazole 500 mg orally twice a day for 7 days*

OR

Metronidazole gel 0.75%, one full applicator (5 g) intravaginally, once a day for 5 days

OR

Clindamycin cream 2%, one full applicator (5 g) intravaginally at bedtime for 7 days†

From Diseases Characterized by Vaginal Discharge: Sexually Transmitted Diseases Treatment Guidelines, 2015. www.cdc.gov. *Consuming alcohol should be avoided during treatment and for 24 hours thereafter. †Clindamycin cream is oil-based and might weaken latex condoms and diaphragms for 5 days after use (refer to clindamycin product labeling for additional information).

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poor (50%). For this reason, nucleic acid amplification  testing  is  recommended  when  trichomoniasis  is  sus- pected but not confirmed by microscopy.

Because of the sexually transmitted nature of tricho- monas  vaginitis,  women  with  this  infection  should  be  tested for other STIs, particularly Neisseria gonorrhoeae  and Chlamydia trachomatis. Serologic testing for syph- ilis  and  human  immunodeficiency  virus  (HIV )  infec- tion should be considered.

Metronidazole is the drug of choice for treatment of vaginal trichomoniasis.  Both  a  single-dose  (2 g  orally) and a multidose (500 mg twice daily for 7 days)  regimen  are  highly  effective  and  have  cure  rates  of  about 95%. The sexual partner should be treated.

Women who do not respond to initial therapy should  be  treated  again  with  metronidazole,  500 mg,  twice  daily  for  7  days.  If  repeated  treatment  is  not  effective,  the patient should be treated with a single 2-g dose of  metronidazole  once  daily  for  5  days  or  tinidazole  2 g,  in a single dose for 5 days. Patients who do not respond  to repeated treatment with metronidazole or tinidazole  and for whom the possibility of reinfection is excluded  should  be  referred  for  expert  consultation.  In  these  uncommon  refractory  cases,  an  important  part  of  management  is  to  obtain  cultures  of  the  parasite  to  determine  its  susceptibility  to  metronidazole  and  tinidazole.

VULVOVAGINAL CANDIDIASIS An estimated 75% of women will experience at least one episode of vulvovaginal candidiasis ( VVC) during their lifetimes.  Nearly  45%  of  women  will  experience  two or more episodes. A few are plagued with a chronic,  recurrent infection. Candida albicans is responsible for  85-90% of vaginal yeast infections. The extensive areas  of  pruritus  and  inflammation,  often  associated  with  minimal  invasion  of  the  lower  genital  tract  epithelial  cells, suggest that an extracellular toxin or enzyme may  play a role in the pathogenesis of this disease. A hyper- sensitivity phenomenon may be responsible for the irritative symptoms associated with VVC,  especially  for patients with chronic, recurrent disease.

Factors that predispose women to the develop- ment of symptomatic VVC include antibiotic use, pregnancy, and diabetes.  Pregnancy  and  diabetes  are  associated  with  a  qualitative  decrease  in  cell- mediated  immunity,  leading  to  a  higher  incidence  of  candidiasis.

The symptoms of VVC consist of vulvar pruritus associated with a discharge that can vary from watery to homogeneously thick. Vaginal  soreness,  dyspareu- nia,  vulvar  burning,  and  irritation  may  be  present.  Examination  may  reveal  erythema  and  edema  of  the  labia and vulvar skin. Discrete pustulopapular periph- eral  lesions  may  be  present.  The vagina may be ery- thematous with an adherent, whitish discharge. The  cervix appears normal. Fungal elements, either budding 

The transmission rate is high; 70% of men contract the disease after a single exposure to an infected woman,  which  suggests  that  the  rate  of  male-to-female  trans- mission is even higher. The parasite, which exists only  in trophozoite form, is an anaerobe that has the ability  to generate hydrogen to combine with oxygen to create  an anaerobic environment. Bacterial vaginosis can be  diagnosed  in  as  many  as  60%  of  patients  with  tricho- monas vaginitis.

Trichomonas vaginitis is associated with a profuse, purulent, malodorous vaginal discharge that may be accompanied by vulvar pruritus. In patients with high  concentrations  of  organisms,  a  patchy  vaginal  ery- thema  and  colpitis  macularis  (“strawberry” cervix)  may  be  observed.  Microscopy  of  the  secretions  may  reveal motile trichomonads (Figure 22-2) and increased  numbers of leukocytes, but the sensitivity of this test is 

TABLE 22-2

2015 CENTERS FOR DISEASE CONTROL (CDC) RECOMMENDED ALTERNATIVE REGIMEN FOR BACTERIAL VAGINOSIS

Tinidazole 2 gm orally once daily for 2 days

OR

Tinidazole 1 g orally once daily for 5 days

OR

Clindamycin 300 mg orally twice daily for 7 days

OR

Clindamycin ovules 100 mg intravaginally once at bedtime for 3 days

From Diseases Characterized by Vaginal Discharge: Sexually Transmitted Diseases Treatment Guidelines, 2015. Available at http://www.cdc.gov/std/ treatment/2015/vaginal-discharge.htm. Accessed February 19, 2015.

FIGURE 22-2 Microscopic view (high power) of a trichomonad (arrow) in a saline wet-mount preparation. The organisms are usually motile in this type of preparation.

C H A P T E R 22 Infectious Diseases of the Female Reproductive and Urinary Tract 279

yeast  forms  or  mycelia,  appear  in  as  many  as  80%  of  cases (Figure 22-3).

Treatment The  treatment  of  VVC  involves  the  use  of  topically  applied  azole  drugs,  which  are  more  effective  than  nystatin. Table 22-3 illustrates the 2010 CDC guidelines  for the treatment of VVC. Treatment with azoles results in relief of symptoms and negative cultures in 80-90% of patients.  Symptoms  usually  resolve  in  2  to  3  days.  Short-course regimens up to 3 days are recommended.  The oral antifungal agent, fluconazole, used in a single 150-mg dose, is also recommended  for  the  treatment of VVC. It has equal efficacy when compared  with topical azoles in the treatment of mild to moder- ate VVC. Symptoms will persist for 2 to 3 days. Adjunc- tive  treatment  with  a  weak  topical  steroid,  such  as  1%  hydrocortisone  cream,  may  be  helpful  in  relieving  some of the external irritation.

RECURRENT VULVOVAGINAL CANDIDIASIS A  small  number  of  women  develop  recurrent  VVC  (RVVC), defined as four or more episodes in a year. The treatment of patients with RVVC consists of inducing a remission of chronic symptoms with fluconazole  (150 mg  every  3  days  for  three  doses),  then  maintain- ing a suppressive dose of this agent  (fluconazole,  150 mg weekly) for 6 months. On this regimen, 90% of  women with RVVC will remain in remission. After sup- pressive  therapy,  approximately  half  will  remain  asymptomatic. Recurrence will occur in the other half  and should prompt reinstitution of suppressive therapy.

ATROPHIC VAGINITIS Estrogen  plays  an  important  role  in  the  maintenance  of  normal  vaginal  ecology.  Hypoestrogenic women having undergone natural or surgical menopause may have dyspareunia and postcoital bleeding result-

FIGURE 22-3 Mycelial tangles of yeast (arrow) pseudohyphae in potassium hydroxide wet-mount preparation.

TABLE 22-3

2015 CENTERS FOR DISEASE CONTROL (CDC) RECOMMENDED FIRST-LINE REGIMEN FOR VULVOVAGINAL CANDIDIASIS

Over-the-Counter Intravaginal Agents

Clotrimazole 1% cream 5 g intravaginally for 7-14 days

OR

Clotrimazole 2% cream 5 g intravaginally for 3 days

OR

Miconazole 2% cream 5 g intravaginally for 7 days

OR

Miconazole 4% cream 5 g intravaginally for 3 days

OR

Miconazole 100 mg vaginal suppository, one suppository for 7 days

OR

Miconazole 200 mg vaginal suppository, one suppository for 3 days

OR

Miconazole 1200 mg vaginal suppository, one suppository for 1 day

OR

Tioconazole 6.5% ointment 5 g intravaginally in a single application

Prescription Intravaginal Agents

Butoconazole 2% cream (single dose bioadhesive product), 5 g intravaginally for 1 day

OR

Terconazole 0.4% cream 5 g intravaginally for 7 days

OR

Terconazole 0.8% cream 5 g intravaginally for 3 days

OR

Terconazole 80 mg vaginal suppository, one suppository for 3 days

Oral Agent

Fluconazole 150 mg oral tablet, one tablet in single dose

From Diseases Characterized by Vaginal Discharge: Sexually Transmitted Diseases Treatment Guidelines, 2015. Available at http://www.cdc.gov/std/ treatment/2015/vaginal-discharge.htm. Accessed February 19, 2015.

ing from atrophy of the vaginal and vulvar epithe- lium.  Examination  reveals  atrophy  of  the  external  genitalia,  along  with  a  loss  of  the  vaginal  rugae.  The  vaginal  epithelium  may  be  somewhat  friable  in  areas.  Microscopy of the vaginal secretions shows a predomi- nance  of  parabasal  epithelial  cells  and  an  increased  number of leukocytes.

Atrophic vaginitis is treated with vaginal estrogen cream. Maintenance estrogen therapy, either topical or  systemic,  should  be  considered  to  prevent  recurrence  of this disorder.

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Treatment Table  22-4  illustrates  the  2015  CDC  guidelines  for  the  treatment of uncomplicated gonococcal and chlamyd- ial infections of the cervix, urethra, and rectum. There  is an ongoing problem with the emergence of strains of  gonococcal isolates that are resistant to the fluoroqui- nolones,  tetracyclines,  and  now  the  cephalosporins.  For  this  reason,  dual therapy is recommended,  and  should  include  an  intramuscular  injection  of  ceftriax- one  250 mg,  and  a  single  oral  dose  of  azithromycin  (1 g). The azithromycin is added not for the presump- tive treatment of chlamydia, but to insure treatment of  gonococci that are potentially resistant to ceftriaxone.

It is imperative that all sexual partners be treated with a similar antibiotic regimen.  Cervicitis  is  com- monly associated with BV, which, if not treated concur- rently, leads to significant persistence of the symptoms  and signs of cervicitis.

PELVIC INFLAMMATORY DISEASE Microorganisms colonizing the endocervix and ascending to the endometrium and fallopian tubes cause PID.  This  is  a  clinical  diagnosis  implying  that  the  patient  has  upper  genital  tract  infection  and 

INFLAMMATORY VAGINITIS Desquamative inflammatory vaginitis (DIV ) is a fairly rare clinical syndrome characterized by diffuse exu- dative vaginitis, epithelial cell exfoliation, and a profuse purulent vaginal discharge.  DIV  presents  as  vaginal  erythema.  There  may  also  be  an  associated  vulvar  erythema,  vulvovaginal  ecchymotic  spots,  and  colpitis  macularis  (“strawberry cervix”).  DIV  can  resemble  atrophic  vaginitis,  but  can  also  occur  in  women with normal estrogen levels. By the time women  are  diagnosed,  their  symptoms  have  usually  been  present for years, and they have typically been treated  repeatedly  for  a  “vaginal  infection”  without  any  long- term improvement.

Initial therapy should be with 2% clindamycin cream, one applicator full (5 g) intravaginally daily for 7 days. If this is not effective, intravaginal 10% hydrocortisone daily for 14 days may be tried.

Uterine and Adnexal Infections ENDOCERVICITIS N. gonorrhoeae and C. trachomatis are associated with  mucopurulent  endocervicitis  50%  of  the  time.  Other  etiologies  include  M. genitalium,  bacterial  vaginosis,  and birth control pills.

The diagnosis of cervicitis is based on the finding of a purulent endocervical discharge, generally yellow or green in color, and referred to as “mucopus”  (see  Figure 22-4). In addition, the zone of ectopy (glandular  epithelium) is friable or easily induced to bleed. Touch- ing  the  ectropion  with  a  cotton  swab  or  spatula  can  assess this characteristic sign. Tests for gonorrhea and  chlamydia, preferably using nucleic acid amplification  tests,  should  be  performed.  The  microbial  etiology  of  endocervicitis  is  unknown  in  about  50%  of  cases  in  which neither gonococci nor chlamydia is detected.

FIGURE 22-4 Uterine cervix at the time of speculum examination with yellow mucopus protruding from the os (arrow).

TABLE 22-4

2015 CENTERS FOR DISEASE CONTROL (CDC) RECOMMENDED FIRST-LINE REGIMEN FOR UNCOMPLICATED GONOCOCCAL AND CHLAMYDIAL INFECTIONS OF THE CERVIX, URETHRA, AND RECTUM

Recommended Regimen

Ceftriaxone 250 mg in a single intramuscular dose

PLUS

Azithromycin 1 g orally in a single dose or doxycycline 100 mg orally twice daily for 7 days*

Alternative Regimens

If ceftriaxone is not available: cefixime 400 mg in a single oral dose

PLUS

Azithromycin 1 g orally in a single dose or doxycycline 100 mg orally twice daily for 7 days*

PLUS

Test-of-cure in 1 week

If the patient has severe cephalosporin allergy: azithromycin 2 g in a single oral dose

PLUS

Test-of-cure in 1 week

From Centers for Disease Control and Prevention. Updated recommended treatment regimens for gonococcal infections and associated conditions— United States, April 2015. www.cdc.gov. *Because of the high prevalence of tetracycline resistance among Gonococ- cal Isolate Surveillance Project isolates, particularly those with elevated minimum inhibitory concentrations to cefixime, the use of azithromycin as the second antimicrobial is preferred as dual therapy.

C H A P T E R 22 Infectious Diseases of the Female Reproductive and Urinary Tract 281

inflammation.  The  inflammation  may  be  present  at  any point along a continuum that includes endometri- tis,  salpingitis,  and  peritonitis.  PID is commonly caused by the sexually transmitted microorganisms N. gonorrhoeae and C. trachomatis.  Recent  evidence  suggests  that  Mycoplasma genitalium  can  cause  PID  and  may  present  with  mild  clinical  symptoms  similar  to chlamydial PID. Endogenous microorganisms found  in the vagina, particularly the BV microorganisms, are  often  isolated  from  the  upper  genital  tract  of  women  with  PID.  The  BV  microorganisms  include  anaerobic  bacteria  such  as  Prevotella  and  peptostreptococci,  as  well as G. vaginalis. Less frequently, respiratory patho- gens such as Haemophilus influenzae, group A strepto- cocci, and pneumococci can colonize the lower genital  tract and cause PID.

Traditionally, the diagnosis of PID has been based on a triad of symptoms and signs, including pelvic pain, cervical motion and adnexal tenderness, and the presence of fever. There is wide variation in many  symptoms  and  signs  among  women  with  this  condi- tion, which makes the diagnosis of acute PID difficult.  Many  women  with  PID  exhibit  subtle  or  mild  symp- toms that are not readily recognizable as PID. The diag- nosis  should  be  considered  in  women  with  any  genitourinary symptoms, including, but not limited to,  lower  abdominal  pain,  excessive  vaginal  discharge,  heavy  and  irregular  vaginal  bleeding,  fever,  chills,  and  urinary symptoms.

Pelvic organ tenderness, either uterine tenderness alone or uterine tenderness with adnexal tenderness, is usually present in patients with PID.  Cervical  motion tenderness suggests the presence of peritoneal  inflammation,  which  causes  pain  when  the  perito- neum  is  stretched  by  moving  the  cervix  and  causing  traction of the adnexa on the pelvic peritoneum. Direct  or rebound abdominal tenderness may be present.

Evaluation  of  both  vaginal  and  endocervical  secre- tions  is  an  important  part  of  the  workup  of  a  patient  with PID. In women with PID, an increased number of  polymorphonuclear  leukocytes  may  be  detected  in  a  wet  mount  of  the  vaginal  secretions  or  the  cervix  may  have a mucopurulent discharge.

Therapeutic regimens for PID must provide empir- ical, broad-spectrum coverage of likely pathogens, including N. gonorrhoeae, C. trachomatis, M. geni- talium, gram-negative facultative bacteria, anaer- obes, and streptococci.  Recommended  first-line  outpatient  treatment  regimens  for  PID,  per  the  2015  CDC guidelines, are listed in Table 22-5, and parenteral  treatment is illustrated in Table 22-6.

An outpatient regimen of cefoxitin and doxycy- cline is as effective as an inpatient parenteral regimen of the same antimicrobials.  Box  22-1  lists  the  clinical  criteria  for  hospitalization  with  parenteral  treatment.  Hospitalized  patients  can  be  considered  for  discharge  when  their  fever  is  less  than  99.5°  F  for  more  than  24 

TABLE 22-5

2015 CENTERS FOR DISEASE CONTROL (CDC) RECOMMENDED FIRST-LINE REGIMEN FOR OUTPATIENT TREATMENT OF PELVIC INFLAMMATORY DISEASE

Recommended Regimen

Ceftriaxone 250 mg intramuscularly in a single dose

PLUS

Doxycycline 100 mg orally twice a day for 14 days

WITH or WITHOUT

Metronidazole 500 mg orally twice a day for 14 days

OR

Cefoxitin 2 g intramuscularly in a single dose and probenecid, 1 g orally administered concurrently in a single dose

PLUS

Doxycycline 100 mg orally twice a day for 14 days

WITH or WITHOUT

Metronidazole 500 mg orally twice a day for 14 days

OR

Other parenteral third-generation cephalosporin (e.g., ceftizoxime or cefotaxime)

PLUS

Doxycycline 100 mg orally twice a day for 14 days

WITH or WITHOUT

Metronidazole 500 mg orally twice a day for 14 days

From Pelvic Inflammatory Disease: Sexually Transmitted Diseases Treatment Guidelines, 2015. Available at http://www.cdc.gov/std/treatment/2015/ pid.htm. Accessed February 19, 2015.

hours, the white blood cell count is decreasing, rebound  tenderness  is  absent,  and  repeat  examination  shows  marked amelioration of abdominal tenderness.

Sexual partners of women with PID should be eval- uated and treated for urethral infection caused by chlamydia or gonorrhea.  One  of  these  STIs  is  usually  found in the male sexual partners of women with PID  even if her diagnosis is not associated with chlamydia  or gonorrhea.

TUBO-OVARIAN ABSCESS Tubo-ovarian abscess (TOA), an endstage process of acute PID, is diagnosed when a patient with PID has a pelvic mass that is palpable during bimanual exam- ination. The condition usually reflects an agglutination  of pelvic organs (tube, ovary, and bowel) forming a pal- pable  complex.  Occasionally,  an  ovarian  abscess  can  result from the entrance of microorganisms through an  ovulatory site. Tubo-ovarian abscess is treated with an  antibiotic regimen administered on an inpatient basis.  Table  22-6  illustrates  the  parenteral  treatment  of  PID,  as per the 2015 CDC guidelines. About 75% of women with a tubo-ovarian abscess respond to antimicrobial therapy alone. Failure of medical therapy suggests

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Chancroid,  lymphogranuloma  venereum  (LGV ),  and granuloma inguinale (donovanosis) round out the  infectious  diagnoses.  These infections are associated with an increased risk for HIV.  Other  infrequent  and  noninfectious  causes  of  genital  ulcers  include  abra- sions,  fixed  drug  eruptions,  carcinoma,  and  Behçet  disease.  Genital  ulcers  in  nonsexually  active  girls  are  usually apthmous ulcers and are not related to sexually  transmitted infections.

A diagnosis based on history and physical examina- tion  alone  is  often  inaccurate.  Therefore,  all women with genital ulcers should undergo a serologic test for syphilis. Because of the consequences of inappro- priate  therapy,  such  as  tertiary  disease  and  congenital  syphilis  in  pregnant  women,  diagnostic  efforts  should  be directed at excluding syphilis. Optimally, the evalu- ation  of  a  patient  with  a  genital  ulcer  should  include  dark-field  examination  or  direct  immunofluorescence  testing  for  Treponema pallidum,  culture  or  antigen  testing  for  HSV,  and  culture  for  Haemophilus ducreyi.  Dark-field  or  fluorescent  microscopes  and  selective  media  to  culture  for  H. ducreyi  often  are  not  available  in  most  offices  and  clinics.  Even after complete testing, the diagnosis remains unconfirmed in one-fourth of patients with genital ulcers.  For  this  reason, most clinicians base their initial diagnosis and  treatment  recommendations  on  their  clinical  impression.

Several  clinical  presentations  are  highly  suggestive  of specific diagnoses. A painless and minimally tender ulcer, not accompanied by inguinal lymphadenopa- thy, is likely to be syphilis,  especially  if  the  ulcer  is  indurated. A nontreponemal rapid plasma reagin (RPR)  test,  or  venereal  disease  research  laboratory  (VDRL)  test, and a confirmatory treponemal test—syphilis IgG 

FIGURE 22-5 Gross appearance of bilateral tubo-ovarian abscesses. (From Kumar V, Fausto N, Abbas A: Robbins and Cotran pathologic basis of disease, ed 7, Philadelphia, 2005, Saunders.)

BOX 22-1

PELVIC INFLAMMATORY DISEASE: CLINICAL CRITERIA FOR HOSPITALIZATION AND PARENTERAL TREATMENT

1.  Surgical emergencies (e.g., appendicitis) not ruled out 2.  Failed  oral  treatment  (no  improvement  with  short-

term treatment) 3.  Compliance questionable (i.e., patient unable to follow 

or tolerate outpatient regimen) 4.  Severe illness (toxicity: nausea, vomiting, high fever) 5.  Tubo-ovarian  abscess  demonstrated  on  ultrasonogra-

phy or suspected clinically

TABLE 22-6

CENTERS FOR DISEASE CONTROL (CDC) RECOMMENDED FIRST-LINE REGIMEN FOR PARENTERAL TREATMENT OF PELVIC INFLAMMATORY DISEASE

Recommended Parenteral Regimen A

Cefotetan 2 g IV every 12 hours

OR

Cefoxitin 2 g IV every 6 hours

PLUS

Doxycycline 100 mg orally or IV every 12 hours

Recommended Parenteral Regimen B

Clindamycin 900 mg IV every 8 hours

PLUS

Gentamicin loading dose IV or IM (2 mg/kg of body weight), followed by a maintenance dose (1.5 mg/kg) every 8 hours. Single daily dosing (3 to 5 mg/kg) can be substituted.

Alternative Parenteral Regimens

Ampicillin/sulbactam 3 g IV every 6 hours

PLUS

Doxycycline 100 mg orally or IV every 12 hours

From Pelvic Inflammatory Disease: Sexually Transmitted Diseases Treatment Guidelines, 2015. Available at http://www.cdc.gov/std/treatment/2015/pid .htm. Accessed February 19, 2015. IM, Intramuscularly; IV, intravenously.

the need for drainage of the abscess. Although drain- age  may  require  surgical  exploration,  percutaneous drainage, guided by imaging studies (ultrasonogra- phy or computed tomography) should be used as an initial option if possible.  Trocar  drainage,  with  or  without placement of a drain, is successful in up to 90%  of  cases  in  which  the  patient  has  failed  to  respond  to  antimicrobial  therapy  after  72  hours.  Figure  22-5  depicts a surgical specimen with bilateral TOAs.

Genital Ulcer Diseases HERPES SIMPLEX AND SYPHILIS In the United States, most patients with genital ulcers have genital herpes simplex virus (HSV ) infection or syphilis.

C H A P T E R 22 Infectious Diseases of the Female Reproductive and Urinary Tract 283

and  number  of  warts,  and  the  expense,  efficacy,  con- venience,  and  potential  adverse  effects.  Treatment  of  genital warts is noted in Table 22-7. Recurrences more often result from reactivation of subclinical infection than reinfection by a sexual partner; therefore, exam- ination  of  sexual  partners  is  not  absolutely  necessary.  However,  many  partners  may  have  external  genital  warts  and  may  benefit  from  therapy  and  counseling  concerning transmission of warts. HPV infection with types 6, 11, 16, 18, 31, 33, 45, 52, and 58 can be pre- vented with the nonavalent HPV vaccine.

Urinary Tract Infections ACUTE CYSTITIS Women  with  acute  cystitis  generally  have  an  abrupt  onset  of  multiple,  severe  urinary  tract  symptoms  including  dysuria,  frequency,  and  urgency  associated  with suprapubic or low-back pain. Suprapubic tender- ness may be noted on physical examination. Urinalysis  reveals  pyuria  and  sometimes  hematuria.  Several factors increase the risk for cystitis, including sexual intercourse, the use of a diaphragm and a spermicide, delayed postcoital micturition, and a history of a recent urinary tract infection.

Escherichia coli is present in the urine of 80% of young women with acute cystitis  and  Staphylococcus saprophyticus  is  present  in  an  additional  5-15%  of  patients.  The  pathophysiology  of  cystitis  in  women  involves  the  colonization  of  the  vagina  and  urethra  with coliform bacteria from the rectum. For this reason,  the  effects  of  an  antimicrobial  agent  on  the  vaginal  flora play a role in the eradication of bacteriuria.

High  concentrations  of  trimethoprim  and  fluo- roquinolone  in  vaginal  secretions  can  eradicate   E. coli while minimally altering normal anaerobic and 

enzyme  immunoassay  (EIA),  fluorescent  treponemal  antibody absorption (FTA ABS) or microhemagglutinin– T. pallidum  (MHA  TP)—should  be  used  to  diagnose  syphilis  presumptively.  Some  laboratories  screen  samples with treponemal EIA tests, the results of which  should  be  confirmed  with  nontreponemal  tests.  The  results  of  nontreponemal  tests  usually  correlate  with  disease activity and should be reported quantitatively.

Grouped vesicles mixed with small ulcers, particu- larly if there is a history of such lesions, are usually pathognomonic of genital herpes. Nevertheless, labo- ratory  confirmation  of  the  findings  is  recommended  because the diagnosis of genital herpes is traumatic for  many women, alters their self-image, and affects their  perceived ability to enter new sexual relationships and  bear children. A culture test is the most sensitive and specific test; sensitivity approaches 100% in the vesic- ular  stage  and  89%  in  the  pustular  stage,  but  drops  to  as low as 33% in patients with ulcers. Nonculture tests  are  about  80%  as  sensitive  as  culture  tests.  Because  false-negative  results  are  common  with  HSV  cultures,  especially  in  patients  with  recurrent  infections,  type- specific  glycoprotein  G-based  antibody  assays  are  useful  in  confirming  a  clinical  diagnosis  of  genital  herpes.

One to three extremely painful ulcers, accompa- nied by tender inguinal lymphadenopathy, are unlikely to be anything except chancroid.  This  is  especially  true  if  the  adenopathy  is  fluctuant.  If  no  vulvar  ulcer  is  present,  the  most  likely  diagnosis  of  an  inguinal  bubo  is  LGV. Treatment  of  diagnoses  specific  to genital ulcers is noted in Table 22-7.

GENITAL WARTS External genital warts are a manifestation of human papillomavirus (HPV ) infection  (Figure  22-6).  The  nononcogenic HPV types 6 and 11 are usually respon- sible.  The  warts  tend  to  occur  in  areas  most  directly  affected by coitus, namely the posterior fourchette and  lateral areas of the vulva. Less frequently, warts can be  found throughout the vulva, in the vagina, and on the  cervix. Minor trauma associated with coitus can cause  breaks  in  the  vulvar  skin,  allowing  direct  contact  between  the  viral  particles  from  an  infected  man  and  the  basal  layer  of  the  epidermis  of  his  susceptible  sexual  partner.  Infection  may  be  latent  or  may  cause  viral particles to replicate and produce a wart. External genital warts are highly contagious; more than 75% of sexual partners develop this manifestation of HPV infection when exposed.

The goal of treatment is removal of the warts; it is not possible to eradicate the viral infection. Treat- ment  is  most  successful  in  patients  with  small  warts  that  have  been  present  for  less  than  1  year.  It  has  not  been  determined  whether  treatment  of  genital  warts  reduces  transmission  of  HPV.  Selection  of  a  specific  treatment regimen depends on the anatomic site, size, 

FIGURE 22-6 Venereal warts (HPV infection). (From Monk BJ, Tewari KS: The spectrum and clinical sequelae of human papillo- mavirus infection. Gynecol Oncol 107:S6–S13, 2007.)

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TABLE 22-7

TREATMENT OF GENITAL (VULVAR) ULCERATIVE INFECTIONS

Disease Microorganism(s) Involved Preferred Treatment Alternative Treatment

Herpes Herpes simplex virus First Episode Acyclovir 400 mg PO three times daily OR Famciclovir 250 mg PO three times daily OR Valacyclovir 1 g PO twice daily for 7-10 days

Recurrent Episode Acyclovir 400 mg PO twice daily OR Famciclovir 250 mg PO twice daily OR Valacyclovir 1 g PO daily

Syphilis Treponema pallidum Primary, Secondary, and Early* Latent Disease

Benzathine Penicillin G 2.4 million units IM in a single dose

ALL immunocompromised patients with a penicillin allergy must be desensitized and given penicillin

Late† Latent Syphilis Benzathine Penicillin G 2.4 million units IM weekly × three

doses

Doxycyline 100 mg PO twice daily for 28 days

Chancroid Haemophilus ducreyi Azithromycin 1 g PO × 1 dose

Ceftriaxone 250 mg IM × 1 dose Ciprofloxacin 500 mg PO twice daily for 3 days Erythromycin base 500 mg PO four times daily for 7 days

Granuloma inguinale (donovanosis)

Klebsiella granulomatis (Calymmatobacterium

granulomatis)

Azithromycin 1 g PO once a week for 3 weeks

Doxycycline 100 mg PO twice daily for 3 weeks Ciprofloxacin 750 mg PO twice daily for 3 weeks Erythromycin base 500 mg PO four times daily for 3

weeks Sulfamethoxazole (800 mg),

Trimethoprim (160 mg), Bactrim (double strength)

1 PO twice daily for 3 weeks

Lymphogranuloma venereum (LGV)

Chlamydia trachomatis Serovars: L1, L2, L3

Doxycycline 100 mg PO twice daily for 21 days or until signs and symptoms have resolved

Erythromycin base 500 mg PO four times daily or for 21 days until signs and symptoms have resolved

Condylomata accuminata

Human papillomavirus Excision of warts using either: Trichloroacetic acid Electrodessication Cautery Laser

Cryotherapy OR Imiquimod 5% cream OR Sinecatechins 15% ointment OR Popofilox 0.5%

From Centers for Disease Control and Prevention. The sexually transmitted infections treatment guidelines. MMWR Morb Mortal Wkly Rep 2015. IM, Intramuscularly; IV, intravenously; PO, orally. *Early latent syphilis—defined at the first year of latent syphilis. †Late latent syphilis—defined as beyond 1 year of latent syphilis.

microaerophilic  vaginal  flora.  There has been an increasing linear trend in the prevalence of resistance of E. coli (>10%) to the fluoroquinolones (e.g., cipro- floxacin). Despite a similar increase in E. coli resistance  (9-18%)  to  trimethoprim-sulfamethoxazole,  therapeu- tic efficacy remains stable. In contrast, no such increase   in  resistance  has  been  noted  with  nitrofurantoin.  Nitrofurantoin  (macrocrystals,  100 mg  orally  twice 

daily  for  5  days)  or trimethoprim-sulfamethoxazole  (160/800 mg  orally  twice  daily  for  3  days)  are the optimal choices for empirical therapy for uncompli- cated cystitis.

In patients with typical symptoms, an abbreviated laboratory workup followed by empirical therapy is recommended.  The  diagnosis  can  be  presumed  if  pyuria is detected by microscopy or leukocyte esterase 

C H A P T E R 22 Infectious Diseases of the Female Reproductive and Urinary Tract 285

and flank pain persist after 72 hours of therapy, ultrasonography or computed tomography should be considered to rule out a perinephric or intrarenal abscess or ureteral obstruction.  A  follow-up  culture  should  be  obtained  2  weeks  after  the  completion  of  therapy.

Infections during and after Pregnancy CHORIOAMNIONITIS Intraamniotic  infection  syndrome  (IAIS),  also  referred  to as chorioamnionitis, is a clinically detectable infec- tion of the amniotic fluid and fetal membranes during  pregnancy. Most cases of IAIS originate when vaginal microorganisms ascend into the intrauterine cavity after rupture of the membranes.  In  full-term  preg- nancies,  IAIS  is  associated  with  dysfunctional  labor.  Approximately  75%  of  infected  women  require  aug- mentation  of  labor  with  oxytocin,  and  approximately  35% require cesarean delivery, usually because of arrest of progress in labor. Risk factors for IAIS include  prolonged duration of labor or rupture of membranes,  multiple  vaginal  examinations,  young  age,  low  socio- economic  class,  nulliparity,  and  preexisting  bacterial  vaginosis.

Women  with  IAIS  have  a  select  group  of  high  viru- lence microorganisms, such as Group-B streptococcus,  Escherichia coli, genital mycoplasmas, and pathogenic  anaerobes, e.g., Prevotella bivia, present in significantly  high quantities, causing an inflammatory response and  systemic signs of infection. Many of these microorgan- isms (especially anaerobic bacteria, the mycoplasmas,  and  Gardnerella vaginalis)  are  associated  with  bacte- rial vaginosis.

The  clinical  diagnosis  of  IAIS  is  imprecise  but  is  based on the presence of fever (>38° C or >100.4° F) and  at least two other findings: maternal and/or fetal tachy- cardia, maternal leukocytosis (defined as a white blood  cell  count  >15,000),  uterine  tenderness,  and  foul- smelling  amniotic  fluid.  The  vast  majority  of  these  gravidas  will  have  concomitant  ruptured  membranes.  Practically, clinicians tend to base the diagnosis on the  presence of intrapartum fever plus one additional cri- terion.  Maternal  and  fetal  tachycardia  are  common  with  fever  and  add  little  additional  information.  Uterine tenderness is often obscured by conduction anesthesia, and foul-smelling amniotic fluid is rare.  Maternal  white  blood  cell  counts  increase  with  dura- tion of labor, but no reliable breakpoint has been estab- lished to reliably distinguish fever from infectious and  noninfectious causes.

Given the imprecision of the diagnosis of IAIS, antibiotic therapy should be considered in laboring gravidas with fever  (>38°  C  or >  100.4°  F).  Antimicro- bial therapy for IAIS is aimed at preventing bacteremia 

testing.  Urine  culture  is  not  necessary,  and  a  short  course  of  antimicrobial  therapy  should  be  given.  No  follow-up visit or culture is necessary unless symptoms  persist or recur.

RECURRENT CYSTITIS About 20% of premenopausal women have recurrent episodes of cystitis.  More  than  90%  of  these  recur- rences are caused by exogenous reinfection. Recurrent cystitis should be documented by culture to rule out resistant microorganisms. Patients may be treated by  one of three strategies: (1) continuous prophylaxis, (2)  postcoital  prophylaxis,  or  (3)  therapy  initiated  by  the  patient when symptoms are first noted.

Postmenopausal women may have frequent reinfec- tions.  Hormonal  therapy  or  topically  applied  estrogen  cream, along with antimicrobial prophylaxis, is helpful  in these patients.

URETHRITIS Women  with  dysuria  caused  by  urethritis  have  a   more  gradual  onset  of  mild  symptoms,  which  may   be  associated  with  abnormal  vaginal  discharge  or  bleeding related to concurrent cervicitis. Patients may  have  a  new  sexual  partner  or  experience  lower  abdominal  pain.  Physical  examination  may  reveal  the  presence  of  mucopurulent  cervicitis  or  vulvovaginal  herpetic  lesions.  C. trachomatis, N. gonorrhoeae, or genital herpes may cause acute urethritis.  Pyuria  is  present  on  urinalysis,  but  hematuria  is  rarely   seen.

ACUTE PYELONEPHRITIS The  clinical  spectrum  of  acute,  uncomplicated  pyelo- nephritis in young women ranges from gram-negative  septicemia to a cystitis-like illness with mild flank pain.  E. coli accounts for more than 80% of these cases.  Microscopy of unspun urine reveals pyuria and gram- negative  bacteria.  A  urine  culture  should  be  obtained  in all women with suspected pyelonephritis; blood cul- tures  should  be  performed  in  those  who  are  hospital- ized, because results are positive in 15-20% of cases. In  the absence of nausea and vomiting and severe illness,  outpatient  oral  therapy  can  be  given  safely.  Patients  who have nausea and vomiting, and are moderately to  severely ill, should be hospitalized. Pyelonephritis in a pregnant patient can cause premature labor and preterm delivery if not treated promptly.

Outpatient  treatment  regimens  include  trime- thoprim-sulfamethoxazole (160/800 mg every 12 hours  for  14  days)  or  a  quinolone  (e.g.,  levofloxacin  750 mg  daily for 7 days). Inpatient treatment regimens include  the  use  of  parenteral  levofloxacin  (750 mg  daily),  cef- triaxone (1 to 2 g daily), ampicillin (1 g every 6 hours),  and gentamicin (especially if Enterococcus species are  suspected)  or  aztreonam  (1 g  every  8  to  12  hours).  Symptoms should resolve after 48 to 72 hours. If fever

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comes.  Many  patients  who  develop  postcesarean  endometritis despite antibiotic prophylaxis have histo- logic evidence of incipient infection.

PPE is a polymicrobial infection caused by a wide variety of bacteria. Group B streptococci, enterococci, other aerobic streptococci, G. vaginalis, E. coli, P. bivia, Bacteroides spp., and peptostreptococci are the most common endometrial isolates,  with  group  B  streptococci  and  G. vaginalis  the  most  common  iso- lates from the blood.

Chlamydia trachomatis  has  been  associated  with  a  late  form  of  PPE  that  occurs  more  than  2  days  to  6  weeks  after  delivery  in  women  who  deliver  vaginally.  Group  A  β-hemolytic  streptococcal  endometritis  is  rare.  It  is  characterized  by  early  onset  and  rapid  pro- gression,  with  few  localizing  symptoms  or  physical  signs.

The diagnosis of PPE is suggested by the develop- ment of fever, usually on the first or second postpar- tum day.  Significant  fever  is  defined  as  an  oral  temperature  of  38.5°  C  or  higher  in  the  first  24  hours  after  delivery  or  38°  C  or  higher  for  at  least  four  con- secutive  hours  24  or  more  hours  after  delivery.  Other  consistently  associated  findings  are  lower  abdominal  pain,  uterine  tenderness,  and  leukocytosis.  These  women  may  also  exhibit  a  delayed  postoperative   return  of  bowel  function  due  to  an  associated  local  peritonitis.

Patients with suspected PPE should have the uterus  assessed for size, consistency, and tenderness. A test for  Chlamydia should be performed in patients with mild  PPE commencing more than 7 days after delivery. Ado- lescents  in  particular  are  at  high  risk  of  chlamydial  infection.

Clindamycin plus gentamicin has proved to be the most effective regimen in treating PPE, especially if PPE occurs after cesarean delivery.  Alternative  regimens  used  for  the  treatment  of  PPE  include  one  of  the  extended-spectrum  penicillins  or  second-generation  cephalosporins  (e.g.,  ampicillin/ sulbactam,  ticarcillin/clavulanic  acid,  piperacillin/ tazobactam,  cefotetan,  cefoxitin).  Antimicrobial  regi- mens  used  in  the  treatment  of  postcesarean  endo- metritis  should  provide  satisfactory  coverage  of  penicillin-resistant  anaerobic  microorganisms  (e.g.,   P. bivia).

Parenteral  therapy  should  be  continued  until  the  temperature  has  remained  lower  than  37.8°  C  (100o  F)  for 24 hours, the patient is pain free, and the leukocyte  count is normalizing. The use of oral antibiotics after discharge has been shown to be unnecessary. Women  with late-onset PPE can be treated as outpatients with  oral  azithromycin  or  doxycycline  therapy,  with  or  without  metronidazole,  depending  on  whether  or  not  they have coexistent bacterial vaginosis.

Early-onset PPE should respond to parenteral antimicrobial therapy within 48 hours, with the

in  the  mother  as  well  as  initiating  intrapartum  treat- ment  of  the  fetus  while  awaiting  delivery.  Improved neonatal and maternal outcome is noted when anti- biotic therapy is begun intrapartum rather than immediately postpartum.  Delivery  of  the  fetus  and  placenta  removes  the  sites  of  infection,  much  like  draining an abscess, making this intervention a signifi- cant part of therapy. Because group B streptococci and  E. coli  are  the  most  common  isolates  from  infected  newborns and maternal therapy initiates fetal therapy,  a combination of ampicillin plus gentamicin is a rea- sonable initial regimen for IAIS. This  regimen  is  suf- ficient to treat the mother if the delivery is vaginal with  only  one  additional  dose  of  the  antibiotic  regimen  needed  postpartum.  If cesarean delivery is required, up to 15% of patients given only ampicillin and gen- tamicin will develop postpartum endometritis. These  patients  require  continued  broad-spectrum  antibiotic  coverage, and a drug such as clindamycin or metroni- dazole should be added to the treatment regimen. This  antibiotic  regimen  should  be  continued  until  the  patient has been afebrile (temperature <38° C or <100°  F) for 24 hours.

Although  delivery  is  essential  for  cure,  no  critical  diagnosis-to-delivery  interval  has  been  identified.  Accordingly,  labor  must  be  managed  actively,  but  cesarean  delivery  should  be  performed  only  for  accepted obstetric indications.

POSTPARTUM ENDOMETRITIS Postpartum infection of the uterus, the most common  cause of puerperal fever, is designated endomyometri- tis.  Cesarean delivery, particularly after labor or rupture of the membranes of any duration, is the most accurate predictor of postpartum endomyome- tritis (PPE). The pathogenesis of this infection involves  inoculation  of  the  amniotic  fluid  after  membrane  rupture  or  during  labor  with  vaginal  microorganisms.  The  myometrium,  leaves  of  the  broad  ligament,  and  the peritoneal cavity are then exposed to this contami- nated fluid during cesarean surgery. The reported inci- dence of PPE after cesarean delivery is less than 10% in patients receiving appropriate antibiotic prophy- laxis.  The  diagnosis  is  uncommon  after  vaginal  delivery.

Risk factors for postcesarean endomyometritis include prolonged labor or rupture of the mem- branes, presence of bacterial vaginosis, frequent vaginal examinations, and use of internal fetal moni- toring.  Antimicrobial  prophylaxis  is  associated  with  a  50%  reduction  in  infection  in  all  populations  studied.  All  patients  undergoing  cesarean  delivery,  either  elec- tive or emergent, are candidates for antibiotic prophy- laxis. When  given  before  the  skin  incision  rather  than  after  cord  clamping,  the  incidence  of  postcesarean  endomyometritis  and  total  infectious  morbidities  are  decreased,  without  adversely  affecting  neonatal  out-

C H A P T E R 22 Infectious Diseases of the Female Reproductive and Urinary Tract 287

Surgical removal of infected tissue is essential in all but the mildest of postabortal infections.  Pelvic  ultrasonography  can  be  used  to  confirm  the  presence  of retained tissue. In most cases, prompt curettage con- trols  the  infection.  Indications for laparotomy and possible hysterectomy include failure to respond to uterine evacuation and appropriate medical therapy, perforation and infection with suspected bowel injury, pelvic or adnexal abscess, and clostridial nec- rotizing myonecrosis (gas gangrene).

Avoidance of unwanted pregnancies by making contraceptives widely available is the most important preventive measure  (see  Chapter  27).  Screening  for  sexually transmitted infections and bacterial vaginosis  before performance of elective abortion is optimal but  often  impractical.  Routine  use  of  periabortal  antibiot- ics,  such  as  doxycycline,  may  prevent  up  to  half  of  all  cases of postabortal infections.

patient becoming afebrile within 96 hours. If fever persists  despite  apparently  appropriate  antimicrobial  therapy, the differential diagnosis includes a wound or  pelvic  abscess,  refractory  postpartum  fever,  and  non- infectious fever (e.g., drug fever, breast engorgement).  Appropriate imaging studies,  usually  pelvic  ultraso- nography or computed tomography, may confirm the presence of a wound or pelvic hematoma or abscess. Pelvic collections  usually  involve  the  space  between  the lower uterine segment and bladder. If present, per- cutaneous drainage by interventional radiology should  be considered.

POSTABORTAL INFECTION Infection after abortion is an ascending process that occurs most commonly in the presence of retained products of conception or operative trauma.  Risk  factors  include  greater  duration  of  pregnancy,  technical  difficulties  with  the  procedure,  and  the  unsuspected  presence  of  sexually  transmitted  patho- gens  or  bacterial  vaginosis.  Symptoms  include  fever,  chills,  abdominal  pain,  and  vaginal  bleeding,  often  with the passage of placental tissue. Postabortal infec- tion  typically  has  its  onset  within  4  days  of  the  procedure.

Physical findings include an elevated temperature, tachycardia, tachypnea, and abdominal tenderness.  Along  with  bacteremia,  hypotension  and  frank  shock  may occur, and the patient may be agitated and disori- ented.  Pelvic  examination  reveals  a  sanguinopurulent  discharge  and  uterine  tenderness,  with  or  without  adnexal and parametrial tenderness. It is important to inspect for cervical or vaginal lacerations, especially with a suspected illegal abortion.  Transvaginal  ultra- sonography  can  assess  the  intrauterine  cavity  for  the  presence  of  retained  products  of  conception,  suggest- ing the need for uterine curettage.

Simple  endometritis,  defined  as  low-grade  fever  associated  with  mild  uterine  tenderness  after  uncom- plicated elective abortion, can be treated with oral regi- mens  recommended  for  the  treatment  of  PID  (see  Table 22-6).

Laboratory  evaluation  of  patients  with  more  than  early  uncomplicated  postabortal  endometritis  should  include  a  complete  blood  count,  urinalysis,  culture  of  a  specimen  of  the  endometrial  cavity  taken  with  an  endometrial  suction  curette,  blood  cultures,  a  com- puterized tomographic (CT) scan of the abdomen and  pelvis, and an upright chest x-ray, looking for a foreign  body or the presence of intrauterine gas. Patients with established infection, as indicated by fever >38° C, pelvic peritonitis, or tachycardia, should be hospital- ized for parenteral antibiotic therapy and prompt uterine evacuation if retained products of concep- tion are suspected.  Table  22-8  contains  the  first- line  antibiotic  regimen  for  women  with  suspected   sepsis.

TABLE 22-8

RECOMMENDED ANTIBIOTIC REGIMENS FOR POSTPARTUM/POSTABORTAL INFECTION*

Oral Regimens for Patients with Milder Disease Treated as Outpatients

Trimethoprim/sulfamethoxazole 160/800 mg by mouth every 12 hours

PLUS

Metronidazole 500 mg by mouth every 12 hours

OR

Amoxicillin-clavulanic acid 875 mg/125 mg by mouth twice daily

Parenteral Regimen for Moderate to Severe Disease in Hospitalized Patients

Triple Antibiotics

Ampicillin 2 g then 1 g IV every 6 hours

PLUS

Gentamicin 3 mg/kg of body weight IV daily

PLUS

Clindamycin 900 mg IV every 8 hours

OR

Carbapenems

Ertapenem 1 g IV daily

Meropenem 1 g IV every 8 hours

Imipenem-cilastatin 500 mg IV every 6 hours

OR

Extended Spectrum Penicillins with β-lactamase Inhibitors* Penicillin-tazobactam 4.5 g IV every 8 hours

From Centers for Disease Control and Prevention. The sexually transmitted infections treatment guidelines. MMWR Morb Mortal Wkly Rep 2015. IV, Intravenously. *Outpatient and inpatient regimens should include antimicrobial therapy against anaerobes.

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Impact on Pregnancy The course of acute hepatitis is unaltered in preg- nancy.  Fetal  infection  may  occur  and  is  most  likely  if  maternal  infection  occurs  in  the  third  trimester.  Chronic active hepatitis is associated with an increased risk of prematurity, low birth weight, and neonatal death. Maternal prognosis is very poor if the  disease  is  complicated  by  cirrhosis,  varices,  or  liver  failure.

If a pregnant woman is found on screening to be HBsAg-positive, liver function tests and a complete hepatitis panel should be performed.  Household  members  and  sexual  contacts  should  be  tested  and  offered  vaccination  if  they  are  susceptible.  Transmis- sion to the infant is believed to occur by direct contact during delivery.  Therefore  the  newborn  should  be  given hepatitis immune globulin and hepatitis vaccine  soon after delivery, which will reduce the risk of infec- tion to less than 10%. Pregnant women at high risk for becoming infected with hepatitis B who test negative for the HBsAg should be offered vaccination.  Avail- able vaccines are produced by recombinant DNA tech- nology and are therefore safe for use in pregnancy. The  Centers  for  Disease  Control  and  Prevention  has  also  recommended  that  all  children  receive  vaccination  against hepatitis B.

Hepatitis C (HCV ) is the most common chronic blood borne infection in the United States.  Vertical  transmission  is  reported  in  3-6%  of  pregnant  women.  Co-infection with HIV has been shown to increase the  risk  of  vertical  transmission  of  HCV.  In  HIV-negative  women,  route  of  delivery  does  not  influence  vertical  transmission.  Amniocentesis  is  a  potential  risk  for  transmission. There is no evidence of an increased risk  of  HCV  transmission  in  HIV-negative  women  who  breastfeed.

Treatment for HCV has recently become available for infected individuals. Treatment during pregnancy,  however,  has not been adequately studied  and  all  treatment  (for  pregnant  and  nonpregnant  women)  is  evolving.  The  latest  information  regarding  potential  treatment  should  be  obtained  from  the  American  College  of  Obstetricians  and  Gynecologists  (ACOG)  website  at  www.acog.org,  the  Centers  for  Disease  Control  at  www.cdc.gov,  or  www.perinatology.com;  search for “infections during pregnancy.”

PERINATAL INFECTIONS Perinatal infections are sometimes listed using the acronym “TORCH,” the letters standing for Toxoplas- mosis, Other, Rubella, Cytomegalovirus, and Herpes simplex virus.  The  category “other”  includes  syphilis,  hepatitis  B  and  C,  and  HIV.  Hepatitis  and  HIV  have  been  discussed  above.  The  potential  perinatal  effects  from  HSV,  syphilis,  and  the  other  TORCH  infections   are covered briefly below.

Human Immunodeficiency Virus, Hepatitis B and C, and Perinatal Infections HUMAN IMMUNODEFICIENCY VIRUS

Women who are infected with other STIs are at least two to five times more likely to acquire HIV. Without  treatment, nearly all HIV-infected individuals will prog- ress  to  acquired  immunodeficiency  disease  syndrome  (AIDS)  and  die  of  the  illness.  It  is  therefore  recom- mended by the Centers for Disease Control (CDC) in the  United  States  to  screen for HIV in those seeking care for any STIs. Despite the predictable effect on morbid- ity and mortality from HIV, some women may be inad- equately treated. This is often due to, or complicated by,  inadequate adherence to therapy, once started.

The estimated prevalence of HIV in the United States  has  been  reported  to  be  0.32%  of  all  adults  based  on  testing  a  sample  of  over  11,000  individuals  between  1988 and 1994. Although all patients who acquire HIV  should be treated, the commencement of antiretroviral  (ARV )  therapy  should  be  individualized,  especially in pregnant patients, where vertical transmission is a concern and may cause a perinatal problem.

Recommendations  regarding  HIV  screening  and  treatment  of  pregnant  women  and  prophylaxis  for  perinatal  transmission  of  HIV  have  evolved  consider- ably  and  continue  to  do  so  worldwide  over  the  last  25  years,  reflecting  changes  in  the  epidemiology  and  the  science of prevention. With the implementation of rec- ommendations  for  universal  prenatal  HIV  counseling  and  testing,  ARV  prophylaxis,  scheduled  cesarean  delivery,  and  avoidance  of  breastfeeding,  the rate of perinatal transmission of HIV has decreased to less than 2% in the United States and Europe.

The benefits of ARV drugs for a pregnant woman must be weighed against the risks of adverse events to her, the fetus, and newborn.  Combination  drug  regimens  are  considered  the  standard  of  care  both  for  treatment of HIV infection and for prevention of peri- natal transmission of HIV. After counseling and discus- sion about ARV drug use during pregnancy, a pregnant  woman’s informed choice should be respected.

The  latest  perinatal  HIV  guidelines  are  constantly  being  updated  and  can  be  accessed  at  http://aidsinfo  .nih.gov/guidelines/html/3/perinatal-guidelines/0.

HEPATITIS B AND C The hepatitis B virus is a DNA virus that is transmitted  via blood, saliva, vaginal secretions, semen, and breast  milk and across the placenta. The population at great- est risk includes intravenous drug users, homosexuals,  individuals  of  Asian  descent,  and  health  care  workers.  Infection  with  the  virus  is  either  asymptomatic  or  expressed as acute hepatitis. Ten percent of individuals  go on to develop chronic active or persistent hepatitis.

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pregnancy.  Pregnant  women  who  are  affected  are  usually  exposed  to  children  with  the  infection.  The highest rate of transmission is in the third trimester but the severity of fetal effects is highest in the first trimester.  The  infection  may  also  be  “reactivated”  during pregnancy. Perinatal fetal effects include jaun- dice, thrombocytopenia, intrauterine growth restric- tion (IUGR), and microcephaly.

The  “blueberry muffin baby”  has  been  described  with the appearance caused by numerous petechiae on  the  skin.  Amniotic  fluid  is  positive  (by  PCR)  for  CMV  with  active  infection,  and  for  4  to  8  months  maternal  IgM antibodies for CMV may be detected and are also  indicative of active infection. IgG avidity testing is rec- ommended  in  those  women  with  IgM  antibodies.  Avidity  testing  provides  an  estimate  of  the  duration  of  a primary CMV infection.

Treatment  has  not  been  well  studied  during  preg- nancy. Ganciclovir and valacyclovir have been used in nonpregnant women and in neonates after birth. For  the latest recommendations on vaccination, diagnosis,  and  treatment  of  CMV,  consult  the  ACOG  website  at  www.acog.org,  the  Centers  for  Disease  Control  at  www.cdc.gov,  or  www.perinatology.com;  search  for  “infections during pregnancy.”

Herpes Simplex It is estimated that 20-30% of pregnant women are IgG positive for HSV-2 before pregnancy and are therefore at risk for shedding virus during preg- nancy.  Gravidas  with  a  history  of  genital  herpes  should  receive  antiviral  prophylaxis  during  the  third  trimester.  About  2-4%  of  IgG  negative  women  acquire  HSV-2  during  pregnancy  and  are  usually  not  diag- nosed  because  of  a  lack  of  symptoms.  Immunocom- promised women and those who have another STI are  at highest risk. The mother may develop disseminated  HSV disease that can cause hepatitis and encephalitis.  The neonatal effects may be severe and are due to exposure to the virus in utero or during delivery. The  complications  of  disseminated  neonatal  disease  are  seizures,  tremors,  poor  feeding,  and  bulging  fonta- nelles.  Up  to  30%  of  newborns  may  die,  with  more  than  50%  having  neurological  damage  despite  antivi- ral therapy.

Syphilis A perinatal infection with Treponema pallidum may cause stillbirth, IUGR, nonimmune hydrops, rhinitis, hepatosplenomegaly, “mulberry molars” and “saber shins,” “saddle nose deformity,” and interstitial kera- titis. Prenatal testing for syphilis is mandated in the United States.

VERTICAL TRANSMISSION OF SYPHILIS •  Primary: 90-100% •  Secondary: 70-90%

Toxoplasmosis Toxoplasmosis  is  caused  by  an  obligate  intracellular  protozoan  organism  Toxoplasma gondii.  It  is  uncom- mon and occurs most often in Europe. Household cats  may  play  a  role  in  contaminating  soil,  which  is  then  transferred  to  a  litter  box  in  the  house.  Uncooked/ undercooked food from infected beef, lamb, and other  animals  is  another  source.  The infection is usually without symptoms in the mother, but when symp- toms do occur they involve fever, rash, and fatigue.  Testing  of  the  mother  is  by  serology,  although  poly- merase chain reaction (PCR) testing is under develop- ment  and  about  7%  of  infected  pregnant  women  will  have  neonates  with  congenital  toxoplasmosis.  This  infection  can  result  in  an  enlarged  placenta  and  fetal  hepatomegaly and ascites. Fetal microcephaly occurs in 5% of affected cases.  Routine  screening  is  not  rec- ommended  because  of  the  relatively  rare  occurrence  with  the  following  preventive  activities  encouraged:  avoidance of raw or undercooked meat or eggs; washing  fruits and vegetables; avoidance of cat litter when preg- nant;  and  keeping  household  cats  away  from  outside  (potentially contaminated) soil.

Treatment during pregnancy for infected women is available using spiramycin.  The  latest  dosage  and  duration  should  be  obtained  from  the  ACOG  website,  the  Centers  for  Disease  Control  at  www.cdc.gov,  or  www.perinatology.com;  search  for  “infections  during  pregnancy.”

Rubella Rubella is caused by an RNA virus with primary infec- tions  occurring  mostly  in  unvaccinated  children  and  adolescents.  Vaccination has reduced the rate of infection in pregnant women with a reported inci- dence of <0.1% of pregnancies. The vaccine should not be given during pregnancy.  Rubella  spreads  by  respiratory  droplets,  and  has  an  incubation  period  of  2  to  3  weeks.  The  symptoms  are  malaise  and  myalgia  in  the  presence  of  a  nonpruritic,  maculopapular,  reddish rash. The highest risk to the fetus is associated  with infection during the first trimester. Deafness, reti- nopathies,  and  central  nervous  system  and  cardiac  malformations  are  the  most  common  teratogenic  manifestations.  No  treatment  is  available  for  rubella,  but prevention using the measles, mumps and rubella  (MMR)  vaccine  is  strongly  recommended.

Cytomegalovirus Cytomegalovirus (CMV ) is the most common intra- uterine viral infection. Some studies show up to 2.5%  of  all  neonates  may  be  affected.  The transmission is via contaminated urine, blood, saliva, semen, or cer- vical secretions.  There  are  usually  no  symptoms,  resulting  in  a  low  rate  of  diagnosis.  A vaccine is available but should not be administered during

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disease.  In  those  patients  with  a  history  of  penicillin- allergy,  a  penicillin  skin  test  to  check  that  a  genuine  allergy  exists  should  be  offered.  If  the  penicillin  skin   test  is  negative,  treatment  with  penicillin  should  proceed.

Patients who have a positive penicillin skin test should be desensitized and treated with penicillin,  because the risks associated with syphilis during preg- nancy  outweigh  the  risks  of  inpatient  treatment  of  a  penicillin  allergy.  Close  monitoring  of  nontreponemal  tests  (RPR  or  VDRL)  should  be  followed  to  ensure  an  appropriate  response  to  therapy.  Because  syphilis  is  a  sexually transmitted infection, all the patient’s partners  should be tested and treated appropriately, to decrease  the risk of reinfection.

•  Early latent: 40-60% •  Late latent: 10% •  Tertiary: 5%

Pregnancy can be affected at any gestational age. As  the  pregnancy  advances,  the  frequency  of  infection  increases  and  the  severity  of  fetal  infection  decreases.  ACOG  recommends  that  all  patients  be  tested  at  their  first  prenatal  visit.  Repeat  testing  is  recommended  in  the  third  trimester  (at  28  to  32  weeks)  and  again  at  delivery in women who are at high risk for syphilis, or  those who had a positive screening test in the first tri- mester. Any woman who delivers a stillborn infant after  20 weeks should also be tested.

The treatment for syphilis in pregnancy is benza- thine penicillin.  Dosage  depends  on  the  stage  of  the 

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23  Pelvic Floor Disorders Pelvic Organ Prolapse, Urinary Incontinence, and Pelvic Floor Pain Syndromes

C H

A P

T ER

AMY E. ROSENMAN

■  Effective clinical evaluation of patients with disorders of  the  female  pelvic  floor,  such  as  pelvic  organ  prolapse  (POP)  and  stress  urinary  incontinence  (SUI),  requires  a  clear understanding of female pelvic anatomy. Defects of  vaginal support include anterior vaginal prolapse (cysto- cele),  posterior  vaginal  prolapse  (rectocele  and  entero- cele),  and  apical  uterine  prolapse.  Symptoms  of  POP  generally affect quality of life, but when complete uterine  prolapse  (procidentia)  occurs,  ureteral  obstruction  and  kidney damage may result.

■  A  staging  system  has  been  developed  for  POP  so  that  outcomes  of  surgical  and  nonsurgical  treatment  can  be  quantified,  followed,  and  improved.  Medical  manage- ment  of  mild  to  moderate  cases  of  POP  includes  pelvic  muscle  exercises  and  the  use  of  pessaries.  Surgical  pro- cedures  include  anterior  and  posterior  repairs  (colpor- rhaphy) using existing natural tissue and synthetic mesh  materials,  vaginal  vault  suspension  (colpopexy)  for  apical  vaginal  prolapse,  and  complete  vaginal  closure  procedures  (colpocleisis)  for  some  women  who  no  longer desire coital function. Robot-assisted procedures  are now used for some of these interventions.

■  Urinary incontinence is defined as the involuntary loss of  urine that is a social or hygienic problem. It is estimated  that as many as 50% of women have some urinary incon- tinence  at  some  time  during  their  lives.  SUI  occurs  in  response  to  physical  exertion,  coughing,  or  sneezing.  After appropriate testing to document SUI, surgical pro- cedures  include  retropubic  urethropexy,  suburethral  sling placement, or bulking injections.

■  Overactive bladder (OAB) and urge urinary incontinence  (UUI) are used interchangeably to describe incontinence  that occurs when there is a strong urge to pass urine with  a  decreased  ability  to  prevent  passage.  Treatments  include behavior modification (bladder training), medi- cations, electrical stimulation, or injections.

■  Overflow  incontinence  and  urinary  fistulas  may  also  be  causes  of  involuntary  passing  of  urine.  Neuropathies  account  for  most  of  the  cases  of  overflow  incontinence,  whereas pelvic surgery and radiation damage cause 95%  of  fistulas.  Surgical  repair  of  fistulas  is  almost  always  needed.  Pelvic  pain  disorders  include  painful  bladder  and myofascial pelvic pain syndrome.

CLINICAL KEYS FOR THIS CHAPTER

An  accurate  knowledge  of  the  anatomy  of  the  female  pelvic  floor  enables  the  student  to  understand  pelvic  organ  prolapse  and  its  management.  Female  pelvic  medicine  and  reconstructive  surgery  (FPMRS)  is  the  newest board-certified subspecialty within the special- ties  of  obstetrics  and  gynecology  as  well  as  urology.  This  new  certification  process  recognizes  the  impor- tance  of  disorders  of  the  female  pelvic  floor  and  the  increased  knowledge  and  skills  necessary  to  evaluate  and treat these disorders.

Normal Pelvic Anatomy and Supports The bony pelvis acts like a basket, supporting the mus- cular  attachments,  pelvic  organs,  vessels,  and  nerves  contained  within  it.  The  pelvic  organs,  including  the  vagina,  uterus,  bladder,  urethra,  and  rectum,  are  sup- ported  within  the  pelvis  by  the  bilaterally  paired  and  posteriorly  fused  levator  ani  muscles.  The anterior separation between the levator ani is called the

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Pelvic Organ Prolapse Pelvic organ prolapse (POP) refers to the protrusion of  the pelvic organs into the vaginal canal or beyond the  vaginal opening. It occurs because of a weakness in the  endopelvic  fascia  investing  the  vagina,  along  with  its  ligamentous supports. Defects in vaginal support may occur in isolation (e.g., anterior vaginal wall only), but they are more commonly combined.  The  nomencla- ture of POP has evolved such that older terms such as  cystocele, rectocele,  and  enterocele  have  been  replaced  by more anatomically precise terms (Figure 23-1).

ANTERIOR VAGINAL PROLAPSE (CYSTOCELE) The anterior vagina is the most common site of vaginal prolapse. Women  with  this  type  of  defect  will  describe symptoms of vaginal fullness, heaviness, pres- sure,  and/or  discomfort  that  often  progress  over  the 

levator hiatus. Inferiorly, the levator hiatus is covered by the urogenital diaphragm. The urethra, vagina, and rectum pass through the levator hiatus and uro- genital diaphragm as they exit the pelvis. The endo- pelvic fascia is a visceral pelvic fascia that invests the pelvic organs and forms bilateral condensations referred to as ligaments (i.e., pubourethral, cardinal, and uterosacral ligaments).  These  ligaments  attach  the  organs  to  the  fascia  of  the  pelvic  side  walls  and  bony  pelvis.  Damage  to  the  vagina  and  its  support  system  allows  the  urethra,  bladder,  rectum,  and  small  bowel to herniate and protrude into the vaginal canal.

The perineal body is a central point for the attach- ment  of  the  perineal  musculature.  Although the con- tents of the abdominal cavity bear down on the pelvic organs, they remain suspended in relation to each other and to the underlying levator sling and perineal body.

FIGURE 23-1 Diagrammatic representation of the four types of vaginal uterine prolapse.

Anterior vaginal prolapse (cystocele) Lower posterior vaginal

prolapse (rectocele)

Apical vaginal/uterine prolapse Upper posterior vaginal

prolapse (enterocele)

C H A P T E R 23 Pelvic Floor Disorders 293

Symptoms of POP mainly affect a woman’s quality of life. However, significant sequelae of POP can occur  in neglected cases of procidentia, which may be com- plicated  by  excessive  purulent  discharge,  decubitus  ulceration,  and  bleeding.  Ureteral obstruction with hydronephrosis is also a possible result of complete procidentia.

ETIOLOGY OF PROLAPSE The pelvic fascia, ligaments, and muscles may become attenuated from excessive stretching during preg- nancy, labor, and difficult vaginal delivery, especially with forceps or vacuum assistance.  Asian  and  black  women appear less likely than white women to develop  prolapse.

Increased intraabdominal pressure resulting from a chronic cough, ascites, repeated lifting of heavy weights, or habitual straining as a result of constipa- tion may predispose women to prolapse.  Atrophy  of  the  supporting  tissues  with  aging,  especially  after  menopause, also plays an important role in the initia- tion  or  worsening  of  pelvic  relaxation.  Iatrogenic factors include failure to adequately correct all pelvic support defects at the time of pelvic surgery, such as hysterectomy.

DIAGNOSIS Vaginal  examination  is  facilitated  by  using  a  single- blade  speculum.  While  the  posterior  vaginal  wall  is  being  depressed,  the  patient  is  asked  to  strain  down.  This  demonstrates  the  descent  of  the  anterior  vaginal  wall  consistent  with  prolapse  and  urethral  displace- ment.  Similarly,  retraction  of  the  anterior  vaginal  wall  during  straining  will  accentuate  posterior  vaginal  defects  and  uncover  an  enterocele  and  rectocele  if  present.  Rectal and vaginal examinations are often useful to demonstrate a rectocele and to distinguish it from an enterocele.

QUANTIFYING AND STAGING PELVIC ORGAN PROLAPSE The preferred method for describing and documenting  the severity of POP is the Pelvic Organ Prolapse Quan- tification (POP-Q) system.  The  extent  of  prolapse  is  evaluated  and  measured  relative  to  the  hymen,  which  is  a  fixed  anatomic  landmark. The  anatomic  positions  of the six defined points for measurement are denoted  in  centimeters  above  the  hymen  (negative  number)   or  centimeters  below  the  hymen  (positive  number).  The  plane  at  the  level  of  the  hymen  is  defined  as  zero  (Figure 23-3).

Stages of POP can be assigned according to the most  severe portion of the prolapse after the full extent of the  protrusion has been determined. An ordinal system is  used  for  measurements  of  different  points  along  the  vaginal  canal,  which  allows  for  better  communication 

course  of  the  day  and  are  most  noticeable  after  pro- longed  standing  or  straining.  Women  may  have  to  apply  manual  pressure  to  empty  their  bladder  com- pletely.  Other  symptoms  include  stress  urinary  incon- tinence  (SUI),  urinary  urgency,  and  frequency.  Significant  anterior  vaginal  wall  prolapse  that  pro- trudes beyond the vaginal opening (hymen) can cause  urethral  obstruction  caused  by  kinking,  resulting  in  urinary retention or incomplete bladder emptying.

POSTERIOR VAGINAL PROLAPSE (RECTOCELE AND ENTEROCELE) Posterior vaginal defects occur when there is weakness  in the rectovaginal septum. Symptoms can be indistin- guishable  from  other  types  of  prolapse  because  the  discomfort,  pressure,  and  the  sense  of  a  vaginal  bulge  are nonspecific. When difficulties with bowel function and defecation occur, lower posterior vaginal pro- lapse is likely. Straining or the need to manually splint  for complete bowel elimination may occur. Upper pos- terior vaginal wall prolapse is nearly always associated  with herniation of the pouch of Douglas, and because  this  is  likely  to  contain  loops  of  bowel,  it  is  called  an  enterocele.

APICAL VAGINAL UTERINE PROLAPSE Although  vaginal  prolapse  can  occur  without  uterine  prolapse,  the  uterus  cannot  descend  without  carrying  the upper or apical portion of the vagina with it.

Complete procidentia (uterine prolapse through the vaginal hymen) represents failure of all the vaginal supports (Figure 23-2). Hypertrophy, elongation, con- gestion, and edema of the cervix may sometimes cause  a large protrusion of tissue beyond the hymen that may  be mistaken for a complete procidentia. Vaginal vault prolapse or eversion of the vagina may be seen after vaginal or abdominal hysterectomy  and  represents  failure of the supports around the upper vagina.

FIGURE 23-2 Complete uterine prolapse (procidentia). Note the lesions on either side of cervical dimple (arrows), representing pressure ulcerations from clothing/undergarments. (Courtesy C.M. Tarnay, MD, Ronald Reagan—UCLA Medical Center.)

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useful  for  interim  treatment  in  those  wishing  to  delay  surgery.

Pessaries require proper fitting and must be selected  in  the  appropriate  type  and  size.  They  should  be  removed, cleaned, and reinserted every 6 to 12 weeks.  They  may  cause  vaginal  irritation  and  ulceration.  Neglect may result in serious consequences,  includ- ing  fistula  formation,  impaction,  bleeding,  and  infec- tion.  Many  patients  are  capable  of  caring  for  their  pessaries themselves. In those cases, the patient inserts,  removes,  and  cleans  her  pessary  several  times  each  week,  if  not  daily.  It  is  similar  to  the  care  and  use  of  a  contraceptive diaphragm.

Surgical Treatment The main objectives of surgery are to relieve symptoms  and restore normal anatomic relationships and visceral  function.  Preservation  or  restoration  of  satisfactory  coital  function,  when  desired,  and  a  lasting  operative  result are also important goals.

REPAIR OF VAGINAL PROLAPSE. Anterior colporrhaphy  corrects  anterior  vaginal  wall  prolapse  and  helps  support the urethra. It involves plication of the pubo- cervical fascia  to  support  the  bladder  and  urethra.  When  the  anterior  prolapse  involves  a  direct  detach- ment  of  lateral  vaginal  support,  it  is  considered  a 

between  clinicians.  This  staging  system  enables  more  objective tracking of surgical outcomes.

MANAGEMENT Prophylactic  measures  to  mitigate  the  symptoms  of  POP  include  identifying  and  treating  chronic  respira- tory  and  metabolic  disorders,  correction  of  constipa- tion  and  intraabdominal  disorders  that  may  cause  repetitive  increases  in  intraabdominal  pressure,  and,  for  menopausal  women,  administration  of  estrogen.  Failure to recognize and treat significant support defects at the time of concomitant gynecologic surgery may lead to progression of existing prolapse  and the development of urinary incontinence or reten- tion and urinary tract infections (UTIs).

Nonsurgical Treatment When only a mild degree of pelvic relaxation is present, pelvic floor muscle exercises may improve the tone of the pelvic floor musculature. Pessaries  (Figure 23-4), which provide intravaginal support, may be used to correct prolapse by internally supporting the vagina. They can be considered when the patient is medically unfit  or  refuses  surgery  or  during  preg- nancy and the postpartum period. They are also useful  to promote healing of a decubitus ulcer before surgery.  In many patients, pessaries are the treatment of choice,  as they are almost risk-free, immediately available, and 

FIGURE 23-4 Some types of vaginal pessaries used for prolapse. A, Gellhorn; B, Shaatz; C, ring; D, ring with support; E, cube; F, Smith; G, Hodge; H, Hodge with support for cystocele; I, Infla- toball; J, Gehrung; K, donut.

A

F

G I

H

J

K

E

B C

D

FIGURE 23-3 Illustration showing a side view of the female pelvis. Six sites (points Aa, Ba, C, D, Bp, and Ap), genital hiatus (gh), perineal body (pb), and total vaginal length (Tvl) used for pelvic organ support quantitation. (Reproduced with permission from Bump RC, Mattiasson A, Bø K, et al: The standardization of termi- nology of female pelvic organ prolapse and pelvic floor dysfunc- tion. Am J Obstet Gynecol 175:10–17, 1996.)

Pubic symphysis

gh pb

Ap

Aa

3 cm Ba C

D

Bp

Tvl

C H A P T E R 23 Pelvic Floor Disorders 295

or relatively young patient or for a woman with a prior  failed prolapse repair. Abdominal sacrocolpopexy with  polypropylene  mesh  has  been  performed  for  over  30  years  using  an  open  incision,  and  more  recently  lapa- roscopically assisted procedures have been used. Since  2008, sacrocolpopexy has been performed with the aid  of a surgical robot. This is a minimally invasive abdom- inal  operation  in  which  mesh  is  placed  between  the  bladder  and  vagina,  the  rectum  and  the  vagina,  and  over  the  apex  of  the  vagina  or  the  cervical  stump. The  mesh is supported by attaching it to the sacral promon- tory. The robot-assisted procedure is now considered to give the longest-lasting results for POP.

VAGINAL CLOSURE PROCEDURES. For women with advanced vaginal prolapse who no longer desire coital function, there are less invasive surgical options. A LeFort colpocleisis  involves  suturing  the  partially  denuded  anterior  and  posterior  vaginal  walls  together  in  such  a  way  that  the  uterus  remains  in  situ  and  is  supported  above  the  partially  occluded  vagina.  In women with posthysterectomy prolapse, a com- plete colpocleisis  involves  total  obliteration  of  the  vagina. These “obliterative” procedures have tradition- ally been reserved for elderly women who are not likely  to tolerate more invasive reparative operations. Most of  these  women  will  get  complete  resolution  of  their  symptoms with a repair that is much less invasive and  is associated with fewer risks and complications.

Urinary Incontinence Urinary incontinence is defined as the involuntary loss of urine that is a social or hygienic problem.  Urinary  incontinence  has  been  reported  to  affect  15-50%  of  women.  The  problem  increases  in  preva- lence  with  age,  rising  above  50%  in  elderly  persons   in  nursing  homes.  It is estimated that the direct financial cost of urinary incontinence in the United States is between $10 billion and $15 billion per year.

ANATOMY AND PHYSIOLOGY OF THE LOWER URINARY TRACT In  the  adult  woman,  the  urethra  is  a  muscular  tube,  3  to  4 cm  in  length,  lined  proximally  with  transitional  epithelium  and  distally  with  stratified  squamous  epi- thelium.  It  is  surrounded  mainly  by  smooth  muscle.  The striated muscular urethral sphincter, which sur- rounds the distal two-thirds of the urethra, contrib- utes about 50% of the total urethral resistance and serves as a secondary defense against incontinence.  It is also responsible for the interruption of urinary flow  at the end of micturition.

The two posterior pubourethral ligaments provide a strong suspensory mechanism for the urethra and serve to hold it forward and in close proximity to the

paravaginal defect.  Paravaginal  defect  repairs  involve  exposure of the retropubic space. Interrupted perma- nent sutures are used to reattach bilaterally the ante- rior superior vaginal sulci to the arcus tendineus fasciae (“white line”), extending from the ischial spine  to the lower edge of the pubic ramus. When the defect  is more central, a midline plication of endopelvic fascia  is  effective  in  adding  support  to  the  anterior  vaginal  wall. Polypropylene mesh may be used in appropriate  patients to augment the weakened native tissue repair.  In the presence of SUI, additional supportive measures  are  taken  to  achieve  suspension  of  the  bladder  neck  and proximal urethra.

Posterior colporrhaphy corrects a posterior vaginal wall prolapse and is similar in principle to anterior colporrhaphy. Site-specific posterior vaginal repairs can be performed after identification of the discrete endopelvic fascial breaks and reapproximation of this thicker tissue identified during rectal examina- tion. Perineorrhaphy repairs a deficient perineal body.  The  outcomes  of  the  site-specific  repair  are  similar  to  the results of midline plication of the endopelvic fascia.

Recent  modifications  of  these  procedures  involve  the  use  of  permanent  suture  or  the  addition  of  graft  materials  to  augment  the  durability  of  the  repair.   These modifications can be accomplished using mini- mally  invasive  techniques  such  as  endoscopic  repair.  Permanent mesh grafts are not recommended in the posterior compartment,  because  the  incidence  of  complications is higher and outcomes are not as good  as those achieved with repairs performed using native  tissues.

REPAIR OF APICAL PROLAPSE. When  the  uterus  is  present,  hysterectomy  may  be  performed  to  facilitate  exposure  of  the  apical  support  structures.  Hysterec- tomy,  however,  is  not  an  absolute  requirement  in  set- tings where uterine removal is not otherwise indicated  or  desired.  The  repair  of  apical  defects  may  require  peritoneal  entry  for  the  repair of an enterocele.  After  identification  of  the  enterocele,  the  contents  are  reduced,  the  neck  of  the  peritoneal  sac  is  ligated,  and  the defect is repaired by approximating the uterosacral  ligaments and levator ani muscles to restore continuity  in  the  endopelvic  fascia.  The uterosacral ligaments can be reattached to the cervix by either the vaginal or abdominal route.

Vaginal vault suspension (colpopexy) for apical prolapse is performed to secure a durable fixation point for the top of the vagina. This can be accom- plished vaginally or abdominally  by  suspending  the  vaginal  vault  to  the  sacrum,  the  sacrospinous  liga- ments,  the  uterosacral  ligaments,  or  other  firm  points  of  fixation.  This  can  be  done  with  natural  existing  tissues or with polypropylene mesh.

Robot-assisted surgery  for  POP  may  be  performed  when a stronger attachment is needed in a very active 

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the intraurethral pressure exceeds the intravesical pressure.  The  pubourethral  ligaments  and  surround- ing endopelvic fascia support the urethra so that abrupt  increases  in  intraabdominal  pressure  are  transmitted  equally to the bladder and proximal third of the urethra,  thus maintaining a pressure gradient between the two  structures.  In  addition,  a  reflex  contraction  of  the  levator ani compresses the mid-urethra, decreasing the  likelihood of urine loss.

Stress Urinary Incontinence Stress urinary incontinence (SUI) is involuntary leakage of urine in response to physical exertion, sneezing, or coughing.

ETIOLOGY The most commonly accepted theory for the patho- genesis of SUI is urethral hypermobility due to vaginal wall relaxation that displaces the bladder neck and proximal urethra downward.  When  this  occurs,  increased  intraabdominal  pressure  caused  by  coughing,  sneezing,  or  physical  exertion  is  no  longer  transmitted  equally  to  the  bladder  and  proximal  urethra. The normal urethral resistance is overcome by  this  increased  bladder  pressure,  and  leakage  of  urine  results.

The second possible mechanism is intrinsic sphincter deficiency whereby the urethra fails to close  in  response  to  increases  in  intraabdominal  pressure.  This cause of SUI is analogous to having a leaky “valve”  in the urethra.

Factors that contribute to SUI include childbearing,  previous  urogenital  surgery  or  trauma,  pelvic  radia- tion,  estrogen  deficiency  (menopause),  and  medica- tions, such as diuretics and α-adrenergic blockers.

PELVIC EXAMINATION Inspection  of  the  vaginal  walls  should  be  performed  with  a  single-blade  speculum,  which  allows  optimal  visualization  of  the  anterior  vaginal  wall  and  urethro- vesical  junction.  Scarring,  tenderness,  and  rigidity  of  the  urethra  from  previous  vaginal  surgeries  or  pelvic  trauma may be indicated by a scarred anterior vaginal  wall. Because the distal urethra is estrogen-dependent,  the  patient  with  urogenital  atrophy  also  has  atrophic  urethritis.

DIAGNOSTIC TESTS AND PROCEDURES Cough Stress Test The patient is examined with a full bladder in the lithotomy position. While the physician observes the urethral meatus, the patient is asked to cough. SUI is  present  if  short  spurts  of  urine  escape  simultaneously  with  each  cough.  A  delayed  leakage,  or  loss  of  large  volumes  of  urine,  suggests  uninhibited  bladder  con- tractions.  If  loss  of  urine  is  not  demonstrated  in  the 

pubis under conditions of stress.  They  extend  from  the  lower  part  of  the  pubic  bone  to  the  urethra  at  the  junction of its middle and distal thirds.

INNERVATION The  lower  urinary  tract  is  under  the  control  of  both  parasympathetic  and  sympathetic  nerves.  The para- sympathetic fibers originate in the sacral spinal cord segments S2 through S4.  Stimulation  of  the  pelvic  parasympathetic nerves and administration of cholin- ergic drugs cause the detrusor muscle to contract. Anti- cholinergic drugs reduce vesical pressure and increase  bladder capacity.

The sympathetic fibers originate from thoraco- lumbar segments (T10-L2) of the spinal cord.  The  sympathetic  system  has  α-  and  β-adrenergic  compo- nents. The β-fibers terminate primarily in the detrusor  muscle, whereas the α-fibers terminate primarily in the  urethra. α-Adrenergic stimulation contracts the bladder  neck and the urethra and relaxes the detrusor muscle.  β-Adrenergic  stimulation  relaxes  the  urethra  and  the  detrusor  muscle.  The pudendal nerve (S2-S4) pro- vides motor innervation to the striated urethral sphincter.

FACTORS INFLUENCING BLADDER BEHAVIOR Sensory Innervation Afferent impulses from the bladder, trigone, and proxi- mal  urethra  pass  to  the  S2  through  S4  levels  of  the  spinal cord by means of the pelvic hypogastric nerves.  The sensitivity of these nerve endings may be enhanced  by acute infection, interstitial cystitis, radiation cystitis,  and  increased  intravesical  pressure.  The  latter  may  occur  in  the  standing  or  bending-forward  position  or  in association with obesity, pregnancy, or pelvic tumors.

Inhibitory impulses, probably relayed by the puden- dal nerve, also pass to S2 through S4 following mechan- ical stimulation of the perineum and anal canal. Their  passage may explain why pain in this region can cause  urinary retention or urgency and frequency.

Central Nervous System In infancy, the storage and expulsion of urine are auto- matic and controlled at the level of the sacral reflex arc.  Later, connections to the higher centers become estab- lished,  and  by  training  and  conditioning,  this  spinal  reflex becomes socially influenced so that voiding can  be voluntarily accomplished. Although organic neuro- logic diseases may interrupt the influence of the higher  centers on the spinal reflex arc, patterns of micturition  may  also  be  profoundly  altered  by  mental,  environ- mental, and sociologic disturbances.

CONTINENCE CONTROL The bladder must store and hold urine painlessly and then, in the appropriate social setting, empty urine effectively. The normal bladder holds urine because

C H A P T E R 23 Pelvic Floor Disorders 297

sidered normal. This determination of PVR is helpful in  diagnosing the cause of the incontinence and in assist- ing  with  the  formulation  of  a  treatment  plan.  If  a  woman  has  a  high  PVR,  it  is  important  to  avoid  treat- ments  that  interfere  further  with  emptying  or  that  increase bladder outlet resistance or obstruction.

Urethrocystoscopy Urethrocystoscopy  allows  the  physician  to  examine  inside  the  urethra,  urethrovesical  junction,  bladder  walls, and ureteral orifices. This procedure is useful to  detect  bladder  stones,  tumors,  diverticula,  or  sutures  or mesh from prior surgeries.

Cystometry Cystometry  consists  of  distending  the  bladder  with  known  volumes  of  water  and  observing  pressure  changes  in  bladder  function  during  filling.  The most important observation is the presence of a detrusor reflex and the patient’s ability to control or inhibit this reflex.

The first sensation of bladder filling should occur at volumes of 150 to 200 mL. The critical volume (400 to 500 mL) is the capacity that the bladder muscula- ture tolerates before the patient experiences a strong

lithotomy  position,  the  test  should  be  repeated  with  the patient in a standing position.

Cotton Swab (Q-Tip) Test This test determines the mobility and descent of the urethrovesical junction on straining and allows differentiation from anterior vaginal laxity alone.  With  the  patient  in  the  lithotomy  position,  the  exam- iner  inserts  a  lubricated  cotton  swab  into  the  urethra  to the level of the urethrovesical junction and measures  the angle between the cotton swab and the horizontal.  The  patient  then  strains  maximally,  which  produces  descent  of  the  urethrovesical  junction.  Along  with  the  descent,  the  cotton  swab  moves,  producing  a  new  angle with the horizontal. The normal change in angle is up to 30 degrees. In patients with pelvic relaxation and SUI, the change in cotton swab angle ranges from 50 to 60 degrees or more (Figure 23-5).

Postvoid Residual (PVR) Test This test determines how well the patient empties her  bladder. Within 10 minutes of voiding into the toilet, a  catheter  is  introduced  into  the  bladder  to  see  how  much urine is left behind. This can also be determined  noninvasively  by  ultrasound.  Less  than  50 mL  is  con-

FIGURE 23-5 Diagrammatic representation of the Q-tip (cotton swab) test showing mobility of the urethrovesical junction in a continent patient and in a patient with stress urinary incontinence.

Resting Valsalva

∆ < 30°

∆ > 30°

Resting

NORMAL

STRESS URINARY INCONTINENCE

Valsalva

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(see Figure 23-6, A). In patients with urologic or neuro- logic  abnormalities,  the  detrusor  reflex  may  appear  without the specific instruction to void, and the patient  cannot inhibit it (see Figure 23-6, B). This observation  is  referred  to  as  an  uninhibited detrusor contraction.  Other terms for this disorder include overactive bladder, detrusor hyperreflexia, irritable bladder, unstable bladder, and uninhibited neurogenic bladder.

These  cystometric  procedures  allow  differentiation  between  patients  who  are  incontinent  as  a  result  of  uninhibited  detrusor  contraction  and  those  who  have  SUI. Conversely, the hypotonic bladder accommodates  excessive  amounts  of  gas  or  water  with  little  increase  in intravesical pressure, and the terminal detrusor con- traction is absent when the patient is asked to void (see  Figure  23-6,  C).  The  hypertonic  bladder  is  a  result  of  either  neurologic  disorders  or  fibrosis  of  the  bladder  secondary to inflammation or radiation.

Urethral Pressure Measurements A low urethral pressure may be found in patients with SUI, whereas an abnormally high urethral closing pressure may be associated with voiding difficulties, hesitancy, and urinary retention.

Urethral function can be evaluated with cystomet- ric testing.  The  urethral  closing  pressure  profile  is  a  graphic  record  of  pressure  along  the  length  of  the  urethra. The  urethral  closing  pressure  normally  varies  between 50 and 100 cm H2O. A Valsalva maneuver and/ or  an  abdominal  leak  point  pressure  less  than  60 cm  H2O  or  a  urethral  closure  pressure  of  less  than  20 cm  H2O are suggestive of the diagnosis of intrinsic sphinc- teric deficiency (ISD).

Uroflowmetry Uroflowmetry is performed to record rate of urine flow  through  the  urethra  when  the  patient  is  asked  to  void  spontaneously.

Voiding Cystourethrography In  this  radiologic  investigation,  fluoroscopy  is  used  to  observe bladder filling, the mobility of the urethra and  bladder  base,  and  the  anatomic  changes  during  voiding. The procedure provides valuable information  regarding  bladder  size  and  the  competence  of  the  bladder  neck  during  coughing.  It  may  detect  any  bladder  trabeculation;  vesicoureteral  reflux  during  voiding; funneling of the bladder neck, bladder, or ure- thral diverticula; and outflow obstruction.

Complex Urodynamics This combination of tests includes a cystometrogram, urethral pressure profile and flow study, a Valsalva leak point pressure reading, and an electromyogram.  Complex urodynamics should be reserved for patients  with  severe  incontinence,  those  who  have  had  prior  surgery  for  incontinence,  or  patients  whose  condition 

desire to urinate.  At  this  point,  if  the  patient  is  asked  to void, a terminal contraction may appear and is seen  as a sudden rise in intravesical pressure. At the peak of  the contraction, the patient is instructed to inhibit this  reflex  (indicated  by  arrows  in  Figure  23-6,  A  and  B).  A  healthy  person  should  be  able  to  inhibit  this  detrusor  reflex  and  thereby  bring  down  intravesical  pressure 

FIGURE 23-6 Water cystometry in a healthy patient (A), a patient with detrusor hyperreflexia (B), and a patient with detrusor are- flexia (hypotonic bladder) (C). Arrows in A and B indicate peak of bladder contraction.

100 AREFLEXIA

75

50

25

6004002000

100 HYPERREFLEXIA

75

50

25

0

0

100 NORMAL

75

50

25

0A

B

C INTRAVESICULAR VOLUME (mL)

IN T

R A

V E

S IC

U L

A R

P R

E S

S U

R E

( cm

H 2 O

)

C H A P T E R 23 Pelvic Floor Disorders 299

incontinence.  Kegel exercises before and after deliv- ery may help patients with postpartum urinary incontinence.

Intravaginal Devices Larger  sizes  of  pessaries  (see  Figure  23-5)  have  been  used  to  elevate  and  support  the  bladder  neck  and  urethra. They have been shown to be effective for SUI.  Some are designed to give added support to the urethra.

Surgical Therapy Surgery  is  the  most  successful  and  expeditious  treat- ment  for  SUI.  The  aim  of  all  surgical  procedures  is  to  correct the pelvic relaxation defect and to stabilize and  restore  the  normal  supports  of  the  urethra.  The  approach may be vaginal or abdominal, or a combined  abdominovaginal approach may be used.

ABDOMINAL APPROACH. Abdominal  retropubic  ure- thropexy has a long-term success rate of 80%. The ret- ropubic urethropexy is performed extraperitoneally (in the space of Retzius) by placing sutures in the fascia lateral to and on each side of the bladder neck and proximal urethra and elevating the vesicoure- thral junction by attaching the sutures to the sym- physis pubis (Marshall-Marchetti-Krantz procedure) or to the Cooper ligament (Burch procedure).

Postoperatively, a transurethral or suprapubic cath- eter is left in the bladder for continuous bladder drain- age  for  48  to  72  hours  before  instituting  spontaneous  voiding.  Some  patients  (20-30%)  may  need  prolonged  postoperative  bladder  drainage  (more  than  7  days).  Occasionally, a patient may develop osteitis pubis after  the Marshall-Marchetti-Krantz procedure.

The  recent  popularity  of  operative  laparoscopy  for  many  gynecologic  procedures  has  resulted  in  the  use of the laparoscope for bladder neck suspension pro- cedures. When the laparoscopic procedure is per- formed by placing two sutures on each side of the bladder neck, the long-term success is similar to that achieved with the open abdominal approach for ret- ropubic urethropexy. Figure 23-7 illustrates the suture  placement for a typical retropubic urethropexy.

VAGINAL APPROACH. Suburethral sling procedures have long been used to treat patients whose condition has been refractory to therapy or patients with severe SUI.  Conventional  slings  often  required  harvesting  a  patient’s  own  fascial  tissue  to  be  placed  under  the  bladder neck, but their effectiveness has been plagued  by high rates of urinary retention.

The tension-free synthetic (polypropylene) mesh placed at the level of the mid-urethra was introduced  into  the  United  States  from  Sweden  in  the  late  1990s.  The tension-free vaginal tape was developed as a mini- mally  invasive  technique,  and  traditionally a mid- urethral sling has been placed retropubically. A

has  been  refractory  to  all  conservative  treatment.  Patients with simple stress incontinence do not usually  benefit  from  extra  testing,  unless  their  prior  surgery  has failed.

Other Imaging By  performing  real-time  or  sector  ultrasonography,  information  can  be  obtained  about  the  inclination  of  the  urethra,  flatness  of  the  bladder  base,  and  mobility  and  funneling  of  the  urethrovesical  junction,  both  at  rest and with a Valsalva maneuver. In addition, bladder  or urethral diverticula may be identified.

Video urodynamics  incorporate  fluoroscopy  with  concurrent measurement of bladder and urethral pres- sures.  Dynamic  magnetic resonance imaging (MRI)  studies  are  used  to  detect  pelvic  floor  and  relaxation  defects in patients with incontinence.

SUMMARY For a significant percentage of patients with SUI, a good history and physical examination, the cotton swab test, and the cough stress test are adequate investigations.  The  addition  of  uroflowmetry,  cysto- urethroscopy,  and  cystometry  are  appropriate  when  more detailed information is needed for diagnosis and  treatment. Additional urodynamic, electromyographic,  electrophysiologic, and radiologic studies may be nec- essary  in  patients  with  a  history  of  multiple  previous  surgeries  for  urinary  incontinence  and  for  patients  with associated neurologic disease.

TREATMENT Medical Therapy In  postmenopausal  women  with  incontinence,  estro- gens improve urethral closing pressure, vaginal epi- thelial thickness and vascularity, and reflex urethral function although paradoxically, estrogen has not been shown to reduce loss of urine.  α-Adrenergic  stimulants,  such  as  phenylpropanolamine  or  pseudo- ephedrine, may enhance urethral closure and improve  continence,  but  they  are  unproven  in  placebo- controlled trials. The search for an effective medication  to treat SUI is ongoing.

Physical Therapy Pelvic floor muscle exercises, also known as Kegel exercises, constitute a proven first-line therapy to improve or cure mild to moderate forms of SUI. These  exercises  involve  instructing  a  woman  with  SUI  to  tighten her pelvic muscles repeatedly over time. When  performed  correctly,  the  Kegel  technique  leads  to  stronger  pelvic  floor  muscles  and  decreased  urethral  hypermobility.  The  exercises  require  diligence  and  a  willingness  to  practice  at  home  and/or  at  work.  Some  women  find  them  difficult,  fatiguing,  or  time- consuming,  but  when  they  are  performed  diligently,  about  80%  of  women  report  decreased  episodes  of 

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variation is the transobturator approach. Rather than  using  a  retropubic  passage,  in  this  approach  the  sling  is passed through the obturator foramen laterally. The  potential  advantage  of  this  approach  is  a  reduction  in  bladder, bowel, or vascular injury. The retropubic mid- urethral sling has better success rates than the trans- obturator sling when there is sphincter compromise as well. The  success  rate  of  both  approaches  is  about  85-90%.  Another variant of the mid-urethral sling is the one-incision sling or minisling.  These  small  lengths  of  polypropylene  mesh  are  attached  to  the  obturator  fascia  with  small  tissue  hooks.  Although  there are fewer complications with this approach, it is  somewhat less effective.

The mid-urethral sling is now considered a gold standard for the treatment of SUI.  It  is  the  most  studied  procedure  in  the  history  of  randomized  con- trolled surgical trials. Figure 23-8 is an illustration of a  mid-urethral sling procedure for patients with SUI.

Bulking Injections Conventional  surgical  procedures  for  incontinence  sometimes fail in patients with a diagnosis of urethral ISD.  ISD  is  a  subtype  of  SUI  marked  by  a  very  poorly  functioning  urethral  sphincter.  These  patients  are 

FIGURE 23-8 Illustration of a mid-urethral sling procedure.

Sling

FIGURE 23-9 Illustration of the bulking injection procedure for urethral hypermobility.

Bulking injection

FIGURE 23-7 Illustration of a typical retropubic urethropexy with suture placement.

Bladder

Retropubic suspension

Urethra

Vagina

treated  with  a  suburethral  sling  procedure  or  peri- or transurethral bulking injections  to  improve  urethral  function. A commonly used bulking material is nonab- sorbable calcium hydroxylapatite, which is nontoxic,  nonantigenic,  and  unlikely  to  degrade.  Figure  23-9  illustrates  the  bulking  injection  procedure  for  the  ISD  form of SUI.

Overactive Bladder/Urge Urinary Incontinence

The terms overactive bladder (OAB) and urge urinary incontinence (UUI) are often used interchangeably to describe a problem with bladder control that is asso- ciated with a strong desire to pass urine with a decreased ability to control it. UUI  is  defined  as  the  involuntary leakage of urine accompanied by or imme- diately  preceded  by  urgency.  UUI  can  be  associated  with small losses of urine between normal micturitions  or  large  volume  losses  with  complete  bladder  empty- ing. OAB, previously described as UUI associated with  detrusor  muscle  instability,  is  a  more  descriptive,  symptom-based  term  that  more  accurately  encom- passes  the  common  clinical  presentation.  OAB is defined as “urgency, usually with but sometimes without urge incontinence and with frequency and nocturia.”  OAB  has  become  the  preferred  term  as  it  comprises  symptoms  of  urgency,  UUI,  frequency,  and  nocturia.

The  incidence  of  OAB  increases  with  age  and  is  approximately 30% in the geriatric patient population.  In most patients, the exact etiology of OAB remains unknown,  but  a  number  of  risk  factors  (Box  23-1)  are  associated with its development.

Classically,  women  with  OAB  describe  a  sudden,  strong urge to urinate with an inability to suppress the  feeling,  rushing  to  the  bathroom,  and  experiencing  leaking before making it to the toilet. Awakening several  times  a  night  to  urinate  is  also  a  prominent  feature  (nocturia).

C H A P T E R 23 Pelvic Floor Disorders 301

BOX 23-1

TYPES OF URINARY INCONTINENCE

Stress Urinary Incontinence (SUI) •  Involuntary  leakage  of  urine  in  response  to  physical 

exertion, sneezing, or coughing •  Etiology:  Urethral  hypermobility  due  to  vaginal  wall 

relaxation  displacing  the  bladder  neck  and  proximal  urethra  downward;  intrinsic  sphincter  deficiency  (leaky  valve)

•  Contributing factors include childbearing, previous uro- genital  surgery,  trauma,  pelvic  radiation,  estrogen  defi- ciency, and medications (e.g., diuretics and α-adrenergic  blockers)

•  Diagnosis:  Cotton  swab  (Q-tip)  and  cough  stress  tests;  additional urodynamic testing in appropriate women

•  Treatments:  Retropubic  urethropexy,  urethral  sling  pro- cedure,  and  bulking  injection  procedures  (see  Figures  23-8 through 23-10)

Overactive Bladder (OAB)/Urge Urinary Incontinence (UUI) •  Both  terms  (OAB  and  UUI)  are  used  interchangeably; 

both describe problems with bladder control associated  with  a  strong  desire  to  urinate  with  decreased  ability  to  control flow

•  Etiology:  Poorly  understood;  risk  factors  include  older  age, chronic disorders, pregnancy, menopause (estrogen  deficiency), operative trauma, medications (e.g., diuret- ics and psychotropic agents), and smoking

•  Diagnosis:  Unstable  bladder  as  demonstrated  during  urodynamic testing

•  Treatments: Behavior modification first, then add medi- cations, Botox injections, or neuromodulation

Overflow Urinary Incontinence (OUI) •  Urinary retention and OUI may result from detrusor are-

flexia or a hypotonic bladder •  Etiology:  Lower  motor  neuron  disease,  spinal  cord  

injury,  neuropathy  due  to  diabetes  mellitus,  or  outflow  obstruction

•  Diagnosis:  Symptoms  of  bladder  fullness,  pressure,  and  frequent urination

•  Treat  the  underlying  causes  if  possible;  intermittent  or  continuous bladder drainage (suprapubic catheter)

Mixed and Other Urinary Incontinence •  Some women may have signs and symptoms of both SUI 

and  OAB;  fistulas  are  an  uncommon  cause  of  inconti- nence  in  countries  where  modern  obstetric  care  is  available

•  Etiology:  For  mixed  incontinence,  the  causes  are  the  same as for SUI and OAB; in developed countries, fistulas  usually result from surgical injuries

•  Diagnosis: The  diagnosis  of  mixed  incontinence  can  be  challenging and inconsistent; incontinence from fistulas  presents as painless leakage of urine from the vagina

•  Treatment:  A  combination  of  treatments  for  SUI  and  OAB is usually initiated; fistulas may heal spontaneously  or with estrogen cream, but surgical repair is usually nec- essary (e.g., muscle flap or diversion procedure)

TREATMENT The  optimal  treatment  of  OAB  starts  with  behavior  modification (see below). Pharmacologic and physical  interventions,  such  as  electrical  stimulation,  can  be  added as needed. Identification of any dietary triggers,  such as caffeine, alcohol, acidic or spicy foods, or car- bonated  beverages,  is  important.  The  use  of  a  self- report  bladder  diary  can  be  helpful  for  obtaining  this  information.

Behavior Modification Reducing fluid intake and avoiding liquids during the evening hours are good initial behavior changes. Grad- ually  increasing the intervals between voidings,  as  well  as  pelvic  floor  muscle  strengthening  exercises,  such  as  Kegel exercises,  are  effective  for  attaining  better bladder control.

Pharmacologic Treatment Antimuscarinics, or anticholinergics, have become the mainstay of drug treatment for OAB. They work by  suppressing uninhibited bladder contractions.

Current  drug  therapies  include  oxybutynin chlo- ride (Ditropan) and tolterodine (Detrol). Oxybutynin  chloride  has  been  shown  to  improve  symptoms  of 

urinary urgency in approximately 70% of patients. Tolt- erodine also has anticholinergic activity. Because of its  bladder  specificity,  tolterodine  has  a  more  favorable  side effect profile than oxybutynin. It is also dosed less  frequently,  which  improves  patient  compliance.  Both  are available in immediate-release and long-acting for- mulations.  Oxybutynin  is  also  available  for  delivery  in  a transdermal patch.

Trospium chloride, solifenacin,  and  darifenacin  are newer agents used in the treatment of OAB. All sig- nificantly  improve  OAB  symptoms  compared  with  placebo. Evidence suggests that side effect profiles will  be  similar  to  or  lower  than  those  of  the  less  specific  antimuscarinics.

Mirabegron, the most recent agent, is a β3-adrenergic  agonist  that  aids  in  the  storage  of  urine  by  assisting  relaxation of the detrusor muscle.

Imipramine hydrochloride is a tricyclic antidepres- sant that acts through its anticholinergic properties to  increase  bladder  storage.  The  drug  improves  bladder  compliance  rather  than  counteracting  uninhibited  detrusor  contractions.  It  is  given  in  doses  lower  than  those  recommended  for  use  as  an  antidepressant.  It  also  blocks  postsynaptic  noradrenaline  uptake  and  thereby  increases  bladder  outlet  resistance.  With  its 

PA R T 3 Gynecology302

Urinary Fistulas Fistulas are an uncommon cause of urinary inconti- nence in developed countries, because obstetric inju- ries,  once  the  leading  cause  of  urinary  fistulas,  have  almost disappeared. When they do occur, they usually  result  from  operative  deliveries  (e.g.,  forceps)  rather  than  from  neglected  labor  and  pressure  necrosis.  Obstetric fistulas remain a tremendous source of social and physical distress in developing countries.

Pelvic surgery, irradiation, or both now account for 95% of the vesicovaginal fistulas in the United States. More than 50% occur following simple abdominal or vaginal hysterectomy  (Figure  23-10).  Approximately  1-2% of radical hysterectomies are followed in 10 to 21  days by a urinary fistula that is usually ureterovaginal.  These  fistulas  are  usually  caused  by  devascularization  of  the  ureter  rather  than  by  direct  injury.  Of  all  approaches to hysterectomy, vaginal hysterectomy has  the lowest incidence of urinary tract injury.

Urethrovaginal fistulas  generally  occur  as  compli- cations  of  surgery  for  urethral  diverticula,  anterior  vaginal  wall  prolapse,  or  SUI.  Urethral  diverticula  are  rare,  can  cause  incontinence,  and  are  best  diagnosed  by MRI.

DIAGNOSIS OF A FISTULA The  usual  history  of  painless  and  continuous  vaginal  leakage  of  urine  soon  after  pelvic  surgery  is  strongly  suggestive  of  a  fistula.  Instillation of methylene blue dye into the bladder will discolor a vaginal tampon or pack if a vesicovaginal fistula is present. Intravenous indigo carmine is excreted in the urine and will dis- color a vaginal tampon or pack in the presence of a vesicovaginal or ureterovaginal fistula.  In  addition,  cystourethroscopy  should  be  performed  to  determine  the site and number of vesical fistulas. The majority of  posthysterectomy  vesicovaginal  fistulas  are  located  just  anterior  to  the  vaginal  vault.  A computed tomo- graphic (CT) scan with contrast dye or a retrograde pyelogram should be obtained to localize a uretero- vaginal fistula.

dual  action,  imipramine may be effective in patients with mixed incontinence (both SUI and OAB).  It  should  be  taken  in  the  evening,  as  it  may  be  sedat- ing,  and  it  should  be  used  with  caution  in  elderly  patients  because  of  its  potential  to  cause  orthostatic  hypotension.

Functional Electrical Stimulation Functional  electrical  stimulation  offers  an  alternative  for  treating  stress  or  urge  incontinence  when  other  treatments  fail.  A  vaginal  or  rectal  probe  is  inserted,  usually  twice  daily  for  15  to  30  minutes,  to  provide   electrical  stimulation  to  the  pelvic  floor  muscles  or  to  the nerves to these structures. Stimulation of the affer- ent fibers of the pudendal nerve can produce contrac- tions  of  the  pelvic  floor  and  periurethral  skeletal  muscles, improving their tone and function in women  with SUI.

Posterior Tibial Nerve Stimulation Posterior  tibial  nerve  stimulation  (PTNS)  involves  the  placement of an acupuncture-like needle into the pos- terior tibial nerve near the ankle and the application of  electrical stimulation to this site. It is a form of neuro- modulation that may reduce OAB symptoms with 3 to  4 months of treatment.

Sacral Stimulation (InterStim Device) In appropriate patients, an implantable device used to  stimulate the sacral nerve directly in the spine is effec- tive for the treatment of OAB (or fecal incontinence).

Botulinum Toxin A Injection Botulinum  toxin  A  (Botox)  can  be  injected  into  the  bladder  submucosa  and  detrusor  muscle  for  6  to  9  months of relief from OAB. It is as efficacious as other  medications, has far fewer side effects, and gives longer  benefit. Cost-effectiveness studies show it to be more beneficial than oral medication.

Overflow Incontinence Urinary retention and overflow incontinence may result from detrusor areflexia or a hypotonic bladder, as is seen with lower motor neuron disease, spinal cord injuries, or autonomic neuropathy (diabetes mellitus).  These  patients  are  best  managed  by  inter- mittent self-catheterization.

Overflow incontinence may also occur when there is an outflow obstruction.  Straining  to  void,  poor  stream,  retention  of  urine,  and  incomplete  emptying  may indicate an obstructive disorder. Overdistention of  the bladder because of unrecognized urinary retention  may  occur  in  the  postoperative  period. This  is  a  tem- porary problem related to postoperative pain and may  be  managed  by  continuous  bladder  drainage  by  cath- eter for 24 to 48 hours.

FIGURE 23-10 Illustration of a typical vesicovaginal fistula.

Bladder

Vesicovaginal fistula

C H A P T E R 23 Pelvic Floor Disorders 303

dyspareunia, and a feeling of incomplete bladder emptying, all in the absence of detectable infection or anatomical abnormality.

Diagnosis is based on a careful history and physical  examination  to  localize  the  pain  in  the  bladder  and  urethra, negative urine cultures, and otherwise nondi- agnostic  cystourethroscopic  and  urodynamic  studies.  One  theory  of  causation  is  a  defect  in  the  waterproof  mucopolysaccharide  lining  of  the  bladder  that  allows  caustic  urine  to  seep  into  the  submucosal  tissue,  causing inflammation and pain.

Treatment of PBS,  starting  with  bladder  training  and  behavior  management,  includes pentosan poly- sulfate sodium (Elmiron),  an  oral  form  of  heparin;  hydroxyzine,  an  oral  antihistamine  and  anti-inflam- matory  agent;  and amitriptyline (Elavil),  a  potent  agent  for  treating  neuropathy.  When  women  are  not  responding,  an  intravesical  combination  of  heparin,  lidocaine,  and  sodium  bicarbonate  may  be  instilled  weekly  for  relief,  in  addition  to  the  oral  agents  listed  above.  Urethritis,  which  is  usually  caused  by  an  infec- tion  with  Mycoplasma  or  Ureaplasma  species,  may  contribute  to  pelvic  floor  pain.  This  infection  can  be  treated  with  2  weeks  of  tetracycline  or  erythromycin  after cultures have been obtained.

MYOFASCIAL PELVIC PAIN SYNDROME Myofascial pelvic pain syndrome (MFPPS) is most likely a reaction of pelvic floor tissues to the other causes of pelvic floor pain  mentioned  above.  The  muscles  of  the  pelvis  that  form  the  basket  containing  the  pelvic  organs  react  with  chronic  contraction  and  spasm  to  pain  from  other  causes,  resulting  in  more  pain.  MFPPS  is  diagnosed  on  the  basis  of  physical  examination by identifying a painful reaction when the  levator  and  lateral  obturator  muscles,  along  with  the  anterior  retropubic  attachments  of  the  pubourethral  ligaments,  are  palpated.  This  condition  can  cause  severe  pain  at  trigger  points. The  pain  and  spasm  can  interfere  with  defecation  or  voiding.  The treatment includes medications such as amitriptyline, gabapen- tin, duloxetine, or specialized transvaginal physical therapy. Intramuscular injection of botulinum toxin A is also effective in stopping the spasm in some cases.  The prognosis for relief of pain is good with appropri- ate treatment.

FISTULA REPAIR Most obstetric fistulas can be repaired immediately on  detection.  For  postsurgical  fistulas,  it  is  usual  to  wait  some  weeks  to  allow  the  inflammation  to  resolve.  During this waiting period, UTIs should be treated and  estrogen therapy instituted in postmenopausal women.  Steroids have been advocated to hasten resolution of inflammatory changes and allow early surgical inter- vention. Their use in this circumstance is controver- sial. Bladder rest with a Foley catheter, with or without tissue glue, may be effective in resolving isolated, small vesicovaginal fistulas. The majority of cases require surgical repair.

Vesicovaginal Fistula The vaginal approach (Latzko operation) is the proce- dure  of  choice.  A bulbocavernosus muscle flap or fat pad (Martius graft) may be interposed between the bladder and vagina to provide support, vascularity, and strength to the suture line, especially in patients who have had multiple previous attempted repairs and in those with a postradiation fistula.  Large  radiation-induced  fistulas  may  necessitate  urinary  diversion.

Ureterovaginal Fistula Treatment  of  a  ureterovaginal  fistula  depends  on  its  size and location. Small fistulas usually close sponta- neously after placement of a ureteric stent (double J), provided the tissues have not been irradiated.

If  the  fistula  is  close  to  the  ureterovesical  junction,  the  ureter  proximal  to  the  fistula  can  be  reimplanted  into the bladder (ureteroneocystostomy). If the fistula  is  several  centimeters  from  the  bladder,  a  Boari flap  may be useful, a segment of ileum may be interposed  between the proximal ureter and the bladder, or, rarely,  a transureteroureterostomy may be employed.

Pelvic Floor Pain Syndromes PAINFUL BLADDER SYNDROME Painful bladder syndrome  (PBS)  refers  to  the  contin- uum  of  lower  urinary  tract  symptoms  of  discomfort  that begin with mild OAB and end with interstitial cys- titis. PBS includes the following symptoms and signs: bladder pain, frequency, urgency, nocturia, dysuria,

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24 

Ectopic Pregnancy

C H

A P

T ER

ANITA L. NELSON • JOSEPH C. GAMBONE

■  Ectopic pregnancy  refers  to  those  pregnancies  that  implant  outside  the  uterine  cavity.  Although  more  than  95% of ectopic pregnancies implant in the fallopian tube,  occasionally they may implant in other sites, such as the  ovary, the uterine cervix, or, very rarely, in the abdominal  cavity  or  a  cesarean  uterine  scar.  Following  the  use  of  assisted reproductive technologies (ARTs), the incidence  of  ectopic  pregnancy  has  more  than  doubled  to  2-3%,  and the likelihood of implantation in more unusual sites  has increased.

■  The  trophoblast  of  an  early  ectopic  pregnancy  that  implants  in  the  fallopian  tube  erodes  through  the  tubal  mucosal  layer  and  into  the  tubal  vessels.  As  the  fetus  grows,  the  blood  from  the  eroded  vessels  dissects  along  the tubal wall, resulting in any of the following: (1) tubal  rupture  and  intraperitoneal  hemorrhage,  (2)  resorption  of  the  pregnancy  because  of  restricted  blood  supply,  or  (3) tubal abortion into the peritoneal cavity, where it may  rarely result in an abdominal pregnancy.

■  Clinical  presentation  of  ectopic  pregnancies  may  vary,  but  the  classic  triad  of  symptoms  is  (1)  missed  menses,  (2)  vaginal  bleeding  (usually  spotting),  and  (3)  lower  abdominal  pain.  For  individual  women,  there  are  three 

possible  clinical  presentations:  (1)  an  acutely  ruptured  ectopic  pregnancy,  (2)  a  probable  ectopic  pregnancy  with  significant  pelvic  pain  and  vaginal  spotting  or  bleeding, or (3) a possible ectopic pregnancy.

■  Most  often,  the  workup  begins  with  testing  to  locate  a  “pregnancy  of  unknown  location”  (PUL).  Other  kinds  of  abnormal  early  pregnancies  and  other  illnesses  in  early  pregnancy  may  account  for  the  signs  and  symptoms  of  ectopic  pregnancy.  The  two  most  important  diagnostic  tests  performed  to  diagnose  an  ectopic  pregnancy  are  serial  serum  human  chorionic  gonadotropin  (hCG)  levels  in  maternal  serum  and  sequential  ultrasonic  imaging.

■  The  key  to  proper  management  of  ectopic  pregnancy  is  early  diagnosis. Treatment  options  depend  on  the  clini- cal  situation  and,  where  possible,  patient  preferences.  Surgery  is  necessary  when  rupture  has  occurred  or  is  threatened or if the diagnosis remains uncertain. Medical  therapy with methotrexate (MTX) is now widely used for  probable and possible ectopic pregnancies. Irrespective  of  the  type  of  treatment,  most  patients  should  be  informed  that  they  are  at  an  increased  risk  of  a  future  ectopic pregnancy.

CLINICAL KEYS FOR THIS CHAPTER

An ectopic pregnancy is one that implants outside the  endometrial  cavity.  The  most  common  site  for  an  ectopic  pregnancy  is  in  the  fallopian  tube,  but  a  wide  range  of  implantation  sites  is  possible.  Some  treat- ments for infertility significantly increase the risk. They  may  also  affect  where  the  implantation  occurs  (Table  24-1).  Although  early  diagnosis  has  enabled  more  effective  intervention  and  lowered  maternal  mortality  caused  by  ectopic  pregnancies,  the  disorder  is  still  a  leading cause of maternal death in the first trimester of  pregnancy.

Etiology and Risk Factors Ectopic pregnancies generally result from abnormal- ities in the structure or function of the fallopian tube.  The  role  that  the  conceptus  itself  may  play  is  not  known, but it is clear that chromosomal abnormalities  do not cause ectopic pregnancies.

The most common cause of tubal abnormality associated with ectopic pregnancy is internal inflam- mation (salpingitis).  Other  causes  include  external  tubal  scarring  secondary  to  endometriosis,  ruptured 

C H A P T E R 24 Ectopic Pregnancy 305

1 : 30,000  to  1 : 100  pregnancies.  Other  risk  factors  include a history of infertility and smoking.

Incidence and Classification Now that many cases of ectopic pregnancy are managed  medically  in  ambulatory  settings,  the  incidence  of  ectopic  pregnancy  is  not  as  well  documented.  The  latest statistics from the mid-1990s indicated that 1-2%  of  all  pregnancies  in  the  United  States  were  ectopic.  Minority  women  have  twice  the  risk  of  white  women  and a fourfold higher risk of ectopic pregnancy–related  mortality. Recently, there have been counterbalancing  shifts in the prevalence of risk factors for ectopic preg- nancy (less pelvic infection but more advanced infertil- ity treatment), so it is reasonable to assume that about 1 in 80 pregnancies in the United States will be located outside the uterine cavity.

The fallopian tubes are the site of over 95% of ectopic pregnancies.  Those  ectopic  pregnancies  are  characterized  by  the  portion  of  the  salpinx  in  which   the  pregnancy  implants:  ampullary  (75-80%),  isthmic  (12%), infundibular or fimbrial (6-10%), and interstitial  or  cornual  (2-4%).  Cornual  ectopic  pregnancies  are  particularly  dangerous,  because  the  pregnancy  can  continue to expand throughout the first trimester, and  its rupture can lead to a sudden and rapid fatal exsan- guination  in  less  than  1  hour.  Bilateral  fallopian  tube  pregnancies  occur  in  1  in  200,000  pregnancies.  Other  sites for ectopic pregnancy include the cervix, the ovary  (implantation below the ovarian cortex), the abdomen,  and  cesarean  delivery  scars. There  has  been  a  distinct  increase  in  the  numbers  of  cesarean  scar  pregnancies  as  cesarean  delivery  has  become  more  common.  Het- erotopic pregnancies, in which pregnancies simultane- ously  implant  in  both  the  endometrium  and  in  an  extrauterine  site,  may  occur  as  frequently  as  1  in  100  IVF pregnancies.

Natural History The  trophoblasts  of  the  conceptus  implanted  in  the  mucosa  of  the  fallopian  tube  rapidly  erode  through  that layer and invade into the underlying blood vessels.  This  induces  local  bleeding,  some  of  which  dissects  into  the  tubal  lumen  and  spills  into  the  endometrial  cavity (causing spotting), and some of it passes into the  peritoneal cavity (causing a hemoperitoneum). Most of  the blood generally is trapped between the serosal and  mucosal layers and distends the tube with clot, which  explains  the  common  finding  of  cervical  motion  ten- derness.  If  the  bleeding  is  extensive  enough,  it  can  cause  pressure  necrosis  of  the  overlying  tubal  serosa,  resulting  in  acute  rupture  and  causing  a  significant  hemoperitoneum. Occasionally, the local blood supply  to  the  pregnancy  is  so  compromised  that  the  preg- nancy is resorbed (spontaneously resolved) or aborted 

appendicitis, or previous surgery. Classically, gonococ- cal salpingitis  causes  significant  symptoms  of  fever  and pelvic pain and results in visible tubal damage. The  fallopian tubes become distended with purulent mate- rial;  the  fimbriae  can  be  clubbed;  and  the  passage  through the tube becomes tortuous with blind pouches  (diverticuli)  that  physically  block  the  progress  of  the  fertilized  egg  into  the  endometrial  cavity.  Chlamydial salpingitis is usually associated with milder symptoms,  and  the  tubal  damage  is  more  subtle.  The  heat  shock  protein  released  by  Chlamydia trachomatis  destroys  the cilia lining the tubal mucosa, which are responsible  for sweeping the conceptus through the tube.

Salpingitis isthmica nodosa  is  another  inflamma- tory  process  that  distorts  the  portion  of  the  fallopian  tube closest to the tubal ostia (opening into the uterine  cavity).  Thirty  percent  of  all  pregnancies  that  follow  tubal ligation  are  ectopic.  Other  tubal  surgeries  (e.g.,  anastomosis,  lysis  of  adhesions)  also  increase  the  risk  of  ectopic  pregnancy.  One of the greatest risk factors is a history of a previous ectopic pregnancy. Recur- rence rates are about 30%. Uterine fibroids  located  near  the  ostia  can  distort  or  block  tubal  patency  and  increase the risk of ectopic pregnancy.

Tubal peristalsis is slowed by progestins,  such  as  those that are released by the hormonal contraceptive  intrauterine  devices  (IUDs),  contraceptive  implants,  injections,  and  oral  contraceptives.  Although  all  of  these methods of birth control significantly reduce the  absolute  risk  of  any  pregnancy,  when  a  failure  (preg- nancy)  occurs  during  their  use,  the  relative  risk  of  an  ectopic pregnancy is greatly increased. For example, it  is  estimated  that  40-60%  of  pregnancies  that  occur  during  use  of  the  levonorgestrel  IUDs  are  ectopic  (see  Chapter 27).

The higher levels of progesterone induced by ovarian hyperstimulation during use of assisted reproductive technologies (ARTs) can also slow tubal motility.  When  multiple  embryos  are  transferred  during  in  vitro  fertilization  (IVF),  the  risk  of  ectopic  pregnancy  and  the  risk  of  heterotopic  pregnancy  (simultaneous intrauterine and ectopic) increase from 

TABLE 24-1

INCIDENCE AND SITES OF ECTOPIC PREGNANCY

Natural Conception

Assisted Reproductive Technologies

Overall incidence About 1% 2-3%

Fallopian tube >95% <90%

Ovarian and abdominal 1-2% 5%

Cervical 0.15% 1.5%

Cesarean scar 1 in 1800 Unknown

Heterotopic* 1 in 30,000 1 in 100

*More than one site.

PA R T 3 Gynecology306

disease processes that may present with similar symp- toms  in  early  pregnancy  have  been  ruled  out  (Box  24-1). Such patients generally have other clinical signs,  such  as  tenderness  of  the  abdomen  with  adnexal  or  cervical  motion  tenderness.  On  ultrasound,  a  variable  amount of free fluid may be detected in the cul-de-sac.  Only occasionally will the ectopic pregnancy be seen on ultrasound as a “double-ring” sign in the adnexa, but a corpus luteal cyst is often present. In such symp- tomatic  women,  even  though  they  have  stable  vital  signs,  surgical  exploration  is  generally  recommended.  Conservative surgical procedures that preserve the fal- lopian tube are generally performed in women desiring  future fertility (see Management section below).

POSSIBLE ECTOPIC PREGNANCY Most ectopic pregnancies fall into the category of possible ectopic pregnancy and are initially diag- nosed as PUL. In the face of a positive pregnancy test,  all  of  the  differential  diagnoses  listed  in  Table  24-2  should  be  considered  and  ruled  out.  For  women  with  possible  ectopic  pregnancies,  the  symptoms  are  more  subtle than they are in the other two ectopic categories.  Lower  abdominal  pain  is  present  in  most  cases,  although it is usually mild. Missed menses or an abnor- mal  last  menstrual  period  is  seen  in  75-90%  of  cases.  More  than  one-half  present  with  abnormal  vaginal  bleeding that can range from minor spotting to bleed- ing consistent with a normal menstrual flow.

A  physical  examination  reveals  most  patients  to  be  afebrile,  and  fewer  than  half  are  found  to  have  a  dis- cernable  adnexal  mass  on  pelvic  examination.  Often,  the  mass  is  palpated  on  the  side  opposite  the  ectopic  pregnancy  and  represents  a  corpus  luteum  in  that  ovary. The uterus is soft and is either of normal size or  is slightly enlarged. On ultrasound, a thin, triple-layered  endometrial  stripe  (lining)  may  be  seen,  or  it  may  be  thickened  because  of  human  chorionic  gonadotropin  (hCG) stimulation induced by placental hCG (an Arias- Stella reaction). There may be a small amount of fluid 

BOX 24-1

OTHER PAIN-PRODUCING PROBLEMS THAT MAY OCCUR EARLY IN PREGNANCY

Gynecologic Problems 1.  Threatened or incomplete abortion 2.  Ruptured corpus luteal cyst 3.  Acute pelvic inflammatory disease (rare) 4.  Adnexal torsion 5.  Degenerating leiomyoma (especially in pregnancy)

Nongynecologic Problems 1.  Acute appendicitis 2.  Pyelonephritis 3.  Pancreatitis

into  the  peritoneal  cavity,  a  process  that  may  be  asymptomatic.

Clinical Presentation The clinical presentation of tubal ectopic pregnan- cies can vary from subtle lower abdominal discom- fort and light uterine spotting to symptoms consistent with hypovolemic shock due to massive internal hemorrhage from tubal rupture. Ectopic pregnancies  in other sites may have slightly different presentations,  but  the  common  finding  of  all  ectopic  pregnancies  is  that  the  symptoms  occur  in  the  setting  of  a  positive  pregnancy test. Clinical presentations should be evalu- ated in terms of three possibilities: (1) an acutely rup- tured (or rupturing) ectopic pregnancy, (2) a probable  ectopic pregnancy in a symptomatic woman, and (3) a  possible  ectopic  pregnancy  in  a  mildly  symptomatic  woman with a pregnancy of unknown location (PUL).

ACUTELY RUPTURED ECTOPIC PREGNANCY Fortunately,  only a small number of women with fal- lopian tube pregnancies present with symptoms indicative of massive internal hemorrhage from acute tubal rupture. This presentation is particularly likely to  occur in women with poor access to care and occasion- ally in those whose medical therapy fails. Women may  present  with  dizziness  or  loss  of  consciousness  and  sudden onset of severe pain. Some shoulder pain may be present because of irritation of the phrenic nerve by blood and clotting in the abdominal cavity.

During a physical examination, hemodynamic instability is indicated by tachycardia, diaphoresis, and hypotension.  The  abdomen  may  be  distended,  and both abdominal guarding and rebound tenderness  may  be  present.  There  may  be  only  minor  bleeding  from  the  cervix  found  by  speculum  examination,  but  noticeable  cervical  motion  tenderness  and  a  slightly  enlarged, globular uterus may be detected by bimanual  examination. A palpable adnexal mass may or may not  be present.

An acute rupture of an ectopic pregnancy represents  a  surgical  emergency.  Large-bore  intravenous  lines  must  be  established,  and  fluid  resuscitation  must  be  started  immediately.  Blood  transfusion  should  follow  as soon as possible, but surgery should not be delayed.  In the hemodynamically unstable patient, laparot- omy is usually required.  Laparoscopy  may  be  per- formed in less compromised patients. Generally, tubal  damage  after  rupture  is  so  extensive  that  salpingec- tomy is required.

PROBABLE ECTOPIC PREGNANCY Hemodynamically  stable  women  who  have  a  positive  pregnancy  test  and  present  with  notable  pelvic  pain  and  vaginal  spotting  or  bleeding  should  be  classified   as  having  a  “probable  ectopic  pregnancy”  after  other 

C H A P T E R 24 Ectopic Pregnancy 307

HUMAN CHORIONIC GONADOTROPIN TESTING hCG  is  a  glycoprotein  consisting  of  two  linked  sub- units:  α  and  β.  The  α-subunit  consists  of  92  amino  acids  and  is  the  same  in  luteinizing  hormone  (LH),  follicle-stimulating  hormone  (FSH),  and  thyroid- stimulating  hormone.  The  β-subunit  is  larger,  with  145  amino  acids;  is  different  for  each  glycoprotein  hormone;  and  provides  for  unique  biologic  activity.  Before the development of sensitive and specific assays  for the entire hCG molecule, tests for only the β-subunit  of  hCG  were  routinely  used  for  assessment  in  early  pregnancy, and especially to rule out ectopic pregnan- cies.  This  was  because  of  the  increased  likelihood  of  false-positive  results  due  to  the  cross-reactivity  with  other  glycoprotein  hormones  (e.g.,  LH  and  FSH),  which  have  the  same α-subunits.  Although  the  possi- bility of false-positive results still exists because of cir- culating  factors  in  the  serum  that  may  interact  with  hCG antibody, the more common laboratory test per- formed today is for the entire hCG molecule. Although  results  of  the  more  recent  specific  assay  are  still  fre- quently referred to as β-hCG, we use the designation of  hCG in this chapter.

The conceptus produces hCG before implantation, but the hormone does not enter the maternal circula- tion until after implantation. Sensitive assays for hCG can detect its presence within hours of implantation.  The serum levels of hCG increase rapidly in a nonlinear  fashion. The  doubling  time  of  serum  hCG  varies  from  1.2  days  shortly  after  implantation  to  3.5  days  at  2  months’ gestational age. Healthy, normally developing  pregnancies  can  be  detected  by  a  normal  increase  of 

seen in the cul-de-sac, representing some intraperito- neal  blood.  Rarely  is  the  ectopic  pregnancy  actually  visualized.  A  diagnosis  of  PUL  is  made  until  a  longer- term  evaluation  can  be  conducted  to  determine  if  a  more definitive diagnosis can be made. The final diag- nosis  may  be  a  normal  intrauterine  pregnancy,  an  abnormal uterine pregnancy, or an ectopic pregnancy.  In the face of an early failing or failed pregnancy, the location of the implantation may never be deter- mined and the diagnosis of PUL will thus remain.

Diagnostic Tests for Pregnancies of Unknown Location Because the consequences of ectopic pregnancy can be  so  serious,  a  high  index  of  suspicion  for  ectopic  preg- nancy  must  be  maintained  until  testing  can  establish  the normalcy of the early pregnancy and its implanta- tion site. Ectopic pregnancy must be included in the list  of differential diagnoses in women who present with a  positive  pregnancy  test,  abnormal  bleeding,  and/or  abdominopelvic  pain.  Generally,  serial  testing  is  needed  over  the  course  of  several  days  during  which  time the patient must be reassessed clinically. The two most important diagnostic tests are serial quantita- tive hCG levels in serum and sequential ultrasonic imaging. The first test establishes the well-being of the  pregnancy. The second is used to identify the implanta- tion  site  and  to  determine  a  possible  treatment  plan.  Endometrial  evacuation  and  tissue  identification  pro- cedures can also provide valuable information.

TABLE 24-2

DIFFERENTIAL DIAGNOSIS FOR PREGNANCY OF UNKNOWN LOCATION

Diagnosis hCG Levels Ultrasonic Findings

Intrauterine Pregnancies

Normal, ongoing pregnancy Appropriately rising Yolk sac or embryo in gestational sac in endometrial cavity

Anembryonic gestation Variable pattern Empty gestational sac in face of hCG > discriminatory zone or no appearance of embryo at appropriate time

Embryonic demise Variable pattern Embryo visualized with no cardiac activity

Incomplete abortion Variable pattern Retained placental tissue seen after (presumed) passage of fetus

Pregnancy Loss

Complete abortion: intrauterine spontaneous or elective

Appropriately falling Empty uterus, no suspicious adnexal findings

Complete abortion: ectopic Appropriately falling Empty uterus, no suspicious adnexal finding

Ectopic pregnancy (or persistent PUL)

Abnormally low increase, stable or abnormally decreasing

Empty uterus (without evacuation or following evacuation with no chorionic villi seen histologically)

Possible visualization of extrauterine gestational sac or embryo

hCG, Human chorionic gonadotropin; PUL, pregnancy of unknown location.

PA R T 3 Gynecology308

centrally located “pseudodecidual sac” that can be seen in ectopic pregnancies. To confirm the diagnosis  of  intrauterine  pregnancy,  the  patient  is  generally  fol- lowed until a yolk sac or a fetal pole can be seen within  the gestational sac.

OTHER TESTS FOR PREGNANCIES OF UNKOWN LOCATION If the diagnosis of an abnormal pregnancy is made on  the  basis  of  a  low  rate  of  increase  in  hCG  titers  (<35%  in 48 hours) or a decrease in hCG titers that is too slow  to  represent  a  complete  abortion  (<30%  in  48  hours),  or if the pregnancy is unwanted, an endometrial curet- tage  can  be  performed. The  absence  of  chorionic  villi  on  examination  of  the  biopsy  specimen  makes  the  diagnosis of ectopic pregnancy much more likely.

Serum Progesterone Serum progesterone levels can help distinguish normal  from abnormal pregnancies. The levels of progesterone  remain relatively constant from 5 to 10 weeks of gesta- tion,  so  only  a  single  specimen  is  needed.  Levels  less  than  5 ng/mL  are  consistent  with  an  abnormal  preg- nancy with high specificity and a 60% sensitivity. Levels  greater  than  20 ng/mL  indicate  a  healthy  pregnancy  with 95% sensitivity and 40% specificity. Unfortunately,  most  ectopic  pregnancies  have  levels  of  progesterone  in the 6 to 19 ng/mL range, which is not useful for diag- nostic purposes.

OTHER IMAGING MODALITIES AND PROCEDURES Magnetic resonance imaging (MRI)  is  used  to  help  identify  cesarean  scar  pregnancies  and  cornual  preg- nancies,  both  of  which  are  potentially  dangerous.  Ultrasound  may  not  be  able  to  identify  these  ectopic  sites because of their proximity to the endometrium.

Culdocentesis  (needle  aspiration  of  pelvic  perito- neal  fluid  through  the  posterior  fornix)  has  largely  been  replaced  by  ultrasonic  imaging  of  free  fluid  in  the cul-de-sac. However, aspiration of peritoneal fluid  can  help  distinguish  nonclotting  blood  (hemoperito- neum)  from  clear  fluid  (ruptured  ovarian  cyst)  and  purulent  material  (acute  infection).  This  information  may be useful when the clinical presentation is confus- ing  and  the  results  would  influence  the  choice  of  therapy.

Laparoscopy  can  be  used  as  a  diagnostic  tool  for  PULs if questions remain about the patient’s pathology.  It has the advantage of providing treatment if an ectopic  gestation  is  found  (see  below),  but  it  does  entail  increased  surgical  risks  and  costs.  Even  with  laparos- copy,  there  is  a  2-5%  rate  of  misdiagnosis,  either  because the ectopic pregnancy was too small to be rec- ognized  (false-negative)  or  because  other  processes  were responsible for the suspicious appearance of the  fallopian tube (false-positive).

maternal serum hCG levels. More than 66% of normal pregnancies have a doubling time of 48 hours in the first few weeks of pregnancy. The  expected  rise  in  48  hours  for  a  viable  intrauterine  pregnancy  is  generally  acknowledged to be at least 50%, although researchers  in one recent, large study suggested that a threshold of  35% should be used to capture all normal intrauterine  pregnancies.

Approximately 60% of ectopic pregnancies show an initial increase in hCG levels, and 40% show a decrease.  In  fact,  more  than  one-fourth  of  ectopic  pregnancies  initially  show  hCG  increases  consistent  with  a  normal  intrauterine  pregnancy. Therefore,  hCG  titers  need  to  be  followed  over  time  to  document  a  pattern of sustained normal increase until they reach a  threshold, at which time the embryo can be visualized  within the endometrial cavity by ultrasound. This dis- criminatory zone (DZ) is defined as the range of hCG values in which an ultrasonic image can first detect the signs of an intrauterine pregnancy.  Each  institu- tion  sets  its  own  DZ,  depending  upon  the  hCG  assay  used, the ultrasonic equipment available, and the skill  of  the  ultrasonographers.  Most centers quote a range of 1500 to 2000 mIU/mL of hCG as the DZ. When the  hCG  level  exceeds  the  upper  limit  of  the  DZ  and  no  signs  of  an  intrauterine  pregnancy  are  seen  on  ultra- sound,  suspicion  of  an  ectopic  pregnancy  increases.  The  possibility  of  multiple  gestations  must  also  be  considered.

In the case of declining hCG levels, the differential diagnosis includes a complete spontaneous abortion and an abnormal PUL. Two days following a complete  spontaneous  abortion,  the  hCG  levels  decrease  by  35-52%,  and  by  7  days,  they  should  be  reduced  by  66-87%.  Levels  that  fail  to  decline  appropriately  are  consistent  with  an  ongoing  PUL,  which  could  be  ectopic.

TRANSVAGINAL ULTRASONOGRAPHY Ultrasound  is  used  to  determine  the  presence  of  an  intrauterine  pregnancy  and  to  check  for  the  presence  of free fluid in the peritoneal cavity. With transvaginal ultrasonography, a gestational sac is usually visible between 4.5 and 5 weeks of gestational age. The  yolk  sac can be visualized between 5 and 6 weeks and a fetal  pole  with  cardiac  motion  appears  between  5.5  and   6 weeks.

Early  in  pregnancy,  inaccurate  dating  based  on  the  last menstrual period can be a problem, so knowing the  hCG level and the DZ for the reported level can be very  helpful.  When  the  upper  level  of  hCG  for  the  DZ  is  reached, an intrauterine pregnancy should be seen.

On  ultrasound,  an  early  normal  intrauterine  preg- nancy  has  an  eccentrically  located  echolucent  area  with  a  “double-ring”  sign  representing  the  decidual  lining  and  the  chorion  around  the  early  decidual  sac.  This early gestational sac can be confused with a

C H A P T E R 24 Ectopic Pregnancy 309

FIGURE 24-1 Algorithm for the workup and management of early pregnancy in a hemodynamically stable woman with pain, bleeding, and a closed uterine cervix. hCG, Human chorionic gonadotropin.

POSITIVE PREGNANCY TESTS

PREGNANCY IN HEMODYNAMICALLY STABLE WOMAN1 WITH PAIN/BLEEDING AND CLOSED CERVIX

1. If at any time patient’s symptoms worsen or she becomes hemodynamically unstable, provide prompt urgent surgical treatment. 2. Definite or probable ectopic pregnancy indicated on ultrasound by presence of significant free fluid in cul-de-sac, extrauterine gestational sac with yolk sac and/or embryo, or inhomogeneous adnexal mass or extrauterine sac-like structure. 3. Abnormal intrauterine pregnancy indicated on ultrasound by gestational sac with fetus, but no cardiac motion or large, anembryonic sac.

ULTRASOUND

INTRAUTERINE PREGNANCY

NORMAL INTRAUTERINE PREGNANCY

ABNORMAL INTRAUTERINE PREGNANCY3

EVALUATE FOR THREATENED

SPONTANEOUS ABORTION OR HETEROTOPIC PREGNANCY

TREAT

ECTOPIC PREGNANCY OR ABNORMAL

INTRAUTERINE PREGNANCY: 2 TREATMENT OPTIONS

TREAT ECTOPIC

PREGNANCY MEDICALLY

ENDOMETRIAL CURETTAGE +/– SERIAL POST-

EVALUATION hCG

REPEAT hCG IN 48 HOURS

REPEAT hCG IN 48 HOURS

CONTRACEPTION

REPEAT hCG UNTIL

UNDETECTABLE

CHRONIC VILLI OR NORMAL FALL

IN hCG

NO CHRONIC VILLI OR ABNORMAL FALL

IN hCG

NORMAL FALL IN hCG

NORMAL RISE IN hCG AND PATIENT

STILL STABLE

ABNORMAL RISE OR

FALL IN hCG

PREGNANCY OF UNKNOWN LOCATION

DRAW SERUM hCG TITER

hCG ≥ UPPER LIMIT DISCRIMINATORY ZONE WITH NO INTRAUTERINE

PREGNANCY ON REPEAT ULTRASOUNDS

hCG ≤ UPPER LIMIT DISCRIMINATORY ZONE WITH NO INTRAUTERINE

PREGNANCY ON REPEAT ULTRASOUNDS

TREAT ECTOPIC (USUALLY SURGICALLY)

DEFINITIVE OR PROBABLE ECTOPIC PREGNANCY2

Differential Diagnosis A  number  of  other  disorders  need  to  be  considered   in  the  differential  diagnosis  of  ectopic  pregnancy.  Although  pelvic  pain  and  a  positive  pregnancy  test 

should  strongly  suggest  ectopic  pregnancy,  on  occa- sion  some  other  pain-producing  disorder  may  occur   in  conjunction  with  an  early  intrauterine  preg- nancy  and  may  need  to  be  considered  (see  Box  24-1).  Figure  24-1  presents  an  algorithm  for  the  workup  and  

PA R T 3 Gynecology310

Partial salpingectomy  (removal  of  a  portion  of  the  fallopian  tube)  is  generally  performed  only  if  the  ectopic  pregnancy  is  implanted  in  the  mid-ampullary  portion.  A  laparoscopic  Endoloop  partial  salpingec- tomy is illustrated in Figure 24-3, B. Salpingotomy and  salpingostomy are both procedures in which vasocon- strictive  agents  are  injected  beneath  the  implantation  site. An incision is then made through the antimesen- teric border of the fallopian tube, the products of con- ception  are  removed,  and  hemostasis  is  established.  With  salpingotomy,  the  incision  is  closed,  whereas   it  is  left  open  in  a  salpingostomy.  A  laparoscopic   linear  salpingostomy  is  illustrated  in  Figure  24-3,  C.  Most  studies  have  shown  that  salpingostomy  results  in  better  long-term  tubal  function  compared  with  salpingotomy.

If a patient’s contralateral fallopian tube appears to be normal, there does not seem to be any advan- tage regarding future fertility if salpingectomy is per- formed instead of salpingostomy. In addition, there is a 10-20% risk of residual trophoblastic tissue when- ever the products of conception are dissected from the fallopian tube (i.e., when salpingostomy or salpin- gotomy is performed). Patients who do not have resec- tion of the affected tubal area should have repeat hCG  titers  3  to  7  days  postoperatively  to  confirm  that  no  hCG-producing  cells  remain  to  reinvade  the  tube.  When  repeat  hCG  titers  fail  to  decline  appropriately,  methotrexate  (MTX)  therapy  can  be  started  (see  the  following section). The risk for incomplete trophoblas- tic tissue removal is greatest when the ectopic products  of conception are “milked” through the tube to extrude  through  the  fimbria.  This  technique  should  never  be  used, even when it appears that the pregnancy is spon- taneously aborting through the fimbria.

MEDICAL MANAGEMENT WITH METHOTREXATE Ambulatory medical management of women with early, unruptured ectopic pregnancies has replaced surgical diagnosis and treatment in most cases. Ran- domized  trials  have  shown  no  difference  in  overall  tubal preservation, tubal patency, repeat ectopic preg- nancy, or future pregnancy rates in women treated with  medical  management  compared  with  tube-sparing  laparoscopic  surgery.  The  success  of  MTX  diminishes  rapidly with higher levels of hCG. Therefore, each insti- tution  should  have  its  own  criteria  for  offering  MTX.  However,  in  most  cases,  women  treated  with  medical  therapies avoid any surgical risk. The most commonly  used agent is MTX, which is a folic acid antagonist that  inhibits DNA synthesis and cell replication. Because of  the  side  effects  of  MTX  and  the  potential  for  tubal  rupture,  careful  evaluation  of  the  patient  for  possible  contraindications,  as  shown  in  Box  24-2,  is  needed.  Before MTX is considered, the woman should demon- strate a normal serum creatinine level, as well as normal  liver and blood count studies.

management  of  a  hemodynamically  stable  woman  with  a  positive  pregnancy  test,  pelvic  pain  and  bleed- ing, and a closed uterine cervix.

Management The management of ectopic pregnancy in the fallopian  tube depends on the stability of the patient, the avail- ability  of  resources,  and  the  patient’s  desire  for  future  fertility. In general, medical management is preferred for an early ectopic pregnancy, and surgery is reserved for unstable patients, those whose diagnosis is uncer- tain, and those whose medical therapy has failed.

SURGERY Laparotomy is the preferred surgical approach for women who are hemodynamically unstable, because  rapid access to the bleeding site is critical. It is also the  preferred  approach  whenever  it  is  anticipated  that   laparoscopy  would  not  be  successful  (e.g.,  because  of  extensive intraperitoneal adhesions). If it is determined  intraoperatively  that  laparoscopy  is  not  possible,  the  surgery can always be converted to laparotomy. Lapa- roscopy is discussed further in Chapter 31. Figure 24-2  shows  a  tubal  ectopic  pregnancy  viewed  through  the  laparoscope.

The actual surgery performed on the fallopian tube  itself depends on the amount of tubal damage and the  patient’s  wishes  for  future  fertility.  Salpingectomy  (removal of the entire fallopian tube) is recommended  when  there  has  been  significant  damage  to  the  tube,  when a patient who previously has been sterilized veri- fies  that  she  still  does  not  desire  future  fertility,  and  when there is a high likelihood of retained products of  conception.  A  laparoscopic  salpingectomy  is  illus- trated in Figure 24-3, A.

FIGURE 24-2 Tubal ectopic pregnancy as seen at the time of lapa- roscopy. (Courtesy B. Beller, MD, Eugene, Ore.)

Tubal ectopic

Tubal ectopic

C H A P T E R 24 Ectopic Pregnancy 311

other criteria continue to be met. If the patient becomes  more  symptomatic  or  if  hCG  titers  increase  during  therapy, surgical intervention is required.

Some  centers  prefer  to  routinely  provide  two  doses  of MTX—the first on day 1 and the second on day 4. If  the  response  to  these  injections  is  suboptimal  (<15%  decline  in  hCG  level),  another  course  of  therapy  with  MTX  is  given  on  days  7  and  11.  Surgery  is  considered  when  the  response  is  inadequate.  Sometimes  this   protocol  is  followed  when  the  baseline  hCG  levels  approach the upper limits of the institution’s threshold  for MTX use.

The  fixed  multidose  therapy  today  is  generally  reserved  for  cases  in  which  the  patient’s  hCG  level  is  much higher than normal or embryonic cardiac motion 

There  are  three  popular  protocols  used  for  MTX  treatment:  (1)  the  single-dose/flexible-dose  protocol,  (2)  the  two-dose  protocol,  and  (3)  the  fixed  multidose  protocol. The  most  commonly  used  is  the  single-dose  approach, in which the patient’s response to therapy is  monitored and a second dose is prescribed only if the  hCG levels do not fall adequately. In this protocol, MTX  is  administered  in  a  dose  of  50 mg/m2  initially.  The  patient  returns  on  days  4  and  7  for  repeat  hCG  deter- minations.  If  the  hCG  titers  fall  at  least  15%  between  the  return  days,  the  patient  can  be  followed  at  weekly  intervals  to  verify  at  least  a  continued  15%  decline  every 7 days until the hCG level is undetectable (usually  <5 mIU/mL). When  the  hCG  levels  plateau  or  fall  too  slowly,  another  dose  of  MTX  may  be  given  if  all  the 

FIGURE 24-3 Methods of laparoscopic management of tubal pregnancy. A, Salpingectomy using Endoloop and cautery scissors for isthmic tubal pregnancy. B, Partial salpingectomy with Endoloop. C, Linear salpingostomy for an ampullary ectopic pregnancy.

B

C

A

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EXPECTANT MANAGEMENT Selected  patients  may  qualify  for  expectant  manage- ment (watchful waiting) if they are stable and the diag- nosis of ectopic pregnancy is not yet certain or if their  symptoms  are  resolving.  Patients managed expec- tantly should be reliable and relatively asymptomatic with hCG titers low enough that rupture is unlikely  (<200 mIU/mL  and  declining).  When  hCG  levels  are  less  than  200 mIU/mL,  85%  of  ectopic  pregnancies  resolve  spontaneously.  These  women  should  be  care- fully followed with serial hCG testing and monitoring.

IMPORTANT THERAPUETIC CONSIDERATIONS All Rh-negative, unsensitized women who have ectopic pregnancies should receive anti-Rh immuno- globulin (RhoGAM).  After  an  ectopic  gestation,  preg- nancy should be avoided for at least 3 months to permit  the fallopian tube to normalize and to allow complete  elimination of MTX if that agent has been given. Highly  effective  contraception  should  be  provided  as  soon  as  the ectopic pregnancy starts to resolve.

TREATMENT OF UNCOMMON TYPES OF ECTOPIC PREGNANCIES An  ovarian ectopic pregnancy  produces  the  same  symptoms as a tubal pregnancy. The treatment is aimed  at  removing  the  pregnancy  and  preserving  as  much  normal ovarian tissue as possible. When ovarian pres- ervation  is  not  possible,  usually  because  of  profuse  bleeding, oophorectomy is indicated. If identified early  enough,  ovarian  ectopic  pregnancies  may  be  treated  successfully with MTX.

Cervical ectopic pregnancy  usually  presents  with  profuse  vaginal  bleeding,  and  attempts  at  removal  of  the pregnancy are often unsuccessful. MTX and arterial  embolization are used to manage cervical pregnancy if  the patient is not actively bleeding. An alternative is to  aspirate the cervical ectopic using an oocyte aspiration  needle, traversing the cervical stroma. Hysterectomy is reserved for large cervical ectopic pregnancies not amenable to nonsurgical intervention and for actively bleeding cervical pregnancies that cannot be con- trolled conservatively.

Pregnancies rarely implant in the abdominal cavity (e.g., on the omentum, bowel, or parietal or vis- ceral  peritoneum),  but when they do, the pregnancy may proceed to near or full term. At the time of lapa- rotomy  in  advanced  gestations,  the  placenta  presents  a major technical difficulty. Vital organs may be entirely  or  partially  covered  by  the  firmly  attached  placenta,  and any attempt at removal may cause massive bleed- ing.  Partial  bowel  resection  may  be  required  if  the  bowel  is  involved.  In most cases, it is best to leave the placenta attached, especially if the pregnancy is in  the second or third trimester. Expectant management,  allowing spontaneous reabsorption of placental tissue, 

is detected. In this 8-day regimen, MTX is administered  intramuscularly every other day and folic acid rescue is  provided on alternate days.

Patients being treated with MTX should be instructed to avoid folate supplements, nonsteroidal antiinflammatory agents, and alcohol. Pelvic rest (no  sexual  activity)  is  required,  and  women  should  also  avoid sunlight exposure and vigorous physical exercise.  Women should be warned about potential side effects  of  MTX.  Gastrointestinal  side  effects,  stomatitis,  and  hair  loss  are  possible,  especially  with  more  prolonged  therapy. Women  may  experience  abdominal  pain  2  to  3  days  after  injection,  which  is  potentially  caused  by  continued  expansion  of  the  pregnancy  mass.  They  should  return  immediately  if  they  have  any  sudden  severe abdominal pain, shoulder pain, or dizziness. To  avoid confusion about abdominal pain, gas-producing  foods  should  be  avoided.  Women  should  be  assured  that  treatment  with  MTX  will  not  compromise  their  future fertility.

OTHER THERAPEUTIC INTERVENTIONS When  ectopic  pregnancy  is  diagnosed  at  the  time  of  laparoscopy,  MTX, prostaglandins, or hyperosmolar glucose can be injected into the amniotic sac to destroy the ectopic pregnancy without the need for any other procedure. This  technique  can  also  be  per- formed  transvaginally  using  ultrasonographic  guid- ance  without  laparoscopy. The  potential  advantage  of  this  technique  is  that  it  is  a  one-time  injection  that  reduces  systemic  side  effects.  However,  the  success  of  this approach has had mixed results, and therefore its use should be considered experimental.

Modified from American College of Obstetricians and Gynecologists (ACOG): Medical management of tubal pregnancy, Practice Bulletin No. 94, Washington, DC, June 2008, ACOG.

BOX 24-2

MEDICAL MANAGEMENT OF ECTOPIC PREGNANCY

Contraindications to the Use of Methotrexate (MTX) Patient-Related 1.  Hemodynamic instability 2.  Unreliable for return visits 3.  Known sensitivity to MTX 4.  Overt or laboratory evidence of immunodeficiency 5.  Hepatic, renal, or hematologic dysfunction 6.  Active pulmonary disease 7.  Peptic ulcer disease 8.  Breastfeeding

Ectopic Pregnancy–Related 1.  Gestational sac ≥ 3.5 cm 2.  Embryonic cardiac motion seen 3.  Human chorionic gonadotropin levels > institutionally 

predetermined  value  (usually  between  6000  and  15,000 mIU/mL)

C H A P T E R 24 Ectopic Pregnancy 313

nancy  and  ongoing  problems  with  infertility.  In  one  encouraging study, researchers reported that the preg- nancy rate is just over 80% after either medical or surgi- cal treatment for ectopic pregnancy, with a mean time  to  conception  of  9  to  12  months.  Fertility  rates  are  similar  after  expectant  management  or  surgical  inter- vention.  All  patients  who  have  had  an  ectopic  preg- nancy  should  receive  counseling  about  the  increased  risk  of  having  another  ectopic  pregnancy  before  attempting pregnancy.

and  treatment  with  MTX  to  enhance  placental  reab- sorption have both been reported to be successful.

The presence of an ectopic pregnancy in an old cesarean scar is reported with increasing frequency.  Contrast-enhanced MRI may be needed to distinguish  this from an intrauterine implantation. MTX given sys- temically  combined  with  uterine  artery  embolization  and  curettage  have  been  successful,  but  more  exten- sive surgery is required in some cases.

Implications for Future Fertility Patients  who  have  had  an  ectopic  pregnancy  are  at  a  7-  to  13-fold  increased  risk  for  another  ectopic  preg-

314

25  Endometriosis and Adenomyosis

C H

A P

T ER

JOSEPH C. GAMBONE

■  Endometriosis is defined as the presence of endometrial  glands and stroma in extrauterine locations. An accurate  prevalence for endometriosis is not known, but it is esti- mated  that  about  10%  of  women  of  reproductive  age  have  the  disease.  Most  women  are  without  symptoms,  but some have severe pain often manifested by dysmen- orrhea,  dyspareunia,  and,  less  often,  dyschezia.  Infertil- ity is often the initial sign of endometriosis.

■  Retrograde menstruation, metaplastic transformation of  peritoneal  mesothelium,  and  lymphatic  spread  are  the  three  most  often  cited  hypotheses  for  the  origins  and  locations  of  endometriosis.  An  immunologic  factor  is  presumed  to  explain  why  some  women  who  have  risk  factors  similar  to  those  that  are  affected  do  not  develop  the disease. Genetic predisposition is highly likely, based  on polygenetic, multifactorial inheritance.

■  The staging of endometriosis is based upon the location,  extent, and appearance of the lesions. Implants of glands  and stroma may be dark red, brown, bluish gray, or even  white. The lesions are frequently surrounded by fibrosis,  which  results  in  puckering.  Ovarian  cysts  filled  with  hemosiderin-laden, “chocolate”-colored  fluid  may  form  metaplastic endometriomas.

■  The amount of endometriosis does not always correlate  with the severity of symptoms. Women with minimal or 

no  symptoms  may  be  managed  expectantly.  Medical  treatments consist of initial trials of nonsteroidal antiin- flammatory  drugs  (NSAIDs)  and  low-dose  progestins,  including  oral  contraceptives  (OCs).  More  advanced  medical  therapy  includes  the  androgenic  danazol  and  gonadotropin-releasing  hormone  (GnRH)  analogues.  When  fertility  is  desired  but  is  not  occurring  spontane- ously and medical therapy has failed, conservative lapa- roscopic surgery to reduce the amount of endometriosis  and  reactive  adhesions  is  indicated.  More  definitive  extirpative surgery involves removal of all endometriosis  and adhesions, along with the uterus and adnexal tissues.  One  or  both  ovaries  may  be  preserved  if  they  are  com- pletely free of endometriosis.

■  Adenomyosis is the extension of endometrial glands and  stroma into the uterine musculature more than 2.5 mm  beneath  the  basalis  layer. The  uterus  is  homogeneously  enlarged. Although many women with adenomyosis are  without  symptoms,  some  have  severe  dysmenorrhea,  and  the  disorder  may  adversely  affect  fertility.  Medical  therapy  with  NSAIDs  is  indicated  initially  for  the  pain  and uterine bleeding. Endometrial ablation may be per- formed  for  heavy  bleeding,  and  hysterectomy  is  some- times  indicated  when  more  conservative  treatment  has  failed.

CLINICAL KEYS FOR THIS CHAPTER

It  is  estimated  that  5-15%  of  women  of  reproductive  age have some degree of endometriosis, defined as the  presence  of  endometrial  glands  and  stroma  in  extra- uterine  locations.  Both endometriosis and adeno- myosis (growth of endometrial glands and stroma into  the  uterine  muscle)  are associated with pelvic pain and infertility.  Endometriosis  and  adenomyosis  often  present difficult diagnostic and therapeutic challenges. 

In  the  case  of  endometriosis,  few  gynecologic  condi- tions can require such difficult surgical dissections.

Endometriosis Endometriosis is a benign condition in which endo- metrial glands and stroma are present outside the uterine cavity and walls.  Endometriosis  is  important 

C H A P T E R 25 Endometriosis and Adenomyosis 315

Most authorities believe that several factors are involved in the initiation and spread of endometrio- sis, including retrograde menstruation, coelomic metaplasia, immunologic changes, and genetic pre- disposition.  A  fundamental  question  is  why  all  men- struating women do not develop endometriosis, given  that  most,  if  not  all,  women  have  retrograde  flow  into  the  pelvic  peritoneum  during  menstruation.  The  amount of exposure to retrograde flow and the woman’s  immunologic response seem to be critical. Researchers  have  identified  differences  in  the  chemical  composi- tion  and  biologic  pathways  of  endometrial  cells  from  women  with  endometriosis  compared  with  those  of  unaffected  women.  They  have  also  found  significant  differences  in  the  inflammatory  and  growth  factors  in  the peritoneal fluid of affected women. A clearer under- standing  of  the  pathophysiology  of  endometriosis  would  provide  insights  into  more  effective  strategies  for prevention and treatment.

SITES OF OCCURRENCE Endometriosis occurs most commonly in the depen- dent portions of the pelvis.  Specifically,  implants  can  be found on the ovaries, the broad ligament, the peri- toneal surfaces of the cul-de-sac (including the utero- sacral  ligaments  and  posterior  cervix),  and  the  rectovaginal  septum  (Figure  25-1).  Quite  frequently,  the  rectosigmoid  colon  is  involved,  as  is  the  appendix  and  the  vesicouterine  fold  of  peritoneum.  Endome- triosis is occasionally seen in laparotomy scars, devel- oping  especially  after  a  cesarean  delivery  or  myomectomy  in  which  the  endometrial  cavity  has  been  entered.  It  is  probable  that  endometrial  tissue  is  seeded into the surgical incision. Two of three women with endometriosis have ovarian involvement.

PATHOLOGY Islands of endometriosis respond cyclically to ovarian steroidal hormone production. The implants prolifer- ate  under  estrogenic  stimulation  and  slough  when  support  from  estrogen  and  progesterone  is  removed  with  involution  of  the  corpus  luteum.  The  sloughed  material  induces  a  profound  inflammatory  response,  resulting in pain immediately and fibrosis in the longer  term.  The  macroscopic  appearance  of  endometriosis  depends  on  the  site  of  the  implant,  the  activity  of  the  lesion,  the  day  of  the  menstrual  cycle,  and  the  time  since implantation.

Lesions  may  be  raised  and  flat  with  red,  black,  or  brown coloration; fibrotic, scarred areas that are yellow  or  white  in  hue;  or  vesicles  that  are  pink,  clear,  or  red  (Figure  25-2).  The  color  of  the  implant  is  generally  determined by its vascularity, the size of the lesion, and  the  amount  of  residual  sloughed  material.  Newer  implants  tend  to  be  red,  blood-filled,  active  lesions.  Older  lesions  tend  to  be  much  less  active  hormonally,  scarred,  and  bluish  gray  in  color,  with  a  puckered 

in  gynecology  because  of  its  frequency,  distressing  symptomatology,  association  with  infertility,  and  potential for invasion of adjacent organ systems, such  as the gastrointestinal and urinary tracts.

OCCURRENCE The prevalence of endometriosis in the general popu- lation  is  not  known,  but  it is estimated that 5-15% of women have some degree of the disease. At least one- third  of  women  with  chronic  pelvic  pain  have  visible  endometriosis,  as  do  a  significant  number  of  infertile  women. Interestingly, endometriosis is noted in 5-15%  of  women  undergoing  gynecologic  laparotomies,  and  it  is  an  unexpected  finding  in  approximately  half  of  these cases.

The typical patient with endometriosis is in her 30s, nulliparous, and infertile.  However,  in  practice,  many women with endometriosis do not fit the classic  picture.  Occasionally,  endometriosis  may  occur  in  infancy,  childhood,  or  adolescence,  but  at  these  early  ages,  it  is  usually  associated  with  obstructive  genital  anomalies  such  as  a  uterine  or  vaginal  septum.  Although  endometriosis  should  regress  following  menopause unless estrogens are prescribed, 5% of new  cases develop in that age group. In addition, the scari- fying involution from preexisting lesions may result in  obstructive problems, especially in the gastrointestinal  and urinary tracts.

PATHOGENESIS The pathogenesis of endometriosis is not completely understood.  Genetic  predisposition  clearly  plays  a  role. The following three hypotheses have been used to  explain  the  various  manifestations  of  endometriosis  and  the  different  locations  in  which  endometriotic  implants may be found: 1.  The retrograde menstruation theory  of  Sampson 

proposes  that  endometrial  fragments  transported  through the fallopian tubes at the time of menstrua- tion  implant  and  grow  in  various  intraabdominal  sites. Endometrial tissue, which is normally shed at  the  time  of  menstruation,  is  viable  and  capable  of  growth  in  vivo  or  in  vitro.  To  explain  some  rare  examples  of  endometriosis  in  distant  sites,  such  as  the lung, forehead, or axilla, it is necessary to postu- late hematogenous spread.

2.  The müllerian metaplasia theory  of  Meyer  pro- poses that endometriosis results from the metaplas- tic  transformation  of  peritoneal  mesothelium  into  endometrium under the influence of certain gener- ally unidentified stimuli.

3.  The lymphatic spread theory  of  Halban  suggests  that  endometrial  tissues  are  taken  up  into  the  lym- phatics  draining  the  uterus  and  are  transported  to  the various pelvic sites where the tissue grows ectop- ically.  Endometrial  tissue  has  been  found  in  pelvic  lymphatics in up to 20% of patients with the disease.

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FIGURE 25-1 Common sites of endometriosis in decreasing order of frequency: (1) ovary, (2) cul-de-sac, (3) uterosacral ligaments, (4) broad ligaments, (5) fallopian tubes, (6) uterovesical fold, (7) round ligaments, (8) vermiform appendix, (9) vagina, (10) recto- vaginal septum, (11) rectosigmoid colon, (12) cecum, (13) ileum, (14) inguinal canals, (15) abdominal scars, (16) ureters, (17) urinary bladder, (18) umbilicus, (19) vulva, and (20) peripheral sites.

18

15 12

13

16

8 7

17

19

10

6

4

3 2

9

11

1

5

14

20

appearance.  These  older,  inactive  lesions  have  been  called the tattooing of endometriosis.

Endometriomas of the ovary are cysts filled with thick, chocolate-colored fluid that sometimes has the black color and tarry consistency of crankcase oil.  This  characteristic  fluid  represents  aged,  hemolyzed  blood and desquamated endometrium. Usually, endo- metrial glands and stroma are present in the cyst wall.  Sometimes, however, the pressure of the enclosed fluid  destroys  the  endometrial  lining  of  the  endometrioma,  leaving  only  a  fibrotic  cyst  wall  infiltrated  with  large  numbers  of  hemosiderin-laden  macrophages.  Gener- ally,  ovarian  implants  are  associated  with  significant  scarring  of  the  ovary  to  the  pelvic  sidewall  or  broad  ligament.  Histologically, two of four characteristics must be found in the endometrioma specimen to confirm the diagnosis: endometrial epithelium, endometrial glands, endometrial stroma, and hemosiderin-laden macrophages.

Although  endometriosis  is  a  benign  process,  it  shares  many  characteristics  with  malignancy.  It  is  locally  infiltrative,  invasive,  and  widely  disseminated.  It  is  also  curious  that  cyclic  hormones  tend  to  induce  growth, whereas continuous hormonal exposure, espe- cially  in  high  doses,  generally  induces  significant  regression.

STAGING The  American  Society  of  Reproductive  Medicine  employs  a  staging  protocol  in  an  attempt  to  correlate  fertility  potential  with  a  quantified  stage  of  endome- triosis.  This  staging,  which  was  initially  based  on  the  allocation  of  points  depending  on  the  sites  involved  and the extent of visualized disease (Figure 25-3), was  modified  to  include  a  description  of  the  color  of  the  lesions and the percentage of surface involved in each  lesion  type,  as  well  as  a  more  detailed  description  of  any  endometrioma.  The  lower  portion  of  Figure  25-3  provides sketches of normal and abnormal uterine and  adnexal anatomy where mapping of implants of endo- metriosis and adhesions can be documented for accu- rate staging.

SYMPTOMS The characteristic triad of symptoms associated with endometriosis is dysmenorrhea, dyspareunia, and, less frequently, dyschezia. The pain that women expe- rience  with  endometriosis  varies  with  the  time  since  the  onset  of  the  disease.  Early  in  the  clinical  course,  women  tend  to  have  cyclic  pelvic  pain,  which  starts  1  to 2 days before the menstrual flow and resolves at the  end  of  the  menses.  This  secondary  dysmenorrhea  is  thought  to  be  related  to  the  premenstrual  swelling   and  extravasation  of  blood  and  menstrual  debris,  which induces an intense inflammatory reaction in the  surrounding  tissue  mediated  by  prostaglandins  and  cytokines that are more directly responsible for trigger- ing  the  pain  sensation.  Deep,  infiltrating  implants,  especially those in the retroperitoneal space, are asso- ciated  with  more  pain  than  are  superficial  lesions.   Over  time,  the  pain  may  become  more  chronic,  with  exacerbations at the time of the menses. Interestingly,  there is no clear relationship between the stage of endometriosis and the frequency and severity of pain symptoms.

Dyspareunia is generally associated with deep- thrust penetration during intercourse  and  occurs  mainly  when  the  cul-de-sac,  uterosacral  ligaments,  and portions of the posterior vaginal fornix are involved.  Deep-thrust  dyspareunia  can  also  result  from  uterine  immobility  caused  by  significant  internal  scarring  caused by endometriosis. Endometriomas in these cir- cumstances may be exquisitely tender to palpation.

Dyschezia is experienced with uterosacral, cul-de- sac, and rectosigmoid colon involvement. As the stool  passes between the uterosacral ligaments, the charac- teristic dyschezia is experienced.

Premenstrual and postmenstrual spotting is a characteristic symptom of endometriosis.  Heavy  menstruation  is  uncommon,  with  the  amount  of  flow  usually diminishing with endometriosis. If the ovarian  capsule is involved with endometriosis, ovulatory pain  and  midcycle  vaginal  bleeding  often  occur.  Rarely,  as 

C H A P T E R 25 Endometriosis and Adenomyosis 317

corpus  luteum,  (3)  benign  or  malignant  ovarian  neo- plasm, and, occasionally, (4) ectopic pregnancy.

DIAGNOSIS The diagnosis of endometriosis should be suspected in an afebrile patient with the characteristic triad of pelvic pain; a firm, fixed, tender adnexal mass; and tender nodularity in the cul-de-sac and uterosacral ligaments. The characteristic sharp, firm, exquisitely tender “barb” (so called because it is reminiscent of barbed wire) felt in the uterosacral ligament is the diagnostic sine qua non of endometriosis,  but  this  finding  is  generally  present  only  in  severe  cases.  An  ultrasonic evaluation may indicate an adnexal mass of  complex echogenicity, with internal echoes consistent  with old blood. Imaging studies are of limited value in  most cases. Serum levels of the cancer antigen CA-125  are frequently elevated in women with endometriosis.  However,  the  positive  predictive  value  of  CA-125  for  detecting  endometriosis  is  low  (about  20%),  and  this  test should not be used to diagnose endometriosis.

The definitive diagnosis is generally made on the basis of the characteristic gross and histologic findings obtained at laparoscopy or laparotomy.  Unfortunately,  even  the  most  experienced  surgeon  may  fail  to  identify  endometriotic  implants  visually, 

other  organ  systems  are  involved,  menstrual  hemato- chezia,  hematuria,  and  other  forms  of  endometriotic  sloughing become evident.

The association between mild to moderate endo- metriosis and infertility is not clear. When more advanced stages of endometriosis distort the pelvic structures, the role of endometriosis in infertility is more predictable.

SIGNS Endometriosis  presents  with  a  wide  variety  of  signs,  ranging from the presence of a small, exquisitely tender  nodule  in  the  cul-de-sac  or  on  the  uterosacral  liga- ments  to  a  huge,  relatively  nontender,  cystic  abdomi- nal  mass.  Occasionally,  a  small,  tender,  mulberry-like  spot may be seen in the posterior fornix of the vagina.  Characteristically, a tender, fixed adnexal mass is appreciated on bimanual examination. The  uterus  is  fixed and retroverted in a substantial number of women  with  endometriosis.  Occasionally, no signs at all are appreciated during a physical examination.

DIFFERENTIAL DIAGNOSIS The  main  differential  diagnoses  in  the  acute  phase   of  endometriosis  are  (1)  chronic  pelvic  inflammatory  disease or recurrent acute salpingitis, (2) hemorrhagic 

FIGURE 25-2 Appearance of red (B), brown (C), and black (D) raised lesions (arrows) of active endometriosis at the time of laparoscopy. The common finding of blue-gray lesions (A) represents less active “tatooing” of old endometriosis.

B

DC

A

FIGURE 25-3 Modification of the revised American Society for Reproductive Medicine classification of endometriosis. (Reprinted with permission from American Society for Reproductive Medicine: Revised American Society for Reproductive Medicine classification of endo- metriosis: 1996. Fertil Steril 67:819–820, 1997.)

American Society for Reproductive Medicine Revised Classification of Endometriosis

DatePatient’s name

Laparoscopy Recommended treatment

Prognosis

Endometriosis <1 cm 1-3 cm >3 cm

<1/3 EnclosureAdhesions

O va

ry T

u b

e O

va ry

P e

ri to

n e

u m

1/3 –2/3 Enclosure >2/3 Enclosure

Superficial 1 2 4

Deep 2 4 6

R Superficial 1 2 4

Deep 4 16 20

Deep

Posterior cul-de-sac obliteration

4 16

Partial Complete

4 40

20

L Superficial

Dense

R Filmy

Dense

L Filmy

Dense

R Filmy

Dense

*If the fimbriated end of the fallopian tube is completely enclosed, change the point assignment to 16. Denote appearance of superficial implant types as red [(R), red, red-pink, flamelike, vesicular blobs, clear vesicles], white [(W), opacifications, peritoneal defects, yellow-brown], or black [(B), black, hemosiderin deposits, blue]. Denote percent of total described as R__%, W__%, and B__%. Total should equal 100%.

L Filmy

1 2 4

1 2 4

4 8 16

1 2 4

4 8 16

4* 8* 16

1 2 4

4* 8* 16

1 2 4

Total

Laparotomy Photography

Stage I (minimal) Stage II (mild) Stage III (moderate) Stage IV (severe)

— — — —

1 – 5 6 – 15

16 – 40 > 40

Additional endometriosis:

To be used with normal tubes and ovaries

To be used with abnormal tubes and/or ovaries

L RL R

Additional pathology:

C H A P T E R 25 Endometriosis and Adenomyosis 319

suppress  menstruation.  Through  its  weak  androgenic  properties,  danazol  decreases  the  plasma  levels  of  sex  hormone–binding  globulin.  The  resulting  increase  of  free testosterone may cause hirsutism and acne. Three years after cessation of danazol, 40% of patients will have recurrence of endometriosis. After a full course of danazol therapy, use of a cyclic OC may help to delay or prevent such recurrence.

GnRH agonists cause a temporary medical castra- tion, thereby bringing about a marked, albeit tempo- rary, regression of endometriosis.  Treatment  of  women with endometriosis with GnRH agonists usually  produces relief of pain and involution of implants. The  disadvantages of these agonists are related to cost, hot  flashes,  and  side  effects,  including  vaginal  dryness.  They  also  cause  calcium  loss  from  bone  and  an  unfa- vorable lipid profile. If treatment with a GnRH agonist  is effective in relieving chronic pelvic pain and if surgery  is  not  indicated,  low-dose  estrogen-progestin  add- back therapy can permit longer-term use of GnRH ago- nists  by  mitigating  the  adverse  impact  of  estrogen  deficiency  without  reducing  the  efficacy  of  GnRH  agonists.

OCs and oral medroxyprogesterone acetate are more effective than placebos in treatment of endometriosis-associated pelvic pain. The levonorgestrel-releasing intrauterine system reduces dysmenorrhea and may be helpful for inducing regres- sion of cul-de-sac implants without diminishing circu- lating estrogen levels in the serum.

Surgical Treatments The most comprehensive procedure (extirpative surgery) includes total abdominal hysterectomy, bilateral salpingo-oophorectomy with destruction of all peritoneal implants, and dissection of all adhe- sions.  Usually,  an  appendectomy  is  also  performed.  A  single ovary or both ovaries may be spared only if they  are  free  of  endometriosis  and  all  other  implants  have  been resected. Because of extensive adhesions, surgery  for endometriosis is often technically very challenging.  If  the  patient’s  endometriosis  involves  the  cul-de-sac   or  uterosacral  ligaments,  the  proximity  to  the  ureter,  bladder, and sigmoid colon must be considered. If the  endometriosis obstructs the ureter, resection and ure- teroplasty may be necessary to preserve renal function.  Nearly 25% of kidneys are lost when endometriosis blocks the ureter.  Obstruction  of  the  rectosigmoid,  and even obstruction of the small intestine, may require  resection of the involved intestinal segment. The surgi- cal risks must be explained carefully to the woman, as  well  as  her  subsequent  need  for  treatment  for  loss  of  ovarian  steroids.  She  also  needs  to  understand  that,  postoperatively,  there  is  a  20%  recurrence  rate  for  endometriosis, usually involving the bowel.

Often the desire for future fertility precludes this extirpative surgical option.  In  such  circumstances,  a 

because  the  older  implants  may  have  a  very  subtle  appearance and the deeper infiltrating lesions may not  be visible at the peritoneal surface. Biopsy of any suspi- cious lesions improves diagnostic accuracy.

MANAGEMENT The management of endometriosis depends on certain  key  considerations:  (1)  the  certainty  of  the  diagnosis,  (2)  the  severity  of  the  symptoms,  (3)  the  extent  of  the  disease,  (4)  the  desire  for  future  fertility,  (5)  the  age  of  the patient, and (6) the threat to the gastrointestinal or  urinary tract or both.

Treatment is indicated for endometriosis- associated pelvic pain, dysmenorrhea, dyspareunia, abnormal bleeding, ovarian cysts, and infertility caused by gross distortion of tubal and ovarian anatomy. Surgical intervention is required for an endo- metrioma  larger  than  3 cm,  gross  distortion  of  pelvic  anatomy,  involvement  of  bowel  or  bladder,  and  adhe- sive  disease.  Surgery  may  improve  fertility  for  women  with severe endometriosis. Medical therapy is generally  the first-line treatment for other symptomatic women.  There is no convincing evidence that treatment sig- nificantly improves fertility in women with mild endometriosis.

Asymptomatic  women  found  incidentally  to  have  endometriosis  may  not  require  any  therapy.  Some  women  who  have  minimal  symptoms  may  choose  to  be  managed  expectantly  if  they  are  trying  to  conceive  or if they are approaching menopause, when endome- triosis generally becomes less symptomatic.

Medical Treatments Therapy  should  be  targeted  toward  relieving  the  patient’s  individual  complaints  and  reducing  the  risk   of  disease  progression.  Dysmenorrhea  that  results  from  endometriosis  can be approached  as  outlined  in  Chapter  21,  using  nonsteroidal antiinflammatory drugs (NSAIDs) and reduction of menstrual flow with hormonal regimens such as low-dose oral contracep- tives (OCs).

For  relief  of  noncyclic  pelvic  pain,  short-term  medical treatment may be used. NSAIDs, OCs, and pro- gestins (e.g., medroxyprogesterone acetate) should be considered the appropriate first-line medical treat- ments for symptomatic endometriosis. When an inadequate response occurs, second-line medical treatment with a gonadotropin-releasing hormone (GnRH) agonist, higher-dose progestins, or danazol appears to be equally effective. Cost, individual patient  response,  and  potential  side  effects  generally  guide  selection of one agent or the other.

Danazol is an androgenic derivative that may be used in a “pseudomenopause” regimen to suppress symptoms of endometriosis if fertility is not a present concern. It is given over a period of 6 to 9 months, and  doses of 600 to 800 mg daily are generally necessary to 

PA R T 3 Gynecology320

this is an incidental finding during a pathologic exami- nation, where it is seen in up to 60% of women in their  40s.  About 15% of patients with adenomyosis have associated endometriosis.  Islands  of  adenomyosis  do  not participate in the proliferative and secretory cycles  induced by the ovary.

PATHOLOGY Generally, the gross appearance of the uterus consists of diffuse enlargement with a thickened myometrium containing characteristic glandular irregularities, with implants containing both glandular tissue and stroma  (Figure  25-4).  The  endometrial  cavity  is  also  enlarged.  Occasionally,  the  adenomyosis  may  be  con- fined  to  one  portion  of  the  myometrium  and  take  the 

more  conservative  laparoscopic  or  open  surgical  approach  is  designed  to  destroy  all  endometriotic  implants and remove all adhesive disease. This usually  involves  excision  (not  lysis)  of  all  adhesions  and  laser  ablation  or  electrocautery  of  suspected  implants.  Endometriomas  present  a  challenge  when  fertility  is  desired.  Any  surgery  on  the  ovary,  particularly  in  women with low ovarian reserve, could adversely affect  follicular  function  and  decrease  fertility  (see  Chapter  34).  Large endometriomas (>3 cm) are usually ame- nable only to surgical resection. Because of extensive  adhesive  disease  that  generally  surrounds  these  cysts,  cystectomy  is  not  always  possible,  and  an  oophorec- tomy  may  be  necessary.  Extensive  tubal  disease,  with  or  without  ovarian  involvement,  may  be  treated  by  removal of the affected organs but with uterine preser- vation for in vitro fertilization when at least one ovary  remains or for donor embryo transfer when both have  been  removed.  Preoperative treatment with medical agents such as GnRH agonists for 3 to 6 months can improve surgical success.

The role of medical therapy postoperatively remains  controversial,  although  it  is  indicated  to  treat  women  who have known residual disease diagnosed at surgery.  There is a risk of recurrence of endometriosis throughout a woman’s life,  so  measures  should  be  taken to reduce the risk of retrograde menstruation or  cyclic ovarian sex steroid production. Depot medroxy- progesterone  acetate  (DMPA),  continuous  OCs,  and  the  levonorgestrel-releasing  intrauterine  device  (IUD)  are all attractive long-term options. Medical and surgi- cal  treatment  options  for  endometriosis  are  summa- rized in Box 25-1.

PREVENTION Whenever  severe  dysmenorrhea  occurs  in  a  young  patient,  the  possibility  of  varying  degrees  of  obstruc- tion  to  the  menstrual  flow  must  be  considered.  The  possibility  of  a  blind  uterine  horn  in  a  bicornuate  uterus  or  an  obstructing  uterine  or  vaginal  septum  should be kept in mind. In more than half the patients who are noted to develop endometriosis during child- hood and adolescence, varying degrees of genital tract obstruction may be found. Whenever a congeni- tal  abnormality  of  the  urinary  or  intestinal  tract  is  detected, the genital tract should be investigated for an  obstructive  lesion.  Infants  with  genital  tract  obstruc- tion have been noted to develop endometriosis even in  the  first  year  of  life.  In all women, minimization of menstrual flow and suppression of ovarian cycling can reduce the risk of endometriosis.

Adenomyosis Adenomyosis is defined as the extension of endome- trial glands and stroma into the uterine musculature more than 2.5 mm beneath the basalis layer.  Often 

BOX 25-1

OPTIONS FOR TREATING ENDOMETRIOSIS

Watchful Waiting There is a limited role for expectant management without  any  medical  or  surgical  intervention.  Women  who  are  attempting  pregnancy  with  little  or  no  symptoms  may  consider  this  option.  In  addition,  women  who  are  approaching  menopause  and  have  minimal  symptoms  may choose to wait for the cessation of cyclic ovarian func- tion, at which stage endometriosis is usually far less active.

Medical Treatment First-line therapy:  Nonsteroidal  antiinflammatory  drugs, 

low-dose  oral  contraceptives,  or  progestins  (e.g.,  medroxyprogesterone  acetate).  Note:  This  treatment  should  be  given  an  adequate  trial  of  3  to  6  months  before initiating second-line therapy.

Second-line therapy: Higher-dose progestins (e.g., medroxy- progesterone  acetate  or  megestrol  acetate  [Megace]),  danazol, or gonadotropin-releasing hormone analogues  appear  to  be  equally  effective.  Note:  Laparoscopic  con- firmation  of  the  diagnosis  of  endometriosis  before  ini- tiation  of  second-line  treatment  is  usually  performed,  but  it  is  not  required  according  to  some  guidelines.  Biopsy of visualized lesions, however, is the only defini- tive way to diagnose endometriosis.

Surgical Treatment Most definitive therapy:  Total  abdominal  hysterectomy 

with bilateral salpingo-oopherectomy with destruction  and/or  removal  of  all  peritoneal  endometriotic  implants and adhesions. Note: There is always a risk of  recurrence, even with “definitive” treatment.

Fertility-preserving treatment:  Laparoscopic  or  open  surgery (laparotomy) with destruction and/or removal  of  all  peritoneal  endometriotic  implants  and  adhe- sions.  Note: Removal of endometriomas may decrease  fertility  potential,  especially  in  women  with  already- reduced ovarian reserve (see Chapter 34). Large endo- metriomas  >3 cm  in  diameter  should  be  removed  surgically.  Preoperative  suppressive  treatment  for  3  to  6 months may improve surgical success.

C H A P T E R 25 Endometriosis and Adenomyosis 321

do not cycle in response to ovarian hormonal stimula- tion,  prostaglandin  release  and  local  inflammatory  changes  persist  that  can  induce  pain  and  tenderness  and  may  disrupt  the  vasoconstriction  of  the  arterial  arcade  supplying  the  endometrium.  Deep-thrust  dys- pareunia,  especially  premenstrually,  can  be  caused  by  adenomyosis.

SIGNS Pelvic examination reveals the uterus to be generally symmetrically enlarged and somewhat boggy and tender if the examination is conducted premenstru- ally. Occasionally, it may enlarge asymmetrically, which  makes it very difficult to distinguish adenomyosis from  a  myomatous  uterus. The  consistency  of  the  enlarged  adenomyomatous  uterus  is  generally  softer  than  that  of a fibroid uterus.

TREATMENT The treatment of adenomyosis depends entirely on the  patient’s symptoms and the possibility of other diagno- ses.  Any  history  of  new  onset  or  worsening  of  uterine  bleeding, particularly in a woman with risk factors for  endometrial  cancer,  should  be  investigated  by  endo- metrial biopsy or fractional dilation and curettage and/ or  hysteroscopy  to  rule  out  malignancy.  Conservative management with NSAIDs and hormonal control of the endometrium are mainstays of therapy.  Com- bination  OCs  or  hormone-containing  patches  and  vaginal  rings  may  be  used  to  reduce  cyclic  blood  loss  and  menstrual  pain.  DMPA,  levonorgestrel  IUD,  and  continuous  OC  pills  can  be  used  to  try  to  achieve  amenorrhea. If the woman is not a candidate for any of  these  medical  interventions  or  if  medical  treatments  do  not  sufficiently  control  her  symptoms,  hysterec- tomy may be indicated. Endometrial ablation to control the bleeding is another option.

FIGURE 25-4 Histologic illustration of adenomyosis causing enlargement of the uterus. A hyperplastic nodule of myometrium can be seen. Note the endometrial glands and stroma.

Endometrial glands

Hyperplastic nodule of myometrium

Endometrial stroma

form of a fairly well-circumscribed adenomyoma. Con- trary to the situation with a uterine leiomyoma (fibroid),  no  distinct  capsular  margin  can  be  detected  on  cut  sections between the adenomyoma and the surround- ing myometrium. The distinction between adenomyo- sis  and  a  uterine  fibroid  may  not  always  be  clear  on  ultrasonic  examination.  Figure  25-5  illustrates  the  typical  gross  appearance  of  an  enlarged  uterus  with  extensive adenomyosis.

SYMPTOMS Although many women with adenomyosis are asymp- tomatic, those who have this condition typically complain of severe secondary dysmenorrhea and heavy menstrual bleeding.  Even  though  the  islands 

FIGURE 25-5 Enlarged uterus cut open to demonstrate homoge- neous enlargement caused by adenomyosis. A diagnosis of leio- myomata may be incorrectly made at the time of pelvic examination. (Courtesy Dr. Sathima Nataratan, Ronald Reagan— UCLA Medical Center.)

322

26 

Abnormal Uterine Bleeding

C H

A P

T ER

ANITA L. NELSON • JOSEPH C. GAMBONE

■  During  the  reproductive  years  (puberty  to  menopause),  menstrual bleeding normally occurs every 24 to 38 days,  except during the first few years of menstruation, during  and  for  a  short  time  after  pregnancy  and  lactation,  and  in  the  perimenopausal  period.  The  normal  duration  of  bleeding is 4.5 to 8 days, and the amount of normal flow  is less than 80 mL of blood. Brief deviations from normal  bleeding  patterns  occur  in  many  women.  Once  preg- nancy  and  malignancy  are  ruled  out,  short  episodes  of  abnormal uterine bleeding (AUB) resolve spontaneously  with little or no treatment.

■  Some  women  may  experience  heavy  irregular  AUB  during their reproductive years. The causes of most cases  of  heavy  bleeding  are  benign,  and  symptoms  are  often  effectively managed with hormonal treatment alone. Up  to  20%  of  women  experience  debilitating  symptoms  caused  by  heavy  bleeding  at  some  point  during  their  reproductive years. Heavy menstrual bleeding may result 

from systemic disorders, coagulation defects, or diseases  of the reproductive system.

■  Traditional  terminology  for  AUB  has  been  replaced  by  more  accurate  descriptions  of  the  frequency,  regularity,  duration, and amount of menstrual flow. A newer system  for categorizing the causes of AUB (PALM-COEIN) helps  to organize the evaluation and treatment of women with  bleeding disorders.

■  After  first  determining  that  the  source  of  vaginal  bleed- ing  is  the  uterus,  a  series  of  tests  is  recommended  to  determine the cause of the AUB. Except in extreme cases,  the initial therapy is medical, with a variety of hormonal  and  nonhormonal  regimens  available  to  control  the  bleeding.

■  Surgical  therapy  is  reserved  for  those  women  for  whom  medical  management  fails  or  for  those  who  have  obvi- ously significant pathology (e.g., polyps) or life-threaten- ing hemorrhage when they first present with AUB.

CLINICAL KEYS FOR THIS CHAPTER

Abnormal  uterine  bleeding  (AUB)  patterns  (unrelated  to  pregnancy)  are  common  and  can  range  from   complete  absence  of  bleeding  (amenorrhea)  to  life- threatening  hemorrhage. The  etiology  of  the  bleeding  irregularities  includes  benign  or  malignant  growths,  systemic  disease,  coagulation  defects,  and  hormonal  imbalance.  Bleeding  pattern  disruptions  caused  by  imbalance  of  hormones  were  previously  termed  dys- functional uterine bleeding (DUB). Newer terminology  has been introduced to more accurately describe most  abnormal bleeding patterns, and a new, more inclusive  classification  system  has  been  adopted  to  categorize  the various causes of AUB.

Diagnosis Initially,  abnormal  vaginal  bleeding  is  assumed  to  emanate from the uterus. A pelvic examination, includ-

ing  the  insertion  of  a  vaginal  speculum,  is  essential  to  eliminate the possibility that the vulva, vagina, exocer- vix  (or  ectocervix),  or  even  the  rectum  or  bladder  is  actually  the  source  of  the  bleeding.  Early pregnancy and its complications should always be ruled out as the cause of AUB in women of reproductive age.

The newer terminology for menstrual bleeding provides information about four dimensions of a woman’s cycle: (1) frequency, (2) regularity, (3) dura- tion, and (4) blood loss. Table 26-1 outlines the normal  and abnormal values for each of these dimensions and  provides  the  newer  terms  to  describe  the  abnormali- ties. As an example, the assessment of abnormal bleed- ing  in  a  woman  with  complaints  of  “irregular  menstruation”  can  be  categorized  as  follows:  If  her  cycle length (first day of menses to the first day of the  next menses) is 23 days, she bleeds for 10 days during  each  cycle,  and  she  loses  100 mL  of  blood,  this  would 

C H A P T E R 26 Abnormal Uterine Bleeding 323

is  needed  to  differentiate  the  various  causes  of  AUB.  The classification system takes into account that there  are two different influences on AUB. On the one hand,  a  woman  may  have  structural  abnormalities  of  her  uterus  that  are  the  likely  causes  of  her  bleeding,  with  the PALM elements standing for polyps, adenomyosis,  leiomyomas  (fibroids),  and  malignancies.  Rare  prob- lems such as imperforate hymen or transverse vaginal  septum are more likely to present with primary amen- orrhea  and  not  with  chronic  bleeding  problems.  The  COEIN  portion  of  the  classification  system  refers  to  important  functional  disorders  such  as  coagulation  defects, ovarian dysfunction (formerly DUB), endome- trial  (uterine  cavity  lining)  causes,  and  iatrogenic.  A  “not  yet  classified”  category  completes  the  acronym  and is available for a cause of bleeding that is not cur- rently included or idiopathic.

Chapter  33  covers  the  causes  of  infrequent  menses  (oligomenorrhea)  and  both  primary  and  secondary TABLE 26-1

TERMINOLOGY USED TO DESCRIBE BLEEDING PATTERNS

Clinical Dimensions Descriptive Terms

Normal Limits (5th to 95th Percentiles)

Frequency of menses (days)

Frequent <24 Normal 24-38 Infrequent >38 Absent —

Regularity of menses, cycle-to-cycle variation over 12 mo

Regular Variation ± 2-20 days Irregular Variation >20 days

Duration of flow (days)

Prolonged >8.0 Normal 4.5-8.0 Shortened <4.5

Volume of monthly blood loss (mL)

Heavy >80 Normal 5-80 Light <5

*Less descriptive terms that are no longer recommended.

BOX 26-1

TRADITIONAL TERMINOLOGY FOR ABNORMAL UTERINE BLEEDING*

•  Polymenorrhea:  Abnormally  frequent  menses  at  inter- vals of less than 24 days

•  Menorrhagia (hypermenorrhea): Excessive and/or pro- longed  menses  (>80 mL  and  >7  days)  occurring  at  normal intervals

•  Metrorrhagia: Irregular episodes of uterine bleeding •  Menometrorrhagia:  Heavy  and  irregular  uterine 

bleeding •  Dysfunctional uterine bleeding:  Bleeding  caused  by 

ovulatory dysfunction

FIGURE 26-1 PALM-COEIN classification system for abnormal uterine bleeding that has been approved by the International Federation of Gynecology and Obstetrics. (Modified from Munro MG, Critchley HO, Fraser IS: The FIGO classification of causes of abnormal uterine bleeding in the reproductive years. Fertil Steril 95:2204–2208, 2011.)

Polyp Adenomyosis Leiomyoma (fibroid) Malignancy and hyperplasia

Coagulopathy Ovulatory dysfunction Endometrial Iatrogenic Not yet classified

Submucosal; Other

be  described  as  “frequent,  prolonged,  and  heavy  menses.”  Other  important  traditional  terms  include  amenorrhea,  which  refers  to  the  absence  of  any  men- strual bleeding or spotting for at least 3 months; inter- menstrual bleeding,  which  refers  to  bleeding  between  normally  spaced  menses;  and  postcoital bleeding,  which refers to bleeding after vaginal intercourse.

This  newer,  more  descriptive  terminology  for  pat- terns of AUB replaces the older, less precise terms listed  in Box 26-1. However, it is important to become famil- iar  with  these  older  terms,  because  they  have  been  used for decades in clinical practice and in the medical  literature  and  are  still  used  for  diagnostic  coding  purposes.

The  newer  classification  system,  called  PALM- COEIN, is depicted in Figure 26-1. Appropriate testing 

PA R T 3 Gynecology324

ments, liver, renal, and thyroid function tests may help  to  identify  other  systemic  causes  of  excessive  uterine  bleeding.

Many  of  the  test  results  may  not  be  available  for  days, but the heavy bleeding needs to be promptly con- trolled. First-line therapy is generally medical. Surgical approaches are usually reserved for women whose condition does not respond to medical therapies and for those who are bleeding so heavily that there is insufficient time to consider medical treatments.  First-line  medical  therapy  usually  involves  hormonal  manipulations (Box 26-3).

In the past, it was believed that high doses of estro- gen  were  needed  to  induce  cell  proliferation  over  the  denuded  areas  of  endometrium  that  were  thought  to  be actively bleeding. Both high-dose intravenous estro- gen  and  high  doses  of  combined  oral  contraceptive  pills  were  recommended.  More recently, it has been recognized that high doses of estrogen may not be necessary to control the bleeding. Furthermore, hem- orrhage  is  known  to  induce  a  hypercoagulable  state,  and  the  addition  of  high-dose  estrogen  may  increase  the  risk  of  dangerous  clotting,  especially  in  women  with  reactive  thrombocytosis.  As  a  result,  the  doses  used  in  these  estrogen-based  therapies  have  been   significantly  reduced,  and  high-dose progestin-only therapies have been recommended as first-line treat- ment for acute heavy menstrual bleeding, particu- larly in the outpatient setting.

Although  many  hormonal  regimes  have  been  used  in  clinical  practice,  prospective  clinical  trials  have  shown  that  only  three  therapies  are  reliably  effective  for  the  treatment  of  acute  excessive  bleeding  in  

amenorrhea.  Chapters  35  and  41  address  perimeno- pausal  and  postmenopausal  bleeding.  This  chapter  is  focused  on  the  etiology,  differential  diagnosis,  evalua- tion, and treatments for both acute and chronic heavy  menstrual bleeding.

Heavy menstrual bleeding occurs in 9-14% of healthy women of reproductive age and is the reason for up to 20% of outpatient clinic visits by women.  Heavy  menstrual  bleeding  can  cause  severe  anemia,  but less significant blood loss can diminish a woman’s  quality  of  life  and  even  her  income  when  workplace  activity is adversely affected.

Acute Excessive Bleeding in Nonpregnant Women of Reproductive Age The  etiologies,  workups,  and  therapies  of  excessive  bleeding can differ for acute heavy bleeding compared  with  chronic  heavy  bleeding,  although  often  there  is  considerable  overlap.  A  woman  who  presents  with  heavy bleeding needs to be assessed for hemodynamic  stability,  anemia,  and  always  the  possibility  of  preg- nancy.  She  should  be  asked  about  symptoms  of  dizzi- ness, shortness of breath, or loss of consciousness. Her  vital signs must be assessed for hemodynamic stability.  It is helpful to get a description of her current bleeding  episode  as  well  as  her  recent  and  usual  bleeding  pat- terns,  along  with  any  previous  evaluations  or  treat- ments.  A  complete  history,  including  medication  history,  can  provide  insight  into  which  of  the  PALM- COIEN  categories  is  more  likely,  but  a  broad  differen- tial  should  be  developed.  It  is  quite  possible  for  a  woman to have more than one problem as the cause of  her  abnormal  bleeding.  Obvious  causes  requiring  immediate  surgeries  should  be  ruled  out,  such  as  vaginal trauma or bleeding lacerations, as well as abort- ing fibroids (leiomyomata).

Hospitalization and transfusion are generally rec- ommended for women who have severe anemia (hemoglobin ≤7 g/dL) and those who are hemody- namically unstable.  Outpatient  transfusion  is  an  option  for  women  with  borderline  presentations.  Patients who decline blood transfusions or blood prod- ucts in spite of severe anemia should be cared for by a  team experienced with other treatment options. Before  a  transfusion  is  started,  blood  tests  should  be  per- formed. Box 26-2 lists the tests that should be consid- ered for the workup of AUB.

Baseline hemoglobin is mandatory, and a complete  blood count (with red blood cell indices) is performed  to determine the chronicity of the problem, to rule out  thrombocytopenia,  and  to  identify  possible  hemato- logic  malignancies.  Coagulation  factors  should  be  obtained, as well as serum iron, iron-binding capacity,  and serum ferritin levels. Following these initial assess-

BOX 26-2

INITIAL DIAGNOSTIC TESTS FOR ACUTE EXCESSIVE BLEEDING IN WOMEN OF REPRODUCTIVE AGE

Urine tests Pregnancy test

Blood tests Blood count with reticulocyte count and differential Serum iron and iron-binding capacity Serum ferritin Coagulation tests (PT, PTT, and INR) Thyroid function tests Liver function tests Creatinine, BUN

Imaging tests, if indicated Pelvic ultrasonography Saline infusion sonography

Biopsies as necessary Cervical biopsy Endocervical biopsy Endometrial biopsy

BUN, Blood urea nitrogen; INR, international normalized ratio; PT, prothrom- bin time; PTT, partial thromboplastin time.

C H A P T E R 26 Abnormal Uterine Bleeding 325

causes identified in the workup (e.g., providing thyrox- ine  when  hypothyroidism  is  diagnosed)  and  using  therapies  listed  in  Box  26-3  for  ongoing  treatment   of  chronic  heavy  bleeding.  Short-term  treatments   to  suppress  the  endometrium  may  be  needed  after  hospital  discharge  while  awaiting  test  results.  This   can  be  hormonal  (continuation  of  the  initial  therapy)  or  may  involve  longer-acting  medications,  such  as  gonadotropin-releasing hormone analogues.

Chronic Heavy Menstrual Bleeding Therapies  should  be  targeted  to  the  underlying  struc- tural  or  medical  problems  that  are  detected  in  the  workup  (e.g.,  endometrial  polypectomy,  thyroid  hormone  replacement,  desmopressin  treatment).  All  medical  therapies  are  intended  to  control  bleeding  from the endometrium. They can be organized as sum- marized  in  Box  26-4.  The  following  steps  should  be  considered: (1) normalize prostaglandins, (2) antifibri- nolytic therapy, (3) coordinate endometrial sloughing,  and (4) endometrial suppression. Each of these is dis- cussed in turn in the following sections.

NORMALIZE PROSTAGLANDINS Nonsteroidal  antiinflammatory  agents  (NSAIDs)  may  be  used  to  normalize  prostaglandins.  Many women

women  of  reproductive  age.  This  is  true  regardless   of  the  underlying  etiology  of  the  heavy  bleeding   or the status of the endometrium (e.g., hyperplastic or  atrophic).

Imaging studies can usually be delayed until the heavy bleeding is controlled.  More  urgent  imaging  may  be  needed  if  there  are  other  symptoms,  such  as  significant pain. In a woman with suspicious ultrasonic  findings  or  increased  risk  factors  for  cancer,  biopsy  is  indicated  once  the  bleeding  has  been  stabilized  and  her hemoglobin level is normal. Biopsies in women of  reproductive  age  seldom  reveal  problems  missed  by  the  other  tests.  In  fact,  outpatient  biopsies  often  miss  the more common causes, such as endometrial polyps  and fibroids.

When a woman with heavy uterine bleeding does not respond to the initial therapy within 12 to 24 hours, surgery is indicated. A dilation and curettage  is  performed  to  remove  the  remaining  endometrium.  When  needed,  a balloon may be placed within the uterine cavity  to  tamponade  bleeding  vessels.  Selec- tive embolization of uterine blood vessels can be done  by  an  interventional  radiologist  if  persistent  active  bleeding  continues.  As a last resort, and only rarely, hysterectomy is indicated.

After  the  initial  episode  has  been  resolved,  efforts  should be made to prevent a recurrence of the uterine  bleeding. This  usually  involves  correcting  any  specific 

BOX 26-3

MEDICAL THERAPEUTIC OPTIONS FOR ACUTE HEAVY UTERINE BLEEDING

Older Estrogen-Based, High-Dose Treatments Conjugated  equine  estrogen  30 mg  intravenously  every 

3 hr for up to 24 hr OR 50 µg  of  ethinyl  estradiol  (EE),  0.15 mg  of  levonorgestrel, 

one tablet orally every 6 hr for 5 days

Newer Therapies Prospectively Studied and Validated in Outpatient Settings Medroxyprogesterone acetate 20 mg orally every 8 hr for 7 

days, then once daily for 21 days OR Oral contraceptive pills with 35 µg of EE, 1.0 mg of noreth-

indrone acetate, one tablet orally every 8 hr for 7 days,  then 20 µg of EE, 1.0 mg of norethindrone acetate pills,  one tablet orally once daily for 21 days

OR Medroxyprogesterone acetate 20 mg orally every 8 hr for 3 

days  with  intramuscular  injection  of  depot  medroxy- progesterone acetate 150 mg

Lower-Dose Oral Contraceptive Pill Treatment Proposed Any  35-µg  EE  oral  contraceptive  pill  for  1  day,  then  one 

tablet orally every 12 hr for two doses, then one tablet  orally once daily for 19 days

BOX 26-4

MEDICAL TREATMENT OPTIONS FOR CHRONIC HEAVY MENSTRUAL BLEEDING

Normalize Prostaglandins Ibuprofen  800 mg  orally  every  8 hr  from  start  of  menses 

through last days of heavy bleeding (<5 days) Naproxen  500 mg  orally  every  12 hr  from  the  start  of 

menses through the last day of heavy bleeding (<5 days) Antifibrinolytic Therapy Tranexamic acid 650 mg, two tablets orally every 8 hr from 

start of menses for up to 5 days

Coordinate Endometrial Sloughing (Best for Anovulation) MPA 10-mg tablet orally each day for last 10 days of cycle Estrogen-containing  oral  contraceptive  pills,  transdermal 

patches, or vaginal rings

Endometrial Suppression (Lighter Bleeding or to Create Amenorrhea) Progestin-only  oral  contraceptive  or  implant,  MPA  or 

NETA daily Extended-cycle oral contraceptives, vaginal rings DMPA 150-mg intramuscular injection every 11-13 wk LNG-IUS 20 µg/24 hr May be combined with hormonal therapies Do not use with estrogen-containing products

DMPA, Depot medroxyprogesterone acetate; LNG-IUS, levonorgestrel intra- uterine system; MPA, medroxyprogesterone acetate; NETA, norethisterone acetate.

PA R T 3 Gynecology326

but the levonorgestrel intrauterine system (LNG-IUS)  20 µg/24  hours  and  depot  medroxyprogesterone  acetate  injections  induce  complete  amenorrhea  in  a  significant percentage of women with longer use.

The  higher-dose  LNG-IUS  is  the  most  effective  medical  treatment  for  idiopathic  heavy  menstrual  bleeding and treats excessive bleeding at least as well as endometrial ablation.  It  can  prevent  one-half  of  women  from  undergoing  hysterectomy.  Extended- cycle  use  of  oral  contraceptives  or  uninterrupted  use   of  vaginal  contraceptive  rings  for  3  to  12  months  can  also prevent scheduled bleeding for substantial periods   of time.

If a woman does not respond appropriately to treat- ment, her evaluation must be reinitiated. Hysteroscopy  can provide direct visualization of the endometrium to  identify  previously  undetected  causes  of  bleeding  in  about  25%  of  women  whose  bleeding  persists  despite  appropriate therapy.

SURGICAL TREATMENT Surgery is generally reserved for women whose medical  therapy fails or for those in whom significant pathology  has been identified in the initial evaluation. Commonly  indicated  procedures  include  polypectomy  and  myo- mectomy (see Chapter 19). After malignancy or prema- lignancy has been excluded, endometrial ablation is an  option  if  the  woman  does  not  desire  to  become  preg- nant  again  and  has  not  sufficiently  responded  to  medical therapies. The endometrium can be ablated by  a  variety  of  destructive  methods,  such  as  freezing,  heating,  or  applying  ultrasonic  energy.  Over  70%  of  women who are treated with ablation have satisfactory  bleeding  patterns,  including  some  with  amenorrhea.  Twenty  percent  of  these  women  will  need  a  second  ablation,  and  10%  will  ultimately  undergo  hysterec- tomy. Following ablation, women must be given effec- tive contraception. Ablation causes significant damage  to the endometrium, so spontaneous abortion rates are  high, and there is a significant risk of abnormal placen- tation, such as placenta percreta.

with heavy bleeding have an imbalance of prosta- glandins.  For  example,  levels  of  vasodilating  prosta- glandin E2 (PGE2) may exceed levels of vasoconstricting  PGF2α, or there may be excessive numbers of receptors  for PGE2 compared with those for PGF2α. An increased  PGE2/PGF2α ratio is more common among anovulatory  women. NSAIDs taken in higher doses alter the prosta- glandin ratios, but correct dosing and timing is needed  to avoid interfering with platelet function. This therapy  reduces  blood  loss  by  20-30%  and  can  be  combined  with hormonal therapies.

ANTIFIBRINOLYTIC THERAPY Antifibrinolytic agents can be used to stabilize clots in  uterine  arterioles  or  capillaries  of  women  who  may  have  excessive  fibrinolytic  activity.  Successive  clots  formed  in  the  vessels  feeding  the  endometrium  are  lysed  in  these  women,  and  antifibrinolytic  therapy   can  reduce  blood  loss  by  about  40%.  These  agents  should  not  be  combined  with  estrogen-containing  medications.

COORDINATE ENDOMETRIAL SLOUGHING Lack  of  ovulation  results  in  very  low  progesterone  levels. To prevent unopposed estrogenic stimulation of  the  endometrium  that  is  usually  seen  in  women  with  anovulatory  cycles,  a  progestin  such  as  oral  medroxy- progesterone  acetate  or  norethindrone  can  be  added  to emulate a luteal phase. Another approach is to pre- scribe  additional  progestin  daily  with  conventional  cycling  with  estrogen-progestin  contraceptive  pills  or  with  patches  or  vaginal  rings.  This  limits  endometrial  growth  and  provides  lighter,  predictable  bleeding  pat- terns.  One oral contraceptive pill has been approved by the Food and Drug Administration as treatment for heavy menstrual bleeding (a product containing estradiol valerate and dienogest), but this benefit has  been  reported  clinically  for  all  combined  hormonal  contraceptives.

ENDOMETRIAL SUPPRESSION Progestin-only  pills  and  the  contraceptive  implant  have  modest  but  measurable  impacts  on  blood  loss, 

327

27  Family Planning Reversible Contraception, Sterilization, and Abortion

C H

A P

T ER

ANITA L. NELSON

■  There are three types of interventions available in family  planning  to  prevent  unwanted  pregnancies.  The  first  is  contraception,  which  prevents  fertilization  by  blocking  the  union  of  the  gametes.  The  second  is  interception,  which  works  after  fertilization  but  before  implantation.  The  third  is  abortion,  which  is  defined  as  the  interrup- tion of an established pregnancy. The patient’s perspec- tive and preferences for family planning must always be  the primary focus.

■  Ongoing  contraceptive  options  are  grouped  into  three  tiers that are based on their efficacy in typical use. Tier 1  methods  (implants,  intrauterine  devices  [IUDs],  and  permanent  contraception)  have  the  lowest  failure  rates.  Tier 2  methods  include  injections,  pills,  patches,  and  rings.  Tier 3  methods  include  barrier  and  behavioral  methods.

■  Emergency  contraception  provides  pregnancy  protec- tion  after  intercourse  has  taken  place.  It  involves 

hormonal (oral contraceptives) or mechanical methods,  which may be interceptive (e.g., placement of an IUD).

■  Permanent contraception (previously referred to as ster- ilization) may be performed just after childbirth, between  pregnancies,  or  as  an  interval  procedure  at  any  time.  Tubal interruption is the most common technique. There  has been a recent recommendation that fimbriectomy or  complete salpingectomy should be used because it may  reduce  the  risk  of  subsequent  serous  ovarian  or  perito- neal cancer.

■  Elective termination of a pregnancy (abortion) is contro- versial  and  is  unavailable  in  some  areas  of  the  United  States. Medical and surgical abortion are as safe as other  common  procedures,  such  as  tonsillectomy.  Better  access  to  effective  contraception  has  been  shown  to  reduce abortion rates.

CLINICAL KEYS FOR THIS CHAPTER

Family  planning  plays  a  significant  role  in  improving  the  health  of  women  and  provides  a  unique  opportu- nity  to  optimize  pregnancy  outcomes  by  helping  couples  to  control  childbearing  until  conditions  are  favorable  for  them.  As  such,  family  planning  contrib- utes  substantially  to  individual  health  care,  to  public  health,  and  even  to  population  control  and  environ- mental well-being.

Despite these recognized benefits, there is no other  area  of  women’s  health  that  is  as  controversial  and  polarizing as family planning. Much of the controversy  is  based  on  a  misunderstanding  about  reproductive  facts,  the  safety  of  modern  contraception,  and  the  health  risks  posed  by  pregnancy  and  childbirth.  Box  27-1  lists  some  important  family  planning  facts  and  misconceptions held by many women and men.

Overview Before  going  into  detail  about  the  various  methods  of  family  planning,  it  is  important  to  note  several  facts  about  reproductive  health.  About 85% of sexually active couples having unprotected intercourse for 1 year will experience pregnancy.  Pregnancy  is  not  established  within  the  uterus  until  about  7  days  after  conception, which itself may not occur for up to 5 to 7  days  following  intercourse.  Half  of  all  conceptions  are  lost before implantation, and at least 10-15% of estab- lished pregnancies spontaneously abort.

Although  the  goal  of  family  planning  is  to  provide  couples  with  the  ability  to  plan  and  prepare  for  preg- nancy, efforts to date have fallen far short of that goal.  More than half of pregnancies that occur in the United

PA R T 3 Gynecology328

unprotected intercourse, and even one of the lower-tier  methods can be made quite effective if the gap between  typical  use  and  correct  and  consistent  use  is  reduced.  Different forms of emergency contraception are avail- able  after  coitus  to  provide  a  second  chance  of  preg- nancy  prevention  when  nonuse  or  method  misuse  occurs.

Contraceptive practice in the United States has been  greatly simplified by the publication of two important  documents by the Centers for Disease Control and Pre- vention  (CDC):  the  United  States  Medical  Eligibility  Criteria  (US  MEC)  for  Contraceptive  Use  and  the  U.S.  Selected Practice Recommendations (US SPR) for Con- traceptive Use. Each of these sets of guidelines is peri- odically updated based on the latest available evidence,  and both sets in their entirety can be accessed online: 

States are unintended,  meaning  that  the  woman  did  not want to become pregnant at the time she did. More  than  half  of  these  unplanned  pregnancies  are  eventu- ally accepted.

Most women underestimate the health risks of pregnancy and overestimate the risks of contracep- tion. There is no method of contraception that a clini- cian would prescribe to a woman that is as hazardous  to  her  health  as  pregnancy  itself.  The  contraceptive  needs  of  a  couple  are  often  given  lower  priority  and  may not be mentioned, even when clinicians prescribe  drugs that may be teratogenic to women of reproduc- tive  age.  The  controversy  that  surrounds  family  plan- ning  makes  it  essential  for  those  caring  for  women  of  reproductive age to be informed about all the available  methods  of  birth  control  and  to  be  dedicated  to  edu- cating couples about their importance and safety.

Contraception Ongoing  contraceptive  methods  themselves  may  be  categorized into reversible methods used before inter- course  and  those  methods  that  are  permanent.  The efficacy of a method is estimated by first-year failure rates measured under two different conditions: (1) correct and consistent use  (reflecting  a  method’s  full  potential)  and (2) typical use  (estimates  are  derived  from  surveys  of  everyday,  “real-world”  users).  Table  27-1 lists all the methods and their failure rates for both  perfect and typical use. The differences in failure rates  between the reversible Tier 1 methods and those in Tier  2 or 3 are so remarkable that most authorities recom- mend that first-line contraceptive options for women of all ages be implants and intrauterine devices (IUDs) (Tier 1).  Any  method  is  more  effective  than 

TABLE 27-1

FIRST-YEAR FAILURE RATES

Percentage of Women

Experiencing an Unintended

Pregnancy within the First Year of

Use

Method Typical Use

Perfect Use

No method 85 85

Spermicides 28 18

Fertility awareness–based methods 24 Standard days method 5 2-Day method 4 Ovulation method 3 Symptothermal method 0.4

Withdrawal 22 4

Sponge Parous women 24 20 Nulliparous women 12 9

Condom Female (FC2) 21 5 Male 18 2

Diaphragm 12 6

Combined pill and progestin-only pills 9 0.3

ORTHO EVRA patch 9 0.3

NuvaRing 9 0.3

Depo-Provera 6 0.2

Intrauterine contraceptives ParaGard T 380A intrauterine copper

contraceptive 0.8 0.6

Mirena LNG-IUS (20 µg/24 hr) 0.2 0.2

IMPLANON/NEXPLANON 0.05 0.05

Female sterilization 0.5 0.5

Male sterilization 0.15 0.10

LNG-IUS, Levonorgestrel intrauterine system.

BOX 27-1

FAMILY PLANNING FACTS

•  All  methods  of  birth  control  that  would  typically  be  prescribed to a woman today are far less hazardous to  a woman’s health than a pregnancy would be.

•  In  the  United  States,  nearly  half  of  all  pregnancies  are  unintended. This has been the case for more than two  decades.

•  The maternal mortality rate in the United States is at its  highest point in 15 years. There is currently 1 maternal  mortality for every 30,000 live births.

•  The  mortality  rate  for  healthy,  young,  nonsmoking  women using oral contraceptives for 1 year is approxi- mately 1 death in 1 million user-years.

•  In spite of this, a large majority of women of reproduc- tive age rate oral contraceptives to be more hazardous  to a woman’s health than pregnancy.

•  A first-trimester elective pregnancy termination is safer  than a tonsillectomy.

•  Providing  safe,  affordable,  and  effective  methods  of  contraception reduces the rates of abortion.

C H A P T E R 27 Family Planning 329

http://www.cdc.gov/reproductivehealth/unintended  pregnancy/usmec.htm  and  http://www.cdc.gov/ reproductivehealth/unintendedpregnancy/usspr.htm.  The  US  MEC  rates  the  eligibility  of  women  with  a  variety of medical conditions for each of the reversible  Tier 1 and Tier 2 methods of birth control on a scale of  1 to 4, where 1 represents no concern and 4 represents  an absolute contraindication. Added to this evaluation  is a consideration of the risks that a woman would face  with  pregnancy  and  the  likelihood  she  would  experi- ence  a  pregnancy  if  she  were  to  use  the  method.  For  example,  a  woman  with  advanced  diabetes  may  not  experience  any  direct  medical  harm  by  using  male  condoms, but the 18% chance of pregnancy with typical  use  of  condoms  poses  significant  risks  to  her  health. 

Table  27-2  contains  a  sample  of  the  entire  US  MEC  to  illustrate its usefulness. The complete chart can also be  accessed electronically at StudentConsult.com.

The  US  SPR  separates  the  elements  of  well-woman  care  from  those  needed  for  contraception,  provides  clear  direction  about  the  evaluations  needed  (beyond  taking a complete medical history) before offering the  method, and describes what follow-up is needed after  method  initiation.  It  also  offers  advice  on  managing  potential  side  effects  associated  with  each  of  the  methods.  Table  27-3  highlights  the  recommended  testing  for  each  method  and  emphasizes  the  impor- tance  and  feasibility  of  initiating  every  method  of   contraception  at  the  time  a  patient  is  seen  (any  time   in  a  woman’s  cycle  as  long  as  she  is  not  pregnant). 

TABLE 27-2

SAMPLE CHART OF U.S. MEDICAL ELIGIBILITY CRITERIA FOR CONTRACEPTIVE USE

C o

n d

it io

n

S u

b -c

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I C I C I C I C I C I C Age Menarche to

<40 = 1 Menarche to

<18 = 1 Menarche to

<18 = 2 Menarche to

<18 = 1 Menarche to

<20 = 2 Menarche to

<20 = 2 >40 = 2 18-45 = 1 18-45 = 1 18-45 = 1 >20 = 1 >20 = 1

>45 = 1 >45 = 2 >45 = 1 Diabetes mellitus (DM)

a) History of gestational DM only

1 1 1 1 1 1

b) Non-vascular disease

i) non-insulin dependent 2 2 2 2 2 1

ii) insulin dependent‡ 2 2 2 2 2 1

c) Nephropathy/retinopathy/ neuropathy‡

2 3 2 2 1

d) Other vascular disease or diabetes of >20 years’ duration‡

2 3 2 2 1

Headaches a) Non-migrainous 1* 2* 1* 1* 1* 1* 1* 1* 1* 1* 1*

b) Migraine

i) without aura, age <35 2* 3* 1* 2* 2* 2* 2* 2* 2* 2* 1* ii) without aura, age >35 3* 4* 1* 2* 2* 2* 2* 2* 2* 2* 1*

iii) with aura, any age 4* 4* 2* 3* 2* 3* 2* 3* 2* 3* 1*

Key:

1 No restriction (method can be used) 2 Advantages generally outweigh theoretical or proven risks 3 Theoretical or proven risks usually outweigh the advantages 4 Unacceptable health risk (method not to be used)

3/4*

3/4*

From Centers for Disease Control and Prevention. Updated June 2012. This summary sheet only contains a subset of the recommendations from the US MEC. For complete guidance, see: http://www.cdc. gov/reproductivehealth/unintendedpregnancy/USMEC.htm. Most contraceptive methods do not protect against sexually transmitted infections (STIs). Consistent and correct use of the male latex condom reduces the risk of STIs and HIV. C, Continuation of contraceptive method; I, initiation of contraceptive method; NA, not applicable. *Please see the complete guidance for a clarification to this classification: www.cdc.gov/reproductivehealth/unintendedpregnancy/USMEC.htm. ‡Condition that exposes a woman to increased risk as a result of unintended pregnancy.

PA R T 3 Gynecology330

FIGURE 27-1 The contraceptive implant (NEXPLANON; left) and the three intrauterine devices currently available in the United States: the levonorgestrel intrauterine system (LNG-IUD; middle two) and the ParaGard T 380A intrauterine copper contraceptive (right).

Single rod hormonal implant

LONG-ACTING REVERSIBLE CONTRACEPTION

LNG IUD 20 µg/24 hr

LNG IUD 13.5 mg

ParaGard T 380A IUD

TABLE 27-3

ROUTINE EXAMINATIONS AND TESTS NEEDED BEFORE INITIATION OF CONTRACEPTIVE METHODS BY HEALTHY WOMEN

Examination Needed IUD Implant Injectable

Combined Hormonal Contraceptive

Progestin-Only Pills

BP C C C A C

BMI C C C C C

Breast examination C C C C C

Pelvic examination* A C C C C

Adapted from Centers for Disease Control and Prevention: U.S. selected practice recommendations for contraceptive use, 2013. MMWR Morb Mortal Wkly Rep 62(5):1–46, 2013. A, Essential and mandated; BMI, body mass index; BP, blood pressure; C, Does not contribute substantially to safe and effective method use; IUD, intrauterine device. Laboratory tests: All methods were rated Category C for the following tests: glucose, lipids, liver enzymes, hemoglobin, presence of thrombogenic mutations, cervical cytology, and human immunodeficiency virus. Note: Use of IUDs is the only contraceptive method for which sexually transmitted infection screening has any potential benefit; a woman may need risk- or age-related testing done at the time of placement if she has not previously had routine testing as recommended by the Centers for Disease Control and Prevention guidelines. *Bimanual and speculum examinations.

Immediate  initiation  of  birth  control  and  provision  of  adequate contraceptive supplies have both been shown  to reduce unintended pregnancy rates and abortions.

TIER 1 REVERSIBLE CONTRACEPTIVE METHODS: IMPLANTS AND INTRAUTERINE DEVICES The contraceptive implant (NEXPLANON) is a plastic rod mixed with the progestin etonogestrel.  It  mea- sures  4 cm  in  length  and  2 mm  in  diameter  (Figure  27-1),  and  it  releases  the  etonogestrel  through  a  sur- rounding  releasing  membrane  that  is  0.06 mm  thick.  This contraceptive implant can be used by virtually any  woman;  only  a  history  of  recent  breast  cancer  is  an  absolute  contraindication.  In  addition,  it  has  unsur- passed  contraception  effectiveness,  is  extremely  con- venient, and is rapidly reversible. It can be placed in a  woman’s arm in an office procedure that takes less than  5 minutes. This method provides 3 years of protection.  In  U.S.  trials  involving  over  20,000  women-cycles,  no  pregnancies were seen when the implant was in place. 

With  counseling,  the  continuation  rate  for  implants  is  considerably higher than for any of the Tier 2 methods.

The implant suppresses ovulation in all users for at least 30 months and in virtually all women (97%) for  at least its full 36 months of approved life. The proges- tin also thickens cervical mucus to prevent sperm from  ascending  into  the  upper  genital  tract,  which  would  prevent  fertilization  in  any  case  where  ovulation  may  occur.  Decreased  efficacy  is  demonstrated  only  in  women taking medications that increase hepatic clear- ance  of  sex  steroids,  particularly  anticonvulsants  and  St.  John’s  wort.  As  with  most  progestin-only  methods,  the  risk  of  endometrial  cancer  is  reduced,  but  uterine  bleeding may be more unpredictable.

IUDs are the most commonly used method of reversible contraception worldwide, but they have only recently started to regain popularity in the United States. A problem with infection that occurred  years ago with one particular IUD that is no longer on  the  market  resulted  in  decreased  acceptance  of  the  method.  Like  the  implant,  IUDs  are  also  remarkably  effective  methods  that  provide  convenient,  uninter- rupted contraception that is rapidly reversible.

Currently there are three different IUDs available in  the  United  States.  Their  features  are  summarized  in  Table 27-4, and they are illustrated in Figure 27-1. Each  of the IUDs can be used by most women; the only con- traindications to all IUD use are pelvic infection, cancer  of the uterus, or distortion or inappropriate size of the  uterine cavity. In addition, copper IUDs should not be  used by women with copper allergies or Wilson disease,  and levonorgestrel IUDs should not be used by women  with  recent  breast  cancer.  IUDs  are  placed  into  the  endometrial  cavity  in  a  minor  office-based  procedure  that takes less than 5 minutes.

The  main  differences  among  the  three  currently  available IUDs are in their duration of action and their  impact on uterine bleeding. Levonorgestrel is used in each of the hormonal IUDs because it is a potent and 

C H A P T E R 27 Family Planning 331

TABLE 27-4

DISTINGUISHING FEATURES OF AVAILABLE INTRAUTERINE DEVICES

ParaGard T 380A Intrauterine Copper Contraceptive IUD Mirena LNG-IUS 20 µg/24 hr Skyla LNG-IUS 13.5 mg

Duration of action 10 years 5 years 3 years

Mechanism of action

Functional spermicide Thickens cervical mucus to block sperm entry

Thickens cervical mucus to block sperm entry

Impact on bleeding Increased duration and flow* Significant decrease in blood loss with increasing amenorrhea over time

Lighter flow over time

Noncontraceptive Nonhormonal method Treatment for heavy menstruation, dysmenorrhea, adenomyosis, and endometriosis

Smaller size for nulliparous women

IUD, Intrauterine device; LNG-IUS, levonorgestrel intrauterine system. *Increases may be reversed by use of nonsteroidal antiinflammatory drugs.

long-acting progestin requiring the release of low doses  into the uterus to thicken the cervical mucus. The levo- norgestrel  intrauterine  system  (LNG-IUS)  20 µg/24  hours  is  approved  for  up  to  5  years  of  contraceptive  use. It is associated with a 5-year cumulative pregnancy  rate of less than 1%. It also is the most effective medical  therapy  for  heavy  menstrual  bleeding  because  it  induces high rates of amenorrhea by directly suppress- ing  the  endometrium,  thus  leaving  estradiol  levels  in  the normal range.

The  lower-dose  LNG-IUS  13.5 mg  is  a  smaller  IUD  with a narrower diameter designed for up to 3 years of  use.  It  can  be  more  easily  (and  more  comfortably)  placed  into  a  woman  who  has  not  delivered  vaginally,  and  its  lower  progestin  dose  induces  amenorrhea  for  fewer women (only about 12%).

The ParaGard T 380A intrauterine copper contra- ceptive IUD is the most effective nonhormonal con- traceptive method.  It  is  approved  for  10  years  of  use,  but may be effective for 12 to 20 years. The copper ions  released  from  the  IUD  immobilize  sperm  and  inacti- vate  the  sperm’s  acrosomal  enzymes  that  are  needed  for the sperm to penetrate through the zona pellucida  of  the  ovum.  Union  of  the  gametes  is  prevented.  Because  the  copper  IUD  is  known  to  increase  men- strual blood loss by 35-50%, it is not recommended for  women with heavy menstrual bleeding at baseline.

TIER 2 CONTRACEPTIVE METHODS: INJECTIONS, PILLS, PATCHES, AND RINGS Although  formal  estimates  of  typical-use  failure  rates  differ  slightly  between  the  injections  and  the  other  members  of  this  group,  in  the  Contraceptive  CHOICE  study  in  the  United  States,  researchers  found  that  the  first-year failure rates for pills, patches, and rings were  20  times  higher  than  those  for  IUDs  or  implants.  The  most  common  reason  for  the  comparatively  high  failure  rate  was  inconsistent  use  or  nonuse.  However,  Tier 2 methods remain the most popular in the United States, partially for historical reasons and partially for  the  noncontraceptive  benefits  (e.g.,  acne  improve- ment) that some of them offer.

In the United States, there are two types of progestin-only injections with depot medroxypro- gesterone acetate (DMPA):  one  that  is  injected  intra- muscularly  every  11  to  13  weeks  and  one  that  is  administered  subcutaneously  every  12  to  14  weeks.  Each  offers  very  high  efficacy  if  reinjected  on  time.  Being  progestin-only  methods,  the  only  contraindica- tion (Category 4 condition) to their use in the US MEC  is a history of recent breast cancer.

DMPA profoundly thickens cervical mucus and suppresses ovulation. Mean return to fertility is 9 months following injection,  but  it  is  delayed  even  longer in obese women. DMPA also thins the endome- trium, which can initially cause irregular bleeding and  can increase rates of amenorrhea over time. The label  warns  that  use  beyond  2  years  is  not  recommended,  because  of  potential  bone  loss.  However,  because  the  bone  impacts  have  been  shown  to  be  reversible,  pro- fessional  organizations  universally  recommend  that  this  warning  should  not  affect  long-term  use.  Some women gain weight with DMPA use,  and  experience  with  the  first  injection  may  help  to  predict  future  weight  gain.  The noncontraceptive benefits of DMPA are impressive, including reduction of heavy bleed- ing, dysmenorrhea, sickle cell crises, pain from endo- metriosis, and future risk of endometrial hyperplasia and cancer.

The combined hormonal contraceptives (CHCs) have both estrogen and a progestin to provide cycle control.  There  are  over  90  different  brands  of  com- bined oral contraceptives with different hormonal for- mulations,  different  regimens,  and  different  doses.  In  addition,  the  transdermal  patch  and  vaginal  ring  are  more convenient delivery options.

The primary mechanisms of action of all CHCs are to thicken cervical mucus and suppress ovulation.  Traditionally,  combination  birth  control  pills  were  given in packets with 21 active pills and 7 placebo pills  to  provide  monthly  scheduled  bleeding.  As  the  doses  of  hormones  in  the  active  pills  dropped,  it  was  noted  that  ovarian  function  returned  after  4  days  of  placebo  use,  so  the  number  of  active  pills  in  the  low-dose 

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formations was increased to at least 24, with 4 or fewer  placebo  pills.  Estrogen-containing pills significantly reduce menstrual blood loss and menstrual discom- fort and offer noncontraceptive health benefits as well, including treatment of acne. These methods also significantly reduce the risk of endometrial and ovarian cancer.  Extended-cycle  products  provide  dis- tinct benefits to women with menstrual discomfort or  medical  problems  that  flare  with  bleeding  (e.g.,  men- strual  migraine  and  catamenial  (monthly)  seizures)   by  reducing  the  numbers  of  scheduled  bleeding  episodes.

The addition of estrogen to progestin adds rare but  serious  medical  risks  and  more  medical  contraindica- tions.  Risks that are clearly attributable to use of CHCs include increases in both venous and arterial thrombosis, resulting in pulmonary embolism, myo- cardial infarction, and stroke. Melasma  (facial  pig- mentation) and, uncommonly, a reversible increase in blood pressure  are  seen  as  a  result  of  estrogen- containing contraceptive use.

Other side effects that have traditionally been attrib- uted  to  oral  contraceptive  use,  including  headaches,  breast  tenderness,  weight  gain,  mood  changes,  and  gastrointestinal  upsets,  have  been  shown  in  prospec- tive,  double-blinded,  placebo-controlled  studies  to  occur at no higher frequency or with any greater inten- sity in pill users than in placebo users. It is not clear if  the  risk  of  gallbladder  disease,  hepatic  adenoma,  or  breast  cancer  is  increased  with  the  use  of  oral  contra- ceptives, because data derived from modern low-dose  formulations are not consistent and at best show only  minor impacts. Oral contraceptive use in BRCA1 muta- tion  carriers  has  not  been  shown  to  increase  the  inci- dence  of  breast  cancer.  Long-term  studies  have  provided  reassuring  data  that  former  use  of  oral  con- traceptives  does  not  pose  harm.  In  a  large-scale  study  in which women who had ever used contraceptive pills  were  compared  with  never-users,  those  women  who  had ever used pills had lower overall mortality rates as  well as lower mortality rates associated with cardiovas- cular disease and gynecologic and breast cancers.

The contraceptive patch and the vaginal ring were developed to relieve pill users of the requirement of daily administration.  In  the  United  States,  consistent  and correct use of oral contraception is infrequent. The  once-a-week  patch  and  the  once-a-month  vaginal  rings  demonstrated  more  consistent  ongoing  use  in  clinical trials than was seen with comparable pill users.  Both patches and the ring are designed to be used for 3 weeks and stopped for 1 week to induce scheduled bleeding. When estrogen absorbed from the patch was  found to be higher than doses absorbed from modern  pills, the patch largely fell out of favor. The vaginal ring  has  increased  in  popularity  as  women  have  become  more  familiar  with  it.  It  is  frequently  used  off-label  without removal for 4 weeks at a time to induce amen-

orrhea.  Newer  formulations  of  both  of  these  products  may increase their use in the future.

Progestin-only pills (POPs) in the United States are generally reserved for breastfeeding women, but they  have  a  much  larger  potential  for  use  by  women  with  medical problems. Because each pill in the packet is an  active  pill,  instructions  are  easy  to  follow.  For  typical  use, the failure rates of POPs are similar to those associ- ated  with  any  CHC.  Because  of  their  safety  and  rapid  onset  of  action,  POPs  are  clearly  a  “go  to”  choice  for  women  whose  evaluation  for  other  methods  is  still  pending.

TIER 3 CONTRACEPTIVE METHODS: BARRIERS AND BEHAVIORAL METHODS There  are  several  features  of  barrier  and  behavioral  methods that set them apart from other methods. They are generally available without a prescription (except  for  diaphragms).  That  makes  many  of  them  available  for  episodic  need  when  other  methods  are  not  avail- able,  as  well  as  for  ongoing  use.  However,  their  over- the-counter  availability  also  shifts  the  burden  of  the  cost onto the consumer (out-of-pocket expense) in the  United States. Tier 3 methods need to be used only at the time of intercourse, but that is the feature that most profoundly decreases their use and increases their failure rate.  Many  offer  varying  levels  of  protec- tion from sexually transmitted infections (STIs) as well  as other noncontraceptive benefits, which can be very  important  to  public  health.  They  can  generally  be  added  to  other  methods  or  used  together  to  enhance  STI  and/or  pregnancy  protection.  The  one  notable  exception is that male and female condoms should not  be  used  together,  because  their  effectiveness  is  decreased when they are combined.

Barrier Methods When  male  condoms  are  used  correctly  and  consis- tently, their first-year failure rate is 2%, but with typical  use,  their  failure  rate  is  18%.  Male  condoms  are  the  most commonly used method by adolescents at sexual  debut. The use of condoms should continue to be sup- ported as part of dual protection in that population for  STI risk reduction.

Most male condoms used in the United States are made of latex. They are available in three sizes (snugger  fit, large, and extra large), with variations in the diam- eter  and  lengths  of  the  shaft  as  well  as  in  the  size  and  configuration of the portion of the condom that covers  the  glans.  Some  are  smooth-tipped  so  that  the  man  must  leave  room  at  the  end  to  collect  the  ejaculate,  whereas  others  are  reservoir-tipped.  Latex  condoms  are  quite  elastic,  but  they  do  not  transmit  heat  and  therefore  can  feel  almost  cold.  Latex allergies are found in 2-4% of the general population and at greater  rates  in  health  care  workers,  people  who  work  with  latex, and those who need to self-catheterize. Nonlatex

C H A P T E R 27 Family Planning 333

her cycle. To be effective, these methods must take into  account the life expectancy of sperm (5 to 7 days) and  the  duration  of  an  ovum’s  ability  to  be  fertilized  (24  hours).  Aids  such  as  cycle  beads  for  counting  fertile  days and smartphone apps can help a woman track her  cycles and calculate her “at-risk days.” These methods work well only when cycles are reasonably regular (26 to 32 days).  The  most  easily  implemented  fertility  awareness technique is called the 2-day method. Each  morning,  the  woman  touches  her  vaginal  introitus  to  determine if there is any moisture. Coitus is permitted  only  when  her  examination  is  dry  of  all  secretions  for  2 consecutive days.

Emergency Contraception There are two FDA-approved hormonal methods for use following coitus. One is a series of products with high doses of the progestin levonorgestrel. Levonorg- estrel  suppresses  ovulation  up  to  the  beginning  of  the  luteinizing  hormone  (LH)  surge.  The  efficacy  of  these  products is inversely related to the time since exposure  (4%  failure  rate  at  72  hours)  and  to  the  woman’s  body  mass index (BMI). These products are available by pre- scription or over the counter. The patient must pay full  price  for  the  over-the-counter  packs.  The other hor- monal product is the antiprogestin ulipristal acetate, which is given as a single dose within 5 days of expo- sure.  It  is  able  to  suppress  ovulation  until  the  peak  of  the  LH  surge.  Its  effectiveness  does  not  diminish  with  time, although for obese women the pregnancy protec- tion is less than for women with lower BMIs. It is avail- able only by prescription.

The most effective method of postcoital pregnancy prevention (with a failure rate of 1 in 1000) is the placement of a copper IUD within 5 days of coitus. If  placed late, after fertilization, it may work as an inter- ceptive  due  to  endometrial  disruption  caused  during  its  placement.  Another  potential  benefit  with  this  placement is that the woman may enjoy up to 10 years  of very effective contraception.

PERMANENT CONTRACEPTION Also  called  sterilization,  permanent  contraceptive  methods are available for both men and women. Vasec- tomy is a safe, minor, office-based procedure that can be performed on men under local anesthesia in most situations. There are various techniques available, but  one of the most popular is the no-scalpel technique, in  which  the  vas  deferens  is  identified  and  grasped  through the anesthetized skin. After it has been grasped,  the vas deferens can be interrupted thermally, or it can  be  ligated.  Complications  include  pain,  hemorrhage,  and  infection,  but  long-term  autoimmune  problems  have  been  disproven.  Although  no  long-term  efficacy  trials  have  been  done,  vasectomy is generally recog- nized to be a very effective method once azoospermia is achieved. The man is asked to return 2 to 3 months 

condom options include a synthetic plastic isoprene  (which has been used for years in surgical gloves) and lamb cecum condoms. The isoprene condoms are less  elastic  and  are  therefore  available  only  in  larger-sized  condoms,  but  they  do  transmit  heat.  The isoprene condoms also effectively block passage of the small- est viral particles and have high potential for reduc- ing STI risk. The so-called natural or cecum condoms  block sperm and larger-size STI agents, but they do not  block  viruses  as  small  as  human  immunodeficiency  virus  (HIV ),  human  papillomavirus  (HPV ),  or  herpes  simplex virus (HSV ).

Female  condoms  have  also  been  revised  in  recent  years. To reduce costs, the FC2 female condom is now  available in nitrite material. Female condoms can also reduce STI risk. They  are  best  used  by  women  whose  partners will not use male condoms, because they have  higher  failure  rates  and  are  more  expensive.  The FemCap is a silicone device shaped like a sailor’s hat that applies spermicide to the cervix, which it covers with the bowl of the hat, while the brim of the hat is stabilized by the vaginal walls. It is sized according to  the patient’s obstetrical history, “nulliparous,” “parous”  but  no  vaginal  deliveries,  and  “parous”  with  “vaginal  deliveries.” The cap can be ordered online. Traditional  diaphragms are rimmed silicone domes that need to be  sized  to  fit  across  the  vagina  to  cover  the  cervix  with  spermicide. A smaller, one-size diaphragm (SILCS) has  been approved by the U.S. Food and Drug Administra- tion  (FDA).  The only available spermicide in the United States is nonoxynol-9 (N-9),  a  detergent  that  disrupts the cellular membranes of sperm but also can  disrupt vaginal epithelium and increase HIV transmis- sion.  Spermicides are available as immediate-action foams and gels and delayed-action, but less messy, suppositories and films.  Newer,  less  destructive  sper- micides have been found to be as effective as N-9, and  they may become available in the near future.

Behavioral Methods Lactational amenorrhea is the most effective method in this category.  Its  low  failure  rate  (2%)  is  limited  to  women  who  consistently  (and  exclusively)  breastfeed  during the first 6 months postpartum and who remain  amenorrheic.  After  that  time,  pregnancy  protection  diminishes  significantly,  and  ovulation  often  returns  before  the  first  menses.  Coitus interruptus (with- drawal) is one of the most commonly used behavioral methods historically.  Even  for  typical  use,  it  works  as  well  as  many  of  the  female  barrier  methods.  Counsel- ing about coital positioning is important to the success  of  coitus  interruptus  in  that  the  man  must  learn  to  detect impending ejaculation and be able to withdraw  his penis from the woman’s vagina and direct the ejacu- late away from her genital area before release.

Fertility awareness methods are designed to detect when a woman is at the greatest risk to conceive in

PA R T 3 Gynecology334

but if pregnancy should occur, the chance that it will be an ectopic pregnancy is increased to at least 20%.  The  greatest  mortality  risk  associated  with  interval  sterilization is the anesthetic risk (3 deaths per 100,000  cases).  Figure  27-3  illustrates  interval  tubal  occlusion  with the Hulka clip (A) and the Falope ring (B).

Transcervical sterilization techniques  have  been  introduced  that  can  be  done  with  local  and  intrave- nous anesthetic agents. Under hysteroscopic visualiza- tion,  small  coils  are  placed  into  the  proximal  ends  of  the fallopian tubes. These coils are filled with irritating  fibers that induce local fibrosis of each tube. Complete  tubal occlusion is documented 3 months later, usually  with  a  hysterosalpingogram  showing  that  none  of  the  dye injected into the uterine cavity has entered into the  tubes.  Until  tubal  occlusion  has  been  documented,  couples must use other contraceptive methods.

Because it has been demonstrated that some serous  ovarian and peritoneal carcinomas first develop in the  fimbrial  ends  of  the  fallopian  tubes,  many  have  sug- gested  that  if  a  woman  desires  permanent  contracep- tion,  it  should  be  provided  by  fimbriectomy  (removal  of the distal end of the fallopian tube) or by salpingec- tomy (removal of the complete fallopian tube).

Abortion Legal issues concerning the availability of abortion, the  conditions  under  which  consent  for  the  procedure 

after  the  procedure  for  a  follow-up  semen  analysis.  Couples  must  use  other  contraceptive  methods  until  lack of sperm in the ejaculate is demonstrated.

Female permanent contraception is slightly more common in the Unites States, even though vasectomy is a safer procedure.  Many  tubal  interruption  proce- dures are performed at the time of delivery. With cesar- ean  delivery,  a  partial  salpingectomy  can  be  done  following  closure  of  the  uterine  incision.  Following  a  vaginal delivery, a small infraumbilical incision can be  made just above the fundus. The fallopian tubes can be  identified by tracing each tube out to the fimbria. A site  along the fallopian tube without adjacent large vessels  can  be  tented  and  the  tube  tied  off  and  interrupted.  Different techniques have been used to reduce the risk  of  fistula  formation  and  future  failure.  Figure 27-2  illustrates the Pomeroy method of tubal interruption (ligation) performed soon after delivery.

Tubal interruption is also available as an interval procedure. Traditionally,  women  have  had  the  proce- dure  done  while  they  are  under  general  or  regional  anesthesia, with laparoscopic techniques used to ther- mally destroy, remove, or clamp a narrow portion of the  tube  on  each  side. The  success  rates  for  these  perma- nent contraceptive methods vary with the woman’s age  (higher  failure  rates  are  seen  in  younger  women)  and  with  the  technique  used  (interval  procedures  have  higher  failure  rates).  The  chance  of  subsequent  preg- nancy  associated  with  any  of  these  techniques  is  low, 

FIGURE 27-2 Pomeroy method of tubal liga- tion. A, Tube is grasped with Babcock forceps. B, A loop is ligated. C, The loop is excised. D, Several months later, the fibrosed ends of the tube separate.

A B

C D

C H A P T E R 27 Family Planning 335

surgical procedures done later in pregnancy.  In  the  second  trimester,  both  labor  induction  abortion  with  mifepristone  and  misoprostol  (or  with  misoprostol  alone if mifepristone is not available) and surgical dila- tion and evacuation procedures are available.

Women who present with septic abortion need emergency treatment with high-dose antibiotic therapy and surgical evacuation of the uterine con- tents by an experienced surgeon (see Chapter 22).

Abortion,  with  all  of  its  controversial  aspects,  remains  a  safe  and  important  method  of  family  plan- ning. The greater the availability of temporary and per- manent  methods  of  contraception,  and  the  more  informed women (and men) become about their safety  and acceptability, the less demand there should be for  abortion.

must  be  obtained,  and  governmental  regulations  of  specifics of the procedure frequently change, and they  vary from state to state. Some areas of the United States  lack readily available abortion services.

From a medical standpoint, abortions are low-risk procedures with few serious adverse outcomes.  Mil- lions  of  abortions  are  performed  each  year  in  the  United States, with mortality rates that are only a small  fraction  of  the  maternal  mortality  rate.  Abortions  also  compare  favorably  in  terms  of  complications  with  other routine procedures, such as tonsillectomy.

Before  49  days’  gestational  age,  or  with  early  failed  pregnancies, both medical and surgical treatments are  available. Mifepristone 200 mg followed by misopros- tol can induce complete abortion in 96-98% of preg- nancies before 42 days’ gestational age,  and  success  rates  of  91-95%  can  be  achieved  in  pregnancies  from  42  to  49  days’  gestation.  Medical  abortion  is  preferred  in  women  at  risk  for  surgical  or  anesthetic  complica- tions  and  in  those  presenting  technical  challenges,  such  as  morbid  obesity,  cerebral  palsy,  or  hip  disorders.

Surgical management with vacuum aspiration (5 to 6 weeks’ gestation) or dilation and curettage (6 to 13 weeks’ gestation) is preferred over medical abor- tion in situations where anesthesia may help with anxiety and with pain or when mifepristone is con- traindicated  (e.g.,  adrenal  insufficiency,  hemorrhagic  disorders, severe hepatic impairment, or renal failure).  Women  with  medical  problems  should  be  referred  to  hospital-based  providers.  Antibiotic  prophylaxis  has  been  shown  to  significantly  reduce  the  incidence  of  infectious  complications  associated  with  pregnancy  termination.  Softening  the  cervix  mechanically  (with  laminaria,  as  illustrated  in  Figure  27-4)  or  pharmaco- logically  (with  misoprostol)  reduces  concerns  about  cervical  damage  and  future  cervical  incompetence.  Cervical preparation is generally less of an issue in first-trimester pregnancy, but it may greatly facilitate

FIGURE 27-3 Tubal occlusion with (A) the Hulka clip and (B) the Falope ring. Cautery procedures use electric energy to destroy por- tions of each fallopian tube.

BA

FIGURE 27-4 Laminaria tents (osmotic dilators) used to gradually dilate the uterine cervix by absorbing body fluid. This technique reduces the risks of more rapid dilation during abortion proce- dures. Alternatively, prostaglandins placed vaginally can dilate the cervix medically.

Before use

5 mm

After 1

hour

Gradual swelling

After 24 hours

336

28  Sexuality and Female Sexual Dysfunction

C H

A P

T ER

JOSEPH C. GAMBONE

■  Sexuality and sexual expression are important aspects of  human behavior. Recent liberalization of attitudes about  sexuality and sexual expression has allowed the diversity  of sexual behavior to be acknowledged. Although sexual  expression  is  unlikely  to  begin  before  puberty,  gender  identity is expressed as early as 3 to 4 years of age. Gender  identity disorder exists when children are unable to iden- tify with their assigned gender.

■  Studies document that physicians are mostly unaware of  the sexual concerns of their patients. One survey showed  that  a  high  percentage  of  postmenopausal  women  with  dyspareunia  had  never  discussed  this  condition  with  their  physician.  The  obstetrician  gynecologist  is  in  a  unique position to inquire about, diagnose, initiate treat- ment  of,  or  refer  for  sexual  concerns  and  dysfunction,  because women frequently report that sexual function is  affected by reproductive events.

■  Female  and  male  physical  sexual  response  cycles  are  similar,  but  they  have  some  important  differences.   Most  women  need  to  experience  a  caring  relationship  and  nongenital  physical  stimulation  before  satisfactory  sexual  arousal  occurs.  Men  have  a  refractory  phase 

during which no amount of stimulation will allow for an  ejaculation  and/or  orgasm.  Women  may  be  capable  of  multiple orgasms, but an orgasm is not always necessary  for sexual satisfaction.

■  An assessment of sexual functioning is an important part  of the complete medical evaluation. Including questions  about sexual orientation and difficulties with sexual rela- tions  can  lead  to  important  information  about  female  and male sexual dysfunction and may reveal episodes of  intimate partner and childhood sexual abuse.

■  Female  sexual  dysfunction  may  be  primary  (lifelong),  secondary  (acquired),  or  situational.  The  disorders  include problems with desire, arousal, or orgasm, as well  as  pain  during  sexual  activity.  Referral  to  sex  therapy   specialists  is  appropriate  for  the  first  of  those  three   disorders. The pain disorders frequently involve underly- ing  gynecologic  disease  that  the  gynecologist  can  diag- nose  and  treat.  Lubricants  and  topical  estrogen  are   often helpful. Investigations are underway to determine  the  safety  and  effectiveness  of  several  androgenic  preparations.

CLINICAL KEYS FOR THIS CHAPTER

Sexuality refers to how individuals express them- selves as sexual beings.  Physically,  sexuality  encom- passes  sexual  intercourse  and  other  forms  of  sexual  contact.  Often  patients  may  have  medical  concerns  about  their  sexual  feelings  and  behavior  and  how   these  activities  may  affect  or  be  affected  by  disease.  Obstetrician-gynecologists should be familiar with the  physiology of the human sexual response and the types  of  sexual  dysfunction  that  women  may  experience.  Because female sexuality is most often expressed with  another  individual,  and  because  that  other  individual  is most often male, it is important for health care pro- fessionals who take care of women to know some basic  aspects  of  the  male  sexual  response  and  how  it  may 

differ  from  the  female  response.  The  sociology  of  human sexuality and sexual behavior, such as cultural,  ethical,  moral,  religious,  or  legal  aspects,  are  beyond  the scope of this chapter.

Sexual Development Although  sexuality  and  sexual  expression  rarely  begin  before  puberty,  gender  identity  is  experienced  much  earlier,  starting  at  about  3  to  4  years  of  age.  Children  who  are  unable  to  identify  with  their  assigned  birth  gender  have  gender identity disorder (GID)  and  may  develop  transgender  issues  later  in  life.  The diagnosis of GID can be made in an individual who has a strong

C H A P T E R 28 Sexuality and Female Sexual Dysfunction 337

theories  on  homosexuality  have  been  proposed,  including a genetic predisposition, the maternal use of  prenatal  hormones,  and  other  environmental  factors.  A multifactorial cause is likely.

Many homosexuals feel a need to conceal their sexuality for fear of loss of family, friends, or jobs.  Familiarity  with  homosexuals  has  been  shown  to  decrease the prejudice, and recently many homosexu- als  have “come  out,”  revealing  their  sexual  preference  and expecting equal rights.

Bisexuals are those who engage in sexual activity with both men and women, either concomitantly or in different phases of their lives.  The  reported  inci- dence of bisexuality is 1-7% of men and 1-2% of women.  Many  individuals  briefly  explore  same-sex  activity  at  some time in their lives but do not consider themselves  bisexual.

Transgender or transsexual individuals  are  often  confused with homosexuals. They have a strong belief starting in childhood that they were born into a body with the wrong sex. Most are heterosexual in refer- ence to their identified gender  (i.e.,  men  who  believe  they  are  women  are  attracted  to  men),  and  few  are  homosexual. Children with ambiguous genitalia who are assigned a particular gender may later show regret about their assignment.  Some  experts  recom- mend  that  these  children  be  given  a  name  that  is  appropriate  to  both  genders  to  allow  them  to  decide  their  gender  for  themselves  later  in  life.  Female-to- male  transsexuals  (FTM)  are  women  who  grow  up  as  “tomboys”  and  often  cross-dress.  Male-to-female  transsexuals  (MTF)  are  men  who  grow  up  dressing  as  women.  Transgender  surgery  is  difficult  to  perform,  especially  for  FTM  transsexuals,  and  it  is  performed  only in certain areas of the United States and the world.

Sexual Response The process of sexual response was fully described by Masters and Johnson in 1966  based  upon  extensive  research. They  delineated  the  female  and  male  physi- cal  sexual  response  cycles.  Although  modifications  have been published, the original Masters and Johnson  version  remains  the  classic  description  of  human  sexual  response. The  female  cycle  is  divided  into  four  phases,  whereas  in  men  five  phases  are  described.  Generally, clitoral tissue is the most sexually sensitive anatomic area for women. Most women need to expe- rience  a  caring  relationship  and  nongenital  physical  stimulation  before  satisfactory  sexual  arousal  can  occur.  A  more  recent  conceptualization  of  the  female  (and  male)  sexual  response  recognizes  the  likelihood  that  a  willingness  to  become  aroused  must  come  first  and is followed by the sensation of desire (Figure 28-1).  Box  28-1  lists  the  reproductive  and  life-cycle  events  that  are  known  to  affect  a  woman’s  sexual  desire  and  response.

and persistent cross-gender identity and a discom- fort about the assigned gender.

During puberty, many teens begin exploring their bodies and experiencing sexual activity with others.  Many  teens,  especially  males,  have  early  intercourse  and  are  not  well  educated  about  contraception  or  the  risks  of  pregnancy  or  sexually  transmitted  infections  (STIs). Young girls often engage in intercourse because  of  feelings  of  love,  whereas  boys  are  usually  driven  by  curiosity.  It  is  especially  important  for  physicians  to  discuss sexuality with teens and to educate them about  contraception  and  STI  prevention.  Teens  are  often  apprehensive  about  discussing  these  issues  and  may  fear  parental  discovery.  They  are  usually  more  recep- tive to open-ended questions.

The early reproductive years are often the time when sexuality is explored and reproduction or its prevention becomes a priority.  Infertility  may  be  an  issue  in  this  age  group,  and  many  emotions  may  be  evoked  in  infertile  patients,  often  leading  to  sexual  problems.

With increasing age, and especially after meno- pause, the frequency of and satisfaction with inter- course may decline.  Decreased  estrogen  production  causes progressive vaginal atrophy, which in turn leads  to  decreased  vaginal  lubrication,  dyspareunia,  and  more  difficulty  in  achieving  orgasm.  The  decreased  estrogen also decreases the acidity of the vaginal secre- tions, predisposing the woman to vaginal infections.

In many older couples, the frequency of inter- course declines because of the male partner’s inabil- ity to have an erection.  Illnesses  or  increased  use  of  medications  may  also  affect  sexual  functioning.  A  better  understanding  of  the  causes,  as  well  as  more  effective  treatment  for  male  erectile  dysfunction,  is  changing  the  sexual  behavior  of  many  older  individuals.

Varied Sexual Expression Human sexual expression is varied and often contro- versial. Health care professionals must be knowledge- able and nonjudgmental about healthy and legal sexual expression and lifestyles to facilitate open and comfortable communication.

Heterosexuals are individuals who engage in sexual activity with the opposite sex. Most individuals  engage  in  heterosexual  behavior,  which  is  considered  “normal.”  Homosexuals are those who engage in sexual activities with members of the same sex.  Men  who  are  homosexual  are  referred  to  as  gay,  whereas  homosexual  women  are  referred  to  as  gay  or  lesbian.  Whereas gay men tend to engage in more physical rela- tionships and may have multiple partners, lesbians are  generally inclined to be monogamous.

The reported incidence of homosexuality ranges from 6-20% in men and 3-18% in women.  Several 

PA R T 3 Gynecology338

its  hood.  The  Bartholin  glands  may  secrete  fluid  near  the vaginal opening, and there is tenting of the uterus  to allow easier passage of sperm. The vagina and labia  become more engorged, and blood pressure, heart rate,  respiratory  rate,  and  muscle  tension  increase  (see  Figure 28-2, B).

Orgasmic Phase During  the  orgasmic  phase,  there  is  release  of  sexual  tension. This  phase  can  occur  without  actual  physical  stimulation.  It  is  concentrated  in  the  clitoris,  vagina,  and  uterus.  There  is  contraction  of  vaginal,  uterine,  lower abdominal, and anal muscles, and usually there  are  5  to  12  synchronized  contractions  1  second  apart.  The  first  few  contractions  are  the  strongest  and  the  closest together. Blood pressure, heart rate, and respira- tory rate peak in this phase, and there is usually loss of  voluntary muscle tone (e.g., most women curl their toes  at orgasm). Women can have multiple orgasms before  they enter the resolution phase (see Figure 28-2, C).

Resolution Phase During  the  resolution  phase,  the  nipples  and  breasts  decrease  in  size  and  the  vagina,  clitoris,  and  uterus  return to normal size and position. The sex flush disap- pears, and the blood pressure, heart rate, and respira- tory rate also return to normal (see Figure 28-2, D).

MALE SEXUAL RESPONSE CYCLE Excitement Phase The  excitement  phase  begins  for  males  with  physical  or  psychologic  stimulation  and  may  last  minutes  or  hours. The nipples and penis become erect, and heart 

FEMALE SEXUAL RESPONSE CYCLE Excitement Phase The  excitement  phase  starts  for  females  with  physical  or  psychologic  stimulation  and  may  last  minutes  or  hours. There is a sex flush, accompanied by erection of  the nipples and engorgement of the breasts. A sex flush  is  an  erythematous  morbilliform  skin  change  over  the  chest, neck, and face that occurs to a noticeable degree  in 75% of women. In addition, the uterus elevates and  vaginal  lubrication  begins.  The  clitoris  and  labia  enlarge, and the heart rate and blood pressure increase.  Most muscles become tense (Figure 28-2, A).

Plateau Phase During  the  plateau  phase,  the  breasts  continue  to  enlarge  and  the  clitoris  may  elevate  and  retract  under 

FIGURE 28-1 The circular sexual response cycle illustrat- ing the probability that willingness is the essential first component. (From Clin Updates Womens Health Care 13[2], 2014, American College of Obstetricians and Gynecologists [ACOG], Washington, DC.)

MOTIVATION FOR SEX

ANTICIPATORY DESIRE

OR DRIVE

PHYSICAL AROUSAL

SUBJECTIVE AROUSAL

SEXUAL STIMULI AND CONTEXT

INFORMATION PROCESSING

BY BRAIN

REWARD (EMOTIONAL AND

PHYSICAL SATISFACTION)

AROUSAL AND RESPONSIVE

DESIRE

WILLINGNESS

Modified from Clin Updates Womens Health Care 13(2), 2014, American College of Obstetricians and Gynecologists (ACOG), Washington, DC.

BOX 28-1

POTENTIALLY DISRUPTIVE REPRODUCTIVE AND LIFE-CYCLE EVENTS ON SEXUAL FUNCTION

•  Healthy pregnancy •  Complicated  pregnancy  precluding  sexual  intercourse 

and orgasm •  Postpartum period •  Miscarriage •  Therapeutic abortion •  Infertility •  Perimenopause •  Natural and premature menopause

C H A P T E R 28 Sexuality and Female Sexual Dysfunction 339

FIGURE 28-2 The four phases of the female sexual response cycle: A, The excitement phase. B, The plateau phase. C, The orgasmic phase. D, The resolution phase.

Vagina becomes

wet

Clitoris grows

Labia enlarge

Uterus elevates more

Vagina enlarges

and expands

Labia enlarge

Contractions in uterus

Contractions in vaginal

muscles Labia Clitoris

Uterus returns to normal position

Vagina returns

to normal size

Clitoris returns to normal size and position

A

C

B

D

Uterus elevates

rate and blood pressure increase. The muscles become  tense, and there is blood pooling in the extremities with  vasocongestion  in  the  penis  and  scrotum,  as  well  as  testicular swelling and elevation (Figure 28-3, A).

Plateau Phase In the plateau phase, the testicles enlarge by 50%, and  the prostate and penis also enlarge. There is increased  blood  flow,  and  the  bulbourethral  or  Cowper  gland  secretes  preejaculatory  fluid,  which  may  contain  sperm. Blood pressure, heart rate, respiratory rate, and  muscle  tension  increase.  There  is  generally  chest  sex  flushing (see Figure 28-3, B).

Orgasmic Phase During  the  orgasmic  phase,  there  is  release  of  sexual  tension;  this  phase  is  possible  without  actual  physical  stimulation.  There  are  rhythmic  contractions  of  the  seminal vesicles, vas deferens, and prostate. The ejacu- latory ducts push semen into the urethra, and ejacula- tion  occurs  with  urethral  contractions.  The  first  few  contractions are the strongest and the closest together.  During  this  phase,  the  anal  sphincter  contracts.  The  “point of imminence”  occurs  a  few  seconds  before  ejaculation; this refers to the point when a man knows  an orgasm is inevitable (see Figure 28-3, C).

Resolution Phase In the resolution phase, the genitals and penis decrease  in size and return to a flaccid state. The testes descend,  and the sex flush disappears. The blood pressure, heart 

rate,  and  respiratory  rate  return  to  normal  (see  Figure  28-3, D).

Refractory Phase The  refractory  phase  occurs  only  in  men.  Because  of  this phase, men are not able to have multiple orgasms.  During this phase, no amount of stimulation will cause  another ejaculation. This phase lasts minutes in young  men and hours to days in older men.

The  similarity  between  the  male  and  female  cycles  is  apparent.  Although  the  average  time  spent  in  each  phase  may  differ  (primarily  as  a  result  of  learned  behaviors),  the  elements  of  each  cycle  are  the  same.  Because  different  neuronal  circuits  mediate  each  of  these  phases,  sexual  dysfunction  may  affect  some  phases without affecting the others.

Sexual Dysfunction The  overall  prevalence  of  sexual  dysfunction  is  not  known,  but  female  sexual  dysfunction  (FSD)  is  common.  It  has  been  estimated  that  one-third of women experience decreased libido in situations where it is desired. Comorbid conditions such as dia- betes  or  obesity  often  play  a  causative  role  in  sexual  dysfunction,  and  not  all  women  who  lack  interest  in  sexual activity are troubled by it.

EVALUATION OF SEXUAL FUNCTION The  assessment  of  sexual  function  should  be  an  inte- gral  part  of  a  complete  medical  evaluation,  especially 

PA R T 3 Gynecology340

•  Have  you  ever  been  in  a  situation  where  you  have  experienced unwanted or harmful sexual activity? There are several factors that may affect taking a

sexual history, including the physician’s own sexual- ity.  A  gay  physician  may  be  either  more  thorough  or  afraid to inquire about a patient’s sexual orientation. At  times,  clinicians  of  both  sexes  may  find  themselves  attracted to patients. In these instances, acceptance of  the feelings as normal is appropriate, as long as behav- ior  is  unaffected  and  a  professional  relationship  is  maintained.

FEMALE SEXUAL DYSFUNCTION Sexual dysfunction  is  characterized  by  the  Sexual  Function  Health  Council  of  the  American  Foundation  of  Urologic  Disease  as  failure  of  one  or  more  of  the  phases of the sexual response cycle. Sexual dysfunction  also includes pain disorders (Box 28-2).

FSD is a common condition  and  often  increases  with  age.  Sexual  dysfunction  can  be  subdivided  into  three  categories,  depending  on  whether  it  is  primary  (realistic  sexual  expectations  have  never  been  met  under any circumstances), secondary (all phases have  functioned  in  the  past,  but  one  or  more  no  longer  does),  or situational  (the  response  cycle  functions  under  some  circumstances,  but  not  others).  When  a  patient  complains  of  hypoactive  sexual  desire,  it  is  important  to  determine  what  her  preferences  are  in 

for  the  obstetrician-gynecologist.  Skills  needed  for  taking a sexual history are often overlooked in medical  schools and sometimes are ignored by physicians. It is  more difficult for a physician to inquire about a patient’s  sexuality  if  the  physician  is  uncomfortable  with  the  topic or is judgmental about sexual orientation. Clini- cians may also be concerned about a patient’s answers,  not  knowing  what  to  say  or  do  if  a  history  of  sexual  trauma  is  revealed.  They  may  also  feel  untrained  to  deal with problems related to and solutions for sexual  inadequacies.  Often  they  worry  that  the  patient  will  misunderstand  or  be  offended  by  the  questions.  The acknowledgement and acceptance of diverse sexual- ity and sexual expression have changed in recent years, and it can be helpful to refer to sexual activity rather than intercourse and to a sexual partner rather than a husband.

In  taking  a  history,  it  is  helpful  to  follow  a  routine  pattern  of  questioning:  (1)  age  of  menarche,  (2)  men- strual  patterns,  (3)  pregnancy  history,  (4)  contracep- tion use, (5) STI prevention, (6) sexual orientation, and  (7)  difficulties  with  sexual  relations.  Intimate  partner  violence  and  sexual  abuse  questions  can  then  follow.  Some sample questions include the following: •  Are  you  currently  sexually  active  and,  if  so,  with 

men, women, or both? •  Are  you  having  any  difficulties  with  sexual 

relations?

FIGURE 28-3 Four of the five phases of the male sexual response cycle. A, The excitement phase. B, The plateau phase. C, The orgasmic phase. D, The resolution phase. The refractory phase is not illustrated.

A

C

B

D

Elevation of testes

Erect penis

Testes Increase in size

Prostate enlarges Cowper gland

Preejaculate

Penile contractions

Urethral contractions

Prostate gland contracts

Seminal vesicles contract

Ejaculation occurs

Penis returns to flaccid state

Testes descend

C H A P T E R 28 Sexuality and Female Sexual Dysfunction 341

precipitate a problem, but if anxiety and fear of failure  sustain the difficulty, discontinuation of the drug alone  may not rectify the problem.

SEXUAL FUNCTION DISORDERS Sexual Desire Disorders Sexual desire appears to be an appetite similar to hunger,  controlled  by  a  dopamine-sensitive  excitatory  center  in  balance  with  a  serotonin  (5-  hydroxytryptamine)-sensitive  inhibitory  center.  In both males and females, testosterone appears to be the hormone responsible for initially programming these centers during gestation and for maintaining their threshold of response. Stimulation and ablation  experiments  in  cats  and  other  mammalian  species  have  located  these  centers  within  the  limbic  system  with significant nuclei in the hypothalamic and preop- tic regions. For a woman, desire and interest in sexual  activity  result  from  a  complex  of  both  biologic  and   psychologic  inputs,  including  her  feelings  about  her  partner.

Disorders of sexual desire and/or interest include hypoactive sexual desire disorder and sexual aversion disorder. Lack of desire involves a decrease or absence  of  fantasy.  Sexual aversion disorder  may  result  from  prior  sexually  associated  trauma  and  personal  aver- sion.  In  established  relationships,  decreased  desire  may  result  from  sexual  activity  becoming  too  predict- able  and  routine.  Lack  of  privacy  or  external  stresses,  especially  stress  in  the  relationship,  may  initiate  this  disorder. Unrelated disease may also cause hypoactive  desire. Women may fear sex with a partner who has had  a heart attack or may have decreased desire themselves  following a mastectomy or hysterectomy.

Arousal Phase Disorder Sexual arousal disorder is defined as the inability to attain or maintain sufficient sexual excitement, expressed as a lack of subjective excitement or somatic response such as genital lubrication. Estro- gen is the hormone responsible for maintaining the vaginal epithelium and allowing transudation and lubrication to occur. Its deficiency (with breastfeeding  or after menopause) is by far the most common cause  of excitement phase dysfunction in women. Extrageni- tal  changes  during  the  excitement  phase  include  an  increase  in  heart  rate  and  blood  pressure,  enhanced  muscle  tension  throughout  the  body,  an  increase  in  breast  size,  nipple  erection,  engorgement  of  the  sur- rounding areolae, and a sex flush. Some women do not  recognize  these  symptoms  as  excitement  and  may  experience  arousal  difficulty  and  even  failure  on  that  basis.

Orgasmic Phase Disorder During the orgasmic phase, a series of reflex clonic contractions of the levator sling and related genital

contrast to those of her partner. A woman who desires  intercourse  twice  per  week  may  be  perfectly  normal,  but she may not function well in a relationship in which  her partner desires coitus daily. Sexual dysfunction can  occur  in  homosexual  or  heterosexual  relationships,  or  even in masturbatory situations.

ETIOLOGY OF SEXUAL DYSFUNCTION As a general rule, primary problems are predomi- nantly psychogenic and tend to be of longer duration. Secondary problems  are  often  associated  with  the  onset of a disease process or the use of a pharmacologic  agent.  If  such  an  association  cannot  be  established,  deterioration in the patient’s relationship or some other  chronologically  related  change  in  the  patient’s  life  experience should be inquired about. It is important to  consider  psychologic causes,  such  as  depression  or  anxiety; organic causes, such as atherosclerosis, diabe- tes,  or  genital  infections;  and  pharmacologic causes  (Box 28-3). Factors initiating a problem may be differ- ent from those maintaining it. For example, drugs may 

BOX 28-3

SOME DRUGS THAT CAN DIMINISH SEXUAL FUNCTION IN WOMEN

Antihypertensive agents:  Reserpine,  propranolol,  methyl- dopa, atenolol, and spironolactone

Antidepressant medications:  Tricyclics  or  selective  sero- tonin reuptake inhibitors

Hypnotic agents:  Alcohol,  barbiturates,  tranquilizers,  and  diazepam

Narcotics: Heroin and methadone Antipsychotic agents: Fluphenazine and chlorpromazine Stimulants: Cocaine and amphetamines Hallucinogens: Lysergic acid (i.e., LSD) and mescaline Diuretics: Acetazolamide

*Each disorder can be subtyped as primary (lifelong) versus secondary (acquired), generalized versus situational, and by origin (organic, psycho- genic, mixed, or unknown).

BOX 28-2

AMERICAN FOUNDATION FOR UROLOGIC DISEASE CONSENSUS CLASSIFICATION OF FEMALE SEXUAL DYSFUNCTION

  I.  Sexual desire disorders* A.  Hypoactive sexual desire disorder B.  Sexual aversion disorder

  II.  Sexual arousal disorder III.  Orgasmic disorder  IV.  Sexual pain disorders

A.  Dyspareunia B.  Vaginismus C.  Other

PA R T 3 Gynecology342

MANAGEMENT OF SEXUAL DYSFUNCTION Women  with  long-standing  and  complex  sexual  dys- function  disorders  may  need  to  be  referred  for  treat- ment,  but  some  sexual  dysfunction  problems  can  be  managed  effectively  by  the  gynecologist.  Hormonal therapy is valuable in a limited number of situations.  Estrogen  (orally  or  vaginally)  may  improve  desire,  arousal, and orgasm by decreasing dyspareunia that is  caused by vaginal atrophy. Testosterone may improve desire and arousal in some women, but it should be used with caution until newer formulations are tested for long-term effects.  Sildenafil  (Viagra),  which  is  used  successfully  in  men  with  erectile  dysfunction,  inhibits  cyclic  guanosine  monophosphate  (cGMP)  breakdown,  thereby  increasing  clitoral  and  vaginal  smooth muscle relaxation as well as improving lubrica- tion.  cGMP  functions  as  a  messenger  in  the  nitric  oxide–mediated  relaxation  of  genital  smooth  muscle.  The use of sildenafil in women for sexual dysfunction has not been proven in controlled studies.  Dehydro- epiandrosterone  is  currently  being  studied  to  deter- mine its safety and effectiveness for desire and arousal  disorders.

A clitoral vacuum device (the EROS-CTD) that has been approved by the U.S. Food and Drug Adminis- tration  is  said  to  improve  clitoral  blood  flow  and  engorgement.  Fantasy therapy is helpful for hypoac- tive desire and sensate focusing therapy is helpful for excitement phase defects.

Some  of  the  most  successful  interventions  for  primary  or  lifelong  FSD  involve  mindfulness-based  and  cognitive  behavioral  therapy  supervised  by  sex  therapists.

TREATMENT SUCCESS As a group, orgasmic difficulties seem to respond to treatment most readily.  For  example,  primary  orgas- mic  difficulties  may  be  resolved  by  means  of  guided  masturbatory  training  and  cognitive  behavioral  sex  therapy.  Secondary  anorgasmia  is  more  often  associ- ated with emotional or psychiatric disorders and rela- tionship issues, so treatment is less effective. Excitement phase dysfunctions do not have such positive out- comes, although problems with lubrication can nearly always be resolved satisfactorily. Lack of desire is the dysfunction most resistant to treatment.  Persons with little desire often have little internal moti- vation to seek more frequent sexual activity or to pursue  help.  Less  than  50%  of  such  patients  show  definite  improvement.  When  the  relationship  is  poor,  behav- ioral approaches directed toward remedying the sexual  problem  are  rarely  successful.  In  contrast  to  erectile  dysfunction  and  premature  ejaculation  in  males,  studies  using  medical  and  pharmacologic  interven- tions for female arousal or orgasmic disorders are still  ongoing, but they do show some promise.

musculature occur, mediated primarily via the sym- pathetic nervous system.

Orgasmic disorder is characterized by difficulty with or failure to attain orgasm following sufficient sexual stimulation and arousal.  Anorgasmia  may  be  situational. Many women experience orgasm only with  manual or oral clitoral stimulation, and not with penile  thrusting  alone.  If  they  are  willing  to  increase  direct  clitoral stimulation before, during, or after penile pen- etration, they may achieve a wholly satisfactory sexual  adaptation.  Women  who  have  been  orgasmic  in  the  past  but  have  lost  that  capacity  should  be  screened   for  organic  or  pharmacologic  causes,  and  changes  in  their  relationship  or  relationships  should  be  carefully  explored.

Most women with primary anorgasmia have had minimal or no effective stimulation from themselves or their partner. These patients should be encouraged  to learn how to achieve orgasm through self-stimulation  and then to share this new information with their part- ners.  Increasing  the  intensity  of  stimulation  should  increase the intensity of response.

Sexual Pain Disorders Dyspareunia  is  genital  pain  associated  with  sexual  intercourse. It is helpful to categorize dyspareunia into  three  groups  for  easier  diagnosis  and  treatment:  (1)  pain with intromission  (often  a  result  of  vestibulitis,  vaginismus,  fissures,  or  other  vulvar  lesions),  (2)  mid- vaginal pain (often caused by lack of lubrication, surgi- cal scars, or urethral diverticulosis), and (3) deep-thrust dyspareunia (often a result of endometriosis, intersti- tial cystitis, pelvic adhesions, or neoplasms).

Vaginismus  is  defined  as  severe  pain  and/or  invol- untary  spasm  of  the  distal  vaginal  and  pelvic  floor  muscles  during  attempted  penetration.  A  physical  examination  will  reveal  no  organic  condition,  but  the  pubococcygeal  muscles  will  be  tight  and  vaginal  pen- etration  by  speculum  or  examining  finger  will  be  painful and difficult, if not impossible. Often, affected  women harbor fantasies about the inadequacy of their  vaginas to accommodate a speculum or penis and fear  that  penetration  will  damage  them.  These  women  respond  remarkably  well  to  education  and  reassur- ance.  Others  may  have  been  traumatized  by  early  sexual or other abuse and require more intensive psy- chologic therapy. One important issue is whether they  are  motivated  to  participate  with  their  partners  in  a  stepwise  desensitization program.  This  involves  the  slow,  gentle  vaginal  insertion  of  dilators  of  gradually  increasing  size  under  the  patient’s  own  control.  Once  sufficient progress has been made, the partner’s fingers  and,  ultimately,  his  penis  may  be  substituted  for  the  dilators.  Alleviation  of  the  problem  is  usually  accom- plished within 3 to 6 months.

Noncoital sexual pain disorder  is  pain  that  is  induced by noncoital sexual stimulation.

343

29  Intimate Partner and Family Violence, Sexual Assault, and Rape

C H

A P

T ER

JOSEPH C. GAMBONE

■  Intimate  partner  violence,  formerly  called  domestic vio- lence,  is  defined  as  intentionally  abusive  or  controlling  behavior  by  a  person  who  is  (or  was)  in  an  intimate  or  close relationship with the victim. The relationship may  be heterosexual or between two people of the same sex.  Most of the time a woman is the victim, but on occasion  the abused person is a man.

■  Although  exact  numbers  for  domestic  violence  events  are  not  known,  intimate  partner  violence,  along  with  other types of family violence, are common. The enabling  feature of these events is feelings of vulnerability that the  victim cannot or will not attempt to overcome.

■  Sexual  assault  includes  sexual  activity  that  ranges  from  sexual  coercion  to  contact  abuse,  such  as  unwanted  kissing or fondling, as well as rape.

■  A  medical  consultation  for  sexual  assault  and  rape  should  involve  providing  acute  medical  care,  gathering  evidence for possible prosecution, and transitioning the  victim into longer-term care.

■  The psychological consequences of intimate partner and  family violence, as well as sexual assault, are significant,  with lifelong problems reported. Providing social as well  as psychological support and counseling are essential for  adequate aftercare.

CLINICAL KEYS FOR THIS CHAPTER

Domestic violence is now more commonly called inti- mate partner violence. The term family violence (covered only briefly in this chapter) also refers to abuse of other vulnerable persons such as the elderly, people with disabilities, or children.  The  American  College  of  Obstetricians  and  Gynecologists  (ACOG)  Committee  Opinion  on  Intimate  Partner  Violence  (Number 518, February 2012) addresses these issues.

Sexual assault and rape are the most violent mani- festations of sexual abuse. ACOG issued a recent com- mittee opinion on the topic of sexual assault (Number  592, April 2014).

The obstetrician-gynecologist is in a unique posi- tion to identify the crimes of intimate partner violence and sexual abuse and help women deal with them.

Intimate Partner Violence and Family Violence The  obstetrician-gynecologist  is  the  health  care  pro- vider  most  likely  to  deal  with  the  effects  of  abusive 

behavior directed against an intimate domestic partner.  Intimate  partner  violence  can  include  verbal  abuse,  intimidation,  social  isolation,  and  physical  assault,  such  as  a  punch,  a  kick,  a  threat,  a  severe  beating,  an  act of sexual assault, or even murder. It occurs in every  age  group,  in  all  ethnic  groups,  in  every  occupation,  and  in  every  socioeconomic  group.  Although  the  obstetrician-gynecologist may be called to see a patient  with acute injuries that result from partner violence or  sexual  assault,  she  or  he  is  more  likely  to  have  to  deal  with  the  nonacute  clinical  manifestations  of  abuse  (Box 29-1). Violence is most often perpetrated by a man  against  a  woman;  however,  the  gender  relationship  may  occasionally  be  reversed.  Intimate  partner  vio- lence can also occur between same-sex partners.

EPIDEMIOLOGY The prevalence and incidence of intimate partner violence are not known, but they are considerable. It has been estimated that as many as 2 million women are abused every year by someone they know. Any estimate of prevalence is likely to be understated, because of the likelihood that a significant number of

PA R T 3 Gynecology344

and more depression and disability  than  nonabused  women.

Social services  for  women  who  are  victims  of  inti- mate  partner  abuse  are inadequate.  Nearly  one-third  of battered women who request refuge are turned away  because of a lack of space. Those turned away and their  children  often  must  return  to  a  violent  home.  Many become homeless and involved in substance abuse as  an escape mechanism or because they are forced into  use and addiction by their partners.

The overall societal cost of intimate partner violence  has been estimated to be in excess of $6 billion annu- ally,  and  individual  costs  are  increased  because  of  higher insurance premiums paid by victims.

The abuser often provides for and is periodically in a caring and loving relationship with the victim, who  may  still  love  her  partner  despite  the  abuse.  Other  obstacles to leaving the abuser include (1) fear of more  abuse,  (2)  loss  of  economic  support,  (3)  fear  of  social  isolation, (4) feelings of failure, (5) promises of change,  (6) previously unanswered calls for help, and, in many  cases, (7) fear of loss of child custody. Figure 29-1 illus- trates the cycle of violence that exists in these abusive  relationships.

ADDRESSING INTIMATE PARTNER/FAMILY VIOLENCE Health  care  providers  may  have  difficulty  bringing  up  the topic of possible intimate partner violence. Because  of the alarming frequency of this problem, it is impor- tant to ask all women, when alone with them, if they feel safe in their own home. This should be a routine practice in taking a social history.  Even  without  a 

victims are fearful of disclosing abuse.  One  study  of  the incidence of partner abuse found that of all women  seeking care in an emergency room (ER), 54% said they  had  been  threatened  or  injured  at  some  time  in  their  lives by a partner, and 24% said they had been injured  by  a  current  partner.  One  in  three  women  presenting  to an ER with injuries has symptoms related to partner  violence.  More than 20% of violent crimes against women and 30% of female murders are committed by intimate partners.  Estimates  of  the  number  of  preg- nant  woman  who  are  victims  of  partner  abuse  range  from less than 1% up to 20%.

Other  forms  of  family  violence  are  prevalent.  The  level of child abuse is epidemic, and it is estimated that  nearly  500,000  elderly  persons  in  domestic  settings  in  the  United  States  are  abused  or  neglected.  Seventy  percent of cases of abuse of the elderly are perpetrated  by a family member, including adult children.

In  all  cases  of  ongoing  family  and/or  intimate  partner abuse, the key enabling feature is some form of  victim  vulnerability  that  the  victim  cannot  or  will  not  attempt to overcome.

ADVERSE EFFECTS OF INTIMATE PARTNER VIOLENCE The  impact  of  intimate  partner  abuse  and  violence  includes  significant  health,  social,  and  economic  effects.  Nearly one-third of female intimate partner violence victims have physical injuries  that  require  medical  attention.  Many victims develop posttrau- matic stress disorder with all of its chronic symptoms  and  an  increased  risk  of  suicide. Women  who  are  bat- tered  and  abused  have  lower overall health status

FIGURE 29-1 Cycle of violence. Elements of the cycle occur on a repetitive, unpredictable, and frequent basis. Verbal and emotional abuse are the most common forms of assault. An alternating kind- ness followed by abuse in an unpredictable manner contributes to the emotional distress and long-term psychological morbidity of victims. (From Gunter J: Intimate partner violence. Obstet Gynecol Clin North Am 34:367–388, 2007. Copyright 2007, with permis- sion from Elsevier.)

Tension building (blaming, arguing,

jealousy)

Honeymoon (excuses, gifts,

denial)

Battering (verbal threats, sexual abuse,

physical battering, use of weapons)

Modified from American College of Obstetricians and Gynecologists (ACOG): Special issues in women’s health—intimate partner and domestic violence, Washington, DC, 2005, ACOG. *No single presentation can confirm intimate partner and/or family violence.

BOX 29-1

CLINICAL MANIFESTATIONS OF POSSIBLE INTIMATE PARTNER VIOLENCE*

Inadequately  explained  injuries,  such  as  bruises  and  abrasions

Unusual  difficulty  during  a  gynecologic  examination,   such  as  excessive  distress,  discomfort,  or  avoidance  behaviors

Chronic and unexplained pelvic pain, urinary symptoms,  sexual dysfunction, or irritable bowel syndrome

Persistent  or  recurrent  vaginitis  or  sexually  transmitted  infections in spite of appropriate treatment

Persistent vague complaints, such as headache, backache,  palpitations, digestive, sleep, or eating disorders

Complaints or signs of depression, anxiety, phobias, panic  attacks, or feelings of shame or worthlessness

Unintended pregnancy Suicidal ideation

C H A P T E R 29 Intimate Partner and Family Violence, Sexual Assault, and Rape 345

Whatever  the  rapist’s  intent,  rape  is  definitely  not  a  welcomed sexual experience for the victim. During any  act  of  rape,  the  victim’s  predominant  feeling  is  one  of  fear for her life or fear of mutilation.

Women  of  all  ages,  ethnicities,  and  socioeconomic  groups  can  be  victims  of  sexual  assault,  although  the  very  young,  people  who  have  mental  and/or  physical  disabilities, and the elderly are most vulnerable. Nearly 75% of assaults are perpetrated by someone known to the victim, such as husbands (marital or partner rape),  boyfriends  (date  rape),  fathers  (incest),  mothers’  boy- friends, other relatives, or work associates. The Ameri- can  Medical  Association  reports  that  20%  of  women  under  21  years  of  age  have  been  sexually  assaulted.  Other  estimates  are  that  41%  of  women  (of  all  ages)  have been victims of actual or attempted sexual assault  and that 50% of these women have been victims more  than once. Death occurs in about 1% of sexual assaults (including rapes), and serious injury occurs in 4%.

MEDICAL CARE FOR SEXUAL ASSAULT The  medical  consultation  should  proceed  only  after  a  supportive,  caring  relationship  has  been  established.  The  adult  or  adolescent  woman  should  be  actively  involved  in  the  consultation  so  that  she  may  regain  a  feeling  of  control  over  what  has  happened  to  her.  The purposes of the consultation are threefold: (1) to provide her acute medical care, (2) to gather evidence, and (3) to transition her into the long-term care she will need for psychological recovery from the extreme loss of control and great fear of death that nearly every rape victim experiences. These objectives should  be  explained  to  her,  and  she  should  be  allowed  to  dictate the pace of the questioning and the order of the  examination.

During the interview and examination phases, a chaperone and/or patient advocate should be present. 

suspicion  of  physical  abuse,  the  woman  should  be  asked directly if a partner has ever hit, kicked, hurt, or  threatened  her.  If  a  positive  response  is  obtained,  it  is  important to document any physical findings. Pictures  and drawings should be used.

It is helpful and reassuring to tell the victim that she is not alone, that help is available to her, and that her partner’s behavior is unacceptable.  Nearly  every  victim  believes  that  she  is  the  only  person  to  experi- ence  such  abuse  because  of  the  isolating  nature  of  abusive behavior. The perpetrator most likely will have  convinced the victim that she is at fault and responsi- ble for the abuse.

In addition to the need to comply with any reporting  requirements  (some  states  mandate  reporting  to  appropriate  authorities  if  there  are  acute  injuries),  social  workers  and  other  professionals  should  always  be consulted when abuse is acknowledged or even if it  is just suspected. Box 29-2 lists the responsibilities that  health  care  providers  have  in  addressing  intimate  partner  and  domestic  violence.  A  useful  checklist  (RADAR) can be used to guide the practitioner during  a  patient  encounter  when  domestic  violence  or  other  forms of abuse are suspected (Box 29-3).

Sexual Assault and Rape Sexual assault and rape have different technical or legal  definitions, depending on the state or country involved.  However,  any sexual act performed on a person without his or her consent is classified as sexual assault. Sexual assault includes any unwanted genital,  anal, or oral penetration by a part of the attacker’s body  or by any object. Rape, on the other hand, is generally a violent attack  that  may  or  may  not  stem  from  the  perpetrator’s  sexual  desire. Very  often,  the  perpetrator  uses  sex  as  a  means  of  control  over  another  person. 

Modified from Alpert EJ: Intimate partner violence: the clinician’s guide to identification, assessment, intervention, and prevention, ed 4, Waltham, MA, 2004, Massachusetts Medical Society.

BOX 29-3

THE RADAR CHECKLIST APPROACH TO DOMESTIC VIOLENCE OR SEXUAL ABUSE

R: Remember  to  always  ask  about  partner  violence  or  sexual abuse in your practice.

A: Ask directly and clearly (in a private setting) about vio- lence  and  abuse  with  questions  such  as, “At  any  time,  has  someone  you  live  with  hit,  kicked,  or  otherwise  physically abused or frightened you?”

D: Document  all  information  about  “suspected  violence  and  abuse”  in  the  patient’s  chart  and  file  reports  in  accordance with local laws.

A: Assess  the  patient’s  safety,  whether  there  are  weapons  in the house, and if any children are in danger.

R: Review possible options that your patient may have to  increase safety, such as shelters and support groups.

Modified from American College of Obstetricians and Gynecologists (ACOG): Special issues in women’s health—intimate partner and domestic violence, Washington, DC, 2005, ACOG.

BOX 29-2

MEDICAL PROFESSIONALS’ RESPONSIBILITIES IN ADDRESSING INTIMATE PARTNER AND/OR FAMILY VIOLENCE

Implement a universal screening program Acknowledge any trauma Assess immediate safety of the patient and any children Help to establish a safety plan Review options Offer educational materials and toll-free hotline informa-

tion (Box 29-4) Provide referrals Document interactions Provide ongoing support at subsequent visits Inform  authorities  when  appropriate  (state  medical  soci-

eties can inform about legal requirements)

PA R T 3 Gynecology346

abuse,  may  also  surface,  particularly  when  such  problems  have  been  evident  in  the  past.  The long- term sequelae include changes in lifestyle, the occurrence of disturbing dreams and nightmares, and the persistence of phobic reactions. Fear per- sists as the predominant feeling.  These  reactions  often  make  it  difficult  for  the  victim  to  concentrate  effectively on everyday activities and relationships.

2.  Integration and resolution phase:  During  this  phase, victims begin to accept the assault, but prob- lems at work or with relationships may persist. The management of the sexual assault victim in the 

acute  phase  influences  long-term  adjustment.  Many  rape victims may manifest posttraumatic stress disor- der. The likelihood of this disorder developing is high,  because of the abrupt nature of the crime, its violence,  the  passivity  and  helplessness  imposed  on  the  victim,  and  the  high  probability  of  sustaining  physical  and  psychologic  trauma.  The lifetime prevalence of post- traumatic stress disorder in rape victims is approxi- mately 50%.

In  addition  to  attending  to  immediate  physical   and  emotional  needs  in  the  initial  evaluation,  the  obstetrician-gynecologist  has  an  opportunity  to  prepare  the  victim  for  the  long-term  psychologic  impact of the experience. This preparation is intended  to diminish the long-term consequences and to enable  the  woman  to  recognize  the  common  psychosocial  sequelae  when  they  occur,  thus  enabling  her  to  seek  professional help at an early stage. Longer-term reac- tions involve nightmares, phobic reactions, and sexual fears. Stimuli associated with the rape, such as  a similar-looking man or similar surroundings, may be  associated with flashbacks. Flashbacks may also occur during pelvic examinations.

Reactions to the sexual assault may result in prob- lems with sexual behavior and functioning.  Loss  of  libido  is  a  common  response  to  stressful  or  traumatic  circumstances  of  any  kind.  Other  complaints  include  vaginismus,  impaired  vaginal  lubrication,  and  loss  of  orgasmic capability. These problems may be even more  likely if the assault occurred at home while the woman  was  asleep.  Preparing  the  woman  for  these  eventuali- ties can be extremely helpful in preventing sexual dys- function  from  developing  or  persisting.  Giving  permission  for  a  lower-than-usual  sexual  drive  during  the period following the assault may remove some per- formance  anxiety.  Explaining  how  anxiety  and  stress  can  inhibit  sexual  responsiveness  and  providing  ways  in which this can be overcome are also important.

Other Victims of Domestic Violence and Sexual Assault The elderly, individuals with disabilities, and children may be particularly vulnerable to both domestic

Careful  attention  must  be  paid  to  the  rules  governing  the  chain  of  evidence  to  maintain  the  legal  integrity  and utility of all the specimens, photographs, and other  materials collected. The woman should be asked about  the detailed specifics of her assault to direct the collec- tion  of  needed  evidence  and  to  address  any  risk  of  injury or infection. Information about her recent men- strual  history,  use  of  medications,  recent  immuniza- tions, contraceptive use, and past medical and surgical  history is important.

A thorough physical examination is needed to eval- uate possible injuries, because 40% of all women who are sexually assaulted sustain injuries.  If  possible,  photographs or sketches of the injured areas should be  obtained. The Centers for Disease Control and Preven- tion  recommends  routine  testing  for  gonorrhea  and  chlamydia  of  specimens  collected  from  any  site  of  penetration or attempted penetration. Wet mounts and  cultures  for  Trichomonas  are  routine,  and  a  micro- scopic  evaluation  for  bacterial vaginosis  and  candi- diasis is prudent in a woman with a vaginal discharge.  Serum  tests  for  human immunodeficiency virus (HIV ), hepatitis B, and syphilis are needed for baseline  evaluation.  Positive  HIV  status  can  be  another  clue  to  identifying victims of abuse.

Prophylaxis is suggested as preventive therapy.  This  includes  hepatitis  B  vaccination  (if  previously  unvaccinated) and appropriate antibiotics for sexually  transmitted infections (see Chapter 22). It is critical to provide any woman at risk for pregnancy with emer- gency contraception  (see  Chapter  27).  If  prophylaxis  for  HIV  is  considered  necessary,  consultation  with  an  HIV specialist is recommended. Tetanus toxoid should  be administered to an unprotected, injured woman.

PSYCHOLOGIC SEQUELAE OF SEXUAL ASSAULT Sexual  assault  is  almost  always  associated  with  both  immediate  and  long-term  effects  on  victims.  These  effects  have  been  termed  the  rape trauma syndrome  and involve the following two phases: 1.  Acute/disorganization phase: This phase lasts from 

days  to  weeks.  Immediately after the experience, victims frequently appear calm, although preoc- cupied and inattentive. They are anxious, have dif- ficulty  sleeping,  and  commonly  express  shock,  disbelief,  fear,  guilt,  and  shame.  The  psychologic problems that may result are varied and can mimic  those  seen  in  the  aftermath  of  other  kinds  of  trau- matic  experiences.  Among  the  psychological  prob- lems expected in the acute phase of adjustment are  irritability, tension, anxiety, depression, fatigue, and persistent ruminations. Somatic symptoms of  a  general  nature  may  occur,  such  as  headaches or irritable bowel syndrome,  or  symptoms  may  be  more  specific  to  the  reproductive  system,  such  as  vaginal irritation or discharge. Behavioral prob- lems, such as overeating and alcohol or substance

C H A P T E R 29 Intimate Partner and Family Violence, Sexual Assault, and Rape 347

be  performed  at  6,  12,  and  24  weeks  after  the  assault,  regardless  of  whether  prophylactic  measures  were  taken.

Before  discharging  the  patient,  ensure  that  she  has  a  safe  place  to  go  and  a  suitable  means  of  transporta- tion.  She  should  also  be  given  (in  writing)  the  names,  addresses,  and  telephone  numbers  of  resources  avail- able in the community to meet her medical, legal, and  psychosocial needs related to the assault (Box 29-4).

violence and sexual abuse. In a recent study, research- ers found that 14% of older adults who were not insti- tutionalized  had  experienced  physical,  psychological,  or  sexual  abuse  during  the  previous  year.  This  abuse  included  neglect  and/or  financial  exploitation.  In  another study, investigators reported that women with  disabilities  were  four  times  more  likely  to  have  been  sexually  assaulted  than  women  without  disabilities.  Children  are  among  the  most  vulnerable  to  domestic  violence  and  sexual  assault.  All  health  care  practitio- ners should be on the lookout for signs of these crimes  in their patient populations.

Aftercare Planning Careful follow-up must be arranged.  If  the  woman  uses the prophylactic therapies, a return visit is needed  in 1 week to review the initial laboratory results and to  monitor  her  progress.  Repeat  testing  is  needed  only  if  the woman is symptomatic. If she did not receive pro- phylaxis, repeat testing for gonorrhea, chlamydia, and  Trichomonas  should  be  performed  in  2  weeks  and  for  syphilis in 6 weeks. Repeat serum tests for HIV should 

BOX 29-4

KEY TELEPHONE NUMBERS FOR MEDICAL PROFESSIONALS AND VICTIMS OF FAMILY VIOLENCE AND SEXUAL ASSAULT

National Domestic Violence Hotline:  1-800-799-SAFE  (7233 or 7234), TTY 1-800-787-3224 (hearing impaired)

RAINN (Rape, Abuse & Incest National Network) Hotline:  1-800-656-HOPE

National Child Abuse Hotline:  1-800-4-A-CHILD  (1-800-422-4453)

Elderly Abuse Hotline: 1-800-922-2275 Disabled Person Abuse Hotline: 1-800-426-9009

348

30  Breast Disease A Gynecologic Perspective

C H

A P

T ER

NEVILLE F. HACKER • MICHAEL L. FRIEDLANDER

■  Mammographic  screening  of  asymptomatic  women  after the age of 40 years decreases the mortality of breast  cancer.  About  40%  of  cancers  detected  by  mammo- graphic screening are not clinically apparent.

■  Hyperplasia is the most common benign breast disorder.  When  associated  with  cellular  atypia,  there  is  an  increased risk of subsequent malignant transformation.

■  About 5-10% of breast cancers are hereditary and result  from a germline mutation in the BRCA1 or BRCA2 gene.  These genetic mutations also confer an increased risk of  ovarian cancer.

■  The  modern  approach  to  breast  cancer  management  requires  a  multidisciplinary  approach  with  breast-

conserving surgery and adjuvant radiation to the breast.  Most  patients  are  offered  adjuvant  chemotherapy  and/ or hormonal therapy, depending on the pathological fea- tures of the cancer and risk factors for recurrence.

■  Although the single most important prognostic factor for  breast  cancer  is  the  status  of  the  axillary  lymph  nodes,  this is an oversimplification, as it is now clear that breast  cancer  is  a  very  heterogeneous  disease.  The  patient’s  estrogen  receptor  status  is  an  independent  prognostic  factor.

CLINICAL KEYS FOR THIS CHAPTER

Breast  cancer  is  not  treated  by  gynecologists  in  most  parts  of  the  United  States,  but  it  is  important  that   gynecologists be expert in breast examination, diligent  about recommending screening asymptomatic women  for  breast  cancer,  familiar  with  common  benign  and  malignant disorders of the breast, and conversant with  the various therapeutic options available.

Screening of the Breast in Asymptomatic Women SELF-EXAMINATION Most  breast  cancers  are  detected  by  using  medical  screening  techniques.  Occasionally,  a  breast  cancer  is  discovered by a woman during self-examination of her  breasts.  Because  there  is  little  scientific  evidence  that  routine  breast  self-examination  reduces  mortality  of  breast  cancer  and  may  in  fact  lead  to  anxiety  and  unnecessary  procedures,  the  United  States  Preventive  Services  Task  Force  (USPSTF)  does  not  recommend  routine  breast  self-examination.  It  seems  reasonable, 

however,  to  encourage  women  to  be  aware  of  any  changes  in  their  breasts  and  for  them  to  seek  profes- sional evaluation of any noted changes.

BREAST EXAMINATION BY A PHYSICIAN A  complete  breast  examination  should  be  performed  by  a  physician  at  least  every  3  years,  especially  for  women older than 35 years of age. The breasts are first  inspected  with  the  patient  in  an  upright  position. The  contour  and  symmetry  are  observed,  and  any  skin  changes or nipple retraction is noted. Skin retraction, because of tethering to an underlying malignancy, may be highlighted by having the patient extend her arms over her head.

Palpation  of  the  breast,  areola,  and  nipple  is  per- formed  with  the  flat  of  the  hand.  If  any  mass  is  pal- pated, its fixation to deep tissues should be determined  by  asking  the  patient  to  place  her  hands  over  her   hips  and  contract  her  pectoral  muscles.  Each  axilla  is  then carefully examined while the patient’s arm is sup- ported.  The  supraclavicular  fossae  are  also  palpated   for  lymphadenopathy.  Following palpation with the

C H A P T E R 30 Breast Disease 349

presence of a large palpable lump, a core biopsy should  make  it  possible  to  diagnose  breast  cancer  without  a  formal excisional biopsy in at least 90% of cases, allow- ing the definitive management of the patient to be dis- cussed preoperatively.

Relative indications for breast biopsy include those  women  with  a  clinically  benign  mass  but  a  positive  family  or  personal  history  of  breast  or  ovarian  cancer,  a  history  of  atypical  hyperplasia,  or  an  equivocal  finding based on mammography or cytology.

Common Benign Breast Disorders FIBROCYSTIC CHANGES The earlier term fibrocystic disease has little clinical value, and the term was abandoned by the College of American Pathologists in 1985.  Lesions  formerly  grouped  together  under  the  designation  of  fibrocystic  disease  represent  a  pathologically  heterogeneous  group  of  diseases  that  can  be  divided  into  three  sepa- rate  histologic  categories:  nonproliferative  lesions,  proliferative  lesions  (hyperplasia)  without  atypia,  and  atypical hyperplasias.

HYPERPLASIA Hyperplasia is the most common benign breast dis- order and is present in about 50% of women.  Histo- logically,  the  hyperplastic  changes  may  involve  any   or  all  of  the  breast  tissues  (lobular  epithelium,  ductal  epithelium,  and  connective  tissue).  When the hyper- plastic changes are associated with cellular atypia, there is an increased risk for subsequent malignant transformation.

It is postulated that the hyperplastic changes are caused by a relative or absolute decrease in production of progesterone or an increase in the amount of estrogen.  Estrogen  promotes  the  growth  of mammary ducts and the periductal stroma, whereas  progesterone  is  responsible  for  the  development  of  lobular  and  alveolar  structures.  Patients  with  hyper- plasia  improve  dramatically  during  pregnancy  and  lactation because of the large amount of progesterone  produced  by  the  corpus  luteum  and  placenta  and   the  increased  production  of  estriol,  which  blocks   the  hyperplastic  changes  produced  by  estradiol  and  estrone.

The  disorder  usually  occurs  in  the  premenopausal  years.  Clinically,  the  lesions  are  usually  multiple  and  bilateral and are characterized by pain and tenderness,  particularly premenstrually.

Treatment  depends  on  the  age  of  the  patient,  the  severity  of  the  symptoms,  and  the  relative  risk  of  the  development  of  breast  cancer.  Women  older  than  25  years  of  age  should  undergo  baseline  mammography  to  exclude  carcinoma.  Cysts may be aspirated to relieve pain  (Figure  30-1).  If  the  fluid  is  clear  and  the  lump  disappears,  careful  follow-up  alone  is  indicated. 

woman in the upright position, the examination is repeated with her in the supine position.

MAMMOGRAPHY Several  randomized  controlled  trials  have  demon- strated  that  mammographic  screening  of  asymptom- atic women older than 40 years of age can decrease the  mortality of breast cancer. Densities and fine calcifica- tions constitute suspicious findings, and clinically inapparent malignancies of less than 1 cm in diame- ter may be detected.

Mammograms  of  high  quality  can  be  made  with  about  0.3 cGy  or  less  of  radiation,  so  there  is  little,  if  any, risk of this technique causing breast cancer.

In  2009,  the  USPSTF  estimated  that  screening  was  associated with 15%, 14%, and 32% reductions in breast  cancer  mortality  for  women  39  to  49,  50  to  59,  and  60  to  69  years  of  age,  respectively.  The  American  Cancer  Society recommends annual mammograms starting at  age 40 years for women at normal risk.

ULTRASONOGRAPHY Ultrasonography can differentiate cystic from solid masses and may demonstrate solid tissue that is potentially malignant within or adjacent to a cyst.  It  is  also  useful  for  imaging  palpable  focal  masses  in  women  younger  than  30  years  of  age  and  in  pregnant  women,  reducing  the  need  for  x-ray  studies  in  this  population.

MAGNETIC RESONANCE IMAGING Magnetic  resonance  imaging  is  a  useful  adjunct  in  breast imaging. Reported advantages include improved  staging  and  treatment  planning,  enhanced  evaluation  of  the  augmented  breast,  better  detection  of  recur- rences,  and  improved  screening  of  high-risk  women,  including those with BRCA gene mutations.

Diagnosis of Breast Lesions Physiologic nodularity and cyclic tenderness caused by  the  changing  hormonal  milieu  must  be  distinguished  from benign or malignant pathologic changes. Defini- tive diagnosis of breast neoplasms may be made by open biopsy, by fine-needle (22-gauge) aspiration cytology, or by core biopsy.

FINE-NEEDLE OR CORE BIOPSY Fine-needle aspiration biopsy of a small, palpably sus- picious  lump  in  the  breast  can  be  performed  in  the  outpatient  clinic.  Smears  are  prepared  from  the  aspi- rate  to  allow  cytologic  evaluation.  In  experienced  hands, the test is both sensitive and specific. A negative result should never be accepted as definitive when there are clinical or mammographic and/or ultra- sonic suspicions that the lesion may be malignant, and a core or open biopsy should be done.  In  the 

PA R T 3 Gynecology350

ductal obstruction, such as inflammation, hyperplasia,  or neoplasia. Often multiple cysts are present. Second- ary infection may produce areas of acute mastitis or abscess formation.  Needle  aspiration  is  usually  cura- tive.  If  the  fluid  is  bloody  or  the  mass  does  not  disap- pear completely, excisional biopsy is required.

Breast Cancer Breast cancer is the most common female malignancy,  accounting  for  26%  of  malignancies  in  women.  It  is  second  only  to  lung  cancer  as  the  leading  cause  of  cancer  deaths  in  women.  The  estimate  for  2013  was  that 232,340 new cases of breast cancer would be diag- nosed in the United States, which would be associated  with approximately 39,620 deaths. In the United States, there is a 1 in 8 chance that a woman will develop breast cancer during her lifetime if she lives to 90 years of age.

ETIOLOGY Established risk factors for breast cancer are shown in  Table 30-1. However, 75% of women develop the disease  despite having no apparently increased susceptibility.

The incidence and mortality rates for breast cancer are approximately five times higher in North America and northern Europe than they are in many Asian and African countries.  Migrants  to  the  United  States  from  Asia  (principally  those  of  Chinese  and  Japanese  ethnicity)  do  not  experience  a  substantial  increase  in  risk,  but  their  first-generation  and  second-generation  descendants have rates approaching those of the white  population in the United States. The difference may be  related to dietary customs.

Menopausal  hormone  replacement  therapy  pro- duces  a  small  increased  risk  of  breast  cancer,  and  the 

Open biopsy is required if the fluid is bloody or if there is any residual mass following aspiration.

FIBROADENOMA Composed of both fibrous and glandular tissue, the fibroadenoma is the most common benign tumor found in the female breast. Clinically, these tumors are  sharply circumscribed, freely mobile nodules that may  occur  at  any  age  but  are  common  before  the  age  of   30  years.  They  usually  are  solitary  and  generally  are  removed  when  they  reach  2  to  4 cm  in  diameter,  although  giant forms up to 15 cm in diameter occa- sionally occur and have malignant potential.  Preg- nancy may stimulate their growth, and regression and  calcification  usually  eventuate  postmenopausally.  These larger tumors require surgical excision for defini- tive diagnosis and cure.

INTRADUCTAL PAPILLOMA Papillary  neoplastic  growths  may  develop  within  the  ducts  of  the  breast,  most  commonly  just  before  or  during  menopause.  They  are  rarely  palpable  and  are  usually  diagnosed  because  of  a  bloody,  serous,  or  turbid discharge from the nipple. Mammographic and cytologic examination of the fluid is helpful in inves- tigating nipple discharge. Excisional biopsy of the lesion and involved duct is the treatment of choice.

Histologically, there is a spectrum of lesions, ranging  from  those  that  are  clearly  benign  to  those  that  are  anaplastic and give evidence of invasive tendencies.

GALACTOCELE A  galactocele  is  a  cystic  dilation  of  a  duct  that  is  filled  with  thick,  inspissated,  milky  fluid.  It  presents  during  or  shortly  after  lactation  and  implies  some  cause  for 

FIGURE 30-1 Aspiration of a breast cyst. Ultrasound may be used to differentiate a solid from a cystic breast mass.

TABLE 30-1

ESTABLISHED RISK FACTORS FOR BREAST CANCER

Risk Factor Relative Risk

Age (≥50 yr vs. <50 yr) 6.5

Family history of breast cancer First-degree relative 1.4-13.6 Second-degree relative 1.5-1.8

Age at menarche (<12 yr vs. ≥14 yr) 1.2-1.5

Age at menopause (≥55 yr vs. <55 yr) 1.5-2.0

Age at first live birth (>30 yr vs. <20 yr) 1.3-2.2

Benign breast disease Breast biopsy (any histologic finding) 1.5-1.8 Atypical hyperplasia 4.0-4.4

Hormone replacement therapy 1.0-1.5

Data from Armstrong K, Eisen A, Weber B: Assessing the risk of breast cancer. N Engl J Med 342:564-571, 2000.

C H A P T E R 30 Breast Disease 351

estrogen-progestin  regimen  increases  the  risk  beyond  that associated with estrogen alone.

About 5-10% of breast cancer cases are hereditary and result from mutations in the BRCA1 or BRCA2 gene. These genetic mutations also increase the risk of ovarian cancer. Hereditary breast cancer is particu- larly common in premenopausal women.  Women  with a mutated BRCA1 or BRCA2 gene have up to a 70%  risk of developing breast cancer by age 65 years.

TUMOR TYPES The  mammary  epithelium  gives  rise  to  a  wide  variety  of  histologic  tumor  types.  About 80% of all breast cancers are nonspecific infiltrating ductal carcino- mas. These tumors usually induce a significant fibrotic  response and are often stony hard upon clinical palpa- tion.  Less common types include infiltrating lobular, medullary, mucinous, tubular, and papillary tumors.  In many tumors, several patterns coexist.

Paget disease of the breast occurs in about 3% of patients with breast cancer.  It  represents  a  specific  subtype  of  intraductal  carcinoma  that  arises  in  the  main  excretory  ducts  of  the  breasts  and  extends  to  involve the skin of the nipple and areola, producing an  eczematoid  appearance.  The underlying carcinoma, although invariably present, can be palpated clini- cally in only about two-thirds of patients.

Inflammatory breast cancer represents 1-4% of cases and typically occurs in younger women. It is characterized clinically by warmth and redness of the overlying skin and induration of the surrounding breast tissues.  Biopsies  of  the  erythematous  areas  reveal  malignant  cells  in  subdermal  lymphatics,  causing  an  obstructive  lymphangitis.  Inflammatory  cells are rarely present. Some patients with inflamma- tory breast cancer have palpable regional lymph nodes at initial presentation.

TUMOR SPREAD Breast cancer spreads by local infiltration as well as by  lymphatic or hematogenous routes. Locally, the tumor  infiltrates directly into the breast parenchyma, eventu- ally  involving  the  overlying  skin  or  the  deep  pectoral  fascia.

Lymphatic spread is mainly to the axillary nodes, involvement of which occurs in up to 50% of patients with symptomatic breast cancer and in 10-20% of patients with breast cancers detected by screening.  The  second  major  area  for  lymph  node  metastases  is  the  internal  mammary  node  chain.  These  nodes  are  most  likely  to  be  involved  when  the  primary  lesion  is  medially  or  centrally  situated.  The supraclavicular nodes are usually involved only after axillary node involvement.

Hematogenous  spread  occurs  mainly  to  the  lungs  and  liver,  but  other  common  sites  of  involvement  include bone, pleura, liver, ovaries, and brain.

STAGING Several  systems  of  staging  for  cancer  of  the  breast   have  been  recommended.  The  one  recommended  by  the  American  Joint  Committee  on  Cancer  is  shown  in  Box 30-1.

CLINICAL FEATURES Carcinoma of the breast is usually painless and may be  freely mobile. A serous or bloody nipple discharge may  be  present.  With  progressive  growth,  the  tumor  may  become fixed to the deep fascia. Extension to the skin may cause retraction and dimpling, whereas ductal involvement may cause nipple retraction. Blockage of skin lymphatics may cause lymphedema and thick- ening of the skin, a change referred to as peau d’orange  (Figure 30-2).

TREATMENT The  modern  management  of  breast  cancer  involves  a  multidisciplinary  team  approach.  As  much  normal  breast  tissue  as  possible  is  left  in  women  who  have  a  wide  local  excision  to  conserve  the  cosmetic  appear- ance of the breast while ensuring clear and uninvolved  margins. Adjuvant radiation is given following the wide  local  excision,  as  well  as  chemotherapy  or  hormonal  therapy,  depending  on  the  woman’s  pathological  risk  factors.

Surgery The  surgical  management  of  breast  cancer  has  been  transformed  over  the  last  50  years.  This  has  occurred  through  an  improved  understanding  of  the  biology  of  breast  cancer,  as  well  as  earlier  diagnosis  through  screening and increased awareness of the disease.

Radical  mastectomy,  as  first  described  in  1894  by  Halsted  and  Meyer,  was  for  many  years  the  standard  operation for operable breast cancer, and it involved en  bloc  dissection  of  the  entire  breast,  together  with  the  pectoralis  major  and  minor  muscles  and  the  contents  of the axilla. It was based on a flawed understanding of  the  biology  and  mode  of  spread  of  breast  cancer,  and  it was a mutilating procedure. It was superseded by less  radical surgery 30 to 40 years ago. Survival rates after conservative surgery with wide local excision in selected patients have been shown to be equal to those after modified radical mastectomy.  Although  the size of the primary carcinoma alone is not a limit- ing factor for breast conservation, if the breast is small,  breast  conservation  is  unsatisfactory  even  for  small  tumors and is impractical for large tumors.

Routine axillary lymph node dissection has pro- gressively been replaced by lymphatic mapping and sentinel lymph node biopsy as a less morbid means of  determining the nodal status in the axilla. If the senti- nel node is negative, the axillary nodes will be negative  with  an  accuracy  of  about  95%,  so  axillary  dissection 

PA R T 3 Gynecology352

BOX 30-1

STAGING OF BREAST CANCER*

Primary Tumor (T) •  TX: Primary tumor cannot be assessed •  T0: No evidence of primary tumor •  Tis:  Carcinoma  in  situ,  intraductal  carcinoma,  lobular 

carcinoma in situ, or Paget disease of the nipple with no  associated invasion of normal breast tissue

•  T1: Tumor ≤2.0 cm in greatest dimension •  T1mic: Microinvasion ≤0.1 cm in greatest dimension •  T1a:  Tumor  >0.1 cm  but  not  >0.5 cm  in  greatest 

dimension •  T1b:  Tumor  >0.5 cm  but  not  >1.0 cm  in  greatest 

dimension •  T1c:  Tumor  >1.0 cm  but  not  >2.0 cm  in  greatest 

dimension •  T2:  Tumor  >2.0 cm  but  not  >5.0 cm  in  greatest 

dimension •  T3: Tumor >5.0 cm in greatest dimension •  T4: Tumor  of  any  size  with  direct  extension  to  (a)  chest 

wall or (b) skin •  T4a: Extension to chest wall •  T4b:  Edema  (including  peau d’orange)  or  ulceration 

of the skin of the breast or satellite skin nodules con- fined to the same breast

•  T4c: Both of the above (T4a and T4b) •  T4d: Inflammatory carcinoma

Regional Lymph Nodes (N) •  NX: Regional lymph nodes cannot be assessed (e.g., pre-

viously removed) •  N0: No regional lymph node metastasis •  N1:  Metastasis  to  movable  ipsilateral  axillary  lymph 

node(s) •  N2: Metastasis to ipsilateral axillary lymph node(s) fixed 

or  matted  or  in  clinically  apparent*  ipsilateral  internal  mammary  nodes  in  the  absence  of  clinically  evident  lymph node metastasis •  N2a:  Metastasis  in  ipsilateral  axillary  lymph  nodes 

fixed to one another (matted) or to other structures •  N2b: Metastasis only in clinically apparent* ipsilateral 

internal mammary nodes and in the absence of clini- cally evident axillary lymph node metastasis

•  N3:  Metastasis  in  ipsilateral  infraclavicular  lymph  node(s)  with  or  without  axillary  lymph  node  involve- ment,  or  in  clinically  apparent*  ipsilateral  internal  mammary lymph node(s) and in the presence of clinically  evident  axillary  lymph  node  metastasis,  or  in  ipsilateral  supraclavicular lymph node(s) with or without axillary or  internal mammary lymph node involvement •  N3a:  Metastasis  in  ipsilateral  infraclavicular  lymph 

node(s) •  N3b:  Metastasis  in  ipsilateral  internal  mammary 

lymph node(s) and axillary lymph node(s) •  N3c:  Metastasis  in  ipsilateral  supraclavicular  lymph 

node(s)

Pathologic Classification (pN)†

•  pNX: Regional lymph nodes cannot be assessed (e.g., not  removed for pathologic study or previously removed)

•  pN0:  No  regional  lymph  node  metastasis  histologically  and no additional examination for isolated tumor cells‡

•  pN0(1−):  No  regional  lymph  node  metastasis  histologi- cally, negative immunohistochemistry (IHC)

•  pN0(1+):  No  regional  lymph  node  metastasis  histologi- cally, positive IHC, and no IHC cluster >0.2 mm

•  pN0(mol−):  No  regional  lymph  node  metastasis  histo- logically  and  negative  molecular  findings  (reverse  tran- scription polymerase chain reaction [RT-PCR])

•  pN0(mol+):  No  regional  lymph  node  metastasis  histo- logically, and positive molecular findings (RT-PCR)

•  pN1:  Metastasis  in  one  to  three  axillary  lymph  nodes,  and/or  in  internal  mammary  nodes  with  microscopic  disease,  detected  by  sentinel  lymph  node  (SLN)  dissec- tion but not clinically apparent§

•  pN1mi: Micrometastasis (>0.2 mm but not >2.0 mm) •  pN1a: Metastasis in one to three axillary lymph nodes •  pN1b:  Metastasis  in  internal  mammary  nodes  with 

microscopic  disease  detected  by  SLN  dissection  but  not clinically apparent§

•  pN1c: Metastasis in one to three axillary lymph nodes  and  in  internal  mammary  lymph  nodes  with  micro- scopic  disease  detected  by  SLN  dissection  but  not  clinically  apparent§  (If  associated  with  more  than  three  positive  axillary  lymph  nodes,  the  internal  mammary  nodes  are  classified  as  pN3b  to  reflect  increased tumor burden.)

•  pN2: Metastasis in four to nine axillary lymph nodes, or  in  clinically  apparent*  internal  mammary  lymph  nodes  in the absence of axillary lymph node metastasis to ipsi- lateral  axillary  lymph  node(s)  fixed  to  each  other  or  to  other structures •  pN2a: Metastasis in four to nine axillary lymph nodes 

(at least one tumor deposit >2.0 mm) •  pN2b:  Metastasis  in  clinically  apparent*  internal 

mammary  lymph  nodes  in  the  absence  of  axillary  lymph node metastasis

•  pN3:  Metastasis  in  10  or  more  axillary  lymph  nodes,  or  in infraclavicular lymph nodes, or in clinically apparent*  ipsilateral internal mammary lymph node(s) in the pres- ence of one or more positive axillary lymph node(s), or in  more  than  three  axillary  lymph  nodes  with  clinically  negative  microscopic  metastasis  in  internal  mammary  lymph  nodes,  or  in  ipsilateral  supraclavicular  lymph  nodes •  pN3a: Metastasis in 10 or more axillary lymph nodes 

(at least one tumor deposit >2.0 mm) or metastasis to  the infraclavicular lymph nodes

•  pN3b:  Metastasis  in  clinically  apparent*  ipsilateral  internal  mammary  lymph  nodes  in  the  presence  of  one  or  more  positive  axillary  lymph  node(s),  or  in  more than three axillary lymph nodes and in internal  mammary  lymph  nodes  with  microscopic  disease  detected  by  SLN  dissection  but  not  clinically  apparent§

•  pN3c: Metastasis in ipsilateral supraclavicular lymph  nodes

C H A P T E R 30 Breast Disease 353

‡Isolated tumor cells (ITCs) are defined as single tumor cells or small cell clusters not larger than 0.2 mm, usually detected only by immunohistochemistry or molecular methods, but that may be verified by hematoxylin and eosin staining. ITCs do not usually show evidence of malignant activity (e.g., proliferation or stromal reaction).

†Classification is based on axillary lymph node dissection with or without sentinel lymph node (SLN) dissection. Classification based solely on SLN dissection without subsequent axillary lymph node dissection is designated “(sn)” for sentinel node (e.g., pN0(1+) [sn]).

¶Stage IIIC breast cancer includes patients with any T stage who have pN3 disease. Patients with pN3a and pN3b disease are considered candidates for surgery and are managed as described in the section on Stages I, II, IIIA, and operable IIIC breast cancer. pN3c disease is considered inoperable, and patients with this stage of breast cancer are managed as described in the section on inoperable Stage IIIB or IIIC or inflammatory breast cancer.

∥T1 includes T1mic.

§Not clinically apparent is defined as not detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination.

*Clinically apparent is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination or grossly visible pathologically.

BOX 30-1

STAGING OF BREAST CANCER—cont’d

Distant Metastasis (M) •  MX: Presence of distant metastasis cannot be assessed •  M0: No distant metastasis •  M1: Distant metastasis

American Joint Commission on Cancer Stage Groupings Stage 0 •  Tis, N0, M0

Stage I •  T1∥, N0, M0

Stage IIA •  T0, N1, M0 •  T1∥, N1, M0 •  T2, N0, M0

Stage IIB •  T2, N1, M0 •  T3, N0, M0

Stage IIIA •  T0, N2, M0 •  T1∥, N2, M0 •  T2, N2, M0 •  T3, N1, M0 •  T3, N2, M0

Stage IIIB •  T4, N0, M0 •  T4, N1, M0 •  T4, N2, M0

Stage IIIC ¶

•  Any T, N3, M0

Stage IV •  Any T, Any N, M1

FIGURE 30-2 Carcinoma of the breast. Note the nipple retraction and the peau d’orange appearance. (From Swartz MH: Textbook of physical diagnosis: history and examination, ed 5, Philadelphia, 2006, Saunders.)

may  be  avoided.  For  a  sentinel  node  that  is  positive,  axillary  dissection  until  recently  was  the  standard  of  care, but this has been challenged by a number of trials  in which researchers have found no evidence support- ing  a  therapeutic  benefit  of  routine  axillary  dissection 

in  patients  with  positive  sentinel  nodes.  This  further  illustrates  just  how  much  the  surgical  management  of  breast cancer has evolved over the last three decades.

Breast reconstruction after mastectomy is an inte- gral part of the treatment of breast cancer. The proce- dure may be performed at the time of the mastectomy,  or it may be delayed.

Radiation Therapy Conservative surgery is always performed in con- junction with radiation therapy to the breast. This approach gives equivalent outcomes to a modified radical or simple mastectomy, and functional and cosmetic results are improved. External beam therapy  is  used,  with  4500  to  5000  cGy  delivered  to  the  entire  breast.  The ipsilateral supraclavicular and internal mammary nodes may be treated on the basis of their clinicopathologic characteristics, including size and nodal status.  A  number  of  trials  of  postmastectomy  radiation  in  women  with  involved  lymph  nodes  have  demonstrated  not  only  a  reduction  in  the  risk  of  locoregional recurrence but also a survival benefit. The  axilla  is  not  routinely  irradiated  following  an  axillary  node  dissection,  because  of  the  high  incidence  of  lymphedema.

PA R T 3 Gynecology354

Adjuvant chemotherapy usually consists of so-called third-generation chemotherapy regimens with anthracycline and taxane combinations  (e.g.,  4  cycles of doxorubicin and cyclophosphamide followed  by weekly paclitaxel for 12 weeks, or 5-fluorouracil, epi- rubicin,  and  cyclophosphamide  every  3  weeks  for  3  cycles followed by docetaxel every 3 weeks for 3 cycles,  or  docetaxel,  doxorubicin,  and  cyclophosphamide  every 3 weeks for 6 cycles). There are a subset of patients  in  whom  four  cycles  of  chemotherapy  with  docetaxel  and cyclophosphamide is adequate therapy.

Approximately 30% of women with early breast cancer develop metastases. The 5-year survival of women with metastatic breast cancer is approxi- mately 25%, and their median survival is 24 to 36 months, but there is a wide range. The most impor- tant prognostic factors include time to recurrence, ER status, HER2 status, site and number of metastases, and performance status. The median survival has increased over time related to more effective thera- pies and a wide range of available agents. Median sur- vival rates are highest in women with luminal type A and HER2-positive breast cancers, and they are short- est in women with triple-negative metastatic breast cancers.

Trastuzumab (Herceptin), a humanized monoclo- nal antibody directed against HER2/neu,  has  been  approved  by  the  U.S.  Food  and  Drug  Administration   for  patients  with  early  breast  cancer  in  conjunction  with  chemotherapy,  as  well  as  for  the  treatment  of  patients with metastatic breast cancer. Its efficiency is  predicted by HER2/neu gene amplification. It has trans- formed  the  prognosis  of  women  with  HER2-positive  breast  cancers,  and  there  are  now  a  number  of  new,  very  effective  anti-HER2  therapies,  including  pertu- zumab  and  ado-trastuzumab  emtansine  (T-DM1,  Kadcyla).

PROGNOSIS Although prognosis is related to the stage of the disease  and the age of the patient (older patients have a better  prognosis), the status of the axillary lymph nodes has been considered to be the single most important prognosticator.  The  ER  status  is  also  of  independent  prognostic  significance;  patients  with  ER-negative  tumors have a poorer prognosis.

In the National Surgical Adjuvant Breast Project, patients with negative lymph nodes had an actuarial 5-year survival of 83%, compared with 73% for patients  with 1 to 3 positive nodes, 45% for those with 4 or more  positive  nodes,  and  28%  for  those  with  more  than  13  positive nodes.

More recently, it has been appreciated that breast cancers are a very heterogeneous group of cancers.  There  are  at  least  four  different  molecular  subtypes  that  have  a  unique  biologic  behavior  and  prognosis,  and  nodal  status  alone  is  no  longer  considered  to  be 

Adjuvant Therapy Adjuvant systemic therapy is used for most patients with early breast cancer, regardless of lymph node status. Overall, adjuvant therapy reducers the risk of relapse by at least one-third and reduces the risk of death by over 30%.

In the Early Breast Cancer Trialists’ meta-analysis of  adjuvant  systemic  therapy,  authors  reported  mortality  reductions  of  38%  (age <50  years)  and  20%  (age  50  to  69  years)  associated  with  adjuvant  chemotherapy,  fol- lowed  by  a  further  reduction  of  31%  with  tamoxifen  therapy  in  patients  with  estrogen  receptor  (ER)–posi- tive breast cancer. It was estimated that the final mor- tality  reductions  would  be  57%  and  45%  for  adjuvant  chemotherapy  and  tamoxifen  therapy,  respectively.  The  absolute  benefit  of  adjuvant  systemic  therapy  depends  on  the  risk  of  recurrence  in  an  individual  woman.

The recommendations regarding adjuvant sys- temic therapy are based on multiple clinicopatho- logic factors  that  cannot  be  summarized  simply  in  a  few  lines.  These factors include age of the patient, tumor size, histological subtype, histologic grade, estrogen (ER) and progesterone receptor status, Ki67 and human epidermal growth factor receptor 2 (HER2) status, and nodal status. It is essential that all  these  factors  be  taken  into  consideration  and  that  the  proportional  reductions  in  recurrence  and  mortality,  the absolute potential gains, and the potential adverse  effects of treatment be discussed with patients.

The  following  is  a  simplified  list  of  current  recom- mendations for adjuvant chemotherapy and hormonal  therapy: •  Premenopausal  patients  with  ER-negative  tumors 

should receive adjuvant systemic chemotherapy. •  Premenopausal  patients  with  ER-positive  tumors 

should  receive  hormonal  therapy  (tamoxifen)  in  addition  to  chemotherapy.  There  is  a  subset  of  patients  in  whom  adjuvant  hormonal  therapy  may  be sufficient.

•  Postmenopausal  patients  with  ER-positive  tumors  who  have  negative  nodes  and  low-risk  features  should  be  treated  with  adjuvant  tamoxifen  for   2 years, followed by an aromatase inhibitor (such as  anastrazole)  for  3  years  or  for  5  years.  Those  with  positive  nodes  should  receive  hormonal  therapy,  and chemotherapy should also be considered.

•  Postmenopausal  patients  with  ER-negative  tumors  should receive adjuvant chemotherapy.

•  Patients  with  HER2-positive  breast  cancers  should  be  given  anti-HER2-directed  therapies  such  as  trastuzumab,  as  well  as  chemotherapy  and  hor- monal therapy if they are ER-positive. An added benefit of adjuvant tamoxifen is a 50%

reduction in the risk of cancer in the contralateral breast.

C H A P T E R 30 Breast Disease 355

performed promptly upon discovery of any suspicious  mass.

The surgical treatment is essentially the same as that  for the nonpregnant patient. Postoperative irradiation  is delayed until after delivery. For patients with nodal metastases, termination should be considered if the patient is early in the first trimester of pregnancy because of the teratogenic risks of the adjuvant che- motherapy.  Adjuvant  chemotherapy  can  be  adminis- tered in the second and third trimesters of pregnancy.  In  the  third  trimester,  chemotherapy  can  usually  be  delayed  until  after  delivery,  although  surgery  should  occur promptly following diagnosis.

Stage for stage, the prognosis for pregnant patients is not much worse than that for nonpregnant patients.  There  is  no  indication  to  advise  against  subsequent  pregnancy for patients with breast cancer who have no  evidence of recurrence.

the  most  important  prognostic  factor.  The  molecular  subtypes include luminal A, which account for 40% of  breast cancers. These cancers are typically of low grade,  strongly  ER-positive,  and  have  a  very  good  prognosis;  luminal B, which are of higher grade, have lower expres- sion of ER, and can be HER2-positive; HER2-enriched  (10-15%);  and  basal-like,  which  are  ER-negative,  pro- gesterone receptor–negative, and HER2-negative. This  illustrates the complexity of breast cancers and how it  is not possible to prognosticate on the basis of a diag- nosis of breast cancer alone.

BREAST CANCER IN PREGNANCY About 3% of breast cancers occur during pregnancy, complicating approximately 1 in every 3000 pregnan- cies. Diagnosis is usually delayed because small masses  are  more  difficult  to  palpate  in  hypertrophied  breasts.  Needle  aspiration  or  core  biopsy,  however,  should  be 

356

31  Gynecologic Procedures Imaging Studies and Surgery

C H

A P

T ER

JOSEPH C. GAMBONE

■  Imaging studies are used in gynecology to evaluate pelvic  masses  and  also  to  assist  in  oocyte  retrieval.  Common  modalities used include ultrasonography, sonohysterog- raphy, computed axial tomography, magnetic resonance  imaging, mammography, and hysterosalpingography.

■  Before  any  gynecologic  procedure  is  performed,  a  process of informed consent should occur during which  the  patient  collaborates  and  makes  a  choice  with  her  surgeon.  Most  procedures  are  elective,  allowing  for  several treatment options to be considered.

■  Training for gynecologic procedures begins in residency  and  continues  throughout  a  surgical  career,  with  newer 

procedures  being  added  as  newer  technologies  are  developed. Privileging refers to the process whereby sur- geons are given the right to perform certain procedures  in the hospital or clinic setting.

■  Common  gynecologic  procedures  range  from  minor  biopsies  of  the  vulva,  cervix,  and  vagina  to  endoscopic  procedures  of  the  uterus  and  pelvic  cavity  and  major  surgeries such as adnexectomy and hysterectomy.

■  New techniques in gynecology are less invasive and may  involve the use of laser technology and surgical robots.

CLINICAL KEYS FOR THIS CHAPTER

Imaging studies using sound wave energy (ultrasound),  magnetic  field  energy  (magnetic  resonance  imaging  [MRI]), or radiation are often ordered, and sometimes  the imaging is performed by the gynecologist to assist  in  the  diagnosis  and  treatment  of  reproductive  tract  disorders. Gynecologic surgical procedures are becom- ing  less  invasive  and  safer,  and  advances  in  surgical  techniques  are  resulting  in  more  effective  and  more  efficient  reproductive  health  care  for  women.  Table  31-1  lists  the  more  common  imaging  modalities  and  procedures used in gynecologic practice.

Imaging Studies in Gynecologic Practice Ultrasonography  is  widely  used  for  diagnostic  pur- poses and even to guide therapeutic applications such  as  oocyte  retrieval  for  in  vitro  fertilization  (IVF).  The  ultrasonic  probe  emits  high-frequency  sound  waves  that provide an image of tissues when reflected back to  the sound source (a probe). Ultrasound is safe for both  pregnant and nonpregnant women and should be used  to  assist  but  not  replace  adequate  physical  examina-

tion  and  history-taking.  Ultrasound  may  be  two-,  three-,  or  even  four-dimensional  when  movement  is  detected  in  real  time.  Two-dimensional  technology  is  the  most  common,  with  three-dimensional  imaging  and  movement  detection  and  interpretation  reserved  for special studies, such as fetal cardiac evaluation. The  sound-generating probe may be placed on the abdom- inal  wall  (transabdominally)  or  into  the  vaginal  canal  (transvaginally).  Transvaginal  insertion  is  more  com- monly used for gynecologic evaluation.

Figure 31-1 illustrates the transvaginal placement of  the  probe  against  the  uterine  cervix.  This  placement  allows  for  excellent  visualization  of  both  normal  anatomy  and  abnormal  pelvic  masses  (uterine  and  adnexal).  The  size  of  ovarian  follicular  cysts  can  be  measured and followed over time to assist fertility eval- uation  and  treatment  as  well  as  oocyte  retrieval  (see  Chapter 34). When saline is infused through a catheter  into the uterine cavity during transvaginal ultrasonog- raphy,  a  sonohysterogram  may  be  visualized  and  recorded.

Computed axial tomography (CAT or CT)  uses  computer  algorithms  to  form  cross-sectional  x-ray  images  of  pelvic  tissues.  Contrast  media  may  be  used 

C H A P T E R 31 Gynecologic Procedures 357

TABLE 31-1

COMMON IMAGING STUDIES AND PROCEDURES IN A GYNECOLOGIC PRACTICE

Diagnostic Indications Therapeutic Indications Comments

Imaging Studies

Ultrasonography (transvaginal)

Evaluation of pelvic cysts and tumors

Oocyte retrieval for in vitro fertilization

See Chapter 34 No radiation exposure

Sonohysterography Evaluation of uterine cavity for polyps and/or tumors

None Also called saline infusion hysterography

Computed axial tomography (CAT or CT)

Evaluation of pelvis and abdomen for cysts and tumors

None Radiation exposure

Magnetic resonance imaging (MRI)

Evaluation of pelvis for cysts, tumors, and uterine abnormalities

None No radiation exposure

Breast imaging (mammography)

Identification of breast pathology; screening criteria remain controversial

None See Chapter 30 Ultrasound and MRI also

used

Hysterosalpingography Evaluation of uterine cavity and fallopian tubes for patency

Some studies show small increase in pregnancy rate with oil-based media

See Chapter 34

Procedures

Endometrial sampling Obtaining tissue for histopathologic examination

Intentional tissue damage is reported to increase implantation rate in some studies

Pipelle endometrial suction See Figure 31-2; see also

Chapter 34

Biopsies Punch Cone (cold knife) Loop (electrosurgical

excision)

Obtaining tissue for histopathology

Complete excision of pathologic tissue in some cases

Common sites for biopsy include the vulva, vagina, cervix, and endometrium

Colposcopy Identification of cervical, vaginal, and vulvar pathology

None See Chapter 38

Cryotherapy, electrotherapy, and laser therapy

Laser may be used for excisional cone biopsy of the cervix

Tissue destruction and ablation See text, this chapter

Dilation and curettage (D&C)

Evaluation of endometrium May temporarily control dysfunctional uterine bleeding

Polyps may be identified and removed

Sterilization and abortion procedures

NA Prevent pregnancy or terminate existing pregnancy

See Chapter 27

Pelvic endoscopy (laparoscopy)

Multiple Multiple See text, this chapter

Pelvic floor procedures NA Surgical repair for stress urinary incontinence and organ prolapse

See Chapter 23

Hysteroscopy Evaluate uterine cavity for the presence of polyps or tumors

Removal of polyps and/or tumors Ablation of tissue

See text, this chapter

Hysterectomy Abdominal Vaginal Laparoscopic and

laparoscopically assisted

Primarily therapeutic but unexpected pathology may be found (e.g., undiagnosed endometrial or endocervical cancer or leiomyosarcoma)

See Table 30-2 See text, this chapter and Chapter 19

Morcellation of malignant uterine tissue can lead to spread of cancer

Adnexal surgery Cystectomy Oophorectomy Salpingectomy

Provision of tissue for histopathologic diagnosis of an adnexal mass

Treatment of adnexal masses, benign or malignant, with hysterectomy or with pathology (e.g., tubal pregnancy)

May be performed separately or at the same time as hysterectomy

Robotic procedures Currently being studied Multiple No apparent advantage for benign indications

See text, this chapter

NA, Not applicable.

PA R T 3 Gynecology358

FIGURE 31-1 Placement of the transvaginal ultrasound probe against the uterine cervix to view the uterus and adnexal structures.

Vaginal transducer

Bladder Uterus

Ovary

to enhance the images. CT scanning uses radiation and  for this reason ultrasound or MRI may be preferred in  pregnant patients.

MRI  takes  advantage  of  differing  characteristics  of  body tissues when the tissues are exposed to magnetic  field energy. By visually distinguishing between tissues  such as fat and body fluids like blood and lymph, MRI  is useful for the evaluation of uterine and ovarian struc- tures.  Uterine  adenomyosis  (see  Chapter  25)  and  certain breast lesions may be detected using MRI.

Mammography uses radiation that penetrates com- pressed breast tissue to screen for breast cancer. There  is  both  a  false-positive  and  false-negative  interpreta- tion  error  associated  with  screening  mammograms.  Both  MRI  and  ultrasound  may  be  used  to  improve  diagnostic accuracy (see Chapter 30).

Hysterosalpingography  (HSG)  employs  fluoros- copy  and  radiopaque  dyes  injected  transcervically  to  create  an  image  of  the  uterine  cavity  and  to  verify  fill  and  spill  of  dye  out  of  the  fallopian  tubes  (tubal  patency).  Uterine  polyps  and  submucous  uterine  fibroids may be detected. Some studies show a statisti- cally  significant  increase  in  the  pregnancy  rate  after  HSG,  especially  when  oil-based  media  are  used,  sug- gesting  therapeutic  value.  Figure  34-2  shows  an  HSG  study.

Gynecologic Procedures The  gynecologic  surgeon  should  have  a  high  level  of  training  during  residency,  followed  by  an  ongoing  commitment  to  retraining  and  retooling  as  effective  procedures  are  added  or  substituted  for  outdated  ones.  Training  methods  now  include  computer- assisted  simulations  of  procedures,  providing  for  greater  patient  safety  while  the  surgeon  is  learning  and  retraining.  All  facilities  should  have  an  active  quality  assessment  program  to  continuously  evaluate  the  safety  and  appropriateness  of  gynecologic  care,  including surgery.

Before  any  procedure  or  surgery  begins,  the  most  appropriate option (when more than one exists) for an  individual  patient  must  be  selected,  with  optimal  patient  involvement  in  the  decision-making  process  included as part of informed consent.

At least 80% of gynecologic surgical procedures are considered to be elective; that is, there are other alter- native  treatments  to  be  considered.  The  appropriate- ness  of  performing  these  procedures  should  be  evaluated  by  physician  and  patient  on  an  individual  basis (Box 31-1). The trend toward minimal invasive- ness in gynecologic surgery should not lead to minimal or questionable indications.

C H A P T E R 31 Gynecologic Procedures 359

tion,  regional  anesthesia,  or  inhalational  agents).  Regional  anesthesia  carries  the  risk  of  infection,  post- procedural spinal headache, and failure, in which case  an  inhalational  agent  must  be  added  to  the  regional  anesthetic. Inhalational agents may be associated with  the  risks  of  aspiration  pneumonia,  allergic  reaction  to  the agent, and damage to teeth or airways if intubation  is  necessary.  Stroke,  myocardial  infarction,  and  death  can  result.  The  intraoperative  risks  include  excessive  bleeding and unintended damage to organs or tissues.  Postoperative risks include infection, persistent bleed- ing, and thrombosis, all of which can lead to significant  morbidity  or  even  mortality. The  specific  risks  of  each  procedure are described below.

Endometrial Sampling Procedures One  of  the  most  common  minor  gynecologic  surgical  procedures is dilation of the cervix and curettage of the  endometrium (D&C). Recent advances in office-based  instrumentation for diagnosis (hysteroscopy, endome- trial biopsy [Figure 31-2], and ultrasonic evaluation of  endometrial thickness) have resulted in an appropriate  decrease  in  the  use  of  D&C.  However, if cancer of the cervix or endometrium is suspected, a thorough frac- tional curettage may be the best procedure to use to confirm its presence.

INDICATIONS D&C may be a diagnostic or a therapeutic procedure.  A diagnostic D&C is performed for irregular menstrual  bleeding,  heavy  menstrual  bleeding,  or  postmeno- pausal  bleeding,  unless  an  endometrial  biopsy  has  already revealed a diagnosis of malignancy. Irregulari- ties  in  the  contour  of  the  endometrial  cavity,  either  congenital (e.g., uterine septum) or acquired (e.g., sub- mucous myomata), are sometimes determined during  the operation. The finding of a thin endometrium on a  transvaginal ultrasound (generally <5 mm) may elimi- nate  the  need  for  biopsy  or  D&C  in  some  women.  In 

Credentialing, Privileging, and Ongoing Training The rapid introduction of new technologies can present  a  challenge  to  the  surgeon,  who  will  need  to  keep  up  with the most advanced procedures, and to the institu- tion, which is required to be certain that those who are  granted surgical privileges have been properly trained  and are currently qualified.

After a surgeon’s credentials (diplomas, training cer- tificates,  and  licenses)  have  been  properly  verified,  a  useful classification for the purpose of privileging strat- ifies procedures into the following levels: •  Level 1:  procedures  not  requiring  additional  train-

ing  after  residency  (e.g.,  dilation  and  curettage  [D&C],  cervical  conization,  adnexal  excision,  and  abdominal or vaginal hysterectomy)

•  Level 2:  procedures  requiring  additional  training  (e.g., laparoscopic myomectomy)

•  Level 3: procedures requiring advanced training and  special skills generally acquired during subspecialty  training (e.g., radical hysterectomy, tubal anastomo- sis, or oocyte harvesting) As new procedures are incorporated into basic resi-

dency training, they can be reclassified.

Informed Consent and General Risks Associated with Procedures The patient should be thoroughly counseled about surgical risks as part of the process of informed consent (see Chapter 1). In general, risks fall into three  categories:  risks  of  anesthesia,  intraoperative  risks,   and  postoperative  complications.  Risks  of  anesthesia  depend  on  the  type  of  anesthesia  used  (awake  seda-