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WHO_Guidelinesfortheidentificationandmanagementofsubstanceuseandsubstanceusedisordersinpregnancy.pdf

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The harmful use of alcohol and

illicit drugs is the third leading

risk factor for premature deaths

and disabilities in the world. It is

estimated that 2.5 million people

worldwide died of alcohol-

related causes in 2004, including

320 000 young people between

15 and 29 years of age.

Contact Management of Substance Abuse Department of Mental Health and Substance Abuse 20, Avenue Appia 1211 Geneva 27 Switzerland Tel: + 41 22 791 21 11 Email: [email protected] www.who.int/substance_abuse

ISBN 978 92 4 154873 1

EXIT THE MAZE OF SUBSTANCE USE FOR BETTER GLOBAL HEALTH

sub stance

use Guidelines for the identification and

management of substance use and substance use disorders

in pregnancy

G uidelines for the identification and m

anagem ent of substance use and substance use disorders in pregnancy

Guidelines for the identification and management of substance use

and substance use disorders in pregnancy

WHO Library Cataloguing-in-Publication Data

Guidelines for the identification and management of substance use and substance use disorders in pregnancy.

1.Substance-Related Disorders – prevention and control 2.Psychotropic Drugs – adverse effects. 3.Pregnancy. 4.Pregnancy Outcome. 5.Prenatal Exposure Delayed Effects. 6.Guideline. I.World Health Organization.

ISBN 978 92 4 154873 1 (NLM classification: WQ 210)

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Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii

Glossary of terms used in these guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v

Acronyms & abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viii

Executive summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Why these guidelines were developed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Existing relevant guidelines on related problems and disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Who should use these guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Objectives and scope of the document . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Individuals and partners involved in development of the guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

How the guidelines were developed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Evidence search and retrieval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Evidence to recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Overarching principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Screening and brief interventions for hazardous and harmful substance use during pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Psychosocial interventions for substance use disorders in pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Detoxification or quitting programmes for alcohol and other substance dependence in pregnancy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Pharmacological treatment (maintenance and relapse prevention) for alcohol and other substance dependence in pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Breastfeeding and maternal substance use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Management of infants exposed to alcohol and other psychoactive substances . . . . . . . . . . . . . . . . . . 17

Research priorities and gaps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Plans for disseminating, adapting and implementing these recommendations . . . . . . . . . . . . . . . . . 21

Evaluating the impact of these recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Review by date . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Annex 1: Evidence Profiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Evidence Profile 1: Screening and brief interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Evidence question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Selection criteria for the systematic review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Evidence to recommendations table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Summary of findings and GRADE tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

CONTENTS

Evidence Profile 2: Psychosocial interventions for harmful use and dependence on alcohol and other substances in pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Evidence question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Selection criteria for the systematic review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Evidence to recommendations table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

Summary of findings and GRADE tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

Evidence Profile 3: Detoxification or quitting programmes for alcohol and other substance dependence in pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

Evidence question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

Selection criteria for the systematic review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

Evidence to recommendations table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

Evidence Profile 4: Pharmacological treatment (maintenance and relapse prevention) for alcohol and other substance dependence in pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

Evidence question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

Selection criteria for the systematic review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

Evidence to recommendations table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

Summary of findings and GRADE tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

Evidence Profile 5: Breastfeeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

Evidence question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

Selection criteria for the systematic review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

Evidence to recommendations table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

Evidence Profile 6: Management of infants exposed to alcohol and other psychoactive substances . 135

Evidence question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

Study selection criteria for the systematic review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

Evidence to recommendations table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136

Summary of findings and GRADE tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

Annex 2: Systematic review methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

Criteria for considering studies for this review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

Data collection and analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183

Main results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188

Annex 3: Screening instruments for substance use in prenatal or pregnant women . . . . . . . . . . . . 198

Annex 4: Composition of guideline groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

WHO Steering Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

Guideline Development Group (GDG) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

External reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

Annex 5: Declarations of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

GDG members . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

Consultants supporting GDG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

External reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204

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ACKNOWLEDGEMENTS These guidelines were produced by the WHO Department of Mental Health and Substance Abuse (Management of Substance Abuse unit), in collaboration with the WHO Prevention of Noncommunicable Diseases Department (PND) and the United Nations Office on Drugs and Crime (UNODC) Prevention, Treatment and Rehabilitation Section (PTRS). The development of these guidelines was coordinated by Vladimir Poznyak and Nicolas Clark under the direction of Shekhar Saxena and in collaboration with Edouard Tursan d’Espaignet and Lubna Bhatti (WHO) and Elizabeth Mattfeld (UNODC).

The project had a WHO Steering Group with the following members: Avni Amin, Lubna Bhatti, Nicolas Clark, Ahmet Metin Gulmezoglu, Mathews Mathai, Mario Merialdi, Vladimir Poznyak, Shekhar Saxena, Edouard Tursan d’Espaignet (see annex for affiliations).

The members of the project’s Guideline Development Group were: Sawitri Assanangkornchai, Guilherme Borges (Co-chair), Grace Chang, Anju Dhawan Dutta, Elizabeth Elliott, Katherine Everett-Murphy, Gabriele Fischer, Erikson Furtado, Hendree Jones, Fareed A. Minhas, Alice Ordean, Gabrielle Katrine Welle-Strand (Co-chair) (see annex for affiliations).

The external peer reviewers were: Steve Allsop, Espen Ajo Arnevik, Matthew Chersich, Andreea Creangea, Marica Ferri, David A. Fiellin, Louise Floyd, Chris Howson, Irma Kirtadze, Yukiko Kusano, Andre B. Lalonde, Carla Marienfeld-Calderon, Nester Moyo, Michael Farrell, Dzianis Padruchny, Roland Simon, Anna Woods (see annex for affiliations).

WHO would like to acknowledge the contributions made by the following individuals to the development of these guidelines:

Consultants: Elizabeth Byrnes, Andrea Gordon, Lauren Jansson, Hendree Jones, Ingunn Olea Lund, Lana Popova, Ed Riley, Kathy Sulik (consultants on the reviews of the harm of substance use in pregnancy and breastfeeding); Margaret Harris (consultant in WHO guideline methodology, who prepared the guideline document and advised at the GDG meeting in Geneva); Keryn Murphy (who wrote the meeting report of the meeting in Washington DC); Nandi Siegfried (WHO consultant on systematic review, GRADE and WHO guideline methodology, and advisor at the GDG meeting in Washington DC, who conducted the reviews and prepared the GRADE tables on the effectiveness of interventions for substance use disorders).

WHO interns: Bonnie Cheuk, Helen Tam-Tham (interns who worked on the evidence of harms from substance use in pregnancy); Elise Gehring, Ifeoma Onyeka, Derrick Ssewanyana (interns who worked on the systematic reviews of effectiveness of interventions in pregnancy, the values and preferences survey and the preparation of the meeting in Geneva).

The contribution of the Pan American Health Organization (PAHO)/WHO Regional Office for the Americas to the organization of the first meeting of the Guidelines Development Group in Washington DC (USA) is greatly acknowledged with special thanks to Maristela Monteiro, Jorge Rodriguez and Luiz Galvão.

Special invitees to the initial meeting of the Guideline Development Group meeting in Washington DC (USA) who provided comment and technical information:

Andreea A. Creanga, Louise Floyd (Centers for Disease Control and Prevention, USA); Anna Woods (Drug and Alcohol Services Council South Australia, Australia); Ed Riley (International Society for Biomedical Research on Alcoholism); Mary-Elizabeth Reeve, Christopher Howson (March of Dimes); Margaret M. Murray, Kathy Sulik (National Institute of Alcohol Abuse and Alcoholism (NIAAA), USA) Cheryl Anne Boyce, Steve Gust, Samia Dawud Noursi (National Institute on Drug Abuse (NIDA), USA); Kathy Mitchell (National Organization on Fetal Alcohol Syndrome (NOFAS), USA); Imani Walker (Rebecca Project for Human Rights, USA); Hedda van 't Land (Trimbos Institute, the Netherlands).

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Special invitees to the final meeting of the Guideline Development Group in Geneva, Switzerland, who provided technical information and contributed to external review:

Andreea A. Creanga (Centers for Disease Control and Prevention, USA); Anna Woods (Drug and Alcohol Services Council, South Australia); Paul Peters (European Fetal Alcohol Spectrum Disorders Alliance); Andre Lalonde (International Federation of Gynecology and Obstetrics (FIGO), Partnership for Maternal, Newborn and Child Health (PMNCH); Mary Hepburn (Glasgow Special Needs in Pregnancy Service); Nester Moyo (International Confederation of Midwives); Yukiko Kusano (International Council of Nurses); Margaret M. Murray, Kathy Sulik (NIAAA, USA) Anne Boyce, Steve Gust, Samia Dawud Noursi (NIDA, USA); Kathy Mitchell (National Organization on Fetal Alcohol Syndrome (NOFAS), USA); Imani Walker (Rebecca Project For Human Rights, USA); Hedda van 't Land (Trimbos Institute, the Netherlands).

Funding: The project was funded by the Government of the United States of America (U.S. Department of State, Bureau for International Narcotics and Law Enforcement Affairs) through the United Nations Office on Drugs and Crime, and the Government of the Kingdom of Norway. The National Institute of Drug Abuse (NIDA), USA, and the National Institute of Alcohol Abuse and Alcoholism (NIAAA), USA, supported some evidence reviews and attendance of participants at the initial scoping meeting held in Washington DC, USA.

GLOSSARY OF TERMS USED IN THESE GUIDELINES Abstinence Refraining from alcohol or drug use. The term “abstinence” should not be confused with the term “abstinence syndrome”, which refers to a withdrawal syndrome.

Alcohol In chemical terminology, alcohols are a large group of organic compounds derived from hydrocarbons and containing one or more hydroxyl (-OH) groups. Ethanol (C

2 H

5 OH, ethyl alcohol) is one of this class of compounds,

and is the main psychoactive ingredient in alcoholic beverages. By extension the term “alcohol” is also used to refer to alcoholic beverages. Alcohol is a sedative/hypnotic with effects similar to those of barbiturates.

Antagonist A substance that counteracts the effects of another agent. Pharmacologically, an antagonist interacts with a receptor to inhibit the action of agents (agonists) that produce specific physiological or behavioural effects mediated by that receptor.

Amphetamines / amfetamines One of a class of sympathomimetic amines with powerful stimulant actions on the central nervous system. The class includes amphetamine, dexamphetamine, and methamphetamine. Pharmacologically related drugs include methylphenidate, phenmetrazine and amphepramone (diethylpropion).

Barbiturate One of a group of central nervous system depressants that chemically are substituted derivatives of barbituric acid; examples are amobarbital, pentobarbital, phenobarbital, and secobarbital. They are used as antiepileptics, anaesthetics, sedatives, hypnotics and, less commonly, as anxiolytics or anti-anxiety drugs (see sedative/ hypnotic). Acute and chronic use induces effects similar to those of alcohol.

Benzodiazepine One of a group of structurally related drugs used mainly as sedatives/hypnotics, muscle relaxants, and anti- epileptics, and once referred to by the now-deprecated term “minor tranquillisers”. These agents are believed to produce therapeutic effects by potentiating the action of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter.

Bloodborne diseases Diseases such as HIV and Hepatitis B and C, which are spread by blood-to-blood contact (e.g. needle-sharing).

Cannabis A generic term used to denote the several psychoactive preparations of the marijuana (hemp) plant, Cannabis sativa. They include marijuana leaf (in street jargon: grass, pot, dope, weed or reefers), bhang, ganja or hashish (derived from the resin of the flowering heads of the plant), and hashish oil.

Cocaine An alkaloid obtained from coca leaves or synthesized from ecgonine or its derivatives. Cocaine hydrochloride was commonly used as a local anaesthetic in dentistry, ophthalmology, and in ear, nose and throat surgery because its strong vasoconstrictor action helps to reduce local bleeding. Cocaine is a powerful central nervous system stimulant used non-medically to produce euphoria or wakefulness. Repeated use produces dependence.

Dependence A cluster of physiological, behavioural and cognitive phenomena in which the use of a substance or a class of substances takes on a much higher priority for a given individual than other behaviours that once had greater value. A central descriptive characteristic of the dependence syndrome is the desire (often strong, sometimes overpowering) to take psychoactive drugs (which may or may not have been medically prescribed), alcohol, or tobacco.

Detoxification Also referred to as a managed withdrawal or supported withdrawal, detoxification refers to the process of an individual being withdrawn from the effects of a psychoactive substance. When referring to a clinical procedure, detoxification refers to a withdrawal process that is carried out in a safe and effective manner, minimizing the withdrawal symptoms, and supporting the person physically and mentally through the process.

Drug-related problem Any of the range of adverse accompaniments of drug use, particularly illicit drug use. “Related” does not necessarily imply causality.

Fetal alcohol syndrome (FAS) A pattern of retarded growth and development, both neuropsychological and physical, with typical facial dysmorphic features, found in some children exposed to alcohol during pregnancy. A spectrum of physical and neurodevelopmental abnormalities, which includes FAS, has been attributed to the effects of alcohol on the fetus. The level of maternal consumption that produces Fetal Alcohol Spectrum Disorders (FASD) has not been established and is influenced by genetic and other maternal and fetal characteristics.

Harmful substance use A pattern of psychoactive substance use that causes damage to health (ICD-10 code F1x.1). The damage may be physical (e.g. in the cases of hepatitis from the self-administration of injected psychoactive substances) or mental.

Hazardous substance use A pattern of substance use that increases the risk of harmful consequences for the user and fetus.

Intoxication A condition that follows the administration or consumption of a psychoactive substance and results in disturbances in the level of consciousness, cognition, perception, judgement, affect, or behaviour, or other psychophysiological functions and responses.

Neonatal Abstinence Syndrome / Neonatal Withdrawal Syndrome When a neonate shows signs of withdrawal from exposure to psychotropic substances in utero, this is referred to as neonatal abstinence or neonatal withdrawal.

Opioid maintenance treatment Also referred to as opioid agonist maintenance treatment, or opioid substitution treatment. Examples of opioid maintenance therapies are methadone and buprenorphine maintenance treatment. Maintenance treatment can last from several months to more than 20 years, and is often accompanied by other treatment (e.g. psychosocial treatment).

Psychosocial intervention Any non-pharmacological intervention carried out in a therapeutic context at an individual, family or group level. Psychosocial interventions range from structured, professionally administered psychological interventions (e.g. cognitive behaviour therapy or insight oriented psychotherapy) to non-professional psychological and social interventions (e.g. self-help groups and non-pharmacological interventions from traditional healers, as well as accommodation, financial support, legal support, information and outreach).

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Substance use disorders The concept of “substance use disorders” includes both the dependence syndrome and the harmful use of psychoactive substances such as alcohol, cannabis, amphetamine-type stimulants (ATS), cocaine, opioids and benzodiazepines.

Volatile substances Substances that vaporize at ambient temperatures. Volatile substances that are inhaled for psychoactive effects (also called inhalants) include the organic solvents present in many domestic and industrial products (such as glue, aerosol, paints, industrial solvents, lacquer thinners, gasoline and cleaning fluids) and the aliphatic nitrites such as amyl nitrite.

Withdrawal syndrome (abstinence syndrome, withdrawal reaction, withdrawal state) A group of symptoms of variable clustering and degree of severity that occur on cessation or reduction of use of a psychoactive substance that has been taken repeatedly, usually for a prolonged period or in high doses (ICD-10 code F1x.3). The onset and course of withdrawal syndrome are time-limited and relate to the type of substance and dose being taken immediately before cessation or reduction of use. Typically, the features of withdrawal syndrome are the opposite of acute intoxication.

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AUDIT alcohol use disorders identification test

ASSIST alcohol, smoking and substance involvement screening test

ALT alanine aminotransferase

AST aspartate aminotransferase

ATS amphetamine-type stimulants

CBT cognitive behavioural therapy

CDT carbohydrate-deficient transferrin

CI confidence interval

CM contingency management

CND Commission on Narcotic Drugs

CNS central nervous system

EUFASD European Fetal Alcohol Spectrum Disorders Alliance

FAS fetal alcohol syndrome

FASD fetal alcohol spectrum disorders

FIGO International Federation of Gynecology and Obstetrics

GABA gamma-aminobutyric acid

GDG guidelines development group

GGT gamma-glutamyl transpeptidase

DSM Diagnostic and Statistical Manual of Mental Disorders

HCW health-care workers

HIV human immunodeficiency virus

ICD International Classification of Diseases

IUGR intrauterine growth retardation

ITT intention-to-treat

IV intravenous

MCV mean corpuscular volume

M-H Mantel-Haenszel

MD mean differences

MI motivational interviewing

N number

NAS neonatal abstinence syndrome

NICU neonatal intensive care unit

OR odds ratio

PAHO/AMRO Pan American Health Organization/WHO Regional Office for the Americas

PCP phencyclidine

PMNCH Partnership for Maternal, Newborn and Child Health

PMTCT prevention of mother-to-child transmission of HIV

RCT randomized controlled trial

ACRONYMS & ABBREVIATIONS

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RevMAN Review Manager

RR risk ratio

SBIRT screening, brief-intervention and referral to treatment

SD standard deviation

SOF summary of findings

STI sexually transmitted infections

TLFB timeline follow back

TAU treatment as usual

THC tetrahydrocannabinol

UN United Nations

UNODC United National Office on Drugs and Crime

WHO World Health Organization

WIC women, infants and children

EXECUTIVE SUMMARY Use of alcohol, illicit drugs and other psychoactive substances during pregnancy can lead to multiple health and social problems for both mother and child. Use of alcohol during pregnancy can lead to fetal alcohol syndrome and other harms such as spontaneous abortion, stillbirth, low birthweight, prematurity and birth defects.

Dependence on alcohol and other drugs can also severely impair an individual’s functioning as a parent, spouse or partner, and instigate and trigger gender-based and domestic violence, thus significantly affecting the physical, mental and emotional development of children.

Pregnancy may be an opportunity for women, their partners and other people living in their household to change their patterns of alcohol and other substance use. Health workers providing care for women with substance use disorders during pregnancy need to understand the complexity of the woman’s social, mental and physical problems in order to provide appropriate advice and support throughout pregnancy and the postpartum period.

Why these guidelines were developed These guidelines have been developed to enable professionals to assist women who are pregnant, or have recently had a child, and who use alcohol or drugs or who have a substance use disorder, to achieve healthy outcomes for themselves and their fetus or infant. They have been developed in response to requests from organizations, institutions and individuals for technical guidance on the identification and management of alcohol and other substance use and substance use disorders in pregnant women. They were developed in tandem with the WHO recommendations for the prevention and management of tobacco use and second-hand smoke exposure in pregnancy. There are currently no global guidelines providing evidence-based recommendations for identifying and managing substance use and substance use disorders in pregnancy. While several high- income countries have developed national guidelines covering these issues, low- and middle-income countries currently lack such guidance.

Who should use these guidelines These guidelines have been primarily written for health-care providers managing women from conception to birth, and during the postnatal period, and their infants.

Objectives and scope of these guidelines These guidelines aim to provide evidence-based technical advice to health-care providers on identifying and managing substance use and substance use disorders in pregnant women, which enables health-care practitioners to apply the scientific principles of a public health approach in their own countries. An equally important objective is to enable pregnant women to make healthy decisions about alcohol and other substance use in the context of pregnancy and breastfeeding.

After a broad review of the needs of this population and challenges faced by health-care providers working with pregnant women with substance use disorders, it was decided that the guidelines should focus on six areas:

1. Screening and brief intervention 2. Psychosocial interventions 3. Detoxification 4. Dependence management 5. Infant feeding 6. Management of infant withdrawal

How these guidelines were developed The development of these guidelines began in mid 2012 as a collaborative effort between the WHO departments of Mental Health and Substance Abuse and the Tobacco Free Initiative with production of the guidelines proposal, a virtual meeting of the Guidelines Development Group (GDG), and subsequent approval of the guidelines proposal by the WHO Guidelines Review Committee. The GDG has conferred through teleconferences and virtual meetings, as well as at two face-to-face meetings. At the first meeting, held in Washington DC, USA, (29 January to 1 February 2013), the evidence for the harms of different patterns of alcohol and drug use in pregnancy was reviewed, and the scope and areas of evidence retrieval were established. At the second and final meeting, held at the WHO Headquarters in Geneva (11–13 September 2013) the evidence retrieved was presented using evidence profiles and GRADE tables (see annex), and final recommendations were formulated. The GDG used the evaluation of the evidence of effect, plus further evidence on harms, benefits, values, preferences, resource use and feasibility, to set the strength of the recommendations (see decision tables and evidence profiles in annex).

The strength of the recommendation was set as either:

‘strong’: meaning that the Guideline Development Group was confident that the quality of the evidence of effect, combined with certainty about the values, preferences, benefits and feasibility, made this a recommendation that should be done in most circumstances and settings;

‘conditional’: meaning there was less certainty about the quality of the evidence and values, preferences, benefits and feasibility of this recommendation. Thus, there may be circumstances or settings in which the recommendation should not apply.

Recommendations

Governing principles It was noted by the GDG that certain principles apply to all the recommendations described below. These overarching principles are proposed to provide guidance in the process of planning, implementing and evaluating the most suitable and relevant recommendations according to the national contexts and available resources.

I. Prioritizing prevention. Preventing, reducing and ceasing the use of alcohol and drugs during pregnancy and in the postpartum period are essential components in optimizing the health and well-being of women and their children.

II. Ensuring access to prevention and treatment services. All pregnant women and their families affected by substance use disorders should have access to affordable prevention and treatment services and interventions delivered with a special attention to confidentiality, national legislation and international human rights standards; women should not be excluded from accessing health care because of their substance use.

III. Respecting patient autonomy. The autonomy of pregnant and breastfeeding women should always be respected, and women with substance use disorders need to be fully informed about the risks and benefits, for themselves and for their fetuses or infants, of available treatment options, when making decisions about her health care.

IV. Providing comprehensive care. Services for pregnant and breastfeeding women with substance use disorders should have a level of comprehensiveness that matches the complexity and multifaceted nature of substance use disorders and their antecedents.

V. Safeguarding against discrimination and stigmatization. Prevention and treatment interventions should be provided to pregnant and breastfeeding women in a way that will prevent stigmatization, discrimination and marginalization, and promote family, community and social support, as well as social inclusion by fostering strong links with available childcare, employment, education, housing and other relevant services.

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IDENTIFICATION AND MANAGEMENT OF SUBSTANCE USE AND SUBSTANCE USE DISORDERS IN PREGNANCY

No. Recommendation Strength of

recommendation Quality of evidence

Screening and brief interventions for hazardous and harmful substance use during pregnancy

 Health-care providers should ask all pregnant women about their use of alcohol and other substances (past and present) as early as possible in the pregnancy and at every antenatal visit.

Strong Low

2 Health-care providers should offer a brief intervention to all pregnant women using alcohol or drugs.

Strong Low

Psychosocial interventions for substance use disorders1 in pregnancy

3 Health-care providers managing pregnant or postpartum women with alcohol or other substance use disorders should offer comprehensive assessment2, and individualized care.3

Conditional Very low

Detoxification or quitting programmes for substance dependence in pregnancy

4 Health-care providers should at the earliest opportunity advise pregnant women dependent on alcohol or drugs to cease their alcohol or drug use and offer, or refer to, detoxification services under medical supervision where necessary and applicable.4

Strong Very low

5 Pregnant women dependent on opioids should be encouraged to use opioid maintenance treatment5 whenever available rather than to attempt opioid detoxification.

Strong Very low

6 Pregnant women with benzodiazepine dependence should undergo a gradual6 dose reduction, using long-acting benzodiazepines.

Strong Very low

7 Pregnant women who develop withdrawal symptoms following the cessation of alcohol consumption should be managed with the short-term use of a long-acting benzodiazepine.7

Strong Very low

8 In withdrawal management for pregnant women with stimulant dependence, psychopharmacological medications may be useful to assist with symptoms of psychiatric disorders but are not routinely required.

Strong Very low

Pharmacological treatment (maintenance and relapse prevention) for substance dependence in pregnancy

9 Pharmacotherapy is not recommended for routine treatment of dependence on amphetamine-type stimulants, cannabis, cocaine, or volatile agents in pregnant patients.

Conditional Very low

 Given that the safety and efficacy of medications for the treatment of alcohol dependence has not been established in pregnancy, an individual risk-benefit analysis should be conducted for each woman.

Conditional Very low

 Pregnant patients with opioid dependence should be advised to continue or commence opioid maintenance therapy with either methadone or buprenorphine.

Strong Very low

Breastfeeding with maternal alcohol and/or substance dependence

 A. Mothers with substance use disorders should be encouraged to breastfeed unless the risks clearly outweigh the benefits.

B. Breastfeeding women using alcohol or drugs should be advised and supported to cease alcohol or drug use; however, substance use is not necessarily a contraindication to breastfeeding.

Conditional Low

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IDENTIFICATION AND MANAGEMENT OF SUBSTANCE USE AND SUBSTANCE USE DISORDERS IN PREGNANCY

No. Recommendation Strength of

recommendation Quality of evidence

 Skin-to-skin contact is important regardless of feeding choice and needs to be actively encouraged for the mother with a substance use disorder who is able to respond to her baby’s needs.

Strong Low

 Mothers who are stable on opioid maintenance treatment with either methadone or buprenorphine should be encouraged to breastfeed unless the risks clearly outweigh the benefits.

Strong Low

Management of infants exposed to alcohol and other psychoactive substances

 Health-care facilities providing obstetric care should have a protocol in place for identifying, assessing, monitoring and intervening, using non-pharmacological and pharmacological methods, for neonates prenatally exposed to opioids.

Strong Very low

 An opioid should be used as initial treatment for an infant with neonatal opioid withdrawal syndrome if required.

Strong Very low

 If an infant has signs of a neonatal withdrawal syndrome due to withdrawal from sedatives or alcohol, or the substance the infant was exposed to is unknown, then phenobarbital may be a preferable initial treatment option.

Conditional Very low

 All infants born to women with alcohol use disorders should be assessed for signs of fetal alcohol syndrome.8

Conditional Very low

1 The concept of “substance use disorders” includes dependence syndrome and harmful use of psychoactive substances such as alcohol, cannabis, amphetamine- type stimulants (ATS), cocaine, benzodiazepines etc.

2 A comprehensive assessment of women using alcohol or drugs in pregnancy and the postpartum period include assessment of patterns of substance use, medical or psychiatric co-morbidity, family context and social problems.

3 Individual care planning involves selecting appropriate psychosocial and pharmacological interventions based on a comprehensive assessment. 4 Pregnant women dependent on alcohol or drugs who agree to undergo detoxification should be offered the supported withdrawal from substance use in an

inpatient or hospital facility, if medically indicated; equal attention should be paid to the health of mother and fetus and treatment adjusted accordingly. 5 Methadone maintenance treatment or buprenorphine maintenance treatment. 6 For as short a time as is medically feasible. 7 Management of alcohol withdrawal usually includes administration of thiamine. 8 Signs of Fetal Alcohol Syndrome (FAS) include growth impairment, dysmorphic facial features (short palpebral fissures, smooth or flattened philtrum, thin upper lip)

and central nervous system abnormalities.

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INTRODUCTION Use of alcohol, illicit drugs and other psychoactive substances during pregnancy is common and can lead to multiple health and social problems for both mother and child. Use of alcohol during pregnancy can lead to fetal alcohol syndrome and other harms such as spontaneous abortion, stillbirth, low birthweight, prematurity and birth defects. Use of alcohol and other drugs can also severely impair an individual’s functioning as a parent, spouse or partner, and trigger gender-based and domestic violence, thus significantly affecting the physical, mental and emotional development of children. Injecting drug use is also associated with an increased risk of transmission of HIV and viral hepatitis to pregnant women and their infants.

Alcohol and other substance use by expectant mothers and other people living in their households is not only detrimental to maternal and child health – the topics of UN Millennium Development Goals 2, 4, 5 and 6 – but can also undermine the social and health gains achieved in many low- and middle-income countries. Pregnancy may be an opportunity for women, their partners and other people living in their household to change their patterns of alcohol and other substance use. Health workers providing care for women with substance use disorders during pregnancy need to understand the complexity of the woman’s social, mental and physical problems and to provide the right advice and support throughout pregnancy and the postpartum period.

WHY THESE GUIDELINES WERE DEVELOPED These guidelines have been developed to enable professionals to assist pregnant women who use alcohol or drugs or with substance use disorders to achieve healthy outcomes. There are currently no global guidelines providing evidence-based recommendations for identifying and managing substance use and substance use disorders in pregnancy. While several high-income countries have developed national guidelines covering these issues, low- and middle-income countries currently lack such guidance.

The project was initiated in response to requests from organizations, institutions and individuals for technical guidance on the identification and management of alcohol and other substance use disorders in pregnant women. These recommendations have been developed in tandem with the WHO recommendations for the prevention and management of tobacco use and second-hand smoke exposure in pregnancy.

These guidelines are also a response to Resolution 63.13 of the World Health Assembly (outlining and endorsing a Global Strategy to Reduce the Harmful Use of Alcohol), and the Political Declaration and Plan of Action on International Cooperation Towards an Integrated and Balanced Strategy to Counter the World Drug Problem (agreed at the High Level Segment of the 52nd Session of the Commission of Narcotic Drugs; CND).

Development of these guidelines is part of a range of activities carried out by the WHO Department of Mental Health and Substance Abuse (MSD). These include the development and dissemination of the ASSIST tool for screening for substance use in health-care settings; the ASSIST-linked brief intervention manual; the WHO mhGAP intervention package for management of priority mental health and behavioural disorders; the WHO guidelines for the psychosocially assisted pharmacological treatment of opioid dependence; the UNODC/WHO discussion paper on the principles of drug dependence treatment; and the UNODC/WHO programme on drug dependence treatment and care.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

EXISTING RELEVANT GUIDELINES ON RELATED PROBLEMS AND DISORDERS

The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST): Manual for use in primary care http://whqlibdoc.who.int/publications/2010/9789241599382_eng.pdf

Brief Intervention. The ASSIST-linked brief intervention for hazardous or harmful substance use. Manual for use in primary care. http://whqlibdoc.who.int/publications/2010/9789241599399_eng.pdf

AUDIT: Alcohol Use Disorders Identification Test: Guidelines for use in primary care* http://whqlibdoc.who.int/hq/2001/WHO_MSD_MSB_01.6a.pdf

Brief Intervention for Hazardous and Harmful Drinking: Manual for use in primary care* http://whqlibdoc.who.int/hq/2001/WHO_MSD_MSB_01.6b.pdf

Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence http://www.who.int/substance_abuse/publications/opioid_dependence_guidelines.pdf

mhGAP – Intervention Guide http://www.who.int/mental_health/publications/mhGAP_intervention_guide/en/ Contains recommendations on the management of alcohol and drug use disorders in non-psychiatric settings which are applicable to antenatal services.

Working with Individuals, Families and Communities to Improve Maternal and Newborn Health http://whqlibdoc.who.int/hq/2010/WHO_MPS_09.04_eng.pdf

Pregnancy, Childbirth, Postpartum and Newborn Care: A guide for essential practice http://www.who.int/maternal_child_adolescent/documents/924159084x/en/index.html

PMTCT Strategic Vision 2010–2015 http://whqlibdoc.who.int/publications/2010/9789241599030_eng.pdf Contains recommendations on the prevention of mother-to-child transmission of HIV in women who inject drugs.

Guidelines on HIV and Infant Feeding 2010 http://www.who.int/maternal_child_adolescent/documents/9789241599535/en/index.html Contains recommendations on postnatal care in HIV-positive women relevant to intravenous drug users.

Acceptable Medical Reasons for Use of Breast-milk Substitutes http://whqlibdoc.who.int/hq/2009/WHO_FCH_CAH_09.01_eng.pdf Contains recommendations on circumstances when breastfeeding is not advised.

* Although these guidelines were published in 2001, prior to establishment of current WHO guideline methodology requiring systematic review of the evidence, the effectiveness of brief interventions for hazardous and harmful alcohol drinking has been confirmed in recent WHO guidelines approved by the WHO Guideline Review Committee, including the mhGAP Intervention Guide in the above table.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

WHO SHOULD USE THESE GUIDELINES These guidelines have been primarily written for health-care providers managing women from conception to birth and the postnatal period, and their infants.

OBJECTIVES AND SCOPE OF THE DOCUMENT These guidelines aim to provide evidence-based technical advice to health-care providers on identifying and managing substance use in pregnant women, which enables users to apply the scientific principles of a public health approach in their own countries. An equally important objective is to enable pregnant women to make healthy decisions about alcohol and other substance use in the context of pregnancy, breastfeeding and the postnatal period.

After a broad search of the needs of this population and challenges faced by health-care providers working with pregnant women with substance use disorders, it was agreed by the Guideline Development Group (GDG) that these guidelines should focus on six areas:

1. screening and brief intervention

2. psychosocial interventions

3. detoxification

4. dependence management

5. infant feeding

6. management of neonatal withdrawal.

INDIVIDUALS AND PARTNERS INVOLVED IN DEVELOPMENT OF THE GUIDELINES WHO steering group An internal steering group was drawn from the WHO departments of Mental Health and Substance Abuse, Reproductive Health and Research, Gender Equity and Human Rights, and the Tobacco Free Initiative. The full list of names is provided in Annex 4.

Guideline Development Group The Guideline Development Group was made up of people with content expertise, relevant experience in health care in low- and middle-income countries and expertise in evidence-based guideline methodology. The Guideline Development Group selection also ensured gender balance and regional diversity. Members have been drawn from all WHO regions.

Consultants with expertise in evidence search and GRADE methodology supported the Guideline Development Group. The full list of the Guideline Development Group members and consultants along with their expertise, affiliations and geographical base is provided in Annex 4.

External review group External reviewers were drawn from end-users, agencies and partners working in the subject area of the guidelines. Their names, affiliations, areas of interest and geographical base are given in Annex 4.

External reviewers were asked to evaluate and comment at different stages of development of the guidelines. Some members of the external review group attended the initial scoping meeting and the final recommendation decision meeting as ‘special invitees’ where they acted as observers providing comments but had no

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

involvement in decision-making. They reviewed the scoping questions, outcomes of interest, evidence profiles, and the final guideline document. Reviewer response was compiled and comments used to refine the scope of the guidelines, the outcomes of interest, and the final recommendations.

Management of conflicts of interest All Guideline Development Group members, external reviewers and consultants completed the WHO declaration of interest forms. Several Guideline Development Group members declared academic and financial interests. These were then reviewed by the secretariat for potential conflicts of interest (see summary in Annex 5). Hendree Jones had received funding from Reckitt Benckiser, a manufacturer of buprenorphine. She received small honoraria for presenting at conferences, and received free buprenorphine for use in her clinical trials. Gabriele Fischer received a small amount of consultancy funding from Reckitt Benckiser, a manufacturer of buprenorphine, Mundipharma, a manufacturer of morphine, and Lannacher, a manufacturer of psychiatric medication. Anju Dhawan had received funding for a clinical trial from Rusan Pharmaceuticals, a manufacturer of both methadone and buprenorphine. As these members are well-recognized researchers and clinicians in this field and, taking into consideration the level of funding, it was agreed that they should not be excluded from the GDG but that these potential competing interests should be managed by excluding them from active discussion and decision-making related to the pharmaceuticals produced by companies from which they had received funds. Both meetings began with an open declaration of interests. It was made clear that those Guideline Development Group members with pharmaceutical industry funding could not participate in discussions on questions related to the medications associated with such companies.

HOW THE GUIDELINES WERE DEVELOPED The development of these guidelines began in mid 2012 as a collaborative effort between the WHO departments of Mental Health and Substance Abuse and the Tobacco Free Initiative with production of the guidelines proposal, a virtual meeting of the Guideline Development Group (GDG), and subsequent approval of the guidelines proposal by the WHO Guideline Review Committee. The GDG has conferred through teleconferences and virtual meetings, as well as at two face-to-face meetings. At the first meeting, held at the WHO offices in Washington DC, USA (29 January to 1 February 2013), the evidence for the harms of different patterns of alcohol and drug use in pregnancy was reviewed, and the scope and areas of evidence retrieval were established. At the second and final meeting, held at the WHO headquarters in Geneva, Switzerland (11–13 September 2013), the evidence retrieved was presented using evidence profiles and GRADE tables (see annex), and final recommendations were formulated. These were then reviewed by the external review group and finalized by the GDG using online discussions and a final teleconference.

EVIDENCE SEARCH AND RETRIEVAL The six focus areas agreed upon by the GDG were used to generate appropriate evidence questions to govern systematic searches for evidence. In April 2013, the GDG were asked to select and rate outcomes on a scale from 1 to 9, where 9 is most important (critical) and 1 is least important. Means were calculated for each outcome and the top seven outcomes used for the evidence review, except where the GDG agreed that more than seven outcomes were necessary (see evidence profiles and GRADE tables in Annex 1).

Four investigators (two consultants, two WHO interns) managed the evidence retrieval. The database search was conducted by Tomas Allen, WHO information specialist, who searched multiple databases: PubMed, EmBase, CENTRAL, Psychinfo, CINAHL (see Annex 2 for details of MeSH terms, etc). Essentially, the search strategy was to identify all randomized controlled trials (RCTs) and systematic reviews conducted in pregnant women using alcohol or drugs, and then to allocate these to the different areas of evidence retrieval. The search identified approximately 6000 articles, which were screened on the basis of title and abstract, then on the full paper (see Figure 1, and Tables 1 & 2, below). Where a recent Cochrane review or other high-quality systematic review was identified, this was used as the evidence base and results presented in GRADE tables. Where a Cochrane review or equivalent was not available, RCTs were identified and a systematic review

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

TABLE 1. NUMBER OF RECORDS BY DATABASE SEARCHED

Database Number of records

PubMed 1479

EmBase 3614

CENTRAL 84

PsychInfo 512

CINAHL 754

TOTAL 6443

Deduplicated 5632

TABLE 2. NUMBER OF ARTICLES AND DISTINCT RCTs BY EVIDENCE RETRIEVAL AREA

Intervention Articles RCTs

Screening and brief intervention 17 10

Psychosocial interventions 30 15

Detoxification 0 0

Dependence management 36 4

Lactation 0 0

Management of the infant 5 4

Unclassified 5 n/a

Total 93 33

FIGURE 1: SCREENING OF RECORDS FROM THE LITERATURE SEARCH TO ELIGIBLE ARTICLES

FULL TEXT OBTAINED

172

ELIGIBLE ARTICLES

SCREENED

5632

conducted using Cochrane methods, including meta-analysis, where appropriate, to generate results that were then evaluated using GRADE.

To supplement gaps in the RCT literature, the other studies identified in the systematic literature search were also allocated to each area of evidence retrieval used to provide supplementary information in the GRADE profiles. There were 598 such articles that were not RCTs but still considered relevant to the key issues covered by the guidelines.

A values and preferences survey was conducted over three weeks in August 2013. Respondents – many of them health-care workers or pregnant (or recently pregnant) women – were asked to rate their preference for each draft recommendation and to provide comments on how it might affect them. At the final face-to-face guideline development group meeting, held in September 2013, an analysis of the responses was presented during discussion of each recommendation. These results were used by the GDG to weigh values and preferences when setting the strength of each recommendation. The form can be accessed at: https://sryyz. enketo.formhub.org/webform

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

EVIDENCE TO RECOMMENDATIONS The GRADE system for assessing quality of evidence and using evidence to inform decisions was applied by the GDG when drafting the final recommendations. For each of the six areas of scoping focus, an evidence profile was provided summarizing the evidence retrieved, including evidence on values, preferences, benefits, harms and feasibility. Wherever possible, the evidence retrieved was evaluated using GRADE and GRADE tables were provided. Evidence of effectiveness was rated as high, moderate, low or very low depending on the certainty of effect measured in the studies evaluated. For many of the EVIDENCE questions the evidence was either lacking or very limited, leading to a rating of very low quality evidence. The GDG recognized that extensive research needs to be done to provide a solid evidence base for management of pregnant women with substance use and substance use disorders. A decision table was used by the Guideline Development Group to assess and agree on the quality of evidence and certainty about harms and benefits, values and preferences, feasibility and resource implications (see annex for details of each decision, presented in Evidence Profiles 1–6).

The strength of the recommendation was set as either:

Decisions were usually made by consensus but where there was disagreement, the GDG members voted and a two-thirds majority was required for a decision to be carried. Where a two-thirds majority was not achieved initially, it was agreed that the recommendation should be reworded and a vote taken again. This was necessary in only one instance – for recommendation 8, concerning management of stimulant withdrawal.

RECOMMENDATIONS Following an extensive review of the evidence in each of the six scoping areas, the GDG agreed on the following recommendations for the identification and management of substance use and substance use disorders during pregnancy. Each recommendation is followed by remarks clarifying contextual issues and relevant aspects of management. During development of the recommendations, the GDG identified considerable research gaps and agreed on a list of research priorities and questions, which are listed after the recommendations.

Overarching principles It was noted by the Guideline Development Group that certain principles apply to all the recommendations described below. These overarching principles are proposed to provide guidance in the process of planning, implementing and evaluating the most suitable and relevant recommendations according to the national contexts and available resources.

This effort requires a multifaceted approach with multidisciplinary actions, including the right to accurate information about the risks of alcohol and drug use in pregnancy, a health-care system that implements

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

prevention strategies and supports healthy choices about substance use among women of childbearing age, and health promotion efforts encouraging a healthy home and social environment, supporting pregnant women and their partners in making healthy choices about their substance use and protecting from pressures to drink alcohol or use drugs.

Health-care services should be able to identify and manage substance use and substance use disorders in pregnancy. Substance use disorders should be identified by the health-care system at the earliest opportunity and quality, affordable and accessible treatment offered. Specialized services for women with substance use disorders should be recognized as an important component of the health system and need to be available proportional to the clinical need. Health-care services for women with substance use disorders should take into consideration the childcare needs of women when considering the accessibility of their services. Confidentiality, a fundamental right of every health-care user, is also affected by the organization of services.

III. Respecting patient autonomy. The autonomy of pregnant and breastfeeding women should always be respected; women with substance use disorders need to be fully informed about the risks and benefits, for themselves and for their fetuses or infants, of available treatment options, when making decisions about their health care.

Patient autonomy and patient-centred care are crucial components of health-care services for pregnant women. Treatment decisions should be based on accepted principles of medical-care ethics, respecting a women’s autonomy in decisions related to her care and the health of her fetus, and her right to privacy and confidentiality when discussing treatment options. It is essential to provide clear, accurate and consistent information to pregnant and breastfeeding women about the risks of alcohol and drug use, and all women with substance use disorders should have access to information about effective contraception.

Comprehensive services for pregnant and breastfeeding women include a range of gender-sensitive prevention and treatment interventions that can respond to multiple needs, including childcare needs, comorbid mental and concurrent medical conditions, bloodborne and other infectious diseases, poor diet and psychosocial problems such as relationships with a partner/other people living in the same household, homelessness, poverty and violence. Comprehensive services that offer a continuity of care are generally much easier for vulnerable groups to access.

V. Safeguarding against discrimination and stigmatization. Prevention and treatment interventions should be provided to pregnant and breastfeeding women in ways that prevent stigmatization, discrimination, marginalization, and promote family, community and social support as well as social inclusion by fostering strong links with available childcare, employment, education, housing and other relevant services.

Health-care providers should seek to establish a clinician-patient relationship without discrimination or stigmatization. All important information about the risks of substance use and the benefits of treatment should be communicated in a non-judgemental, respectful, non-stigmatizing and empathic manner, sensitive to age, culture and language differences. All important information has to be provided verbally, as well as in writing, at reading and comprehension levels that are congruent with the patient’s level of literacy. Health-care providers should respond to disclosure of private and distressing information (e.g. gender-based violence or self-harm) with sensitivity.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Screening and brief interventions for hazardous and harmful substance use during pregnancy (Evidence Profile 1: see Annex 1, page 22) Much of the evidence underlying the effectiveness of screening and brief interventions during pregnancy comes from a period when reporting standards and measures of bias were not in standard use, hence the evidence quality is graded as low or very low. However, the evidence retrieved indicated that being asked about alcohol and other substance use in a detailed and comprehensive manner may increase a woman’s awareness of the risks associated with alcohol and drug use and may function to modify her behaviour.

A brief motivational intervention has been found to reduce the number of drinks and the number of heavy drinking days during the postpartum period. Pregnant women with higher levels of alcohol use may reduce their alcohol use following a brief intervention that includes their partner.

Pregnant adolescent girls with a substance use disorder have been shown to reduce their substance use after a single-session, standardized brief intervention. Full details of studies evaluated, harms and benefits, feasibility and resource use are provided in Annex 1, page 22.

RECOMMENDATION 

Health-care providers should ask all pregnant women about their use of alcohol and other substances (past and present) as early as possible in the pregnancy and at every antenatal visit.

Strength of recommendation: Strong Quality of evidence: Low

Remarks: • Asking at every visit is important as some women are more likely to report sensitive information only after a trusting

relationship has been solidly established. • Pregnant women should be advised of the potential health risks to themselves and to their babies posed by alcohol

and drug use. • Validated screening instruments for alcohol and other substance use and use disorders are available (see Annex 3). • Health-care providers should be prepared to intervene or refer all pregnant women who are identified as using

alcohol and/or drugs (past and present). • It was decided that despite the low quality of evidence of effect, the benefit – potential reduction of alcohol and

substance use – outweighed any potential harms of a brief psychosocial intervention, which were considered minimal. Therefore the balance of benefits versus harms was clearly positive despite uncertainty about the degree of benefit. In addition, the burden of implementation was minimal.

RECOMMENDATION 2

Health-care providers should offer a brief intervention to all pregnant women using alcohol or drugs.

Strength of recommendation: Strong Quality of evidence: Low

Remarks: • Brief intervention is a structured therapy of short duration (typically 5–30 minutes) offered with the aim of assisting

an individual to cease or reduce the use of a psychoactive substance. It is designed in particular for general practitioners and other primary health-care workers.

• Health-care providers should be given appropriate training and resource materials. • The brief intervention should be individualized, and include feedback and advice on ceasing or reducing alcohol

and other substance use during pregnancy. There may need to be follow-up with the patient, with the possibility of referral to treatment for those patients who are unable to reduce or eliminate such use.

• The approach/attitude of health-care providers is an important contributor to the effectiveness of brief interventions. • As for recommendation 1, it was decided that, despite the low quality of evidence of effectiveness, this should be

a strong recommendation because the potential benefit – reduction of alcohol and/other substance use – likely outweighs any potential harms of a brief psychosocial intervention which were considered minimal. Therefore the balance of benefits versus harms was clearly positive, although there was uncertainty about the degree of benefit. In addition the burden of implementation was minimal.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Psychosocial interventions for substance use disorders in pregnancy (Evidence Profile 2: see Annex 1, page 44)

The concept of “substance use disorders” includes dependence syndrome and harmful use of psychoactive substances such as alcohol, cannabis, amphetamine-type stimulants (ATS), cocaine, opioids and benzodiazepines. The evidence review sought trials evaluating the effectiveness of psychosocial interventions, including trials of cognitive behavioural therapy (CBT), motivational interviewing (MI), contingency management (CM), and home visits. All the trials were conducted in services specializing in the management of substance use in pregnancy. “Treatment-as-usual” in this context is best considered a form of unstructured psychosocial intervention rather than the absence of psychosocial support.

o Findings suggest that CBT may be superior to treatment-as-usual in terms of treatment retention, reductions in risky sex and needle use, and occurrence of preterm birth.

o Findings support the superiority of contingency management (CM) to treatment-as-usual in terms of retention in treatment, percentage of negative urines, and weeks of continuous cocaine abstinence.

o Findings do not support the superiority of MI to treatment-as-usual or educational control, with similar results for maternal retention in treatment and maternal substance abuse.

o A review of randomized trials suggests that increased home visits following delivery are not effective in reducing maternal substance use, or alcohol use, nor in improving adherence to treatment of substance use disorders.

RECOMMENDATION 3

Health-care providers managing pregnant or postpartum women with alcohol or other substance use disorders should offer comprehensive assessment and individualized care.

Strength of recommendation: Conditional Quality of evidence: Very low

Remarks: • A comprehensive assessment of women using alcohol or drugs in pregnancy and the postpartum period includes

an assessment of patterns of substance use, medical or psychiatric comorbidity, family context, as well as social problems.

• Individualized care involves selecting appropriate psychosocial interventions of different intensity based on the particular needs of the pregnant women and the resources available. Psychosocial interventions include a number of psychological treatments and social supports, ranging from lesser to higher intensity. The psychosocial treatment and support referred to in this section is a more intensive set of interventions typically delivered by people with specific training in the management of substance use disorders, and usually includes repeated contact with the patient. The kinds of specific psychological techniques considered in this category include cognitive behavioural therapy, contingency management and motivational interviewing/enhancement. The kinds of social support referred to in this section include assistance with accommodation, vocational training, parenting training, life-skills training, legal advice, home-visiting and outreach.

• Despite the benefits of psychosocial treatment outweighing the harms, this recommendation was considered to be conditional given the absence of strong evidence and the potential resource implications.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Detoxification or quitting programmes for alcohol and other substance dependence in pregnancy (Evidence Profile 3: see Annex 1, page 93) A withdrawal syndrome requiring pharmacological treatment in pregnancy can be said to occur for three substances: benzodiazepines, alcohol, and opioids. The withdrawal syndrome associated with the cessation of other substances (such as psychostimulants) has not been considered to justify the use of psychotropic medication. For those pregnant women for whom medication-assisted withdrawal is successful, there does not appear to be any evidence of significant fetal distress during detoxification, no increased risk of fetal demise or premature delivery.

For opioid dependence, in addition to recommending cessation of opioid use, there is the option of prescribing long-acting opioids such as methadone and buprenorphine to maintain stable opioid levels (see also Evidence Profile 4 in Annex 1). Although this treatment approach includes a risk of neonatal opioid withdrawal symptoms, opioids are essentially non-toxic at stable levels. Cessation of opioids, on the other hand carries a higher risk of relapse to unstable patterns of short-acting opioid use (such as heroin). The decision, therefore, is between opioid maintenance treatment approach with a known risk of neonatal withdrawal but a low risk of relapse, and opioid detoxification, which, if successful, carries no risk of neonatal withdrawal, but, if unsuccessful, has a high risk of adverse neonatal outcomes, including neonatal opioid withdrawal and intrauterine growth retardation (IUGR) and also adverse maternal outcomes such as overdose.

For dependence on other substances, there was considered to be no feasible maintenance treatment option.

RECOMMENDATION 4

Health-care providers should, at the earliest opportunity, advise pregnant women dependent on alcohol or drugs to cease their alcohol or drug use and offer, or refer to, detoxification services under medical supervision where necessary and applicable.

Strength of recommendation: Strong Quality of evidence: Very low

Remarks: • Pregnant women dependent on alcohol or drugs who agree to undergo detoxification should be offered the

supported withdrawal from substance use in an inpatient or hospital facility, if medically indicated. • Detoxification can be undertaken at any stage in pregnancy, but at no stage should antagonists (such as naloxone,

or naltrexone – in the case of opioid withdrawal) be used to accelerate the detoxification process. • Equal attention should be paid to the health of mother and fetus during detoxification and treatment adjusted

accordingly. • The exceptions to this recommendation are opioid and benzodiazepine dependence, which are covered by

recommendations 5 and 6 separately. • It was decided that this recommendation should be strong, despite the very low quality of evidence of the

effectiveness of the health-care intervention because there is clear evidence of harm to the fetus of ongoing maternal substance use, and the benefit to both mother and fetus of ceasing alcohol and/or substance use under medical supervision strongly outweighs any potential harms.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

RECOMMENDATION 5

Pregnant women dependent on opioids should be encouraged to use opioid maintenance treatment whenever available rather than to attempt opioid detoxification.

Strength of recommendation: Strong Quality of evidence: Very low

Remarks: • Opioid maintenance treatment in this context refers to either methadone maintenance treatment or buprenorphine

maintenance treatment. • Pregnant patients with opioid dependence who wish to undergo detoxification should be advised that relapse to

opioid use is more likely following medication-assisted withdrawal than while undertaking opioid maintenance treatment.

• Such medication-assisted withdrawal from opioids should be attempted only in an inpatient unit, using a gradual reduction in methadone or buprenorphine doses. Inpatient care should also be considered for the initiation and optimization of maintenance treatment.

• Psychosocial treatment should be an integral component of such treatment. • Pregnant women who fail to complete medication-assisted withdrawal should be offered opioid agonist

pharmacotherapy. • It was decided that this recommendation should be strong despite the low quality of evidence of effectiveness from

randomized controlled trials, as the rate of relapse to opioid use following detoxification has been shown to be high and the risks of harm to both mother and fetus from failed detoxification are catastrophic compared to the very low risks of harm from opioid maintenance treatment.

RECOMMENDATION 6

Pregnant women with benzodiazepine dependence should undergo a gradual dose reduction, using long-acting benzodiazepines.

Strength of recommendation: Strong Quality of evidence: Very low

Remarks: • Long-acting benzodiazepines should only be used for as short a time as is medically feasible in managing

benzodiazepine withdrawal. • Psychosocial interventions should be offered throughout the period of benzodiazepine withdrawal. • Inpatient care should be considered in the withdrawal management of pregnant women with benzodiazepine

dependence. • It was decided that this recommendation should be strong despite the very low quality of evidence of effectiveness

because ongoing benzodiazepine use in pregnancy is associated with significant risk of harm. At the same time, abrupt cessation of benzodiazepines can result in a severe withdrawal syndrome including seizures and psychosis. This leaves gradual reduction as the only practicable alternative. Significant clinical experience indicates that this approach is feasible and safe. Hence the GDG was in agreement that the benefits of gradual dose reduction outweigh the harms of both ongoing use and abrupt cessation.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

RECOMMENDATION 7

Pregnant women who develop withdrawal symptoms following the cessation of alcohol consumption should be managed with the short-term use of a long-acting benzodiazepine.

Strength of recommendation: Strong Quality of evidence: Very low

Remarks: • Management of alcohol withdrawal usually also includes administration of thiamine. • Alcohol withdrawal management may be facilitated by the use of an alcohol-withdrawal scale such as the CIWA-Ar. • Inpatient care should be considered in the withdrawal management of pregnant women with alcohol dependence. • Alcohol withdrawal can be a severe and even life-threatening condition, provoking seizures and delirium. Evidence

from non-pregnant populations has demonstrated the effectiveness of long-acting benzodiazepines for preventing seizures and delirium in alcohol withdrawal. Given the severity of alcohol withdrawal, and the lack of significant harm from short-term benzodiazepine use, and the evidence supporting the use of benzodiazepines in the management of alcohol withdrawal in the general population, the GDG decided that this recommendation should be strong despite the low quality of evidence in pregnant women.

RECOMMENDATION 8

In withdrawal management for pregnant women with stimulant dependence, psychopharmacological medications may be useful to assist with symptoms of psychiatric disorders but are not routinely required.

Strength of recommendation: Strong Quality of evidence: Very low

Remarks: • Except for the management of acute intoxication, withdrawal management in amphetamine-type stimulants (ATS)

dependence or cocaine dependence does not include psychopharmacological medications as a primary approach to treatment in pregnant patients. There is no evidence that medication-assisted withdrawal would benefit pregnant women with these respective disorders.

• Inpatient care should be considered in the withdrawal management of pregnant women with stimulant dependence. • It was decided that this recommendation should be strong despite the very low quality of evidence because the

harms to mother and fetus of ongoing use of psychostimulants have been shown to be high. The risks of providing short-term appropriate non-teratogenic medications for short-term management of psychologically distressing symptoms in pregnancy are very low. Therefore, the potential benefits of this approach strongly outweigh the harms of providing psychopharmacological treatment of symptoms, if required, during psychostimulant withdrawal.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Pharmacological treatment (maintenance and relapse prevention) for alcohol and other substance dependence in pregnancy (Evidence Profile 4: see Annex 1, page 100) Systematic reviews of psychopharmacological treatments, methadone versus buprenorphine and methadone compared to slow-release morphine for pregnant women with substance use disorders were performed and the evidence of effect evaluated (see GRADE tables and summary of findings tables in Annex 1 for full details). Findings in brief:

o Pharmacotherapy has been shown to be successful in the treatment of opioid dependence and benzodiazepine dependence. Methadone and buprenorphine have similar efficacy in the management of opioid dependence. While methadone may result in better maternal retention in treatment, buprenorphine may result in milder NAS, less preterm delivery and higher birthweight.

o Combining psychosocial interventions with pharmacotherapy has been shown to be superior to pharmacotherapy alone.

o No evidence was found on the use of medications for relapse prevention for alcohol dependence in pregnancy (acamprosate, disulfiram, nalmefene, naltrexone).

o No RCT evidence was found on the use of naltrexone in relapse prevention from opioid dependence in pregnancy.

o No evidence was found on the use of benzodiazepine maintenance for benzodiazepine dependence in pregnancy.

RECOMMENDATION 9

Pharmacotherapy is not recommended for routine treatment of dependence on amphetamine-type stimulants, cannabis, cocaine or volatile agents in pregnant patients.

Strength of recommendation: Conditional Quality of evidence: Very low

Remarks: • For pregnant patients who use cannabis, amphetamine-type stimulants, cocaine, and volatile agents, the focus of

treatment should be on psychosocial interventions. • The recommendation was considered conditional given the complete lack of research on this issue.

RECOMMENDATION 

Given that the safety and efficacy of medications for the treatment of alcohol dependence has not been established in pregnancy, an individual risk benefit analysis should be conducted for each woman.

Strength of recommendation: Conditional Quality of evidence: Very low

Remarks: • Pregnant patients with alcohol dependence should be offered psychosocial interventions. • The recommendation was considered conditional given the complete lack of research on this issue.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

RECOMMENDATION 

Pregnant patients with opioid dependence should be advised to continue or commence opioid maintenance therapy with either methadone or buprenorphine.

Strength of recommendation: Strong Quality of evidence: Very low

Remarks: • Pregnant patients with opioid dependence should be encouraged to commence opioid agonist pharmacotherapy,

which should be combined with psychosocial interventions. • Opioid-dependent pregnant women who are already taking opioid maintenance therapy with methadone should

not be advised to switch to buprenorphine due to the risk of opioid withdrawal. Pregnant opioid-dependent women taking buprenorphine should not be advised to switch to methadone unless they are not responding well to their current treatment.

• In opioid-dependent pregnant women, the buprenorphine mono formulation should be used in preference to the buprenorphine/naloxone formulation.

• Regardless of the choice of medication, psychosocial interventions should be an integral component of treatment. • Opioid-dependent pregnant patients who wish to receive opioid antagonist pharmacotherapy should be discouraged

from such a choice. • It was decided that this recommendation should be strong despite the low quality of evidence as the rate of relapse

to opioid use following detoxification is high and the risks of harm from failed detoxification are catastrophic compared to the small risks of harm from opioid maintenance treatment.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Breastfeeding and maternal substance use (Evidence Profile 5: see Annex 1, page 122) Enhanced maternal-infant attachment through breastfeeding is especially important, particularly for women feeling guilty about their prenatal substance use and those who lack self-confidence in parenting skills. Breastfeeding and/or breast milk may reduce the incidence and/or severity of neonatal withdrawal syndrome in opioid-exposed infants.

Evidence of decreased stress response and increased vagal tone, indicating better autonomic regulation, in lactating compared to non-lactating women is salient for drug-dependent women. Stress can be a major factor in the development of psychiatric symptoms, and has been linked to relapse to substance use. Alcohol use, binge drinking, tobacco and cannabis use rates rebound substantially in the postpartum period compared with use during pregnancy. Depression correlates with substance use, and new mothers with postpartum depression may be at high risk for substance use or return to substance use. Maternal psychopathology is more common in substance-dependent women than in the general population, and is not infrequently related to poor judgment, enhancing the physical risk to the breastfed infant. Maternal somnolence, lack of adequate sleep-wake cycling, or decreased reaction times due to alcohol or drug use may increase the risk of infant injury injury, including smothering the child by falling asleep while breastfeeding.

RECOMMENDATION 

A. Mothers with substance use disorders should be encouraged to breastfeed unless the risks clearly outweigh the benefits.

B. Breastfeeding women using alcohol or drugs should be advised and supported to cease alcohol or drug use; however, substance use is not necessarily a contraindication to breastfeeding.

Strength of recommendation: Conditional Quality of evidence: Low

Remarks: • A risk assessment should take into account the risks of exposure to alcohol and drugs in breast milk, HIV status, the

specific pattern of substance use in each case, the availability of safe and affordable breast milk substitutes, as well as access to clean water, sterilizing equipment, and the age of the infant/child. Heavy daily alcohol consumption, such as in alcohol dependence, would constitute high risk to the infant, for example, and in the presence of safe breast milk alternatives, it would be preferable not to breastfeed.

• The message to breastfeeding women who have used alcohol and drugs to cease using alcohol and drugs while breastfeeding should be given in such a way that it does not undermine the potential benefits of breastfeeding.

• It is possible to reduce the risk of exposure through breastfeeding by altering the timing of breastfeeding, or by the use of temporary alternatives, such as stored (frozen) breast milk or breast milk substitutes where they are available and can be safely used. Women who use alcohol intermittently should be discouraged from breastfeeding for 2 hours after consuming one standard drink (10 g of pure alcohol), and 4–8 hours after consuming more than one drink in a single occasion. Breastfeeding advice for women with HIV should also take into consideration the risk of HIV transmission (refer to the WHO guidelines on breastfeeding and HIV).

• Mothers of infants with a neonatal withdrawal syndrome should be offered appropriate breastfeeding information and support.

• This recommendation was considered conditional because the different values and preferences of women and the lack of strong evidence of harms of low levels of substance use in pregnancy.

RECOMMENDATION 

Skin-to-skin contact is important regardless of feeding choice and needs to be actively encouraged for a mother with a substance use disorder who is able to respond to her baby’s needs.

Strength of recommendation: Strong Quality of evidence: Low

Remarks: • It was decided that the recommendation should be strong despite the very low quality evidence as the risk of harm

is minimal, it consumes no resources, the values and preferences were in favour of the recommendation, and there was considered to be certainty about the balance between benefits and harms.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

RECOMMENDATION 

Mothers who are stable on opioid maintenance treatment with either methadone or buprenorphine should be encouraged to breastfeed unless the risks clearly outweigh the benefits.

Strength of recommendation: Strong Quality of evidence: Low

Remarks: • Women prescribed opioids such as methadone and buprenorphine and wishing to stop breastfeeding may wean

their children off breast milk gradually to reduce the risk of developing withdrawal symptoms. • It was decided that the recommendation should be strong, as, despite the low quality of evidence of effect, it was

considered highly likely that the benefit of avoiding withdrawal symptoms in the infant strongly outweighed any potential harms. The values and preferences expressed by end-users surveyed were strongly in favour of the recommendation and there was certainty about the balance between benefits and resources being consumed.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Management of infants exposed to alcohol and other psychoactive substances (Evidence Profile 6: see Annex 1, page 135)

Note: The term “neonatal withdrawal syndrome” is used here to remain consistent with WHO nomenclature, but the term “neonatal abstinence syndrome (NAS)” is commonly used with the same meaning.

The small study size and risk of bias in the studies evaluated mean that the evidence of treatment effectiveness is very uncertain. Protocols for the management of neonatal withdrawal syndrome have changed considerably over the last 40+ years. Initial treatment guidelines were weight-based, and tables for treatment with phenobarbital and paregoric were published. Current treatment involves use of an opioid such as morphine sulfate or tincture of opium, or a sedative, typically phenobarbital, with infrequent use of a benzodiazepine. Systems for scoring withdrawal are usually used to guide treatment initiation, maintenance and weaning. Because there is neither a uniform assessment method for measuring neonatal withdrawal nor an established treatment protocol, and health-care practices worldwide are variable, it is difficult to state with any precision how neonatal withdrawal is treated across the globe.

RECOMMENDATION 

Health-care facilities providing obstetric care should have a protocol in place for identifying, assessing, monitoring and intervening, using non-pharmacological and pharmacological methods, for neonates prenatally exposed to opioids.

Strength of recommendation: Strong Quality of evidence: Low

Remarks: • Evidence of a dose-response relationship between opioid maintenance treatment and neonatal withdrawal

syndrome has been inconsistent, which implies that all infants should be assessed. • Infants exposed to opioids during pregnancy should remain in the hospital at least 4–7 days following birth and

be monitored for neonatal withdrawal symptoms using a validated assessment instrument, which should be first administered 2 hours after birth and then every 4 hours thereafter.

• Non-pharmacological interventions including low lights, quiet environments, swaddling and skin-to-skin contact should be used with all neonates prenatally exposed to alcohol and drugs.

• It was decided that the recommendation should be strong despite the low quality of evidence of effect, as the GDG agreed that the benefits of such an approach strongly outweighed any potential harms. The values and preferences of end-users were in favour of the recommendation, and there was certainty that while resources would be consumed, the benefits strongly outweighed costs. There was a high value placed on identifying preventable suffering in affected neonates.

RECOMMENDATION 

An opioid should be used as initial treatment for an infant with neonatal opioid withdrawal syndrome if required.

Strength of recommendation: Strong Quality of evidence: Very low

Remarks: • Prolonged treatment of neonatal opioid withdrawal syndrome with opioids is generally not necessary and aiming for

shorter treatment is preferable. • Phenobarbital can be considered as an additional therapy if there has been concurrent use of other drugs in

pregnancy, particularly benzodiazepines, and if symptoms of neonatal opioid withdrawal are not adequately suppressed by an opioid alone. If opioids are unavailable, phenobarbital can be used as an alternative therapy.

• Infants with signs of a neonatal withdrawal syndrome in the absence of known maternal opioid use should be fully assessed for possible benzodiazepine, sedative or alcohol exposure.

• The strong recommendation to use opioids rather than phenobarbital despite the very low quality of evidence of effectiveness was based on vast clinical experience with opioids in the management of both adult and neonatal opioid withdrawal. There has only been very limited clinical experience with phenobarbital use. In addition, the values and preferences of end-users were in favour of the recommendation, and the GDG agreed that there was certainty about the balance between benefits and resources being consumed.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

RECOMMENDATION 

If an infant has signs of a neonatal withdrawal syndrome due to withdrawal from sedatives or alcohol or the substance the infant was exposed to is unknown, then phenobarbital may be a preferable initial treatment option.

Strength of recommendation: Conditional Quality of evidence: Very low

Remarks: • Infants with signs of a neonatal withdrawal syndrome in the absence of known maternal opioid use should be fully

assessed for possible benzodiazepine, sedative, or alcohol exposure. • This recommendation was considered conditional because of the lack of high-quality evidence and the lack of

certainty of the balance between benefits and harms.

RECOMMENDATION 

All infants born to women with alcohol use disorders should be assessed for signs of fetal alcohol syndrome.

Strength of recommendation: Conditional Quality of evidence: Very low

Remarks: • Signs of fetal alcohol syndrome (FAS) include growth impairment, dysmorphic facial features (short palpebral

fissures, smooth or flattened philtrum, thin upper lip) and central nervous system abnormalities, including microcephaly.

• When assessing such infants the following information should be recorded: – birthweight and length – head circumference – dysmorphic facial features – gestation – prenatal exposure to alcohol – follow-up of infants with signs of FAS should be provided

• This recommendation was considered conditional because of the lack of high-quality evidence, and questions about the feasibility of implementation in all settings.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

RESEARCH PRIORITIES AND GAPS The extensive search for evidence of effective interventions for managing alcohol and other substance disorders in pregnancy yielded useful baseline information but also highlighted considerable gaps in knowledge. The GDG identified priority areas and questions that need to be researched in order to increase certainty about what works most effectively when managing pregnant women with these disorders.

General Remarks

The GDG calls upon the research community to:

o improve descriptions of current clinical practices – including routine clinical outcome data;

o agree on standardized outcomes;

o perform observational studies on risks and benefits of pharmacotherapies in pregnancy;

o conduct a global cohort study with standardized patient-centred outcome measurements and data repository;

o conduct qualitative research on ethical issues;

o encourage more research in low-income countries;

o evaluate the benefits of comprehensive-care models (e.g. psychosocial, spiritual support, programmes for very young children affected by maternal substance use in utero);

o provide better prevalence data on prescription opioid use.

Exposure to different drugs and medications in utero

The GDG calls upon the research community to conduct further research on the impact of substance use upon:

o maternal outcomes

o fetal outcomes

o neonatal outcomes

o long-term outcomes for the exposed children.

A number of critical questions on the optimal use of specific interventions in pregnancy remain unanswered.

Screening o what is the best way for health-care workers to screen pregnant women for alcohol and other substance

use and substance use disorders without being judgemental?

o which instruments are most effective?

o what sort of training yields effective screening?

o what is the effectiveness and cost-effectiveness of screening in routine clinical practice?

o what are the optimal screening methods – for different substances/different settings, e.g. in low-income countries? A systematic review of screening instruments currently used is needed.

o what are the optimal ways of organizing screening and brief interventions in different settings?

o what factors modify the disclosure level?

Brief interventions

Brief interventions should be clinically trialled, using standardized outcomes and trial designs to determine:

o who should be targeted?

o does this vary according to levels of substance use and type of substance use?

o what elements of the brief intervention are effective?

o what level of brief intervention is most effective?

o what categories of health-care workers can provide brief interventions effectively?

o how late can a brief intervention be given effectively?

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Psychosocial interventions o better reporting and agreement on standardized designs and outcomes is needed.

o stronger RCT evidence of effect is needed, comparing interventions with different levels of intensity and models of care with different levels of comprehensiveness, and including cost-effectiveness analyses.

Detoxification o what type of benzodiazepine reduction regimes work best for which types of patients?

o what medications are the safest and most effective for mother and fetus being withdrawn from alcohol?

o is fetal monitoring useful in determining the relative safety of detoxification during pregnancy?

o what are the best assessment tools to measure withdrawal in pregnant women?

o what are the best ways to manage withdrawal from cocaine, cannabis, ATS, alcohol or volatile solvents in pregnant women?

o how can fetal stress and potential intrauterine withdrawal be monitored when mothers are detoxified from opioids and other drugs?

Pharmacological treatment o a confidential case registry of pregnancies exposed to different substances, including psychotropic

medications used for the treatment of substance use disorders in pregnancy, could help explore the potential risks and benefits of pharmacotherapy in substance use disorders in pregnancy.

o further studies could explore the optimal method of treatment with methadone and buprenorphine in pregnancy (including further dose/response studies).

o data on the safety of pharmacotherapy for alcohol dependence in pregnancy is lacking.

Breastfeeding o effects of breastfeeding and substance use on the neonate still need to be better understood.

o how best to promote the initiation and continuation of breastfeeding in appropriate situations, such as in mothers receiving opioid maintenance treatment?

o to what degree are different drugs and medications excreted in human milk?

o what is the safety of breastfeeding while the mother is using different drugs and psychoactive medications?

o what is the effect of breastfeeding on neonatal withdrawal for mothers receiving methadone or buprenorphine treatment.

Birth and labour o what is the optimal treatment during labour, including pain management?

Management of infants exposed to alcohol or drugs in utero o what is the sensitivity and specificity of screening for FAS in the neonatal period and what are the risks

and benefits of early identification and intervention, including in low resource settings?

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

PLANS FOR DISSEMINATING, ADAPTING AND IMPLEMENTING THESE RECOMMENDATIONS These recommendations will be used to provide guidance on the identification and management of substance use and substance use disorders in pregnancy through a range of derivative publications including training materials and a manual describing how best to put these recommendations into practice. This will be widely disseminated through the WHO regional and country offices, collaborating centres, professional organizations and partner agencies.

Local adaptation/implementation of these recommendations These recommendations will be adapted for the field by developing suitable training materials in consultation with regional, national and local stakeholders. Adaptation will include translation into appropriate languages and ensuring that the interventions are acceptable in local sociocultural contexts suitable for local health systems.

EVALUATING THE IMPACT OF THESE RECOMMENDATIONS The impact of these recommendations will be measured in the following ways:

o use of maternal and child health indicators to assess improvement in maternal and child health outcomes in this population;

o measurement of inclusion of alcohol and drugs into the routine screening protocols in different countries/ guidelines;

o WHO survey of resources for the prevention and treatment of substance use disorders;

o assessment of any increase in specialized services for pregnant women with substance use disorders; and

o assessment of number of references to the WHO guidelines in the medical literature.

REVIEW BY DATE It is not expected that these recommendations will need to be reviewed until 2016. However, developments in the field will be continually monitored and should there be significant changes in practice and/or the evidence base that affect any of the recommendations, review may be undertaken earlier.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

ANNEX 1: EVIDENCE PROFILES

Evidence Profile 1: Screening and brief interventions Evidence question: In pregnant or postpartum women using alcohol or drugs, does screening for alcohol or drug use, followed by a brief intervention (or referral to treatment for those with possible dependence), result in better maternal, fetal or neonatal outcomes (see separate outcome list) than treatment-as-usual (generally the absence of screening, or brief interventions and the occasional referral to treatment)?

Selection criteria for the systematic review: Study design: RCTs

Population: Pregnant or postpartum women using alcohol or drugs (some studies included women who had alcohol or drug use only in the past; studies with up to one third of participants in this category were still eligible for inclusion).

Intervention: Systematic screening of all patients followed by a brief intervention. The Cochrane Review definition of brief intervention in the general population review was used (anything beyond simple advice or information up to 4 sessions), accepting any referral of more severe patients for treatment.

Control: Brief advice or information or no intervention.

Outcomes: The outcomes ranked as important were:

Outcome Importance (0-9)

Maternal: Identification of substance use 8.89

Maternal: Provision of intervention for substance use 8.22

Maternal: Referral to relevant treatment of substance use 8.22

Maternal: Ongoing substance use during pregnancy 7.33

Infant: Birth defects 6.00

Infant: Gestational age at delivery 6.00

Infant: Birthweight 5.89

Infant: Spontaneous abortion 5.44

Infant: Head circumference at birth 5.44

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

EVIDENCE TO RECOMMENDATIONS TABLE

Screening and brief interventions for alcohol and other substance use in pregnancy in general health-care settings

Summary of the Evidence: For GRADING of evidence see summary of findings and GRADE tables below RCT evidence – 10 studies were included in the review. Most studies were underpowered and there were differences in study design and outcome measures used which limited the capacity for meta-analysis. As a result, the level of evidence for most outcomes was low or very low. Nonetheless, there was a small but consistent effect in favour of screening and brief interventions for both alcohol and, to a lesser extent, drugs. Other evidence: • Simply asking about alcohol and other substance use may result in a change in behaviour (Goler et al., 2008; Klesges

et al., 2001; Nilsen, 2009). • Being asked about alcohol or other substance use in a detailed and comprehensive manner may increase a

woman’s awareness of actual levels of consumption and may function to modify her behavior (Delrahim-Howlett, 2011).

• A brief motivational intervention has been shown to reduce the risk of an alcohol-exposed pregnancy (Floyd, 2007). • A brief alcohol intervention has been found to reduce the number of drinks and the number of heavy drinking days

during the postpartum period (Fleming et al., 2008). Pregnant women with higher levels of alcohol use may reduce their alcohol use following a brief intervention that includes their partner (e.g., Chang, 2005).

• Pregnant adolescent girls with a substance use disorder have been shown to reduce their substance use after a single-session, standardized brief intervention (Whicher et al., 2012).

Benefits and harms

Benefits • Discussion of alcohol and illicit substance use during pregnancy is a teachable moment (Chang et al., 2000)

• Depending on the substance of use, brief interventions have been associated with these positive outcomes: – reduction in harmful consumption – reduction in risk to fetus – increase in birthweight – increase in the detection of harmful use and referral to treatment – improved general health of pregnant women – improved maternal psychological well-being – less risk of fetotoxicity – improved perinatal outcomes (e.g. reduction in preterm births, increased overall

birthweights, reduction in number of low-birthweight infants) – reductions in congenital defects or anomalies

Harms • Unpleasant symptoms associated with reduction or cessation of alcohol or substance use • Potential legal or social consequences for disclosing use • Social consequences – problematic interaction with partners/peers associated with reduction

or cessation of alcohol or substance use • Cessation may interfere with activities of daily living • Referral for cessation intervention may induce time and economic burdens

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

EVIDENCE TO RECOMMENDATIONS TABLE

Values and preferences

In favour: Pregnant women

Health-care workers (HCW)

• Value opportunity for greater personal contact and support • Value opportunity for development of coping strategies • Value positive responses from partners, family and, co-workers

• Value opportunity to identify problem early • Value opportunity to intervene • Value opportunity to improve fetal outcomes

Against: Pregnant women

Health-care workers (HCW)

• Resent stigmatization for drinking alcohol or using illicit substances during pregnancy • Resentment of questioning private life/behaviour • Resentment of consequences of referral – perceived time, logistical and financial burden

imposed • Fear of possible negative responses from health-care providers, partners, family, friends and

others in the woman’s community

• HCW may resent extra time taken to screen. Estimates of screening time vary widely given the relatively large number of screening instruments that are available [Although a little bit dated, CSAP Special Report 13: Maternal substance use assessment methods reference manual: a review of screening and clinical assessment instruments for examining maternal use of alcohol, tobacco, and other drugs Rockville, MD: US Department of Health and Human Services, Public Health Service, Substance Abuse and Mental Health Services Administration (Center for Substance Abuse Prevention, 1993) contains an excellent review in regard to all such instruments], which vary in length from 4 questions to more than 100, and which can be administered by the clinician or require paper-and-pencil administration

• HCW may resent difficulties of interaction when identifying a substance user • HCW may resent extra time and difficulty imposed by need to refer • HCW may be unwilling to provide intervention • HCW may believe they are not competent to screen: Gassman (2003) found that the biggest

barrier to the implementation of screening and brief intervention among obstetricians was self- rated competence to deliver the intervention.

Costs and feasibility

Costs and resource use

• Additional cost in terms of staff time should be minimal if integrated into routine care. However, there are no good estimates of cost for either the screening or the brief intervention, given the fact that a brief intervention may be no more than guidance provided in the office or a structured and standardized administration of a behavioural intervention by a counsellor

• Appropriate staff training requires resource use • Appropriate intensive treatment needs to be made available for referral when substance use/

alcohol use is identified and long-term, sustainable support is required. • Brief interventions have been assessed as highly cost-effective (Windsor, 1985; Ershoff, 1989;

Dornelas, 2006: Parker, 2007)

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

EVIDENCE TO RECOMMENDATIONS TABLE

Feasibility (including economic consequences)

• Self-report screening has been shown to be accurate. Yonkers et al. (2011) found a high degree of agreement between urine toxicology and self-report results for cannabis and cocaine testing in 168 pregnant women. Moreover, self-report was found to lead to more positive reporting of use when a larger window was available for such reporting than was available for toxicology screening, leading to the conclusion that self-report may be a better indicator of use.

• Some time is needed for the care provider to either complete and/or review the screening results. Diekman et al. (2000) have reported than only 23% of obstetricians in the USA used a standardized screening tool for the detection of substance use, yet research (e.g. Bailey & Sokol, 2008; Svikis & Reid-Quinones, 2003) has shown that such tools substantially increase the rate of detection of such use. Oser et al. (2011) found that less than 50% of USA obstetricians were using a standardized screening instrument, and of those using such an instrument, most were using the CAGE, which was not specifically developed for use with a pregnant population.

• Effective interventions are labour intensive. Providing reading material is not as effective as a brief intervention. Face-to-face counselling about abstaining from alcohol (and other substances) is needed (Calabro, 1996).

• Other research has shown that non-mental-health specialists can be trained to perform brief interventions in general health-care settings.

REFERENCES

Bailey BA, Sokol RJ. Pregnancy and alcohol use: evidence and recommendations for prenatal care. Clin Obstet Gynecol 2008;51:436-44.

Calabro K, Taylor WC, Kapadia A. Pregnancy, alcohol use and the effectiveness of written health education materials. Patient Educ Couns 1996;29:301-9.

Center for Substance Abuse Prevention. CSAP Special Report 13: Maternal substance use assessment methods reference manual : a review of screening and clinical assessment instruments for examining maternal use of alcohol, tobacco, and other drugs Rockville, MD: US Department of Health and Human Services, Public Health Service, Substance Abuse and Mental Health Services Administration, 1993.

Chang G, McNamara TK, Orav EJ, et al. Brief intervention for prenatal alcohol use: a randomized trial. Obstet Gynecol 2005;105:991-8.

Delrahim-Howlett K, Chambers CD, Clapp JD, et al. Web-based assessment and brief intervention for alcohol use in women of childbearing potential: a report of the primary findings. Alcohol Clin Exp Res 2011;35:1331-8.

Diekman ST, Floyd RL, Decoufle P, et al. A survey of obstetrician-gynecologists on their patients' alcohol use during pregnancy. Obstet Gynecol 2000;95:756-63.

Dornelas EA, Magnavita J, Beazoglou T, et al. Efficacy and cost-effectiveness of a clinic-based counseling intervention tested in an ethnically diverse sample of pregnant smokers. Patient Educ Couns 2006;64:342-9.

Ershoff DH, Mullen PD, Quinn VP. A randomized trial of a serialized self-help smoking cessation program for pregnant women in an HMO. Am J Public Health 1989;79:182-7.

Fleming MF, Lund MR, Wilton G, et al. The Healthy Moms Study: the efficacy of brief alcohol intervention in postpartum women. Alcohol Clin Exp Res 2008;32:1600- 6.

Floyd RL, Sobell M, Velasquez MM, et al. Preventing alcohol-exposed pregnancies: a randomized controlled trial. Am J Prev Med 2007;32:1-10.

Gassman RA. Medical specialization, profession, and mediating beliefs that predict stated likelihood of alcohol screening and brief intervention: targeting educational interventions. Subst Abus 2003;24:141-56.

Goler NC, Armstrong MA, Taillac CJ, et al. Substance abuse treatment linked with prenatal visits improves perinatal outcomes: a new standard. J Perinatol 2008;28:597-603.

Klesges LM, Johnson KC, Ward KD, et al. Smoking cessation in pregnant women. Obstet Gynecol Clin North Am 2001;28:269-82.

Nilsen P. Brief alcohol intervention to prevent drinking during pregnancy: an overview of research findings. Curr Opin Obstet Gynecol 2009;21:496-500.

Oser C, Biebel E, Harris M, et al. Gender differences in provider's use of a standardized screening tool for prenatal substance use. J Addict Med 2011;5:36-42.

Parker DR, Windsor RA, Roberts MB, et al. Feasibility, cost, and cost-effectiveness of a telephone-based motivational intervention for underserved pregnant smokers. Nicotine Tob Res 2007;9:1043-51.

Svikis DS, Reid-Quinones K. Screening and prevention of alcohol and drug use disorders in women. Obstet Gynecol Clin North Am 2003;30:447-68.

Whicher EV, Utku F, Schirmer GD, P., et al. Pilot Project to Evaluate the Effectiveness and Acceptability of Single-session Brief Counseling for the Prevention of Substance Misuse in Pregnant Adolescents. Addictive Disorders & Their Treatment 2012;11:43-9.

Windsor RA, Cutter G, Morris J, et al. The effectiveness of smoking cessation methods for smokers in public health maternity clinics: a randomized trial. Am J Public Health 1985;75:1389-92.

Yonkers KA1, Howell HB, Gotman N, Rounsaville BJ. Self-report of illicit substance use versus urine toxicology results from at-risk pregnant women. J Subst Use. 2011 Oct 1;16(5):372-389.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Draft recommendations: o Screening for use of alcohol and other substance use among all pregnant women is recommended in all

health-care settings (e.g., primary care, obstetrical care).

o Pregnant women reporting hazardous or harmful alcohol or other substance use should receive a brief intervention.

o Pregnant women found to be dependent on alcohol or other substances should be referred to specialist services, where such services exist.

Final recommendations:

RECOMMENDATION 

Health-care providers should ask all pregnant women about their use of alcohol and other substances (past and present) as early as possible in the pregnancy and at every antenatal visit.

Strength of recommendation: Strong Quality of evidence: Low

Remarks: • Asking at every visit is important as some women are more likely to report sensitive information only after a trusting

relationship has been solidly established. • Pregnant women should be advised of the potential health risks to themselves and to their babies posed by alcohol

alcohol and/or drugs (past and present). • It was decided that despite the low quality of evidence of effect, the benefit – potential reduction of alcohol and

RECOMMENDATION 2

Health-care providers should offer a brief intervention to all pregnant women using alcohol or drugs.

Strength of recommendation: Strong Quality of evidence: Low

Remarks: • Brief intervention is a structured therapy of short duration (typically 5-30 minutes) offered with the aim of assisting

an individual to cease or reduce the use of a psychoactive substance. It is designed in particular for general practitioners and other primary health-care workers.

• The approach/attitude of health-care providers is an important contributor to the effectiveness of brief interventions. • As for recommendation 1, it was decided that despite the low quality of evidence of effectiveness, this should be

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Factors in considering the strength of the recommendations (recommendations 1 & 2):

Research gaps

More evidence is needed from low-income countries. Topics in need of further research include training on sceening and brief interventions, how to screen (which instrument), cost-effectiveness, whether to screen for alcohol or drugs together, whether to ask about tobacco at the same time, and whether or not to combine with other issues (such as depression). There is a need for more real-world effectiveness studies, and a systematic review of screening instruments.

Factor Decision

Is there high- or moderate-quality evidence? The higher the quality of evidence, the more likely is a strong recommendation.

Is there certainty about the balance of benefits versus harms and burdens? In case of positive recommendations (a recommendation to do something), do the benefits outweigh harms? In case of negative recommendations (a recommendation not to do something), do the harms outweigh benefits?

Yes

Are the expected values and preferences clearly in favour of the recommendation? Yes

Is there certainty about the balance between benefits and resources being consumed? In case of positive recommendations (recommending to do something) is there certainty that the benefits are worth the costs of the resources being consumed? In case of negative recommendations (recommending not to do something) is there certainty that the costs of the resources being consumed outweigh any benefit gained?

Yes

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

SCREENING AND BRIEF INTERVENTION VERSUS USUAL CARE FOR HARMFUL SUBSTANCE USE IN PREGNANCY

Patient or population: Patients with harmful substance use in pregnancy Settings: Ante-natal and post-natal general health-care settings Intervention: Screening and brief intervention versus usual care

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect

(95% CI)

No. of participants

(studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Control

Screening and brief intervention versus

usual care

Abstinence from drug use in the last 4 weeks – ITT analysis Follow-up: mean 38.6 days

Study population OR 0.55 (0.12 to 2.55)

30 (1 study)

⊕⊕ LOW1,2,3

733 per 1000 602 per 1000 (248 to 875)

Total number of drinks in the past 28 days Follow-up: mean 6 months

The mean total number of drinks in the past 28 days in the control groups was 27.1 standard drinks

The mean total number of drinks in the past 28 days in the intervention groups was 7.3 lower (12.61 to 1.99 lower)

235 (1 study)

⊕⊕ LOW1,4

Number of heavy drinking days in the past 28 days Follow-up: mean 6 months

The mean number of heavy drinking days in the past 28 days in the control groups was 2.6 days

The mean number of heavy drinking days in the past 28 days in the intervention groups was 0.9 lower (1.59 to 0.21 lower)

235 (1 study)

⊕⊕ LOW1,4

Number of standard drinks per week Follow-up: mean 33 days

The mean number of standard drinks per week in the control groups was 0.13 standard drinks

The mean number of standard drinks per week in the intervention groups was 0.19 higher (0.31 lower to 0.69 higher)

50 (1 study)

⊕⊕ LOW1,3

Estimated peak BAC Follow-up: 1–2 months

The mean estimated peak BACin the control groups was 0.004 g/dl

The mean estimated peak BACin the intervention groups was 0 higher (0.01 lower to 0.01 higher)

50 (2 studies)

⊕⊕ LOW1,3

AUDIT score Follow-up: mean 58 days

The mean AUDIT score in the control groups was 2.22 AUDIT score

The mean audit score in the intervention groups was 1.69 lower (2.88 to 0.5 lower)

179 (1 study)

⊕⊕ LOW1,4,6

Motivation to change Follow-up: mean 38.6 days

The mean motivation to change in the control groups was 77.4 Visual analogue scale

The mean motivation to change in the intervention groups was 11.4 higher (0.08 to 22.72 higher)

30 (1 study)

⊕⊕ LOW1,2

Summary of findings and GRADE tables

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect

(95% CI)

No. of participants

(studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Control

Screening and brief intervention versus

usual care

Spontaneous abortion

Study population OR 0.84 (0.34 to 2.06)

753 (3 studies)

⊕ VERY LOW1,2,3,4

28 per 1000 24 per 1000 (10 to 57)

Head circumference Follow-up: mean 33 days

The mean head circumference in the control groups was 34.1 cm

The mean head circumference in the intervention groups was 0.27 lower (1.1 lower to 0.56 higher)

50 (1 study)

⊕⊕ LOW1,3

Depression postpartum Follow-up: mean 6 months

The mean depression postpartum in the control groups was 8.06 Edinburgh postpartum depression scale

The mean depression postpartum in the intervention groups was 1.22 lower (2.71 lower to 0.27 higher)

205 (1 study)

⊕ VERY LOW1,4,6,7

Birthweight – all participants

The mean birthweight – all participants in the control groups was 3240 grams

The mean birthweight – all participants in the intervention groups was 57.8 higher (77.26 lower to 192.86 higher)

555 (3 studies)

⊕ VERY LOW1,2,3,4,6,8,9

Attending substance abuse treatment Follow-up: mean 38.6 days

Study population OR 0.31 (0.01 to 8.28)

30 (1 study)

⊕ VERY LOW1,2,3

67 per 1000 22 per 1000 (1 to 372)

Birthweight – drinking more than 1 drink per occasion or per day (post-hoc analysis)

The mean birthweight – drinking more than 1 drink per occasion or per day (post- hoc analysis) in the control groups was 3134 grams

The mean birthweight – drinking more than 1 drink per occasion or per day (post- hoc analysis) in the intervention groups was 199.63 higher (57.06 to 342.19 higher)

168 (2 studies)

⊕⊕ LOW1,4,6,10

* The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; OR: Odds ratio. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 The control group received a screening session 2 Up to a third of the participants were not heavy drinkers 3 Wide confidence interval 4 Cluster randomized trial not analysed as such 5 High dropout rate 6 Outcome assessment was not blinded 7 Post-hoc analysis, selective outcome reporting 8 No explanation was provided 9 Suggestion on funnel plot of publication bias 10 Post-hoc analysis

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0 no

s er

io us

co ns

is te

nc y

se ri

ou s1

no s

er io

im pr

ec is

io n

no ne

81 87

— M

D 1

99 .6

3 hi

gh er

(5 7.

to 3

42 .1

9 hi

gh er

)

⊕ ⊕

 

LO W

IM P

O R

TA N

1 Th

e co

nt ro

l g ro

up re

ce iv

ed a

s cr

ee ni

ng s

es si

on 2

U p

to a

th ird

o f t

he p

ar tic

ip an

ts w

er e

no t h

ea vy

d rin

ke rs

3 W

id e

co nfi

de nc

e in

te rv

al 4

Cl us

te r R

an do

m iz

ed tr

ia l n

ot a

na ly

se d

as s

uc h

5 H

ig h

dr op

ou t r

at e

6 O

ut co

m e

as se

ss m

en t w

as n

ot b

lin de

d 7

Po st

-h oc

a na

ly si

s, s

el ec

tiv e

ou tc

om e

re po

rt in

g 8

N o

ex pl

an at

io n

w as

p ro

vi de

d 9

Su gg

es tio

n on

fu nn

el p

lo t o

f p ub

lic at

io n

bi as

10 P

os t-

ho c

an al

ys is

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

S C

R E

E N

IN G

A N

D B

R IE

F I

N T E

R V E

N T IO

N S

v s

U S

U A

L C

A R

E f

or h

ar m

fu l su

b st

an ce

u se

i n p

re gn

an cy

TA B

LE O

F C

H A

R A

C TE

R IS

TI C

S O

F IN

C LU

D ED

R C

TS : 9

IN T

O TA

Tr ia

l I D

M et

ho ds

P ar

ti ci

pa nt

s In

te rv

en ti

on s

O ut

co m

es N

ot es

C ha

ng 1

99 9

S TU

D Y

TY P

E: R

C T

C O

U N

TR Y:

U S

S ET

TI N

G : B

ri gh

am a

nd W

om en

’s H

os pi

ta l –

en er

al A

nt e-

na ta

l c lin

D U

R AT

IO N

O F

R EC

R U

IT M

EN T:

O ne

y ea

D U

R AT

IO N

O F

TR IA

22 m

on th

FO LL

O W

-U P

: P os

t p ar

tu m

fo llo

w u

p in

te rv

ie w

IN C

LU S

IO N

C R

IT ER

IA : p

re gn

an t w

om en

es en

tin g

fo r

an te

-n at

al c

ar e

sc re

po si

tiv e

on a

n al

co ho

l s ur

ve y

fo r

ha za

rd ou

s or

h ar

m fu

l u se

EX C

LU S

IO N

C R

IT ER

IA : (

1) g

es ta

tio na

l ag

e gr

ea te

r th

an 2

8 w

ee ks

(4 4%

), (2

) n o

al co

ho l c

on su

m pt

io n

in th

e im

m ed

ia te

m on

th s

be fo

re s

tu dy

p ar

tic ip

at io

n (1

9% ),

(3 ) m

is ca

rr ia

ge in

th e

tim e

be tw

ee n

su rv

co m

pl et

io n

an d

te le

ph on

e in

te rv

ie w

(1 4%

), (4

) i nt

en tio

n to

r ec

ei ve

p re

na ta

l c ar

e el

se w

he re

(7 %

), (5

) n on

-E ng

lis h-

sp ea

ki ng

% ),

(6 ) i

nt en

de d

ab or

tio n

or fa

ls e

pr eg

na nc

y (3

% ),

(7 ) c

ur re

nt s

ub st

an ce

us e

tr ea

tm en

t ( 1%

) a nd

(8 ) o

th er

(9 %

S cr

ee ne

d: 1

16 5

A gr

ee d

to p

ar tic

ip at

e: 8

86 S

cr ee

n po

si tiv

e: 5

32 M

et in

cl us

io n/

ex cl

us io

n cr

ite ri

a: 2

50 N

. o f p

ar tic

ip an

ts r

an do

m iz

ed : 2

50 (1

to in

te rv

en tio

n gr

ou p,

a nd

1 27

to c

on tr

gr ou

p) N

. f ol

lo w

ed u

p: 2

47 N

. i nc

lu de

d in

th e

an al

ys is

: 2 50

IN TE

R V

EN TI

O N

: S cr

ee ni

ng a

nd c

om pr

eh en

si ve

A ss

es sm

en t a

B ri

ef In

te rv

en tio

n Th

e B

I w as

s tr

uc tu

re d

as fo

llo w

s: (1

) r ev

ie w

e su

bj ec

t’s g

en er

al h

ea lth

a nd

c ou

rs e

of p

re gn

an cy

to d

at e,

(2 )

re vi

ew th

e su

bj ec

t’s li

fe -s

ty le

c ha

ng es

m ad

e si

nc e

pr eg

na nc

in cl

ud in

g w

or k

sc he

du le

, e xe

rc is

e, d

ie t,

ci ga

re tt

e sm

ok in

g an

d al

co ho

l c on

su m

pt io

n, (3

) r eq

ue st

th at

th e

su bj

ec t a

rt ic

ul at

e he

r dr

in ki

ng g

oa ls

w hi

le p

re gn

an t a

nd th

ei r

re as

on , (

4) h

av e

th e

su bj

ec t i

de nt

ify c

ir cu

m st

an ce

s w

he n

sh e

m ig

ht b

e te

m pt

ed to

in k,

(5 ) i

de nt

ify a

lte rn

at iv

es to

d ri

nk in

g w

he n

sh e

is te

m pt

to d

ri nk

, a nd

(6 ) s

um m

ar iz

e th

e se

ss io

n by

e m

ph as

iz in

g fo

ke y

po in

ts (d

ri nk

in g

go al

, m ot

iv at

io n,

r is

k si

tu at

io ns

fo r

dr in

ki ng

d al

te rn

at iv

es to

a lc

oh ol

) a nd

n ot

in g

th em

in th

e ta

ke -h

om e

m an

ua l,

“ H

ow to

p re

ve nt

a lc

oh ol

-r el

at ed

p ro

bl em

s” , g

iv en

th e

su bj

ec t.

Th is

m an

ua l w

as b

as ed

o n

m at

er ia

ls p

ro vi

de d

th e

W H

O A

m et

hy st

P ro

je ct

(B ab

or e

t a l.,

1 98

7; B

ab or

& G

ra nt

, 19

92 ; W

H O

B ri

ef In

te rv

en tio

n S

tu dy

G ro

up , 1

99 6)

. A ll

su bj

ec ts

ce iv

in g

th e

B I w

er e

in fo

rm ed

o f t

he r

ec om

m en

da tio

n of

th e

U S

S ur

ge on

G en

er al

, w ith

p re

na ta

l a bs

tin en

ce b

ei ng

th e

m os

t pr

ud en

t d ri

nk in

g go

al . T

im e:

4 5

m in

ut es

C O

N TR

O L:

S cr

ee ni

ng a

nd c

om pr

eh en

si ve

a ss

es sm

en t

Th e

co m

pr eh

en si

ve a

ss es

sm en

t w as

a dm

in is

te re

d by

re se

ar ch

a ss

is ta

nt o

ve r

th e

co ur

se o

f 2 h

ou rs

a nd

c on

si st

of : (

1) th

e al

co ho

l a nd

d ru

g ab

us e

m od

ul es

fr om

th e

S tr

uc tu

re d

C lin

ic al

In -t

er vi

ew fo

r D

S M

-I II

-R to

g en

er at

e st

an da

di ag

no se

s (S

C ID

, S pi

tz er

e t a

l., 1

99 0)

; ( 2)

th e

A dd

ic tio

n S

ev er

ity

In de

x (A

S I,

M cL

el la

n et

a l.,

1 98

0) ; (

3) th

e A

lc oh

ol U

se D

is or

de rs

en tifi

ca tio

n Te

st (A

U D

IT , B

oh n,

B ab

or &

K ra

nz le

r, 19

95 );

(4 ) t

S ho

rt M

ic hi

ga n

A lc

o- h

ol is

m S

cr ee

ni ng

T es

t ( S

M A

S T,

S el

ze r,

Vi no

ku r

& v

an R

oo ije

n, 1

97 5)

; ( 5)

th e

Ti m

el in

e Fo

llo w

- ba

in te

rv ie

w fo

r th

e qu

an tit

y an

d fr

eq ue

nc y

of a

lc oh

ol c

on su

m pt

io n

fo r

th e

90 d

ay s

im m

ed ia

te ly

b ef

or e

st ud

y as

se ss

m en

t ( S

ob el

l &

S ob

el l,

19 92

); (6

) t he

A lc

oh ol

C ra

vi ng

S ca

le , a

v is

ua l a

na lo

g sc

al e

to m

ea su

re th

e de

si re

to d

ri nk

a t t

he m

om en

t a nd

in th

e pa

st w

ee k

(W ew

er s,

R ac

hf al

& A

hi je

vy ch

, 1 99

0) ; (

7) th

e G

lo ba

l A

ss es

sm en

t o f F

un ct

io ni

ng (G

A F,

E nd

ic ot

t e t a

l., 1

97 6)

; a nd

(8 )

th e

S itu

at io

na l C

on fid

en ce

Q ue

st io

nn ai

re , a

m ea

su re

o f t

su bj

ec t’s

c on

fid en

ce in

m an

ag in

g dr

in ki

ng s

itu at

io ns

(A nn

is ,

19 81

). S

ub je

ct s

w er

e as

ke d

to r

ep or

t a ny

a lc

oh ol

c on

su m

ed ,

ev en

a s

ip , w

he n

co m

pl et

in g

th e

Ti m

el in

e Fo

llo w

-b ac

k in

te rv

ie w

lle n

& C

ol um

bu s,

1 99

5) . I

n th

is s

tu dy

, a lc

oh ol

c on

su m

pt io

n w

as q

ua nt

ifi ed

b y

dr in

ks p

er d

ri nk

in g

da y,

s in

ce fe

w p

re gn

an t

w om

en d

ri nk

d ai

ly (J

ac ob

so n

et a

l., 1

99 1)

. D ri

nk in

g ep

is od

es ,

de fin

ed w

ith e

ac h

ep is

od e

be gi

nn in

g w

ith a

d ri

nk in

g da

y an

d en

di ng

w ith

7 c

on se

cu tiv

e da

ys o

f a bs

tin en

ce , w

er e

al so

lc ul

at ed

. A dd

iti on

al d

et ai

ls a

bo ut

th e

al co

ho l a

ss es

sm en

t a re

ai la

bl e

el se

w he

re (C

ha ng

e t a

l., 1

99 8)

M AT

ER N

A L

O U

TC O

M ES

: A lc

oh ol

ns um

pt io

D ri

nk s

pe r

dr in

ki ng

d ay

IN FA

N T

O U

TC O

M ES

: B

ir th

w ei

gh t

A P

G A

R s

co re

ET H

IC S

: A pp

ro ve

d by

e hu

m an

s ub

je ct

s co

m m

itt ee

o f t

B ri

gh am

a nd

W om

en ’s

os pi

ta l

IN FO

R M

ED C

O N

S EN

O bt

ai ne

FU N

D IN

G : T

hi s

st ud

y w

as s

up po

rt ed

b y

R O

I A A

9 67

0 fr

om th

e N

at io

na l I

ns tit

ut e

A lc

oh ol

A bu

se a

A lc

oh ol

is m

(D r

C ha

ng )

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

C ha

ng 2

00 5

S TU

D Y

TY P

E: R

C T

C O

U N

TR Y:

U ni

te d

S ta

te s

S ET

TI N

G : 1

o f 3

o bs

te tr

ic p

ra ct

ic es

(c lin

ic ,

fa cu

lty , o

r pr

iv at

e gr

ou p

af fil

ia te

) o f t

B ri

gh am

a nd

W om

en ’s

H os

pi ta

l i n

B os

to n,

D U

R AT

IO N

O F

R EC

R U

IT M

EN T:

F eb

ru ar

y 20

00 to

S ep

te m

be r

20 02

FO LL

O W

-U P

: P os

t- pa

rt um

fo llo

w -u

p in

te rv

ie w

IN C

LU S

IO N

C R

IT ER

IA : 1

) p os

iti ve

T -A

C E,

ith a

to ta

l s co

re o

f 2 o

r m

or e,

2 ) b

ei ng

a t

ri sk

fo r

pr en

at al

a lc

oh ol

u se

, w hi

ch w

de fin

ed a

s an

y al

co ho

l c on

su m

pt io

n in

th e

3 m

on th

s be

fo re

s tu

dy e

nr ol

m en

t ( w

hi le

eg na

nt ),

or c

on su

m pt

io n

of a

t l ea

st o

dr in

k pe

r da

y in

th e

6 m

on th

s be

fo re

s tu

en ro

lm en

t, or

d ri

nk in

g du

ri ng

a p

re vi

ou s

pr eg

na nc

y, 3

)g es

ta tio

n le

ss th

an 2

8 w

ee ks

d in

te nt

io n

to c

ar ry

p re

gn an

cy to

te rm

EX C

LU S

IO N

C R

IT ER

IA : 1

) c ur

re nt

tr ea

tm en

t fo

r al

co ho

l o r

dr ug

a bu

se , o

r su

bs ta

nc e

ab us

e– re

la te

d m

ed ic

al il

ln es

s, 2

) c ur

re nt

ys ic

al d

ep en

de nc

e on

a lc

oh ol

r eq

ui ri

m ed

ic al

ly s

up er

vi se

d de

to xi

fic at

io n,

3 )

cu rr

en t u

se o

f o pi

at es

, c oc

ai ne

, o r

ot he

r ill

ic it

su bs

ta nc

es .

N . o

f p ar

tic ip

an ts

s cr

ee ne

d: 2

92 7

N . o

f sc

re en

ed p

os iti

ve : 8

02 N

. o f p

ar tic

ip an

su cc

es sf

ul ly

c on

ta ct

ed : 3

99 N

. r an

do m

iz ed

: 30

4 (B

ri ef

in te

rv en

tio n

gr ou

p: 1

52 , l

os s

fo llo

w -u

p in

b ri

ef in

te rv

en tio

n gr

ou p:

1 0.

on tr

ol g

ro up

: 15

2, lo

ss to

fo llo

w -u

p in

c on

tr ol

g ro

up : 6

) N

. i nc

lu de

d in

th e

an al

ys is

: 1 52

fo r

bo th

ou ps

II N

TE R

V EN

TI O

N : S

in gl

e se

ss io

n br

ie f i

nt er

ve nt

io n

gi ve

n to

th e

w om

an a

nd h

er p

ar tn

C O

N TR

O L:

S cr

ee ni

ng a

nd d

ia gn

os tic

in te

rv ie

w o

nl y

M AT

ER N

A L

O U

TC O

M ES

: A

lc oh

ol c

on su

m pt

io n

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Fl em

in g

20 08

S TU

D Y

TY P

E: C

lu st

er r

an do

m iz

co nt

ro lle

d tr

ia l

C O

U N

TR Y:

U S

S ET

TI N

G : 3

4 ob

st et

ri ca

l p ra

ct ic

es fr

om 1

5 co

un tie

s in

W is

co ns

in .

D U

R AT

IO N

O F

R EC

R U

IT M

EN T:

bs te

tr ic

ia ns

w er

e re

cr ui

te d

in 2

00 1.

ct ua

l d ur

at io

n w

as n

ot s

ta te

d. P

os tp

ar tu

w om

en w

er e

re cr

ui te

d be

tw ee

n 20

02 a

20 04

D U

R AT

IO N

O F

TR IA

L: 2

00 2

to 2

00 5

FO LL

O W

-U P

: M ot

he rs

a tt

en de

d tw

o 15

-m in

ut e

fa ce

-t o-

fa ce

v is

its w

er e

sc he

du le

d 1

m on

th a

pa rt

fo r

a br

ie f

in te

rv en

tio n

an d

a re

in fo

rc em

en t s

es si

on ,

fo llo

w ed

b y

a ph

on e-

ca ll

2 w

ee ks

a ft

ea ch

fa ce

-t o-

fa ce

m ee

tin g.

T he

re w

er e

a to

ta l o

f 4 c

on ta

ct s

to th

e pa

rt ic

ip an

sp re

ad o

ve r

an 8

w ee

k pe

ri od

. F ol

lo w

-u p

pr oc

ed ur

es in

cl ud

ed a

te le

ph on

e in

te rv

ie w

6 m

on th

s by

o ne

o f t

he r

es ea

rc he

rs n

as si

gn ed

to p

ar tic

ip an

t’s c

lin ic

IN C

LU S

IO N

C R

IT ER

IA :

P hy

si ci

an s:

T ra

in ed

in o

bs te

tr ic

s an

d gy

ne co

lo gy

, p ra

ct ic

e m

ed ic

in e

at le

as t 5

tim e,

a m

en ab

le to

h av

in g

a re

se ar

ch te

id en

tif y

an d

w or

k w

ith th

ei r

pa tie

nt s,

w ill

in gn

es s

to h

av e

th ei

r of

fic e

st af

f c om

pl et

e re

se ar

ch p

ro to

co ls

P os

tp ar

tu m

w om

en : 1

8 ye

ar s

or o

ld er

, se

ei ng

th ei

r ob

st et

ri ci

an o

r ad

va nc

pr ac

tic e

nu rs

e fo

r a

po st

pa rt

um v

is it,

2 0

or m

or e

st an

da rd

d ri

nk s

in th

e pr

ev io

28 d

ay s

or 4

o r

m or

e dr

in ks

o n

4 or

m or

e oc

ca si

on s

in th

e la

st 2

8 da

ys o

r 20

o r

m or

e dr

in ki

ng d

ay s

in th

e la

st 2

8 da

ys .

A ll

po st

pa rt

um p

at ie

nt s

18 y

ea rs

o r

ol de

r w

er e

as ke

d to

c om

pl et

e a

he al

th s

cr ee

ni ng

rv ey

(H S

S ).

C om

pu te

r- ge

ne ra

te d

al lo

ca tio

n m

et ho

d w

as u

se d

to a

ss ig

n pa

rt ic

ip an

ts to

th e

ex pe

ri m

en ta

l a nd

nt ro

l g ro

up s

in e

ac h

ph ys

ic ia

n’ s

of fic

N um

be r

of p

ar tic

ip an

ts r

an do

m iz

ed :

23 5

(t he

u ni

t o f r

an do

m iz

at io

n w

as th

e in

di vi

du al

p at

ie nt

). 12

2 po

st pa

rt um

w om

en r

an do

m iz

ed to

te rv

en tio

n gr

ou p

an d

11 3

to c

on tr

ol g

ro up

. Th

er e

w er

e no

s ig

ni fic

an t s

ta tis

tic al

ff er

en ce

s in

b as

el in

e da

ta b

et w

ee n

th e

tw o

gr ou

ps .

IN TE

R V

EN TI

O N

: b ri

ef in

te rv

en tio

n G

R O

U P

P ar

tic ip

an ts

in th

e ex

pe ri

m en

ta l g

ro up

r ec

ei ve

d he

al th

b oo

kl et

n ge

ne ra

l h ea

lth is

su es

) p lu

s fa

ce -t

o- fa

ce 3

0- m

in ut

e se

ss io

n an

d w

er e

fo llo

w ed

u p

at 6

m on

th s.

C O

N TR

O L:

u su

al c

ar e

G R

O U

P Th

os e

as si

gn ed

to th

e co

nt ro

l g ro

up r

ec ei

ve d

a he

al th

b oo

kl et

n ge

ne ra

l h ea

lth is

su es

) a nd

w er

e fo

llo w

ed u

p at

6 m

on th

C O

M P

LI A

N C

E: P

ar tic

ip an

ts to

ok th

e w

or kb

oo k

ho m

e be

tw ee

n vi

si ts

a nd

fi lle

d ou

t a n

um be

r of

h om

ew or

k as

si gn

m en

ts , a

w er

e as

ke d

to fi

ll ou

t d ri

nk in

g di

ar y

ca rd

s be

tw ee

n vi

si ts

, a nd

llo w

-u p

ph on

e ca

lls w

er e

m ad

e to

r ei

nf or

ce d

th e

dr in

ki ng

lim

its s

et a

t e ac

h vi

si t,

ch al

le ng

es th

ey fa

ce d

in c

ut tin

g do

w n

dr in

ki ng

a nd

o ff

er in

g co

nt in

ue d

su pp

or t.

C O

-I N

TE R

V EN

TI O

N S

: P ar

tic ip

an ts

w er

e pa

id a

to ta

l o f $

15 0

if th

ey c

om pl

et ed

th e

re qu

ir ed

p ro

ce du

re s.

M AT

ER N

A L

O U

TC O

M ES

: P

ri m

ar y:

A lc

oh ol

u se

m ea

su re

d by

to ta

l nu

m be

r of

d ri

nk s,

m be

r of

d ri

nk in

g da

ys , a

nd n

um be

r of

av y

dr in

ki ng

d ay

s (4

m or

e dr

in ks

in a

d ay

), in

th e

pr ev

io us

2 8

da ys

. S

ec on

da ry

: O

th er

tc om

es o

f i nt

er es

t su

ch a

s de

pr es

si on

, ac

ci de

nt s,

in ju

ri es

, dr

iv in

g w

hi le

to xi

ca te

d, a

nd h

ea lth

re u

til iz

at io

ET H

IC S

: R es

ea rc

h pr

ot oc

ol a

pp ro

ve d

by th

e U

ni ve

rs ity

o f

W is

co ns

in H

ea lth

ci en

ce s

H um

S ub

je ct

s C

om m

itt ee

d 11

a dd

iti on

hu m

an s

ub je

co m

m itt

ee s

sp ec

ifi c

to th

e di

ff er

en t h

ea lth

re s

ys te

m s.

IN FO

R M

ED C

O N

S EN

A ll

pa rt

ic ip

an ts

g av

e w

ri tt

en in

fo rm

co ns

en t.

FU N

D IN

G : N

IH N

IA A

gr an

t n um

be r

R 01

A 12

52 2.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

H an

dm ak

19 99

S TU

D Y

TY P

E: R

an do

m iz

ed c

on tr

ol le

d tr

ia l

C O

U N

TR Y:

U S

S ET

TI N

G : U

ni ve

rs ity

o f N

ew M

ex ic

o (U

N M

) M

ed ic

al C

en te

r ob

st et

ri c

cl in

ic s

D U

R AT

IO N

O F

R EC

R U

IT M

EN T:

N ot

s ta

te d.

D U

R AT

IO N

O F

TR IA

L: N

ot s

ta te

FO LL

O W

-U P

: P re

gn an

t w om

en w

er e

in te

rv ie

w ed

tw o

m on

th s

la te

r us

in g

th e

Fo llo

w -u

p D

ri nk

er P

ro fil

e (F

D P

)

IN C

LU S

IO N

C R

IT ER

IA : N

ot s

ta te

EX C

LU S

IO N

C R

IT ER

IA : N

ot s

ta te

N um

be r

of p

ar tic

ip an

ts r

an do

m iz

ed :

42 (2

0 ra

nd om

iz ed

to in

te rv

en tio

n gr

ou p

an d

22 to

c on

tr ol

g ro

up ).

It w

as n

ot s

ta te

d if

th er

e w

er e

an y

si gn

ifi ca

nt s

ta tis

tic al

ff er

en ce

s in

b as

el in

e da

ta b

et w

ee n

th e

tw o

gr ou

ps .

A ll

pa rt

ic ip

an ts

w er

e in

iti al

ly a

ss es

se d

us in

g th

e B

ri ef

ri nk

er P

ro fil

e (B

D P

), su

pp le

m en

te d

by c

al en

da r

fo r

tim el

in e

re co

ns tr

uc tio

n of

d ri

nk in

g du

ri ng

th e

pr ev

io us

2 m

on th

S ub

se qu

en tly

, t he

in te

rv ie

w er

p ri

va te

ly o

pe ne

d a

pr ep

ar ed

ve lo

pe to

d et

er m

in e

th e

ra nd

om iz

ed g

ro up

a ss

ig nm

en t.

IN TE

R V

EN TI

O N

: P re

gn an

t w om

en in

th e

tr ea

tm en

t g ro

co m

pl et

ed S

O C

R AT

ES , a

m ea

su re

o f m

ot iv

at io

n fo

r ch

an ge

. Th

e m

ot iv

at io

na l i

nt er

vi ew

la st

ed fo

r 1

ho ur

, s ta

rt in

g w

ith

as ce

rt ai

ni ng

p ar

tic ip

an t’s

k no

w le

dg e

of th

e ef

fe ct

s of

a lc

oh ol

o n

pr eg

na nc

y, fe

ed ba

ck o

n se

ve ri

ty o

f p ar

tic ip

an t’s

d ri

nk in

g, a

sh ow

in g

ch ar

t o f f

et al

d ev

el op

m en

t b y

ge st

at io

na l w

ee k.

T he

y w

er e

fo llo

w ed

-u p

2 m

on th

s la

te r.

C O

N TR

O L:

T ho

se a

ss ig

ne d

to th

e co

nt ro

l g ro

up w

er e

se nt

tt er

s in

fo rm

in g

th em

a bo

ut th

e po

te nt

ia l r

is ks

o f d

ri nk

in g

du ri

ng p

re gn

an cy

a nd

r ef

er ri

ng th

em to

th ei

r he

al th

ca re

p ro

vi de

d w

er e

fo llo

w ed

u p

at 2

m on

th s.

C O

M P

LI A

N C

E: N

ot s

ta te

C O

-I N

TE R

V EN

TI O

N S

: T o

co rr

ob or

at e

se lf-

re po

rt , p

ar tic

ip an

ts ’

si gn

ifi ca

nt o

th er

s w

er e

in te

rv ie

w ed

(w ith

th e

pa rt

ic ip

an t’s

rm is

si on

) a t i

nt ak

e an

d fo

llo w

-u p,

u si

ng a

C ol

la te

ra l

In fo

rm at

io n

Fo rm

. A ll

pa rt

ic ip

an ts

w er

e pa

id $

20 .0

0 fo

r co

m pl

et in

g ba

se lin

e as

se ss

m en

t, w

er e

en te

re d

in to

a lo

tt er

y dr

aw in

g fo

r a

$5 0

ca sh

p ri

ze u

po n

co m

pl et

in g

fo llo

w -u

p se

ss io

ns , a

nd th

os e

in th

e in

te rv

en tio

n gr

ou p

w er

e pa

id $

1 0

up on

c om

pl et

in g

S O

C R

AT ES

a ga

in a

ft er

th e

in te

rv ie

w .

M AT

ER N

A L

O U

TC O

M ES

: A lc

oh ol

ns um

pt io

n as

ea su

re d

by to

ta l

st an

da rd

e th

an ol

nt en

t ( S

EC ),

es tim

at ed

p ea

k bl

oo d

al co

ho l c

on ce

nt ra

tio n

(B A

C s)

a nd

to ta

l d ay

s ab

st in

en t d

ur in

g th

e m

os t r

ec en

t 2 m

on th

s of

eg na

nc y.

IN FA

N T

O U

TC O

M ES

: N

ot s

ta te

ET H

IC S

: N ot

s ta

te d

IN FO

R M

ED C

O N

S EN

A ll

pa rt

ic ip

an ts

g av

e in

fo rm

ed c

on se

nt –

w as

n ot

s ta

te d

if it

w as

rb al

o r

w ri

tt en

FU N

D IN

G : P

ar tly

pp or

te d

by a

g ra

fr om

th e

N ew

M ex

ic o

D ev

el op

m en

ta l

D is

ab ili

tie s

P la

nn in

g C

ou nc

il an

d by

g ra

nt s

T3 2-

A A

07 46

0 an

d K

05 -A

A 00

13 3

fr om

th e

N at

io na

l I ns

tit ut

e on

lc oh

ol A

bu se

a nd

lc oh

ol is

m .

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

M ag

nu ss

20 05

S TU

D Y

TY P

E: R

an do

m iz

ed c

on tr

ol le

d tr

ia l

C O

U N

TR Y:

S w

ed en

S ET

TI N

G : T

w o

an te

na ta

l c ar

e cl

in ic

s of

nt ra

l S to

ck ho

D U

R AT

IO N

O F

R EC

R U

IT M

EN T:

S ep

te m

be r

1, 2

00 1,

a nd

M ay

3 0,

2 00

FO LL

O W

-U P

: S cr

ee ni

ng in

te rv

ie w

a ft

st an

da rd

a dm

is si

on in

th e

cl in

ic s.

F ol

lo w

in g

ev al

ua tio

n, b

lo od

w as

o bt

ai ne

d fo

r an

al ys

of b

io m

ar ke

rs fo

r th

e in

te rv

en tio

n gr

ou p.

IN C

LU S

IO N

C R

IT ER

IA : 1

10 6

ad m

is si

on s

be tw

ee n

S ep

te m

be r

1, 2

00 1,

a nd

M ay

3 0,

02 . A

m on

g th

es e,

3 03

w er

e ra

nd om

se le

ct ed

b y

of fe

ri ng

p ar

tic ip

at io

n to

l a dm

is si

on s

to th

e re

sp ec

tiv e

cl in

on r

an do

m ly

a lte

rn at

in g

w ee

kd ay

s to

oi d

bi as

c au

se d

by th

e po

ss ib

ili ty

th at

bj ec

ts w

ith h

az ar

do us

a lc

oh ol

u se

oi d

sc he

du lin

g vi

si ts

im m

ed ia

te ly

a ft

w ee

ke nd

N . o

f p ar

tic ip

an ts

r an

do m

is ed

: 3 03

In te

rv en

tio n

gr ou

p: 1

47 p

ar tic

ip an

ts C

on tr

ol g

ro up

: 1 56

p ar

tic ip

an ts

IN TE

R V

EN TI

O N

: T he

w om

en in

th e

in te

rv en

tio n

gr ou

p w

er e

ev al

ua te

d by

th e

re se

ar ch

m id

w ife

in a

dd iti

on to

a nd

de pe

nd en

tly o

f r eg

ul ar

a nt

en at

al c

ar e.

F ol

lo w

in g

ev al

ua tio

bl oo

d w

as o

bt ai

ne d

fo r

an al

ys is

o f b

io m

ar ke

rs .

S cr

ee ni

ng m

et ho

ds u

se d:

1 ) T

LF B

: t he

p er

io d

as se

ss ed

b y

TL FB

ri ed

d ep

en di

ng o

n th

e w

ee k

of p

re gn

an cy

a t t

he ti

m e

of th

e cl

in ic

v is

it (m

ed ia

n [r

an ge

] = 1

2 [8

-2 4]

w ee

ks ).

A n

in te

rv ie

w er

m in

is te

re d

th e

TL FB

w ith

th e

st an

da rd

e le

m en

ts o

f t hi

s te

ch ni

qu e.

2 ) A

U D

IT : a

pp lie

d to

b eh

av io

r du

ri ng

th e

12 -m

on th

ri od

p re

ce di

ng p

re gn

an cy

. 3 ) B

io m

ar ke

rs : F

ol lo

w in

g th

e in

te rv

ie w

, t og

et he

r w

ith o

rd in

ar y

ro ut

in e

la bo

ra to

ry te

st s,

ve no

us b

lo od

s am

pl e

w as

d ra

w n

an d

an al

yz ed

fo r

th e

fo llo

w in

g bi

om ar

ke rs

(w ith

u pp

er r

ef er

en ce

in te

rv al

li m

it in

di ca

te d

fo r

ea ch

): M

C V

(7 6-

96 f/

L) , G

G T

(< 0

.8 0

pk at

/L ),

A S

T (<

0 .6

0. p

ka t/

L) ,

A LT

(< 0

.6 0

pk at

/L ) a

nd C

D T

(< 1

.5 %

C O

N TR

O L:

T he

w om

en in

th e

co nt

ro l g

ro up

r et

ur ne

d to

nt in

ue d

re gu

la r

ca re

o nl

M AT

ER N

A L

O U

TC O

M ES

: T LF

an d

A U

D IT

s co

re s,

om ar

ke r

le ve

IN FA

N T

O U

TC O

M ES

: no

ET H

IC S

: T he

oj ec

t f ol

lo w

ed th

e D

ec la

ra tio

n of

H el

si nk

i an

d w

as a

pp ro

ve d

by S

to ck

ho lm

S ou

H um

an S

ub je

ct s

Et hi

co m

m itt

ee (1

99 /0

0) .

IN FO

R M

ED C

O N

S EN

S ub

je ct

s ga

ve th

ei r

in fo

rm ed

c on

se nt

FU N

D IN

G : F

un di

ng fo

r th

is s

tu dy

w as

o bt

ai ne

d fr

om th

e C

ou nt

y of

to ck

ho lm

R es

ea rc

h an

d D

ev el

op m

en t

Fu nd

, f ro

m th

e S

w ed

is h

G ov

er nm

en t S

oc ia

l M

in is

tr y

an d

fr om

e S

w ed

is h

A lc

oh ol

on op

ol y

R es

ea rc

h Fo

un da

tio n.

M ar

ai s

20 11

S TU

D Y

TY P

E: C

lu st

er r

an do

m iz

ed tr

ia l

C O

U N

TR Y:

S ou

th A

fr ic

S ET

TI N

G : 8

c lin

ic s

in a

c ho

se n

su b-

di st

ri ct

D U

R AT

IO N

O F

R EC

R U

IT M

EN T:

M ar

ch to

ep te

m be

r 20

D U

R AT

IO N

O F

TR IA

L: T

he r

ec ru

itm en

t pl

us fo

llo w

-u p

in te

rv ie

w s

st re

tc he

d ov

er a

ri od

o f 9

m on

th s

FO LL

O W

-U P

: I ni

tia l a

ss es

sm en

t i nt

er vi

la st

ed o

ne h

ou r.

2 fo

llo w

-u p

in te

rv ie

w s

m on

th a

nd a

h al

f a pa

rt ),

an d

a la

st fo

llo w

- up

in te

rv ie

w b

ef or

e th

e bi

rt h.

IN C

LU S

IO N

C R

IT ER

IA : 1

) A ll

pr eg

na nt

om en

a tt

en di

ng a

ny o

ne o

f t he

e ig

cl in

ic s

in th

e ar

ea , 2

) l es

s th

an 2

0 w

ee ks

eg na

nt , 3

) m or

e th

an 1

5 ye

ar s

of a

ge .

W om

en w

ho r

ep or

te d

no d

ri nk

in g

w er

e no

t ex

cl ud

ed .

N um

be r

of e

lig ib

le p

ar tic

ip an

ts : 7

11 Ex

cl ud

ed : 5

17 S

am pl

e si

ze : 1

94 A

ll cl

in ic

s in

th e

ar ea

, 8 , w

er e

cl us

te r

ra nd

om iz

ed In

te rv

en tio

n gr

ou p:

9 8

w om

en fr

om 4

nd om

iz ed

c lin

ic s

C on

tr ol

g ro

up : 9

6 w

om en

fr om

ra nd

om iz

ed c

lin ic

s ra

nd om

iz ed

to in

te rv

en tio

n gr

ou p,

a nd

co nt

ro l g

ro up

. N

um be

r in

cl ud

ed in

th e

an al

ys is

in th

e in

te rv

en tio

n gr

ou p:

9 7

N um

be r

in cl

ud ed

in th

e an

al ys

is in

th e

co nt

ro l g

ro up

: 8 2

IN TE

R V

EN TI

O N

: 1 ) I

ni tia

l a ss

es sm

en t i

nt er

vi ew

– la

st in

g an

ur –

in cl

ud ed

th e

co ns

en t f

or m

, t he

p er

so na

l q ue

st io

nn ai

re ,

th e

A lc

oh ol

U se

D is

or de

rs Id

en tifi

ca tio

n Te

st (A

U D

IT ),

ex pl

ai ni

th e

m ea

ni ng

o f A

U D

IT r

es ul

ts , B

ri ef

In te

rv en

tio n

(B I)

w ith

tt in

g dr

in ki

ng g

oa ls

, a nd

m ak

in g

no te

s in

a ta

ke -h

om e

al co

ho l

bo ok

le t.

2) In

tw o

fo llo

w -u

p in

te rv

ie w

s (a

m on

th a

nd a

h al

f ap

ar t)

, t he

B I c

on si

st ed

o f f

ee db

ac k

on d

ri nk

in g

be ha

vi ou

r, ne

go tia

tio ns

, g oa

l s et

tin g,

a nd

r ei

nf or

ce m

en t.

A q

ue st

io nn

ai re

c ha

ng es

in d

ri nk

in g

be ha

vi ou

r an

d bo

nd in

g w

as c

om pl

et ed

. Th

es e

in te

rv ie

w s

la st

ed 2

0 m

in ut

es o

n av

er ag

e. 3

) T he

la st

llo w

-u p

in te

rv ie

w b

ef or

e th

e bi

rt h

co m

pr is

ed a

B I a

fe ed

ba ck

o n

dr in

ki ng

b eh

av io

ur , c

om pl

et in

g a

qu es

tio nn

ai re

c ha

ng es

in d

ri nk

in g

be ha

vi ou

r, an

d co

m pl

et in

g a

se co

A U

D IT

. I nt

er vi

ew s

w er

e co

nd uc

te d

by tw

o tr

ai ne

d fie

ld w

or ke

rs .

In ce

nt iv

es in

th e

fo rm

o f a

fo od

p ar

ce l w

er e

gi ve

n to

a ll

pa rt

ic ip

an ts

in th

e tr

ia l.

C O

N TR

O L:

In vo

lv em

en t w

ith r

es po

nd en

ts w

as k

ep t t

o th

e m

in im

um th

at w

as a

llo w

ed e

th ic

al ly

: 1 ) T

he in

iti al

a ss

es sm

en t

in te

rv ie

w in

cl ud

ed th

e co

ns en

t f or

m , t

he p

er so

na l q

ue st

io nn

ai re

, th

e A

U D

IT , w

ri tt

en m

at er

ia l,

i.e . t

he ta

ke -h

om e

al co

ho l b

oo kl

et ,

an d

ap po

in tm

en t f

or th

e fo

llo w

-u p

in te

rv ie

w , 2

) t he

la st

fo llo

w -

up in

te rv

ie w

ju st

b ef

or e

th e

bi rt

h co

ns is

te d

of a

s ec

on d

A U

D IT

d a

qu es

tio nn

ai re

o n

ch an

ge s

in d

ri nk

in g

be ha

vi ou

M AT

ER N

A L

O U

TC O

M ES

: A

U D

IT s

co re

a t

po st

-i nt

er ve

nt io

n w

us ed

to m

ea su

re th

e in

te rv

en tio

n ef

fe ct

IN FA

N T

O U

TC O

M ES

: no

ET H

IC S

: T he

p ro

to co

l fo

r th

e st

ud y

w as

hi ca

lly a

pp ro

ve d

by a

u ni

ve rs

ity e

th ic

s co

m m

itt ee

IN FO

R M

ED C

O N

S EN

T: A

ll pa

rt ic

ip an

ts w

er e

gi ve

n th

e co

ns en

t f or

at th

e fir

st in

te rv

ie w

FU N

D IN

G Th

e st

ud y

w as

fu nd

by th

e W

es te

rn C

ap e

D ep

ar tm

en t o

f S oc

ia l

D ev

el op

m en

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

O ’C

on no

r 20

07 S

TU D

Y TY

P E:

C lu

st er

r an

do m

iz ed

nt ro

lle d

tr ia

C O

U N

TR Y:

U ni

te d

S ta

te s

S ET

TI N

G : c

om m

un ity

-b as

ed s

et tin

g; 1

2 ce

nt er

s of

th e

P ub

lic H

ea lth

F ou

nd at

io n

En te

rp ri

se s

M an

ag em

en t S

ol ut

io ns

S pe

ci al

up pl

em en

ta l N

ut ri

tio n

P ro

gr am

fo r

W om

en , I

nf an

ts , a

nd C

hi ld

re n;

P H

FE -W

D U

R AT

IO N

O F

R EC

R U

IT M

EN T:

J un

e 20

01 to

ar ch

2 00

FO LL

O W

-U P

: W om

en w

er e

sc re

en ed

a t

ev er

y m

on th

ly p

re na

ta l v

is it

an d,

if th

w er

e st

ill d

ri nk

in g,

w er

e pr

ov id

ed b

ri ef

te rv

en tio

n or

a ss

es sm

en t o

nl y.

W om

w er

e fo

llo w

ed to

th e

th ir

d tr

im es

te r

S cr

ee ne

d: 4

98 0

A gr

ee to

p ar

tic ip

at e:

4 08

4 U

se o

f a lc

oh ol

p os

t c on

ce pt

io n:

9 72

C ur

re nt

ly d

ri nk

in g

al co

ho l:

36 9

N um

be r

of p

ar tic

ip an

ts r

an do

m iz

ed : 3

45 In

te rv

en tio

n gr

ou p:

1 62

C on

tr ol

g ro

up : 1

83 N

um be

r in

cl ud

ed in

th e

an al

ys is

: In

te rv

en tio

n gr

ou p:

1 17

C on

tr ol

g ro

up a

t f ol

lo w

-u p:

13 8

O f 3

69 c

ur re

nt ly

d ri

nk in

g, 2

4 w

er e

re fe

rr ed

a n

al co

ho l t

re at

m en

t p ro

gr am

m e

(p ri

to r

an do

m iz

at io

n) .

IN TE

R V

EN TI

O N

: W ith

in th

e 6

ce nt

er s

in th

e br

ie f i

nt er

ve nt

io n

co nd

iti on

, p ar

tic ip

an ts

r ec

ei ve

d th

e sa

m e

co m

pr eh

en si

as se

ss m

en t o

f a lc

oh ol

u se

p lu

s a

st an

da rd

iz ed

w or

kb oo

k- dr

iv en

ie f i

nt er

ve nt

io n,

d es

ig ne

d sp

ec ifi

ca lly

to h

el p

w om

en r

ed uc

e al

co ho

l c on

su m

pt io

n du

ri ng

p re

gn an

cy . W

om en

w er

e sc

re en

at e

ve ry

m on

th ly

p re

na ta

l v is

it an

d, if

th ey

w er

e st

ill d

ri nk

in g,

er e

pr ov

id ed

b ri

ef in

te rv

en tio

n or

a ss

es sm

en t o

nl y.

T he

b ri

in te

rv en

tio n

re pr

es en

te d

a lo

gi ca

l e xt

en si

on o

f t he

in di

vi du

nu tr

iti on

e du

ca tio

n th

at w

om en

e nr

ol le

d in

W IC

a lr

ea dy

ce iv

e. A

b ri

ef in

te rv

en tio

n w

or kb

oo k

w as

d es

ig ne

d by

s tu

in ve

st ig

at or

s to

h el

p nu

tr iti

on is

ts s

ta nd

ar di

ze a

nd a

dm in

is te

r th

e in

te rv

en tio

n. T

he w

or kb

oo k

co ns

is te

d of

tr ad

iti on

al b

ri ef

te rv

en tio

n te

ch ni

qu es

, i nc

lu di

ng e

du ca

tio n

an d

fe ed

ba ck

, co

gn iti

ve b

eh av

io ra

l p ro

ce du

re s,

g oa

l s et

tin g,

a nd

c on

tr ac

tin g.

C O

N TR

O L:

W ith

in th

e 6

ce nt

er s

in th

e as

se ss

m en

t- o

nl y

co nd

iti on

, c ur

re nt

d ri

nk er

s re

ce iv

ed a

c om

pr eh

en si

as se

ss m

en t o

f a lc

oh ol

u se

a nd

w er

e ad

vi se

d to

s to

p dr

in ki

du ri

ng p

re gn

an cy

M AT

ER N

A L

O U

TC O

M ES

: 1)

M ax

im um

d ri

nk p

dr in

ki ng

o cc

as io

n 2)

T W

EA K

m ea

n 3)

C an

na bi

s us

e 4)

C oc

ai ne

u se

IN FA

N T

O U

TC O

M ES

: 1)

G es

ta tio

na l a

ge a

t de

liv er

y 2)

B ir

th w

ei gh

t 3)

B ir

th le

ng th

ET H

IC S

: P ro

to co

an d

co ns

en t f

or m

s w

er e

ap pr

ov ed

b y

th e

U ni

ve rs

ity o

f C

al ifo

rn ia

, L os

A ng

el es

, in

st itu

tio na

l r ev

ie w

ar d,

a nd

a C

er tifi

ca te

C on

fid en

tia lit

y w

ob ta

in ed

fr om

th e

N at

io na

l I ns

tit ut

e on

lc oh

ol A

bu se

a nd

lc oh

ol is

IN FO

R M

ED C

O N

S EN

W om

en p

ar tic

ip at

in g

in th

is s

tu dy

w er

e pr

ov id

ed w

ith a

c le

de sc

ri pt

io n

of th

e st

ud y

pr ot

oc ol

a nd

s ig

ne d

in fo

rm ed

c on

se nt

fo rm

O nd

er sm

a 20

05 S

TU D

Y TY

P E:

R an

do m

iz ed

c on

tr ol

le d

tr ia

C O

U N

TR Y:

U S

S ET

TI N

G : L

ar ge

u rb

an o

bs te

tr ic

h os

pi ta

l in

D et

ro it

D U

R AT

IO N

O F

R EC

R U

IT M

EN T:

b et

w ee

n S

ep te

m be

r 9,

2 00

3, a

nd F

eb ru

ar y

26 , 2

00 4

D U

R AT

IO N

O F

TR IA

L: N

ot s

ta te

FO LL

O W

-U P

: A r

es ea

rc h

as si

st an

t, bl

in d

to e

xp er

im en

ta l c

on di

tio n,

c on

ta ct

ed th

e pa

rt ic

ip an

ts a

ga in

b y

te le

ph on

e at

a n

av er

ag e

fo llo

w -u

p du

ra tio

n of

3 8.

6 da

(r an

ge 2

5– 77

IN C

LU S

IO N

C R

IT ER

IA : A

ll pa

rt ic

ip an

w er

e po

st pa

rt um

w om

en w

ho h

ad g

iv en

rt h

at a

la rg

e ur

ba n

ob st

et ri

c ho

sp ita

l an

d w

ho e

nd or

se d

an y

ill ic

it dr

ug u

se in

e m

on th

b ef

or e

be co

m in

g pr

eg na

nt .

P ar

tic ip

at io

n w

as fu

rt he

r lim

ite d

to th

os e

w ho

h ad

s le

pt s

in ce

g iv

in g

bi rt

h, th

os e

w ho

ul d

un de

rs ta

nd s

po ke

n En

gl is

h, w

er e

be tw

ee n

18 a

nd 4

5 ye

ar s,

a nd

h ad

n ot

b ee

n ad

m in

is te

re d

na rc

ot ic

p ai

n m

ed ic

at io

n in

e pa

st 3

h ou

rs .

EX C

LU S

IO N

C R

IT ER

IA : N

ot s

ta te

d N

um be

r of

p ar

tic ip

an ts

r an

do m

iz ed

: 3 0

(1 5

ra nd

om iz

ed to

in te

rv en

tio n

gr ou

p, a

nd 1

5 to

nt ro

l g ro

up ).

P ar

tic ip

an ts

h ad

h ig

h ra

te s

of c

an na

bi s

an d

co ca

in e

us e.

T he

re w

er e

no s

ig ni

fic an

t di

ff er

en ce

s be

tw ee

n in

te rv

en tio

n an

d co

nt ro

l g ro

up s

on a

ny b

as el

in e

su bs

ta nc

e- us

e va

ri ab

le s.

IN TE

R V

EN TI

O N

: a ss

es sm

en t p

lu s

in te

rv en

tio n

co nd

iti on

s G

R O

U P

P ar

tic ip

an ts

v ie

w ed

p er

so na

liz ed

fe ed

ba ck

, t he

p ro

s an

d co

of d

ru g

us e,

a nd

o pt

io na

l g oa

l- se

tt in

g in

c ou

nt er

ba la

nc ed

de r.

Th re

e vi

su al

a na

lo gu

e- sc

al e

ite m

s fr

om th

e m

ot iv

at io

n to

an ge

m ea

su re

w er

e pr

es en

te d

af te

r ea

ch c

ou nt

er ba

la nc

co m

po ne

nt .

C O

N TR

O L:

A ss

es sm

en t o

nl y

G R

O U

P P

ar tic

ip an

ts w

er e

on ly

a ss

es se

d fo

r dr

ug u

se .

M AT

ER N

A L

O U

TC O

M ES

: D

ru g

us e

S er

vi ce

in vo

lv em

en t

M ot

iv at

io n

at fo

llo w

-u p

IN FA

N T

O U

TC O

M ES

: N

on e

ET H

IC S

: W ay

ne S

ta te

ni ve

rs ity

In st

itu tio

na l

R ev

ie w

B oa

rd .

IN FO

R M

ED C

O N

S EN

A ll

pa rt

ic ip

an ts

ov id

ed v

er ba

l in

fo rm

ed c

on se

fo r

th e

sc re

en in

g an

d w

ri tt

en in

fo rm

co ns

en t f

or th

e fu

ll st

ud y.

FU N

D IN

G : G

ra nt

s D

A 00

51 6

an d

D A

14 62

1 fr

om th

e N

at io

na l

In st

itu te

o n

D ru

g A

bu se

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Tz il

os 2

01 1

S TU

D Y

TY P

E: R

an do

m iz

ed c

on tr

ol le

d tr

ia l

C O

U N

TR Y:

U S

S ET

TI N

G : I

nn er

c ity

p re

na ta

l c ar

e cl

in ic

a t

M ic

hi ga

n (e

xa ct

c ity

n ot

s ta

te d)

D U

R AT

IO N

O F

R EC

R U

IT M

EN T:

N ot

s ta

te d.

D U

R AT

IO N

O F

TR IA

L: N

ot s

ta te

FO LL

O W

-U P

: W om

en w

er e

fo llo

w ed

-u p

on e

m on

th a

ft er

th e

in te

rv en

tio n,

w ith

a ve

ra ge

llo w

-u p

tim e

of 3

3 da

ys (S

D : 7

.9 , r

an ge

: 2 5

– 72

d ay

s) . F

ol lo

w -u

p w

as c

on du

ct ed

o ve

r th

e te

le ph

on e

fo r

ap pr

ox im

at el

y 10

– 1

5 m

in ut

es , a

nd in

cl ud

ed T

LF B

a ss

es sm

en t o

f dr

in ki

ng in

th e

pa st

m on

th .

IN C

LU S

IO N

C R

IT ER

IA : B

ei ng

p re

gn an

t, be

tw ee

n ag

es 1

8 an

d 45

(w ith

a t l

ea st

m on

th e

xp ec

te d

ge st

at io

n re

m ai

ni ng

), ab

to u

nd er

st an

d sp

ok en

E ng

lis h,

a nd

e ith

(1 ) m

ee tin

g T-

A C

E cr

ite ri

a fo

r pr

ob le

al co

ho l u

se , (

2) e

xc ee

di ng

th e

N at

io na

l In

st itu

te o

n A

lc oh

ol A

bu se

a nd

A lc

oh ol

is m

IA A

A ) ‘

‘n or

m al

’’ se

ns ib

le d

ri nk

in g

lim its

fo re

p re

gn an

cy (m

or e

th an

s ev

st an

da rd

d ri

nk s

a w

ee k

or m

or e

th an

tw o

dr in

ks a

t a ti

m e)

, o r

(3 ) r

ep or

tin g

dr in

ki ng

a t

le as

t o ne

ti m

e pe

r m

on th

d ur

in g

pr eg

na nc

EX C

LU S

IO N

C R

IT ER

IA : I

na bi

lit y

to p

ro vi

in fo

rm ed

c on

se nt

(e .g

., du

e to

p sy

ch os

is ,

in to

xi ca

tio n,

o r

ot he

r cl

ea r

co gn

iti ve

pa ir

m en

t) , i

na bi

lit y

to c

om m

un ic

at e

En gl

is h,

a nd

n ot

h av

in g

ac ce

ss to

a p

ho ne

or fo

llo w

-u p)

N um

be r

of p

ar tic

ip an

ts r

an do

m iz

ed : 5

0 (2

7 ra

nd om

iz ed

to in

te rv

en tio

n gr

ou p,

a nd

2 3

co nt

ro l g

ro up

IN TE

R V

EN TI

O N

: C om

pu te

r- de

liv er

ed s

in gl

e- se

ss io

n br

ie f

in te

rv en

tio n

P ar

tic ip

an ts

s el

f- ad

m in

is te

re d

an d

so le

ly c

om pu

te r-

de liv

er ed

, w ith

a ss

is ta

nc e

av ai

la bl

e fr

om th

e in

ve st

ig at

or a

s ne

ed ed

a nd

it la

st ed

fo r

15 –

2 0

m in

ut es

. Th

e so

ft w

ar e

ta ilo

re d

co nt

en t b

as ed

o n

th e

cu rr

en t d

ri nk

in g

st at

us o

f e ac

h pa

rt ic

ip an

t. Fo

r w

om en

w ho

r ep

or te

d th

al re

ad y

qu it,

th e

na rr

at or

p re

se nt

ed a

s ec

tio n

th at

fo cu

se d

re la

ps e

pr ev

en tio

n (‘‘

M y

pl an

to r

em ai

n ab

st in

en t’’

) w hi

le a

sk in

g th

e pa

rt ic

ip an

t t o

pr ov

id e

th e

re as

on s/

be ne

fit s

to th

em o

f h av

in g

m ad

e th

is c

ha ng

e. Th

e re

m ai

ni ng

w om

en w

er e

as ke

d ab

ou t t

he ir

c ur

re nt

in te

re st

q ui

tt in

g. T

ho se

r ep

or tin

g a

go al

o f i

m m

ed ia

te a

bs tin

en ce

ov ed

m or

e qu

ic kl

y to

a s

ec tio

n co

ns is

te nt

w ith

p ha

se 2

o f M

I (p

ri m

ar ily

g oa

l s et

tin g)

, w he

re as

th os

e w

ho d

id n

ot w

is h

to q

ui t

re ce

iv ed

e le

m en

ts c

on si

st en

t w ith

p ha

se 1

o f M

I ( e.

g. p

ro s

an d

co ns

, f ee

db ac

k) .

C O

N TR

O L:

P ar

tic ip

an ts

w er

e ad

m in

is te

re d

se ri

es o

f q ue

st io

ab ou

t T V

s ho

w s,

v id

eo s

of p

op ul

ar e

nt er

ta in

er s/

sh ow

s, fo

llo w

by r

eq ue

st s

fo r

ra tin

gs o

f s ub

je ct

iv e

pr ef

er en

ce . D

ur at

io n

w as

ui va

le nt

to th

at o

f i nt

er ve

nt io

n gr

ou p.

C O

-I N

TE R

V EN

TI O

N S

: A ll

el ig

ib le

p ar

tic ip

an ts

r ec

ei ve

d gi

ft c

ar ds

qu iv

al en

t t o

$3 0)

fo r

th ei

r pa

rt ic

ip at

io n

at th

e ba

se lin

e vi

si t.

.W om

en w

ho c

om pl

et ed

th e

fo llo

w -u

p se

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

REFERENCES TO STUDIES

Chang 1999 Published and unpublished data Chang G, Wilkins-Haug L, Berman S, Goetz M A. Brief intervention for alcohol use in pregnancy: a randomized trial. Addiction 1999;94(10):1499-1508.

Chang 2005 Published and unpublished data Chang Grace, McNamara Tay K, Orav E John, Koby Danielle, Lavigne Alyson, Ludman Barbara, et al. Brief intervention for prenatal alcohol use: a randomized trial. Obstetrics and Gynecology 2005;105(51):991-998. McNamara, T. K.Orav, E. J.Wilkins-Haug, L.Chang, G.. Risk during pregnancy--self-report versus medical record. Am J Obstet Gynecol 2005;193(6):1981-5.

Fleming 2008 Fleming Michael F, Lund Michael R, Wilton Georgiana, Landry Mary, Scheets Dawn. The Healthy Moms Study: the efficacy of brief alcohol intervention in postpartum women. Alcoholism, clinical and experimental research 2008;(9):1600-6. Wilton, G.Moberg, P.Fleming, M. F.. The effect of brief alcohol intervention on postpartum depression. MCN The American Journal of Maternal/Child Nursing 2009;34(5):297-302.

Handmaker 1999 Handmaker, N. S.Miller, W. R.Manicke, M.. Findings of a pilot study of motivational interviewing with pregnant drinkers. Journal of Studies on Alcohol 1999;(2):285-7.

Magnusson 2005 Magnusson Asa, Göransson Mona, Heilig Markus. Unexpectedly high prevalence of alcohol use among pregnant Swedish women: failed detection by antenatal care and simple tools that improve detection. Journal of Studies on Alcohol 2005;(2):157-64.

Marais 2011 Published and unpublished data Marais Sandra, Jordaan Esmé, Viljoen Dennis, Olivier Leanade, Waal Johanna, Poole Caroline. The effect of brief interventions on the drinking behaviour of pregnant women in a high-risk rural South African community: a cluster randomized trial. Early Child Development and Care 2011;181(4):463-474.

O'Connor 2007 Published and unpublished data O'Connor Mary J, Whaley Shannon E. Brief intervention for alcohol use by pregnant women. American Journal of Public Health 2007;97(2):252-258.

Ondersma 2005 Published and unpublished data Ondersma Steven J, Chase Sara K, Svikis Dace S, Schuster Charles R. Computer-based brief motivational intervention for perinatal drug use. J Subst Abuse Treat 2005;28(4):305-12.

Tzilos 2011 Published and unpublished data Tzilos, G. K.Ondersma, S. J.. A Randomized phase i trial of a brief computer-delivered intervention for alcohol use during pregnancy. Journal of Women's Health 2011;20(10):1517-1524.

Whaley 2003 Published and unpublished data Whaley Shannon E, O'Connor Mary J. Increasing the report of alcohol use among low-income pregnant women. Am J Health Promot 2003;17(6):369-72.

EXCLUDED STUDIES

Armstrong 2009 Armstrong Mary Anne, Kaskutas Lee Ann, Witbrodt Jane, Taillac Cosette J, Hung Yun-Yi, Osejo Veronica M, et al. Using drink size to talk about drinking during pregnancy: a randomized clinical trial of Early Start Plus. Soc Work Health Care 2009;48(1):90-103.

Hingson 1986 Hingson R, Zuckerman B, Amaro H, Frank D A, Kayne H, Sorenson J R, et al. Maternal marijuana use and neonatal outcome: uncertainty posed by self-reports. Am J Public Health 1986;76(6):667-9.

Osterman 2012 Osterman Robin L, Dyehouse Janice. Effects of a motivational interviewing intervention to decrease prenatal alcohol use. West J Nurs Res 2012;34(4):434-54.

ONGOING STUDIES

Van der Wulp 2012 Published and unpublished data Van Der Wulp, N. Y.Hoving, C.Van Dalen, W.De Vries, H.. Preventing prenatal alcohol use via health counseling by midwives and Internet-based computer tailored feedback: A randomized controlled trial. Journal of Population Therapeutics and Clinical Pharmacology 2012;19(3):e419-e420.

Wilson 2012 Unpublished data only Wilson Graeme B, McGovern Ruth, Antony Grace, Cassidy Paul, Deverill Mark, Graybill Erin, et al. Brief intervention to reduce risky drinking in pregnancy: study protocol for a randomized controlled trial. Trials 2012;13:174.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

FIGURES

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Evidence Profile 2: Psychosocial interventions for harmful use and dependence on alcohol and other substances in pregnancy

Evidence question: For pregnant and postpartum women with harmful alcohol or drug use, do some psychosocial interventions result in better maternal, fetal and infant outcomes than other psychosocial interventions or usual care?

Selection criteria for the systematic review: Study design: RCTs

Population: Pregnant or postpartum women with harmful use of alcohol or drugs.

Interventions: Psychological or social interventions longer in duration and intensity than brief interventions.

Control: Other psychosocial interventions or usual care (usual obstetric care or usual specialist care).

Outcomes: The key outcomes selected were:

Outcome Importance (0-9)

Maternal: Substance use 8.22

Maternal: Retention in substance use treatment 7.89

Infant: Birthweight 6.78

Custody of infant 6.56

Infant: Gestational age at delivery 6.44

Infant: Birth defects 6.00

Infant: Neonatal death 5.89

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

EVIDENCE TO RECOMMENDATIONS TABLE

Psychosocial interventions for harmful use and dependence on alcohol and other substances in pregnancy

Summary of evidence: see also summary of findings and GRADE tables below

Summary of RCT evidence: With the exception of home visits, all RCTs compared a specific form of psychosocial intervention to treatment-as- usual in the specialist drug and alcohol treatment service, not usual obstetric care. As such, they are comparing one form of psychosocial intervention with another, since all specialist treatment is considered to include a component of psychosocial care. Motivational Interviewing (MI) Two randomized clinical trials have compared motivational interviewing (MI) to treatment-as-usual or educational control. Findings do not support the superiority of MI to treatment-as-usual or educational control, with similar results for maternal retention in treatment and maternal substance abuse. Data are absent regarding neonatal outcomes. Both samples were identified as needing substance-abuse treatment.

Cognitive Behavioural Therapy (CBT) Two randomized clinical trials compared cognitive behavioural therapy (CBT) to treatment-as-usual. Findings suggest that CBT may be superior to treatment-as-usual in terms of treatment retention, reductions in sex and needle risk, and occurrence of preterm birth. One sample was in methadone treatment and the other sample was using alcohol or another illicit substance exclusive of opiates.

Contingency Management (CM) Five randomized clinical trials compared contingency management (CM) to treatment-as-usual. Findings support the superiority of CM to treatment-as-usual in terms of retention in treatment, percentage of negative urines, and weeks of continuous cocaine abstinence. Three of the samples met requirements for methadone maintenance, one sample met requirements for opioid or cocaine dependence, and one met criteria for cocaine dependence.

Other Standard management home visits have been shown not to be effective. A review of randomized trials (Turnbull & Osborn, 2012) suggests that home visits following delivery are not effective in reducing maternal retention in treatment, substance use or alcohol use. Findings from 4 other studies (Butz et al., 1998; Grant et al., 1996; Quinlivan et al., 2000; Schuler et al., 2000) omitted by Turnbull and Osborn (2013) are consistent with their conclusion.

Educational and counselling interventions may encourage women to cease alcohol use or reduce the amount of alcohol consumed during pregnancy (Stade, 2009).

Benefits and harms

Benefits • Pregnancy presents a unique opportunity to help support women to reduce and ideally cease alcohol and/or illicit substance use (Chang et al., 2000)

• Depending on the substance of use, psychosocial interventions are considered to be superior to usual care in terms of: – reduction in harmful consumption – reduction in risk to fetus – increase in birthweight – improved general health of pregnant women – improved maternal psychological well-being – less risk of fetotoxicity – improved perinatal outcomes (e.g. reduction in preterm births, increased overall

birthweights, reduction in number of low-birthweight infants) – reductions in congenital defects or anomalies (Lui, Terplan, & Smith, 2008; Terplan & Lui,

2007) • There is a high incidence of mental health disorders in opioid-dependent pregnant women and

psychosocial interventions may be appropriate in many instances (Martin et al., 2009) • Considerable research supports a variety of psychosocial interventions for substance use and

co-occurring mental disorders in non-pregnant populations (Drake, O’Neal, & Wallach, 2008) • Retention in substance abuse treatment is an important factor in reducing illicit substance use

(Laken, 1997)

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

EVIDENCE TO RECOMMENDATIONS TABLE

Harms • Physical and mental symptoms associated with reduction or cessation of alcohol or substance use

• Possible development of depression or anxiety as a result of cessation or reduction of alcohol or illicit substance use

• Possible verbal and/or physical abuse by the partner as a result of the pregnant woman’s behaviour change

• Possible risk of switching from one substance to another substance • Between 7% and 15% of individuals participating in psychosocial interventions to treat

substance use disorders may be worse off after treatment than before treatment. This decline in functioning may be due to a lack of bonding with the provider, lack of goal direction and monitoring, confrontation, criticism, and high emotional arousal and stigma (Moos, 2012)

• Stigmatization-risk of incarceration/loss of infant in punitive systems • Economic and time burdens imposed by need to attend interventions • Conflict with partner/family/employer over time/ commitment to intervention

Values and preferences

In favour: Pregnant woman

Health-care worker

Community

• Personal contact and support • Development of coping strategies • Commitment to behaviour change

• Opportunity to intervene • Positive means of intervening • Effective means of intervening

• Possible reduction of crime in the community • Possible reduction of sexually transmitted infection (STI) risk in the community • Possible positive responses from partners, family and, co-workers

Against: Pregnant woman

Health-care workers

Community

• Stigmatization of pregnant women who drink alcohol or use illicit substances during pregnancy • Stigmatization of women who are in need of counselling • Negative responses from partners, family and co-workers

• Time and inconvenience involved in referral for intervention • Concern about effectiveness of intervention • Resentment of diversion of resources to intervention

• Resentment of resources used for intervention • Disbelief in effectiveness • Partners/family may see changes in woman undergoing intervention as harmful

Costs and feasibility

Costs • Additional costs beyond routine care • Trained staff and a sustainable programme are required. Training for management of substance

use disorders on the part of obstetricians and their staff can increase their self-efficacy regarding the treatment of patients who use substances (Schumacher, 2000).

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

EVIDENCE TO RECOMMENDATIONS TABLE

Feasibility (including economic consequences)

• Inconvenient for women • Requires patient monitoring to ensure patient remains enrolled in and engaged in the

psychosocial intervention • A comprehensive care model in which obstetrical care is part of a women-centered, trauma-

informed program would be the best model of care – and also potentially the costliest • A therapeutic workplace has been shown to be superior to usual care in reducing opioid and

cocaine use in pregnant women with substance use disorders (Silverman et al., 2001) • Well-child care visits may not be sufficient to prevent deterioration in competence and social

isolation in postpartum women who use substances (Taylor, 1998)

REFERENCES

Butz AM, Lears MK, O'Neil S, et al. Home intervention for in utero drug-exposed infants. Public Health Nurs 1998;15:307-18.

Chang G, Goetz MA, Wilkins-Haug L, et al. A brief intervention for prenatal alcohol use: an in-depth look. J Subst Abuse Treat 2000;18:365-9.

Drake RE, O'Neal EL, Wallach MA. A systematic review of psychosocial research on psychosocial interventions for people with co-occurring severe mental and substance use disorders. J Subst Abuse Treat 2008;34:123-38.

Grant BF. Toward an alcohol treatment model: a comparison of treated and untreated respondents with DSM-IV alcohol use disorders in the general population. Alcohol Clin Exp Res 1996;20:372-8.

Laken MP, McComish JF, Ager J. Predictors of prenatal substance use and birthweight during outpatient treatment. J Subst Abuse Treat 1997;14:359-66.

Lui S, Terplan M, Smith EJ. Psychosocial interventions for women enrolled in alcohol treatment during pregnancy. Cochrane Database Syst Rev 2008:CD006753.

Martin PR, Arria AM, Fischer G, et al. Psychopharmacologic management of opioid-dependent women during pregnancy. Am J Addict 2009;18:148-56.

Moos RH. Iatrogenic effects of psychosocial interventions: treatment, life context, and personal risk factors. Subst Use Misuse 2012;47:1592-8.

Schuler ME, Nair P, Black MM, et al. Mother-infant interaction: effects of a home intervention and ongoing maternal drug use. J Clin Child Psychol 2000;29:424-31.

Schumacher L, Pruitt JN, 2nd, Phillips M. Identifying patients "at risk" for alcohol withdrawal syndrome and a treatment protocol. J Neurosci Nurs 2000;32:158-63.

Silverman K, Svikis D, Robles E, et al. A reinforcement-based therapeutic workplace for the treatment of drug abuse: six-month abstinence outcomes. Exp Clin Psychopharmacol 2001;9:14-23.

Stade BC, Bailey C, Dzendoletas D, et al. Psychological and/or educational interventions for reducing alcohol consumption in pregnant women and women planning pregnancy. Cochrane Database Syst Rev 2009:CD004228.

Taylor JA, Kemper KJ. Group well-child care for high-risk families: maternal outcomes. Arch Pediatr Adolesc Med 1998;152(6):579-84.

Terplan M, Lui S. Psychosocial interventions for pregnant women in outpatient illicit drug treatment programs compared to other interventions. Cochrane Database Syst Rev 2007:CD006037.

Turnbull C, Osborn DA. Home visits during pregnancy and after birth for women with an alcohol or drug problem. Cochrane Database Syst Rev 2012;1:CD004456.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Draft recommendations: o Pregnant women with dependent alcohol or other substance use (or harmful alcohol or other substance

use not responding to brief interventions) should be offered intensive psychosocial support and treatment.

o Postpartum women with substance dependence should be offered intensive psychosocial support and treatment including home visits, parenting support, psychotherapy and social assistance.

Final recommendations:

RECOMMENDATION 3

Health-care providers managing pregnant or postpartum women with alcohol or other substance use disorders should offer comprehensive assessment and individualized care.

Strength of recommendation: Conditional Quality of evidence: Very low

Remarks: • A comprehensive assessment of women using alcohol or drugs in pregnancy and the postpartum period includes

an assessment of patterns of substance use, medical or psychiatric comorbidity, family context, as well as social problems.

• Individualized care involves selecting appropriate psychosocial interventions of different intensity based on the particular needs of the pregnant women and the resources available. Psychosocial interventions include a number of psychological treatments and social supports, ranging from lesser to higher intensity. The psychosocial treatment and support referred to in this section is a more intensive set of interventions typically delivered by people with specific training in the management of substance use disorders, and usually includes repeated contact with the patient. The kinds of specific psychological techniques considered in this category include cognitive behavioural therapy, contingency management and motivational enhancement. The kinds of social support referred to in this section include assistance with accommodation, vocational training, parenting training, life-skills training, legal advice, home visiting and outreach.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Factors in considering the strength of the recommendation (recommendation 3):

Research recommendations

o Better reporting and agreement on standardized designs and outcomes is needed.

o Stronger RCT evidence of effect is needed, in particular comparing interventions with different levels of intensity and models of care with different levels of comprehensiveness, and including cost-effectiveness analyses.

Factor Decision

Is there high or moderate quality evidence? The higher the quality of evidence, the more likely is a strong recommendation.

Yes

Are the expected values and preferences clearly in favour of the recommendation? Yes

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

FOREST PLOTS OF CASE MANAGEMENT COMPARISON

RISK OF BIAS IN EACH TRIAL INCLUDED IN THE CASE MANAGEMENT COMPARISON

Random sequence generation (selection

bias)

Allocation concealment

(selection bias)

Blinding of participants

and personnel

(performance bias)

Blinding of outcome

assessment (detection

bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting

bias) Other bias

Jansson 2005

Walton-Moss 2006 was an incompletely reported trial and as a result a risk of bias assessment was not conducted.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

INTENSIFIED CASE MANAGEMENT COMPARED TO ROUTINE CASE MANAGEMENT FOR PREGNANT OR POSTPARTUM WOMEN WITH PROBLEMATIC SUBSTANCE USE

Patient or population: Pregnant or postpartum women with problematic substance use Settings: Specialist treatment outpatient Intervention: Intensified case management Comparison: Routine case management

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Routine case management

Intensified case management

Maternal treatment retention (intention to treat analysis) Follow-up: 0–4 months

382 per 1000 409 per 1000 (210 to 791)

RR 1.07 (0.55 to 2.07)

56 (1 study)

⊕ VERY LOW1,2

Maternal urine positive for opiates other than methadone Follow-up: 0–4 months

160 per 1000 267 per 1000 (78 to 912)

RR 1.67 (0.49 to 5.7)

40 (1 study)

⊕ VERY LOW1,2

Maternal urine positive for cocaine Follow-up: 0–4 months

160 per 1000 29 per 1000 (2 to 502)

RR 0.18 (0.01 to 3.14)

40 (1 study)

⊕ VERY LOW1,2

Infant birthweight See comment See comment Not estimable

50 (1 study)

See comment Not measured

Infant gestational age

See comment See comment Not estimable

50 (2 studies)

See comment Not measured

Infant custody See comment See comment Not estimable

179 (1 study)

See comment Not measured

Infant head circumference

See comment See comment Not estimable

30 (1 study)

See comment Not measured

Infant birth defects See comment See comment Not estimable

See comment Not measured

CI: Confidence interval; RR: Risk ratio. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Risk of bias: rated as very serious. Randomization did not result in similar numbers in each group indicating a possible effect of chance or selection bias. Random

generation and allocation concealment methods were not reported. Blinding was not possible for participants or providers and attrition was high. 2 Imprecision: The sample size is small and the confidence interval wide.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Tr ia

l I D

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nt ry

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ti on

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

RISK OF BIAS IN EACH TRIAL INCLUDED IN THE COGNITIVE BEHAVIOURAL THERAPY COMPARISON

Random sequence generation (selection

bias)

Allocation concealment

(selection bias)

Blinding of participants

and personnel

(performance bias)

Blinding of outcome

assessment (detection

bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting

bias) Other bias

O'Neill 1996

Yonkers 2012

FOREST PLOTS OF COGNITIVE BEHAVIOURAL THERAPY COMPARISON

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

COGNITIVE BEHAVIOURAL THERAPY COMPARED TO CONTROL FOR PREGNANT OR POSTPARTUM WOMEN WITH PROBLEMATIC SUBSTANCE USE

Patient or population: Pregnant or postpartum women with problematic substance use Settings: General treatment settings (antenatal) and specialist substance use programmes: Outpatient Intervention: Cognitive behavioural therapy Comparison: Control (usual care or brief advice)

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Control

Cognitive Behavioural Therapy

Maternal treatment retention Participants retained after 6 weeks of treatment or participants attending at least one session Follow-up: 6–24 weeks

919 per 1000 846 per 1000 (781 to 928)

RR 0.92 (0.85 to 1.01)

275 (2 studies)

⊕⊕ LOW1,2

Maternal substance use % days used drugs or alcohol in past month measured at delivery Follow-up: mean 12 weeks3

The proportion of days with drug or alcohol use in the intervention group was 1% higher (5.05 lower to 7.05 higher)

163 (1 study)

⊕⊕ LOW4

Mixed effects negative binomial regression test for group by time interaction found no significant dif- ferences between groups at delivery and 3 mnths pp

Low birthweight < 2500g Medical records

202 per 1000 146 per 1000 (73 to 289)

RR 0.72 (0.36 to 1.43)

160 (1 study)

⊕⊕ LOW4,5

3 women had an unknown birthweight and were not included in the analysis

Preterm birth < 37 weeks From medical records

202 per 1000 101 per 1000 (47 to 221)

RR 0.5 (0.23 to 1.09)

163 (1 study)

⊕⊕ LOW4,5

Infant birth defects See comment See comment Not estimable

— See comment Not measured

Infant custody See comment See comment Not estimable

— See comment Not measured

Infant head circumference

See comment See comment Not estimable

— See comment Not measured

CI: Confidence interval; RR: Risk ratio. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Risk of bias: Rated as Serious: Lack of reporting of sequence generation and allocation concealment in O'Neill 1996 and the loss-to-follow up > 10% resulted in

down-grading for risk of bias. A likely lack of blinding for providers and participants in both trials may have introduced performance bias. 2 Indirectness: Rated as Serious. The measurement for treatment retention used in the analysis is a proxy measure for both trials. In O'Neill 1996 completion and

availability for 6 week follow-up is used but not all sessions would have been attended as appointments were missed at an average of mean 2.9 (SD 6.45) with a range of 0–11. In Yonkers 2012 the proxy measure is attending at least one of 6 session during the entire study period which continued to 3 months postpartum.

3 Inclusion criteria was women of < 28 weeks pregnant. The mean duration of follow-up was calculated as from 28 weeks to delivery although women may have been in treatment for longer if enrolled before 28 weeks.

4 Risk of Bias: Rated as Serious. This well-conducted trial Yonkers 2012 was down-graded on the basis of a likely lack of blinding which may have introduced performance bias.

5 Imprecision: The event rate is very low < 300.

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

FOREST PLOTS OF CONTINGENCY MANAGEMENT COMPARISON

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Usual Care Contingency Management

Maternal % urine positive for opioids1 Follow-up: 13–31 weeks

See comment See comment Not estimable1

14 (1 study)

⊕ VERY LOW2,3

The GRADE assessment is specific to this single trial. Results of other trials from which data could not be extracted are included in the footnotes.

Maternal % urine negative for cocaine4 Follow-up: 24 weeks

The mean maternal % urine negative for cocaine in the intervention groups was 13.9 higher (0.53 to 27.27 higher)

71 (1 study)

⊕ VERY LOW5,6

This trial also reported weeks of continuous cocaine abstinence & reported a statistically significant favourable effect of CM (F (1.141) = 7.76; p < 0.01)

Maternal % urine positive for cocaine7 Follow-up: 13–31 weeks

See comment See comment Not estimable7

14 (1 study)

⊕ VERY LOW2,3

The GRADE assessment is specific to this single trial. Results of other trials from which data could not be extracted are included in the footnotes.

Maternal retention in treatment8 Various proxy measures Follow-up: 2–24 weeks

See comment See comment Not estimable8

165 (3 studies)

⊕ VERY LOW2,9,10,11

Treatment duration was varying across trials and different proxy measures were used for retention e.g. no of prenatal visits. The results were thus not pooled.

Birthweight Grams

The mean birthweight ranged across control groups from 2942-2996 gm

The mean birthweight in the intervention groups was 17.29 lower (573.03 lower to 538.45 higher)

103 (2 studies)

⊕ VERY LOW12,13,14

CONTINGENCY MANAGEMENT COMPARED TO USUAL CARE FOR PREGNANT OR POSTPARTUM WOMEN WITH PROBLEMATIC SUBSTANCE USE

Patient or population: Pregnant or Postpartum women with problematic substance use Settings: Residential, inpatient and outpatient Intervention: Contingency Management Comparison: Usual Care

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

CI: Confidence interval. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Jones 2001 reported a significant effect of CM on the rate of opioid positive urine samples in day 8 - 14 (outpatient) (F (1.78) = 5.76; p =< 0.05) and this effect

disappeared after vouchers were no longer provided after week 2. Jones 2011 reported that there was no statistically significant difference between heroin positive urines in the last 30 days between the groups. Tuten 2012 reported no statistically significant difference in the first opioid-positive assessment time point between the fixed combined with escalating voucher group compared with the control group (F(1,78.0) = 1.05; p = 0.31) and between the fixed and escalating groups (F(1,92.4) = 1.23; p = 0.27).

2 Risk of Bias: Rated as Very serious. No reporting of randomization sequence, no blinding and high attrition. 3 Imprecision: Rated as Very Serious. This is a very small trial (N = 20) with 14 analysed. The risk of imprecision is very high. 4 Tuten 2012 reported no statistically significant differences in the the number of cocaine-negative urine tests between the combined fixed with escalating voucher

group compared with the control group (F1,54.3) = 0.01; p = 0.91) and between the fixed and escalating voucher groups (F(1,88.7) = 0.09; p = 0.76). 5 Risk of bias: Rated as Very Serious. The high rate of attrition and lack of blinding resulted in down-grading this trial. 6 Imprecision: Rated as VERY SERIOUS. The 95% confidence interval is very wide. 7 Jones 2001 reported a statistically significant favourable effect of CM on the rate of cocaine-positive urine from day 8 to 14 (F(1,78) - 7.05); p =< 0.05). This effect

disappeared after the vouchers were stopped at the end of week 2. Jones 2011 reported no statistically significant effect between groups for cocaine-positive urine.

8 The results from the three trials favoured contingency management over usual care for maternal retention in treatment. Carroll 1995 (N = 14 analysed) found no of prenatal visits was statistically significantly higher (CM: Mean = 14.7; SD: 5.9)(Usual Care: Mean = 5.1; SD: 3.6). In Jones 2001 (N = 80 analysed) participants in CM attended statistically significant more treatment days (CM: Mean = 12.1; SD: 2.3)(Usual Care: Mean = 10.6; SD: 2.4). In Schottenfeld 2011 (N = 71 analysed) participants in CM attended statistically significantly more therapy sessions (CM: Mean: 25.3; SD: 13.7)(Usual Care: Mean = 19.9; SD: 12.8).

9 Risk of bias: Rated as Very Serious. Jones 2001 and Schottenfeld 2001 randomized adequately. However the lack of provider blinding across all three trials and the high attrition in two of the three trials, resulted in overall downgrading.

10 Indirectness: Rated as Serious. Treatment duration was varying across trials and different proxy measures were used for retention e.g. no of prenatal visits versus no of groups attended

11 Imprecision: Rated as Serious. This was difficult to rate as the measures were varying, but within each trial the 95% confidence intervals were large and so overall it was down-graded for imprecision.

12 Risk of Bias: Rated as Very Serious. The high rate of attrition in Jones 2011 and Carroll 1995 resulted in the risk of bias rated as very serious. In addition, lack of blinding may result in a high risk of performance bias.

13 Inconsistency: Rated as Serious. There was unexplained heterogeneity present. 14 Imprecision: The confidence interval was wide and the overall sample size small.

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Usual Care Contingency Management

Infant gestational age at delivery Weeks

The mean infant gestational age at delivery in the intervention groups was 1.4 higher (0.96 lower to 3.76 higher)

14 (1 study)

⊕ VERY LOW2,3

GA at delivery also reported in Jones 2011 (N = 89) by Poisson regression: GA on delivery: CM (Mean 37.2; SE 1.1); Usual Care (Mean: 38.5; SE 1.6); P = 0.52

Infant custody See comment See comment Not estimable

— See comment None of the five included trials measured or reported this as an outcome.

Infant birth defects See comment See comment Not estimable

— See comment None of the five included trials measured or reported this as an outcome.

Infant head circumference

See comment See comment Not estimable

— See comment None of the five included trials measured or reported this as an outcome.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

RISK OF BIAS IN EACH STUDY INCLUDED IN THE HOME VISITS COMPARISON

FOREST PLOTS OF HOME VISITS (FROM COCHRANE REVIEW SO NUMBERING NOT SEQUENTIAL)

Random sequence generation (selection

bias)

Allocation concealment

(selection bias)

Blinding of participants

and personnel

(performance bias)

Blinding of outcome

assessment (detection

bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting

bias) Other bias

Bartu 2006

Black 1994

Butz 1998

Dakof 2003

Grant 1996

Quinlivan 2000

Schuler 2000

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

No home visits

Home visits during pregnancy and after birth

Maternal retention in treatment Failure of retention in program at latest time measured

325 per 1000 299 per 1000 (224 to 400)

RR 0.92 (0.69 to 1.23)

315 (3 studies)

⊕ VERY LOW1,2,3

The GRADE assessment is specific to this single trial. Results of other trials from which data could not be extracted are included in the footnotes.

Maternal continued illicit drug use

569 per 1000 598 per 1000 (507 to 706)

RR 1.05 (0.89 to 1.24)

384 (3 studies)

⊕⊕ LOW4,5,6

This trial also reported weeks of continuous cocaine abstinence & reported a statistically significant favourable effect of CM (F (1.141) = 7.76; p < 0.01)

Maternal continued alcohol use

435 per 1000 513 per 1000 (417 to 635)

RR 1.18 (0.96 to 1.46)

379 (3 studies)

⊕⊕ LOW4,6,7

The GRADE assessment is specific to this single trial. Results of other trials from which data could not be extracted are included in the footnotes.

Infant birthweight See comment See comment Not estimable

See comment Not reported

Infant gestational age at delivery

See comment See comment Not estimable

See comment Not reported

Infant custody See comment See comment Not estimable

See comment Not reported

Infant birth defects See comment See comment Not estimable

See comment Not reported

Infant head circumference

See comment See comment Not estimable

See comment Not reported

HOME VISITS DURING PREGNANCY AND AFTER BIRTH COMPARED TO NO HOME VISITS FOR WOMEN WITH AN ALCOHOL OR DRUG PROBLEM

Patient or population: Women with an alcohol or other substance use disorder Settings: Community Intervention: Home visits during pregnancy and after birth Comparison: No home visits

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

1 The meta-analysis included three RCTs (Black 1994, Bartu 2006, and Dakof 2003). Two were judged to be at low risk of selection bias (although allocation concealment was unclear in Bartu 2006) and Black 1994 was judged to be at unclear risk of selection bias. All trials were judged to be at high risk of performance bias as blinding was not possible for the intervention. All trials were judged for this outcome (failure of retention in program) to be at high or unclear risk of detection bias. Attrition bias was a high risk for Black 1994 at 28% loss-to-follow-up.

2 Heterogeneity is present (I-squared = 49%). There are multiple sources of heterogeneity including differences in the type of home visitor, frequency and duration of the home visit and differences in content of visit. These subgroups are explored in additional analyses and may explain some of the heterogeneity; however, given the uncertainty and extent of the heterogeneity, the analysis was downgraded for inconsistency.

3 The sample size is small, and the event rate is less than 300. 4 This meta-analysis includes three RCTs (Bartu 2006, Butz 1998 and Schuler 2000). Two trials were judged to be at low risk of selection bias and one was of unclear

risk. All three trials were judged to be at high risk of performance bias as the visits could not be blinded. Two of three trials ensured outcome assessment was blinded reducing the risk of detection bias. Two trials had very high loss-to-follow-up (> 40%) at 18 months and are therefore at high risk of attrition bias.

5 Heterogeneity is present (I-squared = 64%). As there is moderate heterogeneity, it may be more appropriate to use a random effects model. This provides a RR = 1.04 (95% CI: 0.78, 1.38). This does not differ qualitatively from the fixed effects model. However, there are multiple sources of heterogeneity including differences in the type of home visitor, frequency and duration of the home visit and differences in content of visit. These sub-groups are explored in additional analyses and may explain some of the heterogeneity; however, given the uncertainty and extent of the heterogeneity, the analysis was downgraded for inconsistency.

6 The event rate is less than 300. However, given the relatively large event rate and narrow confidence interval, the analysis was not downgraded for imprecision. 7 There was no statistical heterogeneity in the results. However, there are multiple potential causes of clinical heterogeneity including differences in the type

of home visitor, frequency and duration of the home visit and differences in content of visit. These subgroups are explored in additional analyses but given the uncertainty regarding heterogeneity, the analysis was downgraded for inconsistency.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

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ho r(

s) : C

at he

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nb ul

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sb or

n D

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2 01

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Q ue

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H O

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R IN

G P

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ED IN

W O

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ti ng

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. H om

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om en

w ith

a n

al co

ho l o

r dr

ug p

ro bl

em . C

oc hr

an e

D at

ab as

e of

S ys

te m

at ic

R ev

ie w

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Q ua

li ty

a ss

es sm

en t

N o.

o f p

at ie

nt s

Ef fe

Q ua

li ty

Im po

rt an

ce N

o. o

f s tu

di es

D es

ig n

R is

k of

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s In

co ns

is te

nc y

In di

re ct

ne ss

Im pr

ec is

io n

O th

co ns

id er

at io

H om

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af te

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N o

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R el

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bs ol

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ep or

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0 —

— —

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— —

IM P

O R

TA N

1 Th

e m

et a-

an al

ys is

in cl

ud ed

th re

e RC

Ts (B

la ck

1 99

4, B

ar tu

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6, a

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ak of

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3) . T

w o

w er

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dg ed

to b

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lo w

ri sk

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tio n

bi as

(a lth

ou gh

a llo

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t w as

u nc

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in B

ar tu

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nd B

la ck

1 99

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as ju

dg ed

to b

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u nc

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as . A

ll tr

ia ls

w er

e ju

dg ed

to b

e at

h ig

h ris

k of

p er

fo rm

an ce

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s as

b lin

di ng

w as

n ot

p os

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r t he

in te

rv en

tio n.

A ll

tr ia

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r t hi

s ou

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o f r

et en

tio n

in p

ro gr

am ) t

o be

a t h

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or u

nc le

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sk o

f d et

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as .

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rit io

n bi

as w

as a

h ig

h ris

k fo

r B la

ck 1

99 4

at 2

8% lo

ss -t

o- fo

llo w

-u p.

H et

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ty is

p re

se nt

(I -s

qu ar

ed =

4 9%

). Th

er e

ar e

m ul

tip le

s ou

rc es

o f h

et er

og en

ei ty

in cl

ud in

g di

ff er

en ce

s in

th e

ty pe

o f h

om e

vi si

to r,

fr eq

ue nc

y an

d du

ra tio

n of

th e

ho m

e vi

si t a

nd d

iff er

en ce

s in

c on

te nt

o f v

is it.

T he

se s

ub -g

ro up

s ar

e ex

pl or

ed in

di tio

na l a

na ly

se s

an d

m ay

e xp

la in

s om

e of

th e

he te

ro ge

ne ity

; h ow

ev er

, g iv

en th

e un

ce rt

ai nt

y an

d ex

te nt

o f t

he h

et er

og en

ei ty

, t he

a na

ly si

s w

as d

ow ng

ra de

d fo

r i nc

on si

st en

cy .

3 Th

e sa

m pl

e si

ze is

s m

al l,

an d

th e

ev en

t r at

e is

le ss

th an

3 00

. 4

Th is

m et

a- an

al ys

is in

cl ud

es th

re e

RC Ts

(B ar

tu 2

00 6,

B ut

z 19

98 a

nd S

ch ul

er 2

00 0)

. T w

o tr

ia ls

w er

e ju

dg ed

to b

e at

lo w

ri sk

o f s

el ec

tio n

bi as

a nd

o ne

w as

o f u

nc le

ar ri

sk . A

ll th

re e

tr ia

ls w

er e

ju dg

ed to

b e

at h

ig h

ris k

of p

er fo

rm an

ce b

ia s

as th

e vi

si ts

ul d

no t b

e bl

in de

d. T

w o

of th

re e

tr ia

ls e

ns ur

ed o

ut co

m e

as se

ss m

en t w

as b

lin de

d re

du ci

ng th

e ris

k of

d et

ec tio

n bi

as . T

w o

tr ia

ls h

ad v

er y

hi gh

lo ss

-t o-

fo llo

w -u

p (>

4 0%

) a t 1

8 m

on th

s an

d ar

e th

er ef

or e

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ig h

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of a

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. 5

H et

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en ei

ty is

p re

se nt

(I -s

qu ar

ed =

6 4%

). A

s th

er e

is m

od er

at e

he te

ro ge

ne ity

, i t m

ay b

e m

or e

ap pr

op ria

te to

u se

a ra

nd om

e ff

ec ts

m od

el . T

hi s

pr ov

id es

a R

R =

1. 04

(9 5%

C I:

0. 78

, 1 .3

8) . T

hi s

do es

n ot

d iff

er q

ua lit

at iv

el y

fr om

th e

fix ed

e ff

ec ts

m od

el .

H ow

ev er

, t he

re a

re m

ul tip

le s

ou rc

es o

f h et

er og

en ei

ty in

cl ud

in g

di ff

er en

ce s

in th

e ty

pe o

f h om

e vi

si to

r, fr

eq ue

nc y

an d

du ra

tio n

of th

e ho

m e

vi si

t a nd

d iff

er en

ce s

in c

on te

nt o

f v is

it. T

he se

s ub

-g ro

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ar e

ex pl

or ed

in a

dd iti

on al

a na

ly se

s an

d m

ay e

xp la

so m

e of

th e

he te

ro ge

ne ity

; h ow

ev er

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en th

e un

ce rt

ai nt

y an

d ex

te nt

o f t

he h

et er

og en

ei ty

, t he

a na

ly si

s w

as d

ow ng

ra de

d fo

r i nc

on si

st en

cy .

6 Th

e ev

en t r

at e

is le

ss th

an 3

00 . H

ow ev

er , g

iv en

th e

re la

tiv el

y la

rg e

ev en

t r at

e an

d na

rr ow

c on

fid en

ce in

te rv

al , t

he a

na ly

si s

w as

n ot

d ow

ng ra

de d

fo r i

m pr

ec is

io n.

7 Th

er e

w as

n o

st at

is tic

al h

et er

og en

ei ty

in th

e re

su lts

. H ow

ev er

, t he

re a

re m

ul tip

le p

ot en

tia l c

au se

s of

c lin

ic al

h et

er og

en ei

ty in

cl ud

in g

di ff

er en

ce s

in th

e ty

pe o

f h om

e vi

si to

r, fr

eq ue

nc y

an d

du ra

tio n

of th

e ho

m e

vi si

t a nd

d iff

er en

ce s

in c

on te

nt o

f v is

it.

Th es

e su

b- gr

ou ps

a re

e xp

lo re

d in

a dd

iti on

al a

na ly

se s

bu t g

iv en

th e

un ce

rt ai

nt y

re ga

rd in

g he

te ro

ge ne

ity , t

he a

na ly

si s

w as

d ow

ng ra

de d

fo r i

nc on

si st

en cy

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

M O

T IV

AT IO

N A

L I

N T E

R V IE

W IN

G d

u ri

n g

p re

gn an

cy a

n d a

ft er

b ir

th f

or w

om en

w it

h a

n a

lc oh

ol o

r d ru

g p ro

b le

TA B

LE O

F C

H A

R A

C TE

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TI C

S O

F IN

C LU

D ED

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Ts : 2

IN T

O TA

Tr ia

l I D

C ou

nt ry

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es ta

ti on

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a nd

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et ti

ng (d

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io n

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do m

iz ed

g ro

up s

P ri

m ar

y ou

tc om

IN TE

R V

EN TI

O N

D U

R IN

G P

R EG

N A

N C

Y O

N LY

G en

er al

tr ea

tm en

t s et

ti ng

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tr ia

ls w

er e

id en

tifi ed

fr om

th es

e se

tt in

gs .

S pe

ci al

is t t

re at

m en

t s et

ti ng

W in

hu se

n 20

08 U

S A

20 0

R 20

0 A

in IT

T 17

1 A

ev al

ua bl

e sa

m pl

< 32

w ks

Id en

tifi ed

n ee

di ng

bs ta

nc e

ab us

e tr

ea tm

en t v

th e

C lin

ic al

ia ls

N et

w or

k (C

TN ) s

ite

ac co

rd in

g to

u su

sc re

en in

g pr

oc ed

ur es

ed o

n si

te .

O ut

pa tie

nt . M

ul tis

ite tr

ia l i

n fo

ur C

TN s

ite s:

A ll

pr ov

id e

co m

pr eh

en si

ve tr

ea tm

en t

pr og

ra m

m es

s pe

ci fic

al ly

fo r

pr eg

na nt

w om

en a

bu si

su bs

ta nc

1 m

on th

a ct

iv e

tr ea

tm en

t; 3

m on

th s

fo llo

w -u

M ot

iv at

io na

l e nh

an ce

m en

t t he

ra py

: Th

re e

in di

vi du

al s

es si

on s

ba se

d on

b ri

m ot

iv at

io na

l t ec

hn iq

ue s

of M

ill er

R ol

ln ic

k. T

hr ee

in di

vi du

al s

es si

on s:

fi rs

t sc

he du

le d

fo r

at tr

ia l e

nt ry

(1 .5

–2 h

rs )

to e

st ab

lis h

ra pp

or t;

se co

nd a

nd th

ir d

sc he

du le

d du

ri ng

th e

fo llo

w in

g m

on th

ac h

of 1

h r)

to r

ev ie

w a

nd p

ro gr

es s

an d

de ve

lo p

ch an

ge p

la n.

lin ic

ia ns

r ec

ei ve

d 20

h ou

rs tr

ai ni

w ith

a n

M I e

xp er

t. Tr

ea tm

en t-

as -u

su al

: I n

ad di

tio n

to u

su al

ea tm

en t o

ff er

ed in

th e

pr og

ra m

m e,

rt ic

ip an

ts w

er e

of fe

re d

at le

as t 3

di vi

du al

s es

si on

s w

ith a

c lin

ic ia

n in

cl ud

in g

th e

in ta

ke s

es si

on . T

hi s

w as

t b as

ed o

n M

I t ec

hn iq

ue s.

M AT

ER N

A L

P ri

m ar

y: 1.

T r

ea tm

en t u

til iz

at io

n (r

at io

o f

tr ea

tm en

t h rs

a tt

en de

d to

n o.

o f h

sc he

du le

d) 2.

o. o

f w ks

in w

hi ch

o ne

tr ea

tm en

t se

ss io

n w

as a

tt en

de d

N o.

o f w

ks u

nt il

tr ea

tm en

t d ro

p- ou

t S

ec on

da ry

: 1.

ub st

an ce

u se

a. S

el f-

re po

rt b.

U ri

ne to

xi co

lo gy

U ni

ve rs

ity o

f R ho

de Is

la nd

C ha

ng e

A ss

es sm

en t (

U R

IC A

) r ea

di ne

sc or

e IN

FA N

T N

IN TE

R V

EN TI

O N

A FT

ER P

R EG

N A

N C

Y O

N LY

G en

er al

tr ea

tm en

t s et

ti ng

N o

tr ia

ls w

er e

id en

tifi ed

fr om

th es

e se

tt in

gs .

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Tr ia

l I D

C ou

nt ry

N G

es ta

ti on

ag e

A lc

oh ol

a nd

ug u

se S

et ti

ng (d

ur at

io n)

S tu

dy d

ur at

io n

R an

do m

iz ed

g ro

up s

P ri

m ar

y ou

tc om

S pe

ci al

is t t

re at

m en

t s et

ti ng

M ul

lin s

20 04

U S

A 71

R P

os tp

ar tu

m S

el f-

re po

rt ed

m is

si on

d ru

g us

e du

ri ng

eg na

nc y

or p

os iti

to xi

co lo

sc re

en a

t b ir

O ut

pa tie

nt .

C om

pr eh

en si

ve , 1

2- m

on th

de ra

l d em

on st

ra tio

n pr

oj ec

t pr

ov id

in g

fr ee

s er

vi ce

s fo

r w

om en

w ho

u se

d ill

ic it

su bs

ta nc

es d

ur in

g pr

eg na

nc y.

2 m

on th

s M

ot iv

at io

na l I

nt er

vi ew

in g:

T hr

in di

vi du

al 1

-h r

se ss

io ns

s ch

ed ul

fo r

at tr

ia l e

nt ry

, 1 w

k af

te r

en tr

an d

2 m

on th

s af

te r

en tr

y. N

o m

an ua

l. Th

er ap

is ts

in st

ru ct

ed to

u til

is e

st ra

te gi

es c

on si

st en

t w ith

p ar

tic ip

an t’s

ag e

of c

ha ng

e. Ed

uc at

io na

l C on

tr ol

: A t i

nt ak

e pa

rt ic

ip an

ts w

at ch

ed 3

0 m

ed uc

at io

na l v

id eo

o n

su bs

ta nc

e us

e, a

t 1

w k

po st

-i nt

ak e

pa rt

ic ip

an ts

w at

ch ed

si m

ila r

vi de

o an

d at

2 m

on th

s po

st -i

nt ak

e, p

ar tic

ip an

ts r

ec ei

ve d

a su

pp le

m en

ta ry

6 0-

m in

h om

e vi

si t

co m

pr is

in g

ca se

m an

ag em

en t.

M AT

ER N

A L

A tt

en da

nc e

at s

tu dy

s es

si on

s 2.

eq ue

nc y

of a

tt en

da nc

e at

w ee

kl y

ps yc

ho th

er ap

y an

d su

bs ta

nc e

ab us

e gr

ou ps

U ri

ne s

cr ee

n ne

ga tiv

e fo

r al

l d ru

IN FA

N T

N ot

a pp

lic ab

RC T

– Ra

nd om

iz ed

c on

tr ol

le d

tr ia

l R

– N

um be

r r an

do m

iz ed

A –

N um

be r a

na ly

se d

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Random sequence generation (selection

bias)

Allocation concealment

(selection bias)

Blinding of participants

and personnel

(performance bias)

Blinding of outcome

assessment (detection

bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting

bias) Other bias

Mullins 2004

Winhusen 2008

RISK OF BIAS IN EACH TRIAL INCLUDED IN THE MOTIVATIONAL INTERVIEWING COMPARISON

FOREST PLOTS OF MOTIVATIONAL INTERVIEWING COMPARISON

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Any control (treatment- as-usual or Educational Control)

Motivational Interviewing

Maternal retention in treatment Follow-up: 1–2 months

716 per 1000 695 per 1000 (609 to 788)

RR 0.97 (0.85 to 1.1)

271 (2 studies)

⊕⊕ LOW1,2

Maternal substance use Mean proportion of negative urine screens Follow-up: mean 2 months

The mean maternal substance use in the intervention groups was 0.06 higher (0.12 lower to 0.24 higher)

71 (1 study)

⊕⊕ LOW3,4

Winhusen 2008 (N = 200) measured proportion of positive urines in months 1 and 3. There were no statistically significant differences between the MI and TAU groups.

Infant birthweight See comment See comment Not estimable

See comment Not reported

Infant gestational age at delivery

See comment See comment Not estimable

See comment Not reported

Infant custody See comment See comment Not estimable

See comment Not reported

Infant birth defects See comment See comment Not estimable

See comment Not reported

Infant head circumference

See comment See comment Not estimable

See comment Not reported

MOTIVATIONAL INTERVIEWING COMPARED TO ANY CONTROL (TREATMENT-AS-USUAL OR EDUCATIONAL CONTROL) FOR PREGNANT OR POSTPARTUM WOMEN WITH PROBLEMATIC SUBSTANCE USE

Patient or population: Pregnant or postpartum women with problematic substance use Settings: Outpatient in specialist substance use treatment programmes Intervention: Motivational interviewing Comparison: Any control (treatment-as-usual or educational control)

CI: Confidence interval; RR: Risk ratio. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Risk of Bias: Serious. Both trials were unblinded so the risk of performance bias is high. Attrition bias is also likely to be present due to the loss-to-follow-up. 2 Imprecision: Rated as Serious. The number of events is less than 300. 3 Risk of Bias: Serious. The trial was unblinded so the risk of performance bias is high. Attrition bias is also likely to be present due to the differential loss-to-follow-

up between the groups. 4 Imprecision: Rated as Very Serious. The sample size is very small.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Q ua

li ty

a ss

es sm

en t

N o.

o f p

at ie

nt s

Ef fe

Q ua

li ty

Im po

rt an

ce N

o. o

f s tu

di es

D es

ig n

R is

k of

b ia

s In

co ns

is te

nc y

In di

re ct

ne ss

Im pr

ec is

io n

O th

co ns

id er

at io

ns M

ot iv

at io

na l

In te

rv ie

w in

A ny

c on

tr ol

re at

m en

t- as

-u su

al o

r Ed

uc at

io na

l C

on tr

ol )

R el

at iv

e (9

5% C

I) A

bs ol

ut e

M at

er na

l r et

en ti

on in

tr ea

tm en

t ( fo

ll ow

-u p

1– 2

m on

th s)

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nd om

iz ed

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se ri

ou s1

no s

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in co

ns is

te nc

y no

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ct ne

ss se

ri ou

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ne 97

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) 96

/1 34

1. 6%

) R

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(0 .8

5 to

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fe w

er p

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(f ro

m 1

fe w

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m or

⊕ ⊕

 

LO W

C R

IT IC

A L

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er na

l s ub

st an

ce u

se (f

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w -u

p m

ea n

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Random sequence generation (selection

bias)

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(selection bias)

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and personnel

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assessment (detection

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bias) Other bias

Silverman 2001

RISK OF BIAS IN EACH TRIAL INCLUDED IN THE THERAPEUTIC WORKPLACE COMPARISON

FOREST PLOTS OF THERAPEUTIC WORKPLACE COMPARISON

33:6 52:8

32:6 54:9

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Control

Therapeutic Workplace versus Usual Care

Treatment retention Mean weeks of treatment Follow-up: 24 weeks

The mean treatment retention in the intervention groups was 3.5 higher (1.35 lower to 8.35 higher)

40 (1 study)

⊕ VERY LOW1,2

Maternal substance use Urine-negative for opioids Follow-up: 24 weeks

See comment See comment 40 (1 study)

⊕ VERY LOW1,3

There was a statistically significant difference favouring the Therapeutic Workplace group over Usual Care for urines negative for opioids.

Maternal substance use Urine-negative for cocaine Follow-up: 24 weeks

See comment See comment 40 (1 study)

⊕ VERY LOW1,3

There was a statistically significant difference favouring the Therapeutic Workplace group over Usual Care for urines negative for cocaine.

Birthweight See comment See comment Not estimable

— See comment

Not reported

Infant gestational age at delivery

See comment See comment Not estimable

— See comment

Not reported

Infant custody See comment See comment Not estimable

— See comment

Not reported

Infant birth defects

See comment See comment Not estimable

— See comment

Not reported

Infant head circumference

See comment See comment Not estimable

— See comment

Not reported

THERAPEUTIC WORKPLACE VERSUS USUAL CARE FOR PREGNANT OR POSTPARTUM WOMEN WITH PROBLEMATIC SUBSTANCE USE

Patient or population: Pregnant women with problematic substance use Settings: Specialist substance use treatment setting: Outpatient Intervention: Therapeutic Workplace versus Usual Care

CI: Confidence interval. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Risk of bias: Rated as Very Serious. There was no blinding which may introduce performance bias. Detection bias is less likely as the primary outcome was

objectively measured: urine screens. The high rate of attrition across the study period and the differential between the groups resulted in a very serious risk of bias rating.

2 Imprecision: Rated as Very Serious. The confidence interval is very wide and the sample size is very small (N = 40). 3 Imprecision: Rated as Serious. The data is presented as a t test and 95% Confidence intervals (CI) are not reported so imprecision cannot be interpreted from the CI.

The very small sample size of the participants (N = 40) indicates that imprecision is likely, despite this measurement being for 24 weeks of urine specimens per each participant.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Evidence Profile 3: Detoxification or quitting programmes for alcohol and other substance dependence in pregnancy

Evidence question: For pregnant women with alcohol or other substance dependence, do detoxification or quitting programmes result in better maternal, fetal or infant outcomes compared to treatment-as-usual, maintenance treatment (in the case of opioids), or other methods of detoxification?

Selection criteria for the systematic review: Study design: RCTs

Population: Pregnant women with alcohol or other substance dependence.

Interventions: Detoxification, either inpatient or outpatient.

Control: Non-detoxification, delayed detoxification, gradual detoxification, maintenance treatment (in the case of opioids), treatment-as-usual.

Outcomes: The following outcomes were selected by the guidelines group:

Outcome Importance (0-9)

Maternal: Substance use 8.11

Maternal: Withdrawal 8.00

Maternal: Retention in substance use treatment 8.00

Infant: Neonatal Abstinence Syndrome 7.56

Infant: Gestational age at delivery 7.11

Infant: Birthweight 7.00

Infant: Spontaneous abortion 6.78

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

EVIDENCE TO RECOMMENDATIONS TABLE

Detoxification or quitting programmes for alcohol and other substance dependence in pregnancy

There were no randomized clinical trials identified by the systematic literature search on this evidence profile, hence the GRADE profile is based on a narrative review of the literature.

Summary of evidence A withdrawal syndrome requiring pharmacological treatment in pregnancy can be said to occur for three substances: benzodiazepines, alcohol and opioids. The withdrawal syndrome associated with the cessation of other substances (such as psychostimulants) has not been considered severe enough to justify the routine use of psychotropic medication. For those pregnant women for whom medication-assisted withdrawal is successful, there does not appear to be any evidence of fetal distress during detoxification, nor any increased, no increased risk of fetal demise or premature delivery (Dashe et al., 1998). However, the nature and extent of withdrawal of the fetus from opioids or other substances is largely unknown, because there have been no methods developed to measure such withdrawal directly, and there is insufficient information available to distinguish the effects of fetal withdrawal from fetotoxicity. Benzodiazepines Medication-assisted withdrawal for benzodiazepines typically consists of a gradual withdrawal regimen with the goal of having the women benzodiazepine-free at the time of delivery, or later in the postpartum period. Withdrawal from benzodiazepines has typically been managed by transfer to a long-acting benzodiazepine (e.g. diazepam) followed by a gradual dose reduction, with the goal of being benzodiazepine-free at birth, or earlier if possible, without provoking significant withdrawal symptoms for the pregnant woman. There are no reliable data regarding the relative success or failure of such an approach in pregnant women, although the general belief is that relapse to use is common, particularly if the taper is too fast or too short.

Alcohol Medication-assisted withdrawal for alcohol use in pregnant women typically uses a benzodiazepine, often diazepam, as primary pharmacotherapy. There are no reliable data related to outcome following detoxification during the different trimesters.

Opioids Medication-assisted withdrawal from opioids typically involves tapered doses of methadone over a period of 3 to 14 days. Withdrawal from opioids is typically managed by tapered doses of methadone. The safety profile of methadone is well known but both conflicting and incomplete. Methadone maintenance pharmacotherapy has been found superior to detoxification in terms of treatment retention and heroin use (Mattick, Breen, Kimber, & Davoli, 2009). During pregnancy, methadone-maintenance pharmacotherapy has been found superior to detoxification for treatment retention, attending more obstetrical visits, and more often delivering at the program hospital (Jones et al., 2008).

Although there are considerable data regarding the failure of medication-assisted withdrawal for opioids, there are few data specific to trimester.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

EVIDENCE TO RECOMMENDATIONS TABLE

Benefits and harms

Benefits • Pregnancy presents a unique opportunity to support women to reduce and ideally cease alcohol and/or illicit substance use (Chang et al., 1992)

• Depending on the substance of use, medication-assisted withdrawal that results in continued non-use of substances following medication-assisted withdrawal is considered to be superior to usual care in terms of: – reduction in harmful consumption – reduction in risk to the fetus – increase in birthweight – improved general health of pregnant women – improved maternal psychological well-being – less risk of fetotoxicity – improved perinatal outcomes (e.g. reduction in preterm births, increased overall

birthweights, reduction in number of low-birthweight infants – reductions in congenital defects or anomalies noting that: a meta-analysis by Enato et al.

(2011) suggests that benzodiazepines are unrelated to an increased risk of major congenital abnormalities. However, research on the longer-term effects of benzodiazepines on the child exposed to benzodiazepines is largely lacking.

• Improved general health of pregnant women • Improved maternal psychological well-being • Shorter hospitalizations, lower peak neonatal abstinence syndrome scores, and less likelihood

of withdrawal treatment for neonates of mothers who had successfully completed medication- assisted withdrawal than for neonates of mothers who had been unsuccessful (Stewart, 2013)

• Medication-assisted withdrawal has been associated with a significantly lower mean NAS peak score, a significantly lower mean amount of morphine to treat NAS, significantly fewer days medicated for NAS, significantly fewer number of days in the hospital relative to methadone, and significantly lower mean amount of morphine to treat NAS and significantly fewer days medicated for NAS than buprenorphine (Lund et al., 2012)

Harms • The success of medication-assisted withdrawal during pregnancy is generally considered to be poor, with estimates of failure as low as 41% (Dashe et al., 1998) and as high as 96% (e.g., Luty et al., 2003). Failure rate is difficult to estimate precisely, because some authors have defined failure as failure to complete detoxification, while others have defined failure as return to substance use. This failure is associated with a number of negative outcomes, including increased fetal exposure to illicit substances and other maternal risk behaviors, reduced compliance with obstetrical care, and poorer neonatal birth parameters (Jones et al., 2008; summarized in Kaltenbach et al., 1998).

• High risk of relapse to opioids following opioid detoxification (see above) • High risk of relapse to benzodiazepines following detoxification • Often stressful short-term symptoms associated with reduction or cessation of alcohol or

substance use • Little development of coping skills • Increased risk of fetal stress (depending on the substance) • Increased risk of fetal morbidity or mortality, including miscarriage and stillbirth • Possible development of depression or anxiety as a result of cessation or reduction of alcohol

or illicit substance use • Possible risk of switching from one substance to another substance • Damage to relationships/loss of employment

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

EVIDENCE TO RECOMMENDATIONS TABLE

Values and preferences

In favour: Pregnant woman

Health-care worker

Community

• Increased personal contact and support • Opportunity to be substance free • Belief that it will lead to a healthier baby • Belief in positive response from family/society

• Opportunity to intervene and assist with achievement of substance-free status • Opportunity to support health of fetus

• Possible reduction of crime in the community • Possible reduction of STI risk in the community • Possible positive responses from some health-care providers, partners, family and co-workers

Against: Pregnant woman

Health-care worker

Community

• Fear of stigmatization for needing detoxification or for refusing detoxification in favour of maintenance medication treatments (being seen as ‘weak-willed’)

• Dislike approach, sense of coercion • Fear of negative responses from partners, family and co-workers

• Resent time and resources used • Do not believe treatment is appropriate or effective

• Resent resources spent on detoxification programmes • Partner/family/employer may resent time and commitment to detoxification

Costs and feasibility

Costs • Trained staff and sustainable detoxification programme required • Financial implications for woman-care of other children, time lost from work

Feasibility (including economic consequences)

• Inconvenient for women • Likely to fail any other goal beyond being drug-free at the completion of detoxification

REFERENCES

Chang G, Carroll KM, Behr HM, et al. Improving treatment outcome in pregnant opiate-dependent women. J Subst Abuse Treat 1992;9:327-30.

Dashe JS, Jackson GL, Olscher DA, et al. Opioid detoxification in pregnancy. Obstet Gynecol 1998;92:854-8.

Enato E, Moretti M, Koren G. The fetal safety of benzodiazepines: an updated meta-analysis. J Obstet Gynaecol Can 2011;33:46-8.

Jones HE, O'Grady KE, Malfi D, et al. Methadone maintenance vs. methadone taper during pregnancy: maternal and neonatal outcomes. Am J Addict 2008;17:372- 86.

Kaltenbach K, Finnegan L. Prevention and treatment issues for pregnant cocaine-dependent women and their infants. Ann N Y Acad Sci 1998;846:329-34.

Lund IO, Fitzsimons H, Tuten M, et al. Comparing methadone and buprenorphine maintenance with methadone-assisted withdrawal for the treatment of opioid dependence during pregnancy: maternal and neonatal outcomes. Subst Abuse Rehab 2012;3 (Supplement 1):17-25.

Luty J, Nikolaou V, Bearn J. Is opiate detoxification unsafe in pregnancy? J Subst Abuse Treat 2003;24:363-7.

Mattick RP, Breen C, Kimber J, et al. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev 2009:CD002209.

Stewart RD, Nelson DB, Adhikari EH, et al. The obstetrical and neonatal impact of maternal opioid detoxification in pregnancy. Am J Obstet Gynecol 2013;209:267 e1-5.

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Draft recommendations: o Pregnant women dependent on alcohol, amphetamine type stimulants, cocaine, cannabis, volatile agents,

(everything except opioids and benzodiazepines), should be advised and encouraged to cease their alcohol or other substance use, and provided with the opportunity to do so in a safe and supportive manner, both for the health of the pregnant woman and to reduce the possibility of damage to the fetus.

o Pregnant women dependent on opioids should be advised to use opioid-agonist maintenance treatment (such as methadone or buprenorphine) rather than to attempt opioid detoxification.

o Pregnant patients with benzodiazepine-use disorder should be transferred to a long-acting benzodiazepine (e.g., diazepam) and undergo a gradual dose reduction, with the goal of being benzodiazepine-free at birth, if possible. Psychosocial treatment should serve as an integral component of any dose-reduction strategy.

o Pregnant women who wish to undergo detoxification should be invited to withdraw from substance use in an inpatient or hospital facility to increase the chances of successful completion of substance withdrawal and to monitor the health of the fetus.

o The health of the fetus should be monitored during detoxification by fetal heart monitoring, and by the monitoring of fetal movements. If there are signs of fetal distress associated with the detoxification, then medication should be used to reduce the severity of withdrawal and the process of withdrawal should be slowed or temporarily halted.

o Withdrawal symptoms from the cessation of alcohol consumption should be managed with a long-acting benzodiazepine, titrated to the severity of withdrawal.

o Psychotropic medication should not be routinely used in pregnant women to assist detoxification from stimulants (including cocaine), cannabis and volatile agents, but should be reserved for specific symptoms which emerge.

o Given the high risk of relapse in opioid dependence, detoxification from opioids should be advised only for carefully selected patients. Such pregnant women who make an informed choice to cease opioid use should be supported to do so either with gradual tapering of opioids in an ambulatory treatment setting or with more rapid tapering in a residential treatment facility.

Final recommendations:

RECOMMENDATION 4

Strength of recommendation: Strong Quality of evidence: Very low

Remarks: • Pregnant women dependent on alcohol or drugs who agree to undergo detoxification should be offered the

accordingly. • The exceptions to this recommendation are opioid and benzodiazepine dependence, which are covered by

recommendations 5 and 6 separately. • It was decided that this recommendation should be strong, despite the very low quality of evidence of the

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

RECOMMENDATION 5

Pregnant women dependent on opioids should be encouraged to use opioid maintenance treatment whenever available rather than to attempt opioid detoxification.

Strength of recommendation: Strong Quality of evidence: Very low

Remarks: • Opioid maintenance treatment in this context refers to either methadone maintenance treatment or buprenorphine

maintenance treatment. • Pregnant patients with opioid dependence who wish to undergo detoxification should be advised that relapse to

opioid use is more likely following medication-assisted withdrawal than while undertaking opioid maintenance treatment.

• Psychosocial treatment should be an integral component of such treatment. • Pregnant women who fail to complete medication-assisted withdrawal should be offered opioid agonist

pharmacotherapy. • It was decided that this recommendation should be strong despite the low quality of evidence of effectiveness from

RECOMMENDATION 6

Pregnant women with benzodiazepine dependence should undergo a gradual dose reduction, using long-acting benzodiazepines.

Strength of recommendation: Strong Quality of evidence: Very low

Remarks: • Long-acting benzodiazepines should only be used for as short a time as is medically feasible in managing

dependence. • It was decided that this recommendation should be strong despite the very low quality of evidence of effectiveness

RECOMMENDATION 7

Pregnant women who develop withdrawal symptoms following the cessation of alcohol consumption should be managed with the short-term use of a long-acting benzodiazepine.

Strength of recommendation: Strong Quality of evidence: Very low

Remarks: • Management of alcohol withdrawal usually also includes administration of thiamine. • Alcohol withdrawal management may be facilitated by the use of an alcohol withdrawal scale such as the CIWA-Ar. • Inpatient care should be considered in the withdrawal management of pregnant women with alcohol dependence. • Alcohol withdrawal can be a severe and even life-threatening condition, provoking seizures and delirium. Evidence

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

RECOMMENDATION 8

In withdrawal management for pregnant women with stimulant dependence, psychopharmacological medications may be useful to assist with symptoms of psychiatric disorders but are not routinely required.

Strength of recommendation: Strong Quality of evidence: Very low

Remarks: • Except for the management of acute intoxication, withdrawal management in amphetamine-type stimulants (ATS)

harms to mother and fetus of ongoing use of psychostimulants use have been shown to be high. The risks of providing short-term appropriate non-teratogenic medications for short-term management of psychologically distressing symptoms in pregnancy are very low. Therefore, the potential benefits of this approach strongly outweigh the harms of providing psychopharmacological treatment of symptoms, if required, during psychostimulant withdrawal.

Factors in considering the strength of the recommendations (recommendations 4–8):

Research gaps

o What type of benzodiazepine tapers work best for which types of patients?

o What medications are the safest and most effective for mother and fetus being withdrawn from alcohol?

o What intensity of fetal monitoring is needed to determine the relative safety of detoxification during pregnancy?

o What are the best withdrawal-severity assessment tools to measure withdrawal in pregnant women?

o What are the best ways to manage withdrawal from cocaine, cannabis, amphetamine, alcohol or volatile solvents in pregnant women?

Factor Decision

Is there high or moderate quality evidence? The higher the quality of evidence, the more likely is a strong recommendation.

Yes

Are the expected values and preferences clearly in favour of the recommendation? Yes

Yes

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Evidence profile 4: Pharmacological treatment (maintenance and relapse prevention) for alcohol and other substance dependence in pregnancy

Evidence question: In pregnant women dependent on alcohol or other substances, does pharmacological treatment (either maintenance or relapse prevention) result in better maternal, fetal or infant outcomes than no pharmacological treatment or other pharmacological treatment?

Study selection criteria for the systematic review: Study design: RCTs

Population: Pregnant women dependent on alcohol or other substances.

Interventions: Any pharmacotherapy used for agonist maintenance treatment (such as methadone or buprenorphine in opioid dependence) or relapse prevention treatment (such as naltrexone in opioid or alcohol dependence).

Control: No pharmacotherapy or other pharmacotherapy.

Outcomes: The outcomes of interest were:

Outcome Importance (0-9)

Maternal: Substance use 8.11

Maternal: Withdrawal Severity 8.00

Maternal: Retention in substance use treatment 8.00

Infant: Neonatal Abstinence Syndrome 7.56

Infant: Gestational age at delivery 7.11

Infant: Birthweight 7.00

Infant: Spontaneous abortion 6.78

EVIDENCE TO RECOMMENDATIONS TABLE

Pharmacological treatment (maintenance and relapse prevention) for alcohol and other substance dependence in pregnancy

Summary of evidence • Siegfried and Clark (2013) have performed systematic reviews of psychopharmacological treatments: methadone

versus buprenorphine and a single study of methadone compared to slow-release morphine for pregnant women with a substance use disorder. See GRADE tables and summary of findings tables (below) for full details. Pharmacotherapy has been shown to be successful in the treatment of opioid use disorder. Methadone and buprenorphine have similar efficacy. Methadone appears to result in better maternal retention in treatment. Buprenorphine is associated with a number of better neonatal outcomes, specifically increased birthweight, reduced prematurity, and possibly a milder NAS. There is a lack of data on the safety and efficacy of the buprenorphine/naloxone combination in pregnancy.

• Psychosocial interventions in addition to pharmacotherapy have been shown to be superior to pharmacotherapy alone (Amato et al., 2011).

• There was no evidence found on the use of medications for relapse prevention for alcohol dependence in pregnancy (acamprosate, disulfiram, nalmefene, naltrexone).

• There was no RCT evidence on the use of naltrexone in relapse prevention from opioid dependence in pregnancy. • There was no evidence found on the use of benzodiazepine maintenance for benzodiazepine dependence in

pregnancy.

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

EVIDENCE TO RECOMMENDATIONS TABLE

Benefits and harms

Benefits • Pregnancy presents a unique opportunity to support women to reduce and ideally cease alcohol and/or illicit substance use

• Although research in this area is extremely limited, given the history of exclusion of women from pharmacotherapy trials, and depending on the substance of use, pharmacotherapeutic interventions (specifically opioid agonist treatment in opioid dependence) are thought to be superior to usual care (e.g., Rayburn & Bogenschutz, 2004) in terms of: – reduction in harmful consumption – reduction in risk to the fetus – increase in birthweight – increase in the detection of harmful use and referral to treatment – improved general health of pregnant women – improved maternal psychological well-being – less risk of fetotoxicity – improved perinatal outcomes (e.g., reduction in preterm births, increased overall

birthweights, reduction in number of low-birthweight infants) – reductions in congenital defects or anomalies

Harms • Unpleasant side effects due to the pharmacological intervention or uncovered withdrawal from alcohol or substance use

• Possible development of depression or anxiety as a result of cessation or reduction of alcohol or illicit substance use

• Methadone and buprenorphine both reduce additional opioid use in pregnancy, but the neonate often develops a withdrawal syndrome referred to as neonatal abstinence syndrome (NAS)

• Possible risk of drug substitution • Increased risk of fetotoxicity • Possible increased risk of congenital defects and anomalies related to exposure to the

pharmacological intervention (particularly for acamprosate, naltrexone, nalmefene, disulfiram, benzodiazepines)

Values and preferences

In favour: Pregnant woman

Health-care worker

Community

• May value increased personal contact and support • May value positive responses from partners, family and co-workers • May value stability of substance supply • May value increased psychosocial support

• May value opportunity to intervene • May value opportunity for improved monitoring of health of mother and child

• Partners/employers may value increased stability • May value potential for reduced crime/STI

Against: Pregnant woman

Health-care worker

Community

• Stigmatization when identified as drinking alcohol or using illicit substances during pregnancy • Stigmatization for being in need of drug treatment • Little development of coping strategies • Little commitment to behaviour change • Fear of negative responses from partners, family and co-workers • Resentment of intensive time and resources required for treatment

• Ideological objection to maintenance treatment • Anxiety about ability to manage complex interactions with substance users • Dislike working with population considered difficult

• May consider resource use inappropriate • Ideological objection to maintenance of substance use/or failure to withdraw • Employers/partners /families may resent extra time devoted to management

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

EVIDENCE TO RECOMMENDATIONS TABLE

Costs and feasibility

Costs • Potentially substantial additional cost beyond costs of detoxification, depending on the medication

• Trained professional staff and sustainable programme required

Feasibility (including economic consequences)

• Inconvenient for women, particularly maintenance treatment requiring daily dosing • There are some suggestions in the literature that pregnant and postpartum women maintained

on opioid agonists may have pain management needs different from those of non-opioid- agonist-maintained women (Jones et al., 2009; Höflich et al., 2012)

• Requires patient monitoring to ensure patient continues taking her medication • A comprehensive care model in which pharmacotherapy is part of a women-centred, trauma-

informed programme would be the best model of care – and also the costliest

REFERENCES

Amato L, Minozzi S, Davoli M, et al. Psychosocial combined with agonist maintenance treatments versus agonist maintenance treatments alone for treatment of opioid dependence. Cochrane Database Syst Rev 2011:CD004147.

Höflich A, Langer M, Jagsch R, Bäwert A, Winklbaur B, Fischer G, Unger A. Peripartum pain management in opioid dependent women. Eur J Pain. 2012 April; 16(4): 574–584.

Jones HE, Martin PR, Heil SH, Stine SM, Kaltenbach K, Selby P, Coyle MG, O’Grady KE, Arria AM, Fischer G. Treatment of Opioid Dependent Pregnant Women: Clinical and Research Issues. J Subst Abuse Treat. 2008 October; 35(3): 245–259

Rayburn WF, Bogenschutz MP. Pharmacotherapy for pregnant women with addictions. Am J Obstet Gynecol 2004;191:1885-97.

Draft recommendations: o Pharmacotherapy is not recommended for routine treatment of dependence on amphetamine-type

stimulants, cannabis, cocaine, or volatile agents in pregnant patients

o Medications for the treatment of alcohol dependence (acamprosate, naltrexone and disulfiram) should generally not be used in pregnancy.

o Pregnant patients with benzodiazepine dependence should undergo a gradual taper.

o Pregnant patients with an opioid use disorder should be encouraged to commence opioid agonist pharmacotherapy with either methadone or buprenorphine, in preference to detoxification, or detoxification followed by naltrexone.

Final recommendations:

RECOMMENDATION 9

Pharmacotherapy is not recommended for routine treatment of dependence on amphetamine-type stimulants, cannabis, cocaine or volatile agents in pregnant patients.

Strength of recommendation: Conditional Quality of evidence: Very low

Remarks: • For pregnant patients who use cannabis, amphetamine-type stimulants, cocaine, and volatile agents, the focus of

treatment should be on psychosocial interventions. • The recommendation was considered conditional given the complete lack of research on this issue.

RECOMMENDATION 

Strength of recommendation: Conditional Quality of evidence: Very low

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

RECOMMENDATION 

Pregnant patients with opioid dependence should be advised to continue or commence opioid maintenance therapy with either methadone or buprenorphine.

Strength of recommendation: Strong Quality of evidence: Very low

Remarks: • Pregnant patients with opioid dependence should be encouraged to commence opioid agonist pharmacotherapy,

which should be combined with psychosocial interventions. • Opioid-dependent pregnant women who are already taking opioid maintenance therapy with methadone should

• In opioid-dependent pregnant women, the buprenorphine mono formulation should be used in preference to the buprenorphine/naloxone formulation.

from such a choice. • It was decided that this recommendation should be strong despite the low quality of evidence as the rate of relapse

to opioid use following detoxification is high and the risks of harm from failed detoxification are catastrophic compared to the small risks of harm from opioid maintenance treatment.

Factors in considering the strength of the recommendations (recommendations 9–11):

Factor Recommendations

9 & 10 Recommendation

Is there high or moderate quality evidence? The higher the quality of evidence, the more likely is a strong recommendation.

No No

No Yes

Are the expected values and preferences clearly in favour of the recommendation?

Yes Yes

Research recommendations

o A potential case registry of pregnancies exposed to different substances, including psychotropic medication used for the treatment of substance use disorders in pregnancy, which can help explore the potential risks and benefits of pharmacotherapy in substance use disorders in pregnancy.

o The optimal treatment with methadone and buprenorphine in pregnancy (including further dose/response studies).

o Safety of pharmacotherapy for alcohol dependence in pregnancy.

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

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d 12

s ub

lin gu

pl ac

eb o

ta bl

et s

fo llo

w ed

b y

he r

do se

o f m

et ha

do ne

H C

l ( 20

–1 00

m g)

in 4

0 m

l l iq

ui d.

T he

d os

e co

nv er

si on

r at

io u

se d

fo r

th e

tr an

si tio

n w

as 6

m g

m or

ph in

e fo

r ev

er y

1m g

m et

ha do

ne .

O n

th e

su bs

eq ue

nt 2

d ay

s, d

os es

o f m

et ha

do ne

w er

e sy

st em

at ic

al ly

in cr

ea se

d on

a n

in di

vi du

al b

as is

(5 –1

0 m

g m

et ha

do ne

/d ay

) t ha

t w as

d ep

en de

nt o

n pa

tie nt

r ep

or t a

nd c

lin ic

ia n

as se

ss m

en t u

nt il

da y

4 w

he n

pa tie

nt s

ac hi

ev ed

a n

in di

vi du

al s

ta bi

liz at

io n

do se

. C

o- in

te rv

en ti

on s:

V ou

ch er

p ay

m en

ts fo

r pr

ov id

in g

an e

th an

ol -n

eg at

iv e

br ea

th s

am pl

e an

d a

ur in

e sa

m pl

e fr

ee o

f o pi

oi d,

c oc

ai ne

, b en

zo di

az ep

in es

, T H

C , b

ar bi

tu ra

te s,

a m

itr yp

til in

es ,

am ph

et am

in es

, c lo

na ze

pa m

s, d

ox ep

in s,

P C

P, p

he no

th ia

zi ne

s, a

nd p

ro po

xy ph

en e.

ar tic

ip an

ts e

ar ne

d a

U S

$7 .5

0 vo

uc he

r fo

r th

ei r

fir st

d ru

g- ne

ga tiv

e br

ea th

a nd

u ri

ne s

am pl

an d

vo uc

he rs

fo r

su bs

eq ue

nt c

on se

cu tiv

e dr

ug -n

eg at

iv e

sa m

pl es

in cr

ea se

d by

U S

$1 .

M ax

im um

p os

si bl

e ea

rn in

gs w

er e

U S

$ 12

00 .

IN FA

N T

• N

um be

r of

n eo

na te

s re

qu ir

in g

m or

ph in

e dr

op s

fo r

N A

S •

P ea

k N

A S

s co

m ea

su re

d by

1 9-

ite m

od ifi

ed F

in ne

ga n

S ca

le •

T o ta

l a m

ou nt

o f

m or

ph in

e dr

op s

ad m

in is

te re

d to

tr ea

t N

A s

• T o

ta l d

ay s

of n

eo na

ta l

ho sp

ita l s

ta y

fr om

liv er

y un

til

di sc

ha rg

e fr

om th

e ho

sp ita

S u m

m ar

y of

fi n d in

gs a

n d G

R A

D E

t ab

le s

104

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Tr ia

l I D

C ou

nt ry

N G

es ta

ti on

ag e

A lc

oh ol

a nd

d ru

g us

e S

et ti

ng R

an do

m iz

ed g

ro up

s P

ri m

ar y

ou tc

om es

Fi sc

he r

20 06

A us

tr ia

, si

ng le

nt re

18 R

14 A

24 –2

9 w

ks O

pi oi

d- de

pe nd

en t

di ag

no se

d by

S M

IV w

ith

po si

tiv e

op io

ur in

e to

xi co

lo gy

o n

sc re

en in

A dd

ic tio

n cl

in ic

o f t

M ed

ic al

U ni

ve rs

ity

Vi en

na : t

re at

m en

t pr

ov id

ed a

s ou

tp at

ie nt

, bu

t a dm

itt ed

fo r

at le

as t

3 da

ys d

ur in

g in

du ct

io n

pe ri

P ar

tic ip

an ts

w er

e ad

m itt

ed to

th e

cl in

ic fo

r a

m in

im um

o f 3

d ay

s in

du ct

io n.

A ll

pa rt

ic ip

an ts

er e

m ai

nt ai

ne d

on o

ra l s

lo w

-r el

ea se

m or

ph in

e hy

dr oc

hl or

id e.

P ar

tic ip

an ts

r ec

ei ve

d a

m ea

n da

ily d

os e

of 3

30 .5

6m g

(r an

ge : 9

0– 60

0m g)

o ve

r 24

h ou

rs ; t

he fi

na l d

os e

of s

lo w

-r el

ea se

or ph

in e

(m ea

n: 1

64 .4

4m g

S D

: 9 5.

50 ; r

an ge

: 3 0–

46 0m

g) a

m ea

n of

1 7

ho ur

s pr

io r

to th

e fir

do se

o f m

ed ic

at io

n. B

up re

no rp

hi ne

: P ar

tic ip

an ts

w er

e st

ar te

d on

8 m

g bu

pr en

or ph

in e

at th

e on

se t o

f m od

er at

e w

ith dr

aw al

s ym

pt om

s on

d ay

1 (W

an g

sc or

e be

tw ee

n 5

an d

10 ).

P ar

tic ip

an ts

w ho

r ec

ei ve

d m

or e

th an

4 00

m g/

da y

of o

ra l s

lo w

-r el

ea se

m or

ph in

e, c

om m

en ce

d tr

ea tm

en t w

ith 1

2 m

g bu

pr en

or ph

in e.

D os

es w

er e

tit ra

te d

fo r

5 da

ys a

cc or

di ng

to a

p re

de fin

ed ti

tr at

io n

al go

ri th

m :

da y

1 do

si ng

w as

fo llo

w ed

b y

12 m

g bu

pr en

or ph

in e

if w

ith dr

aw al

w as

p re

se nt

. D os

e tit

ra tio

n in

cr em

en ts

to 1

6, 2

0 an

d 24

m g

pe r

da y

w er

e av

ai la

bl e

du ri

ng b

up re

no rp

hi ne

in du

ct io

n. P

ar tic

ip an

ts r

ec ei

ve d

pl ac

eb o

sy ru

p co

m pr

is in

g 30

m g

de xt

ra m

et ho

rp ha

n or

al s

ol ut

io n

ta st

e- m

at ch

ed to

m et

ha do

ne . D

os es

o f b

up re

no rp

hi ne

w er

e be

tw ee

n 8

an d

24 m

g/ da

y th

ro ug

ho ut

e st

ud y.

M et

ha do

ne : P

ar tic

ip an

ts w

er e

st ar

te d

on 4

0 m

g m

et ha

do ne

a t t

he o

ns et

o f m

od er

at e

w ith

dr aw

al s

ym pt

om s

on d

ay 1

(W an

g sc

or e

be tw

ee n

5 an

d 10

). P

ar tic

ip an

ts w

ho r

ec ei

ve d

m or

e th

an 4

00 m

gd ay

o f o

ra l s

lo w

-r el

ea se

m or

ph in

e, c

om m

en ce

d tr

ea tm

en t w

ith 5

5 m

g m

et ha

do ne

. D os

es w

er e

tit ra

te d

fo r

5 da

ys a

cc or

di ng

to a

p re

de fin

ed ti

tr at

io n

al go

ri th

m :

da y

1 do

si ng

w as

fo llo

w ed

b y

55 m

g m

et ha

do ne

if w

ith dr

aw al

w as

p re

se nt

. D os

e tit

ra tio

n in

cr em

en ts

to 7

0, 8

5 an

d 10

0 m

g pe

r da

y w

er e

av ai

la bl

e du

ri ng

in du

ct io

n on

to m

et ha

do ne

ep en

di ng

o n

cl in

ic al

s ta

tu s)

. P

ar tic

ip an

ts r

ec ei

ve d

su b-

lin gu

al p

la ce

bo ta

bl et

s to

ta st

e- m

at ch

ed to

b up

re no

rp hi

ne . D

os es

m et

ha do

ne r

an ge

d be

tw ee

n 40

a nd

1 00

m g/

da y

th ro

ug ho

ut th

e st

ud y.

C o-

in te

rv en

ti on

s: A

ll pa

rt ic

ip an

ts r

ec ei

ve d

fo od

v ou

ch er

s as

c om

pe ns

at io

n (t

he m

ax im

am ou

nt p

os si

bl e

w as

th e

eq ui

va le

nt o

f 1 00

0 eu

ro s

fo r

20 w

ee ks

p ar

tic ip

at io

n) .

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co m

es w

er e

no t c

le ar

ly d

efi ne

d as

P R

IM A

R Y

S EC

O N

D A

R Y.

M AT

ER N

A L:

•

Fr eq

ue nc

y an

d am

ou nt

o f a

dd iti

on al

io id

s us

ed b

y th

e m

ot he

r as

m ea

su re

d by

u ri

ne to

xi co

lo gy

• Fr

eq ue

nc y

an d

am ou

nt o

f u se

o f

ot he

r su

bs ta

nc es

o f

ab us

e by

th e

m ot

he r

as m

ea su

re d

by u

ri ne

xi co

lo gy

• R

et en

tio n

tr ea

tm en

t a s

m ea

su re

d by

m pl

et io

n of

th e

st ud

y IN

F A N

T :

• S

ev er

ity a

nd d

ur at

io n

of th

e N

A S

a s

m ea

su re

d by

th e

Fi nn

eg an

S ca

105

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Tr ia

l I D

C ou

nt ry

N G

es ta

ti on

ag e

A lc

oh ol

a nd

d ru

g us

e S

et ti

ng R

an do

m iz

ed g

ro up

s P

ri m

ar y

ou tc

om es

Jo ne

s 20

10 U

S A

a nd

us tr

ia ,

m ul

ti- ce

nt re

s ite

17 5

R 13

1 A

6– 30

w ks

O pi

oi d-

de pe

nd en

t w

om en

(c ur

re nt

v ia

S M

IV c

ri te

ri a

ha ve

a h

is to

ry o

f op

io id

d ep

en de

nc e

an d

be a

t r is

k of

r el

ap se

) a nd

ov id

e an

o pi

oi d-

po si

tiv e

ur in

e sa

m pl

U ni

ve rs

ity h

os pi

ta l

se tt

in g

on a

n ou

tp at

ie nt

si s,

b ut

w om

en w

er e

ad m

itt ed

fo r

at le

as t

3 da

ys in

a r

es id

en tia

l or

in pa

tie nt

s et

tin g

du ri

ng in

du ct

io n

on to

ub le

-b lin

d st

ud y

m ed

ic at

io n.

W om

ha d

ac ce

ss to

a n

ar ra

y of

s er

vi ce

s in

cl ud

in g

ca se

m an

ag em

en t,

gr ou

p an

d in

di vi

du al

un se

lin g,

o bs

te tr

ca re

, p sy

ch ia

tr ic

al ua

tio n

an d

tr ea

tm en

t, ge

ne ra

l m

ed ic

al m

an ag

em en

t, an

d ac

ce ss

to c

hi ld

re a

nd p

ed ia

tr ic

re . N

eo na

te s

w er

e ho

sp ita

liz ed

fo r

a m

in im

um o

f 4 d

ay s

an d

as se

ss ed

fo r

N A

S fo

r at

as t 1

0 da

ys .

B ef

or e

ra nd

om iz

at io

n, a

ll pa

rt ic

ip an

ts r

ec ei

ve d

ra pi

d- re

le as

e m

or ph

in e

su lfa

te a

s in

pa tie

nt s

to a

ch ie

ve m

ed ic

al s

ta bi

liz at

io n

an d

to e

as e

th e

tr an

si tio

n to

th e

do ub

le -b

lin d

m ed

ic at

io n.

b lin

de d

in di

vi du

al is

ed d

os in

g sc

he du

le w

as u

se d

to im

pl em

en t d

os e-

un it

in cr

ea se

s or

cr ea

se s

w ith

d os

e ad

ju st

m en

ts o

f 2 m

g fo

r bu

pr en

or ph

in e

an d

5 or

1 0

m g

fo r

m et

ha do

ne .

D os

e ad

ju st

m en

ts w

er e

ba se

d on

c lin

ic al

d ec

is io

ns , p

ar tic

ip an

t r eq

ue st

, u ri

ne to

xi co

lo gy

a nd

lf- re

po rt

ed w

ith dr

aw al

s ym

pt om

s. B

up re

no rp

hi ne

: D ai

ly s

ev en

ta bl

et s

(t hr

ee in

th e

si ze

o f a

n 8-

m g

ta bl

et a

nd fo

ur in

th e

si ze

a 2

-m g

ta bl

et ) t

o pl

ac e

un de

r th

e to

ng ue

fo r

5 m

in ut

es , o

r un

til th

e ta

bl et

s di

ss ol

ve d.

ch ta

bl et

c on

ta in

ed b

up re

no rp

hi ne

o r

pl ac

eb o.

A fl

ex ib

le d

os e

ra ng

e of

2 to

3 2

m g

bu pr

en or

ph in

e in

s ub

lin gu

al ta

bl et

s w

as e

st im

at ed

to b

e eq

ui va

le nt

to 2

0 to

1 40

m g

m et

ha do

ne o

n th

e ba

si s

of p

re vi

ou sl

y pu

bl is

he d

da ta

fr om

c lin

ic al

tr ia

ls . A

ft er

r ec

ei vi

ng th

es e

ta bl

et s,

p ar

tic ip

an ts

r ec

ei ve

d liq

ui d

co nt

ai ni

ng m

et ha

do ne

p la

ce bo

. O ra

l m et

ha do

ne p

la ce

w as

g iv

en in

th e

sa m

e fix

ed v

ol um

e an

d in

cl ud

ed th

e sa

m e

fla vo

ur -m

as ki

ng c

on ce

nt ra

te s

th e

ac tiv

e dr

ug c

on ce

nt ra

te .

M et

ha do

ne : D

ai ly

s ev

en ta

bl et

s of

p la

ce bo

b up

re no

rp hi

ne fo

llo w

ed b

y m

et ha

do ne

d os

e in

liq

ui d

pr ep

ar at

io n

di lu

te d

to p

ro vi

de th

e do

se in

a fi

xe d

vo lu

m e

(e .g

., 40

m l a

t U .S

. s ite

s an

d 50

l i n

Vi en

na ).

C o-

in te

rv en

ti on

s: M

on et

ar y

vo uc

he rs

in e

xc ha

ng e

fo r

pr ov

id in

g ur

in e

sa m

pl es

th at

w er

e ne

ga tiv

e fo

r op

io id

s (o

th er

th an

b up

re no

rp hi

ne a

nd m

et ha

do ne

), ot

he r

ill ic

it dr

ug s,

a nd

is us

e of

p re

sc ri

pt io

n m

ed ic

at io

ns .

IN FA

N T:

• N

um be

r of

n eo

na te

s re

qu ir

in g

tr ea

tm en

t fo

r N

A S

• P

ea k

N A

S s

co re

• To

ta l a

m ou

nt o

f m

or ph

in e

ne ed

ed fo

r N

A S

tr ea

tm en

t •

Le ng

th o

f h os

pi ta

l st

ay •

H ea

d ci

rc um

fe re

nc e

RC T

– Ra

nd om

iz ed

c on

tr ol

le d

tr ia

l R

– N

um be

r r an

do m

iz ed

A –

N um

be r a

na ly

se d

106

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

RISK OF BIAS IN EACH TRIAL INCLUDED IN THE METHADONE VS BUPRENORPHINE COMPARISON

FOREST PLOTS OF METHADONE VS BUPRENORPHINE COMPARISON

Random sequence generation (selection

bias)

Allocation concealment

(selection bias)

Blinding of participants

and personnel

(performance bias)

Blinding of outcome

assessment (detection

bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting

bias) Other bias

Fischer 2006

Jones 2005

Jones 2010

107

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

108

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

109

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Methadone Buprenorphine

Maternal toxicology positive at delivery Urine screening

145 per 1000 80 per 1000 (30 to 207)

RR 0.55 (0.21 to 1.43)

149 (2 studies)

⊕⊕ LOW1,2

Jones 2010 applied Poisson regression with OR = 0.5 (95% CI: 0.1, 2.7). RevMan OR = 0.53 (95% CI: 0.17, 1.63). Meta-analysis was deemed appropriate.

Maternal withdrawal Wang Withdrawal Scale

See comment See comment Not estimable

0 (2 studies)

⊕ VERY LOW3,4

Jones 2005 reported no difference (F 0.67(df 1,16); p = 0.426); Fischer 2006 provided overall sample means but reported no differences between groups in text

Maternal retention in substance treatment – Retention in trial (proxy measure) Follow-up: 14-28 days post-partum

796 per 1000 653 per 1000 (565 to 757)

RR 0.90 (0.70 to 1.17)

223 (3 studies)

⊕⊕⊕ MODERATE5,6

Birthweight The mean birthweight in the intervention groups was 321.85 gm higher (30.81 gm to 612.88 gm higher)

164 (3 studies)

⊕⊕ LOW5,7

Premature delivery before week 37 Intention to treat (ITT) analysis

230 per 1000 74 per 1000 (37 to 150)

RR 0.28 (0.13 to 0.61)

223 (3 studies)

⊕⊕ LOW5,7

Jones 2010 applied Poisson regression with OR = 0.3 (95% CI: 0.1, 2.0). RevMan OR = 0.32 (95% CI: 0.12, 0.85). Meta- analysis using ITT was deemed appropriate.

Neonatal Abstinence Syndrome requiring treatment Intention to treat (ITT) analysis

540 per 1000 464 per 1000 (286 to 756)

RR 0.86 (0.53 to 1.4)

223 (3 studies)

⊕⊕ LOW2,5

Jones 2010 applied Poisson regression with OR = 0.7 (95% CI: 0.2, 1.8). RevMan OR = 0.83 (95% CI: 0.62, 1.11). Meta- analysis using ITT was deemed appropriate.

BUPRENORPHINE COMPARED TO METHADONE FOR MATERNAL SUBSTANCE DEPENDENCE

Patient or population: Maternal substance dependence Settings: Residential and clinic-based Intervention: Buprenorphine Comparison: Methadone

110

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

CI: Confidence interval. RR: Risk ratio. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Risk of Bias: Both trials (Jones 2005 and Jones 2010) were well-conducted with appropriate randomization and blinding. However, the high rate of attrition in Jones

2010 and the magnitude of the differential between the groups (18% in methadone and 33% in the buprenorphine groups) results in the overall risk of bias rated as serious

2 Imprecision: The event rate is low and the confidence interval is wide. 3 Risk of Bias: Attrition was high and poses a serious risk of bias. 4 Imprecision: Two trial reported withdrawal data (Jones 2005 and Fischer 2006). Trial samples sizes were very small (18 in each trial) and there is a high likelihood of

imprecision in the results although confidence intervals are not reported for the estimates. 5 Risk of Bias: All three trials were well-conducted but attrition was high in all three trials. In the larger trial (Jones 2010) the magnitude of the differential attrition

between the groups (18% in methadone and 33% in the buprenorphine groups) results in the overall risk of bias rated as serious. 6 Indirectness: Retention in the trial was deemed a suitable proxy measure for retention in substance use treatment. The evidence was not downgraded for

indirectness. 7 Imprecision: The confidence interval is wide and the sample size is less than 400 (GRADE guideline for assessing continuous data) 8 Imprecision: Event rate was very low and the confidence interval was wide. 9 Imprecision: Event rate is very low and the confidence interval is very wide.

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Methadone Buprenorphine

Spontaneous abortion

27 per 1000 0 per 1000 (0 to 0)

Not estimable

223 (3 studies)

⊕ VERY LOW5,9

There were zero events in the buprenorphine group and 3 events in the methadone group.

111

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Q ua

li ty

a ss

es sm

en t

N o.

o f p

at ie

nt s

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li ty

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rt an

ce N

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D es

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co ns

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nc y

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re ct

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co ns

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at io

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up re

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ha do

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el at

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)

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k 37

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112

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

1 Ri

sk o

f B ia

s: B

ot h

tr ia

ls (J

on es

2 00

5 an

d Jo

ne s

20 10

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e w

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w ith

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d bl

in di

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ig h

ra te

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tt rit

io n

in J

on es

2 01

0 an

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ul ts

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k of

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as s

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po se

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a (J

on es

2 00

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sc he

r 2 00

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ria l s

am pl

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iz es

w er

e ve

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m al

l ( 18

in e

ac h

tr ia

l) an

d th

er e

is a

h ig

h lik

el ih

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of im

pr ec

is io

n in

th e

re su

lts a

lth ou

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on fid

en ce

in te

rv al

s ar

e no

t r ep

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r t he

tim at

es .

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sk o

f B ia

s: A

ll th

re e

tr ia

ls w

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w el

l-c on

du ct

ed b

ut a

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w as

h ig

h in

a ll

th re

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. I n

th e

la rg

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ia l (

Jo ne

s 20

10 ) t

he m

ag ni

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en tia

l a tt

rit io

n be

tw ee

n th

e gr

ou ps

(1 8%

in m

et ha

do ne

a nd

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in th

e bu

pr en

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gr ou

ps ) r

es ul

in th

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di re

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ss : R

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tio n

in th

e tr

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as d

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m ea

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ra de

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r i nd

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ne ss

. 7

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io n:

T he

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te rv

al is

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m pl

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th an

4 00

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gu id

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on tin

uo us

d at

a) 8

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io n:

E ve

nt ra

te w

as v

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lo w

a nd

th e

co nfi

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te rv

al w

as w

id e.

9 Im

pr ec

is io

n: E

ve nt

ra te

is v

er y

lo w

a nd

th e

co nfi

de nc

e in

te rv

al is

v er

y w

id e.

Q ua

li ty

a ss

es sm

en t

N o.

o f p

at ie

nt s

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Q ua

li ty

Im po

rt an

ce N

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f s tu

di es

D es

ig n

R is

k of

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s In

co ns

is te

nc y

In di

re ct

ne ss

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io n

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co ns

id er

at io

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up re

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(9 5%

C I)

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ol ut

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eo us

a bo

rt io

3 ra

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se ri

ou s5

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er io

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ns is

te nc

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s er

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⊕ 

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113

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

M E

T H

A D

O N

E v

s S

L O

W -R

E L E

A S

E M

O R

P H

IN E

d u ri

n g

p re

gn an

cy f

or w

om en

w it

h o

p io

id d

ep en

d en

ce TA

B LE

O F

C H

A R

A C

TE R

IS TI

C S

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LU D

ED R

C Ts

: 1 IN

T O

TA L

Tr ia

l I D

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nt ry

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do m

iz ed

g ro

up s

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m ar

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tc om

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R V

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R IN

G P

R EG

N A

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Y O

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G en

er al

tr ea

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tr ia

ls w

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tifi ed

fr om

th es

e se

tt in

gs .

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ci al

is t t

re at

m en

t s et

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19 99

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tr ia

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at io

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cl us

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cr ite

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se lin

e EG

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on e

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D : 5

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ta nc

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pa tie

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Fr om

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st d

el iv

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– sp

ec ifi

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ra tio

n no

t re

po rt

M et

ha do

ne : P

ar tic

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ts w

er e

st ar

te d

on a

fl ex

ib le

d os

in g

sc he

du le

w ith

10 d

ay in

du ct

io n

pe ri

od . M

et ha

do ne

lu tio

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as a

dm in

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on ce

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ay .

P ar

tic ip

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w he

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s. A

ft er

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st ab

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d un

til w

ee k

32 w

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a sm

al l d

os ag

e in

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as n

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m ea

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as 5

3. 48

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be r a

na ly

se d

114

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

FOREST PLOTS OF METHDAONE VS MORPHINE COMPARISON

RISK OF BIAS IN EACH TRIAL INCLUDED IN THE METHADONE VS MORPHINE COMPARISON

Random sequence generation (selection

bias)

Allocation concealment

(selection bias)

Blinding of participants

and personnel

(performance bias)

Blinding of outcome

assessment (detection

bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting

bias) Other bias

Fischer 1999

115

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

116

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

117

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Slow-release Morphine Methadone

Maternal substance use Proxy measure for opioid use is identification of injection sites

208 per 1000 500 per 1000 (208 to 1000)

RR 2.4 (1 to 5.77)

48 (1 study)

⊕ VERY LOW1,2,3

Statistically significantly fewer benzodiazepines were consumed by women in the morphine group compared with the methadone group. Cocaine use was low for both.

Maternal withdrawal

See comment See comment Not estimable

— See comment Not reported

Maternal retention in treatment – Proxy measure of retention in trial

1000 per 1000 1000 per 1000 (920 to 1000)

RR 1 (0.92 to 1.08)

48 (1 study)

⊕⊕ LOW1,4

No women were lost from the trial.

Infant birthweight in grams

The mean infant birthweight in the intervention groups was 123.54 higher (187.58 lower to 434.66 higher)

48 (1 study)

⊕⊕ LOW1,5

Infant prematurity Estimated gestational age at delivery in weeks

The mean infant prematurity in the intervention groups was 1.13 higher (0.11 lower to 2.37 higher)

48 (1 study)

⊕⊕ LOW1,5,6

Methadone group EGA at delivery range 36–42 wks and Morphine EGA at delivery range 31–41 wks. N of premature delivery was not reported.

Neonatal Abstinence Syndrome (NAS) Mean duration of NAS in days

The mean neonatal abstinence syndrome (nas) in the intervention groups was 5 lower (11.2 lower to 1.2 higher)

48 (1 study)

⊕⊕ LOW1,7

No reported statistical differences between groups for consumption of phenobarbitone or intensity of NAS. N for numbers with NAS in each group was not reported.

METHADONE COMPARED TO SLOW-RELEASE MORPHINE FOR PREGNANT OR POSTPARTUM WOMEN WITH OPIOID DEPENDENCE

Patient or population: Pregnant or postpartum women with opioid dependence Settings: Outpatient in specialist substance use treatment setting Intervention: Methadone Comparison: Slow-release Morphine

118

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Slow-release Morphine Methadone

Spontaneous abortion

See comment See comment Not estimable

48 (1 study)

⊕⊕ LOW1,6

No women experienced a spontaneous abortion in the trial

CI: Confidence interval. RR: Risk ratio. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Risk of Bias: Rated as Serious. Lack of reporting results in the randomization process being marked as unclear. The lack of blinding is a high risk due to the possible

presence of performance and detection bias. 2 Indirectness: Rated as Serious. Illicit opioid use could not be determined by urinalysis so identification of injection sites served as a proxy measure. 3 Imprecision: Rated as Serious. The event rate is low and the confidence interval is wide. 4 Indirectness: The proxy measure of retention in the trial is used to indicate treatment retention. The report states that women participated actively in the treatment

programme but no comparison between groups is provided. 5 Indirectness: The number of premature births was not reported. The range of EGA indicates that there were some premature < 37 week births. 6 Imprecision: Rated as Serious: There is a likelihood of imprecision due to the small overall sample size. 7 Imprecision: Rated as Serious: The confidence interval is wide.

119

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Q ua

li ty

a ss

es sm

en t

N o.

o f p

at ie

nt s

Ef fe

Q ua

li ty

Im po

rt an

ce N

o. o

f s tu

di es

D es

ig n

R is

k of

b ia

s In

co ns

is te

nc y

In di

re ct

ne ss

Im pr

ec is

io n

O th

co ns

id er

at io

ns M

et ha

do ne

S lo

w -r

el ea

M or

ph in

e R

el at

iv e

(9 5%

C I)

A bs

ol ut

M at

er na

l s ub

st an

ce u

se (a

ss es

se d

w it

h: P

ro xy

m ea

su re

fo r

op io

id u

se is

id en

ti fic

at io

n of

in je

ct io

n si

te s)

1 ra

nd om

iz ed

ia ls

se ri

ou s1

no s

er io

in co

ns is

te nc

y se

ri ou

s2 se

ri ou

s3 no

ne 12

/2 4

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Evidence profile 5: Breastfeeding

Evidence question: In the management of postpartum women using alcohol or drugs or with substance use disorders, does encouraging breastfeeding result in better maternal or infant outcomes than not encouraging breastfeeding, discouraging breastfeeding (recommending breast milk substitutes), or recommending intermittent use of breast milk substitutes following periods of substance use?

Study selection criteria for the systematic review: Study design: RCTs

Population: Postpartum women using alcohol or drugs or with substance use disorders.

Interventions: Encouraging breastfeeding.

Control: Not encouraging breastfeeding (treatment-as-usual), discouraging breastfeeding (recommending breast milk substitutes), or recommending short-term use of breast milk substitutes for periodic substance use.

Outcomes: The following outcomes were of interest:

Outcome Importance (0–9)

Infant: Weight gain 7.78

Infant: Attachment 7.56

Infant: Failure to thrive 7.44

Infant: Neurobehaviour (lethargy, sedation, irritability) 7.44

Infant: Neonatal Abstinence Syndrome 7.22

Infant: Infections 7.11

Infant: Feeding issues 7.00

Maternal: Bonding with child 6.89

Maternal: Substance use 6.33

Maternal: Well-being 6.22

Infant: Death 6.00

Maternal: Mastitis 5.11

Termination of maternal rights (e.g. baby taken into care) 4.11

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

EVIDENCE TO RECOMMENDATIONS TABLE

Breastfeeding with maternal alcohol and/or other substance dependence

There were no randomized controlled trials identified for this evidence profile. The evidence summary is based on a narrative review of the evidence.

Summary of evidence (see the longer narrative review of evidence following this table) • Enhanced maternal-infant attachment through breastfeeding (Luijk et al., 2012) is especially important, particularly

for women feeling guilty about their prenatal drug use and those with lack of self-confidence in parenting skills. • Breastfeeding and/or breast milk may reduce the incidence and/or severity of neonatal abstinence syndrome in

opioid exposed infants (McQueen et al., 2012). • Evidence of decreased stress response (Mezzacappa et al., 2005) and increased vagal tone, indicating better

autonomic regulation, in lactating versus non-lactating women is salient for drug dependent women. Stress can be a major factor in the development of psychiatric symptoms, and has been linked to relapse to substance abuse (Sinha, et al. 2007) Further maternal dysregulation of the stress and reward systems is associated with drug seeking and neglectful parenting behaviors (Rutherford et al., 2011).

• For alcohol, binge alcohol, tobacco and cannabis use, breastfeeding rates rebound substantially in the postpartum period compared with use during pregnancy (National Survey on Drug Use and Health, combined data from 2002- 2007).

• Depression correlates with substance use, and new mothers with postpartum depression may be at high risk for substance use or return to substance use (Chapman & Wu, 2013).

• Maternal psychopathology is more common in substance dependent women than in the general population (Fitzsimons et al., 2007) and is not infrequently related to poor judgment, enhancing the physical risk to the breastfed infant. Maternal somnolence, lack of adequate sleep-wake cycling, or decreased reaction times due to psychoactive medication or drug use may additionally result in infant injury. Women with substance use disorders are more likely to minimize risks, have less self-control, and less regard for their own and other people's safety in situations that can be risky for the breastfed infant, further enhancing the possibility of harm.

• Breastfed infants necessarily accompany their mothers and require attention more frequently than the non- breastfed infant. For women who are medically or psychiatrically unstable, have continued drug use, or live in environments that are unsafe or chaotic, this translates to increased infant exposures to violence, maternal drug seeking/drug trade, or maternal prostitution. Due to brain changes that are associated with drug use, drug dependent women often view normal infant cues as stressful instead of rewarding (Rutherford et al., 2011).

• Women who are regular cocaine or amphetamines/methamphetamines users and unstable should be advised against breastfeeding. Mothers who use these stimulants infrequently may be candidates for breastfeeding, provided that they express and throw away the milk after using, have a supplementary feeding plan in place, and do not breastfeed for 24 hours after use. Mothers need to be advised that these substances have been found in the breast milk, and has been shown to cause toxicity in the infant.

• There is insufficient information regard breastfeeding during cannabis use, although it has been found in breast milk. Its effects on the infant are unknown.

• Two small sample size reports have noted that women prescribed methadone may want to consider weaning their children off breast milk gradually to reduce the risk of developing withdrawal symptoms (Malpas & Darlow, 1999; Isemann et al., 2010).

Benefits and harms

Benefits • Pregnancy and the immediate postpartum period represents an ideal time for mother-child bonding and breastfeeding may increase this bonding

• Breastfeeding represents the single best way for a mother to feed her child • Breastfeeding is likely to lead to better short- and long-term child development outcomes • Breastfeeding may serve as a protective factor from many illnesses • Breastfeeding may help protect babies from developing allergies • Breastfeeding may boost a child's intelligence • Breastfeeding may protect a child from obesity • Breastfeeding may lower a baby's risk of SIDS • Breastfeeding can reduce maternal stress level and risk of postpartum depression • Breastfeeding is less costly, more hygienic and easier to deliver than other feeding methods

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

EVIDENCE TO RECOMMENDATIONS TABLE

Harms • Potential higher risk of difficulties bonding due to neonatal withdrawal symptoms • Short and long term risks of the child being exposed via breast milk to varying amounts of

substances consumed by the mother. These risks depend on the substance consumed by the mother, with little data available for several substances (e.g., hallucinogens, volatile agents). The most harmful exposures are alcohol (>50gms in one occasion)

• Risk that a mother who is using sedative substances may inadvertently suffocate the child • Greater risk exposure of breastfed child to chaotic lifestyle harms such as violence, maternal

drug seeking/ prostitution. • Maternal psychopathology may enhance risk to breast fed child

Values and preferences

In favour: Mother

Health-care worker

Community

• More convenient, less costly means of feeding child • Value support from HCW for breastfeeding

• Value breastfeeding for reduction in gastrointestinal and other childhood infectious disease • Value breastfeeding for potential to reduce NAS • Value breastfeeding as optimal means of child nutrition

• Value breast feeding as means of superior child development • Possible positive responses from partners, family and co-workers

Against: Mother

Health-care worker

Community

• Fatigue, irritability, poor bonding may make breastfeeding undesirable • Lifestyle-need to seek drugs/engage in prostitution may make breastfeeding undesirable • Physical effects – painful enlarged breasts, poor lactation – may make breast feeding

undesirable to mother • May believe breastfeeding will harm infant

• May believe mother is incapable of breastfeeding • May believe mother is likely to smother infant • May find time and commitment needed to support mother burdensome • May believe infant is at risk from mother’s substance use

• Partners/family/employers may believe breast feeding is inappropriate and actively oppose it

Costs and feasibility

Feasibility (including economic consequences)

• Managing breastfeeding in women who use alcohol requires support, trust and clear advice: e.g. women who use alcohol should be discouraged from breastfeeding for 2 hours after consuming one drink, and 4 to 8 hours after consuming more than one drink in a single sitting.

• The availability of safe and affordable breast milk substitutes, including access to clean water, sterilizing equipment, the affordability of breast milk substitutes and the age of the infant/child needs to be considered and balanced against risks of breastfeeding.

• Breastfeeding itself imposes little additional cost beyond providing basic services to the mother and child. However, trained staff and a sustainable programme is needed to support breastfeeding and bonding and teach and support mother with care of the infant.

• A comprehensive care model in which there is a focus on the mother-infant dyad and is part of a women-centred, trauma-informed programme would be the best model of care – and also the costliest.

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Draft recommendations: o The decision to breastfeed should take into account the specifics risks and benefits of breastfeeding

compared to alternatives in each case. In most instances, the benefits will outweigh the risks of breastfeeding and in this situation women with a substance use disorders should be encouraged to breastfeed with appropriate support and precautions.

o Skin-to-skin contact is important regardless of feeding choice and needs to be actively encouraged for the mother who is fully conscious and aware and able to respond to her baby’s needs.

o Mothers who are stably maintained on opioid agonist medication, either methadone or buprenorphine, should be encouraged to breastfeed.

o Mothers who are stably maintained on opioid antagonist medication, such as naltrexone, should be discouraged from breastfeeding because naltrexone does pass into breastmilk, and naltrexone has been shown to cause tumors in animal studies.

Final recommendations: RECOMMENDATION 

A. Mothers with substance use disorders should be encouraged to breastfeed unless the risks clearly outweigh the benefits.

B. Breastfeeding women using alcohol or drugs should be advised and supported to cease alcohol or drug use; however, substance use is not necessarily a contraindication to breastfeeding.

Strength of recommendation: Conditional Quality of evidence: Low

Remarks: • A risk assessment should take into account the risks of exposure to alcohol and drugs in breast milk, HIV status, the

• The message to breastfeeding women who have used alcohol and drugs, to cease using alcohol and drugs while breastfeeding should be given in such a way that it does not undermine the potential benefits of breastfeeding.

• It is possible to reduce the risk of exposure through breastfeeding by altering the timing of breastfeeding, or by the use of temporary alternatives, such as stored (frozen) breast milk or breast milk substitutes where they are available and can be safely used. Women who use alcohol intermittently should be discouraged from breastfeeding for 2 hours after consuming one standard drink (10 g of pure alcohol), and 4 to 8 hours after consuming more than one drink in a single occasion. Breastfeeding advice for women with HIV should also take into consideration the risk of HIV transmission (refer to WHO guidelines on breastfeeding and HIV).

• Mothers of infants with a neonatal withdrawal syndrome should be offered appropriate breastfeeding information and support.

• This recommendation was considered conditional because the different values and preferences of women and the lack of strong evidence of harms of low levels of substance use in pregnancy.

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

RECOMMENDATION 

Skin-to-skin contact is important regardless of feeding choice and needs to be actively encouraged for the mother with a substance use disorder who is able to respond to her baby’s needs.

Strength of recommendation: Strong Quality of evidence: Low

Remarks: • It was decided that the recommendation should be strong despite the very low quality evidence as the risk of harm

is minimal, it consumes no resources, the values and preferences were in favour of the recommendation, and there was considered to be certainty about the balance between benefits and harms.

RECOMMENDATION 

Mothers who are stable on opioid maintenance treatment with either methadone or buprenorphine, should be encouraged to breastfeed unless the risks clearly outweigh the benefits.

Strength of recommendation: Strong Quality of evidence: Low

Remarks: • Women prescribed opioids such as methadone and buprenorphine and wishing to stop breastfeeding may wean

Factors in considering the strength of the recommendations (recommendations 12–14): Factor Decision

Is there high or moderate quality evidence? The higher the quality of evidence, the more likely is a strong recommendation.

Yes

Are the expected values and preferences clearly in favour of the recommendation? Yes

Yes

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Breastfeeding and substance use/misuse: A review of the evidence and estimates of risks associated with individual substances Lauren M. Jansson

Both licit and illicit substance use remain a significant problem among women of childbearing age. The 2007 National Survey on Drug Use and Health (NSDUH) revealed that among pregnant women aged 15 to 44 years, 5.2 percent used illicit drugs in the past month in the US. Although the prevalence of prescribed opioid pain relievers/narcotic analgesics, such a hydrocodone and oxycodone, among pregnant women is not well known, there is growing evidence that misuse of opioid pain relievers/narcotic analgesics is increasing internationally (RADARs system report 2012; Maxwell & McCance-Katz, 2009). In the US, the incidence of NAS and maternal opioid use has tripled between 2000 and 2009 (Patrick et al., 2012). Adolescents are a particular concern; in 2010-11, among young pregnant women between 15 and 17 years the rate of illicit drug use was 20.9% and smoking rates are higher in pregnant vs non-pregnant teens in this group (NIDA). Other substance use during pregnancy is also of significant concern throughout the world: In Barcelona, 11% of meconium tested was positive for drugs of abuse in a random survey of 175 newborns (Concheiro et al., 2012); 14% of Canadian women report alcohol use during their last pregnancy in 2005 (Health Canada, 2005), and worldwide, the incidence on fetal alcohol syndrome is 1:2000 live births (Sachdeva et.al., 2009).

Breast milk is well-known as optimal nutrition for the newborn. There are myriad other recognized benefits from breast milk and lactation that are likely to provide a particular benefit to the drug dependent dyad who are, in general, at higher risk for many acute and chronic physical and psychological conditions. These include reduced infections in the neonate, a diminution of certain chronic health conditions in later life, such as Types I and II diabetes and obesity, and improved cognition and brain development (Isaacs et al., 2010). Breastfeeding is an analgesic for newborns (Gray, et al., 2002) and there is some evidence that breast milk and/or breastfeeding can ameliorate the incidence or severity of neonatal abstinence syndrome (NAS, or withdrawal, typically found in opioid exposed infants after delivery) (Welle-Strand et al., 2013, McQueen, 2011). Mothers also have significant health benefits, such as reduced incidence of breast and ovarian cancer, decreased stress response (Mezzacappa et al., 2005) and increased vagal tone, indicating better autonomic regulation, in lactating vs non- lactating women. This may be a particularly salient benefit for drug dependent women, as stress can be a major factor in the development of psychiatric symptoms, and has been linked to relapse to substance abuse (Sinha, et al. 2007) and maternal dysregulation of the stress and reward systems is associated with drug seeking and neglectful parenting behaviors (Rutherford et al., 2011). Enhanced maternal-infant attachment (Luijk et al., 2012) may be another especially important benefit, particularly for women who may harbor guilt in regards to their prenatal drug use and lack of self-confidence in parenting skills.

Despite the significant and specific benefits of breast milk and breastfeeding for the substance exposed dyad, when considering lactation among this high risk population, there must necessarily be a discussion regarding the risk: benefit ratio of this practice, and several risk factors must be considered. These factors stem from: 1) maternal functioning, 2) infant functioning, and 3) toxicities associated with the substance(s) used.

1. The substance dependent mother

Substance dependent women may have health or other conditions that can increase the risk to the breast fed infant. These include HIV or other infections, poor nutrition, and psychiatric disorders that require psychotropic medications with known toxicity. Research has indicated that the mother’s decision to breastfeed does not necessarily reflect a lifestyle including drug abstinence that would preclude toxic exposures in her offspring (Frank et al., 1992). Drug dependent women frequently use more than one substance (illicit and/or licit), and the incidence of concurrent alcohol use and cigarette smoking is high. Exposure to alcohol or drugs can significantly impair the mother’s judgment and ability to care for the baby, and for chronic drug users, repetitive exposures increase this risk and lead to brain changes that enhance this risk. For women who are able to achieve abstinence during pregnancy, relapse to substance use after delivery is a significant concern. For alcohol, binge alcohol, tobacco and cannabis use, rates rebound substantially in the postpartum period compared with use during pregnancy (National Survey on Drug Use and Health, combined data from 2002-2007). Some women relapse on substances that are not usually detected in the urine toxicology tests that are part of the regular screening for drug use in treatment programs or hospitals (e.g. clonidine, some benzodiazepines). In most

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

societies, pregnant and parenting drug dependent women are usually under considerable social pressure to deny substance use, making detection of perinatal substance dependence both important and problematic. Depression correlates with substance use, and new mothers with postpartum depression may be at high risk for substance use or return to substance use (Chapman & Wu, 2013). Additionally, substance using and/ or dependent women frequently display some behaviors or conditions that can be harmful for the breastfed infant independently or in addition to the drug exposure per se. Maternal psychopathology is more common in substance dependent women than in the general population (Fitzsimons et al., 2007) and is not infrequently related to poor judgment, enhancing the physical risk to the breastfed infant. Maternal somnolence, lack of adequate sleep-wake cycling, or decreased reaction times due to psychiatric medication may additionally result in infant injury. Women with substance use disorders are more likely to minimize risks, have less self-control, and less regard for their own and other people's safety in situations that can be risky for the breastfed infant, further enhancing the possibility of harm.

2. The substance exposed infant

The risks associated with substances in breast milk to the infant are also influenced by factors beyond what is known about the pharmacokinetics of the drug. Certain drugs may accumulate in the infant due to reduced clearance or immature metabolic pathways (AAP, 2013). Specific genotypes may provide increased vulnerability, such as those associated with ultra-rapid metabolism of codeine (Berlin, et al., 2009). The substance exposed infant, particularly the opioid exposed infant, may undergo NAS after birth, which can entail significant morbidity and prolonged pharmacotherapeutic treatment. Infants with NAS may be particularly difficult to breastfeed due to symptoms of the disorder, such as hypertonicity, suck-swallow incoordination, or other feeding difficulties (Jansson et.al., 2004), which can lead to failure to thrive for infants relying solely on breast milk for nutrition in addition to maternal frustration or feelings of guilt or inadequacy which can lead to depression or relapse. An important consideration is that the breastfed infant, as opposed to the infant receiving formula, necessarily accompanies his mother and requires attention more frequently. For women who are medically or psychiatrically unstable, have continued drug use, or live in environments that are unsafe and/or chaotic, this translates to increased infant exposures to harmful situations. Infants in these situations can be at risk for exposure to violence, maternal drug seeking/drug trade, or maternal prostitution. Due to brain changes that are associated with drug use, drug dependent women often view normal infant cues as stressful instead of rewarding (Rutherford et al., 2011), and this can additionally lead to situations of infant neglect and/or abuse.

3. Substances and breast milk/breastfeeding

Risks of breastfeeding in substance dependent women include direct toxicities of the substances transmitted into breast milk and ingested by the infant, as well as secondary exposures resulting in additional toxicities to the infant due to maternal substance use or the environment in which the substance dependent woman lives. Drugs with long half lives are more likely to accumulate in human milk, and drugs with high bioavailability are more easily absorbed by the infant (Hale, 2004). Illicit substances can be cut with dangerous and unknown adulterants. Vaporized substances can provide a secondary exposure to the infant; for example, there are over 450 compounds in THC smoke, many of which are toxic; 6 to 53% of ∆9-THC is released into the air during smoking by side stream (Huestis et al., 1992). For women living in poor environments, as many drug dependent women are, additional environmental exposures such as heavy metals, insecticides, inhaled aromatic hydrocarbons, etc. should be considered (Erlin & van den Anker, 2012).

There exists sparse literature on the subject of substances of abuse and transmission into breast milk in total, as this research is, in general, fraught with ethical and practical dilemmas, and is additionally difficult to perform. There is a near absence of literature on long term effects of exposures via breast milk. Most clinical trials in this arena explore the issues of lactation and medications used to treat opioid dependence. The large majority of literature in the area of illicit substance use and lactation consists primarily of case reports. All suffer from small numbers. While any discussion of individual substances of abuse is somewhat artificial in this population of women due to the high prevalence of poly-substance use, individual substances and toxicities related to infant exposures via breast milk are considered below. Estimates of risk for each substance are included, but it is important to note that most are largely author opinion based on a review and synthesis of available literature.

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Cocaine: Both the parent drug and the metabolite are present in milk, and high concentrations are expected due to the chemical nature of cocaine (Bailey, 1998), which can result in significant exposures (Winecker et al., 2001). There is considerable variability in the concentrations of cocaine reported in breast milk, and cocaine is not consistently detected in the breast milk of known users, so analysis of breast milk is not a sensitive method of exposure. For a 4 kg infant feeding every 3 hours, the blood concentration of cocaine can reach 200ng/mL comparable to an adult blood cocaine concentration measured after administration of 1.5 mg/kg intranasal or 16 mg IV dose of cocaine (Winecker et al., 2001). Newborns are particularly sensitive to cocaine because metabolism of cocaine to benzoylecgonine, its principal metabolite, is delayed due to immaturity of the cholinesterase system. Intoxication in the breastfed infant of the intranasal cocaine using mother has been reported (Chasnoff et al., 1987) as has intoxication in an infant whose mother used cocaine for nipple soreness (Chaney et al., 1988). Guidelines have been developed for the lactating cocaine occasionally using woman (Sarkar et al., 2005). A 24-hour period of breastfeeding abstinence has been recommended for women who occasionally use cocaine (Cressman, 2012).

Estimate of risk: Due to the immaturity of the newborn’s ability to metabolize cocaine ingested via breast milk, high concentrations are possible, and reported intoxications, risks of lactation in chronically cocaine using, or cocaine dependent, women are significant. It is likely that the risks associated with lactation in heavy or chronic cocaine users outweigh benefit when safe alternatives to breastfeeding are available. In non dependent or intermittent users the risk is lower, and can be further reduced by a 24-hours cessation in breastfeeding (when safe and affordable alternatives to breastfeeding are available).

Methamphetamine: Methamphetamine undergoes demethylation to amphetamine which is the active metabolite. Amphetamines often contain other substances with unpredictable effects. Amphetamines are concentrated in breast milk and 2.8 to 7.5 times maternal plasma (ACOG, 2011) and infant symptoms, including irritability and agitation (AAP, 2001) and infant death (Ariagno et al., 1995) have been reported. In one study, two women taking street methamphetamine (doses unknown) intravenously had drug levels measures in plasma and breast milk. Calculated infant doses were 16.7 and 42.2 mcg/kg/day of methamphetamine and 0.8 and 2.5 mcg/kg/day of amphetamine (Bartu, et al., 2009), which are less that therapeutic doses of equipotent dextroamphetamine for older children with ADHD.

Estimate of risk: Accurate information regarding the safety of methamphetamine abuse/misuse is unavailable.

Cannabis: ∆9-THC is the main compound in cannabis, and it is very fat soluble, and it persists in the body fat of users and can be released over long periods of time depending on extent of use. There are many compounds, most toxic, in ∆9-THC smoke. It appears that active components of cannabis are excreted into breast milk in small quantities. There is some concern about cannabis' effect of neurotransmitters, CNS development and endo- cannabinoid functions in the infant exposed via breast milk (Fernandez-Ruiz, et.al., 2004; Schuel, et.al.,2002). ∆9-THC is concentrated to a milk/plasma ratio of 8 in breast milk in heavy users, secreted into breast milk and absorbed and metabolized by the infant (THC metabolites are found in infant feces) (Perez-Reyes & Wall, 1982). In one feeding the infant could ingest 0.8% of the weight adjusted maternal intake of one joint (Bennett, 1997). Cannabis exposure via breast milk in the first month of infant life was associated with decreased motor development, but not growth or intellectual development, at one year (Astley & Little, 1990), and infant effects, such as sedation, growth delay (Hale & Hartman, 2006) low tone and poor sucking (Liston, 1998) have been described. Two studies (Astley & Little, 1990; Tennes, et.al., 1985) found that occasional cannabis use during breastfeeding did not have any discernable effects on breastfed infants. However, because an important phase of brain growth occurs in the period just after birth, THC could theoretically alter brain cell metabolism (Garry et al., 2009) and hence development. Among chronic THC users, 50% report “impaired control over their use”, and THC use itself is associated with a wide range of psychiatric conditions (Hall & Degenhardt, 2004), which implies an additional risk to the breastfed infant of the THC using mother.

Estimate of risk: Due to the potentially high concentrations of THC in breast milk of chronic/heavy users and toxicities present in smoke, the potential for altered development in exposed infants, and frequently altered sensorium of heavily using mothers, there is a significant risk. It is likely that the risks associated with lactation in heavy or chronic THC users outweigh benefit when safe alternatives to breastfeeding are available. However,

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small amounts of available literature regarding light or occasional use point to little effect on the infant. It may be, in the case of light or infrequent maternal THC use, that the benefits of breast milk/breastfeeding, with appropriate supports for infant care during period of maternal use, may outweigh risk in certain circumstances. In cases of heavy cannabis use the risk is greater and it may be safer not to breastfeed when safe and affordable alternatives are available.

Benzodiazepines: Benzodiazepines are frequently prescribed to drug dependent women, and also frequently abused/misused. Based on relatively small numbers, adverse event rates of 0–50% have been reported for various agents (17% alprazolam, 22% diazepam, and 50% clonazepam). These events include lethargy, irritability, poor weight gain and apnea. No adverse events have been reported for other agents (oxazepam, lorazepam, or temazepam) (Rubin et al., 2004). When used as an adjunctive medication, there exists the potential for drug-drug interactions and increased risk for CNS depression (for example, the opioid analgesic morphine and anxiolytic diazepam when taken together potentiate CNS depression) but use alone may present minimal risk. In one study among 124 benzodiazepine prescribed women, adverse outcomes, specifically sedation, was reported in 1.6% of infants. Benzodiazepine use in the postpartum period that is prescribed is usually compatible with breastfeeding (Kelly et al., 2012).

Estimate of risk: While it has been found that prescribed benzodiazepine use is usually compatible with lactation, there is no available literature on benzodiazepine abuse/misuse and breastfeeding. Particularly in women who are polydrug dependent, where the potential exists for drug synergy to produce untoward effects in the infant, the risks are significant and it would appear that the risk of lactation in this population would outweigh benefit, when safe alternatives to breastfeeding are available.

Alcohol: There are many international beliefs that alcohol (particularly beer) intake improves breastfeeding success (Koletzka & Lehner, 2000) and that alcohol will increase milk yield and relax both the mother and the infant (Menella, 2002). Despite these beliefs, the opposite is true. Alcohol blocks the release of oxytocin, resulting in decreased milk yield and milk ejection reflex (Bowen & Tumbach, 2011). Alcohol exposure via breast milk can alter the infant’s milk intake by decreased milk production and increased infant sucking, which may be compensatory (Giglia et al., 2006). Animal research has found that alcohol changes the structure of the mammary gland in rats, leading to impaired mammary gland function during the first few days of lactation (Steven et al., 1989). Early cessation of breastfeeding has been associated with a high frequency of alcohol consumption during lactation, even after controlling for confounders (Howard & Lawrence, 1998). Animal models have demonstrated diminished infant growth (Detering et al., 1979; Hekmatpanah et al., 1994; Vilaro et al., 1985). Alcohol enters breast milk by passive diffusion and reflects maternal blood levels within 30-60 minutes after ingestion (Lawton, 1985, Kesaniemi, 1974, Mennella & Beauchamp, 1993); for heavy drinkers, alcohol levels are higher in breast milk than in blood (Lawton et al., 1985). The infant brain is extremely sensitive to alcohol even in small quantities, and the small quantities ingested during lactation are accumulated in the infant because it is metabolized and excreted more slowly than in adults (Little et al., 1989). Alterations in infant sleep-wake cycles (Menella & Gerrish, 1998), development (Little et al., 1990), and infant growth (Backstrand et al., 2004) have been reported. There has been reported a strong inverse linear relationship between chronic exposure of ethanol in breast milk and the psychomotor developmental index on the Bayley Scales of infant development at one year (Little et al., 1989). Alcohol intake by lactating mothers recommended as “safe” for non-lactating women may have a negative effect on infant development and behavior (Giglia et al., 2006). The Institute of Medicine National Academy of Sciences (1991) concluded that alcohol consumption by lactating women in excess of 0.5 g/kg of maternal weight may be harmful to the infant. The American Academy of Pediatrics advises breastfeeding mothers to avoid alcohol consumption in general (AAP, 2005).

Estimate of risk: Lower levels of alcohol use (i.e. 1 standard drink per day) are unlikely to cause significant short or long term problems in the nursing infant, especially if the mother waits 2 to 2.5 hours per drink before nursing, and the risks are likely to be less than not breastfeeding. Daily heavy use of alcohol (i.e. more than 2 drinks per day) may affect infants negatively; alcohol appears to be eliminated from breast milk more slowly and there is a decrease in the length of time that mothers breastfeed their infants, resulting in significant risk. Chronically alcohol dependent women, or women who binge drink heavily represent a high risk to the infant, and breastfeeding is high risk and not recommended.

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Opioids: The first reports of problems with maternal opioid use and nursing were in 1985, when 4 infants became apneic after breastfeeding from mothers prescribed codeine every 4-6 hours (Davis & Bhutan, 1985). For codeine, 39 adverse events and 1 infant death (Koren et al., 2006) have been reported (Hendrickson et al., 2012). Infant toxicities may be related to a duplication of the CYP2D6 gene, causing mothers to be ultra-rapid metabolizers of codeine to morphine, leading to high plasma and milk levels (Madadi et al., 2009). Since there is no tangible method of assessing cytochrome phenotypes, codeine is not advised in nursing mothers. Other opioids may be equally unsafe. Twenty percent of oxycodone using mothers report neonatal CNS depression after breast feedings (Lam, 2012). One toddler death in a methadone misusing opioid naïve breastfeeding mother has been described (West et al., 2009). Heroin transfers into breast milk and is converted to morphine. Morphine, in acceptable doses and used in the short term for pain control, is safe for breastfeeding women (Wittels et al., 1990; Hendrickson et al., 2012), however, heroin using women frequently consume larger (or unknown) doses making this practice dangerous (D’Appolito, 2013).

In general, agents used for the treatment of opioid dependence are likely to be compatible with breastfeeding. Maternal methadone and buprenorphine maintenance in opioid dependent pregnant woman are associated with improved maternal and neonatal outcomes in the context of comprehensive drug treatment and prenatal care. Methadone is distributed into breast milk in low concentrations, there are low ratios of milk to plasma concentrations (~0.4) and calculated theoretic infant doses are low (0.038-0.0152 mg/day) (Jansson et al., 2008; Bogen et al., 2011). Additionally, concentrations in infant plasma at two weeks of age are low (2.2 – 8.1 ng/mL), making breastfeeding among stable and otherwise abstinent methadone maintained women recommended (Jansson et al., 2004) regardless of maternal methadone dose, as dose is unrelated to milk concentrations (Jansson et al., 2008). Reports on buprenorphine exposure via breast milk are somewhat limited. Buprenorphine is excreted into human milk and achieves a level similar to that in maternal plasma (Johnson, 2001). Extant literature finds low concentrations and low calculated theoretic infant doses (Ilett et al., 2012, Lindemalm et al., 2009); in addition this agent is poorly bioavailable, making it likely that breastfeeding should be encouraged in otherwise abstinence, stable buprenorphine maintained women. It is unlikely that either agent, when delivered to the breastfeeding infant from a medically maintained mother, would be present in substantial amounts necessary to prevent or ameliorate neonatal abstinence syndrome. There is a single report of a naltrexone maintained woman with low concentrations of naltrexone in breast milk and low calculated infant dose. Naltrexone is concentrated in breast milk at a milk:plasma ratio of 1.9 (Chan et al., 2004).

Estimate of risk: Opioid dependent women using heroin or misusing prescription opioid containing medications in a way that results in cycles of intoxication and withdrawal are likely to present a significant risk to their breastfed infant, and therefore this practice is discouraged. Prescribed oxycodone for lactating women has also been found to be unsafe. Prescribed morphine for pain control in the postpartum period is low risk and compatible with lactation. Breastfeeding in methadone and buprenorphine maintained and otherwise abstinent women women is low risk should be encouraged if they meet other criteria.

Conclusions

Advising the substance using woman on breastfeeding can present a dilemma to the treating practitioner. A complete and thorough evaluation of the dyad in the perinatal period would consider several factors, including:

o maternal medical and psychiatric status;

o maternal drug use and substance abuse treatment histories and medication requirements;

o maternal family and community support systems;

o maternal plans for postpartum health and psychiatric care, substance abuse treatment and pediatric care;

o access to and capacity to afford breastmilk substitutes, access to clean water and capacity to sterilize feeding equipment.

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Evidence profile 6: Management of infants exposed to alcohol and other psychoactive substances

Evidence question Does the identification and treatment of neonates with disorders due to alcohol or drug exposure in utero result in better maternal, neonatal or infant outcomes, compared to treatment-as-usual or other forms of treatment of neonatal disorders due to alcohol or drug exposure in utero?

Study selection criteria for the systematic review: Study design: RCTs

Population: Neonates with disorders due to alcohol or drug exposure in utero such as neonatal substance withdrawal and fetal alcohol syndrome.

Interventions: Systematic methods of identification and treatment of disorders due to alcohol and drug exposure in utero, including medication for neonatal withdrawal.

Control: Treatment-as-usual, non systematic identification, other treatments of disorders due to alcohol or drug exposure in utero.

Outcomes: The following outcomes were of interest:

Outcome Importance (0–9)

Infant: Death 8.22

Infant: Treatment failure 8.11

Infant: Seizures 8.11

Infant: Total length of hospital stay 7.78

Infant: Weight gain 7.78

Infant: Days to regain birthweight 7.67

Infant: Duration of withdrawal treatment 7.67

Infant: Attachment 6.44

Maternal: Bonding with child 6.44

Infant: Infections 5.89

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EVIDENCE TO RECOMMENDATIONS TABLE

Identification and treatment of neonatal disorders due to exposure to alcohol or drugs in utero – including pharmacotherapy (opioids and/or barbiturates) and/or supportive treatment (swaddling, skin to skin care) for neonatal withdrawal

Summary of evidence • Osborn et al. (2013) conducted a Cochrane review in which they evaluated (1) the contribution of opioids in

addition to supportive therapy; (2) opioids compared to phenobarbitone; (3) opioids compared to diazepam; (4) buprenorphine compared to an opium solution; (5) oral morphine compared to tincture of opium in the treatment of neonatal withdrawal/neonatal abstinence syndrome (NWS/NAS). See accompanying GRADE tables for evaluation of treatment effect against critical outcomes. The small size and risk of bias in the studies evaluated means the evidence of treatment effect is very uncertain.

• Protocols for the management of NAS have seen significant development over the past 40+ years. Initial NAS treatment guidelines were weight-based, and tables for treatment with phenobarbital and paregoric were published (Finnegan et al., 1975). Current treatment follows similar practices. Either an opioid such as morphine sulfate or tincture of opium, or a sedative, typically phenobarbital, predominate, with infrequent use of a benzodiazepine. A measure of NAS such as the Finnegan scale is typically used to guide treatment initiation, maintenance, and weaning. Because there is neither a uniform assessment method to measure NAS nor an established treatment protocol, and health-care practices and costs worldwide are not uniform, it is difficult to state with any precision how NAS is treated across the globe. Moreover, the availability of opioids as a treatment for NAS varies worldwide, further complicating the ability to make general statements regarding NAS treatment. Patrick and colleagues (Patrick et al., 2012) found that, between 2000 and 2009, per 1,000 hospital live births, prenatal exposure to opioids increased from 1.2 to 5.6 and the incidence of NAS increased from 1.2 to 3.4. Hospital charges for discharges with NAS increased more than 46% during this same 10-year period.

• An opioid probably confers greater benefit than either phenobarbitone or diazepam as first-line pharmacotherapy for NAS (Osborne et al., 2013). Buprenorphine may prove to be an effective alternative front-line pharmacotherapy for NAS (Kraft et al., 2008).Buprenorphine may be superior to methadone in the reduction in NAS severity and time in treatment for NAS [Jones et al. (2005), Fischer et al. (2006), and Jones et al. (2010)].

• Jones et al. (2012a,b) reviewed the comparative efficacy studies of buprenorphine versus methadone. Regardless of whether the study was a randomized controlled trial, prospective study, or case report, there is clear evidence that prenatal buprenorphine exposure is related to NAS, and that such NAS may be less frequent, less severe, and/ or of shorter duration. However, conclusions are limited in regard to NAS due to the fact that most studies fail to adequately define and/or measure NAS and/or specify a treatment protocol.

• There is limited experience with opioid antagonists in pregnancy outside of its investigation in Australia (Hulse et al., 2000, 2001, 2003, 2004; Hulse & O’Neil, 2002). Rapid opioid detoxification using sedation followed by naltrexone, as well as oral and implantable formulations of naltrexone, has been investigated. In all cases, there have been no reports of adverse fetal effects, and neonatal birth parameters were within normal limits. However, maternal outcomes were not reported and relapse to maternal opioid use was evident. Neonatal outcomes following prenatal exposure to implanted naltrexone were within normal limits, with some suggestion of a lower risk of prematurity and a higher 1-minute Apgar scores in naltrexone than methadone-exposed neonates. The small samples sizes and limited focus on outcomes suggest caution in the interpretation of the results of these studies; however, findings do not indicate that prenatal naltrexone exposure results in an increased risk for poor neonatal outcomes.

• A rooming-in approach may help reduce the need for NAS pharmacotherapy, NICU admissions, and length of stay for term infants (Abrahams et al., 2007; Abrahams et al., 2010; Hodgson and Abrahams, 2012). Feeding on demand and swaddling may be sufficient to treat mild withdrawal symptoms (Kieviet et al. (2012)).

• Early identification of Fetal Alcohol Syndrome (FAS) is feasible and can increase the uptake of early intervention programmes for children with FAS and their families, enabling children with FAS to reach their full potential (Bertrand, Floyd & Weber, 2005).

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EVIDENCE TO RECOMMENDATIONS TABLE

Benefits and harms

Benefits • Pregnancy and the immediate postpartum period represents an ideal time for mother-child bonding, an opportunity to develop basic parenting skills.

• Considerable research (e.g., Hudak & Tan, 2012) has found pharmacotherapy for NAS yields these benefits: – Less risk of seizures – Less risk of neonatal morbidity and mortality – Improved outcomes (e.g. weight gain, maternal bonding – provided mother and child are

allowed to be together) – Possible reduction in congenital anomalies

• In non-opioid-agonist maintained postpartum women, immediate and uninterrupted skin-to- skin contact at birth, and rooming-in during the postpartum period is beneficial for establishing maternal-child bonding (Dumas 2013).

• Early identification of Fetal Alcohol Syndrome (FAS) can improve the chances that children with FAS will reach their full potential.

Harms • Risk of adverse neonatal response to pharmacological agent. Buprenorphine may have less adverse impact than methadone on fetal neurobehaviour (Jansson et al., 2012; Salisbury et al., 2012).

• Jones et al (2010) found there may be a higher incidence of non-serious maternal adverse events, particularly non-serious maternal cardiovascular events, associated with methadone than buprenorphine. They found no differences in between the two medications for neonatal adverse events.

• Early identification of Fetal Alcohol Syndrome (FAS) may stigmatize children and their mothers.

Values and preferences

In favour: Mother

Health-care worker

Community

• Value care to support health of baby • Value opportunity to have baby more settled after withdrawal, ultimately easier to look after • Value opportunity to bond with, and learn to care, for baby • Value greater chance of normal neonatal development

• Value opportunity to intervene in care of compromised neonate • Value opportunity to support mother with bonding, breastfeeding, childcare • Value opportunity to monitor health of fragile neonate

• Value better neonatal outcomes-healthier, developmentally normal children • Partners, family co-workers value chance of healthier, developmentally normal baby

Against: Mother

Health-care worker

Community

• Stigmatization as person who ‘made her baby dependent to drugs or alcohol’ • Anxiety about negative responses from partners, family and co-workers • Resent longer hospital stay • Resent interference by hospital staff and other ‘authorities’

• Resent extra time and resources devoted to managing mother and infant with NAS • Negative view of mother’s ability to care for child

• Community may have punitive view-may demand incarceration of mother or removal of child • Community may consider extra resources needed to manage mother and child wasteful

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EVIDENCE TO RECOMMENDATIONS TABLE

Costs and feasibility

Feasibility (including economic consequences)

• Inconvenient for women because infant may need an extended stay in the hospital and/or outpatient pharmacotherapy

• Potentially substantial additional cost beyond no treatment • Trained professional staff and sustainable programme required • Consistent and frequent monitoring of child • Requires long term patient monitoring to ensure patient continues taking her medication • A comprehensive care model in which pharmacotherapy is part of a women-centred, trauma-

informed program would be the best model of care – and also the costliest

REFERENCES

Abrahams RR, Kelly SA, Payne S, et al. Rooming-in compared with standard care for newborns of mothers using methadone or heroin. Can Fam Physician 2007;53:1722-30.

Abrahams RR, MacKay-Dunn MH, Nevmerjitskaia V, et al. An evaluation of rooming-in among substance-exposed newborns in British Columbia. J Obstet Gynaecol Can 2010;32:866-71.

Bertrand J, Floyd LL, Weber MK. Guidelines for identifying and referring persons with fetal alcohol syndrome. MMWR Recomm Rep 2005;54:1-14.

Dumas L, Lepage M, Bystrova K, et al. Influence of skin-to-skin contact and rooming-in on early mother-infant interaction: a randomized controlled trial. Clin Nurs Res 2013;22:310-36.

Finnegan LP, Connaughton JF, Jr., Kron RE, et al. Neonatal abstinence syndrome: assessment and management. Addict Dis 1975;2:141-58.

Finnegan LP, Kron RE, Connaughton JF, et al. Assessment and treatment of abstinence in the infant of the drug-dependent mother. Int J Clin Pharmacol Biopharm 1975;12:19-32.

Fischer G, Ortner R, Rohrmeister K, et al. Methadone versus buprenorphine in pregnant addicts: a double-blind, double-dummy comparison study. Addiction 2006;101:275-81.

Hodgson ZG, Abrahams RR. A rooming-in program to mitigate the need to treat for opiate withdrawal in the newborn. J Obstet Gynaecol Can 2012;34:475-81.

Hudak ML, Tan RC. Neonatal drug withdrawal. Pediatrics 2012;129:e540-60.

Hulse GK, Arnold-Reed DE, O'Neil G, et al. Naltrexone implant and blood naltrexone levels over pregnancy. Aust N Z J Obstet Gynaecol 2003;43:386-8.

Hulse GK, O'Neil G, Arnold-Reed DE. Methadone maintenance vs. implantable naltrexone treatment in the pregnant heroin user. Int J Gynaecol Obstet 2004;85:170-1.

Hulse GK, O'Neill G. A possible role for implantable naltrexone in the management of the high-risk pregnant heroin user. Aust N Z J Obstet Gynaecol 2002;42:93-4.

Hulse GK, O'Neill G, Pereira C, et al. Obstetric and neonatal outcomes associated with maternal naltrexone exposure. Aust N Z J Obstet Gynaecol 2001;41:424-8.

Jansson LM, Di Pietro JA, Elko A, et al. Pregnancies exposed to methadone, methadone and other illicit substances, and poly-drugs without methadone: a comparison of fetal neurobehaviors and infant outcomes. Drug Alcohol Depend 2012;122:213-9.

Jones HE, Finnegan LP, Kaltenbach K. Methadone and buprenorphine for the management of opioid dependence in pregnancy. Drugs 2012;72:747-57.

Jones HE, Heil SH, Baewert A, et al. Buprenorphine treatment of opioid-dependent pregnant women: a comprehensive review. Addiction 2012;107 Suppl 1:5-27.

Jones HE, Johnson RE, Jasinski DR, et al. Buprenorphine versus methadone in the treatment of pregnant opioid-dependent patients: effects on the neonatal abstinence syndrome. Drug Alcohol Depend 2005;79:1-10.

Jones HE, Kaltenbach K, Heil SH, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med 2010;363:2320-31.

Kieviet N, Dolman K, Wennink H, et al. [Withdrawal in newborns after exposure to psychotropic medications during pregnancy]. Ned Tijdschr Geneeskd 2012;156:A4395.

Kraft WK, Gibson E, Dysart K, et al. Sublingual buprenorphine for treatment of neonatal abstinence syndrome: a randomized trial. Pediatrics 2008;122:e601-7.

Osborn DA, Jeffery HE, Cole MJ. Opiate treatment for opiate withdrawal in newborn infants. Cochrane Database Syst Rev 2013:CD002059.

Osborn DA, Jeffery HE, Cole MJ. Sedatives for opiate withdrawal in newborn infants. Cochrane Database Syst Rev 2013:CD002053.

Patrick SW, Schumacher RE, Benneyworth BD, et al. Neonatal abstinence syndrome and associated health care expenditures: United States, 2000-2009. JAMA 2012;307:1934-40.

Salisbury AL, Coyle MG, O'Grady KE, et al. Fetal assessment before and after dosing with buprenorphine or methadone. Addiction 2012;107 Suppl 1:36-44.

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Draft recommendations: o Infants of all opioid-dependent mothers should be monitored for NAS.

o Hospitals providing obstetrical care should have a protocol in place for identifying, assessing, monitoring and intervening using non-pharmacological and pharmacological methods for neonates prenatally exposed to opioids.

o Pharmacological treatment of infants with NAS due to opioids should be initiated according to a validated NAS treatment protocol.

o Non-pharmacological treatments including low lights, quiet environment, swaddling and skin to skin contact should be used with all prenatally opioid exposed neonates.

o An opioid should be used as initial treatment for infants with NAS symptoms severe enough to need intervention due to opioid withdrawal.

o If there has been concurrent use of other drugs in pregnancy, particularly benzodiazepines, and symptoms of NAS are not adequately suppressed by an opioid alone, phenobarbitone may be indicated as an additional therapy. If opioids are unavailable, phenobarbitone may be used as an alternative therapy.

o If an infant has signs of NAS and reaches the treatment threshold and the drugs used by the mother are unknown, or are sedatives, or the infant was born to a mother intoxicated with alcohol, then phenobarbitone may be a preferable initial treatment.

o Mothers of infants at risk of NAS should receive appropriate breastfeeding information and support, parenting support and assessment, and should be taught settling techniques. Women and their partners/ support persons should also receive information about safe sleeping practices, especially if using sedative substances.

Final recommendations: RECOMMENDATION 

Health-care facilities providing obstetric care should have a protocol in place for identifying, assessing, monitoring and intervening, using non pharmacological and pharmacological methods, for neonates prenatally exposed to opioids.

Strength of recommendation: Strong Quality of evidence: Low

Remarks: • Evidence of a dose-response relationship between opioid maintenance treatment and neonatal withdrawal

syndrome has been inconsistent, which implies that all infants should be assessed. • Infants exposed to opioids during pregnancy should remain in the hospital at least 4-7 days following birth and

be monitored for neonatal withdrawal symptoms using a validated assessment instrument which should be first administered 2 hours after birth and then every 4 hours thereafter.

• Non- pharmacological interventions including low lights, quiet environments swaddling and skin to skin contact should be used with all neonates prenatally exposed to alcohol and drugs.

• It was decided that the recommendation should be strong despite the low quality of evidence of effect, as the GDG agreed that the benefits of such an approach strongly outweighed any potential harms. The values and preferences of end-users were in favour of the recommendation and there was certainty that while resources would be consumed, the benefits strongly outweighed costs. There was a high value placed on identifying preventable suffering in affected neonates.

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RECOMMENDATION 

If an infant has signs of a neonatal withdrawal syndrome due to withdrawal from sedatives, or alcohol, or the substance the infant was exposed to is unknown, then phenobarbital may be a preferable initial treatment option.

Strength of recommendation: Conditional Quality of evidence: Very low

Remarks: • Infants with signs of a neonatal withdrawal syndrome in the absence of known maternal opioid use should be fully

assessed for possible benzodiazepine, sedative, or alcohol exposure. • This recommendation was considered conditional because of the lack of high quality evidence and the lack of

certainty of the balance between benefits and harms.

RECOMMENDATION 

An opioid should be used as initial treatment for an infant with neonatal opioid withdrawal syndrome if required.

Strength of recommendation: Strong Quality of evidence: Very low

Remarks: • Prolonged treatment of neonatal opioid withdrawal syndrome with opioids is generally not necessary and aiming for

shorter treatment is preferable. • Phenobarbital can be considered as an additional therapy if there has been concurrent use of other drugs in

• Infants with signs of a neonatal withdrawal syndrome in the absence of known maternal opioid use should be fully assessed for possible benzodiazepine, sedative, or alcohol exposure.

• The strong recommendation to use opioids rather than phenobarbital despite the very low quality of evidence of effectiveness was based on vast clinical experience with opioids in the management of both adult and neonatal opioid withdrawal. There has only been very limited clinical experience with phenobarbital use. In addition, the values and preferences of end-users were in favour of the recommendation and the GDG agreed that there was certainty about the balance between benefits and resources being consumed.

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RECOMMENDATION 

All infants born to women with alcohol use disorders should be assessed for signs of fetal alcohol syndrome.

Strength of recommendation: Conditional Quality of evidence: Very low

Remarks: • Signs of fetal alcohol syndrome (FAS) include growth impairment, dysmorphic facial features (short palpebral

fissures, smooth or flattened philtrum, thin upper lip) and central nervous system abnormalities, including microcephaly.

• This recommendation was considered conditional because of the lack of high quality evidence, and questions about the faesibility of implementation in all settings.

Factors in considering the strength of the recommendations (recommendations 15–18):

Factor 15 & 16 17 18

Is there high or moderate quality evidence? The higher the quality of evidence, the more likely is a strong recommendation.

No No No

Yes No Yes

Are the expected values and preferences clearly in favour of the recommendation?

Yes No Yes

Yes Yes No

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Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Supportive therapy

Opioid and supportive therapy

Death See comment See comment Not estimable

— See comment Not reported

Treatment failure Finnegan score

118 per 1000 152 per 1000 (48 to 479)

RR 1.29 (0.41 to 4.07)

80 (1 study)

⊕ VERY LOW1,2,3

Supportive treatment included pacifier, swaddling, close wrapping, small frequent feeds, and close skin contact by sling or other methods.

Seizures See comment See comment Not estimable

— See comment Not reported

Total length of hospital stay Days in hospital

The mean total length of hospital stay in the intervention groups was 15 higher (8.86 to 21.14 higher)

80 (1 study)

⊕ VERY LOW1,2,4

Infant weight gain See comment See comment Not estimable

— See comment Not reported

Days to regain birthweight

The mean days to regain birthweight in the intervention groups was 2.8 lower (5.33 to 0.27 lower)

72 (1 study)

⊕ VERY LOW1,2,5

Duration of treatment for NAS Days

The mean duration of treatment for nas in the intervention groups was 12.5 higher (7.52 to 17.48 higher)

Not estimable

80 (1 study)

⊕ VERY LOW1,2,4

OPIATES AND SUPPORTIVE THERAPY COMPARED TO SUPPORTIVE THERAPY FOR OPIOID WITHDRAWAL IN NEWBORN INFANTS

Patient or population: Opioid withdrawal in newborn infants Settings: Hospital Intervention: Opioid and supportive therapy Comparison: Supportive therapy

CI: Confidence interval. RR: Risk ratio. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 This is reported as a quasi-randomized trial which allocated participants to groups using the last number of the participant's hospital number. Both random

generation and allocation concealment were judged to be inadequate and there is thus a high risk of selection bias. There was no blinding of providers or parents so performance bias may be present. Blinding was unreported for short-term outcomes and the risk of detection bias is unclear. Long-term outcomes were not measured.

2 Not applicable as results are from one study only. 3 The sample size is small and the event rate is extremely low so imprecision is highly likely in the results. 4 The sample size is small and the confidence interval is very wide. 5 The sample size is small and the confidence interval is wide.

Summary of findings and GRADE tables

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Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Phenobarbitone Opiates

Death – not reported See comment See comment Not estimable

— See comment

Treatment failure See footnote 1

279 per 1000 212 per 1000 (142 to 309)

RR 0.76 (0.51 to 1.11)

302 (4 studies)

⊕⊕ LOW2,3,4

The meta- analysis included both randomized (RCT) and quasi- randomized controlled trials. GRADE assessment was done within the RCT study design.

Seizures 113 per 1000 9 per 1000 (0 to 163)

RR 0.08 (0 to 1.44)

111 (1 study)

⊕⊕ LOW5,6,7

As this was a RCT, the GRADE assessment was done within the RCT study design category.

Total length of hospital stay Days in hospital

The mean total length of hospital stay in the intervention groups was 2.54 lower (7.06 lower to 1.98 higher)

106 (2 studies)

⊕ VERY LOW8,9

As this was a meta-analysis of two quasi- trials, the GRADE assessment was done within the observational study design category.

Infant weight gain See comment See comment Not estimable

— See comment Not reported

Days to regain birthweight

The mean days to regain birthweight in the intervention groups was 1.4 lower (3.47 lower to 0.67 higher)

71 (1 study)

⊕ VERY LOW10,11

As this was a quasi-trial, the GRADE assessment was done within the observational study design category.

Duration of treatment for NAS Days

The mean duration of treatment for nas in the intervention groups was 3.73 lower (7.75 lower to 0.29 higher)

106 (2 studies)

⊕ VERY LOW8,9

As this was a meta-analysis of two quasi- trials, the GRADE assessment was done within the observational study design category.

OPIATES COMPARED TO PHENOBARBITONE FOR OPIOID WITHDRAWAL IN NEWBORN INFANTS

Patient or population: Opioid withdrawal in newborn infants Settings: Hospital Intervention: Opioid Comparison: Phenobarbitone

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1 Treatment failure defined by review as failure to reduce a standardised score of NAS from a clinically significant level to a clinically 'safe' level defined by author of the trial, or the use of additional pharmacological treatments for control of NAS.

2 The meta-analysis combines results from two randomized controlled trials (Jackson 2004 and Madden 1977) and two quasi-randomized trials (Finnegan 1984 and Khoo 1995). Random generation and allocation concealment were lacking in three of the four studies and there is thus a risk of selection bias. Blinding of participants and providers was only performed in one study so performance and measurement bias may be present in the other studies. In Jackson 2004, infants randomly allocated to phenobarbitone tended to have been exposed to benzodiazepines and other classes of drugs compared with those randomized to morphine.

3 Statistical heterogeneity was not present (I squared = 0%). Some clinical heterogeneity may be present as drug types and doses differed but it was not downgraded for unexplained inconsistency. The opiates and dosages used in the four studies were: Finnegan 1984 - Paregoric, dose not reported; Jackson 2004 - Morphine 50 microg/kg/dose four times a day with no titration; Khoo 1995 - Morphine 0.5mg/kg/day in 4–6 divided doses, titrated up to maximum 0.9mg/kg/day; Madden 1977 - Methadone 0.25mg 6 hourly increased every 6 hours to maximum 0.5mg 6 hourly

4 The combined sample size is 302. The event rate is very low. Although the confidence interval is narrow, according to GRADE criteria for dichotomous data, event rates less than 300 are downgraded for imprecision.

5 This RCT (Kandall 1983) was judged to be at unclear risk of selection bias as no method of random generation was reported. The randomized groups were very imbalanced (49 vs 62), increasing the likelihood of selection bias. Detection and performance bias may be present as no blinding was reported. Attrition was not reported and the risk of selective reporting was unclear.

6 Not applicable as results are from one trial only. 7 The sample size is small, the event rate very low (zero events in the opioid group) and the confidence interval is wide. 8 The two studies (Khoo 1995 and Madden 1977) included in this meta-analysis are quasi-randomized trials. There is a high risk of selection bias as random

generation and allocation concealment were inadequate. Blinding was not reported and there is thus an unclear risk of detection and performance bias. Both studies accounted for incomplete outcome data and attrition bias is thus a low risk. Selective reporting bias was unclear.

9 The sample size is small and the confidence interval is very wide. 10 This quasi-RCT (Khoo 1995) is at high risk of selection bias as random generation (use of last number of the participant's hospital number) and allocation

concealment were judged to be inadequate. Blinding was not reported and performance and detection bias may be present. 11 The sample size is small and the confidence interval is wide.

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Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Diazepam Opioid

Death See comment See comment Not estimable

— See comment Not reported

Treatment failure See footnote 1

389 per 1000 167 per 1000 (89 to 311)

RR 0.43 (0.23 to 0.8)

86 (2 studies)

⊕ VERY LOW2,3,4

The meta- analysis included one quasi-trial (Finnegan 1984) and one RCT (Madden 1977). GRADE assessment was done within the RCT study design category.

Seizures See comment See comment Not estimable

— See comment Not reported

Total length of hospital stay Days in hospital

The mean total length of hospital stay in the intervention groups was 2.33 higher (1.79 lower to 6.45 higher)

33 (1 study)

⊕ VERY LOW5,6,7

Madden 1977 is an RCT and GRADE assessment was done within the RCT study design category.

Infant weight gain See comment See comment Not estimable

— See comment Not reported

Days to regain birthweight

See comment See comment Not estimable

— See comment Not reported

Duration of treatment for NAS Days

The mean duration of treatment for nas in the intervention groups was 1.56 higher (1.59 lower to 4.71 higher)

33 (1 study)

⊕ VERY LOW5,6,7

Madden 1977 is an RCT and GRADE assessment was done within the RCT study design category.

OPIOID COMPARED TO DIAZEPAM FOR OPIOID WITHDRAWAL IN NEWBORN INFANTS

Patient or population: Opioid withdrawal in newborn infants Settings: Hospital Intervention: Opioid Comparison: Diazepam

CI: Confidence interval. RR: Risk ratio. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Treatment failure defined by review as failure to reduce a standardised score of NAS from a clinically significant level to a clinically 'safe' level defined by author of

the trial, or the use of additional pharmacological treatments for control of NAS. 2 The risk of selection bias is high for the quasi-trial (Finnegan 1988) as random generation and allocation concealment were judged as inadequate. No method was

reported in the Madden 1977 RCT. Blinding was lacking or unclear and performance and detection bias may be present. Both studies accounted for incomplete outcomes so attrition bias is a low risk.

3 The meta-analysis reported here was conducted using a fixed effects model and a RR = 0.43 (95%CI: 0.23, 0.80) with Finnegan 1984 showing a statistically significant benefit of opiates over diazepam and Madden 1977 showing a benefit of diazepam over opiates. Clinical heterogeneity may explain this result as Finnegan compared Paregoric with diazepam and Madden compared methadone with diazepam. In this situation when heterogeneity is present, a random effects model is more appropriate. This would change the RR = 0.55 (95% CI: 0.10, 2.89) and is no longer statistically significant. The relatively large difference in results following sensitivity analyses reduces the robustness of the results. The assessment is downgraded for unexplained inconsistency.

4 The sample size is very small with very few events. 5 This RCT (Madden 1977) was judged to be at unclear risk of selection bias as no random generation or allocation concealment was reported. Blinding was not

reported for the trial so performance and detection bias may be present. Incomplete outcome data was addressed so attrition bias was minimal. 6 Not applicable as only one study included. 7 The sample size is very small and the confidence interval is wide.

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Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Neonatal Opium Solution

Sublingual Buprenorphine

Death See comment See comment Not estimable

— See comment Not reported

Treatment failure Need for adjunctive treatment

77 per 1000 308 per 1000 (39 to 1000)

RR 4 (0.51 to 31.13)

26 (1 study)

⊕ VERY LOW1,2,3

Primary aim of this RCT was safety, tolerability and feasibility. Efficacy was a secondary goal. The report acknowledges that the RCT was not powered for this.

Seizures 0 per 1000 0 per 1000 (0 to 0)

RR 3 (0.13 to 67.51)

26 (1 study)

⊕ VERY LOW1,2,3

One infant developed generalised seizures in the Buprenorphine group.

Total length of hospital stay Days

The mean total length of hospital stay in the intervention groups was 11 lower (21.69 to 0.31 lower)

25 (1 study)

⊕ VERY LOW1,2,3

Infant weight gain See comment See comment Not estimable

— See comment Not reported

Days to regain birthweight

See comment See comment Not estimable

— See comment Not reported

Duration of treatment for NAS

The mean duration of treatment for nas in the intervention groups was 10 lower (20.69 lower to 0.69 higher)

25 (1 study)

⊕ VERY LOW1,2,3

SUBLINGUAL BUPRENORPHINE COMPARED TO NEONATAL OPIUM SOLUTION FOR OPIOID WITHDRAWAL IN NEWBORN INFANTS

Patient or population: Opioid withdrawal in newborn infants Settings: Hospital Intervention: Sublingual Buprenorphine Comparison: Neonatal Opium Solution

CI: Confidence interval. RR: Risk ratio. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 This RCT (Kraft 2009) was judged to be at low risk of selection bias. Random generation and allocation concealment were adequate as the sequence was generated

centrally by the Hospital Investigational Drug Service. The study was not blinded and detection and performance bias may be present. All outcomes were accounted for and attrition bias was judged to be low. Selective outcome reporting was not present.

2 Not applicable as only one study. 3 The sample size is very small with very few events and the confidence interval is very wide.

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Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Tincture of Opium (TO) Morphine

Death See comment See comment Not estimable

— See comment Not reported

Treatment failure Mean Finnegan score: proxy measure for treatment failure

See comment See comment 33 (1 study)

⊕ VERY LOW1,2,3,4

Mean maximum Finnegan score values for each group: Morphine: 15.4g and Tincture: 15.5g. No SD reported.

Seizures See comment See comment Not estimable

— See comment Not reported

Total length of hospital stay Days in hospital

See comment See comment 33 (1 study)

⊕⊕ LOW1,2,4

The mean duration of hospitalization in the Morphine = 37.5 days; range: 20-66) and in the Tincture of Opium group = 32.4 days; range: 17-55). Not significant.

Infant weight gain See comment See comment 33 (1 study)

⊕⊕ LOW1,5

Mean weight gain per day in the Morphine group = 18.9g and in Tincture of Opium = 24.9g (p = 0.24; 95% CI of mean difference: 15.9g, -4.1g).

Days to regain birthweight

See comment See comment Not estimable

— See comment Not reported

Duration of treatment for NAS Skewed data

See comment See comment 0 (1 study)

⊕⊕ LOW1,4

The mean duration of treatment for NAS in the morphine group = 29.8 days; range: 10- 62; in the TO Opium group (26.9 days; range: 8- 51). Not significant.

MORPHINE COMPARED TO TINCTURE OF OPIUM (TO) FOR OPIOID WITHDRAWAL IN NEWBORN INFANTS

Patient or population: Opioid withdrawal in newborn infants Settings: Hospital Intervention: Morphine Comparison: Tincture of Opium (TO)

147

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

1 This RCT (Langefeld 2005) was well-conducted with adequate random generation and allocation concealment, blinding (solutions identical in appearance and flasks were only identified with a number and name of the newborn) and no attrition nor selection reporting.

2 Not applicable as only one study included. 3 The report did not provide details of treatment failure, but reported mean maximum Finnegan score values for each group: Morphine: 15.4g and Tincture: 15.5g. No

SD reported. 4 The mean and ranges were reported, not standard deviations or a confidence interval of the difference. Based on the sample size being very small and the wide

ranges, the results are judged to be very imprecise. 5 The sample size is very small. As no variance estimates are reported for means, it is not possible to calculate the mean difference nor the variance. The mean

weight gain per day is reported for each group, but not for the mean difference between the groups. However, a 95% confidence interval for the mean difference in weight gain per day between the groups (15.9; -4.1g) is reported.

148

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Specific sedative Specific opioid

Treatment failure – Paregoric versus phenobarbitone

317 per 1000 174 per 1000 (95 to 320)

RR 0.55 (0.3 to 1.01)

178 (2 studies)

⊕ VERY LOW1,2,3

Treatment failure – Methadone versus phenobarbitone

62 per 1000 56 per 1000 (4 to 817)

RR 0.89 (0.06 to 13.08)

34 (1 study)

⊕ VERY LOW4,5,6

Treatment failure – Morphine versus phenobarbitone

403 per 1000 254 per 1000 (157 to 403)

RR 0.63 (0.39 to 1)

149 (2 studies)

⊕⊕ LOW3,7,8

Treatment failure – Paregoric versus diazepam

800 per 1000 192 per 1000 (112 to 344)

RR 0.24 (0.14 to 0.43)

85 (2 studies)

⊕ VERY LOW1,9,10

Treatment failure – Methadone versus diazepam

62 per 1000 0 per 1000 (0 to 0)

RR 2.68 (0.12 to 61.58)

34 (1 study)

⊕ VERY LOW4,5,6

SPECIFIC OPIOID COMPARED TO SPECIFIC SEDATIVE FOR TREATMENT FAILURE IN OPIOID WITHDRAWAL IN NEWBORN INFANTS

Patient or population: Opioid withdrawal in newborn infants Settings: Hospital Intervention: Specific opioid Comparison: Specific sedative

CI: Confidence interval. RR: Risk ratio. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 This meta-analysis combined two quasi-trials (Finnegan 1984 and Kaltenbach 1986). It was unclear whether some of the infants reported in the study were also

included in Finnegan 1984, and there is a risk of double-counting the participants. The studies allocated groups from envelopes designated according to the first letter of the last name. Allocation concealment was judged to be inadequate and selection bias may is a high risk. Blinding was not clearly reported for short-term outcomes but it is unlikely as the treatment regimens were different so there is a high risk of performance and detection bias. Selective reporting of outcomes was unclear and could not be judged.

2 Statistical heterogeneity is present (I squared = 85%). The studies were similar but doses are not reported except for Phenobarbitone in Finnegan 1984), so the heterogeneity is unexplained. This was downgraded for unexplained inconsistency.

3 The sample size is small and the event rate is low and the confidence interval is wide. 4 No method of random generation was reported in the Madden 1977 RCT and allocation concealment was unlikely. There is a high risk of selection bias. Blinding was

not reported performance and detection bias may be present. The study accounted for incomplete outcomes so attrition bias is a low risk. 5 Not applicable as only one trial. 6 The sample size is very small, the event rate is very low and the confidence interval is very wide. 7 This meta-analysis combines a quasi-RCT (Khoo 1995) and a RCT (Jackson 2004). In Khoo 1995 there is a high risk of selection bias as random generation (use of last

number of the participant's hospital number) and allocation concealment were judged to be inadequate. Blinding was not performed for treatment and not reported for assessment so performance and detection bias may be present. Jackson 2004 was well-conducted and at low risk of selection, performance and detection bias. However, the GRADE assessment is done according to the lower quality of evidence so the analysis is downgraded for bias.

8 Statistical heterogeneity is not present and there did not appear to be unexplained clinical heterogeneity. 9 There is statistical heterogeneity (I squared = 67%). The studies were similar but doses are not reported so the heterogeneity is unexplained. This was downgraded

for unexplained inconsistency. 10 Although the confidence interval is narrow, it was downgraded for imprecision due to the small sample size and low event rate.

149

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

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150

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

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151

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

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152

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

1 Tr

ea tm

en t f

ai lu

re d

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m et

ho d

of ra

nd om

g en

er at

io n

w as

re po

rt ed

. T he

ra nd

om iz

ed g

ro up

s w

er e

ve ry

im ba

la nc

ed (4

9 vs

6 2)

, i nc

re as

in g

th e

lik el

ih oo

d of

s el

ec tio

n bi

as . D

et ec

tio n

an d

pe rf

or m

an ce

b ia

s m

ay b

e pr

es en

t a s

no b

lin di

ng w

as re

po rt

ed . A

tt rit

io n

w as

n ot

re po

rt ed

a nd

th e

ris k

of s

el ec

tiv e

re po

rt in

g w

as u

nc le

ar .

6 N

ot a

pp lic

ab le

a s

re su

lts a

re fr

om o

ne tr

ia l o

nl y.

7 Th

e sa

m pl

e si

ze is

s m

al l,

th e

ev en

t r at

e ve

ry lo

w (z

er o

ev en

ts in

th e

op io

id g

ro up

) a nd

th e

co nfi

de nc

e in

te rv

al is

w id

e. 8

Th e

tw o

st ud

ie s

(K ho

o 19

95 a

nd M

ad de

n 19

77 ) i

nc lu

de d

in th

is m

et a-

an al

ys is

a re

q ua

si -r

an do

m iz

ed tr

ia ls

. T he

re is

a h

ig h

ris k

of s

el ec

tio n

bi as

a s

ra nd

om g

en er

at io

n an

d al

lo ca

tio n

co nc

ea lm

en t w

er e

in ad

eq ua

te . B

lin di

ng w

as n

ot re

po rt

ed a

nd th

er e

is th

us a

n un

cl ea

r r is

k of

d et

ec tio

n an

d pe

rf or

m an

ce b

ia s.

B ot

h st

ud ie

s ac

co un

te d

fo r i

nc om

pl et

e ou

tc om

e da

ta a

nd a

tt rit

io n

bi as

is th

us a

lo w

ri sk

. S el

ec tiv

e re

po rt

in g

bi as

w as

u nc

le ar

. 9

Th e

sa m

pl e

si ze

is s

m al

l a nd

th e

co nfi

de nc

e in

te rv

al is

v er

y w

id e.

10 T

hi s

qu as

i-R CT

(K ho

o 19

95 ) i

s at

h ig

h ris

k of

s el

ec tio

n bi

as a

s ra

nd om

g en

er at

io n

(u se

o f l

as t n

um be

r o f t

he p

ar tic

ip an

t's h

os pi

ta l n

um be

r) an

d al

lo ca

tio n

co nc

ea lm

en t w

er e

ju dg

ed to

b e

in ad

eq ua

te . B

lin di

ng w

as n

ot re

po rt

ed a

nd p

er fo

rm an

ce a

de te

ct io

n bi

as m

ay b

e pr

es en

t. 11

T he

s am

pl e

si ze

is s

m al

l a nd

th e

co nfi

de nc

e in

te rv

al is

w id

Q ua

li ty

a ss

es sm

en t

N o.

o f p

at ie

nt s

Ef fe

Q ua

li ty

Im po

rt an

ce N

o. o

f s tu

di es

D es

ig n

R is

k of

b ia

s In

co ns

is te

nc y

In di

re ct

ne ss

Im pr

ec is

io n

O th

co ns

id er

at io

ns O

pi at

es P

he no

ba rb

it on

e R

el at

iv e

(9 5%

C I)

A bs

ol ut

D ur

at io

n of

tr ea

tm en

t f or

N A

S (m

ea su

re d

w it

h: D

ay s;

b et

te r

in di

ca te

d by

lo w

er v

al ue

2 ob

se rv

at io

na l

st ud

ie s

se ri

ou s8

no s

er io

in co

ns is

te nc

y no

s er

io us

di re

ct ne

ss se

ri ou

s9 no

ne 63

43 —

M D

3 .7

3 lo

w er

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lo w

er to

29 h

ig he

⊕ 

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V ER

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R IT

IC A

153

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Q ua

li ty

a ss

es sm

en t

N o.

o f p

at ie

nt s

Ef fe

Q ua

li ty

Im po

rt an

ce N

o. o

f s tu

di es

D es

ig n

R is

k of

b ia

s In

co ns

is te

nc y

In di

re ct

ne ss

Im pr

ec is

io n

O th

co ns

id er

at io

ns op

io id

D ia

ze pa

m R

el at

iv e

(9 5%

C I)

A bs

ol ut

D ea

th –

n ot

r ep

or te

0 —

— —

no ne

— —

C R

IT IC

A L

Tr ea

tm en

t f ai

lu re

(a ss

es se

d w

it h:

S ee

fo ot

no te

1 )

2 ra

nd om

iz ed

ia ls

se ri

ou s2

se ri

ou s3

no s

er io

in di

re ct

ne ss

se ri

ou s4

no ne

9/ 50

8% )

14 /3

6 (3

8. 9%

) R

R 0

.4 3

.2 3

to 0

.8 )

22 2

fe w

er p

10 00

(f ro

m 7

8 fe

w er

to 2

fe w

er )

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W C

R IT

IC A

S ei

zu re

s –

no t r

ep or

te d

0 —

— —

no ne

— —

C R

IT IC

A L

To ta

l l en

gt h

of h

os pi

ta l s

ta y

(m ea

su re

d w

it h:

D ay

s in

h os

pi ta

l; be

tt er

in di

ca te

d by

lo w

er v

al ue

1 ra

nd om

iz ed

ia ls

se ri

ou s5

no s

er io

in co

ns is

te nc

y6 no

s er

io us

di re

ct ne

ss ve

ry s

er io

us 7

no ne

17 16

— M

D 2

.3 3

hi gh

(1 .7

9 lo

w er

6. 45

h ig

he r)

⊕ 

 

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Y LO

W C

R IT

IC A

In fa

nt w

ei gh

t g ai

n –

no t r

ep or

te d

0 —

— —

no ne

— —

C R

IT IC

A L

D ay

s to

r eg

ai n

bi rt

hw ei

gh t –

n ot

r ep

or te

0 —

— —

no ne

— —

C R

IT IC

A L

D ur

at io

n of

tr ea

tm en

t f or

N A

S (m

ea su

re d

w it

h: D

ay s;

b et

te r

in di

ca te

d by

lo w

er v

al ue

1 ra

nd om

iz ed

ia ls

se ri

ou s5

no s

er io

in co

ns is

te nc

y6 no

s er

io us

di re

ct ne

ss ve

ry s

er io

us 7

no ne

17 16

— M

D 1

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(1 .5

9 lo

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4. 71

h ig

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⊕ 

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A ut

ho r(

s) : D

av id

A O

sb or

n, H

ea th

er E

J ef

fe ry

, M ic

ha el

J C

ol e

D at

e: 2

01 3-

01 -1

6 Q

ue st

io n:

S H

O U

LD O

P IO

ID V

S D

IA ZE

PA M

B E

U S

ED IN

O P

IO ID

W IT

H D

R A

W A

L IN

N EW

B O

R N

IN FA

N TS

? S

et ti

ng s:

H os

pi ta

l B

ib li

og ra

ph y:

O sb

or n

D A

, J ef

fe ry

H E,

C ol

e M

J. O

pi at

e tr

ea tm

en t f

or o

pi at

e w

ith dr

aw al

in n

ew bo

rn in

fa nt

s. C

oc hr

an e

D at

ab as

e of

S ys

te m

at ic

R ev

ie w

154

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

1 Tr

ea tm

en t f

ai lu

re d

efi ne

d by

re vi

ew a

s fa

ilu re

to re

du ce

a s

ta nd

ar di

se d

sc or

e of

N A

S fr

om a

c lin

ic al

ly s

ig ni

fic an

t l ev

el to

a c

lin ic

al ly

's af

e' le

ve l d

efi ne

d by

a ut

ho r o

f t he

tr ia

l, or

th e

us e

of a

dd iti

on al

p ha

rm ac

ol og

ic al

tr ea

tm en

ts fo

r c on

tr ol

o f N

A S.

2 Th

e ris

k of

s el

ec tio

n bi

as is

h ig

h fo

r t he

q ua

si -t

ria l (

Fi nn

eg an

1 98

8) a

s ra

nd om

g en

er at

io n

an d

al lo

ca tio

n co

nc ea

lm en

t w er

e ju

dg ed

a s

in ad

eq ua

te . N

o m

et ho

d w

as re

po rt

ed in

th e

M ad

de n

19 77

R CT

. B lin

di ng

w as

la ck

in g

or u

nc le

ar a

nd p

er fo

rm an

an d

de te

ct io

n bi

as m

ay b

e pr

es en

t. Bo

th s

tu di

es a

cc ou

nt ed

fo r i

nc om

pl et

e ou

tc om

es s

o at

tr iti

on b

ia s

is a

lo w

ri sk

. 3

Th e

m et

a- an

al ys

is re

po rt

ed h

er e

w as

c on

du ct

ed u

si ng

a fi

xe d

ef fe

ct s

m od

el a

nd a

R R

= 0.

43 (9

5% CI

: 0 .2

3, 0

.8 0)

w ith

F in

ne ga

n 19

84 s

ho w

in g

a st

at is

tic al

ly s

ig ni

fic an

t b en

efi t o

f o pi

at es

o ve

r d ia

ze pa

m a

nd M

ad de

n 19

77 s

ho w

in g

a be

ne fit

o f

di az

ep am

o ve

r o pi

at es

. C lin

ic al

h et

er og

en ei

ty m

ay e

xp la

in th

is re

su lt

as F

in ne

ga n

co m

pa re

d Pa

re go

ric w

ith d

ia ze

pa m

a nd

M ad

de n

co m

pa re

d m

et ha

do ne

w ith

d ia

ze pa

m . I

n th

is s

itu at

io n

w he

n he

te ro

ge ne

ity is

p re

se nt

, a ra

nd om

e ff

ec ts

m od

el is

m or

e ap

pr op

ria te

. T hi

s w

ou ld

c ha

ng e

th e

RR =

0 .5

5 (9

5% C

I: 0.

10 , 2

.8 9)

a nd

is n

o lo

ng er

s ta

tis tic

al ly

s ig

ni fic

an t.

Th e

re la

tiv el

y la

rg e

di ff

er en

ce in

re su

lts fo

llo w

in g

se ns

iti vi

ty a

na ly

se s

re du

ce s

th e

ro bu

st ne

ss o

f t he

re su

lts . T

he a

ss es

sm en

t i s

do w

ng ra

de d

fo r u

ne xp

la in

ed in

co ns

is te

nc y.

Th e

sa m

pl e

si ze

is v

er y

sm al

l w ith

v er

y fe

w e

ve nt

5 Th

is R

CT (M

ad de

n 19

77 ) w

as ju

dg ed

to b

e at

u nc

le ar

ri sk

o f s

el ec

tio n

bi as

a s

no ra

nd om

g en

er at

io n

or a

llo ca

tio n

co nc

ea lm

en t w

as re

po rt

ed . B

lin di

ng w

as n

ot re

po rt

ed fo

r t he

tr ia

l s o

pe rf

or m

an ce

a nd

d et

ec tio

n bi

as m

ay b

e pr

es en

t. In

co m

pl et

e ou

tc om

e da

ta w

as a

dd re

ss ed

s o

at tr

iti on

b ia

s w

as m

in im

al .

6 N

ot a

pp lic

ab le

a s

on ly

o ne

s tu

dy in

cl ud

ed .

7 Th

e sa

m pl

e si

ze is

v er

y sm

al l a

nd th

e co

nfi de

nc e

in te

rv al

is w

id e.

155

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Q ua

li ty

a ss

es sm

en t

N o.

o f p

at ie

nt s

Ef fe

Q ua

li ty

Im po

rt an

ce N

o. o

f s tu

di es

D es

ig n

R is

k of

b ia

s In

co ns

is te

nc y

In di

re ct

ne ss

Im pr

ec is

io n

O th

co ns

id er

at io

ns S

ub li

ng ua

l B

up re

no rp

hi ne

N eo

na ta

l O

pi um

S ol

ut io

n R

el at

iv e

(9 5%

C I)

A bs

ol ut

D ea

th –

n ot

r ep

or te

0 —

— —

no ne

— —

C R

IT IC

A L

Tr ea

tm en

t f ai

lu re

(a ss

es se

d w

it h:

N ee

d fo

r ad

ju nc

ti ve

tr ea

tm en

1 ra

nd om

iz ed

ia ls

se ri

ou s1

no s

er io

in co

ns is

te nc

y2 no

s er

io us

di re

ct ne

ss ve

ry s

er io

us 3

no ne

4/ 13

0. 8%

) 1/

(7 .7

% )

R R

(0 .5

1 to

3 1.

13 )

23 1

m or

e pe

r 10

00 (f

ro m

3 8

fe w

er to

1 00

0 m

or e)

⊕ 

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Y LO

W C

R IT

IC A

S ei

zu re

1 ra

nd om

iz ed

ia ls

se ri

ou s1

no s

er io

in co

ns is

te nc

y2 no

s er

io us

di re

ct ne

ss ve

ry s

er io

us 3

no ne

1/ 13

.7 %

) 0/

(0 %

) R

R 3

.1 3

to 6

7. 51

) —

⊕ 

 

V ER

Y LO

W C

R IT

IC A

To ta

l l en

gt h

of h

os pi

ta l s

ta y

(m ea

su re

d w

it h:

D ay

s in

h os

pi ta

l; be

tt er

in di

ca te

d by

lo w

er v

al ue

1 ra

nd om

iz ed

ia ls

se ri

ou s1

no s

er io

in co

ns is

te nc

y2 no

s er

io us

di re

ct ne

ss ve

ry s

er io

us 3

no ne

12 13

— M

D 1

1 lo

w er

1. 69

to 0

.3 1

lo w

er )

⊕ 

 

V ER

Y LO

W C

R IT

IC A

In fa

nt w

ei gh

t g ai

n –

no t r

ep or

te d

0 —

— —

no ne

— —

C R

IT IC

A L

D ay

s to

r eg

ai n

bi rt

hw ei

gh t –

n ot

r ep

or te

0 —

— —

no ne

— —

C R

IT IC

A L

A ut

ho r(

s) : D

av id

A O

sb or

n, H

ea th

er E

J ef

fe ry

, M ic

ha el

J C

ol e

D at

e: 2

01 3-

01 -1

6 Q

ue st

io n:

S H

O U

LD S

U B

LI N

G U

A L

B U

P R

EN O

R P

H IN

E V

S N

EO N

AT A

L O

P IU

M S

O LU

TI O

N B

E U

S ED

IN O

P IO

ID W

IT H

D R

A W

A L

IN N

EW B

O R

N IN

FA N

TS ?

S et

ti ng

s: H

os pi

ta l

B ib

li og

ra ph

y: O

sb or

n D

A , J

ef fe

ry H

E, C

ol e

M J.

O pi

at e

tr ea

tm en

t f or

o pi

at e

w ith

dr aw

al in

n ew

bo rn

in fa

nt s.

C oc

hr an

e D

at ab

as e

of S

ys te

m at

ic R

ev ie

w s

156

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

1 Th

is R

CT (K

ra ft

2 00

9) w

as ju

dg ed

to b

e at

lo w

ri sk

o f s

el ec

tio n

bi as

. R an

do m

g en

er at

io n

an d

al lo

ca tio

n co

nc ea

lm en

t w er

e ad

eq ua

te a

s th

e se

qu en

ce w

as g

en er

at ed

c en

tr al

ly b

y th

e H

os pi

ta l I

nv es

tig at

io na

l D ru

g Se

rv ic

e. T

he s

tu dy

w as

n ot

b lin

de d

an d

de te

ct io

n an

d pe

rf or

m an

ce b

ia s

m ay

b e

pr es

en t.

A ll

ou tc

om es

w er

e ac

co un

te d

fo r a

nd a

tt rit

io n

bi as

w as

ju dg

ed to

b e

lo w

. S el

ec tiv

e ou

tc om

e re

po rt

in g

w as

n ot

p re

se nt

. 2

N ot

a pp

lic ab

le a

s on

ly o

ne s

tu dy

. 3

Th e

sa m

pl e

si ze

is v

er y

sm al

l w ith

v er

y fe

w e

ve nt

s an

d th

e co

nfi de

nc e

in te

rv al

is v

er y

w id

Q ua

li ty

a ss

es sm

en t

N o.

o f p

at ie

nt s

Ef fe

Q ua

li ty

Im po

rt an

ce N

o. o

f s tu

di es

D es

ig n

R is

k of

b ia

s In

co ns

is te

nc y

In di

re ct

ne ss

Im pr

ec is

io n

O th

co ns

id er

at io

ns S

ub li

ng ua

l B

up re

no rp

hi ne

N eo

na ta

l O

pi um

S ol

ut io

n R

el at

iv e

(9 5%

C I)

A bs

ol ut

D ur

at io

n of

tr ea

tm en

t f or

N A

S (b

et te

r in

di ca

te d

by lo

w er

v al

ue s)

1 ra

nd om

iz ed

ia ls

se ri

ou s1

no s

er io

in co

ns is

te nc

y2 no

s er

io us

di re

ct ne

ss ve

ry s

er io

us 3

no ne

12 13

— M

D 1

0 lo

w er

0. 69

lo w

er to

69 h

ig he

⊕ 

 

V ER

Y LO

W C

R IT

IC A

157

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Q ua

li ty

a ss

es sm

en t

N o.

o f p

at ie

nt s

Ef fe

Q ua

li ty

Im po

rt an

ce N

o. o

f s tu

di es

D es

ig n

R is

k of

b ia

s In

co ns

is te

nc y

In di

re ct

ne ss

Im pr

ec is

io n

O th

co ns

id er

at io

ns M

or ph

in e

Ti nc

tu re

o f

O pi

um (T

O )

R el

at iv

e (9

5% C

I) A

bs ol

ut e

D ea

th –

n ot

r ep

or te

0 —

— —

no ne

— —

C R

IT IC

A L

Tr ea

tm en

t f ai

lu re

(m ea

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it h:

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nn eg

an s

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ea su

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r tr

ea tm

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ai lu

re ; B

et te

r in

di ca

te d

by lo

w er

v al

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1 ra

nd om

iz ed

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no s

er io

us r

is k

of b

ia s1

no s

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in co

ns is

te nc

y2 se

ri ou

s3 ve

ry s

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us 4

no ne

17 16

— A

re a

un de

r th

e cu

rv e

0 hi

gh er

to 0

h ig

he r)

⊕ 

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Y LO

W C

R IT

IC A

S ei

zu re

– n

ot r

ep or

te d

0 —

— —

no ne

— —

C R

IT IC

A L

To ta

l l en

gt h

of h

os pi

ta l s

ta y

(m ea

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it h:

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s in

h os

pi ta

l; be

tt er

in di

ca te

d by

lo w

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al ue

1 ra

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iz ed

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no s

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us r

is k

of b

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no s

er io

in co

ns is

te nc

y2 no

s er

io us

di re

ct ne

ss ve

ry s

er io

us 4

no ne

17 16

— M

D 0

h ig

he r

to 0

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⊕ ⊕

 

LO W

C R

IT IC

A L

In fa

nt w

ei gh

t g ai

n (b

et te

r in

di ca

te d

by h

ig he

r va

lu es

)

1 ra

nd om

iz ed

ia ls

no s

er io

us r

is k

of b

ia s1

no s

er io

in co

ns is

te nc

y no

s er

io us

di re

ct ne

ss ve

ry s

er io

us 5

no ne

17 16

— M

D 0

h ig

he r

to 0

h ig

he r)

⊕ ⊕

 

LO W

C R

IT IC

A L

D ay

s to

r eg

ai n

bi rt

hw ei

gh t –

n ot

r ep

or te

0 —

— —

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— —

C R

IT IC

A L

D ur

at io

n of

tr ea

tm en

t f or

N A

S (m

ea su

re d

w it

h: S

ke w

ed d

at a;

b et

te r

in di

ca te

d by

lo w

er v

al ue

1 ra

nd om

iz ed

ia ls

no s

er io

us r

is k

of b

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no s

er io

in co

ns is

te nc

y no

s er

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di re

ct ne

ss ve

ry s

er io

us 4

no ne

0 —

— M

D 0

h ig

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to 0

h ig

he r)

⊕ ⊕

 

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C R

IT IC

A L

A ut

ho r(

s) : D

av id

A O

sb or

n, H

ea th

er E

J ef

fe ry

, M ic

ha el

J C

ol e

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e: 2

01 3-

01 -1

6 Q

ue st

io n:

S H

O U

LD M

O R

P H

IN E

V S

T IN

C TU

R E

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IU M

(T O

) B E

U S

ED IN

O P

IO ID

W IT

H D

R A

W A

L IN

N EW

B O

R N

IN FA

N TS

? S

et ti

ng s:

H os

pi ta

l B

ib li

og ra

ph y:

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or n

D A

, J ef

fe ry

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C ol

e M

J. O

pi at

e tr

ea tm

en t f

or o

pi at

e w

ith dr

aw al

in n

ew bo

rn in

fa nt

s. C

oc hr

an e

D at

ab as

e of

S ys

te m

at ic

R ev

ie w

158

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

1 Th

is R

CT (L

an ge

fe ld

2 00

5) w

as w

el l-c

on du

ct ed

w ith

a de

qu at

e ra

nd om

g en

er at

io n

an d

al lo

ca tio

n co

nc ea

lm en

t, bl

in di

ng (s

ol ut

io ns

id en

tic al

in a

pp ea

ra nc

e an

d fla

sk s

w er

e on

ly id

en tifi

ed w

ith a

n um

be r a

nd n

am e

of th

e ne

w bo

rn ) a

nd n

o at

tr iti

on n

se le

ct io

n re

po rt

in g.

2 N

ot a

pp lic

ab le

a s

on ly

o ne

s tu

dy in

cl ud

ed .

3 Th

e re

po rt

d id

n ot

p ro

vi de

d et

ai ls

o f t

re at

m en

t f ai

lu re

, b ut

re po

rt ed

m ea

n m

ax im

um F

in ne

ga n

sc or

e va

lu es

fo r e

ac h

gr ou

p: M

or ph

in e:

1 5.

4g a

nd T

in ct

ur e:

1 5.

5g . N

o SD

re po

rt ed

. 4

Th e

m ea

n an

d ra

ng es

w er

e re

po rt

ed , n

ot s

ta nd

ar d

de vi

at io

ns o

r a c

on fid

en ce

in te

rv al

o f t

he d

iff er

en ce

. B as

ed o

n th

e sa

m pl

e si

ze b

ei ng

v er

y sm

al l a

nd th

e w

id e

ra ng

es , t

he re

su lts

a re

ju dg

ed to

b e

ve ry

im pr

ec is

e. 5

Th e

sa m

pl e

si ze

is v

er y

sm al

l. A

s no

v ar

ia nc

e es

tim at

es a

re re

po rt

ed fo

r m ea

ns , i

t i s

no t p

os si

bl e

to c

al cu

la te

th e

m ea

n di

ff er

en ce

n or

th e

va ria

nc e.

T he

m ea

n w

ei gh

t g ai

n pe

r d ay

is re

po rt

ed fo

r e ac

h gr

ou p,

b ut

n ot

fo r t

he m

ea n

di ff

er en

ce b

et w

ee n

th e

gr ou

ps . H

ow ev

er , a

9 5%

c on

fid en

ce in

te rv

al fo

r t he

m ea

n di

ff er

en ce

in w

ei gh

t g ai

n pe

r d ay

b et

w ee

n th

e gr

ou ps

(1 5.

9; -4

.1 g)

is re

po rt

ed .

159

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Q ua

li ty

a ss

es sm

en t

N o.

o f p

at ie

nt s

Ef fe

Q ua

li ty

Im po

rt an

ce N

o. o

f s tu

di es

D es

ig n

R is

k of

b ia

s In

co ns

is te

nc y

In di

re ct

ne ss

Im pr

ec is

io n

O th

co ns

id er

at io

ns S

pe ci

fic

op io

id S

pe ci

fic

se da

ti ve

R el

at iv

e (9

5% C

I) A

bs ol

ut e

Tr ea

tm en

t f ai

lu re

– p

ar eg

or ic

v er

su s

ph en

ob ar

bi to

2 ob

se rv

at io

na l

st ud

ie s

ve ry

s er

io us

1 se

ri ou

s2 no

s er

io us

di re

ct ne

ss se

ri ou

s1 ,3

no ne

10 /5

5 (1

8. 2%

) 39

/1 23

1. 7%

) R

R 0

.5 5

.3 to

1 .0

1) 14

3 fe

w er

p er

00 (f

ro m

2 fe

w er

to 3

or e)

⊕ 

 

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Y LO

W C

R IT

IC A

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tm en

t f ai

lu re

– m

et ha

do ne

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su s

ph en

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bi to

1 ra

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iz ed

ia ls

se ri

ou s4

no s

er io

in co

ns is

te nc

y5 no

s er

io us

di re

ct ne

ss ve

ry s

er io

us 6

no ne

1/ 18

.6 %

) 1/

(6 .3

% )

R R

0 .8

(0 .0

6 to

1 3.

08 )

7 fe

w er

p er

00 (f

ro m

5 9

fe w

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7 55

or e)

⊕ 

 

V ER

Y LO

W C

R IT

IC A

Tr ea

tm en

t f ai

lu re

– m

or ph

in e

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us p

he no

ba rb

it on

2 ra

nd om

iz ed

ia ls

se ri

ou s7

no s

er io

in co

ns is

te nc

y8 no

s er

io us

di re

ct ne

ss se

ri ou

s3 no

ne 21

/8 7

(2 4.

1% )

25 /6

2 (4

0. 3%

) R

R 0

.6 3

.3 9

to 1

) 14

9 fe

w er

p er

00 (f

ro m

6 fe

w er

to 0

or e)

⊕ ⊕

 

LO W

C R

IT IC

A L

Tr ea

tm en

t f ai

lu re

– p

ar eg

or ic

v er

su s

di az

ep am

2 ra

nd om

iz ed

ia ls

ve ry

s er

io us

1 se

ri ou

s9 no

s er

io us

di re

ct ne

ss se

ri ou

s1 0

no ne

10 /5

5 (1

8. 2%

) 24

/3 0

(8 0%

) R

R 0

.2 4

.1 4

to 0

.4 3)

60 8

fe w

er p

10 00

(f ro

m 4

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w er

)

⊕ 

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V ER

Y LO

W C

R IT

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Tr ea

tm en

t f ai

lu re

– m

et ha

do ne

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su s

di az

ep am

1 ra

nd om

iz ed

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se ri

ou s4

no s

er io

in co

ns is

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y5 no

s er

io us

di re

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ss ve

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us 6

no ne

1/ 18

.6 %

) 0/

(0 %

) R

R 2

.6 8

.1 2

to 6

1. 58

) —

⊕ 

 

V ER

Y LO

W C

R IT

IC A

A ut

ho r(

s) : D

av id

A O

sb or

n, H

ea th

er E

J ef

fe ry

, M ic

ha el

J C

ol e

D at

e: 2

01 3-

01 -1

6 Q

ue st

io n:

S H

O U

LD S

P EC

IF IC

O P

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V S

S P

EC IF

IC S

ED AT

IV E

B E

U S

ED T

O R

ED U

C E

TR EA

TM EN

T FA

IL U

R E

IN O

P IO

ID W

IT H

D R

A W

A L

IN N

EW B

O R

N IN

FA N

TS ?

S et

ti ng

s: H

os pi

ta l

B ib

li og

ra ph

y: O

sb or

n D

A , J

ef fe

ry H

E, C

ol e

M J.

O pi

at e

tr ea

tm en

t f or

o pi

at e

w ith

dr aw

al in

n ew

bo rn

in fa

nt s.

C oc

hr an

e D

at ab

as e

of S

ys te

m at

ic R

ev ie

w s

160

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

1 Th

is m

et a-

an al

ys is

c om

bi ne

d tw

o qu

as i-t

ria ls

(F in

ne ga

n 19

84 a

nd K

al te

nb ac

h 19

86 ).

It w

as u

nc le

ar w

he th

er s

om e

of th

e in

fa nt

s re

po rt

ed in

th e

st ud

y w

er e

al so

in cl

ud ed

in F

in ne

ga n

19 84

, a nd

th er

e is

a ri

sk o

f d ou

bl e-

co un

tin g

th e

pa rt

ic ip

an ts

. T he

ud ie

s al

lo ca

te d

gr ou

ps fr

om e

nv el

op es

d es

ig na

te d

ac co

rd in

g to

th e

fir st

le tt

er o

f t he

la st

n am

e. A

llo ca

tio n

co nc

ea lm

en t w

as ju

dg ed

to b

e in

ad eq

ua te

a nd

s el

ec tio

n bi

as m

ay is

a h

ig h

ris k.

B lin

di ng

w as

n ot

c le

ar ly

re po

rt ed

fo r s

ho rt

-t er

m o

ut co

m es

t i t i

s un

lik el

y as

th e

tr ea

tm en

t r eg

im en

s w

er e

di ff

er en

t s o

th er

e is

a h

ig h

ris k

of p

er fo

rm an

ce a

nd d

et ec

tio n

bi as

. S el

ec tiv

e re

po rt

in g

of o

ut co

m es

w as

u nc

le ar

a nd

c ou

ld n

ot b

e ju

dg ed

. 2

St at

is tic

al h

et er

og en

ei ty

is p

re se

nt (I

s qu

ar ed

= 8

5% ).

Th e

st ud

ie s

w er

e si

m ila

r b ut

d os

es a

re n

ot re

po rt

ed e

xc ep

t f or

P he

no ba

rb ito

ne in

F in

ne ga

n 19

84 ),

so th

e he

te ro

ge ne

ity is

u ne

xp la

in ed

. T hi

s w

as d

ow ng

ra de

d fo

r u ne

xp la

in ed

in co

ns is

te nc

y. 3

Th e

sa m

pl e

si ze

is s

m al

l a nd

th e

ev en

t r at

e is

lo w

a nd

th e

co nfi

de nc

e in

te rv

al is

w id

e. 4

N o

m et

ho d

of ra

nd om

g en

er at

io n

w as

re po

rt ed

in th

e M

ad de

n 19

77 R

CT a

nd a

llo ca

tio n

co nc

ea lm

en t w

as u

nl ik

el y.

T he

re is

a h

ig h

ris k

of s

el ec

tio n

bi as

. B lin

di ng

w as

n ot

re po

rt ed

p er

fo rm

an ce

a nd

d et

ec tio

n bi

as m

ay b

e pr

es en

t. Th

e st

ud y

ac co

un te

d fo

r i nc

om pl

et e

ou tc

om es

s o

at tr

iti on

b ia

s is

a lo

w ri

sk .

5 N

ot a

pp lic

ab le

a s

on ly

o ne

tr ia

l. 6

Th e

sa m

pl e

si ze

is v

er y

sm al

l, th

e ev

en t r

at e

is v

er y

lo w

a nd

th e

co nfi

de nc

e in

te rv

al is

v er

y w

id e.

7 Th

is m

et a-

an al

ys is

c om

bi ne

s a

qu as

i-R CT

(K ho

o 19

95 ) a

nd a

R CT

(J ac

ks on

2 00

4) . I

n Kh

oo 1

99 5

th er

e is

a h

ig h

ris k

of s

el ec

tio n

bi as

a s

ra nd

om g

en er

at io

n (u

se o

f l as

t n um

be r o

f t he

p ar

tic ip

an t's

h os

pi ta

l n um

be r)

an d

al lo

ca tio

n co

nc ea

lm en

t w er

e ju

dg ed

to b

e in

ad eq

ua te

. B lin

di ng

w as

n ot

p er

fo rm

ed fo

r t re

at m

en t a

nd n

ot re

po rt

ed fo

r a ss

es sm

en t s

o pe

rf or

m an

ce a

nd d

et ec

tio n

bi as

m ay

b e

pr es

en t.

Ja ck

so n

20 04

w as

w el

l-c on

du ct

ed a

nd a

t l ow

ri sk

o f s

el ec

tio n,

p er

fo rm

an ce

a nd

d et

ec tio

n bi

as .

H ow

ev er

, t he

G RA

D E

as se

ss m

en t i

s do

ne a

cc or

di ng

to th

e lo

w er

q ua

lit y

of e

vi de

nc e

so th

e an

al ys

is is

d ow

ng ra

de d

fo r b

ia s.

8 St

at is

tic al

h et

er og

en ei

ty is

n ot

p re

se nt

a nd

th er

e di

d no

t a pp

ea r t

o be

u ne

xp la

in ed

c lin

ic al

h et

er og

en ei

ty .

9 Th

er e

is s

ta tis

tic al

h et

er og

en ei

ty (I

s qu

ar ed

= 6

7% ).

Th e

st ud

ie s

w er

e si

m ila

r b ut

d os

es a

re n

ot re

po rt

ed s

o th

e he

te ro

ge ne

ity is

u ne

xp la

in ed

. T hi

s w

as d

ow ng

ra de

d fo

r u ne

xp la

in ed

in co

ns is

te nc

y. 10

A lth

ou gh

th e

co nfi

de nc

e in

te rv

al is

n ar

ro w

, i t w

as d

ow ng

ra de

d fo

r i m

pr ec

is io

n du

e to

th e

sm al

l s am

pl e

si ze

a nd

lo w

e ve

nt ra

te .

161

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Supportive care Phenobarbitone

Death See comment See comment Not estimable

— See comment Not reported

Treatment failure Failure to settle measured with Finnegan score

118 per 1000 321 per 1000 (111 to 934)

RR 2.73 (0.94 to 7.94)

62 (1 study)

⊕ VERY LOW1,2,3

Seizures See comment See comment Not estimable

— See comment Not reported

Duration of treatment (days)

The mean duration of treatment (days) in the intervention groups was 17.9 higher (11.98 to 23.82 higher)

62 (1 study)

⊕ VERY LOW1,2,4

Total length of hospital stay Days in hospital

The mean total length of hospital stay in the intervention groups was 20.8 higher (13.64 to 27.96 higher)

62 (1 study)

⊕ VERY LOW1,2,4

GRADE does not allow for upgrading for large effect sizes unless there are no threats to validity (not downgraded for any other reason).

Infant weight gain See comment See comment Not estimable

— See comment Not reported

Days to regain birthweight

The mean days to regain birthweight in the intervention groups was 1.4 lower (4.07 lower to 1.27 higher)

55 (1 study)

⊕ VERY LOW1,2,5

Measurements were available for 55 of the 62 study participants.

Duration of treatment for NAS

See comment See comment Not estimable

— See comment Not reported

PHENOBARBITONE COMPARED TO SUPPORTIVE CARE FOR OPIOID WITHDRAWAL IN NEWBORN INFANTS

Patient or population: Opioid withdrawal in newborn infants Settings: Hospital Intervention: Phenobarbitone Comparison: Supportive care

CI: Confidence interval. RR: Risk ratio. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 This quasi-randomized trial (Khoo 1995) allocated participants to groups using the last number of the participant's hospital number. Both random generation and

allocation concealment were judged to be inadequate and there is thus a high risk of selection bias. The group numbers are also not balanced (29 vs 36). There was no blinding of providers or parents so performance bias may be present. Blinding was unreported for short-term outcomes and the risk of detection bias is unclear.

2 Not applicable as only one study is included. 3 The sample size is very small and the event rate is very low so imprecision is likely in these results. 4 The sample size is small and the confidence interval is wide. Notwithstanding the very large difference in means and the highly statistically significant finding, the

lack of information about the primary outcome and power of the trial reduces our confidence in this estimate. 5 The sample size is small. The primary outcome is not clearly defined and it is therefore not possible to determine the power of the study for this outcome: time to

regain birthweight. In the light of this uncertainty, the GRADE criteria recommend that a sample size of less than 400 for continuous outcomes be downgraded for imprecision.

162

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Diazepam Phenobarbitone

Death – not reported See comment See comment Not estimable

— See comment Not reported

Treatment failure 389 per 1000 152 per 1000 (93 to 241)

RR 0.39 (0.24 to 0.62)

139 (2 studies)

⊕ VERY LOW1,2,3

The meta- analysis included one quasi-trial (Finnegan 1984) and one RCT (Madden 1977). GRADE assessment was done within the RCT study design category.

Seizures See comment See comment Not estimable

— See comment Not reported

Total length of hospital stay Days

The mean total length of hospital stay in the intervention groups was 3.07 higher (2.02 lower to 8.16 higher)

31 (1 study)

⊕ VERY LOW4,5,6

Madden 1977 is an RCT and GRADE assessment was done within the RCT study design category.

Infant weight gain See comment See comment Not estimable

— See comment Not reported

Days to regain birthweight

See comment See comment Not estimable

— See comment Not reported

Duration of treatment for NAS Days

The mean duration of treatment for nas in the intervention groups was 4.3 higher (0.73 lower to 9.33 higher)

31 (1 study)

⊕ VERY LOW4,5,6

Madden 1977 is an RCT and GRADE assessment was done within the RCT study design category.

PHENOBARBITONE COMPARED TO DIAZEPAM FOR OPIOID WITHDRAWAL IN NEWBORN INFANTS

Patient or population: Opioid withdrawal in newborn infants Settings: Hospital Intervention: Phenobarbitone Comparison: Diazepam

CI: Confidence interval. RR: Risk ratio. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 The risk of selection bias is high for the quasi-trial (Finnegan 1984) as random generation and allocation concealment were judged as inadequate. No method was

reported in the Madden 1977 RCT so risk is unclear. Blinding of clinical and research staff was not reported in Madden 1977 and was unlikely as the treatment regimens were different so performance bias may be present. In Finnegan 1984 the nurses were not blinded but the research staff were blinded for short-term outcome assessment. Detection bias may be present. Both studies accounted for incomplete outcomes so attrition bias is a low risk. The groups are unbalanced in Finnegan 1984 (87 vs 20) as the Diazepam group was found to have excessive complications at interim analysis and enrolment was stopped.

2 The meta-analysis reported here was conducted using a fixed effects model and a RR = 0.39 (95%CI: 0.24, 0.62) with Finnegan 1984 showing a statistically significant benefit of phenobarbitone over diazepam and Madden 1977 showing a non-significant benefit of diazepam over phenobarbitone. In this situation when heterogeneity is present, a random effects model is more appropriate. This would change the RR = 0.60 (95% CI: 0.08, 4.56) and is no longer statistically significant. The relatively large difference in results following sensitivity analyses reduces the robustness of these results. The assessment is downgraded for unexplained inconsistency.

3 The overall sample size is small and there are very few events. 4 This RCT (Madden 1977) was judged to be at unclear risk of selection bias as no random generation or allocation concealment was reported. Blinding was not

reported for the trial so performance and detection bias may be present. Incomplete outcome data was addressed so attrition bias was minimal. 5 Not applicable as only one trial included. - The sample size is very small and the confidence interval is very wide. 163

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Chlorpromazine Phenobarbitone

Death – not reported See comment See comment Not estimable

— See comment Not reported

Treatment failure See comment

316 per 1000 104 per 1000 (25 to 458)

RR 0.33 (0.08 to 1.45)

38 (1 study)

⊕ VERY LOW1,2,3

Treatment failure was rated on a three point severity scale of tremor and irritability with failure being persistent symptoms > 4 days

Seizures See comment See comment Not estimable

40 (1 study)

⊕ VERY LOW1,2,4

Zero events in both groups.

Total length of hospital stay

See comment See comment Not estimable

— See comment Not reported

Infant weight gain See comment See comment Not estimable

— See comment Not reported

Days to regain birthweight

See comment See comment Not estimable

— See comment Not reported

Duration of treatment for NAS

See comment See comment Not estimable

— See comment Not reported

PHENOBARBITONE COMPARED TO CHLORPROMAZINE FOR OPIOID WITHDRAWAL IN NEWBORN INFANTS

Patient or population: Opioid withdrawal in newborn infants Settings: Hospital Intervention: Phenobarbitone Comparison: Chlorpromazine

CI: Confidence interval. RR: Risk ratio. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 In this RCT (Kahn 1969) the method of random generation was not reported and the risk of selection bias is unclear. The study was blinded for personnel and

assessors so the risk of performance and detection bias is low. The risk of selective outcome reporting was unclear as the primary outcome was not explicitly stated and the trial pre-dates trial registration.

2 Not applicable as only one trial included. 3 The sample size is very small and the event rate low with a wide confidence interval. 4 The sample size is very small and zero events.

164

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Phenobarbitone titration alone

Phenobarbitone titration with loading dose

Treatment failure Need for a second drug

500 per 1000 550 per 1000 (295 to 1000)

RR 1.1 (0.59 to 2.07)

36 (1 study)

⊕ VERY LOW1,2,3

Death See comment See comment Not estimable

— See comment Not reported for this comparison

Seizures See comment See comment Not estimable

— See comment Not reported for this comparison

Total length of hospital stay

See comment See comment Not estimable

— See comment Not reported for this comparison

Infant weight gain See comment See comment Not estimable

— See comment Not reported for this comparison

Days to regain birthweight

See comment See comment Not estimable

— See comment Not reported for this comparison

Duration of treatment for NAS

See comment See comment Not estimable

87 (1 study)

See comment Finnegan 1984 (quasi-RCT) reported reduced time to symptom control in loading dose vs none (33 vs 64 hrs; p < 0.01). No other data reported. N = 87 (assumed)

PHENOBARBITONE TITRATION WITH LOADING DOSE COMPARED TO PHENOBARBITONE TITRATION ALONE FOR OPIOID WITHDRAWAL IN NEWBORN INFANTS

Patient or population: Opioid withdrawal in newborn infants Settings: Hospital Intervention: Phenobarbitone titration with loading dose Comparison: Phenobarbitone titration alone

CI: Confidence interval. RR: Risk ratio. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 The quasi-trial (Kaltenbach 1986) allocated groups from envelopes designated according to the first letter of the last name. Allocation concealment was judged to

be inadequate and selection bias may be present. There was no blinding for short-term outcomes and there is a risk of performance and detection bias. Selective reporting of outcomes was unclear and could not be judged.

2 Not applicable as only one trial included. 3 The sample size is small, the event rate low and the confidence interval is wide.

165

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Long course Phenobarbitone (8.4 mg/kg/day in four divided doses x 10 days, then reduced by 1/3rd every 2nd day)

Short course Phenobarbitone (8.4 mg/kg/day in four divided doses x 4 days, then stopped)

Death See comment See comment Not estimable

— See comment Not reported for this comparison

Treatment failure 143 per 1000 83 per 1000 (6 to 1000)

RR 0.58 (0.04 to 7.94)

19 (1 study)

⊕ VERY LOW1,2,3

Seizures See comment See comment Not estimable

— See comment Not reported for this comparison

Total length of hospital stay

See comment See comment Not estimable

— See comment Not reported for this comparison

Infant weight gain See comment See comment Not estimable

— See comment Not reported for this comparison

Days to regain birthweight

See comment See comment Not estimable

— See comment Not reported for this comparison

Duration of treatment for NAS

See comment See comment Not estimable

— See comment Not reported for this comparison

SHORT COURSE PHENOBARBITONE COMPARED TO LONG COURSE PHENOBARBITONE FOR OPIOID WITHDRAWAL IN NEWBORN INFANTS

Patient or population: Opioid withdrawal in newborn infants Settings: Hospital Intervention: Short course Phenobarbitone (8.4 mg/kg/day in four divided doses x 4 days, then stopped) Comparison: Long course Phenobarbitone (8.4 mg/kg/day in four divided doses x 10 days, then reduced by 1/3rd every 2nd day)

CI: Confidence interval. RR: Risk ratio. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 In this RCT (Kahn 1969) the method of random generation was not reported and the risk of selection bias is unclear. The study was blinded for personnel and

2 Not applicable as only one trial is included. 3 The sample size is very small, the number of events is is low and the confidence interval is very wide.

166

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Long course of chlorpromazine (2.8 mg/kg/day in four divided doses x 10 days, then gradual reduction over six days)

Short course of chlorpromazine (2.8 mg/kg/day in four divided doses x 4 days, then stopped)

Death See comment See comment Not estimable

— See comment Not reported

Treatment failure Persistent symptoms > 4 days

125 per 1000 455 per 1000 (65 to 1000)

RR 3.64 (0.52 to 25.41)

19 (1 study)

⊕ VERY LOW1,2,3

Seizures See comment See comment Not estimable

— See comment Not reported

Total length of hospital stay

See comment See comment Not estimable

— See comment Not reported

Infant weight gain See comment See comment Not estimable

— See comment Not reported

Days to regain birthweight

See comment See comment Not estimable

— See comment Not reported

Duration of treatment for NAS

See comment See comment Not estimable

— See comment Not reported

SHORT COURSE OF CHLORPROMAZINE COMPARED TO LONG COURSE OF CHLORPROMAZINE FOR OPIOID WITHDRAWAL IN NEWBORN INFANTS

Patient or population: Opioid withdrawal in newborn infants Settings: Hospital Intervention: Short course of chlorpromazine (2.8 mg/kg/day in four divided doses x 4 days, then stopped) Comparison: Long course of chlorpromazine (2.8 mg/kg/day in four divided doses x 10 days, then gradual reduction over six days)

CI: Confidence interval. RR: Risk ratio. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 In this RCT (Kahn 1969) the method of random generation was not reported and the risk of selection bias is unclear. The study was blinded for personnel and

2 Not applicable as only one trial is included. 3 The sample size is very small, the number of events is low and the confidence interval is very wide.

167

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Opioid alone Phenobarbitone and opioid

Death See comment See comment Not estimable

— See comment Not reported

Treatment failure Needing another drug

See comment See comment Not estimable

20 (1 study)

⊕ VERY LOW1,2,3

There were no events in either group.

Seizures See comment See comment Not estimable

20 (1 study)

⊕ VERY LOW1,3

There were no events in either group.

Total length of hospital stay Days

The mean total length of hospital stay in the intervention groups was 41 lower (59.85 to 22.15 lower)

20 (1 study)

⊕ VERY LOW1,4

Infant weight gain See comment See comment Not estimable

— See comment Not reported

Days to regain birthweight

See comment See comment Not estimable

— See comment Not reported

Duration of treatment for NAS

See comment See comment Not estimable

— See comment Not reported

PHENOBARBITONE AND OPIOID COMPARED TO OPIOID ALONE FOR OPIATE WITHDRAWAL IN NEWBORN INFANTS

Patient or population: Opioid withdrawal in newborn infants Settings: Hospital Intervention: Phenobarbitone and opioid Comparison: Opioid alone

CI: Confidence interval. RR: Risk ratio. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 This study (Coyle 2002) is probably a quasi-randomized trial. Infants were matched on Finnegan scores but the method is incompletely described. If no match was

possible, then infants were randomly assigned. Allocation concealment was judged to be inadequate. Selection bias is a high risk. Performance bias is a low risk as the trial was placebo-controlled and nurses were blinded to the treatment assignments. However, weekly phenobarbitone levels were reported to the physician so there is an unclear risk of detection bias as it is not certain if the physicians were also assessing the outcomes. Of note is that an earlier abstract reported 35 infants but the principal article only reports on 21 infants.

2 Not applicable as only one study included. 3 The sample size is small. Although a sample size calculation was done a priori the outcome used in the formula is reduction in hospital days. This calculation found

that 48 patients were required. However, the trial was stopped early on the basis of significance but no details are provided if formal stopping rules were applied to determine the significance level. A systematic review of RCTs stopped early for benefit found that such RCTs were found to overestimate treatment effects. When trials with events fewer than the median number (n=66) were compared with those with event numbers above the median, the odds ratio for a magnitude of effect greater than the median was 28 (95% CI 11–73) (Montori VM, Devereaux PJ and Adhikari NK et al.. Randomized trials stopped early for benefit: a systematic review. JAMA 2005;294:2203-09.)

4 The sample size is small and the confidence interval is wide. Although a sample size calculation was done a priori for this outcome: reduction in hospital days. This calculation found that 48 patients were required. However, the trial was stopped early on the basis of significance but no details are provided if formal stopping rules were applied to determine the significance level. A systematic review of RCTs stopped early for benefit found that such RCTs were found to overestimate treatment effects. When trials with events fewer than the median number (n=66) were compared with those with event numbers above the median, the odds ratio for a magnitude of effect greater than the median was 28 (95% CI 11-73) (Montori VM, Devereaux PJ and Adhikari NK et al.. Randomized trials stopped early for benefit: a systematic review. JAMA 2005;294:2203-09.)

168

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE) Comments

Assumed risk Corresponding risk

Opioid alone Clonidine and opioid

Death 0 per 1000 0 per 1000 (0 to 0)

RR 7 (0.37 to 131.28)

80 (1 study)

⊕⊕ LOW1,2

All deaths (n = 3) were in the Clonidine and Opioid group. Death occurred after discharge and cessation of clonidine. Causes: myocarditis, SIDS, homicide.

Treatment failure Required >= 0.9ml of diluted Tincture of Opium every 3 hours

125 per 1000 11 per 1000 (1 to 199)

RR 0.09 (0.01 to 1.59)

80 (1 study)

⊕⊕ LOW1,3

All infants with treatment failure were (n = 5) in the Opioid alone group.

Seizures 75 per 1000 10 per 1000 (1 to 201)

RR 0.14 (0.01 to 2.68)

80 (1 study)

⊕⊕ LOW1,4

All seizures (n = 3) were in the Opioid alone group.

Total length of hospital stay

See comment See comment Not estimable

— See comment Not reported

Infant maximum weight loss – % of birthweight5

The mean infant maximum weight loss in the intervention groups was 0.88 lower (2.33 lower to 0.57 higher)

80 (1 study)

⊕⊕ LOW4

Days to regain birthweight

See comment See comment Not estimable

— See comment Not reported

Duration of treatment for NAS

Medians reported 80 (1 study)

⊕⊕ LOW1,4

Median duration was 11 days (95% CI: 8–15) vs 15 days (95% CI: 13–17) in the Clonidine and opioid group vs the opioid alone respectively.

CLONIDINE AND OPIOID COMPARED TO OPIOID ALONE FOR OPIOID WITHDRAWAL IN NEWBORN INFANTS

Patient or population: Opioidwithdrawal in newborn infants Settings: Hospital Intervention: Clonidine and opioid Comparison: Opioid alone

CI: Confidence interval. RR: Risk ratio. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 This placebo-controlled RCT (Agthe 2009) was well-conducted and judged to be at low risk of selection, performance and detection bias. The infants in the Clonidine

and Tincture of Opium group had statistically significantly lower mean birthweights. 61% of infants were also exposed to cocaine in utero and 6 of 80 infants had positive benzodiazepine urine screens.

2 The event rates are very low and the confidence interval is very wide. 3 The event rate is very low and the confidence interval is wide. 4 The sample size is small and according to GRADE criteria for rating continuous data, a sample size of less than 400 indicates imprecision and should be downgraded. 5 Inverse measure for infant weight gain (proxy outcome)

169

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

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an d

it is

th er

ef or

e no

t p os

si bl

e to

d et

er m

in e

th e

po w

er o

f t he

s tu

dy fo

r t hi

s ou

tc om

e: ti

m e

to re

ga in

b irt

hw ei

gh t.

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e lig

ht o

f t hi

s un

ce rt

ai nt

y, th

e G

RA D

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ite ria

re co

m m

en d

th at

sa m

pl e

si ze

o f l

es s

th an

4 00

fo r c

on tin

uo us

o ut

co m

es b

e do

w ng

ra de

d fo

r i m

pr ec

is io

Q ua

li ty

a ss

es sm

en t

N o.

o f p

at ie

nt s

Ef fe

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li ty

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rt an

ce N

o. o

f s tu

di es

D es

ig n

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k of

b ia

s In

co ns

is te

nc y

In di

re ct

ne ss

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ec is

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co ns

id er

at io

ns P

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up po

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at iv

e (9

5% C

I) A

bs ol

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at io

n of

tr ea

tm en

t f or

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S –

n ot

r ep

or te

0 —

— —

no ne

— —

C R

IT IC

A L

171

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Q ua

li ty

a ss

es sm

en t

N o.

o f p

at ie

nt s

Ef fe

Q ua

li ty

Im po

rt an

ce N

o. o

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di es

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ig n

R is

k of

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re ct

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co ns

id er

at io

ns P

he no

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at iv

e (9

5% C

I) A

bs ol

ut e

D ea

th –

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r ep

or te

0 —

— —

no ne

— —

C R

IT IC

A L

Tr ea

tm en

t f ai

lu re

2 ra

nd om

iz ed

ia ls

se ri

ou s1

se ri

ou s2

no s

er io

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re ct

ne ss

se ri

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no ne

21 /1

(2 0.

4% )

14 /3

6 (3

8. 9%

) R

R 0

.3 9

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to 0

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fe w

er p

10 00

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R IT

IC A

S ei

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— —

C R

IT IC

A L

To ta

l l en

gt h

of h

os pi

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ta y

(m ea

su re

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it h:

D ay

s; b

et te

r in

di ca

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by lo

w er

v al

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1 ra

nd om

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se ri

ou s4

no s

er io

in co

ns is

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ss ve

ry s

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15 16

— M

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.0 7

hi gh

(2 .0

2 lo

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8. 16

h ig

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⊕ 

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R IT

IC A

In fa

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t g ai

n –

no t r

ep or

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1 ob

se rv

at io

na l

st ud

ie s

se ri

ou s1

no s

er io

in co

ns is

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y2 no

s er

io us

di re

ct ne

ss se

ri ou

s4 no

ne 28

34 —

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2 0.

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3. 64

to 2

7. 96

gh er

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⊕ 

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D ay

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— —

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— —

C R

IT IC

A L

D ur

at io

n of

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tm en

t f or

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S (m

ea su

re d

w it

h: D

ay s;

b et

te r

in di

ca te

d by

lo w

er v

al ue

1 ra

nd om

iz ed

ia ls

se ri

ou s4

no s

er io

in co

ns is

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y5 no

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io us

di re

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ss ve

ry s

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no ne

15 16

— M

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r (0

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⊕ 

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R IT

IC A

A ut

ho r(

s) : D

av id

A O

sb or

n, H

ea th

er E

J ef

fe ry

, M ic

ha el

J C

ol e

D at

e: 2

01 3-

01 -1

6 Q

ue st

io n:

S H

O U

LD P

H EN

O B

A R

B IT

O N

E V

S D

IA ZE

PA M

B E

U S

ED IN

O P

IO ID

W IT

H D

R A

W A

L IN

N EW

B O

R N

IN FA

N TS

? S

et ti

ng s:

H os

pi ta

l B

ib li

og ra

ph y:

O sb

or n

D A

, J ef

fe ry

H E,

C ol

e M

J. S

ed at

iv es

fo r

op ia

te w

ith dr

aw al

in n

ew bo

rn in

fa nt

s. C

oc hr

an e

D at

ab as

e of

S ys

te m

at ic

R ev

ie w

172

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

1 Th

e ris

k of

s el

ec tio

n bi

as is

h ig

h fo

r t he

q ua

si -t

ria l (

Fi nn

eg an

1 98

4) a

s ra

nd om

g en

er at

io n

an d

al lo

ca tio

n co

nc ea

lm en

t w er

e ju

dg ed

a s

in ad

eq ua

te . N

o m

et ho

d w

as re

po rt

ed in

th e

M ad

de n

19 77

R CT

s o

ris k

is u

nc le

ar . B

lin di

ng o

f c lin

ic al

a nd

re se

ar ch

af f w

as n

ot re

po rt

ed in

M ad

de n

19 77

a nd

w as

u nl

ik el

y as

th e

tr ea

tm en

t r eg

im en

s w

er e

di ff

er en

t s o

pe rf

or m

an ce

b ia

s m

ay b

e pr

es en

t. In

F in

ne ga

n 19

84 th

e nu

rs es

w er

e no

t b lin

de d

bu t t

he re

se ar

ch s

ta ff

w er

e bl

in de

d fo

r s ho

rt -t

er m

o ut

co m

e as

se ss

m en

t. D

et ec

tio n

bi as

m ay

b e

pr es

en t.

Bo th

s tu

di es

a cc

ou nt

ed fo

r i nc

om pl

et e

ou tc

om es

s o

at tr

iti on

b ia

s is

a lo

w ri

sk . T

he g

ro up

s ar

e un

ba la

nc ed

in F

in ne

ga n

19 84

(8 7

vs 2

0) a

s th

e D

ia ze

pa m

g ro

up w

as fo

un d

to h

av e

ex ce

ss iv

e co

m pl

ic at

io ns

a t

in te

rim a

na ly

si s

an d

en ro

lm en

t w as

s to

pp ed

. 2

Th e

m et

a- an

al ys

is re

po rt

ed h

er e

w as

c on

du ct

ed u

si ng

a fi

xe d

ef fe

ct s

m od

el a

nd a

R R

= 0.

39 (9

5% CI

: 0 .2

4, 0

.6 2)

w ith

F in

ne ga

n 19

84 s

ho w

in g

a st

at is

tic al

ly s

ig ni

fic an

t b en

efi t o

f p he

no ba

rb ito

ne o

ve r d

ia ze

pa m

a nd

M ad

de n

19 77

s ho

w in

g a

no n-

si gn

ifi ca

nt b

en efi

t o f d

ia ze

pa m

o ve

r p he

no ba

rb ito

ne . I

n th

is s

itu at

io n

w he

n he

te ro

ge ne

ity is

p re

se nt

, a ra

nd om

e ff

ec ts

m od

el is

m or

e ap

pr op

ria te

. T hi

s w

ou ld

c ha

ng e

th e

RR =

0 .6

0 (9

5% C

I: 0.

08 , 4

.5 6)

a nd

is n

o lo

ng er

s ta

tis tic

al ly

s ig

ni fic

an t.

Th e

re la

tiv el

y la

rg e

di ff

er en

ce in

re su

lts fo

llo w

in g

se ns

iti vi

ty a

na ly

se s

re du

ce s

th e

ro bu

st ne

ss o

f t he

se re

su lts

. T he

a ss

es sm

en t i

s do

w ng

ra de

d fo

r u ne

xp la

in ed

in co

ns is

te nc

3 Th

e ov

er al

l s am

pl e

si ze

is s

m al

l a nd

th er

e ar

e ve

ry fe

w e

ve nt

s. 4

Th is

R CT

(M ad

de n

19 77

) w as

ju dg

ed to

b e

at u

nc le

ar ri

sk o

f s el

ec tio

n bi

as a

s no

ra nd

om g

en er

at io

n or

a llo

ca tio

n co

nc ea

lm en

t w as

re po

rt ed

. B lin

di ng

w as

n ot

re po

rt ed

fo r t

he tr

ia l s

o pe

rf or

m an

ce a

nd d

et ec

tio n

bi as

m ay

b e

pr es

en t.

In co

m pl

et e

ou tc

om e

da ta

w as

a dd

re ss

ed s

o at

tr iti

on b

ia s

w as

m in

im al

. 5

N ot

a pp

lic ab

le a

s on

ly o

ne tr

ia l i

nc lu

de d.

6 Th

e sa

m pl

e si

ze is

v er

y sm

al l a

nd th

e co

nfi de

nc e

in te

rv al

is v

er y

w id

173

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Q ua

li ty

a ss

es sm

en t

N o.

o f p

at ie

nt s

Ef fe

Q ua

li ty

Im po

rt an

ce N

o. o

f s tu

di es

D es

ig n

R is

k of

b ia

s In

co ns

is te

nc y

In di

re ct

ne ss

Im pr

ec is

io n

O th

co ns

id er

at io

ns P

he no

ba rb

it on

e C

hl or

pr om

az in

e R

el at

iv e

(9 5%

C I)

A bs

ol ut

D ea

th –

n ot

r ep

or te

0 —

— —

no ne

— —

C R

IT IC

A L

Tr ea

tm en

t f ai

lu re

(a ss

es se

d w

it h:

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c om

m en

1 ra

nd om

iz ed

ia ls

se ri

ou s1

no s

er io

in co

ns is

te nc

y2 no

s er

io us

di re

ct ne

ss ve

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us 3

no ne

2/ 19

0. 5%

) 6/

(3 1.

6% )

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0 .3

(0 .0

8 to

1 .4

5) 21

2 fe

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00 (f

ro m

2 91

w er

to 1

m or

⊕ 

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s er

io us

di re

ct ne

ss ve

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er io

us 4

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0/ 19

% )

0/ 21

% )

no t p

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l l en

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ta y

– no

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— —

C R

IT IC

A L

In fa

nt w

ei gh

t g ai

n –

no t r

ep or

te d

0 —

— —

no ne

— —

C R

IT IC

A L

D ay

s to

r eg

ai n

bi rt

hw ei

gh t –

n ot

r ep

or te

0 —

— —

no ne

— —

C R

IT IC

A L

D ur

at io

n of

tr ea

tm en

t f or

N A

S –

n ot

r ep

or te

0 —

— —

no ne

— —

C R

IT IC

A L

A ut

ho r(

s) : D

av id

A O

sb or

n, H

ea th

er E

J ef

fe ry

, M ic

ha el

J C

ol e

D at

e: 2

01 3-

01 -1

6 Q

ue st

io n:

S H

O U

LD P

H EN

O B

A R

B IT

O N

E V

S C

H LO

R P

R O

M A

ZI N

E B

E U

S ED

IN O

P IO

ID W

IT H

D R

A W

A L

IN N

EW B

O R

N IN

FA N

TS ?

S et

ti ng

s: H

os pi

ta l

B ib

li og

ra ph

y: O

sb or

n D

A , J

ef fe

ry H

E, C

ol e

M J.

S ed

at iv

es fo

r op

ia te

w ith

dr aw

al in

n ew

bo rn

in fa

nt s.

C oc

hr an

e D

at ab

as e

of S

ys te

m at

ic R

ev ie

w s

1 In

th is

R CT

(K ah

n 19

69 ) t

he m

et ho

d of

ra nd

om g

en er

at io

n w

as n

ot re

po rt

ed a

nd th

e ris

k of

s el

ec tio

n bi

as is

u nc

le ar

. T he

s tu

dy w

as b

lin de

d fo

r p er

so nn

el a

nd a

ss es

so rs

s o

th e

ris k

of p

er fo

rm an

ce a

nd d

et ec

tio n

bi as

is lo

w . T

he ri

sk o

f s el

ec tiv

e ou

tc om

e re

po rt

in g

w as

u nc

le ar

a s

th e

pr im

ar y

ou tc

om e

w as

n ot

e xp

lic itl

y st

at ed

a nd

th e

tr ia

l p re

-d at

es tr

ia l r

eg is

tr at

io n.

2 N

ot a

pp lic

ab le

a s

on ly

o ne

tr ia

l i nc

lu de

d. 3

Th e

sa m

pl e

si ze

is v

er y

sm al

l a nd

th e

ev en

t r at

e lo

w w

ith a

w id

e co

nfi de

nc e

in te

rv al

. 4

Th e

sa m

pl e

si ze

is v

er y

sm al

l a nd

z er

o ev

en ts

174

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Q ua

li ty

a ss

es sm

en t

N o.

o f p

at ie

nt s

Ef fe

Q ua

li ty

Im po

rt an

ce N

o. o

f s tu

di es

D es

ig n

R is

k of

b ia

s In

co ns

is te

nc y

In di

re ct

ne ss

Im pr

ec is

io n

O th

co ns

id er

at io

P he

no ba

rb it

on e

ti tr

at io

n w

it h

lo ad

in g

do se

he no

ba rb

it on

e ti

tr at

io n

al on

e R

el at

iv e

(9 5%

C I)

A bs

ol ut

D ea

th –

n ot

r ep

or te

0 —

— —

no ne

— —

C R

IT IC

A L

Tr ea

tm en

t f ai

lu re

(a ss

es se

d w

it h:

N ee

d fo

r a

se co

nd d

ru g)

1 ob

se rv

at io

na l

st ud

ie s

se ri

ou s1

no s

er io

in co

ns is

te nc

y2 no

s er

io us

di re

ct ne

ss se

ri ou

s3 no

ne 11

/2 0

(5 5%

) 8/

(5 0%

) R

R 1

(0 .5

9 to

2 .0

7) 50

m or

e pe

r 10

00 (f

ro m

2 05

w er

to 5

m or

⊕ 

 

V ER

Y LO

W C

R IT

IC A

S ei

zu re

s –

no t r

ep or

te d

0 —

— —

no ne

— —

C R

IT IC

A L

To ta

l l en

gt h

of h

os pi

ta l s

ta y

– no

t r ep

or te

0 —

— —

no ne

— —

C R

IT IC

A L

In fa

nt w

ei gh

t g ai

n –

no t r

ep or

te d

0 —

— —

no ne

— —

C R

IT IC

A L

D ay

s to

r eg

ai n

bi rt

hw ei

gh t –

n ot

r ep

or te

0 —

— —

no ne

— —

C R

IT IC

A L

D ur

at io

n of

tr ea

tm en

t f or

N A

1 ra

nd om

iz ed

ia ls

no ne

N =

8 7

as su

m ed

Fi nn

eg an

1 98

4 (q

ua si

-R C

re po

rt ed

r ed

uc ed

ti m

e to

m pt

om c

on tr

ol in

lo ad

in g

do se

n on

e (3

3 vs

6 4

hr s;

p <

0 .0

1) .

N o

ot he

r da

C R

IT IC

A L

A ut

ho r(

s) : D

av id

A O

sb or

n, H

ea th

er E

J ef

fe ry

, M ic

ha el

J C

ol e

D at

e: 2

01 3-

01 -1

6 Q

ue st

io n:

S H

O U

LD P

H EN

O B

A R

B IT

O N

E TI

TR AT

IO N

W IT

H L

O A

D IN

G D

O S

E V

S P

H EN

O B

A R

B IT

O N

E TI

TR AT

IO N

A LO

N E

B E

U S

ED IN

O P

IO ID

W IT

H D

R A

W A

L IN

N EW

B O

R N

IN FA

N TS

? S

et ti

ng s:

H os

pi ta

l B

ib li

og ra

ph y:

O sb

or n

D A

, J ef

fe ry

H E,

C ol

e M

J. S

ed at

iv es

fo r

op ia

te w

ith dr

aw al

in n

ew bo

rn in

fa nt

s. C

oc hr

an e

D at

ab as

e of

S ys

te m

at ic

R ev

ie w

1 Th

e qu

as i-t

ria l (

Ka lte

nb ac

h 19

86 ) a

llo ca

te d

gr ou

ps fr

om e

nv el

op es

d es

ig na

te d

ac co

rd in

g to

th e

fir st

le tt

er o

f t he

la st

n am

e. A

llo ca

tio n

co nc

ea lm

en t w

as ju

dg ed

to b

e in

ad eq

ua te

a nd

s el

ec tio

n bi

as m

ay b

e pr

es en

t. Th

er e

w as

n o

bl in

di ng

fo r s

ho rt

-t er

ou tc

om es

a nd

th er

e is

a ri

sk o

f p er

fo rm

an ce

a nd

d et

ec tio

n bi

as . S

el ec

tiv e

re po

rt in

g of

o ut

co m

es w

as u

nc le

ar a

nd c

ou ld

n ot

b e

ju dg

ed .

2 N

ot a

pp lic

ab le

a s

on ly

o ne

tr ia

l i nc

lu de

d. 3

Th e

sa m

pl e

si ze

is s

m al

l, th

e ev

en t r

at e

lo w

a nd

th e

co nfi

de nc

e in

te rv

al is

w id

175

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

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m at

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ev ie

w s

1 In

th is

R CT

(K ah

n 19

69 ) t

he m

et ho

d of

ra nd

om g

en er

at io

n w

as n

ot re

po rt

ed a

nd th

e ris

k of

s el

ec tio

n bi

as is

u nc

le ar

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s tu

dy w

as b

lin de

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r p er

so nn

el a

nd a

ss es

so rs

s o

th e

ris k

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er fo

rm an

ce a

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tio n

bi as

is lo

w . T

he ri

sk o

f s el

ec tiv

e ou

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e re

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u nc

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a s

th e

pr im

ar y

ou tc

om e

w as

n ot

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lic itl

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at ed

a nd

th e

tr ia

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-d at

es tr

ia l r

eg is

tr at

io n.

2 N

ot a

pp lic

ab le

a s

on ly

o ne

tr ia

l i s

in cl

ud ed

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sa m

pl e

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l, th

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m be

r o f e

ve nt

s is

is lo

w a

nd th

e co

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rv al

is v

er y

w id

176

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Q ua

li ty

a ss

es sm

en t

N o.

o f p

at ie

nt s

Ef fe

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in fa

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as e

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ev ie

w s

1 In

th is

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(K ah

n 19

69 ) t

he m

et ho

d of

ra nd

om g

en er

at io

n w

as n

ot re

po rt

ed a

nd th

e ris

k of

s el

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n bi

as is

u nc

le ar

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s tu

dy w

as b

lin de

d fo

r p er

so nn

el a

nd a

ss es

so rs

s o

th e

ris k

of p

er fo

rm an

ce a

nd d

et ec

tio n

bi as

is lo

w . T

he ri

sk o

f s el

ec tiv

e ou

tc om

e re

po rt

in g

w as

u nc

le ar

a s

th e

pr im

ar y

ou tc

om e

w as

n ot

e xp

lic itl

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a s

on ly

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tr ia

l i s

in cl

ud ed

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sa m

pl e

si ze

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l, th

e nu

m be

r o f e

ve nt

s is

lo w

a nd

th e

co nfi

de nc

e in

te rv

al is

v er

y w

id e.

177

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Q ua

li ty

a ss

es sm

en t

N o.

o f p

at ie

nt s

Ef fe

Q ua

li ty

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rt an

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di es

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io n

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co ns

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178

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

1 Th

is s

tu dy

(C oy

le 2

00 2)

is p

ro ba

bl y

a qu

as i-r

an do

m iz

ed tr

ia l.

In fa

nt s

w er

e m

at ch

ed o

n Fi

nn eg

an s

co re

s bu

t t he

m et

ho d

is in

co m

pl et

el y

de sc

rib ed

. I f n

o m

at ch

w as

p os

si bl

e, th

en in

fa nt

s w

er e

ra nd

om ly

a ss

ig ne

d. A

llo ca

tio n

co nc

ea lm

en t w

as ju

dg ed

be in

ad eq

ua te

. S el

ec tio

n bi

as is

a h

ig h

ris k.

P er

fo rm

an ce

b ia

s is

a lo

w ri

sk a

s th

e tr

ia l w

as p

la ce

bo -c

on tr

ol le

d an

d nu

rs es

w er

e bl

in de

d to

th e

tr ea

tm en

t a ss

ig nm

en ts

. H ow

ev er

, w ee

kl y

ph en

ob ar

bi to

ne le

ve ls

w er

e re

po rt

ed to

th e

ph ys

ic ia

n so

th er

e is

u nc

le ar

ri sk

o f d

et ec

tio n

bi as

a s

it is

n ot

c er

ta in

if th

e ph

ys ic

ia ns

w er

e al

so a

ss es

si ng

th e

ou tc

om es

. O f n

ot e

is th

at a

n ea

rli er

a bs

tr ac

t r ep

or te

d 35

in fa

nt s

bu t t

he p

rin ci

pa l a

rt ic

le o

nl y

re po

rt s

on 2

1 in

fa nt

s. 2

N ot

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lic ab

le a

s on

ly o

ne s

tu dy

in cl

ud ed

. 3

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sa m

pl e

si ze

is s

m al

l. A

lth ou

gh a

s am

pl e

si ze

c al

cu la

tio n

w as

d on

e a

pr io

ri th

e ou

tc om

e us

ed in

th e

fo rm

ul a

is re

du ct

io n

in h

os pi

ta l d

ay s.

T hi

s ca

lc ul

at io

n fo

un d

th at

4 8

pa tie

nt s

w er

e re

qu ire

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ow ev

er , t

he tr

ia l w

as s

to pp

ed e

ar ly

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th e

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ifi ca

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f R CT

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ou nd

th at

s uc

h RC

Ts w

er e

fo un

d to

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re st

im at

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ea tm

en t e

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ts . W

he n

tr ia

w ith

e ve

nt s

fe w

er th

an th

e m

ed ia

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m be

r ( n=

66 ) w

er e

co m

pa re

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w ith

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nt n

um be

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th e

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ni tu

de o

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as 2

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5% C

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A lth

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as d

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tie nt

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H ow

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w er

th an

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m ed

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nu m

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n= 66

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

182

ANNEX 2: SYSTEMATIC REVIEW METHODOLOGY

Methods Criteria for considering studies for this review

Types of studies

1. Randomized controlled trials

2. Systematic reviews and/or meta-analyses categorized as: a. Cochrane reviews from any year b. Non-Cochrane systematic review conducted between 2008 and 2013 c. Non-Cochrane systematic reviews conducted prior to 2008

We determined a priori that systematic reviews conducted prior to 2008 would require extensive updating and we therefore chose to focus on evaluating Cochrane reviews regardless of year and non-Cochrane reviews published since 2008.

Types of participants

Varied according to each evidence question (see Annex 1)

Types of interventions

Intervention

As defined by each evidence question

Comparison

As defined by each evidence question

Types of outcome measures

Maternal outcomes: 1. Withdrawal

2. Substance use

3. Retention in substance use treatment (if necessary, we used retention in the trial as a proxy measure)

4. Termination of maternal rights (e.g. baby taken into care)

Fetal/Infant outcomes: 1. Birthweight

2. Spontaneous abortion

3. Termination

4. Foetal death

5. Intra-uterine growth retardation (IUGR)

6. Gestational age at delivery

7. Premature delivery (before 37 weeks)

8. Neonatal Abstinence Syndrome (NAS)(drug-specific)

9. Neonatal death

10. Sudden Infant Death Syndrome

11. Birth defects

12. Head circumference at birth

13. Length at birth

14. Custody of infant

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Summary of findings table

We used the GRADE approach to interpret findings (Schünemann 2008) and used the GRADE profiler to import data from Review Manager (RevMan) to create 'Summary of findings' (SOF) tables. These tables provide outcome-specific information concerning the overall quality of evidence from each included study in the comparison, the magnitude of effect of the interventions examined, and the sum of available data on all outcomes we rated as important to patient-care and decision making. The outcomes were rated independently by nine members of the Pregnancy and Substance Use Guidelines Committee. We selected seven patient-centred outcomes for each evidence question for inclusion in the SOF tables on the basis of these ratings.

Search methods for identification of studies

The search was conducted by using a search strategy developed in consultation with the WHO Pregnancy and Substance Use Guidelines Technical Team. The search was iterative and the strategy was refined to ensure that it had maximum sensitivity to identify all relevant RCTs.

Electronic searches

We developed the search strategy with the assistance of the World Health Organization Information Specialist. We formulated a comprehensive and exhaustive search strategy in an attempt to identify all relevant randomized controlled trials, systematic reviews and meta-analyses regardless of language or publication status (published, unpublished, in press, and in progress).

We combined the RCT strategy developed by The Cochrane Collaboration and detailed in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) with the PUBMED strategy for Systematic Reviews together with database-specific terms for pregnancy, lactation and the postpartum period. This was combined with database-specific terms for substance use, abuse and dependence. We did not limit the search to specific substances or interventions as the search was intentionally general to be applicable to all evidence questions to be addressed during the guideline process.

The search was iterative and a number of trial searches were run first to ensure maximal sensitivity.

We searched the following databases:

1. Journal databases o Medline via Pubmed – see search strategy conducted on 9 June 2013 below

o EmBase – see search strategy conducted on 10 June 2013 below

o PsychInfo – see search strategy conducted on 10 June 2013 below

o CINAHL – see search strategy conducted on 10 June 2013 below

o Cochrane Central Register of Controlled Trials (CENTRAL) – see search strategy conducted on 13 June 2013 below

Searching other resources

We checked the reference lists of all studies identified by the above methods and examined any systematic reviews, meta-analyses, or guidelines we identified during the search process for references.

We were in close contact with individual researchers working in the field, and policymakers based in inter- governmental organizations including WHO and UNODC.

Data collection and analysis Selection of studies

Two review authors (NS for all; NC for records from 2012 and an intern for records pre-2012) inspected all citations from the electronic search and identified relevant abstracts of trials and systematic reviews for inclusion criteria. The full text articles were obtained for all potentially relevant studies and NS assessed each of these for eligibility. This process was duplicated by NC and two interns.

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Where there were uncertainties or disagreements, or where disputes could not be resolved, these studies remained in awaiting assessment or ongoing studies and the authors were contacted for clarification. NS and NC made final decisions regarding inclusion.

Data extraction and management

1. Extraction

NS extracted data from included studies. NC checked each data entry. We resolved disputes by discussion. If it was not possible to extract data or if further information was needed, we attempted to contact the authors. We extracted data presented only in tables and figures whenever possible, and when further information was necessary, we contacted authors of studies in order to obtain missing data or for clarification of methods.

2. Management

2.1 Forms

We extracted data onto standardized, simple forms, including: o Administrative details: Trial or study identification number; author(s); published or unpublished; year of

publication; number of studies included in paper; year in which study was conducted; details of other relevant papers cited;

o Details of the study: Study design; type, duration and completeness of follow-up; country and location of study (e.g. higher-income vs. lower-income country); informed consent and ethics approval;

o Details of participants: Setting, numbers, relevant baseline characteristics including age;

o Details of intervention: Type of intervention, timing and duration of intervention, additional co-interventions;

o Details of comparison: Type and comparison, timing and duration of comparative intervention;

o Details of outcomes: Maternal and infant outcomes;

o Details of the analysis: For RCTs, details of the type of analysis (intention-to-treat or per protocol).

2.2 Scale-derived data

We included continuous data from rating scales only if:

o the psychometric properties of the measuring instrument have been described in a peer-reviewed journal; and

o the measuring instrument has not been written or modified by one of the trialists for that particular trial.

Ideally the measuring instrument should either be i) a self-report or ii) completed by an independent rater or relative (not the therapist). We realize that this is not often reported clearly and noted this to assist in the Risk of Bias assessment.

2.3 Endpoint versus change data

There are advantages of both endpoint and change data. Change data can remove a component of between- person variability from the analysis. On the other hand, calculation of change needs two assessments (baseline and endpoint), which can be difficult in unstable and difficult to measure conditions such as substance dependence. We decided to primarily use endpoint data, and only use change data if the former were not available. We combined endpoint and change data in the analysis as we used mean differences (MD) rather than standardized mean differences throughout (Higgins 2011, Chapter 9.4.5.2).

2.4 Skewed data

Continuous data on clinical and social outcomes are often not normally distributed. To avoid the pitfall of applying parametric tests to non-parametric data, we aimed to apply the following standards to all data before inclusion:

o standard deviations and means are reported in the paper or obtainable from the authors;

o when a scale starts from the finite number zero, the standard deviation, when multiplied by two, is less than the mean (as otherwise the mean is unlikely to be an appropriate measure of the centre of the distribution (Altman 1996).

Endpoint scores on scales often have a finite start and end point and these rules can be applied. We entered skewed endpoint data from studies of fewer than 200 participants as other data within Data and analyses rather

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than into a statistical analysis. Skewed data pose less of a problem when looking at means if the sample size is large; we entered such endpoint data into syntheses.

When continuous data are presented on a scale that includes a possibility of negative values (such as change data), it is difficult to tell whether data are skewed or not. For these cases, we entered skewed change data into analyses regardless of size of study.

2.5 Common measure

To facilitate comparison between trials, we intended to convert variables that can be reported in different metrics, such as days in hospital (mean days per year, per week or per month) to a common metric (e.g. mean days per month).

2.6 Direction of graphs

Where possible, we entered data in such a way that the area to the left of the line of no effect indicated a favourable outcome for the treatment intervention. Where keeping to this made it impossible to avoid outcome titles with clumsy double-negatives (e.g. 'Not improved') we reported data where the left of the line indicates an unfavourable outcome. This was noted in the relevant graphs.

Assessment of risk of bias in included studies

NS worked independently by using criteria described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to assess trial quality. This set of criteria is based on evidence of associations between overestimate of effect and high risk of bias of the article such as sequence generation, allocation concealment, blinding, incomplete outcome data and selective reporting.

Full details of the Risk of Bias tool can be viewed in the table below.

Item Low risk High risk Unclear risk

Sequence generation

Investigators described a random component in the sequence generation process such as the use of random number table, coin tossing, cards or envelope shuffling

Investigators described a non-random component in the sequence generation process such as the use of odd or even date of birth, algorithm based on the day/date of birth, hospital or clinic record number

Insufficient information to permit judgment of the sequence generation process

Allocation concealment

Participants and the investigators enrolling participants cannot foresee assignment, e.g. central allocation; or sequentially numbered, opaque, sealed envelopes

Participants and investigators enrolling participants can foresee upcoming assignment, e.g. an open random allocation schedule (e.g. a list of random numbers); or envelopes were unsealed or non¬opaque or not sequentially numbered

Insufficient information to permit judgment of the allocation concealment or the method not described

Blinding Blinding of the participants, key study personnel and outcome assessor, and unlikely that the blinding could have been broken. Or lack of blinding unlikely to introduce bias. No blinding in the situation where non-blinding is not likely to introduce bias.

No blinding, incomplete blinding and the outcome is likely to be influenced by lack of blinding

Insufficient information to permit judgment of adequacy or otherwise of the blinding

Incomplete outcome data

No missing outcome data, reasons for missing outcome data unlikely to be related to true outcome, or missing outcome data balanced in number across groups

Reason for missing outcome data likely to be related to true outcome, with either imbalance in number across groups or reasons for missing data

Insufficient reporting of attrition or exclusions

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Item Low risk High risk Unclear risk

Selective reporting

A protocol is available which clearly states the primary outcome as the same as in the final trial report

The primary outcome differs between the protocol and final trial report

No trial protocol is available or there is insufficient reporting to determine if selective reporting is present

Where inadequate details of randomization and other characteristics of trials were provided, we contacted authors of the studies in order to obtain additional information.

We have noted the level of risk of bias in the text of the review.

Measures of treatment effect

1. Binary data

For binary outcomes we calculated a standard estimation of the risk ratio (RR) and its 95% confidence interval (CI).

2. Continuous data

For continuous outcomes we estimated mean difference (MD) between groups. We would prefer not to calculate effect size measures (standardised mean difference (SMD)). However, if scales of very considerable similarity were used, we presumed there was a small difference in measurement, and we would have calculated effect size and transformed the effect back to the units of one or more of the specific instruments.

Unit of analysis issues

1. Cluster trials

Studies increasingly employ 'cluster randomization' (such as randomization by clinician or practice), but analysis and pooling of clustered data poses problems. Authors often fail to account for intra-class correlation in clustered studies, leading to a 'unit of analysis' error (Divine 1992) whereby P values are spuriously low, confidence intervals unduly narrow and statistical significance overestimated. This causes type I errors (Bland 1997).

Where study authors were unable to provide the information needed to correct for flawed analysis of cluster randomized trials, the data was analysed as a non cluster RCT but with downgrading of the certainty of effect in the GRADE table.

2. Cross-over trials

None of the present included studies employed a cross-over trial design.

3. Studies with multiple treatment groups

Dealing with missing data

1. Overall loss of credibility

At some degree of loss of follow-up data must lose credibility. We chose that, for any particular outcome, should more than 50% of data be unaccounted for, we would not reproduce these data or use them within analyses. If, however, more than 50% of those in one arm of a study were lost, but the total loss is less than 50%, we would address this within the Summary of Findings table(s) by down-rating quality. Finally, we would also downgrade quality within the Summary of Findings table(s) should loss be 25-50% in total.

2. Binary

In the case where attrition for a binary outcome is between 0 and 50% and where these data are not clearly described, we presented data on a 'once-randomized-always-analysed' basis (an intention to treat analysis). Those leaving the study early were assumed to have the same rates of negative outcome as those who completed in that particular arm of the trial. We undertook a sensitivity analysis testing how prone the primary

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

outcomes are to change when data only from people who complete the study to that point were compared to the intention to treat analysis using the above assumptions.

3. Continuous Data

3.1 Attrition

In the case where attrition for a continuous outcome is between 0 and 50%, and data only from people who complete the study to that point are reported, we reproduced these.

3.2 Standard deviations

If standard deviations are not reported, we first tried to obtain the missing values from the authors. If not available, where there are missing measures of variance for continuous data, but an exact standard error and confidence intervals available for group means, and either 'p' value or 't' value available for differences in mean, we can calculate them according to the rules described in the Cochrane Handbook for Systemic reviews of Interventions (Higgins 2011): when only the standard error (SE) is reported, standard deviations (SDs) are calculated by the formula SD = SE * square root (n). Chapters 7.7.3 and 16.1.3 of the Cochrane Handbook for Systemic reviews of Interventions (Higgins 2011) present detailed formula for estimating SDs from p-values, t or F values, confidence intervals, ranges or other statistics.

3.3 Last observation carried forward

We anticipated that in some studies the method of last observation carried forward (LOCF) would be employed within the study report. As with all methods of imputation to deal with missing data, LOCF introduces uncertainty about the reliability of the results (Leucht 2007). Therefore, where LOCF data have been used in the trial, if less than 50% of the data have been assumed, we would present and use these data and indicate that they are the product of LOCF assumptions.

Assessment of heterogeneity

1. Clinical heterogeneity

We considered all included studies initially, without seeing comparison data, to judge clinical heterogeneity. We inspected all studies for clearly outlying people or situations which we had not predicted would arise. When such situations or participant groups arose, we fully discussed these.

2. Methodological heterogeneity

We considered all included studies initially, without seeing comparison data, to judge methodological heterogeneity. We inspected all studies for clearly outlying methods which we had not predicted would arise. When such methodological outliers arose, we fully discussed these.

3. Statistical heterogeneity

3.1 Visual inspection

We visually inspected graphs to investigate the possibility of statistical heterogeneity.

3.2 Employing the I2 statistic

We investigated heterogeneity between studies by considering the I2 method alongside the Chi2 P value. The I2 provides an estimate of the percentage of inconsistency thought to be due to chance (Higgins 2003). The importance of the observed value of I2 depends on i) magnitude and direction of effects and ii) strength of evidence for heterogeneity (e.g. P value from Chi2 test, or a confidence interval for I2). I2 estimate greater than or equal to around 50% accompanied by a statistically significant Chi2 statistic was interpreted as evidence of substantial levels of heterogeneity (Higgins 2011). When substantial levels of heterogeneity were found in the primary outcome, we explored reasons for heterogeneity (Subgroup analysis and investigation of heterogeneity).

Assessment of reporting biases

Reporting biases arise when the dissemination of research findings is influenced by the nature and direction of results (Egger 1997). These are described in Section 10 of the Handbook (Higgins 2011). We are aware that funnel plots may be useful in investigating reporting biases but are of limited power to detect small-study effects. We did not plan to use funnel plots for outcomes where there were 10 or fewer studies, or where

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

all studies were of similar sizes. As no meta-analyses of more than five studies were undertaken, we did not conduct funnel plot analysis.

Data synthesis

Where RCTs are found to be methodologically or clinically comparable, we pooled trial results in a meta-analysis. Where we found the presence of statistical heterogeneity we combined the data using the random effects model.

For meta-analysis of RCTs, we combined the results and the relative risk and the 95% confidence intervals for dichotomous data. For continuous data, we combined the mean differences to calculate a weighted mean difference and standard deviation.

Subgroup analysis and investigation of heterogeneity

We will explore heterogeneity by conducting sub-group analyses between:

1. Type of substance dependence

2. Setting of treatment (e.g. inpatient versus outpatient)

Main results Results of the search The number of records retrieved from each database can be seen in the table below:

Database Number of records

PUBMED 1479

EMBASE 3614

PsychInfo 512

CINAHL 754

CENTRAL 84

Total 6443

FIGURE 1: FLOW DIAGRAM OF LITERATURE SEARCH

FULL TEXT OBTAINED

172

ELIGIBLE ARTICLES

SCREENED

5632

After electronic and manual deduplication using ENDNOTE software, we screened 5632 records of which 172 were identified as potentially eligible RCTs and 73 systematic reviews and the full texts for these were obtained – see Figure 1.

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

TABLE OF EVIDENCE QUESTIONS (PICO) BY NUMBER OF ARTICLES IDENTIFIED AND NUMBER OF RCTS

PICO Intervention Articles RCTs

1 Screening and brief intervention 17 10

2 Psychosocial interventions 30 15

3 Detoxification 0 0

4 Dependence management 36 4

5 Lactation 0 0

6 Management of infant withdrawal 5 4

Unclassified 5

Total 93 33

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Deeks J. Issues in the selection for meta-analyses of binary data. In: Abstracts of 8th International Cochrane Colloquium; 2000 Oct 25-28th; Cape Town, South Africa. 2000.

Divine GW, Brown JT, Frazer LM. The unit analysis error in studies about physicians' patient care behavior. Journal of General Internal Medicine 1992;7:623-9.

Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315(7109):629-34.

Furukawa TA, Barbui C, Cipriani A, Brambilla P, Watanabe N. Imputing missing standard deviations in meta-analyses can provide accurate results. Journal of Clinical Epidemiology 2006;59(7):7-10.

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011, Available from www.cochrane-handbook.org..

Leucht S, Engel RR, Bäuml J, Davis JM. Is the superior efficacy of new generation antipsychotics an artifact of LOCF? Schizophr Bull. 2007 Jan;33(1):183-91

Schünemann HJ, Oxman AD, Vist GE, Higgins JPT, Deeks J, Glasziou P, et al. Chapter 12: Interpreting results and drawing conclusions. In: Higgins JPT, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration, 2008:359-83.

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Guidelines for the identification and management of substance use and substance use disorders in pregnancy

PUBMED search strategy

Search Add to builder Query Items found

#9 Add Search (#5) AND #8 1476

#8 Add Search (#6) OR #7 1242301

#7 Add Search (((systematic review [ti] OR meta-analysis [pt] OR meta-analysis [ti] OR systematic literature review [ti] OR (systematic review [tiab] AND review [pt]) OR consensus development conference [pt] OR practice guideline [pt] OR cochrane database syst rev [ta] OR acp journal club [ta] OR health technol assess [ta] OR evid rep technol assess summ [ta] OR drug class reviews [ti]) OR (clinical guideline [tw] AND management [tw])OR ((evidence based[ti] OR evidence-based medicine [mh] OR best practice* [ti] OR evidence synthesis [tiab]) AND (review [pt] OR diseases category[mh] OR behavior and behavior mechanisms [mh] OR therapeutics [mh] OR evaluation studies[pt] OR validation studies[pt] OR guideline [pt] OR pmcbook)) OR ((systematic [tw] OR systematically [tw] OR critical [tiab] OR (study selection [tw]) OR (predetermined [tw] OR inclusion [tw] AND criteri* [tw]) OR exclusion criteri* [tw] OR main outcome measures [tw] OR standard of care [tw] OR standards of care [tw]) AND (survey [tiab] OR surveys [tiab] OR overview* [tw] OR review [tiab] OR reviews [tiab] OR search* [tw] OR handsearch [tw] OR analysis [tiab] OR critique [tiab] OR appraisal [tw] OR (reduction [tw]AND (risk [mh] OR risk [tw]) AND (death OR recurrence))) AND (literature [tiab] OR articles [tiab] OR publications [tiab] OR publication [tiab] OR bibliography [tiab] OR bibliographies [tiab] OR published [tiab] OR unpublished [tw] OR citation [tw] OR citations [tw] OR database [tiab] OR internet [tiab] OR textbooks [tiab] OR references [tw] OR scales [tw] OR papers [tw] OR datasets [tw] OR trials [tiab] OR meta-analy* [tw] OR (clinical [tiab] AND studies [tiab]) OR treatment outcome [mh] OR treatment outcome [tw] OR pmcbook))))

212906

#6 Add Search (((clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR "clinical trials as topic"[mesh: noexp] OR randomly [tiab] OR trial [tiab]) NOT (animals [mh] NOT humans [mh])))

1081782

#5 Add Search (#3) AND #4 18324

#4 Add Search (((pregnant women[mh] OR pregnancy[mh] OR pregnant[tiab] OR pregnancy[tiab] OR antenatal[tiab] OR ante-natal[tiab] OR prenatal[tiab] OR breast feeding[mh] OR breast feed*[tiab] OR breastfeed*[tiab] OR postnatal[tiab] OR post-natal[tiab] OR postpartum[tiab] OR postpartum period[mh] OR lactat*[tiab] OR maternal exposure[mh] OR maternal exposure*[tiab])))

942452

#3 Add Search (#1) OR #2 350542

#2 Add Search (((substance-related disorders[mh] OR prescription drug misuse[mh] OR street drugs[mh] OR street drugs[tiab] OR recreational drugs[tiab] OR illicit drugs[tiab] OR cocaine[tiab] OR designer drugs[mh] OR designer drugs[tiab] OR cannabis[mh] OR cannabis[tiab] OR marijuana*[tiab] OR hashish[tiab] OR bhang*[tiab] OR ganja*[tiab] OR hemp[tiab] OR heroin[mh] OR heroin[tiab] OR amphetamine[mh] OR amphetamine*[tiab] OR (drug[tiab] OR benzodiazepine [tiab] OR opioids[tiab] OR prescription[tiab] OR barbiturate[tiab] OR tramadol[tiab] OR oxycodone[tiab] OR substance[tiab]) AND (misuse[tiab] OR use[tiab] OR abuse[tiab] OR abuses[tiab] OR dependence[tiab] OR dependency[tiab] OR addiction[tiab] OR habituation[tiab] OR disorder*[tiab] OR consumption[tiab]))))

168206

#1 Add Search (((alcohol drinking[mh] OR alcoholism[mh] OR alcohol-related disorders[mh] OR fetal alcohol syndrome[mh] OR alcohol[tiab])))

227539

190

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

EmBase search strategy

# Searches Results

1 'drinking behavior'/exp OR 'drinking behaviour':ti,ab OR 'alcohol abstinence'/exp OR 'alcoholism'/exp OR 'alcohol':ti,ab OR alcoholic:ti,ab OR alcoholism:ti,ab OR 'fetal alcohol syndrome'/exp

306,329

2 'addiction'/exp OR 'substance-related disorders' OR 'substance-related disorder' OR 'chemical dependence' OR 'addictive behavior' OR 'addictive behaviour' OR 'addictive behaviors' OR 'addictive behaviours' OR 'drug misuse'/exp OR 'drug misuse' OR 'street drug'/exp OR 'street drugs' OR 'recreational drugs' OR 'recreational drug' OR 'illicit drugs' OR 'illicit drug' OR cocaine OR 'cannabis'/exp OR cannabis:ti,ab OR 'cannabis smoking'/exp OR marijuana*:ti,ab OR hashish:ti,ab OR bhang:ti,ab OR ‘ C indica’:ti,ab OR cannador*:ti,ab OR charas*:ti,ab OR ganja*:ti,ab OR ganjah*:ti,ab OR hemp*:ti,ab OR marihuana*:ti,ab OR heroin OR 'amphetamine'/exp OR amphetamine OR ‘actedron’ OR ‘ actemin’ OR ‘ adderall’ OR ‘ adderall ir’ OR ‘ adderall xr’ OR ‘ adipan’ OR ‘ aktedrin’ OR ‘ aktedron’ OR ‘ alentol’ OR ‘ allodene’ OR ‘ alpha amphetamine’ OR ‘ alpha methylphenethylamine’ OR ‘ alpha methylphenylethylamine’ OR ‘ amfetamine’ OR ‘ amphamed’ OR ‘ amphamine’ OR ‘ amphetaime’ OR ‘ amphetamin’ OR ‘ amphetamine base phosphate’ OR ‘ amphetamine base sulfate’ OR ‘ amphetamine detection’ OR ‘ amphetamine hydrochloride’ OR ‘ amphetamine intoxication’ OR ‘ amphetamine metabolism’ OR ‘ amphetamine phosphate’ OR ‘ amphetamine resin complex’ OR ‘ amphetamine sulfate’ OR ‘ amphetamine toxicity’ OR ‘ amphetaminyl’ OR ‘ amphethamine’ OR ‘ amphezamin’ OR ‘ anara’ OR ‘ astedin’ OR ‘ badrin’ OR ‘ benzafinyl’ OR ‘ benzebar’ OR ‘ benzedrine’ OR ‘ benzolone’ OR ‘ benzpropamin’ OR ‘ benzpropamine’ OR ‘ beta aminopropylbenzene’ OR ‘ beta phenyl isopropylamine’ OR ‘ beta phenylisopropylamine’ OR ‘ betafen’ OR ‘ bluzedrin’ OR ‘ centramina’ OR ‘ centramine’ OR ‘ d l amphetamine’ OR ‘ delta amphetamine’ OR ‘ desoxynorephedrin’ OR ‘ dextro levo 2 methylphenethylamine’ OR ‘ dextro levo 2 methylphenetylamine’ OR ‘ dextro levo alpha methylphenethylamine’ OR ‘ dextro levo amphetamine’ OR ‘ dextrolevo amphetamine’ OR ‘ diethamine’ OR ‘ diethanine’ OR ‘ dipan’ OR ‘ elastonin’ OR ‘ elastonon’ OR ‘ euphobine’ OR ‘ euphodine’ OR ‘ euphodyn’ OR ‘ fabedrine’ OR ‘ fenara’ OR ‘ fenedrin’ OR ‘ ibiozedrine’ OR ‘ isoamin’ OR ‘ isoamine’ OR ‘ isoamyn’ OR ‘ isoamyne’ OR ‘ isomyn’ OR ‘ l amphetamine’ OR ‘ levamfetamine’ OR ‘ levamphetamine’ OR ‘ levedrine’ OR ‘ levo amphetamine’ OR ‘ levo amphetamine sulphate’ OR ‘ levoamphetamine’ OR ‘ linampheta’ OR ‘ mecodrin’ OR ‘ mimetina’ OR ‘ monetamin’ OR ‘ monophos’ OR ‘ noclon’ OR ‘ norephedrane’ OR ‘ norphedrane’ OR ‘ novydrine’ OR ‘ obesin andromacro’ OR ‘ obetrol’ OR ‘ oktedrin’ OR ‘ oraldrina’ OR ‘ ortedrine’ OR ‘ percomon’ OR ‘ pharmamedrine’ OR ‘ pharmedrine’ OR ‘ phenamin’ OR ‘ phenedrine’ OR ‘ phenoprominum’ OR ‘ phenpromin’ OR ‘ phenyl isopropylamine’ OR ‘ phenylaminopropane’ OR ‘ profamina’ OR ‘ profetamine’ OR ‘ propisamine’ OR ‘ psychedrin’ OR ‘ psychedrine’ OR ‘ psychoton’ OR ‘ racemic desoxy nor ephedrine’ OR ‘ racemic desoxy norephedrine’ OR ‘ racephen’ OR ‘ raphetamine’ OR ‘ rhinalator’ OR ‘ sedolin’ OR ‘ simpamina’ OR ‘ simpamine’ OR ‘ simpatedrin’ OR ‘ simpatedrine’ OR ‘ stimulan’ OR ‘ sympametin’ OR ‘ sympamine’ OR ‘ sympatedrine’ OR ‘ theptine’ OR ‘ vapedrine’ OR ‘ zedrin’ OR ‘ zedrine’ OR (Drug:ti,ab OR 'sedative agent'/exp OR benzodiazepine OR ‘opiate’/exp OR opioids OR 'tramadol'/ exp OR ‘adamon’ OR ‘ amanda’ OR ‘ analab’ OR ‘ analdol’ OR ‘ andalpha’ OR ‘ bellatram’ OR ‘ biodalgic’ OR ‘ calmador’ OR ‘ calmol’ OR ‘ cg 315e’ OR ‘ cg315e’ OR ‘ contramal’ OR ‘ contramal lp’ OR ‘ dolana’ OR ‘ dolika’ OR ‘ dolmal’ OR ‘ dolotral’ OR ‘ dolzam’ OR ‘ dromadol’ OR ‘ e 381’ OR ‘ e 382’ OR ‘ e381’ OR ‘ e382’ OR ‘ eufindol’ OR ‘ exopen’ OR ‘ katrasic’ OR ‘ kontram xl’ OR ‘ kontram xl sr’ OR ‘ mabron’ OR ‘ melanate’ OR ‘ mosepan’ OR ‘ newdorphin’ OR ‘ nobligan’ OR ‘ nonalges’ OR ‘ o.p. pain’ OR ‘ omnidol’ OR ‘ pengesic’ OR ‘ penimadol’ OR ‘ prontofort’ OR ‘ radol’ OR ‘ rofy’ OR ‘ ryzolt’ OR ‘ sefmal’ OR ‘ sensitram’ OR ‘ takadol’ OR ‘ tamolan’ OR ‘ tandol’ OR ‘ tarol’ OR ‘ topalgic’ OR ‘ trabar’ OR ‘ trabilan’ OR ‘ trabilin’ OR ‘ tradol’ OR ‘ tradol-puren’ OR ‘ tradolan’ OR ‘ tradonal’ OR ‘ tralic’ OR ‘ tramada’ OR ‘ tramadex’ OR ‘ tramadol hydrochloride’ OR ‘ tramadolium chloride’ OR ‘ tramagetic’ OR ‘ tramagit’ OR ‘ tramahexal’ OR ‘ tramake’ OR ‘ tramal’ OR ‘ tramal sr’ OR ‘ tramazac’ OR ‘ tramed’ OR ‘ tramol’ OR ‘ tramundin’ OR ‘ tramundin retard’ OR ‘ trans 2 [(dimethylamino) methyl] 1 (3 methoxyphenyl) cyclohexanol’ OR ‘ trans 2 [(dimethylamino) methyl] 1 (meta methoxyphenyl) cyclohexanol hydrochloride’ OR ‘ trans 2 dimethylaminomethyl 1 (3 methoxyphenyl) cyclohexanol’ OR ‘ trasedal’ OR ‘ trasik’ OR ‘ trd-contin’ OR ‘ trexol’ OR ‘ tridol’ OR ‘ trodon’ OR ‘ trondon’ OR ‘ u 26225a’ OR ‘ u26225a’ OR ‘ ultram’ OR ‘ ultram er’ OR ‘ unitral’ OR ‘ urgendol’ OR ‘ zamadol’ OR ‘ zamudol’ OR ‘ zodol’ OR ‘ zumatran’ OR ‘ zydol’ OR ‘ zytram bd’ OR ‘ zytram xl sr’ OR 'oxycodone'/exp OR ‘bionine’ OR ‘ bionone’ OR ‘ bolodorm’ OR ‘ broncodal’ OR ‘ bucodal’ OR ‘ cafacodal’ OR ‘ cardanon’ OR ‘ codenon’ OR ‘ codix 5’ OR ‘ col 003’ OR ‘ col003’ OR ‘ dihydrohydroxycodeinone’ OR ‘ dihydrohydroxydodeinone’ OR ‘ dihydrone’ OR ‘ dinarkon’ OR ‘ endone’ OR ‘ eubine’

418,269

191

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

EmBase search strategy

# Searches Results

OR ‘ eucodal’ OR ‘ eucodale’ OR ‘ eucodalum’ OR ‘ eudin’ OR ‘ eukdin’ OR ‘ eukodal’ OR ‘ eumorphal’ OR ‘ eurodamine’ OR ‘ eutagen’ OR ‘ hydrocodal’ OR ‘ hydroxycodeinoma’ OR ‘ ludonal’ OR ‘ m-oxy’ OR ‘ medicodal’ OR ‘ narcobasina’ OR ‘ narcobasine’ OR ‘ narcosin’ OR ‘ nargenol’ OR ‘ narodal’ OR ‘ nsc 19043’ OR ‘ nucodan’ OR ‘ opton’ OR ‘ ossicodone’ OR ‘ oxanest’ OR ‘ oxecta’ OR ‘ oxicone’ OR ‘ oxicontin’ OR ‘ oxiconum’ OR ‘ oxikon’ OR ‘ oxy ir’ OR ‘ oxycod’ OR ‘ oxycodeinonhydrochloride’ OR ‘ oxycodone hydrochloride’ OR ‘ oxycodonhydrochlorid’ OR ‘ oxycodyl’ OR ‘ oxycone’ OR ‘ oxycontin’ OR ‘ oxycontin cr’ OR ‘ oxycontin lp’ OR ‘ oxydose’ OR ‘ oxyfast’ OR ‘ oxygesic’ OR ‘ oxyir’ OR ‘ oxykon’ OR ‘ oxynorm’ OR ‘ pancodine’ OR ‘ pavinal’ OR ‘ percolone’ OR ‘ pronarcin’ OR ‘ remoxy’ OR ‘ roxicodone’ OR ‘ roxycodone’ OR ‘ sinthiodal’ OR ‘ stupenal’ OR ‘ supeudol’ OR ‘ tebodal’ OR ‘ tekodin’ OR ‘ thecodin’ OR ‘substance’:ti,ab) AND (misuse:ti,ab OR use:ti,ab OR abuse:ti,ab OR dependence:ti,ab OR dependency:ti,ab OR addiction:ti,ab OR habituation:ti,ab OR disorder*:ti,ab OR consumption:ti,ab)

3 #1 AND #2 650,852

4 'pregnant woman'/exp OR 'pregnancy'/exp OR 'child bearing':ti,ab OR 'childbearing':ti,ab OR pregnant:ti,ab OR pregnancy:ti,ab OR 'breast feeding education'/exp OR 'breastfed':ti,ab OR breastfeed*:ti,ab OR breast NEXT/2 feed* OR 'puerperium'/exp OR 'postpartum':ti,ab OR postpartum:ti,ab OR 'ante natal':ti,ab OR prenatal:ti,ab OR postnatal:ti,ab OR 'postnatal':ti,ab OR lactat*:ti,ab OR 'prenatal drug exposure'/exp OR 'maternal exposure':ti,ab

990,027

5 #3 AND #4 29,732

6 'Clinical trial'/exp OR 'Randomized controlled trial'/exp OR 'Randomization'/exp OR 'Single blind procedure'/exp OR 'Double blind procedure'/exp OR 'Crossover procedure'/exp OR 'Placebo'/exp OR 'Randomized controlled trials':ti,ab OR 'Randomized controlled trial':ti,ab OR 'Randomized controlled trials':ti,ab OR 'Randomized controlled trial':ti,ab OR rct:ti,ab OR 'Random allocation':ti,ab OR 'Randomly allocated':ti,ab OR 'allocated randomly':ti,ab OR (allocated NEAR/2 random):ti,ab OR ('Single' NEAR/2 blind*):ti,ab OR ('double' NEAR/2 blind*):ti,ab OR ((treble or triple) NEAR/3 blind*):ti,ab OR Placebo*:ti,ab OR 'Prospective study'/exp

1,361,716

7 'systematic review'/exp OR 'systematic review (topic)'/exp OR 'review'/exp/mj OR 'medlars':ti,ab OR 'pubmed':ti,ab OR 'scisearch':ti,ab OR 'bibliographic database'/ exp OR 'psychlit':ti,ab OR 'psyclit’:ti,ab OR biosis:ti,ab OR ‘british nursing index’:ti,ab OR ‘cinahl’:ti,ab OR ‘cochrane library’:ti,ab OR ‘campbell library’:ti,ab OR ‘full text databases’:ti,ab OR ‘international pharmaceutical abstracts’:ti,ab OR toxlit:ti,ab OR 'electronic databases':ti,ab OR 'electronic database':ti,ab OR (hand NEAR/3 search*) OR (manual* NEAR/3 search*) OR (bibliographic NEAR/3 database*) OR (pooled NEAR/3 analys*) OR pooling OR peto OR sesimonian OR (fixed NEAR/3 effect) OR 'mantel haenszel':ti,ab OR 'meta analysis'/exp OR 'meta analysis' OR 'retracted article'/ exp OR 'retracted article' OR (systematic* NEAR/3 review*) OR (systematic* NEAR/5 overview*) OR (quantitative* NEAR/3 review*) OR (quantitative* NEAR/3 overview*) OR (methodologic* NEAR/3 review*) OR (methodologic* NEAR/5 overview*) OR (integrative NEAR/3 review*) OR (research NEAR/3 integration) OR (quantitative* NEAR/3 synthesi*) OR (systematic* NEAR/3 search*) OR medline:ti,ab OR embase:ti,ab

256,647

8 #6 OR #7 1,525,780

9 #5 AND #8 3614

192

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

PsychInfo search strategy

# Searches Results

1 (((DE "Alcohol Drinking Attitudes" OR DE "Alcohol Drinking Patterns" OR DE "Alcohol Abuse" OR DE "Alcohol Intoxication" OR DE "Social Drinking" OR DE "Alcohol Intoxication" OR DE "Acute Alcoholic Intoxication" OR DE "Chronic Alcoholic Intoxication" OR DE "Alcohol Rehabilitation" OR DE "Alcoholics Anonymous" OR DE "Detoxification" OR DE "Alcohol Withdrawal" OR DE "Alcoholic Beverages" OR DE "Beer" OR DE "Liquor" OR DE "Wine" OR DE "Alcoholism" OR DE "Alcoholic Psychosis" OR DE "Alcohols" OR DE "Ethanol" OR DE "Isoproterenol" OR DE "Methanol" OR DE "Methoxamine") AND (DE "Alcohol Withdrawal" OR DE "Alcoholism")) AND (DE "Fetal Alcohol Syndrome" OR DE "Prenatal Exposure")) OR (DE "Fetal Alcohol Syndrome") OR TI "alcohol drinking" OR TI alcoholism OR TI alcohol OR AB "alcohol drinking" OR AB alcoholism OR AB alcohol

83,667

2 (DE "Addiction" OR DE "Alcoholism" OR DE "Drug Addiction" ) AND (DE "Drug Abuse" OR DE "Drug Addiction" OR DE "Drug Dependency") OR TI "recreational drug*" OR TI "street drug*" OR TI "designer drug*" OR TI "illicit drug*" OR AB "recreational drug*" OR AB "street drug*" OR AB "designer drug*" OR AB "illicit drug*" OR DE "Heroin" OR DE "Heroin Addiction" OR DE "Cannabis" OR DE "Hashish" OR DE "Marijuana" OR DE "Amphetamine" OR DE "Dextroamphetamine" OR DE "Methamphetamine" OR 'addiction' OR 'substance- related disorders' OR 'substance-related disorder' OR 'chemical dependence' OR 'addictive behavior' OR 'addictive behaviour' OR 'addictive behaviors' OR 'addictive behaviours' OR 'drug misuse'/exp OR 'drug misuse' OR 'street drug’ OR 'street drugs' OR 'recreational drugs' OR 'recreational drug' OR 'illicit drugs' OR 'illicit drug' OR cocaine OR 'cannabis' OR cannabis OR 'cannabis smoking' OR marijuana* OR hashish OR TI bhang OR ‘ C indica’ OR cannador* OR charas* OR ganja* OR ganjah* OR hemp* OR marihuana* OR heroin OR 'amphetamine' OR amphetamine OR ‘actedron’ OR ‘ actemin’ OR ‘ adderall’ OR ‘ adderall ir’ OR ‘ adderall xr’ OR ‘ adipan’ OR ‘ aktedrin’ OR ‘ aktedron’ OR ‘ alentol’ OR ‘ allodene’ OR ‘ alpha amphetamine’ OR ‘ alpha methylphenethylamine’ OR ‘ alpha methylphenylethylamine’ OR ‘ amfetamine’ OR ‘ amphamed’ OR ‘ amphamine’ OR ‘ amphetaime’ OR ‘ amphetamin’ OR ‘ amphetamine base phosphate’ OR ‘ amphetamine base sulfate’ OR ‘ amphetamine detection’ OR ‘ amphetamine hydrochloride’ OR ‘ amphetamine intoxication’ OR ‘ amphetamine metabolism’ OR ‘ amphetamine phosphate’ OR ‘ amphetamine resin complex’ OR ‘ amphetamine sulfate’ OR ‘ amphetamine toxicity’ OR ‘ amphetaminyl’ OR ‘ amphethamine’ OR ‘ amphezamin’ OR ‘ anara’ OR ‘ astedin’ OR ‘ badrin’ OR ‘ benzafinyl’ OR ‘ benzebar’ OR ‘ benzedrine’ OR ‘ benzolone’ OR ‘ benzpropamin’ OR ‘ benzpropamine’ OR ‘ beta aminopropylbenzene’ OR ‘ beta phenyl isopropylamine’ OR ‘ beta phenylisopropylamine’ OR ‘ betafen’ OR ‘ bluzedrin’ OR ‘ centramina’ OR ‘ centramine’ OR ‘ d l amphetamine’ OR ‘ delta amphetamine’ OR ‘ desoxynorephedrin’ OR ‘ dextro levo 2 methylphenethylamine’ OR ‘ dextro levo 2 methylphenetylamine’ OR ‘ dextro levo alpha methylphenethylamine’ OR ‘ dextro levo amphetamine’ OR ‘ dextrolevo amphetamine’ OR ‘ diethamine’ OR ‘ diethanine’ OR ‘ dipan’ OR ‘ elastonin’ OR ‘ elastonon’ OR ‘ euphobine’ OR ‘ euphodine’ OR ‘ euphodyn’ OR ‘ fabedrine’ OR ‘ fenara’ OR ‘ fenedrin’ OR ‘ ibiozedrine’ OR ‘ isoamin’ OR ‘ isoamine’ OR ‘ isoamyn’ OR ‘ isoamyne’ OR ‘ isomyn’ OR ‘ l amphetamine’ OR ‘ levamfetamine’ OR ‘ levamphetamine’ OR ‘ levedrine’ OR ‘ levo amphetamine’ OR ‘ levo amphetamine sulphate’ OR ‘ levoamphetamine’ OR ‘ linampheta’ OR ‘ mecodrin’ OR ‘ mimetina’ OR ‘ monetamin’ OR ‘ monophos’ OR ‘ noclon’ OR ‘ norephedrane’ OR ‘ norphedrane’ OR ‘ novydrine’ OR ‘ obesin andromacro’ OR ‘ obetrol’ OR ‘ oktedrin’ OR ‘ oraldrina’ OR ‘ ortedrine’ OR ‘ percomon’ OR ‘ pharmamedrine’ OR ‘ pharmedrine’ OR ‘ phenamin’ OR ‘ phenedrine’ OR ‘ phenoprominum’ OR ‘ phenpromin’ OR ‘ phenyl isopropylamine’ OR ‘ phenylaminopropane’ OR ‘ profamina’ OR ‘ profetamine’ OR ‘ propisamine’ OR ‘ psychedrin’ OR ‘ psychedrine’ OR ‘ psychoton’ OR ‘ racemic desoxy nor ephedrine’ OR ‘ racemic desoxy norephedrine’ OR ‘ racephen’ OR ‘ raphetamine’ OR ‘ rhinalator’ OR ‘ sedolin’ OR ‘ simpamina’ OR ‘ simpamine’ OR ‘ simpatedrin’ OR ‘ simpatedrine’ OR ‘ stimulan’ OR ‘ sympametin’ OR ‘ sympamine’ OR ‘ sympatedrine’ OR ‘ theptine’ OR ‘ vapedrine’ OR ‘ zedrin’ OR ‘ zedrine’ OR (TI Drugs OR AB Drugs OR benzodiazepine OR ‘opiate’ OR opioids OR 'tramadol' OR ‘adamon’ OR ‘ amanda’ OR ‘ analab’ OR ‘ analdol’ OR ‘ andalpha’ OR ‘ bellatram’ OR ‘ biodalgic’ OR ‘ calmador’ OR ‘ calmol’ OR ‘ cg 315e’ OR ‘ cg315e’ OR ‘ contramal’ OR ‘ contramal lp’ OR ‘ dolana’ OR ‘ dolika’ OR ‘ dolmal’ OR ‘ dolotral’ OR ‘ dolzam’ OR ‘ dromadol’ OR ‘ e 381’ OR ‘ e 382’ OR ‘ e381’ OR ‘ e382’ OR ‘ eufindol’ OR ‘ exopen’ OR ‘ katrasic’ OR ‘ kontram xl’ OR ‘ kontram xl sr’ OR ‘ mabron’ OR ‘ melanate’ OR ‘ mosepan’ OR ‘ newdorphin’ OR ‘ nobligan’ OR ‘ nonalges’ OR ‘ o.p. pain’ OR ‘ omnidol’ OR ‘ pengesic’ OR ‘ penimadol’ OR ‘ prontofort’ OR ‘ radol’ OR ‘ rofy’ OR ‘ ryzolt’ OR ‘ sefmal’ OR ‘ sensitram’ OR ‘ takadol’ OR ‘ tamolan’ OR ‘ tandol’ OR ‘ tarol’ OR ‘ topalgic’ OR ‘ trabar’ OR ‘ trabilan’ OR ‘ trabilin’ OR ‘ tradol’ OR ‘ tradol-puren’ OR ‘ tradolan’ OR ‘ tradonal’ OR ‘ tralic’ OR ‘ tramada’ OR ‘ tramadex’ OR

170,118

193

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

PsychInfo search strategy

# Searches Results

‘ tramadol hydrochloride’ OR ‘ tramadolium chloride’ OR ‘ tramagetic’ OR ‘ tramagit’ OR ‘ tramahexal’ OR ‘ tramake’ OR ‘ tramal’ OR ‘ tramal sr’ OR ‘ tramazac’ OR ‘ tramed’ OR ‘ tramol’ OR ‘ tramundin’ OR ‘ tramundin retard’ OR ‘ trasedal’ OR ‘ trasik’ OR ‘ trd-contin’ OR ‘ trexol’ OR ‘ tridol’ OR ‘ trodon’ OR ‘ trondon’ OR ‘ u 26225a’ OR ‘ u26225a’ OR ‘ ultram’ OR ‘ ultram er’ OR ‘ unitral’ OR ‘ urgendol’ OR ‘ zamadol’ OR ‘ zamudol’ OR ‘ zodol’ OR ‘ zumatran’ OR ‘ zydol’ OR ‘ zytram bd’ OR ‘ zytram xl sr’ OR 'oxycodone' OR ‘bionine’ OR ‘ bionone’ OR ‘ bolodorm’ OR ‘ broncodal’ OR ‘ bucodal’ OR ‘ cafacodal’ OR ‘ cardanon’ OR ‘ codenon’ OR ‘ codix 5’ OR ‘ col 003’ OR ‘ col003’ OR ‘ dihydrohydroxycodeinone’ OR ‘ dihydrohydroxydodeinone’ OR ‘ dihydrone’ OR ‘ dinarkon’ OR ‘ endone’ OR ‘ eubine’ OR ‘ eucodal’ OR ‘ eucodale’ OR ‘ eucodalum’ OR ‘ eudin’ OR ‘ eukdin’ OR ‘ eukodal’ OR ‘ eumorphal’ OR ‘ eurodamine’ OR ‘ eutagen’ OR ‘ hydrocodal’ OR ‘ hydroxycodeinoma’ OR ‘ ludonal’ OR ‘ m-oxy’ OR ‘ medicodal’ OR ‘ narcobasina’ OR ‘ narcobasine’ OR ‘ narcosin’ OR ‘ nargenol’ OR ‘ narodal’ OR ‘ nsc 19043’ OR ‘ nucodan’ OR ‘ opton’ OR ‘ ossicodone’ OR ‘ oxanest’ OR ‘ oxecta’ OR ‘ oxicone’ OR ‘ oxicontin’ OR ‘ oxiconum’ OR ‘ oxikon’ OR ‘ oxy ir’ OR ‘ oxycod’ OR ‘ oxycodeinonhydrochloride’ OR ‘ oxycodone hydrochloride’ OR ‘ oxycodonhydrochlorid’ OR ‘ oxycodyl’ OR ‘ oxycone’ OR ‘ oxycontin’ OR ‘ oxycontin cr’ OR ‘ oxycontin lp’ OR ‘ oxydose’ OR ‘ oxyfast’ OR ‘ oxygesic’ OR ‘ oxyir’ OR ‘ oxykon’ OR ‘ oxynorm’ OR ‘ pancodine’ OR ‘ pavinal’ OR ‘ percolone’ OR ‘ pronarcin’ OR ‘ remoxy’ OR ‘ roxicodone’ OR ‘ roxycodone’ OR ‘ sinthiodal’ OR ‘ stupenal’ OR ‘ supeudol’ OR ‘ tebodal’ OR ‘ tekodin’ OR ‘ thecodin’ OR ‘substance’:ti,ab) AND (TI misuse OR AB misuse OR TI use OR AB use OR TI abuse OR AB abuse OR TI dependence OR AB dependence OR TI dependency OR AB dependency OR TI addiction OR AB addiction OR TI habituation OR AB habituation OR TI disorder* OR AB disorder* OR TI consumption OR AB consumption)

3 #1 AND #2 207,330

4 DE "Pregnancy" OR DE "Adolescent Pregnancy" OR DE "Pregnancy Outcomes" OR DE "Birth" OR DE "Induced Abortion" OR DE "Premature Birth" OR DE "Spontaneous Abortion" OR DE "Prenatal Care" OR DE "Childbirth Training" OR DE "Prenatal Development" OR DE "Prenatal Developmental Stages" OR DE "Prenatal Developmental Stages" OR DE "Embryo" OR DE "Fetus" OR DE "Prenatal Exposure" OR TI Pregnancy OR AB Pregnancy OR TI pregnant OR AB Pregnant OR DE "Postnatal Period" OR DE "Perinatal Period" OR DE "Prenatal Care" OR DE "Prenatal Development" OR DE "Prenatal Developmental Stages" OR DE "Prenatal Exposure" OR DE "Prenatal Care" OR DE "Childbirth Training" OR DE "Prenatal Development" OR DE "Prenatal Developmental Stages" OR DE "Prenatal Developmental Stages" OR DE "Prenatal Exposure" OR TI postpartum OR AB postpartum OR TI postnatal OR AB Postnatal OR TI perinatal OR AB perinatal OR TI postpartum OR AB postpartum OR "maternal exposure" OR TI lactat* OR AB lactat*

63,174

5 #3 AND #4 7,796

6 (((DE "Placebo") OR (DE "Clinical Trials")) OR (DE "Evidence Based Practice" OR DE "Treatment Effectiveness Evaluation")) OR (DE "Random Sampling") OR TX allocat* random* OR TX placebo* OR TX random* allocate* OR TX randomi* control* trial* OR TX ( (singl* n1 blind*) or (singl* n1 mask*) ) or TX ( (doubl* n1 blind*) or (doubl* n1 mask*) ) or TX ( (tripl* n1 blind*) or (tripl* n1 mask*) ) or TX ( (trebl* n1 blind*) or (trebl* n1 mask*) ) OR TX clinic* n1 trial*

92,996

7 (MH "Meta Analysis") OR "meta analysis" OR (MH "Literature Review+") OR "literature review" OR (MH "Systematic Review") OR "meta analys*" OR metaanalys* OR (Systematic AND (review OR overview)) OR TI medlars OR AB medlars OR TI pubmed OR AB pubmed OR TI scisearch OR AB scisearch OR TI “british nursing index” OR AB “british nursing index” OR “Cochrane library” OR “Campbell library” OR “full text databases “ OR “electronic databases” OR handsearching OR systematic n3 literature OR systematic review* OR meta-analy* OR metaanaly* OR "research synthesis" OR embase OR medline OR psyclit OR pubmed OR scopus OR "sociological abstracts" OR "web of science" OR "systematic review" or "meta analysis"

66,904

8 #6 OR #7 152,807

9 #5 AND #8 512

194

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

CINAHL search strategy

# Searches Results

1 "alcohol drinking" OR (MH "Drinking Behavior+") OR (MH "Alcohol Rehabilitation Programs+") OR (MH "Alcohol Withdrawal Syndrome+") OR (MH "Alcohol-Induced Disorders, Nervous System+") OR (MH "Alcohol-Related Disorders") OR (MH "Substance Abuse+") OR (MH "Alcohol Abuse Control (Saba CCC)") OR (MH "Alcohol Abuse (Saba CCC)") OR (MH "Alcohol Deterrents+") OR (MH "Alcoholism") OR (MH "Substance Use Treatment: Alcohol Withdrawal (Iowa NIC)") OR (MH "Alcoholics") OR (MH "Fetal Alcohol Syndrome") OR (MH "Substance Abuse Detection") OR TI "alcohol drinking" OR TI alcoholism OR TI alcohol OR AB "alcohol drinking" OR AB alcoholism OR AB alcohol

65,704

2 (MH "Addictions Nursing") OR (MH "Infant, Drug-Exposed") OR (MH "Substance Addiction Consequences (Iowa NOC)") OR (MH "Analgesics, Opioid+") OR (MH "Substance Dependence+") OR (MH "Street Drugs") OR "illicit drugs" OR (MH "Substance Abuse Detection") OR (MH "Substance Abusers") OR (MH "Drug Abuse (Saba CCC)") OR (MH "Drug Abuse Control (Saba CCC)") OR (MH "Designer Drugs") OR (MH "Cannabis") OR (MH "Cocaine+") OR "cocaine" OR (MH "Heroin") OR (MH "Amphetamine") OR (MH "Albuterol") OR 'addiction' OR 'substance-related disorders' OR 'substance-related disorder' OR 'chemical dependence' OR 'addictive behavior' OR 'addictive behaviour' OR 'addictive behaviors' OR 'addictive behaviours' OR 'drug misuse'/exp OR 'drug misuse' OR 'street drug’ OR 'street drugs' OR 'recreational drugs' OR 'recreational drug' OR 'illicit drugs' OR 'illicit drug' OR cocaine OR 'cannabis' OR cannabis OR 'cannabis smoking' OR marijuana* OR hashish OR TI bhang OR ‘ C indica’ OR cannador* OR charas* OR ganja* OR ganjah* OR hemp* OR marihuana* OR heroin OR 'amphetamine' OR amphetamine OR ‘actedron’ OR ‘ actemin’ OR ‘ adderall’ OR ‘ adderall ir’ OR ‘ adderall xr’ OR ‘ adipan’ OR ‘ aktedrin’ OR ‘ aktedron’ OR ‘ alentol’ OR ‘ allodene’ OR ‘ alpha amphetamine’ OR ‘ alpha methylphenethylamine’ OR ‘ alpha methylphenylethylamine’ OR ‘ amfetamine’ OR ‘ amphamed’ OR ‘ amphamine’ OR ‘ amphetaime’ OR ‘ amphetamin’ OR ‘ amphetamine base phosphate’ OR ‘ amphetamine base sulfate’ OR ‘ amphetamine detection’ OR ‘ amphetamine hydrochloride’ OR ‘ amphetamine intoxication’ OR ‘ amphetamine metabolism’ OR ‘ amphetamine phosphate’ OR ‘ amphetamine resin complex’ OR ‘ amphetamine sulfate’ OR ‘ amphetamine toxicity’ OR ‘ amphetaminyl’ OR ‘ amphethamine’ OR ‘ amphezamin’ OR ‘ anara’ OR ‘ astedin’ OR ‘ badrin’ OR ‘ benzafinyl’ OR ‘ benzebar’ OR ‘ benzedrine’ OR ‘ benzolone’ OR ‘ benzpropamin’ OR ‘ benzpropamine’ OR ‘ beta aminopropylbenzene’ OR ‘ beta phenyl isopropylamine’ OR ‘ beta phenylisopropylamine’ OR ‘ betafen’ OR ‘ bluzedrin’ OR ‘ centramina’ OR ‘ centramine’ OR ‘ d l amphetamine’ OR ‘ delta amphetamine’ OR ‘ desoxynorephedrin’ OR ‘ dextro levo 2 methylphenethylamine’ OR ‘ dextro levo 2 methylphenetylamine’ OR ‘ dextro levo alpha methylphenethylamine’ OR ‘ dextro levo amphetamine’ OR ‘ dextrolevo amphetamine’ OR ‘ diethamine’ OR ‘ diethanine’ OR ‘ dipan’ OR ‘ elastonin’ OR ‘ elastonon’ OR ‘ euphobine’ OR ‘ euphodine’ OR ‘ euphodyn’ OR ‘ fabedrine’ OR ‘ fenara’ OR ‘ fenedrin’ OR ‘ ibiozedrine’ OR ‘ isoamin’ OR ‘ isoamine’ OR ‘ isoamyn’ OR ‘ isoamyne’ OR ‘ isomyn’ OR ‘ l amphetamine’ OR ‘ levamfetamine’ OR ‘ levamphetamine’ OR ‘ levedrine’ OR ‘ levo amphetamine’ OR ‘ levo amphetamine sulphate’ OR ‘ levoamphetamine’ OR ‘ linampheta’ OR ‘ mecodrin’ OR ‘ mimetina’ OR ‘ monetamin’ OR ‘ monophos’ OR ‘ noclon’ OR ‘ norephedrane’ OR ‘ norphedrane’ OR ‘ novydrine’ OR ‘ obesin andromacro’ OR ‘ obetrol’ OR ‘ oktedrin’ OR ‘ oraldrina’ OR ‘ ortedrine’ OR ‘ percomon’ OR ‘ pharmamedrine’ OR ‘ pharmedrine’ OR ‘ phenamin’ OR ‘ phenedrine’ OR ‘ phenoprominum’ OR ‘ phenpromin’ OR ‘ phenyl isopropylamine’ OR ‘ phenylaminopropane’ OR ‘ profamina’ OR ‘ profetamine’ OR ‘ propisamine’ OR ‘ psychedrin’ OR ‘ psychedrine’ OR ‘ psychoton’ OR ‘ racemic desoxy nor ephedrine’ OR ‘ racemic desoxy norephedrine’ OR ‘ racephen’ OR ‘ raphetamine’ OR ‘ rhinalator’ OR ‘ sedolin’ OR ‘ simpamina’ OR ‘ simpamine’ OR ‘ simpatedrin’ OR ‘ simpatedrine’ OR ‘ stimulan’ OR ‘ sympametin’ OR ‘ sympamine’ OR ‘ sympatedrine’ OR ‘ theptine’ OR ‘ vapedrine’ OR ‘ zedrin’ OR ‘ zedrine’ OR (TI Drugs OR AB Drugs OR benzodiazepine OR ‘opiate’ OR opioids OR 'tramadol' OR ‘adamon’ OR ‘ amanda’ OR ‘ analab’ OR ‘ analdol’ OR ‘ andalpha’ OR ‘ bellatram’ OR ‘ biodalgic’ OR ‘ calmador’ OR ‘ calmol’ OR ‘ cg 315e’ OR ‘ cg315e’ OR ‘ contramal’ OR ‘ contramal lp’ OR ‘ dolana’ OR ‘ dolika’ OR ‘ dolmal’ OR ‘ dolotral’ OR ‘ dolzam’ OR ‘ dromadol’ OR ‘ e 381’ OR ‘ e 382’ OR ‘ e381’ OR ‘ e382’ OR ‘ eufindol’ OR ‘ exopen’ OR ‘ katrasic’ OR ‘ kontram xl’ OR ‘ kontram xl sr’ OR ‘ mabron’ OR ‘ melanate’ OR ‘ mosepan’ OR ‘ newdorphin’ OR ‘ nobligan’ OR ‘ nonalges’ OR ‘ o.p. pain’ OR ‘ omnidol’ OR ‘ pengesic’ OR ‘ penimadol’ OR ‘ prontofort’ OR ‘ radol’ OR ‘ rofy’ OR ‘ ryzolt’ OR ‘ sefmal’ OR ‘ sensitram’ OR ‘ takadol’ OR ‘ tamolan’ OR ‘ tandol’ OR ‘ tarol’ OR ‘ topalgic’ OR ‘ trabar’ OR ‘ trabilan’ OR ‘ trabilin’ OR ‘ tradol’ OR ‘ tradol-puren’ OR ‘ tradolan’ OR ‘ tradonal’ OR ‘ tralic’ OR ‘ tramada’ OR ‘ tramadex’ OR ‘ tramadol hydrochloride’ OR ‘ tramadolium chloride’ OR ‘ tramagetic’ OR ‘ tramagit’ OR

105,036

195

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

CINAHL search strategy

# Searches Results

‘ tramahexal’ OR ‘ tramake’ OR ‘ tramal’ OR ‘ tramal sr’ OR ‘ tramazac’ OR ‘ tramed’ OR ‘ tramol’ OR ‘ tramundin’ OR ‘ tramundin retard’ OR ‘ trasedal’ OR ‘ trasik’ OR ‘ trd-contin’ OR ‘ trexol’ OR ‘ tridol’ OR ‘ trodon’ OR ‘ trondon’ OR ‘ u 26225a’ OR ‘ u26225a’ OR ‘ ultram’ OR ‘ ultram er’ OR ‘ unitral’ OR ‘ urgendol’ OR ‘ zamadol’ OR ‘ zamudol’ OR ‘ zodol’ OR ‘ zumatran’ OR ‘ zydol’ OR ‘ zytram bd’ OR ‘ zytram xl sr’ OR 'oxycodone' OR ‘bionine’ OR ‘ bionone’ OR ‘ bolodorm’ OR ‘ broncodal’ OR ‘ bucodal’ OR ‘ cafacodal’ OR ‘ cardanon’ OR ‘ codenon’ OR ‘ codix 5’ OR ‘ col 003’ OR ‘ col003’ OR ‘ dihydrohydroxycodeinone’ OR ‘ dihydrohydroxydodeinone’ OR ‘ dihydrone’ OR ‘ dinarkon’ OR ‘ endone’ OR ‘ eubine’ OR ‘ eucodal’ OR ‘ eucodale’ OR ‘ eucodalum’ OR ‘ eudin’ OR ‘ eukdin’ OR ‘ eukodal’ OR ‘ eumorphal’ OR ‘ eurodamine’ OR ‘ eutagen’ OR ‘ hydrocodal’ OR ‘ hydroxycodeinoma’ OR ‘ ludonal’ OR ‘ m-oxy’ OR ‘ medicodal’ OR ‘ narcobasina’ OR ‘ narcobasine’ OR ‘ narcosin’ OR ‘ nargenol’ OR ‘ narodal’ OR ‘ nsc 19043’ OR ‘ nucodan’ OR ‘ opton’ OR ‘ ossicodone’ OR ‘ oxanest’ OR ‘ oxecta’ OR ‘ oxicone’ OR ‘ oxicontin’ OR ‘ oxiconum’ OR ‘ oxikon’ OR ‘ oxy ir’ OR ‘ oxycod’ OR ‘ oxycodeinonhydrochloride’ OR ‘ oxycodone hydrochloride’ OR ‘ oxycodonhydrochlorid’ OR ‘ oxycodyl’ OR ‘ oxycone’ OR ‘ oxycontin’ OR ‘ oxycontin cr’ OR ‘ oxycontin lp’ OR ‘ oxydose’ OR ‘ oxyfast’ OR ‘ oxygesic’ OR ‘ oxyir’ OR ‘ oxykon’ OR ‘ oxynorm’ OR ‘ pancodine’ OR ‘ pavinal’ OR ‘ percolone’ OR ‘ pronarcin’ OR ‘ remoxy’ OR ‘ roxicodone’ OR ‘ roxycodone’ OR ‘ sinthiodal’ OR ‘ stupenal’ OR ‘ supeudol’ OR ‘ tebodal’ OR ‘ tekodin’ OR ‘ thecodin’ OR ‘substance’:ti,ab) AND (TI misuse OR AB misuse OR TI use OR AB use OR TI abuse OR AB abuse OR TI dependence OR AB dependence OR TI dependency OR AB dependency OR TI addiction OR AB addiction OR TI habituation OR AB habituation OR TI disorder* OR AB disorder* OR TI consumption OR AB consumption)

3 #1 AND #2 105,036

4 (MH "Expectant Mothers") OR "pregnant women" OR "pregnant woman" OR (MH "Pregnancy+") OR (MH "Pregnancy in Adolescence+") OR (MH "Attitude to Pregnancy") OR (MH "Prenatal Exposure Delayed Effects") OR (MH "Pregnancy, Unwanted") OR (MH "Pregnancy, Unplanned") OR (MH "Pregnancy Trimesters") OR (MH "Pregnancy, Multiple") OR (MH "Breast Feeding+") OR (MH "Knowledge: Breastfeeding (Iowa NOC)") OR (MH "Breastfeeding Impairment (Saba CCC)") OR (MH "Attitude to Breast Feeding") OR (MH "Breast Feeding Promotion") OR (MH "Perinatal Care") OR (MH "Postnatal Care+") OR (MH "Intrapartum Care+") OR (MH "Prenatal Care") OR (MH "Prepregnancy Care") OR (MH "Postpartum Care (Saba CCC)") OR (MH "Postpartum (Omaha)") OR (MH "Maternal Exposure") OR "maternal exposure" OR (MH "Maternal Behavior") OR (MH "Maternal Attitudes") OR (MH "Postexposure Follow-Up") OR (MH "Substance Abuse, Perinatal")

131,778

5 #3 AND #4 5,985

6 TX allocat* random* OR (MH "Quantitative Studies") OR (MH "Placebos") OR TX placebo* OR TX random* allocate* OR (MH "Random Assignment") OR TX randomi* control* trial* OR TX ( (singl* n1 blind*) or (singl* n1 mask*) ) or TX ( (doubl* n1 blind*) or (doubl* n1 mask*) ) or TX ( (tripl* n1 blind*) or (tripl* n1 mask*) ) or TX ( (trebl* n1 blind*) or (trebl* n1 mask*) ) OR TX clinic* n1 trial* OR PT Clinical trial OR (MH “Clinical trial+”)

70,555

7 (MH "Meta Analysis") OR "meta analysis" OR (MH "Literature Review+") OR "literature review" OR (MH "Systematic Review") OR "meta analys*" OR metaanalys* OR (Systematic AND (review OR overview)) OR TI medlars OR AB medlars OR TI pubmed OR AB pubmed OR TI scisearch OR AB scisearch OR TI psychlit OR AB psychlit OR TI psycINFO OR AB psycINFO OR TI “british nursing index” OR AB “british nursing index” OR “Cochrane library” OR “Campbell library” OR “full text databases “ OR “electronic databases” OR handsearching

211,972

8 #6 OR #7 211,972

9 #5 AND #8 754

196

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

CENTRAL search strategy

ID Search Hits

#1 MeSH descriptor: [Alcohol Drinking] explode all trees 2140

#2 MeSH descriptor: [Alcohol-Related Disorders] explode all trees 3234

#3 MeSH descriptor: [Alcoholism] this term only 2215

#4 MeSH descriptor: [Fetal Alcohol Syndrome] explode all trees 33

#5 alcohol:ti,ab 8351

#6 #1 or #2 or #3 or #4 or #5 9549

#7 MeSH descriptor: [Substance-Related Disorders] explode all trees 10670

#8 MeSH descriptor: [Prescription Drug Misuse] explode all trees 7

#9 MeSH descriptor: [Street Drugs] explode all trees 203

#10 MeSH descriptor: [Designer Drugs] explode all trees 5

#11 MeSH descriptor: [Cannabis] explode all trees 247

#12 MeSH descriptor: [Heroin] explode all trees 240

#13 MeSH descriptor: [Amphetamines] explode all trees 1039

#14 street drugs:ti,ab or "recreational drugs":ti,ab or "illicit drugs":ti,ab or cocaine:ti,ab or designer drugs:ti,ab or cannabis:ti,ab or marijuana*:ti,ab or hashish:ti,ab or bhang*:ti,ab or ganja*:ti,ab or hemp:ti,ab or heroin:ti,ab or amphetamine*:ti,ab (Word variations have been searched)

4251

#15 (drug or benzodiazepine or opioids or prescription or barbiturate or tramadol or oxycodone or substance):ti,ab next/6 (misuse or use or abuse or abuses or dependence or dependency or addiction or habituation or disorder or consumption):ab,ti (Word variations have been searched)

9715

#16 #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 20886

#17 MeSH descriptor: [Pregnant Women] explode all trees 74

#18 MeSH descriptor: [Pregnancy] explode all trees 5318

#19 MeSH descriptor: [Breast Feeding] explode all trees 1154

#20 MeSH descriptor: [Postpartum Period] explode all trees 957

#21 MeSH descriptor: [Maternal Exposure] explode all trees 27

#22 pregnant:ti,ab or pregnancy:ti,ab or antenatal:ti,ab or ante-natal:ti,ab or prenatal:ti,ab or "breast feed*":ti,ab or breastfeed*:ti,ab or postnatal:ti,ab or post-natal:ti,ab or postpartum:ti,ab or lactat*:ti,ab or "maternal exposure*":ti,ab (Word variations have been searched)

22381

#23 #17 or #18 or #19 or #20 or #21 or #22 24867

#24 #6 and #16 and #23 in Trials 84

197

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

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199

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

200

ANNEX 4: COMPOSITION OF GUIDELINE GROUPS

WHO Steering Group

Name WHO Department

Avni Amin Reproductive Health and Research

Lubna Bhatti Tobacco Free Initiative

Nicolas Clark Mental Health and Substance Abuse

Ahmet Metin Gulmezoglu Reproductive Health and Research

Rajat Khosla Gender Equity and Human Rights

Mathews Mathai Maternal and Child Health

Mario Merialdi Reproductive Health and Research

Vladimir Poznyak Mental Health and Substance Abuse

Shekhar Saxena Mental Health and Substance Abuse

Edouard Tursan d’Espaignet Tobacco Free Initiative

200

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

N am

F/ M

A FF

IL IA

TI O

N O

R IG

IN (W

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201

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

Name Gender Affiliation Country of residence WHO Region

Steve Allsop Male Professor, Director National Drug Research Institute Curtin University

Australia WPRO

Espen Ajo Arnevik Male Head of National resource centre for addiction treatment Oslo University

Norway EURO

Matthew Chersich Male Associate Professor Centre for Health Policy, School of Public Health University of Witwatersrand

South Africa AFRO

Andreea Creangea Female US Centers for Disease Control and Prevention, Atlanta United States of America

AMRO

Marica Ferri Female Head of sector — Best practice, knowledge exchange and economic issues European Monitoring Centre for Drugs and Drug Addiction (EMCDDA)

United States of America

AMRO

David A. Fiellin Male Professor of Medicine, Investigative Medicine and Public Health Yale University School of Medicine

Portugal EURO

Louise Floyd Female US Centers for Disease Control and Prevention, Atlanta United States of America

AMRO

Chris Howson Male March of Dimes United States of America

AMRO

Irma Kirtadze Female Sr. Researcher Alternative Georgia Addiction Research Center Tbilisi

Georgia EURO

Yukiko Kusano Female Consultant, Nursing & Health Policy International Council of Nurses, Geneva

Switzerland EURO

Andre B. Lalonde Male Professor Of Obstetrics and Gynaecology, University of Ottawa, McGill

Canada AMRO

Carla Marienfeld- Calderon

Female Assistant Professor of Psychiatry, Yale University School of Medicine Course Director and Council Chair, Yale Global Mental Health Program, New Haven

United States of America

AMRO

Nester Moyo Female International Federation of Midwives Kenya AFRO

Michael Farrell Male Director National Drug and Alcohol Research Centre University of New South Wales

Australia WPRO

Dzianis Padruchny Male Information and Training Centre of Belarusian Psychiatric Association

Belarus EURO

Svetlana Popova Female Senior Scientist Social and Epidemiological Research, Centre for Addiction and Mental Health Assistant Professor, Epidemiology Division, Dalla Lana School of Public Health, University of Toronto

Canada AMRO

Roland Simon Male Head of unit — Interventions, best practice and scientific partners European Monitoring Centre for Drugs and Drug Addiction (EMCDDA)

Portugal EURO

Anna Woods Female Senior Consultant Eastern DASSA 92 Osmond Tce Norwood SA

Australia WPRO

External reviewers

202

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

203

ANNEX 5: DECLARATIONS OF INTEREST

Guidelines development group members

Name Current affiliation Competing interest declared?

Nature of declared competing interest (as expressed in declaration of interest form)

Sawitri Assanangkornchai

Prince of Songkla University

None

Guilherme Borges Instituto Nacional de Psiquiatria Ramon de la Fuente Muñiz

None

Grace Chang Harvard Medical School

None

Anju Dhawan All India Institute of Medical Sciences (AIIMS)

Yes: 1b,2a,2b Funding from UNODC for a study on the effectiveness and feasibility of buprenorphine Funding from DFID (TAST) for supporting opioid maintenance treatment in Punjab Funding from UNDOC for a study on the effectiveness and feasibility of methadone Funding from Rusan Pharmaceuticals (manufacturer of methadone and buprenorphine) for a post-marketing study on methadone

Elizabeth Elliott University of Sydney None

Gabriele Fischer Medical University of Vienna

Yes: 2a Approximately 5000 EUR per year from a combination of Mundipharma, Lannacher, and Reckitt Benckiser (pharmaceutical companies manufacturing morphine, psychiatric medications and buprenorphine respectively)

Erikson F. Furtado University of Sao Paulo

Yes: 2a Funding from research support from Brazilian National Council for Scientific and Technological Development

Hendree Jones Johns Hopkins School of Medicine University of North Carolina

Yes: 2b Travel costs and medication costs from Reckitt Benckiser (pharmaceutical company manufacturing buprenorphine) for conduct and reporting of the MOTHER study on buprenorphine in pregnancy

Fareed Minhas Insitute of Psychiatry, Rawalpindi General Hospital

None

Katherine Murphy University of Cape Town

None

Alice Ordean Toronto Centre for Substance Use in Pregnancy

None

Gabrielle Welle- Strand

Norwegian Directorate of Health

None

Consultants supporting GDG Nandi Siegfried: no interest declared Margaret Harris: no interest declared

203

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

External reviewers

Name Current affiliation Competing interest declared?

Nature of declared competing interest (as expressed in declaration of interest form)

Steve Allsop Professor, Director National Drug Research Institute Curtin University

None

Espen Ajo Arnevik Head of National Resource Centre for Addiction Treatment, Oslo University

None

Matthew Chersich Associate Professor Centre for Health Policy, School of Public Health University of Witwatersrand

None

Andreea Creangea US Centers for Disease Control and Prevention, Atlanta

None

Michael Farrell Director National Drug and Alcohol Research Centre University of New South Wales

None

Marica Ferri Head of sector — Best practice, knowledge exchange and economic issues European Monitoring Centre for Drugs and Drug Addiction (EMCDDA)

None

David A. Fiellin Professor of Medicine, Investigative Medicine and Public Health Yale University School of Medicine

Yes: 1a Honorarium from Pinney Associates for involvement in post-marketing surveillance of buprenorphine

Louise Floyd US Centers for Disease Control and Prevention, Atlanta

None

Chris Howson March of Dimes None

Irma Kirtadze Sr. Researcher Alternative Georgia Addiction Research Center Tbilisi

None

Yukiko Kusano Consultant, Nursing & Health Policy International Council of Nurses, Geneva

None

Andre B. Lalonde Professor Of Obstetrics and Gynaecology, University of Ottawa, McGill

None

Carla Marienfeld- Calderon

Assistant Professor of Psychiatry, Yale University School of Medicine Course Director and Council Chair, Yale Global Mental Health Program, New Haven

None

Nester Moyo International Federation of Midwives None

Dzianis Padruchny Information and Training Centre of Belarusian Psychiatric Association

None

Svetlana Popova Senior Scientist Social and Epidemiological Research, Centre for Addiction and Mental Health Assistant Professor, Epidemiology Division, Dalla Lana School of Public Health, University of Toronto

None

Roland Simon Head of unit — Interventions, best practice and scientific partners European Monitoring Centre for Drugs and Drug Addiction (EMCDDA)

None

Anna Woods Senior Consultant Eastern DASSA 92 Osmond Tce Norwood SA

None

204

Guidelines for the identification and management of substance use and substance use disorders in pregnancy

The harmful use of alcohol and

illicit drugs is the third leading

risk factor for premature deaths

and disabilities in the world. It is

estimated that 2.5 million people

worldwide died of alcohol-

related causes in 2004, including

320 000 young people between

15 and 29 years of age.

ISBN 978 92 4 154873 1

EXIT THE MAZE OF SUBSTANCE USE FOR BETTER GLOBAL HEALTH

sub stance

use

Guidelines for the identification and management of substance use

and substance use disorders in pregnancy

G uidelines for the identification and m

anagem ent of substance use and substance use disorders in pregnancy