Analytical Piece

Received: 26 February 2019 Revised: 6 May 2019 Accepted: 30 May 2019

DOI: 10.1002/pd.5495

10970223, 2019, 10, D ow

nloa

de

OR I G I N A L A R T I C L E

d

fr

om https://obgyn.onlinelibrary.w

iley.

Pandora's pregnancy: NIPT, CMA, and genome sequencing— A new era for prenatal genetic testing

com /doi/10.1002/pd

Yael Hashiloni‐Dolev† | Tamar Nov‐Klaiman† | Aviad Raz

.5495 by U niversity O

f W ollongong U

niversity of W ollongong L

ibrary, W iley O

n

Department of Sociology and Anthropology,

Ben‐Gurion University of the Negev,

Beersheba, Israel

Correspondence

Yael Hashiloni‐Dolev, School of Government

and Society, The Academic College of Tel Aviv‐ Yaffo, Rabenu Yeruham St, PO Box 8401, Tel

Aviv, Israel.

Email: [email protected]

Funding information

Deutsche Forschungsgemeinschaft

†These authors contributed equally to this work.

Data sharing is not applicable to this article as no new data

study.

Prenatal Diagnosis. 2019;39:859–865.

line L ibrary on [06/03/2023]. See the T

erm s and C

onditions (https://onli

Abstract

Objectives: We delineate in this article a shift from the “traditional” technologies of

karyotyping in PND to the current phase of advanced genetic technologies including

noninvasive prenatal testing (NIPT), chromosomal microarray analysis (CMA), and

whole‐exome sequencing (WES) with their higher detection rate and related

abundance of uncertain data.

Methods: Conceptual analysis based on seminal works that shaped the socioethical

discourse surrounding the experiences of parents as well as professionals with

prenatal diagnosis in the last 30 years.

Results: We consider the implications of this new era of PND for patients and

health professionals by drawing on previous studies documenting how probability

and uncertainty affect informed consent/choice, health risks communication,

customer satisfaction and decision making, and parent‐child bonding.

Conclusions: We argue that these changes move us beyond the idioms and realities

of the tentative pregnancy and moral pioneering, to uncertainty, probability‐based

counseling, and moral/translational gambling. We conclude by discussing what is

needed to maintain hope in the era of Pandora's pregnancy.

nelib

rary.w iley.com

/term s-and-conditions) on W

iley O nline L

ibrary for rules of use; O A

articles are governe

1 | INTRODUCTION

The new technologies of prenatal genetic diagnosis (PND) mark a

watershed of change fueled by growing commercialization and abun-

dance of information (often in the form of probabilities and chance),

joining and augmenting previous torrents of anxiety, tentativeness,

and hard moral decisions. We argue that while there are prospects

and perils that have been in the field of PND all along, now, there

are more challenges involving very complex risk information and com-

munication, exacerbating previously existing issues.

In our time, more people get more information and options for pre-

natal testing. Yet, information and knowledge are not the same. While

information is processed data about something, knowledge is filtered

were created or analyzed in this

wileyonlinelibrary.com

d by the applicable C reative C

information made relevant and useful for the subject. As a result, at

least two main trajectories open up. On the one hand, many people

are satisfied with knowing that the result is negative, find it beneficial

to know a positive result, or even feel capable of dealing with the infor-

mation overload. On the other hand, many users are faced with an

odyssey of testing, with one test leading to another (eg, serum screen-

ing leading to noninvasive prenatal testing [NIPT], leading to amniocen-

tesis), with an uncertainty that is paradoxically increased by testing (eg,

the detection of VUS—genetic variants of uncertain clinical significance),

or with the risk of “being at risk” (a murky diagnosis that sometimes lin-

gers for years after birth). While certain risks—such as those related to

miscarriage—may decrease following noninvasive procedures, we focus

here on the general experience of the “risk of being at risk,” arguing that

its growing presence has become a critical new landmark of this era of

PND, as more information needs to be considered.

In what follows, we will not return to the broad questions of

enhancement, eugenics, or designing of future generations, all

© 2019 John Wiley & Sons, Ltd./journal/pd 859

om m

ons L icense

What's already known about this topic?

• Prenatal diagnosis is known to transform the experience

of pregnancy. Present‐day technologies offer higher

detection rate and related abundance of uncertainty,

increasing the complexities involved in interpreting test

results.

What does this study add?

• It distinguishes two phases in the development of the

field.

• It summarizes former discussions and offers a new

860 HASHILONI‐DOLEV ET AL.

10970223, 2019, 10, D ow

nloaded from https://obgyn.onlinelibrary.w

iley.com /doi/10.1002/pd.5495 by U

ni

extensively studied ethical and social issues in this field. Our commentary

will follow another strand of scholarly work, focusing on the experiences

of professionals and expecting parents, mainly, of course–pregnant

women, ever since the introduction of amniocentesis as an increasingly

common prenatal diagnostic test during pregnancy, in the 1970s.

In the following, we distinguish two phases in the development of

the field. First, we focus on seminal works that provided key meta-

phors for the initial era. Second, we discuss the current era that we

suggest calling “Pandora's pregnancy,” based on former studies,1,2

which used Pandora's box as a metaphor for what lurks in advanced

prenatal genomic tests. We substantiate our claim through a meta‐

analysis of seminal studies concerning the experiences of parents as

well as of professionals with PND.

conceptual analysis of the current phase.

• It argues that the current “Pandora's pregnancy” era calls

for nondeterministic counselling and an acknowledgment

of the moral/translational gambling experience,

complicating the ability to provide patients with

information that they will find helpful.

versity O f W

ollongong U niversity of W

ollongong L ibrary, W

iley O nline L

ibrary on [06/03/2023]. See the T erm

s and C onditions (https://onlinelibrary.w

iley.com /term

s-and-conditions) on W iley O

nline L ibrary for rules of use; O

A articles are governed by the applicable C

reative C

2 | FIRST STAGE—THE TENTATIVE PREGNANCY, MORAL PIONEERING, AND GENETICIZATION

Katz‐Rothman,3 as early as 1986, and Rapp4 in 1999, wrote the most

classical works about this then newmedical experience of pregnancy at

the age of the diagnosable embryo/fetus. At the early days of amnio-

centesis, Katz‐Rothman suggested that mothers were expected to see

their children as products in the making, which have to be carefully

examined for quality control before leaving “the factory.” Some critical

sociological and feminist scholars then saw this as part of the general

process of the commodification of the human/female body in late cap-

italism. Katz‐Rothman3 further claimed that what were then new med-

ical tests posed contradictory demands on women, to love their child

and take care of it from the moment of conception, but also to be will-

ing to abort it in case a genetic problem was detected. Hence, she

coined the term “tentative pregnancy” to describe this ambivalence.3

Thirteen years later, in 1999, Rapp used the term “moral pioneers”

to complement the description of modern pregnant women's emo-

tional and cognitive morass. Situated in the research frontier of the

expanding capacity for PND, Rapp described future mothers as forced

to judge the quality of their fetuses and to make concrete and embod-

ied decisions about their own motherhood and the standards for entry

into the human community. But how were they to judge? What med-

ical information were they faced with?

Technology of stage 1 was mainly karyotyping. While it did not

produce black and white predictions about the child's future health

and characteristics, as diagnosable conditions always varied based on

severity, penetrance, and treatment availability, it produced far less

information than stage 2 (current) technologies. While counselees

might have construed results concerning chromosomal conditions as

binary—either positive or negative—prenatal karyotyping also had its

share of uncertainty.5

While there are studies estimating the morbidity risks associated

with certain chromosomal rearrangements identified via karyotyping,6

it is hard to find studies indicating a general number representing the

overall prevalence of uncertain findings found in karyotyping. This is in

contrast to the well‐documented incidence of findings of uncertain

significance in the new methods (for instance, a prevalence of approx-

imately 1%‐2% of VUS in CMA7-9). We could not find large‐scale stud-

ies explicitly comparing karyotyping and CMA with regard to the

prevalence of findings with uncertain clinical significance, let alone

when both methods were used on the same fetal samples. However,

a study based on a smaller cohort demonstrates a much higher inci-

dence of such findings detected on CMA compared with karyotyping,

and the difference between the methods is dependent on the resolu-

tion of the CMA used.10 In light of the aforementioned, we cannot

determine the precise increase in uncertain findings between

karyotyping and current methods. Yet such an increase apparently

goes hand in hand with the higher resolution and abundance of data

that are the hallmarks of the current era, as demonstrated in new gen-

eration sequencing methods.11 The epitome of this increase is argu-

ably the new term “variants of uncertain significance” (VUS), which

had not existed previously in the context of karyotyping and the many

debates regarding communicating such information to users of the

new technologies. It is apparent that the issue of uncertainty appears

much more often in the literature on new generation methods com-

pared with karyotyping and that it is central to current discussions in

the field. The discourse has shifted and now focuses much more on

uncertainty—both in terms of test performance, ie, indicating numbers,

and in terms of its implications, ie, the role uncertainty plays in clinical

routines and its impact on professionals and users.

Notwithstanding karyotyping's share of uncertainty, in the 90s, it

became common for sociologists of medicine to criticize PND as

reductionist, essentialist, and deterministic. Lippman12 had coined

the term “geneticization” (1991) to criticize the hope and hype of reas-

surance, choice, and control provided by PND. Geneticization also

addressed the false understanding of genetics among policy makers,

the public, and the media whose views of genetics were considered

too simplistic. Another strand of important criticism came from the

om m

ons L icense

HASHILONI‐DOLEV ET AL. 861

10970223, 2019, 10, D ow

nloaded from https://obgyn.onli

disability advocacy critique13,14 as well as from feminist critics.15 By

now, we believe that the “DNA mystique”16 of the 90s has faded

away, as it is quite generally understood that we are not simply our

genes. But how does this effect the experience of pregnancy? Can it

be that to know more, and to be aware of complexity, is sometimes

to know less?

nelibrary.w iley.com

/doi/10.1002/pd.5495 by U niversity O

f W ollongon

3 | SECOND STAGE: PANDORA'S PREGNANCY

3.1 | Increasing the variety of PND

With the increasing variety of PND methods (see Figure 1), choices

are often illusory, since new technologies imply a social moral duty

toward uptake.17

FIGURE 1 Evolution of prenatal genetic testing (based on the Hasting's prenatal‐testing/)

Testing cell‐free fetal DNA (cffDNA) circulating in the pregnant

woman's blood is quite a recent innovation. The screening test known

as NIPT requires just a blood test and can be performed starting week

9, hence providing results early in pregnancy. Although it is not con-

sidered diagnostic, unlike amniocentesis and CVS, it poses no risk of

miscarriage, thus changing the balance of risk versus chances of detec-

tion of anomaly. The ease and lack of risk of NIPT may lead women to

feel less justified in saying no to testing, since there is no longer an

“excuse” to decline it.18 Another major reason for its fast diffusion is

the fact it is highly commercialized19 and often pushed forward

direct‐to‐consumer (DTC), potentially bypassing traditional profes-

sional barriers. The commodification process Katz‐Rothman3

discussed in the 80s mostly in the sense of the view of the human

body as yet another capitalist commodity is accelerating in the most

simplistic economic sense of profit‐motivated companies, which are

constantly taking a larger role in shaping the field of PND.

Center report, https://www.thehastingscenter.org/prenatal/evolution‐

g U niversity of W

ollongong L ibrary, W

iley O nline L

ibrary on [06/03/2023]. See the T erm

s and C onditions (https://onlinelibrary.w

iley.com /term

s-and-conditions) on W iley O

nline L ibrary for rules of use; O

A articles are governed by the applicable C

reative C om

m ons L

icense

862 HASHILONI‐DOLEV ET AL.

10970223, 2019, 10, D ow

nloaded from https://obgyn.onlinelibrary.w

iley.com /doi/10.1002/pd.5495 by U

niversity O f W

ollongong U niversity of W

ollongong L ibrary, W

iley O nl

For many future parents, NIPT is reassuring, given the high perfor-

mance of the test (especially in the detection of trisomy 21), ie, its

lower rates of false‐positive and false‐negative results, compared with

traditional biochemical screening tests.20 Yet NIPT may still involve

false‐positives, which imply further testing, as well as false reassur-

ance in the form of false‐negatives (rates of FP and FN require clinical

follow‐up and therefore vary by research, location, product, and

medical condition). Continuing the disability critique of the “old”

turn‐of‐the‐century PND, NIPT has also been opposed as eugenic by

disability activists in Europe.21,22

Nowadays, NIPT is not replacing the traditional diagnostic

amniocentesis/CVS, which are expanded by Chromosomal Microarray

Analysis (CMA, see Figure 1). Rather, in case of an abnormal test

result, NIPT leads to further diagnostic tests, as recommended by

the ACMG.23

In the future, it is predicted that NIPT will be merged with contem-

porary advances in molecular genetics to allow detailed investigations

of the fetal genome. It is probable that such tests will become acces-

sible or even routinized for a large number of women in the general

population, most of whom at “low‐risk,” as is already the case in the

Netherlands.24 This will form a dramatic change in the quantity of

pregnant women having to face the unique dilemmas of these tests,

discussed in the following.

ine L ibrary on [06/03/2023]. See the T

erm s and C

onditions (https://onlinelibrary.w iley.com

/term s-and-conditions) on W

iley O nline L

ibrary for rules of use; O A

articles are governed by the applicable C reative C

3.2 | Future parents' experiences

CMA, whereby small gains and losses of genetic material are identi-

fied, has become the recommended first‐line genetic investigation in

pregnancies with fetal abnormalities detected in ultrasound.25 A grow-

ing number of centers are offering CMA to all women undergoing

amniocentesis and CVS. Some claim that CMA should be performed

in prenatal diagnosis, instead of karyotyping, regardless of the clinical

indication for testing.26 Additionally, exome‐sequencing whereby the

encoding part of the genome is examined has been increasingly intro-

duced in pregnancies with structural anomalies.27,28

The main benefit of advanced genomic diagnostic tests such as

CMA and exome sequencing is their higher detection rate compared

with karyotyping. They produce much more genetic data with much

higher resolution. Nevertheless, the higher resolution in which the

genome is examined has its downsides as well. These tests are usually

not meant to look for a known risk variant. Rather, more like throwing

a fishing net into the sea, they are scanning the whole “genomic

ocean” waiting to see what comes up. Furthermore, they are often

not executed due to a condition established following examination

of the phenotype. In many cases, it is the genotype and not the phe-

notype that leads the process. As a result, finding a genetic variant

(where the reference point for variation is genomic rather than pheno-

typic) may have no currently determined significance. Thus, detection

of a genetic “aberration” in contemporary methods has become far

more common, complex, and open to interpretations and reclassifica-

tion as either benign or pathogenic. Only in some of the cases can a

definite diagnosis be reached.

The challenging nature of VUS is the result of limited data

concerning these variants, or because of variable phenotypes associ-

ated with them.25 Therefore, it is a common event that probabilistic

rather than deterministic information is reached. Such findings are

obviously stress factors for parents and professionals, as knowledge

has brought along increasing uncertainty.29,30 For example, Werner‐

Lin et al17 found that couples describe being thrown into a state of

crisis, due to the gap between their expectations before testing and

their actual confrontation with the test's limitations. Reactions to

uncertain test results were strong, to the point where women

described the gained information as “toxic” and regretted having

it.31 Similar trends of uncertainty‐related stress were found in

CMA testing performed postnatally.32 Moreover, this uncertainty

may stigmatize the fetus and cause anxiety and overdiagnosis during

pregnancy and possibly post birth. Genetic knowledge, like all medi-

cal knowledge, was never completely certain. Nonetheless, current

tendencies force future parents to increasingly deal with probabilistic

knowledge, and uncertainty may take its toll affecting parent‐child

bonding also in the long run, as some parents report ongoing worry

and constant looking for signs of abnormal development of their

child, linked to the detected uncertain finding. This includes turning

to medical evaluation and intervention even without apparent health

problems.33 Similar concerns were shared by parents with regard to

disclosing prenatally detected susceptibility loci (SL) (findings associ-

ated with an unquantifiable risk of neurodevelopmental disorders,

with phenotypic heterogeneity and/or of variable expressivity).

Therefore, participants presented their wish to be able to individually

choose in the pretest setting whether or not to be informed of

detected SL.34 Such individualized choice in the form of opt‐out

possibility can support, according to the authors, reproductive

autonomy.

Advanced genomic tests also increasingly lead to secondary find-

ings, such as risks for adult‐onset conditions.35 This may also indicate

that one of the parents has the same adult‐onset disease but has not

yet developed symptoms,7 which can obviously benefit the parent as

well as the wider family. However, a greater risk for developing, in

the far future, common diseases such as heart disease or cancer, is

very hard to think through. That is, since we are ignorant of our

children's future life circumstances, will they live long enough to

develop the disease? Will they be among the ones who do or do not

develop it? What will be the severity of the condition, and what will

future therapies look like?

What can a supposedly rational person/future parent make of such

an “informed” “choice”? Knowledge is considered essential to allow

informed uptake of tests and decision making in case of an abnormal

finding. Yet is informed consent, that is, voluntary consent by a com-

petent patient to whom full disclosure has been made, and who fully

understands all that has been disclosed, still relevant in its “traditional,”

broad and one‐off format?

In light of this abundance of uncertainty, we suggest terming

today's future parents not just moral pioneers,4 but moral gamblers,

as parents understand that in some cases, whatever their decision, it

is not based on definite medical facts.

om m

ons L icense

HASHILONI‐DOLEV ET AL. 863

10970223, 2019, 10, D ow

nloaded from https://obg

Moreover, as van der Steen et al36 argue, the quality of the

decision‐making process should be measured not solely by how much

it was based on knowledge and understanding of the information, but

equally on whether the decision reached is in consistency with the

woman's values.

yn.onlinelibrary.w iley.com

/doi/10.1002/pd.5495 by U niversity O

f W ollongong U

niversity of W ollongong L

ibrary, W iley O

nline L ibrary on [06/03/2023]. See the T

erm s and C

onditions (https://onlinelibrary.w iley.com

/term s-and-conditions) on W

iley O nline L

ibrary for rules of use; O A

articles are governed by the applicable C reative C

3.3 | Professionals' dilemmas

The new era of PND carries far‐reaching implications not only for

users but also for professionals as well. A study of pregnant genetic

counselors showed that they too described genetic information as

providing both a sense of control and a source of dilemmas and

stress.37 Of course, professionals are affected by the new technolo-

gies not only as patients themselves but also mainly as service pro-

viders. Due to the increase in informing parents of uncertain results

and since patients do not respond well to uncertainty, professional‐

patient relationship is affected. Professionals described very angry

reactions from patients when reporting uncertain findings.38 The

currently common situation, in which professionals cannot offer clear

predictions, adds a nondeterministic principle to the traditional dictum

of nondirectiveness. The ideal of nondirectiveness on its own has

inherent ethical as well as practical complexities,39 and the presently

frequent addition of probabilistic information dramatically increases

the challenge experienced by professionals. Studies have stressed that

in order to minimize users' misunderstanding and frustration and to

reduce tension between professionals and their patients, it is

important to discuss with users their expectations from the tests and

to emphasize their limitations before obtaining consent. However,

especially in the new era of PND, this goal is considered difficult to

achieve.40,41

Studies on professionals' views regarding advanced genomic

tests demonstrate the complexities in communicating test results

with users. The difficulties described fall within different areas

including communicating test results to users; achieving informed

consent; information overload; disclosing secondary findings; the

level of users' freedom in deciding what information they wish to

receive; and the lack of sufficient time/resources for a proper

consultation.1,38,40,42,43

Furthermore, in the era of defensive medicine, minor uncertainties

lead to a directive to disclose all information and to offer extra diag-

nostic tests, which are presented in order to protect the physician

against the patient becoming a potential plaintiff, and not necessarily

for her medical good.44 Moreover, whereas professionals' ethical per-

spective highlights justice and beneficence/non‐maleficence, lay

groups emphasize autonomy and hence receiving all information.2

The new technologies challenge the scope of professionals' responsi-

bilities toward patients and their families. For instance, the reclassifi-

cation of VUS calls for ethical, legal, and practical examination with

regard to the responsibility of health professionals to recontact users

and patients (and/or their at‐risk relatives) whose interpretation of

test results has changed.45 Another obscurity relates to whether pro-

fessionals have a responsibility toward a person who was tested while

being a fetus. Whose responsibility is it to inform such people of their

test results1?

4 | THE WAY FORWARD

When Pandora opened the jar, all evil escaped it, but then she also

held hope inside the jar by closing the lid. By opening up the lid of

pregnancy and inspecting the fetus through the growing variety of

modern PND technologies, we also unleash complexity and

uncertainty. This is Pandora's pregnancy. It adds new elements while

continuing and amplifying old ones. As before, complex difficult deci-

sions have to be reached during the delicate phase of pregnancy, a

stressful physical and emotional situation, and under time pressure.

The old challenges have not lost their relevance. The tentative

pregnancy and moral pioneering are still here, involving hard decisions,

but not just about abortion. In addition to asking myself if I am willing

to abort or raise a disabled child, now, an additional question involves

translational pioneering: How to translate the abundance of informa-

tion of variants and probabilities into lay phenomenology that can

inform my decision. This also involves what we termed as moral

gambling.

Pandora's pregnancy, as a new reality of advanced prenatal testing,

is not alone. It demonstrates and joins other examples of the current

implementation of personalized/precision genomic medicine, where

patients and their families are placed in increasingly uncertain situa-

tions. In such settings, the sociopsychological burden of uncertainty

is shifted to patients, with physicians (as well as human geneticists

and genetic counselors) performing “bridging work” instead of manag-

ing users' or patients' complaints/expectations.46 To maintain hope in

the era of Pandora's pregnancy and provide users with information

that they will find helpful, we need today new foci as well as more

of the same emphases that were needed in the 90s, including (a)

accounting for uncertainty in genetic counseling; (b) promoting repro-

ductive choice rather than test uptake as the preferred measure of

screening program's “success” (such concrete efforts should include

balanced information, including on life with disability, presented in

genetic counseling before testing); (c) educating health professionals

about prenatal testing in the context of political and social issues

related to disability; (d) promoting genetic literacy among users of

PND; and (e) developing new counseling methods and allowing more

time in order to provide a sensitive service, acknowledging the

moral/translational gambling experience, which complicates the ability

to provide patients with information that they will find helpful.

ACKNOWLEDGEMENT

None

CONFLICTS OF INTEREST

None declared.

om m

ons L icense

864 HASHILONI‐DOLEV ET AL.

10970223, 2019, 10, D ow

nloaded from https://obgyn.onlinelibrary.w

iley.com /doi/10.1002/pd.5495 by U

niversity O f W

ollongong U niversity of W

ollongong L ibrary, W

iley O nline L

ibrary on [06/03/2023]. See the T erm

s and C onditions (https://onlinelibrary.w

iley.com /term

s-and-conditions) on W iley O

nline L ibrary for rules of use; O

A articles are governed by the applicable C

reative C

FUNDING SOURCES

Grant of the German Research Foundation (Deutsche

Forschungsgemeinschaft, DFG). “Meanings and Practices of Prenatal

Genetics in Germany and Israel: A Comparative Empirical and

Prospective Study of the Views and Ethical Concerns of Users, Non‐

Users and Providers of Prenatal Genetic Services in Their Social and

Cultural Contexts.”

ORCID

Yael Hashiloni‐Dolev https://orcid.org/0000-0002-8791-6964

REFERENCES

1. Horn R, Parker M. Opening Pandora's box?: ethical issues in prenatal

whole genome and exome sequencing. Prenat Diagn.

2018;38(1):20‐25. https://doi.org/10.1002/pd.5114

2. Townsend A, Adam S, Birch PH, Lohn Z, Rousseau F, Friedman JM. “I want to know what's in Pandora's box”: comparing stakeholder per-

spectives on incidental findings in clinical whole genomic sequencing.

Am J Med Genet, Part A. 2012;158(10):2519‐2525.

3. Katz–Rothman B. The Tentative pregnancy: How Amniocentesis Changes

the Experience of Motherhood. 1st ed. New‐York: W.W. Norton &

Company; 1986.

4. Rapp R. Testing Women, Testing the Fetus: The Social Impact of

Amniocentesis in America. 1st ed. New York: Routledge; 1999.

5. van Zwieten MC, Willems DL, Litjens LL, Schuring‐Blom HG, Leschot

N. How unexpected are unexpected findings in prenatal cytogenetic

diagnosis? A literature review. Eur J Obstet Gynecol Reprod Biol.

2005;120(1):15‐21.

6. Halgren C, Nielsen NM, Nazaryan‐Petersen L, et al. Risks and recom-

mendations in prenatally detected de novo balanced chromosomal

rearrangements from assessment of long‐term outcomes. Am J Hum

Genet. 2018;102(6):1090‐1103.

7. Dugoff L, Norton ME, Kuller JA. & Society for Maternal‐Fetal Medicine

(SMFM). The use of chromosomal microarray for prenatal diagnosis.

Am J Obstet Gynecol. 2016;215(4):B2‐B9.

8. Wapner RJ, Martin CL, Levy B, et al. Chromosomal microarray versus

karyotyping for prenatal diagnosis. N Engl J Med. 2012;367(23):

2175‐2184.

9. Hillman SC, McMullan DJ, Hall G, et al. Use of prenatal chromosomal

microarray: prospective cohort study and systematic review and

meta‐analysis. Ultrasound Obstet Gynecol. 2013;41(6):610‐620.

10. Hillman SC, McMullan DJ, Silcock L, Maher ER, Kilby MD. How does

altering the resolution of chromosomal microarray analysis in the pre-

natal setting affect the rates of pathological and uncertain findings? J

Matern Fetal Neonatal Med. 2014;27(7):649‐657.

11. Srebniak MI, Van Opstal D, Joosten M, et al. Whole‐genome array as a

first‐line cytogenetic test in prenatal diagnosis. Ultrasound Obstet

Gynecol. 2015;45(4):363‐372.

12. Lippman A. Prenatal genetic testing and screening: constructing needs

and reinforcing inequities. Am J Law Med. 1991;17(1‐2):15‐50.

13. Parens E, Asch A. Prenatal Testing and Disability Rights. Washington D.

C: Georgetown Uni. Press; 2000.

14. Kerr A, Shakespeare T. Genetic politics: from eugenics to genome.

Ethical Theory Moral Pract. 2007;10(4):409‐418.

15. Ettore E. Reproductive Genetics, Gender and the Body. London:

Routledge; 2002.

16. Nelkin D, Lindee MS. The DNA Mystique: The Gene as a Cultural Icon.

Ann Arbor: University of Michigan Press; 1994.

17. Werner‐Lin A, Barg FK, Kellom KS, et al. Couple's narratives of com-

munion and isolation following abnormal prenatal microarray testing

results. Qual Health Res. 2016;26(14):1975‐1987.

18. van Schendel RV, Kleinveld JH, Dondorp WJ, et al. Attitudes of preg-

nant women and male partners towards non‐invasive prenatal testing

and widening the scope of prenatal screening. Eur J Hum Genet.

2014;22(12):1345. https://doi.org/10.1038/ejhg.2014.32

19. Murdoch B, Ravitsky V, Ogbogu U, et al. Non‐invasive prenatal testing

and the unveiling of an impaired translation Process. J Obstet Gynaecol

Can. 2017;39(1):10‐17.

20. Norton ME, Jacobsson B, Swamy GK, et al. Cell‐free DNA analysis for

noninvasive examination of trisomy. N Engl J Med. 2015;372(17):

1589‐1597. https://doi.org/10.1056/NEJMoa1407349

21. Braun K, Könninger S. Realizing responsibility. Institutional

routines, critical intervention, and the “big” questions in the

controversy over non‐invasive prenatal testing in Germany. New Genet

Soc. 2018;37(3):248‐267. https://doi.org/10.1080/14636778.2018.

1495555

22. Don't screen us out campaign. https://dontscreenusout.org. Accessed

February 07, 2019.

23. Gregg AR, Skotko BG, Benkendorf JL, et al. Noninvasive prenatal

screening for fetal aneuploidy, 2016 update: a position statement of

the American College of Medical Genetics and Genomics. Genet Med.

2016;18(10):1056‐1065.

24. Pieters, J. Dutch hospitals expect rush on NIP‐test, NLTimes March 30,

2017, https://nltimes.nl/2017/03/30/dutch‐hospitals‐expect‐rush‐ nip‐test‐belgians‐sue‐nl‐illegal‐state‐aid‐test. Accessed 5‐3‐2019.

25. ACOG ‐American College of Obstetricians and Gynecologists. Microar-

rays and next‐generation sequencing technology: the use of advanced

genetic diagnostic tools in obstetrics and gynecology. ACOG Commit-

tee opinion no. 682, 2016. https://www.acog.org/‐/media/Committee

‐Opinions/Committee‐on‐Genetics/co682.pdf?dmc=1&ts=

20170705T0003145503. Accessed January 14, 2019.

26. Hay SB, Sahoo T, Travis MK, et al. ACOG and SMFM guidelines for

prenatal diagnosis: is karyotyping really sufficient? Prenat Diagn.

2018;38(3):184‐189. https://doi.org/10.1002/pd.5212

27. International Society for Prenatal Diagnosis, Society for Maternal and

Fetal Medicine, Perinatal Quality Foundation. Joint position statement

from the International Society for Prenatal Diagnosis (ISPD), the Soci-

ety for Maternal Fetal Medicine (SMFM), and the Perinatal Quality

Foundation (PQF) on the use of genome‐wide sequencing for fetal

diagnosis. Prenat Diagn. 2018;38(1):6‐9.

28. Best S, Wou K, Vora N, van der Veyver IB, Wapner R, Chitty LS. Prom-

ises, pitfalls and practicalities of prenatal whole exome sequencing.

Prenat Diagn. 2018;38(1):10‐19.

29. Stivers T, Timmermans S. Negotiating the diagnostic uncertainty of

genomic test results. Soc Psychol Q. 2016;79(3):199‐221.

30. Timmermans S, Tietbohl C, Skaperdas E. Narrating uncertainty: vari-

ants of uncertain significance (VUS) in clinical exome sequencing.

BioSocieties. 2017;12(3):439‐458.

31. Bernhardt BA, Soucier D, Hanson K, Savage MS, Jackson L, Wapner RJ.

Women's experiences receiving abnormal prenatal chromosomal

microarray testing results. Genet Med. 2013;15(2):139‐145.

32. Reiff M, Bernhardt BA, Mulchandani S, et al. “What does it mean?”: uncertainties in understanding results of chromosomal microarray test-

ing. Genet Med. 2012;14(2):250‐258.

33. Werner‐Lin A, Walser S, Barg FK, Bernhardt BA. “They can't find any-

thing wrong with him, yet”: mothers' experiences of parenting an

om m

ons L icense

HASHILONI‐DOLEV ET AL. 865

10970223, 2019, 10, D ow

nloaded from https://obgyn.onlinelibrary.w

iley.com /doi/10.1002/pd.5495 by U

niversity O f W

ollongong U niversity of W

ollongong L ibrary, W

iley O nline L

infant with a prenatally diagnosed copy number variant (CNV). Am J

Med Genet, Part A. 2017;173(2):444‐451.

34. Van Der Steen SL, Riedijk SR, Verhagen‐Visser J, et al. The psycholog-

ical impact of prenatal diagnosis and disclosure of susceptibility loci:

first impressions of parents' experiences. J Genet Couns.

2016;25(6):1227‐1234.

35. Westerfield L, Darilek S, van den Veyver IB. Counseling challenges

with variants of uncertain significance and incidental findings in prena-

tal genetic screening and diagnosis. J Clin Med. 2014;3(3):1018‐1032.

36. van der Steen SL, Bunnik EM, Polak MG, et al. Choosing between

higher and lower resolution microarrays: do pregnant women have suf-

ficient knowledge to make informed choices consistent with their

attitude? J Genet Couns. 2018;27(1):85‐94.

37. Shkedi‐Rafid S, Hashiloni‐Dolev Y. Pregnant genetic counselors in an

era of advanced genomic tests: What do the experts test prenatally?

Journal of Genetic Counseling. 2018;27(5):1167‐1174. https://doi.org/ 10.1007/s10897‐018‐0234‐8

38. Quinlan‐Jones E, Kilby MD, Greenfield S, et al. Prenatal whole exome

sequencing: the views of clinicians, scientists, genetic counsellors and

patient representatives. Prenat Diagn. 2016;36(10):935‐941.

39. Williams C, Alderson P, Farsides B. Is nondirectiveness possible within

the context of antenatal screening and testing? Soc Sci Med.

2002;54(3):339‐347.

40. Horn R, Parker M. Health professionals' and researchers' perspectives

on prenatal whole genome and exome sequencing: ‘We can't shut

the door now, the genie's out, we need to refine it’. PLoS ONE.

2018;13(9):e0204158. https://doi.org/10.1371/journal.pone.0204158

41. Cacioppo CN, Chandler AE, Towne MC, Beggs AH, Holm IA. Expecta-

tion versus reality: the impact of utility on emotional outcomes after

returning individualized genetic research results in pediatric rare dis-

ease research, a qualitative interview study. PLoS ONE. 2016;11(4):

e0153597. https://doi.org/10.1371/journal.pone.0153597

42. Shkedi‐Rafid S, Fenwick A, Dheensa S, Wellesley D, Lucassen AM.

What results to disclose, when, and who decides? Healthcare profes-

sionals' views on prenatal chromosomal microarray analysis. Prenat

Diagn. 2016;36(3):252‐259.

43. Sukenik‐Halevy R, Ludman MD, Ben‐Shachar S, Raas‐Rothschild A.

The time‐consuming demands of the practice of medical genetics in

the era of advanced genomic testing. Genet Med. 2016;18(4):372‐377.

44. Marchant GE, Lindor RA. Personalized medicine and genetic malprac-

tice. Genet Med. 2013;15(12):921‐922. https://doi.org/10.1038/

gim.2013.142

45. Pyeritz RE. The coming explosion in genetic testing—is there a duty to

recontact? N Engl J Med. 2011;365(15):1367‐1369. https://doi.org/ 10.1056/NEJMp1107564

46. Eyal G, Sabatello M, Tabb K, et al. The physician–patient relationship in

the age of precision medicine. Genet Med. 2019;21(4):813‐815.

How to cite this article: Hashiloni‐Dolev Y, Nov‐Klaiman T,

Raz A. Pandora's pregnancy: NIPT, CMA, and genome sequenc-

ing—A new era for prenatal genetic testing. Prenatal Diagnosis.

2019;39:859–865. https://doi.org/10.1002/pd.5495

ibrary on [06/03/2023]. See the T erm

s and C onditions (https://onlinelibrary.w

iley.com /term

s-and-conditions) on W iley O

nline L ibrary for rules of use; O

A articles are governed by the applicable C

reative C om

m ons L

icense