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Open Access

OBM Genetics

Opinion

Moving Towards Routine Non-Invasive Prenatal Testing (NIPT): Challenges Related to Women’s Autonomy

Stanislav Birko 1,*, Marie-Eve Lemoine 1, Minh Thu Nguyen 2, Vardit Ravitsky 1

1. School of Public Health, University of Montreal, Montreal, Canada; E-Mails:

[email protected], [email protected], [email protected]

2. Centre of Genomics and Policy, Faculty of Medicine, Department of Human Genetics, McGill

University, Montreal, Canada; E-Mail: [email protected]

* Correspondence: Stanislav Birko; E-Mail: [email protected]

Academic Editors: Joanne Traeger-Synodinos and François Rousseau

Special Issue: Genetic Screening

OBM Genetics

2018, volume 2, issue 2

doi:10.21926/obm.genet.1802018

Received: February 10, 2018

Accepted: March 19, 2018

Published: April 20, 2018

Abstract:

Women’s reproductive autonomy, and its translation into informed free choice regarding

prenatal screening, is a dominant concept in the bioethical discourse concerning prenatal

screening. This discourse is based on the premise that access to information regarding the

pregnancy promotes autonomous decision-making. However, studies show that the offer of

prenatal screening as a routine part of pregnancy care is not supported, to a large degree, by

appropriate informed consent mechanisms. This means that the implementation of the concept

of autonomy faces significant challenges. On the backdrop of these ongoing challenges, the

introduction of Non-Invasive Prenatal Testing (NIPT) offers numerous benefits for pregnant

women. The main advantages of NIPT are early availability of results, non-invasiveness and

absence of risk for the fetus, as well as increased accuracy compared with earlier screening

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technologies. These advantages may lead to routinization of the test, which will have the

advantage of facilitated access to the test. However, such routinization also raises unique issues

and challenges regarding the respect of women’s autonomous decision-making. To shed light

on the developments in the implementation of NIPT, this paper presents some longstanding

ethical concerns regarding prenatal screening and examines what makes NIPT different from

earlier screening technologies. It also charts possible future uses of NIPT, such as first-tier

screening, diagnosis, expanded targeted use, and whole-genome sequencing, while anticipating

the ethical and social implications of the various signposts potentially encountered, particularly

as they relate to reproductive autonomy.

Keywords

NIPT; prenatal screening; prenatal test; autonomy; informed consent

1. Introduction

Innovation in prenatal screening re-opens and re-frames old ethical debates in this area [1]. Since

the introduction of amniocentesis in the mid-20th century, questions surrounding access to prenatal

genetic information and its effect on society have been raised [2]. However, the translation and

implementation processes for such prenatal testing technologies have encouraged broad uptake

before their clinical, ethical and social ramifications have been thoroughly considered [3, 4].

Therefore, as cell-free fetal DNA, or non-invasive prenatal testing (NIPT), gradually establishes itself,

with the potential to perhaps someday completely replace traditional methods of screening, it is

essential to reassess classic ethical and social debates in view of the technology’s new clinical

attributes. This paper briefly presents some longstanding ethical concerns regarding prenatal

screening, examines what makes NIPT different from earlier screening technologies, and charts the

possible future courses of NIPT while anticipating the ethical and social implications of the various

signposts potentially encountered, particularly as they relate to reproductive autonomy.

Prenatal screening refers to any technology that identifies pregnancies with a high probability of

being affected with a certain condition. Prenatal screening differs from prenatal diagnosis in that

screening only yields probabilistic result such as 1:100, 1:10 000, and thus never completely rules out

the possibility of the disease or condition being present. Diagnostic tests do provide a definitive

positive or negative result. A diagnostic procedure is thus needed to confirm screening results before

deciding on a further course of action (e.g., preparation for a child with possible special needs,

prenatal intervention, or pregnancy termination).

Non-invasive prenatal screening has had considerable success internationally since its introduction

in 2011 [5]. It is already being offered as a second-tier screening test for high risk pregnancies under

public insurance in some Canadian provinces (e.g., Ontario and British Columbia) [6, 7]. NIPT is based

on the finding that cell-free fetal DNA (originating in the placenta) is circulating in pregnant women’s

plasma in quantities sufficient for performing genetic testing. What distinguishes NIPT from

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previously available prenatal screening technologies is the fact that it can be performed earlier in the

pregnancy (as early as week 10) and that the results are more accurate [8, 9].

The fact that results can be available earlier provides parents more time to make decisions about

the course of action and outcome of the pregnancy. Likewise, NIPT’s improved accuracy reduces the

number of false-positive and false-negative results thereby diminishing the drawbacks associated

with traditional modes of screening. False-negative results can generate a false sense of reassurance,

while false-positive results can provoke unnecessary anxiety and stress. NIPT also reduces the need

for invasive procedures since it has higher detection rates and lower false-positive rates compared to

any previous prenatal screening tests. NIPT thus has the great benefit of reducing the number of fetal

losses associated with invasive tests. When it comes to a positive NIPT result, professional societies

recommend confirming the result with invasive diagnostic testing prior to making any decision

regarding termination [7].

The benefits NIPT may offer pregnant women are significant, and therefore, not offering it may

constitute an infringement on reproductive autonomy. However, it is precisely these purported

benefits of NIPT that ethicists warn may lead to an exacerbation of some ethical issues associated

with prenatal testing. While the benefits of NIPT are evident, this paper focuses on these less obvious

implications of NIPT for reproductive autonomy.

2. Longstanding Issues Raised by Prenatal Screening

At its inception in the 60’s and 70’s, prenatal screening was presented as a means of preventing

disease and “mental retardation” [10]. It is only in the 90’s that the concept of reproductive

autonomy became dominant in the discourse concerning prenatal screening. Following criticism from

feminist and disability rights activists, the various professional bodies involved in providing prenatal

screening services distanced themselves from accusations of eugenic practices by framing prenatal

screening as a matter of personal choice regarding one’s life as opposed to a matter of public health

[10].

Since then, autonomy and choice have been heralded as the main goals of prenatal screening [11],

fitting into ‘free-market’ narratives that medical innovations are adopted as a result of sufficient

demand by free and rational homo oeconomicus [12]. This would mean that women of child-bearing

age must have demonstrated sufficient interest for market forces to drive the development of

relevant tests. However, in the case of prenatal screening, this scenario has been questioned:

“programs were initiated by government organizations, interested sectors of the medical profession,

and the medical supply industry for their own purposes” [11, 13]. This strengthens the argument that

autonomy might be used as a fig leaf hiding different interests [14].

Paradoxically, while being touted as enhancing choice, prenatal screening has, from its infancy,

been criticized for undermining parents’ autonomy [4]. Press and Browner claimed that when

screening programs were first introduced by the government (in their case, in California),

stakeholders had no interest in promoting reproductive autonomy via processes of informed consent.

Stakeholders included the attending healthcare professionals who feared that if women reject

screening they may face malpractice liability for “later claims of inadequate test explanation,” policy-

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makers whose interests were in increasing screening for economic and public health reasons, and

expecting women who wanted access to available services but preferred to not engage in

complicated deliberations that would involve the possibility of pregnancy termination. It is therefore

important to contextualize the concept of “choice” that allegedly underlies prenatal screening within

the broader social context, in order to effectively frame these choices (or lack thereof). Prenatal

screening has thus been criticized for raising a slew of issues that ultimately inhibit reproductive

autonomy, precisely the opposite of what it was lauded for.

2.1. Effects of Societal Pressures on Reproductive Autonomy

Societal pressure to screen, to diagnose or to terminate a pregnancy in case of positive results

negatively affects the possibility of exercising reproductive autonomy. These are three separate, but

interconnected, pressures. It is argued that, given the nature of our “performance society” [15],

prenatal screening for conditions perceived as disabilities is framed as the responsible choice. As

such, pregnant women often feel obligated to screen for these conditions and accede to the

“collective silence” that positive results should eventually lead to pregnancy termination [16]. Many

people, when faced with the decision of whether to pursue prenatal screening, may believe that it

would be irresponsible to decline participation in a publicly funded program seemingly designed for

the benefit of society as a whole. After all, the implementation of such tests by the medical system

“establishes screening as a legitimate use of scarce medical resources and thereby surreptitiously

underlin[es] its importance” [11].

Pressures from the medical community also exacerbate the onus felt by parents to screen

prenatally. There is evidence that medicine and preventive care are playing an increasing role in

influencing decisions related to personal and social life. Great importance is placed on early detection

and prevention of diseases and conditions, which has resulted in societal beliefs that people should

participate in prevention programs and can be “morally blamed” if they fail to do so [17]. Pregnancy,

essentially a personal life event, has been affected by this social emphasis on disease prevention and

is often perceived as requiring medical intervention and preventive care.

Furthermore, clinicians are often criticized for being too directive when counselling patients

regarding prenatal screening options [16]. Logistical constraints, fears of malpractice and negligence

litigation as well as clinicians’ own perceptions of the value of screening are all factors that can lead to

clinicians – consciously or unconsciously – placing undue pressure on women to undergo prenatal

screening. Likewise, when discussing possible future results of screening, high-risk results are often

framed in ways that do not allow much space for deciding not to continue on the testing pathway.

When results become available, problems in communicating them clearly, transparently,

meaningfully, and in a non-directive manner have been documented, with practitioners more often

recommending screening, diagnosis and pregnancy termination [18-20].

Lippman noted as early as 1986 that “implicit in the model is the acceptance […] that women

whose fetuses are found to be affected will abort the pregnancy, since for most of the conditions for

which screening can be done there is, at present, no treatment” in utero [21]. Indeed, until today, the

vast majority of pregnancies found to be affected with Down syndrome are terminated [22]. The lack

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of social support for those raising children with special needs is thought to contribute to this sense of

limited choice: “without extensive social support systems, termination may be the only viable

reproductive option even when women or families may be willing or may desire to raise a child with

special needs” [23].

Intimately related to the pressure to terminate are the so-called eugenics concerns, or what is

often referred to as the “disability critique” of prenatal screening. The disability critique claims that

not only does the elimination of persons with certain conditions lead to further stigmatization of the

condition, but that such practices may affect individuals already living with the condition. As such, if

there is a decrease in the birth rate of individuals with a particular condition, the number of public

resources and support services may also decrease [24]. In attempting to enhance reproductive

autonomy, it is important not to decrease the choices available to those who may want to pursue a

pregnancy diagnosed with a disability or condition.

2.2. Reproductive Autonomy and Informed Choice

In addition to feeling undue pressure when presented with the allegedly free choice of whether to

screen, diagnose, and terminate, infringements on reproductive autonomy can occur when women

do not sufficiently understand the implications of the test. Research has revealed that a significant

number of women undergo screening without being aware that they were being tested [25, 26]. Even

if they are made aware that they are being screened and agree to it, many women report having

received inadequate information about the conditions screened for, and what these conditions imply

on a day-to-day basis, or having been led to believe that screening was mandatory or medically

required [27-30]. Such practices reflect the lack of time allowed for counseling: “As almost all results

will be reassuring, professionals may also find it less important to inform women about the choices

they may be faced with down the line of a further screening trajectory” [31].

Disability rights scholars and activists claim that many people make prenatal screening decisions

based on misconceptions about disability [24], therefore making uninformed choices, and that these

misconceptions may be reinforced by health professionals who share them [32]. Accordingly, the

disability rights critique has been making use of the language of informed choice in articulating its

charges against current practices of prenatal screening [24, 33].

Even if all relevant information regarding screening is made available and precautions to avoid any

undue pressure are taken, the question regarding whether more information necessarily translates

into greater autonomy remains. Evidence shows that prospective parents may experience

bewilderment at the amount of information provided by prenatal screening [18]. Information

overload can be a cause of anxiety and stress and prospective parents may be left feeling perplexed

when faced with the subsequent decisions they must make. It is important to note that this “burden

of choice imposed on women” [34] is difficult because of the sensitive nature of the information

presented. This type of information can unnecessarily increase anxiety for the prospective parents

[35], negatively affect the pregnancy experience and present parents with difficult reproductive

choices – choices that they might not have had to face if they had forgone prenatal screening [31, 36].

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Additionally, this “bewilderment” applies not only to results provided by prenatal screening but

also to information provided about prenatal screening at various stages of the process. Hence, while

Press and Browner [4] pointed out that prospective parents prefer not to dwell on the social and

ethical dimensions of prenatal screening, Kukla [37] suggested that parents often make a conscious

choice to defer decisions to healthcare practitioners as a way of avoiding the burdens of information

overload and decision-making regarding screening.

While respecting autonomy necessarily requires doing so throughout the process of prenatal

screening, the social contexts outlined above create barriers to achieving this goal [14]. Seavilleklein

[11] concludes that “there is incontrovertible evidence that women are not making free informed

choices about prenatal screening”, that “whether choice is interpreted narrowly as informed consent

or broadly as relational, there are reasons to worry that women’s autonomy is not being protected or

promoted by the routine offer of screening” and that “incorporating the offer of prenatal screening

into routine prenatal care for all pregnant women is not supported by the value of autonomy and

ought to be reconsidered.” These conclusions regarding prenatal screening were reached before the

advent of NIPT. Ultimately, the introduction of any new prenatal screening technology into

mainstream practice would require an attentive assessment of whether its implementation would

contribute to or conversely undermine reproductive autonomy.

3. How NIPT Affects the Ethics Landscape

Prenatal screening is seen by many women as part of routine prenatal care [38]. Although NIPT has

been rapidly implemented into publicly-funded screening pathways in some countries (e.g. the

Netherlands, Belgium) [39-41], in most countries it is still offered only privately [5, 23] and is not yet

considered standard of care, despite strong commercial interests that strive to make it a routine part

of prenatal care [3, 24]. NIPT offers great benefits and is thus a laudable, as well as ethically

acceptable, step forward when it comes to enhancing women’s access to information they desire. At

the same time, issues inherent in prenatal screening concerning reproductive autonomy have not yet

been resolved and can now be exacerbated by NIPT.

First, NIPT can provide results earlier in the pregnancy than previous screening tests. This provides

a crucial benefit to pregnant women and their families, as it allows earlier diagnostic testing and – in

case of a positive diagnostic result – either more time to prepare for possible early therapeutic

interventions or just to prepare for the birth of a child with special needs, or an earlier pregnancy

termination. At the same time, the timing, reliability and safe nature of NIPT exacerbate concerns

regarding the pressure placed on parents to screen and possibly terminate due to positive diagnostic

results. Prior to the introduction of NIPT, parents could decline screening under the ‘pretext’ of poor

performance of conventional screens, the risk of miscarriage associated with invasive diagnostic

testing and the fact that results are only available at an advanced stage of the pregnancy

(approaching 20 weeks) even if they actually had other reasons for not screening [42]. Such reasons

could include a preference for a less medicalized pregnancy or an acceptance of the possibility of

having a disabled child, reasons which they might fear care providers, family members or society

would not approve of [43].

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Second, the non-invasive (i.e. safe for the fetus) nature of NIPT, may lead to further undermining

of informed consent and reproductive autonomy. Empirical studies have shown that some healthcare

professionals believe NIPT warrants less formal informed consent procedures because it presents no

increased risk of miscarriage [44, 45]. In addition, the common practice of same day pre-test

counselling, directly followed by NIPT, further erodes informed consent because it eliminates the

reflection period during which patients can discuss and decide whether to undergo screening [34].

Third, the increased accuracy of NIPT results, as compared with previous screening techniques,

changes the nature of the information the test yields. Whereas previous technologies provided a

probability that the pregnancy is at high risk, NIPT now yields results (at least for trisomy 21) that may

be perceived by parents as quasi-diagnostic. If consent is lacking or not fully informed, parents may

receive results that they are unprepared for, or even do not wish to know. It may be argued that

disclosure of an unwanted from NIPT result that is more reliable violates parents’ reproductive

autonomy more extensively than the disclosure of more uncertain risk information [14].

On the other hand, some may view the disclosure of more reliable results, even without

appropriate consent, as less damaging than the disclosure of risk information. This is because risk

information can create much anxiety for no reason (since with previous screening technologies most

cases ended up being false positives), whereas NIPT results provide more certainty and significantly

reduce the number of individuals unnecessarily exposed to anxiety and stress. This is the rationale

behind the recently proposed mechanism of ‘reflex testing’ [46], in which two blood samples are

taken when women go through conventional serum screening. If a woman’s first-tier screen comes

back as high-risk, her second blood sample is automatically sent for NIPT, and the woman is only

informed of the NIPT result, without ever having been exposed to the less reliable result of the first-

tier screen. The researchers who proposed this model argue that this eliminates the unnecessary

anxiety suffered by all those for whom first-tier serum screening produces false-positive high-risk

results. However, there is no assurance of women being properly counseled and understanding the

testing pathway they have unknowingly embarked upon. Thus, the advantage of reduced anxiety is

achieved at the expense of informed consent and the woman’s right to choose [47-49].

4. NIPT’s Future Expansion

4.1. NIPT as First-Tier Screening

As recently as 2015, Dondorp et al. stated that the introduction of NIPT “lead[ing] to abandoning

two-step screening” was “unrealistic” [31]. This statement is proving to be premature since there

seems to be a shift in policies and standards adopted by different jurisdictions, recommending the

use of NIPT as a first-tier screen. For instance, in 2015 and 2016, the Society for Maternal Fetal

Medicine (SMFM), the American Congress of Obstetricians and Gynecologists (ACOG), the American

College of Medical Genetics and Genomics (ACMG) and the International Society for Prenatal

Diagnosis (ISPD) all modified their positions on NIPT in favour of making the technology available to

all pregnant women, regardless of their risk status [50-52]. Likewise, more recently in 2017, the

Society of Obstetricians and Gynaecologists of Canada (SOGC) and the Canadian College of Medical

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Genetics (CCMG) released a joint guideline stating that NIPT can be offered as an option to all

pregnant women provided that they understand it may not be provincially funded [7].

However, the risks NIPT poses to reproductive autonomy as a first-tier screening test are

substantial. If NIPT becomes an option available to the general population of pregnant women and

not only to those considered at high-risk, this will have an important impact on the current medical

practices of general health practitioners, who are rarely specialized in the area of genetics. Onus will

fall on front-line healthcare providers to discuss screening and testing options, along with

communicating NIPT results [53], even though it is possible that they may not fully understand

neither the complexity of the genetic results nor the evolving prenatal screening options.

This is further complicated by the fact that health care providers may believe informed consent is

even less important when using NIPT compared with diagnostic tests [45]. The emerging scenario of

NIPT as first-tier screening may mean that, in reality, reproductive autonomy will be more difficult to

protect through informed consent. This highlights the importance of policies aiming to reduce the

stigma associated with having children with special needs and ensuring that resources are in place to

support any reproductive decision women and families make [14, 54].

4.2. Non-Invasive Prenatal Diagnosis (“NIPD”)

If NIPT is further expanded to become a diagnostic tool, replacing classic diagnostic techniques

such as amniocentesis, this could further exacerbate autonomy-related concerns, since women and

their partners, as noted above, would no longer be able to use the risk of miscarriage as a reason to

reject testing. NIPT is currently used as diagnostic for achondroplasia and thanatophoric dysplasia

[55], but its use to diagnose common aneuploidies is not currently foreseeable from a technical point

of view. At the same time, it is useful and important to start thinking about possible ways to prepare

the healthcare system for the autonomy-related challenges NIPT may pose as a diagnostic test.

4.3. Expanded Targeted Use

In the future, the use of NIPT has the potential to expand to screen for a growing number of

conditions such as additional and more rare chromosomal aneuploidies (other than those currently

screened for), fetal CNV detection, paternity testing [56], as well as a host of more ethically

contentious uses (e.g., late onset diseases or futuristic applications such as non-medical traits). The

currently booming industry for genetic testing, from ancestry to direct-to-consumer ‘recreational

genetics’ [57], attests to the fact that there is great public interest in genetic information, even if

based on pure curiosity, and that weak scientific reliability is therefore no obstacle to marketing

efforts [58]. Without proper regulation, future uses of NIPT that are ethically contentious, such as

non-medical attributes, may end up being marketed aggressively. This may increase the pressure

women and their families feel to screen for a growing number of conditions, providing them with a

large amount of unreliable or difficult to interpret information that is not actionable and increases

anxiety without any benefit.

Expanding the conditions NIPT screens for will further complicate pre- and post-screening

counselling, and will likely lead to even more health providers forgoing informed consent altogether,

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thus depriving women of choice. In addition, such expanded screening is paradoxically likely to lead to

increased invasive diagnostic testing due to the low sensitivity and specificity NIPT has when

screening for some of the rarer aneuploidies [59]. Moreover, it will increase the likelihood of

incidental findings regarding health risks for family members, either the parents or other close

relatives, who may not wish to know such risks [31]. While there are frameworks for dealing with such

situations [60, 61], this outcome would still add layers of challenges and stress in the management of

pregnancy.

The future expanded use of NIPT makes it critical for pregnant women to understand the purpose

and potential consequences of screening, since the decision to screen can have important

implications for them, their relatives, and future children. To promote reproductive autonomy,

policies and guidelines must underscore the need to offer different prenatal screening choices, one of

which must remain the explicit option to forego screening altogether, framed as a reasonable choice

[16, 62]. Notably, this was recommended by the SOGC and the CCMG in their recent guideline on

prenatal screening [7].

4.4. Non-Invasive Prenatal Whole-Genome Sequencing (“NIPW”)

Recent papers explore the possibility of using NIPT to sequence the entire genome or exome of the

fetus [63, 64], dubbed NIPW (W for “whole”). The ethical and social concerns described above

regarding the expanded use of NIPT are further aggravated by NIPW since the result would be an

enormous amount of information, most of which would lack certainty and clinical significance [59,

63].

The highly complex and complicated nature of the information acquired through NIPW would

necessitate proper informed consent and pre- and post-test education and counselling about the

interpretation of the results and the possible impact of the information, not only on the fetus, but on

other family members [65]. This would prove to be a difficult logistical hurdle for most clinics offering

NIPW. Furthermore, such extensive information about the genetic basis of risks to the health of the

fetus has the potential to further increase patient anxiety surrounding the pregnancy, especially if the

reason for undergoing screening is seen as a way to satisfy patients’ “desire [for] reassurance that

their fetus is healthy” [66].

Aside from autonomy concerns, routinely offering NIPW would result in “high associated costs and

increase the burden on the healthcare system” [59]. From a practical standpoint, the ways in which

implementing NIPW has been proposed by some authors [67] opens the door for health professionals

and/or parents to set their own severity thresholds and to forego nondirective genetic counseling in

some cases, thus implicitly encouraging possible eugenic practices [59, 68].

5. Conclusion

This paper began by examining the ethical and social issues associated with reproductive

autonomy that are inherent in prenatal screening. It went on to present the significant benefits NIPT

offers pregnant women and their families, while also explaining why, given its current

implementation, NIPT poses challenges to respecting women’s reproductive autonomy in the context

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of prenatal screening. It then outlined some probable future uses of NIPT and the impact those could

have on reproductive autonomy.

If any of the future uses of NIPT outlined in this paper materializes – and the current regulatory

landscape suggests that they very well may – they will further complicate the amount, nature, and

complexity of information women have access to, as well as the implications such information may

have for others. This may contribute to the challenges healthcare professionals face in respecting

women’s reproductive autonomy. We thus suggest that the future uses of NIPT should consider

respect for women’s reproductive autonomy as a leading factor in responsible and appropriate

implementation.

Acknowledgements

The authors would like to thank the members of the NIPT research team: Dr. Anne-Marie Laberge,

Dr. Charles Dupras, Dr. Hazar Haidar, Aliya Affdal, Cynthia Henriksen, and Jessica Leclerc-Blain for

fruitful discussions, as well as the peer reviewers for their extremely pertinent comments that

considerably improved the manuscript. The authors would also like to thank Dr. Francois Rousseau

and Dr. Sylvie Langlois for their leadership on the PEGASUS project.

Author Contributors

All authors contributed to all aspects of this study.

Funding

Vardit Ravitsky is lead-investigator and Stanislav Birko is project coordinator in a Research Project

(PEGASUS) funded under the auspices of Genome Canada and the Canadian Institutes for Health

Research (both non-for- profit organizations funded by the Canadian government) but that call for a

small proportion of mandatory in-kind contributions from other partners. This Research Project thus

receives in-kind funding from private corporations which either offer commercial NIPT tests (Ariosa

Diagnostics Inc, San Jose, CA) or offer reagents and/or equipment that can be used to perform NIPT

assays (Life Technologies Inc, NY, USA; Illumina, San Diego, CA, USA; QIAGEN, Hilden, GER; Perkin

Elmer, Waltham, MASS, USA). This funding is at arm’s-length from the scientific component of the

Research Project and has no impact on the study design or its results.

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