Cell-Free DNA-Based NIPT: A New Test in an Old Debate

Discussions on ethical and social issues have accompanied the emergence of prenatal testing and screening since the 1970s. Developments in prenatal diagnosis and screening as well as the ethical and social aspects involved can be traced back in many excellent academic and nonacademic publications. Rather than aiming at an exhaustive overview, in this chapter we will first briefly highlight some key developments underlying current prenatal testing and screening and the debate on ethical and social issues involved, then discuss to what extent cell-free DNA-based noninvasive prenatal testing (cfDNA NIPT) differs from earlier diagnostic and screening tests, and how that influences the debate on social and ethical issues. Finally, we will address the challenges for current policies to organize responsible prenatal testing and screening services with cfDNA NIPT.

Prenatal Diagnosis and Screening for Fetal Anomalies

Genetic testing emerged in the 1970s allowing families in which children had been born with severe congenital disorders to make reproductive decisions . Until that time the only option for couples to avoid having another affected child was to refrain from having further children. Via invasive procedures, amniocentesis, and later chorionic villus sampling, couples who had experienced the impact of genetic disorders from close by could find out whether the fetus was affected. For instance, in case of neural tube defects (NTDs) it was shown in the early 1970s that elevated alpha-fetoprotein (AFP) levels could be detected in amniotic fluid of mothers carrying a child with a NTD such as spina bifida . As a result, in many hospitals, amniocentesis was promptly offered to women who had had a child with NTD in an earlier pregnancy or in whose family NTDs had occurred, though this was not considered justifiable for the general obstetric population because of the costs and procedure-related miscarriage risk . In these years invasive testing was also used to identify Down syndrome pregnancies by means of karyotyping, and it was offered to women at higher risk for carrying a fetus with Down syndrome because of their age or obstetric history .

Options for screening all pregnant women for NTD and not just high-risk pregnancies emerged when it became clear that elevated AFP levels could also be detected in maternal serum . Serum screening combined with ultrasound aided in detecting anomalies , and large-scale studies were performed to assess whether the introduction of a screening program for all pregnant women would be feasible .

When, in the 1980s, it was shown that low levels of AFP were related to fetal chromosomal abnormalities , also the possibility of serum screening for Down syndrome based on AFP and other markers was studied. Test accuracy was relatively low and proved closely related to maternal age . In subsequent years accuracy was improved by adding and refining markers, and including the use of ultrasound to obtain a more accurate gestational age . However, the false-positive rate of serum screening remained problematic, causing many women to undergo unnecessary invasive testing with a small risk of procedure-related miscarriage (i.e., 0.5%–1%) . In the 1990s, in many European countries and the United States, serum screening for Down syndrome became available, but several countries restricted offering the test to women over 36 or 38 years of age who otherwise would be directly eligible for amniocentesis . In this context serum screening was used as a risk selection instrument to avoid unnecessary invasive testing.

Social and Ethical Issues

In the 1970s, patient groups started to share experiences and information on living with a disorder to improve support and care ( www.nads.org/about-us/history-of-nads/ ). The possibility of prenatal genetic testing soon was also discussed and was welcomed by some families, though rejected by others . Parents might opt to terminate a pregnancy in case of a serious disorder, for instance, because they wish to avoid the suffering of the future child or think the burden would be too high for them. In the media and scholarly publications, accounts can be found expressing understanding for parents choosing such new reproductive options. At the same time concerns and fears were voiced about testing for more disorders and becoming available for all pregnant women . Comparisons with eugenic aspirations of the first half of the 20th century were made, and fears of “playing God” were expressed, as if lives of people with disabilities would not be worth living . Other scholars and health care professionals pointed toward positive aspects of being allowed individual choices and denied any connotation with the negative past eugenic practices, arguing that there was no official obligation or pressure to test and abort affected fetuses . Others pointed to more subtle and yet pervasive mechanisms of pressure, implying eugenics to enter again via the “back door” . Parents might feel that they should accept an offer of screening, either by social pressure , or by the mere fact that screening is offered and in some countries seemed to have become a routine part of prenatal care.

In the early clinical literature on prenatal testing, prenatal tests to assess whether the unborn child had a congenital genetic or structural abnormality were described as a form of prevention However, it was argued that reducing the prevalence of a condition through selective abortion could not be subsumed under this heading . Rather than “prevention,” in the years that followed “reproductive choice” became more standard terminology. For screening programs not the uptake or reduction of live births of a certain disorder, but the degree to which parents were able to make an informed reproductive choice was chosen as the measure of success .

Efforts were made to improve the process of autonomous informed decision-making and organize screening in such a way to avoid that prenatal screening would be a routine element of normal prenatal care. In this regard, it is crucial to distinguish between prenatal screening for severe fetal abnormalities, on the one hand, and screening tests that aim at early detection of pregnancy-related problems to lower perinatal and maternal morbidity and mortality, on the other hand. Assessment of risk in pregnancy includes obstetric risk factors (e.g., prior preterm birth delivery), medical conditions in the mother (e.g., anemia, diabetes), substance use (e.g., smoking, alcohol use), prenatal screening for infectious diseases (e.g., hepatitis B, rubella), and maternal—and in some countries noninvasive fetal —blood group typing . In this context the aim of screening is unquestionable, it is preferably offered to and accepted by all pregnant women as it is to prevent health problems in mother and child through timely interventions. In prenatal genetic screening for fetal abnormalities that cannot be cured or substantially alleviated, however, the mother’s only current option is to decide whether to accept the child’s impairment or to terminate the pregnancy. Consequently, the main argument for offering prenatal genetic screening is to enhance the reproductive autonomy of the pregnant woman .

In the discussion on prenatal screening some raised fundamental objections against abortion, while others questioned whether the severity of a disorder, such as Down syndrome, justified screening and selective termination . Some argued that the severity of Down syndrome was exaggerated and that the public and health professionals should be educated more about the disorder . In public and ethical discussions on prenatal screening this became a focal point of attention. Patient groups sought media attention influencing public opinion on having a child with Down syndrome. This was fueled after the death of “baby Doe” in 1982. In this case, treatment for a correctable gastrointestinal birth defect was withheld in a newborn with Down syndrome, and a surgeon began a campaign to prevent such discrimination against children with disabilities . The disability rights movement stressed that people living with disability can also have a meaningful life, and it was contended that the offer of prenatal testing suggests that disability is bad, which could be regarded as discriminatory . In addition, it was stressed that prospective parents should be better informed about living with disabilities to be able to make a truly informed choice .

Studies started to focus on the psychological burden and moral implications of having to take a decision on prenatal testing and on experiences of women and parents . Criticism was voiced about genetic screening being another example of unnecessary medicalization of childbirth, and as a way for society to control women’s bodies for reproduction .

Much of the social and ethical aspects of prenatal testing as described previously have been discussed and documented in Northern American and European countries. Countries that adopted prenatal screening later used existing practices as examples. However, ideas on abortion and the ethical dimensions of prenatal testing for fetal abnormalities vary between and within countries . Public perceptions and acceptance of disability vary and may also influence variation in uptake of prenatal screening . In Israel, for example, prenatal screening meets with great public support . In other countries testing would not be an option because of the prohibition on abortion . Cultural motives have been shown to influence also nonmedical uses of prenatal screening . Most notably in India and China sex selection against girls has led to an unbalanced gender ratio . Whereas in western countries and bioethical literature a strong emphasis is put on genetic testing as a decision of the individual or the couple, in many parts of the world such decisions may involve the wider family . In addition to culture or religious motives, financial circumstances can influence the uptake of prenatal screening. In some countries women do not have access to testing because they cannot afford to take a test or the country has few facilities for such testing .

Though the offer of screening for fetal anomalies in some countries may have become more or less routine, having the test is not meant to be. Decisions to have prenatal screening or not should be informed by knowledge on the test and the nature of the disorder screened for, and based on the personal values and the circumstances of the future mother or future parents .

CELL-FREE DNA NIPT: What Is New and How Does That Impact Social and Ethical Issues?

Early academic papers on cfDNA NIPT focussed on high-risk pregnancies . Research using cell-free DNA (cfDNA) in maternal plasma showed a high detection rate and a low false-positive rate for fetal aneuploidy , and all that was needed was a maternal blood sample. Accurate test results could now be obtained safely since there was no miscarriage risk, unlike other forms of prenatal testing, requiring chorionic villus sampling or amniocentesis. Health care professionals, especially obstetricians having experienced women suffering an iatrogenic miscarriage after invasive prenatal diagnosis, felt a noninvasive test as a great relief .

Another positive aspect of cfDNA NIPT was that testing can be performed early in pregnancy, which may have less impact on women because of a less-intense emotional bond between mother and unborn child, and because it allows for safer termination of pregnancy. Because cfDNA NIPT requires only a blood draw, testing is also more accessible in countries with less resources and trained personnel for invasive testing .

Whereas initially cfDNA NIPT’s accuracy was based on, and viewed to be most appropriate in, high-risk pregnancies , both researchers and health care professionals were eager to ascertain whether cfDNA NIPT would have similar accuracy in low-risk pregnancies. While large-scale clinical studies comparing cfDNA NIPT to conventional screening methods were only to confirm high accuracy in the general obstetric population after 2014 , a huge interest in cfDNA NIPT became evident both in academia, health care, commercial parties, and the public domain already after its introduction in 2011in China and the United States . The expectation of an accurate and safe test helped fast introduction in prenatal care . Commercial parties started offering cfDNA NIPT irrespective of maternal age and this accelerated the introduction of cfDNA NIPT across the globe , despite official statements recommending against its use in low-risk groups because of lack of evidence . The positive test characteristics of the test soon became known by many women who shared this information and their experiences on the Internet, leading to a growing demand from pregnant women and health care professionals.

Content analyses of media reports in the United Kingdom until mid-2014 showed a predominantly positive view about cfDNA NIPT, focusing on the accuracy and safety of testing . The rapidly growing demand put pressure on the health care systems of various countries. In countries where cfDNA NIPT was not available or not allowed to be offered because of legislation, for example, in the Netherlands, this led to “prenatal tourism” to other countries. In Europe, restrictive national legislations and lack of harmonization of health care services may lead to such reproductive tourism as has also been reported for assisted reproductive technologies .

The rapid introduction of cfDNA NIPT also raised concerns. One concern was that more women who otherwise would not have chosen for first trimester combined testing (FCT), because of its low accuracy (only a risk estimation) and relatively high risk of being referred for invasive testing, would now opt for screening. Furthermore, earlier testing might lead to trivialization of selective abortions . “Routinization” of prenatal screening for fetal anomalies might be imminent, in the sense that such screening would be seen as a standard and required element of prenatal care and if more women would use prenatal screening an increase in termination of Down syndrome pregnancies might be expected . Moreover, a reduction in the number of invasive procedures because of cfDNA NIPT might imply that the experiences of clinicians who perform these procedures would decline, potentially increasing the risk of procedure-associated miscarriages .

The involvement of commercial companies also raised concern. Most notably questions on whether adequate information and pretest counselling would be provided, and the high costs of testing were mentioned . Another fear concerned the possible use cfDNA NIPT for sex-selection. Parents in countries where officially returning information about fetal sex to parents is not allowed might find ways to use online services or resort to “sex-selection tourism” to other countries .

Expectations of CELL-FREE DNA NIPT: (Un)certainty, the Ultimate Diagnostic Test?

Already in the early 1990s the question was raised whether noninvasive methods for prenatal testing will make women’s decisions to have prenatal diagnosis more or less complicated . The introduction of cfDNA NIPT in 2011, quickly spreading to countries around the world, created a paradigm shift in prenatal care . In the early days of testing some even suggested that cfDNA NIPT could eventually be used in a one-step diagnostic approach . It was expected that a new test had become available to diagnose, as opposed to predict, the presence of fetal trisomies. Although cognitively this may be less demanding for women , this one-step diagnostic procedure was actually seen as problematic, especially when offered as first-line screening test in prenatal screening programs. It was argued that because there would only be one contact moment between the pregnant woman and the health professional, this could potentially undermine autonomous decision-making, and cfDNA NIPT could easily be perceived as “an offer you cannot refuse” . In addition, Hewison argued that noninvasive diagnosis could make decision-making more emotionally burdensome, especially when more conditions are involved, by removing a so-called psychological shelter: previously people had been protected from having to make decisions because the rationale for not having a test—avoidance of miscarriage risk—had simplified decision-making for many women.

The earlier presumed one-step diagnostic test procedure appeared to be an unrealistic scenario. For biological reasons—fetal cfDNA being derived from the placenta—confirmatory testing should always be advised to confirm the diagnosis. It is however known from clinical studies that this is not always acted upon. For example, in a large study in the United States in 2013 6.2% of the women with positive (unfavorable) cfDNA NIPT results terminated the pregnancy without confirmation . Since some health professionals still consider cfDNA NIPT a diagnostic test, education of those offering cfDNA NIPT is crucial . To emphasize that cfDNA NIPT is not diagnostic some started to refer to the test as NIPS (noninvasive prenatal screening ). Counseling women with positive results to wait before taking action until their diagnosis is confirmed is of utmost importance, and it is even more important in the general obstetric population. This is because of the lower positive predictive value (PPV) in low-risk populations given the lower prevalence rates of aneuploidy compared to high-risk groups . The concept of PPV, indicating the probability that a positive test result is true positive, is difficult to understand for most women, but also health professionals and scholars have difficulty understanding what it means. In addition, most websites providing information on cfDNA NIPT seem to focus on the test accuracy (detection rate) and not on the possibility of a false-positive result . In Belgium, lack of attention for the PPV of cfDNA NIPT led to a critical debate in 2017. cfDNA NIPT is an almost free test offered by genetics centers and laboratories in Belgium: in 2017 pregnant women covered by the public health insurance only paid ∼€ 8. The test was voted “Product of the year” in 2017 by readers of the national newspaper De Standaard ( www.standaard.be/cnt/dmf20180101_03275535 ). Academic researchers explained that the sensitivity and specificity communicated in the media are not the same as PPV, and that the test incorrectly had been portrayed as an almost diagnostic test ( https://www.demaakbaremens.org/is-hype-rond-nipt-terecht/ ). To understand implications of testing, the PPV for the population a woman belongs to should be considered .

Being Prepared for the Birth of a Handicapped Child

Prenatal screening for fetal anomalies aims to provide autonomous reproductive choices to the pregnant couple including termination of pregnancy, preparing for having a child with a condition and, in some cases, fetal therapy. Fetal therapy offers an intervention before birth for the purpose of correcting, treating, or diminishing the deleterious effects of a fetal condition. Though the idea may be appealing, fetal therapy is still in its infancy (see Chapter 20 ). Most parents decide to terminate the pregnancy of a child with a congenital and/or genetic condition after the diagnosis is confirmed but there are differences between countries . Some current studies on decisions after cfDNA NIPT testing, however, mentioned that parents increasingly choose to use the test results to prepare for a child with a condition and not necessarily for decision-making about termination of pregnancy . Thus while the uptake of screening may increase with cfDNA NIPT, either as contingent test or as a first-line test, the impact of the introduction of this new technology on the live birth prevalence of Down syndrome may be less linear than expected.

Visions of Fetal Medicine

The results of prenatal testing, including ultrasound, may also be useful for pregnancy and childbirth management and enable the best possible start for the affected child. In this context the use of cfDNA NIPT for “fetal personalized medicine” has been discussed . Recently, studies have started to find out whether administration of substances, such as choline and fluoxetine, to mothers pregnant of a fetus with Down syndrome might be beneficial to brain development and cognitive abilities . If such interventions would be successful, prenatal diagnosis of Down syndrome would have a new rationale besides reproductive choice or preparing for the birth of child with Down syndrome. In such cases the fetus would be regarded as a patient, which would raise new ethical questions. If a treatment would be safe and effective it has been argued future parents might be morally obliged to use prenatal testing to promote the health of their future child . Similarly, new neonatal treatment options for serious disorders might change our views on prenatal screening.

Expanding Scope

Since the entire fetal genome is represented in the maternal plasma , it is possible to use cfDNA NIPT to screen and diagnose disorders beyond aneuploidy. Noninvasive prenatal diagnosis (NIPD) can increasingly be used for the detection or exclusion of several single-gene de novo, dominant, or recessive conditions because of a known family history (e.g., cystic fibrosis) or ultrasound abnormalities (e.g., achondroplasia) .

In fetal aneuploidy screening, when sequencing and analysis are performed in a nontargeted way, and depending on resolution, other chromosome aberrations than the common aneuploidies can be detected . This may identify other fetal aberrations, pregnancies at risk due to placental insufficiency, and in rare cases maternal aberrations including signs of maternal cancer . With cfDNA NIPT, an increasing number of test providers include (optional) screening for rare microdeletion syndromes, large duplications, and sex chromosomal aneuploidies. It is expected that cfDNA and cfRNA NIPT will also be used to detect feto-maternal risk factors, for example, for preeclampsia and preterm birth .

Due to technology-driven improvements in DNA sequence analysis and decreasing costs it is thus very likely that cfDNA NIPT/D will lead to major changes in the landscape of prenatal care. In the long run screening may also become available for many other (non)treatable conditions ranging from congenital lethal disorders, serious nonlethal cognitive and mental disorders, to milder genetic conditions, and for feto-maternal risk factors. In light of these future developments it becomes increasingly important to consider “what to offer” and “how to offer” , and who decides what to include, not only from a medical perspective but also from an ethical perspective. Survey research has shown that prenatal screening for mild disorders, gender for nonmedical purposes, and nonmedical traits (e.g., height) generally receives little support . Some studies, however, showed that about one-third of both health professionals and pregnant women are positive about fetal screening for late-onset disorders such as predisposition for hereditary cancer. In case of a continuing pregnancy, which will most often be the case, this information might entail an infringement of the child’s autonomy, of its “right to an open future” . It is therefore widely endorsed that predictive genetic testing for late-onset conditions in minors has to be discouraged .

cfDNA NIPT may increasingly be used to detect both untreatable and treatable or actionable conditions and therefore the distinction between parental “autonomy,” the traditional goal of prenatal screening, and “prevention,” may become blurred . The comparable tension between prenatal ultrasound for pregnancy monitoring and the detection of congenital anomalies has not led to much ethical debate. Dondorp et al. have argued that this is probably because ultrasound is routinely seen as a pregnancy monitoring tool and for future parents an opportunity to see their child. The challenge will be to give pregnant women the amount of information needed for taking a well-informed decision, including the aim(s) of screening, and at the same time avoiding “information overload” . The uncertainty about health implications of certain findings may further complicate counseling. As more conditions are added, more false-positive results and additional findings will be seen leading to an increase in invasive procedures for confirming findings that, because of their low prevalence, have a low PPV .

When broadening the scope, one solution could be to group conditions into (optional) categories containing disorders similar in type and severity, and to develop an approach based on “generic” consent . It is unclear whether this is feasible and desirable, also because individual variation in preferences and cultural differences of what to include in those packages will remain . Pregnant women themselves seem, in principle, in favor of “having a free choice” of what conditions are included in the test, but also acknowledge that the decision-making process might become too complex and might overburden women . Expanding the scope of prenatal screening by cfDNA NIPT thus demands reflection on the ethical, psychological, social, and legal consequences.