Cell-Free DNA-Based Noninvasive Prenatal Testing and Society

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 .