Analytical Piece

Social Science & Medicine 304 (2022) 113064

Available online 20 May 2020 0277-9536/© 2020 Elsevier Ltd. All rights reserved.

Non-invasive prenatal testing: A diagnostic innovation shaped by commercial interests and the regulation conundrum

Ilana Löwy Cermes3 : INSERM, U 988, CNRS, UMR 8211, EHESS and Paris Descartes University, France

A R T I C L E I N F O

Keywords: Pregnancy Fetus Selective abortion Amniocentesis Circulating free fetal DNA Non-invasive prenatal diagnosis Genetic testing Down syndrome

A B S T R A C T

Non-invasive prenatal testing (NIPT) is grounded in the analysis of free circulating fetal DNA (cfDNA) in preg- nant women’s blood. The rolling out of this screening method was in large part driven by commercial firms, which hoped to reach a huge potential market by offering a test that was expected to be risk-free, reliable, inexpensive, and able to detect a wide range of genetic traits of the future child. To date, most predictions about the scope and uses of NIPT have not materialized: in 2020 NIPT detects only a limited number of genetic anomalies, while results have to be confirmed by amniocentesis. NIPT has become a commercial success. Nevertheless the implementation of NIPT has tended to diverge across different national settings. In countries that already have state-sponsored screening for Down risk, NIPT has been offered by the state health insurance to women defined as “high risk”, using a variant of the test that detects only three autosomal aneuploidies: trisomy 21, 13 and 18. These countries effectively regulate the supply of NIPT on grounds of cost-effectiveness and reliability. In countries without state-sponsored screening for Down risk, in contrast, multiple versions of NIPT covering a wider range of birth defects are commonly available on the free market, and purchased by women at low as well as high risk of having an affected child. Market-based healthcare systems tend to present women who can afford to pay for NIPT with a largely unregulated choice of technologies – though reimbursement rules imposed by private insurance providers may serve in effect to regulate use by those consumers who cannot afford to pay for tests from their own pockets. This regulatory divergence is shaped by the presence or absence of prior state-sponsored screening programs for Down risk.

1. Introduction: NIPT—distinct trajectories of a diagnostic innovation

Noninvasive prenatal testing (NIPT) examines free circulating fetal DNA (cfDNA) in maternal blood in order to identify fetal anomalies. First introduced in 2011, NIPT is now offered by numerous biotechnology companies who compete in a world-wide prenatal testing market. The declared aim of cfDNA-based NIPT, when first introduced, was to pro- vide a reliable and risk-free method of identifying selected genetic anomalies of the fetus, above all the presence of an abnormal number of chromosomes (aneuploidy). In the longer term, it was expected that cfDNA analysis would be expanded to provide a “reading” of the entire fetal genome aimed at identifying a much wider range of genetic con- ditions and risks (e.g., Benn and Chapman, 2010; Greely, 2011). As of 2020, it is still too early to decide what the future of NIPT will be. Looking back over the first eight years of diffusion of this approach (2011–2019), however, alerts us to a development that was scarcely anticipated in the debates that preceded its marketing – namely that the

way NIPT has been rolled out in different national settings has tended to diverge, depending, among other things, on whether countries already have state-sponsored screening for Down syndrome risk, or whether NIPT is delivered via market-based healthcare.

In countries with pre-existing, nation-wide structures of screening for Down syndrome risk, NIPT is distributed mainly through national health systems and is limited to a search for three major autosomal aneuploidies: trisomy 21 (Down syndrome), 13 and 18. In these settings, NIPT is usually (as of early 2020) a “second level screen” – proposed only to women previously defined as being at high risk of carrying a trisomic fetus through first level screening using a combination of serum markers and obstetrical ultrasound – and is regulated according to the same criteria (reliability, reproducibility) as those which govern the use of serum markers to test for “Down risk”.

This contrasts with the US a devoid of a national health care system, where NIPT is distributed primarily as a consumer item, available on the market, or with Brazil where, since abortion is criminalized, national health system does not include prenatal testing for fetal anomalies. In

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these countries NIPT can be purchased by high and low risk women, and its users can decide whether they want to know only if the fetus has trisomy 21, 13 or 18, or whether they wish also to receive additional information about other genetic anomalies.

This divergence is far from being absolute. In countries where a national health system confines NIPT to screening for the three major autosomal aneuploidies in high risk women, affluent health care users can often circumvent these restrictions by directly purchasing other cfDNA-based tests. Moreover, the provision of prenatal screening by a national health service does not neceserily mean that the majority of pregnant women elect the variant of NIPT it proposes (Metzler, 2020). Meanwhile in countries where NIPT is distributed mainly through market mechanisms, the choices available to women and couples who cannot afford to pay directly for cfDNA tests may still be restricted by the reimbursement rules operated by their private health insurance pro- viders, who act in effect to regulate the scope of NIPT use.

In any given country, the adoption and use of cfDNA-based tests is thus shaped by the structure of health care, local regulatory framework, legal constraints, cost/efficacy considerations governing health insur- ance, and, above all by previous approaches to screening for “Down risk.” Nevertheless, between 2011 and 2020, the distribution and use of NIPT in each country has generally tended to follow one of two broadly divergent patterns. This paper illustrates these by describing the diffu- sion of NIPT in the USA on the one hand and in Western European countries on the other. It then highlights how these patterns of diffusion may be affected and modulated by local circumstances by looking first at the situation in Brazil and secondly, and more briefly, at China. The paper concludes by stressing that although NIPT is grounded in shared technology, its adoption is shaped by situated variables.

The view of NIPT presented in this paper is grounded in a mixed methods approach to contemporary history, using a combination of direct observations, collection of testimonies, and a historically-oriented reading of printed sources. The research was undertaken as part of a collective program of comparative investigation of the history and current practices of prenatal diagnostics and testing in Europe and Brazil, which included numerous interviews with key actors (Ville et al., 2013). In this context, the author conducted three years of observation of fetal pathology and clinical genetic practices in France and Brazil, including interviews with the clinical specialists (Löwy, 2018). Addi- tional information on China derives from shorter collaboration on local uses of NIPT (Zeng et al., 2016). The present text is primarily based on a reading of the literature relating to the implementation of Down risk screening and NIPT in the different countries, informed by the findings of the project as a whole and selected to illuminate the different ways that NIPY was developed implemented in the different countries. Where interview data are reported in the present text, they are from the au- thor’s research with clinicians in Brazil.

2. Screening for Down risk before NIPT

The first prenatal tests for genetic disorders, introduced in the late 1960s, employed invasive technologies to collect fetal cells, either from the amniotic fluid (amniocentesis) or the fetal part of the placenta (chorionic villus sampling (CVS)). The fetal cells could then be tested for the presence of an abnormal number of chromosomes (aneuploidy) or for biochemical markers of a hereditary metabolic disease. Gynecolo- gists and public health experts were especially concerned about the risk of Down syndrome (trisomy 21). Women of “advanced maternal age” were understood to be at higher risk than younger women of giving birth to a Down syndrome child, so were advised to undergo amniocentesis or CVS to determine the fetus’s chromosomal status. However, amnio- centesis and CVS were also linked with risk of spontaneous abortion of a healthy fetus. In younger women, the risk of losing a pregnancy following an invasive test was seen as higher than the risk of having a Down syndrome child. Consequently, physicians did not recommend such tests to women under 35 (Löwy, 2014).

In the early 1970s some experts did propose to offer amniocentesis for Down risk to all pregnant women (Stein et al., 1973), but this was a programmatic statement rather than a realistic suggestion: amniocen- tesis was too risky and expensive to become a generalized prenatal test. In the 1980s and early 1990s, however, experts discovered that fetuses with increased nuchal translucency (accumulation of liquid behind the fetal neck, visible using ultrasound) at 11–12 weeks of pregnancy were at higher risk of trisomy 21. They also found that changes in levels of certain biochemical markers in a pregnant woman’s serum indicated a higher probability that the fetus had an abnormal number of chromo- somes. An algorithm combining data from ultrasound and serum tests, together with a woman’s age, was developed to calculated the woman’s individual “risk number,” that is her odds of carrying a fetus with a chromosomal anomaly. Those with a “risk number” higher than a pre- determined value (typically 1 in 150 to 1 in 300) were offered the possibility of undergoing an invasive test. The introduction of these preliminary non-invasive tests made it possible to implement screening of all pregnant women for “Down syndrome risk.” This in turn favored a rapid extension of prenatal diagnosis, and would become the moving force behind the development of cfDNA-based NIPT (Löwy, 2017).

Screening for Down risk was introduced in several Western European countries where prenatal care is partly or totally covered by national health insurance, but the specific form of such screening and its uptake have been highly variable (Boyd and Game, 2011). Often screening was first offered in the framework of large-scale clinical trials. When these trials showed screening to be effective, it was integrated into national systems of pregnancy care and surveillance. In the US women’s decisions about screening for Down risk were often affected by advice provided from their healthcare providers and by their access to resources. By consequence fewer women underwent testing for Down risk: experts estimated that fewer than 2% of pregnant women in the US underwent amniocentesis for this indication, compared to 5–7% in Western Europe (Greely, 2011). In the absence of organized screening for Down risk, women, especially those from lower socioeconomic strata, thus had fewer opportunities to learn about health problems affecting their future child, and to elect to terminate the pregnancy where that option was available. This was seen as a problem by advocates of screening, and as a blessing in disguise by its opponents (Vassy, 2006).

Important differences in organization of screening for Down among Western European countries stem from differences in local health care cultures and organization of prenatal care (Crombag et al., 2014; Vassy et al., 2014). In France, screening for Down risk was introduced in the early 1990s, and in 2009 the French Health Ministry officially recom- mended that all women be offered first semester screening for Down. Screening is voluntary, and women have to sign an informed consent form, but refusals to undergo screening are relatively rare (Vassy, 2006; Dommergues et al., 2010). The UK implemented several pioneering programs for first semester screening around 2000; and these were gradually extended in the following years (Williams et al., 2005; Thomas, 2017). Overall uptake of screening for Down syndrome in the UK is lower than in France, as is the (official) number of terminations of pregnancy following a diagnosis of fetal anomaly. However the French and the UK data are not strictly comparable since in the UK women can abort without providing a medical reason until 24 weeks of pregnancy, compared with only 14 weeks in France (Vassy et al., 2014). Denmark has a very high acceptance rate of screening for Down, as does Finland. By contrast, in Norway screening for Down is offered only to women over 38 years and those known to have an increased risk of giving birth to a disabled child, and the uptake of screening for Down is relatively low. In Sweden and Iceland women receive detailed information about screening for Down, but are not actively encouraged to undergo it (Schwennesen et al., 2010; Meskus, 2012). In the Netherlands women are not encouraged to screen for Down risk and the test is not covered by the national health insurance, while Belgium adopted a similar screening model to the French one (Crombag et al., 2014; Rosman, 2016).

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Visibility of the risk of Down syndrome and, by extension, of other fetal chromosomal anomalies is thus a situated entity. It reflects complex interactions between legal, economic, material, sociocultural and pro- fessional considerations. Differences in the implementation and diffu- sion of tests to reveal the presence of fetuses with chromosomal anomalies produce what, following anthropologist Margaret Lock, we might call “local fetal biologies” (Lock, 2001). Meanwhile, debates over the diffusion and regulation of “screening for Down” reflect persistent unease with a diagnostic approach which, although often presented as intended to help parents prepare for the birth of a “special needs” child, in practice often results in a decision to terminate a pregnancy. In this regard, prenatal diagnosis of a genetic condition is radically different from other genetic tests. Where debates over such tests typically include considerations of their clinical utility (Parthasarathy, 2007), the highly emotional tenor of debates over abortion for non-lethal fetal indications, entangled as they are with discussions of disability rights and fears of presumed eugenic aspirations to exterminate imperfect humans, have made it very difficult to establish a single, agreed evaluation of the clinical utility of screening for Down syndrome.

3. Marketing of an industry-driven innovation

Industry—especially the pharmaceutical, biotechnology or medical instruments industries—has long been a major driver of biomedical innovation (e.g., Hobby, 1985; Blume, 1992; Marks, 2015). This was especially evident in the case of NIPT. Initial efforts to develop ap- proaches to examine fetal hereditary material using cells or free nucleic acids in maternal serum were made in public sector research labora- tories. But industry soon came to play a key role in the large-scale testing and validation of this technology.

Scientists first attempted to isolate fetal cells present in the maternal circulation in the late 1970s using the newly developed cell sorter in- strument (Herzenberg et al., 1979). The inventor of the cell sorter, Leonard Herzenberg, had a son with Down syndrome, and was espe- cially interested in prenatal diagnosis of this condition (Bianchi, 2010). However, despite partial successes in the research laboratory, scientists failed to develop clinical applications of this method. The breakthrough came with the discovery of significant amounts of circulating free fetal DNA (cfDNA) in the blood of pregnant women by Denis Lo, then at Oxford university, and his collaborators ( Lo et al., 1989, 1997; Bianchi, 1998; Landau, 2012; Romero, 2018). In the 2000s, the increasing power of computers led to the development of a new genomic tech- nology—next generation sequencing—which made possible the devel- opment of cfDNA-based tests to detect Down syndrome. In 2008, Denis Lo’s group at the Chinese University, Hong Kong and Stephen Quake’s group at Stanford university independently patented cfDNA-based tests for Down. Though working in academic institutions and funded by public money, Lo’s group was at that point collaborating with the biotechnology firm Sequenom, and Quake’s group with the firm Ver- inata, who funded and promoted the large-scale tests of the new tech- nology, with diagnosis of trisomy 21 as their first stated goal (Landau, 2012; Davis , 2013; Agarwal et al., 2013; Twiss et al., 2014; Lo, 2015). Marketed as a radical revolution in prenatal diagnosis, the cfDNA-based tests rapidly entered a period of commercial exploitation, patent wars and intense competition for markets. The predictions of high profit- ability that motivated this competition were quickly fulfilled: in 2018, prenatal tests –which include cfDNA based tests, but also multi-gene panel tests – dominated the market for genetic testing (Evans and Ver- meesch, 2016; Philips et al., 2018).

The new technology, first known as non-invasive prenatal diagnosis (NIPD) then non-invasive prenatal testing (NIPT), was initially conceived as a replacement for the existing methods of screening for Down syndrome, particularly serum tests. In 2012 clinical trials vali- dated NIPT’s capacity to detect trisomy 21, 13 and 18 (Palomaki et al., 2012), and four cfDNA-based tests—Seqenoms’s Materni T21 Plus, Verinata’s Verifi, Ariosa’s Harmony, and Nantera’s

Panorama—obtained marketing permission in the US. Initially priced between $800 and $1400, by 2018 the price-range for NIPT was re- ported to be $500-$2100. This was more expensive than alternative methods of testing for Down risk (Allyse and Wick, 2018)—one of the main reasons why national health systems did not rapidly adopt this technology as a first-tier test. In 2013, tests for abnormal numbers of sex chromosomes and for fetal sex were added to Sequenom’s Materni T21 Plus, Verinata’s Verify, and Nantera’s Panorama (Agarwal et al., 2013). While women could elect to test only for trisomy 21, 13 and 18, many women opted for the full range of tests, despite the fact that screening for sex chromosome anomalies has lower predictive value than screening for trisomy 21 (Allyse and Wick, 2018; Ramdaney et al., 2018; Bianchi, 2019).

Initially NIPT was proposed only to women defined as being at high risk of a chromosomal anomaly. However, NIPT producers were keen to prove that the test was efficient in low-risk women too—a much larger market for their products.

The first studies of the use of NIPT by low-risk women, published in 2014, and funded by the genetic testing company Illumina, supported this view. In half of the “low risk” women who received a positive NIPT result for Down, this result was confirmed by amniocentesis. By contrast, only about 4% of women classified as being at higher than average risk of carrying a Down syndrome fetus using a combination of serum and ultrasound markers had that result confirmed by amniocentesis (Greene, 2014). This result was not seen as entirely reliable, as the trial enrolled only a relatively small sample of women. Moreover, some experts favored first-level screening with a combination of serum and ultra- sound markers because it made possible the detection of a wider range of fetal anomalies. Consequently, guidelines issued in 2015 by the Amer- ican College of Obstetrics and Gynecology (ACOG) did not validate the use of NIPT in low-risk women (ACOG, 2015; Benn et al., 2015).

Despite the lack of official endorsement, however, the use of NIPT as a “first screen” rapidly came to dominate the diffusion of this test in the US. By the end of 2016, several North American professional societies such as the Society for Maternal Fetal Medicine (SMFM), the American Congress of Obstetricians and Gynecologists (ACOG), and the American College of Medical Genetics and Genomics (ACMG) had altered their position to recommend that NIPT can be made available to all pregnant women. This view was also endorsed in 2017 by the Society of Obste- tricians and Gynaecologists of Canada (SOGC) and the Canadian College of Medical Genetics (CCMG), though noting that NIPT might not be funded by the public (provincial) health insurance systems (Birko et al., 2018). Data from tests performed by Ariosa company show that while in 2014, 70% of the demands originated from women over 35, the pro- portion of older women had decreased to 50% in 2017 (Chen et al., 2019).

One of the consequences of the rapid diffusion of NIPT in the US was that many women who primarily sought reassurance that their fetus did not have Down syndrome, but who accepted the additional tests for sex chromosome aneuploidy (SCA), learned that their fetus had a high probability of an anomaly they might otherwise never have heard about. In some cases this information may have influenced women’s decisions about the future of their pregnancy; in others, it might have influenced parents’ perception of their child, potentially depriving that child of the opportunity to have a childhood unburdened by parental knowledge of their genetic difference (Howard-Bath et al., 2018; Kornman et al., 2018).The problem of unanticipated findings of NIPT was amplified in 2014 when several companies proposed “extended” NIPT that tested for additional chromosomal anomalies (mostly deletions) linked with other inborn impairments—some of which, such as DiGeorge syndrome (22q11.2 del), have variable expression (Hayden, 2014). Offered at a somewhat higher price than “basic” NIPT, this “extended” or “complete” NIPT was marketed, like the more basic versions, as a means of pre- paring parents for the birth of a “special needs” child (Löwy, 2017). Presented as a non-problematic improvement of the existing test, it was criticized nevertheless by some obstetricians, who pointed out to

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uncertainties produced by the “complete” NIPT (Allyse and Chan- drasekharan, 2015; Hashiloni-Dolev et al., 2019; Metzler, 2020).

NIPT is not presented as providing a firm diagnosis of a genetic anomaly; rather, pregnant women are told that the results have to be confirmed by amniocentesis or CVS (Stoll, 2013; Dondorp et al., 2015a, b; Taneja et al., 2016). Not all women accept this principle, however. In the US, 6% of women whose NIPT results indicate a high probability of fetal chromosomal anomaly elected to abort without further verifica- tion, while a significant proportion of those diagnosed with a high probability of sex chromosome aneuploidy elected not to perform additional tests (Dar et al., 2014; Ramdaney et al., 2018). In many such cases, it is likely that women decided to terminate a pregnancy on the basis of early NIPT results alone because they preferred not to wait until it was possible to confirm those results with amniocentesis and risk facing a more complicated second-trimester abortion.

The introduction of NIPT followed a very different trajectory in Western European countries which implemented the technology through their national health systems. These countries followed the recommendations set out in a shared position document on the uses of NIPT, issued in 2015 by the European Society of Human Genetics and the American Society of Human Genetics. This document recommended that, for the time being, the use of NIPT be limited to searching for just three autosomal aneuploidies: trisomy 21 (Down syndrome) and trisomy 13 and 18—these last two conditions being linked with very high rates of prenatal and postnatal mortality. It also recommended that NIPT be offered only to women already defined as being at “high risk” of chro- mosomal anomalies. Those with positive results of NIPT are then offered an invasive test. This use of NIPT as “second-level screen” markedly increases the odds that an invasive test will confirm the presence of a trisomy (Dondorp et al., 2015a,b). In early 2019, the French national health system adopted such use of NIPT, and at the same time increased the threshold definition of “higher than average risk of Down” from 1:250 to 1:1000 (HAS, 2019). The British NHS proposes to gradually do the same, but without modifying its definition of “high risk of Down” from the current level of 1:150.

The decision not to offer NIPT as a first screen reflects mainly cost/ efficacy considerations. While advocates of NIPT as a first screen argued that this approach detects more cases of autosomal trisomy than the combination of serum markers and nuchal translucency (Hashiloni-Do- lev et al., 2019), health administrators in several European countries were not persuaded that the small increase in detection rate justifies the higher cost of screening. By contrast, testing for conditions such as sex chromosome anomalies and deletions was rejected because these tests are perceived to be less reliable, leading to a risk of undesirable out- comes and posing difficult ethical dilemmas. While a fall in the cost of NIPT may therefore make it more acceptable as a first screen, it is less likely to lead to the adoption of “extended NIPT” (Birko et al., 2018; Ramdaney et al., 2018; Metzler, 2020).

In countries with pre-existing screening for Down, NIPT is presented as simply a technical improvement of such screening, while the possi- bility of replacing serum tests for Down risk with the use of NIPT as a first screen for trisomy 21, 13 and 18 is not expected to produce a dra- matic shift in pre-existing patterns of prenatal screening. While affluent users in Europe, including “low risk” women, can go private to purchase either a “basic” or an “extended” NIPT test, it seems likely that only a small fraction of women in countries with a national health insurance system will purchase NIPT on the private market.

Rather, the introduction of NIPT into countries with national health systems and pre-existing Down screening is expected to produce a sig- nificant decrease in the number of amniocenteses performed, thus sparing women the pain and stress linked with this invasive test (Chitty and Kroese, 2015; Dondorp et al., 2015a,b; Horn, 2019). It is expected to reduce the number of spontaneous miscarriages due to invasive tests, though a prospective French clinical trial failed to detect such an effect (Malan et al., 2018). The introduction of cfDNA-based tests in countries with pre-existing screening for Down has thus produced (for now) only

relatively modest changes in prenatal diagnosis rather than the revolu- tion that some predicted (Zeng et al., 2016; Lewis et al., 2017).

4. Discussing NIPT before and after the marketing of this diagnostic technology

In 2007, as commercial marketing of cfDNA-based tests looked increasingly imminent, US jurist Carolyn Jacobs Chachkin produced a detailed and thoughtful review of the potential advantages and pitfalls of the new diagnostic technology. Chachkin assumed that cfDNA-based tests would provide a definitive diagnosis of fetal anomalies, and would be much cheaper than existing diagnostic approaches (she estimated that their price would be between $100 and $200). On that basis, Chachkin predicted that these tests would rapidly become integrated into routine prenatal care, dramatically increasing the number of US women who use prenatal genetic testing. Such testing, she anticipated, would rapidly become the standard of care, would be fully covered by insurance companies, and would become as popular as prenatal ultra- sound. A probable consequence would be a significant increase in abortions for fetal anomalies and a significant decrease in the proportion of babies born with genetic disorders. The introduction of cfDNA-based diagnosis might therefore increase the pressure to abort impaired fe- tuses, leading to a subtle form of eugenics. Overall, however, Chachkin viewed the arrival of the new tests as a very positive development (Chachkin, 2007).

Other US scholars shared Chachkin’s assumptions and concerns. They too assumed that the new technology, then coming to be known as noninvasive prenatal diagnosis (NIPD), would rapidly became accurate and inexpensive, and would detect a great number of hereditary or ge- netic disorders. They viewed large-scale diffusion of commercially- produced NIPD as an ineluctable development, and pointed both to its potential advantages (enlargement of parental choice and a probable reduction of prevalence of severe hereditary disorders) and to its possible dangers (overwhelming parents-to-be with confusing and stress-generating information; a push toward abortion for moderate and minor fetal impairments; and greater stigmatization and social exclusion of those living with disabilities) (Benn and Chapman, 2009, 2010; Greely and King, 2010; Greely, 2011; Proffitt, 2013). These risks might be amplified by direct-to-consumer (DTC) diffusion of NIPD (Haymon, 2011; De Jong et al., 2011).

UK experts who evaluated NIPD’s future were more cautious. They predicted that the new technology would be employed to detect auto- somal aneuploidies, but were less certain that it would move rapidly beyond this indication. They were also less sure that NIPD would swiftly replace testing for serum markers of fetal anomalies. Nevertheless, they too assumed that cfDNA-based tests for a wide range of genetic condi- tions would reach the market in the relatively near future, amplifying the ethical dilemmas associated with selective abortion for fetal indi- cation. Such dilemmas, they added, might be exacerbated by the fact that NIPD was being developed exclusively by private companies and would be commercially marketed (e.g. Hall et al., 2009; Wright, 2009). Discussions about the future of cfDNA-based tests did not invoke “clin- ical utility” since it is difficult to frame potential prevention of the birth of impaired children in terms of “utility”, but they did discuss potential social harms associated with these tests. They also did not explicitly debate the possibility of prohibiting specific uses of NIPD, nor of their marketing directly to consumers.

Scholars who participated in the early debates on NIPD in the USA and the UK did not predict that the results of cfDNA-based tests would need to be confirmed by an invasive test, nor did they doubt that the diffusion of tests for selected chromosomal anomalies would quickly be followed by cfDNA-based tests to “read” the entire fetal genome. This did not happen: while in 2020 it is technically possible to sequence the fetal genome using cfDNA, it is simpler and less expensive to sequence DNA extracted from fetal cells in the amniotic liquid. Experts failed to predict the persistently high price of cfDNA sequencing. And they did

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not discuss the possibility that the inclusion of NIPT into already- existing national screening programs for “Down risk” would follow a different path from the market-based diffusion of the same test. Finally, they did not anticipate that in some cases a cfDNA-based test would reveal an unsuspected maternal pathology, usually a malignancy (Bianchi et al., 2015).

Once the tests—now renamed NIPT—were available on the market, the questions asked about them, especially in countries with a national health system changed. Some scholars continued to invoke the potential consequences of cfDNA-based whole-genome scans (e.g. Ravitsky, 2015; Shakespeare and chair, 2017). But discussions now focused mainly on the implications for existing screening programs for major chromosomal anomalies. Many of the questions asked in these debates, for instance about evaluating the specificity and reliability, cost and efficacy of a given test, its reimbursement by insurers, or the need for informed consent, had already been raised in earlier debates about the use of serum markers to determine “Down risk”. Debates about NIPT also shared with earlier discussions a tendency to eschew the thorny issue of selective abortion for fetal indications, and an implicit consensus that professionals would be the main gate keepers for access to tests, while such access would also be indirectly regulated through health insurers’ reimbursement policies (CCNE, 2013; Belgium Advisory Committee, 2016; Horn, 2019).

Other potentially problematic aspects of NIPT were seen as specific to this technology, including the exclusive development and diffusion of NIPT by commercial firms, and the risk that NIPT would be integrated into routine surveillance of pregnancy without adequate counseling. The rapid development of genetic counseling in the 1970s had been linked to the need to help women decide whether to undergo amniocentesis, associated as it was with increased risk of a spontaneous abortion (Stern, 2012). Since NIPT does not carry such a risk, it was feared that women would take this “simple blood test” without being adequately informed about the nature of the test and the precise meaning of a “positive” result. Women who underwent NIPT, but also some health care pro- viders, might confuse NIPT’s high specificity and sensitivity with posi- tive predictive value—that is, the probability that a woman who tests positive for a specific fetal anomaly does indeed carry a fetus with this anomaly, a variable which depends on the frequency of that anomaly in the tested population (Shakespeare and chair, 2017; Lewis et al., 2017; Birko et al., 2018).

5. NIPT outside North America and Western Europe: Brazil and China

Diagnostic technologies based on examining cfDNA in the maternal circulation rapidly reached Brazil, where they took a specific form. From the early 2000s on, several years before cfDNA-based tests for Down syndrome became available, Brazilian laboratories developed cfDNA- based tests to detect fetal sex (Levi et al., 2003), Women do not have Y chromosome markers, and the presence of Y chromosomal DNA in the blood of a pregnant woman thus indicates that she is carrying a male fetus. Testing for fetal sex is possible from the sixth to seventh week of pregnancy, and is much simpler and cheaper than cfDNA-based tests for abnormal chromosome number. Medical reasons to detect fetal sex early in pregnancy include when a woman is at risk of giving birth to a child with congenital adrenal hyperplasia (CAH). In such cases, some experts recommend early tests to determine if the fetus is female, followed by treatment with the steroid dexamethasone to attenuate “virilization” of the fetus—whereas such treatment, and its secondary effects on the mother, can be avoided if the fetus is male (New et al., 2014). However, there are also many non-medical reasons why a woman might want early knowledge of the fetus’s sex, from curiosity and a desire to know more about her future child, to a wish to abort a fetus of the “wrong” sex.

Similar tests, including Baby Gender Mentor™ (manufactured by Acu-Gen Biolab Inc.) and Pink or Blue® (Consumer Genetics Inc.), also quickly became available in the USA—marketed directly to pregnant

women as a means of determining their fetus’s sex using blood from a finger prick, at a price of approximately $250. Experts were critical of these tests, mainly because firms were not required to maintain high standards of reliability, but also because of the risk of prenatal sex se- lection, especially in societies which favor male children (Bianchi, 2006; Hall et al., 2009). With the commercialization of “basic” NIPT which included an option to reveal the fetus’s sex, tests that detected only fetal sex became less visible, at least in Western Europe and North America.

Such tests remained popular in Brazil, however. Indeed, locally- produced tests that reveal the “baby’s sex” early in pregnancy continue to be offered to middle-class women, sometimes as a part of a prenatal care package in a private clinic. The tests are relatively inex- pensive, their price in 2015 was at around 300–400 reals (approximately $80-$100), an acceptable sum for a middle-class woman. Street corner obstetrical ultrasound clinics can reveal fetal sex for a much lower price (in some cases as little as 20–30 reals), but this is only possible in the second trimester of pregnancy, typically at 20–22 weeks (Mirlesse, 2014). The widespread preference for earlier tests is linked to the cul- tural importance, in Brazil, of knowing the fetus’s sex: as soon as this is known, the future child becomes “our baby,” is given a name, and middle-class families start shopping for gender-appropriate clothes and accessories (Chazan-Krakowsky, 2008). Announcement of a fetus’s sex is becoming a culturally significant event in the US too, celebrated in the increasingly popular “sex revealing” parties (Vincent, 2018). But detection of fetal sex as a key milestone in making the future child “real” is not a universal trait. In Israel, pregnancy is perceived as fraught with danger, and Israeli-Jewish families do not celebrate baby showers or organize sex-revealing parties; some even refrain from purchasing baby clothes and furniture until the child’s birth. On the other hand, Israeli anxiety about pregnancy encourages the use of a wide range of prenatal tests (Ivry, 2009; Zielinska and Löwy, 2017).

Brazilian families do not have a strong preference for male children, and Brazilian gynecologists state that the detection of fetal sex has no incidence on rates of termination of pregnancy. Detection of chromo- somal anomalies in the fetus has a very different meaning. Abortion for fetal indications is illegal in Brazil, with the sole exception of anen- cephaly, and the Brazilian national health system does not offer prenatal diagnosis of fetal impairments (Diniz and Medeiros, 2010). However, only poor Brazilian women use the state-provided maternity services, while middle- and upper-class women use the services of private gyne- cologists. These gynecologists, especially those working in upper-end maternity clinics, tend to prescribe numerous diagnostic tests which, together with the use of sophisticated medical imaging equipment, are seen to stand for cutting-edge, high-quality medicine. Among other tests, middle- and upper-class pregnant women frequently undergo serum marker and nuchal translucency tests for “Down risk” at the end of the first trimester of pregnancy. If these tests indicate a higher than average risk of fetal anomaly, the woman usually undergoes amniocentesis, and if the result is “positive,” she can elect to have an illegal—but safe- —abortion in Brazil or travel abroad to legally terminate the pregnancy. The small number of children with inborn defects born in private hos- pitals and clinics indirectly indicates that affluent Brazilian women commonly undergo selective termination of pregnancy (Horovitz et al., 2013).

In 2013, two US producers of NIPT—Ariosa, producer of the Har- mony test, and Natera, producer of the Panorama test—signed agree- ments with Brazilian laboratories to offer NIPT to Brazilian women. Regulation was not an issue, since the tests were offered only in the weakly regulated private health sector. Discussion of these tests in the Brazilian media, and publicity leaflets issued by commercial test pro- viders, stressed that the new technology would help families to prepare for the birth of a “special needs” child. Laboratories offering NIPT in Brazil also took into account the fact that the average maternal age there is lower than in industrialized countries. Brazilian publicity for the Panorama test, for instance, explains that while “conventional” NIPT detects only trisomy 21, 13 and 18, a “complete” test also detects several

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chromosomal deletions. Down syndrome, the leaflet adds, is more frequent in older women, while the risk of microdeletions does not depend on woman’s age, and pregnant women under thirty are therefore at higher risk of having a child with a microdeletion than with Down syndrome, so are advised to have a “complete” test.

Initially, many specialists thought that NIPT would only find a limited distribution in Brazil, mainly because the price—at that time approximately $1200—was four to five times higher than screening for Down risk through a combination of serum tests and ultrasound. In only a year, however, NIPT had become firmly integrated into prenatal testing in the Brazilian private health sector. Again, cultural factors explain this rapid take-up. In Brazil, private health insurance does not reimburse many of the services provided by private maternity clinics, and women who choose such clinics are often willing to pay for services from their own pockets. Gynecologist interviewed for my study of pre- natal diagnosis in Brazil explained that in a sub-culture that puts to the fore the consumerist aspect of maternity, the purchase of an expensive cfDNA-based test may be seen by some women as a less frivolous pregnancy- and childbirth-related expense than the purchase of items such as an expensive baby pram. Besides, the price of NIPT, though high, is lower than other health expenses such as a consultation with a well- known ultrasound expert. Consequently, while the majority of Brazil- ian users of NIPT are “low risk” women, the test’s cost does not discourage affluent women who want rapid reassurance that “the baby is all right”, and ultrasound experts working in upper-end gynecological clinics attested that their patients often arrive for their 12-weeks ultra- sound examination with NIPT results.

The free-market trajectory of cfDNA-based tests in Brazil is in marked contrast to what happened in another intermediate economy, namely China. Chinese NIPT was a local product. Between 2011 and 2014 several Chinese private companies, including Beijing Genomic Institute (BGI) and Berry Genomics (active also on the European market), mar- keted NIPT for Down syndrome and other aneuploidies (Heger, 2014, 2015). Chinese cfDNA-based tests were less expensive than Western ones, but their price (2000–3000 RMB, about $250–350, in 2016) still made them too expensive for lower-class users. The Chinese NIPT tests circulated freely on the internal market for about three years, but in February 2014, the Chinese Food and Drug Administration and the National Health and Family Planning Commission announced that the diffusion of all prenatal genetic tests, including NIPT, was suspended until the implementation of a new regulation. This decision was taken on the grounds that the commercial market for genetic testing was chaotic, the quality of the tests was highly variable, and there was no guarantee that the companies that produced genetic tests could deliver what they promised. In June 2014 the Chinese regulatory agencies granted con- ditional marketing permits to a small number of cfDNA-based tests produced by well-known manufacturers. These tests are available on the private market. In addition, however, several Chinese provinces incor- porated NIPT for selected indications into state-sponsored parental care, and proposed partial reimbursement of the tests’ costs (Zeng et al., 2016; Jin et al., 2017). The Chinese approach, in which NIPT is assimilated to other genetic tests and its providers are strictly controled by the state, contrasts with the attitude of Western European countries and the US which do not regulate private purchase of cfDNA-based tests prescribed by a woman’s doctor.

6. Discussion: global markets, situated uses

The short history of NIPT displays the complicated relationship be- tween the global and the local in health care. Social scientists increas- ingly recognize the need to pay attention to the contexts that shape the production, diffusion and regulation of new diagnostic and therapeutic approaches, and acknowledge that one size does not fit all. Diagnostic innovations—like other technological innovations—come into being in a full world. They compete with already existing technologies and are shaped by institutional and organizational variables, economic and

political considerations, local medical cultures, and legal and regulatory frameworks. In the case of NIPT, the regulation of marketing and use tended to follow the general rules already in place in different countrie to govern the marketing of related tests, notably those that detect other serum markers for elevated risk of having a child with Down syndrome. National regulatory instances were mainly concerned about cost- efficacy and reliability. In practice, the diffusion of this biomedical innovation reflected national and regional differences in structure of health insurance, cultural variables” writ large, and, in many Western European countries, the history of implementation of nationwide screening for “Down risk.”

NIPT was introduced by biotechnology companies that prioritized private or semi-private markets and tests that detect major chromosomal anomalies (Chandrasekharan et al., 2014; Minear et al., 2015). How- ever, one could imagine a different configuration, in which this diag- nostic technology was supported by public or charitable funding, and harnessed to the goal of improving prenatal care in lower-income countries. In such countries, women—especially those who live outside urban centers—have limited access to advanced diagnostic ap- proaches such as high-quality obstetrical ultrasound and amniocentesis. NIPT could partly compensate for the shortage of qualified gynecologists and ultrasound experts because blood samples of pregnant women can be collected by community health workers and sent to a central labo- ratory. As a result, more women could receive information about fetal anomalies and—if they live in a society in which abortion is not crimi- nalized—could make an informed choice about the future of their pregnancy (Allyse et al., 2015). One can also imagine cfDNA-based tests tailored to the health needs of populations outside North America and Western Europe, by being calibrated to detect locally important diseases such as thalassemia or sickle cell anemia (Mozersky et al., 2017). For now, however, the latter possibility is purely theoretical. Technologies incorporate in their design the values that have guided their develop- ment. We cannot know how a cfDNA-based diagnostic approach shaped by different values and considerations might have looked, or how it could have been distributed and regulated.

In 2009 the UK-based Public Health Genomics Foundation published a report on the ethical, legal and social issues arising from cell-free nucleic acid technologies. The report included a disclaimer, stating that since the field of non-invasive prenatal diagnosis is extremely dy- namic and technology is developing very rapidly, its analysis was only accurate as of the publication date (Hall et al., 2009). The same disclaimer is valid for the present paper too; it provides a—surely incomplete—overview of the rolling out of NIPT as of spring 2020. The observation that many of the publications that discussed cfDNA-based tests before they came into practice rapidly became obsolete, is an invitation to be modest. It is not possible to know whether NIPT will continue to be employed in its present form, will undergo important modifications, or will be replaced by a very different approach to screening. Nor can we know whether it will be submitted to more formal regulation, or if its use will continue to be shaped by the decisions of doctors who prescribe this test and by women’s access to it. However, it is reasonable to assume that whatever the future of NIPT will be, it will continue to be strongly affected by situated variables. It is also reason- able to assume that while it is possible to collect at least partial infor- mation on cfDNA-based tests prescribed by health professionals and employed in the framework of medical supervision of pregnancy, other, less visible, and, in some, countries illegal uses of this technology, such as sex selection, may exist as well. The central role of industry in the development of this diagnostic innovation, strong links between NIPT and the highly contentious topic of selective abortion, and the weak regulation of marketing of tests, may favor the existence of gray zones of cfDNA-based prenatal testing.

Acknowledgement

I am indebted to the organizers of the workshop “Celebrating 50

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Years of Wilson and Jungner" (London, June 19–19, 2018): Stuart Hogarth, Steve Sturdy and Fiona Miller, and to all the participants in this workshop for stimulating discussions that greatly improved my under- standing of screening. My other debt is to Diane Paul, Robert Resta and Kathy Stoll for helping me to improve my statements about prenatal screening in the US and the uses of NIPT in that country, and to Steve Sturdy for his generous help with reviewing the text, clarifying my ar- guments, and correcting my English.

Part of this study was supported by Agence Nationale de la Recher- che (ANR) program, “Sciences, technologies et savoirs en société”, ANR- 09-SSOC-026-01.

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