By Jessica Mozersky, Rayna Rapp

from GeneWatch 28-2 | June-Sept 2015


Prenatal testing in the United States and throughout the developed world came of age as several forces intersected: the legalization or partial legalization of abortion, demographic changes toward fewer and later pregnancies by many sectors of the population, and technical advances following the discovery of the chromosomal difference causing trisomy 21 (Down syndrome). Prenatal testing has now become a relatively routine part of prenatal care in many, although by no means all, parts of the world.

The first available prenatal test, amniocentesis, was diagnostic, but it was only available late in pregnancy (after 16 weeks) and carried with it a small but significant risk of miscarriage. Attempts to push prenatal diagnosis earlier in pregnancy led to the availability of chorionic villus sampling (CVS) in the 1980s, which still carried a risk of miscarriage. The advent of serum screening, initially in the form of a blood test to measure maternal serum alpha fetoprotein (MSAFP), did not bring a corresponding risk of miscarriage, but it is only a screening test: it provides risk information but is not diagnostic. "Positive" screening results indicate an elevated risk and that further testing is required for definitive confirmation of the result (usually in the form of invasive testing). The next major development, integrated screening, was introduced in the early 2000s and involves two blood tests, one in each of the first two trimesters of pregnancy, combined with an ultrasound, all of which are "cooked" algorithmically along with the age of the pregnant woman to produce a risk estimate. Prenatal screening tests are not, and have never been, diagnostic - a point that becomes particularly salient with Non-Invasive Prenatal Testing (NIPT).

Screening proved a popular option and it quickly replaced direct diagnosis by amniocentesis or CVS, enabling many women to avoid the risk of miscarriage, except for a very small minority of pregnant women whose screening results suggested elevated risk for Down syndrome, other trisomies, or open neural tube defects such as spina bifida. Those at an increased risk were generally referred for genetic counseling to discuss their results and further testing options. Importantly, screening tests always carry risks of false positives and negatives, and in the case of integrated screening, the false positive rate is 5%. This means that 5% of women who undergo integrated screening will get a "positive" screen result, the majority only to discover upon further testing that it was a false positive - a relief, but only after bringing significant anxiety and the risk of miscarriage as a result of invasive confirmatory testing.

Recent figures suggest that since the 1970s, when screening was first introduced, an estimated 30% of fetuses who would have otherwise been born with Down Syndrome were terminated following positive diagnostic prenatal testing results.[1] Three points are important to note here: There is a relationship between prenatal screening, abortion, and the number of children ultimately living with Down syndrome; not all women/couples choose to terminate; and these figures predate the introduction of NIPT.

So what is NIPT?

NIPT has been in development since the 1980s and has rapidly entered the market since its commercial introduction in late 2011. Through a blood draw, NIPT measures cell free placental DNA (cfDNA) circulating in the pregnant woman's blood to provide risk estimates for particular fetal chromosomal anomalies, such as Down syndrome, as early as 10 weeks in pregnancy. NIPT moves from the biochemical to the molecular, providing sequence-based information and making claims to replace integrated screening.

NIPT is almost exclusively available through for-profit companies - four US companies and two based in China - most of which remain embroiled in ongoing legal battles over intellectual property or regulatory battles regarding oversight. Some of the original US companies are being bought up by larger pharmaceutical and diagnostic companies which continue to file intellectual property suits against one another. Roche, for example, just purchased Ariosa Diagnostics, while its competitor Illuminia quickly filed suit against them for patent infringement. Meanwhile the Chinese behemoths, BGI and Berry Genomics, are expanding throughout Asia and into Northern Europe, where comprehensive national healthcare plans are prime, potentially lucrative targets. NIPT remains outside of FDA oversight in the US, but this too is subject to current scrutiny. This fast changing and complex battleground is not yet settled, and final market shares, costs, and regulatory regimes remain open. What is clear however is that NIPT is big business, estimated to be worth $250 million in 2012 and to grow to roughly $3.6 billion in 2019. [2]

NIPT was originally validated for use in "high risk" women (due to age, family history, or prior screening findings indicating an increased risk) by each company using its own proprietary algorithms, making it hard to assess their claims. When NIPT first came to market, it only provided information on the risk of trisomy 21, 18 and 13, all of which increase with maternal age and were detectable with previous screening methods. While algorithms and data remain proprietary, each company initially published just one validation study in a peer reviewed journal on the sensitivity and specificity of its test for the detection of Down syndrome. And importantly, the initial figures reported for NIPT's detection of trisomy 21 were, and remain, very high. NIPT can detect approximately 99% of Down syndrome cases, with a low false positive rate (less than 1%). In fact, recent studies show that it is a more accurate Down syndrome screen for all women, not just those at high risk. NIPT is therefore poised to replace integrated screening altogether, and one of the most sought-after aspects of NIPT is its lower false positive rate compared to previous screening methods, enabling many women to avoid invasive confirmatory testing. Another potential advantage is that NIPT's simplicity could reduce the need in resource-poor areas for skilled practitioners to perform invasive confirmatory procedures or more complex screening protocols.

This seems like good news. And it may be. Many women want to avoid the very small but real miscarriage risk of invasive tests. Integrated screening is a time sensitive, multi-step, and complex screening protocol that requires expert input (such as ultrasonographers and maternal fetal medicine specialists). And it has a relatively high false positive rate. In contrast, NIPT is a one time blood draw in most cases, available as early as 10 weeks in pregnancy, and promising a 99% detection rate - what's not to like about this new and "simple" blood test?

If only it were so simple.

Companies have a vested interest in increasing their market share, and these competing NIPT businesses are now staking claims to markets throughout not only North America but also Europe, South America, Asia and beyond. NIPT is now available in over 60 countries across 6 continents and spanning the continuum of economic development.[3] But before we return to the global explosion of NIPT, we need to contextualize some of the complexity of the commercial drive to expand NIPT.

The various companies offering NIPT have been rapidly expanding the conditions included in the test, including sex chromosome anomalies, rare subchromosomal microdeletions, and fetal sex (which let us remember is not a "condition," and has huge implications for sex-selection worldwide). But there are significant differences between these conditions and the trisomies, leading some to argue that highly disparate clinical realities are now being inappropriately lumped together.[4] These conditions are not age related, some have variable or negligible clinical significance, and many of the microdeletions are extremely rare, yet these additional tests are now being offered as optional "add-ons" with the choice to opt in or out of various parts of the test on a payment scale. The ability to sequence the entire fetal genome, screen for monogenic disorders, and adult onset conditions are all technically possible (or will soon be) with NIPT, and given how rapidly testing has expanded there is no reason to think these processes will not be added over time.

The validation studies for most of these additional conditions, if present at all, have used progressively smaller numbers of pregnancies to report their outcomes. In a competitive commercial environment, the rationale for adding more conditions is presumably to carve out ever bigger shares of the market under the assumption that more information is always better for the consumer - an assumption which has been significantly critiqued by both disability rights' activists and feminist coalitions. But something important happens as additional, and especially rare, conditions are added to NIPT: the test's positive predictive value goes down and the false positive rate goes up. This is an inevitable artifact of including rare conditions: the rarer the condition, the more likely you are to have a false positive result. The increasing high false positive rate will potentially undermine the major benefit of NIPT: to reduce the number of invasive tests women undergo as a result of positive screen results. This will be further exacerbated as the population of women deemed eligible for testing - the general low-risk population - are swept up in the NIPT net.

It has been hard to assess the companies' claims. Go to their websites and you will see that this is not your mother's amniocentesis, but rather a "lifestyle choice" being sold to individual consumers. The companies do their due diligence by advertising their test as a screening, as opposed to diagnostic test, but you'd be forgiven if you didn't read the fine print. You'd also be forgiven if you found yourself convinced that this test was over 99% accurate - which it is, but only for one condition, Down syndrome; or if you struggled to understand the differences between trisomies, rare microdeletions, sex chromosome anomalies, and the differing predictive ability of NIPT for each of these categories.

Patients and providers are confused about interpreting test results, with published and anecdotal reports emerging of women very nearly, or actually, aborting fetuses based on an NIPT result without confirmatory testing, or giving birth to babies affected with conditions that they were falsely reassured about following a "negative" NIPT result - sometimes based on incorrect guidance from doctors. [5] While genetic counselors, specialists in maternal fetal medicine, and obstetric providers may be well placed to interpret NIPT results, many health care providers are not. And the vast majority of prenatal care takes place outside of medical centers with such concentrated medical expertise.

Given the uncertainty raised by NIPT, a recent joint statement by the European Society for Human Genetics (ESHG) and American Society for Human Genetics (ASHG) urges caution and expresses concern about the rapid expansion of NIPT. [6] They recommend that NIPT currently only be used for serious congenital childhood disorders that have been validated clinically - such as trisomy 21, 18 and 13 - and not for fetal sex, sex chromosome anomalies, or rare microdeletions. These professional societies recommend that testing only be offered by a health care professional who can provide adequate pre- and post-test counseling to help individuals understand the test and its limitations (a salient concern with direct-to-consumer genetic tests in other healthcare arenas). Another concern is that the addition of rare, complex conditions will be much less familiar to many health care professionals, making the provision of accurate and balanced information to prospective parents especially challenging. Pre- and post-test counseling could become unmanageably complex as multiple conditions are included, creating additional barriers to truly informed decision making, especially when genetic counseling is an "add on" service with an additional price tag, not included with complex results. Thus professional societies are urging caution, while companies continue to expand their markets.

And if your head is not already spinning with the current uncertainties raised by NIPT, let us come to the last and perhaps most unsettling aspect of NIPT: its rapid global expansion. NIPT is now available in over 60 countries across the globe. The companies, costs, and conditions included in testing in each of these global spaces remains relatively unknown, and in some places data is altogether unavailable. But genomic technologies that originate in one place (whether it be Hong Kong or California) and diffuse to others will inevitably play out differently depending on the context. Past experiences of the implementation of genomic technologies in these areas suggest that there are likely to be inequities in terms of access, provider expertise, patient understanding, cost, national regulation of laboratories, biomedical technology metrics, access to abortion, and more. There likely are also diverse socio-ethical implications of NIPT, given the range of local cultural, economic, political contexts and available infrastructures; reflecting the salience of religious, kinship, and other communitarian values.

Take for instance fetal sex information, which NIPT provides as early as 10 weeks in pregnancy. In areas where sex-selection is practiced (such as India or China), NIPT's ability to provide accurate and early fetal sex information could exacerbate the selective abortion of female fetuses and demographic trends of males outnumbering females. What will happen in places where there is no legal access to abortion, as is common in Latin America? What choices will these "consumers" of NIPT have following their results? Does NIPT encourage reproductive autonomy in a context where there is no legal and/or access to abortion? Even in the US, many state-based insurance plans cover prenatal screening but not abortion. In areas of limited public health resources, how might implementing NIPT conflict with, or lead to potential misuse of, the allocation of scarce resources? How will NIPT "fit" into regions where access to prenatal care is non-existent?

Despite the clear recommendation of ASHG/ESHG that NIPT be accompanied by pre- and post-test genetic counseling, will this really be feasible in most regions of the world? How will informed decision making, consent and reproductive autonomy - so highly valued and prioritized in North America and Europe - be upheld in these varying contexts? Perhaps most worrisome, the consequences are unclear in places with highly limited resources and no backup or confirmatory options available to confirm positive NIPT results. Given existing US reports of physicians and women misinterpreting NIPT results as diagnostic without confirming findings, the possibility of this happening in other areas of the world is a looming and legitimate concern.

This brings us to another important area of concern: disability and the complex ways in which reproductive technologies such as NIPT are implicated in notions of impairment. In the US alone, there is significant geographic and ethnic variation in attitudes towards terminating Down syndrome pregnancies, with much higher rates in the Northeast, for example.[7] Disability rights activists argue that prenatal screening and termination of "affected" fetuses could ultimately lead to fewer resources being made available for those individuals living with the condition, especially as birth rates go down. How might global variation in attitudes toward disability, combined with a mind-boggling array of new "conditions" included in NIPT, play out? Will the myriad of conditions being added to NIPT also become labeled as disabilities, or will there be new spaces opened up for debate and inclusion? How might alternative notions of disability, local social support, and kinship networks affect what is considered a "disability" or part of natural human variation?

Before we slip into an all too easy "us" versus "them" binary mode of thinking, we must remember that many of the above mentioned issues exist right here in the US, albeit perhaps in different guises. Abortion laws are being rolled back, making abortion less available in many states; a 2011 study found that 17% of US mothers could not access prenatal care as early as they wanted, and 6% had very late prenatal care, or none at all.[8] In some states, such as Alaska, there are no registered medical geneticists.[9] The privatized fractured health care system means that access to and cost of NIPT are highly variable across states. NIPT could potentially be used for what is known as "family balancing" in the US, rather than the less acceptable label of sex-selection used to describe "elsewhere." Ethical challenges abound right here at home, as well as in non-Western or developing countries, albeit different issues will arise at the local, national, and regional levels. Yet there has been little comparative knowledge-sharing about the heterogeneous dissemination of this technology or the social and ethical implications of NIPT in these different national contexts.

This "simple blood test" being offered by competing NIPT companies turns out to be quite complicated, thanks to a combination of aggressive marketing and advertising,  uneven professional publication of study results, and proprietary rights and algorithms that make comparison across tests difficult. These practices may all make great market sense, but they mask many issues of which consumers should be aware: the need for but potential lack of genetic counseling when complex results are reported; insufficient genetics laboratories, infrastructure, and expertise to conduct backup testing in resource-poor settings; and confusion of primary healthcare physicians everywhere. These issues lead us to highlight the cautious approach being advocated by professional societies in North America and Europe with the rapid global expansion of NIPT. Despite these doubts, market share appears to be reason enough for the testing companies to forge ahead.

But the successful business model for NIPT that has enabled its expansion at great velocity selectively across the globe should not muffle public discussion of the social and ethical issues it raises. Scientific and highly technical innovations always play out under conditions that appear "new" while masking the older familiar social ground on which they are built. In the case of NIPT, a "simple blood test" raises very old concerns regarding equity, policy, bias, disability, and reproductive autonomy - problems that are "hidden in plain view" as pregnant women and their supporters are enrolled in a testing market that differentiates and brands itself as new.


Jessica Mozersky, PhD, is a postdoctoral fellow in advanced biomedical ethics in the Department of Medical Ethics and Health Policy at the University of Pennsylvania.  She is the author of Risky Genes: Genetics, Breast Cancer and Jewish Identity (Routledge 2013).

Rayna Rapp, PhD, is professor and associate chair in the Anthropology Department, NYU. Her award-winning books include Testing Women, Testing the Fetus, and Conceiving the New World Order.  She is currently writing a book on the growing presence of disability consciousness in the US with anthropologist Faye Ginsburg.




1.      De Graaf G, Buckley F, Skotko BG. Estimates of the live births, natural losses, and elective terminations with Down syndrome in the United States. Am J Med Genet. 2015 Apr 1;167(4):756-67. Available from:

2.      Allyse M, Minear MA, Berson E, Sridhar S, Rote M, Hung A, et al. Non-invasive prenatal testing: a review of international implementation and challenges. Int J Womens Health. 2015 Jan 16;7:113-26. Available from:

3.      Ibid.

4.      Allyse M, Chandrasekharan S. Too much, too soon?: Commercial provision of noninvasive prenatal screening for subchromosomal abnormalities and beyond. Genet Med. 2015 Mar 19. Advanced online publication. doi: 10.1038/gim.2015.23

5.      Daley B. 2014. Oversold prenatal tests leading to abortions. The Boston Globe. Dec 14. Available from:

6.      Dondorp W, de Wert G, Bombard Y, Bianchi DW, Bergmann C, Borry P, et al. Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening. Eur J Hum Genet. 2015 Mar 18; Available from:

7.      De Graaf et al.

8.      Child Health USA 2013. Available from:

9.      Allyse, Minear, et al.

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