Tag Archives: prenatal diagnosis

Imperfect Pregnancies: What Ilana Löwy Has To Tell Us About The History of Prenatal Testing

“It seems to me that all the gentlemen agree, some more explicitly than others, that to abort is a good thing and should be encouraged.”
– from a discussion reported in Early Diagnosis of Human Genetic Defects: Scientific and Ethical Considerations, Maureen Harris (ed). National Institutes of Health, 1970.

I sometimes feel like a lone voice howling in the wind-swept darkness when I argue that any opinion, policy, or analysis of prenatal testing must be rooted in historical context. Often these endeavors are informed by technical aspects of a test, such as sensitivity, specificity, cost, and positive predictive value, sometimes accompanied by vague mumblings about “ethical considerations” and “women’s choices.” But these discussions are inadequate unless they also take into account the historical, social, cultural, and economic factors behind the development, expansion, acceptance, and critiques of genetic testing technologies.

To develop a full understanding of prenatal testing, we need to ask difficult questions with thorny, complicated and uncomfortable answers. What was the impetus for the introduction of prenatal diagnosis in the 1960s and 1970s? Why were researchers studying birth defects, cell culturing techniques, and karyotypes at that particular time? How have changing attitudes toward disability, abortion, and reproductive rights shaped, and been shaped by, prenatal diagnosis? What path does a test follow from being offered to a very small and select percentage of the pregnant population to becoming a routine part of every pregnancy? Why are there regional and historical differences in the acceptance, application, and history of prenatal testing? Why is it nearly impossible to have a discussion about prenatal screening that is not also a discussion about abortion?

Well, I don’t feel so lonely anymore after having read Ilana Löwy’s new book, Imperfect Pregnancies: A History of Birth Defects & Prenatal Diagnosis (Johns Hopkins University Press, 2017). The title pretty much tells you what the book is about, but it is more than just a recitation of discoveries and events. The author, an emerita research fellow at the French National Institute of Health and Medical Research, argues that prenatal testing can best be understood in the context of Michel Foucault’s concept of a dispositif – loosely speaking, the institutions, social factors, laws, regulations, scientific and professional practices that create, maintain, and reinforce a body of knowledge and give it power (no doubt some Foucault scholar will take issue with my description, but you get the general idea). But Löwy’s book is not a high falutin’ study of abstract theories of knowledge. It is concretely embedded in a richly detailed analysis – some of it original and some of it summarizing the work of others – of how we have arrived at the point where prenatal testing, particularly ultrasonography and now NIPT, has become integrated into the routine care of nearly all pregnant women in many Westernized countries.

Let me acknowledge some intellectual conflicts of interest up front: the author cites some postings to The DNA Exchange by me and others, references some of my publications, and thanks me – among many others – in her introductory section. No doubt these small ego strokes influenced my perceptions of the book in ways that I can’t fully recognize.

Imperfect Pregnancies opens with the somewhat artibitrary but reasonable starting point in the late 19th century and the work of obstetricians John Ballantyne and Adolphe Pinard, in Scotland and France respectively, on the nature and causes of birth defects and the medical supervision of pregnancy that they felt was necessary to ensure the delivery of a healthy baby. From there she ties in the history of cytogenetics and karyotyping, congenital malformations and dysmorphology, the emergence of amniocentesis and prenatal ultrasonography in the 1960s and 1970s, the introduction of serum and sonographic screening for Down syndrome in the 1980s and 1990s, and right up to the  latest testing technologies of the early 21st century such as comparative genomic arrays and noninvasive prenatal testing (NIPT).

This is not a scolding work that draws a straight historical line from eugenics to prenatal diagnosis. While eugenic criticisms are certainly valid concerns about the potential ramifications of prenatal testing and that is true that the development of prenatal diagnosis was a clear reflection of negative attitudes toward disability, the Eugenics Movement per se was not a driving historical engine behind prenatal testing. Still, Löwy makes it clear that prenatal diagnosis was established in the context of a public health model to permit and passively encourage abortion (as the introductory quote at the start of my posting suggests) of aneuploid or otherwise “defective” fetuses under the justification of allowing parents to have as healthy a baby as possible, and that was maintained by the social, ethical, medical, legal, and economic factors that made this possible (i.e., the dispositif). Pregnant women were enticed by tests that offered reassurance but some were left with the messy situation of what to do when the testing did not come back with normal results and had to make extraordinarily difficult decisions about how to proceed in largely uncharted territory, a situation genetic counselors know all too well. In the words of one researcher, women were forced “to become skilled managers of fetal risk.”

The author brings an international perspective to her narrative, including experiences with prenatal testing in the US, the UK, France, Israel, Brazil, and Scandinavia, among others. Prenatal testing is managed differently in each country according to unique local circumstances and this has an impact on uptake of testing and abortion. For example, in the Netherlands, where a detailed discussion of screening is routinely incorporated into pregnancies largely by midwives in a non-medical setting, the uptake of testing is much lower than in countries where there is less discussion and is physician driven. In Brazil, where abortion for fetal indications is limited to anencephaly, the uptake of NIPT is much greater among upper socio-economic status who have access to safe (if technically illegal) abortion compared to poorer women who do not have such ready access. Laboratory marketing has taken advantage of the social status associated with having the latest medical tests among Brazilian women, especially during pregnancy, to further integrate NIPT into routine care. In places around the world where women are likely to leave the work force and devote themselves full-time to child rearing, the uptake of prenatal testing and abortion is lower than in areas where women continue to work after childbirth.

The limitations of the early technologies are somewhat shocking from the biased perspective of today. When John Edwards analyzed the unbanded karyotype of  the first patient with his eponymous syndrome, he thought the underlying cytogenetic abnormality was trisomy 17 rather than trisomy 18 until Klaus Patau (who first described trisomy 13) set him straight. In Riis and Fuchs first reports of prenatal diagnosis of fetal sex among hemophilia carriers in Denmark in 1960, one woman proved to have a female fetus that she miscarried after amniocentesis, went on to have another female fetus that also miscarried after amniocentesis, a third pregnancy that was a male and was aborted, and finally had a fourth pregnancy in which the patient successfully carried the pregnancy to term after a female fetus was correctly identified by amniocentesis (I can envision many prenatal genetic counselors simultaneously nodding and shaking their heads right now). Of the first 20 attempts at identification of fetal sex among hemophilia carriers in Riis and Fuchs series, 17 were successful, two resulted in failure to establish fetal sex, and one female fetus was mistakenly identified as male and the pregnancy was terminated (I can hear many prenatal genetic counselors now saying “Ouch!”).

There are a few areas I think the author leaves largely under-explored. Although she gives thoughtful discussion to genetic counselors, I think she understates their importance in ushering in, shaping, and managing each new prenatal testing technology. We have been the boots on the ground as each test was introduced into clinical practice, more or less left alone with patients to negotiate the complicated medical, ethical, and psychological ramifications of “simple blood tests” and “routine sonograms” gone awry.

In the early sections of the book Löwy details the role that obstetricians played in the historical pathways leading up to prenatal testing. However, there was little mention of the obstetricians who worked closely with clinical geneticists and sometimes became board certified in genetics themselves in the 1970s and 1980s – Mickey Golbus, Larry Karp, Mike Mennuti, and Joe Leigh Simpson, to name a few.

I would also like to have seen fuller discussion of the Professional Liability Alert issued by the American College of Obstetricians and Gynecologists in May of 1985, which stated: It is now imperative that you investigate the availability of these tests in your area and familiarize yourself with the procedure, location, and mechanism of the follow-up tests to screen for neural tube defects. Although to the best of my knowledge no one has ever studied the impact of this Alert on the uptake of maternal serum screening in the US, I know that the immediate  impact in my neck of the woods was profound and long-lasting. Most of the obstetrical care providers in the Seattle area suddenly started strongly recommending AFP screening to their patients and it set the tone for the ready acceptance of most other prenatal screening tests that followed over the next 30 years. Although the book briefly mentions obstetricians’ concerns about legal liability, she does not go further down this street and I believe incorrectly attributes it to the AMA’s “concerns.”

But these latter points do not detract from the overall achievements and arguments of Imperfect Pregnancies. If you are a supporter or a critic of prenatal testing, or, like many people, decidedly ambiguous, there is much that you will learn and much that will make you pause and re-examine your own views and knowledge base.


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Tony Holzman, now retired from Johns Hopkins and who contributed so much valuable research on the social, ethical, and psychological aspects of genetics, is now a novelist. He has published several novels including Blame, about murder and intrigue in genetics research at the NIH. Tony is now working on publishing his newest novel, The Bethune Murals. The novel is based on the true life story of a physician who was diagnosed with TB and was confined to the Trudeau Sanitarium in the 1920s and who produced a remarkable set of murals on paper used to wrap laundry at the institution. Tony is looking to self published his book through Amazon but needs to get enough votes in an Amazon competition. If you have an Amazon account, you can vote for Tony here.

 

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Is Down Syndrome Disappearing? Well, Not Exactly But….

Iceland has given the world the Eddas, Sigur Rós, Björk, and some magnificent geology.  A more ambiguous achievement, though, is suggested by a recent CBS News story that claimed that Down syndrome is disappearing from Iceland as a result of prenatal testing. The claim has been bouncing around the Internet for a few years. The earliest reference I could find was a November, 2015 letter sent to the Office of The United Nations High Commissioner for Human Rights authored by Downpride, an international advocacy group for people with Down syndrome. The letter is an “[a]ppeal to the United Nations to stop discriminatory use of prenatal genetic screening aimed at eradication of people with Down syndrome and other groups.” It was, in my view, an understandable and justifiable reaction to largely non-critical widespread adoption of Noninvasive Prenatal Testing (NIPT) from a community that has good reason to be concerned. Needless to say, it generated a lot of heated reaction. Just Google “Iceland Down syndrome” and you will see what I mean.

Delving into the story was like getting lost in a hall of mirrors; many sites simply referenced each other. But the claim that Down syndrome is disappearing from Iceland and that 100% of pregnancies with Down syndrome in Iceland are terminated turns out to be not quite so straight-forward. While Iceland represents a microcosm of the larger concerns of people with disabilities, their families, and their supporters, it is not necessarily an accurate reflection of the macrocosm of the larger population dynamics of Down syndrome in other countries, particularly the United States.

The ultimate source of the data, according to the Downpride letter, was testimony presented to The Althing, the Icelandic parliament that is the world’s longest existing legislative body. I tried unsuccessfully to find that testimony. I then searched PubMed but found only limited help. So I decided to do my own back-of-the-napkin calculations. I obtained the birth distribution by maternal age in Iceland for 2016, and grouped the ages by quinquennia. The expected frequency of Down syndrome was based on data from 1976, prior to the advent of widespread prenatal diagnosis.

Age Group # of Births Exp. Frequency of Down S. Exp. # of births with Down S.
15-19 72 1/1667 0
20-24 592 1/1587 0.37
25-29 1305 1/1087 1.2
30-34 1218 1/763 1.6
35-39 672 1/248 2.7
40-44 165 1/79 2
45+ 10 1/24 0.4
Total 4034  1/488 8.27

 

Thus, in Iceland in 2016, there were 4034 births. In the absence of prenatal diagnosis and selective termination, 8 or 9 babies with Down syndrome would be born, for a frequency of ~1/450-500 births. I then made the following assumptions, acknowledging that each has some potential error:

  • Based on a 2016 publication, about 80% of pregnant Icelandic women will choose to undergo prenatal screening
  • According to Dr. Hulda Hjartardóttir, chief of obstetrics at Iceland’s National University Hospital, among Icelandic woman who have a positive screen, about 25% decline diagnostic testing and continue the pregnancy. Thus, roughly 1/3 of Icelandic pregnant women either do not undergo screening to begin with or decide to continue the pregnancy and not proceed to diagnostic testing if a screening test is positive. The impact of these percentages on Down syndrome frequency depends on the age distribution of those who declined screening or diagnostic testing, but for argument’s sake, I assumed an equal distribution across maternal ages.
  • 100% of women whose pregnancies are diagnosed with Down syndrome will choose to terminate. I could not verify this claim, but I decided to go with the most extreme scenario. This has not been the experience in many countries, where termination rates have been high but not typically 100%.
  • The CBS News story mentions the Combined Screen, so I assumed this was the standard screening test in Iceland when the claims were made in The Althing. I therefore set the detection rate for Down syndrome to 90%, that is, of all women undergoing screening, about 10% of pregnancies with Down syndrome will be screen normal and would not proceed to termination (some studies suggest that the Combined Screen may have a sensitivity somewhat less than 90% but because about 21% of pregnancies in Iceland occur in women 35 and older, a higher sensitivity – and false positive – rate is expected).

Based on these assumptions and the above table, of the potential 8-9 babies born with Down syndrome, about 2-3 would actually be born because their mothers did not undergo either prenatal screening or diagnostic testing, and another baby with Down syndrome would be born because the Combined Screen would be expected to miss about one case. In other words, the total number of newborns with Down syndrome in Iceland would be expected to drop from 8-9 every year to about 3, maybe 4, per year. These numbers could increase or decrease with many factors, such as changes in fertility rates, maternal age distribution, the sensitivity of screening tests, social trends that influence the choice of abortion, and random fluctuations that occur with any demographic trend especially with the small number of births in Iceland (about that many babies were born last year in the hospital where I work in Seattle). If readers know of empirical data from Iceland to support or refute my estimates, please share it.

Of course, for advocates, every loss of a pregnancy with Down syndrome is serious, no matter how small the number. But these estimates put the concerns in some perspective. Among other things, it is fair to say that most, but not 100%, of pregnancies with Down syndrome are terminated in Iceland, and the birth prevalence of Down syndrome in Iceland is falling considerably but not likely, in my view, to disappear entirely.

I think a more realistic picture of the impact of prenatal screening on Down syndrome, in the US at least, is provided by Brian Skotko and his colleagues Frank Buckley, Jennifer Dever, and Gert de Graaf in a recent publication in the American Journal of Medical Genetics. Over the last few years, they have consistently provided some of the most reliable estimates of the demographics of Down syndrome and the effects of prenatal screening.

According to the de Graaf et al. paper, a detailed look at changes over time in the demographics of Down syndrome in 9 states, the number of people living with Down syndrome has steadily increased since 1950. The two major factors driving that growth have been longer survival due to better medical care along with the unrelenting trend of the last 35-40 years of delayed childbearing. This growth, however, has been partially offset by a loss of births with Down syndrome due to prenatal screening. The loss varies with geographic region, but overall, the prevalence of Down syndrome is roughly 70% of what it would be if prenatal screening were not available. Interestingly, the most growth in the Down syndrome population occurred among Hispanics and Native Americans. So, unlike the near elimination of Tay-Sachs disease in many Ashkenazi Jewish communities, the prevalence of Down syndrome is dropping, but not close to disappearing, at least in the US.

Other factors may affect the Down syndrome birth frequency, such as changes in maternal age distribution, availability of abortion, and access to health insurance. For example, in the highly unlikely event that every woman 35 and older refrained from pregnancy, the birth frequency of Down syndrome in the US and many Western European countries would be reduced by more than 50%. On the other hand, if abortion were to become illegal (not highly unlikely), then presumably the birth frequency of Down syndrome would increase. Limiting access to good medical care (unfortunately also not highly unlikely in the US) could lower the overall prevalence of Down syndrome because of reduced survival.

Current trends suggest that, for the immediate future, prenatal screening will continue to reduce the birth prevalence of Down syndrome. It is becoming increasingly easier for women to undergo prenatal screening and more difficult to just say no. This is due to aggressive marketing by commercial labs of “newer, better, bigger, cheaper” screening tests like NIPT; the dearth of time and resources devoted to unbiased education about Down syndrome and the pros and cons of screening tests; inequitable social distribution of medical resources and social support; and the rarity of long, difficult discussions between pregnant women/couples and their providers about whether they should even enter the prenatal screening cascade to begin with. It also does not help matters that the current US President lacks any moral decency and takes pleasure in mocking people with disabilities.

Although I am a strong supporter of women’s reproductive rights and well-informed, gut-wrenching decisions to terminate a pregnancy, it is becoming increasingly difficult to provide ethical justification for further expansion of prenatal screening, or expanded carrier screening for that matter. This is something that society needs to address but particularly genetic counselors because we are in the thick of it.

As I have previously argued, almost no research has been conducted that has tried to demonstrate whether prenatal screening can improve the medical, social, and emotional lives of people with disabilities and their families. Some women undergo prenatal screening because they think it will prepare them for raising a child with Down syndrome, but we really can’t tell them if screening does help or if it is worth their emotional and psychological investment. Carrying out such research is critical. If we can demonstrate broader benefit of prenatal screening, then we can open up a dialogue with the disability community rather than continue the shouting matches, and offer greater and more equitable justification for NIPT and other screening technologies.

Or we can continue shouting at or dismissing one another.

 

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1193 to 4

Prenatal diagnosis of Down syndrome has long presented an ethical dilemma for the genetic counseling profession. As genetic counselors are fond of saying , we strongly support women’s reproductive decisions, including both continuing and terminating pregnancies wherein a fetus has been diagnosed with Down syndrome or other condition. But also in the oath that genetic counselors swear to,* we claim to be strong supporters of the rights and dignity of people with disabilities. The disconnect between these ethical imperatives leaves genetic counselors open to justifiable criticism from people with disabilities, their families, and their advocates. How can we simultaneously support people with disabilities while at the same time participate in a screening program whose primary purpose is to sort out fetuses who have certain disabilities?

The typical response to this criticism is that patients have choices about whether or not to undergo prenatal screening for Down syndrome, and genetic counselors try to be value neutral in supporting patient choices (for the moment leaving aside the economic and social realities that limit women’s choices and that genetic counselors have no control over). One of the purported benefits of prenatal screening for Down syndrome is that it allows couples to prepare for the birth of a child who may have special needs. And as many of my patients’ obstetricians used to say to them, we can be better prepared medically for the baby’s birth. Seem like reasonable points, no?

Well, they do seem like reasonable counterpoints. But this got me thinking – just how much research has been done on the extent to which prenatal diagnosis enhances familial adaptation to a diagnosis of Down syndrome, and how much does it improve the medical and developmental picture for the newborn with Down syndrome? In short, I wanted to know how much benefit people with Down syndrome and their families gain from prenatal diagnosis.

To help answer this question, I performed a PubMed search using these broad terms: Down syndrome, prenatal diagnosis, prenatal screening. I set the parameters to English language articles with abstracts for the ten years prior to September 18, 2015. This produced 1373 articles, 176 of which I eliminated because they were not primarily about prenatal screening for Down syndrome, leaving 1197 articles. I then read the abstract of each article for evidence that the research addressed the benefit of prenatal screening to postnatal adaptation of families or improved medical outcomes for liveborn children with Down syndrome.

1193 articles addressed sensitivity, specificity, assessing test performance, comparison of screening techniques, patient anxiety, ethical critiques both pro and con, program implementation, patient education, economic/cost benefit analysis, circulating placental DNA, maternal serum biochemical analytes, ultrasound markers, psychological responses, termination rates, decision making, etc..

The number of articles that addressed my primary question? Four.

And even this number is a bit of a stretch. Two of the four articles were speculative pieces about how prenatal diagnosis may one day allow options for treatment. These two articles shared a primary author and one article was basically a slight update of the earlier article.

The other two articles reported on the experiences of women who received a prenatal versus a postnatal diagnosis of Down syndrome. One article reported that women had a difficult time with how the diagnosis was delivered whether it was prenatal or postnatal. The other article reported that a majority of women who received a prenatal diagnosis of Down syndrome and continued the pregnancy felt that they would undergo prenatal screening in future pregnancies for emotional preparation.

I recognize the shortcomings of my quick analysis. No doubt I missed a few articles. PubMed search results vary significantly with the search terms and parameters, and I swear sometimes with the phase of the moon (speaking of which, the upcoming eclipse of the Blood Moon/Harvest Moon September 27-28 should be spectacular, though it may affect PubMed searches that are conducted during the event). Abstracts may not accurately convey the research findings. And of course the search does not include articles published in languages other than English or that were published before September, 2005. So if you know of articles that I missed, please point them out in the Comments section below. Heck, do a PubMed search yourself and see what you come up with. Prove me wrong, please.

If we are going to honestly present prenatal screening as a choice, the choices have to be more than Abort or Carry To Term, unless of course we want to make the uncomfortable acknowledgement that the primary purpose of prenatal screening is to avoid the birth of children with Down syndrome. Pregnancy termination is important for many couples and we should support patients in their reproductive decisions whatever their motivations, but we also need to show a wider range of benefits from prenatal screening.

Ten years and not even a handful of published research about the benefits of prenatal screening for people who have the very condition that is being screened for. Come on, we can do better than this. Our patients deserve better. Shame on us.

 

* – Okay, I admit that I made up the oath part, but it is so ingrained into our core ethos when we are trained that it may as well be the genetic counseling equivalent of the Hippocratic oath.

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Ohio seeks to criminalize abortion based on a prenatal diagnosis of Down Syndrome. Can they do that? The answer may be more complicated than you think.

This fall, the Ohio State Legislature will vote on a bill that would make it illegal for a woman to get an abortion if she is terminating the pregnancy because her fetus has Down syndrome. If passed – and it is expected to pass – the bill must be signed by Governor John Kasich, who happens to be running for the Republican nomination for president. That should tell you everything you need to know about the chance of a veto.

Ohio is poised to join North Dakota as the second state to restrict abortion from being used to prevent the birth of a child based on a prenatal diagnosis. North Dakota’s law does not specify Down Syndrome, but makes it a crime to perform an abortion that is sought because of a “genetic anomaly.” You might think this restriction is unconstitutional under Roe v Wade — and you might be right about that – but as of today the North Dakota law remains on the books. Abortion rights advocates considered a challenge, but decided that the law was impossible to enforce, and therefore not worth the time and expense.

Beyond the Orwellian specter of a law that parses women’s motivation — and the perversity of allowing abortion only when a fetus is healthy – these laws demonstrate a deeper truth: anti-abortion activists have taken aim at prenatal diagnosis. Rick Santorum’s attack on amniocentesis in 2012 may have been badly articulated, but ideologically like-minded employers have embraced his call to cut off funds for prenatal testing. Genetic counselors may not feel that prenatal testing and abortion are two sides of the same coin, but it is important to understand that the rest of the world sees a clear and causative relationship between testing and termination.

Geneticists are not fortune tellers – a point we are forced to make frequently – and it is hard to predict what will happen in the courts BUT you have to assume these laws would not survive a legal challenge. If it stands it is hard to imagine a prosecution. How do you prove motivation?

Does that mean it doesn’t matter? A recent Bioethics Forum post noted that It seems odd to allow prenatal testing for Down syndrome – which the American College of Obstetricians and Gynecologists has recommended should be offered to all pregnant women – and then deny women the opportunity to decide what to do with the information.” This was meant as a criticism of the law, but there’s amore chilling implication. If you want to prevent abortions based on prenatal diagnosis, you can restrict the right to abortion OR you can restrict the right to prenatal diagnosis. One of these things is unconstitutional. What about the other?

There are objections you could raise. Free speech! Yes, but telling your patient about prenatal diagnosis isn’t going to help if her health plan refuses to pay for it. The sacred doctor-patient relationship! Yes, but remember that many states already have laws requiring doctors to read from a script to any woman seeking termination. In some states women seeking abortion are told, by law, that abortions are associated with breast cancer. Are you surprised to hear about this alarming association? That’s because it isn’t true.

If you believe that a fetus is exactly the same thing as a baby – and despite widespread uneasiness with abortion most people do not – then prenatal diagnosis is offensive. One typical and less confrontational approach to this attack is to talk about the value of prenatal diagnosis apart from termination. This feels like safer ground, but I would argue that it is short-sighted. Even if prenatal therapies improve, and there are some promising things in the works, testing will remain a vehicle for giving couples the option of termination, and when we deny that fact we look cagey and defensive. We open ourselves to the same charges of hypocrisy that we throw at anti-abortion advocates who cloak themselves in the language of the women’s rights movements. “We are just empowering women,” they say of mandated anti-abortion scripts. No, you are not. “We are fighting for women’s health,” they say, of regulations that put abortion providers out of business. No, you are not.

We need to be prepared to make the argument for what we do. Carefully and sensitively, but transparently, and without shame. We help families have healthy children and that’s a good thing and not a bad thing. We help people make the choices that are right for them. People in this field know that restrictions on prenatal diagnosis are not empowering. We know who they will end up hurting – the poor the young, the vulnerable – all the usual suspects. Prenatal diagnosis is not going away anytime soon. But keeping it available to everyone is going to take work and vigilance.

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Guest Post: Sometimes It’s Okay To Fail

by Lisa Demers and Stephanie Snow

Stephanie Snow, MS, CGC has 11 years of prenatal genetic counseling experience. She worked as a clinical site coordinator and genetic counselor for the FASTER study and as a clinical research coordinator for the NEXT study. Lisa Demers, MS, LGC has 12 years of prenatal genetic counseling experience and currently works with Ariosa Diagnostics as a Medical Science Liaison.

The landscape of prenatal screening is changing. The use of non-invasive prenatal testing (NIPT) in clinical practice is already common and is being adopted quickly by generalist obstetricians and maternal fetal medicine specialists. While the cell-free DNA technology is innovative and the impact on patient care is significant, there is a rising chatter about NIPT failures – the 1-8% (depending on the company) of reports that return without a test result. This is a dual issue – there’s the underlying “annoyance” that NIPT occasionally fails to produce a result, and then there are publications suggesting an association between fetal aneuploidy and test failure. The latter is a conversation for another day.

Although these “no call” results frustrate patients and their doctors, the negativity surrounding these failures is surprising. The concept of a test failing is not new in medicine, and certainly not within prenatal medicine. Increasing rates of maternal obesity are just one reason for limited prenatal surveillance, with one study demonstrating that 41% or less of fetal survey ultrasounds on patients with a BMI of 30 or higher were able to be completed on the first try. When it comes to first trimester measurement of nuchal translucency (NT), the FASTER trial noted an overall 7.5% failure rate, either because of an inability to measure or due to inaccurate measurement. In a review of patients within one clinic, where nearly 50% of patients had a BMI over 25 and 25% had a BMI of 30 or more, 4% of patients had an NT failure on the first attempt and of those who opted for a second attempt, 18% failed. Overall in this population, 2.7% of patients did not achieve a NT measurement.

This is not to say that test failures are necessarily bad. When an NIPT test fails, it is often because quality metrics are in place to ensure proper test performance – just as there are standards for NT measurement which are established by the Fetal Medicine Foundation (FMF) and the Nuchal Translucency Quality Review (NTQR) program. An NT may “fail” because a patient presents for screening outside of the appropriate gestational age requirements or because of suboptimal fetal positioning. The nuchal translucency measurement is critical in obtaining aneuploidy risk assessment when combined with serum biochemistry, and even the slightest over or under estimation dramatically impacts clinical care. Such is the case with NIPT quality metrics. These metrics are in place to ensure appropriate risk assessment for the pregnancy, with the most important of these being fetal fraction. Fetal fraction is greatly affected by maternal weight, with obese women less likely having the required minimum concentration of fetal DNA in circulation. Here again, maternal obesity reduces our ability to accurately assess the well-being of a fetus.

In reality, any test failure rate can be a nuisance to a busy clinic. Having patients return for an additional visit is inconvenient to patient and provider alike. However, there are biological and technical reasons for at least some NIPT tests to fail. The thoughtful provider will consider the various metrics involved with the NIPT options and select one that balances high quality metrics (including fetal fraction) and low rate of technical failures.

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Guest Post: PPV Puffery? Sizing Up NIPT Statistics

by Katie Stoll and Heidi Lindh

Heidi and Katie are genetic counselors and both work with the newly established charitable nonprofit, the Genetic Support Foundation (twitter @GeneticSupport), geneticsupportfoundation.org.

The importance of the Positive Predictive value (PPV) in interpreting Noninvasive Prenatal Testing (NIPT) results is increasingly on the minds of providers as evidenced by frequent discussions, presentations, and publications on the topic. But what if, in an effort to make their lab look like the best lab, the NIPT PPV was overstated in marketing materials or even on test reports? And what if providers and patients believed this information without question or further investigation?

Until 2014, four labs (Sequenom, Verinata Health/Illumina, Ariosa and Natera) were the only companies in the United States that offered NIPT. Over the past year, we have seen a burgeoning of new labs offering their own branded NIPT tests. In some cases, the 4 original companies act as “pass-through” labs in which the testing is branded and advertised through a secondary lab however the sample is ultimately sent to the primary lab for analysis and interpretation. In other cases, referral labs have brought NIPT testing in-house, developing their own algorithms and reporting, such as the case for the InformaSeqTM test offered by LabCorp and Integrated Genetics. In a recently published marketing document, Illumina lists 16 laboratory “partners” that all offer a version of the Illumina NIPT. The other primary NIPT labs are also distributing their tests through other labs as well; Quest Diagnostics and the Mayo Clinic have been secondary labs for the Sequenom NIPT (Quest also has their own brand, the “Q-Natal Advanced”and Natera’s NIPT is available through GenPath and ARUP).

The growing number of laboratories that offer some version of NIPT presents a significant challenge for healthcare providers who are struggling to navigate the various testing options to determine what is in the best interest of their patients. The competitive commercial landscape and aggressive marketing of NIPT to both patients and providers can further confound clinical decision-making given the paucity of information available to providers that is not delivered with an angle aimed at selling the test.

NIPT Statistics in Marketing Materials

We have noted that multiple labs offering testing have promoted extraordinarily high positive predictive values (PPVs) in their marketing materials distributed over the past year and on their websites ^ and on laboratory test reports. These tables include information regarding PPV frequently reference data from the Illumina platform and VerifiTM methodology and a study by Futch et al. as the source.

 

Performance Data Presented in Marketing Brochures for NIPT
Condition PPV NPV Sensitivity Specificity
T21 0.994 0.999 >99.9% 99.8%
T18 0.910 0.999 97.4% 99.6%
T13 0.843 0.999 87.5% >99.9%

These figures (or slight variations thereof) have been observed in the marketing materials for multiple laboratories offering NIPT. These specific statistics were reproduced from an InformaSeq brochure and sample test reports available online

 

The PPVs reported in this table – being widely distributed on test reports and as educational information for providers – have NOT been demonstrated by the referenced study by Futch et al. or any published NIPT studies of which we are aware.

Of course, the PPV of a screening test depends on the prevalence of the condition in the population being screened. Using the sensitivity and specificity of testing accompanying these predictive value data in the same brochure, one could only derive PPV of >99% if the prevalence of Down syndrome in the screened population was 25% or 1 in 4 pregnancies, far higher than the a priori risk for the vast majority of women undergoing prenatal screening.

PPV = (sensitivity x prevalence) / ((sensitivity x prevalence) + (1 – specificity)(1 – prevalence))

.994 = (.999x.25)/((.999x.25) + (1-.998)(1-.25)

In contrast, if we utilize performance statistics provided by the laboratories, we calculate a PPV of 33% in a population with a prevalence of 1 in 1,000 (which is similar to the prevalence for women in their 20’s) and a PPV of 83% in a population with a prevalence of 1 in 100 (which is similar to the prevalence in women age 40).

The Futch Factor

The study by Futch and colleagues that is frequently cited in marketing materials for NIPT does not demonstrate the high PPVs that are referenced, although we suspect that these statistics were arrived at through a series of assumptions about the Futch data that we will attempt to outline.

This study reported that in a cohort of 5,974 pregnant women tested, there were 155 positive calls for T21, 66 positive calls for trisomy 18, and 19 positive calls for trisomy 13. In this published report, only a fraction of the positive NIPT results had confirmation of the fetal karyotype, 52/155 cases of Down syndrome (33.5%); 13/66 cases of trisomy 18 (19.7%); and 7/19 cases of trisomy 13 (53.8%). There was 1 case of Trisomy 21 that had a normal NIPT result (false negative result), however negative test results were not methodically followed-up, so the true false negative rate for the screened conditions is unknown.

In analyzing the data presented by Futch et al, for marketing materials to derive PPVs of >99% for Down syndrome, 91% for trisomy 18 and 84% for trisomy 13 would require that all of the positive calls WITHOUT follow-up by karyotype confirmation were true positives.

 

Outcomes data from Futch et al, 2013 and projected PPVs based on category inclusion or exclusion as true positive.
T21 T18 T13
NIPT Positive 155 66 19
Confirmed (karyotype or birth outcome) 52 13 7
Discordant (Unexplained NIPT results that do not match karyotype from a source or birth outcome) 1 6 3
No information (laboratory did not obtain any information on outcomes) 22 12 0
Pregnancy loss (miscarriage , demise or termination without karyotype) 7 5 2
Unconfirmed (no karyotype or birth outcome known but history of clinical findings suspicious of aneuploidy such as ultrasound findings or high-risk biochemical screening results ) 73 30 7
Total Positive NIPTs where follow-up karyotype not confirmed 102 47 9
High End PPV* 99.4 90.1 84.2
Low end PPV** 33.5 19.7 36.8

*High end PPV- It appears that marketing material PPVs are considering all categories, including confirmed, no information, pregnancy loss, and unconfirmed to be TRUE positives in determination of PPVs.

**Low end PPV- calculated considering all cases, which were not discordant to be false positive results. A minority of positive NIPT results were confirmed with birth outcome or fetal karyotype information.

 

Given that Futch et al. did not have confirmed fetal karyotype or birth outcome follow-up for the majority of positive calls, it seems at best unlikely, and at worst impossible, that all of these positive NIPT results were correctly called, rendering claims of such high PPVs in the marketing materials based on this assumption to be unfounded. On the other end of the spectrum, if the PPV was calculated to include the not-karyotyped/no-birth outcome information pregnancies as false positive, the assumed PPVs would be 33.5% for Down syndrome, 19.7% for trisomy 18 and 36.8% for trisomy 13. Since the study does not report follow-up karyotype for the majority of positive test results, the true PPV for these NIPTs test likely lies somewhere in-between the high end PPV and low end PPV, perhaps closer to the 40-45% (for T18 and T21) previously reported in another Illumina sponsored study.

While the PPV of NIPT for Down syndrome, trisomy 18 and trisomy 13 exceeds that of traditional biochemical screening, no studies have demonstrated test performance as high as those presented in many of the PPV/NPV tables that are being provided to healthcare providers in marketing materials and, in some cases, on test reports.

A Call For Truth In Advertising And In Test Reporting

Honest communication about test performance metrics must be available to providers so that they can provide accurate counseling to patients making critical decisions about their pregnancies. While most labs do state that NIPTs are screening tests and that confirmatory testing of positive results is recommended, it is not surprising that providers and patients are having difficulty appreciating the possibility of false positive results when the laboratories are incorrectly reporting positive predictive values that exceed 99%. The consequences of relying on lab-developed materials rather than a careful analysis of the available literature are significant. There are reports of patients terminating pregnancies based on NIPT results alone. It is not surprising that some women choose not to pursue diagnostic testing to confirm abnormal NIPT results given the very high stated predictive value.

It is imperative that we recognize not only the potential benefits of these new technologies but also their risks and limitations. Testing companies are primarily responsible to their shareholders and investors, so information provided by companies about their products is largely aimed at increasing test uptake. Professional societies need to call for independent data and federal funds need to be made available to support independent research related to NIPT. Policies and best practices cannot arise from the industry-influenced studies that are currently available. While some regulatory oversight of marketing materials will likely be necessary, we urge the laboratories to consider their marketing approach and how it is affecting patients and providers. If laboratories want to truly partner with patients and providers, they need to provide accurate and straight-forward information to limit provider liability and likewise, help patients avoid making life-changing decisions based on inaccurate and/or confusing information related to test performance. As a medical profession can we come together and make this change without regulatory oversight? Now that would be a medical breakthrough.

^ – Notably, Counsyl has also recently produced a table that provides more accurate estimates of their NIPT predictive values

 

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Guest Post: NIPS: Microdeletions, Macro Questions

by Katie Stoll

Katie Stoll is a genetic counselor in Washington State. She graduated from the Brandeis University training program in 2003 and since that time has held positions in the areas of prenatal, pediatric and cancer genetics. 

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At the recent National Society of Genetic Counselors Annual Education Conference in New Orleans, a presentation raised some important questions about noninvasive prenatal screening (NIPS). According to the speaker, a woman with a vanishing twin pregnancy underwent NIPS with an expanded microdeletion panel and the results showed findings “suggestive” of a chromosomal microdeletion syndrome.

The patient underwent amniocentesis with a SNP microarray and the results were normal. In a follow-up call with the NIPS lab, the genetic counselor learned that multiple copy number variants were observed (not originally reported) in the original sample. The lab suggested that these variants could be associated with a malignancy or fibroid tumor (and were of course unlikely to be associated with a microdeletion syndrome in the fetus).

As a result of this genetic counselor’s follow-up phone call and due diligence, the patient underwent an extensive work up for possible cancer, but no explanation was found. NIPS was repeated and this follow-up study was normal.

My first thought in hearing this case was – That poor woman! First a lost twin pregnancy, then concern for a severe condition in her baby, anxiety about the amnio, and worry that she may have Cancer. Although I am not a health economist, my second thought was – Holy Cow! How can our healthcare system afford all of the follow-up testing that may come downstream from these tests? NIPS is promoted as a test that will lessen the need for follow-up procedures such as amniocentesis, but will that remain true as the list of screened conditions increases?

In October 2013 Sequenom expanded their NIPS test to include screening for microdeletion syndromes and Natera followed suit in Spring 2014. Some new companies entering the NIPS market are also advertising screening for microdeletion syndromes.

The addition of microdeletions is a brilliant business strategy for expanding the testing market to include all pregnant women. Even though microdeletions are rare, their incidence—unlike that of Down syndrome –is not linked to maternal age. Women who are currently not offered NIPS because they are not included in the high-risk categories proposed by the American College of Obstetricians and Gynecologists (ACOG) guidelines could now be given a reason to undergo NIPS—even though the predictive ability of the NIPS for rare conditions is less than impressive.

Women who elect the test because of an interest in Down syndrome or because they are eager to learn fetal gender may unknowingly be screened for rare microdeletion syndromes which they know little to nothing about. To add to the complexity, a maternal microdeletion condition may be an incidental finding. In a poster presented at the NSGC meeting this year, Sequenom presented a series of 22q11 deletions detected with their MaterniT21 PLUS test. Included in this report were two mothers who were themselves incidentally diagnosed with 22q11 deletion syndrome. Based on the consent form on the Sequenom website it seems unlikely that these women had any idea such a result may occur.

Where is the evidence to support this expanded screening?

These tests are being performed despite there being no published clinical validation studies. There have been some case reports and proof of concept studies; however given that this testing has been commercially available for over a year now, there is shockingly little published about cell free DNA screening for microdeletions. An abstract from a poster presentation at the ACOG annual meeting in April 2014 evaluated 6 samples (or is it 7? – it is not clear from the abstract) from pregnancies known to be affected with microdeletions and 8 simulated samples. They conclude, “This is the most comprehensive, accurate validation of noninvasive microdeletion detection hitherto… This approach will enable accurate, noninvasive, prenatal population screening for these severe disorders.”

Proof of concept is one thing; proof of clinical validity is another. If we value evidence-based medicine, a sample of six (or seven) affected pregnancies is a long way from being a basis for population screening. Whether population-wide screening for extremely rare disorders is worth paying for is, of course, a question in itself.

But in the unregulated environment of laboratory-developed tests, we adopt first and report out results later. Accompanying this process is a lack of transparency – labs performing NIPS with microdeletions have not made performance statistics publicly available and thus patients and providers have no way of determining the accuracy of microdeletion NIPS. In a webinar hosted by Sequenom , the presenters were asked about the positive predictive value (PPV) of Sequenom’s screen for microdeletions. One speaker replied, “We have calculated them. However, what we would like is essentially to wait a little bit to give you more clinically relevant results. Because so much depends on the fetal fraction of the sample and so on and so forth, so we feel that the more appropriate number to release is after we have done 50,000 samples, how many have we found, how many have we reported back, how many were confirmed, how many were in line with the clinical picture.”

Shouldn’t the accuracy of the test be publicly known before it is run clinically on 50,000 women?

Labs have given us only a glimpse of their performance statistics. I was previously provided information from Natera regarding estimated PPVs for the microdeletions on their panel, but I cannot locate this information anywhere in the public forum. The table I was provided stated a 1/19 PPV (5.3%) for 22q11 with a Fetal Fraction >6% and dropping much lower (to 1/45) with decreased fetal fraction (interesting thread here of multiple women with a 1/19 chance of 22q11 on their NIPS result).

In a letter to the editor, former CMO of Sequenom Allan Bombard and colleagues reported that they had evaluated 264 samples from pregnancies with known microdeletion and microduplications or “enriched genomic mixtures” and report a 100% sensitivity and 99.3% specificity. Applying these statistics to 22q11.2 deletion syndrome (the most common microdeletion syndrome on the panel with an incidence of 1 in 4,000) indicates a PPV of about 0.036 or 3.6% . The overall PPV would be expected to be lower given the very low incidence of the other microdeletions on the panel. At the NSGC meeting this year, Sequenom presented some preliminary data from a series of 120,726 samples screened from October 2013 – July 2014 with test performance that exceeds those estimates. Although they did not have complete follow-up data for positive and negative results, a press release from the company following the NSGC meeting reports “high positive predictive values (estimated combined PPV ranged from 62% to 94%)”.

The limited information available suggests PPVs for microdeletion syndromes fall within a broad range of <3% – >90%. Published peer-reviewed studies are needed to help clarify the PPV associated with this testing so that healthcare providers and patients can make informed decisions about utilizing and interpreting this testing.

About a year and a half ago I published a piece on the DNA Exchange that discussed the importance of PPV in interpreting NIPS results. This was written for an audience of genetic counselors, but the posting is being increasingly used as a venue for patients to share their stories and seek information about their test results. Many patients report considerable anxiety – “the waiting is killing us…we have been devastated for the better part of 3 weeks now” – and some express regret for undergoing this testing at all, “I too wish I would of just done the typical old fashion test so nothing was in the back of my mind and hours of my life would be given back…” Recently, a woman remarked that she did not consent to additional testing for microdeletions and indicates her frustration with not being able to find information about the PPV for this test, “Not only are they essentially experimenting on us…they are not transparent about the potential problems with validity or low PPV.”

As genetic counselors, we are implicated in these companies’ approach. We should be demanding better evidence before leading our patients towards testing that could create this kind of distress. We need to be asking good questions, and we should demand good answers. If we cannot figure out how reliable a screening test is from a thorough review of the literature, I think we really need to ask ourselves if we should be offering it in a clinical setting.

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