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Prenatal Genomic Screening

New technologies bring new and old problems.

By Subhashini Chandrasekharan, PhD featured image Illustration by Lauren Crow

It has been known by many names — noninvasive prenatal testing (NIPT), noninvasive prenatal screening (NIPS), and noninvasive prenatal diagnosis (NIPD). More recently it’s been called cell-free DNA (cfDNA) screening, a term adopted by most professional societies. Since the tests first hit the market in 2011, much more than the name has changed.

NIPT has grown remarkably fast and is becoming the first-tier screen for most pregnant women in the developed world. We now know a lot more about how these tests perform in real-world clinical settings too, especially their limitations. Clinical studies now provide good evidence that NIPT can detect trisomies for chromosomes 21, 18, and 13 with greater accuracy both in high- and low-risk pregnant women than biochemical marker screening, which has been the standard of care. All major professional societies now recommend offering NIPT for screening of these three aneuploidies (chromosome-level genetic disorders) to all women, either as a primary screen or following positive results of biochemical serum screening.

The number of conditions included in tests has grown as well. Test panels now include sex chromosome anomalies, chromosomal micro-deletions, micro-duplications, and other rare autosomal aneuploidies. However, to date, clinical studies show NIPT’s ability to reliably detect these conditions is poor. Yet a variety of expanded NIPT test panels are on the market, despite a high rate of false positives.

Increasingly, health providers without maternal fetal medicine expertise or medical genetics training are gatekeepers of NIPT.

We’ve been down this road before: New technologies bring new — and old — challenges. Increasingly, health providers without maternal fetal medicine expertise or medical genetics training are gatekeepers of NIPT, helping families make decisions about testing options and decisions after testing. Outside academic medical centers, general OB-GYNs, family practitioners, and nurse midwives are on the frontlines. Yet these providers have few opportunities for acquiring and maintaining competency in prenatal genetics or genetic counseling. A recent study found that nearly a third of OB-GYNs learn about NIPT tests from company sales representatives and through company-generated education materials. Over half of the providers performed pre-test counseling themselves, and only about a third referred to a genetic counselor. In this study, most OB-GYNs also identified continuing medical education (CME) courses as their primary source of reliable information on NIPT.

My colleagues and I took a look at freely available online CME courses on prenatal genomic screening and found that, depending on the expertise of the educator delivering the CME, content varies considerably. In our analysis, most CME courses had poor coverage of topics like the lower accuracy of these tests for conditions other than common trisomies. Many courses did not discuss incidental findings and reasons for false positives. In one case the test was described as “near diagnostic.” Physician understanding about false positive results and the need for confirmatory diagnostic testing is critical for guiding families so that they do not make decisions about termination based on NIPT results alone. And the discussion of ethical issues, like termination or informed consent, was limited, if present at all.

In reality, most physicians and patients do understand NIPT is a screening test and not a diagnostic test, like invasive chorionic villus sampling (CVS) and amniocentesis. But some might think of NIPT as replacing the need for more invasive testing. Company-generated
patient-education materials that gloss over possible false-positive and false-negative results compound this misconception. Some women will still need diagnostic testing through invasive procedures like CVS and amniocentesis to confirm positive findings or to look for other potential genetic abnormalities not covered by NIPT.

Stakeholders in our research, including patient advocacy group representatives, maternal fetal medicine specialists, and genetic counselors, all shared anecdotes from personal experiences with patients who had undergone inappropriate testing, received incorrect interpretations of test results, and/or received outdated information on clinical and quality-of-life issues associated with copy-number-variation syndromes or sex-chromosome aneuploidies.

If NIPT is to have a meaningful impact on maternal and child health over the long term, we will need to get serious about figuring out whether our educational strategies are working and whether they are leading to better patient experiences and outcomes.

In an environment where marketing to nonspecialist providers remains aggressive and consumer advertising for these tests is pervasive, patient demand is often the driver of testing. General-practice physicians are likely to both fear malpractice liability and lack genetics education; thus, they will frequently order testing for all possible conditions, even if it is not medically appropriate.

The problem of educating physicians and patients about new genomic tests is hardly new. In a policy study, my colleagues and I found that issues related to physician and patient education made up half of the barriers to appropriate adoption of NIPT. And health providers themselves identified the need for reliable and unbiased information to improve their decision-making about test choices and follow-up options. More than 30 percent of clinicians recently surveyed sought more information on ethical issues and looked to professional societies for guidance on what to do.

No fewer than five professional societies, including the American Congress of Obstetricians and Gynecologists, offer NIPT guidelines for medical practices. But is that enough? Top-down approaches like guidelines and CME courses rarely integrate the actual needs and preferences of nonspecialist physicians. For example, nonspecialist OB-GYNs frequently mention lack of time to take online courses or long, web-based learning modules. Even hour-long recorded webinars and CME courses are often difficult to squeeze into their busy lives. The CME courses on NIPT that we analyzed dedicated a lot of time to describing the underlying technology platform (like massively parallel DNA sequencing) but failed to explain core concepts important for a practitioner, such as what “positive predictive value” of a test means.

The Genetic Support Foundation (GSF) and Perinatal Quality Foundation (PQF) have recently launched educational modules for patient and physicians, respectively. Patient education materials designed by GSF are visual, concepts are described in simple terms, and the videos are translated into Spanish to begin to address the needs of a diverse U.S. patient population. GSF even has a free positive predictive value (PPV) calculator on its site.

These developments are laudable, but we need more. Listening to the needs of OB-GYNs, nurses, and family practitioners, understanding the context of their practices, and allowing them to user-test and contribute to the design of courses can go a long way. We can learn a lot from patient advocacy groups about their experiences, quality-of-life issues, and how their members discuss NIPT results with other patients and family members. We can learn from genetic counselors and identify ways to distill and communicate core counseling concepts to nonspecialists who will increasingly perform pre- and post-test counseling themselves. We can learn from women and families about what they want to know when making decisions. And we can learn from industry, too, which has been very successful at creating and disseminating user-friendly education materials. Finally, how do we incentivize busy nonspecialists to take and complete education courses?

If NIPT is to have a meaningful, long-term impact on maternal and child health, we need to get serious about figuring out whether our educational strategies are working and whether they are leading to better patient outcomes. This is not a sexy area of research and it does not receive much attention or funding.

So, what to do? Relying on industry, government, or even professional societies, as we have until now, is problematic and unsustainable. No one group has the resources to do it all. Making sure that genomic technologies like NIPT can be used effectively and ethically clearly requires collective action by all stakeholders. It is time to come together.