NEW YORK (GenomeWeb) — Hundreds of thousands of pregnant women have undergone noninvasive prenatal testing of circulating free DNA from the mother's blood, and the tests are beginning to move from high-risk to average-risk populations. As such, adopters are becoming aware of the challenges associated with replacing existing tests with NIPT.
Earlier this month at Cambridge Healthtech Institute's Advances in Prenatal Molecular Diagnostics conference in Boston, clinicians and researchers discussed the effects of the widespread use of NIPT in maternal fetal medicine, and pointed to noninvasive fetal cell analysis as a potential future alternative.
A concern voiced by many at the conference is that NIPT, currently a screening test for chromosomal aneuploidies and some deletions, reports on far fewer genetic abnormalities than invasive diagnostic testing by amniocentesis or chorionic villus sampling does, and cannot detect some problems that first trimester screening and ultrasound pick up. Yet many women seem to be unaware of this difference and perceive NIPT as a safe alternative to invasive diagnostic testing.
"Screening is becoming more like diagnostics, but for fewer potential phenotypes," said Ronald Wapner, a professor of maternal fetal medicine and the director of reproductive genetics at Columbia University Medical Center. "If we're going to use NIPT as a replacement for invasive testing, patients really need to understand the limitations and the differences in the information they will get."
For example, Wapner reported that of about 3,000 samples from the state of California's screening program that tested positive in conventional first trimester screening and had an abnormal result from the invasive tests that followed, only 85 percent would have been picked up by NIPT. The 500 or so abnormalities that NIPT would have missed included mosaics, other trisomies, insertions and deletions, structural variants, triploidies, and others. Thus, for patients that opt to undergo NIPT instead of invasive testing after a positive first trimester screen, the residual risk of carrying a fetus with a chromosomal abnormality remains 1 in 47, he said.
Yet, pregnant women seem to opt for the greater safety of NIPT, which does not carry the risk of miscarriage that an invasive test does but is a much narrower test. Several conference participants said they have witnessed a steep decline in invasive prenatal testing, both for amniocentesis and CVS, over the last couple of years, which correlates with the availability of NIPT. Women "have voted with their feet," according to Joe Leigh Simpson, senior vice president of research and global programs at the March of Dimes, so practitioners "have to look at noninvasive approaches, because that's what people want."
Others disagreed. For example, Arthur Beaudet, chair of the department of molecular and human genetics at Baylor College of Medicine, said he would recommend invasive diagnostic testing to women who are willing to terminate their pregnancy if a severe disability was detected. He said he does not favor the current replacement of invasive diagnostic testing by NIPT, which he said has resulted in the birth of children with very severe deletion syndromes that would have been detected by invasive testing.
But there are other reasons why more comprehensive diagnostic testing might be preferable over NIPT. According to Wapner, early knowledge about genetic disorders allows parents, for example, to be better prepared for a child with special needs and, in some cases, to intervene early with treatments. While the risk of miscarriage from an amniocentesis reported in different studies varies, it declines with increased experience of the clinician performing the procedure, Wapner said, and can be as low as 1 in 400 or 500.
Numerous participants called for better patient pre-counseling to make pregnant women aware of the differences, both in content and risk, between NIPT and invasive diagnostic testing, but the resources for such counseling are limited.
Wapner and others pointed out that pre-test counseling for NIPT in the US is currently mostly performed by obstetricians and gynecologists during the first prenatal visit, when there is little time to explain the test and alternatives in detail. While in-person genetic counseling for all obstetric patients seems impossible — because of a lack of genetic counselors and a lack of budget and reimbursement for such counseling — he said potential solutions could come from group and video counseling.
In the past, he said, the cost of genetic counseling was often built into the price charged by centers for invasive testing, but because the volume of invasive tests has gone down, and NIPT is performed by outside commercial providers, this is no longer possible to the same extent.
Non-invasive testing from fetal cells
An alternative to both current NIPT and invasive diagnostic testing could be noninvasive testing of fetal cells from the mother's blood, and several research groups — from Baylor College of Medicine, the University of Sherbrooke in Canada, and Columbia University — presented their approaches at the meeting.
According to Baylor's Beaudet, noninvasive fetal cell analysis "could blow everything else out of the water" and various groups have recently made progress on isolating such cells. The idea is to develop a test that can detect everything an invasive test can, as well as de novo mutations in the fetal genome, early in pregnancy and without the risk of miscarriage.
Such an analysis could be done with three to five fetal cells collected from the mother's blood in the first trimester — either nucleated red blood cells or trophoblasts — that could be analyzed by array CGH, SNP arrays, or next-generation sequencing after whole-genome amplification. However, the number of these fetal cells is small, and they are difficult to isolate, he said.
Several companies and academic groups are already developing methods for the isolation and analysis of rare cells, including fetal cells. Baylor has been collaborating with RareCyte on the recovery of fetal cells from maternal samples, followed by genotyping, Beaudet said, and is launching a new company, called Libra Genetics, that will focus on cell-based noninvasive prenatal diagnosis.
As clinicians have been dealing with the implementation of NIPT in their practice, others have been exploring ethical issues associated with the test. Vardit Ravitsky, a researcher in the bioethics program at University of Montreal, reported findings from research she conducted as part of the Personalized Genomics for Prenatal Aneuploidy Screening Using Maternal Blood (PEGASUS) study, which is comparing different noninvasive prenatal aneuploidy tests with conventional screening approaches.
Prenatal testing in general has been raising complex ethical and social issues since it was introduced in the 1960s, she said, and NIPT is likely to intensify those. Despite its benefits of decreased miscarriage risk, compared to invasive testing, and its ability to be conducted early in pregnancy, there have been a number of concerns around the test, Ravitsky said.
For example, as testing shifts from women at high risk for chromosomal aneuploidies to the general population, test volumes will increase, and some predict the number of abortions for Down syndrome will grow and fewer babies with the condition will be born, leading to less support and research for those affected by the disability. In Europe, she said, there has already been a backlash against NIPT from Down syndrome advocacy groups for that reason.
On an individual level, there is fear that NIPT will further increase pressure on women who test positive to terminate their pregnancies, she said, making it "socially unviable" to have a child with a trisomy, an issue that is already known from invasive diagnostic testing. And because NIPT carries no risk of miscarriage, it will be harder for women to refuse testing because they fear to be seen as "irresponsible and irrational."
As NIPT becomes routine, it will also get more difficult to offer pre-test genetic counseling to all women undergoing testing, who might be exposed to "unwanted diagnostic information" as a result.
Finally, NIPT might be used in the future to test for less severe or treatable conditions, as well as to obtain non-medical information, such as fetal sex, paternity, or physical traits. A particular concern is around fetal sex selection based on NIPT results, Ravitsky said, especially in countries such as India and China that already experience a gender imbalance. In response, there have been proposals in some countries, including Eastern Europe and Canada, to not reveal fetal sex from NIPT, she said.