Early findings regarding cell-free DNA screening for the detection of fetal aneuploidy in high-risk populations generated a great deal of buzz, but more recent research on the lower positive predictive value in the general population has tempered that excitement.
Further, reports that women are basing decisions about whether to continue their pregnancies solely on the results of the noninvasive prenatal tests has spurred some health organizations to try to better educate physicians and the public about the limitations of this new technology.
Education and tracking
The Perinatal Quality Foundation ( PQF ) has launched an educational initiative to promote more clinically appropriate use of noninvasive prenatal screening methods. The national campaign is designed to “improve understanding of the advantages, limitations, and clinically appropriate interpretation of results of noninvasive prenatal screening and other diagnostic tests for pregnant women and their health care providers,” according to a press release.
The “comprehensive education and quality-tracking program” will also involve development of an online patient registry for the purpose of collecting data. The initiative is supported by a grant from Quest Diagnostics, as well as by funding from a growing number of other supportive laboratories that provide prenatal tests.
Dr. Mary Norton, PQF president, stressed the value of cell-free DNA tests for screening, particularly for Down syndrome, but she added that many of the caveats with respect to testing were not publicized by labs eager to market their products.
The fact that most lab reports based on the testing will state either that aneuploidy is present or is not present contributed to the sense that the testing was diagnostic, and therefore to misinterpretation of results, said Dr. Norton, who is also professor of obstetrics, gynecology, and reproductive sciences at the University of California, San Francisco. Dr Norton reported receiving institutional research funding from Ariosa Diagnostics and Natera.
Inappropriate use
“Cell-free DNA screening as a screening technology became clinically available only a few years ago. It has been surrounded by immense interest since its introduction,” said Dr. Joseph R. Biggio Jr., professor of obstetrics and gynecology and director of the division of maternal-fetal medicine at the University of Alabama at Birmingham.
That interest, based largely on findings in “the select population of women at highest risk,” coupled with extensive marketing to both physicians and consumers, contributed to rapid uptake into clinical practice, he said. And despite a 2012 committee opinion from the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine endorsing the testing only in women at higher risk for aneuploidy, many obstetricians began offering the testing regardless of risk status, he added.
In the general population, the prevalence of aneuploidy is lower, thus the positive predictive value is lower than was initially associated with the testing.
Consequently, ACOG and SMFM updated that earlier committee opinion, stressing the limits of cell-free DNA testing for aneuploidy and the importance of conventional prenatal screening methods for most pregnant women.
The updated opinion , published online in June, emphasizes the need for confirmation of any cell-free DNA screen-positive result, because false-positive results do occur, said Dr. Biggio, chair of the SMFM Committee on Genetics, which coauthored the opinion. Dr. Biggio reported serving as a site investigator at the University of Alabama for noninvasive prenatal testing (NIPT) studies supported by Sequenom and Natera.
“The committee opinion emphasizes that this technology is a screening test – not a diagnostic test – and it is associated with limitations,” he said.
A particularly concerning issue demonstrated by several recent studies is an increased risk for fetal aneuploidy among patients in whom cell-free DNA screening fails or is uninterpretable, he said.
In one study presented in February at the annual SMFM meeting, the rate of chromosomal abnormalities was 13.8% in 65 patients with no final results on cell-free DNA screening, compared with 2.4% in the overall cohort of 4,446 patients.
Such patients should receive further genetic counseling and be offered further evaluation, Dr. Biggio said, adding that “many obstetric providers have been unaware of the magnitude of this risk, and this has been associated with delays in diagnosis or failure to make a diagnosis.
“The committee opinion emphasizes this issue and the need for further follow-up for these patients,” he said.
A role for genetic counseling
Another important part of the process is genetic counseling, according to Dr. R. Curtis Rogers , senior clinical geneticist at Greenwood Genetic Center, Greenville, S.C., who prefers the term noninvasive perinatal screening (NIPS) over NIPT because of the confusion surrounding the diagnostic ability of the technology.
The genetic counselors he supervises at Greenwood Genetic Center see about 1,000 patients each year, but countless others are never seen by a counselor.
Too often, time-pressed primary care physicians are offering the testing without allotting the necessary time for in-depth counseling, he said.
“Yes, it is an exciting test and a good test, but it certainly is not a perfect test … and I am hesitant for families to make decisions about pregnancy management based solely on NIPS unless there were obvious birth defects detected on prenatal ultrasound that were consistent with the NIPS findings,” he said.
For example, if an ultrasound shows holoprosencephaly, and NIPS shows trisomy 13, the likelihood of trisomy 13 is greater than 95%, he explained, adding that other scenarios, such as detecting partial deletions or duplications, is much less clear.
“Most patients who receive this screening should receive genetic counseling from a certified genetic counselor prior to having the test,” he said. “When we’re talking about very significant diagnoses that may alter the management of pregnancy, I think we need to be 100% correct. Yes, there is high specificity and sensitivity, and for most of the disorders – especially the trisomies – it has good positive predictive value. But it is not perfect, and I think we need to go into that with our eyes open, and families need to go in with their eyes open.”
Jennifer Stallworth, one of the genetic counselors at Greenwood Genetic Center, explained that her role is to counsel patients who may be considering the test, including informing them about the risk for chromosomal conditions in their pregnancies, and discussing the pros and cons of NIPT, compared with other screening and diagnostic testing options.
“I also counsel patients who have already had the test completed, and whether the results are normal or abnormal, I try to help them understand how that result has changed our understanding of the risk for a chromosome disorder in the pregnancy,” she said.
She, too, noted that the excitement about these tests stems largely from a desire to improve upon existing screening methods.
“I think everyone would like to have a risk-free alternative to amniocentesis and [chorionic villi sampling], but we are not yet to that point with NIPT,” Ms. Stallworth said. “I would continue to advise doctors and patients that these tests are a good way to screen for major chromosome conditions, but it is still important to consider all of a patient’s risk factors and to remember that invasive diagnostic testing offers the most complete information at this time.”
