This finding further strengthens the argument that the technology should be available to the general obstetric population. "The amount of the DNA was the same when we stratified the relatively high risk from the relatively low risk," said Dr. Bianchi. "That will be a surprise to some people who postulated that the high-risk women would have more DNA circulating. They don’t."
The consistent fetal fraction also lends itself to greater flexibility when prenatal screening occurs, allowing women to be screened anytime between 10 and 40 weeks gestational age. This could mean better prenatal care for women who do not have their first prenatal visit until late in the second trimester, for example. Because the current screening methods are specific to certain gestational times, if a woman is erratic with her prenatal visits, testing may be impossible.
Regarding its utility in women carrying multiple fetuses, Dr. Bianchi said that about 10% of the time, the fetal fraction per fetus tends to be too low to get an accurate reading.
‘Throwing down the gauntlet’
The test’s unparalleled accuracy could give greater peace of mind to women who might have had difficulty getting pregnant and so are wary of the miscarriage risks posed by invasive diagnostic testing, according to Dr. Bianchi. Fewer invasive diagnostic tests could also lower costs across the system.
When all results for trisomies 21 and 18 were combined, the researchers found that the false positive rates for standard screening were 4.2%, compared with 0.5% for cell-free DNA testing. "If all pregnant women had undergone cell-free DNA testing as a primary screening method and if all women with positive results had undergone post-test counseling and had decided to undergo an invasive procedure," wrote the authors, "there would have been a relative reduction of 89% in the number of diagnostic invasive procedures required to confirm a positive screening result."
The data should move professional societies to take action, according to Dr. Bianchi. "That’s kind of the gauntlet that we’re throwing down." More data are on the way, she said, which will "enable the professional societies to take a cumulative look and decide what their recommendations are going to be."
As it stands, the Society for Maternal-Fetal Medicine and the American College of Obstetricians and Gynecologists state that the testing be used only in women at higher risk for giving birth to children with aneuploidies, such as women aged 35 years or older or those with a history of pregnancy with trisomy, and that positive cell-free DNA results should be confirmed by invasive diagnostic testing.
For now, because the tests are not considered routine prenatal care, low-risk patients usually pay out of pocket for these tests, which Dr. Bianchi said many women are willing to do. The cost of the test ranges anywhere from $1,200 to upward of $2,700, although some careful Internet searching for deals can net tests at substantially lower prices, she said.
Market pressures
For some physicians in the field, this public demand for a screening test not subject to Food and Drug Administration (FDA) regulation has not outweighed the level of proof it offers in the clinical setting. One of these critics was, until recently, Dr. Greene.
"Companies have been free to build consumer demand for cell-free DNA testing by aggressively marketing the tests, emphasizing data that do not answer key questions," wrote Dr. Greene in July 2013, in an editorial he coauthored (N. Engl. J. Med. 2013;369:499-501). "As a result, cell-free DNA testing seems to be drifting into routine practice ahead of the evidence," stated Dr. Greene, who is also chief of obstetrics at Massachusetts General Hospital in Boston, and who wrote with his colleagues that the test’s positive predictive value, largely unreported by manufacturers, was still in question.
"The problem is that the proof-of-principle studies that all these companies have published to date have been with ratios of ‘Down’s’ to ‘normals’ ranging from 1 to 7, 1 to 13, or 1 to 20," said Dr. Greene in an interview. "All were done in retrospective populations at extraordinarily high risk."
However, with the CARE study, "what’s impressive is the positive predictive value in a low-incidence group of patients," he said.
Sponsored by Illumina/Verinata, the study puts pressure on other companies to publish their own data in peer-reviewed journals, said Dr. Greene. "Once this paper appears in print, [Verinata] will get a leg up, and the other companies won’t want to let them get too far ahead of them."
According to Dr. Bianchi, Verinata is now seeking FDA approval to market the testing as an in vitro diagnostic product. She expects demand for the testing to be led not by physicians but by patients. "People often ask me why the DNA testing took off so quickly," said Dr. Bianchi. "I think a factor is social media. I find there is a discrepancy between what the average patient knows and the general obstetrician knows because of the discussions [online]. "