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Large Clinical Trial Suggests NIPT Better at Detecting Fetal Trisomy than First Trimester Screening

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In a head-to-head comparison of noninvasive prenatal testing to standard first trimester screening for detecting Down syndrome, researchers found that analyzing cell-free DNA from maternal plasma comes out on top.

The study, which was led by researchers from the University of California, San Francisco and Columbia University and sponsored by Ariosa Diagnostics, compared Ariosa's Harmony test to standard of care first trimester screening in women of average risk for fetal aneuploidy. Harmony is a targeted next-generation sequencing-based test that uses proprietary target enrichment and analysis techniques to analyze chromosomes 21, 18, and 13 as well as the sex chromosomes X and Y for aneuploidy from cell free fetal DNA in maternal plasma. The test runs on Illumina's HiSeq instrument.

Last week, Mary Norton, co-PI of the study and a professor of maternal-fetal medicine at UCSF, presented results at the American College of Medical Genetics and Genomics meeting in Nashville, Tenn.

Following the meeting, CSN spoke with Ron Wapner, director of maternal-fetal medicine at Columbia University and co-PI of the study, about the results and their implications.

The researchers enrolled 18,955 women across 38 centers in the US, Canada, and Europe with a mean age of 30.6 years and a mean gestational age of 12.4 weeks. Of those patients, 15,086 have been compared head to head.

The women had both first trimester screening and testing with Ariosa's Harmony. The study was blinded, so the results of the cell-free DNA test were not returned, and after birth, the two methods were compared.

According to Wapner, in every measure, the cell-free DNA test outperformed standard first trimester screening. The detection rate of Down syndrome was higher, the screen positive rate was "dramatically lower," and the positive predictive value was higher, he said.

"It demonstrates that this is not a test that should be limited in high risk women," Wapner said. It showed "significantly better performance in all patients, including low-risk patients."

Among the 15,086 pregnancies evaluated, 36 were positive for trisomy 21. First trimester screening detected just under 80 percent of those (28 cases), while the Harmony test identified all 36, "even in young women and women who were first-trimester-screen negative," Wapner said.

Additionally, the Harmony test had a false positive rate of .06 percent, while first trimester screening had a false positive rate of 5.4 percent. The positive predictive value of Harmony was 80 percent compared to 3 percent for first trimester screening.

Wapner said that the researchers now plan to submit the results of the study for publication in a peer reviewed medical journal.

The study adds to one published in the New England Journal of Medicine in February by researchers from Tufts Medical Center, Illumina, and elsewhere that tested Verinata Health's Verifi test in around 2,000 women.

A smaller observational study published in Prenatal Diagnosis and led by Ariosa that looked at the clinical experience of 289 women who were offered both NIPT and first trimester screening also found that NIPT could be an effective screening method to assess fetal trisomy in the general population.

While such smaller studies have shown that noninvasive prenatal testing is accurate in the general population, the trial results that were presented at ACMG represent the largest study so far that compares NIPT directly with the current standard of care.

"There's enough evidence now," Wapner said. The next step, he said, after the study is published in a peer reviewed journal, is to figure out how the test is implemented into clinical care for the general population.

The study could have major implications for the implementation of noninvasive prenatal testing in the general population, although a number of issues remain about how to do so.

Currently, professional organizations such as the American College of Obstetrics and Gynecology recommend the use of such tests only in women that have an elevated risk for fetal aneuploidy because of advanced maternal age, an abnormal ultrasound, a positive first serum screen, or other factors.

Insurance companies currently only reimburse for tests performed in women at higher risk and will likely not reimburse the test in the general population unless it is demonstrated to be cost effective, so such analyses will have to be done, Wapner said.

Additionally, whether NIPT would replace first trimester screening or be offered in addition to it is another issue that will have to be examined. NIPT currently only looks for a limited number of fetal trisomies, but first trimester screening has the potential to detect other abnormalities, such as birth defects, so replacing first trimester screening may not be an ideal solution.

Norton previously told CSN that she thought NIPT may replace serum markers, but that it would likely not replace nuchal translucency testing due to its ability to detect birth defects.

"There are a number of questions that still need to be answered," Wapner said.

At Columbia, noninvasive prenatal testing is currently offered to women at an elevated risk for fetal trisomy, Wapner said. "We follow the ACOG recommendations that everyone gets first trimester screening and high-risk patients are counseled about NIPT and invasive testing," he said.

Going forward, he anticipates that the group will discuss whether to change its practices after this study is published to offer NIPT to the general population, as well. The study "makes a very good case to offer [noninvasive] screening to all of our patients. But again, we would have to give further thought as to whether we change our policy," he said. Whether insurance companies decide to reimburse or not for the test in the general population will also play a role in how noninvasive testing is implemented, Wapner said.

"The real question is no longer how well does the technology work [in the general population], but how does one integrate this into clinical care," he said.

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