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Cell-Free DNA Screening, Invasive Testing Show Similar Miscarriage Rates, Study Suggests

NEW YORK (GenomeWeb) – A new study suggests miscarriage rates may not drop significantly when cell-free DNA screening is incorporated into the trisomy 21 testing protocol for women with "high risk" pregnancies.

Members of the SAFE21 Study Group randomized thousands of pregnant women from France into two trisomy 21 testing arms: one that relied solely on invasive testing procedures such as amniocentesis or chorionic villus sampling, and another that used invasive testing only after a positive cfDNA sequencing screen for trisomy 21. All of the women included in the study were believed to be more likely than usual to have an affected fetus based on maternal age and other clinical factors picked up during first trimester screens. 

Although the cfDNA screening and confirmatory invasive testing approach reliably identified trisomy 21 cases, the research team noted that the rates of miscarriage prior to 24 weeks gestation were similar in women from both arms of the study, with no significant differences detected. The findings appeared online today in the Journal of the American Medical Association.

"To our knowledge, this is the first randomized clinical trial comparing miscarriage rates following cfDNA and invasive testing in women with pregnancies at high risk of trisomy 21 by combined screening in the first trimester of pregnancy," corresponding author Laurent Salomon, a researcher at Paris Descartes University, and his colleagues wrote.

The authors further noted that the study "did not show a reduction of miscarriage or intrauterine fetal death associated with use of cfDNA in high-risk cases," despite a pronounced decrease in invasive procedures in the cfDNA arm of the study. Still, they cautioned that the work "may have been underpowered to detect clinically important differences in miscarriage rates."

For the study, which was supported with funding from the French Ministry of Healthy, the researchers focused on 2,592 pregnant women with a mean age of about 36 years who had between an estimated 1 in 5 and 1 in 250 chance of having a trisomy 21-affected pregnancy.

The authors noted that "safety has been the most widely used argument for implementing cfDNA testing in high-risk patients without evidence of its superiority over immediate use of invasive testing."

After excluding individuals who opted against participating in all parts of the study, they were left with 2,051 women, including 1,017 who received invasive testing and 1,034 women who got cfDNA screening. In the cfDNA arm of the study, they noted, women received invasive testing when an in-house next-generation sequencing method pointed to trisomy 21 in cell-free circulating DNA in maternal blood samples.

In each arm of the study, the team reported that 0.8 percent of women had miscarriages before reaching 24 weeks gestation. The miscarriages occurred at 19.9 weeks gestation, on average, in both the invasive testing group and the group that received initial cfDNA screening.

Even so, the researchers noted that just 8.3 percent of women from the cfDNA screening arm of the study had gone on to get amniocentesis or chorionic villus sampling, compared to nearly 77 percent of women in the invasive testing arm of the study. In the cfDNA group, they found all 27 instances of trisomy 21, with a false-positive rate of 5.6 percent, along with one additional case of chromosomal abnormality.

On the other hand, they detected 49 chromosomal abnormalities in the group that underwent invasive testing from the get-go, including 11 non-trisomy 21 chromosomal abnormalities.

"Given the randomized nature of the study, a similar incidence of abnormalities in the cfDNA group would be expected," the authors wrote, "although only one was detected following a finding of fetal anomaly on ultrasound."