Detecting Trisomy

Published - Written by Rena Xu

A simple prenatal blood test made national headlines last year after a study published in NEJM reported its superiority to standard prenatal screening. The test, called cell-free fetal DNA (cfDNA), identified common trisomies (21, 18, and 13) by detecting fragments of fetal DNA in maternal blood. Screening could be done early in a pregnancy and at no risk to the fetus.

While cfDNA was already recognized as a more effective screen for “high-risk” pregnancies, experts had cautioned that it was not recommended for everyone. Last year’s study, which enrolled relatively low-risk women, suggested it might in fact be a better screen across the board. This week, NEJM reports findings from a second and larger multicenter study confirming that cfDNA is superior to routine screening for detecting trisomies among pregnant women in general.

In this study, over 15,000 pregnant women who were between 10 and 14 weeks’ gestation underwent cfDNA testing in addition to standard screening. Participants were informed of the standard screening results but kept blinded to the cfDNA results. Birth outcomes were then determined based on diagnostic genetic testing or newborn exam.

Among pregnancies with an interpretable cfDNA result, there were thirty-eight cases of trisomy 21. The cfDNA assay identified all of them – it was 100% sensitive — whereas standard screening only identified thirty out of the thirty-eight cases, for a sensitivity of 79%. Additionally, the rate of false positives was nearly a hundred times lower with cfDNA: there were only nine false-positive cases, versus 854 with standard screening. All told, the positive predictive value of cfDNA was nearly 81%, whereas for standard screening it was 3.4%.

It should be noted that among three percent of women in the study, a cfDNA result could not be obtained. This was attributed to a low amount of fetal DNA in the maternal blood, or in some cases, to assay variance or failure. Among these 488 women without a cfDNA result, 13 aneuploidies were ultimately found — a higher than average rate, compared to the overall study population. Had these women been included in the study as “not detected” by cfDNA, the calculated effectiveness of the assay would have been lower.

The authors write, “While these data support use of cfDNA screening in women regardless of age or risk status, further cost utility studies are warranted.” Among women who get a negative result with standard screening, nearly 1900 cfDNA tests would need to be done to find a single case of trisomy 21; the costs associated with this would be considerable. On the other hand, reducing the number of false positive results could reduce the need for invasive testing and avoid the associated financial as well as emotional and physical costs.

NEJM associate editor and chief of obstetrics at Massachusetts General Hospital, Dr. Michael Greene states, “Although still a screen and not a definitive diagnostic test, the major advantages of cfDNA screening compared to the prior standard are the increased reassurance that a negative screen really does mean that the fetus is normal and the reduced number of false positives sparing many women invasive diagnostic testing of normal fetuses.”

Ask the authors about this study in the NEJM Group Open Forum on (free registration required).