Failed cfDNA screen may signal increased risk of fetal aneuploidy

Findings from a recent study designed specifically to investigate the incidence of chromosomal abnormalities among high-risk pregnancies with a screen failure provide important information for patients and providers to consider when choosing follow-up.

Researchers found that the risk of fetal chromosomal abnormalities is increased significantly when noninvasive prenatal testing (NIPT) generates a “redraw request” (RR), and the risk is even higher if the repeat NIPT also fails. 

The investigation analyzed results from cell-free DNA (cfDNA) screening performed from October 2012 to June 2014 in the Kaiser Permanente Northern California Regional Prenatal Screening Program and included NIPT draws in 4446 high-risk pregnancies. An initial result of RR was obtained in 102 (2.3%) pregnancies; of those women, 39 declined another NIPT and 63 chose to redraw. Almost half of the women who had a second test had another RR result (41%), while the outcome was low risk in 32 (51%) women and high risk in 5 women (8%).

Of the 65 women with no results after 1 or 2 tests, 43 (66.2%) had no chromosomal analysis, 13 (20%) had normal chromosomes, and 9 (13.8%) had abnormal chromosomes. The rate of chromosomal abnormalities was similar whether the failed test was due to high variance in cfDNA counts (15%) or insufficient fetal cfDNA (13%).

Chi-square analysis showed the incidence of chromosomal abnormalities was significantly higher for the subgroup of women with no results after 1 or 2 tests compared with the overall cohort (13.8% vs 2.4%; P=0.0001). Additionally, when compared to the overall cohort, the risk of finding a chromosomal abnormality was increased 2.5-fold among women who had 1 failed NIPT (P=0.0001) and 4.6-fold for those with 2 failed tests (P=0.0003).

Mary Norton, MD, a co-author of the study and Professor and Vice Chair, Clinical and Translational Genetics, University of California San Francisco, noted that at her institution, a repeat the cfDNA screen is offered to high-risk women who have a failed test. Taking into account the results of the Kaiser study, such women are also counseled that they are at increased risk of having a fetus with a chromosomal abnormality and so, might choose to have diagnostic testing with either chorionic villus sampling or amniocentesis instead. Ultrasound, however, may also be a reasonable option as initial follow-up testing in some cases, noted Dr. Norton.

“Among women who fail NIPT, the increased risk of chromosomal abnormalities is mostly for trisomy 13, trisomy 18, and triploidy, all of which cause such serious defects that they might be found on ultrasound,” she explained.

As a caveat to generalization of the study results, Dr. Norton noted that all of the NIPT specimens from the Kaiser population were analyzed at a single laboratory. Rates of screen failure vary among laboratories due to differences in methodology.

Regardless of that potential difference, as stated in the recently updated joint American College of Obstetricians and Gynecologists/Society for Maternal-Fetal Medicine Committee Opinion on cfDNA screening for fetal aneuploidy, women whose NIPT results are not reported, indeterminate, or uninterpretable should receive further genetic counseling and be offered comprehensive ultrasound evaluation and diagnostic testing because of the increased risk of aneuploidy.