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ACMG Review Finds NIPS Accurately Detects Common Trisomies in General-Risk Pregnancies

NEW YORK — Noninvasive prenatal screening (NIPS) is highly accurate in detecting common trisomies in general-risk pregnancies, a new analysis has found. The results will inform upcoming clinical practice guidelines by the American College of Medical Genetics and Genomics. 

NIPS using cell-free DNA was introduced about a decade ago to identify fetal aneuploidies in the blood of mothers-to-be. But in addition to screening for trisomies 13, 18, and 21 among singleton pregnancies, labs have also adapted NIPS for additional uses, including the detection of rare trisomies and copy number variants, as well as screening in twin pregnancies.

"Noninvasive prenatal screening (NIPS) is an accepted method of antenatal screening for aneuploidy. However, most of the original studies of efficacy were performed in high-risk populations and there were no existing systematic evidence reviews on its use in a general-risk population," coauthor Nancy Rose from the University of Utah said in an email. "Additionally, there are a greater number of disorders that NIPS can detect — some of which cannot be screened for using traditional prenatal screening with serum analytes."

To address this issue, Rose, along with her colleagues from an ACMG working group, weighed the evidence supporting the use of NIPS in a general-risk population. Their analysis of nearly 90 studies, reported on Tuesday in Genetics in Medicine, found that NIPS is highly accurate in its detection of trisomies 13, 18, and 21 within both singleton and twin pregnancies. Its performance was more variable, though, when applied to other conditions. This evidence review is further paving the way for new guidelines for the use of NIPS.

To conduct its review, the ACMG working group combed through the literature to identify 87 studies that examined the use of NIPS to detect trisomies and other conditions, or the effects of such screening.

For the three most common trisomies, the review found NIPS had generally high performance. For trisomy 21, for which there were 35 different studies characterizing screening performance, NIPS had a sensitivity of 98.80 percent, a specificity of 99.96 percent, a positive predictive value of 91.78 percent, and an accuracy of 99.94 percent.

Though there were fewer studies of NIPS for trisomy 18 or trisomy 13, they, too, had high sensitivities, specificities, and accuracies. However, they had lower PPVs of 65.77 percent and 37.23 percent, respectively. NIPS for all three trisomies had low false positive rates, ranging from 0.04 percent for trisomy 21 and trisomy 13 to 0.07 percent for trisomy 18. These findings suggested that NIPS is a highly accurate screening method for common trisomies.

Though there was limited data, the group found that the diagnostic performance of NIPS to detect common trisomies among twin pregnancies was generally high, too.

NIPS accuracy was also high for sex chromosome aneuploidies but it had more variable performance in detecting rare autosomal trisomies and CNVs in the studies the group analyzed. For CNVs, for instance, performance varied by CNV size — three studies found that NIPS could detect CNVs larger than 5 Mb with a sensitivity of more than 90 percent, which dropped to 68.42 percent for smaller CNVs.

The working group cautioned that even with its high accuracy in screening for trisomies 21, 18, and 13, NIPS is a screening test, and a positive result should be followed up with diagnostic testing. Their analysis further indicated that although the number of invasive diagnostic tests has declined with NIPS, most individuals who receive a high-risk result seek diagnostic testing.

These findings will form the basis for upcoming guidelines from ACMG. According to Jennifer Malinowski, a senior methodologist at ACMG, the draft guideline is in the final stages of being prepared for comment and a final guideline is expected in the fall.