ACMG Strongly Recommends NIPS for Common Fetal Trisomies

Citing superior accuracy, the American College of Medical Genetics and Genomics (ACMG) published a new practice guideline that “strongly recommends” the use of non-invasive prenatal screening (NIPS) over traditional ultrasound and biochemical screening methods on all pregnant patients for detecting common fetal trisomies. The practice guideline published on December 16, 2022, also “strongly recommends” that NIPS be offered to patients to screen for fetal sex chromosome aneuploidy (SCA).¹

NIPS Tests and Their Limitations

NIPS uses cell-free DNA (cfDNA) to detect trisomy, a genetic condition in which an extra copy of a chromosome is present in the cell nuclei of an unborn child that may cause developmental abnormalities and severe health issues. Unlike conventional screening methods, NIPS analyzes the entire fetal genome. First introduced into practice in 2011 to identify trisomy 21 (T21) associated with Down syndrome, the use of NIPS has expanded to other trisomies, including those that traditional screening does not cover. 

However, questions have arisen over the accuracy of NIPS tests. While NIPS tests are widely used, none have yet received authorization, clearance, or approval from the US FDA. Last April, the FDA issued a Safety Communication noting this fact and warning of the risk of false results from NIPS, “such as reporting a genetic abnormality when the fetus does not actually have one.” The Safety Communication recommends that patients talk to a genetic counselor or other healthcare provider and get confirmatory testing before relying on the results of NIPS tests to make decisions about whether to end a pregnancy.²  

The FDA Safety Communication came on the heels of a January 2022 New York Times article documenting questions about NIPS test performance and accuracy and concerns over how they have been marketed to consumers and healthcare providers.³

ACMG Research Supports NIPS Test Accuracy

The ACMG has been the leading source of evidence for rebutting these concerns over the accuracy of NIPS tests. In 2013, the organization issued a policy statement cautioning that use of genetic technology for prenatal applications “needs to be supported by prospective clinical trials and considered carefully before its incorporation into routine clinical care.”⁴

However, on May 24, 2022, the ACMG replaced its 2013 policy statement with a new systematic evidence-based review (SER) evaluating NIPS performance in detecting the most common chromosomal disorders such as Down syndrome in general-risk pregnancies, as well as in detecting SCAs, copy-number variant disorders like Edwards syndrome and other rare trisomies. Based upon a review of 87 different studies, the ACMG concluded that NIPS had an accuracy of over 99 percent in detecting SCA and common trisomies in both singleton and twin pregnancies, including not only T21 for Down syndrome but also:⁵

• Trisomy 13 (T13), aka Patau syndrome, a condition involving physical abnormalities as well as severe intellectual disability; and
• Trisomy 18 (T18), aka Edwards syndrome, a condition involving abnormalities in many parts of the body.

The SER reiterates previous ACMG recommendations that pregnant patients be made aware of the availability of NIPS and advised that it offers better sensitivity than conventional ultrasound and biochemistry screening for detecting T21, T18, and T13. Although ACMG noted in a press release that NIPS tests are less accurate for SCA, rare autosomal trisomies, and copy number variants, it also pointed out that NIPS “is the only laboratory-based prenatal screen that can identify these at all at this time.”⁶

The New ACMG Recommendations

In the new practice guideline, the ACMG revises its recommendations for using NIPS tests based on the SER findings. The headline is that the ACMG now “strongly recommends” NIPS over traditional screening approaches for the general-risk population for certain applications. “The SER demonstrated consistently superior performance of NIPS, which outperformed traditional screening in all parameters and across all studies in general-risk populations of individuals with a singleton pregnancy,” the guideline notes. Specifically:⁵

• The detection rate of T21 is 98.8 percent with a corresponding false-positive rate (FPR) of 0.04 percent;
• The detection rate for T18 is 98.83 percent with a corresponding FPR of 0.07 percent; and
• The detection rate for T13 is 92.85 percent, with a corresponding FPR of 0.04 percent.

The SER found equivalent performance rates for twin pregnancies with:

• NIPS testing for T21 demonstrating 98.2 percent sensitivity and 99.9 percent specificity;
• NIPS testing for T18 demonstrating 90 percent sensitivity and 99.95 percent specificity; and
• NIPS testing for T13 demonstrating 80 percent sensitivity and 99.83 percent specificity.   

The ACMG is also now strongly recommending use of NIPS for SCA in singleton pregnancies. Because traditional screening techniques cannot detect fetal SCA, the working group of researchers that created the new practice guidance were unable to compare NIPS to those approaches. However, the ACMG notes that screening performance was high, with a 99.6 percent overall detection rate of four common SCAs—monosomy X, XXX, XXY and XYY. Positive predictive valued ranged by condition, the guidance adds.

However, the ACMG researchers found that there was insufficient evidence to recommend NIPS for any other copy number variants or for rare autosomal trisomies.

Takeaway

The new ACMG recommendations may lead to increased utilization and availability of NIPS for fetal trisomies 21, 18, and 13, as well as for SCA. Providers may now feel more comfortable ordering NIPS tests, and insurers might be more likely to cover them.

“NIPS has been a practice-changing advance in prenatal care,” the practice guidance concludes. “Its expansion into use for a general-risk population should be applied with the diligence and attentiveness it deserves.”

References:

1. https://www.acmg.net/PDFLibrary/EBG-Noninvasive-Prenatal-Screening.pdf
2. https://www.fda.gov/medical-devices/safety-communications/genetic-non-invasive-prenatal-screening-tests-may-have-false-results-fda-safety-communication
3. https://www.nytimes.com/2022/01/01/upshot/pregnancy-birth-genetic-testing.html
4. https://www.nature.com/articles/gim201329
5. https://www.gimjournal.org/article/S1098-3600(22)00714-6/fulltext
6. https://www.newswise.com/articles/the-application-of-noninvasive-prenatal-screening-using-cell-free-dna-in-general-risk-pregnancies-the-american-college-of-medical-genetics-and-genomics-publishes-its-highly-anticipated-evidence-based-review