Noninvasive prenatal screening is the primary method for assessing fetal risk of common chromosomal anomalies. It estimates the risk of these abnormalities by using small fragments of placental DNA circulating in a pregnant patient’s blood (cell-free DNA) and a variety of laboratory-based analytic techniques.1 The American College of Obstetricians and Gynecologists, Society for Maternal-Fetal Medicine, and American College of Medical Genetics and Genomics recommend that all pregnant patients be offered screening or diagnostic testing for aneuploidy with appropriate pre- and posttest counseling.2,3 Aneuploidy screening may include noninvasive prenatal screening, first-trimester combined screening, quad screening, or some combination of first- and second-trimester analytes with or without nuchal translucency. Noninvasive prenatal screening is the most sensitive and specific modality to screen for trisomy 13, 18, and 21.2,3
In January 2022, a New York Times article highlighted the dominance of noninvasive prenatal screening compared with other strategies for prenatal genetic screening and pointed out its significant false-positive rates for subchromosomal anomalies.4 In April 2022, the U.S. Food and Drug Administration released a safety communication noting the possibility of false-positive results with the use of noninvasive prenatal screening methods.1
The New York Times article and the U.S. Food and Drug Administration’s safety communication explain the impact of prevalence on positive predictive value. Although a screening test may have excellent specificity, the positive predictive value will be low if the prevalence of a condition is low in a population. Chromosomal aneuploidies affect 1 in 150 live births, whereas subchromosomal anomalies (i.e., copy number variants or microdeletions) are cumulatively common (1 in 270) but individually rare (1 in 2,000 to 20,000).2
With this context in mind, noninvasive prenatal screening remains the most sensitive and specific method for detecting common aneuploidies and sex chromosome aneuploidies (e.g., Turner syndrome, Klinefelter syndrome).2 False-positive results can occur with any screening test; therefore, noninvasive prenatal screening should not be used to guide pregnancy decision-making, such as maternal management, termination of pregnancy, or timing of delivery. Results from noninvasive prenatal screening should be considered with ultrasound findings and pregnancy and family history. Diagnostic methods, such as amniocentesis or chorionic villus sampling, are recommended in patients with positive noninvasive prenatal screening results, although not all patients will consent to these procedures.2,3
The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine recommend against the routine use of noninvasive prenatal screening to assess fetal risk of subchromosomal or monogenic abnormalities.2,5 Although the American College of Medical Genetics and Genomics recommends informing pregnant patients that noninvasive prenatal screening is available, it should be offered with appropriate pre- and posttest counseling and a referral to a trained genetics professional.6
Should primary care clinicians offer noninvasive prenatal screening to assess the fetal risk of subchromosomal abnormalities? For low-risk pregnancies in populations where the prevalence of these conditions is low, the answer is no. However, risk must be individualized and contextualized. For pregnant patients with a history of a fetus affected by a subchromosomal abnormality, a significant family history of genetic disease, or the presence of abnormalities on ultrasonography, noninvasive prenatal screening may aid in complex maternal-fetal management. These patients benefit from referral to a maternal-fetal medicine specialist for targeted ultrasonography and diagnostic testing, and to a clinician with genetics expertise for pre- and posttest counseling to interpret and contextualize individual risk.