Affecting 1 in 150 live births, chromosomal abnormalities pose a significant health concern. Using blood tests for biochemical markers and ultrasound measurements during the first and second trimesters, standard prenatal screening gauges the risk of fetal chromosomal abnormalities. These markers—plasma protein-A (PAPP-A), human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP), and unconjugated estriol (uE3)—reflect placental function and fetal well-being. Simultaneously, ultrasound measures nuchal translucency, with higher values suggesting potential anomalies like trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), and trisomy 13 (Patau syndrome).
The advent of next-generation sequencing technologies (also referred to as massively parallel sequencing) has revolutionized prenatal screening for fetal chromosomal anomalies.
In addition to the trisomies identified by standard screening methods, noninvasive prenatal testing (NIPT) can also detect sex chromosome aneuploidies, including Turner syndrome (monosomy X) and Klinefelter syndrome (XXY). NIPT requires a simple blood draw and uses cell-free fetal DNA circulating in maternal blood to detect genetic abnormalities.
Compared to conventional screening techniques, NIPT is more sensitive and accurate, consistently demonstrating significantly lower false positive rates for trisomy 21 and trisomy 18.1 Consequently, since NIPT became available in 2011, the average number of invasive diagnostic tests, such as amniocentesis and chorionic villus sampling, has dropped by 50 to 75 percent.
The American College of Obstetricians and Gynecologists (ACOG) recommends universal prenatal genetic screening, irrespective of age or chromosomal abnormality risk.2 While the risk of fetal chromosomal abnormalities increases with maternal age, it is not affected by race or ethnicity.
What factors can affect noninvasive prenatal testing?
Diana Bianchi, MD, was the lead author on the 2014 study that compared NIPT with standard prenatal screening and is currently the director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
“Unlike single gene analysis, in which it is important to understand racial and ethnic variation at the DNA sequence level, NIPT works by sequencing long segments of DNA, and counting ratios between a reference sample and a patient-specific sample,” she says. However, socioeconomic and demographic factors may affect the NIPT workflow, access, and uptake.
One of the key aspects of NIPT is determining the proportion of DNA that comes from the fetus (fetal fraction) versus the mother. Accurate estimation of the fetal fraction is essential for reliable results. Maternal age and weight are inversely related to fetal fraction, with higher age or weight correlating to lower fetal fraction. Some studies indicate that African American or South Asian pregnant women have lower fetal fractions than White women.3 Nevertheless, extensive research is required to pinpoint the contribution of race and ethnicity to this observation.
Inadequate fetal fraction may also be associated with non-reportable NIPT results.
A recent multicenter prospective study across three countries involving more than 17,000 pregnant patients outlined higher maternal weight, chronic hypertension, advanced gestational age, lower fetal fraction, and Black race as possible factors associated with non-reportable results. The study also reported that patients with non-reportable NIPT results had greater risk of fetal aneuploidy, preeclampsia, and preterm birth.4
However, studies need to more clearly delineate whether non-reportable results and the associated risk for adverse perinatal outcomes stem from structural barriers, such as limited access to quality prenatal care for Black patients.
Since NIPT is predictive and not diagnostic, patient perspectives are important.
Although NIPT is intended to help patients make informed decisions about a fetus with a potential chromosomal anomaly, the non-confirmatory results often evoke anxiety. A qualitative survey that included a high percentage of Black women in their sample noted patients’ desire for clarity on test results, the cost of second opinions, and insurance coverage.5
Insurance is an important consideration to ensure that all pregnant people have access to NIPT, acknowledges Bianchi: “About half of the pregnancies in the US are covered by state Medicaid programs, and each of these programs differs in their policies regarding coverage of NIPT. Some states will cover the test for women at high risk of having an aneuploid fetus, others will cover all pregnant women regardless of risk, and still others do not cover NIPT at all,” she says.
Should race-based adjustments of biomarkers be discontinued?
For patients without access to NIPT, biochemical markers like AFP and PAPP-A continue to be used to provide information on fetal abnormalities, including congenital disorders, such as spina bifida.
Laboratories routinely adjust the test result values of these markers for Black individuals. For example, AFP values are adjusted by approximately 10 percent and PAPP-A values are adjusted by approximately 50 percent compared to those for White individuals.6,7 Such adjustments could produce false negatives for spina bifida or false positives for Down Syndrome.
A recent retrospective review of a large dataset of more than 27,000 pregnant patients found no clinically significant difference in AFP levels after adjusting for maternal weight and gestational age, advocating for the discontinuation of race-based adjustments.8
An important gap in NIPT research
Despite variance in the geographic, cultural, socioeconomic, and lived experiences of Black individuals, the medical community tends to treat Black patients as a monolith.
In a scoping review published earlier this year, Thomas and colleagues assessed patient perspectives of NIPT among Black women and explored how different types of Black women are incorporated into clinical studies on NIPT.9
They found that only half of the studies in the review included Black women in their study populations and none included Black women with genetic conditions.
As NIPT is becoming a routine aspect of prenatal care and test makers attempt to expand its use to screen for genetic conditions such as sickle cell disease, limited inclusion of Black patients with comorbidities or preexisting health conditions represents an important gap in the field of NIPT research.
Advancements in NIPT are shifting the landscape of prenatal care and counseling. Despite the advances, complexities linger for historically vulnerable and underrepresented minorities such as Black women.
Debates about race-based adjustments persist for biochemical markers used in standard prenatal screening. Insurance coverage stands as a gateway to equitable access to NIPT. Inclusion gaps remain, underscoring the necessity for diverse representation in clinical studies.
As the medical community evolves, it must confront biases and rethink the role of race as a social rather than biological construct.
- Bianchi DW et al. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med. 2014;371(6):578. doi:10.1056/NEJMc1405486
- Deng C, Liu S. Factors Affecting the Fetal Fraction in Noninvasive Prenatal Screening: A Review. Front Pediatr. 2022;10:812781. doi:10.3389/fped.2022.812781
- Norton ME, MacPherson C, Demko Z, et al. Obstetrical, perinatal, and genetic outcomes associated with nonreportable prenatal cell-free DNA screening results. Am J Obstet Gynecol. 2023;229(3):300.e1-300.e9. doi:10.1016/j.ajog.2023.03.026
- Farrell RM et al. What women want: lead considerations for current and future applications of noninvasive prenatal testing in prenatal care. Birth. 2014;41(3):276-282. doi:10.1111/birt.12113
- Crandall BF et al. Alpha-fetoprotein concentrations in maternal serum: relation to race and body weight. Clin Chem. 1983;29(3):531-533.
- Spencer K et al. The influence of ethnic origin on first trimester biochemical markers of chromosomal abnormalities. Prenat Diagn. 2000;20(6):491-494.
- Burns RN et al. Reconsidering Race Adjustment in Prenatal Alpha-Fetoprotein Screening [published correction appears in Obstet Gynecol. 2023 Jun 1;141(6):1229]. Obstet Gynecol. 2023;141(3):438-444. doi:10.1097/AOG.0000000000005045
- Thomas SP et al. Patient perspectives on noninvasive prenatal testing among black women in the United States: a scoping review. BMC Pregnancy Childbirth. 2023;23(1):183. doi:10.1186/s12884-023-05423-w