Aneuploidy Screening: Newer Noninvasive Test Gains Traction

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CARE was a prospective, blinded, multicenter (21 US sites across 14 states) study that compared the aneuploidy detection rates of ­cfDNA to those of standard screening. Standard aneuploidy screening included assays of first- or second-trimester serum biomarkers with or without fetal nuchal translucency measurement.

This study enrolled 2,042 pregnant patients ages 18 to 49 (mean, 29.6) with singleton pregnancies. The population was racially and ethnically diverse (65% white, 22% black, 11% Hispanic, 7% Asian). This study included women with diabetes, thyroid disorders, and other comorbidities. cfDNA testing was done on 1,909 maternal blood samples for trisomy 21 and 1,905 for trisomy 18.

cfDNA and standard aneuploidy screening results were compared to pregnancy outcomes. The presence of aneuploidy was determined by physician-documented newborn physical exam (97%) or karyotype analysis (3%). In both live and nonlive births, the incidence of trisomy 21 was 5 of 1,909 cases (0.3%) and the incidence of trisomy 18 was 2 of 1,905 cases (0.1%).

The NPV of cfDNA in this study was 100% (95% confidence interval, 99.8%-100%) for both trisomy 21 and trisomy 18. The positive predictive value (PPV) was higher with cfDNA compared to standard screening (45.5% vs 4.2% for trisomy 21 and 40% vs 8.3% for trisomy 18). This means that approximately 1 in 25 women with a positive standard aneuploidy screen actually has aneuploidy. In contrast, nearly 1 in 2 women with a positive cfDNA result has aneuploidy.

Similarly, false-positive rates with cfDNA were significantly lower than those with standard screening. For trisomy 21, the cfDNA false-positive rate was 0.3% compared to 3.6% for standard screening (P < .001); for trisomy 18, the cfDNA false-positive rate was 0.2% compared to 0.6% for standard screening (P = .03).

NEXT was a prospective, blinded cohort study that compared cfDNA testing with standard first-trimester screening (with measurements of nuchal translucency and serum biochemical analysis) in a routine prenatal population at 35 centers in six countries.

This study enrolled 18,955 women ages 18 to 48 (mean, 31) who underwent traditional first-trimester screening and cfDNA testing. Eligible patients included pregnant women with a singleton pregnancy with a gestational age between 10 and 14.3 weeks. Prenatal screening results were compared to newborn outcomes using a documented newborn physical examination and, if performed, results of genetic testing. For women who had a miscarriage or stillbirth or chose to terminate the pregnancy, outcomes were determined by diagnostic genetic testing.

The primary outcome was the area under the receiver-operating-characteristic (ROC) curve for trisomy 21. Area under the ROC curve is a measure of a diagnostic test’s accuracy that plots sensitivity against 1 – specificity; < .700 is considered a poor test, whereas 1.00 is a perfect test. A secondary analysis evaluated cfDNA testing in low-risk women (ages < 35).

The area under the ROC curve was 0.999 for cfDNA compared with 0.958 for standard screening (P = .001). For diagnosis of trisomy 21, cfDNA had a higher PPV than standard testing (80.9% vs 3.4%; P < .001) and a lower false-positive rate (0.06% vs 5.4%; P < .001). These findings were consistent in the secondary analysis of low-risk women.

Both the CARE and NEXT trials also evaluated cfDNA testing versus standard screening for diagnosis of trisomy 13 and 18 and found higher PPVs and lower false-positive rates for cfDNA, compared with traditional screening.

Previously, cfDNA was recommended only for women with high-risk pregnancies. The new data demonstrate that cfDNA has substantially better PPVs and lower false-positive rates than standard fetal aneuploidy screening for the general obstetric population.

So while conventional screening tests remain the most appropriate methods for aneuploidy detection in the general obstetric population, according to ACOG and SMFM, the two groups now recommend that all screening options—including cfDNA—be discussed with every woman. Any woman may choose cfDNA but should be counseled about the risks and benefits.8

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