Our appreciation of the vast potential and major challenges posed by new genetic prenatal diagnostic testing seems to grow with each passing week. In particular, we now have a far better understanding of the utility and limitations of fetal cell-free DNA (cfDNA) testing and of expanded parental carrier testing. Beyond the ethical and economic issues raised by these new diagnostic modalities, their rapid introduction into clinical practice raises practical management questions that obstetricians must now address.
Is cfDNA the best screening test for common fetal aneuploidies?
A recent article in The New England Journal of Medicine appears to definitively answer this question.1 Mary Norton and her colleagues reported the results of a large, industry-sponsored, prospective, blinded study comparing the effectiveness of cfDNA testing at 10 to 14 weeks with standard first-trimester screening using ultrasound nuchal translucency and maternal serum pregnancy-associated plasma protein A and human chorionic gonadotropin measurements for the detection of trisomies 21, 18, and 13. Of 18,955 women seeking routine prenatal screening, 15,841 were available for analysis with both screening modalities. Amongst these patients, cfDNA proved far more effective and efficient at detecting fetal trisomy. For example, fetal Down syndrome was detected using cfDNA testing in all 38 women bearing affected fetuses (100% sensitivity; 95%CI: 90.7–100) while standard testing identified only 30 of 38 women with affected fetuses (78.9% sensitivity; 95% CI: 62.7–90.4; P=0.008). Equally important, cfDNA had a 90-fold lower false-positive rate than standard testing (0.06%; 95% CI: 0.03–0.11 vs 5.4%; 95% CI: 5.1–5.8; P<0.001). Crucially, the positive predictive value of cfDNA for detecting fetal Down syndrome was an astonishingly high 80.9% (95% CI: 66.7–90.9) compared with only 3.4% (95% CI: 2.3–4.8) for standard first-trimester aneuploidy screening (P<0.001).
Although the numbers of affected fetuses were too low to draw definitive conclusions, the efficiency of screening for trisomy 18 and 13 also appeared much higher for cfDNA. For trisomy 18, cfDNA yielded a higher sensitivity (90.0%; 95% CI: 55.5–99.7) and positive predictive value (90.0%; 95% CI: 55.5–99.7) than standard testing (80.0%; 95%CI: 44.4–97.5) and (14.0%; 95% CI: 6.2–25.8), respectively. For trisomy 13, cfDNA screening also yielded a higher sensitivity (100.0%; 95%CI: 15.8–100) and positive predictive value (50.0%; 95%CI: 6.8–93.2) than standard testing (50.0%; 95%CI: 1.2–98.7) and (3.4%; 95% CI: 0.1–17.8), respectively. Thus, cfDNA testing, when obtainable, is far more efficient than standard testing for the detection of trisomies 21, 18, and 13 in a routine obstetric population. Of course, standard testing provides other useful data such as the presence of potential skeletal dysplasias, cardiac abnormalities, and a number of other aneuploidies.