Loading...
Fetal aneuploidy screening with analysis of cell-free DNA (cfDNA) in maternal plasma has revolutionized genetic screening of high-risk pregnancies. However, studies in the general obstetric population have yielded positive predictive values (PPVs) just below 50% — much higher than conventional screening, but still far from ideal. Now, sponsored by one of the companies that offers cfDNA analysis, investigators conducted a head-to-head comparison of standard first-trimester screening versus cfDNA testing in a large unselected obstetric population. Another group used modeling to explain the potential contribution of maternal-genetic-copy-number variation on the occurrence of false-positive cfDNA screens.
Among >15,800 test results, sensitivity of cfDNA for detecting trisomy 21 was 100% (vs. 79% for standard screening) and the PPV was 81% (vs. 3% for standard screening). Three quarters of samples came from women younger than 35 (with lower a priori risk for a fetus with trisomy 21). Among these women, the PPV was 76%. Overall, cfDNA also outperformed standard screening for trisomies 13 and 18. Modeling confirmed the possibility of maternal-copy-number gains as an important causative factor underlying false-positive cfDNA results.
Norton ME et al. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med 2015 Apr 2; [e-pub]. (http://dx.doi.org/10.1056/NEJMoa1407349)
Snyder MW et al. Copy-number variation and false positive prenatal aneuploidy screening results. N Engl J Med 2015 Apr 2; [e-pub]. (http://dx.doi.org/10.1056/NEJMbr1408408)
Comment
Fortunately, the push to move entirely to cfDNA-based screening has been quickly followed by a series of high-quality investigations of this strategy's potential merits. It's reassuring that, in this large cohort, the PPV for diagnosing trisomy 21 remained high for women at all levels of risk for fetal aneuploidy. Nonetheless, standard screening may be better for detecting other genetic abnormalities (e.g., translocations) that present proportionately greater threats to pregnancies in younger women. Lastly, cost — to individuals as well as the healthcare system — should be taken into consideration before widespread best-practice approaches can be determined.