Analysis of cell-free DNA in maternal blood in screening for fetal aneuploidies: updated meta-analysis.

Abstract

Objective: To review clinical validation or implementation studies of maternal blood cell-free (cf) DNA analysis and define the performance of screening for fetal trisomies 21, 18 and 13 and sex chromosome aneuploidies. Data sources: Searches of PubMed, Embase and the Cochrane library were performed to identify all peer-reviewed articles on cfDNA testing in screening for aneuploidies between January 2011, when the first such study was published and 31 December 2016. Results: In total, 35 relevant studies were identified and these reported cfDNA results in relation to fetal karyotype from invasive testing or clinical outcome. In the combined total of 1,963 cases of trisomy 21 and 225,032 non-trisomy 21 singleton pregnancies the pooled weighted detection rate (DR) and false positive rate (FPR) were 99.7% (95% CI 99.1-99.9%) and 0.04% (95% CI 0.02-0.08%), respectively. In a total of 560 cases of trisomy 18 and 212,019 unaffected singleton pregnancies the pooled weighted DR and FPR were 98.2% (95% CI 95.5-99.2%) and 0.05% (95% CI 0.03-0.07%). In a total of 119 cases of trisomy 13 and 212,883 unaffected singleton pregnancies the pooled weighted DR and FPR were 99.0% (95% CI 65.8-100%) and 0.04% (95% CI 0.02-0.07%). In a total of 36 cases of monosomy X and 7,677 unaffected singleton pregnancies the pooled weighted DR and FPR were 95.8% (95% CI 70.3-99.5%) and 0.14% (95% CI 0.05-0.38%). In a combined total of 17 cases of sex chromosome abnormalities other than monosomy X and 5,383 unaffected singleton pregnancies the pooled weighted DR and FPR were 100% (95% CI 83.6-100%) and 0.003% (95% CI 0-0.07%). For twin pregnancies, in a total of 24 cases of trisomy 21 and 1,111 unaffected cases the DR was 100% (95% 95.2-100%) and FPR was 0% (95% CI 0-0.003%). Conclusion: Screening by analysis of cfDNA in maternal blood in singleton pregnancies could detect >99% of fetuses with trisomy 21, 98% of trisomy 18 and 99% of trisomy 13 at a combined FPR of 0.13%. The number of reported cases of sex chromosome abnormalities is too small for accurate assessment of performance of screening. In twin pregnancies performance of screening for trisomy 21 is encouraging but the number of cases reported is small.