DNA Sequencing versus Standard Prenatal Aneuploidy Screening

BackgroundIn high-risk pregnant women, noninvasive prenatal testing with the use of massively parallel sequencing of maternal plasma cell-free DNA (cfDNA testing) accurately detects fetal autosomal aneuploidy. Its performance in low-risk women is unclear. MethodsAt 21 centers in the United States, we collected blood samples from women with singleton pregnancies who were undergoing standard aneuploidy screening (serum biochemical assays with or without nuchal translucency measurement). We performed massively parallel sequencing in a blinded fashion to determine the chromosome dosage for each sample. The primary end point was a comparison of the false positive rates of detection of fetal trisomies 21 and 18 with the use of standard screening and cfDNA testing. Birth outcomes or karyotypes were the reference standard. ResultsThe primary series included 1914 women (mean age, 29.6 years) with an eligible sample, a singleton fetus without aneuploidy, results from cfDNA testing, and a risk classification based on standard screening. For trisomies 21 and 18, the false positive rates with cfDNA testing were significantly lower than those with standard screening (0.3% vs. 3.6% for trisomy 21, P<0.001; and 0.2% vs. 0.6% for trisomy 18, P=0.03). The use of cfDNA testing detected all cases of aneuploidy (5 for trisomy 21, 2 for trisomy 18, and 1 for trisomy 13; negative predictive value, 100% [95% confidence interval, 99.8 to 100]). The positive predictive values for cfDNA testing versus standard screening were 45.5% versus 4.2% for trisomy 21 and 40.0% versus 8.3% for trisomy 18. ConclusionsIn a general obstetrical population, prenatal testing with the use of cfDNA had significantly lower false positive rates and higher positive predictive values for detection of trisomies 21 and 18 than standard screening. (Funded by Illumina; ClinicalTrials.gov number, NCT01663350.) Sequencing of fetal DNA in maternal blood to detect trisomies had a significantly lower false positive rate than the standard method of biochemical assay and measurement of nuchal translucency in women at low risk for carrying an affected child. Noninvasive prenatal testing performed with the use of massively parallel sequencing of cell-free DNA (cfDNA testing) in maternal plasma came into use in clinical prenatal care in the United States in late 2011. This transition occurred after multiple clinical validation studies all showed high sensitivities, specificities, and negative predictive values for detection of the most common autosomal aneuploidies.(1)-(9) Plasma samples for the validation studies were either acquired retrospectively from populations with known karyotypes or collected prospectively from high-risk populations to ensure an adequate enrichment of aneuploid fetal samples for testing. The results of these studies were sufficiently robust to ...