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In this large, routine prenatal-screening population, cfDNA testing for trisomy 21 had higher sensitivity, a lower false positive rate, and higher positive predictive value than did standard screening with the measurement of nuchal translucency and biochemical analytes. (Funded by Ariosa Diagnostics and Perinatal Quality Foundation; NEXT ClinicalTrials.gov number, NCT01511458.).

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Objective To determine the effects of gestational age and maternal weight on percent fetal cell-free DNA (cfDNA) in maternal plasma and the change in fetal cfDNA amounts within the same patient over time. MethodsThe cfDNA was extracted from maternal plasma from 22 384 singleton pregnancies of at least 10 weeks gestation undergoing the Harmony TM Prenatal Test. The Harmony Prenatal Test determined fetal percentage via directed analysis of cfDNA.Results At 10 weeks 0 days to 10 weeks 6 days gestation, the median percent fetal cfDNA was 10.2%. Between 10 and 21 weeks gestation, percent fetal increased 0.1% per week (p < 0.0001), and 2% of pregnancies were below 4% fetal cfDNA. Beyond 21 weeks gestation, fetal cfDNA increased 1% per week (p < 0.0001). Fetal cfDNA percentage was proportional to gestational age and inversely proportional to maternal weight (p = 0.0016). Of 135 samples that were redrawn because of insufficient fetal cfDNA of the initial sample, 76 (56%) had greater than 4% fetal cfDNA in the sample from the second draw.Conclusion Fetal cfDNA increases with gestation, decreases with increasing maternal weight, and generally improves upon a blood redraw when the first attempt has insufficient fetal cfDNA.

While cell-free DNA (cfDNA) testing for fetal aneuploidy has been shown to have a high detection rate for trisomy, most large studies have included only high-risk populations. This blinded, prospective study tested the performance of screening with cfDNA for common trisomies in the general population.Maternal blood samples were collected from women at 35 centers in the United States, Canada, and Europe with a singleton pregnancy between 10.0 and 14.3 weeks' gestation. Samples were sent to a single clinical laboratory for cfDNA testing. The patients were also screened for aneuploidy using measurement of nuchal translucency and biochemical analytes. Participants and providers were blinded to the cfDNA testing results but were informed of the standard screening results. Medical records of physical examination at birth and genetic testing were used to inform newborn outcomes. The area under the receiver operating characteristic curve (AUC) for cfDNA testing for trisomy 21 compared with standard testing was the primary outcome. The AUC of the 2 types of testing for trisomies 13 and 18 were the secondary outcomes.A total of 18,955 women were enrolled between March 2012 and April 2013, and after all exclusions, 15,841 patients were included in the cohort. Mean gestational age was 12.5 weeks, and mean maternal age was 31 years. In the cohort, 1 in 236 pregnancies (n = 68) had chromosomal abnormalities. For trisomy 21, the AUC for cfDNA testing was 0.999, and for standard screening, the AUC was 0.958 (P = 0.001). Cell-free DNA identified all 38 cases of trisomy 21 with 100% sensitivity (95% confidence interval [CI], 90.7%-100%), and standard screening had a sensitivity of 78.0%, identifying 30 of the 38 cases (95% CI, 62.7%-90.4%; P = 0.008). However, if one considered the 3 trisomy 21 cases among those patients with "no results," the sensitivity was really 38 of 41, or 92%, which is not that different from traditional combined screening. In women without trisomy 21, cfDNA had a false-positive rate of 0.06% (95% CI, 0.03%-0.11%), and standard screening had a falsepositive rate of 5.4% (95% CI, 5.1%-5.8%; P < 0.001). In the 11,994 low-risk pregnancies (maternal age <35 years), cfDNA had 6 false-positive results for trisomy 21 but identified all 19 cases. For trisomy 18, cfDNA had a positive predictive value of 90.0% (95% CI, 55.5%-99.7%) and a false-positive rate of 0.01% (95% CI, 0%-0.04%) compared with a 14.0% positive predictive value for standard screening (95% CI, 6.3%-25.8%) and a false-positive rate of 0.31% (95% CI, 0.23%-0.41%). For trisomy 13, cfDNA identified both confirmed cases, and standard screening identified 1 of the 2.In the detection of trisomy 21, cfDNA was found to have a higher sensitivity and specificity with a far lower false-positive rate than standard screening. Further studies on the cost-effectiveness of cfDNA are recommended.

Our observations indicate that Smad4 cooperates with Smad1, Smad2 and Smad3 to act as a common mediator of signaling by TGF-beta-related factors, and provide a mechanism that explains the dominant-negative interference with receptor signaling that results from expression of the naturally occurring Smad4/DPC 4 truncation mutant.

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