Noninvasive Fetal Sex Determination Using Cell-Free Fetal DNA

Devaney, Stephanie A.; Palomaki, Glenn E.; Scott, Joan A.; Bianchi, Diana WContext Noninvasive prenatal determination of fetal sex using cell-free fetal DNA provides an alternative to invasive techniquesfor some heritable disorders. In some countries this testing has transitioned to clinical care, despite the absence of a formalassessment of performance.Objective To document overall test performance of noninvasive fetal sex determination using cell-free fetal DNA and to identify variablesthat affect performance.Data Sources Systematic review and meta-analysis with search of PubMed (January 1, 1997-April 17, 2011) to identify English-language humanstudies reporting primary data. References from review articles were also searched.Study Selection and Data Extraction s were read independently to identify studies reporting primary data suitable for analysis. Covariates included publicationyear, sample type, DNA amplification methodology, Y chromosome sequence, and gestational age. Data were independently extractedby 2 reviewers.Results From 57 selected studies, 80 data sets (representing 3524 male-bearing pregnancies and 3017 female-bearing pregnancies) wereanalyzed. Overall performance of the test to detect Y chromosome sequences had the following characteristics: sensitivity,95.4% (95% confidence interval [CI], 94.7%-96.1%) and specificity, 98.6% (95% CI, 98.1%-99.0%); diagnostic odds ratio (OR),885; positive predictive value, 98.8%; negative predictive value, 94.8%; area under curve (AUC), 0.993 (95% CI, 0.989-0.995),with significant interstudy heterogeneity. DNA methodology and gestational age had the largest effects on test performance.Methodology test characteristics were AUC, 0.988 (95% CI, 0.979-0.993) for polymerase chain reaction (PCR) and AUC, 0.996(95% CI, 0.993-0.998) for real-time quantitative PCR (RTQ-PCR) (P = .02). Gestational age test characteristics were AUC, 0.989 (95% CI, 0.965-0.998) (<7 weeks); AUC, 0.994 (95% CI, 0.987-0.997)(7-12 weeks); AUC, 0.992 (95% CI, 0.983-0.996) (13-20 weeks); and AUC, 0.998 (95% CI, 0.990-0.999) (>20 weeks) (P = .02 for comparison of diagnostic ORs across age ranges). RTQ-PCR (sensitivity, 96.0%; specificity, 99.0%) outperformedconventional PCR (sensitivity, 94.0%; specificity, 97.3%). Testing after 20 weeks (sensitivity, 99.0%; specificity, 99.6%)outperformed testing prior to 7 weeks (sensitivity, 74.5%; specificity, 99.1%), testing at 7 through 12 weeks (sensitivity,94.8%; specificity, 98.9%), and 13 through 20 weeks (sensitivity, 95.5%; specificity, 99.1%).Conclusions Despite interstudy variability, performance was high using maternal blood. Sensitivity and specificity for detection of Ychromosome sequences was greatest using RTQ-PCR after 20 weeks' gestation. Tests using urine and tests performed before 7weeks' gestation were unreliable.