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JAMA. 2011 Aug 10;306(6):627-36. doi: 10.1001/jama.2011.1114.

Noninvasive fetal sex determination using cell-free fetal DNA: a systematic review and meta-analysis.

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  • 1Genetics and Public Policy Center, Johns Hopkins University, Washington, DC, USA.



Noninvasive prenatal determination of fetal sex using cell-free fetal DNA provides an alternative to invasive techniques for some heritable disorders. In some countries this testing has transitioned to clinical care, despite the absence of a formal assessment of performance.


To document overall test performance of noninvasive fetal sex determination using cell-free fetal DNA and to identify variables that affect performance.


Systematic review and meta-analysis with search of PubMed (January 1, 1997-April 17, 2011) to identify English-language human studies reporting primary data. References from review articles were also searched.


Abstracts were read independently to identify studies reporting primary data suitable for analysis. Covariates included publication year, sample type, DNA amplification methodology, Y chromosome sequence, and gestational age. Data were independently extracted by 2 reviewers.


From 57 selected studies, 80 data sets (representing 3524 male-bearing pregnancies and 3017 female-bearing pregnancies) were analyzed. 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%) outperformed conventional 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%).


Despite interstudy variability, performance was high using maternal blood. Sensitivity and specificity for detection of Y chromosome sequences was greatest using RTQ-PCR after 20 weeks' gestation. Tests using urine and tests performed before 7 weeks' gestation were unreliable.

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