Noninvasive Fetal Sex Determination Using Cell-Free Fetal DNA: A Systematic Review and Meta-Analysis

Abstract

Context-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.Objective-To document overall test performance of noninvasive fetal sex determination using cell-free fetal DNA and to identify variables that affect performance.Data Sources-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.Study Selection and Data Extraction-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. Disclaimer:The research that is the basis of this study was conducted prior to Dr Devaney starting at the National Institutes of Health (NIH), and the views expressed in the article do not necessarily represent the views of the NIH or the United States Government.Online-Only Material: eTables 1 and 2 are available at http://www.jama.com. Conclusions-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. HHS Public AccessNoninvasive prenatal determination of fetal sex could provide an important alternative to invasive cytogenetic determination, which is currently the gold standard for ambiguous genitalia, X-linked conditions, and single-gene disorders such as congenital adrenal hyperplasia. Chorionic villus sampling and amniocentesis have small but measurable rates of procedure-related pregnancy loss. [1][2][3] The availability of a reliable noninvasive alternative to determine fetal sex would reduce unintended fetal losses and would presumably be welcomed by pregnant women carrying fetuses at risk for disorders. A much broader potential application for fetal sex detection is family balancing, which poses ethical concerns.Fetal sex determination can be performed by sonography at as early as 11 weeks' gestation, although not reliably. Test performance across published studies varies significantly. According to a review by Odeh et al, 4 fetal sex cannot be determined by ultrasound examination in 7.5% to 50% of pregnancies at 11 weeks' gestation, and this decreases to 3% to 24% at 13 weeks. When reported, the sex determination is incorrect as often as 40% of the time at 11weeks, although by 13 weeks, accuracy (when reported) is close to 100%. A subsequent prospective study reported that fetal sex could be determined by ultrasound 90% of the time, with 86% accuracy from 11 to 14 weeks' gestation. 5The presence of cell-free circul...

Haplotype-based approach for noninvasive prenatal tests of Duchenne muscular dystrophy using cell-free fetal DNA in maternal plasma

“…Here we correctly predicted the existence of chromosome Y for eight fetuses from unspecific sequences, and many other approaches could also be used to noninvasively determine the fetal gender based on maternal plasma. Indeed, several reports of noninvasive fetal sex determination using PCRbased amplification of Y-chromosome-specific sequences, such as the DYS marker or the SRY gene, 11,12 have been published, and this method is reliable, with high sensitivity and specificity, as confirmed by numerous studies. 36,37 Considering the factors of cost and time, our future work will aim to develop specific Y chromosome probes on the capture array or to detect specific sequences on chromosome Y that can be used to estimate the fetal gender.…”

“…[9][10][11][12][13] Most studies thus far, however, have been restricted to the identification of paternal-specific sequences. 27 The ability to predict noninvasively whether the genetic variants that are passed from the mother to the fetus are at risk of single-gene disorders remains challenging, mainly because of the high background of maternal DNA in the plasma mixture that prevents an accurate prediction of fetal status.…”

“…9,10 The fetal sex in pregnancies at risk of X-linked genetic disorders and the Rhesus factor status in RhD-negative women represent additional noninvasive applications that have begun to transition from research to routine clinical service. [11][12][13] NIPTs for single-gene disorders remain challenging, however, because most (~90%) of the DNA in the maternal plasma is derived from the mother. throughout the 79 exons in the DMD gene without clusters make this locus-specific test laborious and time-consuming.…”

Noninvasive fetal sex determination in maternal plasma: a prospective feasibility study

“…27 Real-time PCR assays using MGB probes allow better sequence specificity and lower fluorescent background in comparison with no-MGB probes. Using this technology, fetal sex can be reliably determined in maternal plasma from the 7th week of gestation.…”

Non-invasive prenatal diagnosis for fetal sex determination: benefits and disadvantages from the service users’ perspective

“…9 When used for determination, NIPD has a number of advantages over ultrasound and invasive testing. It is feasible from 7 weeks' gestation, 1,10,11 has been shown to be 499% accurate 11 and as it is non-invasive, carries no risk of miscarriage. Furthermore, it reduces the need for invasive procedures by up to 50% 1 and has also been shown to be cost neutral for those conditions, such as DMD, where the majority of carriers choose to have invasive testing.…”