Non‐invasive prenatal testing for the prenatal screening of sex chromosome aneuploidies: A systematic review and meta‐analysis of diagnostic test accuracy studies

Background There is little evidence on the performance of non‐invasive prenatal testing (NIPT) for the detection of fetal sex chromosomal imbalances. In this review, we aimed to appraise and synthesize the literature on the performance of NIPT for the prenatal detection of fetal sex chromosome aneuploidies. Methods We performed our literature search in PubMed, Embase, Cochrane Library, Web of Science, and CADTH. Study selection and data extraction were performed by two reviewers independently. There were no restrictions on the study population. Meta‐analyses were performed with “R” software. Pooled sensitivities and specificities with their 95% CI were estimated using a random‐effects model. Heterogeneity between studies was assessed by a Q test. Results Based on 11 studies in high prior risk pregnancies, including 116 affected fetuses in aggregate, Massively Parallel Shotgun Sequencing (MPSS) had a sensitivity of 93.9% (95% CI 84.1%, 97.8%) and a specificity of 99.6% (95% CI 98.7%, 99.9%) for the detection of 45,X. Based on four studies in high‐risk pregnancies, with 83 affected fetuses in aggregate, Targeted Massively Parallel Sequencing (TMPS) had a sensitivity of 83.2% (95% CI 49.6%, 96.2%) and specificity was 99.8% (95% CI 98.3%, 100%) for the detection of 45,X. In mixed‐risk pregnancies, the sensitivity of TMPS for the detection of 45,X was 90.9% (2 studies; 95% CI 70%, 97.7%) and specificity 99.9% (2 studies; 95% CI 99.4%, 100%); MPSS data were not available in such pregnancies. Based on smaller numbers of studies, and small numbers of affected fetuses in either high‐risk or mixed‐risk pregnancies (using either MPSS or TMPS), the sensitivities and specificities were equal to or greater than 76.2% for 47,XXX, 47,XXY and 47, XYY. The test failures for SCAs were 0.2% (95% CI 0%, 13.6%) for MPSS and 5.6% (95% CI 3.7%, 8.4%) for TMPS. Conclusion High‐quality studies are still desirable in order to estimate the performance of NIPT for the detection of sex chromosome imbalances.
MPSS based‐NIPT can be considered as performant for the detection of 45,X in high‐risk pregnancies, although this result is based on studies that might contain biases. For the other SCAs including 47,XXX, 47,XXY, and 47,XYY, more quality studies are still needed.