Objective: To assess the outcomes of pregnancies at high-risk for rare autosomal trisomies (RATs) and segmental imbalances (SIs) on cell-free DNA (cfDNA) screening.Method: A retrospective study of women who underwent cfDNA screening between September 2019 and July 2021 at three ultrasound services in Australia.Positive predictive values (PPVs) were calculated using fetal chromosomal analysis.Results: Among 23,857 women screened, there were 93 high-risk results for RATs (0.39%) and 82 for SIs (0.34%). The PPVs were 3.8% (3/78, 95% CI 0.8%-10.8%) for RATs and 19.1% (13/68, 95% CI 10.6%-30.5%) for SIs. If fetuses with structural anomalies were also counted as true-positive cases, the PPV for RATS increased to 8.5% (7/82, 95% CI 3.5%-16.8%). Among 85 discordant cases with birth outcomes available (65.4%), discordant positive RATs had a significantly higher proportion of infants born below the 10th and 3rd birthweight percentiles than expected (19.6% (p = 0.022) and 9.8% (p = 0.004), respectively), which was not observed in the SI group (2.9% < 10th (p = 0.168) and 0.0% <3rd (p = 0.305)). Conclusion:The PPVs for SI and RAT results are low, except when a structural abnormality is also present. Discordant positive RATs are associated with growth restriction. Key points What is already known about this topic?� Prenatal cell-free DNA (cfDNA) screening has high accuracy in screening for trisomies 21, 18 and 13. � The positive predictive values of cfDNA screening for rare autosomal. Trisomies rare autosomal trisomies (RATs) and segmental imbalances (SIs) are lower than that for common autosomal trisomies. � Fetal exclusion of chromosomal anomaly following high-risk cfDNA screen may indicate confined placental involvement.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Background The performance of cell‐free DNA (cfDNA) screening for microscopic copy number variants (CNVs) is unclear. Objectives This was a systematic review and meta‐analysis to investigate the sensitivity, specificity and positive predictive value (PPV) of cfDNA screening for CNVs. Search Strategy Articles published in EMBASE, PubMed or Web of Science before November 2022 were screened for inclusion. This protocol was registered with PROSPERO (23 March 2021, CRD42021250849) prior to initiation. Selection Criteria Articles published in English, detailing diagnostic outcomes for at least 10 high‐risk CNV results with cfDNA were considered for inclusion. Data Collection and Analysis The PPV was calculated and pooled with random‐effects models for double‐arcsine transformed proportions, using cases with diagnostic confirmation. Overall sensitivity, specificity and a summary receiver‐operating characteristics (ROC) curve were calculated using bivariate models. The risk of bias was assessed using QUADAS‐2. Main Results In all, 63 articles were included in the final analysis, detailing 1 591 459 cfDNA results. The pooled PPV was 37.5% (95% confidence interval [CI] 30.6–44.8), with substantial statistical heterogeneity (I2 = 93.9%). Bivariate meta‐analysis estimated sensitivity and specificity to be 77.4% (95% CI 65.7–86.0) and 99.4% (95% CI 98.0–99.8), respectively, with an area under the summary ROC curve of 0.947 (95% CI 0.776–0.984). Conclusions Approximately one‐third of women who screen high‐risk for CNVs with cfDNA will have an affected fetus. This value is of importance for screening counselling.

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