Objective: To characterize the spectrum of genetic abnormalities and identify predictive factors for pathogenic findings in mid-trimester viable pregnancies among women with a history of recurrent spontaneous abortion (RSA). Design: Retrospective cohort study. Setting: a national study conducted at a tertiary hospital in China Sample: 473 Chinese women with a history of RSA who underwent invasive prenatal diagnosis (IPD) between 2018 and 2025. Methods: Women were stratified by fetal ultrasound findings. We assessed the diagnostic yield of karyotyping and the incremental yield of chromosomal microarray analysis (CMA) and whole-exome sequencing (WES). Multivariable logistic regression identified independent risk factors for pathogenic findings. Main outcome measures: Diagnostic yield of pathogenic findings for each testing method and adjusted odds ratios (aOR) with 95% confidence intervals (CI) for identified risk factors. Results: The karyotype yield increased from 1.77% in isolated RSA to 4.35% and 13.11% in cases with soft markers and structural anomalies, respectively (none in FGR/abnormal appendages group). CMA/WES provided significant incremental diagnostic yield alongside inconclusive results. Multivariable analysis established fetal structural anomalies (aOR, 4.47; 95% CI, 1.13 – 16.47; P = 0.033) and soft markers (aOR, 3.71; 95% CI, 1.04 – 12.51; P = 0.044) as independent risk factors, whereas advanced age, prior fetal aneuploidy/structural anomalies, and abnormal serum screening showed no independent associations. Conclusions: Real-time fetal phenotype is the dominant factor, overriding traditional risk factors in predicting outcome. A tiered strategy with karyotyping/CMA first-line and WES reserved for selected cases is proposed.
