Polycystic ovary syndrome and miscarriage risk: dual evidence from cohort study and Mendelian randomization

Huihuang Chi, Zhe Yang, Zhe Yang, Jing Dong, Pan Jiexue, JianZhong Sheng, Hefeng Huang, Zuwei Yang, Zuwei Yang

Objective To investigate the association between polycystic ovary syndrome (PCOS) and miscarriage risk and to explore the potential causal effect. Methods We conducted a retrospective cohort study of 445 women who conceived via in vitro fertilization/intracytoplasmic sperm injection, comprising 191 PCOS women and 254 controls. The primary outcome was miscarriage. Logistic regression adjusted for maternal age, body mass index, endometrial thickness on hCG day, the number of embryos transferred, embryo transfer/fertilization methods yielded adjusted odds ratios (aORs) with 95% confidence intervals (CIs). Subgroup analyses assessed the association of PCOS with miscarriage across key demographic and clinical variables. Additionally, two-sample Mendelian randomization (MR) analyses were performed to evaluate the causal effect of PCOS on miscarriage risk. Results Compared with controls, women with PCOS had higher risks of miscarriage (18.4% vs. 11.0%, p = 0.029) and biochemical pregnancy rates (5.2% vs. 1.2%, p = 0.012), alongside lower live birth rates (73.3% vs. 81.9%, p = 0.03). The increased risk was mainly driven by early miscarriage (14.2% vs. 8.3%, p = 0.048). In logistic regression, PCOS was significantly associated with miscarriage in univariate analysis (OR = 1.795, 95% CI: 1.049–3.072, p = 0.033), and remained an independent risk factor after multivariable adjustment (aOR = 1.851, 95% CI: 1.019–3.362, p = 0.043). Subgroup analyses revealed consistent trends, though some strata lacked statistical significance. The primary MR analysis using the inverse-variance weighted (IVW) method demonstrated a significant causal effect of PCOS on the risk of sporadic miscarriage (OR = 1.08, 95% CI: 1.01–1.14, p = 0.0203). The replicated MR analysis yielded similar effect sizes, and genetically predicted PCOS liability aligned with the cohort study results. Sensitivity analyses showed no significant heterogeneity or horizontal pleiotropy, supporting the robustness of the results. Conclusion Integrating dual evidence from clinical cohort and MR analyses, PCOS is associated with increased miscarriage risk, potentially independent of traditional risk factors. These findings underscore the importance of early pregnancy management in women with PCOS and establish a basis for future research into underlying mechanisms and potential interventions.