Genetic liability to endometriosis and pregnancy outcomes: a two-sample Mendelian randomization study with maternal-fetal effect decomposition

Background Endometriosis is associated with adverse pregnancy outcomes in standard observational studies, including placental complications, preterm birth, and caesarean delivery. However, causal inference from these studies is complicated by residual confounding, differential clinical management, and the presence of intermediate factors such as subfertility and the use of assisted reproductive technologies, which may lie on the causal pathway between endometriosis and adverse outcomes. We applied Mendelian randomization (MR) to estimate the causal effects of genetic liability to endometriosis on a broad range of maternal and perinatal outcomes. Methods We conducted a two-sample MR study using summary-level GWAS data. Forty-one independent genetic instruments for endometriosis were derived from the largest available GWAS meta-analysis (60,674 cases; 701,926 controls; mean F-statistic = 279). SNP-outcome associations were obtained for 30 outcomes from the MR-PREG collaboration, FinnGen Release 12, and a postpartum haemorrhage GWAS meta-analysis, spanning placental disorders, pregnancy timing, labour and delivery, hypertensive disorders, fetal growth, and neonatal outcomes. Primary analyses used the inverse-variance weighted method, complemented by MR-Egger, weighted median, weighted mode, and MR-PRESSO. Trio-based models disentangled maternal from fetal genetic contributions. Multiple testing was addressed using false discovery rate correction. Findings Across 30 outcomes, only placenta praevia reached FDR-corrected significance, with a robust and consistent causal signal across four of five sensitivity methods (IVW OR 1.62, 95% CI 1.33-1.97; q<0.001). Within the placental disorders domain, estimates for premature placental separation and the broader placental disorders phenotype were directionally concordant but imprecise. For premature rupture of membranes, estimates were concordant across three methods, though the association was sensitive to cohort exclusion and did not survive multiple testing correction and should be interpreted cautiously. By contrast, hypertensive disorders, gestational diabetes, postpartum haemorrhage, stillbirth, and most neonatal outcomes showed estimates consistently close to the null across all methods. Trio-based analyses suggested predominantly maternal genetic pathways for most outcomes; fetal genetic contributions were not significant after correction for multiple testing, with exploratory signals observed for birthweight-related outcomes requiring independent replication. Interpretation A robust causal signal for placenta praevia alongside directionally consistent estimates across the placental disorders domain, suggests that mechanisms related to abnormal implantation and placentation may constitute a major mechanism for how endometriosis liability influences pregnancy. These results suggest that previously reported associations with broader obstetric outcomes may partly reflect confounding or clinical management patterns, and support targeted surveillance for abnormal placentation rather than a generalised elevation of obstetric risk.