Association of Oral Contraceptives with Adverse Pregnancy Outcomes: A Mendelian Randomization and Colocalization Study

Introduction: This study aimed to investigate the causal relationship and biological mechanism between oral contraceptives (OCs) and adverse pregnancy outcomes using Mendelian randomization (MR) methods. Methods: We conducted a drug-target MR analysis, identifying five OC target genes and using “Ever taken oral contraceptive pill” as an additional genetic instrument. Summary- data-based MR (SMR) and inverse-variance-weighted MR (IVW-MR) were applied, followed by sensitivity, colocalization, and preliminary bioinformatic analyses. Results: IVW-MR analysis revealed no causal association between ever taking OCs and eight adverse pregnancy outcomes (e.g., ectopic pregnancy, preeclampsia). SMR showed suggestive links between NR1I2 expression and placental abruption (OR=13.51, P=0.04) and between SRD5A1 expression and preterm premature rupture of membranes (OR=0.90, P=0.03), which were not statistically significant after false discovery rate correction. Colocalization analysis did not support shared causal variants (posterior probabilities <50%). Enrichment analysis implicated steroid hormone metabolism pathways. Discussion: Our findings do not support a causal effect of OCs on most adverse pregnancy outcomes, suggesting prior observational associations may reflect confounding. The suggestive roles of NR1I2 and SRD5A1 warrant further investigation, given their involvement in placental steroid metabolism and barrier function. Conclusion: Our drug-target MR analysis found no causal association between OCs use and adverse pregnancy outcomes. However, the role of steroid hormone metabolism pathways involving genes such as NR1I2 and SRD5A1 requires validation in future studies.