The causal associations between 25(OH) vitamin D levels and ectopic pregnancy

Previous research has indicated a potential link between 25-hydroxyvitamin D [25(OH)D] and ectopic pregnancy (EP), but the underlying causal relationship remains unclear. We performed a 2-sample Mendelian randomization (MR) study to investigate the causal association between circulating 25(OH)D and ectopic pregnancy (EP). The primary analysis used summary statistics from a 25(OH)D GWAS of 4,96,946 European-ancestry participants and FinnGen summary statistics for EP (3111 cases and 89,340 controls). To assess whether the finding was robust to the choice of 25(OH)D GWAS, we repeated the MR analysis using a separate 25(OH)D GWAS (n = 4,41,291 European-ancestry participants) as a replication analysis; it was not used solely as a within-analysis sensitivity test. The primary and replication analyses used inverse-variance weighting (IVW) as the main method, complemented by weighted mode, simple mode, weighted median, and MR-Egger analyses. Heterogeneity and pleiotropy assessments, leave-one-out analyses, and other sensitivity analyses were conducted within each MR analysis. IVW estimates showed that increased serum 25(OH)D levels promoted EP (OR = 1.323, 95% CI = 1.024-1.710, P = .032). The replication analysis also revealed similar trends (OR = 1.383, 95% CI = 1.041-1.836, P = .025). The primary and replicated analyses were combined in a meta-analysis, and the result showed a significant causal influence (OR = 1.350, 95% CI = 1.116-1.632, P = .002). Sensitivity analysis confirmed the robustness of the MR estimations. In this MR study of European-ancestry participants, genetically predicted higher circulating 25(OH)D levels were associated with a higher risk of EP. These findings do not establish serum 25(OH)D as a diagnostic marker for EP. Rather, if confirmed in further clinical studies, elevated vitamin D may be considered a potential associated risk factor only in the context of established clinical signs and symptoms of EP.