Calcium, 25-hydroxyvitamin D, and postpartum hemorrhage: A 2-sample Mendelian randomization study

We aimed to evaluate the causal effect of calcium and 25-hydroxyvitamin D [25(OH)D] on the risk of postpartum hemorrhage (PPH) using a 2-sample Mendelian randomization (MR) study. Instrumental variables for calcium and 25(OH)D were selected from corresponding large-scale genome-wide association studies. Summary-level data on PPH were obtained from the latest R10 release of the FinnGen consortium. Inverse-variance weighting (IVW) was performed as the main MR analysis, and MR-Egger and weighted median were performed to strengthen the final MR estimates. Sensitivity analyses were applied to detect possible heterogeneity or pleiotropy. One hundred and four single-nucleotide polymorphisms (SNPs) for calcium and 117 SNPs for 25(OH)D were selected as candidate instrumental variables. In this study, the MR estimates for calcium and 25(OH)D remained consistent before and after removing confounder-related SNPs. The IVW method suggested a potential inverse association between genetically predicted calcium and PPH (odds ratio [OR] = 0.89, 95% confidence interval [CI]: 0.80, 0.99, P = .036); however, this finding was not supported by the pleiotropy‑robust MR‑Egger (OR = 0.89, 95% CI: 0.72-1.11, P = .303) or weighted median (OR = 0.90, 95% CI: 0.74-1.10, P = .302) methods. No heterogeneity or pleiotropy was observed in Cochran's Q test (P = .825), MR-Egger intercept test (P = .976), or the MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) Global Test (P = .842) in the determination of the role of calcium levels in PPH. However, no significant genetic evidence was found to support a causal relationship between 25(OH)D and PPH (IVW: OR = 0.98, 95% CI: 0.85-1.12, P = .735; MR-Egger: OR = 1.01, 95% CI: 0.82-1.25, P = .912; Weighted median: OR = 1.08, 95% CI: 0.85-1.36, P = .525). In summary, our primary analysis suggested a potential inverse association between serum calcium and PPH, but this was not supported by sensitivity analyses robust to pleiotropy, warranting cautious interpretation. For 25(OH)D, our analysis did not provide sufficient evidence to support or refute a causal role in PPH, largely due to limited statistical power.