The Mediating Role of Blood Metabolites in the Association between Basal Metabolic Rate and Obstetrical Disorders: A Mendelian Randomization Analysis.

Introduction: Previous studies suggest a link between Basal Metabolic Rate (BMR) and obstetrical disorders; however, causality remains unclear. We investigated the causal effects of BMR on 14 obstetric disorders and evaluated the potential mediating effects of blood metabolites in these relationships.

Methods: Using Genome-Wide Association Study (GWAS) summary data, we conducted both univariate and multivariable Mendelian Randomization (MVMR) analyses. The primary causal inference was based on Inverse Variance Weighted (IVW), MR-Egger, weighted median, and sensitivity analyses (Cochran's Q, MR-PRESSO). Mediation analysis was employed to quantify the proportion of effects operating through metabolite-regulated pathways.

Results: BMR was inversely associated with hyperemesis gravidarum (OR=0.73, 95%CI: 0.59-0.90, P=0.008), Intrahepatic Cholestasis of Pregnancy (ICP) (OR=0.67, 95%CI: 0.56-0.80, P<0.001), poor fetal growth (OR=0.80, 95%CI:0.71-0.90, P=0.001), and preterm delivery (OR=0.78, 95%CI:0.70-0.87, P<0.001). MVMR identified elevated BMR and mannose levels as protective against ICP, with BMR showing a positive correlation with mannose. Mediation analysis revealed that BMR reduced ICP risk partly through increased mannose (OR = 1.38, 95% CI: 1.19-1.59, P = 2.03 × 10^-5), accounting for 29.93% of the effect.

Discussion: Elevated BMR significantly reduced risks of intrahepatic cholestasis (HR=0.67), fetal distress (HR=0.80), and preterm birth (HR=0.78), mediated partly by mannose levels. Mendelian randomization established causality, linking metabolic adaptation to improved pregnancy outcomes. However, these findings, based on European genetic data, limit generalizability, and unmeasured confounders may persist despite MR methods.

Conclusion: Higher BMR may lower risks of hyperemesis gravidarum, ICP, poor fetal growth, and preterm delivery. Mannose mediates the protective effect of BMR on ICP, highlighting potential metabolic pathways for intervention.