Abstract
INTRODUCTION: Obstetrical disorders critically impact maternal and fetal health. Sex hormone-binding globulin (SHBG) regulates pregnancy maintenance and maternal-infant outcomes through hormonal, metabolic, and inflammatory pathways, yet causal relationships with obstetrical disorders remain unclear. This Mendelian randomization (MR) study examined SHBG's causal effects on 12 obstetrical conditions. METHODS: Using cis-protein quantitative trait loci (cis-pQTLs) of SHBG as instrumental variables, we conducted MR analyses in FinnGen and UK Biobank (UKBB), followed by meta-analyses. Inverse variance weighting (IVW) was primary method, with sensitivity analyses ensuring robustness. RESULTS: IVW-MR demonstrated reduced risks with elevated SHBG: gestational diabetes (OR[95%]=0.835[0.785-0.889], P (FDR)=2.03×10(-7)), hyperemesis gravidarum (OR[95%]=0.823[0.728-0.931], P (FDR)=5.94×10(-3)), gestational hypertension (OR[95%]=0.917[0.852-0.987], P (FDR)=0.041), and early-pregnancy hemorrhage (OR[95%]=0.853[0.794-0.916], P (FDR)=6.90×10(-5)). Meta-analysis confirmed SHBG's causal role in gestational diabetes (P_combined<0.05). COLOC revealed shared loci between SHBG and five disorders: gestational diabetes, hyperemesis, early hemorrhage, preterm delivery, and postpartum hemorrhage. CONCLUSION: SHBG causally lowers risks of gestational diabetes, hypertension, hyperemesis, miscarriage, and preterm delivery, highlighting its clinical relevance in obstetrical pathophysiology.