Mendelian Randomization Study of Sex Hormone Binding Globulin and Its Influence on Adverse Pregnancy Outcomes

The relationship between sex hormone-binding globulin (SHBG) levels and the risk of adverse pregnancy outcomes (APOs) remains controversial. A two-sample Mendelian randomization (MR) study was performed to clarify the causality of SHBG on the risk of APO. Significant single-nucleotide polymorphisms (SNPs) associated with SHBG levels were obtained from the genome-wide association study (GWAS) in the European population. Summary statistics of the number of spontaneous miscarriages, preeclampsia, gestational diabetes mellitus (GDM), intrahepatic cholestasis of pregnancy (ICP), and female infertility were utilized as the outcome. The causality was examined primarily by inverse-variance weighted (IVW), along with MR-Egger regression, weighted median estimator, and weighted mode method. Based on the IVW model, every genetically predicted standard deviation (SD) increase in SHBG levels was causally associated with 0.023 SDs decrease of the number of spontaneous miscarriages (Beta ± SE: -0.023 ± 0.010, p = 0.018), 11.3% decrease of the risk of preeclampsia (OR = 0.887, 95% CI: 0.806-0.977, p = 0.015), 17% decrease of the risk of GDM (OR = 0.830, 95% CI: 0.753-0.914, p = 0.000), 23.6% decrease of the risk of ICP (OR = 0.764, 95% CI: 0.584-0.999, p = 0.049), and 14% decrease of the risk of infertility (OR = 0.860, 95% CI: 0.777-0.951, p = 0.003). Our study indicated that the increased levels of SHBG could significantly reduce the risk of APO. SHBG may be helpful as the indicator for preconception risk assessment and pregnancy risk monitoring. These findings are limited to European and require further validation in diverse populations.