Causal Relationship between Hypothyroidism and Adverse Pregnancy Outcomes: A Multivariate Mendelian Randomization Study

Hypothyroidism has been associated with adverse pregnancy outcomes in observational studies, but these associations may be influenced by residual confounding or reverse causation. We conducted a pioneering two-sample Mendelian randomization (MR) investigation using aggregated data from a large-scale genome-wide association study to examine the correlation between hypothyroidism and preeclampsia, gestational diabetes, miscarriage, placental abruption, and preterm labor. Inverse variance weighting served as the primary analytical approach, complemented by MR Egger regression, weighted median, simple modal, and weighted methods. Sensitivity analyses, including MR-PRESSO, MR-Egger regression, and leave-one-out analysis, were performed to test the robustness of the findings. Multivariable MR (MVMR), adjusting for smoking and body mass index, was further conducted to validate the MR results. The IVW analysis indicated that hypothyroidism may increase the risk of miscarriage and preeclampsia (OR = 1.004, 95% CI = 1.000–1.008, p = 0.039; OR = 1.588, 95% CI = 1.027–2.456, p = 0.038). MVMR demonstrated that the causal effect of hypothyroidism on miscarriage and preeclampsia persisted after adjusting for body mass index (OR = 0.016, 95% CI = 1.005–0.995, p = 0.005; OR = 1.7169, 95% CI = 1.065–2.767, p = 0.0264). These findings furnish compelling evidence supporting a causal association between hypothyroidism and miscarriage, as well as preeclampsia.