Causal Associations Between Pre-Pregnancy Diabetes Mellitus and Pre-Eclampsia Risk: Insights from a Mendelian Randomization Study.

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Pre-eclampsia (PE) is a serious pregnancy complication defined by the onset of hypertension and multi-organ dysfunction occurring after 20 weeks of gestation. Studies have indicated the correlation between diabetes mellitus (DM) and PE, but the causal relationship remains unclear. The two-sample Mendelian randomization (MR) approach, including the inverse variance weighted random effects (IVW-RE) model and the traditional sensitivity model, was employed to assess the causal effects of pre-pregnancy type 1 diabetes (T1D) and type 2 diabetes (T2D) on PE using summary-level data obtained from genome-wide association studies. Additionally, diabetes-related factors, such as glycated hemoglobin (HbA1c) levels, fasting insulin levels, and body mass index (BMI), were evaluated for their potential causal effects on the risk of PE. Pleiotropy-robust and multivariable Mendelian randomization (MVMR) methods were further used because of the intricate associations among the traits. Insulin and metformin use was also assessed for their causal role in PE risk. Our findings show that genetically predicted T1D (OR = 1.06, 95% CI: 1.03-1.09, p < 0.001), T2D (OR = 1.09, 95% CI: 1.04-1.14, p < 0.001), and BMI (OR = 1.64, 95% CI 1.49 to 1.80, p < 0.001) had causal effects on the incidence of PE, while the effects of HbA1c (OR = 0.77, 95% CI 0.59 to 1.02, p = 0.064) and fasting insulin levels (OR = 1.35, 95% CI 0.89 to 2.05, p = 0.153) on the occurrence of PE were not significant. The results were verified by MVMR analysis. Additionally, insulin use increased the risk of pre-eclampsia (OR = 1.11, 95% CI 1.05-1.17, p < 0.001). Our findings demonstrate a causal relationship between pre-pregnancy diabetes (DM) and obesity and the risk of PE from a genetic epidemiological perspective. Adverse maternal factors, including DM and obesity prior to pregnancy, should be considered in mechanistic studies of PE. In addition, comprehensive interventions for risk factors such as pre-pregnancy DM and obesity should be emphasized in clinical practice.