Assessing the causal association of pregnancy complications with diabetes and cardiovascular disease

Background To the best of our knowledge, numerous observational studies have linked pregnancy complications to increased risks of diabetes and cardiovascular disease (CVD), causal evidence remains lacking. Our aim was to estimate the association of adverse pregnancy outcomes with diabetes and cardiovascular diseases. Methods A two-sample Mendelian randomization (MR) analysis was employed, which is not subject to potential reverse causality. Data for pregnancy complications were obtained from the FinnGen consortium. For primary analysis, outcome data on diabetes, related traits, stroke, and coronary heart disease (CHD) were extracted from the GWAS Catalog, MAGIC, MEGASTROKE, and CARDIoGRAMplusC4D consortium. The MAGIC and UKB consortium datasets were used for replication and meta-analysis. Causal effects were appraised using inverse variance weighted (IVW), weighted median (WM), and MR-Egger. Sensitivity analyses were implemented with Cochran’s Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out (LOO) analysis and the funnel plot. Results Genetically predicted gestational diabetes mellitus (GDM) was causally associated with an increased diabetes risk (OR=1.01, 95% CI=1–1.01, P 0.0001), yet correlated with lower 2-hour post-challenge glucose levels (OR=0.89, 95% CI=0.82–0.97, P =0.006). Genetic liability for pregnancy with abortive outcomes indicated decreased fasting insulin levels (OR=0.97, 95% CI=0.95–0.99, P =0.02), but potentially elevated glycated hemoglobin levels (OR=1.02, 95% CI=1.01–1.04, P =0.01). Additionally, hypertensive disorders in pregnancy was tentatively linked to increased risks of stroke (OR=1.11, 95% CI=1.04–1.18, P =0.002) and CHD (OR=1.3, 95% CI=1.2–1.4, P =3.11E-11). Gestational hypertension might have a potential causal association with CHD (OR=1.11, 95% CI=1.01–1.22, P =0.04). No causal associations were observed between preterm birth and diabetes, stroke, or CHD. Conclusion The findings of this study provide genetic evidence that gestational diabetes, pregnancy with abortive outcomes, and hypertensive disorders in pregnancy may serve as early indicators for metabolic and cardiovascular risks. These insights are pivotal for the development of targeted screening and preventive strategies.