Novel Insights into the Causal Relationship between Antidiabetic Drugs and Adverse Perinatal Outcomes: A Mendelian Randomization Study.

Abstract

Background: Hyperglycemia during pregnancy increases the risk of adverse perinatal outcomes and birth defects. Evidence regarding the long-term safety of antidiabetic drugs during pregnancy is still lacking.

Methods: A two-sample Mendelian randomization (MR) study was performed to assess the causal association between six antidiabetic drug targets (ABCC8, DPP4, INSR, GLP1R, PPARG, and SLC5A2) and seven adverse perinatal outcomes and five congenital malformation outcomes. Inverse variance weighted (IVW) was adopted as the main MR method, and sensitivity analysis using traditional MR methods was performed to evaluate the robustness of the results.

Results: We observed strong evidence that sodium-glucose cotransporter 2 (SGLT2) inhibitors (odds ratio [OR], 0.084; 95% confidence interval [CI], 0.009 to 0.834; P=0.034) reduces the risk of preterm birth; genetic variation in sulfonylurea drug targets (OR, 0.015; 95% CI, 2.50E-04 to 0.919; P=0.045) and genetic variation in thiazolidinedione drug targets (OR, 0.007; 95% CI, 4.16E-04 to 0.121; P=0.001) reduced the risk of eclampsia/preeclampsia; glucagon-like peptide 1 (GLP-1) analogues target (β=-0.549; 95% CI, -0.958 to -0.140; P=0.009) was inversely associated with fetal birth weight; thiazolidinedione target was inversely associated with gestational age (β=-0.952; 95% CI, -1.785 to -0.118; P=0.025); SGLT2 inhibitors reduced the risk of cardiocirculatory malformations (OR, 0.001; 95% CI, 8.75E-06 to 0.126; P=0.005).

Conclusion: Most antidiabetic drugs are safe when used during the perinatal period. Of note, GLP-1 analogues may lead to a risk of low birth weight, while thiazolidinediones may lead to a reduction in fetal gestational age.