Sodium glucose transporter 2 inhibitor exposure and the risk of congenital malformations: nationwide birth cohort study

BACKGROUND AND AIM: Sodium-glucose cotransporter-2 (SGLT2) inhibitors, a widely used class of oral antidiabetic agents provide additional cardioprotective and renoprotective benefits, but their use during pregnant remains limited. This study aimed to evaluate the association between SGLT2 inhibitor exposure during pregnancy and the risk of congenital malformations. METHODS AND RESULTS: This population-based cohort study utilized data from the National Health Insurance Service Database (2016-2022). Pregnancies with known teratogen exposure were excluded. SGLT2 inhibitor or insulin (as active comparator) use during the first trimester was defined as exposure. The primary outcomes were congenital malformations and heart defects. Propensity score matching controlled for confounders, and generalized linear regression estimated relative risks (RRs) with 95 % confidence intervals (CIs). Negative control outcomes were employed to assess residual confounding. Among 536,654 pregnancies, 121 pregnancies were exposed to SGLT2 inhibitors (mean [SD] age: 35.07 [4.26]), and 2007 to insulin (mean [SD] age: 34.89 [4.28]). Adjusted RRs (95 % CIs) for congenital malformations and heart defects were 0.88 (0.52-1.46) and 0.83 (0.44-1.58), respectively. In sensitivity analysis restricted to the organogenesis period (gestational weeks 4-10), risk of congenital heart defects was 2.79 (1.16-7.06). No residual confounding detected in negative control outcome. CONCLUSIONS: In this study, SGLT2 inhibitor use during the first trimester was not associated with an increased risk of congenital malformations. Nonetheless, the observed increased risk of congenital heart defects during the organogenesis period highlights the importance of exposure timing and warrants cautious interpretation. These findings provide evidence to guide clinical decision-making regarding antidiabetic medication use during pregnancy.