Maternal Diabetes and Risk of Early-Onset Cardiovascular Diseases in Offspring

Importance: The long-term risks of specific cardiovascular diseases (CVDs) among offspring exposed to various types of maternal diabetes in utero and the mechanisms underlying these risks remain unclear. Objective: To investigate the association between maternal diabetes during pregnancy and risks of overall CVD and specific CVD subtypes in offspring and whether adverse perinatal and early-life outcomes mediate associations. Design, Setting, and Participants: This nationwide population-based cohort study using linked national registers included individuals born in Sweden between January 1, 1973, and December 31, 2014, with follow-up through December 31, 2023. Exposures: Maternal diabetes during pregnancy, including gestational diabetes and pregestational diabetes (type 1 and type 2). Main Outcomes and Measures: The main outcomes were incident overall CVD and specific CVD subtypes in offspring, identified from national inpatient and outpatient registers. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs. Sibling analyses were conducted to account for shared familial factors. Mediation analyses assessed the contribution of congenital heart disease (CHD), preterm birth, and large for gestational age (LGA). Results: The study included 4 274 414 individuals (51.39% male; mean [SD] age, 27.4 [15.0] years at the end of follow-up), of whom 61 336 (1.46%) were exposed to maternal diabetes and 4 213 078 (98.56%) were not exposed. During a median 27.6 years (IQR, 17.2-37.4 years) of follow-up, 7.36% of total participants had a diagnosis of CVD. Any maternal diabetes was associated with an increased risk of overall CVD in offspring (HR, 1.16; 95% CI, 1.12-1.20); risk of CVD was higher for pregestational diabetes (HR, 1.29; 95% CI, 1.21-1.38) than for gestational diabetes (HR, 1.11; 95% CI, 1.05-1.17). These associations were also found in sibling analyses. Increased risks in offspring prenatally exposed to maternal diabetes were found for some CVD subtypes, including venous thromboembolism (HR, 1.20; 95% CI, 1.07-1.34), cerebrovascular diseases (HR, 1.31; 95% CI, 1.12-1.52), atrial fibrillation (HR, 1.27; 95% CI, 1.05-1.54), and heart failure (HR, 1.65; 95% CI, 1.37-2.00). In mediation analyses, CHD, preterm birth, and LGA directly and/or indirectly mediated 31.87%, 16.06%, and 14.18% of the association between any diabetes and offspring CVD risk, respectively. Conclusions and Relevance: This cohort study found that maternal diabetes during pregnancy was associated with increased long-term risks of overall CVD and some CVD subtypes in offspring, particularly following pregestational diabetes. These findings highlight the importance of associations of perinatal and early-life factors and offspring CVD risk later in life, especially in mothers with diabetes.