Long-term neurobehavioral and metabolic outcomes in offspring of mothers with diabetes during pregnancy: a large, population-based cohort study in Ontario, Canada

Objective — Offspring of women with diabetes are at increased risk of developing neurobehavioral and cardiometabolic disorders, but there is scant evidence regarding the association between glycemic level during pregnancy and these long-term offspring outcomes.

Research design and methods — We conducted a population-based, cohort study of deliveries in Ontario between April 1991 and March 2018. Women had preexisting diabetes, gestational diabetes, or no diabetes. We applied a Cox proportional hazard model to examine the risk of developing attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and cardiometabolic outcomes in offspring and assessed the association between pregnancy HbA1c levels and risk of outcomes, adjusting for confounders.

Results — A total of 3,407,961 mother/infant pairs were followed up to 29 years. Using a Cox proportional hazard model, offspring of women with type 1 diabetes had the highest risk of ADHD (adjusted hazard ratio [aHR] 1.43 [95% CI 1.36-1.49]), ASD (aHR 1.94 [1.80-2.09]), diabetes (aHR 4.73 [4.34-5.16]), hypertension (aHR 2.32 [2.07-2.61]), and cardiovascular disease (CVD) (aHR 1.72 [1.56-1.90]), followed by offspring of women with type 2 diabetes and gestational diabetes compared with those unexposed. Among women with preexisting diabetes, there was an association between level of pregnancy HbA1c and offspring diabetes (aHR 1.22 [95% CI 1.12-1.32]), hypertension (aHR 1.42 [1.29-1.57]), and CVD (aHR 1.20 [1.11-1.29]) but no statistically significant association with neurobehavioral outcomes.

Conclusions — In utero exposure to maternal diabetes was associated with an increase in ADHD, ASD, and cardiometabolic outcomes in offspring, with differences seen across diabetes subtypes. Pregnancy glycemia was associated with cardiometabolic outcomes, but not neurobehavioral outcomes, and provides a potentially modifiable risk factor to decrease cardiometabolic outcomes in offspring.