Association of pre-existing maternal cardiovascular diseases with neurodevelopmental disorders in offspring: a cohort study in Sweden and British Columbia, Canada

Importance Maternal cardiac disease is associated with impaired placentation and adverse neonatal outcomes, but whether it increases the risk of subsequent neurodevelopmental disorders in offspring remains unknown. Objective To assess the associations between pre-existing maternal cardiovascular disease (CVD) and attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID) in offspring. Design Population-based cohort study. Setting Sweden and British Columbia (BC), Canada. Participants Singletons live-born without major malformations between 1990 and 2019. The Swedish Medical Birth Register and the BC Vital Statistics were linked to hospital and physician billing records for identification of exposure and outcomes. All children were followed from age 1 until the outcome, death, emigration, or December 2020. Exposure A composite of pre-conception maternal CVDs: cerebrovascular disease, arrhythmia, heart failure, valvular, and congenital heart diseases. Main Outcomes and Measures Diagnoses of ADHD, ASD, and ID. The incidence of ADHD, ASD, and ID, comparing offspring of mothers with versus without CVD, was calculated as adjusted hazard ratios (aHRs). These results were compared to models using paternal CVD as negative-control exposure. Fixed-effect meta-analysis was performed to combine the aHRs from Sweden and BC. Results We analysed 3,587,257 offspring (48.9% female) – 2,699,675 in Sweden and 887,582 in BC. The meta-analysis suggests that compared with offspring of mothers without CVD, offspring of mothers with CVD had 1.15-fold higher aHRs of ADHD (95% CI: 1.10-1.20) and ASD (95% CI: 1.07-1.22). No association was found between maternal CVD and ID. Stratification by maternal CVD subtypes showed increased hazards of ADHD for maternal heart failure (aHR 1.31; 95% CI: 1.02-1.61), cerebrovascular disease (aHR 1.20; 95% CI: 1.08-1.32), congenital heart disease (aHR 1.18; 95% CI: 1.08-1.27), arrhythmia (aHR 1.13; 95% CI: 1.08-1.19), and valvular heart disease (aHR 1.12; 95% CI: 1.00-1.24). Increased hazards of ASD were observed for maternal cerebrovascular disease (aHR 1.25; 95% CI: 1.04-1.46), congenital heart disease (aHR 1.17; 95% CI: 1.01-1.33), and arrythmia (HR 1.12; 95% CI: 1.01-1.21). Paternal CVDs, except for cerebrovascular disease, did not show associations. Conclusion and Relevance Pre-existing maternal CVD was associated with excess risk of ADHD and ASD in offspring. The associations were broadly robust to genetic confounding, warranting further research to identify the underlying intrauterine mechanisms.