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

Abstract

Background: We aimed to investigate the associations of pre-existing maternal cardiovascular disease (CVD) with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and intellectual disability (ID) in offspring.

Methods: This population-based cohort study included singletons live-born without major malformations in Sweden (n = 2 699 675) and British Columbia (BC), Canada (n = 887 582) during 1990-2019, with follow-up from age 1 year until the outcome, death, emigration or December 2020, whichever came first. The primary exposure was defined as a composite CVD diagnosed prior to conception: cerebrovascular disease, arrhythmia, heart failure, valvular and congenital heart diseases. The incidences of ADHD, ASD and ID, comparing offspring of mothers with versus without CVD, were calculated as adjusted hazard ratios (aHRs). These results were compared with models using paternal CVD as negative control exposure.

Results: Compared with offspring of mothers without CVD, offspring of mothers with CVD had 1.15-fold higher aHRs of ADHD [95% confidence interval (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 (HR 1.31, 95% CI 1.02-1.61), cerebrovascular disease (HR 1.20, 95% CI 1.08-1.32), congenital heart disease (HR 1.18, 95% CI 1.08-1.27), arrhythmia (HR 1.13, 95% CI 1.08-1.19) and valvular heart disease (HR 1.12, 95% CI 1.00-1.24). Increased hazards of ASD were observed for maternal cerebrovascular disease (HR 1.25, 95% CI 1.04-1.46), congenital heart disease (HR 1.17, 95% CI 1.01-1.33) and arrythmia (HR 1.12, 95% CI 1.01-1.21). Paternal CVD did not show associations with ADHD, ASD or ID, except for cerebrovascular disease which showed associations with ADHD and ASD.

Conclusions: In this large cohort study, pre-existing maternal CVD was associated with increased risk of ADHD and ASD in offspring.

Keywords: Maternal cardiovascular disease; attention-deficit/hyperactivity disorder; autism spectrum disorder; intellectual disability; negative control exposure; paternal cardiovascular disease.

Figure 1.

Plots showing pooled adjusted hazard ratios of neurodevelopmental disorders according to pre-existing maternal and paternal cardiovascular diseases: singleton offspring live-born without major malformations in Sweden 1990 to 2019 and in British Columbia, Canada, 1992 to 2019. ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; CI, confidence interval; CVD, cardiovascular disease; ID, intellectual disability; NDD, neurodevelopmental disorder. The pooled hazard ratios represent the estimates combined by meta-analysing the pre-calculated hazard ratios and standard errors in the two countries. The hazard ratios were adjusted for child’s sex and birth year, and mother’s age at delivery, parity, education (Sweden only), region of birth, marital status/cohabitation with partner, smoking during early pregnancy (Sweden only), pre-gestational diabetes, pre-gestational hypertension and parental history of any neurodevelopmental or psychiatric disorders. The hazard ratios for paternal CVD were further adjusted for maternal CVD