Maternal hypertensive disorders and neurodevelopmental disorders in offspring: a population-based cohort in two Nordic countries

Hui Wang,Yongfu Yu,Fei Li,Krisztina D László,Jiong Li,Jun Zhang,Mika Gissler

doi:10.1007/s10654-021-00756-2

Abstract

Maternal hypertensive disorders during pregnancy (HDP) have been associated with neuropsychiatric problems in offspring. We aim to investigate the associations between specific types of maternal HDP and offspring neurodevelopmental disorders and further examine whether the timing of onset and severity of HDP would affect these associations. The study population consisted of 4,489,044 live-born singletons in Denmark during 1978–2012 and Sweden during 1987–2010. Maternal HDP was categorized into chronic hypertension, gestational hypertension, and pre-eclampsia; pre-eclampsia was further stratified according to timing (early-onset, late-onset), or severity (moderate, severe) of the disease. Neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID), were defined by ICD-coded register diagnosis. Cox regression was used to calculate hazard ratios (HR) while adjusting for potential confounders, and sibling analyses assessed the influence of unmeasured shared familial factors. Maternal HDP was associated with increased risks of ADHD (HR, 1.24; 95% confidence interval [CI], 1.20–1.28), ASD (1.29 [1.24–1.34]), and ID (1.58 [1.50–1.66]) in offspring, respectively, which was mostly driven by pre-eclampsia. The strongest associations were observed for early-onset and severe pre-eclampsia, and the corresponding HRs for ADHD, ASD and ID were 1.93 [1.73–2.16], 1.86 [1.61–2.15], and 3.99 [3.42–4.65], respectively. The results were similar in the sibling analyses. The associations between maternal HDP and offspring neurodevelopmental disorders were consistent across the subgroups of sex, preterm status, parity, maternal age and psychiatric disorders. Maternal HDP, especially early-onset pre-eclampsia, are associated with increased risks of ADHD, ASD, and ID in particular, independent of shared familial factors.

Highlights

Neurodevelopmental disorders, such as attention-deficit/ hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), affect about 10% of children worldwide [1]
One recent population-based study found that maternal Hypertensive disorders during pregnancy (HDP) was associated with increased risks of mental disorders in offspring, but the timing of pre-eclampsia and unmeasured familiar risk factors were not taken into consideration [23]
We identified 184 033 (4.1%) individuals born to mothers with HDP

Summary

Introduction

Neurodevelopmental disorders, such as attention-deficit/ hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), affect about 10% of children worldwide [1]. HDP may affect maternal health and pregnancy outcomes [11], and predispose the offspring to neurobehavioral disorders later in life through impacting developing fetal brain due to poor vascularization of the placenta [12, 13]. Previous studies have reported that maternal HDP is associated with increased risks of ADHD [14], ASD [15, 16], cerebral palsy [17], and emotional and behavioral problems in offspring [18,19,20,21]. One recent population-based study found that maternal HDP was associated with increased risks of mental disorders in offspring, but the timing of pre-eclampsia and unmeasured familiar (genetic or environmental) risk factors were not taken into consideration [23]. There is a need to evaluate whether unmeasured familial factors exert an influence on the associations between maternal HDP and neurodevelopmental disorders in offspring

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