Introduction

Hypertensive disorders of pregnancy (HDPs) are the most common complications of pregnancy estimated to affect approximately 5%–15% of all pregnancies.1 2 HDPs are classified into four categories, as recommended by the International Society for the Study of Hypertension in Pregnancy3: ‘chronic hypertension’, ‘gestational hypertension’, ‘pre-eclampsia—de novo or superimposed on chronic hypertension’ and ‘white coat hypertension’. While HDPs are not fully understood, risk factors include advanced maternal age and elevated body mass index, both of which are increasingly common in modern society.4 HDP create a hostile in utero environment as a result of multiple pathophysiological changes including reduced placental blood flow, maternal inflammation and oxidative stress.5 These can potentially alter fetal developmental trajectories, which may increase the risk of long-term vascular, cognitive and psychiatric sequelae in the offspring.4 6–8

Neurodevelopmental disorders including autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) are a group of conditions with onset during the developmental period and may lead to impairments in personal, social, academic or occupational functioning.9 10 Though these disorders have a strong genetic basis,11 12 there is increasing evidence suggesting that environmental risk factors during prenatal development may also play a role.11 13–18 In support of this, a population-based study conducted on a Swedish population estimated that genes and environmental exposure each contribute approximately half of the overall risk of ASD, with this 50/50 contribution remaining consistent across the study’s 24-year span.11 Furthermore, recent work demonstrated focal patches of abnormal laminar architecture and laminar disorganisation in the prefrontal and temporal cortices of children with ASD suggesting there may be alterations in brain development at prenatal stages, as cortical lamination is ongoing during the second trimester of pregnancy.19 20 Moreover, there is some evidence for alterations in brain structural and vascular anatomy21 and reduced cognitive functioning22 in offspring of pregnancies complicated by pre-eclampsia pregnancies. There is therefore a need to determine the impact of HDP exposure on the risk of adverse neurodevelopmental outcomes in the children.

Early identification and intervention There is a growing consensus that early identification and intervention are key to improving long-term neurodevelopmental outcomes.23 24 Previously published work has indicated that early behavioural intervention if commenced before 30 months old, can lead to improvements in cognitive and adaptive behaviour among individuals with ASD.25 26 Despite this increasing recognition for surveillance, the average age of ASD diagnosis remains at approximately 4–5 years, meaning the window for intervention has closed.23 27 28 However, research suggests that a stable diagnosis can be made as young as 2 years, allowing earlier access to specialised services.29 Therefore, by examining the potential impact of HDP on neurodevelopment in offspring, it can inform the need for increased paediatric surveillance of infants who have been exposed to HDP. This in turn could allow for early intervention that may aid improvement of neurodevelopmental outcome.23 25 26 30

Rationale for current systematic review Evidence suggests that HDP may lead to an increased risk of ASD, ADHD as well as other neurodevelopmental disorders in children.15 31 32 Conversely, other studies have reported no association,13 31 highlighting the need for further study in this area. Therefore, the aim of this systematic review and meta-analysis is to summarise the available evidence examining the association between pre-eclampsia and gestational hypertension, and subsequent risk of neurodevelopmental disorders in exposed children, and if possible to identify an overall pooled estimate of association. The systematic review will be based on the following requirements:

Population Pregnant women and their children.

Intervention/exposures HDP. Primary exposure: pre-eclampsia. Secondary exposure: other HDP.

Comparison No diagnosis of HDP.