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Neurodevelopmental outcomes in offspring of mothers with hypertensive disorders of pregnancy

Hypertensive disorders of pregnancy (HDP) are a major cause of maternal mortality and morbidity, and complicate up to 10% of pregnancies globally. HDP are responsible for adverse perinatal outcomes such as preterm birth, low birthweight, and intrauterine growth restriction. They have also been found to be associated with long-term adverse outcomes for children, including an increased risk of cardiovascular and metabolic disorders. While the link between HDP and physical health is well researched, its impact on children’s neurodevelopmental outcomes remains relatively unexplored. Chen et al. examined whether maternal chronic hypertension and pregnancy-induced hypertension/pre-eclampsia are associated with childhood neurodevelopmental disorders such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), developmental delay, intellectual disability, cerebral palsy (CP), and epilepsy/infantile spasms. The study used three Nationwide Databases in Taiwan and included 877 233 children born between 2004 and 2008. The authors found that in utero exposure to pregnancy-induced hypertension/pre-eclampsia was associated with an increased risk of a wide spectrum of neurodevelopmental disorders. Chronic hypertension was also associated with all types of neurodevelopmental disorders except for ASD. Chen et al.’s findings add to existing evidence suggesting that perinatal exposure to environmental adversities in utero can alter fetal development and increase disease risk later in life. The large sample size allowed for the authors to examine the effect of HDP on a wide range of neurodevelopmental disorders. However, it remains unclear whether the observed associations reflect a true effect of maternal HDP or whether these are due to residual and/or unmeasured confounding factors. Chen et al. recognized they lacked data on some potentially important confounders such as physical activity, pre-pregnancy body mass index, smoking, and alcohol consumption during pregnancy. However, it is also important to note that the authors did consider several other potential confounders and the estimates only slightly attenuated after adjustment, except for CP and intellectual disability. Another limitation is that the study neither considered the onset nor the severity of pregnancy-induced hypertension/pre-eclampsia. Evidence suggests that severe pre-eclampsia (systolic ≥160mm Hg) is more likely to be associated with a high risk of neurodevelopmental disorders than mild to moderate pre-eclampsia. The effects may also differ amongst offspring exposed to early onset of pre-eclampsia, which develops before 34 weeks’ gestation, compared to offspring exposed to later onset of pre-eclampsia. A further limitation is that the study did not differentiate between gestational hypertension and pre-eclampsia. This additional analysis would have provided stronger evidence for causal inference. For example, an analysis based on the Avon Longitudinal Study of Parents and Children data found that maternal pre-eclampsia (but not gestational hypertension) was associated with emotional and behavioural problem trajectories, suggesting that pre-eclampsia and gestational hypertension are distinct entities with different clinical characteristics. Apart from fetal growth restriction, Chen et al. did not speculate about other possible biological mechanisms of HDP with neurodevelopmental disorders. It is evident that reduced placental perfusion can lead to inadequate fetal nutrition and adverse fetal neurodevelopment. If fetal growth restriction were the mechanism for the observed relationship, we would expect reduced or no observed effects after adjustment for preterm birth and small for gestational age, but this was not the case. On the other hand, one can argue that preterm birth and small for gestational age are mediator variables, and adjusting for these variables in a standard regression model (instead of accounting for them using a mediation analysis) may produce flawed conclusions. Despite these limitations, the study by Chen et al. highlights the need for early screening for neuropsychiatric and other developmental delays in children of mothers with HDP. Replicating these findings using a genetically informed study design would inform current evidence.