Hypertensive Disorders with Placental Insufficiency Associated with Increased Autism and Intellectual Disability Risk

Background:  Pregnancies complicated by hypertensive disorders have been linked to poor neurodevelopmental outcomes, such as autism and intellectual disability (ID). Hypertensive disorders can lead to inflammation, vascular damage, and restricted nutrient transfer at the placental level; these physiologic changes may result in aberrant neurodevelopment. Although we have previously investigated preeclampsia and placental insufficiency (PI) in relation to neurodevelopmental outcomes, we were unable to examine the finer categories of hypertensive disorders, including chronic hypertension only and hypertension with superimposed preeclampsia.

Objectives:  To determine whether the risk for autism or ID relative to the general population (GP) differed across specific categories of hypertensive disorders and whether the presence of PI changed these associations.

Methods:  We used a large population-based cohort of California births from 1991 to 2008 with linked information on autism and ID diagnoses from the California Department of Developmental Services (DDS). Hypertensive disorders were identified by ICD-9-CM codes and grouped into chronic hypertension (HTN), preeclampsia (PE), and HTN with superimposed PE (HTN+PE), and evidence of PI included intrauterine growth restriction, oligohydramnios and/or small-for-gestational-age birthweight. We conducted log-binomial regression models with mutually exclusive categories of hypertensive disorders plus or minus PI as predictors of interest and neurodevelopmental disorders autism and ID as outcomes relative to GP. All models were adjusted for birth year, maternal age, race, delivery payer, and parity to estimate risk ratios (RR) and 95% confidence intervals (CI).

Results:  Women with any type of hypertensive disorder had approximately a 20% increased risk for having a child with autism relative to GP.  Although PI alone was only modestly associated with autism, the risk for autism increased in relation to these hypertensive disorders in the presence PI:  19% to 32% for HTN and 23% to 35% for PE. HTN+PE was associated with a 39% increased risk for ASD; however, HTN+PE in the presence of PI was not associated with ASD.  Associations between hypertensive disorders and ID were more pronounced. Women with HTN+PE had a nearly 2-fold increased risk for having a child with ID; whereas women with PE or HTN only each had a 1.4-fold increased risk for ID. In contrast to autism, PI alone was associated with a nearly 3-fold increased risk for ID. Similar to autism, the presence PI with any hypertensive disorder elevated the risk for ID: 40% to 214% for HTN+PE; 40% to 214 for HTN, and 31% to 186% for PE.

Conclusions:  Risks for autism and especially for ID were increased in fetuses whose mothers had any form of hypertensive disorder during pregnancy, particularly when PI was present.  Suboptimal placentation limits oxygen and nutrient transfer creating oxidative stress, growth restriction and progressive hypoxemia. Although the exact causal mechanisms linking hypertensive disorders and adverse neurodevelopmental outcomes are unknown, improved prepregnancy health may help to reduce the likelihood of developing these conditions.