Pregnancy Hypertensive Disorders Linked to Increased ADHD, Autism Risks

Ali S. Khashan, PhD

The long-held clinical speculation that hypertensive disorders of pregnancy (HDP) are associated with neurodevelopmental disease just became more evidential.

A systematic review and meta-analysis of 61 articles from the past 3 decades have found that increased risks of childhood autism spectrum disorder (ASD) or attention-deficit hyperactivity disorder (ADHD) could be associated with infant exposure to HDP. As one of the most common and increasingly prevalent prenatal complications — affecting 5-15% of all pregnancies — HDP and its possible link to the neurodevelopment disorders gives caution to researchers.

A team of investigators from the University College Cork, Ireland, conducted the review and meta-analysis to better synthesized published literature on the association between HDP and neurodevelopment risk. Corresponding author Ali S. Khashan, PhD, School of Public Health, University College Cork, told MD Magazine research into the field has been documented since the 1960s and 1970s.

“The idea is not new,” Khashan said. “What has changed in recent years is we have more data and we have better methodologies that allow us explore these associations and outcomes in more details.”

In focusing particularly on ADHD and ASD risk analysis, the researchers found 30 unique articles with inclusion criteria among the 1166 identified studies. Adjusted pooled results indicated that HDP exposure was associated with a 35% increased odds of ASD diagnosis, compared to non-exposure cases. For preeclampsia, the prenatal complication characterized by high blood pressure and hand and foot swelling, was significantly associated with ASD (OR 1.50).

In analyzing offspring exposure to HDP in utero, researchers reported a 30% greater chance of such patients having ADHD compared to unexposed offspring. Association with other HDP aside from preeclampsia increased the odds of ADHD by 70% — however, this rate was statistically insignificant.

Researchers noted other obstetric risk factors — from cesarean delivery (23-26%) and maternal age above 35 years (30%) — being similarly linked to an increased association with ASD. Though the combination of these associations and the more distinct ones detailed in this most recent analysis lead to belief there’s a causality from HDP, they are not willing to rule out the possibility antihypertensive therapy during pregnancy may have adverse effects.

Truth be told, physicians are not certain of any causality. Khashan pointed to the possibility of maternal inflammation playing a role in the association, as a Finnish population-based study showed increased levels of C-reactive protein associated with preeclampsia was significantly linked to a 43% increased risk of autism in offspring.

“But the ones found, we’re not sure, and we have to be cautious in testing these results,” Khashan said. “There are several limitations to the study. One potential mechanism is placental dysfunction, which could lead to poor neurodevelopmental outcomes.”

Placental dysfunction’s association with HDP is due to reduced perfusion and oxidative stress, which results in reduced nutrient and oxygen availability for the fetus that can affects its developing brain. From there, researchers believe it could increase the risk for neurodevelopmental damage.

Researchers concluded that more robust research on these associations is needed before definitive conclusions are reached. Khashan said next steps should include a larger cohort study, with validated methods to measure outcomes and neurodevelopmental disorder diagnoses. He would also want to see more control for outside factors that may influence the association between ADHD, ASD risk and HDP.

“We need to do more research on this topic, bridging the gap and addressing the limitations we’ve identified, and hopefully we can understand the true association,” Khashan said.

The analysis, "Association of Hypertensive Disorders of Pregnancy With Risk of Neurodevelopmental Disorders in Offspring," was published online in JAMA Psychiatry on Wednesday.