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Maternal HbA1c influences autism risk in offspring

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SAN FRANCISCO — Children born to women with an HbA1c of at least 6.5% were nearly twice as likely to receive a diagnosis of autism in the first 4 years of life vs. offspring of mothers with HbA1c below 5.7%, according to a speaker at the American Diabetes Association Scientific Sessions.

Anny H. Xiang

“We can now better understand the influence of diabetes during pregnancy and risk for autism and attention deficit hyperactivity disorder in offspring, oweing to the electronic medical records and stable health plan membership in Kaiser Permanente Southern California,” Anny H. Xiang, PhD, director of biostatistics research in the department of research and evaluation at Kaiser Permanente Southern California, Pasadena, told Endocrine Today.

Epidemiologic data suggest that maternal diabetes influences the risk for autism in offspring, whereas the prevalence of autism has steadily risen in the U.S., currently affecting 1 in 59 children, Xiang said during a symposium presentation. Boys are four to five times more likely to receive an autism diagnosis; the etiology is largely unknown and likely multifactorial, Xiang said.

“Maternal diabetes, if not well treated, which means hyperglycemia in utero, that increases uterine inflammation, oxidative stress and hypoxia and may alter gene expression,” Xiang said. “This can disrupt fetal brain development, increasing the risk for neural behavior disorders, such as autism.”

In a retrospective cohort study, Xiang and colleagues analyzed electronic medical records data from 35,819 mother-infant pairs (51% boys) born in Kaiser Permanente Southern California hospitals from 2012 to 2013 (maternal mean maternal age, 31 years; mean prepregnancy BMI, 27.2 kg/m²; 51% Hispanic). In 2012, Kaiser implemented HbA1c screening in the early prenatal period for all pregnancies, Xiang said. Median gestational age at HbA1c testing was 9 weeks, with 83% of testing completed during the first trimester (median HbA1c, 5.4%).

Children born to women with an HbA1c of at least 6.5% were nearly twice as likely to receive a diagnosis of autism in the first 4 years of life vs. offspring of mothers with HbA1c below 5.7%. Shutterstock

Researchers followed children until they received a diagnosis of autism with at least one diagnostic code or Dec. 31, 2017. The last maternal HbA1c level in the first two trimesters of pregnancy was obtained from the electronic laboratory database. HbA1c was analyzed as a continuous variable and a categorical variable, classified as less than 5.7%, 5.7% to 5.9%, 6% to 6.5%, and greater than 6.5%. Researchers used Cox regression analyses to estimate HRs for autism diagnosis associated with HbA1c exposure. Interaction with gestational age at HbA1c testing was also assessed.

Within the cohort, 84.9% of mothers had an HbA1c less than 5.7%; 11.7% had an HbA1c between 5.7% and 5.9; 2.4% between 6% and 6.5%; and 1% greater than 6.5%.

During a median follow-up of 4.5 years, 707 children (2%) had a clinical diagnosis of autism. After adjusting for prepregnancy BMI and race, the HR for autism associated with each 1% increase of HbA1c level was 1.12 (95% CI, 0.96-1.31) for the continuous measure. Compared with children with a maternal HbA1c of less than 5.7%, children born to women with an HbA1c greater than 6.5% were nearly twice as likely to receive a diagnosis of autism during follow-up (HR = 1.79; 95% CI, 1.06-3), according to researchers.

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The risk associated with HbA1c levels did not vary by gestational age at HbA1c testing (P for interaction > .19), Xiang said.

“The early trimester seems to be critical, and this is consistent with the literature looking at the windows of vulnerability in risk for autism,” Xiang said. “This is evident in pregnancies with type 1 or type 2 or gestational diabetes diagnosed early, or when HbA1c was high in the first two trimesters, but there is no association [observed] in the third trimester.”

In analyses assessing the risk for ADHD with maternal diabetes, researchers found no clear window of vulnerability, Xiang said; however, the severity of maternal diabetes influenced overall ADHD risk.

“ADHD and [autism spectrum disorder] are very heterogenous. ... Some children will have normal function and others have a serious disability,” Xiang said. “It would be interesting to look at the degree of hyperglycemia and the timing of the exposure and how that affects the severity of both [disorders].

“For women planning to become pregnant or already pregnant, make sure you check the blood sugar before pregnancy and monitor the blood sugar throughout pregnancy,” Xiang said. – by Regina Schaffer

References:

Xiang AH. Effect of maternal diabetes on autism spectrum disorders and ADHD risk in offspring, epidemiology. Presented at: American Diabetes Association 79th Scientific Sessions; June 7-11, 2019; San Francisco.

Xiang AH, et al. JAMA. 2019;doi:10.1001/jama.2019.8584.

Disclosure: Xiang reports no relevant financial disclosures.