Gestational Diabetes Before 26 Weeks May Raise Autism Risk

Marlene Busko

April 15, 2015

In a large observational study, pregnant women with gestational diabetes that was diagnosed up to week 26 of the pregnancy had a greater risk of having a child with autism spectrum disorder (ASD) than pregnant women without, independent of other confounders.

However, women with gestational diabetes that was diagnosed after week 26 and those with known prepregnancy type 2 diabetes had the same risk of having a child with ASD as women without diabetes. The study was published in the April 14 issue of the Journal of the American Medical Association.

The findings suggest that "the fetus may be exposed to elevated glucose levels during early pregnancy, which may have some impact on fetal development, leading to a later risk of autism," lead author Anny H Xiang, PhD, from Kaiser Permanente Southern California, in Pasadena, told Medscape Medical News.

However,"because this is an observational study, no causal inferences can be drawn," and further research is needed, Dr Xiang and colleagues caution. Nevertheless, the results reinforce the importance of screening for elevated blood glucose levels in women who plan to become pregnant and making sure that blood glucose remains in the normal range throughout the entire pregnancy, Dr Xiang stressed.

Asked to comment, Arshya Vahabzadeh, MD, a member of the Council on Communications of the American Psychiatric Association and a physician in child and adolescent psychiatry at Massachusetts General Hospital in Boston, cautioned that the study findings "should be placed in context, since the vast majority of pregnant women, with or without diabetes, will not have children with autism." However, "the study adds to the emerging body of evidence that in utero conditions are important factors when considering the risk of subsequent autism in the children born from those pregnancies," he agreed.

Does Fetal Exposure to High Glucose Up Risk of Autism?

Little is known about the timing of fetal exposure to hyperglycemia and the subsequent risk of ASD — defined as Asperger syndrome, autistic disorders, and pervasive developmental disorder not otherwise specified (PDD-NOS) — Dr Xiang and colleagues write.

They performed a retrospective cohort study of children born in Kaiser Permanente Southern California Hospitals from 1995 to 2009, excluding children born to mothers with type 1 diabetes or those with congenital abnormalities.

Of the 322,323 children in the study, 6496 (2.0%) were exposed to preexisting type 2 diabetes, 25,035 (7.8%) were exposed to gestational diabetes, and 290,792 (90.2%) were not exposed to maternal type 2 diabetes.

During a median follow-up of 5.5 years, 3388 children (1.05%) were diagnosed with ASD, mostly autistic disorders (79%) and less commonly Asperger syndrome (18%) or PDD-NOS (3%).

Older maternal age, being first born, high maternal education, low household income, history of comorbidity, preeclampsia/eclampsia, early delivery, and being male were significantly associated with increased risk for ASD.

The risk of having a child with ASD was not significantly greater for mothers who had preexisting diabetes or for the overall group of mothers with gestational diabetes compared with the mothers without diabetes, after adjustment for relevant confounders.

But dividing the women into tertiles based on when they were diagnosed with gestational diabetes revealed that the women who were diagnosed at 26 weeks of gestation or earlier had a higher risk of having a child with ASD.

The risk of having a child with ASD was not significantly elevated but was similar in women who were diagnosed with gestational diabetes at more than 26 weeks' but less than 30 weeks' gestation and in women diagnosed at 30 weeks and beyond — so those two tertiles were combined for the subsequent analysis.

Risk for ASD Associated With In Utero Exposure to Maternal Diabetes or GDM

Maternal Diabetes or GDM Number With ASD/Total HR (95% CI)* P
None 2963/290,792 1.00  
Preexisting type 2 diabetes 115/6496 1.21 (0.97–1.52) 0.09
GDM 310/25,035 1.04 (0.91–1.19) 0.57
GDM diagnosed <26 wk gestation 130/7456 1.42 (1.15– 1.74) 0.001
GDM diagnosed >26 wk gestation 180/17579 0.87 (0.74–1.03) 0.11
GDM = gestational diabetes mellitus
ASD = autism spectrum disorder
*Adjusted for maternal age, parity, education, household income, race/ethnicity, history of comorbidity, and sex of the child. The risks were similar after adjustment for preeclampsia/eclampsia or adjustment also for child birth weight and gestational age at delivery as well.

Autism Spectrum Disorder a Complex Condition

Exposure to antidiabetic medication was not independently associated with risk for ASD. Adjustment for a mother or older sibling with ASD in the full cohort and for maternal smoking, prepregnancy body mass index, and gestational weight gain in the subset with available data (n = 68,512) did not affect the results.

"We know that autism spectrum disorder is a complex condition…caused by a combination of environmental and genetic factors," and a lot of research has focused on early childhood, but "this study should prompt researchers to look at even earlier stages of life," Dr Vahabzadeh said. For example, other studies have found that pregnant mothers who take folic-acid supplements may have a lower risk of having a child with autism, while mothers who are exposed to high levels of fine particulate pollution may have a higher risk, he explained.

"Exploring variations in the in utero environment and elucidating their effects on brain development and the subsequent risk of autism are crucial next steps," which will likely require larger registries to find more nuanced associations, he said.

Dr Xiang and colleagues said that potential biological mechanisms to explain the link between intrauterine hyperglycemia and ASD risk in the child may include hypoxia in the fetus, oxidative stress in cord blood and placental tissue, chronic inflammation, and epigenetics.

Meanwhile, "our results suggest that early screening for ASD in offspring of women with GDM diagnosed by 26 weeks' gestation may be warranted…[and] screening for GDM and control of glucose levels early in pregnancy may be important in reducing ASD risk for offspring," they write.

The study was supported by Kaiser Permanente Southern California Direct Community Benefit Funds. The authors have reported that they have no relevant financial relationships.

JAMA. 2015;313:1425-1434. Article

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