A major study conducted by researchers affiliated with the UC Davis MIND Institute has found strong links between maternal diabetes and obesity and the likelihood of having a child with autism spectrum disorder (ASD) or another developmental disorder.
The study, which investigated the relationships between maternal metabolic conditions and the risk of neurodevelopmental disorders, found that mothers who were obese were 67 percent more likely to have a child with ASD than normal-weight mothers without diabetes or hypertension, and were more than twice as likely to have a child with another developmental disorder.
Mothers with diabetes were found to have nearly 67 percent more likely to have a child with developmental delays as healthy mothers. However, the proportion of mothers with diabetes who had a child with ASD was higher than in healthy moms but did not reach statistical significance.
The study also found that the children of diabetic mothers who had ASD were more disabled -- had greater deficits in language comprehension and production and adaptive communication -- than were the children with ASD born to healthy mothers.
However, even children without ASD born to diabetic mothers exhibited impairments in socialization in addition to language comprehension and production, when compared with the non-ASD children of healthy women. Children without ASD of mothers with any of the metabolic conditions displayed mild deficits in problem solving, language comprehension and production, motor skills and socialization.
"Over a third of U.S. women in their childbearing years are obese, and nearly one-tenth have gestational or type 2 diabetes during pregnancy. Our finding that these maternal conditions may be linked with neurodevelopmental problems in children raises concerns and therefore may have serious public-health implications," said Paula Krakowiak, a PhD Candidate in Epidemiology affiliated with the MIND Institute. "And while the study does not conclude that diabetes and obesity cause ASD and developmental delays, it suggests that fetal exposure to elevated glucose and maternal inflammation levels adversely affect fetal development."
The study, "Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders," is published online April 9 in Pediatrics, the Journal of the American Academy of Pediatrics. Its authors said that it is the first study to examine the associations between neurodevelopmental disorders and maternal metabolic conditions not restricted solely to type 2 or gestational diabetes. It is also the first to include obesity and hypertension, which have similar underlying biological characteristics, and to investigate correlations between these conditions and impairments in the skills and abilities of children in specific developmental domains.
Over 60 percent of U.S. women of childbearing age are overweight; 34 percent are obese; and 16 percent have metabolic syndrome. Nearly 9 percent of U.S. women of childbearing age are diabetic, and more than 1 percent of U.S. pregnancies were complicated by chronic hypertension. In California, where the study was conducted, 1.3 percent of women had type 2 diabetes, and 7.4 percent had gestational diabetes.
Autism spectrum disorder is characterized by impairments in social interaction, communication deficits and repetitive behaviors and often is accompanied by intellectual disability. An estimated 1 in 88 children born today will be diagnosed with autism spectrum disorder, according to statistics recently released by the U.S. Centers for Disease Control and Prevention. An estimated 1 in 83 U.S. children has another developmental disorder, which includes other disorders resulting in intellectual disability.
The study included 1,004 mother/child pairs from diverse backgrounds enrolled in the Childhood Autism Risks from Genetics and the Environment Study (CHARGE), most of them living in Northern California, with a small subset living in Los Angeles. The children were between 24 and 60 months old, born in California and resided with at least one biological parent who spoke either English or Spanish. There were 517 children who had ASD; 172 who had other developmental disorders but not ASD; and 315 who were developing typically. The participants were enrolled between January 2003 and June 2010.
The researchers obtained demographic and medical information for the mothers and their children using the CHARGE Study Environmental Exposure Questionnaire, a telephone survey, the study participants' birth files and medical records. The primary metabolic conditions of interest were type 2 diabetes or gestational diabetes.
Women were considered diabetic if the condition was noted in their medical records or if during the telephone surveys they answered "yes" to the questions "During this pregnancy were you ever told by a physician or nurse that you had gestational diabetes?" or "At any time before you became pregnant were you told by a doctor that you had [type 2] diabetes?" The same wording was used to obtain information about hypertension. BMI was calculated using height and weight prior to pregnancy from medical records or telephone interviews.
To confirm the developmental diagnoses of the children with ASD researchers used the Autism Diagnostic Interview-Revised (ADIR) and the Autism Diagnostic Observation Schedules (ADOS). All of the children were administered the Mullen Sales of Early Learning and the Vineland Adaptive Behavior Scales to assess their cognitive and adaptive development. Spanish-speaking children were administered the tests in Spanish. The participants were then divided into groups of children with ASD, developmental delay or typical development.
Among children whose mothers were diabetic during their pregnancies, the study found that the percentage of children with ASD born to women with type 2 diabetes or gestational diabetes (9.3 percent) or developmental disability (11.6 percent) was higher than the 6.4 percent of children with ASD born to women without these metabolic conditions.
Over 20 percent of the mothers of children with ASD or developmental delay were obese, compared with 14 percent of the mothers of typically developing children.
Approximately 29 percent of the children with ASD had mothers with a metabolic condition, and nearly 35 percent of the children with developmental delay had mothers with metabolic conditions. In contrast, 19 percent of the typically developing children had mothers with a metabolic condition.
The study also examined the link between hypertension and ASD or developmental disorders. The prevalence of high blood pressure was low for all groups, but more than two times higher among mothers of children with ASD or developmental delay than among mothers of children with typical development, though the finding did not reach statistical significance.
Analyses of the children's cognitive abilities found that, among the children with ASD, children of mothers with diabetes exhibited poorer performance on tests of expressive and receptive language and communication skills of everyday living when compared with the children of healthy mothers. And the presence of any metabolic condition was associated with lower scores on all of the tests among children without ASD.
The authors note that obesity is a significant risk factor for diabetes and hypertension, and is characterized by increased insulin resistance and chronic inflammation, as are diabetes and hypertension. In diabetic, and possibility pre-diabetic pregnancies, poorly regulated maternal glucose can result in prolonged fetal exposure to elevated maternal glucose levels, which raises fetal insulin production, resulting in chronic fetal exposure to high levels of insulin.
Because elevated insulin production requires greater oxygen use this may result in depleted oxygen supply for the fetus. Diabetes also may result in fetal iron deficiency. Both conditions can adversely affect fetal brain development, the authors said.
"The sequence of events related to poorly regulated maternal glucose levels is one potential biological mechanism that may play a role in adverse fetal development in the presence of maternal metabolic conditions," Krakowiak said.
Maternal inflammation, which accompanies metabolic conditions, may also adversely affect fetal development. Certain proteins involved in cell signaling that are produced by cells of the immune system can cross the placenta from the mother to the fetus and disturb brain development.
Other study authors are Irva Hertz-Picciotto, Cheryl Walker, Alice Baker, Sally Ozonoff and Robin Hansen of the UC Davis MIND Institute and Andrew Bremer of UC Davis and Vanderbilt University.
The study was supported by the National Institutes of Health (P01 ES11269 and R01 ES015359), the U.S. Environmental Protection Agency through the Science to Achieve Results (STAR) program (R829388 and R833292), and the UC Davis MIND Institute.
- Paula Krakowiak, Cheryl K. Walker, Andrew A. Bremer, Alice S. Baker, Sally Ozonoff, Robin L. Hansen and Irva Hertz-Picciotto. Maternal Metabolic Conditions and Risk for Autism and Other Neurodevelopmental Disorders. Pediatrics, April 2012 DOI: 10.1542/peds.2011-2583
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