Metabolic Programming of Child Gastrointestinal Symptoms in Children with Autism Spectrum Disorder

Background:  Gastrointestinal (GI) symptoms are highly prevalent in children with autism spectrum disorder (ASD), and growing evidence suggests that their etiology involves alterations in gut microflora, intestinal permeability, and activation of specific immune and metabolic pathways.

Objectives:  Our goal was to explore whether fetal programming via maternal dysmetabolism during gestation might be associated with GI symptoms in child participants in the CHARGE (CHildhood Autism Risks from Genetics and the Environment) study.

Methods:  The CHARGE Study is a population-based case-control investigation of ASD etiology. Children aged 24-60 months and living in catchment areas with a biological parent fluent in English or Spanish were enrolled 1/29/2013-5/7/2013. Children with ASD (n=550) and delayed development (DD, n=218) were recruited through the California Department of Developmental Services, the Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, and referrals. Controls with typical development (TD) (n=425) were randomly selected from birth records and frequency-matched on age, sex, and broad geographic region. Diagnoses of maternal metabolic conditions – including prepregnancy obesity, diabetes and chronic hypertension; maternal irritable bowel syndrome (IBS); mode of delivery and duration of breastfeeding were drawn from medical records and responses to structured interviews. Child GI symptoms of interest were drawn from maternal report, and included frequent diarrhea or constipation within three months of enrollment or at any time in the past. The Autism Diagnostic Observation Schedule and Autism Diagnostic Interview-Revised were used to confirm ASD, whereas children with DD and TD were confirmed by Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales and were free of ASD symptoms. Preliminary analyses of symptom frequencies were compared across groups using Chi-square tests.

Results:  As reported previously, both past and recent diarrhea and constipation frequency were 4-6 times more common in children with ASD and DD compared to TD controls (26.0%, 18.8% vs. 4.7%; p<0.0001). Current and past GI symptoms were more common in children born to mothers diagnosed with metabolic conditions (23.7% vs. 16.7%; p=0.07). Statistically significant differences were seen in children born by cesarean (19.5% vs. 14.7%; p=0.04), and whose mothers had IBS (28.7% vs. 15.1%; p=0.002). In analyses stratified by diagnostic group, current GI symptoms remained more prevalent in all children whose mothers had IBS (ASD: 34.1% vs. 24.1% p=0.15; DD: 40.0% vs. 18.2% p=0.04; 14.3% vs. 3.4% p=0.01).

Conclusions:  Our findings support a relationship between maternal dysmetabolism during pregnancy and increased frequency of GI symptoms in children, suggesting a disruption in the development of beneficial gut microflora in the offspring. Metabolic conditions are associated with both IBS and labor complications that increase risk for cesarean delivery. Children of mothers with IBS or birth by cesarean were likely to have frequent GI symptoms. It has been postulated that cesarean birth alters “seeding” of the intestinal microbiome, leading to long-term changes in colonization and immune development. Other environmental and genetic factors likely play a role in GI disturbances particularly prevalent among children with ASD or DD. Further efforts are needed to characterize mechanisms underlying the relationship between maternal dysmetabolism and GI symptoms in the offspring.