Mid-Pregnancy Glucose Intolerance, Gestational Metabolic Conditions and Autism Spectrum Disorder and Developmental Delay

Background:  A growing body of evidence suggests that maternal pre-pregnancy obesity and related conditions – including diabetes and hypertensive disorders – are associated with autism spectrum disorder (ASD) and broader developmental delay (DD).  Biological mechanisms underlying associations between maternal gestational metabolic dysregulation and adverse neurodevelopment are poorly understood.

Objectives:  The objectives of this study are:  1) to confirm whether maternal glucose intolerance is associated with obesity, hypertensive and diabetes disorders, 2) to examine the degree to which mid-pregnancy glucose intolerance is associated with ASD and DD, and 3) to determine whether glucose intolerance is associated with cognitive development.

Methods:  Previously, maternal metabolic conditions were shown to be associated with ASD and DD in comparison to children with typical development (TD) in this population, the CHildhood Autism Risk from Genetics and the Environment (CHARGE) study.  Children were born in California, 24-60 months old at the time of recruitment, and living in catchment areas with a biologic parent fluent in English or Spanish.  Children with ASD (N=224) and DD (N=82) were recruited through the California Department of Developmental Services, the MIND Institute and referrals.  TD controls (N=199) were randomly selected from birth records and frequency-matched to ASD cases on age, sex, and broad geographic region.  Maternal pre-pregnancy body mass index, and evidence of metabolic dysfunction (gestational or type 2 diabetes mellitus, preeclampsia and/or chronic hypertension), and late 2^nd-trimester one-hour 50-g oral glucose challenge test (GCT) results (mg/dL), were abstracted from medical records.  ASD was confirmed by ADOS and ADIR.  DD and TD controls were confirmed by Mullen Scales of Early Learning (MSEL) and Vineland Adaptive Behavior Scales and were free of autistic symptoms.  We calculated MSEL developmental quotients (MSEL-DQs).  Statistical analyses to examine the relationships between GCT results and outcomes included: ANOVA for maternal conditions, multinomial logistic regression for child diagnosis, and linear regression for MSEL-DQ.

Results:  A dose-response relationship between GCT values and the severity of metabolic conditions was evident, with the highest GCT values among obese mothers with diabetes and either preeclampsia or hypertension (Table).  Each 10 mg/dL increase in 2^nd-trimester GCT response was associated with an 8% increased odds of ASD, after adjustment for maternal education, race and age (OR 1.08, 95% CI 1.01-1.16); in the same model, there was no significant change in DD odds with similar GCT elevations.   An analysis controlling for the same maternal factors and child’s diagnoses revealed that maternal glucose intolerance of >150 mg/dL was associated with MSEL-DQs that were 5.9 points lower on average compared to scores in children whose mothers had levels <90 (P=0.03).

Conclusions:  This study presents the first direct evidence that fetal exposure to maternal impaired glucose tolerance is associated with later development of ASD and diminished cognitive function in the exposed child.   Maternal glucose intolerance is part of a dysmetabolic cascade that includes progressive insulin production, increased metabolism, systemic inflammation, accelerated consumption of oxygen and micronutrients such as iron, and oxidative stress – mechanisms implicated in disruption of fetal neuronal proliferation, maturation, differentiation, migration and cortical connectivity.