Autism-Specific Maternal Autoantibodies Associated with Metabolic Conditions

Background: Approximately 23% of mothers whose child has ASD produce specific patterns of autoantibodies to fetal brain proteins that have been detected in less than 1% of mothers of typically developing children. The biological mechanisms underlying the development of these ASD-specific maternal autoantibodies are poorly understood. Mothers of children with ASD are also more likely, than mothers of typically developing children, to have pregnancies complicated by metabolic conditions including diabetes (type 2 or gestational), chronic hypertension, preeclampsia, and/or obesity. These conditions are characterized by sustained low-grade inflammation and insulin resistance. Chronic inflammation during pregnancy might create an unstable immune environment that is susceptible to generating maternal antibodies that are reactive to fetal brain proteins.

Objectives: This study examines whether these ASD-specific maternal autoantibodies are associated with metabolic conditions during gestation. 

Methods: This study included 225 mothers enrolled in the CHARGE (Childhood Autism Risk from Genetics and the Environment) Study whose child (2-5 years old) had a diagnosis of ASD confirmed on both ADI-R and ADOS. Maternal blood specimens collected at study enrollment were analyzed for autoantibodies. Metabolic conditions during pregnancy were ascertained from medical records or structured telephone interview with the mother and included pre-pregnancy body mass index (BMI) ≥30, gestational and type 2 diabetes, chronic hypertension, and preeclampsia. Autism severity was measured using calibrated ADOS scores. We conducted log-linear regression analyses (Poisson regression with robust error variance) to examine associations between maternal metabolic conditions and the presence of ASD-specific maternal autoantibodies. The strength of association was measured by prevalence ratio (PR) and 95% confidence interval (CI).

Results: Forty-four (19.6%) out of 225 mothers had ASD-specific autoantibodies to fetal brain proteins. Mothers with and without autoantibodies did not differ with respect to age, parity, or inter-pregnancy interval. Diabetes and preeclampsia were more common among mothers who had autoantibodies than those who did not (diabetes: 13.6% vs. 7.2%; preeclampsia: 15.9% vs. 9.4%) although these differences did not reach statistical significance. However, when we restricted to mothers of children with severe autism symptoms (autism severity score ≥7; 28 mothers with and 116 without autoantibodies), those with diabetes were 3.6 times more likely to have autoantibodies relative to mothers without metabolic conditions and with a BMI <25 (21.4% vs. 8.6%; PR=3.6; 95% CI 1.4, 9.7). Similarly, mothers who developed preeclampsia were 3 times more likely to have autoantibodies (17.9% vs. 9.5%; PR=3.0; 95% CI 1.1, 8.6). Maternal obesity was not associated with an increased likelihood of autoantibodies.

Conclusions: The biological mechanisms that lead mothers to become sensitized to fetal brain proteins are not yet understood. These preliminary findings suggest that metabolic conditions during pregnancy, particularly diabetes and preeclampsia, may be associated with ASD-specific maternal autoantibodies. Given that metabolic conditions are more prevalent in mothers of children with ASD than mothers of typically developing children, and these conditions are characterized by dysregulated immune responses (e.g., chronic inflammation, autoantibodies to other proteins), these findings reveal a plausible mechanism that warrants further investigation.