Maternal Mid-Gestational Serum Cytokines and Chemokines and the Risk of Autism with Intellectual Disability: The Early Markers of Autism (EMA) Study

Background:  Increasing evidence suggests a link between immune system dysregulation and autism spectrum disorders (ASD), with immune abnormalities described in individuals with ASD as well as their family members. Furthermore, numerous studies have suggested that maternal immune activation during gestation may negatively impact fetal development, potentially resulting in ASD-like behaviors in the offspring. However, few studies have directly investigated the role of prenatal cytokine and chemokine profiles on neurodevelopmental outcomes in humans.   

Objectives:  To characterize mid-gestational serum profiles of cytokines and chemokines in mothers of children with ASD, of children with developmental delay without ASD, and of children considered to be typically developing. 

Methods:  Using a large, population-based, nested case-control study design, maternal serum samples were collected during weeks 15-19 of gestation. The mothers included in this study gave birth to: A) a child with ASD (n = 397), B) a child without ASD but with a developmental delay (DD, n = 163), or C) a child with no known neurodevelopmental disability (TD, n = 439). The ASD group was further divided into those with intellectual disabilities (DQ<70) (ASD-ID; n = 187) and those without (DQ≥70) (ASD-no ID; n = 210). All maternal mid-gestational samples were quantified for 22 cytokines and chemokines using Luminex multiplex analysis technology. Levels of cytokines and chemokines were compared between groups using crude and multivariate logistic regression analyses, adjusting for maternal age, ethnicity, birth country of mother, and weight, as well as matching criteria of infant gender, birth year, and birth month.

Results:  Mothers of children subsequently diagnosed with both ASD and intellectual disability (ASD-ID) had significantly elevated mid-gestational serum cytokine and chemokine levels compared to mothers of other children. For example, this group displayed significantly elevated levels of serum GM-CSF, IFN-γ, IL-1α, and IL-6 compared to mothers of children with ASD without intellectual disability (ASD-no ID), of children with DD, as well as those with TD children. Conversely, mothers of children with ASD-no ID had significantly lower levels of IFN-γ, IL-8, and MCP-1 than mothers of TD children, and they showed no significant differences compared to mothers of children with DD. Similarly, mothers of children with DD had significantly lower levels of IL-8 and MCP-1 compared to mothers of TD children. 

Conclusions: Our results suggest that mothers whose children have both ASD and intellectual disability have significantly elevated mid-gestational levels of numerous cytokines and chemokines in comparison to all other groups examined. The immunologic distinction between mothers of children with ASD-ID and those with ASD-no ID or DD suggests that the intellectual disability associated with ASD might be etiologically distinct from DD without autism. This differential gestational immune profile could provide a better understanding of the early mechanisms leading to altered neurodevelopment. Additionally, these findings contribute to the ongoing efforts toward identification of biological markers specific to sub-phenotypes of autism.