Maternal Metabolic Conditions and Neonatal Cytokine and Chemokine Levels of Children with ASD

Background:  Previous studies have reported increased blood concentrations of pro-inflammatory cytokines and chemokines, such as Tumor Necrosis Factor (TNF)α, interleukin (IL)-6, IL-1β, Monocyte Chemotactic Protein (MCP)-1, Macrophage Inflammatory Protein (MIP)-1α, and Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES), among individuals with metabolic conditions (MCs; obesity, diabetes, hypertension) compared with healthy controls. Moreover, higher IL-6 levels have been detected in the cord blood of newborns born to obese mothers compared to lean mothers. Animal model studies have linked maternal inflammation to microglial activation and stimulation of pro-inflammatory cytokine production within the fetal hippocampus resulting in increased neurocognitive effects in offspring that continued into adulthood. Several clinical and epidemiologic studies have also reported associations between metabolic conditions in pregnancy and adverse neurodevelopmental outcomes in offspring including autism spectrum disorder (ASD).  Aberrations in the immune response of individuals with ASD compared with typically developing (TD) controls have been documented in numerous studies. These studies led us to our hypothesis that some dysregulation in immune function of individuals with ASD may be attributed to prenatal exposure to maternal metabolic conditions.

Objectives:  In this preliminary study, we examined whether neonatal cytokine and chemokine levels differed in ASD cases versus controls with and without prenatal exposure to maternal metabolic conditions.

Methods:  A subset of 2 to 5 year-old participants from the CHARGE (CHildhood Autism Risks from Genetics and the Environment) Study with (1) a confirmed diagnosis of ASD or TD, (2) cytokines and chemokines measured in newborn blood spots (archived as part of the California Newborn Screening Program), and (3) data on maternal metabolic conditions were included in the study. Median concentrations of analytes (IL-1β, IL-6, TNFα, IL-10 MCP-1, MIP-1α, and RANTES) were estimated using quantile regression models adjusted for child’s age at blood spot collection, time between collection and sample elution, cesarean delivery, labor duration, and gestational age. Analyte concentrations were normalized to total protein content.

Results:  Among ASD cases, children of mothers with MCs had significantly higher median IL-6 concentrations compared to children without exposure to maternal MCs (P=0.04). No differences in IL-6 levels were detected according to maternal MCs among controls. Conversely, among controls, lower median TNFα concentrations were observed in children of mothers with MCs (P=0.01). No differences in TNFα levels were found among ASD cases with respect to maternal MCs. MIP-1α concentrations were marginally higher in children with maternal MCs among controls (P=0.06). Among children exposed to maternal MCs, ASD cases had marginally lower MIP-1α levels than controls (P=0.06). No other differences in cytokines or chemokines were detected with respect to child’s case status or maternal MCs.

Conclusions:  These preliminary findings suggest that newborns later diagnosed with ASD appear to exhibit a different immune profile in association with maternal MCs compared with controls.  Given the link between inflammation and metabolic conditions, prenatal exposure to maternal metabolic conditions may potentially contribute to immune dysregulation in offspring.