Neonatal Levels of Acute Phase Proteins and Risk of Autism Spectrum Disorder

BACKGROUND: Immune signaling pathways influence neurodevelopment and are hypothesized to contribute to the etiology of autism spectrum disorder (ASD). We aimed to assess risk of ASD in relation to levels of neonatal acute phase proteins (APPs), key components of innate immune function, measured in neonatal dried blood spots. METHODS: We included 924 ASD cases, 1092 unaffected population-based controls, and 203 unaffected siblings of ASD cases in this case-control study nested within the register-based Stockholm Youth Cohort. Concentrations of 9 different APPs were measured in eluates from neonatal dried blood spots from cases, controls, and siblings using a bead-based multiplex assay. RESULTS: Neonatal C-reactive protein was consistently associated with odds of ASD in case-control comparisons, with higher odds associated with the highest quintile compared with the middle quintile (odds ratio [OR] = 1.50, 95% confidence interval [CI] = 1.10-2.04) in adjusted analyses. In contrast, the lowest quintiles of a-2-macroglobulin (OR = 3.71, CI = 1.21-11.33), ferritin (OR = 4.20, CI = 1.40-12.65), and serum amyloid P (OR = 3.05, CI = 1.16-8.01) were associated with odds of ASD in the matched sibling comparison. Neonatal APPs varied with perinatal environmental factors and maternal/fetal phenotypes. Significant interactions in terms of risk for ASD were observed between neonatal APPs and maternal infection during late pregnancy, maternal anemia, and maternal psychiatric history. CONCLUSIONS: Indicators of the neonatal innate immune response are associated with risk of ASD, although the nature of these associations varies considerably with factors in the perinatal environment and the genetic background of the comparison group.