Neonatal Inflammation and Autism Risk in a Swedish Birth Cohort

Background: Mounting evidence from both animal and human studies indicates that early life immune function can influence neurodevelopmental outcomes relevant to autism. However, there are few biomarker-based studies of larger birth cohorts.

Objectives: We aimed to measure acute phase proteins in neonatal dried blood spots, as markers of neonatal inflammation, and determine associations with later risk of autism spectrum disorders (ASD).

Methods: We performed a case-control study of 851 ASD cases and 1,132 controls born 1996-2000 in Sweden, with case ascertainment as of December 2011. Blood spots were collected from a central biobank. Nine acute phase proteins were measured using a magnetic bead-based multiplex panel: α-2 microglobulin, C-reactive protein, haptoglobulin, serum amyloid P, procalcitonin, ferritin, tissue plasminogen activator, fibrinogen, and serum amyloid A. We examined logistic regression models of the inflammatory markers adjusted for total protein content, sex of child, maternal age, and birth year. Inflammatory markers were individually examined, as well as combined into an acute phase protein risk score based on ridge regression coefficients.

Results: All neonatal acute phase proteins were moderately to highly correlated, ranging from Spearman correlations of 0.31 (fibrinogen and C-reactive protein) to 0.80 (ferritin and α-2 microglobulin). Higher levels of 6 of the 9 acute phase proteins were individually associated at p < 0.05 with increased risk of ASD in a monotonic fashion. For example, the highest tertile of serum amyloid P had a 1.49 (95% CI: 1.17, 1.90) times higher odds of ASD, compared to the lowest tertile. Factors including maternal hospitalization with infection in the third trimester, low Apgar score, and higher gestational age appeared to be associated with higher levels of the acute phase proteins. A 1 standard deviation increase in the acute phase protein risk score was associated with a 21% increase in odds of ASD, OR: 1.21, 95% CI 1.10-1.33.

Conclusions: Because acute phase proteins are not thought to cross the placenta, the results suggest that the perinatal innate immune system may influence later risk of ASD. We discuss the results in the context of environmental obstetric influences of early life immune function.