Neonatal Levels of Acute Phase Proteins May Affect Risk for Autism Spectrum Disorder

autism on chalkboard
autism on chalkboard
Investigators assessed the risk of autism spectrum disorder in relation to levels of neonatal acute phase proteins, which are key components of innate immune function, measured in neonatal dried blood spots.

Study data published in Biological Psychiatry suggest that neonatal C reactive protein (CRP) levels may be associated with risk for autism spectrum disorder (ASD). In a case-control study of children with and without ASD, neonatal CRP levels were significantly higher in the latter cohort. However, the relationship between CRP and odds of ASD was mediated by several factors, including maternal infection during pregnancy, maternal anemia, and maternal psychiatric history.

Investigators extracted data from the Stockholm Youth Cohort, a register-based cohort of all children living in Stockholm County, Sweden. For the study, children diagnosed with ASD before the end of 2011 were enrolled as cases. Controls were randomly sampled from the remaining members of the Youth Cohort. When possible, unaffected siblings of children with ASD were also enrolled.

Neonatal dried bloodspots were collected from all participants 3 to 5 days after birth, per national protocol in Sweden. Blood spot samples were analyzed for 9 neonatal acute phase proteins, including -2-macroglobulin (A2M), ferritin, CRP, haptoglobin, and serum amyloid P.

Covariates of interest included maternal age, body mass index (BMI), psychiatric history, infection during late pregnancy, anemia, parental income, birth order, gestational age and size at birth, mode of delivery, and Apgar score. Logistic regression was used to assess the relationship between neonatal proteins and odds of ASD.

The study cohort comprised 924 children with ASD, 1092 unaffected population-based controls, and 203 unaffected siblings of cases. Median levels of all 9 acute phase proteins (APPs) were higher in cases compared to population-based controls, with the exception of ferritin. Compared to matched sibling controls, however, cases tended to have lower APP levels. Neonatal CRP was significantly associated with increased risk for ASD in case-control comparisons.

When APP data were divided into quintiles, increased odds of ASD were observed among participants in the highest quintiles of CRP (odds ratio [OR], 1.50; 95% CI, 1.10-2.04) compared to participants in the middle quintile. In matched sibling comparisons, however, the lowest quintiles of A2M (OR, 3.71 95% CI, 1.21-11.33), ferritin (OR, 4.20; 95% CI, 1.40-12.65), and serum amyloid P (OR, 3.05; 95% CI, 1.16-8.01) were associated with greater odds of ASD compared to the middle quintiles.

Neonatal APPs displayed significant interactions with other ASD risk factors. Maternal hospitalization for infections during the third trimester appeared to affect the impact of neonatal APPs on ASD risk. Among children whose mothers were hospitalized, increasing levels of certain APPs were associated with lower odds of ASD.

By contrast, ASD risk increased with APP levels among those whose mothers were not hospitalized for infection. Similarly, cases whose mothers had anemia during pregnancy displayed an inverse relationship between APP levels of ASD risk. Finally, the relationship between elevated CRP and ASD was stronger among cases whose mothers had no history of psychiatric illness compared to those whose mothers did have a history of psychiatric illness.

These results suggest that neonatal APP levels may have an impact on risk for ASD. However, the significant interactions between APP levels and other ASD risk factors prevent a clear assertion of causality. Additional research is necessary to further explore the effects of the perinatal environment on ASD risk.

“Our findings suggest that it is not the levels of early-life inflammatory or regulatory markers per se that may influence ASD risk,” the investigators wrote. “Rather, the strength of those signals in the genetic and environmental contexts of the developing nervous system must be considered.”


Gardner RM, Lee BK, Brynge M, Sjöqvist H, Dalman C, Karlsson H. Neonatal levels of acute phase proteins and risk of autism spectrum disorder [published online September 10, 2020]. Biol Psychiatry. doi: 10.1016/j.biopsych.2020.09.005