Autism is a complex neuropsychiatric syndrome with a largely unknown etiology. Inflammation during pregnancy may represent a common pathway by which infections and other insults increase risk for the disorder.
We investigated the association between early gestational C-reactive protein (CRP), an established inflammatory biomarker, prospectively assayed in maternal sera, and childhood autism in the Finnish Prenatal Study of Autism (FiPS-A), a large national birth cohort (N=1.6 million pregnancies).
The FiPS-A is based on a nested case-control design. The sampling frame consisted of all offspring born in Finland from 1987-2005, and subjects were followed up until 2007. All offspring were derived from the Finnish Maternity Cohort, which consists of virtually all pregnancies with archived serum specimens from the first and early second trimesters (one per pregnancy) beginning in 1983. The Finnish Hospital/Outpatient Discharge Registry was used to identify all cases with childhood autism (ICD-10 F84.0). Cases (N=677) were matched 1:1 to controls from the birth cohort who were without ASD or severe/profound mental retardation on date of birth, sex, birthplace, and residence in Finland. CRP was quantified by a latex immunoassay.
The analysis revealed a significant association between increasing maternal CRP and risk of autism in the offspring (OR=1.12, 95% CI=1.02-1.24, p=.02). There was a greater than 40% increase in risk of childhood autism following exposure to elevated maternal CRP, defined a priori as a CRP level in the highest quintile (>5.84 mg/dl), compared to maternal CRP in the lowest quintile (0.10-0.92 mg/dl) (OR=1.43, 95% CI=1.02-2.01, p=.039). We observed an 80% increase in risk of childhood autism following exposure to elevated maternal CRP, defined a priori as a CRP level in the highest decile (>9.55 mg/dl), compared to the lowest decile (0.10-0.57 mg/dl) (OR=1.80, 95% CI=1.09-2.97, p=.02). The findings were not confounded by maternal age, paternal age, number of previous births, maternal socioeconomic status, pre-term birth, low birthweight, maternal/parental history of psychiatric disorders, and gestational week of the blood draw. There were associations between maternal CRP and risk of autism in both sexes, with a numerically greater association for females, but the findings for both sexes fell short of statistical significance (males: OR=1.10, 95% CI=0.98-1.24, p=0.09; females: OR=1.20, 95% CI=0.97-1.49, p=0.10). There was no statistical evidence of interaction between maternal CRP and sex on the relationship with autism (p=0.50). The relationships were similar for cases with mental retardation (MR) (OR=1.17, 95% CI=0.94-1.45, p=0.17) and without MR (OR=1.11, 95% CI=0.99-1.25, p=0.06).
Elevated maternal CRP during pregnancy is related to an increased risk of autism in offspring. This exposure may represent a common pathway by which infections, other inflammatory insults, and the cytokine response, elevate risk for autism and these outcomes. The findings are consistent with previous associations between elevations in maternal serum and amniotic fluid cytokines and risk of ASD in offspring. The present investigation may stimulate work on possible molecular mechanisms by which elevated CRP disrupts placental function and alters fetal brain development. These findings may also have important implications for prevention of autism.
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