Maternal infection – but not inflammation – is associated with attention-deficit/hyperactivity disorder symptoms during childhood: a population-based cohort study

BACKGROUND: Studies are equivocal on whether prenatal exposure to infection and inflammation is linked to higher risk of attention-deficit hyperactive disorder (ADHD) in the offspring. The current study investigated the relationship between prenatal exposure to maternal cytokines, C-reactive protein (CRP), fever and the risk of ADHD in childhood and early adolescence in the general pediatric population. METHOD: Data came from 6,555 mother-child pairs enrolled in Generation R, a Dutch prospective population-based cohort. The primary predictors were 1) self-reported fever and/or infections in each trimester; 2) a composite cytokine index of IL-1β, IL-6, IL-17a, IL-23, and IFN-γ and 3) CRP. The primary outcome was ADHD symptoms measured using the Child Behavioral Checklist (parent-reported) and Teacher Report Form (teacher-reported), obtained at three time points (ages 6, 10 and 14 years). Linear mixed models were used to estimate overall associations, adjusted for maternal factors (i.e., education, national origin, age, current psychopathology, psychosocial stress, smoking, pre-pregnancy BMI, parity) and child factors (i.e., age, sex, polygenic score for neurodevelopmental disorders). We also investigated if the associations were moderated by 1) the child's polygenic score for neurodevelopmental disorders and 2) maternal stress during the pregnancy. RESULTS: We found a small, but significant association between fever and ADHD symptoms (ß=0.06 95 %CI = 0.01, 0.11). No significant association was found between the cytokine composite index, individual cytokines, or CRP and ADHD symptoms. No interactions were detected for any of the exposures with a polygenic score for neurodevelopmental disorders (all interactions p-values > 0.198) or maternal stress (all p-values > 0.403). CONCLUSIONS: Our findings suggest that maternal fever and infections during pregnancy are linked to offspring ADHD symptomatology. The standardized effect size was smaller than that of other reported perinatal risk factors for ADHD. Cytokine levels and CRP as markers for chronic inflammation were not associated with ADHD.