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Maternal infection - but not inflammation - is associated with attention-deficit/hyperactivity disorder symptoms
Milan Zarchev1, Frederieke A J Gigase2, Lot de Witte3
1Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC, Rotterdam, the Netherlands; Department of Psychiatry, Erasmus MC, Rotterdam, the Netherlands; The Generation R Study Group, Erasmus MC, Rotterdam, the Netherlands.
Insights
Maternal fever during pregnancy was linked to a small increase in offspring ADHD symptoms. However, markers of chronic inflammation like cytokines and CRP showed no association with ADHD risk in children.
Area of Science:
- Neuroscience
- Developmental Pediatrics
- Immunology
Background:
- Prenatal exposure to infection and inflammation is a suspected risk factor for attention-deficit hyperactivity disorder (ADHD).
- Existing research on this link is inconclusive, necessitating further investigation.
Purpose of the Study:
- To investigate the relationship between prenatal exposure to maternal cytokines, C-reactive protein (CRP), and fever with the risk of ADHD in offspring.
- To examine potential moderating effects of polygenic scores and maternal stress on these associations.
Main Methods:
- A prospective cohort study of 6,555 mother-child pairs (Generation R) was conducted.
- Data included self-reported maternal fever/infections, a composite cytokine index (IL-1β, IL-6, IL-17a, IL-23, IFN-γ), CRP, and ADHD symptoms (parent/teacher-reported at ages 6, 10, 14).
- Linear mixed models were used for analysis, adjusting for multiple maternal and child factors.
Main Results:
- A significant, albeit small, association was found between maternal fever during pregnancy and increased ADHD symptoms in offspring (ß=0.06).
- No significant associations were observed between the composite cytokine index, individual cytokines, CRP, and ADHD symptoms.
- No significant interactions were detected between exposures and polygenic scores for neurodevelopmental disorders or maternal stress.
Conclusions:
- Maternal fever during pregnancy is associated with offspring ADHD symptomatology, though the effect size is modest.
- Markers of chronic inflammation such as cytokines and CRP were not associated with ADHD risk in this cohort.
- The findings contribute to understanding perinatal risk factors for ADHD.
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.
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