Prenatal and postnatal exposure to acetaminophen in relation to autism spectrum and attention-deficit and hyperactivity symptoms in childhood: Meta-analysis in six European population-based cohorts

Abstract

The potential etiological role of early acetaminophen exposure on Autism Spectrum Conditions (ASC) and Attention-Deficit/Hyperactivity Disorder (ADHD) is inconclusive. We aimed to study this association in a collaborative study of six European population-based birth/child cohorts. A total of 73,881 mother-child pairs were included in the study. Prenatal and postnatal (up to 18 months) acetaminophen exposure was assessed through maternal questionnaires or interviews. ASC and ADHD symptoms were assessed at 4-12 years of age using validated instruments. Children were classified as having borderline/clinical symptoms using recommended cutoffs for each instrument. Hospital diagnoses were also available in one cohort. Analyses were adjusted for child and maternal characteristics along with indications for acetaminophen use. Adjusted cohort-specific effect estimates were combined using random-effects meta-analysis. The proportion of children having borderline/clinical symptoms ranged between 0.9 and 12.9% for ASC and between 1.2 and 12.2% for ADHD. Results indicated that children prenatally exposed to acetaminophen were 19% and 21% more likely to subsequently have borderline or clinical ASC (OR = 1.19, 95% CI 1.07-1.33) and ADHD symptoms (OR = 1.21, 95% CI 1.07-1.36) compared to non-exposed children. Boys and girls showed higher odds for ASC and ADHD symptoms after prenatal exposure, though these associations were slightly stronger among boys. Postnatal exposure to acetaminophen was not associated with ASC or ADHD symptoms. These results replicate previous work and support providing clear information to pregnant women and their partners about potential long-term risks of acetaminophen use.

Keywords: Acetaminophen; Attention-deficit/hyperactivity disorder; Autism; Paracetamol; Pregnancy.

Fig. 1

Associations between early acetaminophen exposure and autistic autism spectrum condition (ASC) (a, c) and attention-deficit and hyperactivity (ADHD) symptoms (b, d) within the borderline/clinical range. Associations for prenatal (a, b) and postnatal (c, d) exposure are shown. Symptoms were assessed using parent and teacher reported questionnaires in all cohorts. Odds Ratio (OR) and 95% confidence intervals (CI) by cohort and overall estimate obtained from random-effects meta-analysis. Models were adjusted for maternal characteristics (education, age at delivery, pre-pregnancy body mass index, prenatal smoking, mental health during pregnancy, parity and alcohol consumption, fever and infections during pregnancy) and child’s characteristics (sex, age at the behavioural assessment). Postnatal models were further adjusted by child’s cold or respiratory infections. Models on postnatal exposure and ADHD symptoms were not possible to conduct in RHEA cohort (limited sample size)