Prescription Use of Paracetamol During Pregnancy and Risk of Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder in Early Childhood

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OBJECTIVE: Paracetamol is the drug of choice for treating pain and fever during pregnancy. Concerns exist regarding risk of neurodevelopmental disorders in prenatally exposed offspring, especially autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Since September 2013, most paracetamol sales in Denmark have been prescription based, enabling investigation in a population-based setting. We investigated the association between prescription-based paracetamol use during pregnancy and the risk of clinically diagnosed ASD and ADHD detected in early childhood among exposed offspring. METHOD: We included all singleton children live-born between October 1, 2014, and December 31, 2021 and their linked mothers using Danish nationwide health registers. Exposure was defined as ≥1 prescriptions redeemed for paracetamol during pregnancy. Children were followed up until 6 years of age or the end of the study period (December 31, 2022). Using a triangulation approach, we did the following: (1) compared exposed children to unexposed children; (2) compared exposed children to children of mothers who redeemed prescriptions before, but not during, pregnancy; and (3) used a paternal negative-exposure group. RESULTS: Adjusted risk ratios (aRR) for ASD and ADHD at 6 years of age among exposed children compared to unexposed children were 1.15 (95% CI = 0.96-1.39) and 1.09 (95% CI = 0.85-1.40), respectively. No increased risks were observed when comparing to children of mothers redeeming prescriptions before-but not during-pregnancy (aRR = 1.01, 95% CI = 0.76-1.32, and aRR = 1.01, 95% CI = 0.67-1.53), suggesting confounding by underlying maternal illness. In the paternal negative-exposure group, aRRs were similar (ASD = 1.06, 95% CI = 0.88-1.28) and were slightly higher (ADHD = 1.23, 95% CI = 0.96-1.58) compared to the primary estimates, the latter suggesting unmeasured familial confounding. CONCLUSION: Our findings suggest that prenatal exposure to prescription-based paracetamol is unlikely to confer a clinically meaningful increased risk of ASD or ADHD diagnosed by 6 years of age. Because of limited follow-up time, our findings only apply to early-diagnosed neurodevelopmental disorders, which are likely to be the more severe cases. STUDY REGISTRATION INFORMATION: APAP in pregnancy; https://osf.io/kjced/overview.

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