Erika B Gram, Lars Christian Lund, Peter Bjødstrup Jensen, Jesper Hallas, Mette Bliddal, Anne Broe Lambourne, Christina Chambers, Trine Munk-Olsen, Rikke Wesselhoeft, Hedvig Nordeng, Per Damkier
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. Due to limited follow-up time, our findings only apply to early-diagnosed neurodevelopmental disorders which are likely to be the more severe cases.
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 2,013, most paracetamol sales are prescription-based in Denmark, 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 01 October 2,014 and 31 December 2,021, and their linked mothers using Danish nationwide health registers. Exposure was defined as ≥1 prescriptions redeemed for paracetamol during pregnancy. Children were followed until 6 years of age or the end of the study period (31 December 2,022). Using a triangulation approach, we compared i) exposed children to unexposed children, ii) exposed children to children of mothers who redeemed prescriptions before - but not during - pregnancy, and iii) 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 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 slightly higher (ADHD: 1.23 (95% CI, 0.96-1.58)) 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. Due to limited follow-up time, our findings only apply to early-diagnosed neurodevelopmental disorders which are likely to be the more severe cases.