Paracetamol versus ibuprofen as required for fever or pain in the first year of life and the risk of eczema and bronchiolitis at age 1 year in New Zealand (PIPPA Tamariki): a multicentre, open-label, parallel-group, superiority, randomised controlled trial

Background: In non-experimental studies, early-life exposure to paracetamol is associated with an increased risk of eczema and wheeze. We aimed to compare paracetamol with ibuprofen, as required for fever or pain in the first year of life, for the risk of eczema and bronchiolitis at age 1 year. Methods: PIPPA Tamariki is a multicentre, open-label, two-arm, parallel-group, superiority, randomised controlled trial done at three sites in Auckland and Wellington in New Zealand. Infants younger than 8 weeks and born in New Zealand were randomly assigned (1:1) to paracetamol alone (15 mg/kg every 6 h at age <1 months and every 4 h at age ≥1 months) or ibuprofen alone (5 mg/kg every 6 h at age <3 months and 10 mg/kg every 6 h at age ≥3 months), received orally as required for fever or pain, until age 1 year. Dosing was based on the New Zealand Formulary for Children. Research staff used REDCap for randomisation, which was stratified by recruitment site, maternal asthma status, and multiple birth. Key outcomes were eczema as defined by the UK Diagnostic Criteria or eczema hospitalisation in the first year of life, and hospitalisation for bronchiolitis as defined by at least one hospitalisation for bronchiolitis, viral-induced wheeze, or asthma in the first year of life. Analysis was according to the intention-to-treat principle. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12618000303246 (active, not recruiting). Findings: Between April 18, 2018, and July 28, 2023, 3923 infants were enrolled. 15 participants withdrew, leaving 3908 infants (1985 were randomly assigned to the paracetamol group, and 1923 to the ibuprofen group) in the intention-to-treat population. Of these participants, 1914 (49·0%) were female and 1994 (51·0%) were male; 609 (15·6%) were Māori, 607 (15·5%) were Pacific, 926 (23·7%) were Asian, and 1754 (44·9%) were New Zealand European or other. Eczema occurred in 322 (16·2%) of 1985 participants in the paracetamol group and 296 (15·4%) of 1923 participants in the ibuprofen group (absolute risk difference 0·8% [95% CI –1·5 to 3·1]; p=0·48; adjusted odds ratio [OR] 1·10 [95% CI 0·92 to 1·32]; p=0·29). Bronchiolitis occurred in 98 (4·9%) participants in the paracetamol group and 82 (4·3%) participants in the ibuprofen group (absolute risk difference 0·7% [95% CI –0·6 to 2·0]; p=0·32; adjusted OR 1·23 [95% CI 0·82 to 1·71]; p=0·21). 19 serious adverse events were reported in 17 participants (eight [0·4%] of 1985 in the paracetamol group and nine [0·5%] of 1923 in the ibuprofen group; adjusted OR 0·47 [95% CI 0·14–1·56; p=0·21]); none were attributed to trial medication. Interpretation: There was no evidence of an important difference between paracetamol and ibuprofen in the risk of eczema or bronchiolitis at age 1 year. Funding: Health Research Council of New Zealand, Cure Kids New Zealand, University of Auckland.