Introduction: Challenging the Paracetamol-Atopy Hypothesis
For over two decades, a persistent debate has permeated pediatric medicine regarding the safety of early-life paracetamol (acetaminophen) exposure. Numerous observational studies, most notably the International Study of Asthma and Allergies in Childhood (ISAAC), have reported associations between paracetamol use in infancy and an increased prevalence of asthma, wheezing, and eczema. These findings led to the biological hypothesis that paracetamol might deplete systemic glutathione, inducing oxidative stress and shifting the immune response toward a Th2-mediated allergic profile.
However, observational data are inherently susceptible to confounding by indication—where the underlying infection or fever that necessitates the antipyretic, rather than the drug itself, is the true driver of subsequent atopic disease. To address this critical evidence gap, the PIPPA Tamariki trial was designed as a robust, randomized controlled trial (RCT) to compare paracetamol with ibuprofen for fever or pain in the first year of life, focusing on the development of eczema and bronchiolitis.
Highlights
1. The PIPPA Tamariki trial found no statistically significant difference in the incidence of eczema at age one between infants randomized to paracetamol versus ibuprofen.
2. Hospitalization rates for bronchiolitis, viral-induced wheeze, or asthma in the first year of life were comparable between the two treatment arms.
3. The results provide high-level evidence that clinicians can continue to recommend either paracetamol or ibuprofen for symptomatic relief in infants without concern for differential risks of atopy or lower respiratory morbidity.
Study Design and Methodology
The PIPPA Tamariki trial was a multicentre, open-label, parallel-group, superiority RCT conducted across three sites in Auckland and Wellington, New Zealand. The study enrolled 3,923 infants younger than 8 weeks of age between April 2018 and July 2023.
Randomization and Intervention
Participants were randomly assigned (1:1) to receive either paracetamol alone or ibuprofen alone for the management of fever or pain until they reached one year of age. The dosing followed the New Zealand Formulary for Children:
- Paracetamol: 15 mg/kg every 6 hours (age <1 month) or every 4 hours (age ≥1 month).
- Ibuprofen: 5 mg/kg every 6 hours (age <3 months) or 10 mg/kg every 6 hours (age ≥3 months).
Randomization was stratified by recruitment site, maternal asthma status, and multiple births to ensure balanced groups for known risk factors of atopy.
Primary Endpoints
The trial focused on two key outcomes at age one:
- Eczema: Defined by the UK Diagnostic Criteria or hospital admission for eczema during the first year of life.
- Bronchiolitis: Defined by at least one hospital admission for bronchiolitis, viral-induced wheeze, or asthma in the first year of life.
Key Findings: No Superiority for Either Antipyretic
The intention-to-treat (ITT) population included 3,908 infants (1,985 in the paracetamol group and 1,923 in the ibuprofen group). The cohort was demographically diverse, including Māori (15.6%), Pacific (15.5%), and Asian (23.7%) participants.
Eczema Outcomes
Eczema was diagnosed in 16.2% (322/1985) of the paracetamol group compared to 15.4% (296/1923) of the ibuprofen group. The absolute risk difference was a negligible 0.8% (95% CI -1.5 to 3.1; p=0.48). After adjusting for stratification variables, the odds ratio (OR) was 1.10 (95% CI 0.92 to 1.32; p=0.29), indicating no significant difference between the two treatments.
Bronchiolitis and Respiratory Outcomes
Hospitalization for bronchiolitis occurred in 4.9% (98/1985) of the paracetamol group and 4.3% (82/1923) of the ibuprofen group. The absolute risk difference was 0.7% (95% CI -0.6 to 2.0; p=0.32), with an adjusted OR of 1.23 (95% CI 0.82 to 1.71; p=0.21). These results suggest that the choice of antipyretic does not modify the risk of severe early-life respiratory infections or wheezing episodes leading to hospitalization.
Safety and Adverse Events
The safety profile for both drugs was excellent. There were 19 serious adverse events (SAEs) reported in 17 participants (8 in the paracetamol group and 9 in the ibuprofen group). Crucially, none of these SAEs were attributed to the trial medications by the investigators. The adjusted OR for SAEs was 0.47 (95% CI 0.14-1.56; p=0.21), confirming that both medications are safe for use as required in the first year of life.
Expert Commentary: Resolving the Confounding by Indication
The PIPPA Tamariki trial represents a significant milestone in pediatric pharmacology. For years, clinicians have grappled with the possibility that paracetamol might be a modifiable risk factor for the global increase in allergic diseases. By using a randomized design, this study effectively bypasses the “confounding by indication” that plagued earlier observational research. If paracetamol were truly causative, we would expect to see a higher incidence of eczema and bronchiolitis in the paracetamol arm compared to the ibuprofen arm; the lack of such a difference strongly suggests that the previously observed associations were likely due to the underlying illnesses for which the drugs were administered.
Study Strengths and Limitations
The strengths of this trial include its large sample size, high follow-up rates, and the use of standardized diagnostic criteria for eczema. Furthermore, the inclusion of hospitalization data for bronchiolitis provides a concrete, objective measure of respiratory morbidity. One limitation is the open-label design, which was necessary for practical reasons regarding different dosing frequencies and formulations. However, the primary outcomes were based on standardized diagnostic criteria and hospital records, which minimizes the risk of observer bias.
Conclusion: Clinical Implications
The PIPPA Tamariki trial provides reassurance to parents and healthcare providers that neither paracetamol nor ibuprofen, when used as required during the first year of life, increases the risk of eczema or bronchiolitis. This evidence supports the continued use of both agents for managing infant pain and fever based on individual clinical needs, local guidelines, and patient preference. The findings effectively decouple the use of these common antipyretics from the development of early-life atopic and respiratory morbidity.
Funding and Trial Registration
This study was funded by the Health Research Council of New Zealand, Cure Kids New Zealand, and the University of Auckland. It is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12618000303246.
References
1. Tan E, McKinlay CJD, Riley J, et al. 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. Lancet Child Adolesc Health. 2026;10(3):156-166. doi:10.1016/S2352-4642(25)00341-4.
2. Beasley R, Clayton T, Crane J, et al. Association between paracetamol use in infancy and childhood, and risk of asthma, rhinoconjunctivitis, and eczema in children aged 6-7 years: analysis from Phase Three of the ISAAC programme. Lancet. 2008;372(9643):1039-1048.
3. Henderson AJ, Shaheen SO. Acetaminophen and asthma. Paediatr Respir Rev. 2013;14(1):9-15.
