The Association Between Acetaminophen and Asthma

Should Its Pediatric Use Be Banned?

Antonio Martinez-Gimeno; Luis García-Marcos

Expert Rev Resp Med. 2013;7(2):113-122.

Review of the Bradford Hill Criteria

As an overview to the case against acetaminophen as a wheezing disorders promoter, the authors can check the nine classic criteria proposed by Bradford Hill in 1965 to differentiate among association and causation.^[27] Table 1 shows that most of the criteria have been fulfilled but the most important from the practicing pediatrician's point of view, that is, removal of exposure prevents disease, has been evaluated satisfactorily in only one clinical trial in wheezing children in the short term^[15] but has not been satisfactorily addressed to date in the general pediatric population.

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Table 1. Bradford Hill criteria applied to the hypothesis of acetaminophen as wheezing diseases promoter.
Criteria	Evidence
Strength of effect	Increased risk after acetaminophen exposure ≥1.5
Dose response	Present for acetaminophen exposure in utero, childhood and adult life
Consistency/coherence	Consistency among studies, age groups, sex, geography and culture
Exposure before response	Observed in prospective studies of acetaminophen exposure in utero, infancy and adult life Observed in the only prospective double-blind randomized clinical trial in children
Biological plausibility	Increased oxidant-induced airway inflammation Enhanced Th2 response Decreased immune response to rhinovirus infection
Removal of exposure prevents disease	Partially examined in the only double-blind randomized clinical trial on the subject published to date: using ibuprofen instead of acetaminophen in febrile children with concomitant use of anti-asthma drugs reduced the risk for an outpatient visit for asthma in the following month Effect of removal of exposure on prevalence to be determined
Specificity	No increased risk of asthma associated with aspirin or other NSAID
Analogy	Weak, protective effects of antioxidant diet in asthma

Adapted with permission from [17].

Table 2. Overview of arguments in the case against acetaminophen as a promoter of wheezing disorders in children.
Arguments that support a detrimental effect of acetaminophen in asthma	Arguments against a detrimental effect of acetaminophen in asthma
Epidemiologic association between acetaminophen exposure and asthma
Strength of the association Consistency of the association across geography, culture, age and studies Dose dependency of the epidemiologic association Coincidence in time of increase in asthma prevalence and increase in acetaminophen use Ecologic relationship among asthma prevalence and per-capita sales of acetaminophen Uniqueness of this association, more consistent than any other environmental factor	The whole epidemiologic association may be spurious, acetaminophen being an innocent bystander falsely accused due to several bias or confounding factors: Confounding by indication (real culprit, respiratory virus infections producing fever) Confounding by reverse causation (real culprit, asthma itself which induces acetaminophen use) Confounding by preferential use of acetaminophen by children at higher risk of asthma or already asthmatics
Clinical trials
A randomized clinical trial with 1879 children 6 months to 12 years old with asthma exacerbation and fever, showing a lower incidence of outpatient visits for asthma in those randomly assigned to ibuprofen compared with acetaminophen (adjusted relative risk: 0.56 [95% CI: 0.34–0.95] compared with those receiving acetaminophen)	No placebo group included. The lower relative risk for children who received ibuprofen could be due to a protective effect of ibuprofen instead of a detrimental effect of acetaminophen No clinical trials have been performed on the effect of acetaminophen on the prevalence of asthma
Biological plausibility
Acetaminophen depletes glutathione from the airways Acetaminophen reduces immune response to, and prolongs, rhinovirus infection