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.

Epidemiological Evidence

The epidemiological evidence comes from almost every type of epidemiological design: case–control studies,^[6] ecological studies,^[7] large cross-sectional studies,^[8,9] and large prospective cohort studies,^[10] in children and adults. To put some order and appropriately summarize these studies, several systematic reviews and meta-analyses have been published. In 2009, Etminan et al. reported a comprehensive systematic review and meta-analysis of the published literature on acetaminophen use and the risk of wheezing disorders in children and adults up to the end of October 2008 and after a thorough review and selection process, included 19 studies comprising 425,140 subjects, including children and adults (13 cross-sectional studies, four cohort studies and two case–control studies).^[11] Throughout the paper, it can be seen that point estimates of the odds ratios (ORs) always fell, in each and every study, against acetaminophen exposure and only in a small minority of studies does the confidence interval cross the line of no statistical significance. The pooled OR for all studies, for adults, for children and for almost any other subgroup of studies is consistently near 1.5, with a narrow 95% CI.

In 2011, García-Marcos et al. published an even more comprehensive systematic review and meta-analysis on early exposure to acetaminophen and allergic disorders, which included the studies of the meta-analysis by Etminan et al. (although appropriately dissected into substudies when appropriate) and some others published since 2008, totaling an outstanding number of 41 substudies.^[12] After several meta-analyses with different criteria, the authors concluded that, "no matter what type of study, age or time of exposure, there is always a positive association between [acetaminophen] exposure and respiratory symptoms." The pooled ORs obtained in this paper are also around 1.5. The consistency of the association found in almost every epidemiological study urged the authors to investigate the possibility of publication bias. Even after correcting for the possible unpublished negative results using the Duval and Tweddie's 'trim and fill' method, the pooled OR remained statistically and scientifically significant. In 2011 and 2012, some other epidemiological studies have shown the same results.^[13,14] It is highly improbable that studies with negative results have remained unpublished because, from the journals editors' point of view, adding new studies to the large list of positive results is far less attractive than showing off a negative study.

Another feature of this epidemiological association which deserves special attention is dose-response relationship, which was already found in the first epidemiological case–control study^[6] and also in the two large ISAAC studies in adolescents and children aged 6–7 years^[8,9] and a recent longitudinal birth cohort study in Ethiopia.^[10] For instance, in this study a dose-dependent increased risk of incident wheeze was found with acetaminophen exposure, with an adjusted OR for one to three acetaminophen tablets per month of 1.88 (1.03–3.44) and 7.25(2.02–25.95) for ≥ four tablets.

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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