The issue of whether or not epidemiologic evidence can be judged strong enough despite potential confounding factors to take preventive action appears to be alive and well in the debate on the relationship between acetaminophen and asthma. 

Saying that he cannot tolerate further delay to obtain incontrovertible evidence of a strong causal association between acetaminophen and asthma, a clinician writing in Pediatrics in December 2011 is now recommending a halt in the use of in the use of acetaminophen to treat children with asthma or at risk for asthma.

Risk Estimates

According to John McBride, professor of pediatrics at Northeast Ohio Medical University, the epidemiologic association between acetaminophen use and asthma is well established. He cites in his Pediatrics review a meta-analysis of studies in children which estimated a pooled odds ratio for wheezing in the previous year of 1.97, and an analysis of studies in adults which found an estimate of 1.74.

Particularly striking are the high population attributable risks which have been calculated for children ranging from 38-41% for different child age groups.

Furthermore, according to McBride, increased acetaminophen use after the recognition of the role of aspirin and Reye syndrome, is correlated with the increased prevalence of asthma from 3.6% to 5.8% which has taken place between 1980-2003. 

Another SIDS Situation?

Says McBride, “the possibility that a measure as simple as limiting acetaminophen use might result in so great a decrease in suffering of children throughout the world (and a reduction in the cost of their medical care) is both sobering and exciting. The situation could recapitulate experience with the ‘Back to Sleep’ campaign during which the estimated PAR of prone sleeping for sudden infant death syndrome was confirmed by the resulting reduction in its incidence.”

 Reasons To Hold Off

The call for more evidence before accepting the conclusion that acetaminophen causes asthma comes from investigators who are concerned that asthma itself might be the cause of increased use of acetaminophen (reverse causation), or that alternative analgesics might exacerbate asthma and therefore cause persons with asthma to increase their use of acetaminophen to avoid alternatives, or that increased viral illnesses or fever in asthmatics leads to increased acetaminophen use (confounding by indication).

Hill Criteria Met

However, while not able to eliminate the possibility of confounding, McBride believes that several of the Hill criteria have been met, including the 1) strength of the association, 2) consistency of results across ages, geography, and cultures, 3) the timing of the exposure before the occurrence of asthma, 4) the specificity of the association for acetaminophen and not other analgesics, 5) the pronounced dose-response relationship, 6) a plausible biologic mechanism, 7) consistent experimental data, and 8) the coherence of the evidence with the increased use of acetaminophen following the decrease in aspirin use for Reye syndrome. 

Policy Tension

McBride concludes by alluding to a divide between his interests as a pediatrician treating children and the interests of government or professional associations who may be waiting for “incontrovertible evidence”. “I can understand how those responsible for regulation or policy statements of professional organizations might be more comfortable waiting for incontrovertible evidence…however, I need further studies not to prove that acetaminophen is dangerous but, rather, to prove that it is safe.”