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Is acetaminophen responsible for the worldwide rise in childhood asthma over the past 30 years? Citing a mounting pile of circumstantial evidence from epidemiologic observational studies, John McBride of Akron's Children's Hospital in Ohio believes so, and that it's time to officially push the worry button.
The theory is that the fear of aspirin-induced Reye's syndrome in the 1980s resulted in a large increase in the amount of acetaminophen prescribed to children, causing the observed spike in asthma incidence we've seen since then. How? Acetaminophen depletes glutathione, an antioxidant peptide that can curb inflammation in the airways. This hypothetical etiology was proposed by Varner back in 1998, and McBride reiterated it in his review in the November Pediatrics, in which he argues the acetaminophen-asthma link is now strong enough that doctors should counsel the parents of children with asthma (or at risk for asthma) to avoid acetaminophen when possible.
Strong words. What's the evidence?
- Children who took acetaminophen in the first year of life had a 50% greater risk of developing asthma symptoms, compared to kids who took no acetaminophen, in the "Isaac" observational study of 200,000 children in 31 countries, published in Lancet in 2008. There was a dose-response relationship: children taking acetaminophen monthly had a 3-fold likelihood of asthma symptoms.
- In an analysis in ERJ in 2000 tracking acetaminophen (paracetamol) sales in 36 countries, amount of paracetamol sold correlated directly with the prevalence of asthma in that country.
- A 2009 meta-analysis in Chest aggregated 13 observational studies including 425,000 children and adults, and found an odds ratio of 1.63 for asthma and/or wheezing for children and adults who took acetaminophen.
- Only one randomized trial in Pediatrics 2002 suggests acetaminophen might worsen wheezing or asthma: among 1,879 children taking asthma inhalers, those randomized to take ibuprofen as needed for a febrile illness were less likely to see a doctor for asthma than those randomized to acetaminophen as needed.
Not all Dr. McBride's colleagues share his confidence in the acetaminophen-asthma link (including the author of the Chest study), pointing out the inherent flaws of these types of association studies. For example, could an unmeasured confounder be responsible for the observed association between acetaminophen and childhood asthma? Viral infections are also a risk factor for development of asthma, and children with viral infections often receive acetaminophen. In a study by Lowe et al in BMJ 2010, controlling for the number of viral infections abolished any independent effect of acetaminophen on risk for childhood asthma.
Longitudinal cohort studies or randomized trials are the only way to answer questions like these with any surety. At least one small randomized trial is underway to test the effects of paracetamol on lung function in children. Clinicaltrials.gov doesn't show any others listed under acetaminophen or paracetamol and asthma.
McBride JT. The Association of Acetaminophen and Asthma Prevalence and Severity. Pediatrics 2011;128:1181-1185.