Acetaminophen, Asthma, ADHD and Autism: At what point do we change our practice?

By Claudia Morris
claudia.r.morris @emory.edu

Acetaminophen (APAP, Tylenol) is the most commonly dispensed medication in the United States, representing 5% of all treatments, and is generally used to alleviate pain and/or fever. Most agree that treating pain is important, however, treatment to reduce fever is not “medically necessary”. Fever is an evolutionarily conserved natural protective mechanism to fight infection, yet unfounded fever phobia is common among parents and practitioners. This creates an ideal market for antipyretics like acetaminophen, the drug of choice for fever in young children. Originally marketed internationally in the 1950s, its use increased significantly in the 1980s due to concerns of aspirin use and Reye’s syndrome. However nearly 20 years ago, new concerns were raised about the safety of acetaminophen and its potential link to asthma1, including a case-control study that suggested that frequent acetaminophen use in adults was associated with asthma, and among those who already had asthma, with more severe disease2. The mechanism for this association was thought to be the depletion of glutathione in the lung, leading to greater oxidative stress3,4. With asthma prevalence increasing world-wide, this concern leads to more than a decade of observational research on acetaminophen use and asthma in adults, children and pregnant women, with over 2500 publications now in the literature on this topic5-19. A 2009 meta-analysis that considered all clinical and observational studies at the time, ultimately including 425,140 subjects, found a pooled odds ratio for asthma in patients using acetaminophen to be 1.6 [1.46-1.77], increased risk of asthma with prenatal acetaminophen use, and an increased risk of asthma and wheezes in both children and adults exposed to acetaminophen, with a dose-dependent response noted in many studies12. Some experts in the field have begun to take a stand: Dr. Holgate wrote “There is now overwhelming evidence establishing a link between APAP and asthma20, while Dr. McBride stated in Pediatrics “In my opinion, the balance between the likely risks and benefits of acetaminophen has shifted for children with a history or family history of asthma. I can understand how those responsible for regulation or policy statements of professional organizations might be more comfortable waiting for incontrovertible evidence. There remains a possibility that confounding variables might explain some or all of the association between APAP and asthma. For this reason, we need further studies. At present, however, I need further studies not to prove that APAP is dangerous but, rather, to prove that it is safe. Until such evidence is forthcoming I will recommend avoidance of APAP by all children with asthma or those at risk for asthma and will work to make patient’s, parents, and primary care providers aware of the possibility that APAP is detrimental to children with asthma”21. Fortunately, some reassurance was recently provided by Sheehan and colleagues, in the Acetaminophen versus Ibuprofen in Children with Asthma (AVICA) trial, a 48-week prospective, blinded, randomized controlled trial that compared the as–needed use of acetaminophen with that of ibuprofen for fever or pain in 300 children 12-59 months of age with mild-persistent asthma receiving treatment with asthma controller therapies. The investigators did not find any significant difference in the primary outcome of asthma exacerbations leading to treatment with systemic glucocorticoids or in any of the secondary outcomes between the two groups, suggesting no greater risk of asthma exacerbation with acetaminophen use compared to ibuprofen22,23. However, the AVICA trial does not address whether acetaminophen use can lead to the development of asthma in otherwise healthy children, nor whether it is associated with worsening of symptoms in children with moderate to severe asthma. Questions and clinical equipoise remain. Several large epidemiologic studies linking acetaminophen use in pregnancy and ADHD 24-26 warrant further investigation. Recent studies identifying an association of ADHD with asthma and allergies 27-30 may foreshadow a potentially unrecognized mechanistic overlap between these conditions. Epidemiologic studies linking maternal use of acetaminophen during pregnancy to increased risk of autism gives further pause 31-34. A small study linking acetaminophen but not ibuprofen use with MMR, and autism, may warrant the discouragement of acetaminophen use during vaccination until more information is available35,36.

According to a 2007 CDC report, acetaminophen is responsible for approximately 56,000 emergency department visits, 26,000 hospitalizations, and over 450 deaths per year. Now, large epidemiologic studies have found an association with acetaminophen use and asthma as well as ADHD and autism. Although a causal relationship cannot be assumed based on the current literature, more studies of safety are needed. In the meantime, just like cold medicines and antibiotic overuse, the risks of acetaminophen need to be reassessed. I personally echo the sentiments of Dr. McBride, and have changed my practice in pediatric emergency medicine. Fever is your friend. It is a physiologic mechanism with benefits. Worried caregivers need reassurance to combat fever phobia and education on appropriate use of antipyretics. Treat misery and discomfort rather than a cut-off temperature. Alternatives to acetaminophen may also be considered, however all medications have risks that need to be weighed against their true benefits.      

References

  1. Varner AE, Busse WW, Lemanske RF, Jr. Hypothesis: decreased use of pediatric aspirin has contributed to the increasing prevalence of childhood asthma. Ann Allergy Asthma Immunol. 1998;81(4):347-351.
  2. Shaheen SO, Sterne JA, Songhurst CE, Burney PG. Frequent paracetamol use and asthma in adults. Thorax. 2000;55(4):266-270.
  3. Fitzpatrick AM, Teague WG, Holguin F, Yeh M, Brown LA. Airway glutathione homeostasis is altered in children with severe asthma: evidence for oxidant stress. J Allergy Clin Immunol. 2009;123(1):146-152 e148.
  4. Stephenson ST, Hadley G, Brown LA, Fitzpatrick AM. Decreased expression of acetaminophen-metabolizing enzymes and glutathione in asthmatic children after acetaminophen exposure. J Allergy Clin Immunol. 2012;129(3):867-869.
  5. Lesko SM, Louik C, Vezina RM, Mitchell AA. Asthma morbidity after the short-term use of ibuprofen in children. Pediatrics. 2002;109(2):E20.
  6. Barr RG, Wentowski CC, Curhan GC, et al. Prospective study of acetaminophen use and newly diagnosed asthma among women. American journal of respiratory and critical care medicine. 2004;169(7):836-841.
  7. Eneli I, Sadri K, Camargo C, Jr., Barr RG. Acetaminophen and the risk of asthma: the epidemiologic and pathophysiologic evidence. Chest. 2005;127(2):604-612.
  8. Koniman R, Chan YH, Tan TN, Van Bever HP. A matched patient-sibling study on the usage of paracetamol and the subsequent development of allergy and asthma. Pediatr Allergy Immunol. 2007;18(2):128-134.
  9. Persky V, Piorkowski J, Hernandez E, et al. Prenatal exposure to acetaminophen and respiratory symptoms in the first year of life. Ann Allergy Asthma Immunol. 2008;101(3):271-278.
  10. 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.
  11. Rebordosa C, Kogevinas M, Sorensen HT, Olsen J. Pre-natal exposure to paracetamol and risk of wheezing and asthma in children: a birth cohort study. Int J Epidemiol. 2008;37(3):583-590.
  12. Etminan M, Sadatsafavi M, Jafari S, Doyle-Waters M, Aminzadeh K, Fitzgerald JM. Acetaminophen use and the risk of asthma in children and adults: a systematic review and metaanalysis. Chest. 2009;136(5):1316-1323.
  13. Bakkeheim E, Mowinckel P, Carlsen KH, Haland G, Carlsen KC. Paracetamol in early infancy: the risk of childhood allergy and asthma. Acta Paediatr. 2011;100(1):90-96.
  14. Farquhar H, Stewart A, Mitchell E, et al. The role of paracetamol in the pathogenesis of asthma. Clin Exp Allergy. 2009;40(1):32-41.
  15. Shaheen SO, Newson RB, Sherriff A, et al. Paracetamol use in pregnancy and wheezing in early childhood. Thorax. 2002;57(11):958-963.
  16. Perzanowski MS, Miller RL, Tang D, et al. Prenatal acetaminophen exposure and risk of wheeze at age 5 years in an urban low-income cohort. Thorax. 2010;65(2):118-123.
  17. Lowe A, Abramson M, Dharmage S, Allen K. Paracetamol as a risk factor for allergic disorders. Lancet. 2009;373(9658):120; author reply 120-121.
  18. Thomsen SF, Kyvik KO, Skadhauge L, Steffensen I, Backer V. Intake of paracetamol and risk of asthma in adults. J Asthma. 2008;45(8):675-676.
  19. Beasley RW, Clayton TO, Crane J, et al. Acetaminophen use and risk of asthma, rhinoconjunctivitis, and eczema in adolescents: International Study of Asthma and Allergies in Childhood Phase Three. American journal of respiratory and critical care medicine. 2011;183(2):171-178.
  20. Holgate ST. The acetaminophen enigma in asthma. American journal of respiratory and critical care medicine. 2011;183(2):147-148.
  21. McBride JT. The association of acetaminophen and asthma prevalence and severity. Pediatrics. 2011;128(6):1181-1185.
  22. Sheehan WJ, Mauger DT, Paul IM, et al. Acetaminophen versus Ibuprofen in Young Children with Mild Persistent Asthma. N Engl J Med. 2016;375(7):619-630.
  23. Litonjua AA. Acetaminophen and Asthma–A Small Sigh of Relief? N Engl J Med. 2016;375(7):684-685.
  24. Thompson JM, Waldie KE, Wall CR, Murphy R, Mitchell EA, group ABCs. Associations between acetaminophen use during pregnancy and ADHD symptoms measured at ages 7 and 11 years. PloS one. 2014;9(9):e108210.
  25. Liew Z, Ritz B, Rebordosa C, Lee PC, Olsen J. Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr. 2014;168(4):313-320.
  26. Brandlistuen RE, Ystrom E, Nulman I, Koren G, Nordeng H. Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol. 2013;42(6):1702-1713.
  27. Chen MH, Su TP, Chen YS, et al. Asthma and attention-deficit/hyperactivity disorder: a nationwide population-based prospective cohort study. J Child Psychol Psychiatry. 2013;54(11):1208-1214.
  28. Tsai CJ, Chou PH, Cheng C, Lin CH, Lan TH, Lin CC. Asthma in patients with attention-deficit/hyperactivity disorder: a nationwide population-based study. Ann Clin Psychiatry. 2014;26(4):254-260.
  29. Borschuk AP, Rodweller C, Salorio CF. The influence of comorbid asthma on the severity of symptoms in children with attention-deficit hyperactivity disorder. J Asthma. 2017:1-7.
  30. Miyazaki C, Koyama M, Ota E, et al. Allergic diseases in children with attention deficit hyperactivity disorder: a systematic review and meta-analysis. BMC Psychiatry. 2017;17(1):120.
  31. Olsen J, Liew Z. Commentary: Acetaminophen use in pregnancy and neurodevelopment: attention function and autism spectrum symptoms. Int J Epidemiol. 2016;45(6):1996-1997.
  32. Avella-Garcia CB, Julvez J, Fortuny J, et al. Acetaminophen use in pregnancy and neurodevelopment: attention function and autism spectrum symptoms. Int J Epidemiol. 2016;45(6):1987-1996.
  33. Andrade C. Use of acetaminophen (paracetamol) during pregnancy and the risk of autism spectrum disorder in the offspring. J Clin Psychiatry. 2016;77(2):e152-154.
  34. Liew Z, Ritz B, Virk J, Olsen J. Maternal use of acetaminophen during pregnancy and risk of autism spectrum disorders in childhood: A Danish national birth cohort study. Autism Res. 2016;9(9):951-958.
  35. Schultz ST, Klonoff-Cohen HS, Wingard DL, Akshoomoff NA, Macera CA, Ji M. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey. Autism. 2008;12(3):293-307.
  36. Schultz ST, Gould GG. Acetaminophen Use for Fever in Children Associated with Autism Spectrum Disorder. Autism Open Access. 2016;6(2).

 

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