Acetaminophen has been the topic of this column on many
occasions in the past years. This commonly used medication can be useful for
symptom relief for infants and children, from a wide variety of infectious
diseases and other disorders.
Edward A. Bell, PharmD, BCPS
Acetaminophen’s availability as an over-the-counter
product may cause it to be used with little or no direction from a health care
professional. This likely has contributed to its misuse, resulting in
significant adverse effects. The recent change in the strengths and
concentrations of the pediatric liquid formulations was done to limit
inappropriate use and dosing of acetaminophen. Another potential difficulty
facing this important therapeutic agent is gaining increasing attention in the
medical and lay literature. Evidence has been accumulating that acetaminophen
use may be an important risk factor for the development of asthma in infants
and children. Although this evidence is largely based upon epidemiologic
information and data from observational and cohort studies, the implication
that this commonly used medication may contribute to the prevalence of asthma
The largest published study describing an association
between acetaminophen and asthma is the International Study of Asthma and
Allergies in Childhood (ISAAC). ISAAC is a cross-sectional study of randomly
sampled children in two age groups (6 to 7 years and 13 to 14 years) that was
conducted in more than 30 countries. Questionnaires were administered to
caregivers and adolescents and designed to obtain prevalence data about asthma,
rhinoconjunctivitis and eczema, and environmental data about risk factors for
the development of asthma and allergic disorders.
These environmental data included questions about
frequency of acetaminophen use within the past 12 months. The primary outcome
measure was the association between acetaminophen use for fever in the first
year of life and asthma symptoms at 6 to 7 years of age. The major strength of
this study is the large sample size: 205,487 children 6 to 7 years of age from
73 centers in 31 countries. Analysis of data revealed that use of acetaminophen
for fever in the first year of life was associated with an increased risk of
asthma symptoms at age 6 to 7 years, with an OR of 1.46 (95% CI, 1.36-1.56).
Current acetaminophen use was also associated with a
dose-dependent increased risk of asthma symptoms for medium and high use
(OR=1.61 and 3.23, respectively, with neither including 1.0 for 95% CI) vs. no
use. Medium and high use were defined as “at least once a year,” and
“at least once per month,” respectively. Acetaminophen use was
additionally associated with similar, significantly increased risks of symptoms
of rhinoconjunctivitis and eczema.
Data obtained from the adolescent study group (13 to 14
years) in ISAAC were reported in a separate publication. Data from 322,959
adolescents in 115 centers in 50 countries were analyzed. The primary outcome
measure was the association between current acetaminophen use and current
asthma symptoms. Acetaminophen use and asthma symptoms (“wheezing or
whistling in the chest”) were assessed within the past 12 months and
included definitions of medium (“at least once a year”) and high
(“at least once per month”) use of acetaminophen vs. no use. ORs
demonstrated that recent use of acetaminophen was associated with increased
risks of current asthma symptoms for medium and high use — 1.43 (95% CI,
1.33-1.53) and 2.51 (95% CI, 2.33-2.70), respectively, compared with no use of
acetaminophen. Acetaminophen use was additionally associated with similar,
significantly increased risks of symptoms of rhinoconjunctivitis and eczema.
A recently published meta-analysis of published studies
on acetaminophen use and its associations with asthma evaluated 19
observational studies, with 425,140 participants (prenatal use and use by
children and adults). The ISAAC study (6- to 7-year-old children) was included.
Observational trials included in this analysis were required to have clearly
defined acetaminophen use and asthma diagnosis. The pooled OR for asthma among
users of acetaminophen was 1.63 (95% CI, 1.46-1.77). An increased risk for
asthma was found in children born to mothers who used acetaminophen during
pregnancy, with an OR of 1.28 (95% CI, 1.13-1.39).
The risk for asthma in children who used acetaminophen
in the year before diagnosis and within the first year of life was increased
(OR=1.60 and 1.47, respectively, with neither including 1.0 for 95% CI). A
strength of this meta-analysis is the large sample size evaluated. However,
these data are limited by the heterogeneous nature of data collection among the
studies and inclusion of self-reporting of asthma diagnoses.
Acetaminophen vs. ibuprofen
A review of the literature and data on acetaminophen use
and asthma includes a description of data obtained from only one randomized
controlled trial. This randomized, double blind trial was conducted initially
to evaluate the safety of ibuprofen suspension for the use of fever in children
aged 6 months to 12 years (n=83,915). Two doses of ibuprofen (5 mg/kg and 10
mg/kg) were compared with acetaminophen (12 mg/kg). A placebo control group was
Data from this study were used in part to gain approval
for ibuprofen suspension availability as an OTC pediatric product. Of the total
sample size, 1,879 children were described as receiving treatment for asthma
(receiving a beta-agonist, theophylline or inhaled corticosteroid). The
objective of this additional data analysis was to evaluate the hypothesis that
short-term use of ibuprofen increases asthma morbidity. Thus, the initial study
producing these data was not designed to investigate an association between
asthma and acetaminophen.
The data demonstrate that children receiving ibuprofen
had a lower risk of requiring an outpatient visit for asthma, with an RR of
0.56 (95% CI, 0.34-0.95) vs. children receiving acetaminophen. Rates of
hospitalization for asthma did not differ among children receiving ibuprofen or
acetaminophen. The study researchers concluded that a difference in risk for
asthma symptoms cannot be attributed to an increased risk from acetaminophen as
compared with a decreased risk from ibuprofen.
It is important to consider the strengths and weaknesses
of the data obtained from these studies. Strengths of these data include the
large sample sizes evaluated in the ISAAC studies; similar data from other
observational studies; statistically significant associations; an association
of asthma and acetaminophen use across various countries and cultures; an
association across age groups (prenatal, children, adults); and an associated
Proposed biologic and pharmacologic mechanisms
underlying an acetaminophen-asthma relationship are additionally plausible. A
significant weakness of these data includes their source from observational
studies. These observational studies are limited by recall bias (retrospective
data collection), reporting bias and reporting of asthma diagnosis or symptoms
by caregivers or self. Observational studies are subject to confounding
variables, and although the ISAAC and other studies attempted to control for
many potentially confounding variables, other variables not assessed (such as
hygiene practices or use of ibuprofen or other nonsteroidal anti-inflammatory
drugs) may be important. Thus, association does not imply causation.
Several researchers have additionally reported on some
data that suggest that increased respiratory tract infection morbidity is more
likely to be associated with later development of asthma, and not use of
acetaminophen. Although data from a randomized controlled trial are described
in the literature, as discussed, this study did not include a placebo control
and was not initially designed to address a potential relationship between
acetaminophen use and asthma. An important question raised by this controlled
trial is the potential for a protective effect of NSAIDs vs. a deleterious
effect of acetaminophen on asthma. Randomized trials in adults have
additionally shown that aspirin (an NSAID) can have a protective effect against
Proposed biologic and pharmacologic mechanisms
underlying a potential association between acetaminophen use and asthma include
an acetaminophen-induced reduction in pulmonary glutathione. Glutathione acts
as an antioxidant, and reduced levels may contribute to pulmonary tissue
damage, inflammation and the development of asthma. Reduced glutathione may
also alter differential cytokine production, potentially increasing risk of
development of allergic disorders.
The findings from these studies are interesting and
certainly cannot be ignored. Studies with large sample sizes have identified an
association between acetaminophen use in children and asthma. Most study and
editorial authors do not believe we should change our current practices of this
commonly used medication in infants and children at this time.
One author of a recently published discussion on this
topic, however, does believe that acetaminophen should not be used by children
with asthma or those at risk for asthma. Until stronger data are available from
additional studies, it seems premature to alter our current practice patterns.
Although ibuprofen is an alternative antipyretic and analgesic agent that is
additionally available for infants and children, it is not labeled for use in
children aged younger than 6 months, and there are children with specific
underlying disorders that can be at increased risk of adverse effects (eg,
renal disorders) from its use. A prospective, controlled trial is urgently
needed to address this potential problem, with perhaps the most commonly used
medication in the pediatric population.
For more information:
- Barr RG. Lancet. 2008;372:1011-1012.
- Beasley R. Am J Respir Crit Care Med. 2011;183:171-178.
- Beasley R. Lancet. 2008;372:1039-1047.
- Etminan M. Chest. 2009;136:1316-1323.
- Farquhar H. J Allergy Clin Immunol. 2009;124:649-651.
- Holgate ST. Am J Respir Crit Care Med. 2011;183:147-151.
- Lesko SM. Pediatrics. 2002;109:E20.
- McBride JT. Pediatrics. 2011;128:1181-1185.
- Schnabel E. J Allergy Clin Immunol. 2010;126:1071-1073.
Edward A. Bell, PharmD, BCPS, is professor of
clinical sciences at Drake University College of Pharmacy, Blank
Children’s Hospital, in Des Moines, Iowa. He is also a member of the
Infectious Diseases in Children Editorial Board. Disclosure: Dr. Bell
reports no relevant financial disclosures.