Letter to the editor

Respiratory tract infections and not paracetamol medication during infancy are associated with asthma development in childhood

When conducting clinical trials comparing over-the-counter (OTC) medications, the wide availability of these treatments are a potential challenge to maintaining study integrity. We seek to describe adherence to a study protocol involving widely available OTC medications.

To prospectively evaluate associations between acetaminophen use and asthma in 300 children aged 1–5 years, we conducted a double blind, randomized, controlled trial where parents administered blinded forms of either acetaminophen or ibuprofen as needed to their children over a 48 week period. Written and verbal instructions encouraged the exclusive use of the blinded study medication and discouraged OTC use. Adherence was determined by evaluating the frequency of use of per-protocol blinded study medication compared to off-protocol use of OTC medications.

4195 doses of acetaminophen or ibuprofen were received by children during the study which included 3664 doses (87.3%) of blinded study medication adhering to the protocol and 531 doses (12.7%) of OTC products deviating from the protocol with better adherence among those randomized to ibuprofen as compared to acetaminophen (89.5% vs. 85.5% of doses, p < 0.01). Individually, 227 participants (75.7%) remained fully adherent by not receiving any OTC medications. Pre-study preference for either acetaminophen or ibuprofen by the participants' families was not associated with differential rates of adherence to the blinded medication.

This parallel study demonstrated greater than 85% of acetaminophen or ibuprofen doses were blinded study medications adhering to the protocol while less than 15% were OTC deviations from the protocol. This successfully implemented study design provides a template to comparatively evaluate these and other OTC medications.

Although the impact of early life acetaminophen on asthma risk is still not clear, potential interactions with glutathione S-transferase (GST) genes due to reduced antioxidant function in particular polymorphisms, and possible impact on lung function, have never been investigated in adolescents.

We aimed to investigate associations between early life acetaminophen use and adolescent asthma and lung function and to assess potential interactions by GST polymorphisms.

Acetaminophen use was recorded 18 times up to age 2 years (n = 575 [92.7%]). Participants were genotyped for GST polymorphisms (GSTM1/T1/P1) (n = 429 [69.2%]). Asthma and lung function were measured at 12 (n = 365 [58.9%]) and 18 years (n = 413 [66.6%]). Regression models assessed associations and interactions.

Doubling of days of acetaminophen use was associated with reduced prebronchodilator FEV₁/forced vital capacity (β coefficient, −0.10; 95% CI, −0.19 to −0.01) and midexpiratory flow (−0.09; 95% CI, −0.18 to 0) at 18 years, but this association was not found when restricted for nonrespiratory reasons, suggesting confounding by indication. However, in children with GSTM1 null and GSTT1 present, increasing acetaminophen use for nonrespiratory reasons was associated with reduced FEV₁ and midexpiratory flow at 18 years (interaction between GSTM1/T1 and acetaminophen P < .05). Increased acetaminophen use was associated with asthma at 18 years for children with GSTP1 Ile/Ile (odds ratio, 1.66; 95% CI, 1.07 to 2.57), but not other GSTP1 genotypes.

These novel findings need to be investigated for consistency in other studies but suggest that children carrying risk genotypes may be susceptible to respiratory consequences from acetaminophen use.

Several studies have reported an association between use of over-the-counter antipyretics during pregnancy or infancy and increased asthma risk. An important potential limitation of these observational studies is confounding by indication.

We investigated the association of antipyretic intake during pregnancy and during the first year of life (infancy) with asthma-related outcomes before and after controlling for early-life respiratory tract infections.

We included 1490 mother-child pairs in Project Viva, a longitudinal prebirth cohort study. We categorized prenatal acetaminophen exposure as the maximum intake (never, 1-9 times, or ≥10 times) in early pregnancy or midpregnancy and ibuprofen intake as presence or absence in early pregnancy. We expressed intake of antipyretics in infancy as never, 1 to 5 times, 6 to 10 times, or more than 10 times. We examined the associations of acetaminophen and ibuprofen (per unit increase in exposure category) during pregnancy and infancy with wheeze, asthma, and allergen sensitization in early childhood (3-5 years of age, n = 1419) and midchildhood (7-10 years of age, n = 1220).

Unadjusted models showed an increased asthma risk in early childhood for higher infant acetaminophen (odds ratio [OR], 1.21; 95% CI 1.04-1.41) and ibuprofen (OR, 1.35; 95% CI, 1.19-1.52) intake. Controlling for respiratory tract infections attenuated estimates for acetaminophen (OR, 1.03; 95% CI, 0.88-1.22) and ibuprofen (OR, 1.19; 95% CI, 1.05-1.36). Prenatal acetaminophen was associated with increased asthma (OR, 1.26; 95% CI, 1.02-1.58) in early childhood but not midchildhood.

Adjustment for respiratory tract infections in early life substantially diminished associations between infant antipyretic use and early childhood asthma. Respiratory tract infections should be accounted for in studies of antipyretics and asthma to mitigate bias caused by confounding by indication.

Acetaminophen is a widely used medication for the treatment of pain and fever in children and pregnant women. There is substantial epidemiological evidence in adults and children that acetaminophen use is associated with asthma symptoms. There is also a considerable body of evidence that supports a modest but consistent association of acetaminophen use in pregnancy and early infancy with asthma in later childhood. This relationship is robust to adjustment for a large range of potential confounding factors and, in some studies, shows clear evidence of a dose-dependent association but the possibility of confounding by indication has remained a concern. However, the epidemiological evidence is now compelling and there is a clear need to establish causation so that appropriate advice and interventions can be developed for children at risk of asthma. This requires randomised trials of analgesics and antipyretics, including acetaminophen, in a variety of clinical settings