Exposure to acetaminophen in the second and third trimesters of pregnancy predicted current wheeze at age 5 years in addition to other measures of asthma and seroatopy among African-American and Dominican Republic children living in an inner-city community with a high burden of asthma. The association of prenatal exposure to acetaminophen and current wheeze was modified by a common polymorphism in the GSTP gene, suggesting a glutathione-related mechanism.
Prenatal exposure to acetaminophen predicted current wheeze in children age 4–6 years in earlier studies from the UK, Denmark and Spain5–7
and also predicted wheeze in the first year of life in one US study.29
The frequency of acetaminophen use during pregnancy and the magnitude of association in the UK study were similar to that in New York City. The prevalence of current wheeze at 6 years, however, was only 10% in the UK study, such that the attributable risk of acetaminophen was 1%.5
In contrast, the prevalence of current wheeze in the present study was 27%, resulting in a population attributable risk from acetaminophen exposure assuming a causal relationship of 6%.
The relevant timing of acetaminophen exposure during pregnancy is not clear, with the UK study and our study showing similar point estimates for risk with exposure early and late in pregnancy and the Danish study showing stronger associations with exposure early in pregnancy.5 6
Other differences include effect modification by maternal asthma in the study from Spain, which we did find in our inner-city cohort.7
In contrast to the multicentre European study, we observed no association between postnatal acetaminophen use and wheeze.4
One reason for the larger potential impact of prenatal exposure to acetaminophen on current wheeze in this minority cohort may be differences in the GSTP1 minor allele frequency. Prenatal acetaminophen exposure was strongly associated with wheeze in participants with the GSTP1 minor allele, whereas no association was evident among those homozygous for the major allele. The minor allele frequency of GSTP1 was not reported in the predominantly Caucasian UK cohort; however, another study of Caucasians in the UK found a minor allele frequency of 32%.30
Similar frequencies have been observed in asthma studies from Taiwan (18%) and Sweden (33%)11 12
and among non-Hispanic white subjects (32%) in Southern California.10
In contrast, the observed minor allele frequency of 44% among African-Americans and Dominican Republic subjects in the current study was similar to that among African-Americans (43%) and Hispanics (43%) in Southern California.10
The mechanism of the association between acetaminophen and asthma has been hypothesised to involve the glutathione pathway which is downregulated following acetaminophen exposure and among subjects with asthma.31
GSTP catalyses the conjugation of reduced glutathione to a wide variety of substrates for detoxification and is responsible for 90% of the GSTactivity in the lungs. Also, a small portion of acetaminophen is converted to n-acetylbenzoquinonimine (NAPQI) by cytochrome p450, which can be cytotoxic.17
Shaheen et al
have suggested the drug-induced upregulated action of NAPQI in the cells of the developing fetal lungs as a potential mechanism between prenatal acetaminophen and asthma.5
Furthermore, GSTP catalyses conjugation of NAPQI to glutathione at a rate faster than other GSTs.32
Since GSTP itself can be damaged NAPQI, pulmonary toxicity could occur as a result of direct activity by NAPQI or indirectly by decreased GSTP conjugation activity of other toxicants.17
The common polymorphism in GSTP (GSTP1 A105G) leads to expression of GSTPs with functionally different catalytic capacities.15 33
Recently, polymorphisms in GSTP1 have been reported to alter asthma and allergy susceptibility to diesel, ETS and ambient air pollution.9–13
GSTP is also involved in other pathways, including regulation of the stress-activated proteins c-Jun N-terminal kinases (JNK), which can activate transcription factors within the allergic pathway, potentially offering a connection between acetaminophen and atopy through GSTP.35
We observed an interaction between the GSTT deletion and acetaminophen on atopy but not wheeze, suggesting that the acetaminophen relationship with atopy and wheeze may act via the glutathione pathway, although not necessarily in identical ways. Our finding of a significant interaction between acetaminophen and GSTP1 offers the first evidence of a direct connection between acetaminophen exposure and asthma through the glutathione pathway.
We observed an association between prenatal exposure to acetaminophen and persistent but not transient wheeze. This, combined with our observation of increased risk for outcomes associated with more severe asthma (eg, emergency department visits for asthma) and atopy, suggests that prenatal exposure to acetaminophen increases the risk for phenotypes of asthma that are more likely to persist throughout childhood.21
The observational nature of this study means that the findings may be confounded by unmeasured or mismeasured covariates that cause asthma and were associated with prenatal acetaminophen exposure. However, we adjusted for the major known risk factors for paediatric asthma and the observed associations were not attenuated. A limitation was not ascertaining the reason for prenatal acetaminophen use, but the observed associations with headaches suggest pain management as likely. However, other host factors that caused mothers to take acetaminophen and also cause asthma may explain their association. Infection is one such potential confounder; however, we found no association between the reported use of antibiotics and acetaminophen, and adjustment for antibiotic use during pregnancy did not affect the results. An anxious personality also could have confounded the association; however, it is unlikely that this would explain the observed genetic interaction. Systematic reporting bias for both prenatal exposure to acetaminophen and wheeze at different ages seems unlikely given the prospective design of the study, the observed relationship of acetaminophen exposure with seroatopy and the effect modification by GSTP1. An additional limitation is the sample size and possibility of a false-positive result owing to multiple comparisons. However, we specified one primary end point a priori (wheeze) and the statistical significance of the association between prenatal exposure to acetaminophen and this outcome was at the level of p<0.001. Our tests for interactions with genotype polymorphisms were limited to three functional gene polymorphisms related to a previously hypothesised pathway (glutathione), and these three were tested for interaction with one primary (wheeze) and one secondary (atopy) outcome. The interaction with GSTP1 and prenatal acetaminophen on wheeze was statistically significant at the level of p<0.01. The 31% of the children who were lost to follow-up at age 5 years were more likely to be African-American and their mothers were more likely to complain of severe headaches and abdominal cramps in pregnancy, but there was no difference in reported prenatal acetaminophen use with these mothers and regression models were adjusted for race/ethnicity and complaints about headaches and pain. A further limitation of our study was the generalisability since mothers who smoked during pregnancy and those younger than 18 were excluded from the study.
In conclusion, prenatal acetaminophen exposure predicted asthma symptoms among African-American and Dominican Republic children—a relationship that was stronger among children with the common GSTP1 minor allele. These findings might provide an explanation for some of the increased asthma risk in minority communities and suggest caution in the use of acetaminophen in pregnancy.