Prenatal paracetamol exposure and risk of wheeze at preschool age†
Ethical approval: The study was approved by the ethics committee at the University of Gothenburg.
E Goksör, M.D., Department of Paediatrics, University of Gothenburg, Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46-31-343-40-00 | Fax: +46-31-84-36-53 | Email: firstname.lastname@example.org
Aim: To analyse the association between prenatal paracetamol exposure and preschool wheeze.
Methods: Data were obtained from a prospective, longitudinal study of a cohort of children born in the region of western Sweden in 2003; 8176 families were randomly selected. The parents answered questionnaires at 6 and 12 months and at 4.5 years of age. The response rate was 55%, i.e. 4496 of the 5398 questionnaires distributed at 4.5 years (83%). Inhaled corticosteroid (ICS) treated wheeze during the last year was regarded as a proxy for doctor-diagnosed asthma. Episodic viral wheeze was defined as wheezing only with viral infections and multiple-trigger wheeze as wheezing also in between infections.
Results: In the multivariate analysis, the risk of ICS-treated wheeze was increased by paracetamol (OR 1.6; 95% CI 1.01–2.6). Within the ICS-treated group, the effect was significant for multiple-trigger wheeze (OR 2.4; 1.2–4.8) but not for episodic viral wheeze (OR 1.1; 0.5–2.3).
Conclusion: Prenatal paracetamol exposure was an independent risk factor for ICS-treated wheeze at preschool age, especially among children with ICS-treated multiple-trigger wheeze. Although the analysis adjusted for e.g. maternal asthma and antibiotic use, the possibility of residual confounding by maternal indication (respiratory illness) should be acknowledged.
- • In a prospective, longitudinal cohort study, prenatal paracetamol exposure was associated with an increased risk of inhaled corticosteroid (ICS) treated wheeze at preschool age.
- • In the children with ICS-treated wheeze, the effect of prenatal paracetamol exposure was significant for multiple-trigger wheeze.
- • Prenatal paracetamol exposure did not increase the risk of episodic viral wheeze.
There is growing concern about a possible increase in the risk of asthma or allergy following exposure to paracetamol (acetaminophen) early in life (1). Furthermore, a temporal connection between the increased use of paracetamol and the increase in allergic diseases in the Western world has been noted (2).
Several studies have reported an increased risk of asthma following paracetamol exposure both in utero and during infancy (3–6). However, in the case of postnatal exposure, it has been difficult to rule out confounding by indication; i.e. that paracetamol might be a proxy for respiratory morbidity, which could explain an association (7,8).
Various definitions have been used to describe wheezing disorder in early childhood. Recurrent wheeze, which includes children with repeated symptoms, can be regarded as a proxy for asthma (9,10). Inhaled corticosteroid (ICS)-treated wheeze can be regarded as a proxy for doctor-diagnosed asthma, since these children have been evaluated by physicians as being in need of asthma treatment (11). In addition, the temporal pattern and trigger factors of preschool wheeze have been used to delineate the phenotypes of ‘episodic viral’ and ‘multiple-trigger’ wheeze (12). Children with multiple-trigger wheeze have symptoms not only with viral infections but also in between the infections. These children are more likely to develop allergic asthma as they grow up (12).
The aim of this study was to analyse the association between prenatal paracetamol exposure and preschool wheeze, including episodic viral wheeze and multiple-trigger wheeze.
Material and Methods
Data were obtained from a prospective, longitudinal cohort study of children born in the region of western Sweden in 2003. The region has 1.5 million inhabitants, one-sixth of the Swedish population. It comprises urban, rural and coastal areas and the largest city is Gothenburg, with 500 000 inhabitants. The initial, random sample comprised 8176 families (50% of the birth cohort).
After written informed consent had been obtained, the parents answered questionnaires at 6 and 12 months and at 4.5 years of age. Information regarding pregnancy and postnatal factors was collected at 6 months of age. At 12 months and at 4.5 years of age, questions were asked regarding current health and disease.
Of the families that were initially contacted, the response rate at 6 months of age was 69%, while it was 60% at 12 months of age. Details regarding the questionnaires at 6 and 12 months have been published previously (11,13).
At 4.5 years, questionnaires were distributed to those who had participated at 6 and/or 12 months. The response rate at 4.5 years was 55%, i.e. 4496 of the families that were initially contacted. This equals 83% of the 5398 questionnaires distributed at 4.5 years of age. After supplementation with data from the Swedish Medical Birth Register (MBR), the database consists of 4171 infants with a full data set (all three questionnaires and the MBR). The MBR was the basis of information on: gender, gestational age, caesarean section, Apgar score, small for gestational age and large for gestational age.
As reported earlier, the material appears to be largely representative of the population (11). In this follow-up, we found that the non-responders had a higher percentage of parents with a low educational level, mothers smoking during pregnancy and preterm birth. Also, a slightly lower percentage of atopic heredity and breast-feeding was found (14).
In the statistical analysis, contingency tables with the chi-squared test and binary logistic regression were used. Odds ratios (OR) were estimated with 95% confidence intervals (CI). A p-value of <0.05 was considered as significant in the multivariate analysis.
Data on maternal intake of medical drugs during pregnancy were obtained from the 6-month questionnaire, with the following question: ‘Did the mother take any medication during pregnancy? If yes, please specify….’ If paracetamol use was specified, this was denoted as prenatal paracetamol exposure and compared with no prenatal paracetamol exposure.
As major outcome variables, recurrent wheeze and ICS-treated wheeze at 4.5 years of age were used. Recurrent wheeze was defined as children with three or more episodes of wheezing during the last 12 months while ICS-treated wheeze was defined as wheeze treated with ICS during the last 12 months (10,11). In Sweden, many of the children with repeated wheezing are treated with ICSs, regardless of whether the wheezing is multiple triggered or episodic viral. The responders to this treatment might have fewer than three episodes of wheezing during the last 12 months and would thus be lost in the group with recurrent wheeze. Furthermore, children with ICS-treated wheeze have been evaluated by a physician and found to be in need of treatment. Accordingly, the definition of ICS-treated wheeze can be regarded as a proxy for doctor-diagnosed asthma. Among the children with recurrent or ICS-treated wheeze, the phenotypes of ‘episodic viral wheeze’ (without symptoms between colds) and ‘multiple-trigger wheeze’ (wheeze also triggered by factors other than colds) were analysed (12).
The multivariate model included plausible confounding factors for the association with paracetamol exposure based on previous analyses of risk factors for preschool wheeze in the same cohort (14) as summarized in the Table 1 footnote. Firstly, factors with substantially large marginal effect (p < 0.01) were identified in the univariate analysis. In addition, we included factors previously shown to influence the risk of childhood wheeze like maternal smoking during pregnancy and breast-feeding (15,16). Maternal antibiotic use during pregnancy was included as partially reflecting maternal respiratory infection. Apgar score <7 at 5 min was included as a proxy for postnatal vulnerability and parental educational level as a marker of socioeconomic status.
Table 1. Univariate and multivariate analyses of the association between maternal paracetamol medication during pregnancy and wheeze at age 4.5 years. The results are shown for recurrent wheeze and ICS-treated wheeze. In addition, the results are shown for multiple-trigger wheeze and episodic viral wheeze in both wheeze groups, respectively
| No paracetamol||3805||212||Ref.||84||Ref.||124||Ref.||Ref.||Ref.||Ref.|
| Paracetamol||311||23||1.3 (0.9–2.1)||14||2.0 (1.1–3.6)||8||0.8 (0.4–1.6)||1.1 (0.6–2.0)||1.6 (0.7–3.4)||0.7 (0.3–1.8)|
| No paracetamol||3791||226||Ref.||77||Ref.||121||Ref.||Ref.||Ref.||Ref.|
| Paracetamol||302||32||1.8 (1.2–2.6)||13||2.1 (1.2–3.9)||12||1.2 (0.7–2.3)||1.6 (1.01–2.6)||2.4 (1.2–4.8)||1.1 (0.5–2.3)|
We also performed the multivariate analysis for exclusive prenatal paracetamol exposure compared with no medication exposure during pregnancy. Exclusive paracetamol exposure was defined as exposure to paracetamol but not to any other medication during pregnancy.
In addition, the results of the multivariate analyses were confirmed using an extended model including factors with p < 0.1 in the univariate analyses (Table S1).
The attributable fraction (AF) was calculated using the formula: AF = (the proportion of cases exposed to the factor) * (OR − 1)/OR (17). The SPSS statistical package version 17.0 (SPSS Inc., Chicago, IL, USA) was used for calculations.
Medicine had been taken by 28.4% of the mothers during pregnancy. Paracetamol had been taken by 7.7%, while exclusive paracetamol use was reported in 5.3%.
Children with recurrent wheeze reported treatment with asthma medications in 74.6%, treatment with ICSs in 55.5% and asthma diagnosis in 54.7%. By definition, all children with ICS-treated wheeze had treatment with asthma medications and ICSs and 73.1% reported asthma diagnosis.
Prenatal paracetamol exposure increased the risk of multiple-trigger wheeze in the univariate analysis (Table 1). However, the association did not remain significant in the multivariate analysis (Table 1). The risk of episodic viral wheeze was not increased by paracetamol. The results were similar using the extended model (Table S1).
Prenatal paracetamol exposure increased the risk of ICS-treated wheeze in both the univariate and multivariate analyses (Table 1). This was significant for the subgroup of children with multiple-trigger wheeze. The risk of episodic viral wheeze was not increased by paracetamol. The results were similar using the extended model (Table S1).
The effect of exclusive paracetamol exposure during pregnancy, i.e. no other medication during pregnancy reported, was similar to that of paracetamol as presented above. Accordingly, the risk of ICS-treated wheeze was independently increased (OR 2.1; 1.1–4.0) and especially among children with multiple-trigger wheeze (OR 3.3; 1.2–9.0). The risk of episodic viral wheeze was not increased.
The prevalence of prenatal paracetamol exposure in children with ICS-treated wheeze was 12.4%. The prevalence was 14.4% in the subgroup of children with multiple-trigger wheeze compared with 9.0% among the children with episodic viral wheeze (Table 1).
The AF for paracetamol exposure in ICS-treated wheeze was 4.7% (95% CI 0.1–7.6) and 8.4% (2.4–11.4) in ICS-treated multiple-trigger wheeze.
Maternal use of paracetamol during pregnancy increased the risk of ICS-treated wheeze at preschool age. In particular, the risk of multiple-trigger wheeze was increased but not the risk of episodic viral wheeze.
Other studies have reported an increased risk of wheezing following paracetamol exposure in utero and during the first year of life (3–6,18–21). Recent meta-analyses have confirmed the association, and call for further studies of the impact of paracetamol during pregnancy on the risk of wheezing, so that appropriate public health recommendations can be made (22,23). Furthermore, a dose-dependent effect has been described (4). In addition, paracetamol use has been reported to increase the risk of other allergic manifestations such as eczema and rhinoconjunctivitis (4,21,24).
The timing of paracetamol exposure during pregnancy has been suggested to be of importance, but the results are divergent. For example, the ALSPAC study reports that exposure during late pregnancy increases the risk of wheezing in childhood (3). However, Rebordosa et al. (5) found an increased risk of asthma at any time of exposure during pregnancy. In fact, the risk of persistent wheezing was highest in children exposed during the first trimester. The reason for these different results is unclear. In our study, we do not have information on the time of exposure.
A causal relationship between paracetamol exposure and asthma has been disputed. Confounding by indication has been suggested to explain the association seen. Children with respiratory infections in early childhood often receive paracetamol. Paracetamol might therefore be a proxy for respiratory morbidity (7,8). However, our study and other studies that only consider paracetamol exposure during pregnancy still find an association (3,6,24). On the other hand, maternal use of paracetamol could be a proxy for maternal respiratory infection, which we were not able to control for. However, we did adjust for maternal antibiotic use and maternal asthma, since asthmatic mothers have a higher risk of respiratory infections.
The association might also be confounded by the possibility of asthmatic mothers taking less aspirin/NSAID and more paracetamol instead, making paracetamol use a proxy of asthma in the mother. Thus, studies of paracetamol use during pregnancy adjust for maternal asthma. We adjusted for asthma, eczema and rhinoconjunctivitis in both the mother and father.
In addition, paracetamol use in pregnancy might be argued to be a proxy for a difficult pregnancy increasing the vulnerability of the child. Thus, we adjusted for caesarean section, prematurity and low Apgar score at 5 min. In addition, paracetamol use could be a proxy for other diseases and possibly also for the intake of other medication. However, in our study the effect of paracetamol was not altered when considering only exclusive paracetamol exposure, excluding the use of other medication, including asthma and allergy medication.
Not all studies find such an association between paracetamol exposure and the risk of wheeze. In a study by Kang et al. (25), no association was found between paracetamol exposure during pregnancy and asthma in the offspring. The authors suggest that the definition of asthma in different studies might explain the divergent results. In our study, we see different impact of paracetamol exposure on the outcomes recurrent and ICS-treated wheeze. Wheezing at preschool age is heterogeneous and it is difficult to predict who will develop true asthma. Recurrent wheeze denotes children with repeated symptoms. Although the definition, i.e. number of episodes last year, varies between studies, recurrent wheeze can be regarded as a proxy for asthma in the child (9,10). In our study, the children with recurrent wheeze report of less treatment with asthma medications and less doctor-diagnosed asthma than children with ICS-treated wheeze. By definition, all children with ICS-treated wheeze are treated with asthma medications and 73% report of an asthma diagnosis. We find an increased risk among children with ICS-treated wheeze, which can be regarded as a proxy for doctor-diagnosed asthma, since these children have been evaluated by a physician as being in need of treatment. These differences between recurrent and ICS-treated wheeze may explain why we do not see the same impact of prenatal paracetamol on the two groups. Furthermore, as discussed by an ERS task force on preschool wheeze, children with multiple-trigger wheeze are more prone to develop allergic and persistent asthma (12). In our study, paracetamol exposure during pregnancy increased the risk of multiple-trigger wheeze, but not of episodic viral wheeze, within the ICS-treated group. This may suggest a link between paracetamol exposure and the development of allergic asthma.
Via which mechanisms could paracetamol increase the risk of asthma or allergy? Paracetamol has been described as increasing oxidant-induced inflammation by lowering the glutathione levels when it is metabolized in the liver (26–28). As a result, the pulmonary antioxidant defence is diminished and airway inflammation is increased (29). The lowering of glutathione levels by paracetamol has also been suggested to enhance the T-helper type 2 response, altering antigen presentation and recognition (2,27). Unlike acetylsalicylic acid, paracetamol does not affect the COX-2 pathway (29), which is activated during respiratory viral infections. The COX-2 pathway increases the production of prostaglandin E2, which in turn inhibits the production of Th-1 cytokines, shifting the balance towards Th-2 (29). Paracetamol has been shown to have immune-modulating effects, altering the immunological response to vaccination if it is given prior to the fever reaction (30). The recent findings that maternal antioxidant polymorphisms modify the association between paracetamol exposure and childhood asthma further support a causal relationship (31). However, therapeutic doses of paracetamol have been argued not to affect the gluthatione levels enough to alter antioxidant defence (32).
The weaknesses of this study are those inherent in questionnaire-based studies, i.e. there can always be some uncertainty regarding the validity of answers. The outcome variables were based on parental report of symptoms and diagnoses. No objective measures of atopy or asthma were available. The question about medication during pregnancy was asked retrospectively (6 months post partum) and not about paracetamol use in particular. As a result, information on dose or time of intake was not available. However, it might be argued that the mothers who reported paracetamol use during pregnancy in our study considered their use substantial enough to report. Furthermore, we do not have information on paracetamol use by the child itself during the first years of life. This has been reported to increase the risk of subsequent asthma and could influence the outcome at preschool age (4). We consider our multivariate model to be stable and reliable, adjusting for the plausible confounders available. This is supported by the similar results using an extended multivariate model that included factors with p < 0.1 in the univariate analyses. However, the possibility of residual confounding must be recognized. Paracetamol might still be a proxy for maternal respiratory infection or other diseases. As can be expected in a cohort study, the responders were somewhat more diligent and health-conscious than the non-responders. In addition, the response rate of 55% at preschool age of the initially contacted families could result in selection bias.
The strengths of the study are the large size of the birth cohort. In all, we have data from all the questionnaires for more than 4000 children. As reported earlier, the material appears to be largely representative of the population (11).
To summarize, we find that the maternal intake of paracetamol during pregnancy increases the risk of ICS-treated wheeze, and especially that of multiple-trigger wheeze at preschool age, but not the risk of episodic viral wheeze.
We thank our colleagues Nils Åberg, Laslo Erdes, Per Möllborg and Rolf Pettersson for valuable discussions. The study was supported by the Sahlgrenska Academy at the University of Gothenburg, the Research Foundation of the Swedish Asthma and Allergy Association, the Swedish Foundation for Health Care Sciences and Allergy Research and the Health & Medical Care Committee of the Regional Executive Board, Västra Götaland Region.