Paracetamol asthma link 'uncertain'

Babies given paracetamol are twice as likely to develop asthma by the age of six, the Daily Express has reported.

The news is based on research that found that use of paracetamol before the age of 15 months was associated with a higher risk of children being predisposed to allergies at the age of six, as defined by skin prick tests. It also found that greater paracetamol at 5-6 years of age was linked to a greater chance of wheeze or asthma symptoms.

Parents should not be concerned by this research or assume that paracetamol-based medicines may give their children asthma. This study has only found associations between paracetamol and asthma symptoms in a cross-sectional analysis, meaning that it has not established any cause-and-effect relationship between the two. As it stands, it may be the case that children with symptoms such as wheezing, a potential sign of asthma, were given paracetamol due to their existing symptoms. The study has a number of further limitations that mean its results need further verification, ideally through good quality clinical research.

Where did the story come from?

The study was carried out by researchers from the University of Otago, the University of Canterbury and Christchurch Hospital, all in New Zealand. It was funded by the Health Research Council of New Zealand and the David and Cassie Anderson Bequest (Wellington). The study was published in the peer-reviewed journal Clinical and Experimental Allergy.

The headline in the Daily Express, suggesting that paracetamol can double the risk of asthma for babies, is misleading since the study did not prove that paracetamol use caused asthma, merely that the two factors were associated. Furthermore, early paracetamol use was associated with an increased risk of atopy – a predisposition to allergy rather than allergy itself – as defined in a skin prick test.

However, the Express did include comments from the study’s lead author stating that more research is needed and from independent experts who say that the benefits of using paracetamol currently outweigh the potential risks. The Daily Mirror’s headline suggesting that childhood asthma may be “boosted by Calpol” is perhaps confusing. Calpol is only one brand name for paracetamol.

What kind of research was this?

This was a prospective cohort study that set out to investigate any possible association between paracetamol use in babies up to 15 months and the risk of asthma and allergic disease at 5-6 years. Cohort studies can follow large groups of people for several years and are often used to look at possible links between an exposure (in this case, paracetamol use) and health outcomes (allergy and asthma). However, on their own they cannot prove causation. Prospective cohort studies track people forward in time and their results are more reliable than retrospective studies.

Researchers also used a cross-sectional analysis to look at possible association between paracetamol use at six years and the incidence of reported wheeze and asthma. A cross-sectional analysis is less reliable than a cohort study, since it looks at two factors simultaneously. It is possible, for example, that in this case, children with wheeze might be more likely to take paracetamol rather than vice versa.

The researchers point out that other studies have shown “positive associations” between paracetamol use and asthma but, so far, the potential role of paracetamol is unclear.

What did the research involve?

Between 1997 and 2001, researchers randomly recruited 1,105 pregnant women for their study from two centres in New Zealand. The women were given questionnaires at recruitment and then regularly until the children were six years old. At three months, 15 months and six years of age participating children were assessed at the research centres, but at other times nurses conducted questionnaires on their mothers by phone. During assessments mothers were asked about the prevalence of symptoms of wheeze, hay fever, rhinitis and eczema, asthma and rash using questions that had been validated in international research.

When the children were six years old, researchers used skin prick tests to assess their sensitivity to certain allergens including rye grass, cow’s milk, and cat, dog and horse hair. Blood samples were also collected and analysed for the presence of IgE antibodies, which are associated with allergy.

At three and 15 months, one of the centres (Christchurch) also asked mothers about paracetamol use. This was not possible in the other centre (Wellington), which had started the study before the development of the paracetamol hypothesis. Both centres collected information on paracetamol use in children at six years. Mothers were asked to choose one of five categories, depending on how often the painkiller was used.

The researchers used standard statistical techniques to analyse associations between paracetamol use at 15 months and atopy at six years. Atopy is defined as a predisposition to allergy, but does not mean allergy is necessarily present. They also analysed associations between how often paracetamol was used at six years and the presence of wheeze and asthma in the previous 12 months.

The figures were adjusted for other factors (called confounders) that might have affected results, including number of chest infections and the use of antibiotics.

What were the basic results?

They found that at the Christchurch centre (which assessed infant paracetamol use), babies who had been given paracetamol before the age of 15 months were more than three times as likely to be predisposed to allergy (atopy) at six years (adjusted odds ratio 3.61, 95% CI 1.33 to 9.77), as defined by skin prick tests. There was no association between paracetamol use at 15 months and presence of allergy-associated IgE antibodies.

In both centres, there was a trend for higher reported paracetamol use in children between five and six years and greater risk of wheeze and asthma; however, not all relationships were statistically significant.

• The children of mothers who reported using the medicine 3-10 times between the ages of five and six years were 1.83 times more likely (95% CI 1.04 to 3.23) to have wheeze than children of mothers using it twice or less over the year. The relationship with asthma was, however, not significant (adjusted odds ratio 1.63, 95% CI 0.92 to 2.89).
• The children of mothers who reported using the medicine more than 10 times between the ages of five and six years were more than twice as likely to have wheeze (adjusted odds ratio 2.30, 1.28 to 4.16) or asthma (adjusted odds ratio 2.16, 1.19 to 3.92) compared with children of mothers using it twice or less over the year.
• Reported frequency of paracetamol use between five and six years was not associated with atopy, as defined by skin prick tests.

How did the researchers interpret the results?

The researchers say their findings suggest that paracetamol has a role in the development of atopy and the maintenance of asthma symptoms. Randomised controlled trials are needed to determine if the association is causal before recommendations for clinical practice can be made, they say.

Conclusion

While this research has found associations between paracetamol use and asthmatic symptoms, parents should not automatically assume that paracetamol itself causes asthma.

While this might initially seem logical, the results were from a cross sectional analysis: children who had reportedly been given more paracetamol between five and six years were more likely to have wheeze and asthma symptoms during that same time period than children who were given less. This analysis cannot show that paracetamol played a role in the development of asthma or wheeze since it is possible that children with these conditions took more paracetamol. We cannot confidently assume a simple cause-and-effect relationship between the two factors, and news reports of this research should not be a cause for concern.

Other factors further complicate the issue, such as testing for predisposition to allergy (atopy) rather than allergy itself.

Further points to note:

• The researchers relied on parental reports of both use of paracetamol and the prevalence of symptoms such as asthma and wheeze. This could affect the reliability of the results, particularly as asthma is notoriously difficult to diagnose in young children and can have variable presentation. Often a night-time cough is the only symptom. Likewise, wheeze can occur with an acute chest infection and does not necessarily mean the person has asthma. The fact that the researchers adjusted their findings for reports of infection is, however, a strength.
• Only one of the centres, which enrolled about half the participants, collected information about paracetamol use before 15 months. In addition, nearly 90% of these children had reportedly been given paracetamol by 15 months. This decreases the reliability of the results and gives a smaller comparison group of children who had not been given paracetamol.
• Both centres seemed to have a high drop-out rate. For example, of 553 participants recruited in one centre, only 469 (84.8%) had data available at 15 months and six years and only 391 (70.7%) were given skin prick tests. This decreases the reliability of the results, particularly those suggesting an association between paracetamol and atopy.

Current advice is that paracetamol use in babies and children is safe, provided the dosage instructions are correctly followed. Paracetamol should never be taken with other products containing paracetamol. When buying over-the-counter painkillers and other products, always check the information on the patient leaflet.

Another painkiller, aspirin, should never be given to anyone under 16 except on specialist advice. It can cause a condition called Reye’s syndrome in this age group, which can be fatal.