NPC Archive Item: No reason to stop using paracetamol in children

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Beasley R et al. Association between paracetamol use in infancy and childhood, and risk of asthma, rhinoconjunctivitis and eczema in children aged 6-7 years: analysis from Phase Three of the ISAAC programme. Lancet 2008;372:1039-48

Use of paracetamol for fever in the first year of life was associated with a small increased chance of having wheeze, rhinoconjunctivitis-like or eczema-like symptoms later in childhood. Current use of paracetamol in 6-7 year olds was also associated with these conditions. The study does not prove causation and one possible alternative interpretation is that parents are more likely to give paracetamol to children who have these symptoms.

Clinicians should follow NICE guidance on feverish illness in children. This states that antipyretic drugs should not routinely be given to children with fever who are otherwise well with the sole aim of reducing body temperature or preventing febrile convulsions. Either paracetamol or ibuprofen may be used if the child appears distressed or is unwell. Paracetamol or ibuprofen are options for fever or pain. However, ibuprofen may provoke or worsen asthma symptoms in some children.

What is the background to this?
The prevalence of asthma has been increasing over the last 50 years, but the reason for this is unknown.  Paracetamol use has also increased markedly in this time. Some earlier studies have suggested a link between paracetamol use and asthma. This study reports some cross-sectional study findings from phase three of ISAAC, an ongoing, international, multicentre observational study looking at asthma and allergies in childhood. It includes children from a random sample of schools.

Parents of children aged 6-7 years were asked about the child’s use of paracetamol in the previous 12 months (data from 105,023 children, 20 countries included), and about their use of paracetamol for fever in the child’s first year of life (data from 105,041 children, 20 countries included). Parents were also asked about symptoms of wheeze (which the researchers took to indicate asthma), symptoms related to the nose and eyes (indicating allergic rhinoconjunctivitis), and symptoms related to itchy skin rashes (indicating eczema). Multivariate analyses considered each child’s sex, their region of the world, their country’s socioeconomic status, and factors such as parental smoking, whether or not they were breastfed, diet, etc.

What did this study claim?
Children whose parents said they “usually” gave them paracetamol for fever in their first 12 months of life were more likely to have had symptoms of asthma (“wheezing or whistling in the chest”) in the previous 12 months (odds ratio [OR] 1.46, 95% confidence interval [CI] 1.36 to 1.56) than those whose parents did not. They were also more likely to have symptoms suggestive of rhinoconjunctivitis (runny/blocked nose with itchy, watery eyes, not linked with a cold or flu) in the previous 12 months (OR 1.48, 95%CI 1.38 to 1.60); and more likely to have symptoms of eczema (a persistent itchy skin rash with a typical eczema-like body distribution) in the previous 12 months (OR 1.35, 95%CI 1.26 to 1.45).

There was also an association between the presence of these symptoms in the previous 12 months and reported use of paracetamol in the previous 12 months, which was classified as medium (paracetamol use at least once a year) or high (paracetamol use at last once a month). Compared with non-users, more medium users had “asthma” (OR 1.61, 95%CI 1.46 to 1.77), “rhinoconjunctivitis” (OR 1.32, 95%CI 1.20 to 1.46) or “eczema” (OR 1.18, 95%CI 1.08 to 1.30). The ORs (95%CI) for high users compared with non-users were greater than those for medium users compared with non-users: “asthma” 3.23 (2.91 to 3.60); “rhinoconjunctivitis” 2.81 (2.52 to 3.14); “eczema” 1.87 (1.68 to 2.08)

Finally, medium and high paracetamol current users were more likely to have “severe asthma” than never users. Severe symptoms included four or more attacks in the past year, sleep disturbed by wheeze one or more nights a week in the past 12months/year, or at least one episode in the past 12 months when the child could not speak more than one or two words between breaths. The OR (95%CI) for medium versus never users was 1.33 (1.15 to 1.53) and for high versus never users it was 3.54 (3.05 to 4.11).

So what?
Observational studies, especially cross-sectional studies like this, are valuable in identifying signals of association, but we should be careful before assuming causation (see Austin Bradford-Hill’s classic 1965 paper). There are several limitations to it. Possible sources of bias include recall bias (e.g. parents of children who are unwell may have been more likely to remember infant paracetamol use), reporting bias (e.g. parents more likely to pick up and report childhood illness may be more likely to use paracetamol), and even diagnostic bias  and confounding (e.g. illnesses which might lead to paracetamol use, eg colds, lower respiratory tract infections might also produce symptoms identified as asthma, allergic rhinoconjunctivitis or eczema and also lead to increased paracetamol use) – though this last possibility is unlikely. The ORs observed are also not particularly great, except for frequent (defined as “high”) current use of paracetamol and “asthma” and “rhinoconjunctivitis”.

The authors suggest that exposure to paracetamol may be a risk factor for asthma and related allergic disorders. Nevertheless, as they state in their concluding paragraph:

“Evidence is insufficient to advise parents and health-care workers of the risk–benefit of taking paracetamol in childhood, or its comparative efficacy and safety with other approaches. Further research is urgently needed, including randomised controlled trials, into the long-term effects of paracetamol to enable evidence-based guidelines for the recommended use of paracetamol in childhood to be made.”

Another recent observational study has also reported an association between paracetamol and asthma: adults with asthma were more likely to have taken paracetamol regularly (i.e. weekly as opposed to less than weekly) than people without asthma. However, this study also has methodological limitations (see the NHS Choices review)

NICE guidance on feverish illness in children states that antipyretic drugs should not routinely be given to children with fever who are otherwise well, but recommends either paracetamol or ibuprofen if the child appears distressed or is unwell. With regard to its use as an analgesic, paracetamol has advantages over NSAIDs including generally better gastrointestinal safety.  NSAIDs may provoke or worsen asthma symptoms in some children.

For more information on paracetamol and its role as an analgesic, see the pain section of NPC

Study details
Patients: 205,487 children in 31 countries (105,041 children from 20 countries included in multivariate analysis of paracetamol use in first year of life, and 105,023 children from 20 countries in multivariate analysis of current paracetamol use)

Design: Cross-sectional observational study

Outcomes and results: parent-reported prevalence of paracetamol use for fever in first year of life; paracetamol use and frequency in previous 12 months; symptoms of wheeze, rhinorrhoea and lacrimation, and itchy skin. The primary outcome was the association between paracetamol use for fever in the first year of life and asthma symptoms at 6-7 years of age, expressed as OR, as measured by the multivariate analysis (see text for results).

Sponsorship: The BUPA Foundation, the Health Research Council of New Zealand, the Asthma and Respiratory Foundation of New Zealand, the Child Health Research Foundation, the Hawke’s Bay Medical Research Foundation, the Waikato Medical Research Foundation, Glaxo Wellcome New Zealand, the New Zealand Lottery Board, Astra Zeneca New Zealand, and Glaxo Wellcome International Medical Affairs.

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