Intrauterine Acetaminophen Exposure Linked to Asthma in Offspring

Increases in the prevalence of asthma, especially in children, have raised concern in the medical community, resulting in research to find possible causes and to explore potential means of prevention. Recently there has been some evidence linking acetaminophen (known as paracetamol in New Zealand) use in pregnant women and subsequent increased risk for asthma in their offspring. To better understand this link, Dr Sally Eyers of the Medical Research Institute of New Zealand and colleagues conducted a systematic review and meta-analysis of 6 studies reporting this association.

The researchers only included studies that evaluated the effect of acetaminophen use during pregnancy on offspring, with wheeze or asthma as a primary outcome. In their analysis, Eyers and associates included randomized control studies and observational studies that included a control group; if the study did not make the raw data available they excluded it. Age of offspring during the studies ranged from 30 months to 84 months. The study authors did not have access to specific information about dose or frequency of acetaminophen use.

An overall increased risk of current wheeze in the children whose mothers were exposed to any acetaminophen during any stage of pregnancy was found. Specifically, the authors noted a random effects odds ratio for risk of asthma in offspring following acetaminophen use in pregnancy of 21%, with the 95% confidence interval ranging from a 2% to a 44% increased risk.

The researchers did, however, find some variance among the individual studies as to the effects of acetaminophen during pregnancy. For instance, in a cross-sectional survey conducted in Spain, there was a significant association between asthma and prenatal exposure of acetaminophen for women without asthma but there was not a similar association for mothers with asthma. Meanwhile, according to data from a Danish national birth cohort study, there was no significant association between asthma and prenatal exposure to ibuprofen or aspirin. And while the association was found in most of the studies, a prospective study of 1505 women in the United States noted no increase in asthma risk. In fact, that study found a significant reduction of risk of asthma associated with acetaminophen use during the first and third trimesters.

“The effect of the timing of paracetamol [acetaminophen] use during pregnancy is relevant to the consideration of the potential mechanisms by which paracetamol may have an effect, if the association is causal,” explained Eyers and colleagues. “Glucuronidation, the main pathway for metabolism of paracetamol in adults, is markedly reduced in the foetus in the first trimester, whereas [glutathione-S-transferase], which detoxifies the oxidative paracetamol metabolites, is reduced in the third trimester. The balance between these two pathways could determine whether paracetamol exposure in the first or third trimester increased the predisposition to subsequent asthma, through the build-up of toxic oxidative metabolites.”

In a statement to the press, Dr Richard Beasley, professor of medicine at the Medical Research Institute of New Zealand and co-author of the study, emphasized that the results should not cause great alarm in pregnant women and their clinicians. “The message would be that this study raises some concern, and that it really reinforces the general principle to avoid unnecessary medication during pregnancy," he said. "This [report] does not change the recommendation."

Beasley added that acetaminophen would ''remain as the preferred analgesic'' to reduce fevers in pregnant women, and noted, "But we would caution against the regular use, particularly regular unnecessary use, during pregnancy.”
 

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Reference

Eyers S, Weatherall M, Jeffries S, Beasley R. Paracetamol in pregnancy and the risk of wheezing in offspring: a systematic review and meta-analysis. [http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2222.2010.03691.x/full] Clin Exp Allergy. 2011;41(4):482-489.