Paracetamol and antibiotics in childhood and subsequent development of wheezing/asthma: association or causation?

Background Several studies found an association between early administration of paracetamol and antibiotics and development of wheezing. This could be due to confounding: wheeze and asthmatic symptoms in early childhood are difficult to distinguish from respiratory tract infections that are widely treated with these drugs; in case of persistence of symptoms up to school age, this could explain the observed relationship. Methods We investigated the association between paracetamol and antibiotics use in the first year of life and wheezing phenotypes, i.e. wheezing starting in different time periods (early, persistent and late-onset) in the SIDRIA-2 study, a cross-sectional survey of 16933 children aged 6-7 years. Directed acyclic graph (DAG) was used to depict the causal structure. Results Paracetamol and antibiotics administration in the first year were associated with early wheezing (first 2 years of life only) [odds ratio (OR): 2.27; 95% confidence interval (95% CI): 1.98-2.62 and OR = 3.76, 95% CI: 3.31-4.27] and with persistent wheezing (first 2 years + last 12 months) ( OR = 1.77, 95% CI: 1.49-2.10 and OR=3.06, 95% CI: 2.60-3.60), whereas the association with late-onset wheezing (in the last 12 months only) was weak (OR= 1.12, 95% CI: 0.97-1.31 and OR=1.18, 95% CI: 1.02-1.38 for paracetamol and antibiotics, respectively). DAG shows that even in the absence of a direct (causal) arrow from early drugs use to wheezing at school age, the two are associated due to confounding (through the 'infection' node). Conclusions It is important to take into account different phenotypes in order to disentangle the association of paracetamol and antibiotics with wheezing.