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 16,933 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.
Unit of Epidemiology, 'Anna Meyer' Children's University Hospital, Florence, Italy. f.rusconi@meyer.it
Franca
F
Rusconi
Luigi
L
Gagliardi
Claudia
C
Galassi
Francesco
F
Forastiere
Luigia
L
Brunetti
Stefania
S
La Grutta
Silvano
S
Piffer
Fiorella
F
Talassi
D000082:Acetaminophen / Q000009:adverse effects* / Q000627:therapeutic use; D000293:Adolescent; D017677:Age Distribution; D017668:Age of Onset; D000900:Anti-Bacterial Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001249:Asthma / Q000453:epidemiology* / Q000209:etiology*; D002648:Child; D003430:Cross-Sectional Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D007558:Italy / Q000453:epidemiology; D016015:Logistic Models; D008297:Male; D016017:Odds Ratio; D012135:Respiratory Sounds / Q000209:etiology*; D018570:Risk Assessment; D017678:Sex Distribution; D011795:Surveys and Questionnaires
D000900:Anti-Bacterial Agents; D000082:Acetaminophen