Associations of Prenatal Exposure to Antibiotics and Paracetamol with Trajectories of Wheezing up to 2 Years of Age

Background: Several studies have reported an increased risk of wheezing in children of mothers who used antibiotics or paracetamol during pregnancy. These studies, however, did not address the complex patterns of medication use throughout pregnancy and trajectories of wheezing in childhood.

Objectives: To determine whether prenatal exposure to antibiotics and paracetamol is associated with trajectories of wheezing up to 2 years of age, taking into account timing of exposure.

Methods: We included 5,864 pregnancies with a delivery in 2012-2019 enrolled in the PRIDE Study, a prospective cohort study among pregnant women and their offspring in The Netherlands. Data were collected through web-based questionnaires and pharmacy records. We used k-means clustering to identify pregnancies with similar patterns of cumulative exposure to antibiotics and paracetamol in the first 34 weeks of gestation, whereas group-based trajectory modelling was used to identify children with similar patterns of wheezing. We estimated risk ratios (RRs) with 95% confidence intervals (CI) for the association between trajectory groups and wheezing, adjusted for a sufficient set of confounders and weighted using inverse probability of censoring weights.

Results: For paracetamol, 3 clusters best described exposure: low dose (median cumulative dose 1,500 mg), moderate dose (27,750 mg), and high dose (87,750 mg). We did not identify trajectories that described antibiotic use fulfilling the selection criteria. Five distinct trajectories of wheezing in the first 2 years of life were identified. Compared with the unexposed group, none of the paracetamol trajectories were associated with wheezing (low dose: RR 0.9, 95% CI 0.7-1.2; moderate dose: RR 0.9, 95% CI 0.5-1.3; high dose: RR 0.6, 95% CI 0.2-2.2). Any use of antibiotics was associated with wheezing in the first two months (RR 1.3, 95% CI 1.0-1.6), whereas third trimester antibiotic use was associated with any wheezing (RR 1.3, 95% CI 1.0-1.6).

Conclusions: We found no evidence that paracetamol exposure in gestational weeks 0-34 is associated with wheezing. Prenatal antibiotic use is associated with wheezing in the first 2 months of life, but this association diminishes for wheezing at later ages.