Background: The effect of prenatal antibiotic exposure on respiratory morbidity in infancy and the involved mechanisms are still poorly understood.

Objectives: We aimed to examine whether prenatal antibiotic exposure in third trimester is associated with nasal microbiome and respiratory morbidity in infancy and school-age, and whether this association with respiratory morbidity is mediated by the nasal microbiome.

Methods: We performed 16S rRNA gene sequencing on nasal swabs obtained from 296 healthy term infants from the prospective Basel-Bern birth cohort (BILD) at age 4-6 weeks. Information about antibiotic exposure was derived from birth records and a standardized interview. Respiratory symptoms were assessed by weekly phone interviews in the first year of life and a clinical visit at age 6 years. Structural equation modelling was used to test direct and indirect associations accounting for known risk factors.

Results: ?-diversity indices were lower in infants with antibiotic exposure compared to non-exposed infants (e.g. Shannon index p-value=0.006). Prenatal antibiotic exposure was also associated with a higher risk of any as well as severe respiratory symptoms in the first year of life (risk ratio (RR) 1.38, 95% confidence interval (CI) 1.03;1.84, padj-value=0.032 and RR 1.75, 95% CI 1.02;2.97, padj-value=0.041, respectively), but not with wheeze or atopy in childhood. However, we found no indirect mediating effect of the microbiome explaining these clinical symptoms.

Conclusion: Prenatal antibiotic exposure was associated with lower diversity of nasal microbiome in infancy and independently of microbiome with respiratory morbidity in infancy, but not with symptoms later in life.