Prenatal Antibiotic Exposure and Subsequent Infections in Infancy: A Register-based Cohort Study in Sweden with Sibling Analysis

Background: Prenatal antibiotic use, the ensuing maternal dysbiosis and subsequent acquisition of altered microbiota in early life have been linked to the offsprings' increased susceptibility to childhood infections. However, infection risk during the first year of life associated with antibiotics used prenatally, has not been comprehensively explored.

Objectives: To investigate the associations between exposure to antibiotics in-utero anAll data were retrieved from Swedish population-based registers. Singletons live-born between 2006 and 2018 were followed from birth until their first birthday. Exposure was maternal filling of at least one antibiotic prescription between the last menstrual period and delivery. Outcomes were the infants' filled antimicrobial prescriptions, infections diagnosed in specialist care and deaths with infections indicated as underlying or contributing causes ("infection-related deaths"). Birth year, birth season, maternal age, place of residence, parity, co-morbidities, body mass index, general health status, education level and smoking were considered as covariates. Poisson regression was used to estimate adjusted incidence rate ratios (aIRRs) with 95% confidence intervals (95% CIs) for the number of antimicrobial prescriptions filled for the infant. Cox regression was used to estimate adjusted hazard ratios (aHRs) with 95% CIs for infections diagnosed in specialist care and at death. Sibling analyses accounted for shared familial factors. Exposure misclassification and perinatal factors prognostic for the outcomes were explored in supplementary analyses.

Results: Of 1,347,018 infants in the full cohort, 294,657 (21.9%) were prenatally exposed to antibiotics. There were 677,430 antimicrobial prescriptions filled (1.38 per 1000 person-days), 423,705 incident infections diagnosed in specialist care (0.87 per 1000 person-days) and 2,800 infection-related deaths during follow-up (0.006 deaths per 1000 person-days) during follow-up. Compared to unexposed, exposed infants had higher rates of antimicrobial prescription fills (aIRR 1.34; 95% CI 1.33—1.34); incident infections diagnosed in specialist care (aHR 1.28; 95% CI 1.27—1.29); and infection-related mortality (aHR 1.15; 95% CI 1.05—1.25). For antimicrobial prescriptions and infections diagnosed in specialist care, associations were consistent across most antibiotic classes but were attenuated in the sibling analyses: aIRR 1.05 (95% CI 1.04—1.06) and aHR 1.05 (95% CI 1.03-1.07), respectively. No associations with infant mortality were found in the sibling cohort (aHR 0.93; 95% CI 0.81—1.08).

Conclusions: The minor associations between prenatal antibiotic exposure and infections during infancy were largely explained by shared familial factors and did not differ across frequently used antibiotic classes.