In-utero antibiotic exposure and subsequent infections in infancy: a register-based cohort study with sibling analysis

Abstract

Background: Prenatal antibiotic use, the ensuing maternal dysbiosis, and subsequent acquisition of altered microbiota in early life have been linked to the offspring's increased susceptibility to childhood infections. However, infection risks during the first year of life associated with in-utero antibiotic exposure have not been comprehensively explored.

Objective: To investigate the associations between exposure to antibiotics in utero and subsequent infections during infancy and whether such associations differ by antibiotic class.

Study design: All data were retrieved from Swedish population-based registers. Singletons live-born between 2006 and 2018 were followed up from birth to their first birthday. Exposure was maternal filling of at least 1 antibiotic prescription between the last menstrual period and delivery. Outcomes were the infants' antimicrobial prescription fills, incident 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, comorbidity indicator, body mass index, proxies for general health status, education level, and smoking status were considered covariates. Poisson regression was used to estimate crude and adjusted incidence rate ratios with 95% confidence intervals for the number of antimicrobial prescriptions filled to the infant. Cox regression was used to estimate crude and adjusted hazard ratios with 95% confidence intervals for incident infections diagnosed in specialist care and at death. Sibling analyses were used to account for shared familial factors. Sensitivity of the results to exposure definition and perinatal factors prognostic for the outcomes were assessed in supplementary analyses.

Results: Of 1,347,018 infants in the full cohort, 294,657 (21.9%) were exposed to antibiotics in utero. There were 677,430 antimicrobial prescriptions filled (1.380 per 1000 person-days), 423,705 incident infections diagnosed in specialist care (0.870 per 1000 person-days), and 2800 infection-related deaths (0.006 deaths per 1000 person-days) during follow-up. Compared to unexposed, infants exposed to antibiotics in utero had higher rates of antimicrobial prescription fills (adjusted incidence rate ratio, 1.34; 95% confidence interval, 1.33-1.34), incident infections diagnosed in specialist care (adjusted hazard ratio, 1.28; 95% confidence interval, 1.27-1.29), and infection-related mortality (adjusted hazard ratio, 1.15; 95% confidence interval, 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: adjusted incidence rate ratio of 1.05 (95% confidence interval, 1.04-1.06) and adjusted hazard ratio of 1.05 (95% confidence interval, 1.03-1.07), respectively. No association with infant mortality was found in the sibling cohort (adjusted hazard ratio, 0.93; 95% confidence interval, 0.81-1.08).

Conclusion: The minor associations between exposure to antibiotics in utero and infections during infancy were partly explained by shared familial factors and did not differ across frequently used antibiotic classes.

Keywords: Antibiotics; Cohort study; Deaths; Infant; Infections; Pharmacoepidemiology; Population-based registers; Pregnancy; Siblings.