Prenatal and postnatal exposure to antibiotics and risk of food allergy in the offspring: a nationwide birth cohort study in South Korea

Abstract

Background: There are only preliminary studies examining the associations of postnatal antibiotic exposure with food allergy in childhood, and the effect of antibiotic exposure in utero has not been resolved. Thus, we aimed to investigate the effect of prenatal and postnatal antibiotic exposure on the risk of food allergy in childhood. Methods: Using the nationwide birth cohort in South Korea, all 3,163,206 infants (pairing mother; n= 2,322,735) born in South Korea between 2010 and 2017 were included in the analysis. The primary outcome was the diagnosis of food allergy, and the observation period was between January 1, 2009, and December 31, 2020. We implemented four different designs for the study, which consisted of a full unmatched cohort, 1:1 propensity-matched cohort, sibling comparison cohort, and health screening cohort along with multiple subgroup analyses.Results: During the follow-up period (median 6.92 years [IQR, 4.72–9.00]) of the 3,161,858 infants (52.6% male) in the birth cohort, 29,973 (1.9%) were diagnosed with food allergies. After a 1:1 propensity score matching, the use of antibiotics increased the risk of overall food allergy (prenatal [HR, 1.05; 95% CI, 1.04–1.09] and postnatal [HR, 1.05; 95% CI, 1.01–1.10] periods). The association was more significantly accentuated when antibiotic exposure was used in the short term, and the children were born preterm or with low birthweight; however, a trimester-specific effect was not observed. We observed more pronounced risks of food allergy in the health screening cohort (prenatal, 17%; postnatal, 15%), thus addressing the adverse effects of critical factors including maternal BMI, smoking status, and type of infant feeding. Similar trends were observed across all four differnt cohorts. 2 of 12 | OH et al. 1 | INTRODUCTION Food allergy is a serious health concern across the globe, especially among children.1 Recent studies from the United States have reported that the prevalence of food allergy among children reached 7.6%2 and continued to grow rapidly due to urbanization and westernization.1 Food allergy can induce life-threatening anaphylaxis and cause significant morbidity and mortality.1 Several genetic and environmental factors have been reported to lead to a lack or loss of tolerance to specific foods3–5 thereby resulting in the development of food allergy. In murine models, the gut microbiome performs critical functions in the development of immune tolerance to food allergens.6 Further, it is well-established that the gut microbiome can be perturbed by numerous factors including antibiotic treatment.7 The administration of antibiotics during pregnancy and young infancy is become increasingly prevalent and antibiotics account for ~30% and ~80% of total prescribed medications dispensed to preschool children and pregnant women, respectively.8 At the same time, mounting evidence suggests that prenatal exposure to antibiotics may increase the risk of chronic diseases including asthma9–14 and atopic dermatitis.15 However, only one study has investigated the association between early antibiotic exposure and childhood food allergy at the population level.16 This previous study has several limitations: not taking the potential confounding factors (e.g., familial history of allergic diseases and maternal smoking status) into consideration and only examining postnatal exposure to antibiotics; therefore, excluding prenatal exposure to antibiotics. Detailing the relationship between maternal antibiotic use and the risk of food allergy in the offspring has clinical and scientific significance ascribed to the fact that maternal antibiotic use in pregnancy may make adverse modifications to the microbiome, resulting in the development of food allergy in offspring. Thus, we designed and executed four different cohorts within the same population, using International Classification of Diseases, 10th edition (ICD-10) codes, and predetermined criteria for both maternal antibiotics and food allergy in offspring to control for a great number of potential confounders using nationwide birth cohort study in South Korea. We aimed to understand the potential association of fetal and postnatal antibiotic exposure on the development of food allergies among children. 2 | METHODS 2.1 | Data source A large-scale population-based birth cohort of the National Health Insurance Service (NHIS) in South Korea was conducted in this study.17–19 We established a mother–child paired birth cohort among all infants born between January 1, 2010, and December 31, 2017. We used a unique insurance identification number shared within a family to construe the mother–child pairs.20 South Korea has a national health insurance that covers approximately 98% of all Korean citizens and the Korean government provides the first general health examination to all infants aged 6 months.20 The government anonymized all patient-related data to robust confidentiality. A previous study indicated that the overall positive predictive value for diagnostic records of the NHIS data was 82%.21 This study was approved by the Institutional Review Board of Kyung Hee University (KHSIRB-23-241(EA)). The requirement for informed consent was waived as this study used de-identified administrative data. 2.2 | Study design and participants: (1) full unmatched cohort; (2) Propensity score-matched cohort; (3) health-screening cohort; and (4) sibling cohort We set the “index date” as the birth date of each child. The followup ended on December 31, 2020, on the date of the first diagnosis of food allergy, or at the death of a child, whichever happened first. The observation period was between January 1, 2009, and December 31, 2020 (Figure S1). Among the mother–child pairs enrolled from 2009Conclusion: This study reported a moderate association between early-life antibiotic use and subsequent food allergy during childhood throughout four different designs of analyses. This study suggests that clinicians need to consider the risks and benefits of antibiotics when administering antibiotics to individuals in the prenatal and postnatal periods.</p