This nationwide retrospective cohort study identified a significant association between neonatal exposure to systemic antibiotics and approximately a threefold increase in the prevalence of childhood food allergies (OR = 2.89, 95% CI = 1.34–6.92, P = 0.01). These findings were consistent across univariate analysis, multivariate logistic regression, and sensitivity analyses using a Bayesian approach, with adjustments for inflammatory markers at admission, maternal atopy, and family socioeconomic status. The majority of the impact occurs within the first 2 years of life. This aligns with the proposed mechanism involving gut microbiota and immune system development, supporting the idea that neonatal antibiotic exposure primarily influences early-onset FAs.

There is growing evidence of the association between early-life antibiotic exposure and food allergy in the literature, yet, the potential confounding effect of infection (for which the antibiotics was prescribed) had not fully been accounted for [26]. A large-scale study on Medicaid patients found a strong association between antibiotic prescriptions during the first year of life and food allergy [27], while a nationwide South Korean study reported a 5% increased risk of food allergy associated with antibiotic use during the first six months of life [18]. Notably, most studies have focused on antibiotic prescriptions during infancy (up to six months of age) rather than the neonatal period, often facing limitations such as small sample sizes and insufficient adjustment for genetic factors, including maternal food allergies or asthma [28, 29].

Several factors may modify the relationship between neonatal antibiotic exposure and food allergies. The mode of delivery, for instance, can independently influence the composition of the neonatal microbiome, potentially interacting with the effects of antibiotics [13]. A plausible mechanism underlying this association is the disruption of the neonatal gut microbiome [30, 31]. Early life, particularly the neonatal period, is critical for the establishment of a healthy microbiome, which plays a central role in immune system maturation [13, 32]. Systemic antibiotic use during this time can disturb the gut microbiota, reducing microbial diversity and altering the balance of beneficial bacteria [13]. It is caused by several mechanisms including reduction of microbial diversity, altering gut composition, and impairing the production of essential metabolites [33]. This disruption can impair regulatory T-cell function, increase gut permeability, and lead to immune dysregulation, raising the risk of allergies and autoimmune diseases [33]. This dysbiosis may hinder the development of oral tolerance to dietary antigens, potentially increasing the risk of food allergies. Genetic predisposition, including maternal food allergies or asthma, may also play a significant role [34]. Additionally, disentangling the effects of the antibiotics themselves from those of the underlying infections for which they were prescribed remains challenging. Socioeconomic status was also found to be associated with the likelihood of food allergies, with lower socioeconomic status linked to a higher risk of developing food allergies [35]. This relationship was evident in the results of this study, prompting an adjustment for this variable in the analysis.

The rate of food allergy in this cohort was approximately 2%, which is much lower than the reported prevalence of childhood food allergies in North America and Europe, which was estimated as 8–10% [1]. However, the food allergy prevalence detected in our study is very similar to the prevalence previously reported in Israel [36]. The lower prevalence of food allergy in Israel compared to North America is likely related to the earlier introduction of allergenic foods [37] but may be related to other environmental factors. Nevertheless, the detected food allergy prevalence in our cohort suggests that the cohort is representative of the general population [38].

This is a large study, including the majority of hospitalized infants, leveraging the comprehensive and universal EHRs used in the CHS. To minimize confounding factors, we selected a control group of neonates admitted with fever, assuming an infectious etiology even when not explicitly identified. This approach helped mitigate the potential influence of the underlying infection. Additionally, we accounted for baseline differences in immune activation by adjusting for inflammatory markers. Notably, the antibiotic-treated group exhibited higher CRP levels compared to the untreated group; a clinically reasonable finding that likely explains the decision to administer antibiotics at the time of admission. By addressing these complexities, our study provides a more refined understanding of the relationship between neonatal antibiotic exposure and the subsequent risk of developing food allergies.

A key strength of this study is the ability to link maternal records, allowing for the identification of diagnoses indicative of genetic atopic predisposition. Furthermore, unlike many previous studies that relied on antibiotic prescriptions, which do not always reflect actual usage, this study focused exclusively on hospitalized patients, enhancing the accuracy of antibiotic exposure assessment. By recruiting a control group of hospitalized neonates with fever, the study also effectively adjusted for factors such as early-life infections and their severity, as both groups shared similar clinical contexts of hospitalization.

However, this study has several limitations. A major limitation of this study is its cross-sectional design, which prevents the establishment of causality and only allows for the identification of associations. Its retrospective design relies on ICD- 9 codes, which may underreport the true incidence of diagnoses. Although this method of identifying FAs has been used in large database studies [39, 40], relying on ICD- 9 codes may result in misclassifying true IgE-mediated food allergies. Furthermore, diagnoses made by private physicians may not be recorded in real-time or may be missing from the electronic medical system altogether. This issue is more pronounced for conditions like allergic rhinitis, mild atopic dermatitis, and asthma in patients who do not receive preventive treatment, which may be documented less consistently by physicians due to less pronounced clinical symptoms. In contrast, the clinical significance of food allergies likely ensures more consistent documentation, reducing the extent of underreporting for this specific condition. Furthermore, atopic dermatitis may be both a potential outcome of antibiotic use and a contributing factor to the development of food allergies. This complex interplay makes it challenging to distinguish between cause and effect [41]. Additionally, due to the nature of big-data studies, detailed information on individual patient skin prick tests, food challenges, or dietary and environmental exposures was unavailable.This study provides strong evidence of an association between neonatal antibiotic exposure and an increased risk of childhood food allergies, with a threefold higher prevalence in those exposed to systemic antibiotics. The findings highlight the importance of judicious antibiotic use in neonates and emphasize the need for further prospective research into the mechanisms underlying the association between antibiotic use in the neonatal period and food allergies in childhood, as well as strategies for preventing gut microbiome disruption following such exposure.