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Tome V, 2 vols. The results were unchanged from the original model for both unadjusted and adjusted models aOR 1.

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Multiple antibiotic prescriptions are more strongly associated with increases in the odds of FA diagnosis. Food allergy contributes significantly to healthcare utilization with an estimated average of , ambulatory visits per year to emergency departments or physician offices [ 3 ].

A threefold increase in overall hospitalizations related to food allergy has been reported from to through — [ 1 , 3 ]. Newborn children need exposure to immunogenic material to develop a healthy, functional immune system. Changes in the composition, richness, and abundance of microbiota that colonize the human gut during infancy has been theorized to play a role in development in atopic disease, including food allergen sensitization [ 4 ].

Commensal bacteria have been shown to protect against food allergen sensitization in mice [ 5 ]. Attempts to translate these findings to early infancy in one study revealed that infants with low gut microbiota richness and elevated proportion of Enterobacteriaceae relative to Bacteroides spp. In this study, we sought to explore the association between antibiotic prescription in the first year of life and the presence of any food allergy diagnosis code in young children.

We performed a matched case—control study using Medicaid billing data for children from birth to age 3 in were obtained from the South Carolina Office of Research and Statistics, a clearinghouse for administrative and vital records data in South Carolina SC. Controls were selected from among children from birth to age 3 who were enrolled in SC Medicaid in and never had a diagnosis of food allergy documented in Medicaid billing records since their birth.

Both cases and controls were limited to children who were enrolled in SC Medicaid for the entirety of their first year of life. The primary exposure of interest was systemic antibiotic prescription in the first year of life. Information about all antibiotic and epinephrine prescriptions in the first year of life was obtained, along with the timing of the purchase since birth, from pharmacy billing records submitted to Medicaid. Additional analyses categorized antibiotics by class using the American Hospital Formulary System classification.

Prior to estimating any regression models, antibiotic exposure for cases was limited to prescriptions that were filled prior to the first diagnosis of food allergy. Significant variables were then used to examine the association between any antibiotic prescription and case status using multivariable, conditional logistic regression models.

We performed several sensitivity analyses. We repeated unadjusted and adjusted conditional logistic regression models only when the FA diagnosis code was submitted by an allergy or immunology provider. Additionally, we developed a model where only cases with epinephrine prescription and corresponding matching controls were considered.

Finally, we considered a model that excluded diagnoses that were felt to have lower sensitivity or specificity, dermatitis, rhinitis, and urticaria. Hypothesis tests were 2-sided with a type I error of 0. Data utilized for this study was obtained via the South Carolina Revenue and Fiscal Affairs Office, and information on obtaining data is available through their website http: The Data Oversight Council reviews and approves applications for the release of health care data at the encounter level.

The authors are not permitted to share the raw data through a data use agreement. The final study sample included controls and cases with at least one food allergy related diagnosis code. Vaginal birth was the preferred delivery approach in the control group, and breastfeeding upon hospital discharge was more common in the case group. A total of antibiotic prescriptions were dispensed in cases and controls. The overall proportion of patients receiving antibiotics by class were as follows: These antibiotic classes represented nearly all antibiotics prescribed.

The mean number of antibiotic prescriptions received was 1. Significantly more controls did not receive any antibiotic course during the first year of life compared to cases with food allergy, We also modeled specific types of food allergy based on available diagnostic coding; however, only peanut allergy diagnosis aOR 2. Children receiving three aOR 1. Unadjusted conditional logistic regression analyses assessing the association between antibiotic exposure and food allergy diagnosis.

Two controls also received epinephrine prescription for unknown reasons. Unadjusted and adjusted conditional logistic regression analyses assessing the association between antibiotic drug classification and food allergy diagnosis.

The odds of antibiotic exposure were not significant when limiting the analysis to FA cases with diagnosis by allergy or immunology provider aOR 1. The results were unchanged from the original model for both unadjusted and adjusted models aOR 1. The odds of antibiotic exposure were significantly increased relative to the original model when only cases with epinephrine prescription were considered aOR 2. In our sample of children enrolled in the South Carolina Medicaid Program, we identified an association between antibiotic prescription and presence of food allergy diagnosis code in young children.

Children with diagnosis of food allergy received significantly more antibiotics than controls even though we censored further antibiotics after the initial FA diagnosis in the case group. Our approach could have reduced the observed association between antibiotics and food allergy, since controls had an unlimited number of antibiotic exposures up to the end of month 12, while for cases the potential for exposure continued only until the initial food allergy diagnosis.

However, we felt it was important to enforce this restriction since considering antibiotic prescriptions filled after the initial food allergy diagnosis as potential risk factors would have been nonsensical. In our study, increasing quantity of antibiotic prescriptions was associated with a higher incidence of food allergy. We theorize that this could affect the likelihood of food allergen sensitization in several ways. Multiple courses of antibiotics increase the likelihood that children are on an antibiotic while introducing a new food.

Secondly, there are more opportunities for microbiota dysbiosis with more frequent antibiotic administration. Commensal gut flora serves an important role in both immune system development and immune tolerance. Studies with germ free animals show impaired humoral and cell mediated immune function [ 7 , 8 ]. Also, the interaction with normal gut flora is important in the development of regulatory T-cells and IgA antibody, both of which are important in developing tolerance to foreign proteins such as food [ 9 , 10 ].

Emerging evidence suggests that alterations in commensal flora due to early antimicrobial use may increase the risk of obesity, inflammatory bowel disease, and allergic diseases [ 11 — 18 ]. Recent articles suggest that even antimicrobial food additives or antimicrobials in health care products may be associated with increased allergic disease [ 19 , 20 ].

Conflicting findings are available for the few studies which have examined the association between antibiotic exposure and diagnosis of food allergy. Another study was designed to look at several allergic diseases and was not powered to identify food allergy specifically.

Of the children studied, had food allergy at age 4, and had food allergy at age 8. While antibiotic use was associated with food allergy, the association was not significant in adjusted models [ 24 ]. Most of these prescriptions are for otitis media, although most cases are caused by viral infection. Additionally, some studies have suggested high rates of antimicrobial prescribing for viral infections such as bronchitis and upper respiratory infection.

Data suggests that this pattern continues despite educational efforts and increasing reports of bacterial resistance [ 29 — 31 ]. Antibiotics are not devoid of adverse effects: Nausea, vomiting, diarrhea, and rash are common and well known short-term side effects reported in children receiving antimicrobial agents. Antibiotics are known to affect the GI flora, with the potential to cause antibiotic—induced diarrhea or Clostridium difficile associated disease [ 32 — 35 ].

Antibiotics with broader spectrum of activity are more likely to have an impact on commensal flora than narrower spectrum agents. We are just beginning to understand the potential long-term effects of microbiotia dysbiosis due to antibiotic exposure. Strengths of our study include matching on demographic variables including month and year of birth, multivariate analysis that controlled for variables previously associated with food allergen sensitization in other studies, and a large sample of FA children; however, our study has several limitations.

First, we defined food allergy using ICD-9 codes; thus, we cannot determine whether patients had food allergy versus food intolerance. The only definitive diagnostic test for food allergy is a double-blind, placebo-controlled challenge [ 36 ], but this is not frequently done in clinical practice. Additionally, there is not one single diagnostic code for food allergy, but rather several codes exist which define the allergen or clinical presentation of allergy. In clinical practice, inconsistent or varied use of diagnosis codes between providers could lead to under or over reporting of true food allergy.

On the other hand, we chose FA diagnosis codes for our study based upon prior retrospective analyses of administrative records, and we conducted sensitivity analyses comparing diagnosis by provider type, receipt of epinephrine, and exclusion of diagnoses to examine this. Second, children at risk for food allergy often have other associated allergic diseases; therefore, such children may receive more antibiotics simply because of these illnesses.

Atopic dermatitis predisposes to recurrent skin infections such as impetigo and Staphylococcal abscesses, and asthma exacerbations or wheezing episodes are often treated with antibiotics.

We controlled for asthma, wheezing and atopic dermatitis in all logistic regression models to account for this. Finally, our study population consisted of patients receiving Medicaid benefits, thus our study may be more representative of a lower socioeconomic group than the general population.

Lower socioeconomic status has been associated with higher rates of asthma and allergic rhinitis [ 37 ], but recent data cite higher rates of peanut sensitization among higher socioeconomic families [ 38 — 40 ].

Additional investigation in a more socioeconomically diverse population would also be beneficial. In summary, we identified an association between antibiotic prescription and presence of food allergy diagnosis code in young children. Our results require cautious interpretation due to the limitations as discussed; however, our findings offer a plausible hypothesis for increasing food allergy prevalence since increased antibiotic use is common in many westernized countries.

Further research is needed to examine this association in larger, more diverse patient populations with confirmed food allergy. Conception and design of the study: Analysis and interpretation of the data: Preparation or critical revision of the manuscript: All authors read and approved the final manuscript. Antibiotic exposure and the risk of food allergy in young children.