Potential therapeutic implications
Previously, associations between disrupted gut flora and atopic dermatitis have been identified
[11, 12, 35–37]. Furthermore, physiologic evidence links atopic dermatitis with food allergies
. Therefore, we wished to determine if an association exists between factors that disrupt perinatal gut flora acquisition and subsequent food allergy diagnosis.
We hypothesized that specific factors known to cause gastrointestinal dysbiosis in newborns -- namely perinatal antibiotic exposure, cesarean section delivery, and NICU admission -- are associated with subsequent food hyper-responsiveness. However, we did not find such correlations to be present in children with confirmed evidence of IgE-mediated food allergies.
In our cohort, we did find, however, that increasing maternal age at delivery is associated with food allergy diagnosis in children. A similar relationship was recently reported by Metsala and colleagues
. Although the biologic mechanisms responsible for this association are unclear, it is possible that disrupted maternal normal flora may be involved. It is known that changes in normal flora occur across the lifespan from medications or changes in gastrointestinal tract function. Specifically, with advancing age, levels of gut bifidobacteria and lactobacilli decrease, whereas clostridia and yeast increase
. These same changes in gut flora have been previously noted in children with atopy
. Thus, while it has not yet been studied, there may be a critical time point during adult life in which mothers may begin to develop disruptions in gut flora, which may then be transferred to children during the delivery process.
We also observed that the number of allergic males in our cohort significantly exceeded the number of allergic females. We are not alone in identifying these gender disparities in atopic sensitization of children. Males have previously been found to have food allergies and other atopic diseases with a higher prevalence than females during childhood and early adolescence
[41–46]. Certainly, there may be genetic causes underlying this predisposition, but environmental factors may also play a role. It has been suggested that gender differences in atopic development may reflect a tendency for mothers to breastfeed male infants for a shorter period of time due to the misconception that male infants require a greater level of nutrition than can be provided by breast milk alone
[47–50]. Breastfeeding has been reported to provide protection against atopic dermatitis and/or food allergies
[51–54]. In addition to nutritive and immunological benefits, breast milk is also known to stimulate growth of bifidobacterial populations. Thus, it is conceivable that breastfeeding duration may play a role in gut flora acquisition and subsequent atopic development. In support of this theory, there is evidence that male infants are indeed more likely than female infants to experience benefits of early probiotic interventions
In our study, we found that maternal breastfeeding intent at time of delivery was associated with increased risk of food allergies. Given the retrospective nature of our data collection and since we did not contact mothers directly, we do not know the extent to which maternal intent to breastfeed at time of delivery translated into initiation/duration of breastfeeding. With 79% of mothers in our cohort indicating initial intent to breastfeed, the observed correlation between breastfeeding and food allergies in our data may be attributed to reverse causation, as has been reported previously, since breastfeeding intent and exclusive breastfeeding after hospital discharge may differ considerably
[56–59]. Given the limitations imposed by retrospective data collection regarding breast-feeding decision and duration, we cannot draw definitive conclusions about its role in food-allergy development in our cohort.
Although we did not find an association between food allergies and type of delivery, maternal intrapartum receipt of antibiotics, or NICU placement, these relationships warrant further study. Technical limitations were imposed by our dependence upon the ICD-9-CM coding system to identify children with food allergies, as this system is an imperfect surrogate for allergy diagnosis. As a result, we were not able to identify the number of food allergic children that we had initially set out to include in our dataset. When initially established, ICD-9-CM codes were created for insurance reimbursement purposes, not for research purposes. Furthermore, there may be tendencies, on the part of clinicians, to assign specific ICD-9-CM codes to a particular group of signs and symptoms based on reimbursement levels. This may explain why we initially identified 235 children with food allergy-diagnosis-codes born at our institution, but whose diagnosis was only substantiated (by IgE or SPT) in 85 of them. Indeed, we observed that food allergy specific ICD-9-CM codes were used for parent-reported food intolerances, as well as allergies to non-food items (e.g., latex allergy). Recently, Clark et al. also observed that exclusive reliance upon food-allergy-specific ICD-9-CM codes to identify patients with food allergies, would have led to a ~50% discrepancy from the true number of patients with food hypersensitivities
However, a particular strength of our data set is the rigor with which we identified children as “cases” only if an IgE-mediated food allergic reaction had been confirmed
[61, 62]. By focusing exclusively on children with IgE-mediated food allergies, we may have failed to identify children with food allergic manifestations that are mediated by non-IgE mechanisms
[63, 64]. Rather than relying upon retrospective review of medical and billing records, future investigations into the role of perinatal and immunological factors impacting food allergies should be initiated prospectively at birth.