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Is folic acid exposure a risk factor for food allergy?

Published online: June 25, 2019

Food allergies have been on the rise over the past several decades and various hypotheses for this increase have been proposed. It has been suggested that folate exposure may be a risk factor for the development of allergic disease because folate is involved in many biologic processes, but studies so far have produced inconsistent results. Folic acid is the stable, synthetic form of naturally occurring folate, and this is the form that is added to fortified grains, infant formula, supplements, and prenatal vitamins. The metabolism of synthetic folic acid is different from that of naturally occurring folate, and this process leads to the production of a by-product called unmetabolized folic acid (UMFA) at levels of consumption exceeding ~250 ug/day. To put this in context, a typical prenatal multi-vitamin tablet contains 800 ug of folic acid. In contrast, the principle form of folate that is involved in DNA methylation is 5-methyltetrahydrofolate (5-MTHF). No studies to date have examined the association between these specific folate forms (UMFA and 5-MTHF) and the development of allergic disease.  

In a recent article published in The Journal of Allergy and Clinical Immunology: In-Practice, McGowan et al examined the prospective association between plasma total folate, UMFA, and 5-MTHF, and the development of food allergy and food sensitization in children. This study was conducted in the Boston Birth Cohort (BBC), a predominantly urban, low-income, minority birth cohort that was designed to study pregnancy and child health outcomes. Starting in 2004, children who enrolled in the BBC at birth and continued to receive primary care at Boston Medical Center had information collected regarding their demographics, medical histories, symptoms of food allergy, dietary intake, and lifestyle through standardized questionnaires at follow-up visits in alignment with pediatric primary care visits. A blood sample was also collected at the time of birth and later in life, and a subset of children had measurements for food specific IgE (sIgE) to cow’s milk, egg white, peanut, soy, shrimp, walnut, wheat, and cod.  

For this study, children were included if they had samples available for folate measurements, had prior measurements of food specific IgE, and had completed questionnaires at follow-up visits assessing food allergy clinical symptoms. Children were classified as food allergic if they had evidence of clinical symptoms with food ingestion, food-specific sensitization (IgE > 0.35 kU/L) to the food, and dietary avoidance of the foods to which they were sensitized. Total folate, UMFA, and 5-MTHF were then measured in stored plasma samples collected at birth and in early childhood.

Of a total of 1,394 children included in this study, 507 children were found to have food sensitization (sIgE > 0.35 kU/L), and 78 children met the strict criteria for food allergy.  While total folate concentrations at birth were lower among those who developed food allergy (30.2 vs. 35.3 nmol/L; p=0.02), UMFA concentrations were higher (1.7 vs. 1.3 nmol/L, p=0.001). Higher concentrations of UMFA in cord blood were associated more strongly with the development of food allergy, and children with the highest cord blood UMFA concentrations had an 8.5-fold higher risk (95% CI 1.7-42.8).  Interestingly, there was no association between these folate forms in early childhood and the development of either food sensitization or food allergy. This is the first study to show that UMFA concentrations may be associated with the development of food allergy. The study authors discussed limitations of this work in the report and underscored the need of additional investigations to confirm the study findings.   

The Journal of Allergy and Clinical Immunology: In Practice is an official journal of the AAAAI, focusing on practical information for the practicing clinician.

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