ILLUSTRATIVE CASE
You are seeing a 2-month-old female infant for a routine well-child visit. The birth history was unremarkable. The infant is meeting appropriate developmental milestones. Growth is appropriate at the 40th percentile. The infant is exclusively breastfed. The parents report that they have heard confusing information about when to introduce solid foods, including bread, to their child’s diet. There is no known family history of CD. What anticipatory guidance can you offer regarding gluten introduction and the risk of CD?
CD is an inflammatory disease of the small intestine caused by an immune-based reaction to dietary gluten. The worldwide incidence of CD in children younger than 15 years is 21.3 per 100,000 person-years; this incidence has increased by 7.5% per year over the past several decades.2 CD has a range of both gastrointestinal and nongastrointestinal manifestations, including diarrhea, weight loss, abdominal pain, abnormal liver function test results, and iron deficiency anemia.
Diagnosis of CD in adults is based on a combination of clinical symptoms, elevated levels of immunoglobulin A anti-tissue transglutaminase antibody (tTG-IgA), and biopsy-confirmed villous atrophy of the duodenum on upper endoscopy.3 European pediatric guidelines suggest that use of certain criteria, including very high results of tTG-IgA antibody testing (> 10 times the upper limit of normal), can help to avoid endoscopic biopsies and/or human leukocyte antigens (HLA) testing for diagnosis in children.4
The mainstay of CD management is strict adherence to a gluten-free diet.3 Because this can be difficult, and yield an incomplete disease response, emphasis has been placed on primary prevention by modifying introduction of dietary gluten. Multiple prior studies examining the risk of CD have failed to demonstrate a significant association between timing of gluten introduction and development of CD among high-risk infants (eg, those with HLA-DR3 alleles or first-degree relatives with CD or type 1 diabetes).5-7 A 2016 meta-analysis concluded that there was not enough evidence to support early introduction of gluten (at 4-6 months).8 RCTs have not previously been conducted to examine the timing of gluten introduction on CD prevalence for infants at average risk, using age-appropriate doses of gluten prior to age 6 months.
Current dietary guidelines in the United States and the United Kingdom recommend introduction of nutrient-dense foods, including potentially allergenic foods, at about age 6 months to complement human milk or infant formula feedings.9,10 These guidelines do not specify the exact timing or quantity of gluten- containing food introduction for infants. A 2016 position paper by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition indicated that gluten could be introduced into the infant’s diet any time between 4 and 12 months. They did indicate that the amount of gluten introduced into the diet should be low to start and then increased, and that infants at high risk for CD should wait longer for gluten introduction (4 vs 6 months or 6 vs 12 months).11
STUDY SUMMARY
Gluten introduced at 4 months may be linked to lower occurrence of CD
The Enquiring About Tolerance (EAT) Study was an open-label RCT (N = 1303) with children from the general population in England and Wales. The EAT Study sought to test the prevention of food allergy by introducing allergenic foods to infants at age 4 months compared with exclusively breastfeeding until age 6 months. The median age at enrollment was 3.4 months, but allergenic food was not started until age 4 months.1,12 Most patients were White (84.%-85.4%) and lived in an urban area (77.3%-77.4%). The mean gestational age at delivery was 39.7 to 39.9 weeks.12
Infants were exclusively breastfed until age 13 weeks, at which time they were randomized into an early introduction group (EIG) or a standard introduction group (SIG). In addition to breast milk, infants in the EIG consumed 6 allergenic foods (peanut, sesame, hen’s egg, cow’s milk, cod fish, and wheat [gluten]) in a specified pattern per protocol, starting at age 4 months. Wheat (gluten) was introduced during Week 5 of the EIG protocol (median age, 20.6 weeks).12 The recommended minimum dose of gluten was 3.2 g/wk from age 16 weeks, or 4 g/wk of wheat protein (given as 2 cereal biscuits or the equivalent). Infants in the SIG avoided allergenic foods, following UK infant feeding recommendations for exclusive breastfeeding until about age 6 months. The EIG had a significantly higher rate of cesarean births than the SIG, but the study groups were otherwise balanced.13
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