Timing of gluten introduction in high-risk infants does not appear to influence the risk of celiac disease at age 3-5 years

EBM Focus - Volume 9, Issue 40

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Reference: N Engl J Med 2014 Oct 2;371(14):1304, N Engl J Med 2014 Oct 2;371(14):1295 (level 2 [mid-level] evidence)

Celiac disease affects approximately 1% of people in western populations, but the prevalence increases to as high as 20% in first-degree relatives of patients with celiac disease (Gastroenterology 2005 Apr;128(4 Suppl 1):S57), suggesting a genetic association. It has been observed that 95% of patients with celiac disease express the HLA-DQ2 genotype and almost all remaining patients express HLA-DQ8 (Curr Allergy Asthma Rep 2013 Aug;13(4):347), but 30-40% of the general population also express HLA-DQ2, indicating the risk is a combination of genetic and environmental factors. Previous observational studies have suggested that age of introduction to gluten-containing foods and breastfeeding may influence the development of celiac disease in high-risk populations (Aliment Pharmacol Ther 2012Oct;36(7):607). Specifically, these studies suggest that introduction of gluten between ages 4-7 months might reduce the risk of celiac disease. Two recent randomized trials sought to further investigate the effect of timed introduction of dietary gluten (pasta, semolina, and biscuits) for infants at high risk for celiac disease.

The PreventCD trial (N Engl J Med 2014 Oct 2;371(14):1304) randomized 944 infants with at least 1 first-degree relative with celiac disease to 100 mg immunologically active gluten vs. placebo daily from age 16 weeks to 24 weeks. All infants included in this trial were also positive for HLA-DQ2, HLA-DQ8, or HLA-DQB1*02 heterodimer. At age 3 years, there were no significant differences comparing gluten vs. placebo in development of overt celiac disease (5.9% vs. 4.5%) and breastfeeding did not influence the development of celiac disease.

Similarly, the CELIPREV trial (N Engl J Med 2014 Oct 2;371(14):1295) randomized 823 infants with at least one first-degree relative with celiac disease to introduction of dietary gluten at age 6 months vs. age 12 months. Only 553 children who completed at least 3 years of follow-up and were found to be positive for HLA-DQ2 or HLA-DQ8 were included in the analysis. Overt celiac disease was significantly greater at age 2 years in children randomized to introduction of gluten at 6 months vs. 12 months (12% vs. 5%, p = 0.01 NNH 14). However by age 5 years, there was no significant difference between groups in diagnosis of overt celiac disease (16% in each). This trial also found no association between breastfeeding and the development of celiac disease.

The results from these trials suggest that the introduction of dietary gluten at a specific time during infancy does not significantly influence the development of celiac disease. These are the first large randomized trials specifically evaluating the association of timing of gluten introduction and risk of celiac disease. Based on these new findings, specific timeframes for introducing gluten for the prevention of celiac disease in high risk infants do not appear warranted.

For more information, see the Celiac disease topic in DynaMed.