There was no benefit to early introduction of dietary gluten in infants who were at high risk for celiac disease, in terms of reducing their chances of having the disease by age 3, researchers said.
In an international cohort of nearly 1,000 children who received small quantities of gluten at ages 16 to 24 weeks, the incidence of celiac disease at 3 years was 5.9% (95% CI 3.7%-8.1%) versus 4.5% (95% CI 2.5%-6.5%) among those who received placebo, according to Maria Luisa Mearin, MD, PhD, from Leiden University Medical Center in the Netherlands, and colleagues.
Among girls, in fact, the intervention appeared to increase the risk of celiac disease, with a doubled incidence by age 3 compared with girls assigned to placebo.
In addition, breast feeding did not significantly influence the development of celiac disease, regardless of whether it was done exclusively or was ongoing during gluten introduction, they wrote in the New England Journal of Medicine.
Their findings cast some doubt on current guidance that calls for the early addition of gluten to a child’s diet, including the American Academy of Pediatrics’ recommendation that infants start consuming gluten while still breast-feeding.
“The present European guidelines recommend the introduction of small amounts of gluten gradually while the child is breast-fed and the avoidance of both the early (<4 months) or late (>7 months) introduction of gluten,” Mearin’s group wrote. “Our results do not provide evidence to support these guidelines or any specific feeding recommendation with respect to the timing of gluten introduction for infants at risk for celiac disease.”
The prospective, randomized study was part of the European Prevent Coeliac Disease project to investigate primary prevention of the disease. Infants up to 3 months old were recruited in eight countries, and enrolled from 2007 to September 2013, when the youngest participant turned 3 and the oldest participant was 6.
Infants were required to have the HLA-DQ2, HLA-DQ8, or HLA-DQB1*02 heterodimer, which are all common haplotypes in celiac disease. They also had to have at least one first-degree family member with biopsy-confirmed celiac disease.
Participants were randomly assigned to receive 200 mg of vital wheat gluten mixed with 1.8 g of lactose or 2 g of lactose as placebo. The gluten mixture or placebo were given daily for 8 weeks, starting at 16 weeks of age. Successful adherence meant that at least 75% of the gluten mixture or placebo was consumed and no additional gluten was ingested.
The study’s primary outcome was the frequency of celiac disease at age 3.
A total of 983 children were randomly assigned to either arm, and ultimately 944 children completed the study. Families left the study because of a lack of adherence, or withdrew for practical reasons (travel distance) or adverse events.
Data on breast-feeding were available for 943 children; 55.9% were breast fed at 6 months of age.
A total of 101 small-bowel biopsies were done in 94 children and celiac disease was confirmed in 77. Three patients whose parents declined biopsies received a positive diagnosis based on 2012 ESPGHAN diagnostic criteria. The median age at diagnosis was 2.8, and 59% were girls. All children had an elevated level of anti–transglutaminase type 2 antibodies (TG2A), a hallmark of celiac disease.
The hazard ratio for the development of celiac disease in the gluten group was 1.23 (95% CI 0.79-1.91), the authors reported, although they cautioned that the confidence interval for this risk meant that that they were “not able to rule out a protective effect smaller than 21% or a harmful effect as large as 91%.”
Breast feeding had no impact on celiac disease development. At age 3, the cumulative incidence among children who were never exclusively breast fed was 5%, virtually identical to rates in other participants. The duration of exclusive breast feeding (less than 3 months and more than 6 months) also led to nonsignificant incidence rates (P=0.45).
The authors also found that the disease developed “more frequently and earlier” in the group who were homozygous for HLA-DQ2, with a cumulative incidence of 14.9% at age 3 (P<0.001 versus other genotypes).
They noted that celiac disease was significantly more frequent in girls at age 3 for a cumulative incidence of 7.2% versus 3.4% in boys. Cumulative incidence of the disease was higher among girls randomized to gluten at 8.9% versus 5.5% in the placebo group (HR 1.99, 95% CI 1.09-3.65, P=0.02).
They pointed out that this finding may be due to chance or to the larger number of girls with HLA-DQ2 homozygosity who were randomly assigned to the gluten group. However, previous research has shown that celiac disease is more common among women, they said.
Finally, the rates of elevated levels of TG2A and antigliadin antibodies were similar in the two study arms: 7% (95% CI 4.7%-9.4%) for the gluten group and 5.7% (95% CI 3.5%-2.9%) in the placebo group (HR 1.14, 95% CI 0.76-1.73).
Mearin and colleagues noted that a great deal of the information on infant feeding and celiac disease came from studies done during the 1980s Swedish celiac disease epidemic.
But data from those studies on the timing of gluten introduction in relation to breast feeding and the amount of gluten were obtained retrospectively, and the research was done in a single country.
“Our results are derived from a study population comprising children from high-risk families in seven European countries and Israel,” they said.
The study was supported by the European Commission, the Azrieli Foundation, Deutsche Zöliakie Gesellschaft, Eurospital, Fondazione Celiachia, Fria Bröd, Instituto de Salud Carlos III, Spanish Society for Pediatric Gastroenterology, Hepatology, and Nutrition, Komitet Badań Naukowych, Fundacja Nutricia, Hungarian Scientific Research Funds, Stichting Coeliakie Onderzoek Nederland, Thermo Fisher Scientific, and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.
Mearin disclosed no relevant relationships with industry. She is an associate editor of the Journal of Pediatric Gastroenterology and Nutrition.
Several co-authors disclosed relevant relationships with Falk, Chr. Hansen, PharmaS, AbbVie, BioGai, MSD/Merck, Abbott, Arlafoods, Fresenius, Medis, Nutricia/Danone, Nestle, Podravka, Mead Johnson, Eurospital, IL-Instrumentation, INOVA, Nestle Nutrition Institute, Euroimmun, R-Biopharm, ThermoFisher, Schär, Immundiagnostik, Centocor, Merck Sharp & Dohme, Danone, Merck, Vifor, Hipp, Infectopharm, Phadia GmbH, Deutsche Zöliakie Gesellschaft BV.
Primary source: New England Journal of Medicine
Source reference: Vriezinga SL, et al “Randomized feeding intervention in infants at high risk for celiac disease” N Engl J Med 2014; 371: 1303-1315.