Celiac Disease: New Data May Change Recommendations for Kids

Norra MacReady

October 02, 2014

Timing of gluten exposure and duration of breast-feeding do not appear to influence the development of celiac disease in high-risk children, according to two new randomized controlled trials published in the October 2 issue of the New England Journal of Medicine.

These findings "will change the conceptual landscape of celiac disease," Jonas F. Ludvigsson, MD, PhD, from the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, and the Department of Pediatrics, Örebro University Hospital, Örebro University, Sweden, and Peter H. R. Green, MD, from the Celiac Disease Center, Department of Medicine, Columbia University College of Physicians and Surgeons, New York City, write in an editorial about the studies. "From now on, it will be hard for anyone to continue to recommend the introduction of gluten specifically at the age of 4 to 6 months."

They continue, "Although we recognize the overall importance of breast-feeding for child health, breast-feeding does not appear to protect against celiac disease in children."

Is Early Exposure Protective?

Previous observational studies have suggested that introduction of gluten between the ages of 4 and 6 months could decrease the risk of developing celiac disease. Therefore, Sabine L. Vriezinga, MD, from the Department of Pediatrics, Leiden University Medical Center, the Netherlands, and colleagues tested whether introduction of small quantities of gluten during this period would alter the rate of celiac disease at 3 years in high-risk children.

The authors enrolled children through celiac disease organizations in Europe and Israel, starting in May 2007. Eligible participants had to have at least a single first-degree relative with a diagnosis of celiac disease confirmed through small-bowel biopsy and to have the human leukocyte antigen (HLA) dimer DQ2 or DQ8 or the heterodimer HLA-DQB1*02.

The researchers randomly assigned children to receive either 200 mg vital wheat gluten mixed with 1.8 g lactose (equivalent to 100 mg immunologically active gluten) or a placebo ( 2 g lactose) daily, starting at 16 weeks of age and lasting for 8 weeks. Parents and investigators were blinded as to which preparation the children received.

At the time follow-up was closed in September 2013, the children ranged from 3 to 6 years of age. Of 475 children in the gluten group, 52 had symptoms that warranted a diagnostic small-bowel biopsy, and 43 children underwent the procedure. Similarly, of 469 children in the placebo group, 53 had symptoms that warranted a biopsy and 47 underwent the procedure. To avoid underestimating the incidence of celiac disease, the authors included three children, one child in the gluten group and two in the placebo group, who were not biopsied but who met the diagnostic criteria established by the European Society for Gastroenterology, Hepatology, and Nutrition.

By 3 years of age, the cumulative incidence of celiac disease among children in the gluten group was 5.9% (95% confidence interval [CI], 3.7% - 8.1%) compared with 4.5% (95% CI, 2.5% - 6.5%) in the placebo group (P = .47 by a stratified log-rank test). Duration of breast-feeding had no influence on the intervention (P = .70 for exclusive breast-feeding; P = .83 for nonexclusive breast-feeding).

However, the cumulative incidence of celiac disease was higher among girls in the gluten intervention group than in the placebo group (8.9% and 5.5%, respectively; hazard ratio [HR], 1.99; 95% confidence interval [CI], 1.09 - 3.65; P = .02). This difference was not seen in boys (cumulative incidence, 3.2% and 3.6%, respectively; HR, 0.62; 95% CI, 0.31 - 1.24; P = .17 [P = .01 for interaction of sex and intervention]). Celiac disease is known to be more prevalent in women than men, the authors write, but the difference they observed occurred too early for androgens to play a protective effect. They speculate that gut microbiota may account for the finding, as demonstrated in recent animal studies.

"In conclusion," they write, "this randomized trial did not show the hypothesized benefit of early exposure to small quantities of gluten with regard to reducing the incidence of celiac disease among children from high-risk families. In addition, we did not observe a reduced risk of celiac disease associated with the maintenance of breast-feeding at the time of gluten introduction."

Is Delayed Exposure Protective?

In the second study, lead author Elena Leonetti, MD, and colleagues also attempted to clarify the relationship between the age at which gluten is introduced into a child's diet and celiac disease risk. "The introduction of gluten at 6 months of age is a long-standing practice," they write. However, "[m]any clinicians advise that the introduction of gluten to the diet of infants who have a familial risk of the disease should be delayed. Depending on timing, this delay may permit the maturation of the small intestinal barrier and the mucosal immune response."

Dr Leonetti, from the Department of Pediatrics, University of Catania, Italy, and coauthors tested this hypothesis in the Risk of Celiac Disease and Age at Gluten Introduction (CELIPREV) trial, in which early and delayed introduction of gluten were compared in children whose family histories placed them at high risk for celiac disease.

Newborns were eligible if they had at least a single first-degree relative with celiac disease. The researchers recruited children from 20 centers across Italy between 2003 and 2008 and randomly assigned them either to the introduction of gluten-containing food, such as pasta, at 6 months of age or to gluten introduction at 12 months.

The final analysis included 297 children in the early gluten group and 256 in the late gluten group. All children tested positive for HLA-DQ2, HLA-DQ8, or both. By the time the study terminated in October 2013, the median age of the cohort was 7.9 years (range, 5.2 - 10.6 years).

Of 117 children whose symptoms fulfilled the criteria for small-bowel biopsy, 112 actually underwent the procedure. Overt celiac disease was diagnosed in 86 of those children, and two more were diagnosed later on the basis of a second biopsy. The other five children, all of whom had symptoms of celiac disease, were started on a gluten-free diet; their symptoms improved, so they were included among the patients with overt celiac disease.

Overt celiac disease was diagnosed by 2 years of age in 12% of the children in early gluten group and 5% in the late gluten group (P = .01). However, by 5 years of age, 16% of children in both groups had been diagnosed (HR, 0.9; 95% CI, 0.6 - 1.4; P = .78). No further differences between the groups had emerged by ages 8 or 10 years. The early gluten group had a median age of diagnosis of 26 months compared with 34 months in late gluten group (P = .01).

Similarly, the prevalence of celiac disease autoimmunity was greater among children in the early group than in those in the late group at 2 years of age (16% vs 7%; P = .002), but by 5 years of age, this difference had resolved (21% vs 20%, respectively; P = .59). No relationship was observed between duration of breast-feeding and risk for celiac disease in either group.

Although delaying a child's introduction to gluten does not affect his or her long-term risk of developing celiac disease, it may still have at least two beneficial effects. "First, it delayed the development of celiac disease, which might reduce the negative effect of the disease on vulnerable organs such as the brain. Second, it reduced the prevalence, albeit nonsignificantly, of celiac disease autoimmunity at any age among children carrying the high-risk HLA genotype," the authors write.

"Early dietary factors, particularly the child's age at the introduction of gluten, seem to play a minor role in the risk of the development of celiac disease," the authors conclude. "However, delaying the introduction of gluten in at-risk infants may delay the onset of the disease, with potential benefit related to maintenance of a state of health during a crucial period of child development." As for prolonging breast-feeding, although it may be salutary in other ways, "we did not discern a protective effect against celiac disease."

The findings of these two studies suggest that other environmental factors may be responsible for the increased incidence in celiac disease noted in recent years in Finland, the United States, and the United Kingdom, Dr Ludvigsson and Dr Green state in their editorial. Possible culprits may include "elective cesarean section, perinatal and childhood infections, and the use of antibiotics and proton-pump inhibitors," they write. "Some of these factors implicate changes in the microbiome."

The first study was supported by grants from 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. The second study was supported by the Fondazione Celiachia.

N Engl J Med. 2014;371:1295-1315, 1341-1343. Vriezinga full text, Lionetti abstract, Editorial extract

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