Timing of Starting Gluten in Infant Diet Linked to Appearance of Celiac Disease Autoimmunity

Laurie Barclay, MD

May 18, 2005

May 18, 2005 — A prospective observational study reported in the May 18 issue of JAMA supports the current recommendations of starting gluten-containing foods at four to six months of age. Those otherwise at high risk for celiac disease have an increased risk if fed gluten earlier or later than this range. The editorialists recommend long- term follow-up to confirm these findings.

"While gluten ingestion is responsible for the signs and symptoms of celiac disease, it is not known what factors are associated with initial appearance of the disease," write Jill M. Norris, MPH, PhD, from the University of Colorado at Denver, and colleagues. "It is problematic to examine infant diets after celiac disease appears because the participant (or the parents) may be sensitized to the fact that something in the diet 'caused' celiac disease and may respond to dietary surveys in a different way than controls, creating bias."

From 1994 to 2004, the investigators followed 1,560 children at increased risk for celiac disease or type 1 diabetes, defined by possession of either HLA-DR3 or DR4 alleles, or by having a first-degree relative with type 1 diabetes. The primary outcome was risk of celiac disease autoimmunity (CDA) based on timing of introduction of gluten-containing foods into the diet. CDA was defined as positivity for tissue transglutaminase (tTG) autoantibody on two or more consecutive visits, or being positive for tTG once and having a positive small bowel biopsy for celiac disease.

During follow-up (mean duration 4.8 years), 51 children developed CDA. After adjustment for HLA-DR3 status, children exposed to gluten-containing foods (wheat, barley, or rye products) in the first three months of life (3 [6%] CDA positive vs. 40 [3%] CDA negative) had a fivefold increased risk of CDA, compared with children exposed to gluten-containing foods at four to six months (12 [23%] CDA positive vs 574 [38%] CDA negative; hazard ratio [HR], 5.17; 95% confidence interval [CI], 1.44-18.57).

Risk of CDA was marginally increased for children not exposed to gluten until the seventh month or later (36 [71%] CDA positive vs. 895 [59%] CDA negative), compared with those exposed at four to six months (HR, 1.87; 95% CI, 0.97-3.60).

When the case group was restricted to only the 25 CDA-positive children who had biopsy-diagnosed celiac disease, initial exposure to wheat, barley, or rye in the first three months (3 [12%] CDA positive vs. 40 [3%] CDA negative) or in the seventh month or later (19 [76%] CDA positive vs. 912 [59%] CDA negative) increased the risk of CDA, compared with exposure at four to six months (3 [12%] CDA positive vs. 583 [38%] CDA negative; HR, 22.97; 95% CI, 4.55-115.93; P = .001; and HR, 3.98; 95% CI, 1.18-13.46; P = .04, respectively).

Study limitations include use of CDA as a marker for celiac disease; findings generalizable only to children at increased risk for celiac disease; small number of CDA-positive children and wide confidence intervals.

"Timing of introduction of gluten into the infant diet is associated with the appearance of CDA in children at increased risk for the disease," the authors write. "Our results support continuing current US feeding recommendations for introduction of cereal in infants at four to six months."

An addendum indicates that the American Academy of Pediatrics recently published a policy statement recommending exclusive breastfeeding for the first six months of life, with gradual introduction of complementary foods, such as cereals, beginning around six months of age. However, the Academy recognizes that "unique needs or feeding behaviors of individual infants [could] indicate a need for introduction of complementary foods as early as four months of age."

The National Institutes of Health supported this study. The authors report no financial disclosures.

In an accompanying editorial, Richard J. Farrell, MD, from Harvard Medical School in Boston, Massachusetts, notes that these findings must be interpreted with caution because of methodological limitations including being based on a very small number of end points.

"Ultimately, much larger, international prospective studies are required to unravel the complex interplay between multiple infant diet factors and an immature immune system in a genetically predisposed individual at risk for celiac disease," Dr. Farrell writes. "Only then will it be possible to know the true effect of HLA-DQ2 homozygosity vs. heterozygosity, exclusive vs partial breastfeeding, gluten amount vs. gluten timing, and infant cereal vs. follow-up infant formula on celiac disease risk and presentation. In light of such complexity, it is perhaps reassuring that for now, the results of this study do not suggest any change from the current US recommendations for introduction of cereal in infants at four to six months."

Dr. Farrell reports no financial disclosures.

JAMA. 2005;293:2343-2351, 2410-2412

Reviewed by Gary D. Vogin, MD

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