Avoidance of Cow's Milk-Based Formula for At-Risk Infants Does Not Reduce Development of Celiac Disease: A Randomized Controlled Trial

Gastroenterology. 2017 Oct;153(4):961-970.e3. doi: 10.1053/j.gastro.2017.06.049. Epub 2017 Jul 5.


Background & aims: Feeding during the first months of life might affect risk for celiac disease. Individuals with celiac disease or type 1 diabetes have been reported to have high titers of antibodies against cow's milk proteins. Avoidance of cow's milk-based formula for infants with genetic susceptibility for type 1 diabetes reduced the cumulative incidence of diabetes-associated autoantibodies. We performed a randomized controlled trial in the same population to study whether weaning to an extensively hydrolyzed formula reduced the risk of celiac disease autoimmunity or celiac disease.

Methods: We performed a double-blind controlled trial of 230 infants with HLA-defined predisposition to type 1 diabetes and at least 1 family member with type 1 diabetes. The infants were randomly assigned to groups fed a casein hydrolysate formula (n = 113) or a conventional formula (control, n = 117) whenever breast milk was not available during the first 6-8 months of life. Serum samples were collected over a median time period of 10 years and analyzed for antibodies to tissue transglutaminase (anti-TG2A) using a radiobinding assay, to endomysium using an immunofluorescence assay, and antibodies to a deamidated gliadine peptide using an immunofluorometry assay. Duodenal biopsies were collected if levels of anti-TG2A exceeded 20 relative units. Cow's milk antibodies were measured during the first 2 years of life.

Results: Of the 189 participants analyzed for anti-TG2A, 25 (13.2%) tested positive. Of the 230 study participants observed, 10 (4.3%) were diagnosed with celiac disease. We did not find any significant differences at the cumulative incidence of anti-TG2A positivity (hazard ratio, 1.14; 95% confidence interval, 0.51-2.54) or celiac disease (hazard ratio, 4.13; 95% confidence interval, 0.81-21.02) between the casein hydrolysate and cow's milk groups. Children who developed celiac disease had increased titers of cow's milk antibodies before the appearance of anti-TG2A or celiac disease.

Conclusions: In a randomized controlled trial of 230 infants with genetic risk factors for celiac disease, we did not find evidence that weaning to a diet of extensively hydrolyzed formula compared with cow's milk-based formula would decrease the risk for celiac disease later in life. Increased titers of cow's milk antibody before anti-TG2A and celiac disease indicates that subjects with celiac disease might have increased intestinal permeability in early life. ClinicalTrials.gov Number: NCT00570102.

Keywords: Diet; Immune System Development; Pediatric; TRIGR Study.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantibodies / blood*
  • Autoimmunity*
  • Biopsy
  • Caseins / adverse effects
  • Caseins / immunology
  • Caseins / therapeutic use*
  • Celiac Disease / diagnosis
  • Celiac Disease / immunology
  • Celiac Disease / prevention & control*
  • Child
  • Child, Preschool
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / diagnosis
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Double-Blind Method
  • Duodenum / immunology
  • Duodenum / pathology
  • Finland
  • GTP-Binding Proteins / immunology*
  • Gliadin / immunology
  • Humans
  • Infant
  • Infant Formula / adverse effects*
  • Milk Hypersensitivity / diagnosis
  • Milk Hypersensitivity / immunology
  • Milk Hypersensitivity / prevention & control*
  • Milk Proteins / adverse effects*
  • Milk Proteins / immunology
  • Risk Assessment
  • Risk Factors
  • Serologic Tests
  • Time Factors
  • Transglutaminases / immunology*
  • Treatment Outcome


  • Autoantibodies
  • Caseins
  • Milk Proteins
  • casein hydrolysate
  • Gliadin
  • transglutaminase 2
  • Transglutaminases
  • GTP-Binding Proteins

Associated data

  • ClinicalTrials.gov/NCT00570102