Hydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial

Abstract

Importance: The disease process leading to clinical type 1 diabetes often starts during the first years of life. Early exposure to complex dietary proteins may increase the risk of β-cell autoimmunity in children at genetic risk for type 1 diabetes. Extensively hydrolyzed formulas do not contain intact proteins.

Objective: To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of diabetes-associated autoantibodies in young children.

Design, setting, and participants: A double-blind randomized clinical trial of 2159 infants with HLA-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1078 were randomized to be weaned to the extensively hydrolyzed casein formula and 1081 were randomized to be weaned to a conventional cows' milk-based formula. The participants were observed to April 16, 2013.

Interventions: The participants received either a casein hydrolysate or a conventional cows' milk formula supplemented with 20% of the casein hydrolysate.

Main outcomes: AND MEASURES: Primary outcome was positivity for at least 2 diabetes-associated autoantibodies out of 4 analyzed. Autoantibodies to insulin, glutamic acid decarboxylase, and the insulinoma-associated-2 (IA-2) molecule were analyzed using radiobinding assays and islet cell antibodies with immunofluorescence during a median observation period of 7.0 years (mean, 6.3 years).

Results: The absolute risk of positivity for 2 or more islet autoantibodies was 13.4% among those randomized to the casein hydrolysate formula (n = 139) vs 11.4% among those randomized to the conventional formula (n = 117). The unadjusted hazard ratio for positivity for 2 or more autoantibodies among those randomized to be weaned to the casein hydrolysate was 1.21 (95% CI, 0.94-1.54), compared with those randomized to the conventional formula, while the hazard ratio adjusted for HLA risk, duration of breastfeeding, vitamin D use, study formula duration and consumption, and region was 1.23 (95% CI, 0.96-1.58). There were no clinically significant differences in the rate of reported adverse events between the 2 groups.

Conclusions and relevance: Among infants at risk for type 1 diabetes, the use of a hydrolyzed formula, when compared with a conventional formula, did not reduce the incidence of diabetes-associated autoantibodies after 7 years. These findings do not support a benefit from hydrolyzed formula. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00179777.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Figures

Figure 1

Screening, Randomization, and Follow-up of TRIGR Study Infants

Figure 2. Cows’ Milk Antibody Titers Over the First 9 Months of Life

IgG (Panels A and B) and IgA (Panels C and D) class antibodies to cows’ milk (infant formula) in cord blood and at the ages of 3, 6, and 9 months in the casein hydrolysate group and control group. The bottom of the box plots indicate the 25th percentile and the top the 75th percentile. The circle symbols indicate the mean. The lower end of the whiskers represent the minimum observation and the upper end the maximum observation below the upper fence (1.5 interquartile range above the 75th percentile).

Figure 3. Cumulative Survival Without at Least 2 Autoantibodies and at Least 1 Autoantibody

The cumulative survival without at least 2 autoantibodies (Panel A) and without at least 1 autoantibody (Panel B) is shown for the casein hydrolysate group and the control group according to the age of the children at the time the autoantibodies were detected.

Figure 4. Cumulative Survival Without Islet Cell Antibodies, Insulin Autoantibodies, and Autoantibodies to Glutamic Acid Decarboxylase (GAD) and the Insulinoma-Associated–2 Molecule (IA-2)

The cumulative survival without islet cell antibodies (Panel A), insulin autoantibodies (Panel B), GAD antibodies (Panel C), and IA-2 autoantibodies (Panel D) is shown for the casein hydrolysate group and the control group according to the age of the children at the time the autoantibodies were detected.