title: Hydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  The participants received either a casein hydrolysate or a conventional cows' milk formula supplemented with 20% of the casein hydrolysate.
  
  
  RESULTS
  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
  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.
authors.affiliation: University of Helsinki, Helsinki, Finland.
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
authors.affiliation: University of Helsinki, Helsinki, Finland.
authors.forename: Hans K
authors.initials: HK
authors.lastname: Åkerblom
authors.affiliation: University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Becker
authors.affiliation: University of Toronto, Toronto, Ontario, Canada.
authors.forename: Hans-Michael
authors.initials: HM
authors.lastname: Dosch
authors.affiliation: University of Western Ontario, London, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Dupre
authors.affiliation: University of Montréal, Montréal, Québec, Canada.
authors.forename: William
authors.initials: W
authors.lastname: Fraser
authors.affiliation: Children's Hospital of Westmead, Sydney, Australia.
authors.forename: Neville
authors.initials: N
authors.lastname: Howard
authors.affiliation: University of Turku, Turku, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
authors.affiliation: University of South Florida, Tampa.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Krischer
authors.affiliation: Kinder- und Jugendkrankenhaus AUF DER BULT, Hannover, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Kordonouri
authors.affiliation: Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Lawson
authors.affiliation: University of Washington, Seattle.
authors.forename: Jerry P
authors.initials: JP
authors.lastname: Palmer
authors.affiliation: University of Helsinki, Helsinki, Finland.
authors.forename: Erkki
authors.initials: E
authors.lastname: Savilahti
authors.affiliation: National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Vaarala
authors.affiliation: National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Suvi M
authors.initials: SM
authors.lastname: Virtanen
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000032:analysis*; D015551:Autoimmunity; D001942:Breast Feeding; D002364:Caseins; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology* / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology / Q000517:prevention & control; D004044:Dietary Proteins / Q000276:immunology; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006868:Hydrolysis; D015994:Incidence; D041943:Infant Formula; D007231:Infant, Newborn; D050417:Insulin-Secreting Cells; D008297:Male; D008892:Milk / Q000276:immunology; D012306:Risk; D014886:Weaning
chemical_list: D001323:Autoantibodies; D002364:Caseins; D004044:Dietary Proteins; C475729:casein hydrolysate