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

Abstract

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.

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  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.

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    Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

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    Nutrition Unit, National Institute for Health and Welfare, Helsinki, Finland; University of Tampere, School of Health Sciences, Tampere, Finland; Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland; The Science Center of Pirkanmaa Hospital District, Tampere, Finland.

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    Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.

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    Immunogenetics Laboratory, University of Turku and Turku University Hospital, Turku, Finland.

    ,

    Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

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    Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.

    ,

    Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Respiratory, Inflammation and Autoimmunity, Innovative Medicine, AstraZeneca, Molndal, Sweden.

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    Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

    ,

    Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland; Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; Folkhälsan Research Center, Helsinki, Finland. Electronic address: mikael.knip@helsinki.fi.

    Source

    Gastroenterology 153:4 2017 10 pg 961-970.e3

    MeSH

    Autoantibodies
    Autoimmunity
    Biopsy
    Caseins
    Celiac Disease
    Child
    Child, Preschool
    Diabetes Mellitus, Type 1
    Double-Blind Method
    Duodenum
    Finland
    GTP-Binding Proteins
    Gliadin
    Humans
    Infant
    Infant Formula
    Milk Hypersensitivity
    Milk Proteins
    Risk Assessment
    Risk Factors
    Serologic Tests
    Time Factors
    Transglutaminases
    Treatment Outcome

    Pub Type(s)

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

    Language

    eng

    PubMed ID

    28687275

    Citation

    Hyytinen, Mila, et al. "Avoidance of Cow's Milk-Based Formula for At-Risk Infants Does Not Reduce Development of Celiac Disease: a Randomized Controlled Trial." Gastroenterology, vol. 153, no. 4, 2017, pp. 961-970.e3.
    Hyytinen M, Savilahti E, Virtanen SM, et al. Avoidance of Cow's Milk-Based Formula for At-Risk Infants Does Not Reduce Development of Celiac Disease: A Randomized Controlled Trial. Gastroenterology. 2017;153(4):961-970.e3.
    Hyytinen, M., Savilahti, E., Virtanen, S. M., Härkönen, T., Ilonen, J., Luopajärvi, K., ... Knip, M. (2017). Avoidance of Cow's Milk-Based Formula for At-Risk Infants Does Not Reduce Development of Celiac Disease: A Randomized Controlled Trial. Gastroenterology, 153(4), pp. 961-970.e3. doi:10.1053/j.gastro.2017.06.049.
    Hyytinen M, et al. Avoidance of Cow's Milk-Based Formula for At-Risk Infants Does Not Reduce Development of Celiac Disease: a Randomized Controlled Trial. Gastroenterology. 2017;153(4):961-970.e3. PubMed PMID: 28687275.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Avoidance of Cow's Milk-Based Formula for At-Risk Infants Does Not Reduce Development of Celiac Disease: A Randomized Controlled Trial. AU - Hyytinen,Mila, AU - Savilahti,Erkki, AU - Virtanen,Suvi M, AU - Härkönen,Taina, AU - Ilonen,Jorma, AU - Luopajärvi,Kristiina, AU - Uibo,Raivo, AU - Vaarala,Outi, AU - Åkerblom,Hans K, AU - Knip,Mikael, AU - ,, Y1 - 2017/07/05/ PY - 2016/11/09/received PY - 2017/06/23/revised PY - 2017/06/27/accepted PY - 2017/7/9/pubmed PY - 2017/10/17/medline PY - 2017/7/9/entrez KW - Diet KW - Immune System Development KW - Pediatric KW - TRIGR Study SP - 961 EP - 970.e3 JF - Gastroenterology JO - Gastroenterology VL - 153 IS - 4 N2 - 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. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/28687275/Avoidance_of_Cow's_Milk_Based_Formula_for_At_Risk_Infants_Does_Not_Reduce_Development_of_Celiac_Disease:_A_Randomized_Controlled_Trial_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(17)35862-6 DB - PRIME DP - Unbound Medicine ER -