Efficacy and safety of hydrolyzed formulas for cow's milk allergy management: A systematic review of randomized controlled trials

Clin Exp Allergy. 2020 Jul;50(7):766-779. doi: 10.1111/cea.13669. Epub 2020 Jun 11.


Objective: To summarize evidence on the efficacy and safety of the use of extensively hydrolyzed formulas (EHFs) for the treatment of children with cow's milk allergy (CMA).

Design: Systematic review of randomized controlled trials (RCTs) per PRISMA guidelines. The risk of bias of included RCTs was assessed using the Cochrane Collaboration's risk of bias tool. In general, a narrative synthesis of the findings was performed. When sufficient data were available, a meta-analysis using the random-effect model was performed.

Data sources: The Cochrane Library, MEDLINE, and EMBASE databases were searched up to February 2020.

Eligibility criteria: RCTs, including cross-over trials, assessing children of any age with any type of CMA that compared use of a formula containing extensively hydrolyzed bovine proteins (whey and/or casein) with use of any other formula for CMA management, were eligible for inclusion. Each type of EHF was evaluated separately. Outcome measures included allergic reactions (ie gastrointestinal, dermatological, and respiratory symptoms), growth, tolerance acquisition to cow's milk proteins, health-related quality of life, and safety.

Results: Fifteen trials reported in 18 publications (1285 children) fulfilled the inclusion criteria. The study findings were limited by numerous methodological issues, including differences in outcome measures and their definitions, lack of pre-specified protocols and/or trial registration, and poor reporting of adverse events, methods of sequence generation and allocation concealment. The EHF products evaluated to date appear to be well-tolerated by most children with CMA. However, published studies do not allow for any conclusion to be reached regarding the benefit of one formula over another formula intended for CMA management.

Conclusions: This systematic review highlights the need for standardized treatment protocols, including an agreed-upon standardized set of outcomes that should be measured and reported in all clinical trials of specialized milk formula for the management of CMA.

Keywords: caseins; cow milk allergy; extensively hydrolyzed formula; infant formula; milk hypersensitivity; probiotics; proteins; whey.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Humans
  • Milk Hypersensitivity / therapy*
  • Protein Hydrolysates / adverse effects
  • Protein Hydrolysates / therapeutic use*
  • Randomized Controlled Trials as Topic
  • Risk Factors


  • Protein Hydrolysates