The Role of Partially Hydrolyzed Whey Formula for the Prevention of Allergic Disease

Evidence and Gaps

Adrian J Lowe; Shyamali C Dharmage; Katrina J Allen; Mimi LK Tang; David J Hill


Expert Rev Clin Immunol. 2013;9(1):31-41. 

In This Article

Abstract and Introduction


Hydrolyzed formulae are created by using enzymatic processes to break native proteins into smaller fragments. They may prevent development of allergic diseases by reducing exposure to intact allergens. Partially hydrolyzed whey formula (pHWF) is particularly promising for allergy prevention, as it is cheap to manufacture and palatable. Scientific organizations have recommended the use of hydrolyzed formula in the first 4–6 months of life for the prevention of allergic disease based on a limited number of trials. Three recent developments challenge these recommendations: our growing understanding of the importance of allergen exposure for induction of immune tolerance, recently published evidence that failed to identify a protective effect of pHWF, which the authors and other experts believe will necessitate updating of systematic reviews, and methodological limitations of available trials and systematic reviews on which these recommendations are based. Until more definitive evidence is obtained, the authors recommend continuing to advocate that 'breast is best', and caution against overstating the potential for pHWF to prevent allergic disease.


Allergic conditions cause a substantial burden of illness worldwide both in children and adults.[1,2] These conditions impact on the individual, their family and the healthcare system. The common manifestations of allergic disease shift with increasing age of the child; in early infancy, eczema and food allergy are the most common symptoms, while asthma and allergic rhinitis become more important as the child ages. There was a rapid rise in the prevalence of allergic conditions in the later part of the 20th century.[3–5] While prevalence of childhood asthma appears to have reached a plateau, or declined in some countries,[1] it remains a major cause of hospitalization and healthcare expenditure. The rates of allergic rhinitis and eczema in children continue to increase in many parts of the world,[1] and there is also evidence that the rate of other systemic allergic conditions, including anaphylaxis and food allergy, are increasing.[6–8] Despite active research, the reasons for these shifts in prevalence of disease remain unclear.

Research in this area aims at identifying interventions that can prevent children from developing these conditions in the first place. If early forms of disease can be prevented, there is a potential for sustained long-term benefits and reduced risk of other forms of allergic disease in later life.[9] Despite substantial research efforts, there are currently no interventions that have been clearly demonstrated to prevent children developing these conditions, although it is known that early life exposures (during pregnancy and early infancy) may be critical.[10] The infant diet, including breast or formula feeding and the introduction of solid foods, has attracted particular attention as early life exposures that may influence allergic disease risk and importantly, have the potential to be easily modified.

Currently, international expert guidelines from the USA (American Academy of Pediatrics),[11] Europe (European Academy of Allergy and Clinical Immunology/European Society for Paediatric Gastroenterology, Hepatology and Nutrition)[12] and Australia (Australasian Society of Clinical Immunology and Allergy)[101] recommend a limited number of interventions for prevention of allergic disease. All guidelines advise to breastfeed for the first 4–6 months of life, and if breastfeeding is not possible, the use of hydrolyzed formula in infants with a family history of allergic disease in a first-degree relative is recommended. Hydrolyzed formulae are created by using enzymatic processes to break native proteins into smaller fragments,[13] and the enzymatic digestion may be partial or extensive resulting in larger (partially hydrolyzed) or smaller (extensively hydrolyzed) peptide fragments, respectively. This process can be used for a range of base proteins, including soy and cows' milk-based proteins. Furthermore, specific major protein fractions from cows' milk (casein vs whey) may be used rather than whole cows' milk protein. There are no agreed upon criteria to define partially (as compared with extensively) hydrolyzed formulae, and protein size is generally used to identify a formula as partially hydrolyzed. Whole cows' milk-based formula contains proteins in the range of 14 kD (α-lactalbumin) to 67 kD (bovine serum albumin).[14] Based on industrial sources, extensively hydrolyzed formula only contain peptides of ≤3 kD, and partially hydrolyzed formula contains peptides of <5 kD.[11] Despite these proposed definitions, both partially and extensively hydrolyzed formulae have been shown to contain a wide range of peptide sizes.[14] It has been estimated that commercially available partially hydrolyzed whey formula (pHWF) contain 18% of peptides over 6 kD, while extensively hydrolyzed formula contain between 1 and 5% over 3.5 kD.[15] Peptides need to be in the range of 10–70 kD (particularly 10–40 kD) to be able act as an allergen.[16]

This review focuses on the role of pHWF in the prevention of allergic disease in healthy children, recommending future directions for research in this area. The creation of a pHWF offered great hope in the field of allergy prevention, as it is relatively cheap to manufacture and is quite palatable, both of which are essential for widespread use as a preventative strategy. Although other forms of hydrolyzed formula are available, the cost and poor palatability of these formulae limit their utility as an intervention for allergic disease prevention. It is important to note that pHWF is not recommended as a treatment for allergic disease (specifically cows' milk allergy), as it has been repeatedly demonstrated that a proportion of children with proven cows' milk allergy will react to pHWF. The authors begin this article by outlining the current recommendations concerning hydrolyzed formula, and then the changing theories concerning allergic disease prevention are summarized. Following this, the authors summarize the evidence concerning the effect of pHWF for allergic disease prevention, highlighting the critical issues with this research, and make recommendations as to how this area can be progressed.