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

How to Move Forward

As the authors have outlined earlier, there are a number of key issues with how to interpret the results of the trials assessing the effect of pHWF for allergic disease prevention. A primary challenge is how to design studies that allow the ITT analyses to accurately estimate biological effect of pHWF. Since ITT analyses require studies that randomize children prior to birth to analyze all children, even if they do not receive the allocated formula within a specific time, a true biological effect of pHWF may be missed. There are three options to deal with this issue.

Option 1: An External Group Specifies a PP Analysis Plan, Obtains Data from Original Study Authors, and Analyzes Pooled Data Within a Meta-analysis

This is an attractive option, as it utilizes data that have already been generated, so should allow for a summary estimate of the biological effect of pHWF in a short-time frame. While the authors support this concept in principle, there are a number of issues that would arise. Knowledge of study results (based on previously published PP results) may influence the PP analysis plan, leading to bias, as the thinking in this area has already been impacted on by the available body of evidence. Furthermore, independence of this group would be critical, as they would need to be free from potential financial vested interests.

Option 2: Conduct New Studies That Only Recruit Mothers who do not Intend to Breastfeed

By only recruiting mothers who cannot, or chose not to, breastfeed, a clear assessment of the biological effect of pHWF could be obtained, without the potential influence of combined breastfeeding. The limitations of such a study would be substantial. Identifying sufficient number of mothers who do not intend to breastfeed would be challenging, and ethically, the researchers would need to demonstrate that mothers are not being coerced into formula feeding. Identifying this group of mothers is further complicated by maternity settings in westernized countries where any form of feeding apart from breastfeeding is actively discouraged. Furthermore, such a study does not represent how these formulae are being used in the community – in most westernized settings, where allergic diseases are a major concern, mothers generally breastfeed for some duration, and then may move onto an infant formula (or some form of combined feeding) at some point in the first year of life. As such, not only would such a trial be very difficult to conduct, the results would be of limited generalizability.

Option 3: Recruit Mothers Prior to Birth, but Only Randomize Infants at the Point when Formula is to be Introduced, and Only if This is Within the Prespecified Time Window (e.g., First 4–6 Months of Life)

This is probably the best way to address the issues that have been raised in this area of research. This design would require only randomized infants, who are exposed to the study formula by a particular age, to be included in the final analysis. Children who are exclusively breastfeed beyond the critical time window are never randomized, so do not need to be included in the ITT analysis. Block randomization, based on age of introduction to formula, could be used to ensure that the groups are equivalent on this potentially important factor. 'Over-recruitment' of mother/baby pairs would be needed to allow for a substantial proportion of infants to be excluded from the final analysis. This design would require rapid randomization and provision of study formula to mothers at the point they decide to cease exclusive breastfeeding.

Other Issues

There are also a number of broader issues that have not been fully explored in this area. No randomized controlled trial has assessed the effect of pHWF in low-risk children. All clinical trials of pHWF have recruited children at increased risk of allergic disease, primarily based on a history of allergic disease in a first-degree relative. While it is possible that high-risk infants may be the most probable to receive benefit from this formula, and a demonstrated benefit in this group would be important, it has been suggested that the use of pHWF may be more effective in children with a less severe family history of allergic disease.[51] This suggestion is yet to be confirmed. Given the rapid rise in the prevalence of allergic diseases in westernized countries, many children who are at 'low risk' do in fact develop these conditions. The advantage of studying high-risk children is that the prevalence of allergic disease is greater in these children, which enhances statistical power, and families with a history of allergic disease may be more willing to accept interventions to prevent these conditions.

There has been limited assessment of extensively hydrolyzed formula for allergic disease prevention. Few studies that have examined extensively hydrolyzed casein formula (eHCF) have suggested that this form of formula may be more effective than pHWF.[50,52] The issues with this formula will relate to cost and acceptability as a preventative strategy, due to taste and odor.

There is a critical need for studies in this area to better define and validate allergic disease outcomes in early life, and in particular, the definition of eczema. The available evidence has consistently shown an absence of effect of pHWF on the development of asthma.[18,53] Where there are conflicting findings relates to the outcome of early life eczema. At this time, a wide variety of diagnostic criteria for eczema have been used, including variants on the Hanifin and Rajka,[62] the UK working party[63] and other criteria.[64,65] This makes comparability of study results highly questionable. Furthermore, none of these definitions have been validated in children younger than 12 months of age.[66] Concern has been raised that many of the definitions used have a low sensitivity (miss cases) or include elements (particularly persistence of symptoms) that are not appropriate to define incidence of eczema in very young children.[67] A uniformly agreed definition will need to be identified to help move research in this area forward. A limitation of the published studies is that it is generally assumed that all eczema is allergic in nature. We[68] and others[69] have found that a large proportion of eczema in infancy is nonatopic in nature.

It may also be necessary to conduct further in vitro and animal-based studies to clarify the mechanisms of action for hydrolyzed formula, and whether there are differences between partially and extensively hydrolyzed formulae. It is currently unclear which cows' milk protein component (whey versus casein), or length of peptide, may have the greatest beneficial effect on infant immune function. One of the most compelling suggested mechanisms is that the small proportion of intact proteins in pHWF is sufficient to induce oral tolerance. The study by Fritsché et al. demonstrated, in rats, feeding partially hydrolyzed CMF from day 1 induces antigen specific (anti-β-lactoglobulin) suppression of IgE and IgG antibodies in a dose-dependant manner.[70] Furthermore, intact cows' milk protein formula showed a similar effect, whereas extensively hydrolyzed proteins did not. How this translates to humans is uncertain, particularly given the suggestion from some studies that extensively hydrolyzed casein formula may have a greater impact on reducing the incidence of allergic disease than pHWF.[50,52,71]

The effect of hydrolyzed formula may be influenced by the period of exclusivity of this intervention. There is concern that 'contamination' by exposure to whole cows' milk protein will dilute the effect of hydrolyzed formula feeding. At this time, the available literature does not allow us to directly assess how long this period of exclusivity needs to be, or even how relevant this contamination effect is for allergic disease prevention. Unfortunately, many of the published trials do not report how long the period of exclusivity was maintained.

There does not appear to be any evidence of harm caused to children by feeding them pHWF. As such, does it really matter what recommendation is made concerning the use of pHWF for allergic disease prevention? There are very few concrete recommendations that we can currently make for how parents may help reduce the risk that their child develops allergic disease,[72] which makes it tempting to retain the recommendations to use pHWF if there remains some possibility that this formula reduces this risk. Nevertheless, this desire to provide concrete recommendations should be balanced with not overstating the claims of the beneficial effects of pHWF. If the proposed benefits of pHWF are overstated to parents, this may have negative impacts on the duration of breastfeeding. The evidence is unclear if breastfeeding reduces risk of allergic disease,[73–75] but it is clear that breastfeeding is beneficial for a range of nonallergic disease outcomes,[76] and should be promoted as a public health priority.