In healthy infants and in infants with a high risk of developing allergy, exclusive breast-feeding for approximately 6 months is a desirable goal. Hydrolyzed formulas contain cow milk proteins (CMPs) that are subjected to chemical and enzymatic hydrolysis to reduce the molecular weight, the peptide size, and, consequently, the allergenicity of the proteins. The differentiation between extensively hydrolyzed formulas (eHFs) and partially hydrolyzed formulas (pHFs) is generally performed by molecular weight profile and clinical demonstration of reduced allergenicity. The protein molecular weight profile is an analytical classification measure that offers a straightforward differentiation between intact, partially, and extensively hydrolyzed protein formulas (1). The methods use molecular weight markers that enable to qualify and quantify the proteins/peptides as percentage of total protein. The most important protein fractions present in cow milk (whey, casein) are used for the hydrolysis process instead of whole CMP (2). Whole cow milk–based formulas contain proteins in the range of 14 kD (α-lactalbumin) to 67 kD (bovine serum albumin). pHFs contain reduced oligopeptides that have a molecular weight of generally <5 kD (ranges between 3 and 10 kD), and peptides in eHFs have, in >90%, a molecular weight of <3 kD (2,3). Both pHFs and eHFs consist of a wide range of peptide sizes. Protein molecular weight profile enables to only differentiate the protein characteristics of formulas, but does not determine the allergenic formula properties. Moreover, there is no regulatory definition of eHFs and pHFs.
In addition, commercially available whey pHFs (pHF-Ws) contain 18% of peptides >6 kD, whereas eHFs contain between 1% and 5% of peptides >3.5 kD. Peptides need to be in the range of 10 to 70 kD (predominantly 10–40 kD) to be able to act as an allergen (4,5).
The degree of hydrolysis may be characterized by biochemical techniques, such as the spectrum of peptide molecular weights or the ratio of α-amino nitrogen to total nitrogen (6). Assuming the theory that the shorter the peptides, the less allergenic the product is, much work has been performed to determine the molecular weight of residual peptides in the hydrolysates (7). As a practical guideline for the industry, the appropriate cutoff for the absence of larger peptides has been determined to be approximately 1.5 kD (7).
The term “hypoallergenicity” or “HA” does not have a globally uniform interpretation. In the European Union, the term is associated with the health claim “reduction of risk to allergy to milk protein” as defined by Commission Directive 2006/141/EC of 22 December 2006 on infant formulae and follow-on formulae and amending Directive 1999/21/EC. eHFs also comply with the above conditions and are also “HA.” These are used for “the dietary management of cow milk allergy.” In the United States the term HA is a health claim that requires premarket approval by FDA (similar in Canada). Basically only eHFs are considered HA and thus can be used for the dietary management of CMP. Because the wording hypoallergenicity, abbreviated as HA, does have such a different meaning in different parts of the world, we should no longer use the wording “hypoallergenic” in scientific papers to avoid confusion, and instead use “partial” or “extensive” hydrolysates.
Despite the evidence available, there is still uncertainty regarding the choice, if at all, of a hydrolyzed formula in the feeding of infants and uncertainty regarding the actual efficacy to prevent allergy of a particular formula. Efficacy and safety should be established especially for CMP hydrolyzed formulas, because factors such as the protein source, hydrolysis method, and degree of hydrolysis that depend on the manufacturer contribute to differences among hydrolysates.
Although acknowledging that breast-feeding is the recommended feeding for infants with and without risk of developing allergy (3,8), the authors joined forces to provide recommendations on the use of hydrolysates in infants when formula feeding is initiated.
The objectives of this statement were to systematically review and update data on the efficacy and safety of using a CMP hydrolyzed formula of any degree of hydrolysis compared with a standard infant formula in reducing the risk of allergy in healthy infants at high risk of allergy or in those without a risk, and to formulate recommendations.
An overview of reviews followed by a systematic review of subsequently published trials was carried out. The guidelines from the Cochrane Collaboration for overview of reviews, and comments by Smith et al (9), were followed for the overview of reviews. All relevant systematic reviews/meta-analyses of randomized controlled trials (RCTs) and quasi-RCTs were considered for inclusion. The participants in the included trials had to be infants at high risk of developing allergy, as assessed by a family history (the presence of allergy in at least 1 parent and/or sibling) and/or other markers (as determined by the study investigators), or without any risk. The included trials compared use of formulas based on CMP hydrolysates with standard infant formula or follow-on formula. The primary outcomes of interest in included trials were those related to allergic disease, such as all allergic diseases, including atopic eczema/atopic dermatitis, gastrointestinal symptoms, food allergy/hypersensitivity, respiratory symptoms (wheezing and/or asthma), allergic rhinitis, and urticaria (if reported together); atopic eczema/atopic dermatitis; respiratory symptoms (wheezing, asthma as diagnosed by a physician), allergic rhinitis, food allergy/hypersensitivity, urticaria, and anaphylaxis. Search methods are outlined in the online-only appendix (http://links.lww.com/MPG/A301).
Overview of Reviews
Eight systematic reviews with or without a meta-analysis met the inclusion criteria (10–17). Two reviews (12,13) included trials coauthored by the investigator (R.K. Chandra) whose data have been questioned (18); thus, these reviews were excluded. Two reviews (14,16) covered data included in the 2006 Cochrane review, and, therefore, were excluded. Finally, 1 review (11) was a duplicate of the same data that were published in another journal at the same time (10); thus, this review was also excluded. The 3 included reviews (10,15,17) and methodological quality of the reviews are described in supplementary Tables 1 and 2 (http://links.lww.com/MPG/A301). Both the reviews of Osborn and Sinn (15) and Szajewska and Horvath (17) included unpublished data. Of importance, Szajewska and Horvath (17) obtained unpublished data from clinical trials from the Nestlé Nutrition Institute, whereas no data were obtained from other formula manufacturers. Osborn and Sinn (15) also contacted the authors to obtain unpublished data from other manufacturers.
Hydrolyzed Formulas and Allergy Risk
The Cochrane review (15) showed that compared with human milk feeding, feeding a hydrolyzed formula (all types) from birth onwards during the first few days of life in low-risk infants resulted in no significant difference in infant allergy or childhood cow's-milk allergy (CMA). Compared with cow's-milk formula, there was no benefit of short-term feeding (average 4 days) of a hydrolyzed formula (all types). One large quasi-RCT reported a reduction in infant CMA of borderline significance in low-risk infants (1 RCT, n = 3473; relative risk [RR] 0.62, 95% confidence interval [CI] 0.38–1.00). Compared with standard cow's-milk formula, prolonged (in the first 4–6 months of life) feeding with a hydrolyzed formula (all types) in high-risk infants resulted in a significant reduction in infant allergy (7 RCTs, n = 2514; RR 0.79, 95% CI 0.66–0.94) and a significant reduction in CMA (1 RCT, n = 67; RR 0.36, 95% CI 0.15–0.89). The duration of intervention in the long-term prevention studies was 4 to 6 months; the different reviews define this as prolonged feeding. There were no significant differences between groups in the incidence of childhood allergy, infant eczema, childhood eczema incidence and prevalence, and infant or childhood asthma, rhinitis, and food allergy. Subgroup analysis of trials blinded to the formula revealed no significant difference in infant allergy or childhood allergy incidence between groups. No eligible trial examined the effect of 4 to 6 months of HF feeding beyond early childhood on allergy. Compared with cow's-milk formula, feeding with a pHF (any type) showed a significant reduction in infant allergy (7 RCTs, n = 1482; RR 0.79, 95% CI 0.65–0.97) but not in childhood allergy, infant or childhood asthma, eczema, or rhinitis. One small RCT showed a significant reduction in CMA (1 RCT, n = 67; RR 0.36, 95% CI 0.15–0.89). Compared with standard cow's-milk formula, there was no clear effect of feeding eHF (any type) on any of the outcomes. Infants fed an eHF compared with a pHF had a significant reduction in food allergy (2 RCTs, n = 341; RR 0.43, 95% CI 0.19–0.99), but there was no significant difference between groups in all allergies or any other specific allergy incidence. Compared with cow's-milk formula, 4 to 6 months of feeding with an “extensively hydrolyzed casein formula” was associated with a significant reduction in childhood allergy incidence (1 RCT, n = 431; RR 0.72, 95% CI 0.53–0.97), a significant reduction in infant eczema (3 RCTs, n = 1237; RR 0.71, 95% CI 0.51–0.97), and a significant reduction in childhood eczema incidence (1 RCT, n = 431; RR 0.66, 95% CI 0.44–0.98) and prevalence (1 RCT, n = 431; RR 0.50, 95% CI 0.27–0.92). Compared with cow's-milk formula, 4 to 6 months of feeding with an “extensively hydrolyzed whey formula” resulted in no significant difference in the outcomes of any allergy, asthma, and eczema.
Methodological concerns included small sample sizes in many studies and methodological limitations such as unclear randomization, unclear allocation concealment, and no true blinding. Also, the effects were not clear when analysis was restricted to trials with blinding of measurement to study formula or to studies of adequate methodology.
Partially Hydrolyzed Whey Formulas and Allergy Risk
In a systematic review (10), 18 articles representing 12 independent study populations met the inclusion criteria. Among them, 6 studies representing 4 infant populations were considered methodologically superior. For atopic dermatitis, meta-analysis of all reviewed studies that specifically reported data for atopic dermatitis and studies that reported outcomes that included atopic dermatitis (eg, atopy, skin symptoms) showed that feeding with pHF-W statistically significantly reduced the risk of atopic manifestations (11 trials; summary relative risk estimate 0.56, 95% CI 0.4–0.77). Meta-analysis of studies of higher methodological quality also documented significant risk reduction (4 trials; summary relative risk estimate 0.45, 95% CI 0.30–0.70). The effect was consistent, regardless of study design, infant population, follow-up time, or study location. Alexander and Cabana concluded that feeding with pHF instead of cow's-milk formula reduced the risk of atopic dermatitis in infants with a family history of allergy.
Similar conclusions were reached by Szajewska and Horvath (17). The 12 populations described in the 15 publications involving 3284 participants (1027 in the pHF groups and 2257 in the control groups) were eligible for inclusion. Sample sizes ranged from 30 to 2252 patients. Follow-up ranged from 6 months up to 6 years. One of the largest trials (the German Infant Nutrition Intervention study) was assigned a “yes” for 4 criteria on the validity scale (adequate sequence generation, allocation concealment, blinding, and incompleteness of outcome data addressed), and 1 trial was assigned a “yes” for 3 criteria. The remaining trials had a number of methodological limitations.
For all allergic diseases (7 RCTs), using a random effects model, use of pHF-W was statistically significantly more effective in reducing the risk of all allergic diseases (incidence) compared with standard formula at 3 to 6 months (5 RCTs; RR 0.48, 95% CI 0.23–1.00), at 1 year (4 RCTs; RR 0.62, 95% CI 0.45–0.85; number needed to treat 12), and at 30 to 36 months (1 RCT; RR 0.42, 95% CI 0.19–0.90) but not at 2 years (2 RCTs). There was evidence of statistical heterogeneity at 3 to 6 months (I2 = 58%).
For atopic dermatitis or atopic eczema (8 RCTs), using a random effects model, the use of pHF compared with standard formula statistically significantly reduced the incidence of eczema at 1 year (4 RCTs; RR 0.68, 95% CI 0.48–0.98; I2 = 0%), but not at 4 to 6 months (5 RCTs), 2 years (3 RCTs), or 30 to 36 months (2 RCTs).
There were no statistically significant differences between pHF-W and eHF-W or eHF-C formula in the risk reduction for all allergic diseases or for atopic dermatitis or atopic eczema. Sensitivity analyses did not significantly alter these results.
Szajewska and Horvath concluded that pHF-W was effective, compared with standard formula, in preventing allergy, particularly atopic dermatitis or atopic eczema, in children at a high risk of allergy at most time points. These findings should be interpreted with caution because of methodological concerns. The strongest evidence came from a well-designed and conducted, publically funded RCT (German Infant Nutrition Intervention Study).
See supplementary Tables 3 to 6 for detailed results (http://links.lww.com/MPG/A301).
Studies Identified After the Systematic Review/Meta-analysis
We identified 1 single-blind RCT designed to assess the effect of using a pHF-W at weaning on the risk of allergic disease that was published subsequent to the latest meta-analyses (19). At age 2 years, 575 (93%) of 620 infants were followed up, and at 6 to 7 years, 495 (80%). Feeding with pHF compared with cow's-milk formula did not significantly affect the risk of developing any allergic disease at 0 to 1 year (odds ratio 1.02, 95% CI 0.67–1.54) or at 0 to 2 years (odds ratio 1.21, 95% CI 0.81–1.8). There was no difference between the group fed pHF and the group fed cow's-milk formula for the secondary outcomes within the first 2 years and at 6 to 7 years. There are methodological issues that call for cautions, including the unclear reason for publishing the results 15 years after collecting the data, outcome assessment through telephone interviews with parents, and changing definitions of outcome indicators compared with previous publications on this cohort (20).
Certain extensively hydrolyzed casein and certain pHF-Ws are appropriate for reducing the risk of allergy in infants at high risk when breast-feeding is not or no longer possible and formula feeding is initiated.
Formulas with documented safety and efficacy should be the preferred choice (as shown in the online-only tables, http://links.lww.com/MPG/A301). Many formulas presently available differ from those used in clinical trials because of further modifications. Worldwide, not all products are available everywhere. One could consider that it may be preferable to use a nonstudied hydrolysate instead of no hydrolysate in such a case. Because hydrolyzed formulas have not been studied in the prevention of allergy in low-risk infants, they cannot be recommended in this group.
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