eHF fulfill the criteria to be classified as a formula for therapy, but they are also recommended by the American and the European Pediatric Societies for allergy prevention [4, 5].
The most intensively tested eHF is based on 100% casein (eHF-C). Its allergy-preventive effect has been investigated in several birth cohorts of high-risk infants and compared with breast milk, cow's milk formula and pHF [10, 27-34], and in two of these studies also with eHF-W [10, 27].
Most of the pHFs available today are based on 100% whey (pHF-W). The pHFs fulfill 2 of 3 criteria for the definition to be 'hypoallergenic' as recommended by the American Academy of Pediatrics : they have a reduced antigenicity of the protein and induce limited immunological reactions. However, they are not suitable for the therapy of cow's milk allergy/intolerance. Nevertheless, in several clinical studies pHF has demonstrated a potential for prevention of allergic disease, and here mainly with regard to atopic dermatitis and food allergy [8, 28, 34-36].
Taking together the results of the intervention studies with hydrolysates, a preventive effect with regard to the prevalence and the cumulative incidence of allergic manifestations, mainly atopic dermatitis and food allergy could be demonstrated for both eHF and pHF .
In general it is not possible to compare these dietary intervention studies because of methodological differences in their design and their performance [28, 34, 36]. All of these studies were performed in children at risk of atopy; however, not always with the same level of risk (uniparental, biparental). All of the studies mentioned in the reviews tried to randomize the children to the study formula that would be fed as a supplement if breastfeeding was insufficient. However, some children were randomized before birth , some at birth , at weaning  or by the day of randomization (even, uneven) . Not all of the studies were blinded, and only two of them were double-blinded [10, 30]. In case the formula is tested versus breast milk, blinding and randomization are not possible for ethical reasons. Additional differences between the studies are the result of the time of weaning and duration of feeding study formula, as well as of co-interventions such as recommendations for the diet of the lactating mother, solid food introduction, or avoidance of inhalant allergens. And not least important are the differences in the outcome definitions and the criteria for diagnosis in the various studies.
A direct comparison between eHF and pHF was performed only in two studies, showing that, with regard to the reduction of atopic dermatitis and food allergy, mainly cow's milk allergy, eHF was borderline significantly superior over pHF [27, 30, 34]. However, from results of the GINI study, where the allergy-preventive effect of three different hydrolysates (pHF-W, eHF-W and eHF-C) was compared with a regular cow's milk formula in children at high risk of atopic diseases, it became obvious that the effect of a formula was modified by the specific allergic phenotype in the child's immediate family. While the incidence of atopic dermatitis in children without atopic dermatitis in a first-degree family member was reduced with all 3 hydrolysates - and even significantly so with pHF-W, a significant reduction of atopic dermatitis in children with atopic dermatitis in the family could only be shown with eHF-C. This finding may have implications for the cost/benefit ratio, as pHF-W is much cheaper than eHF-C. The use of eHF-C should be reserved for infants at the highest risk of developing atopic dermatitis.
In conclusion, the concept of hypoallergenic infant formulas for atopy prevention in children at high risk of developing atopic diseases has been demonstrated efficacious in reducing the incidence of allergic manifestations, mainly atopic dermatitis and food allergy, in infancy and early childhood. So far there has been no evidence for a preventing effect of hypoallergenic infant formulas on respiratory allergic diseases.
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