The nutritional value of hypoallergenic formulas

As food allergy is an increasing problem in children worldwide, numerous strategies for prevention are under investigation. Currently, recommendations for infants at high risk of atopic disease (affected parent or sibling), are breastfeeding and delayed introduction of solid foods, as well as dietary products with reduced allergenicity for supplementation, if needed. These include partially hydrolysed formulas (pHF) and extensively hydrolysed formulas (eHF) based on whey, casein or bovine collagen. Soya based formulas have been suggested as a standard option in infants with cow’s milk allergy, aged older than 6 months, but they are currently not recommended for allergy prevention due to the wide debate on genetically modified organisms (OGM). It is recommended that the safety of breast milk substitutes be evaluated carefully before they are introduced on the market (1). An important part of this evaluation is assessing the impact on growth and metabolism. In spite of this recommendation, significant uncertainty exists with respect to the nutritional efficiency of partially and extensively hydrolysed formulas intended for allergy prevention.

Expert panels in Europe issued commentaries that the nutritional adequacy of dietary products for infants should be based on the comparison of outcomes in infants fed such products with the outcomes of healthy infants exclusively breastfed for six months, rather than on composition of human milk. In the absence of adequate data, consideration should be given to including a breastfed reference group in the trials. The Commission of the European Communities indicates that the nutritional efficacy of infant formulas claimed to have hypoallergenic or hypoantigenic properties should be demonstrated by a longitudinal study on weight and height development over at least three months, involving at least twenty babies born at full term and aged less than 1 month at the beginning of the study (2).
   
In considering prospective controlled trials comparing the use of hydrolysed infant formula to human milk or an adapted cow’s milk formula (3-20), no major differences in the anthropometric and biochemical parameters are demonstrated in infants fed pHF compared with infants fed an adapted cow’s milk or human milk. There is also no evidence of major differences between infants fed eHF and an adapted cow’s milk formula on growth parameters and biochemical parameters, except on protein and nitrogen utilization. Blood urea nitrogen (BUN) concentrations in some investigations (Rigo 1994, -ref 17 - with pHF, Giovannini1994 –ref 6 -, with a casein-based eHF;  Vandenplas 1993, - ref. 9 - with an intermediate hydrolysate of whey) have been found increased at different time points. On the other hand, Decsi et al (12) found lower total serum protein and BUN concentrations in infants fed eHF than in those fed a conventional infant formula. Total amino acid concentrations were found to be significantly higher in infants fed pHF  (17) and eHF too (6).

While the use of hydrolysed formulas is recommended for the prevention and/or treatment of atopic disorders, few studies directly address their nutritional evaluation as a primary outcome measure. New studies in this perspective are of outstanding interest, even if the numbers of subjects included are small, and especially for blood hematochemical analyses. In a recent report with the nutritional evaluation as primary outcome, three types of eHF (two, casein-based; one, whey-based) have been considered, showing again higher serum urea nitrogen for one group on a casein-based eHF together with major blood amino acid imbalances (21).

On the whole, available data suggest that there is no evidence that feeding pHF impairs the growth and biochemical parameters of term infants. There is also no evidence of differences between infants fed eHF and an adapted cow’s milk formula and/or human milk on growth parameters and biochemical parameters, except on indices of protein metabolism. BUN concentrations that were either increased or, in one study, reduced in infants fed eHF, and differences of the amino acid pattern were often reported, suggesting a different protein utilization according to the degree of hydrolysis (the minor the utilization for protein synthesis, the higher the degree of hydrolysis). Some Authors have suggested that the use of combinations of both casein and whey for hydrolysate products, rather than the exclusive use of just one, may decrease these differences (21).

In the case of hydrolyzed formulas, both ethical and practical issues do not allow for the same number of infants and homogeneity as is the case for standard infant formulas vs human milk. On an ethical standpoint, before giving alternative sources of proteins to babies that cannot be breastfed, one should at least try to define the individual risk of atopy, thus justifying the choice of a product alternative to human milk. Only recently, some official bodies have indicated eHF as a first choice for prevention, but the discussion on the possible use of pHF vs eHF has been ongoing for many years. For this reason we have a series of study designs including different protein forms (after partial or extensive hydrolysis processes) and sources (casein, whey proteins, soy, collagen), according to both science-based issues and technological points. Whether and how local intestinal reactions and/or higher energy needs directly connected with the atopic state may also concur to impair growth is just matter of speculation, but these questions emphasize the fact that infants who should represent the main target of this type of formula feeding are at further major nutritional risk (22).

In conclusion, in spite of many suggestions, little scientifically sound evidence links the use of hydrolysate formulas to an impairment of growth progression. There are some reports suggesting the possibility of an altered metabolism of nitrogenous compounds with hydrolysates (particularly those with eHF). However, these results should be interpreted with caution, as only a small number of trials are available and they include very small study groups. Further research is needed, particularly considering formulas based on eHF. We need more studies with standardized scientific methodology (randomized, double-blind, placebo-controlled trials, with sample sizes adequate to estimate growth) and a follow-up prolonged through the first 12-24 months of life. In the meantime, a regular check of growth, blood urea and (where it is feasible) blood amino acid values (compared with reliable, local reference values from breastfed infants) is recommended for infants in prolonged treatment with casein or whey eHF (23).

References

1. Aggett O, Agostoni C, Goulet O, Hernell O, Koletzko B, Blafeber HL, et al. The nutritional and safety assessment of breast milk substitutes and other dietary products for infants: a commentay by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr 2001; 32:256-8. 
   
2. Commission of the European Communities. Food science and techniques. Reports of the Scientific Committee for Food. Luxemburg: Office for Official Publicatios of the European Communities. 1990.
   
3. Hauser B, Keymolen K, Blecker U, Suys B, Bougatef A, Loeb H, Vandenplas Y.
   A comparative evaluation of whey hydrolysate and whey-predominant formulas. How well do infants accept and tolerate them? A comparative evaluation of whey hydrolysate and whey-predominant formulas. How well do infants accept and tolerate them? Clin Pediatr (Phila) 1993;32:433-7.
   
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5. Exl BM, Deland U, Secretin MC, Preysch U, Wall M, Shmerling DH. Improved general health status in an unselected infant population following an allergen-reduced dietary intervention programme: the ZUFF-STUDY-PROGRAMME. Part II: infant growth and health status to age 6 months. ZUg-FrauenFeld. Eur J Nutr 2000;39:145-6.
   
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7. Odelram H, Vanto T, Jacobsen L, Kjellman NI. Whey hydrolysate compared with cow's milk-based formula for weaning at about 6 months of age in high allergy-risk infants: effects on atopic disease and sensitization. Allergy 1996 Mar;51:192-5.
   
8. Bergmann RL, Dannemann A, Edenharter G, Bergmann KE, Monch E, Dudenhausen JW. Wahn U. [Influence of ultrafiltrated, partially hydrolysed formula on growth and health of young infants].  Monatsschrift fur Kinderheilkunde 1996; 144:152-8.
   
9. Vandenplas Y , Hauser B, Blecker U, Suys B, Peeters S, Keymolen K, Loeb H.
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11. Decsi T, Veitl V, Burus I. Plasma amino acid concentrations, indexes of protein metabolism and growth in healthy, full-term infants fed partially hydrolyzed infant formula. JPGN 1998; 27:12-6.
    
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15. Rigo J, Verloes A, Senterre J.  Plasma amino acid concentrations in term infants fed human milk, a whey-predominat formula, or a whey hydrolysate formula. J Pediatr 1989; 115:752-5.
    
16. Rigo J, Salle BL, Putet G, Senterre J. Nutritional evaluation of various protein hydrolysate formulae in term infants during the first month of life. Acta Paediatr Suppl 1994 Sep;402:100-4.
    
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18. Rigo J, Salle BL, Picaud JC, Putet G, Senterre J. Nutritional evaluation of protein hydrolysate formulas. Eur J Clin Nutr 1995; 49 (suppl 1): S26-S38.
    
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21. Hernell O, Lonnerdal B. Nutritional evaluation of protein hydrolysate formulas in healthy term infants: plasma amino acids, hematology, and trace elements. Am J Clin Nutr 2003;78:296-301.
    
22. Agostoni C, Grandi F, Scaglioni S, Giannì ML, Torcoletti M, Radaelli G, Fiocchi A, Riva E. Growth pattern of breastfed and nonbreastfed infants with atopic dermatitis in the first year of life. Pediatrics 2000; 106/5/e73.
    
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This material has been prepared by members of the IFM’s Advisory Committee on Child Health and Nutrition.

June 2004