Criteria for labelling infant formulas as "hypoallergenic"

Allergy Section, Canadian Paediatric Society (CPS)

CMAJ 1994;150(6):883-4
Reference No. AL 1994-02

Revision in progress February 2004

Index of position statements from the Allergy Section

The manifestations of allergy to cow's milk proteins during infancy are becoming better recognized and understood,¹ and strategies for treatment have been discussed.² Allergy to cow's milk may affect as many as 5% of infants,³ although the true prevalence is unknown. Once symptoms develop the treatment of choice still remains strict avoidance of the protein until the sensitization has diminished. Because infants may absorb more food allergen during their first year than later in life, owing to decreased secretory immunity of the small intestine and immaturity of intestinal function, the best strategy to prevent food sensitization is to avoid the relevant allergenic proteins.^4-8

Soy-protein formulas are as allergenic as cow's milk in some infants.^9-11 Cow's milk casein hydrolysates, in which the proteins are significantly reduced in size, may be useful therapeutically in highly allergic infants but are frequently unsatisfactory in taste and price, leading to problems with compliance. Recently, there has been great interest in the newer "hypoallergenic" formulas, including those using less hydrolysed whey proteins from cow's milk, which taste better and are less expensive than the traditional casein hydrolysates.

The main factors affecting allergic sensitization to a food protein are the characteristics of the protein.¹² In general, the lower the molecular weight of a protein, the less likelihood of antigenic effects. Complex proteins with numerous antigenic determinants are more likely to be good immunogens than smaller proteins with fewer antigenic determinants. In type I IgE-mediated hypersensitivity reactions, cellular activation and mediator release require the allergens to bridge two IgE-antibody molecules on the surface of cell membranes. Consequently, allergens must have appropriate molecular dimensions to effect such bridging. The relatively small size (molecular weight between 10 000 and 70 000 daltons [Da]) of most of the allergens found in cow's milk formulas may be ideal for this bridging. Proteins weighing less than 10 000 Da are probably less immunogenic, although they may act as haptens. Proteins weighing more than 70 000 Da are unlikely to be efficiently absorbed through normal mucosa and are thus less likely to cause problems.

Preclinical testing of infant formulas is necessary to characterize the molecular properties and residual antigenicity of the proteins.^13-15 The antigenicity of extensively hydrolysed casein, with a molecular weight below 5000 Da, should be reduced by at least 99.99% with methods such as enzyme-linked immunoassay inhibition. The sine qua non for declaring a formula hypoallergenic is the absence of significant reactions during double-blind, placebo-controlled trials involving an appropriate number of infants with a carefully documented allergy to cow's milk. The crucial criterion is for the level of allergen to be sufficiently low as to cause no significant reaction even in infants who are highly allergic to cow's milk. Although in some trials casein-hydrolysate formulas have been found to be significantly less allergenic than whey-hydrolysate ones, which in turn are less allergenic than ordinary cow's milk formulas, there still have been reports of reactions to whey^16,17 and casein hydrolysates^18-20 in highly allergic infants.

Therefore, even though casein-hydrolysate formulas fulfil preclinical and most clinical testing criteria, the labels on such formulas should state that their consumption by infants who are highly allergic to milk may not be risk free.

Since decreased dietary exposure to allergenic proteins should diminish the risk of sensitization to cow's milk, formulas modified to be less allergenic may prevent or delay an allergic reaction. A recent prospective study compared casein-hydrolysate supplementation and maternal antigen avoidance during lactation with normal infant feeding in infants at increased risk for atopic disorders.²¹ The authors found a significantly reduced incidence of atopic disease with the casein-hydrolysate formula in infants at 12 to 18 months of age but not in those at 24 months. Another study, which compared. a whey-hydrolysate formula with a soy or cow's milk formula given for the first 6 months, showed reduced manifestations of atopy with the whey-hydrolysate formula over the following 6 months.²²

To further assess this hypothesis, there should be additional randomized controlled clinical trials involving infants with a strong first-degree family history of atopy or elevated cord blood levels of IgE, or both. These infants should be followed up for at least 1 year and have a significantly reduced prevalence of allergic reaction to cow's milk formula, confirmed by double-blind, placebo-controlled trials.

Formulas that fulfil these criteria may be said to prevent or delay allergic reactions to milk. So that children who are highly allergic to milk can avoid inadvertent exposure to allergens such formulas should be called hypoallergenic only if they fulfil the criteria for that label.

References

1. Hill DJ, Hosking CS: The Melbourne milk allergy study, 1976 to 1988. In Hamburger RN (ed): Food intolerance in Infancy: Allergology, Immunology and Gastroenterology. Vol 1 of Carnation Nutrition Education Series. Raven. New York, 1989: 203-222
2. American Academy of Pediatrics Committee on Nutrition: Hypoallergenic infant formulas. Pediatrics 1989; 83: 1068-1069
3. Bock SA: Prospective appraisal of complaints of adverse reactions to food in children during the first three years of life. Pediatrics 1987; 79: 683-688
4. Hattevig G, Kjellman B, Sigurs N et al: The effect of maternal avoidance of eggs, cow's milk, and fish during lactation on the development of IgE and IgA antibodies in infants. J Allergy Clin Immunol 1990: 85: 108-115
5. Chandra RK, Puri S, Cheesma PS: Predictive value of cord blood IgE in the development of atopic disease and the role of breastfeeding in its prevention. Clin Allergy 1985; 15: 517-522
6. Dannaeus A, Johansson SGO, Foucard T: Clinical and immunological aspects of food allergy in childhood. II. Development of allergic symptoms and humoral immune response to food in infants of atopic mothers during the first 24 months of life. Acta Paediatr Scand 1978; 67: 497-504
7. Rowntree S, Cogswell JJ, Platts-Mills TAE et al: Development of IgE and IgG antibodies to food and inhalant allergens in children at risk for allergic disease. Arch Dis Child 1985; 60: 727-735
8. Bousquet J, Michel FB: Overview of the concept of prevention of allergy. Allergy Proc 1991; 12: 239-244
9. Eastham EJ, Lichauco T, Grady MI et al: Antigenicity of infant formulas: role of immature intestine on protein permeability. J Pediatr 1978; 93: 561-564
10. Eastham EJ, Lichauco T, Pang K et al: Antigenicity of infant formulas and the induction of systemic immunological tolerance by oral feeding: cow's milk versus soy milk. J Pediatr Gastroenterol Nutr 1982; 1: 23-28
11. Fries JH: Studies on the allergenicity of soybean. Ann Allergy 1971; 29: 1-7
12. Aas K: What makes an allergen an allergen. Allergy 1978: 33: 3-14
13. Richter WO, Jacob B. Schwandt P: Molecular weight determination of peptides by high performance gel permeation chromatography. Anal Biochem 1983, 133: 288-291
14. Hames BD (ed): Get Electrophoresis of Proteins: a Practical Approach, IRL Pr. Mclean, Va. 1981
15. Coombs RRA, Devey ME, Anderson KJ: Refractoriness to anaphylactic shock after continuous feeding of cow's milk to guinea pigs. Clin Exp Immunol 1978: 32: 271-283
16. Ellis MH, Short JA, Heiner DC: Anaphylaxis after ingestion of a recently hydrolyzed whey protein formula. J Pediatr 1991; 118: 74-77
17. Businco L, Cantani A, Loghi A et al: Anaphylactic reactions to a cow's milk whey protein hydrolysate (Alfa-Ré, Nestlé) in infants with cow's milk allergy. Ann Allergy 1989; 62: 333-335
18. Saylor JD, Bahna SL: Anaphylaxis to casein hydrolysate formula. J Pediatr 1991, 118: 71-74
19. Bock SA: Probable allergic reaction to casein hydrolysate formula. [C] J Allergy Clin Immunol 1989; 84: 272
20. Sampson HA, Bernhisel-Broadbent J, Yang E et al: Safety of casein hydrolysate in children with cow milk allergy. J Pediatr 1991; 118: 520-525
21. Zeiger RS, Heller S, Mellon MH et al: Effect of combined maternal and infant food-allergen avoidance on development of atopy in early infancy: a randomized study. J Allergy Clin Immunol 1989, 84: 72-89
22. Chandra RK, Singh G, Shridhara B: Effect of feeding whey hydrolysate, soy and conventional cow milk formulas on incidence of atopic diseases in high risk infants. Ann Allergy 1989; 63: 102-106

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Allergy Section Members: Zave Chad, MD (chairman and principal author), Department of Pediatrics, University of Montreal, Montreal, Que.; Alexander Ferguson, MB, ChB, Allergy Service, Department of Pediatrics. University of British Columbia, Vancouver, BC; F. Estelle R. Simons, MD, Section of Allergy and Clinical Immunology, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Man., and Wade T.A. Watson, MD, Section of Allergy and Clinical immunology, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Man.