Hypoallergenic Infant Formulas

The American Academy of Pediatrics is committed to breastfeeding as the ideal source of nutrition for infants. For those infants who are formula-fed, either as a supplement to breastfeeding or exclusively during their infancy, it is common practice for pediatricians to change the formula when symptoms of intolerance occur. Decisions about when the formula should be changed and which formula should be used vary significantly, however, among pediatric practitioners. This statement clarifies some of these issues as they relate to protein hypersensitivity (protein allergy), one of the causes of adverse reactions to feeding during infancy. ABBREVIATION. IgE, immunoglobulin E. Symptoms of food protein allergy include those commonly associated with immunoglobulin E (IgE)-associated reactions, such as angioedema, urticaria, wheezing, rhinitis, vomiting, eczema, and anaphylaxis.1 Non–IgE-associated, immunologically mediated conditions have also been associated with the ingestion of cow’s milk, soy, and other dietary proteins in infant feedings. These disorders include pulmonary hemosiderosis,2 malabsorption with villous atrophy,3 eosinophilic proctocolitis,4 enterocolitis,5 and esophagitis.6 Finally, some infants may experience extreme irritability or colic as the only symptom of food protein allergy.7 The prevalence in infancy of milk protein allergy is low—2% to 3%.8–10 Thus, the use of hypoallergenic-labeled infant formulas, which cost as much as 3 times more than standard formulas, should be limited to infants with well-defined clinical indications. Adverse reactions to cow’s milk associated with other conditions such as phenylketonuria and lactose intolerance may also be alleviated by the use of alternative formulas, although not necessarily those intended to treat infants with protein allergy. FORMULA DEVELOPMENT AND LABELING Before new potential hypoallergenic formulas are tested in trials using human infants, comprehensive preclinical testing must be conducted to examine for toxicity and suitability to maintain a positive nitrogen balance and to attempt to predict whether infants allergic to cow’s milk will react adversely to them. This testing should include efforts to determine the molecular weight profile of residual peptides, the amount of immunologically recognizable material present, and the ability of the product to sensitize or provoke reactions in animal models of allergenicity.11–14 To establish the risk of hypersensitivity in infants, carefully conducted preclinical studies must be performed that demonstrate a formula may be hypoallergenic. The formula needs to be tested in infants with hypersensitivity to cow’s milk or cow’s milkbased formula and the findings verified by properly conducted elimination-challenge tests.15 These tests should, at a minimum, ensure with 95% confidence that 90% of infants with documented cow’s milk allergy will not react with defined symptoms to the formula under double-blind, placebo-controlled conditions.16 Such formulas can be labeled hypoallergenic. If the formula being tested is not derived from cow’s milk proteins, the formula must also be evaluated in infants or children with documented allergy to the protein from which the formula was derived. It is also recommended that after a successful double-blind challenge, the clinical testing should include an open challenge using an objective scoring system to document allergic symptoms during a period of 7 days.16 This is particularly important to detect late-onset reactions to the formula.17 Any formula with residual peptides may provoke reactions in infants allergic to cow’s milk.17,18 Extensively hydrolyzed proteins derived from cow’s milk, in which most of the nitrogen is in the form of free amino acids and peptides ,1500 kDa, have been used in formulas for .50 years for infants with severe inflammatory bowel diseases or cow’s milk allergy. These formulas, as well as the newer free amino acid-based formulas, have been subjected to extensive clinical testing and meet the standard for hypoallergenicity.19–21 Hypoallergenic formulas are intended for use by infants with existing allergic symptoms. Recently formulas have also been promoted to prevent the development of allergy in infants at high risk for developing allergic symptoms. The ability to determine which infants are at high risk is imperfect, although many markers, including elevated levels of cord blood IgE and serum IgE in infancy and an atopic family history, have been identified.22 Because a family history of allergy is at least as sensitive and specific as any other marker,23 infants from families with a history of allergy should serve as the study participants in clinical testing of formulas that claim the ability to prevent allergy from developing. These infants should be fed the formula exclusively from birth for at least 6 months under the conditions of a The recommendations in this statement do not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate. PEDIATRICS (ISSN 0031 4005). Copyright © 2000 by the American Academy of Pediatrics. 346 PEDIATRICS Vol. 106 No. 2 August 2000 by guest on December 30, 2017 http://pediatrics.aappublications.org/ Downloaded from controlled, randomized study and observed for at least 12 additional months. Allergic symptoms during the period of observation should be documented with a validated clinical scoring system and allergic symptoms verified by double-blind, placebo-controlled testing. When compared with infants fed a standard cow’s milk formula, infants fed formulas that claim to prevent or delay allergy should have a statistically significant lower prevalence of allergy at the end of the observation period.16 CLINICAL PRACTICE TREATMENT Breast milk is the optimal sole source of nutrition for healthy infants for the first 6 months of life. Breastfeeding should be continued for the first 12 months of life or longer. Although the incidence of food allergy is very low in breastfed infants compared with formula-fed infants, rare cases of anaphylaxis to cow’s milk proteins have been reported in those breastfed as well as more frequent cases of cow’s milk-induced proctocolitis.24–26 The pathophysiology of these reactions in the breastfed infant is not well-understood. However, immunologically recognizable proteins from the maternal diet can be found in breast milk.27,28 Elimination of cow’s milk, eggs, fish, peanuts and tree nuts, and other foods from the maternal diet may lead to resolution of allergic symptoms in the nursing infant. For those infants whose symptoms do not improve or whose mothers are unable to participate in a very restricted diet regimen and for formula-fed infants with cow’s milk allergy, alternative formulas can be used to relieve the symptoms. In infants allergic to cow’s milk, milk from goats and other animals29 or formulas containing large amounts of intact animal protein are inappropriate substitutes for breast milk or cow’s milk-based infant formulas. Soy formulas have a long history as alternative formulas in infants who are allergic. Eight to 14% of infants with symptoms of IgE-associated cow’s milk allergy will also react adversely to soy,30 but reports of anaphylaxis to soy are extremely rare. Those infants allergic to cow’s milk and who do not have an adverse reaction at the start of feeding on a soy formula tolerate it very well.31 Thus, although soy formulas are not hypoallergenic, they can be fed to infants with IgE-associated symptoms of milk allergy, particularly after the age of 6 months.29 There is a significantly higher prevalence of concomitant reactions between cow’s milk and soy proteins (25%– 60%) among those infants with proctocolitis and enterocolitis32 and therefore soy is not recommended for the treatment of infants with these non–IgE-associated syndromes.31 Formulas based on partially hydrolyzed cow’s milk proteins (1000–100 000 times higher concentrations of intact cow’s milk proteins compared with extensively hydrolyzed protein) have provoked significant reactions in a high percentage of infants allergic to cow’s milk33,34 and are not intended to be used to treat cow’s milk allergy. Extensively hydrolyzed formulas have also provoked allergic reactions in infants allergic to cow’s milk,17,18 but at least 90% of these infants tolerate extensively hydrolyzed formulas as well as the more recently introduced free amino acid-based infant formulas. Although the majority of infants with colic will not respond to a hypoallergenic formula, those with severe colic may benefit from a 1to 2-week trial of a hypoallergenic formula.7