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Hypoallergenic Feeds For Infants Allergic To Cow Milk
By - Danone Nutricia Academy

Fact: Amino acid-based feed with docosahexaenoic acid (DHA) and arachidonic acid (ARA) support growth in infants and are hypoallergenic and safe.

This "Journal Watch" discusses a comparative study (Extensively hydrolyzed feed vs. Amino-acid based feed) validating that infants with the most severe cow’s milk allergy(CMA)may react to the most extensively hydrolyzed formulas despite being hypoallergenic.

The hypoallergenic feed can provide adequate nutrition to children with cow’s milk allergy and support their growth. However, infants with the most severe CMA react to extensively hydrolyzed infant feed (EHF) that is considered to be a “hypoallergenic” alternative. This warrants the need for amino acid-based feed (AAF).1This Journal Watch brings to light the fact that EHFs may not be suitable for all infants with CMA and provides clinical evidence for AAFs to be truly “hypoallergenic” worldwide.

Breastmilk is the gold standard for infant and is highly recommended, yet, several infants are compelled to consume alternative feed as the only source of nutrition or in addition to breastmilk.1 The American Academy of Pediatrics (AAP) recommends cows’ milk-based feed for such infants. Around 2.5% of infants develop allergies or intolerance to cow’s milk, and hence, require an alternative feed. The search for an appropriate nutrient source further aggravates because infants with CMA frequently develop allergies to other foods as well. Poor management of food allergies can potentially hamper growth at such a tender age.2

Dietary options in CMA

Soy-based formula (SF): Although SF has been used as an alternative, its use depends on the type of CMA. Around 14% of infants with IgE-mediated and up to 60% of infants with non-IgE-mediated CMA show allergy to SF.2The European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) and the AAP do not recommend SF in the first six months of life.3

EHF: EHFs are modified cow’s milk-based feeds with proteins that are extensively broken down, thereby reducing their allergenicity.1 EHF has been recommended by the AAP as the first choice for managing nutrition in infants with CMA. However, the small peptide fragments in EHF are capable of eliciting allergic reactions.Few of them exhibited allergic reactions towards multiple foods and may display poor growth.2Thus, despite being successful in most of the infants, the conditions for a small fraction of infants don’t seem to improve with EHF.2

AAF: AAF contains only free amino acids; this may have a different implication on protein metabolism. AAF is used in cases in which EHF is not tolerated or well responded to, characterized by severe allergic reactions and multiple food allergies.4

Hypoallergenic tests to evaluate infant feed

Some commercially available EHFs are deemed to be “hypoallergenic”; however, the AAP recognizes a formula to be hypoallergenic only after being tested in subjects hypersensitive to cow’s milk or cow’s milk-based feed via the elimination-challenge tests. It is required for the tests to ensure 95% confidence that nine out of ten subjects with CMA will not develop reactions to the formula under a double-blind placebo-controlled food challenge (DBPCFC). The feed must then be tested to document allergic reactions over a seven-day period in an open challenge using an objective scoring system.1.

Infants and children with the most severe CMA have been observed to react to the EHFs and require AAFs that contain synthetic amino acids that are completely free of cow’s milk proteins.1 The evidence has been compiled in the next section in Table 1.

Evaluation of hypoallergenicity of EHF vs. AAF

Table 1: Clinical evidence on the hypoallergenicity of AAF for infants1,2

Study 11 Study 21 Study 32
Study design
  • Double-blind, randomized, controlled, parallel-design, prospective trial conducted at 14 clinical sites
  • DBPCFC followed by open challenge
  • Double-blind, randomized,placebo-controlled followed by food challenge using a crossover design
Inclusion criteria Healthy infants 14±2 days of age with established CMA Infants and children ≤10 years with established CMA at three clinical sites Infants between 2 months and 12 years with established CMA who were otherwise healthy from six sites
No. of participants 110 29 33
Study groups and tests conducted
  • Control group (received casein EHF; n= 52)
  • Experimental group (received the new AAF named “N”;n= 58)
  • Placebo group (received a commercially available AAF)
  • Treatment group (received the new AAF named “N”)
  • Open challenge
  • Both the feeds had identical nutrient composition (protein, DHA, ARA) except the protein equivalent source.
  • Amino acid composition in AAF similar to that reported for breast milk.
  • 24 out of 29 subjects had concomitant allergic manifestations at the study entry including atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, or gastrointestinal manifestations
  • All subjects were to observe a strict milk elimination diet before and during the study.
Parameters to be evaluated Growth, Tolerance, Adverse events Hypoallergenicity Hypoallergenicity
Results Growth:
  • Similar growth rate in terms of body weight and head circumference achieved, although not statistically significant.
  • 24 had positive diagnostic milk-specific IgE value to cow’s milk.
  • Five had positive DBPCFC to cow’s milk.
  • 23 had multiple food allergies as reported by parents/guardians.
  • 19 had two or more food allergies (eggs, peanuts, soy, wheat, tree nuts, and beef)along with CMA.
  • No subjects experienced an allergic reaction to either product.
  • The interim analysis revealed the lower bound of the 95% confidence interval was 91.3%, above the 90% requirement set forth by the AAP.
Adverse events:
  • Diarrhea was reported for nine infants in the control group vs. no infants in the experimental group (P<0.001).
  • No significant differences in the incidence of serious adverse events.
  • 29 had positive skin prick reactions to histamine and cow’s milk but negative responses to “N” and placebo AAF.
Open challenge:
  • No unusual stool patterns or characteristics, the incidence of flatulence, or spit-up were reported. Other events included vomiting episodes attributed to palatability, erythema around the mouth, itchy skin on the back, and mild stomach ache.
  • Plasma amino acid evaluation at age 90 days: Though considered clinically irrelevant, significantly higher concentrations of the essential amino acids* in the experimental group (P<0.05) were observed when compared with the control group.
  • However, all 29 had negative responses to both the DBPCFC and open challenge.
  • As all these events were self-resolving, and not related to allergic reactions, there was no discontinuation observed in the consumption of the feed under study.
  • No serious adverse events occurred during DBPCFC, open challenge, or extended 7-day feeding period.

*Essential amino acids: isoleucine, leucine, lysine, phenylalanine, tyrosine, threonine, and tryptophan

AAF: Amino acid-based feed, AAP: American Academy of Pediatrics, ARA: Arachidonic acid, CMA: Cow’s milk allergy, DHA: Docosahexaenoic acid, DPBCFC: Double-blind placebo-controlled food challenge, EHF: extensively hydrolyzed feed

Key takeaways:

  • The AAP recommends the use of an EHF or an AAF in infants with food allergies.2
  • In the case of most severe CMA, infants develop allergic reactions to EHFs.1
  • Hence, AAF supplemented with DHA and ARA are hypoallergenic and safe, and supports growth in infants with allergies to cow’s milk or multiple foods.1


  1. Nowak-Węgrzyn A, Czerkies LA, Collins B, Saavedra JM. Evaluation of Hypoallergenicity of a New, Amino Acid–Based Formula. Clin Pediatr. 2015 Mar;54(3):264-72.
  2. Burks W, Jones SM, Berseth CL, Harris C, Sampson HA, Scalabrin DM. Hypoallergenicity and effects on growth and tolerance of a new amino acid-based formula with docosahexaenoic acid and arachidonic acid. J Pediatr. 2008 Aug 1;153(2):266-71.
  3. Koletzko S, Niggemann B, Arató A, Dias JA, Heuschkel R, Husby S, Mearin ML, Papadopoulou A, Ruemmele FM, Staiano A, Schäppi MG. Diagnostic approach and management of cow's-milk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines. Journal of pediatric gastroenterology and nutrition. 2012 Aug 1;55(2):221-9.
  4. Canani RB, Nocerino R, Frediani T, Lucarelli S, Di Scala C, Varin E, Leone L, Muraro A, Agostoni C. Amino Acid-based Formula in Cow's Milk Allergy: Long-term Effects on Body Growth and Protein Metabolism. Journal of pediatric gastroenterology and nutrition. 2017 Apr 1;64(4):632-8.

    CVM code: 1610086372523