12 Infant Formulas

[Application of Infant Formulas in CMA] [Allergenicity / Safety] [Prophylaxis of Atopic Disease]

12.1 Application of Infant Formulas in CMA
 

Parameters / Subjects	Outcome	References
Nutritional Status 18 children with CMA (age of 1-3.5 years)	Diets based on soy or CAS hydrolysate formula (taken by 72%) supplemented with calcium and in 11 children with vitamins A and D resulted in adequate mean intakes of nutrients	Tiainen  et al. 1995
Infant Formulas 60 children with infantile colic	Improvement in 18% of children after receiving a soy formula, while symptoms were unchanged or worse in 53% (cow's milk formula and soy formula fed children), improvement with extensively hydrolyzed CAS formula (Nutramigen)	Lothe et al. 1982
Infant Formulas 36 children with CMA (age of 1 month to 3 years)	Application of a) soybean and b) partially hydrolyzed milk formula: No improvement in a) 10% (Prosobee), b) 12% (Humana SL) Partial or total relief of symptoms in a) 69% (Prosobee), b) 76% (Humana SL)	Iwanczak et al. 1995
Infant Formulas 100 children with CMA (age of 5 months to 9 years)	Application of a) soybean and b) extensively hydrolyzed CAS formula: Partial or total relief of symptoms in a) 37% (Prosobee), b) 42% (Nutramigen)	Korol et al. 1995
Casein Hydrolyzed Formula a 4-day-old female with cow's milk induced eosinophilic colitis	Rectal bleeding resolved upon an extensively hydrolyzed CAS formula, and endoscopy one week later showed improvement, with only scattered areas of erythema, and no friability	Wilson et al. 1990
Whey Hydrolyzed Formulas 79 infants with CMA / CMI (age of <3 months)	Application of 2 extensively whey hydrolyzed formulas (1 lactose free): during application / follow-up of 10 weeks improvement of symptoms in about 80% of children and normal growth with both formulas	Verwimp et al. 1995
Whey Hydrolyzed / Amino Acid Formulas 22 infants with CMA (mean age of 6 months)	Atopic eczema improved significantly and progressively in extensively hydrolyzed whey and amino acid formula- fed groups; downward trend of serum total and milk- specific IgE levels proving the efficacy of both formulas (follow-up study of 9 months)	Isolauri et al. 1995
Probiotics / Whey Hydrolyzed Formula 31 infants with atopic eczema and CMA	1-month study period: infants fed with extensively hydrolyzed whey formula a) fortified with Lactobacillus GG or b) not fortified formula clinical score of atopic dermatitis improved significantly in a); decreased concentrations of alpha 1-antitrypsin and fecal TNF-alpha in a); concentration of fecal eosinophil cationic protein unaltered in a) and b)	Majamaa & Isolauri 1997
Amino Acid Formula 12 infants with adverse reactions to soy formula, whey hydrolysate, or CAS hydrolysate	Infant formula composed of individual amino acids: no symptoms	Hill et al. 1995
Chestnut Formula >50 infants with CMA or lactose intolerance	Supplemented chestnut formula: normal infant's development, 2 cases of intolerance	Osvaath et al. 1976
Soy Protein Formula 20 children with CMA and atopic dermatitis	Cow's milk- free diet using as a soy protein formula improved the skin lesions, in addition to insuring a regular growth in all infants; possible secondary sensitization to soy 1 infant	Cantani et al. 1990
Soy Milk Formula 17 children with CMA / CMI (age of 6 months to 3 years)	Clinical tolerance to follow-up soybean formula in 16 children, one patient developed a severe diarrhoea within 72 hours after introduction of the soybean formula	Buts et al. 1993
Soy Milk 20 infants with CMA	Incidence of allergic symptoms in 17% of infants fed a 2S protein fraction depleted soy milk	Marano et al. 1989
Soy / Beef Hydrolyzed Formula (a) 12 infants with protracted enteritis  (b) 10 infants with atopic eczema	Fed with lactose-free soy and beef hydrolysate based formula:  improvement of symptoms in both groups, allergic symptoms in 1 (a) and 3  (b) infants who were previously fed with intact soy protein	Donzelli et al. 1990
Hypoallergenic Rice, Amino Acid Formula 1child with cow's milk and soybean allergy (age of 11 months)	Biotin deficiency in an Japanese infant fed with an amino acid formula and hypoallergenic rice processed by protease; symptoms disappeared after oral supplementation with biotin	Higuchi et al. 1996
Lamp-Meat Based Formula 10 infants with adverse reactions to CAS hydrolyzed formulas (age of 6 months to 3 years)	Application of a modular lamb- meat- based formula, prompt resolution of symptoms (follow-up for 3 months to 5 years)	Weisselberg et al. 1996
Ass' Milk 9 unweaned infants with multiple food hypersensitivity presenting severe symptoms of CMA	Ass' milk plus medium chain triglycerides well tolerated by all patients	Iacono et al. 1992

12.2 Allergenicity / Safety of Infant Formulas
 

Reported Adverse Reactions	References
Human Milk	see 11 Allergen Sources Reported Adverse Reactions
Infant Formulas 20 children with CMA (age of 15 to 76 months) allergic reactions (challenge tests) to a) extensively hydrolyzed CAS formula in 10%, b) extensively hydrolyzed whey formula 13%, c) partially hydrolyzed whey formula in 45%	(1) Ragno et al. 1993
Infant Formulas Acute allergic reactions in a 7-year old girl with CMA after challenge with 6 different partially and extensively hydrolyzed whey and CAS formulas (DBPCFC); anaphylactic reactions to a extensively hydrolysed CAS formula (Alimentum) (1, 2)	(1) Amonette et al. 1991 (2) Schwartz & Amonette 1991
Casein Hydrolyzed Formula Anaphylaxis  in a newborn infant after ingestion of extensively hydrolyzed CAS formula (Pregestimil) (1)	(1) Lifschitz et al. 1988
Casein Hydrolyzed Formula Systemic urticaria in 1 of 11 children with CMA after DBPCFC with extensively hydrolyzed CAS formula (Alimentum) (1)	(1) Oldaeus et al. 1991
Casein Hydrolyzed Formula Anaphylaxis in a newborn infant after ingestion of extensively hydrolyzed CAS formula (Nutramigen) (1)	(1) Saylor & Bahna 1991
Whey Hydrolyzed Formula Anaphylaxis after ingestion of extensively hydrolysed whey protein formula (Alfa-ré) in infants aged 3 to 8 months (1)	(1) Businco et al. 1989
Whey Hydrolyzed Formula Sytemic urticarial and respiratory reactions in 8 of 13 children with more severe sytemic IgE- mediated CMA (groups B and C: positive SPT to cow's milk, whey and CAS hydrolyzed formulas) when fed a partially hydrolysed whey formula (Good Start) (1)	(1) Schwartz et al. 1991
Whey Hydrolyzed Formula Anaphylaxis after ingestion of partially hydrolyzed whey formula (Good Start) (1) Anaphylaxis after ingestion of partially hydrolyzed whey formula in 2 infants (2)	(1) Ellis et al. 1991 (2) Businco et al. 1994
Extensively Hydrolyzed Formula 13 infants allergic to extensively hydrolyzed cow's milk protein formulas fed for treatment of chronic digestive symptoms (1)	(1) de Boissieu et al. 1997
Soy Hydrolyzed Formula 43 patients with possible milk- and/or soy-protein enterocolitis: 23% had positive challenge with cow's milk, and 33% and 30% had positive challenge to 2 hydrolyzed soy protein isolates	(1) Burks et al. 1994

 

Reportedly Safe Applications	References
Casein Hydrolyzed Formula 1 extensively hydrolyzed CAS infant formula tested by DBPCFC in 5 children with IgE- mediated CMA, no symptoms occured (1)	(1) Host & Samuelsson 1988
Casein Hydrolyzed Formula 1 extensivelyhydrolyzed CAS infant formula tested by SDS-PAGE immunoblot, ELISA and DBPCFC in 25 cow's milk allergic children, even in open challenge no reactions occured (1)	(1) Sampson et al. 1991
Whey Hydrolyzed Formula All of 13 children with mild topical IgE- mediated CMA (group A: positive SPT to cow's milk, negative to whey and CAS hydrolyzed formulas) tolerated a whey hydrolysate formula (Good Start) when fed for at least 2 weeks (1)	(1) Schwartz et al. 1991
Whey Hydrolyzed Formula 1 ultrafiltrated (<8 kDa) whey hydrolysate infant formula could be administered safely to 66 children with CMA (elimination/challenge procedure)	(1) Halken et al. 1993a
Casein / Whey Hydrolyzed Formula 1 CAS-whey hydrolyzed infant formula tested by PBMC proliferation in 10 children with CMA: no significant T-cell activation (1)	(1) Eigenmann et al. 1995
Casein / Whey Hydrolyzed Formula Hydrolysate well tolerated by 31/33 cow's milk allergic children (1)	(1) Martin-Esteban et al. 1998

Skin Tests and in vitro Tests of Infant Formulas
 

Allergens in Infant Formulas	Content / Products	References
Hydrolyzed Formulas 26 children with CMA (age of 1.3 to 13.8 years)	Positivity in SPT with a) whey hydrolyed formula 69% b) extensively hydrolyzed CAS formula 38%	Schwartz et al. 1989
Hydrolyzed Formulas 45 children with CMA (age of 3 months to 16 years)	Positivity in SPT (n=34-41) with a) partially and extensively hydrolysed whey formulas: Beba 24% and Profylac 15% b) extensively hydrolysed CAS formulas: 2.5% each (Alimentum and Nutramigen) Positivity in RAST with Beba 24%, other hydrolyzed formulas 7-13% Relative IgE- binding potency <0.06% for all tested formulas (RAST inhibition) Detectable amounts of bovine beta-LG in Beba 200 µg/g dry weight, other hydrolysed formulas 0.006-0.066 µg/g (ELISA)	Oldaeus et al. 1991
Hydrolyzed Formulas 15 children with CMA (age of 3 to 13 years)	Positivity in SPT with a) partially and extensively hydrolyed whey formulas: Beba 47% and Alfare 6.7% (1/15) b) extensively hydrolyzed CAS formulas: Nutramigen 0% (regular cow's milk formula 87%)	Oldaeus et al. 1992
Hydrolyzed Formulas 7 different infant formulas	Detectable amounts of bovine beta-LG in hydrolyzed formulas from cows' milk whey or CAS, and from bovine collagen and soy in (range 0.0056 to 200 µg/g dry weight, 0.84 to 31200 ng/mL ready-to-use product)	Makinen-Kiljunen & Sorva 1993
Hydrolyzed Formulas 13 children with CMA	Serum IgE against protein hydrolysates in 6 children	Plebani et al. 1990
Hydrolyzed Formulas children with CMA	6 hydrolyzed formulas tested: certain hydrolysates induced positive skin reactions and allergic symptoms after oral challenge; CAS hydrolysates had the least residual allergenic activity	Rugo & Wahn 1992 Wahn et al. 1992
Hydrolyzed Formulas 16 children with CMA	1 and 2 positive results to 2 extensively hydrolysed CAS formulas; 7 positive results to a extensively hydrolysed whey formula (RAST)	Dean et al. 1993
Whey Hydrolyzed Formula 1 ultrafiltrated (<8 kDa), extensively hydrolysed whey infant formula	35 patients with IgE- mediated reactions: 6% had positive SPT, 11% positive RAST against formula (no reactions in oral challenge test)	Halken et al. 1993a
Whey Hydrolyzed Formula 1 ultrafiltrated, extensively hydrolysed whey infant formula	5 children with CMA: Hydrolysate positive in 4/5 patients in SPT, inhibition of IgE-binding to cow's milk proteins  by the formula ranged from 51-96%; Peptides of > 2600 Da positive in SPT and RAST inhibition; peptides of < 1400 Da negative in SPT but still able to inhibit to a small extent IgE- binding to the hydrolysate (SEC, SPT, RAST)	Van Hoeyveld et al. 1998
Casein Hydrolyzed Formula 10 children with CMA	Proliferative responses of PBMCs to hydrolysate formula: higher in 3 patients whose symptoms were not reduced by CAS hydrolysate formula	Nishida et al. 1995
Hydrolyzed Infant Formulas a) extensively hydrolyzed CAS formula b) extensively hydrolyzed whey formula c) partially hydrolyzed whey formula	20 children with CMA (age of 15 to 76 months); positive SPT and specific RASTto  a) in 15% and 15%, b) in 15% and 20% c) in 45% and 65%, respectively	Ragno et al. 1993
Hydrolyzed Infant Formulas a) non hydrolysed formula b) whey-based formula c) whey-based and ultra-filtrated formula d) CAS/whey-based formula	12 children with CMA: All hydrolysed formulas showed reduced IgE- binding capacity; 25% of patients sera showed IgE- binding to b) and c), and 42% to d); b) and d) contained bovine serum albumin, beta-LG, CAS and their fragments (3-67 kDa) c) contained CAS fragments (3-6 kDa) and beta-LG and its fragments (6-18 kDa) (RAST, immunoblot)	Gortler et al. 1995
Hydrolyzed Infant Formulas 11 whey and 1 CAS hydrolysed formulas	Inhibition of IgE binding to    positive samples inhibition alpha-LA 12 18-93% beta-LG 12 2-84% BSA 6 2-75% bovine IgG 8 3-72% CAS 11 3-89%  (RAST inhibition)	(1) van Beresteijn et al. 1995
Hydrolyzed Infant Formulas 9 whey or CAS hydrolysed formulas	CAS- specific mAb: 0.05-0.67% CAS components in all partly and 2 extensively whey hydrolysate formulas, not detectable in 2 extensively CAS hydrolysate and the amino acid based formulas (SDS-PAGE immunoblot, ELISA inhibition)	(1) Restani et al. 1995, 1996 (2) Plebani et al. 1997
Extensively Hydrolyzed Formulas children with CMA	IgE-binding to residual protein fractions less than 20 kDa in several extensively hydrolyzed cow milk- based formulae (RAST inhibition)	Hoffman & Sampson 1997
Infant Formulas a) partially hydrolysed whey formula b) partially hydrolysed whey/CAS formula c) soy/pork collagen hydrolysate d) amino acid formula	20 cow's milk allergic children (mean age 1.6 years): Inhibition of IgE- binding to cow's milk by cow's milk > a > b > c > d (RAST inhibition); SPT to d) all negative	Niggemann et al. 1999a
Human Milk	Cow's milk proteins	see 11 Allergen Sources

12.3 Infant Formulas for Allergy Prophylaxis

It should be noticed that multiple parameters are involved in (food) allergy prevention. Nutritional intervention and environmental allergen avoidance are factors in allergy prevention. The role of infant formulas is controversial because the results of several studies have not been reproduced and the objective experimental conditions are difficult to achieve and maintain when studying human subjects. Please notice the disclaimer !
 

Prevention of	Feeding / Formula	References
Atopic Disease 328 children with a positive family history of allergy (15 years follow up)	Breast fed infants were found to have approximately one-half the incidence of atopy of cow's milk or soy based formula fed infants	Gruskay 1982
Atopic Disease 101 newborn infants of atopic parents (total serum IgE)	development of atopic disease in breast-fed group: 38% with IgE > 0.8 U/ml 12% with IgE < 0.8 U/ml  soy-fed group: 33% with IgE > 0.8 U/ml 16% with IgE < 0.8 U/ml cow's milk-fed group: 90% with IgE > 0.8 U/ml 17% with IgE < 0.8 U/ml	Businco et al. 1983b
Atopic Eczema 97 brest fed and 124 non brest fed infants	development of atopic eczema breast-fed group: 22%  (restricted maternal diet) 48% (no restricted maternal diet) soy-fed group:  in 63% cow's milk-fed group:  in 70% CAS hydrolysate-fed group:  in 21%	Chandra et al. 1989a
Atopic Disease 72 infants with family history of atopy (each group)*	incidence of atopic eczema, wheezing, rhinitis, gastrointestinal symptoms, or colic breast-fed group: in 20% soy-fed group:  in 37% cow's milk-fed group:  in 36% partially hydrolysed whey-fed group: in 7% cumulative incidence of atopic disease: breast-fed and whey hydrolysate-fed group < cow's milk and soy-formula fed group	Chandra et al. 1989b Chandra & Hamed 1991 Chandra 1997
Atopic Disease 155 infants with family history of atopy	incidence of atopic symptoms (at 18 months) extensively CAS hydrolysate fed group: in 51% partially hydrolysate fed group: in 64% regular cow's milk formula fed group: in 84%	Oldaeus et al. 1997
Atopic Disease, Cow's Milk Allergy 91 high risk infants (follow-up to 18 months of age)	development of atopic diseases similar in all groups; development of cow's milk allergy / intolerance: exclusively breast fed group: none regular cow's milk formula fed group: in 3 infants with skin symptoms ultrafiltered, extensively hydrolysed whey-fed group: none	Odelram et al. 1996
Atopic Disease, Humoral Response high risk infants (formula fed >3 months) a) 31 fed with extensively CAS hydrolyzed formula b) 29 fed with partially hydrolyzed formula c) 34 fed with regular cow's milk formula	development of any atopic disease: a) in 29%, b) in 38%, c) in 50% (at 9 months) a) in 35%, b) in 48%, c) in 62% (at 18 months) associated to detection of spec. IgE and high spec. IgG responses Cow's milk specific IgE: a) in 6.5%, b) in 10%, c) in 65% beta-LG specific IgG: a < b < c	Oldaeus et al. 1999
Cow's Milk Allergy 21 infants with gastrointestinal symptoms of cow's milk and/or soy protein intolerance	fed with whey protein hydrolysate formula: improvement of symptoms	Merrit et al. 1990
Cow's Milk Allergy 158 high-risk infants (1 year of age, prospective study)	development of cow's milk allergy / intolerance: exclusively breast-fed group:  in 1/20 extensively hydrolysed CAS formula-fed group: in 1/59 extensive whey hydrolysate-fed group: in 3/62 (no symptoms to formulas occurred)	Halken et al. 1993b
Cow's Milk Allergy 58 formula-fed "at risk" infants (all children not breast-fed, formulas fed for first 6 months of life)	development of cow's milk allergy / intolerance at age of 6, 12, 36, and 60 months: regular cow's milk formula fed group: in 43%, 53%, 57%, and 60% partially whey hydrolysate-fed group: in 7%, 21%, 25%, and 29%	Vandenplas et al. 1995
Cow's Milk Allergy unselected healthy, full-term infants a) 1789 fed with cow's milk formula b) 1859 with pasteurized human milk c) 1737 with extensively hydrolysed whey formula  d) 824 exclusively breast-fed	18 to 34 months follow-up cumulative incidence of cow's milk allergy: in a) 2.4%, b) 1.7%, c) 1.5%, d) 2.1% of infants	Saarinen et al. 1999a
Humoral Response infants at risk of atopy (age of 6 months) a) breast fed group b) regular cow's milk formula fed group c) partially whey hydrolysate fed group	IgE, IgG, and IgG subclasses: lower total IgE, cow's milk specific IgG, and alpha- lactalbumin and beta- lactoglobulin specific IgG4 in a) and c) than in b) (no significant differences at 5 days of age)	Chirico et al. 1997
Humoral Response 129 unselected infants a) breast fed b) cow's milk formula fed c) CAS hydrolysate fed during the first 3 days of life, otherwise exclusively breast fed	Follow-up for 2 years: Exposure to cow’s milk stimulated cow's milk proteins specific IgG production, while feeding with a CAS hydrolysate was associated with low specific IgG levels	Juvonen et al. 1999

* Studies may be experimental, unproved, or controversial. Please notice the disclaimer !