Allergy to extensively hydrolyzed cow's milk proteins in infants: safety and duration of amino acid-based formula

Infants (n = 52) allergic to cow's milk protein and extensively hydrolyzed formulas received an amino acid-based formula. The amino acid-based formula proved to be safe, with infants exhibiting an overall gain in length and weight. Children with allergy restricted to extensively hydrolyzed formulas were diagnosed earlier and tolerated cow's milk protein earlier than children with multiple food allergy.     

Safety and efficacy of a new extensively hydrolyzed formula for infants with cow's milk protein allergy

Cow's milk protein allergy (CMPA) is best treated by complete elimination of cow's milk from the diet. For infants with CMPA who cannot be breast-fed, formulas based on extensively hydrolyzed proteins or on amino acids are the preferred substitutes for cow's milk-based formulas. In this study, we compared the tolerance and growth of infants with CMPA who were fed a new extensively hydrolyzed formula containing lactose (eHF) with those who were fed an amino acid formula (AAF). This was a prospective, multi-center, randomized, reference-controlled study. Seventy-seven infants <12 months old with suspected CMPA were enrolled. In 66 of these, CMPA was confirmed by oral challenge in a double-blind, placebo-controlled food challenge (DBPCFC) or by a medical history of severe allergic reaction to cow's milk and a positive skin prick test. These infants were then tested for their reaction to eHF and AAF in a DBPCFC. All infants tolerated both formulas and were randomized to receive either eHF (n = 34) or AAF (n = 32) for 180 days. Growth (weight, length, and head circumference) and tolerance [skin, gastro-intestinal, and respiratory tract symptoms of allergy] were evaluated after 30, 60, 90, and 180 days. There were no significant differences between the two groups in any of the growth measurements. Length and head circumference were similar to Euro-growth standards, but weight was slightly lower. Gastro-intestinal and respiratory tract symptoms of allergy were also similar in the two groups. However, whereas SCORAD scores for atopic dermatitis remained constant throughout the study in infants-fed eHF, there was a slight decrease in those fed AAF. Infants-fed eHF had significantly fewer incidents of vomiting than infants-fed AAF and a significantly higher frequency of soft stools. The new eHF is safe and well tolerated in infants diagnosed with CMPA.     

Safety and efficacy of a new extensively hydrolyzed formula for infants with cow's milk protein allergy.

Cow's milk protein allergy (CMPA) is best treated by complete elimination of cow's milk from the diet. For infants with CMPA who cannot be breast-fed, formulas based on extensively hydrolyzed proteins or on amino acids are the preferred substitutes for cow's milk-based formulas. In this study, we compared the tolerance and growth of infants with CMPA who were fed a new extensively hydrolyzed formula containing lactose (eHF) with those who were fed an amino acid formula (AAF). This was a prospective, multi-center, randomized, reference-controlled study. Seventy-seven infants <12 months old with suspected CMPA were enrolled. In 66 of these, CMPA was confirmed by oral challenge in a double-blind, placebo-controlled food challenge (DBPCFC) or by a medical history of severe allergic reaction to cow's milk and a positive skin prick test. These infants were then tested for their reaction to eHF and AAF in a DBPCFC. All infants tolerated both formulas and were randomized to receive either eHF (n = 34) or AAF (n = 32) for 180 days. Growth (weight, length, and head circumference) and tolerance [skin, gastro-intestinal, and respiratory tract symptoms of allergy] were evaluated after 30, 60, 90, and 180 days. There were no significant differences between the two groups in any of the growth measurements. Length and head circumference were similar to Euro-growth standards, but weight was slightly lower. Gastro-intestinal and respiratory tract symptoms of allergy were also similar in the two groups. However, whereas SCORAD scores for atopic dermatitis remained constant throughout the study in infants-fed eHF, there was a slight decrease in those fed AAF. Infants-fed eHF had significantly fewer incidents of vomiting than infants-fed AAF and a significantly higher frequency of soft stools. The new eHF is safe and well tolerated in infants diagnosed with CMPA.     

Time course of allergy to extensively hydrolyzed cow's milk proteins in infants

We report on the follow-up of 22 infants allergic to cow's milk proteins who did not tolerate extensively hydrolyzed protein formulas. After successful use of an amino acid-based diet for a duration of 11.8 +/- 8.7 months, evolution differed according to the presence or absence of associated allergy to other foods. Cow's milk protein tolerance occurred earlier in the patients (n = 9) whose allergy was limited to cow's milk proteins and to extensively hydrolyzed protein formulas.     

Comparison of a partially hydrolyzed infant formula with two extensively hydrolyzed formulas for allergy prevention:A prospective, randomized study

The aim of this study was to compare the allergy‐preventive effect of a partially hydrolyzed formula with two extensively hydrolyzed formulas, in infants with a high risk for development of allergic disease. High‐risk infants from four Danish centres were included in the period from June 1994 to July 1995. Five‐hundred and ninety‐five high‐risk infants were identified. High‐risk infants were defined as having bi‐parental atopy, or a single atopic first‐degree relative combined with cord blood immunoglobulin E (IgE) ≥ 0.3 kU/l. At birth all infants were randomized to one of three different blinded formulas. All mothers had unrestricted diets during pregnancy and lactation and were encouraged to breast‐feed exclusively. If breast‐feeding was insufficient, one of the three formulas, according to randomization, was given during the first 4 months. It was recommended not to introduce cow's milk, cow's milk products, and solid foods until the age of 4 months. After the age of 4 months a normal unrestricted diet and conventional cow's milk‐based formula were given when needed. All infants were followed‐up prospectively with interview and physical examination at the age of 6, 12, and 18 months, and if any possible atopic symptoms were reported. If food allergy was suspected, controlled elimination/challenge procedures were performed in a hospital setting. Of 550 infants included in the study, 514 were seen at all visits and 36 were excluded owing to non‐compliance. Of 478 infants who completed the study, 232 were exclusively breast‐fed, 79 received an extensively hydrolyzed casein formula (Nutramigen), 82 an extensively hydrolyzed whey formula (Profylac), and 85 a partially hydrolyzed whey formula (Nan HA), during the first 4 months of life. These four groups were identical in regard to atopic predisposition, cord blood IgE, birthplace, and gender. Exclusively breast‐fed children were exposed less to tobacco smoke and pets at home and belonged to higher social classes, whereas the three formula groups were identical concerning environmental factors. The frequency of breast‐feeding was high; only eight (2%) children were not breast‐fed at all. The three formula groups were identical in regard to duration of breast‐feeding and age at introduction of formula and solid foods. No significant differences were found in the three groups of infants receiving formula milk regarding the cumulative incidence of atopic dermatitis or respiratory symptoms. The cumulative incidence of parental‐reported cow's milk allergy was significantly higher in children fed partially hydrolyzed formula (Nan HA) compared with extensively hydrolyzed formula (Nutramigen or Profylac) at 12 and 18 months (NanHA, 7.1%; Nutramigen, 2.5%; Profylac, 0%; p = 0.033). The cumulative incidence of confirmed cow's milk allergy was 1.3% (three of 232) in exclusively breast‐fed infants, 0.6% (one of 161) in infants fed extensively hydrolyzed formula (Nutramigen or Profylac), and 4.7% (four of 85) in infants fed partially hydrolyzed formula (Nan HA). Partially hydrolyzed formula was found to be less effective than extensively hydrolyzed formula in preventing cow's milk allergy, 0.6% vs. 4.7% (p = 0.05), but because of the small number of cases the results should be interpreted with caution. Compared with other similar studies the frequency of atopic symptoms was low, even though the dietetic intervention did not include either maternal diet during lactation or dietary restrictions to the children after the age of 4 months.     

Feeding a soy formula to children with cow's milk allergy: the development of immunoglobulin E-mediated allergy to soy and peanuts.

Peanut allergy has been associated with the intake of soy milk or a soy formula. We studied the development of immunoglobulin E antibodies specific to soy and peanuts and of allergic reactions caused by peanuts, in children with confirmed cow's milk (CM) allergy fed either a soy formula or an extensively hydrolyzed formula (EHF). One hundred and seventy infants with documented CM allergy (CMA) were randomly assigned to receive either a soy formula or an EHF. The children were followed to the age of 4 yr. Peanut-specific immunoglobulin E was measured at the age of 4. A detailed history of the occurrence of allergic reactions caused by peanuts was recorded by the parents. Soy-specific immunoglobulin E antibodies were measured at the time of diagnosis and at the ages of 1, 2 and 4 yr. Immunoglobulin E antibodies to soy (> or =0.35 kU/l) were found in 22 of 70 children fed the soy formula, and in 14 of 70 of the children fed the EHF (p = 0.082). In an open challenge with soy at the age of 4, no immediate reactions were observed. One of 72 children from the soy group had a delayed reaction. immunoglobulin E antibodies to peanuts (> or =0.35 kU/l) were found in 21 of 70 children fed the soy formula and 17 of 69 infants fed the EHF (p = 0.717). The incidence of reported peanut allergy in the soy group was two of 72 (3%) and four of 76 (5%) in the EHF group (p = 0.68). Development of immunoglobulin E-associated allergy to soy and peanuts was rare in our study group of milk allergic children. The use of a soy formula during the first 2 yr of life did not increase the risk of development of peanut-specific immunoglobulin E antibodies or of clinical peanut allergy.     

Safety of a new extensively hydrolysed formula in children with cow's milk protein allergy: a double blind crossover study

Background

Formulae for infants with cow's milk protein allergy (CMA) should be based on extensively hydrolysed protein. 'Extensively' however is not strictly defined. Differences in molecular weight and peptide chain length may affect its clinical outcome. We studied the safety of a new extensively hydrolysed casein based formula (Frisolac Allergycare^®: FAC) for children with IgE mediated CMA.

Methods

Thirty children, aged 1.5 – 14.8 years old (median 4.9 years) with persistent CMA were enrolled in this double-blind reference product (Nutramigen^®: NUT) controlled crossover study. All had positive skin prick tests (SPT) and IgE mediated allergy, showing immediate reactions after ingestion of small amounts of milk. Twenty-five children also had positive radio allergen sorbent tests (RAST) to cow's milk. Formulae provided consisted of 80% elementary formula in combination with 20% reference or test product. Crossover periods lasted for two weeks. From both products molecular weight (MALDI-TOF method and HPLC) and peptide chain length distribution (adapted Edman degradation) were determined.

Results

Maximum molecular weights of NUT and FAC are 2.1 and 2.56 kDa, respectively. The contribution of free amino acids and small peptides <0.5 kDa is 46% for FAC and 53% for NUT. About 50% of the protein fraction of both products consists of peptides longer than four amino acids. Three children did not complete the study. The other children all tolerated FAC very well; no adverse reactions were reported.

Conclusions

The new extensively hydrolysed casein-based formula (FAC) can safely be used in children with IgE mediated cow's milk allergy.

     

A prospective study of cow's milk allergy in exclusively breast-fed infants. Incidence, pathogenetic role of early inadvertent exposure to cow's milk formula, and characterization of bovine milk protein in human milk

A cohort of 1,749 newborns in the municipality of Odense were followed prospectively for the development of cow's milk allergy (CMA) during their first year of life. Altogether 39 fulfilled the criteria for CMA (2.2%). Out of the 39 infants, 17 developed symptoms of CMA during breast-feeding, in all cases before the age of 3 months. Nine of these were solely breast-fed at the time of diagnosis, giving a one year incidence of CMA in exclusively breast-fed infants of 0.5% (9/1,749) in a study population with a frequency of exclusive breast-feeding of 52% at 3 months of age. None of the infants had signs of CMA in the neonatal period. Review of records from the newborn nursery revealed that all 9 infants had been exposed to cow's milk formula in amounts corresponding to approximately 0.4-3.0 g of beta-lactoglobulin (BLG) during the first three days of life. Human milk samples were analyzed by enzyme-linked immunosorbent assay (ELISA) for the content of bovine BLG. Detectable amounts (0.5-45 ng/ml) were found in 3/9 samples of human milk against which the infants reacted clinically. Analysis of the size distribution by high pressure liquid gel permeation chromatography in combination with ELISA indicated a molecular weight of BLG corresponding to that of monomeric BLG (18 kD). Possibly early inadvertent and occasional exposure to cow's milk proteins may initiate sensitization in predisposed neonates. Subsequent exposure to minute amounts of bovine milk proteins in human milk may act as booster doses eliciting allergic reactions.     

The natural history of intolerance to soy and extensively hydrolyzed formula in infants with multiple food protein intolerance.

Infants (n = 18) with intolerance to extensively hydrolyzed formulas and soy who responded to an L-amino acid-based elemental formula (AAF) were studied until 3 years of age. By 2 years of age most tolerated non-formula foods, and by 3 years only 3 required AAF. Growth normalized during AAF feeding in 4 infants with failure to thrive.     

Z-score of weight for age of infants with atopic dermatitis and cow's milk allergy fed with a rice-hydrolysate formula during the first two years of life

Background: Recently, rice-based formulas have been widely used in hypoallergenic diets, but data on nutritional values are scarce. Aim: To evaluate the growth of infants fed with a rice-based hydrolysate formula, compared to those infants fed with a soy formula or an extensively hydrolysed casein formula, in the first 2 y of life. Methods: A total of 88 infants were enrolled between March 2002 and March 2004. Fifty-eight infants with atopic dermatitis (AD) and cow's milk allergy (CMA), confirmed by open challenge, were enrolled as study group: 15 were fed with a rice-based hydrolysate formula (RHF), 17 with a soy-based formula (SF) and 26 with an extensively hydrolysed casein formula (eHCF). Thirty infants with AD without cow's milk allergy were recruited as a control group (CG) and fed with a free diet. Weight was recorded on enrolment and at 3-monthly intervals in the first year of life, and at 6-monthly intervals in the second year. Infants were weighed naked, before feeding, by means of an electronic integrating scale. The z-scores of weight for age were calculated. Statistics: One-way analysis of variance and Student's t -test were used for statistical comparison. Significance was set at p <0.05. Results: No significant differences between the RHF, SF and eHCF groups were observed for the z-score of weight for age during the first 2 y of life, but a significantly lower difference was seen in the RHF group compared to the control group in the intervals 9 mo–1 y ( p =0.025) and 1–1.5 y ( p =0.020) of age. In contrast, the SF and eHCF groups were comparable to the control group, but the eHCF group was significantly lower ( p =0) in the first trimester of life.
Conclusion: Even if our findings show no significant difference between RHF and control, low weight observed in infants fed with RHF raises doubts about the nutritional adequacy of rice-hydrolysate formulas.     

Z-score of weight for age of infants with atopic dermatitis and cow's milk allergy fed with a rice-hydrolysate formula during the first two years of life

BACKGROUND: Recently, rice-based formulas have been widely used in hypoallergenic diets, but data on nutritional values are scarce. Aim: To evaluate the growth of infants fed with a rice-based hydrolysate formula, compared to those infants fed with a soy formula or an extensively hydrolysed casein formula, in the first 2 y of life. METHODS: A total of 88 infants were enrolled between March 2002 and March 2004. Fifty-eight infants with atopic dermatitis (AD) and cow's milk allergy (CMA), confirmed by open challenge, were enrolled as study group: 15 were fed with a rice-based hydrolysate formula (RHF), 17 with a soy-based formula (SF) and 26 with an extensively hydrolysed casein formula (eHCF). Thirty infants with AD without cow's milk allergy were recruited as a control group (CG) and fed with a free diet. Weight was recorded on enrolment and at 3-monthly intervals in the first year of life, and at 6-monthly intervals in the second year. Infants were weighed naked, before feeding, by means of an electronic integrating scale. The z-scores of weight for age were calculated. Statistics: One-way analysis of variance and Student's t-test were used for statistical comparison. Significance was set at p<0.05. RESULTS: No significant differences between the RHF, SF and eHCF groups were observed for the z-score of weight for age during the first 2 y of life, but a significantly lower difference was seen in the RHF group compared to the control group in the intervals 9 mo-1 y (p=0.025) and 1-1.5 y (p=0.020) of age. In contrast, the SF and eHCF groups were comparable to the control group, but the eHCF group was significantly lower (p=0) in the first trimester of life. CONCLUSION: Even if our findings show no significant difference between RHF and control, low weight observed in infants fed with RHF raises doubts about the nutritional adequacy of rice-hydrolysate formulas.     

Soy allergy in infants and children with IgE-associated cow's milk allergy

OBJECTIVES: To determine the prevalence of soy allergy in IgE-associated cow's milk allergy (CMA). STUDY DESIGN: Children <3.5 years with documented IgE-associated CMA (n = 93) were evaluated for soy allergy by double-blind, placebo-controlled food challenge, open challenge, or convincing previous history of an anaphylactic reaction to soy. Children tolerant to soy at entry received soy formula and were followed up for 1 year. RESULTS: Of this IgE-associated CMA cohort (ages 3 to 41 months), 14% (95% CI = 7. 7%-22.7%) were determined to have soy allergy, 12 definitely at entry and 1 possibly after 1 year of soy ingestion. The latter child experienced severe failure to thrive at enrollment and exhibited improved growth while receiving soy during follow-up but was diagnosed with eosinophilic esophagitis at study completion. Improved growth (P <.05) occurred in the non-soy-allergic cohort ingesting soy formula (579 31 mL/d) during the year of follow-up. CONCLUSIONS: Soy allergy occurs in only a small minority of young children with IgE-associated CMA. As such, soy formula may provide a safe and growth-promoting alternative for the majority of children with IgE-associated CMA shown to be soy tolerant at the time of introduction of soy formula.     

Vomiting and gastric motility in infants with cow's milk allergy

BACKGROUND: Regurgitation and vomiting are common manifestations of cow's milk protein allergy (CMPA) in infants and are usually ascribed to gastroesophageal reflux (GER). Gastric anaphylaxis can induce antral dysmotility in the rat, and therefore the hypothesis for the current study was that cow's milk in sensitized infants may impair antral motility, thereby promoting GER and reflex vomiting. METHODS: Seven vomiting infants with CMPA and nine with primary GER underwent a challenge with cow's milk formula. Electrogastrography (EGG) was used to measure the spectral frequency (bradygastria = 1.5-2.4 cycles per minute [cpm], normogastria = 2.5-3.9 cpm, tachygastria = 4.0-9.0 cpm) and the postprandial-to-fasting power ratio of gastric electrical activity, whereas gastric half-emptying time (T1/2) was measured by electrical impedance tomography (EIT). RESULTS: In CMPA and GER, respectively, during fasting, the frequency distribution (mean +/- SD) of the EGG was as follows: normogastria 47.9%+/-12.5% versus 52.2%+/-9.8%, bradygastria 24.1%+/-5.7% versus 22.8%+/-8.3%, and tachygastria 28.0% 8.5% versus 25.0% 8.3%. In contrast, after the cow's milk challenge, the difference between the two groups was statistically significant: normogastria 33.1%+/-8.8% versus 70.6%+/-8.6% (P < 0.0001). bradygastria 38.0%+/-15.5% versus 15.7%+/-5.2% (P = 0.002), and tachygastria 28.9%+/-10.6% versus 13.4%+/-4.6% (P = 0.001. The postprandial/ fasting power ratio (mean +/- SD) was 3.2+/-1.9 in CMPA and 8.1+/-2.1 in GER (P < 0.0001). Gastric T1/2 (mean +/- SD) of the cow's milk meal was 89.0+/-26.3 minutes versus 54.0+/-12.6 minutes (P = 0.003). In infants with GER all EGG parameters and gastric T1/2 were similar to that in 10 healthy control infants. CONCLUSIONS: In sensitized infants, cow's milk induces severe gastric dysrhythmia and delayed gastric emptying, which in turn may exacerbate GER and induce reflex vomiting. Electrogastrography and EIT can be useful in the assessment of vomiting, GER, and CMPA in infants.     

Status of children with cow's milk allergy in infancy by 10 years of age

To assess the development of milk protein tolerance and atopic diseases in children diagnosed for cow's milk allergy (CMA) in infancy, we conducted re-examinations of 56 CMA subjects at the age of 10 y using 204 age-matched controls. The children underwent clinical examinations and skin prick tests (SPT), and their IgE-specific antibodies to milk and five other food allergens were determined. By the age of 10 y, all but four subjects had become tolerant to at least small amounts of milk protein. However, gastrointestinal symptoms relating to more abundant milk consumption were reported by 45% of the study subjects and 15% of the controls (p < 0.001). The incidence figures for asthma, allergic rhinitis and dermatitis, as well as the occurrence of recurrent otitis, were three to four times higher than in the controls. Positive SPTs were seen in two-thirds of the subjects, the figure being highest (83%) in those with dermatitis onset CMA. Seven subjects showed positive titres of IgE-class milk-specific antibodies, and five showed a clinical response. CONCLUSION: This re-examination study showed that CMA in infancy, even when properly treated, has significant clinical consequences by posing special risks for respiratory atopy and persistence of atopic dermatitis as well as positive SPT and recurrent ear infections. However, each of these clinical manifestations seems to have an independent curriculum unrelated to the persistence of CMA itself.     

Cow's milk allergy, incidence and pathogenetic role of early exposure to cow's milk formula

A study was performed in infants under the age of 12 months born during 1974 and admitted to St. G?ran's Children's Hospital with symptoms suggestive of cow's milk allergy (CMA). The aims of the study were to determine the role of early exposure to cow's milk formulas as a predisposing factor to CMA and to estimate the incidence of CMA in infancy. Twenty-five infants fulfilled the criteria for CMA. Available records were reviewed and a careful history was obtained from the mothers on two occasions. The patient group was compared with a control group. Sixteen of the 25 infants were exposed to cow's milk protein during their first week in the nursery for newborns, 6 were exposed before the end of the fourth week of life, and 3 infants were apparently not exposed. All infants were breast fed 3 to 26 weeks before re-exposure and occurrence of symptoms. Infants with CMA were given cow's milk formulas during their first 4 weeks of life significantly more often than infants in the control group (p less than 0.01). The incidence of CMA was approximately 1 : 200. The first 4 weeks after birth seem to be a particularly vulnerable period. Hence, in order to prevent CMA, infant formula should not be given--even occasionally--during this period.