Effects of an Extensively Hydrolyzed Formula Supplemented with Two Human Milk Oligosaccharides on Growth, Tolerability, Safety and Infection Risk in Infants with Cow's Milk Protein Allergy: A Randomized, Multi-Center Trial.

This randomized clinical trial (Registration: NCT03085134) assessed if an extensively hydrolyzed formula (EHF) supplemented with two human milk oligosaccharides (HMO) and reduced protein content (2.20 g/100 kcal) supports normal growth in infants with cow's milk protein allergy (CMPA). Secondary outcomes were gastrointestinal tolerability, safety, and effect on infections. Nonbreastfed infants aged 0−6 months with CMPA were enrolled. Body weight, length, and head circumference were measured monthly for 4 months (primary study endpoint), after 6 months, and at the age of 12 months. Of 200 infants screened, 194 (mean age 3.2 months) were randomized. At the 4-month follow-up, daily weight gain for the test formula was noninferior to the control formula; p < 0.005. There were no significant group differences in anthropometric parameters. Both formulas were safe and well tolerated. Infants in the HMO group had a statistically significant reduction in the frequency of upper respiratory tract infections and a lower incidence of ear infections at 12 months (per protocol analysis). The relative risk of lower respiratory tract and gastrointestinal infections was reduced by 30−40%, but this was not statistically significant due to sample size limitations. In summary, the HMO-supplemented formula supports normal growth in infants with CMPA and suggests a protective effect against respiratory and ear infections in the first year of life.

The role of milk feeds and other dietary supplementary interventions in preventing allergic disease in infants: Fact or fiction?

Exclusive breastfeeding ideally up to 6 months of life is the feed of choice for infants and should be promoted by healthcare professionals. However, when human milk is not sufficient or not available, infant formula, generally cow's milk-based, meeting strictly regulated nutritional and safety requirements, are recommended. Human breastmilk feeding has a positive health impact for both mother and child, but there is limited evidence that it has a long-term protective effect on the development of allergic disease. Some studies have found an association of an increased risk to develop cow's milk allergy with early exposure to cow's milk protein in formula milk. As a result, over the last 30 years, partially hydrolyzed formulas (pHF) have gained popularity and, more recently, become embroiled in a debate about their role in the primary prevention of allergic outcomes. Similar debates exist in regards to the potential preventative effects of pre-, pro- and synbiotics as well as nutritional factors, notably vitamin D and omega-3 fatty acids. This paper aims to critically address these aspects, drawing information from published data interpreted by an international expert group in paediatrics, allergy, gastro-intestinal diseases and nutrition. This group of experts emphasize that human milk is the optimal source of infant nutrition. With regards to pHFs, whilst no harm has been shown with their use and some studies have suggested potential benefit preventing atopic dermatitis in at risk infants, there is insufficient evidence for or against their routine recommendation for primary allergy prevention. The method of hydrolysation differs for every formula. There is insufficient evidence to recommend supplementation with vitamin D, omega-3 LCPUFA, specific prebiotic oligosaccharides or specific probiotic strains during pregnancy, lactation and early life to prevent the development of allergic disease in children. There remains a need for well-designed trials with the currently commercialised pHFs and supplements to allow for better clarity and evidence-based recommendations.

Maternal antioxidant intake during pregnancy and the development of cows' milk allergy in the offspring.

Cows' milk allergy (CMA) is the most common food allergy in young children, and it is often the first manifestation of atopic diseases. Accordingly, very early environmental factors, such as maternal diet during pregnancy, may play a role in the development of CMA, but the evidence is limited. The aim of this study was to investigate the association between maternal intake of antioxidant nutrients during pregnancy and the subsequent development of CMA in the offspring in a prospective, population-based birth cohort within the Finnish Type 1 Diabetes Prediction and Prevention Study. Maternal dietary information during pregnancy was collected with a detailed, validated FFQ. The maternal dietary information and the information on putative confounding factors were available for 4403 children. Information on diagnosed CMA (n 448) was obtained from a medical registry and queried from the parents up to child's age of 3 years. The Finnish food composition database was used to calculate the average daily intake of nutrients. Logistic regression was applied for statistical analyses, and the nutrient intakes were adjusted for energy intake. OR are presented per 1 sd increment of the particular nutrient intake. Maternal total and dietary intake of ß-carotene was associated with an increased risk of CMA in the offspring when adjusted for the putative confounding factors (total OR 1·10, 95 % CI 1·02, 1·20; dietary OR 1·10; 95 % CI 1·01, 1·19). Using dietary supplements containing antioxidants in addition to a balanced diet may not confer any additional benefits.

Hydrolyzed Rice Protein-Based Formulas, a Vegetal Alternative in Cow's Milk Allergy.

Formulas adapted to infant feeding, although most of the time made from cow's milk proteins, can be made from hydrolyzed rice protein but they must be classified as "formulas for specific medical needs", according to European regulations. The nutritional quality of rice proteins is thus suitable to be used in infant formulas giving that it is supplemented by certain amino acids which can be lacking. Besides, hydrolysis is required to facilitate their water solubility and digestibility. Owing to a low allergenicity of rice and to the absence of the cross-allergy between milk proteins and rice proteins, these formulas are adapted to the diet of children with cow's milk protein allergy (CMPA), which explains their growing use in some countries. However, CMPA, an expanding disorder, has consequences for growth, bone mineralization, and often has an association with allergy to other foods, including cow's milk extensive hydrolysate, so that a surveillance of the adaption of hydrolyzed rice protein formulas (HRPF) to CMPA, the absence of unexpected side effects, and the appropriate response to its various health hazards seems mandatory. This paper analyses the health problem deriving from CMPA, the industrial development of hydrolyzed rice protein formulas, and the limited number of clinical studies, which confirms, at the moment, a good allergic tolerance and safety. The goal is to better advise heath care professionals on their use of HRPFs during CMPA.

Maternal dietary folate, folic acid and vitamin D intakes during pregnancy and lactation and the risk of cows' milk allergy in the offspring.

Maternal nutrient intake during pregnancy and lactation potentially influences the development of allergic diseases. Cows' milk allergy (CMA) is often the first manifestation of atopic diseases, but the impact of early nutritional influences on CMA has not been explored. The associations between maternal intakes of folate, folic acid and vitamin D during pregnancy and lactation were addressed in a prospective, population-based birth cohort within the Finnish Type 1 Diabetes Prediction and Prevention Study. Mothers of 4921 children during pregnancy and 2940 children during lactation provided information on maternal dietary intake during the 8th month of pregnancy and the 3rd month of lactation using a detailed, validated FFQ. Information on diagnosed CMA in the offspring was obtained from a medical registry as well as queried from the parents. The Finnish food composition database was used to calculate nutrient intake. Logistic regression was applied for statistical analyses. Folate intake and folic acid and vitamin D supplement use were associated with an increased risk of CMA in the offspring, whereas vitamin D intake from foods during pregnancy was associated with a decreased risk of CMA. Thus, maternal nutrient intake during pregnancy and lactation may affect the development of CMA in offspring. Supplementation with folic acid may not be beneficial in terms of CMA development, especially in children of allergic mothers. The association between dietary supplement use and CMA risk can at least partly be explained by increased health-seeking behaviour among more educated mothers who also use more dietary supplements.

Increased intake of vegetable oil rich in n-6 PUFA enhances allergic symptoms and prevents oral tolerance induction in whey-allergic mice.

Increased intake of vegetable oils rich in n-6 PUFA, including soyabean oil, has been associated with an increase in allergic disease. The present study aimed to determine the effect of an increasing dose of dietary vegetable oil on allergic outcomes in mice. To study this, mice received a 7 v. 10 % soyabean oil diet before and during oral sensitisation with whey or whey hyperimmune serum transfer. Another group of mice received partial whey hydrolysate (pWH) while being fed the diets before oral sensitisation. The acute allergic skin response, serum Ig level, mouse mast cell protease-1 (mMCP-1) concentration and/or splenic T-cell percentages were determined upon whey challenge. When the diets were provided before and during oral sensitisation, the acute allergic skin response was increased in mice fed the 10 % soyabean oil diet compared with the 7 % soyabean oil diet. Whey IgE and IgG1 levels remained unaltered, whereas mMCP-1 levels increased in mice fed the 10 % soyabean oil diet. Furthermore, allergic symptoms were increased in naive mice fed the 10 % soyabean oil diet and sensitised with whey hyperimmune serum. In addition to enhancing the mast cell response, the 10 % soyabean oil diet increased the percentage of activated Th1 and Th2 cells as well as increased the ratios of Th2:regulatory T cells and Th2:Th1 when compared with the 7 % soyabean oil diet. Oral tolerance induction by pWH was abrogated in mice fed the 10 % soyabean oil diet compared with those fed the 7 % soyabean oil diet during pretreatment with pWH. In conclusion, increased intake of soyabean oil rich in n-6 PUFA suppresses tolerance induction by pWH and enhances the severity of the allergic effector response in whey-allergic mice. Dietary vegetable oils rich in n-6 PUFA may enhance the susceptibility to develop or sustain food allergy.

Whole cow's milk in early life.

Cow's milk is a major food for young children. Whole cow's milk is known to be detrimental to infants, mainly due to its low iron content. The negative association with iron status led to recommending the introduction of formula feeding in infancy during the weaning period or when breastfeeding ceased. More recently, the literature suggests that consuming whole cow's milk in infancy has unfortunate effects on growth, especially weight acceleration and development of overweight in childhood. These issues are discussed in the following chapter. Other suggested reasons for the avoidance of whole cow's milk in infancy are touched upon, such as milk protein allergy and high renal solute load. The hypothesis about early cow's milk introduction in the pathology of certain diseases, mainly through the peptide ß-casomorphin-7, is briefly reviewed, showing that there is no clear evidence for the suggested associations. The chapter gives a recent example of introducing formula at 6 months of age instead of whole cow's milk in infants' diet in Iceland. Several aspects of consuming whole cow's milk in infancy can be found in recent reviews.

[Biotin deficiency in amino acid formula nutrition for an infant with milk protein allergy].

We reported a 4-month-old girl with biotin deficiency caused by amino acid formula. Two weeks after birth, she was diagnosed as having a milk protein allergy. After switching to amino acid formula from usual formula, her symptoms and laboratory findings became normal. About three weeks after the beginning of amino acid formula, she developed intractable skin erosions around the eyes, mouth, neck, and anogenital area. By measuring concentrations of some trace elements, she was diagnosed as having a biotin deficit, because of the organic aciduria and undetectable serum biotin concentration. Her serum biotinidase level was normal. Upon administration of oral biotin supplementation, all her symptoms and laboratory findings were dramatically improved. Since amino acid formula contains very few biotin, we should pay attention to biotin deficiency when infants receiving amino acid formula.

Hypoallergenicity and effects on growth and tolerance of a new amino acid-based formula with docosahexaenoic acid and arachidonic acid.

OBJECTIVE: In study 1, to compare the effect on growth in healthy infants of a new amino acid-based formula (AAF) and a control extensively hydrolyzed formula (EHF), with both docosahexaenoic acid (DHA) and arachidonic acid (ARA) at levels similar to those in human milk worldwide. In study 2, to evaluate the hypoallergenicity of this new AAF in infants and children with confirmed cow's milk allergy (CMA). STUDY DESIGN: In study 1, a total of 165 healthy, full-term, formula-fed infants randomly received the new AAF or control formula. Anthropometric measurements, tolerance, and adverse events were recorded throughout the study. Plasma amino acid profiles were evaluated in a subset of the infants. In study 2, the hypoallergenicity of the new AAF was evaluated in 32 infants and children using a double-blind, placebo-controlled food challenge; an open challenge; and a 7-day feeding. RESULTS: In study 1, overall growth, tolerance, and safety outcomes were similar in both groups. In study 2, 29 of the 32 subjects completed both challenges; no allergic reaction was seen in any of the 32 subjects. CONCLUSIONS: The new AAF with DHA and ARA at levels similar to those in human milk worldwide is hypoallergenic. It also is safe and supports growth in healthy, term infants.

Thresholds of clinical reactivity to milk, egg, peanut and sesame in immunoglobulin E-dependent allergies: evaluation by double-blind or single-blind placebo-controlled oral challenges.

BACKGROUND: The prevalence of food anaphylaxis due to masked allergens has increased within the last 10 years. Contamination of manufactured products by food allergens is a key concern for food industries. OBJECTIVE: To determine quantities eliciting reactions in patients who have an IgE-dependent food allergy, thanks to standardized oral provocation tests. To evaluate the subsequent levels of sensitivity required for the detection tests of allergens for egg, peanut, milk and sesame. METHODS: Prick-in-prick tests, Cap system RAST, and single or double-blind placebo-controlled food challenges (SBPCFC or DBPCFC) were performed. The doses of natural food were gradually increased from 5 to 5000 mg for solid food and from 1 to 30 mL for peanut oil, sunflower oil, soy oil and sesame oil. RESULTS: Data from 125 positive oral challenges to egg, 103 to peanut, 59 to milk and 12 to sesame seeds were analysed. Haemodynamic modifications were observed in 2%, 3%, 1.7%, and 8% of the oral challenges (OCs) to egg, peanut, milk and sesame, respectively. Respiratory symptoms were observed in 12%, 20%, 10% and 42% of egg, peanut milk and sesame allergies, respectively. A cumulative reactive dose inferior or equal to 65 mg of solid food or 0.8 mL of milk characterized 16%, 18%, 5% and 8% of egg, peanut, milk and sesame allergies, respectively. 0.8% of egg allergies, 3.9% of peanut allergies, and 1.7% of milk allergies reacted to 10 mg or less of solid food or to 0.1 mL for milk. The lowest reactive threshold has been observed at less than 2 mg of egg; 5 mg of peanut, 0.1 mL of milk and 30 mg of sesame seed. Ten out of 29 OC with peanut oil, two out of two OC with soy oil and three out of six OC with sunflower oil were positive. Five out six OC with sesame oil were positive: 1 and 5 mL induced an anaphylactic shock. CONCLUSION: The risk of asthma and anaphylactic shock to sesame and peanut is confirmed. Minimal reactive quantities show that, in order to guarantee a 95% safety for patients who are allergic to egg, peanut and milk, and on the basis of consumption of 100 g of food, the detection tests should ensure a sensitivity of 10 p.p.m. for egg, 24 p.p.m. for peanut and 30 p.p.m. for milk proteins. Oil allergies being considered, the limit of sensitivity should fall to 5 p.p.m.

Breast-feeding and the development of cows' milk protein allergy.

Early feeding with cows' milk (CM) may cause cows' milk allergy (CMA). Breast milk contains many immune factors which compensate for the undeveloped defence mechanisms of the gut of the newborn infant. We studied the effect of supplementary CM feeding at the maternity hospital on the subsequent incidence of CMA, the effects of formula and breast feeding on the subsequent immunologic types of CMA, and the importance of immune factors present in colostrum in the immune responses of infants with CMA. In a cohort of 6209 infants, 824 were exclusively breast-fed and 87% required supplementary milk while in the maternity hospital: 1789 received CM formula, 1859 pasteurized human milk, and 1737 whey hydrolysate formula. The cumulative incidence of CMA, verified by a CM elimination-challenge test, was 2.4% in the CM, 1.7% in the pasteurized human milk and 1.5% in the whey hydrolysate group. Among these infants, exposure to CM at hospital and a positive atopic heredity increased the risk of CMA. Of the exclusively breast-fed infants, 2.1% had CMA. Risk factors for the development of IgE-mediated CMA were: exposure to CM at hospital, breast-feeding during the first 8 weeks at home either exclusively or combined with infrequent exposure to small amounts of CM and long breast-feeding. The content of transforming growth factor-beta1 (TGF-beta1) in colostrum from mothers of infants with IgE-mediated CMA was lower than from mothers of infants with non-IgE-mediated CMA. In infants with CMA, TGF-beta1 in colostrum negatively correlated with the result of skin prick test and the stimulation of peripheral blood mononuclear cells to CM, but positively with infants' IgA and IgG antibodies to CM proteins. Feeding of CM formula at maternity hospital increases the risk of CMA, but exclusive breast-feeding does not eliminate the risk. Prolonged breast-feeding exclusively or combined with infrequent exposure to small amounts of CM during the first 8 weeks induces the development of IgE-mediated CMA. Colostral TGF-beta1 may inhibit IgE- and cell mediated reactions and promote IgG-IgA antibody production to CM in infants prone to developing CMA.

Allergic colitis: a mimic of Hirschsprung disease.

BACKGROUND: Allergy to cow milk protein is a common cause of gastrointestinal symptoms in infancy. Milk allergy is usually a clinical diagnosis, and thus there have been few reports of the radiographic findings. OBJECTIVE: To describe the barium enema findings of allergic colitis and differentiate them from Hirschsprung disease. Materials and methods. Four infants (age range 7 days-5 weeks) with constipation underwent barium enema to exclude Hirschsprung disease. Radiographic findings were correlated with the pathologic specimens from suction rectal biopsy. RESULTS: All enemas revealed irregular narrowing of the rectum and a transition zone. Rectal biopsies in each case demonstrated ganglion cells and evidence of an allergic colitis, with inflammatory infiltrates in the lamina propria. A diagnosis of milk allergy colitis was made and symptoms resolved after removal of milk from the diet. CONCLUSIONS: Milk allergy is common in infancy. The rectum is a primary target organ, with allergic colitis often diagnosed on clinical grounds alone. However, a child with allergic colitis may be referred to radiology for barium enema, especially if constipation is present. The radiologist should be aware of the unique imaging findings of allergic colitis, so as to avoid confusion with Hirschsprung disease and perhaps an unnecessary rectal biopsy.

Low colostral IgA associated with cow's milk allergy.

During a nutritional study of 198 infants, seven became allergic to cow's milk. The seven infants showed acute cutaneous manifestations during cow's milk challenge tests in hospital and six had increased levels of IgE cow's milk-specific antibodies. Neither in the development of the levels of immunoglobulins G, A and M, nor in that of the cow's milk-specific antibodies of these isotypes did these seven patients differ from the remaining infants. Beta-lactoglobulin content and levels of cow's milk-, and beta-lactoglobulin-specific antibodies and of immunoglobulins A, G and M were measured in samples of colostrum and milk from the mothers of the seven infants with cow's milk allergy and from a comparison group (non-atopic mothers of non-atopic infants). The milk of the mothers whose infants became allergic to cow's milk contained less IgA through the lactation: 95% confidence intervals of the groups did not overlap. The difference was most marked in the colostrum. All other measurements were similar in the two groups. This suggests that an infant is more likely to develop cow's milk allergy if the mother's colostrum had a low total IgA content.