CMPA should be differentiated from other diagnoses, including allergic reactions to other foods (e.g., eggs, soy, and wheat) or environmental substances, infection, anatomic abnormalities, metabolic abnormalities, celiac disease, pancreatic insufficiency (e.g., as in cystic fibrosis), malabsorption syndromes, and malignancy.5
Comorbid allergic reactions to soy, wheat, peanuts, eggs, fish, and other foods may occur with CMPA, depending on regional dietary practices.5 Symptoms of CMPA also can exist concomitantly with gastroesophageal reflux disease.5 Colic should be considered during the differential diagnosis, although about 10% of formula-fed infants with CMPA have colic episodes as a symptom.5 In addition, atopic dermatitis may exist with CMPA in some infants, particularly in younger infants with more severe atopic dermatitis.5
Parents, caregivers, and clinicians have different perceptions of food allergy and difficulty in recognizing the symptoms.1 In the IFPS II, the mothers of 502 of the 2,441 infants (20%) reported food problems, but fewer than half the infants (200 infants, or 40%) were taken to a clinician for diagnosis and even fewer (123 infants, or 25%) were tested for food allergy. Of the infants seen by a clinician, 6% were considered to have a probable food allergy, and 15% had such other food-related problems as allergy to eggs, peanuts, or wheat. Cow’s milk, including cow’s milk infant formula, was the most common cause of food-associated problems in 95% of the infants diagnosed with probable food allergy.1 Irritability and GI symptoms were common in these infants; they also were more likely to have respiratory congestion.1 Mothers were more likely to report rash or eczema, hives, swollen eyes or lips, and other skin-related symptoms in the infants diagnosed with food allergy.1
CMPA is often overdiagnosed among children with food allergy symptoms. A study of 381 infants exhibiting a possible adverse reaction to cow’s milk found that 243 of them (64%) were mislabeled with CMPA.5 Almost 30% of infants with mislabeled reaction presented within the first month of life, and nearly half presented in the first two months, compared with only 9% and 20% of infants with IgE-confirmed CMPA, respectively (Figure 1).
The symptoms in most infants with mislabeled CMPA involved a single organ, primarily GI or skin; in contrast, IgE-confirmed CMPA affected several organ systems, significantly more skin and respiratory symptoms, and significantly fewer nonspecific symptoms.5 Health-care providers attributed the symptoms to cow’s milk in more than half the infants with mislabeled CMPA. Clinician-diagnosed atopic dermatitis was associated with mislabeled CMPA in 15.3% of infants, compared with only 4.7% of infants with IgE-mediated CMPA.5
Management strategies for infants and children with CMPA
Breast milk provides the ideal nutritional, immunologic, and physiologic nourishment for all newborns while promoting maturation of the infant’s immune system.7 However, breastfeeding exclusively for the first four to six months of life reduces the risk for CMPA and minimizes the most severe allergic manifestations during early childhood.4,7,12 In addition, CMPA can develop in breastfed infants, and different management strategies that take into account the severity of symptoms are required for these breastfed and formula-fed infants.4
Only about 0.5% of infants exclusively breastfed exhibit a clinical reaction to CMPA, usually with mild to moderate GI or dermatologic symptoms.4,12 For those infants, breastfeeding should continue but with cow’s milk eliminated from the mother’s diet.12 In addition, CMP should be strictly avoided in any supplementary feeding given to the infant.12 This maternal elimination diet should be continued for a minimum of two to four weeks.12 The advice of a nutritionist may be recommended to help the mother maintain a nutritionally balanced diet, particularly adequate calcium intake.12 If the child’s symptoms resolve after two to four weeks, cow’s milk should be reintroduced into the maternal diet; recurrence of symptoms requires elimination of CMP for the duration of breastfeeding.12
For the small proportion of formula-fed infants with a true IgE-mediated CMPA and mild-to-moderate symptoms, the preferred source of nutrition is a hypoallergenic formula with extensively hydrolyzed proteins (eHF), which are less likely to stimulate antibody production (Figure 2).12,13 Even partially hydrolyzed cow’s milk formula can be beneficial. This formula has been shown to reduce flares of allergic dermatitis in atopic infants with no negative effect on growth rate and to provide an allergy-preventive effect until age 10 years in children with diagnosed allergic disease.14
During a diagnostic elimination diet, all other foods should be withheld to avoid possible manifestations due to other food allergens, and the cow’s-milk-free diet should be maintained for at least six months.12 Clinical symptoms should resolve with the use of eHF if CMPA is present; CMP then can be reintroduced progressively, with the infant monitored closely for recurring symptoms.12
In rare cases, symptoms of CMPA may persist on eHF, and a chemically made amino acid-based formula, which is not derived from cow’s milk or other native protein, may be effective.12 Symptoms that fail to improve with eHF or amino acid formula may be indicative of another diagnosis and warrant referral to a pediatric allergy specialist.
For infants who are not exclusively breastfed for four to six months or who are formula-fed and at high risk for atopic disease, eHF may provide additional benefit. An AAP 2008 position paper states that eHF may delay or prevent the development of atopic dermatitis in early childhood and may be more effective than partially hydrolyzed formulas.8 The AAP statement is based on clinical evidence, including a study of 2,252 newborns randomly assigned at birth to three different hydrolyzed formulas or cow’s milk formula as a substitute for, or a supplement to, breastfeeding.15
Compared with the use of cow’s milk formula, the relative risk for developing atopic dermatitis in the first six years of life was no different with extensively hydrolyzed whey formula, but was lower with partially hydrolyzed whey formula and extensively hydrolyzed casein formula.15
Treatment of CMPA using an eHF is also a cost-effective option to amino acid-based formula, according to a 12-month study of matched groups of infants with a mean age of about 3 months.16 Approximately 40% of the infants had a combination of GI symptoms and eczema; another 39% had only GI symptoms and 13% presented with eczema only.16
In both groups, the mean time to resolution of symptoms was 1.2 months, although the infants receiving eHF had significantly fewer doctor visits over the 12 months (13.1 vs. 17.5, P<0.001), and the cost of managing the eHF-treated infants was lower.16
Factors contributing to nutritional imbalances in infants and children with CMPA
Given the frequency of reporting of food-related problems during the first year of life, as well as the frequency of mislabeled CMPA among infants with similar symptoms of food allergy, it is important to educate parents, caregivers, and clinicians as to how to differentiate between allergic and non-allergic food-related problems.4,5
Many mothers report food-related problems in their infants, yet relatively few seek medical attention for these problems.1 Furthermore, only a small proportion of those infants who visit are tested for food allergy.1 As a result, mothers may make uninformed decisions based on limited knowledge of food allergy symptoms and restrict nutritionally important foods.1
Equally important, clinicians often overdiagnose CMPA based on symptoms alone, which may lead to unnecessarily restrictive diets that limit the calories and nutrients necessary for growth.1,5 In addition to the adverse nutritional consequences, unfounded strict food-allergen practices negatively affect the quality of life of children and their caregivers.1
Two recent Brazilian studies underscored the high prevalence of nutritional deficits among infants placed on inappropriate substitute formulas for suspected or confirmed CMPA.17,18 In the first, 513 of 9,478 children up to age 24 months (5.4%) were referred by a pediatrician to a pediatric gastroenterologist primarily for GI symptoms; the specialist confirmed the diagnosis in 211 (2.2%).18 Nearly half of these 211 infants had been switched inappropriately to a different formula (i.e., soy, goat’s milk, or lactose-free cow’s milk) by the pediatrician, and only 16% were using an eHF or amino acid-based formula.18 Analysis of z-score deviations suggested that malnutrition or failure to thrive occurred in a substantial proportion of these infants, with weight-for-age deficits in 15.1%, weight-for-height deficits in 11.3%, and height-for-age deficits in 23.9%.18
The second trial was a smaller study of 214 children younger than age 3 years who also primarily had GI symptoms; some also had cutaneous and/or respiratory manifestations.17 At study entry, 67.8% of the children were of normal weight by BMI, 12.9% were considered thin or severely thin, and 20.3% were at risk for overweight or obesity.17 The majority (65.1%) were using soy-based formulas, and 24.5% were on hydrolyzed protein or amino acid-based formulas.17 There was a significant difference in the proportion of children on these formulas who had thin or severely thin BMI compared with the 10% of children on cow’s-milk-based formulas (8.7% vs. 41.7%, P<0.001).17
The findings of both studies support exclusive breastfeeding for the first four to six months of life and indicate that GI manifestations of CMPA, whether confirmed or suspected, lead to nutritional impairment.4,17,18 Highly effective replacement diets are needed to control symptoms and promote nutritional recovery in order to avoid malnutrition.17,18
Although double-blind placebo-controlled food challenges are not universally used in the management of children with CMPA, excluding CMP can convince parents to stop an unnecessary elimination diet in their children with suspected CMPA as well as allow for reintroduction of CMP in some children who exhibit partial tolerance to the protein.19,20 One study found that 70% of infants became tolerant to CMP at age 1 year, and even patients who could tolerate relatively small amounts of CMP reported a significant improvement in quality of life.20
Prognosis for CMPA and other childhood allergies
The prognosis for infants with CMPA is relatively good; the allergy persists in only a small percentage of children who develop it.4,21 Most children (85%) outgrow CMPA by age 3 years, with the allergy spontaneously disappearing in 50% by age 1 year and 70% by age 2 years.7,21 The likelihood that a child will become tolerant to CMP depends on his or her age and the level of specific IgE at the time of diagnosis.4,21 A 2007 study reported that 19% of children with CMPA developed tolerance by age 4 years, 42% by age 8 years, 64% by age 12 years, and 79% by age 16 years.7 Children with the highest levels of cow’s-milk-specific IgE are least likely to outgrown their CMPA, while children who have negative reactions to the radioallergosorbent test or skin-prick test tend become tolerant sooner than those with positive test results.4,7
Atopic dermatitis, another common allergy that often develops in infancy, is frequently associated with food allergy, and 40% to 50% of children younger than age 1 year with CMPA may also be diagnosed with atopic dermatitis.21 Conversely, about one-third of children with atopic dermatitis also have CMPA, and the development of tolerance to CMP appears to be slower than in children with CMPA alone, resolving in 50% by age 7 years.21 As in children with CMPA alone, cow’s-milk-specific IgE levels at diagnosis are a prognostic factor for the time to develop tolerance to CMP in children with concurrent atopic dermatitis.21
In one study, CMPA resolved in only 19% of children with atopic dermatitis and higher cow’s-milk IgE levels by age 5 years.21 In general, children with concurrent atopic dermatitis or respiratory allergy are least likely to outgrow their early CMPA.7 Children with CMPA who develop other atopic conditions need specialized long-term care with follow-up of cow’s-milk-specific IgE levels to predict the appropriate timing for reintroduction of cow’s milk into the diet.21 Special attention is also needed to avoid accidental exposure to cow’s milk and the possible development of other atopic conditions over time.2
Current research to prevent sensitization to foods
Many clinicians believe that the mainstay of therapy for any food allergy is complete avoidance of the culprit food, such as milk or soy.11 Elimination of milk, an important source of fat and protein for young children, from the diet raises concerns about gaps in nutrition.11 Furthermore, CMP is present in many common foods (e.g., puddings, lunch meats, salad dressings), as well as in some milk, cream, and butter substitutes labeled “non-dairy.”11 The practice of food avoidance assumes that preventing or delaying the early onset of food allergy may avoid the “allergic march”—the progression from food allergy to allergic rhinitis or asthma at a later age.7 More recent research, however, supports just the opposite approach to preventing food allergy—exposure to food allergens in early life—while still recognizing the central role of food allergy in the development of other atopic diseases, including eczema.7 In contrast to food avoidance, exposure to food allergens in early life may improve tolerance of the infant immune system to the allergens and prevent sensitization.7 Desensitization protocols expose a child with food allergy through specific oral tolerance induction (SOTI) to the allergen.7 Several studies have demonstrated tolerance achieved in children with CMPA by initiating SOTI with minute quantities of cow’s milk that are increased over time, with the children able to tolerate up to 250 mL of cow’s milk after three to 12 months on the protocol.7 In a study of 118 children, 75% became tolerant after one year and were able to follow an unrestricted diet; another 16% were considered partially tolerant and were able to consume 5 mL to 150 mL of cow’s milk with no allergic reaction.20 Adverse effects were mild, and parent satisfaction was high.20
Another approach to protect against food allergies is the use of such probiotics as lactobacilli.22 Although the pathogenesis and development of oral tolerance in CMPA is not fully understood, differences in the composition of intestinal bacterial of infants with CMPA and healthy infants suggest that this altered composition creates an imbalance in the immune response to food allergens, resulting in both local and systemic reactions.22 Supplementation of formula with Lactobacillus has been effective in reducing the incidence and severity of atopic dermatitis in newborns and infants younger than age 2 years, and in decreasing GI symptoms.7,22 In infants with CMPA, supplementation of eHF with Lactobacillus accelerated the development of tolerance to cow’s milk after food challenge.22 These are promising findings, but more research is needed to provide a better understanding of the role of probiotics for the prevention and treatment of CMPA and other atopic diseases.6
CMPA is the most common cause of food allergy, affecting about 3% of all infants in the first year of life, and can develop in both breastfed and formula-fed infants. Parents and caregivers often attribute GI, dermatologic, or respiratory symptoms to a food allergy, fail to consult with a clinician, and restrict nutritionally important foods from their children’s diets. Even when parents seek medical advice, clinicians may overdiagnose food allergy and recommend unnecessary elimination diets that can pose risks to the child’s health and quality of life.
Breastfeeding exclusively for the first four to six months of life is recommended as the best protection against development of CMPA in the infant. When CMPA is correctly diagnosed, management involves elimination of CMP from the maternal diet of breastfed infants and the use of eHF or partially hydrolyzed infant formula as the sole or supplementary source of nutrition. Differentiation of food allergy from other food-related problems is important to prevent or decrease the incidence of food allergies in young infants and to minimize risks to the child’s growth and development.
- Luccioli S, Ross M, Labiner-Wolfe J, Fein SB. Maternally reported food allergies and other food-related health problems in infants: characteristics and associated factors. Pediatrics. 2008;122:S105. Available at pediatrics.aappublications.org/content/122/Supplement_2/S105.long.
- Santos A, Dias A, Pinheiro JA. Predictive factors for the persistence of cow’s milk allergy. Pediatr Allergy Immunol. 2010;21:1127-1134.
- Metsälä J, Lundqvist A, Kaila M, et al. Maternal and perinatal characteristics and the risk of cow’s milk allergy in infants up to 2 years of age: a case-control study nested in the Finnish population. Am J Epidemiol. 2010;171:1310-1316. Available at aje.oxfordjournals.org/content/171/12/1310.long.
- Vandenplas Y, Koletzko S, Isolauri E, et al. Guidelines for the diagnosis and management of cow’s milk protein allergy in infants. Arch Dis Child. 2007;92:902-908. Available at adc.bmj.com/content/92/10/902.long.
- Elizur A, Cohen M, Goldberg MR, et al. Mislabelled cow’s milk allergy in infants: a prospective cohort study. Arch Dis Child. 2013;98:408-412.
- Vitaliti G, Cimino C, Coco A, et al. The immunopathogenesis of cow’s milk protein allergy (CMPA). Ital J Pediatr. 2012;38:35. Available at www.ijponline.net/content/38/1/35.
- Joneja JM. Infant food allergy: Where are we now? JPEN J Parenter Enteral Nutr. 2012;36:49S-55S.
- Greer FR, Sicherer SH, Burks AW, et al. Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics. 2008;121:183-191. Available at pediatrics.aappublications.org/content/121/1/183.long.
- Kuitunen M, Kukkonen AK, Savilahti E. Impact of maternal allergy and use of probiotics during pregnancy on breast milk cytokines and food antibodies and development of allergy in children until 5 years. Int Arch Allergy Immunol. 2012;159:162-170.
- Coscia A, Orrù S, Di Nicola P, et al. Cow’s milk proteins in human milk. J Biol Regul Homeost Agents. 2012;26(3 Suppl):39-42.
- Kattan JD, Cocco RR, Järvinen KM. Milk and soy allergy. Pediatr Clin North Am. 2011;58:407-426. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3070118/.
- von Berg A, Filipiak-Pittroff B, Kramer U, et al. Allergies in high-risk school children after early intervention with cow’s milk protein hydrolysates: 10-year results from the German Infant Nutritional Intervention (GINI) study. J Allergy Clin Immunol. 2013;131:1565-1573.
- O’Connor NR. Infant formula. Am Fam Physician. 2009;79:565-570. Available at www.aafp.org/afp/2009/0401/p565.html.
- Jin YY, Cao RM, Chen J, et al. Partially hydrolyzed cow’s milk formula has a therapeutic effect on the infants with mild to moderate atopic dermatitis: a randomized, double-blind study. Pediatr Allergy Immunol. 2011;22:688-694.
- von Berg A, Filipiak-Pittroff B, Krämer U, et al. Preventive effect of hydrolyzed infant formulas persists until age 6 years: long-term results from the German Infant Nutritional Intervention Study (GINI). J Allergy Clin Immunol. 2008;121:1442-1447.
- Taylor RR, Sladkevicius E, Panca M, et al. Cost-effectiveness of using an extensively hydrolysed formula compared to an amino acid formula as first-line treatment for cow milk allergy in the UK. Pediatr Allergy Immunol. 2012;23:240-249.
- Aguilar AL, Maranhão CM, Spinelli LC, et al. Clinical and follow up assessment of children in a program directed at the use of formulas for cow’s milk protein allergy. Rev Paul Pediatr 2013;31:152-158.
- Vieira MC, Morais MB, Spolidoro JVN, et al. A survey on clinical
- presentation and nutritional status of infants with suspected cow’s milk allergy. BMC Pediatrics. 2010;10:25. Available at www.biomedcentral.com/1471-2431/10/25.
- Dambacher WM, de Kort EHM, Blom WM, et al. Double-blind placebo-controlled food challenges in children with alleged cow’s milk allergy: prevention of unnecessary elimination diets and determination of eliciting doses. Nutrition J. 2013;12:22. Available at www.nutritionj.com/content/12/1/22.
- Longo G, Berti I, Barbi E, et al. Diagnosed child, treated child: food challenge as the first step toward tolerance induction in cow’s milk protein allergy. Eur Ann Allergy Clin Immunol. 2012;44:54-60.
- Suh J, Lee H, Lee JH, et al. Natural course of cow’s milk allergy in children with atopic dermatitis. J Korean Med Sci. 2011;26:1152-1158. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3172651/.
- Canani RB, De Costanzo M. Gut microbiota as potential therapeutic target for the treatment of cow’s milk allergy. Nutrients. 2013;5:651-662. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3705311/.
All electronic documents accessed October 15, 2013.