Although frequently associated with use of cow’s milk-based infant formulas, CMPA can actually develop in exclusively breastfed infants as well, and when CMP is introduced into the diet of the young child.1,2
It is important to identify CMPA early in order to distinguish symptoms from various other conditions that require a different approach to treatment, and to avoid unnecessary elimination diets.
Mechanisms of CMPA
CMPA results from an immunological reaction to one or more milk proteins. The proteins most frequently and most intensively recognized by specific IgE are casein and lactoglobulin. However, all milk proteins appear to be potential allergens, even those that are present in milk in trace amounts. It is this immunological reaction that differentiates CMPA from other adverse reactions to CMP, notably lactose intolerance. CMPA may be IgE or non-IgE associated.2
Symptoms of CMPA: What and when?
An infant can experience symptoms either very quickly after feeding (rapid onset) or up to several days or even weeks after first consuming the cow's milk protein (slower onset). The most common symptoms are gastrointestinal (50-60%), skin (50-60%) and respiratory (20-30%). Many infants may experience two or more of these symptoms.3
IgE-associated cases of CMPA tend to show an early reaction even to a small quantity of CMP, with symptoms including irritability, urticaria, dermatitis, swelling, or vomiting occurring within minutes. Although anaphylaxis is more common in other food allergies, in rare cases, anaphylaxis can occur in conjunction with CMPA. In these cases, CMPA may be the first expression or predictor of future atopy and other food allergies in the infant, and there is frequently a family history of atopy.1
Common symptoms of cow's milk protein allergy
Frequent regurgitation, vomiting, diarrhea, constipation, blood in stool, iron deficiency anemia
Atopic dermatitis, urticaria not linked to infections or medication, swelling of lips or eyelids
Respiratory tract (not related to RTI)
Runny nose, otitis media, chronic cough, wheezing
Persistent distress, irritability or colic, at least 3 days/week for >3 weeks
Source: Vandenplas et al., 2007.1
In non-IgE-associated cases, the reaction is later – from several days to weeks after initial exposure – and more likely to involve dermatitis or diarrhea. This slower onset reaction is more common. Symptoms may include loose stools (possibly containing blood), vomiting, gagging, refusing food, irritability or colic, and skin rashes. This type of reaction is more difficult to diagnose because the same symptoms may occur with other health conditions. This form of CMPA is not considered to predict future atopy.1,2,4
Diagnosis of CMPA
In the breastfed infant: To distinguish CMPA from other possible sensitivities derived from breastmilk, the mother should exclude cow's milk, peanuts, and hen's eggs from her diet for 2-4 weeks. If the infant’s symptoms improve over this time, the mother should introduce one food back into her diet per week. If there is no improvement after an elimination diet, a specialist in pediatric allergy should be consulted.
In the formula-fed infant: Where CMPA is suspected, elimination of CMP from the infant’s diet is accomplished by switching to a therapeutic formula that is indicated for allergy prevention; this could be an extensively hydrolyzed formula or an amino acid-based formula. It has been found that up to 10% of infants with CMPA will have an allergic reaction to an extensively hydrolyzed formula. Again, a specialist in pediatric allergy should be consulted if neither of these formula types improves symptoms.1
Differential diagnoses: Lactose intolerance, food allergies, colic, GERD
The immunological reaction that characterizes CMPA distinguishes it from other non-immunological adverse reactions to CMP such as lactose intolerance. As well, a number of alternative diagnoses not related to CMP are possible, including allergic reactions to other foods or substances, conditions including celiac disease, and GI or UTI infections. If it is determined that the reaction is non-immunological, it is recommended that the infant be assessed for other conditions such as gastroesophageal reflux disease or colic.1
Delayed diagnosis: Effects of CMPA
When there is a delay in diagnosis of CMPA, continued exposure to CMP can lead to increasing enteric inflammation resulting in bloody diarrhea, anemia, dehydration, and failure to follow normal patterns of growth and weight gain. Intestinal inflammation may be limited to mild proctitis or true enterocolitis with esophagitis, gastritis and colitis.4
There is higher risk of growth restriction when CMPA develops in the very young infant, therefore early diagnosis and treatment via a change to the infant’s diet can decrease risks associated with CMPA, including impaired growth.1
Management of CMPA
Infants at high risk of atopy: For infants at high risk of developing atopy, evidence has shown that exclusive breastfeeding for at least 4 months or supplementing breastfeeding with an infant formula containing partially hydrolyzed or extensively hydrolyzed protein decreases the risk of atopic dermatitis compared with breastfeeding supplemented with standard cow’s milk protein infant formula.5 For infants who are exclusively formula-fed, the German Infant Nutritional Intervention (GINI) Study, which compared 3 hydrolyzed formulas (partially hydrolyzed whey, extensively hydrolyzed whey and extensively hydrolyzed casein), reported reduced incidence of atopic dermatitis with the partially hydrolyzed whey formula and the extensively hydrolyzed casein formula compared with standard cow’s milk formula or extensively hydrolyzed whey formula.5,6
Infants with confirmed CMPA: For exclusively breastfed infants with confirmed CMPA, it has traditionally been recommended that the mother avoid cow’s milk for the duration of breastfeeding; a clinical report released by the AAP in January 2008 now points to a lack of evidence for dietary restrictions during breastfeeding to prevent atopic disease with the possible exception of atopic eczema.5 For formula-fed infants, whether exclusive or in combination with some breastfeeding, formula options include those with specific indication for allergic infants. Extensively hydrolyzed casein formulas are well tolerated by most infants with CMPA, but in some cases, they may still cause an allergic reaction. Amino acid-based formulas contain protein in its simplest form, and may be recommended if the infant’s condition doesn't improve with a hydrolyzed formula.
Soy protein-based formulas are frequently recommended as an alternative formula. However, soybean protein ranks second as an antigen in the first months of life, particularly in infants with primary cow's milk intolerance who are placed on a soy formula.5 The recent AAP report states that there is no conclusive evidence for allergy prevention with soy-based formula.5
It is important to note that only extensively hydrolyzed casein or amino acid-based formulas have official indication for the treatment of known allergic disorders. Partially hydrolyzed formula is not recommended for the treatment of allergy.8
Long-term prognosis: what is the likelihood of becoming tolerant to CMP?
The majority of children with early CMPA will eventually become tolerant to CMP. It is usually assumed that the child will become tolerant of CMP by the age of 5 years when their mucosal immune system matures and they become immunologically tolerant of milk proteins. In most children with non-IgE-associated CMPA, symptoms are likely to resolve by the time the child is 1 to 2 years of age.1,2
Children with a history of IgE-positive CMPA are at increased risk of developing further atopic conditions including atopic dermatitis and asthma as well as food allergies and allergy to environmental allergens. On the other hand, children who are IgE-negative will become tolerant to CMP earlier and are at lower risk to develop other allergies.1,9
CMPA: Is there potential for primary prevention?
The increasing incidence of pediatric allergies including CMPA calls for new primary prevention strategies. It is well understood that exclusive breastfeeding provides early and extensive immune support. For formula-fed infants, a growing body of evidence suggests that primary prevention of CMPA in the form of a nutritional strategy may be possible. This may be of particular interest in families with a history of atopy.
Protein composition: A 2003 meta-analysis conducted by the Cochrane Collaboration indicated that reducing the risk of common allergic manifestations in infancy is possible by feeding either 100% whey protein, partially hydrolyzed formula or extensively hydrolyzed casein formula instead of intact cow's milk protein formula.8 As noted earlier in this article, the GINI study found that feeding a hydrolyzed formula – partially hydrolyzed whey or extensively hydrolyzed casein – vs. intact cow's milk formula or extensively hydrolyzed whey formula during the first 4 months of life reduced the risk of allergic manifestations during the first year of life.5,6
Timing for introduction of solids: In contrast to long-held beliefs regarding introduction of solids, in the recent clinical report, the AAP reversed its stance on delaying the introduction of common allergens including dairy, eggs, and nuts, citing a lack of evidence that delaying introduction beyond age 4-6 months has a significant protective effect on the development of atopic disease.5
Probiotic supplementation: Evidence shows that the intestinal flora in formula-fed infants is influenced by the protein composition of the formula used. A higher proportion of bifidobacteria and lactobacilli has been found in infants fed with whey formula vs. casein formula. Since it is known that oral probiotic supplementation can reduce the prevalence of atopic disease by stabilizing intestinal integrity, increasing numbers of specific intestinal flora and reducing intestinal inflammation, a formula that increases the number of these bacteria could offer benefits in reducing the risk of allergy in infants.9,10
- Vandenplas Y et al. Guidelines for the diagnosis and management of cow’s milk protein allergy in infants. Arch Dis Child 2007;92:902–8.
- Nocerino A. Protein Intolerance. http://www.emedicine.com/ped/topic1908.htm
- Høst A. Frequency of cow’s milk allergy in childhood. Ann Allergy Immunol2002;89(Suppl 1):33–7.
- Lake AM. Dietary protein enterocolitis. Curr Allergy Rep 2001;1(1):76–9.
- Greer FR et al. and the American Academy of Pediatrics Committee on Nutrition and Section on Allergy and Immunology. 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(1):183-91.
- von Berg A et al. The effect of hydrolyzed cow’s milk formula for allergy prevention in the first year of life: The German Infant Nutritional Intervention Study, a randomized double-blind trial. J Allergy Clin Immunol 2003;111(3):533–40.
- Osborn DA, Sinn J. Soy formula for prevention of allergy and food intolerance in infants. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD003741. DOI: 10.1002/14651858.CD003741.pub4. http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD003741/frame.html
- Osborn DA, Sinn J. Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD003664. DOI: 10.1002/14651858.CD003664.pub3. http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD003664/frame.html
- Høst A et al. The natural history of cow’s milk protein allergy/intolerance. Eur J Clin Nutr 1995;49(Suppl 1):S13–8.
- Lara-Villoslada F et al. The Balance Between Caseins and Whey Proteins in Cow’s Milk Determines its Allergenicity. J Dairy Sci 2005 88:1654–60.
- Kalliomaki M et al. Probiotics in primary prevention of atopic disease: A randomized placebo-controlled trial. Lancet 357:1076–79.