Cows’ Milk Protein Allergy in Infants

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This article was originally published in the August/September edition of NHD Magazine and has been peer-reviewed by the brilliant Dr Rosan Meyer (Paediatric Research Dietitian, Honorary Senior Lecturer, Imperial College, London and Chair of the BDA Food Allergy and Intolerance Specialist Group).


Allergy has been called ‘the number one environmental epidemic disease facing children of the developed world’.1,2 Cows’ milk protein allergy (CMPA) is the most common food allergy found in children; with a worldwide prevalence of 1.9-4.9%3 and a UK prevalence of 2-3%.2,4 As milk is a key part of an infant’s diet, the nutritional management of this condition is crucial.

CMPA is a reproducible adverse immune response to one or more of the proteins found in cows’ milk, which usually presents before the age of one and is often outgrown by the age of five.4

The risk of CMPA increases when an infant has a history, or family history, of atopy; for example, eczema or asthma in the infant, or a family history of eczema, asthma, hay fever or food allergies.5 There is evidence that breastfed infants have a lower prevalence of CMPA, with about 7% of formula or mixed-fed infants developing CMPA compared to about 0.5% of exclusively breastfed infants. Furthermore, breastfed infants are reported to have less severe reactions if they do develop CMPA.3,6 The primary factor involved in the development of food allergy in infancy is genetic, with a parental atopic history (asthma, eczema and hayfever) significantly increasing the risk.7-8

Research has also identified contributing environmental factors, which include smoking during pregnancy, the infant’s gut microbiome which may be affected by route of birth (C-section versus vaginal birth), early antibiotic use and dietary diversity.7-8

CMPA is classified as either  immunoglobulin E- (IgE) or non-IgE-mediated, depending on the type of immune response which occurs.

IgE-mediated reactions occur when IgE antibodies form in response to cows’ milk protein, which causes the release of histamine from basophils and mast cells; whereas it is thought that non-IgE- mediated CMPA is caused by T-cells.5 IgE-mediated reactions have a quick onset, usually presenting within minutes to two hours and the symptoms can be severe, such as anaphylaxis, hives and facial swelling.5,10 Non-IgE mediated reactions are more common, often have a more delayed onset (such as two hours to three days) and usually present with less acute symptoms, such as gastrointestinal and skin symptoms. See Table 1 (p28) for a full comparison of symptoms.5,9

Non-IgE-mediated CMPA tends to resolve by the age of three, whereas IgE-mediated CMPA more commonly resolves by the age of five.10

Table 1: Symptoms of IgE and non-IgE mediated CMPA based on the Milk Allergy in Primary Care (MAP) guidelines9

IgE mediated Non-IgE mediated
Respiratory and/or cardiovascular signs of anaphylaxis No sign of anaphylaxis
Skin:

Acute pruritus (itching), erythema (rash), urticaria (hives), angioedema (swelling), flaring of atopic eczema

Skin:

pruritus (itching), erythema (rash), significant atopic eczema

Gastrointestinal:

Vomiting, diarrhoea, abdominal pain/colic

Gastrointestinal:

Vomiting, reflux, food refusal or aversion, abdominal discomfort, loose or frequent stools, perianal redness, constipation, uncomfortable stools, blood and/or mucus in stools in an otherwise well infant, faltering growth

Respiratory:

Acute rhinitis (inflammation of the nasal passage – nasal itching, sneezing, runny nose, congestion), conjunctivitis

Respiratory:

Catarrhal’ airway symptoms (build-up of mucous in the back of the nose, sinus’ or throat) – usually in combination with one or more of the above symptoms

Diagnosis

An allergy focused clinical history and physical examination based on the NICE guidelines for diagnosing food allergy in the under 19s is a crucial part of establishing whether CMPA is present, this usually includes gathering information on the following:10-11

  • the suspected allergen (e.g. cows’ milk);
  •  the history of presenting symptoms (see Table 1) including: age of onset, speed of onset, duration of symptoms, severity of reactions, frequency of reactions, how many organs produced a reaction, locations the reaction has occurred, reproducibility of symptoms, how much of the food causes a reaction;
  •  medication and response to previous treatments;
  • personal history of atopy (eczema, hay fever, dust allergies, asthma);
  • family history of atopy;
  • dietary intake, including cultural factors which affect food choice;
  • history of infant feeding and weaning if applicable;
  • history of response to the elimination and reintroduction of foods;
  • growth and nutritional status.

As well as this allergy-focused history, there are validated tests which can be used to test a suspected IgE-mediated CMPA, such as: skin prick tests to check for IgE antibodies in the skin and specific IgE serum assays to test for circulating IgE antibodies.4,9,11

Oral food challenges are the gold standard to confirm diagnosis, especially if there is any uncertainty about this.

For IgE-mediated reactions, these take place under medical supervision and can be open or blinded.Non-IgE-mediated CMPA can be more difficult to diagnose as there are no validated tests to use, therefore diagnosis is based on a combination of an allergy-focused history and a trial elimination diet and ideally a subsequent reintroduction phase to monitor whether symptoms return.11

It is important to note that there are types of complementary and alternative medicines which offer testing for CMPA, such as kinesiology and hair testing, but as these are not medically approved, they have no place in diagnosis of CMPA.4,11

CMPA can be mistakenly diagnosed as lactose intolerance due to an overlap of symptoms (diarrhoea, abdominal pains, cramps, bloating, flatulence and nausea); however, lactose intolerance is a deficiency of the enzyme lactase rather than an allergy to the protein in cows’ milk, therefore a thorough allergy focused history can avoid misdiagnosis.12

Some patients may have secondary lactose intolerance as a result of damage to the gut lining when CMPA is untreated; however, this is usually a transient condition as long as a strict cows’ milk protein-(CMP) free diet is adhered to.12-13

At the time of writing this article, the updated version of the Milk Allergy in Primary Care (MAP) guideline had not been released; this is called the international Milk Allergy in Primary Care (iMAP) guideline (see here for an infographic explaining the main updates, here for the guideline itself and here for the published paper underpinning this).

Eliminating Cows’ Milk Protein

CMP should be completely eliminated from the diet for two to six weeks to see whether the presenting symptoms improve.4,9,11 The NICE guidelines on food allergies in under 19-year-olds highlight that dietetic input is important in order to support with ‘nutritional adequacies, timings of elimination and reintroduction, and follow-up’.11 Breastfeeding mothers are encouraged to continue to breastfeed. but to exclude cows’ milk from their diet, they also need to be assessed as to whether a daily calcium and vitamin D supplement is indicated, bearing in mind that a breastfeeding mother requires 1,250mg of calcium and 10mcg of vitamin D per day.4,9,14 Formula-fed infants need to switch to a hypoallergenic formula6 (see Table 2).

Table 2: CMP-free infant formulas (List of formulas valid at the time of publishing this table)
Extensively hydrolysed formula (EHF)

e.g. Althera, Nutramigen 1 & 2, Aptimil Pepti 1 & 2, Pepti Junior, Similac Alimentum, Pregestimil

EHF is the first-line treatment used for mild – moderate CMPA. The CMP is broken down using heat and enzymatic treatment into short peptides and are tested to be tolerated by 90% of children with a proven CMPA7,15. Some EHF also contain probiotics, medium-chain triglyceride (MCT) fat and lactose; the exclusion of lactose in CMP-free formulas is no longer advised routinely as lactose is important to aid calcium absorption, promote healthy gut bacteria and may improve palatability of the formula.4,16  There is  emerging evidence that choosing an EHF may assist in inducing tolerance, especially when the formula contains specific strains of probiotics, however further research is needed into this.
Amino-acid formula (AAF)

e.g. Neocate LCP, Nutramigen PurAmino, Alfamino

AAF is totally cow’s milk free and based on into amino acids. Although >90% of infants with CMPA tolerate EHF6,9 there are specific indications for AAF, such as:4,9

    • when symptoms persist on an EHF
    • anaphylaxis
    • severe non-IgE mediated CMPA, e.g. eosinophilic oesophagitis
    • severe eczema not improving on standard treatment
    • faltering growth
    • multiple food allergies
  • severe ongoing symptoms  in persist when exclusively breastfed in spite of a maternal elimination diet
Soya based formula

e.g. Wysoy

Soya-based formulas are only suitable for infants over six months. These are more readily available to buy over the counter and may be more palatable for some infants. It is important to trial soya products with caution as  between 2-14% of children with IgE mediated allergy and up to 50% of non-IgE mediated allergy may react to soya as well4,19-20

Families of infants of weaning age and above should be educated about interpreting food labels, which foods and ingredients contain cows’ milk protein (see Table 3) and the duration, safety and limitations of an elimination diet.

It is crucial to offer alternative food and drinks to ensure a balanced diet while avoiding cow’s milk, with a particular focus on calcium intake

It is also important to highlight that shop-bought CMP-free milks should be fortified with calcium, vitamin D and B vitamins. Unsweetened CMP- free milks are useful for weaning; however, if there is a concern with faltering growth, then a version with a higher calorie content may be a better choice. Higher calorie dairy-free milks also have an overall nutritional profile which is more similar to full fat cows’ milk and so may be a more suitable choice as a main milk drink from one to two years of age if CMP exclusion is still indicated.

Additional high energy high protein dairy- free options in the treatment of faltering growth include: oils, nut butters and dairy free spreads, creams, cheeses, ice creams and puddings. Further nutritional considerations often include general weaning support, minimising reflux, advice on avoiding other allergens where multiple food intolerances occur and aiming to avoid unnecessarily restrictive eating.

Table 3: Food items and ingredients that contain cows’ milk protein4
Butter, butter fat, butter milk, butter oil, casein (curds), caseinates, hydrolysed casein, calcium caseinate, sodium caseinate, cheese, cheese powder, cottage cheese, cows’ milk (fresh, condensed, dried, evaporated, powdered, ordinary infant formulas, UHT, low fat), cream, artificial cream, sour cream, ghee, ice cream, lactalbumin, lactoglobulin, malted milk, margarine, milk protein, milk powder, skimmed milk powder, milk solids, non-fat dairy solids, non-fat milk solids, milk sugar, whey, hydrolysed whey, whey powder, whey syrup sweetener, yoghurt, fromage frais, lactose

Information and fact sheets on alternative dairy options can be obtained from the British Dietetic Association (BDA) website. As CMPA resolves in the majority of cases, it is important that regular reviews need to take place with a healthcare professional to ensure that the child is developing tolerance to CMPA.4,9 For those with an IgE-mediated CMPA and Food Protein Enterocolitis Syndrome (FPIES), a ward-based food challenge is needed to test whether tolerance to CMP has developed.4,9 This involves close medical supervision while introducing incremental dosages of cows’ milk.4

However, for mild to moderate non-IgE mediated CMPA, advice can be given on the gradual reintroduction of cows’ milk using a milk ladder approach; this involves introducing small amounts of products containing well-cooked milk to begin with, as heat treatment alters the protein structure of CMP and reduces allergenicity, and eventually introducing fresh milk if tolerated.10 It is important that parents are advised to continue to include tolerated milk products in their child’s diet and when a step hasn’t been tolerated, to revert to the previous step on the ladder and continue including all foods up to this level, then periodically trying the next step to see if tolerance has been acquired.9

It is best to try reintroductions early in the day to avoid a reaction going unnoticed overnight

A milk ladder approach can also be used when a breastfeeding mother is reintroducing CMP into her diet to test for tolerance in her child. From clinical practice, it may be easier to start reintroductions via one route initially rather than introducing CMP to the mother’s diet and the infant’s diet at the same time.

Conclusion

As CMPA is a nutritionally complex condition, dietitians are central to the management of this, with our involvement spanning from diagnosis through to tolerance development in most cases. Therefore, it is important that we are aware of the full scope of CMPA, so that we can provide the best possible support for the families that we work with.

References

1. World Health Organisation (2007). Global surveillance, prevention and control of chronic respiratory diseases

2. Venter et al. (2013) “Diagnosis and management of non-IgE-mediated cows’ milk allergy in infancy – a UK primary care practical guide”

3. Fiocchi et al (2010). World Allergy organisation diagnosis and rationale for action against cows’ milk allergy (DRACMA) guidelines

4. Luyt et al. (2014) “BSACI guideline for the diagnosis and management of cows’ milk allergy”

5. NICE (2015) “Cows’ milk protein allergy in children” 

6. Caffarelli et al. (2010) “Cows’ milk protein allergy in children: a practical guide”

7. Muraro et al. (2014) “EAACI food allergy and anaphylaxis guidelines. Primary prevention of food allergy. Allergy”

8. Grimshaw et al (2016) “Modifying the infant’s diet to prevent food allergy”

9. The MAP Guideline available at: http://cowsmilkallergyguidelines.co.uk/

10. Skypala et al. (2015) “The development of a standardised diet history tool to support the diagnosis of food allergy”

11. NICE (2011) “Food allergy in under 19s: assessment and diagnosis”

12. De Koker et al. (2014)  “The differences between lactose intolerance and cow’s milk protein allergy”

13. Shaw and Lawson (2014). Clinical Paediatric Dietetics 4th edition

14. Department of Health (1991). Dietary reference values for food and energy and nutrients for the United Kingdom

15. Host et al. (1999) “Dietary products used in infants for treatment and prevention of food allergy. Joint Statement of the European Society for Paediatric Allergology and Clinical Immunology (ESPACI) Committee on Hypoallergenic Formulas and the ESPGHAN Committee on Nutrition”

16. ESPGHAN (2012) “Diagnostic approach and management of cows’ milk protein allergy in infants and children: ESPGHAN GI Committee Practical Guidelines”

17. Canani (2013) “Formula selection for management of children with cows’ milk allergy influences the rate of acquisition of tolerance”

18. Cafferelli et al (2002) “Determination of allergenicity to three cows’ milk hydrolysates and an amino acid-derived formula in children with cows’ milk allergy” 

19. Klemola et al (2002) “Allergy to soy formula and to extensively hydrolyzed whey formula in infants with cows’ milk allergy” 

20. Agostoni et al. (2006) “Soy protein infant formulae and follow-on formulae: a commentary by the ESPGHAN Committee on Nutrition”


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