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Volume 9.15 21st November 2019

UNDERSTANDING COW’S MILK PROTEIN ALLERGY IN INFANTS Olivia Chaffey Student of Nutrition and Dietetics, Leeds Beckett University

The UK currently has the highest cow’s milk allergy (CMA) prevalence in Europe, with 2-3% of one- to three-year olds having a confirmed diagnosis.1 As cow’s milk is an important source of nutrition for infants, it is essential that the condition is effectively managed. Cow’s milk protein allergy (CMPA) is the most common food allergy in infants and young children and is the consequence of an abnormal response to one or more proteins in cow’s milk by the immune system.2 CMPA generally presents in infants before the age of one year and is outgrown by the age of five. Children who have other confirmed food allergies, or a family history of atopy, such as eczema or asthma, have an increased risk of CMPA.3 There is evidence to suggest that breastfeeding for a period of at least four months prevents, or delays, the occurrence of CMPA when compared to the feeding of a formula containing intact cow’s milk protein. There is no current evidence to suggest that maternal dietary restriction in pregnancy, or lactation, influences atopic disease.4 FOOD ALLERGIES

Allergies typically develop during the first decade of life and are directly linked to the maturation of the immune system. Around 90% of food allergies are caused by 14 foods, one of which is cow’s milk.

Food allergies are the consequence of an adverse immune response to a particular food; the immune system mistakes harmless substances as a potential threat. In individuals whose immune system has made this mistake, the immune system becomes sensitised to that food protein. Upon reintroduction of this protein, the immune system remembers the food as a threat and reacts in a way that produces symptoms. For symptoms commonly seen in CMPA, see Table 1 overleaf. Allergies can be either IgE- or nonIgE-mediated depending on how the immune system reacts. Symptoms caused by immunoglobulin E antibody (IgE) have an acute onset, typically less than two hours/within minutes after ingestion of the food. Non-IgE-mediated allergies are characterised by a delayed onset of symptoms from a few hours to days after ingestion. The pathology of nonIgE-mediated CMPA isn't properly understood and the symptoms are caused by a different part of the immune system than in IgE-mediated



*For the dietary management of cow’s milk allergy

Olivia is a nutrition graduate and current dietetic masters student with a keen interest in paediatrics, pregnancy and food allergies. She enjoys interacting with the local community and is a regular food bank volunteer.

Peer reviewed by Mary Feeney Paediatric Allergy Dietitian, King’s College London

This is an independent article reproduced from NHD issue 145 and is free from industry funding and editorial influence.

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Table 1: IgE- and non-IgE-mediated symptoms in CMPA5 IgE-mediated symptoms in CMPA

Non-IgE-mediated symptoms in CMPA

Puritis (itchy skin)

Puritis (itchy skin)


Reddening of the skin

Swelling of the eyes, lips, face

Non-specific rashes coming and going


Significant eczema



Reddening of the skin


Coughing, often sudden and persistent

Straining to pass soft, loose or hard stools

Difficulty breathing, may hear wheezing

Weight loss or not putting on weight

Table 2: A list of foods and ingredients containing cow’s milk protein10 Butter, buttermilk, casein/caseinates, cheese (any form, eg, cheddar, brie), cheese powder, condensed milk, cream, curds, custard, dairy solids, evaporated milk, ghee, butter oil, butter fat, hydrolysates (casein, milk protein, whey), ice cream, infant formula (cow’s milk based which includes lactose-free and partially hydrolysed formula*), lactalbumin, lactoglobulin, low fat milk, malted milk, milk, milk derivative, milk protein, milk solids, non-fat dairy solids, skimmed milk, skimmed milk solids, sour cream, whey, yoghurt

*It’s important to note that the majority of infants with CMPA tolerate extensively hydrolysed formulas.11 allergy. Non-IgE-mediated CMPA is the most common form of CMPA.5 SYMPTOMS OF CMPA

For CMPA, symptoms are typically observed after exposure to cow’s milk in infant formula, during early complementary feeding, or in breastfed infants due to consumption of cow’s milk in the mother’s diet, which passes into breastmilk. How quickly symptoms appear helps identify the type of allergy; delayed symptoms can often make diagnosis more complex as the symptoms may be caused by an altogether different factor. It is rare, but possible to present with a combination of both IgE- and non-IgEmediated symptoms.5 IDENTIFICATION, DIAGNOSIS AND MANAGEMENT

CMPA is the consequence of an adverse reaction to the proteins in the milk, specifically whey and casein. The sugar in cow’s milk, known as lactose, can also cause symptoms in individuals, some of which overlap with the symptoms seen in CMPA.3

CMPA is, therefore, often confused with lactose intolerance, as this sugar is responsible for the most common form of non-immune reaction to cow’s milk.6 Secondary lactose intolerance is generally a temporary condition that can happen after a bout of gastroenteritis (stomach bug). It can also occur alongside coeliac disease or other conditions that cause gut inflammation. Other overlapping conditions include atopic eczema and infantile colic. A survey by Allergy UK found that around 15% of parents visited their GP 10 times before receiving a CMPA diagnosis.7 Misinterpretation or nonidentification of the allergy can lead to faltering growth and chronic unpleasant symptoms. If CMPA is suspected, or diagnosed, guidance should be acquired from a healthcare professional. NICE has published recommendations for the assessment and diagnosis of food allergies in children under 19 years of age.8 Upon seeing a GP, an allergy-focused clinical history should be conducted for those with suspected CMPA. The history aims to identify signs of food allergy and the timing and duration of symptoms. This data



*For the dietary management of cow’s milk allergy

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TOMORROW successfully accelerate return to cow’s milk after 12 months of use**5

IN THE FUTURE reduce the risk of future allergic manifestations by ~50%†6

*For the management of cow’s milk allergy **vs. eHCF without LGG®, rice, soy or amino acids (p<0.001) † During a period of 3 years vs. eHCF without LGG® (p<0.001)


References: 1. Dupont C et al. Br J Nutr 2012; 107:325–338. 2. Lothe L et al. Pediatrics 1989; 83:262–266. 3. Baldassarre ME et al. J Pediatr 2010; 156:397–401. 4. Nermes M et al. Clin Exp Allergy 2011; 41:370–377. 5. Canani RB et al. J Pediatr 2013; 163:771–777. 6. Canani RB et al. J Allergy Clin Immunol 2017; 139:1906–1913. Nutramigen with LGG ® is a food for special medical purposes for the dietary management of cow’s milk allergy and must be used under medical supervision. Nutramigen with LGG ® is not recommended for premature and immunocompromised infants unless directed and supervised by a healthcare professional. IMPORTANT NOTICE: Breastfeeding is best for babies. The decision to discontinue breastfeeding may be difficult to reverse and the introduction of partial bottle-feeding may reduce breast milk supply. The financial benefits of breastfeeding should be considered before bottle-feeding is initiated. Failure to follow preparation instructions carefully may be harmful to your baby’s health. Parents should always be advised by an independent healthcare professional regarding infant feeding. Products of Mead Johnson must be under medical supervision. Trademark of Mead Johnson & Company LGG © 2019 Mead Johnson & Company, LCC. All rights reserved. LGG ® and the LGG ® logo are registered trademark of Chr. Hansen A/S. Date of Preparation: September 2019 (RB-M-00424)

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Table 3: Different types of formula and their suitability in the management of CMPA Suitability for infants (0-6m) with CMPA



Extensively hydrolysed

Broken down cow’s milk protein, tolerated by the majority of infants with CMPA.


Generally used when hydrolysed formulas aren’t tolerated.


Not recommended to infants under six months of age.

Lactose free

Based on cow’s milk protein.

helps indicate whether the issue is likely to be an allergy and whether it is IgE- or non-IgE-mediated. Depending on the results of the clinical history, specific IgE blood tests or skin prick testing may be performed to confirm IgE-mediated CMPA. There are no skin or blood tests for non-IgEmediated allergies. If non-IgE-mediated CMPA is suspected, cow’s milk is eliminated from the diet for a period of two to six weeks, after which cow’s milk is gradually reintroduced into the diet. This is currently the most reliable test for the presence of this form of CMPA.9 Dietetic support will help ensure adequate elimination of cow’s milk, identify the most appropriate duration for the elimination and guide the reintroduction process. Those with an IgE-mediated diagnosis are typically managed in secondary care, and those with a non-IgE-mediated diagnosis can be managed in primary care with the help of a dietitian. Both IgE- and non-IgE-mediated CMPA require strict avoidance of cow’s milk. This may involve modifying the diet of breastfeeding mothers, during complementary feeding, or use of an alternative infant formula depending on the child’s age and mode of feeding. It is important to be aware of the variety of foods that include cow’s milk protein, as any foods containing this protein are likely to trigger symptoms in infants with CMPA. Table 2 on the previous page illustrates a non-exhaustive list of common foods containing cow’s milk protein that should be avoided in the diet of infants with CMPA. It’s important to advise that food labels should always be carefully checked to ensure the food does not contain cow’s milk protein. As cow’s milk contains essential nutrients such as calcium, it’s important to ensure individuals


are provided with appropriate information on maintaining a healthy balanced diet. The BDA has produced food fact sheets on how to follow such a diet, which include alternative sources of nutrition and how to interpret food labels.12 FEEDING INFANTS WITH CMPA

Breastfeeding provides the best source of nutrition for infants, as the composition of breast milk changes to meet requirements for that specific child’s growth. Breastfed babies can react to cow’s milk proteins in the mother’s milk if the mother is consuming cow’s milk in her diet. If CMPA is suspected/diagnosed in an infant, the mother may be advised to abstain from consuming cow’s milk whilst breastfeeding. If the infant’s symptoms do not improve following the mother’s strict exclusion of cow’s milk from the diet, she can return to her normal diet.13 In formula-fed babies who have suspected/ diagnosed CMPA, changing formula feed will be necessary. Choosing the appropriate alternative formula is dependent upon a variety of factors, such as the type of allergy and severity of allergic symptoms (ie, degree of hydrolysis required), as well as age. It is vital that an appropriate formula is identified to ensure that the child is meeting their nutritional requirements for healthy growth and development. UK and international guidance, such as the iMAP algorithm,14 are available to help healthcare professionals identify the most suitable choice. For infants who have a high risk of atopy and are predominantly formula-fed, modest evidence suggests that the onset of atopic disease, such as CMPA, may be delayed/prevented by the use of hydrolysed formulas compared with formula

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NHD CPD eArticle made with intact cow’s milk protein.4 However, a recent Cochrane review advises against the use of a hydrolysed formula for allergy prevention in infants with high risk of atopy.22 Extensively hydrolysed infant formulas still contain cow’s milk protein, but the protein has been broken down into significantly smaller pieces. This makes the protein less likely to be detected as harmful by the immune system and they are tolerated by the majority of infants with CMPA. For those who still react to extensively hydrolysed formula, amino acid-based formulas are used, as they aren’t based on cow’s milk. SWITCHING FORMULAS

Although it can be hard to get a baby to accept a new formula due to a new taste and smell, most formula-fed babies under three to four months will readily accept the change to a hypoallergenic formula. For those who are less willing to accept the change, such as older infants with delayed reactions, mixing the new and old formula together can help with the acceptance process. This can be performed over a few days. If the change still proves hard to accept, adding a few drops of alcohol-free vanilla extract to the bottle may help.13 Typical consequences of feed change to infants include changes in bowel habit, such as temporary constipation, or a change in stool colour. Soya-based formulas aren’t recommended in the UK to infants under the age of six months due to the phytoestrogen content. The consumption of rice milk in children under five years is also not recommended due to their high inorganic arsenic content.15 Lactose-free formulas are based on cow’s milk protein and are, therefore, not suitable for infants with suspected/diagnosed CMPA. REINTRODUCTION OF COW’S MILK AND ESTABLISHING TOLERANCE IN NON-IGEMEDIATED CMPA

Around 90% of children will grow out of CMPA by adulthood.16 In order to assess whether the child has developed tolerance to cow’s milk protein, reassessment should occur every 6 to 12 months.6 This involves the reintroduction of cow’s milk to the diet and monitoring for the return of symptoms. In IgE-mediated CMPA,

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reintroduction is carried out following repeat allergy tests: specific IgE blood tests or skin prick tests, which indicate that the allergy is likely to have been outgrown. The child may undergo a milk challenge in a supervised clinical setting prior to reintroducing at home.23 NICE has devised management guidelines for suspected and confirmed CMPA in children and young people.11 Also, 12 clinical experts came together to create guidance with a specific focus on milk allergy in primary care (MAP guidelines).14 In 2017, these guidelines were updated to become the iMAP milk allergy guidelines; an international interpretation of the original guidelines.17 They are currently undergoing further review.18 The iMAP guidelines were developed in response to the under and delayed recognition of non-IgE-mediated CMPA.19 They aim to help clinicians better recognise, diagnose and manage non-IgE-mediated CMA in infants by providing information on each of these aspects of care. The guidelines also provide information to parents in regard to understanding the allergy and gradually reintroducing cow’s milk into the diet. As the guidelines are based on international resources, some of the recommendations are different to those of the UK. For example, soyabased formulas are recognised as an alternative to cow’s milk for children of all ages in the iMAP guidelines. In the UK, it is only recommended for those aged 6+ months. It must be remembered that a minority of infants suffer with the condition and some associated symptoms are multifactorial which can make CMPA diagnosis particularly challenging. However, in infants whose symptoms are multiple, chronic or resistant to medical treatment, it is important to consider the possibility of CMPA. Information around the condition and exclusion and reintroduction of cow’s milk protein should be discussed with parents/caregiver. If the reintroduction of cow’s milk triggers the initial symptoms, a diagnosis can be made. Failure to do this can lead to unnecessary elimination of cow's milk, or can lead to an inaccurate diagnosis.19 THE MILK LADDER

The iMAP milk ladder helps individuals who are caring for a child with mild/moderate non-

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NHD CPD eArticle IgE CMA to establish tolerance to cow’s milk protein.20 Once cow’s milk has been excluded from the diet for the appropriate amount of time (as agreed with a healthcare professional), it can be gradually reintroduced to establish a tolerance threshold. The ladder typically consists of six steps and dietetic support should be received whilst using the ladder, until all steps have been successfully climbed. The ladder provides advice on how to progress, each step upwards includes foods with increasing amounts of cow’s milk protein or foods where the milk protein is in a less processed or more allergenic form. The steps may be adjusted by a healthcare professional depending on the child. iMAP recipes are available to complement each step of the ladder.21 Baked foods, such as biscuits and cakes, should be introduced initially (step 1 of the milk ladder), as they are less allergenic compared to fresh liquid cow’s milk. However, some infants may begin at a different step depending on their current diet. The child should be symptom-free when starting

Volume 9.15 - 21st November 2019

the ladder. If symptoms occur upon ingestion, cow’s milk elimination should continue and reevaluated after a further six to 12 months. The duration at each stage of the ladder is child-specific.20 The child should continue to consume foods tolerated at each step, along with foods tolerated at any previous steps as part of a healthy diet. CONCLUSION

CMPA is a complex allergy in terms of recognition and diagnosis. It is important that families receive timely support to confirm the diagnosis and to optimally manage this condition. The iMAP guidelines have made a significant contribution to increasing awareness and education of non-IgE-mediated diagnosis, on both a national and international level.17 Allergy UK has announced that a review is currently underway of these guidelines which may further improve detection and management.18 Other guidelines from NICE and BSACI are available to support healthcare professionals.11,23

References 1 Canavan C et al. The epidemiology of irritable bowel syndrome. Clin Epidemiol. 2014; 6: 71-80 2 NICE Clinical Knowledge Summaries: Guidelines for IBS. Available online at: https://cks.nice.org.uk/irritable-bowel-syndrome#!backgroundSub (accessed online 04/05/2019) 3 NICE Clinical Knowledge Summaries: Guidelines for IBS. Available online at: https://cks.nice.org.uk/irritable-bowel-syndrome#!diagnosisSub:1 (accessed online 03/05/2019) 4 Lovell RM and Ford AC (2012). Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin Gastroenterol Hepatol 10, e4 5 Bonfiglio F et al. Female-specific Association between Variants on Chromosome 9 and Self-reported Diagnosis of Irritable Bowel Syndrome. Gastroenterology, 2018 6 Hoi Leong Xavier Wong et al. Early life stress disrupts intestinal homeostasis via NGF-TrkA signalling. Nat Commun 2019 04 15; 10(1): 1745. Epub 2019 Apr 15 7 Hayes PA, Fraher MH and Quigley EM (2014). Irritable bowel syndrome: the role of food in pathogenesis and management. Gastroenterol Hepatol 10, 164-174 8 Lacy BE, Weiser K and De Lee R (2009). The treatment of irritable bowel syndrome. Ther Adv Gastroenterol 2, 221-238 9 McKenzie YA et al. British Dietetic Association systematic review and evidence-based practice guidelines for the dietary management of irritable bowel syndrome in adults (2016 update). J Hum Nutr Diet, 2016. 29(5): p 549-75 10 Rossi M et al. Volatile Organic Compounds in Faeces Associated with Response to Dietary Intervention in Patients with Irritable Bowel Syndrome. Clinical Gastroenterology and Hepatology, Vol 16, Issue 3, March 2018, p 385-391.e1 11 Diduch BK. Gastrointestinal Conditions in the Female Athlete. Clin Sports Med. 2017 Oct; 36(4): 655-669 12 Johannesson E et al. Physical activity improves symptoms in irritable bowel syndrome: a randomised controlled trial. Am J Gastroenterol. 2011 May; 106(5): 915-22 13 Johannesson E et al. Intervention to increase physical activity in irritable bowel syndrome shows long-term positive effects, World J Gastroenterol. 2015 Jan 14; 21(2): 600-608 14 Schumann D, Langhorst J, Dobos G, Cramer H. Randomised clinical trial: yoga vs a low-FODMAP diet in patients with irritable bowel syndrome. Aliment Pharmacol Ther. 2018 Jan; 47(2): 203-211 15 Chey WY et al. Colonic motility abnormality in patients with irritable bowel syndrome exhibiting abdominal pain and diarrhoea. Am J Gastroenterol, 2001; 96(5): p 1499-506 16 Wedlake L et al. Systematic review: the prevalence of idiopathic bile acid malabsorption as diagnosed by SeHCAT scanning in patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther, 2009. 30(7): p 707-17 17 Bajor A et al. Increased colonic bile acid exposure: a relevant factor for symptoms and treatment in IBS. Gut, 2015. 64(1): p 84-92 18 NICE: Irritable bowel syndrome in adults: diagnosis and management, Clinical guideline [CG61] Published date: February 2008. Last updated: April 2017 www.nice. org.uk/guidance/cg61/chapter/1-Recommendations#dietary-and-lifestyle-advice (accessed online 6th May 2019) 19 Moss-Morris R et al. A randomised controlled trial of a cognitive behavioural therapy-based self-management intervention for irritable bowel syndrome in primary care. Psychol Med, 2010. 40(01): p 85-94 20 Ljótsson B et al. Long-term follow-up of internet-delivered exposure and mindfulness based treatment for irritable bowel syndrome. Behav Res Ther, 2011. 49(1): p 58-61 21 Peters SL et al. Randomised clinical trial: the efficacy of gut-directed hypnotherapy is similar to that of the low-FODMAP diet for the treatment of irritable bowel syndrome. Aliment Pharmacol Ther, 2016. 44(5): p. 447-59 22 Everitt HA, Landau S, O’Reilly G, on behalf of ACTIB trial group, et al. Assessing telephone-delivered cognitive–behavioural therapy (CBT) and web-delivered CBT versus treatment as usual in irritable bowel syndrome (ACTIB): a multicentre randomised trial. Gut, Published Online First: 10 April 2019 23 McKenzie YA et al. British Dietetic Association systematic review of systematic reviews and evidence-based practice guidelines for the use of probiotics in the management of irritable bowel syndrome in adults (2016 update). J Hum Nutr Diet. 2016 Oct; 29(5): 576-92 24 Jose-Walter Huaman et al. Effects of Prebiotics vs a Diet Low in FODMAPs in Patients with Functional Gut Disorders. Gastroenterology. 2018 Oct; 155(4): 1004-1007 25 Quigley BM et al. (Can’t Get No) Patient Satisfaction: The Predictive Power of Demographic, GI, and Psychological Factors in IBS Patients. J Clin Gastroenterol. 2018 Aug; 52(7): 614-621 Copyright © 2019 NH Publishing Ltd - All rights reserved. Available for printing and sharing for the use of CPD activities for personal use. Not for reproduction for publishing purposes without written permission from NH Publishing Ltd.

NHD CPD eArticle Volume 9.15 - 21st November 2019

Questions relating to: Understanding cow’s milk protein allergy in infants Type your answers below, download and save or print for your records, or print and complete by hand. Q.1

What is the aetiology of cow’s milk protein allergy (CMPA) in infants?

A Q.2

Describe the differences between IgE- mediated and non-IgE-mediated food allergies.

A Q.3

When are symptoms of CMPA typically observed?

A Q.4

Why can CMPA be confused with lactose intolerance?

A Q.5

Explain the importance of an allergy-focused clinical history in the diagnosis of CMPA.

A Q.6

How is non-IgE-mediated CMPA managed compared with IgE-mediated?

A Q.7

What are the options for feeding infants with CMPA?

A Q.8

Why are extensively hydrolysed formulas tolerated by most infants with CMPA?



What process can help an infant when switching formulas?

Q.10 Explain the reassessment process and use of the milk ladder in establishing tolerance to cow’s milk protein.

Please type additional notes here . . .

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NHD CPD eArticle Vol 9.15: Understanding cow’s milk protein allergy in infants  

The UK currently has the highest cow’s milk allergy (CMA) prevalence in Europe, with 2-3% of one- to three-year olds having a confirmed dia...

NHD CPD eArticle Vol 9.15: Understanding cow’s milk protein allergy in infants  

The UK currently has the highest cow’s milk allergy (CMA) prevalence in Europe, with 2-3% of one- to three-year olds having a confirmed dia...


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