Non-IgE cow's milk protein allergy (CMPA) (Paediatric Guidelines)

TAM (Treatments and Medicines) NHS Highland
NHS Highland

Objectives

Audience

  • All NHS Highland
  • Primary and Secondary care
  • Paediatrics only

Patient Group

This guideline is for infants with Non-IgE mediated reactions to cow's milk. This guideline is NOT appropriate to treat infants showing severe or immediate reactions to cow's milk.

  • To standardise the diagnosis and management of Non-IgE mediated CMPA
  • To help staff including GPs, health visitors, paediatricians and A&E staff initiate the management of symptomatic CMPA.
  • To ensure the most appropriate and cost effective alternative formula are prescribed To ensure children are not following an exclusion diet for longer than necessary.

Exclusion criteria

Children with the following conditions should be excluded from following this pathway and onward referral made to the appropriate service such as general paediatrics or paediatric dermatology.

  • IgE mediated reactions
  • Multiple allergies
  • Severe symptoms which have failed to respond to medical management such as faltering growth, bloody diarrhoea, severe reflux.

Referrals

Evidence base for the treatment of non IgE cow's milk protein allergy (CMPA)

CMPA is often overreported.

  • A double-blind placebo controlled food challenge confirmed the diagnosis in <1%2 whereas while the prevalence based on the perception of parents is often reported to be around 10%1.
  • CMPA in exclusively breast-fed babies is lower (0.5%) compared to formula-fed or mixed fed infants.
  • The guidelines published by ESPGHAN 20242 and the MAP guidelines3 on the diagnosis and management of cow's milk protein allergy in infants have been used as the basis for these guidelines on the management in primary care.
  • The MAP resources can be found at : https://www.allergyuk.org/hcp-resources/map-guidelines/

Introduction

The prevalence of presentation of suspected milk allergy is increasing and, as a result, infants are increasingly referred to Dietetic services for advice regarding the avoidance of milk and supplementation with an appropriate alternative formula.

On presentation an allergy focused history and presenting symptoms can usually determine if the allergy is an IgE or non-IgE mediated reaction and this will also determine the appropriate treatment course.

IgE reactions can be severe and (rarely) lead to anaphylaxis therefore the diagnostic techniques of exclusion and reintroduction, where this may induce a severe reaction, are not recommended.  IgE allergy SHOULD be confirmed by Specific IgE or Skin Prick Test investigations. Repeat monitoring of these investigations SHOULD guide appropriate timing for reintroduction.

In some cases, where symptoms pose significant risk, reintroduction attempts will require to be carried out in the hospital setting.

Non-IgE mediated allergy CANNOT be confirmed using the above investigation techniques, therefore diagnosis is confirmed by symptom response to a period of exclusion followed by challenge with cow's milk.

Many Non-IgE milk allergy symptoms are common in infancy and challenge with milk is required to ensure that infants are not following an exclusion diet unnecessarily.

There are several alternative infant formula which have Advisory Committee of Borderline Substances (ACBS) for the treatment of cow's milk allergy. There is a significant cost difference between Extensively Hydrolysed Formulas (eHFs), Hydrolysed Rice Formula (HRF) and Amino Acid Formulas (AAFs), ensuring appropriate prescription has potential for significant cost savings.

There is evidence to suggest that prolonged avoidance of milk can impact children nutritionally and socially and may lead to long term restrictive eating therefore regular monitoring and timely staged reintroduction of cow's milk is essential.

Alternative milk formulary: ADD LINK ONCE PUBLISHED

Dental health

Hydrolysed formula and soya-based formulas contain alternative sugars, which can cause tooth decay. Once the deciduous teeth start to erupt, they should be brushed twice daily with a small, soft toothbrush and a smear of fluoride toothpaste

IgE and non-IgE mediated allergy

 

Non-IgE mediated allergy

IgE mediated allergy
Reaction time Reactions appear TWO HOURS to TWO DAYS after ingestion and can cause chronic symptoms over a longer period

Reactions appear within MINUTES and up to TWO HOURS after ingestion or contact.
Skin
  • Severe itch (Pruritis)
  • Erythema
  • Atopic eczema / dermatitis
  • Severe itch (Pruritis)
  • Erythema
  • Acute urticaria
  • Acute angioedema: most commonly of the lips, face and around the eyes
Gastrointestinal system
  • Gastro-oesophageal reflux disease
  • Frequent regurgitation
  • Loose or frequent stools or diarrhoea
  • Blood and/or mucus in stools but otherwise thriving
  • Abdominal pain
  • Infantile colic
  • Food refusal or aversion
  • Constipation
  • Perianal redness
  • Pallor and tiredness
  • Faltering growth in conjunction with at least one or more gastrointestinal symptoms above (with or without significant atopic eczema)
  • Angioedema of the lips, tongue and palate
  • Oral pruritis
  • Nausea
  • Colicky abdominal pain
  • Vomiting
  • Diarrhoea
Respiratory tract (unrelated to infection)
  • Lower respiratory tract symptoms (cough, chest tightness, wheezing or shortness of breath
  • Upper respiratory tract symptoms (nasal itching, sneezing, rhinorrhoea or congestion or congestion) (with or without conjunctivitis)
  • Lower respiratory tract symptoms (cough, chest tightness, wheezing or shortness of breath)
General symptoms
  • Persistent distress or colic ( ≥3 hours per day wailing / irritable) at least 3 days / week over a period >3 weeks
  • Signs and symptoms of anaphylaxis or other systemic allergic reactions

NOTE: The list in this table is not exhaustive and the absence of these symptoms does not exclude food allergy

 

Consider food allergy in children whose symptoms do not respond adequately to treatment for:

  • Atopic eczema
  • Gastro-oesophageal reflux disease
  • Chronic gastrointestinal symptoms, including constipation

Adapted from: National Institute for Health and Clinical Excellence (NICE): Food allergy in children and young people https://www.nice.org.uk/Guidance/CG116

Allergy-focused clinical history

As part of the initial assessment of a non-IgE reaction to cow's milk protein it is important for health care professional to take an allergy-focused clinical history appropriate for the age of child and presenting symptoms.

This history should include the following: 

  • History of atopic disease (asthma, eczema or allergic rhinitis) or food allergy in patient, parents or siblings
  • Symptoms that may be associated with food allergy, including: 
    • age at first onset
    • speed of onset
    • duration, severity and frequency
    • setting of reaction (for example, at home or nursery)
    • reproducibility of symptoms on repeated exposure
    • what food and how much exposure to it causes a reaction
  • Cultural and religious factors that affect the child’s diet
  • Who has raised the concern and suspects the food allergy
  • What is the suspected allergen
  • The child’s feeding history, including age of weaning, if appropriate
    • Whether the child was breastfed or formula-fed (if the child is breastfed, consider the mother’s diet)
  • Details of previous treatment
    • Including medication, for the presenting symptoms, and the response to this
  • Any response to the elimination and reintroduction of foods
If allergy history indicates infant likely to have non-IgE reaction to cow's milk protein then follow algorithm: Primary Care management of non-IgE CMPA.

Lactose intolerance

Primary lactose intolerance:

  • This is NOT an allergic reaction and can arise as a result of an inherited deficiency in lactase, the enzyme needed to digest lactose which is the carbohydrate found in all mammalian milk. This is extremely uncommon in the UK.

Secondary lactose intolerance:

  • May occur post gastroenteritis as a result of severe diarrhoea, this is usually transient and should resolve without action within a few weeks. It may also occur secondary to the ongoing gastrointestinal symptoms resulting from undiagnosed CMPA, symptoms should resolve following appropriate treatment of cow's milk protein allergy.

Symptoms:

  • Like all carbohydrate intolerance, lactose intolerance causes osmotic diarrhoea.

Symptoms of non-IgE CMPA

The majority of presentations of Non IgE CMPA are likely to be mild to moderate and most formula fed infants will be successfully treated using EHF. Those with more severe symptoms warrant use of AAF. AAF is significantly more expensive than EHF and should only be used when clinically indicated.

Symptoms of non–IgE CMPA

Mild to Moderate 

  • Most occur within 2 to 72 hours following ingestion of cow’s milk protein

One or more:

  • GI: reflux, food refusal/aversion, loose stools, perianal redness, constipation, abdominal discomfort, small amount of blood and or mucus in stools in otherwise well infant.
  • Skin: pruritus, erythema, eczema.
    Respiratory: catarrhal airway symptoms

Follow: Algorithm: primary care management of non-IgE CMPA

Severe 

  • Most occur within 2 to 72hrs following ingestion of cow’s milk protein

One or more:

  • GI: persistent symptoms e.g. diarrhoea / vomiting / abdominal pain/food refusal / aversion, significant blood in stools and or mucus, irregular or uncomfortable stools +/- faltered growth
  • Skin: severe atopic eczema +/- faltering growth

Refer to General Paediatrics and Paediatric Dietetics, AND

Follow: Algorithm: primary care management of non-IgE CMPA

Algorithm: Primary care management of non-IgE CMPA

Primary Care Management of Non-IgE CMPA

Where referral to a Dietitian is recommended within the algorithm: please refer to the relevant local Dietetic Service

Transitioning information

The following information can be printed and provided to the family along with the prescription. Click here
Alternative formula smell and taste significantly different from breast milk or standard infant formula. To ensure acceptability infants should transition from their existing formula to the alternative formula following the guidance below, altering total volume to mirror usual intake.

Transition volumes

Day 1: 5 oz Cow's milk formula & 1 oz Alternative formula
Day 2: 4 oz Cow's milk formula & 2 oz Alternative formula
Day 3: 3 oz Cow's milk formula & 3 oz Alternative formula
Day 4: 2 oz Cow's milk formula & 4 oz Alternative formula
Day 5: 1 oz Cow's milk formula & 5 oz Alternative formula
Day 6: 6 oz Alternative formula

Breastfed / Mixed feeding Infants:

Breast fed infants need not transition to and alternative formula if mum is following a milk free diet they can continue to breast feed as long as acceptable to the family. However if mixed feeding or if planning to stop breast feeding, to ensure acceptability of the alternative formula infants should if possible transition to the alternative formula following the guidance above or by mixing alternative formula with expressed breast milk if available.

Stool Alterations:

Stool colour may change to green following transition to Extensively Hydrolysed Formula or Amino Acid Formula.

Challenge to confirm diagnosis after 3 to 4 weeks of excluding cow's milk

This advice is for infants with non-IgE mediated food allergy only (i.e. delayed reaction with mild to moderate symptoms that occur 2 hours to 2 days after ingestion of cow’s milk).

  • If your child has had a severe reaction to food consult your doctor BEFORE challenging with cow’s milk.
  • If your child is unwell, do NOT progress with the challenge.
    • Continue avoiding milk and using the alternative formula.
    • Start the challenge when your child is better.
  • If your child is weaning, do NOT introduce any additional new foods during the challenge period.

Cow's milk formula must be reintroduced in order to confirm diagnosis. This should be done gradually over several days using the steps below.

  • If your baby shows any sign of return of their symptoms of cow's milk allergy at any time during challenge do NOT proceed with the next step.
  • Return to using the alternative formula and milk free diet, inform your GP or Health Visitor and they will refer you to a Dietitian who will arrange to see you and your child to monitor your child’s growth and ensure your child’s diet is adequate for their needs while they are excluding cow's milk.

Formula feeding:

  • The volumes below are an example but are useful to show the correct ratio of cow's milk to alternative formula for the challenge period.
  • Allow your baby to feed to appetite, eg, if they are having 7 oz, start with 6 oz alternative formula with 1 oz cow's milk formula. The challenge will take a little longer to complete.

Day 1: 5 oz Alternative formula & 1 oz Cow's milk formula
Day 2: 4 oz Alternative formula & 2 oz Cow's milk formula
Day 3: 3 oz Alternative formula & 3 oz Cow's milk formula
Day 4: 2 oz Alternative formula & 4 oz Cow's milk formula
Day 5: 1 oz Alternative formula & 5 oz Cow's milk formula
Day 6:  6oz Cow’s milk formula

Breast feeding:

  • Cow's milk should be gradually reintroduced to the mother's diet over a period of 1 week.

Patient information:

Milk-free resources:

Further information for health care professionals

  1. NICE - National Institute for Health and Clinical Excellence (NICE): Food allergy in children and young people. Diagnosis and assessment of food allergy in children and young people in primary care and community settings. Clinical guideline 116. February 2011. NICE. London
  2. Vandenplas, Y., Broekaert, I., Domellöf, M., Indrio, F., Lapillonne, A., Pienar, C., Ribes‐Koninckx, C., Shamir, R., Szajewska, H., Thapar, N. and Thomassen, R.A., 2024. An ESPGHAN position paper on the diagnosis, management, and prevention of cow's milk allergy. Journal of paediatric gastroenterology and nutrition, 78(2), pp.386-413.
  3. https://www.allergyuk.org/hcp-resources/map-guidelines/
  4. Patient information https://www.cyans.scot.nhs.uk/health-care-professionals-2/patient-information-leaflets-2/

Abbreviations

  • AAFs: Amino Acid Formulas
  • ACBS: Advisory Committee on Borderline Substances
  • A&E: Accident and Emergency
  • ADTC: Area Drug and Therapeutics Committee
  • CMPA: Cow's Milk Protein Allergy
  • eHF / eHFs: Extensively Hydrolysed Formula / Extensively Hydrolysed Formulas
  • ESPGHAN: European Society for Paediatric Gastroenterology, Hepatology and Nutrition
  • IFDC: Infant Feeding Difficulties Clinic
  • IgE: Immunoglobulin E
  • MAP: Milk Allergy in Primary Care
  • Non-IgE: Non–Immunoglobulin E

 

Editorial Information

Last reviewed: 29/04/2026

Next review date: 29/04/2029

Author(s): Dietetics .

Version: 4.1

Approved By: TAM subgroup of the ADTC

Reviewer name(s): J Chapple, Paediatric Dietitian.

Document Id: TAM331

Related resources

References:

  1. Vandenplas, Y., Broekaert, I., Domellöf, M., Indrio, F., Lapillonne, A., Pienar, C., Ribes‐Koninckx, C., Shamir, R., Szajewska, H., Thapar, N. and Thomassen, R.A., 2024. An ESPGHAN position paper on the diagnosis, management, and prevention of cow's milk allergy. Journal of pediatric gastroenterology and nutrition, 78(2), pp.386-413.
  2. Winberg, A., West, C.E., Strinnholm, Å., Nordström, L., Hedman, L. and Rönmark, E., 2015. Assessment of allergy to milk, egg, cod, and wheat in Swedish schoolchildren: a population based cohort study. PloS one, 10(7), p.e0131804.
  3. Fox, A., Brown, T., Walsh, J., Venter, C., Meyer, R., Nowak-Wegrzyn, A., Levin, M., Spawls, H., Beatson, J., Lovis, M.T. and Vieira, M.C., 2019. An update to the milk allergy in primary care guideline. Clinical and translational allergy, 9(1), p.40.
  4. National Institute for Health and Clinical Excellence (NICE): Food allergy in children and young people. Diagnosis and assessment of food allergy in children and young people in primary care and community settings. Clinical guideline 116. February 2011. NICE. London
  5. Agostoni C, Axelsson I, Goulet O. Medical Position Paper: Soy Protein Infant Formulae and Follow-On Formulae: A Commentary by the ESPGHAN Committee on Nutrition. Journal of Pediatric Gastroenterology and Nutrition 2006;42:352-361.
  6. COT (2003): Phytoestrogens and health. Food Standards Agency.
  7. BDA Paediatric Specialist Group Position Statement. Use of Infant Formula based on Soy Protein for Infants. Executive Summary July 2022
  8. Vandenplas Y, Castrellon PG, Rivas R et al. Safety of soya-based infant formulas in children. Br J Nutr 2014 (Febr 10);1-21.