Non-IgE Cows' Milk Protein Allergy Guidance

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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.
Introduction

The prevalence of 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 (Table 3) 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) 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 termrestrictive eatingtherefore regular monitoring and timely staged reintroduction of cow’s milk is essential.

The aims of this guideline are:
  • To standardise the diagnosis and management of Non-IgE mediated cow’s milk protein allergy (CMPA)
  • To help staff including GPs, health visitors, paediatricians and A&E staff initiate the management of symptomatic cow’s milk protein allergy.
  • 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.

Evidence base for the treatment of non IgE CMPA

Between 1 to 17.5% 1, 2 of all infants show symptoms suggesting adverse reactions to cows' milk.  However evidence also indicates that following a food challenge, confirmed milk reaction is less than 1%3 .  CMPA in exclusively breast-fed babies is lower (0.5%) compared to formula-fed or mixed fed infants. 

The guidelines published by  ESPGHAN 4  Ludman et al5 and Venter et al  6,  on the diagnosis and management of cow’s milk protein allergy in infants (The MAP guideline) have been used as the basis for these guidelines on the management in primary care. Allergy UK

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.

Exclusions are infants with:

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

For Argyll and Bute - Referrals should be sent to the relevant Paediatrician and dietitian - nhsh.dietitiansdirect@nhs.scot

* In North Highland patients with severe reflux should be referred directly to the infant feeding clinic via the Paediatric Dietitians: paediatricdietitians@highland.gov.uk. Referral pathway can be found at: http://intranet.nhsh.scot.nhs.uk/Org/DHS/ChildrensServices/HospitalPaediatrics/Documents/Nutrition/infant feeding clinic/Pathway_for_referral_to_IFDC and IFAC DRAFT2 2018.doc

Table of IgE and Non-IgE mediated allergic reactions

Type Non-IgE mediated allergy IgE mediated allergy
Reaction Reactions appear 2 hours to 2 days after ingestion and can cause chronic symptoms over a longer period Reactions appear within minutes and up to 2 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/ other
  • Persistent distress or colic (3 or more hours per day wailing/irritable) at least 3 days/week over a period more than 3 weeks
  • Signs and symptoms of anaphylaxis or other systemic allergic reactions

Note that 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 and chronic gastrointestinal symptoms including constipation

Adapted from: National Institute for Health and Clinical Excellence (NICE): Food allergy in children and young people. 8

Clinical history: Allergy-focused and assessing severity of symptoms

Allergy-focused clinical history (NICE 20117)

As part of the initial assessment of a non-IgE reaction to cows' milk protein it is important for health care professionals 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

Details of any foods that are avoided and why

Symptoms that may be associated with food allergy, including:

  • age at first onset
  • speed of onset
  • duration, severity and frequency (see assessment table below)
  • 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 breast fed 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

Assessment of severity of symptoms of Non–IgE mediated CMPA

The majority of presentations of Non-IgE CMA 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 are shown in the table below.

Mild to moderate non-IgE symptoms Severe non-IgE symptoms

Most occur within 2 to 72 hours following ingestion of cows' 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

  • Pruritis
  • Erythema
  • Eczema 

Respiratory

  • Catarrhal airway symptoms

GI: Persistent symptoms, eg, 

  • Diarrhoea
  • Vomiting
  • Abdominal pain
  • Food refusal/aversion
  • Significant blood loss and/or mucus in stools
  • Irregular or uncomfortable stools
  • +/- faltered growth

Skin

  • Severe atopic eczema
  • +/- faltering growth

 

  • Follow algorithm: Primary Care management of Non-IgE CMPA 
  • Refer to General Paediatrics and Paediatric Dietetics
  • And follow algorithm: Primary Care management of Non-IgE CMPA 

 

Primary Care management of Non-IgE CMPA: Argyll and Bute

Primary Care management of Non-IgE CMPA: HHSCP

Management of allergic colitis in breastfed Infants (FOLLOWING EXCLUSION OF OTHER CAUSES OF BLOOD IN STOOLS)

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 cows' milk protein allergy.

Symptoms:

Like all carbohydrate intolerance, lactose intolerance causes osmotic diarrhoea. 

Nutritional prescribing advice for suspected non-IgE mediated CMPA

Prescribe a ‘one off’ script. Do not arrange repeat script at this stage.

Argyll and Bute:

  • Nutramigen LGG 400g x 12 tins.
    Neocate LCP should only be used if symptoms are severe (see guidelines)

North Highland

  • Aptamil Pepti Syneo*. Neocate Syneo only be used if symptoms are severe (see guidelines)

*use Aptamil Pepti 1 or Neocate LCP if Syneo products are contraindicated  Syneo products contain Bifidobacterium breve M-16V and are not suitable for use in: premature infants, infants who are immunocompromised, infants with a central venous catheter, infant who have short bowel syndrome

Refer to:

Argyll and Bute: NHSH.dietitiansdirect.@nhs.scot Tel: 01631 789041

North Highland: Infant Feeding Allergy Clinic (IFAC) via SCI gateway or email details to: paediatricdietitians@highland.gov.uk

Dietitians will:

  • Assess growth
  • Advise if repeat script is required
  • Provide milk free weaning advice before 6 months
  • Initiate milk reintroduction advice
    • Argyll and Bute: between 9 to 12 months or following 6 months exclusion
    • North Highland: between 8 to 12 months or following 6 months exclusion

Repeat script required only on dietetic request after 12 months of age.

Soya formula (SMA Wysoy) & Lactose free formula (SMA LF/Aptamil LF): do not prescribe for CMPA. These can be purchased from pharmacies and supermarkets

 

Alternative milks formulary

Alternative Milks Formulary
Extensively hydrolysed formulas (EHF)
Birth onwards   

Lactose free 

Nutramigen LGG 1* (400g)
Mead Johnson
Similac Alimentum (400g)
Abbott Nutrition 
Contains lactose Aptamil Pepti 1(400g)
Nutricia Early Life Nutrition
SMA Althera (450g)
Nestle Health Science
Over  6 months of age Lactose free

Nutramigen LGG 2* (400g)
Mead Johnson

Contains lactose Aptamil Pepti 2 (900g)
Nutricia Early Life Nutirtion

Amino Acid Formulas (AAFs)
NB
 these should not be used routinely and should only be used first line for infants with reaction to breast milk, severe reaction and/or growth failure alongside symptoms of milk allergy.

Birth onwards Lactose Free Neocate LCP (400g)
Nutricia SHS
Nutramigen Puramino (400g)
Mead Johnson
Alfamino (400g)
Nestle Health Science
Lactose Free Elecare (400g)
Abbott Nutrition
Lactose Free Neocate Syneo (400g)
Nutricia SHS

*Nutramigen LGG 1+2 contain the probiotic Lactobicillus GG and therefore should not be fed to premature infants (until they have reached their estimated date of delivery) or infants who might have immune problems.

Gastrointestinal symptoms associated with CMPA can cause secondary lactose intolerance. To reduce the risk of misdiagnosis during the exclusion and challenge process an alternative formula which is also lactose free should be prescribed in those infants presenting with gastrointestinal symptoms.  Lactose containing formula can be used for the treatment of cows' milk allergy, following confirmation of diagnosis or if there is poor palatability of initially prescribed formula.

Soya formula should not be used in infants under 6 months but can be used in an infant over 6 months if EHF are not accepted due to poor palatability. Soya infant formula is available for purchase from a retail outlet therefore, if soya formula is required, it does not require prescription.

All prescriptions for alternative formulas should be prescribed as an acute prescription. Approximately 10 tins will be required per 4 weeks. Prescription should continue until 12 months of age minimum and ongoing if deemed necessary under dietetic review.

Soya, and other formula and milk substitutes

Soya infant formula

This is no longer on the Formulary and should not be prescribed.

Soya infant formula should not be used first line in the diagnosis and treatment of cows' milk protein allergy as, dependent on presenting symptoms, there may be up to a 50% chance that infants will also react to soya formula. 10  

Soya formula should not be used routinely in infants aged 0 to 6 months as it contains phytoestrogens that could pose a risk to long term reproductive health. 11, 12 A recent systematic review and meta-analysis found no significant effect on reproduction function 13 however currently, recommendations remain unchanged in that it is not suitable for under 6 months of age except for:

Exceptions:

  • Vegan mothers who do not exclusively breastfeed, may choose to use soya infant formula
  • Under the advice of special paediatric services may use soya infant formula e.g. galactosaemia
  • Infants who are at nutritional risk as refusing alternative formula.
Other formula and milk substitutes

Goat or other mammalian milk formulas are not suitable for the treatment of Non-IgE CMPA as protein structures are similar to cow’s milk and there is a high risk of cross reaction.

Supermarket soya, oat or nut milks are not nutritionally complete and should not be used as a milk substitute for infants under 12 months. In most cases, following dietetic review, they can be used as the main drink after 12 months.

Rice milk should not be used in children under 4.5 years due to unacceptable levels of naturally occurring arsenic, relative to body weight.

Transitioning to alternative formula

Alternative formula smell and taste significantly differently 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:

  • Day 1: 5oz Cows' milk formula & 1oz Alternative formula
  • Day 2: 4oz Cows' milk formula & 2oz Alternative formula
  • Day 3: 3oz Cows' milk formula & 3oz Alternative formula
  • Day 4: 2oz Cows' milk formula & 4oz Alternative formula
  • Day 5: 1oz Cows' milk formula & 5oz Alternative formula
  • Day 6: 6oz Alternative formula

Breast fed/Mixed feeding Infants:

Breast fed infants need not transition to an 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 cows' milk

This advice is for infants with Non-IgE mediated food allergy only (i.e. delayed reaction with mild to moderate symptoms which occur 2 hours to 2 days after ingestion of cows' 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.

Cows' milk 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 cows' 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. The Dietitian 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 cows' milk.

Formula feeding:

  • Day 1: 5oz Alternative formula & 1oz Cows' milk formula
  • Day 2: 4oz Alternative formula & 2oz Cows' milk formula
  • Day 3: 3oz Alternative formula & 3oz Cows' milk formula
  • Day 4: 2oz Alternative formula & 4oz Cows' milk formula
  • Day 5: 1oz Alternative formula & 5oz Cows' milk formula
  • Day 6: 6oz Cows' milk formula

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

Breast feeding:

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

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

Milk free patient information resources

The National Children and Young peoples allergy Network CYANS has produced a number of useful patient resources that can be accessed and printed for use via the link below:

CYANS patient information leaflets

References

  1. Host A. Frequency of cows’ milk allergy in childhood ANN Allergy Immuno. 2002:89 (suppl 1) 33-7
  2. Rona RJ, Keil T, Summers C et al.The prevalence of food allergy: A Meta analysis The Journal of Allergy and Clinical Immunology 2010;Vol120:3:638-646
  3. Schoemaket A.A. et al. Incidence and natural history of challenge proven cows milk allergy in European children – EuroPrevall birth cohort: European Journal of Allergy and Clinical Immunology 2015; 70(8):963-72 https://doi.org/10.1111/all.12630
  4. Koletzko S, Niggemann B, Arato A et al. Diagnostic approach and management of cow’s-milk protein allergy in infants and children: ESPHAN GI committee Practical Guidelines. JPGN;55;2;August 2012.
  5. Ludman S, Shah N, Fox AT. Managing cows’ milk allergy in children. BMJ 2013;347:f5424
  6. Venter C, Brown T, Shah N et al. Diagnosis and management of non-IgE-medicated cow’s milk allergy in infancy – a UK primary care practical guide. Clinical and Translational Allergy 2013;3:23.
  7. Fiocchi A, Brozek J et al. World Allergy Organisation (WAO) Diagnosis and rationale for action against cow’s milk allergy (DRACMA) guidelines. Paediatric Allergy Immunology 2010;21;1-125
  8. 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.
  9. Du Toit G., Meyer R, Shah N et al. Identifying and Managing cows’ milk protein allergy Arch Dis Child Educ Pract Ed 2010;95:134-144
  10. 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.
  11. COT (2003): Phytoestrogens and health. FSA. Accessed 29 July 2019. foodstandards.gov.uk/multimedia/pdfs/phytoreport0503
  12. BDA Paediatric Group Position Statement on use of soya formula https://www.bda.uk.com/regionsgroups/groups/paediatric/neonatal/publications_position_statements
  13. Vandenplas Y, Castrellon PG, Rivas R et al. Safety of soya-based infant formulas in children. Br J Nutr 2014 (Febr 10);1-21.
  14. SACN (2018). Feeding in the First Year of Life. Accessed 24 April 2019. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/725530/SACN_report_on_Feeding_in_the_First_Year_of_Life.pdf

Written by Jan Chapple, Lead Paediatric Dietitian, NHS Highland (Argyll and Bute) and Julie Johnson, Lead Paediatric Dietitian, NHS Highland (North Highland)

Abbreviation

Abbreviation Meaning
AAF Amino Acid Formulas
ACBS Advisory Committee of Borderline Substances
CMA Cow's milk allergy
CMPA Cows' milk protein allergy
EHF Extensively Hydrolysed Formulas
IgE Immunoglobulin E
Non-IgE Non-Immunoglobulin E

Last reviewed: 19 February 2021

Next review: 19 February 2023

Author(s): Paediatric Dietitian

Version: 4

Approved By: TAM Subgroup of ADTC

Reviewer Name(s): Paediatric Dietitian

Document Id: TAM331