Cow's Milk Protein Allergy

Introduction

Cow's milk protein allergy (CMPA) is an immune-mediated adverse reaction to one or more of the proteins in cow's milk. It is the commonest food allergy of infancy and one of the commonest reasons a young baby is referred with vomiting, unsettledness or blood in the stool.

It is also one of the most over-diagnosed conditions in primary care. Specialist formula prescribing in the UK has risen far faster than any plausible increase in prevalence, and a large number of infants are placed on restricted diets without the elimination-and-reintroduction step that would confirm or refute the diagnosis. Getting this right matters in both directions: a missed diagnosis leaves an infant in pain and failing to grow, and an over-diagnosis commits a family to an expensive, restrictive diet for a problem the child never had.

The first distinction to make is with lactose intolerance, which is not an allergy at all but a deficiency of the brush-border enzyme lactase. In infancy it is almost always secondary and transient - typically following a gastroenteritis that has stripped the intestinal villi - and it causes osmotic diarrhoea, wind and perianal excoriation without any immune involvement, blood in the stool or skin manifestations.

Classification and pathophysiology

Mixed presentations occur, and it is entirely possible for an infant to have immediate urticaria with milk as well as chronic eczema and loose stools. What matters clinically is whether there is any IgE-mediated component, because that determines the risk of anaphylaxis and therefore how reintroduction is managed.

Risk factors and clinical assessment

Risk factors

• A personal history of atopy, particularly early-onset or severe atopic eczema
• A family history of atopy in a parent or sibling - eczema, asthma, allergic rhinitis or food allergy
• Formula feeding, or the introduction of formula top-ups
• Delivery by caesarean section, associated with altered early gut colonisation

The allergy-focused clinical history

NICE CG116 makes this the foundation of diagnosis, and in non-IgE disease it is essentially all there is.¹ Cover:

• What the symptoms are, and in which systems - skin, gut and respiratory
• How long after the feed they appear, which separates IgE from non-IgE mechanisms
• Reproducibility - do the same symptoms follow the same exposure every time?
• Feeding history - breast, formula, brand, volumes, when formula was introduced, and what the mother is eating if breastfeeding
• Growth, plotted on the chart, since faltering growth changes the choice of formula
• Personal and family atopy
• What has already been tried, including any elimination diet and whether symptoms improved
• Impact on the family - sleep, feeding, distress and parental anxiety

Examination

• Plot weight, length and head circumference on the growth chart, and look at the trajectory rather than a single point
• Skin - eczema, its distribution and severity, urticaria, and evidence of scratching
• Abdomen - distension, tenderness, palpable faecal loading
• Perianal area - excoriation and erythema, seen in both CMPA and lactose intolerance
• Signs of an alternative diagnosis - dysmorphism, hepatosplenomegaly, respiratory signs, or evidence of a systemic illness
• Hydration and general wellbeing

Investigations

• Skin prick testing and serum specific IgE - useful only for IgE-mediated disease. A positive result indicates sensitisation, not allergy: it must be interpreted alongside a compatible history, since many sensitised children eat milk without any reaction.
• Elimination and reintroduction - the diagnostic test for non-IgE disease. Exclude cow's milk protein for 2-4 weeks (up to 6 weeks where symptoms are gut-predominant), assess whether symptoms resolve, then reintroduce to see whether they return. Both halves are required; an improvement alone is not diagnostic, because many infantile symptoms settle with time anyway.
• Double-blind placebo-controlled food challenge - the gold standard, reserved for diagnostic uncertainty or where the stakes are high, and performed in a specialist setting
• FBC and ferritin where there is blood loss in the stool or pallor, looking for iron deficiency anaemia
• Coeliac serology, faecal calprotectin, stool culture and a sweat test where the picture suggests an alternative diagnosis

Differential diagnosis

Management

The breastfed infant

• Continue breastfeeding - this is never a reason to stop, and stopping removes the infant's best source of nutrition and immune protection
• Exclude all cow's milk protein from the maternal diet - milk, cheese, butter, yoghurt, cream and hidden sources in processed food - for a trial of 2-4 weeks
• Supplement the mother with calcium 1000 mg daily and vitamin D 10 micrograms daily, since a dairy-free diet is otherwise calcium-deficient
• Refer to a paediatric dietitian, which is essential rather than optional in this situation
• Reintroduce cow's milk protein into the maternal diet after the trial to confirm the diagnosis

The formula-fed infant

Wider management

• Dietitian referral for every child, to ensure adequate calcium, vitamin D, protein and energy intake and to guide weaning
• A written management plan, including what to avoid and how to read food labels
• Treat the eczema properly with emollients and topical corticosteroids - dietary exclusion alone rarely controls it⁶
• An adrenaline auto-injector for any child with IgE-mediated allergy who has had anaphylaxis, or who has a significant reaction plus coexisting asthma, with training for the family and a plan for nursery or school^7,8
• Specialist allergy referral for anaphylaxis, faltering growth, multiple food allergies, severe eczema, or diagnostic uncertainty⁴
• Regular growth monitoring, since both the allergy and the diet used to treat it can impair growth

Reintroduction and the milk ladder

Most infants outgrow CMPA, so the plan from the point of diagnosis should include when and how milk will be tried again. Leaving a child on a hypoallergenic formula indefinitely, without a reintroduction plan, is a common and avoidable failing.

For non-IgE-mediated allergy, reintroduction is usually attempted at home from around 9-12 months of age, and at least 6 months after diagnosis, using the iMAP milk ladder.^3,5 The ladder works because heating denatures the conformational epitopes on milk proteins, so baked milk is far less allergenic than fresh milk. Each step is maintained for several days before moving up.

1. Malted milk biscuit - milk baked at high temperature within a wheat matrix, the least allergenic form
2. Muffin or cake containing milk
3. Pancake
4. Cheese, cooked as in a pizza topping
5. Yoghurt or fromage frais
6. Pasteurised cow's milk and fresh dairy products

Complications and prognosis

Complications

• Faltering growth, from the allergy itself, from feed refusal, or from an over-restricted replacement diet
• Nutritional deficiency - calcium, vitamin D, iodine, protein and energy in particular
• Iron deficiency anaemia from chronic occult blood loss in allergic proctocolitis
• Anaphylaxis in IgE-mediated disease
• Over-diagnosis and unnecessary dietary restriction, with cost, social burden and food-related anxiety - a genuine harm, and increasingly recognised as such
• Feeding aversion and later fussy eating, particularly where many foods have been excluded
• Eosinophilic oesophagitis in a small number, presenting later with dysphagia

Prognosis

The outlook is very good. Around half of infants with non-IgE-mediated CMPA tolerate milk by their first birthday, roughly three-quarters by 3 years, and more than 90% by school age.^2,3 IgE-mediated allergy resolves more slowly, and a minority - typically those with high and persistently rising specific IgE levels, multiple food allergies and severe atopy - continue to react into adolescence and adult life.

Families should be told at diagnosis roughly what to expect: that this is common, that it is not the same as being allergic to milk for life, that the great majority of children are drinking ordinary milk before they start school, and that there will be a planned attempt to reintroduce it rather than an indefinite avoidance. That framing reduces a great deal of anxiety and makes families far more willing to attempt the ladder when the time comes.

Two things predict a good outcome and are within a clinician's control: making the diagnosis properly in the first place, with a documented elimination and reintroduction rather than an assumption; and building the reintroduction plan into the management from the outset, so that the child is challenged at the right time rather than remaining on a specialist formula because nobody revisited it.