Allergy to cows' milk protein and the appropriate use of infant formula

Soy formula and elemental formula are the two main products used for infants with cows’ milk protein allergy (CMPA). The two types of elemental formula available are extensively hydrolysed formula and amino acid based formula.

In New Zealand, more expensive and last-line amino-acid formula products, e.g. Neocate, are being prescribed as an early option. Pharmaceutical dispensing data indicate that 78% of infants with CMPA are being prescribed an amino acid formula without an initial trial of an extensively hydrolysed formula.

The use of amino acid formula as an early option is a concern on two fronts. Firstly, it is out of line with international guidelines which suggest that only approximately 5–10% of infants with CMPA require an amino acid formula.^1,2 Secondly, amino acid formula is significantly more expensive than other options (approximately five to six times the cost of extensively hydrolysed formula per 100 mL). The high cost and the high uptake of amino acid formula in New Zealand (the use of elemental formula is approximately 60% higher in New Zealand than in Australia on a per capita basis)³ is causing expenditure growth in the Special Foods therapeutic group. In 2008/09 expenditure on elemental formula was $5.8 million, with approximately 38% annual growth (Figure 1).

Given that clinical guidelines recommend the use of amino acid formula, only after a trial of an extensively hydrolysed formula (except for infants with anaphylaxis due to CMPA and in eosinophilic oesophagitis) and the unsustainable growth in expenditure, PHARMAC reviewed the access and funding of these products. This has resulted in modification of the access criteria so that:

• The less specialised products such as extensively hydrolysed formula should, in general, be trialled before funding is made available for the last-line amino acid formula
• Patients using these formulae should be reviewed regularly to determine if, as they get older, it is appropriate to transition them to cows’ milk or less specialised products such as extensively hydrolysed or soy formula

PHARMAC also considered which of the milk-replacement options should be considered for funding versus which should be considered a private cost. PHARMAC concluded that the more specialised products, such as extensively hydrolysed formula and amino acid formula, should be fully subsidised (with Special Authority) and less specialised products that are available in supermarkets, such as lactose-free and soy formula, should not be funded (and be a private cost).

Figure 1: Special Foods expenditure in the Pharmaceutical Budget (main categories)

CMPA is an immunologically mediated adverse reaction to cows’ milk protein, with a prevalence of approximately 2% in infants aged under two years.¹ Allergic reaction to cows’ milk protein can be IgE or non-IgE mediated, and the spectrum of reactions ranges from immediate anaphylaxis and food allergy reactions to delayed effects such as atopic eczema. Table 1 (below) provides a summary of the various clinical presentations of CMPA, including key differential diagnoses.

Immediate and delayed CMPA can be differentiated by the timing of the reaction in relation to the intake of cows’ milk. Immediate reactions, such as anaphylaxis, angioedema, urticaria and vomiting, occur within minutes. In contrast, delayed reactions, such as food protein enteropathy, proctocolitis and eosinophilic oesophagitis, can manifest over hours or days. Some disorders have features of both immediate and delayed reactions, e.g. in eczema caused by CMPA, the pruritic rash can occur within minutes, hours or days. CMPA can also occur in exclusively breastfed infants due to allergens present in breast milk from maternal ingestion of dairy products.

Immediate allergic reactions

The most serious form of immediate reaction is anaphylaxis with respiratory tract involvement and/or hypotension. In infants the features of anaphylaxis are not always apparent and they may present with coughing, wheezing, severe distress, floppiness or collapse. Anaphylaxis due to CMPA is extremely rare in exclusively breastfed infants.

CMPA allergy can also present with an acute allergic (non-anaphylactic) reaction with erythema, angioedema, urticaria or vomiting. Infants with CMPA are often allergic to other foods such as eggs and peanuts. Immediate allergic reactions are possible in exclusively breastfed infants.

About 80% of cases of immediate CMPA reactions resolve by age three years.²

Food protein-induced enterocolitis syndrome

This syndrome is a relatively uncommon non-IgE mediated reaction. Infants usually present with rapid onset of projectile vomiting, floppiness, pallor and possibly diarrhoea, one to three hours after ingestion of cows’ milk. The differential diagnosis may include gastroenteritis, sepsis or intestinal obstruction. Food protein-induced enterocolitis syndrome usually occurs when cows’ milk is first introduced and can also be caused by other food allergies such as soy, wheat, rice and chicken. In most infants, symptoms resolve completely by age three years.²

Atopic eczema

CMPA or allergy to other foods (particularly egg, milk and peanuts) should be considered as a possible cause of eczema in children (that is not responding to appropriate treatment), especially if symptoms are moderate to severe.

The main feature of eczema due to CMPA is pruritic rash, which can be severe. Most, but not all, reactions are IgE mediated. The condition tends to improve over time, though the age of clinical resolution is variable.²

Gastrointestinal syndromes

There are a wide range of gastrointestinal syndromes due to CMPA. CMPA may present with vomiting, chronic diarrhoea, malabsorption and failure to thrive. Multiple food allergies are sometimes involved.

Gastro-oesophageal reflux disease (GORD)
In approximately 40% of infants referred for management of GORD, the underlying cause is CMPA.¹ The typical symptoms are frequent regurgitation, poor feeding and aversion to feeding. The reaction is not usually IgE-mediated. In GORD caused by CMPA, symptoms may partially improve with a proton pump inhibitor (PPI) and usually resolve by age 12 – 18 months.²

Allergic eosinophilic gastroenteritis
This condition is characterised by weight loss and failure to thrive associated with vomiting, diarrhoea, severe irritability and sometimes blood loss in the stool after feeding. Iron deficiency and protein-losing enteropathy can occur in severe cases.¹

Food protein-induced enteropathy
Infants with allergic enteropathy presents with persistent diarrhoea, perianal excoriation, failure to thrive and vomiting. The infant may have anaemia and hypoproteinaemia. Chronic malabsorption occurs due to intestinal villous damage.² An association with soy allergy or secondary lactose intolerance is common. If CMPA and lactose intolerance co-exist, a lactose free formula will ameliorate the osmotic diarrhoea but continued exposure to cows’ milk protein will worsen intestinal damage.²

Constipation and infantile colic
The role of CMPA is controversial in these disorders and unequivocal diagnosis is difficult. Both conditions are common in infancy and the causes are multi-factorial, although elimination of cows’ milk from the diet may resolve symptoms. Colic usually resolves by age four to six months and constipation by age 12 – 18 months.²

Food protein-induced proctocolitis
Infants with food protein-induced proctocolitis usually present with mild diarrhoea and low-grade rectal bleeding (often with mucous and flecks of blood) within the first three months of life and most develop tolerance to CMPA by 12 months.² Although CMPA is most often implicated, other food proteins such as soy, rice and wheat may contribute and this condition can also occur in infants who are breast fed. Infants are otherwise generally well although in prolonged or severe cases there may be failure to thrive or anaemia.²

Eosinophilic oesophagitis
This condition is more common in older children than infants. In infants, the usual features are refusal of food, failure to thrive, vomiting, reflux and poor response to anti-reflux treatments. Diagnosis requires endoscopy and is based on histological finding of eosinophilia of the oesophagus. Infants with eosinophilic oesophagitis may have hypersensitivity to multiple foods.¹

As CMPA is not a single, uniform entity, making a clear diagnosis can often be difficult. Many of the symptoms observed in CMPA syndromes are non-specific, e.g. diarrhoea, reflux, constipation and other allergies, and can be caused by other common clinical conditions or allergies. Generally, there is limited evidence for switching formula when infants experience symptoms such as vomiting, spilling, crying, diarrhoea or constipation, unless they are severe or persistent, when further investigation is warranted. There is significant potential for incorrect or over-diagnosis of CMPA, exacerbated by misinformation about the significance of milk and food allergies, targeted marketing of infant formula and a trend for avoidance of cows’ milk products and use of hypoallergenic infant formula. Conversely, under-diagnosis of CMPA may increase the risk of adverse nutritional or behavioural outcomes.

A correct diagnosis is critical and this may often require referral for immunological or other investigations such as biopsy or specialist gastrointestinal examination (see below).

In all cases, diagnosis is usually confirmed by complete elimination of cows’ milk from the diet for two to three weeks and observing if the symptoms resolve.¹ In some situations, a rechallenge to see if symptoms recur may be indicated to confirm a diagnosis. As CMPA may naturally remit over time, a rechallenge after a period of avoidance might be useful to ascertain tolerance.¹

Persistence of symptoms after elimination of cows’ milk from feeds can indicate the possibility of other food allergies, e.g. peanut, egg or wheat, or another condition with similar symptoms, such as lactose intolerance or idiopathic urticaria.²

Management of CMPA

Irrespective of the cause and clinical type of CMPA in an infant, cows’ milk should be removed from the diet and replaced with an elemental or soy based formula.

Mothers should be encouraged to continue breast-feeding whenever possible.² Cows’ milk should be eliminated from maternal diets where the infant has immediate reactions such as anaphylaxis.¹ In cases of delayed reaction, maternal intake of cows’ milk is often tolerated, and avoidance is usually only necessary if there are residual symptoms after elimination of cows’ milk from the infant’s diet.²

If the allergy is IgE mediated, avoidance of cows’ milk should be strictly enforced with provision of an allergy action plan and adrenaline autoinjector if appropriate.²

See “Management of anaphylaxis in primary care”, BPJ 18 (Dec, 2008).

When eliminating cows’ milk, dietary intake should be assessed for nutritional adequacy of the recommended amounts of protein, calories and micronutrients, such as vitamin D and calcium. This also applies to the maternal diet if cows’ milk avoidance is necessary.

Infant formula for CMPA

There are three types of formula available for CMPA; soy-based formula, extensively hydrolysed formula and amino acid formula.

There has been a trend in New Zealand and overseas to prescribe the most hypoallergenic formulas, especially amino acid formula, first line for CMPA.³ This is an expensive option and in most cases not necessary.

The type of infant formula most appropriate as the initial option for CMPA should be determined by the age of the infant and the clinical characteristics of the CMPA. Amino acid formula should only be considered as a first line option in infants with CMPA with anaphylaxis and in infants with a confirmed diagnosis of eosinophilic oesophagitis.^1,2 In the majority of cases of CMPA, extensively hydrolysed formula, (or soy if the infant is aged more than six months) should be considered first. In some cases failure to thrive affects the choice of formula.¹ These recommendations are summarised in Table 2 and form the basis of the current funding pathway.

Table 2: Syndromes associated with cows’ milk protein allergy and appropriate choice of formula feed (adapted from Kemp et al, 2008).¹

Infants should be reviewed regularly (every six months) to check if tolerance to cows’ milk protein has developed. This can be done by taking a history of accidental ingestion of cows’ milk, skin prick testing, measurement of cows’ milk specific serum IgE or food challenges.

In an infant with severe IgE mediated CMPA, tolerance should only be assessed in hospital because of the risk of anaphylaxis.

Other infant formula are not recommended

Soy-based, extensively hydrolysed formula and amino acid formula are the only infant formula recommended for the treatment of CMPA. The following are not recommended or contraindicated; Lactose-free cows’ milk, (e.g. Karicare De-Lact), partially hydrolysed cows’ milk (e.g. Karicare SensiKare), Goat’s milk based formula and other mammalian milks, rice milk and oat milk.¹

Monitoring and re-evaluation

Expert guidelines recommend regular monitoring of growth for children with food allergy in combination with nutrition counselling.⁴ There are, however, no clear guidelines on when re-evaluation of CMPA or other allergies should occur. In practice re-trialling allergenic foods depends on clinical judgement, taking into consideration the severity of symptoms, the age of the child and other medical and social circumstances.⁴ For infants with anaphylaxis, food challenges should be performed in hospital.²

There are also no clear guidelines on when an infant with CMPA should be weaned off a formula and when consideration should be given to changing to a less hypoallergenic formula, e.g. amino acid formula, to extensively hydrolysed formula, or extensively hydrolysed formula to soy-based, or for how long the effect of a switch should be evaluated for. However, given that most CMPA syndromes resolve over time, the requirement for on-going formula should be regularly reviewed.

Re-assessment should be on a case by case basis and it may be appropriate to consult with a paediatrician or dietitian with expertise in the management of CMPA for further advice.