CMPA 
Q&A

When transitioning a baby from a standard cows’ milk formula to an extensively hydrolyzed formula (eHF), changes in their stool patterns may occur.¹ The consistency may change due to the altered protein composition in the eHF, which is designed to be easily digestible; and may result in softer stools, resembling those of a breastfed baby.² Similarly, the modified protein may change the color of the stools to a lighter brown or even greenish.¹  If a baby had initially been experiencing digestive issues, such as discomfort, regurgitation, constipation, or loose stools, due to cow's milk protein allergy, switching to an eHF aims to resolve these symptoms.^1,3-5  Symptoms can take between 2-6 weeks to fully resolve depending on the initial diagnosis.^6,7

<sup>1.Borschel M, and Baggs G.  The Open Nutrition Journal. 2015;9:1-4. 
2. Wu S, et al. Nutrients. 2017;9:1254. 
3. Lemale J, et al. Nutrients. 2022;14(6):1203. 
4. Dupont C, et al. BMC Pediatr. 2016;16:96. 
5. Wilsey MJ, et al.  Nutrients. 2023;15(7):1677.
6. Katta R, & Schlichte M. J Clin Aesthet Dermatol. 2014;7(3):30-6.
7. Vandenplas Y, et al. An ESPGHAN position paper. 2023. https://www.espghan.org/dam/jcr:7100468b-c6df-48bc-a566-6b13c427e756/CMA%20ESPGHAN%202022_V31.pdf;</sup>

Extensively hydrolyzed formula (eHF) and Amino acid formulas (AAF) smell and taste very different to standard infant formula or breastmilk, therefore to ease the transition to the new formula, parents should consider the following:

• waiting until their baby is hungry before trying the new formula
• unless there is anaphylaxis, try a gradual changeover by mixing 1oz (25ml) formula with 3oz usual baby milk (NOTE this is not appropriate when the infant has had a severe reaction to their usual formula!) – the quantity is then increased (~25ml or 1oz/day) until the transition is complete.¹
• if breastfeeding, try to have someone else feed the infant the new formula for the first few feeds
• try to mix the formula with expressed breastmilk just before giving it to the baby.¹
• if complementary foods have been introduced, then mixing the formula with suitable complementary foods is useful before offering it as a drink (NB. It is not advisable to add solid  foods into the bottle).
• parents should be advised to persevere, offering the same formula at least 8–10 times, since repeated exposure is the most effective way of promoting acceptance of new foods in infants and toddlers.²

<sup>1. Frimley Healthier Together. Dec 2022. 
https://frimley-healthiertogether.nhs.uk/application/files/5616/7584/7451/NHS_Starting_a_hypoallergenic_formula_Advice_Feb_2023_Final.pdf; 
2. D’Auria E, et al. Nutrients. 2021;13(8):2762.</sup>

No, the new European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) position paper on the management and prevention of CMPA recommends that extensively hydrolyzed formulas (eHF) (either whey or casein-based) are the first choice for the CMPA diagnostic elimination diet and subsequent management.¹ Amino acid-based formulas (AAF) they suggest should be reserved for those with severe symptoms of CMPA, those with malnutrition or those who do not tolerate eHF.¹ Althéra® HMO is the most extensively hydrolyzed whey-based eHF for the first-line management of CMPA.² This is thought to explain why it is the only eHF to show similar efficacy and safety as an AAF in a randomised controlled trial.³ It was also significantly better tolerated than the AAF, infants had softer stools and less episodes of vomiting.³

<sup>1. Vandenplas Y, et al. An ESPGHAN position paper. 2023. https://www.espghan.org/dam/jcr:7100468b-c6df-48bc-a566-6b13c427e756/CMA%20ESPGHAN%202022_V31.pdf;
2. Nutten S, et al. Allergy. 2020;75(6):1446-9. 
3. Niggemann B, et al. Pediatr Allergy Immunol. 2008;19(4):348-54.</sup>

Similar to eHF, when transitioning a baby from a standard cow’s milk formula or an eHF to an amino acid-based formula (AAF), changes in their stool pattern and color (e.g. green stools) may occur.¹ AAFs are absorbed with minimal digestion and are associated with decreased intestinal faecal volume.² If the infant has been experiencing gastrointestinal symptoms, such as persistent diarrhea, bloody stools or vomiting, due to cow's milk protein allergy, switching to an AAF aims to resolve these symptoms³. Infants taking an AAF often have resolution of symptoms within 14 days.⁴

<sup>1. Adams CB, et al. BMC Pediatr. 2021;21(1):323. 
2. Ribes-Koninckx C, et al. Frontiers in Pediatrics. 2023;11:1110380. 
3.Vanderhoof J, et al. JPGN. 2016;63(5):531 - 533.
4. Vanderhoof JA, et al. J Pediatr. 1997;131(5):741-4.</sup>

It can be challenging to determine an exact time frame for when crying will resolve, as other factors such as tiredness, gas, overfeeding or general discomfort can contribute to infant crying.  In an infant with infantile colic secondary to cow’s milk protein allergy (CMPA), a trial on a specialist formula can be considered.^1,2 A response would usually be expected within 1-5 weeks after starting an eHF, depending on the symptoms and when CMPA is the cause.^2,3,4 In one study they observed a significant improvement in crying in infants with colic after 1 week of treatment with a hydrolyzed formula³, whereas others have only demonstrated a significant improvement in crying after 14 days of feeding – and this was with a thickened extensively hydrolyzed casein-based formula.⁵ A whey-based extensively hydrolyzed formula significantly improved daily crying in infants with non-IgE-mediated CMPA after 3- 5 weeks intervention.⁴

An AAF on the other hand, has been shown to reduce crying and fussing time by an average of 45% within one to two days.⁶ Although these feeds are generally reserved for infants with severe reactions to milk/dairy such as anaphylaxis, CMPA with faltering growth and/or multiple food allergies. 

<sup>1.Leung A, and Suave R. Paediatr Child Health 2003;8(7):449-52.
2. Nocerino R, et al. Nutrients. 2015;7:2015 – 2025.
3. Arikan D, et al. J. Clin. Nurs. 2008 ;17:1754–1761.
4. Lemale J,  et al. Nutrients. 2022;14(6):1203.
5. Dupont C, et al. BMC Pediatr. 2016;16:96.
6. Estep DC ,& Kulczycki A. Jr. Acta Paediatr. 2000;89:22-7.</sup>

The first line feed of choice for the majority of cases with cow’s milk protein allergy (CMPA) is an extensively hydrolyzed (whey or casein-based) formula.¹ However, in more severe cases such as anaphylaxis to cow’s milk or poor growth with CMA, an amino acid-based formula is recommended. After 3 days there may be some symptom resolution, but it depends on the type of allergy the child presented with in the first place. If the child presented with immediate-type symptoms (eg, angioedema, vomiting, rapid onset eczema) to cow’s milk/dairy then symptom resolution commonly takes 3-5 days.² If the child’s symptoms were delayed-type (eg, presented with exacerbations of eczema or rectal bleeding) to cow’s milk/dairy, then it may take longer to see symptom resolution – up to 14 days² or possibly longer¹. International expert opinion is that it can take 2 to 4 weeks on a cow’s milk elimination diet before you see symptom resolution.^1-3  And it may take even longer for some types of non-IgE-mediated CMPA, such as eosinophilic esophagitis.⁴ The European Society of Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) recommends that the duration of the diagnostic elimination should be kept as short as possible, but long enough to judge whether clinical symptoms resolve, or become stable.^1,2

So, if the child’s symptoms have not resolved after 3 days that does not mean that the elimination diet or product you are using is not working, and you should continue with the exclusion diet.

<sup>1. Vandenplas Y, et al. An ESPGHAN position paper. 2023. https://www.espghan.org/dam/jcr:7100468b-c6df-48bc-a566-6b13c427e756/CMA%20ESPGHAN%202022_V31.pdf;  
2 .Koletzko S, et al. J Pediatr Gastroenterol Nutr. 2012;55(2):221-9.
3. Fox A, et al. Clin Transl Allergy. 2019;9:40.
4. Vandenplas Y, et al. J Asthma Allergy. 2021;14:1243-1256.</sup>

At 7 days there may be some symptom resolution, but it depends on the type of allergy the child presented with in the first place. If the child presented with immediate-type symptoms (eg, angioedema, vomiting, rapid onset eczema) to cow’s milk/dairy then they might already see symptom resolution (commonly takes 3-5 days).² However, when the child’s symptoms were delayed-type (eg, presented with exacerbations of eczema or rectal bleeding) to cow’s milk/dairy then it may take longer to see symptom resolution – up to 14 days2 or longer¹. In children with gastrointestinal symptoms (eg, chronic diarrhea, growth faltering), it may take up to 4 weeks on a cow’s milk/dairy-free diet .^1,2 While in a child with esinophilic esophagitis or severe atopic dermatitis (AD), it can take even longer - up to 6 weeks for severe AD has been suggested.³

So, if the child’s symptoms have not resolved after 7 days that does not mean that the elimination diet or product you are using is not working, it very much depends on the allergic reaction and product selected.

<sup>1. Vandenplas Y, et al. An ESPGHAN position paper. 2023. https://www.espghan.org/dam/jcr:7100468b-c6df-48bc-a566-6b13c427e756/CMA%20ESPGHAN%202022_V31.pdf; L
2. Koletzko S, et al. J Pediatr Gastroenterol Nutr. 2012;55(2):221-9.
3. Katta R, & Schlichte M. J Clin Aesthet Dermatol. 2014;7(3):30-6.</sup>

At 14 days there should be quite some symptom resolution, but again it depends on the type of allergy the child presented with in the first place. If the child presented with immediate-type symptoms (eg, angioedema, vomiting, rapid onset eczema) to cow’s milk/dairy then they should have seen symptom resolution by now (commonly takes 3-5 days).² However, when the child’s symptoms were delayed (eg, presented with exacerbations of eczema or rectal bleeding) to cow’s milk/dairy then it may take up to 14 days2 or longer¹. A diagnosis of eosinophilic esophagitis or severe atopic dermatitis (AD), for example, can take up to 6 weeks to resolve.^3,4

Be aware also that improvements in gastrointestinal, skin and respiratory symptoms may take as long as 6 weeks when using an eHF.^5,6 Infants with significant gastrointestinal symptoms with no improvement after the recommended exclusion period on the eHF may benefit from an AAF. This is because there may be residual allergenicity in some eHFs which trigger low grade reactions in sensitive infants.² This is particularly true in those with multiple sensitizations to many foods.² However, if there is still no improvement in symptoms on the AAF, then CMPA is unlikely.¹ In general, children taking an AAF are expected to have resolutions of symptoms by around 14 days.7 Although AAFs are generally reserved for severe cases of CMPA.

So, if the child’s symptoms have not resolved after 14 days that does not mean that the elimination diet or product you are using is not working, it very much depends on the allergic reaction and product selected.

<sup>1. Vandenplas Y, et al. An ESPGHAN position paper. 2023. https://www.espghan.org/dam/jcr:7100468b-c6df-48bc-a566-6b13c427e756/CMA%20ESPGHAN%202022_V31.pdf; 
2. Koletzko S, et al. J Pediatr Gastroenterol Nutr. 2012;55(2):221-9.
3. Vandenplas Y, et al. J Asthma Allergy. 2021;14:1243-1256.
4. Katta R, & Schlichte M. J Clin Aesthet Dermatol. 2014;7(3):30-6.
5. Lemale J, et al. Nutrients. 2022;14(6):1203.
6. Wilsey MJ, et al. Nutrients. 2023;15(7):1677.
7. Vanderhoof J, et al. JPGN. 2016;63(5):531 – 533.</sup>