World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) guideline update - XI - Milk supplement/replacement formulas for infants and toddlers with CMA - Systematic review

Abstract

Background: Cow's milk allergy (CMA) is the most complex and common food allergy in infants. Elimination of cow's milk from the diet and replacement with a specialized formula for infants with cow's milk allergy who cannot be breastfed is an established approach to minimize the risk of severe allergic reactions while avoiding nutritional deficiencies. Given the availability of multiple options, such as extensively hydrolyzed cow's milk-based formula (eHF-CM), aminoacid formula (AAF), hydrolyzed rice formula (HRF), and soy formula (SF), there is some uncertainty regarding which formula might represent the most suitable choice with respect to health outcomes. The addition of probiotics to a specialized formula has also been proposed as a potential approach to possibly increase the benefit. We systematically reviewed specialized formulas for infants with CMA to inform the updated World Allergy Organization (WAO) DRACMA guidelines.

Objective: To systematically review and synthesize the available evidence about the use of specialized formulas for the management of individuals with CMA.

Methods: We searched from inception PubMed, Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and the websites of selected allergy organizations, for randomized and non-randomized trials of any language investigating specialized formulas with or without probiotics. We included all studies irrespective of the language of the original publication. The last search was conducted in January 2024. We synthesized the identified evidence quantitatively or narratively as appropriate and summarized it in the evidence profiles. We conducted this review following the PRISMA, Cochrane methods, and the GRADE approach.

Results: We identified 3558 records including 14 randomized trials and 7 observational studies. Very low certainty evidence suggested that in infants with IgE-mediated CMA, eHF-CM, compared with AAF, might have higher probability of outgrowing CMA (risk ratio (RR) 2.32; risk difference (RD) 25 more per 100), while showing potentially lower probability of severe vomiting (RR 0.12, 95% CI 0.02 to 0.88; RD 23 fewer per 100, 95% CI 3 to 26) and developing food protein-induced enterocolitis syndrome (FPIES) (RR 0.15, 95% CI 0.03 to 0.82; RD 34 fewer per 100, 95% CI 7 to 39). We also found, however, that eHF-CM might be inferior to AAF in supporting a physiological growth, with respect to both weight (-5.5% from baseline, 95%CI -9.5% to -1.5%) and length (-0.7 z-score change, 95%CI -1.15 to -0.25) (very low certainty). We found similar effects for eHF-CM, compared with AAF, also in non-IgE CMA. When compared with SF, eHF-CM might favor weight gain for IgE CMA infants (0.23 z-score change, 95%CI 0.01 to 0.45), and tolerance acquisition (RR 1.86, 95%CI 1.03 to 3.37; RD 27%, 95%CI 1%-74%) for non-IgE CMA (both at very low certainty of the evidence (CoE)). The comparison of eHF-CM vs. HRF, and HRF vs. SF, showed no difference in effect (very low certainty). For IgE CMA patients, low certainty evidence suggested that adding probiotics (L. rhamnosus GG, L. casei CRL431 and B. lactis Bb-12) might increase the probability of developing CMA tolerance (RR 2.47, 95%CI 1.03 to 5.93; RD 27%, 95%CI 1%-91%), and reduce the risk of severe wheezing (RR 0.12, 95%CI 0.02 to 0.95; RD -23%, 95%CI -8% to -0.4%). However, in non-IgE CMA infants, the addition of probiotics (L. rhamnosus GG) showed no significant effect, as supported by low to very low CoE.

Conclusions: Currently available studies comparing eHF-CM, AAF, HRF, and SF provide very low certainty evidence about their effects in infants with IgE-mediated and non-IgE-mediated CMA. Our review revealed several limitations in the current body of evidence, primarily arising from concerns related to the quality of studies, the limited size of the participant populations and most importantly the lack of diversity and standardization in the compared interventions. It is therefore imperative for future studies to be methodologically rigorous and investigate a broader spectrum of available interventions. We encourage clinicians and researchers to review current World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines for suggestions on how to use milk replacement formulas in clinical practice and what additional research would be the most beneficial.

Keywords: GRADE approach; Infant formulas; Meta-analysis; Milk allergy; Systematic review.

Fig. 1

PRISMA diagram of the evidence selection process from the original search (Nov 2018)

Fig. 2a

Summarized effect estimates across the pairwise comparisons of interventions, together with CoE rating for infants with IgE mediated CMA Abbreviations eHF-CM: extensively hydrolyzed cow’s milk formula; AAF: aminoacid formula; HRF: hydrolyzed rice formula; SF: soy formula;CMA: Cow’s milk allergy; FPIES: Food protein-induced enterocolitis syndrome; RR: risk ratio (relative risk); RD: risk difference (absolute risk difference); MD: mean difference; SD: standard deviations; EP: evidence profile; GRADE: Grading of Recommendations, Assessment, Development, and Evaluations; CoE: certainty of evidence Explanations ∗ This outcome was considered to be “Important” for Decision making by the WAO DRACMA guidelines panel for this pairwise comparison of interventions This outcome was considered to be “Critical” for Decision making by the WAO DRACMA guidelines panel for this pairwise comparison of interventions a We also synthesized evidence on the severity of eczema (atopic dermatitis) (follow-up: range 6 to 9 months; assessed with: SCORAD; MID ∼ 8 points; Scale from: 0 to 103): 1.39 points higher (1.08 lower to 3.86 higher) GRADE certainty levels High certainty - reflects a high confidence that the true effect lies close to the synthesized estimate Moderate certainty - indicates a moderate confidence that the true effect is likely close to the estimate, but there is a possibility that it might be substantially different Low certainty - indicates a limited confidence, hence the true effect might be substantially different from the synthesized estimate of effect Very-low certainty - indicates a very little confidence in the estimate of effect and that the true effect is likely substantially different.

Fig. 2b

Summarized effect estimates across the pairwise comparisons of interventions, together with CoE rating for infants with Non-IgE mediated CMA Abbreviations eHF-CM: extensively hydrolyzed cow’s milk formula; AAF: aminoacid formula; HRF: hydrolyzed rice formula; SF: soy formula;CMA: Cow’s milk allergy; FPIES: Food protein-induced enterocolitis syndrome; RR: risk ratio (relative risk); RD: risk difference (absolute risk difference); MD: mean difference; SD: standard deviations; EP: evidence profile; GRADE: Grading of Recommendations, Assessment, Development, and Evaluations; CoE: certainty of evidence Explanations ∗ This outcome was considered to be “Important” for Decision making by the WAO DRACMA guidelines panel for this pairwise comparison of interventions ° This outcome was considered to be “Critical” for Decision making by the WAO DRACMA guidelines panel for this pairwise comparison of interventions a Severity of eczema (atopic dermatitis) (follow-up: range 6 to 9 months; assessed with: SCORAD; MID ∼ 8 points; Scale from: 0 to 103) GRADE certainty levels High certainty - reflects a high confidence that the true effect lies close to the synthesized estimate Moderate certainty - indicates a moderate confidence that the true effect is likely close to the estimate, but there is a possibility that it might be substantially different Low certainty - indicates a limited confidence, hence the true effect might be substantially different from the synthesized estimate of effect Very-low certainty - indicates a very little confidence in the estimate of effect and that the true effect is likely substantially different.