Milk Ladder Efficacy and Safety in IgE‐Mediated Cow's Milk Allergy: A Systematic Review and Meta‐Analysis of Controlled Studies

Background: Milk ladder (ML) is considered a potential therapeutic option for managing cow’s milk allergy (CMA). Although the ML was initially developed to reintroduce cow's milk into the diet for individuals with non-IgE mediated CMA, it has also recently been used in IgE-mediated CMA. Objective: To perform a systematic review and meta-analysis of the safety and efficacy of ML in children with IgE-mediated milk allergy. Methods: We conducted a systematic literature review and meta-analysis of controlled studies in accordance with PRISMA guidelines. ML safety and ML efficacy compared to a strict avoidance diet and oral immunotherapy in children with IgE mediated CMA was evaluated. Meta-analysis was performed where ≥ 3 studies reported data. Methodological quality and risk of bias were systematically assessed. Results: Six controlled studies (two randomized controlled trials and four observational controlled studies) met the inclusion criteria. ML resulted in the development of tolerance in 69% of participants (OR = 4.48; 95% CI = 2.51–8.00), with a significant improvement compared to the elimination diet. The meta-analysis of four studies showed that ML was 4.5 times more effective than a strict avoidance diet in inducing partial or total tolerance in ITT analysis and 8.4 times in PP analysis. Certainty of evidence was moderate, with low heterogeneity among studies. No significant difference in adverse events, severe systemic allergic reactions, and adrenaline use between the ML and avoidance diet groups were found. Only one study reported comparable efficacy between ML and oral immunotherapy with raw milk (OIT). No difference was found in the total number of mild to moderate adverse reactions between the groups (68.2% and 77.8, respectively; p = 0.44). The rates of epinephrine use at home were 14.3% and 11.8%, respectively, without significant difference between ML and OIT groups (p = 1). Conclusions: ML represents a promising therapeutic approach for accelerating tolerance in children with IgE-mediated CMPA. Further research is needed to clarify milk ladder safety, as well as to identify predictive biomarkers for patient selection.