Infants with Cow Milk Protein Allergy May Benefit from Alternative Formulas, Study Finds

A recent network meta-analysis (NMA) investigated the effectiveness of various baby formulas and the potential utility of breastfeeding with the exclusion of cow milk protein for reducing Scoring Atopic Dermatitis (SCORAD) index and promoting growth in infants with cow milk protein allergy (CMPA).

CMPA is an immune system response to cow’s milk proteins, often beginning in infancy. It primarily manifests as skin and gastrointestinal symptoms, including atopic dermatitis (AD), colic, vomiting, diarrhea, constipation, and respiratory manifestations such as wheezing or sneezing. However, diagnosis can be difficult, as lactose intolerance, infantile colic, and gastroesophageal reflux disease all present similarly.2

Previous systematic reviews have established the safety and efficacy of formula-based interventions for infants with CMPA, such as amino acid formula (AAF) and extensively hydrolyzed formula (EHF), both hypoallergenic formulas containing prebiotics. However, investigators say the limited scope and focus of their research makes it difficult to determine the efficacy and safety of the wide variety of alternative formulas.1

“NMA allows for the quantification and ranking of intervention effects for specific outcomes, helping decision-makers choose the optimal treatment option,” wrote Tengfei Li, school of nursing, Gansu University of Chinese Medicine, and colleagues. “Therefore, we conducted an systematic review and network meta analysis of randomized controlled trials to assess the relative efficacy and safety of interventions for milk protein-induced AD and for promoting growth in affected children.”1

Li and colleagues collected data from PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL), among other databases. For inclusion, studies were required to involve children of any age who were diagnosed with CMPA and exhibited immunoglobulin E (IgE)-mediated, non-IgE-mediated, or mixed presentations.1

The team classified the utilized infant formulas into 11 types based on their ingredients; regular, EHF, EHF enriched with probiotics, EHF supplemented with human milk oligosaccharides, EHF containing heat-inactivated probiotics, AAF, pectin-based thickened animo acid-based formula (TAAF), yogurt-type AAF with high purity rice starch, AAF combined with synbiotics, rice hydrolysate formula (RHF), and soy formula.1

A collective 1935 studies were identified during the preliminary search; 1549 were eventually screened, 23 of which the inclusion criteria. These studies included a total of 1997 participants. The median age at enrollment was 5.8 months, and median intervention duration was 6.2 months. The studies included 12 different interventions.1

Certainty of evidence was assessed via the Confidence in Network Meta-Analysis online application – evidence was organized into 3 categories; low certainty, moderate certainty, and high certainty.1

Of these, compared to regular formula, TAAF was found to potentially reduce SCORAD index (-12.49; 95% CI, -20.38 to -4.48, low certainty). At ≤6 months of follow-up, compared with RHF, breastfeeding improved the length-for-age Z score (LAZ) (.47; 95% CI, .13 to .81, moderate certainty). Additionally, breastfeeding (.39; 95% CI, .02 to .77, low certainty) and EHF with probiotics (.38; 95% CI, 0 to .77, low certainty) might improve the weight-for-age Z score (WAZ) and weight-for-length Z score (WLZ), respectively.

At 12-month follow-up, investigators found EHF could improve the LAZ (.41; 95% CI, .11 to .71, low certainty) and WLZ (.37; 95% CI, .18 to .56, low certainty) compared with RHF, whereas AAF may improve the WAZ (.33; 95% CI, .02 to .63, low certainty).1

Li and colleagues noted that the results of this study are in line with several previous studies, although only in that the superiority of different formula types has not yet been clearly determined. The team indicated that, despite not clearly indicating the superior efficacy of a given formula over others, their findings, did support the strategy of breastfeeding and avoiding cow milk protein entirely.1

Additionally, the team noted limitations of the study, including risk of bias because of incomplete data. Notably, many previous studies failed to account for economic costs that may influence treatment accessibility and long-term adherence. Additionally, caregivers’ preferences may influence implementation and family acceptance of interventions. To that end, Li and colleagues encourage further research.1

“Future research should assess the cost-effectiveness of various formulas, incorporating factors such as accessibility and caregiver preferences, to provide comprehensive clinical guidance,” Li and colleagues wrote. “The limited reporting of adverse events calls for further safety verification.”1

References

1. Li T, Zheng Q, Xu J, et al. Comparison of 11 formulas and breastfeeding for atopic dermatitis and growth in pediatric cow’s Milk Protein Allergy: A systematic review and network meta‐analysis of 23 randomized controlled trials. Journal of Evidence-Based Medicine. 2025;18(2). doi:10.1111/jebm.70026

2. Zain-Alabedeen S, Kamel N, Amin M, et al. Fecal Calprotectin and Cow's Milk-Related-Symptoms Score in Children with Cow's Milk Protein Allergy. Pediatr Gastroenterol Hepatol Nutr. 2023;26(1):43-49. doi:10.5223/pghn.2023.26.1.43