Commentary on “Infant Formulas Containing Hydrolysed Protein for Prevention of Allergic Disease and Food Allergy”

Although uncertainty exists about whether exposure to cow milk proteins in infancy affects the risk of developing allergic diseases in childhood, the European Academy of Allergy and Clinical Immunology recommends that young infants who need a supplement to maternal milk, and who are at high risk of developing allergy (usually because of a strong family history), should be fed with a hypoallergenic breast milk substitute (BMS) [1]. The most commonly used BMS in this context is a “hydrolysed” cow milk formula containing proteins digested chemically or enzymatically to oligopeptides. Several brands of hydrolysed formulas are available commercially and these vary by the degree of hydrolysis (extensive or partial) as well as by the main protein source (casein or whey-casein) and carbohydrate and fat type and content.

Is this recommendation evidence-based? In the updated Cochrane review of randomised controlled trials of the effect of feeding young infants at high risk of allergic disease with hydrolysed versus standard formulas, Osborn et al. suggest not [2]. The authors identified, appraised, and synthesised the data from 16 eligible trials. Most trials assessed whether prolonged supplemental or sole feeding with hydrolysed versus standard formula affected the risk of developing allergic diseases including asthma, atopic dermatitis, allergic rhinitis, and food allergy in infants with first-degree relative with allergic disease. Only trials with near-complete (at least 80% of the infants) outcome assessments were included to reduce the risk of attrition bias.

The meta-analysis of available outcome data did not show a difference in the incidence of allergic disease in infants (typical relative risk 0.88, 95% CI 0.76–1.01) (Fig. 1). There was evidence of heterogeneity in the meta-analysis, that is, the results between the trials varied by more than would be expected by chance. This may have been due to differences in the type of participants (level of risk of allergy), or interventions (type of hydrolysed formula), or how allergic diseases were defined and measured as outcomes (parent-reported, clinician- or laboratory-assessed). Furthermore, the analysis showed evidence of possible “publication bias”-asymmetry in the funnel plot indicating that smaller trials with larger effect sizes were over-represented (Fig. 2).

This finding is consistent with another systematic review that additionally included trials with lower rates of outcome assessments [3]. Both this review and the updated Cochrane review highlighted methodological quality issues within many of the included trials and in addition concerns about conflicts of interest related to study sponsorship and funding. Most of the included trials were supported by the manufacturers of the BMS being assessed, but there was no evidence that these conflicts of interest influenced the effect estimates for prespecified outcomes [3]. There remains some concern that BMS manufacturers may promote study findings of trials of specialist formulas selectively as part of a marketing strategy that subverts UNICEF Baby-Friendly Initiative regulations [4]. Policy and practice should now reflect this body of critically appraised evidence that indicates that hydrolysed formula does not prevent allergic disease in infants receiving a BMS.

Cochrane Neonatal Reviews are produced with support from the Vermont Oxford Network, a worldwide collaboration of health professionals dedicated to providing evidence-based care of the highest quality for newborn infants and their families. Editorial support for Cochrane Neonatal comes from a UK National Institute of Health Research (NIHR) Cochrane Programme Grant (16/114/03).