Extensively hydrolyzed versus intact milk protein formula and risk of necrotizing enterocolitis: a meta-analysis

Necrotizing enterocolitis is a life-threatening inflammatory condition that commonly affects the intestinal wall of neonates. Feeding intolerance, rectal bleeding, and bowel perforations are predominant findings of the pathology, of which the etiology is not fully understood. Multiple factors are speculated to contribute to this disease, including formula feeding. Nutrition plays a critical role in neonatal outcomes, and formula composition significantly influences gastrointestinal health and development. This meta-analysis evaluated the impact of extensively hydrolyzed formulas (eHFs) compared to standard intact protein formulas (SPFs) on the incidence of necrotizing enterocolitis (NEC) and feeding intolerance (FI) in preterm infants.

A comprehensive literature search was conducted across Ovid, Cochrane and PubMed: the search terms included combinations of "Necrotizing Enterocolitis," "Hydrolyzed," "Amino Acid," "Intact," "Standard," and "Formula" alongside preterm-related keywords. Eligible studies included randomized controlled trials comparing eHF and SPF diets in preterm infants, defined as being born at less than 37 weeks gestation. Primary outcomes were the incidence of NEC and FI. Odds ratios (OR) for dichotomous outcomes were calculated using a chi-square analysis with 95% confidence intervals (CIs).

Three randomized controlled trials, consisting of a total of 1,180 preterm infants, met the inclusion criteria for this study. Infants that received SPFs had a statistically significant increased risk of NEC (OR=2.54; 95% CI = 1.38-4.68) and FI (OR=1.87; 95% CI = 1.38-2.52) compared to those fed eHFs. Sensitivity analyses confirmed the robustness of these findings.

Standard intact protein formulas significantly increase the risk of NEC and FI in preterm infants compared to extensively hydrolyzed formulas. These findings support the incorporation of eHFs into neonatal feeding guidelines. Previous studies have also highlighted the role of partially hydrolyzed whey formula and extensively hydrolyzed cow's milk protein formula in preventing allergic pathologies, such as atopic eczema, in children up to age 10 without rebound, indicating that the effects of formula extend well beyond infancy. While further research is needed to evaluate long-term clinical outcomes, this research calls for the critical need to refine infant formula manufacturing and feeding guidelines.

https://www.crd.york.ac.uk/PROSPERO/view/CRD42025641145.