• Derek Hang Cheong Ng, Joel Rl Klassen, Nicholas D Embleton, and William McGuire.
• Hull York Medical School & Centre for Reviews and Dissemination, University of York, York, UK.
• Cochrane Db Syst Rev. 2019 Jul 24; 7 (7): CD012412CD012412.

BackgroundWhen human milk is not available for feeding preterm infants, protein hydrolysate, rather than standard cow's milk formulas (with intact proteins), is often used because it is perceived as being tolerated better and less likely to lead to complications. However, protein hydrolysate formulas are more expensive than standard formulas, and concern exists that their use in practice is not supported by high-quality evidence.ObjectivesTo assess the effects of feeding preterm infants hydrolysed formula (vs standard cow's milk formula) on risk of feed intolerance, necrotising enterocolitis, and other morbidity and mortality.Search MethodsWe used the standard Cochrane Neonatal search strategy including electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 1), in the Cochrane Library; Ovid MEDLINE (1966 to 28 January 2019); Ovid Embase (1980 to 28 January 2019); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (28 January 2019), as well as conference proceedings and previous reviews.Selection CriteriaRandomised and quasi-randomised controlled trials that compared feeding preterm infants protein hydrolysate versus standard (non-hydrolysed) cow's milk formula.Data Collection And AnalysisTwo review authors assessed trial eligibility and risk of bias and extracted data independently. We analysed treatment effects as described in the individual trials and reported risk ratios and risk differences for dichotomous data, and mean differences for continuous data, with respective 95% confidence intervals (CIs). We used a fixed-effect model in meta-analyses and explored potential causes of heterogeneity in sensitivity analyses. We assessed quality of evidence at the outcome level using the GRADE approach.Main ResultsWe identified 11 trials for inclusion in the review. All trials were small (total participants 665) and had various methodological limitations including uncertainty about methods to ensure allocation concealment and blinding. Most participants were clinically stable preterm infants of less than about 34 weeks' gestational age or with birth weight less than about 1750 g. Fewer participants were extremely preterm, extremely low birth weight, or growth restricted. Most trials found no effects on feed intolerance, assessed variously as mean pre-feed gastric residual volume, incidence of abdominal distension or other gastrointestinal signs of concern, or time taken to achieve full enteral feeds (meta-analysis was limited because studies used different measures). Meta-analysis showed no effect on the risk of necrotising enterocolitis (typical risk ratio 1.10, 95% CI 0.36 to 3.34; risk difference 0.00, 95% CI -0.03 to 0.04; 5 trials, 385 infants) (low-certainty evidence; downgraded for imprecision and design weaknesses).Authors' ConclusionsThe identified trials provide only low-certainty evidence about the effects of feeding preterm infants protein hydrolysate versus standard formula. Existing data do not support conclusions that feeding protein hydrolysate affects the risk of feed intolerance or necrotising enterocolitis. Additional large, pragmatic trials are needed to provide more reliable and precise estimates of effectiveness and cost-effectiveness.

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