Protein hydrolysate versus standard formula for preterm infants

Review question

Does feeding preterm infants cow's milk formula containing predigested (hydrolysed) proteins, rather than whole proteins, improve digestion and reduce the risk of severe bowel problems?


Preterm infants often find cow's milk formula more difficult to digest than human milk, and cow's milk formula may increase the risk of severe bowel problems for preterm (born before their due date) infants. If preterm infants are fed cow's milk formula (when human milk is unavailable), then using a formula in which the protein is already partially digested (called 'hydrolysed') rather than a standard formula (with intact proteins) might reduce the risk of these problems. However, hydrolysed formulas are more expensive than standard formulas, and may have specific side effects not seen with standard formulas. Given these concerns, we have reviewed all available evidence from clinical trials that compared these types of formula for feeding preterm infants.

Study characteristics

In searches of medical databases up to 28 January 2019, we found 11 relevant trials; most were small (involving 665 infants in total) and had methodological weaknesses.

Key results

Currently available evidence suggests that feeding preterm infants hydrolysed formula (rather than standard formula) during their initial hospital admission has no important benefits or harms. However, this finding is not yet conclusive, and larger trials of better quality are needed to provide evidence to help clinicians and families make informed choices about this issue.

Quality of evidence

Data from these trials provide no strong or consistent evidence that feeding preterm infants hydrolysed formula rather than standard formula improved or worsened digestion or changed the risk of severe bowel problems.

Authors' conclusions: 

The 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.

Read the full abstract...

When 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.


To 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 strategy: 

We 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 criteria: 

Randomised and quasi-randomised controlled trials that compared feeding preterm infants protein hydrolysate versus standard (non-hydrolysed) cow's milk formula.

Data collection and analysis: 

Two 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 results: 

We 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).