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Meta-Analysis
. 2017 Oct 2;10(10):CD012412.
doi: 10.1002/14651858.CD012412.pub2.

Protein hydrolysate versus standard formula for preterm infants

Derek Hang Cheong Ng  1 , Joel Klassen, Nicholas D Embleton, William McGuire
Affiliations
Meta-Analysis

Protein hydrolysate versus standard formula for preterm infants

Derek Hang Cheong Ng et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: When human milk is not available for feeding preterm infants, protein hydrolysate rather than standard cow's milk formulas (with intact proteins) are often used because they are 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.

Objectives: To assess the effect of feeding preterm infants with hydrolysed formula (versus standard cow's milk formulas) on the risk of feed intolerance, necrotising enterocolitis, and other morbidity and mortality in preterm infants.

Search methods: We used the standard Cochrane Neonatal search strategy including electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 4), Ovid MEDLINE, Ovid Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (to April 2017), as well as conference proceedings and previous reviews.

Selection criteria: Randomised and quasi-randomised controlled trials that compared feeding preterm infants with 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 (CI). 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 gestational age less than about 34 weeks or 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 prefeed gastric residual volume, incidence of abdominal distention or other concerning gastrointestinal signs, or time taken to achieve full enteral feeds (meta-analysis was limited because studies used different measures). Meta-analysis found 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 quality evidence; downgraded for imprecision and design weaknesses).

Authors' conclusions: The identified trials provide only low quality evidence about the effects of feeding preterm infants with protein hydrolysate versus standard formula. The existing data did not support conclusions that feeding with protein hydrolysate affects the risk of feed intolerance or necrotising enterocolitis. Further large, pragmatic trials are needed to provide more reliable and precise estimates of effectiveness and cost-effectiveness.

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Conflict of interest statement

Nicholas Embleton has conducted research with support from manufacturers of infant formula including Nestec SA (Switzerland), Wyeth UK and Nutricia UK but did not receive any payment, support or benefit in kind for contribution to this review.

The other authors do not have any declarations of interest.

Figures

Figure 1
Figure 1
Study flow diagram.
Figure 2
Figure 2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figure 3
Figure 3
Forest plot of comparison: 1 Hydrolysed versus non‐hydrolysed formula, outcome: 1.2 Necrotising enterocolitis.
Figure 4
Figure 4
Forest plot of comparison: 1 Hydrolysed versus non‐hydrolysed formula, outcome: 1.4 Weight gain (g/kg/day).
Figure 5
Figure 5
Forest plot of comparison: 1 Hydrolysed versus non‐hydrolysed formula, outcome: 1.7 Serum alkaline phosphatase (IU/L).
Analysis 1.1
Analysis 1.1
Comparison 1 Hydrolysed versus non‐hydrolysed formula, Outcome 1 Feed intolerance.
Analysis 1.2
Analysis 1.2
Comparison 1 Hydrolysed versus non‐hydrolysed formula, Outcome 2 Necrotising enterocolitis.
Analysis 1.3
Analysis 1.3
Comparison 1 Hydrolysed versus non‐hydrolysed formula, Outcome 3 Time to full enteral feeding.
Analysis 1.4
Analysis 1.4
Comparison 1 Hydrolysed versus non‐hydrolysed formula, Outcome 4 Weight gain (g/kg/day).
Analysis 1.5
Analysis 1.5
Comparison 1 Hydrolysed versus non‐hydrolysed formula, Outcome 5 Length gain (mm/week).
Analysis 1.6
Analysis 1.6
Comparison 1 Hydrolysed versus non‐hydrolysed formula, Outcome 6 Head circumference growth (mm/week).
Analysis 1.7
Analysis 1.7
Comparison 1 Hydrolysed versus non‐hydrolysed formula, Outcome 7 Serum alkaline phosphatase (IU/L).
Analysis 1.8
Analysis 1.8
Comparison 1 Hydrolysed versus non‐hydrolysed formula, Outcome 8 Late‐onset invasive infection.
Analysis 1.9
Analysis 1.9
Comparison 1 Hydrolysed versus non‐hydrolysed formula, Outcome 9 Any allergic disease.
See this image and copyright information in PMC

References

References to studies included in this review

    1. Baldassarre ME, Mauro A, Fanelli M, Montagna O, Wampler J, Cooper T, et al. Shorter time to full enteral feedings among infants fed an intact protein (IP) vs an extensively hydrolyzed (EH) formula does not appear to be related to differences in gastric emptying. Journal of Pediatric Gastroenterology and Nutrition 2017;64:920‐1.
    1. Florendo KN, Bellflower B, Zwol A, Cooke RJ. Growth in preterm infants fed either a partially hydrolyzed whey or an intact casein/whey preterm infant formula. Journal of Perinatology 2009;29(2):106‐11. [DOI: 10.1038/jp.2008.124; PUBMED: 18716627] - DOI - PubMed
    1. Huston RK, Murphy DL, Jelen BJ. Preliminary evaluation of casein hydrolysate containing formulas in low birthweight preterm infants. Pediatric Research 1992;31:289A.
    1. Maggio L, Zuppa AA, Sawatzki G, Valsasina R, Schubert W, Tortorolo G. Higher urinary excretion of essential amino acids in preterm infants fed protein hydrolysates. Acta Paediatrica 2005;94(1):75‐84. [PUBMED: 15858965] - PubMed
    1. Mihatsch WA, Franz AR, Hogel J, Pohlandt F. Hydrolyzed protein accelerates feeding advancement in very low birth weight infants. Pediatrics 2002;110(6):1199‐203. [PUBMED: 12456919] - PubMed

References to studies excluded from this review

    1. Agosti M, Pugni L, Ramenghi LA, Mosca F, Marini A. Hydrolysed proteins in preterm formula: influence on plasma aminoacids, blood fatty acids and insulinaemia. Acta Paediatrica Supplement 2003;91(441):34‐8. [PUBMED: 14599039] - PubMed
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References to studies awaiting assessment

    1. EMPTY

    1. Dobryanskyy D, Borysiuk O, Novikova O, Dubrovna Y, Salabay Z, Detsyk O. Clinical effectiveness of hydrolysed protein preterm formula in prevention of feeding intolerance in very low birth weight infants. Journal of Pediatric and Neonatal Individualized Medicine 2015;4(2):e040210. [DOI: 10.7363/040210] - DOI
    1. Luo Z, Wang Y, Wang l. A study on the effects of extensively hydrolyzed formula for very/extremely low birth weight infants. Chinese Journal of Neonatology 2016;31(2):110‐4.

References to ongoing studies

    1. ACTRN12613000481774. Improvement of feeding tolerance by using a new formula in preterm neonates [Effects of a new hydrolyzed powdered formula on feeding tolerance in preterm neonates: a randomized placebo‐controlled study]. www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363880 (first received 30 April 2013); Vol. [Personal communication Prof Terrin March 2017‐ the study was not carried out due to lack of funding. No results were presented or published].
    1. Yin LP, Qian LJ, Zhu H, Chen Y, Li H, Han JN, et al. Application effect of extensively hydrolyzed milk protein formula and follow‐up in preterm children with a gestational age of less than 34 weeks: study protocol for a randomized controlled trial. Trials 2015;16:498. [DOI: 10.1186/s13063-015-1030-5; PUBMED: 26537897] - DOI - PMC - PubMed

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    1. Boyle RJ, Ierodiakonou D, Khan T, Chivinge J, Robinson Z, Geoghegan N, et al. Hydrolysed formula and risk of allergic or autoimmune disease: systematic review and meta‐analysis. BMJ 2016;352:i974. [PUBMED: 26956579] - PMC - PubMed

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