Human milk-derived fortifier versus bovine milk-derived fortifier for prevention of mortality and morbidity in preterm neonates

Cochrane Database Syst Rev. 2019 Nov 7;2019(11):CD013145. doi: 10.1002/14651858.CD013145.pub2.


Background: Preterm infants who are fed breast milk in comparison to infant formula have decreased morbidity such as necrotizing enterocolitis. Multi-nutrient fortifiers used to increase the nutritional content of the breast milk are commonly derived from bovine milk. Human milk-derived multi-nutrient fortifier is now available, but it is not clear if it improves outcomes in preterm infants fed with breast milk.

Objectives: To determine whether the fortification of breast milk feeds with human milk-derived fortifier in preterm infants reduces mortality, morbidity, and promotes growth and development compared to bovine milk-derived fortifier.

Search methods: We searched the following databases for relevant trials in September 2018. Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, Issue 9), electronic journal reference databases including MEDLINE (1980 to 20 September 2018), PREMEDLINE, Embase (1974 to 20 September 2018), CINAHL (1982 to 20 September 2018), biological abstracts in the database BIOSIS and conference abstracts from 'Proceedings First' (from 1992 to 2011). We also included the following clinical trials registries for ongoing or recently completed trials: (, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; www.whoint/ictrp/search/en/) and the ISRCTN Registry (, and abstracts of conferences: proceedings of Pediatric Academic Societies (American Pediatric Society, Society for Pediatric Research and European Society for Paediatric Research) from 1990 in the 'Pediatric Research' journal and 'Abstracts online' (2000 to 2017).

Selection criteria: We included randomized and quasi-randomized controlled trials that compared preterm infants fed breast milk fortified with human milk-derived fortifier versus those fed with breast milk fortified with bovine milk-derived fortifier.

Data collection and analysis: The data were collected using the standard methods of Cochrane Neonatal. Two authors evaluated trial quality of the studies and extracted data. We reported dichotomous data using risk ratios (RRs), risk differences (RDs), number needed to treat (NNT) where applicable, and continuous data using mean differences (MDs). We assessed the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Main results: One randomized trial with 127 infants met the eligibility criteria and had low risk of bias. Human milk-based fortifier did not decrease the risk of necrotizing enterocolitis in exclusively breast milk-fed preterm infants (RR 0.95, 95% CI 0.2 to 4.54; 1 study, 125 infants, low certainty of evidence). Human milk-derived fortifiers did not improve growth, decrease feeding intolerance, late-onset sepsis, or death.

Authors' conclusions: There is insufficient evidence evaluating human milk-derived fortifier with bovine milk-derived fortifier in exclusively breast milk-fed preterm infants. Low-certainty evidence from one study suggests that in exclusively breast milk-fed preterm infants human milk-derived fortifiers in comparison with bovine milk-derived fortifier may not change the risk of necrotizing enterocolitis, mortality, feeding intolerance, infection, or improve growth. Well-designed randomized controlled trials are needed to evaluate short-term and long-term outcomes.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Animals
  • Cattle
  • Enterocolitis, Necrotizing / prevention & control*
  • Food, Fortified
  • Humans
  • Infant
  • Infant Formula
  • Infant Nutritional Physiological Phenomena*
  • Infant, Newborn
  • Infant, Premature / growth & development*
  • Milk
  • Milk, Human
  • Randomized Controlled Trials as Topic
  • Sepsis / prevention & control