Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants

Review question: Does administering lactoferrin with feeds decrease the risk of sepsis or necrotizing enterocolitis in preterm babies?

Background: Preterm babies are at risk for blood infection (sepsis) and/or gastrointestinal injury (necrotizing enterocolitis, or NEC). Many babies with sepsis or NEC die or develop long-term brain and lung injury despite treatment with antibiotics. Lactoferrin, a protein that is present in human milk, has been shown to be effective against infection when tested in animals and in the laboratory. Lactoferrin also enhances the ability of babies to fight infection.

Study characteristics: Through literature searches updated to December 2016, we found six studies that enrolled 1041 preterm babies and tested the role of lactoferrin along with feeds. We also found large ongoing studies that may increase the strength of our findings when their results become available.

Key results: Evidence of low quality suggests that oral lactoferrin with or without a probiotic decreases blood infection and NEC in preterm infants with no adverse effects. Clarification regarding dosing, duration, type of lactoferrin (human or bovine), and development of preterm babies is still needed.

Quality of evidence: Evidence is of low quality.

Authors' conclusions: 

Evidence of low quality suggests that lactoferrin supplementation to enteral feeds with or without probiotics decreases late-onset sepsis and NEC stage II or III in preterm infants without adverse effects. Completed ongoing trials will provide data from more than 6000 preterm neonates, which may enhance the quality of the evidence. Clarification regarding optimal dosing regimens, types of lactoferrin (human or bovine), and long-term outcomes is needed.

Read the full abstract...
Background: 

Lactoferrin, a normal component of human colostrum and milk, can enhance host defenses and may be effective for prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates.

Objectives: 

Primary objective
1. To assess the safety and effectiveness of lactoferrin supplementation to enteral feeds for prevention of sepsis and NEC in preterm neonates

Secondary objectives

1. To determine the effects of lactoferrin supplementation to enteral feeds to prevent neonatal sepsis and/or NEC on duration of positive-pressure ventilation, development of chronic lung disease (CLD) or periventricular leukomalacia (PVL), length of hospital stay to discharge among survivors, and adverse neurological outcomes at two years of age or later

2. To determine the adverse effects of lactoferrin supplementation for prophylaxis of neonatal sepsis and/or NEC

When data were available, we analyzed the following subgroups.

1. Gestational age < 32 weeks and 32 to 36 weeks

2. Birth weight < 1000 g (extremely low birth weight (ELBW) infants) and birth weight < 1500 g (very low birth weight (VLBW) infants)

3. Type of feeding: breast milk versus formula milk

Search strategy: 

We used the search strategy of the Cochrane Neonatal Review Group (CNRG) to update our search in December 2016. We searched the databases Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PREMEDLINE, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), as well as trial registries and conference proceedings.

Selection criteria: 

Randomized controlled trials (RCTs) evaluating oral lactoferrin at any dose or duration to prevent sepsis or NEC in preterm neonates.

Data collection and analysis: 

Review authors used standard methods of the CNRG.

Main results: 

This review includes six RCTs. Trial results show that lactoferrin supplementation to enteral feeds decreased late-onset sepsis (typical risk ratio (RR) 0.59, 95% confidence interval (CI) 0.40 to 0.87; typical risk difference (RD) -0.06, 95% CI -0.10 to -0.02; number needed to treat for an additional beneficial outcome (NNTB) 17, 95% CI 10 to 50; six trials, 886 participants; low-quality evidence) and NEC stage II or III (typical RR 0.40, 95% CI 0.18 to 0.86; typical RD -0.04, 95% CI -0.06 to -0.01; NNTB 25, 95% CI 17 to 100; four studies, 750 participants; low-quality evidence). Lactoferrin supplementation did not have an effect on "all-cause mortality" (typical RR 0.65, 95% CI 0.37 to 1.11; typical RD -0.02, 95% CI -0.05 to 0; six studies, 1041 participants; low-quality evidence).

Lactoferrin supplementation to enteral feeds with probiotics decreased late-onset sepsis (RR 0.27, 95% CI 0.12 to 0.60; RD -0.13, 95% CI -0.19 to -0.06; NNTB 8, 95% CI 5 to 17; one study, 321 participants; low-quality evidence) and NEC stage II or III (RR 0.04, 95% CI 0.00 to 0.62; RD -0.05, 95% CI -0.08 to -0.03; NNTB 20, 95% CI 12.5 to 33.3; one study, 496 participants; low-quality evidence), but not "all-cause mortality" (low-quality evidence).

Lactoferrin supplementation to enteral feeds with or without probiotics decreased bacterial and fungal sepsis but not CLD or length of hospital stay (low-quality evidence). Investigators reported no adverse effects and did not evaluate long-term neurological outcomes and PVL.

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