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

The Cochrane database of systematic reviews

Jun 2017

DOI: 10.1002/14651858.CD007137.pub5

Citations:241

Influential Citations:8

Systematic Reviews / Meta-Analyses

Enhanced Details

Methods

Preterm neonates (<37 weeks gestation) in NICUs; birth weights commonly <2000 g (including ELBW <1000 g in subgroups); randomized controlled trials (some double-blind).

Intervention

Enteral lactoferrin supplementation (predominantly bovine; one trial used dairy lactoferrin added to formula) with regimens varying by trial: typical dose 100 mg/day (range 100–250 mg/day, weight-based); started within the first 1–3 days of life and continued for 28 days (4 weeks) to 6 weeks; one high-dose arm used 150 mg/kg twice daily; in at least one regimen lactoferrin was given with probiotic Lactobacillus rhamnosus GG; one trial added lactoferrin to formula at 1 mg per 100 mL.

Results

Lactoferrin supplementation to enteral feeds reduced late-onset sepsis (RR 0.59; 95% CI 0.40–0.87) and NEC ≥ stage II (RR 0.40; 95% CI 0.18–0.86); all-cause mortality not significantly affected (RR 0.65; 95% CI 0.37–1.11). When given with probiotics, late-onset sepsis decreased (RR 0.27; 95% CI 0.12–0.60) and NEC ≥ stage II decreased (RR 0.04; 95% CI 0.00–0.62). Adverse effects not reported; long-term neurological outcomes and PVL not evaluated. Conclusion: evidence is low quality but suggests lactoferrin (with or without probiotics) may reduce sepsis and NEC in preterm infants; optimal dosing, lactoferrin type (bovine vs human recombinant), and long-term outcomes require further study.

Limitations

Low-quality evidence with potential bias and moderate heterogeneity across six RCTs; small sample sizes in subgroups; variation in dosing regimens and co-interventions (probiotics) and formula types; lack of data on long-term neurodevelopment outcomes and PVL; not all trials blinded for outcomes.

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 later2. To determine the adverse effects of lactoferrin supplementation for prophylaxis of neonatal sepsis and/or NECWhen data were available, we analyzed the following subgroups.1. Gestational age < 32 weeks and 32 to 36 weeks2. 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 METHODS: 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. 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. show less