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Meta-Analysis
. 2020 Mar 31;3(3):CD007137.
doi: 10.1002/14651858.CD007137.pub6.

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

Mohan Pammi  1 , Gautham Suresh  1
Affiliations
Meta-Analysis

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

Mohan Pammi et al. Cochrane Database Syst Rev. .

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: To assess the safety and effectiveness of lactoferrin supplementation to enteral feeds for prevention of sepsis and NEC in preterm neonates. Secondarily, we assessed the effects of lactoferrin supplementation to enteral feeds on the 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.

Search methods: We used the standard search strategy of Cochrane Neonatal to update our search. We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 9), MEDLINE via PubMed (1966 to 20 January 2020), PREMEDLINE (1996 to 20 January 2020), Embase (1980 to 20 January 2020), and CINAHL (1982 to 20 January 2020). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials.

Selection criteria: In our search, we included randomized controlled trials (RCTs) evaluating enteral lactoferrin supplementation at any dose or duration to prevent sepsis or NEC in preterm neonates.

Data collection and analysis: We used the standard methods of Cochrane Neonatal and the GRADE approach to assess the certainty of evidence.

Main results: Meta-analysis of data from twelve randomized controlled trials showed that lactoferrin supplementation to enteral feeds decreased late-onset sepsis (typical RR 0.82, 95% CI 0.74 to 0.91; typical RD -0.04, 95% CI, -0.06, -0.02; NNTB 25, 95% CI 17 to 50; 12 studies, 5425 participants, low-certainty evidence) and decreased length of hospital stay (MD -2.38, 95% CI, -4.67, -0.09; 3 studies, 1079 participants, low-certainty evidence). Sensitivity analysis including only good methodological certainty studies suggested a decrease in late-onset sepsis with enteral lactoferrin supplementation (typical RR 0.87, 95% CI, 0.78, 0.97; typical RD -0.03, 95% CI, -0.05, -0.0; 9 studies, 4702 participants, low-certainty evidence). There were no differences in NEC stage II or III (typical RR 1.10, 95% CI, 0.86, 1.41; typical RD -0.00, 95% CI, -0.02, 0.01; 7 studies, 4874 participants; low-certainty evidence) or 'all-cause mortality' (typical RR 0.90, 95% CI 0.69, 1.17; typical RD -0.00, 95% CI, -0.01, 0.01; 11 studies, 5510 participants; moderate-certainty evidence). One study reported no differences in neurodevelopmental testing by Mullen's or Bayley III at 24 months of age after enteral lactoferrin supplementation (one study, 292 participants, low-certainty evidence). Lactoferrin supplementation to enteral feeds with probiotics decreased late-onset sepsis (RR 0.25, 95% CI 0.14 to 0.46; RD -0.13, 95% CI -0.18 to -0.08; NNTB 8, 95% CI 6 to 13; 3 studies, 564 participants; low-certainty 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; 1 study, 496 participants; very low-certainty evidence), but not 'all-cause mortality' (very low-certainty evidence). Lactoferrin supplementation to enteral feeds with or without probiotics had no effect on CLD, duration of mechanical ventilation or threshold retinopathy of prematurity (low-certainty evidence). Investigators reported no adverse effects in the included studies.

Authors' conclusions: We found low-certainty evidence from studies of good methodological quality that lactoferrin supplementation of enteral feeds decreases late-onset sepsis but not NEC ≥ stage II or 'all cause mortality' or neurodevelopmental outcomes at 24 months of age in preterm infants without adverse effects. Low- to very low-certainty evidence suggests that lactoferrin supplementation of enteral feeds in combination with probiotics decreases late-onset sepsis and NEC ≥ stage II in preterm infants without adverse effects, however, there were few included studies of poor methodological quality. The presence of publication bias and small studies of poor methodology that may inflate the effect size make recommendations for clinical practice difficult.

PubMed Disclaimer

Conflict of interest statement

Agennix, Inc. donated human recombinant lactoferrin for Dr Pammi's laboratory research from 2006 through 2009.

Figures

1
1
Funnel plot of comparison: 1 Lactoferrin supplementation with enteral feeds versus placebo, outcome: 1.1 Any late‐onset sepsis.
2
2
Funnel plot of comparison: 1 Lactoferrin supplementation with enteral feeds versus placebo, outcome: 1.3 All‐cause mortality.
3
3
Study flow diagram for the updated search in January 20, 2020
4
4
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
5
5
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
6
6
Forest plot of comparison: 1 Lactoferrin supplementation with enteral feeds versus placebo, outcome: 1.1 Any late‐onset sepsis.
7
7
Forest plot of comparison: 1 Lactoferrin supplementation with enteral feeds versus placebo, outcome: 1.2 NEC ≥ stage II.
8
8
Forest plot of comparison: 1 Lactoferrin supplementation with enteral feeds versus placebo, outcome: 1.3 All‐cause mortality.
1.1
1.1. Analysis
Comparison 1: Lactoferrin supplementation with enteral feeds versus placebo, Outcome 1: Any late‐onset sepsis
1.2
1.2. Analysis
Comparison 1: Lactoferrin supplementation with enteral feeds versus placebo, Outcome 2: NEC ≥ stage II
1.3
1.3. Analysis
Comparison 1: Lactoferrin supplementation with enteral feeds versus placebo, Outcome 3: All‐cause mortality
1.4
1.4. Analysis
Comparison 1: Lactoferrin supplementation with enteral feeds versus placebo, Outcome 4: Bacterial sepsis
1.5
1.5. Analysis
Comparison 1: Lactoferrin supplementation with enteral feeds versus placebo, Outcome 5: Fungal infection
1.6
1.6. Analysis
Comparison 1: Lactoferrin supplementation with enteral feeds versus placebo, Outcome 6: Chronic lung disease
1.7
1.7. Analysis
Comparison 1: Lactoferrin supplementation with enteral feeds versus placebo, Outcome 7: Duration of mechanical ventilation
1.8
1.8. Analysis
Comparison 1: Lactoferrin supplementation with enteral feeds versus placebo, Outcome 8: Length of stay among survivors
1.9
1.9. Analysis
Comparison 1: Lactoferrin supplementation with enteral feeds versus placebo, Outcome 9: Threshold retinopathy of prematurity
1.10
1.10. Analysis
Comparison 1: Lactoferrin supplementation with enteral feeds versus placebo, Outcome 10: Urinary tract Infection
1.11
1.11. Analysis
Comparison 1: Lactoferrin supplementation with enteral feeds versus placebo, Outcome 11: Late onset sepsis ‐ good methodology studies
1.12
1.12. Analysis
Comparison 1: Lactoferrin supplementation with enteral feeds versus placebo, Outcome 12: Neurodevelopemental outcome by Mullen at 24 months
1.13
1.13. Analysis
Comparison 1: Lactoferrin supplementation with enteral feeds versus placebo, Outcome 13: Neurodevelopmental outcome by Bayley III at 24 months
2.1
2.1. Analysis
Comparison 2: Lactoferrin supplementation with enteral feeds in combination with probiotics versus placebo, Outcome 1: Any late‐onset sepsis
2.2
2.2. Analysis
Comparison 2: Lactoferrin supplementation with enteral feeds in combination with probiotics versus placebo, Outcome 2: NEC ≥ stage II
2.3
2.3. Analysis
Comparison 2: Lactoferrin supplementation with enteral feeds in combination with probiotics versus placebo, Outcome 3: All‐cause mortality
2.4
2.4. Analysis
Comparison 2: Lactoferrin supplementation with enteral feeds in combination with probiotics versus placebo, Outcome 4: Bacterial sepsis
2.5
2.5. Analysis
Comparison 2: Lactoferrin supplementation with enteral feeds in combination with probiotics versus placebo, Outcome 5: Fungal Infection
2.6
2.6. Analysis
Comparison 2: Lactoferrin supplementation with enteral feeds in combination with probiotics versus placebo, Outcome 6: Chronic lung disease
2.7
2.7. Analysis
Comparison 2: Lactoferrin supplementation with enteral feeds in combination with probiotics versus placebo, Outcome 7: Duration of mechanical ventilation
2.8
2.8. Analysis
Comparison 2: Lactoferrin supplementation with enteral feeds in combination with probiotics versus placebo, Outcome 8: Length of stay among survivors
2.9
2.9. Analysis
Comparison 2: Lactoferrin supplementation with enteral feeds in combination with probiotics versus placebo, Outcome 9: Threshold retinopathy of prematurity
2.10
2.10. Analysis
Comparison 2: Lactoferrin supplementation with enteral feeds in combination with probiotics versus placebo, Outcome 10: Urinary tract infection
See this image and copyright information in PMC

Update of

Comment in

References

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King 2007 {published data only}
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References to other published versions of this review

Pammi 2010
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Pammi 2015
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