Oral lactoferrin for the treatment of sepsis and necrotizing enterocolitis in neonates

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Authors

Mohan Pammi1, Steven A Abrams2

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA [top]
2Neonatology and USDA/ARS, Children's Nutrition Research Center, Houston, Texas, USA [top]

Citation example: Pammi M, Abrams SA. Oral lactoferrin for the treatment of sepsis and necrotizing enterocolitis in neonates. Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD007138. DOI: 10.1002/14651858.CD007138.pub3.

Contact person

Mohan Pammi

Section of Neonatology, Department of Pediatrics
Baylor College of Medicine
6621, Fannin, MC.WT 6-104
Houston Texas 77030
USA

E-mail: mohanv@bcm.tmc.edu
E-mail 2: suseela12@hotmail.com

Dates

Assessed as Up-to-date: 08 July 2011
Date of Search: 08 July 2011
Next Stage Expected: 08 July 2013
Protocol First Published: Issue 2, 2008
Review First Published: Issue 1, 2009
Last Citation Issue: Issue 10, 2011

What's new

Date / Event Description
08 July 2011
Updated

This updates the review 'Oral lactoferrin for the treatment of sepsis and necrotizing enterocolitis in neonates' published in the Cochrane Database of Systematic Reviews (Pammi 2009).

Updated search in July 2011 did not identify any new trials for inclusion in the review.

08 July 2011
New citation: conclusions not changed

No change to conclusions.

History

Date / Event Description
07 December 2010
Amended

Contact details updated.

Abstract

Background

Neonatal sepsis and necrotizing enterocolitis (NEC) cause significant neonatal mortality and morbidity in spite of appropriate antibiotic therapy. Enhancing host defence and modulating inflammation by using lactoferrin as an adjunct to antibiotics in the treatment of sepsis and/or NEC may improve clinical outcomes.

Objectives

The primary objective is to assess safety and efficacy of oral lactoferrin as an adjunct to antibiotics in the treatment of neonates with suspected or confirmed sepsis and/or NEC.

Search methods

Relevant trials in any language were searched in July 2011 in the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, PREMEDLINE, EMBASE, CINAHL, web sites: ClinicalTrials.gov and Controlled-Trials.com External Web Site Policy, abstracts from the annual meeting of Pediatric Academic Societies (1990 to July 2011), by contacting authors who have published in this field, from the reference lists of identified clinical trials and in the reviewer's personal files.

Selection criteria

Randomized or quasi-randomized controlled trials evaluating oral lactoferrin (at any dose or duration) used as an adjunct to antibiotic therapy compared with antibiotic therapy alone (with or without placebo) or other adjuncts to antibiotic therapy to treat neonates at any gestational age up to 44 weeks postmenstrual age with confirmed or suspected sepsis or necrotizing enterocolitis (Bell's Stage II or III).

Data collection and analysis

We used the standardized methods of the Cochrane Neonatal Review Group (CNRG) for conducting a systematic review and for assessing the methodological quality of the studies (http://neonatal.cochrane.org/en/index.html). The titles and the abstracts of studies identified by the search strategy were independently assessed by the two review authors and full text version was obtained for assessment if necessary. Forms were designed for trial inclusion/exclusion and data extraction.

Results

We did not identify any eligible neonatal trial evaluating lactoferrin for treatment of neonatal sepsis or NEC.

Authors' conclusions

Implications for practice: Currently there is no evidence to recommend or refute the use of lactoferrin for the treatment of neonatal sepsis or necrotizing enterocolitis as an adjunct to antibiotic therapy.

Implications for research: The safety and efficacy of different preparations and doses of lactoferrin need to be established in neonates. Well designed adequately powered randomized multicenter trials are needed to address the efficacy and safety of lactoferrin in the treatment of neonatal sepsis and necrotizing enterocolitis. These trials should evaluate long-term neurodevelopmental and pulmonary outcomes in addition to short-term outcomes.

Plain language summary

Oral lactoferrin for the treatment of sepsis and necrotizing enterocolitis in neonates

Newborn babies, especially those born prematurely, are at risk from infections in the blood (sepsis) and/or gastrointestinal inflammation and injury (necrotizing enterocolitis). A number of babies with sepsis or necrotizing enterocolitis die or suffer from long-term brain and lung damage in spite of treatment with antibiotics. Lactoferrin, a substance normally present in human milk, may be effective against infections and gastrointestinal injury. This review searched for studies that used lactoferrin to treat babies with infection or gastrointestinal injury and found none. In view of the potential usefulness of lactoferrin, we recommend that well designed studies be done in the future to address this issue.

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Background

Description of the condition

Neonatal sepsis is the most common cause of neonatal deaths worldwide (Lawn 2006). The incidence of neonatal sepsis in the developed world is reported to be between 1 to 4 cases per 1000 live births (Stoll 2004b). In the developing world, the rate of neonatal sepsis is significantly higher (6.5 to 38 per 1000 live hospital births) (Zaidi 2005). Sepsis is a particular problem in very low birth weight infants (VLBW, birth weight < 1500 g); early onset sepsis (sepsis in infants < 72 hrs of life) occurs in about 1.5% and late-onset sepsis in about 21% of VLBW infants (Stoll 2005; Stoll 2002). Most infections are caused by Staphylococci and Candida. Mortality and morbidity (including patent ductus arteriosus, prolonged ventilation, prolonged need for intravascular access, bronchopulmonary dysplasia, necrotizing enterocolitis and length of hospital stay) are significantly increased in infected infants. In a large cohort study of infants born weighing < 1000 g, infected infants had significantly higher incidence of adverse neurodevelopmental outcomes at follow-up when compared to uninfected infants (Stoll 2004a).

Necrotizing enterocolitis (NEC) occurs in 1 to 5% of admissions to the neonatal intensive care unit (Lin 2006). The most consistent risk factors are prematurity and low birth weight. Gastrointestinal immaturity, enteral feeding (especially formula feeding), presence of bacteria and inflammation in the gastrointestinal tract, all contribute to the development of NEC (Lin 2006). Host-pathogen interactions trigger inflammation in the gastrointestinal tract, which may contribute to the pathogenesis of NEC and septic shock (Blackwell 1997; Neish 2004). NEC significantly increases mortality (attributable mortality of 15 to 30%) and morbidity (including surgery in 20 to 40% of infants and neurodevelopmental delay) (Bell 1978; Lin 2006; Stoll 2004a).

Mortality and morbidity due to sepsis and NEC remain high despite the use of potent antimicrobial agents (Stoll 2005; Stoll 2002). Increased use of antimicrobials has led to the emergence of antibiotic resistant strains of bacteria (Levy 1998). Adverse pulmonary and neurodevelopmental outcomes after sepsis or NEC may be due to inflammatory injury (Speer 1999, Adams-Chapman 2006). Agents that modulate inflammation and/or enhance host defenses may have great potential to improve outcome of infants with neonatal sepsis or NEC.

Description of the intervention

The glycoprotein lactoferrin is a component of the innate immune response. It is found in significant concentrations in human colostrum and in lower concentrations in human milk, tears, saliva, seminal fluid and secondary granules of neutrophils. Lactoferrin has broad-spectrum antimicrobial activity against bacteria, fungi, viruses and protozoa resulting either from its ability to sequester iron or to a direct effect on microbial cell membranes (Valenti 2005). Proteolysis of lactoferrin under acidic conditions (as would occur in the stomach or in the phagolysosomes of neutrophils) yields peptides called lactoferricins that have enhanced antimicrobial activity (Gifford 2005).

How the intervention might work

Lactoferrin inhibits the growth of S. epidermidis and C. albicans in vitro (Valenti 2005). It reduces the minimum inhibitory concentrations of vancomycin against S. epidermidis and antifungal agents such as azoles and amphotericin) against Candida (Kuipers 1999, Leitch 1999). Lactoferrin and lactoferrin derived peptides are highly effective against antibiotic resistant Klebseilla and S. aureus in vitro (Nibbering 2001).

Lactoferrin is effective in animal models of systemic and intestinal infection. In transgenic mice over expressing lactoferrin, there is enhanced clearance of S. aureus infection and a reduction in arthritis, septicemia and mortality (Guillen 2002). In a rabbit model of S. flexneri enteritis, lactoferrin treatment in doses equal to that present in human colostrum protects against intestinal inflammation (Gomez 2002). The systemic effects of oral lactoferrin are generally thought to be indirect and probably initiated by contact with intestinal epithelial cells and gut associated lymphoid tissues (GALT). Lactoferrin modulates cytokine and/or chemokine production by the GALT cells, which then enter the systemic circulation and influence circulating leukocytes (Bellamy 1992; Tomita 2002). Lactoferrin and other similar products in milk (prebiotics) create an environment for the growth of beneficial bacteria in the gastrointestinal tract, reducing colonization with pathogenic bacteria. The fact that intestinal receptors for lactoferrin have been demonstrated and that lactoferrin has the ability to modulate intestinal cell differentiation and proliferation (Buccigrossi 2007) makes lactoferrin a promising agent in NEC.

In adult humans, oral recombinant human lactoferrin has been found to be safe and well tolerated. Oral lactoferrin has shown promise as an antitumor agent (Hayes 2006). Oral lactoferrin has been shown to reduce viremia in chronic hepatitis C infection (Tanaka 1999; Iwasa 2002). In patients with acute myeloid leukemia and neutropenia, lactoferrin reduced the incidence, duration and severity of bacteremia due to enteric pathogens (Trumpler 1989). To date, no significant adverse effects have been reported in either animal or human studies.

Why it is important to do this review

The potential beneficial effects without reported adverse effects make lactoferrin a promising agent for the treatment of neonatal sepsis and NEC. This review evaluates the role of oral lactoferrin in the treatment of neonatal sepsis and NEC.

Objectives

Primary objectives

  1. To assess safety and efficacy of oral lactoferrin used as an adjunct to antibiotic therapy in the treatment of neonates with suspected or confirmed sepsis.
  2. To assess safety and efficacy of oral lactoferrin used as an adjunct to antibiotic therapy in the treatment of neonates with NEC.

Secondary objectives

  1. To determine the effect of oral lactoferrin used as an adjunct to antibiotic therapy to treat neonatal sepsis on the duration of positive pressure ventilation, development of chronic lung disease (CLD), necrotizing enterocolitis (NEC) and periventricular leukomalacia (PVL), length of hospital stay in survivors to discharge and adverse neurological outcome at two years of age or later.
  2. To determine the effect of oral lactoferrin used as an adjunct to antibiotic therapy to treat NEC on the duration of positive pressure ventilation, development of chronic lung disease (CLD) and periventricular leukomalacia (PVL), confirmed or suspected sepsis, length of hospital stay in survivors to discharge, and adverse neurological outcome at two years of age or later.
  3. To determine the adverse effects of oral lactoferrin in the treatment of neonatal sepsis and NEC.

Separate comparisons will be made for the following interventions

  1. Oral lactoferrin for the treatment of sepsis:
    1. Oral lactoferrin treatment as an adjunct to antibiotics vs. antibiotics alone (with or without placebo);
    2. Oral lactoferrin treatment as an adjunct to antibiotics vs. antibiotics with other adjuncts (intravenous immunoglobulin, granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, and pentoxifylline).
  2. Oral lactoferrin for the treatment of NEC:
    1. Oral lactoferrin treatment as an adjunct to antibiotics vs. antibiotics alone (with or without placebo);
    2. Oral lactoferrin treatment as an adjunct to antibiotics vs. antibiotics with other adjuncts (intravenous immunoglobulin, granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, and pentoxifylline).

The following subgroups will be analyzed if data are available

  1. Term and preterm (< 37 weeks gestational age) infants.
  2. Birth weight < 1000 g (ELBW infants) and birth weight < 1500 g (VLBW infants).
  3. Early onset (less than/or equal to 72 hrs of life) and late onset sepsis (> 72 hrs of life).
  4. Suspected sepsis, confirmed sepsis, confirmed gram-positive sepsis, confirmed gram-negative sepsis and confirmed fungal sepsis.

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Methods

Criteria for considering studies for this review

Types of studies

Randomized or quasi-randomized controlled trials.

Types of participants

  1. For treatment of sepsis: Neonates (at any gestational age up to 44 weeks postmenstrual age) with confirmed or suspected sepsis on antibiotics.
  2. For the treatment of NEC: Neonates (at any gestational age up to 44 weeks postmenstrual age) with NEC (Bell's Stage II or III) on antibiotics.

Confirmed sepsis is defined as clinical signs and symptoms consistent with infection and microbiologically proven with a positive blood culture, CSF culture, urine culture (obtained by a suprapubic tap) or culture from a normally sterile site (e.g. pleural fluid, peritoneal fluid or autopsy specimens) for bacteria or fungi.

Suspected sepsis is defined as clinical signs and symptoms consistent with sepsis without isolation of a causative organism.

Types of interventions

Oral lactoferrin at any dosage or duration used as adjunct to antibiotics to treat suspected or confirmed neonatal sepsis and/or NEC compared with placebo or no intervention or other adjuncts to antibiotics.

Types of outcome measures

Primary outcomes

All cause mortality during hospital stay and at 28 days.

Secondary outcomes

Neurological outcome at two years of age or more (neurodevelopmental outcome assessed by a validated test).

Chronic lung disease (CLD) in survivors (CLD defined as oxygen requirement at 36 weeks postmenstrual age or at hospital discharge.

Adverse outcomes directly attributable to oral lactoferrin: increased gastric residuals (gastric aspirate greater than 10% of oral feed), vomiting and other GI disturbances during hospital stay.

Periventricular leukomalacia (defined as necrosis of brain white matter in a characteristic distribution, i.e. in the white matter dorsal and lateral to the external angles of lateral ventricles involving particularly the centrum semi ovale, optic and acoustic radiations and diagnosed by magnetic resonance imaging (MRI) or as periventricular cystic lesions by cranial ultrasound) (Volpe 1995) at discharge or at neurodevelopmental follow-up.

Duration of assisted ventilation through an endotracheal tube during hospital stay (days).

Necrotizing enterocolitis (NEC) (definite NEC and perforated NEC, Bell's stage II or III) (Bell 1978) during hospital stay (outcome for infants enrolled with sepsis).

Length of hospital stay for survivors to discharge (days).

Search methods for identification of studies

Please refer to Cochrane Neonatal Review Group's search strategy.

Relevant trials in any language were searched in July 2011 through:

  1. The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library)
  2. Electronic journal reference databases: MEDLINE (1966 to July 2011), PREMEDLINE, EMBASE (1980 to July 2011) and CINAHL (1982 to July 2011)
  3. Ongoing trials were searched in the following databases at the following web sites: ClinicalTrials.gov and Controlled-Trials.com External Web Site Policy.
  4. Abstracts of conferences - proceedings of Pediatric Academic Societies (American Pediatric Society, Society for Pediatric Research and European Society for Pediatric Research) were searched from 1990 from the journal 'Pediatric Research' and 'Abstracts Online'.
  5. Authors who published in this field were contacted for possible unpublished articles.
  6. Additional searches were made from the reference list of identified clinical trials and in the reviewer's personal files.

Search strategy for MEDLINE and PREMEDLINE. This strategy was adapted to suit EMBASE, CINAHL and the Cochrane Controlled Trials Register.

  1. explode 'sepsis' [all subheadings in MIME, MJME]
  2. sepsis or septicemia
  3. septic
  4. NEC
  5. 'necrotizing enterocolitis'
  6. # 1 or # 2 or # 3 or # 4 or # 5
  7. explode 'infant - newborn' [all subheadings in MIME, MJME]
  8. Neonat*
  9. Newborn*
  10. # 7 or # 8 or # 9
  11. # 6 and # 10
  12. "lactoferrin' [all subheadings on MIME, MJME]
  13. Talactoferrin
  14. # 10 or # 11
  15. # 9 and # 12

No language restriction was applied. Randomized and quasi-randomized trials were searched from the results.

Data collection and analysis

The standardized method of the Cochrane Neonatal Review Group (CNRG) for conducting a systematic review was followed (http://neonatal.cochrane.org/en/index.html).

Selection of studies

The titles and the abstracts of studies identified by the search strategy were assessed by the two review authors independently for eligibility for inclusion in this review. If this could not be done reliably by title and abstract, then the full text version was obtained for assessment. Any differences were resolved by mutual discussion.

Data extraction and management

Full text version of all studies will be obtained for quality assessment when eligible trials are identified. Forms were designed for trial inclusion/exclusion, data extraction and for requesting additional published information from authors of the original reports. Data extraction will be done independently by the review authors using specifically designed paper forms when eligible trials are identified. The extracted data will be compared for any differences; if noted, differences will then be resolved by discussion.

Assessment of risk of bias in included studies

The standardized review methods of the Cochrane Neonatal Review Group (CNRG) will be used to assess the methodological quality of the eligible studies when available. The two reviewers independently will use the standard criteria developed by the CNRG and will assess the quality of the included studies. Each trial will be assessed for the validity criteria listed below and mark each criterion as A) yes, B) can't tell or C) no.

  1. Adequate (low risk of bias) allocation concealment
  2. Uncertainty about whether the allocation was adequately concealed
  3. Inadequate (high risk of bias) allocation concealment
  4. No allocation concealment

In addition, blinding of interventions, blinding of outcome assessment and completeness of follow-up of all randomized infants will be reported.

We plan to complete the risk of bias table using the following criteria:

  1. Sequence generation: Was the allocation sequence adequately generated? For each included study we will describe the method used to generate the allocation sequence. We planned to assess the methods as: low risk (any truly random process, e.g. random number table; computer random number generator); high risk (any non-random process, e.g. odd or even date of birth; hospital or clinic record number); unclear risk.
  2. Allocation concealment: Was allocation adequately concealed?For each included study, we will describe the method used to conceal the allocation sequence and determine whether intervention allocation could have been foreseen in advance of, or during recruitment, of changed after assignment. We planned to assess the methods as:
    low risk (e.g. telephone or central randomization; consecutively numbered sealed opaque envelopes); high risk (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth); unclear risk.
  3. Blinding of participants, personnel and outcome assessors: Was knowledge of the allocated intervention adequately prevented during the study?At study entry? At the time of outcome assessment?
    For each included study, we will categorize the methods used to blind study participants and personnel from knowledge of which intervention a participant received. Blinding was assessed separately for different outcomes or classes of outcomes. We planned to categorize the methods as:
    - low risk, high risk or unclear risk for participants;
    - low risk, high risk or unclear risk for personnel;
    - low risk, high risk or unclear risk for outcome assessors.
  4. Incomplete outcome data: Were incomplete outcome data adequately addressed?For each included study and for each outcome, we will describe the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. We planned to assess the methods as: low risk; high risk; unclear risk.
  5. Selective outcome reporting: Are reports of the study free of suggestion of selective outcome reporting?For each included study we will describe how we examined the possibility of selective outcome reporting bias and what we found. We planned to assess the methods as: low risk (where it is clear that all of the study's pre-specified outcomes and all expected outcomes of interest to the review have been reported); high risk (where not all the study's pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported); unclear risk.
  6. Other sources of bias: Was the study apparently free of other problems that could put it at a high risk of bias?For each included study, we will describe any important concerns regarding other possible sources of bias. We planned to assess whether each study was free of other problems that could put it at risk of bias: low risk; high risk; unclear risk.

Measures of treatment effect

Statistical analyses will be performed according to the recommendations of CNRG when eligible trials are identified. All infants randomized will be analyzed on 'an intention to treat basis' irrespective of whether they received their allocated treatment completely. Treatment effects in the individual trials will be analyzed. The statistical package (RevMan 5) provided by the Collaboration will be used. Relative risk (RR) and risk difference (RD) with 95% confidence interval (CI) are reported for dichotomous outcomes and weighted mean differences for continuous outcomes. If there is a statistically significant reduction in RD then the number needed to treat (NNT) will be calculated.

Assessment of heterogeneity

We planned to estimate the treatment effects of individual trials and examine heterogeneity between trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I-squared statistic. The degree of heterogeneity will be graded as low (> 25%), moderate (> 50%) or high (> 75%). If we detected statistical heterogeneity, we planned to explore the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) using post hoc sub group analyses. We planned to use a fixed effects model for meta-analysis.

Data synthesis

If eligible studies are identified, we plan to perform the meta-analysis using Review Manager software (RevMan 5), supplied by the Cochrane Collaboration. For estimates of typical relative risk and risk difference, we planned to use the Mantel-Haenszel method. For measured quantities, we planned to use the inverse variance method. All meta-analyses will be done using the fixed effect model.

Subgroup analysis and investigation of heterogeneity

Separate comparisons will be made for the following interventions when data are available:

  1. Oral lactoferrin for the treatment of sepsis:
    1. Oral lactoferrin treatment as an adjunct to antibiotics vs. antibiotics (with or without placebo).
    2. Oral lactoferrin treatment as an adjunct to antibiotics vs. antibiotics with other adjuncts (intravenous immunoglobulin, granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor and pentoxifylline).
  2. Oral lactoferrin for the treatment of NEC:
    1. Oral lactoferrin treatment as an adjunct to antibiotics vs. antibiotics (with or without placebo).
    2. Oral lactoferrin treatment as an adjunct to antibiotics vs. antibiotics with other adjuncts (intravenous immunoglobulin, granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor and pentoxifylline).

Key subgroups of participants will be based on:

  1. Gestational age:
    1. Preterm neonates (born before 37 completed weeks gestation)
    2. Term infants (born at or after 37 completed weeks of gestation)
  2. Birth weight:
    1. VLBW infants (birth weight < 1500 g)
    2. ELBW infants (birth weight < 1000 g)
  3. Time of onset of sepsis:
    1. Early onset sepsis (sepsis less than/or equal to 72 hrs of life)
    2. Late onset sepsis (sepsis > 72 hrs of life)
  4. Type of sepsis:
    1. Neonates with suspected sepsis
    2. Neonates with confirmed sepsis
    3. Neonates with confirmed gram-negative sepsis
    4. Neonates with confirmed gram-positive sepsis
    5. Neonates with confirmed fungal sepsis

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Results

Description of studies

Our search strategy did not identify any eligible trials or relevant ongoing trials in neonates that were potentially eligible for inclusion.

Excluded Study:

Zavaleta 2007: Reason for exclusion- Not a neonatal study

This double blind randomized controlled study enrolled 140 Peruvian children aged 5-33 months who had acute diarrhea. Children were randomized to one of the three following oral rehydrating solutions (ORS): WHO-ORS (glucose-based-ORS, G-ORS, n=47) or Rice-based ORS (R-ORS, n=45) or Rice-based ORS with added lactoferrin and lysozyme derived from recombinant rice (Lf/Lz-R-ORS, n=48). Intake of ORS and stool output was monitored for 14 days. Children who received Lf/Lz-R-ORS had significantly decreased duration of diarrhea (3.67 vs. 5.21 days, p=0.05) and were more likely to achieve a solid stool at 48 hrs when compared to the other 2 groups combined (85% vs. 69%, p < 0.05).

Risk of bias in included studies

Not applicable as there were no eligible trials.

Effects of interventions

Not applicable as there were no eligible trials.

Discussion

There were no eligible randomised or quasi-randomized trials in neonates using oral lactoferrin as an adjunct to antibiotics in the treatment of neonatal sepsis or necrotizing enterocolitis. We also did not identify any ongoing neonatal trials that are potentially eligible for inclusion on completion. We identified two trials that are ongoing or just completed (Guntapalli 2008; Simonson 2011) that will evaluate lactoferrin or lactoferrin derivatives in adults with sepsis. In a double blind randomized placebo controlled study of talactoferrin alpha (human recombinant lactoferrin), Guntapalli and coworkers have randomized 190 patients who are aged 18 years or more in the first 24 hrs of severe sepsis who are able to take medication by mouth or feeding tube and on antibiotics. The primary outcome is 'all cause mortality' within 28 days and secondary outcomes are 'all cause mortality' within three months' and 'all cause mortality' within six months (Guntapalli 2008) (study completed, no data available). Simonson and colleagues have initiated a multi-center trial to assess the safety and efficacy of talactoferrin alfa in adults with severe sepsis and evaluate mortality and toxicity (Simonson 2011). One trial in children with diarrhea (Zavaleta 2007) found oral rehydration solution containing human recombinant lactoferrin and lysozyme expressed in rice had a significant impact on the duration of diarrhea (3.67 versus 5.21 days, p = 0.05) and the percentage of children having a solid stool in 48 hrs (85% versus 69%, p < 0.05) compared to ORS not containing lactoferrin or lysozyme in children who had acute diarrhea.

Recent increase in interest in lactoferrin stems not only from improved understanding of its physiological functions but also due to its increased availability in various forms and sources. Lactoferrin processed from bovine and human milk is available commercially as a food supplement (Swedish Diaries Association, Tatua Co-operative Dairy Company in New Zealand, Lacto Bretagne Associes' in Belgium, Milei in Germany, Morinaga industries, Japan, DoMO Food Ingredients a subsidiary of Friesland Dairy Foods in the Netherlands, etc.). In the United States, human recombinant lactoferrin (talactoferrin from Agennix. Inc) has an investigational new drug status for clinical research purposes. Lactoferrin expressed in transgenic rice (Ventria Biosciences) and transgenic maize (Meristem therapeutics) is being researched. Bovine lactoferrin is less expensive than human lactoferrin and is affordable even in developing countries where the rate of infections is higher compared to developed countries.

The major hurdle for the development of neonatal trials is the establishment of safety of oral lactoferrin when used in neonates, especially premature and the VLBW infants who are at high risk of sepsis and necrotizing enterocolitis. Although adverse effects due to lactoferrin have not been demonstrated in animal models or in adults, pilot studies establishing safety and tolerability of oral lactoferrin in neonates is of paramount importance before large multicenter randomized trials are undertaken. The dosing and duration of therapy with oral lactoferrin has to be extrapolated from similar adult or animal studies and have not yet been established in neonates. Different preparations of lactoferrin are available including human recombinant, bovine and synthetic lactoferrin-derived peptides and the relative tolerability and efficacy needs to be established before widespread clinical testing in neonates.

Lactoferrin is a normal component of the innate immune system and has broad-spectrum antimicrobial and immunomodulatory effects. Lactoferrin's multimodal functions suggest great promise as a therapeutic agent in neonatal sepsis and NEC but has not been evaluated in randomized clinical trials in neonates. This paucity of evidence needs to be addressed in well designed trials.

Authors' conclusions

Implications for practice

There is no evidence to recommend or refute the use of oral lactoferrin for the treatment of neonatal sepsis and/or necrotizing enterocolitis as an adjunct to antibiotics.

Implications for research

This systematic review has identified a gap in clinical evidence that needs to be addressed. Safety and efficacy of different preparations and doses of lactoferrin need to be established in neonates especially premature neonates. Well designed, adequately powered, randomized multicenter trials are needed to address the efficacy and safety of lactoferrin in neonatal sepsis and neonatal necrotizing enterocolitis and in addition to evaluation of short-term outcomes (e.g. mortality) should also focus on long-term neurodevelopmental and pulmonary outcomes.

Acknowledgements

We sincerely acknowledge the help of Yolanda Montagne, Trials Search Coordinator, Cochrane Neonatal Review Group for performing the literature search in EMBASE.

Contributions of authors

Mohan Pammi

  • Wrote the text of the protocol and the review
  • Formulated the search strategy and performed literature search
  • Is the corresponding author

Steve Abrams

  • Assisted in writing the protocol and review
  • Assisted in incorporating peer-reviewed comments in the review

Declarations of interest

Human recombinant lactoferrin for Dr. Pammi's laboratory research was donated by Agennix. Inc

Differences between protocol and review

  • None noted.

Additional tables

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

  • None noted.

Characteristics of excluded studies

Zavaleta 2007

Reason for exclusion

Participants were not neonates but were children aged 5 - 33 months with acute diarrhea

Characteristics of studies awaiting classification

  • None noted.

Characteristics of ongoing studies

  • None noted.

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References to studies

Included studies

  • None noted.

Excluded studies

Zavaleta 2007

Zavaleta N, Figueroa D, Rivera J, Sanchez J, Alfaro S, Lonnerdal B. Efficacy of rice-based oral rehydration solution containing recombinant human lactoferrin and lysozyme in peruvian children with acute diarrhea. Journal of Pediatric Gasteroenterology and Nutrition 2007;44:258-64.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

Adams-Chapman 2006

Adams-Chapman I, Stoll BJ. Neonatal infection and long-term neurodevelopmental outcome in the preterm infant. Current Opinion in Infectious Diseases 2006;19:290-7.

Bell 1978

Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, Brotherton T. Neonatal necrotising enterocolitis. Therapeutic decisions based upon clinical staging. Annals of Surgery 1978;187:1-7.

Bellamy 1992

Bellamy W, Takase M, Wakabayashi H, Kawase K, Tomita M. Antibacterial spectrum of lactoferricin B, a potent bactericidal peptide derived from the N-terminal region of bovine lactoferrin. Journal of Applied Bacteriology 1992;73:472-9.

Blackwell 1997

Blackwell TS, Christman JW. The role of nuclear factor-kappa B in cytokine gene regulation. American Journal of Respiratory Cell and Molecular Biology 1997;17:3-9.

Buccigrossi 2007

Buccigrossi V, de Marco G, Bruzzese E, Ombrato L, Bracale I, Polito G, Guarino A. Lactoferrin induces concentration-dependent functional modulation of intestinal proliferation and differentiation. Pediatric Research 2007;61:410-4.

Gifford 2005

Gifford JL, Hunter HN, Vogel HJ. Lactoferricin: a lactoferrin-derived peptide with antimicrobial, antiviral, antitumor and immunological properties. Cellular and Molecular Life Sciences 2005;62:2588-98.

Gomez 2002

Gomez HF, Ochoa TJ, Herrera-Insua I, Carlin LG, Cleary TG. Lactoferrin protects rabbits from Shigella flexneri-induced inflammatory enteritis. Infection and Immunity 2001;70:7050-3.

Guillen 2002

Guillen CI, McInnes B, Vaughan DM, Kommajosyula S, Van Berkel PH, Leung BP, Aguila A, Brock JH. Enhanced Th3 response to Staphylococcus aureus infection in human lactoferrin-transgenic mice. Journal of Immunology 2002;168:3950-7.

Guntapalli 2008

Guntapalli. Safety and efficacy study of recombinant human lactoferrin to treat severe sepsis. ClinicalTrials.gov: NCT00630656.

Hayes 2006

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Iwasa 2002

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Lawn 2006

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Leitch 1999

Leitch EC, Willcox MD. Lactoferrin increases the susceptibility of S. epidermidis biofilms to lysozyme and vancomycin. Current Eye Research 1999;19:12-19.

Levy 1998

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Nibbering 2001

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Speer CP. Inflammatory mechanisms in neonatal chronic lung disease. European Journal of Pediatrics 1999;158(suppl):S18-22.

Stoll 2002

Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, Lemons JA, Donovan EF, Stark AR, Tyson JE, Oh W et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics 2002;110:285-91.

Stoll 2004a

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Other published versions of this review

Pammi 2009

Pammi M, Abrams SA. Oral lactoferrin for the treatment of sepsis and necrotizing enterocolitis in neonates. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD007138. DOI: 10.1002/14651858.CD007138.pub2.

Classification pending references

  • None noted.

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Data and analyses

  • None noted.

Figures

  • None noted.

Sources of support

Internal sources

  • None noted.

External sources

  • None noted.

This review is published as a Cochrane review in The Cochrane Library, Issue 10, 2011 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.