Enteral Lactoferrin Research Articles

Role of the protein kinase A signaling pathway and identification of mediators in the cardioprotective effects of enteral lactoferrin for ischemia-reperfusion injury in an isolated rat heart model

ObjectiveLactoferrin is an iron-binding glycoprotein. Enteral lactoferrin attenuates myocardial ischemia-reperfusion (IR) injury, but the underlying mechanism remains unknown. The aim of this study was to investigate protein kinase A (PKA) signaling pathway activation and levels of serum glucagonlike peptide-1 (GLP-1), secreted by intestinal endocrine L cells, and adiponectin, secreted by adipose tissue, after enteral lactoferrin administration. MethodsHearts (N = 32) were excised from Wistar rats and perfused using a Langendorff system. To assess the role of the PKA pathway in the cardioprotective effects of lactoferrin, an inhibitor of PKA (H89) was applied before no-flow ischemia. Rats were randomly divided into four groups: control, lactoferrin (LF), control+H89, and LF+H89. The control and control+H89 groups were administered normal saline by gavage, and the LF and L +H89 groups were administered bovine lactoferrin (1000 mg/kg) by gavage 15 min before intraperitoneal pentobarbital injection. Muscle sampling was performed at the end of reperfusion. When rats were sacrificed, blood was sampled to measure hormone levels. The primary outcome was maximum left ventricular pressure derivative (LV dP/dt max) 15 min after reperfusion. ResultsLV dP/dt max at 10 and 15 min after reperfusion was significantly higher in the LF group than in the control group (P < 0.05), and the effect was diminished by H89. The PKA pathway was significantly activated in the LF group. Enteral lactoferrin increased serum GLP-1 but not serum adiponectin levels. ConclusionsEnteral lactoferrin induces cardioprotective effects against myocardial IR injury via the PKA signaling pathway and increases serum GLP-1 levels.

Cardioprotective effects of enteral vs. parenteral lactoferrin administration on myocardial ischemia-reperfusion injury in a rat model of stunned myocardium

Background:Lactoferrin, an iron-binding glycoprotein, is known to have protective effects against intestinal and cerebral ischemia-reperfusion (IR) injuries; however, its cardioprotective effects against the stunned myocardium are unknown. This study aimed to test the hypothesis that lactoferrin has cardioprotective effects against stunned myocardium.Methods:Using isolated rat hearts (Langendorff system), we determined the effects of lactoferrin administered enterally and by direct cardiac perfusion. Rat hearts were perfused using the Langendorff system, and two experiments were performed. In experiment 1, the hearts were divided into the enteral lactoferrin (E-LF) 7.5 m, 15 m, 30 m, and 60 m groups, where lactoferrin (1000 mg/kg) was administered enterally 7.5, 15, 30, and 60 min, respectively, before perfusion; and a control group, where saline was administered 30 min before perfusion. In experiment 2, hearts were allocated to the perfusate lactoferrin (P-LF) 15 and 100 groups, where 15 mg/L and 100 mg/L lactoferrin were respectively added to the perfusate, and a control group. Each group was perfused for 20 min prior to 15 min of no-flow ischemia with pacing, followed by 20 min of reperfusion. The primary outcome was the maximum left ventricular derivative of pressure development (LV dP/dt max) 15 min after reperfusion. Myocardial phospho-protein kinase B (p-Akt) was assayed using western blotting.Results:The LV dP/dt max 15 min after reperfusion in the E-LF 15 and 30 m groups was significantly higher than that in the control group. However, the effects disappeared in the E-LF 60 m group. In the second experiment, there were no significant differences in LV dP/dt max. Myocardial p-Akt was not significantly activated in any lactoferrin group.Conclusion:Cardioprotection was observed 15–30 min after enteral lactoferrin but not by direct cardiac perfusion with lactoferrin. Myocardial p-Akt was not associated with the cardioprotective effect. The cardioprotective effect may be induced by enteral lactoferrin-induced substances.

Meta-Analysis of Enteral Lactoferrin Supplementation for Reducing the Risk of Preterm Infants Sepsis

Introduction: Severe COVID-19 in pregnancy is strongly associated with preterm infant late-onset sepsis (LOS), which is a major cause of morbidity and mortality in infants. Recently, Lactoferrin, an iron-binding protein significantly discovered in human colostrum, shows potential effect on reducing the risk of preterm infant LOS and mortality by its immunomodulatory properties. Therefore, this study aimed to evaluate the effect of Lactoferrin on reducing the risk of preterm LOS, necrotizing enterocolitis (NEC), and mortality in preterm infants. &#x0D; Methods: This study followed the guidelines provided by PRISMA. A literature search was conducted with PubMed, Cochrane Library, Google Scholar, and ScienceDirect. The combined effect of LOS, NEC and mortality incidence were presented as risk ratios (RR) with a 95% confidence interval (CI) using a random-effects model (REM) or fixed-effects model (FEM) forest plot. Furthermore, the heterogeneity level was checked by I2 and the p-value of the chi2 test.&#x0D; Results: The incidence of LOS was significantly higher in the control than lactoferrin supplementation group [RR=0.65, 95% CI (0.56,0.77), p&lt;0.00001, I2=56%]. However, there were no significant differences in NEC [RR=0.80, 95% CI (0.63,1.02), p=0.10, I2=39%] and mortality [RR=0.94, 95% CI (0.77,1.13), p=0.49, I2=39%], despite the trends are higher in the control group.&#x0D; Conclusion: This meta-analysis showed that enteral lactoferrin supplementation in preterm infants was associated with a significant reduction in LOS, but not NEC stage II or III and all-cause mortality.&#x0D; Registered Protocol: The protocol of this review was already registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the registration number CRD42021279189.

Lactoferrin impact on gut microbiota in preterm infants with late-onset sepsis or necrotising enterocolitis: the MAGPIE mechanisms of action study

Background Preterm infants have high rates of morbidity, especially from late-onset sepsis and necrotising enterocolitis. Lactoferrin is an anti-infective milk protein that may act through effects on gut bacteria, metabolites and epithelial cell function. The impact of supplemental lactoferrin in reducing late-onset sepsis was explored in the Enteral LactoFerrin In Neonates (ELFIN) trial. Objectives The Mechanisms Affecting the Gut of Preterm Infants in Enteral feeding (MAGPIE) study was nested within the ELFIN trial and aimed to determine the impact of lactoferrin on gut microbiota and bacterial function, and changes preceding disease onset. We aimed to explore impacts on the stool bacteria and faecal/urinary metabolome using gas and liquid chromatography–mass spectrometry, and explore immunohistological pathways in resected tissue. Methods Preterm infants from 12 NHS hospitals were enrolled in the study, and daily stool and urine samples were collected. Local sample collection data were combined with ELFIN trial data from the National Perinatal Epidemiology Unit, Oxford. The longitudinal impact of lactoferrin in healthy infants was determined, and samples that were collected before disease onset were matched with samples from healthy control infants. Established, quality-controlled 16S ribonucleic acid, gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry analyses were conducted. Validated databases and standardised workflows were used to identify bacteria and metabolites. Tissue samples from infants undergoing surgery and matched controls were analysed. Results We recruited 479 preterm infants (mean gestation of 28.4 ± 2.3 weeks) and collected &gt; 33,000 usable samples from 467 infants. 16S ribonucleic acid bacterial analysis was conducted on samples from 201 infants, of whom 20 had necrotising enterocolitis and 51 had late-onset sepsis, along with samples from healthy matched controls to explore longitudinal changes. The greatest change in relative bacterial abundance over time was observed in Staphylococcus, which decreased from 42% at aged 7–9 days to only 2% at aged 30–60 days (p &lt; 0.001). Small but significant differences in community composition were observed between samples in each ELFIN trial group (R 2 = 0.005; p = 0.04). Staphylococcus (p &lt; 0.01), Haemophilus (p &lt; 0.01) and Lactobacillus (p = 0.01) showed greater mean relative abundance in the placebo group than in the lactoferrin group. Gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry analyses showed that lactoferrin had limited impact on the metabolome. Liquid chromatography–mass spectrometry showed significant metabolite differences between necrotising enterocolitis or late-onset sepsis infants and healthy controls. The resected gut tissue analysis revealed 82 differentially expressed genes between healthy and necrotic tissue. Limitations Although we recruited a large number of infants, collecting daily samples from every infant is challenging, especially in the few days immediately preceding disease onset. Conclusion We conducted a large mechanistic study across multiple hospital sites and showed that, although lactoferrin significantly decreased the level of Staphylococcus and other key pathogens, the impact was smaller than those of other clinical variables. Immunohistochemistry identified multiple inflammatory pathways leading to necrotising enterocolitis and showed that the use of NHS pathology archive tissue is feasible in the context of a randomised controlled trial. Future work We observed significant changes in the stool and urinary metabolome in cases preceding late-onset sepsis or necrotising enterocolitis, which provide metabolic targets for a future mechanistic and biomarker study. Trial registration Current Controlled Trials ISRCTN12554594. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 14. See the NIHR Journals Library website for further project information.

ELFIN, the United Kingdom preterm lactoferrin trial: interpretation and future questions 1.

Results from previous studies have suggested that supplemental bovine lactoferrin (BLF) given to preterm infants (<32weeks gestation) reduces late-onset sepsis (LOS) and necrotising enterocolitis (NEC). The Enteral Lactoferrin in Neonates (ELFIN) study, performed in the UK, aimed to further address this issue with a well powered double-blind placebo controlled trial of >2200 preterm infants. The results from ELFIN did not demonstrate a reduction in LOS or NEC, or several other clinically important measures. Of the 1093 infants, 316 (29%) in the intervention group developed late-onset sepsis versus 334 (31%) of 1089 in the control group, with an adjusted risk ratio of 0.95 (95%CI = 0.86-1.04; p= 0.233). Reasons for the differences in ELFIN trial results and other studies may include population differences, the routine use of antifungal prophylaxis in the UK, timing of administration of the lactoferrin in relation to disease onset, or specific properties of the lactoferrin used in the different trials. The UK National Institutes for Health Research funded "Mechanisms Affecting the Guts of Preterm Infants in Enteral feeding trials" (MAGPIE) study is further exploring the use of lactoferrin, and the results should be available soon.

Enteral Lactoferrin Supplementation for Preventing Sepsis and Necrotizing Enterocolitis in Preterm Infants: A Meta‑Analysis With Trial Sequential Analysis of Randomized Controlled Trials.

BackgroundSeveral clinical trials investigated the effects of enteral lactoferrin supplementation on the prevention of sepsis and necrotizing enterocolitis (NEC) in preterm infants, but the efficacy and safety remain disputed. Therefore, we systematically evaluated the effect of enteral lactoferrin supplementation in preterm infants through a meta‑analysis with trial sequential analysis (TSA).MethodsWe searched six databases to identify randomized controlled trials (RCTs) that evaluated the effects of lactoferrin supplementation compared with placebo or no intervention in preterm infants. RevMan version 5.3 software was used to estimate pooled relative risks (RRs) with the random-effects model. TSA, subgroup analyses, and meta-regression analyses were also performed.ResultsNine RCTs with 3515 samples were included. With low to moderate quality of evidence, compared with placebo, enteral lactoferrin supplementation did not significantly decrease the incidences of late-onset sepsis (RR = 0.63, 95% CI: 0.38 to 1.02, P = 0.06), NEC stage II or III (RR = 0.68, 95% CI: 0.30 to 1.52, P = 0.35), all-cause mortality (RR = 0.89, 95% CI: 0.51 to 1.57, P = 0.69), bronchopulmonary dysplasia (RR = 1.01, 95% CI: 0.90 to 1.13, P = 0.92), retinopathy of prematurity (RR = 0.80, 95% CI: 0.49 to 1.32, P = 0.38), invasive fungal infection (RR = 0.27, 95% CI: 0.02 to 3.94, P = 0.34), intraventricular hemorrhage (RR = 1.40, 95% CI: 0.39 to 5.08, P = 0.61), and urinary tract infection (RR = 0.35, 95% CI: 0.11 to 1.06, P = 0.06). Subgroup analysis revealed that lactoferrin significantly reduced the incidence of sepsis in infants with a birth weight below 1500 g (RR = 0.43, 95% CI: 0.22 to 0.84, P = 0.01). TSAs of the primary outcomes showed that the evidence is insufficient and further data is required.ConclusionsLimited evidence suggested that enteral lactoferrin supplementation was associated with a reduction of late-onset sepsis in infants with a birth weight below 1500g, however, did not decrease the incidence of NEC stage II or III, all-cause mortality, and other adverse events in preterm infants. The present evidence was insufficient to inform clinical practice.

Evidence from systematic reviews of randomized trials on enteral lactoferrin supplementation in preterm neonates.

In this commentary, we summarize the current evidence from randomized controlled trials on enteral lactoferrin supplementation in preterm neonates. Our recently completed systematic review includes 12 randomized controlled trials performed all over the world. Our meta-analysis suggests clinical benefit in decreasing late-onset sepsis, late-onset fungal sepsis, length of stay in the hospital and urinary tract infections. There were no adverse effects. There was no statistically significant decrease in necrotizing enterocolitis, mortality or neurodevelopmental impairment in lactoferrin supplemented preterm infants. There was significant statistical heterogeneity in the effects of lactoferrin on late-onset sepsis between larger and smaller studies, which may reflect either small study biases, differences in the effectiveness, dose or duration of supplemental lactoferrin products, or differences in underlying population risk, or any or all of these.

Does enteral lactoferrin supplementation prevent sepsis and necrotizing enterocolitis in preterm infants?

Does enteral lactoferrin supplementation prevent sepsis and necrotizing enterocolitis in preterm infants?

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

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

Clinical Trials of Lactoferrin in the Newborn: Effects on Infection and the Gut Microbiome.

Newborn infants, especially those born preterm, are at risk of infections in early life. In preterm infants, necrotizing enterocolitis (NEC), a devastating inflammatory gut condition, and late-onset sepsis (LOS) are important causes of serious morbidity and are the commonest reasons for death after the first week of life. Fresh breast milk from the infant's mother reduces the risks of these serious pathologies in a dose-dependent fashion. Considerable effort has been expended to better understand which specific components of human milk are likely to exert the greatest functional benefits, particularly those that have immune modulatory or anti-infectious properties. Lactoferrin is a whey glycoprotein present in especially high concentrations in colostrum and early milk. Studies show that lactoferrin impacts on immune function and, through a multitude of mechanisms, reduces the risk of viral, fungal, and bacterial infections. Supplemental enteral bovine lactoferrin has been tested in a series of randomized clinical trials, many of which suggested important reductions in LOS in preterm or low-birth-weight infants. However, the largest trial to date - the Enteral Lactoferrin in Neonates (ELFIN) trial - recruited 2,203 infants and failed to show any significant reductions in LOS or NEC. Challenges in conducting clinical research and the translational relevance of these studies for clinical practice will be considered.

Enteral lactoferrin does not reduce late-onset infection in very preterm infants.

Late-onset sepsis is a major cause of morbidity and mortality in neonates, but predominantly in preterm infants. In survivors, it can prolong length of hospital stay, worsen long-term neurodevelopmental outcomes and increase the associated social burden of disease.1 Lactoferrin, a mammalian iron-binding whey glycoprotein with important bacteriostatic and anti-inflammatory properties, plays a role in promoting growth of probiotic bacteria in the gut.2 A recent Cochrane review suggested reductions in both sepsis and necrotizing enterocolitis with oral lactoferrin supplementation.3 Many of these studies enrolled small numbers and had limitations in study design and implementation. The ELFIN randomised, placebo-controlled trial is the largest trial of this intervention. A major strength lies in the large number (>2000) of participating babies with more than 99% of outcome data being available. Important consideration was given to limit bias for the study; randomisation was successful in balancing baseline demographic and prognostic characteristics. Measures were put in place to define the spectrum of late-onset infection in order to reduce potential sources of bias. This is in contrast to most previous studies, in which only culture-proven late-onset sepsis was used as a marker.4 This does not necessarily completely rule out bias. The primary outcome used encompasses both microbiologically confirmed and clinically suspected late-onset infection, from trial entry until hospital discharge. Although these results were confirmed, using pre-defined criteria, by masked central end-point review committees, clinically suspected late-onset infection remains a subjective outcome. As it accounts for more than 40% of the cases in this study, this might be considered a confounding factor. Based on the GRADE system (grading of recommendation, assessment, development and evaluation), due to the relative imprecision of the primary outcome and inconsistency of the main result, lactoferrin is not recommended as a routine intervention to prevent late-onset sepsis in very preterm infants. Although other trials of lactoferrin are ongoing (Mooselmokadem trial; NCT01821989, estimated n = 180), NEOLACTO (NCT01525316, n = 414) and LIFT (ACTRN12611000247976, target sample size of 1500), it would be difficult to anticipate that these would bring about a change in the grade of recommendation, unless a substantial positive effect were seen in the largest of these trials. Although the risk of adverse outcomes in more mature preterm infants is generally lower, the effect size, favouring lactoferrin, was larger in this study in infants born at 30 or more weeks of gestation. Although not statistically significant, this finding may be clinically relevant. Lactoferrin promotes growth of probiotic bacteria, so this finding begs the question of whether this effect could be related to lower rates of exclusive breastmilk feeding and more restricted use of broad-spectrum antibiotics in larger infants. Evidently, there is still a need for novel research into the use of alternative interventions as adjuvants in preventing late-onset sepsis, and reducing mortality and morbidity in the very preterm population. Is there, for example, a need for further large scale studies to look at the effectiveness of using lactoferrin in combination with probiotic therapy or other interventions designed to decrease infection risk?5 https://ebneo.org/2019/11/enteral-lactoferrin-late-onset-infection/ None.

Is Lactoferrin More Effective in Reducing Late-Onset Sepsis in Preterm Neonates Fed Formula Than in Those Receiving Mother's Own Milk? Secondary Analyses of Two Multicenter Randomized Controlled Trials.

Lactoferrin is the major antimicrobial protein in human milk. In our randomized controlled trial (RCT) of bovine lactoferrin (BLF) supplementation in preterm neonates, BLF reduced late-onset sepsis (LOS). Mother's own milk (MM) contains higher concentrations of lactoferrin than donor milk or formula, but whether BLF is more effective in infants who receive formula or donor milk is uncertain. To evaluate the incidence of LOS in preterm infants fed MM and in those fed formula and/or donor milk. This is a (A) post hoc subgroup analysis, in our RCT of BLF, of its effects in preterm infants fed MM, with or without formula, versus those fed formula and/or donor milk (no-MM) and (B) post hoc meta-analysis, in our RCT of BLF and in the ELFIN (Enteral Lactoferrin in Neonates) RCT, of the effect of BLF in subgroups not exclusively fed MM. (A) Of 472 infants in our RCT, 168 were randomized to placebo and 304 were randomized to BLF. Among MM infants, LOS occurred in 22/133 (16.5%) infants randomized to placebo and in 14/250 (5.6%) randomized to BLF (relative risk or risk ratio (RR): 0.34; relative risk reduction (RRR): 0.66; 95% confidence interval (95% CI) for RR: 0.18-0.64; p < 0.0008). Among no-MM infants, LOS occurred in 7/35 (20.0%) randomized to placebo and in 2/54 (3.7%) randomized to BLF (RR: 0.19; RRR: 0.81; 95% CI for RR: 0.16-0.96; p = 0.026). In multivariable logistic regression analysis, there was no interaction between BLF treatment effect and type of feeding (p = 0.628). (B) In 1,891 infants not exclusively fed MM in our RCT of BLF and in the ELFIN RCT, BLF reduced the RR of LOS by 18% (RR: 0.82; 95% CI: 0.71-0.96; p = 0.01). Adequately powered studies should address the hypothesis that BLF is more effective in infants fed formula or donor milk than those fed MM. Such studies should evaluate whether a specific threshold of total lactoferrin intake can be identified to protect such patients from LOS.

Enteral lactoferrin for the treatment of sepsis and necrotizing enterocolitis in neonates.

Neonatal sepsis and necrotizing enterocolitis (NEC) cause significant neonatal mortality and morbidity despite appropriate antibiotic therapy. Enhancing host defense and modulating inflammation by using lactoferrin as an adjunct to antibiotics in the treatment of sepsis, NEC, or both, may improve clinical outcomes. The primary objective was to assess safety and efficacy of oral lactoferrin as an adjunct to antibiotics in the treatment of neonates with suspected or confirmed sepsis, NEC, or both. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 9), MEDLINE via PubMed, PREMEDLINE, (1966 to 20 September 2018) Embase (1980 to 20 September 2018), and CINAHL (1982 to 20 September 2018). We also searched clinical trial databases, conference proceedings, the reference lists of retried articles and clinical trials, and the authors' personal files. We included randomized or quasi-randomized controlled trials evaluating enteral 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). We used the standardized methods of Cochrane Neonatal for conducting a systematic review and for assessing the methodological quality of studies (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 versions were obtained for assessment if necessary. Forms were designed to record trial inclusion/exclusion and data extraction. We used the GRADE approach to assess the quality of evidence. We did not identify any eligible trials evaluating lactoferrin for the treatment of neonatal sepsis or NEC. Implications for practice: currently there is no evidence to support or refute the use of enteral lactoferrin, as an adjunct to antibiotic therapy, for the treatment of neonatal sepsis or necrotizing enterocolitis. given the lack of efficacy of enteral lactoferrin for preventing late-onset sepsis and necrotizing enterocolitis, evaluation of enteral lactoferrin as an adjunctive agent for treatment of sepsis or necrotizing enterocolitis does not appear to be a research priority.

Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial

SummaryBackgroundInfections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice.MethodsIn this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002.FindingsWe recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86–1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention.InterpretationEnteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants.FundingUK National Institute for Health Research Health Technology Assessment programme (10/57/49).

Enteral lactoferrin to prevent infection for very preterm infants: the ELFIN RCT.

Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. To determine whether or not enteral supplementation with bovine lactoferrin (The Tatua Cooperative Dairy Company Ltd, Morrinsville, New Zealand) reduces the risk of late-onset infection (acquired > 72 hours after birth) and other morbidity and mortality in very preterm infants. Randomised, placebo-controlled, parallel-group trial. Randomisation was via a web-based portal and used an algorithm that minimised for recruitment site, weeks of gestation, sex and single versus multiple births. UK neonatal units between May 2014 and September 2017. Infants born at < 32 weeks' gestation and aged < 72 hours at trial enrolment. Eligible infants were allocated individually (1 : 1 ratio) to receive enteral bovine lactoferrin (150 mg/kg/day; maximum 300 mg/day) or sucrose (British Sugar, Peterborough, UK) placebo (same dose) once daily from trial entry until a postmenstrual age of 34 weeks. Parents, caregivers and outcome assessors were unaware of group assignment. Primary outcome - microbiologically confirmed or clinically suspected late-onset infection. Secondary outcomes - microbiologically confirmed infection; all-cause mortality; severe necrotising enterocolitis (NEC); retinopathy of prematurity (ROP); bronchopulmonary dysplasia (BPD); a composite of infection, NEC, ROP, BPD and mortality; days of receipt of antimicrobials until 34 weeks' postmenstrual age; length of stay in hospital; and length of stay in intensive care, high-dependency and special-care settings. Of 2203 enrolled infants, primary outcome data were available for 2182 infants (99%). In the intervention group, 316 out of 1093 (28.9%) infants acquired a late-onset infection versus 334 out of 1089 (30.7%) infants in the control group [adjusted risk ratio (RR) 0.95, 95% confidence interval (CI) 0.86 to 1.04]. There were no significant differences in any secondary outcomes: microbiologically confirmed infection (RR 1.05, 99% CI 0.87 to 1.26), mortality (RR 1.05, 99% CI 0.66 to 1.68), NEC (RR 1.13, 99% CI 0.68 to 1.89), ROP (RR 0.89, 99% CI 0.62 to 1.28), BPD (RR 1.01, 99% CI 0.90 to 1.13), or a composite of infection, NEC, ROP, BPD and mortality (RR 1.01, 99% CI 0.94 to 1.08). There were no differences in the number of days of receipt of antimicrobials, length of stay in hospital, or length of stay in intensive care, high-dependency or special-care settings. There were 16 reports of serious adverse events for infants in the lactoferrin group and 10 for infants in the sucrose group. Enteral supplementation with bovine lactoferrin does not reduce the incidence of infection, mortality or other morbidity in very preterm infants. Increase the precision of the estimates of effect on rarer secondary outcomes by combining the data in a meta-analysis with data from other trials. A mechanistic study is being conducted in a subgroup of trial participants to explore whether or not lactoferrin supplementation affects the intestinal microbiome and metabolite profile of very preterm infants. Current Controlled Trials ISRCTN88261002. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 74. See the NIHR Journals Library website for further project information. This trial was also sponsored by the University of Oxford, Oxford, UK. The funder provided advice and support and monitored study progress but did not have a role in study design or data collection, analysis and interpretation.

Summary Protocol for a Multi-Centre Randomised Controlled Trial of Enteral Lactoferrin Supplementation in Newborn Very Preterm Infants (ELFIN)

In a multi-centre randomised controlled trial (RCT), we are assessing whether giving very preterm (i.e., born at < 32 weeks’ gestation) infants prophylactic enteral bovine lactoferrin supplementation (150 mg/kg/day) from shortly after birth until 34 weeks’ post-menstrual age reduces the incidence of late-onset invasive infection (primary outcome), all-cause mortality, bronchopulmonary dysplasia, necrotising enterocolitis, retinopathy of prematurity, and the duration of antibiotic exposure, intensive care, and hospital admission. The trial is recruiting 2,200 participants from 37 neonatal care centres in the UK over 4 years. We will undertake an economic evaluation within the RCT to evaluate cost-effectiveness and provide an estimate of incremental costs for differences in the pre-specified outcomes in primary and subgroup analyses. If a statistically significant and clinically important effect on the primary outcome is detected, we will seek further funding and approval to assess the impact of enteral lactoferrin supplementation on rates of adverse neuro-developmental outcomes in the participating infants when they are 5 years old.

Enteral Lactoferrin Supplementation for Very Preterm Infants: A Randomised Controlled Trial

Background: Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein usually processed from cow's milk, prevents infections and associated complications. Methods: In this randomised, placebo-controlled trial, very preterm infants (born before 32 weeks' gestation) were recruited within 72 hours of birth from 37 UK hospitals. Infants were allocated randomly (1:1) to receive enteral bovine lactoferrin (150 mg/kg/day; maximum 300 mg/day) versus sucrose (same dose) once daily until 34 weeks' postmenstrual age. Web-based randomisation used an algorithm minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers and outcomes assessors were unaware of group assignment. The primary outcome was microbiologically-confirmed or clinically-suspected late-onset infection until hospital discharge. The trial was registered with the International Standard Randomised Controlled Trial Number 88261002. Findings: We recruited 2203 participants between May 2014 and September 2017. Four infants had consent withdrawn or unconfirmed leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants were available for inclusion in the intention-to-treat analyses. In the intervention group, 316/1093 (28.9%) infants acquired a late-onset infection versus 334/1089 (30.7%) in the control group: risk ratio (RR) adjusted for minimisation factors 0.95 (95% confidence interval [CI] 0.81, 1.10). Pre-specified subgroup analyses did not show statistically significant interactions for gestation at birth (completed weeks') or type of enteral milk received (human, formula, or both). Interpretation: Enteral supplementation with bovine lactoferrin does not reduce the incidence of late-onset infection in very preterm infants. Trial Registration Number: The trial was registered with the International Standard Randomised Controlled Trial Number 88261002. Funding: The ELFIN trial was funded by the UK National Institute for Health Research Health Technology Assessment programme (10/57/49). Declaration of Interest: EJ is a member of the NIHR HTA General Board; WM is a member of the NIHR HTA Commissioning Board and the HTA Journals Library Editorial Board. JD is a member of the NIHR HTA Clinical Evaluation and Trials Board. PTH, WM, EJ, LL report receipt of funding from NIHR, outside the submitted work. NDE reports grants from Prolacta Biosciences US, grants from Danone Early Life Nutrition, personal fees from Nestle Nutrition Institute, and personal fees from Baxter, outside the submitted work. Ethical Approval: The trial protocol was approved by the National Research Ethics Service (NRES) Committee East Midlands - Nottingham 2 (Ref: 13/EM/0118). Local approval and site-specific assessments were obtained from the NHS Trusts for trial sites.

Effect of Enteral Lactoferrin Administration on Iron Status in Neonates

Effect of Enteral Lactoferrin Administration on Iron Status in Neonates

Effect of Enteral Lactoferrin Administration on Invasive Fungal Infections in Preterm Neonates

Effect of Enteral Lactoferrin Administration on Invasive Fungal Infections in Preterm Neonates

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

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. 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. Randomized controlled trials (RCTs) evaluating oral lactoferrin at any dose or duration to prevent sepsis or NEC in preterm neonates. Review authors used standard methods of the CNRG. 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. 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.