Lactoferrin Supplementation Research Articles

Effects of dietary supplementation of bovine lactoferrin on antioxidant status, immune response and disease resistance of yellowfin sea bream (Acanthopagrus latus) against Vibrio harveyi

This study investigated the effect of the dietary supplementation of bovine lactoferrin (LF) on growth performance, hematological and immunological parameters, antioxidant enzymes activity and disease resistance against Vibrio harveyi in yellowfin sea bream (Acanthopagrus latus) fingerling. The fish with initial body weight 10 ± 0.3 g were randomly distributed at 10 fish per each 250 L fiberglass tank, and fed with four experimental diets (a control basal diet and three supplemented diets with 400, 800 and 1200 mg LF kg−1 diet) for 8 weeks. The obtained results showed that fish fed with LF supplemented diets had significantly higher final body weight as compared to control diet (P < 0.05). There were no significant differences between LF-treatments and the control group in white blood cell counts, red blood cell counts, hemoglobin and hematocrit. Total protein and complement activity (ACH50) in the serum of yellowfin sea bream were enhanced with increasing the dietary LF supplementation level (P < 0.05). The mucus lysozyme activity in fish fed on 800 and 1200 mg LF kg−1 was significantly higher than those fed on 400 mg LF kg−1 and control fish (P < 0.05). None of the antioxidant enzymes (catalase, glutathione reductase, glutathione S-transferase) was affected by LF supplementation (P > 0.05). Fish fed with dietary LF had a significantly higher survival rate than those fed with the control diet after challenge with Vibrio harveyi (P < 0.05). These results revealed that diet supplementation in A. latus especially with 1200 mg LF kg−1 improve fish growth performance and immune parameters, as well as survival rate against Vibrio harveyi.

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.

Effect of Lactoferrin Supplementation on Iron Deficiency Anemia in Primary School Children

Background: many other studies were done to evaluate the effect of oral lactoferrin administration on iron deficiency anemia.Objective: This study was designed to assess the effects of lactoferrin supplementation on primary school children having iron deficiency anemia. Patients and Methods: Prospective cohort study was conducted on 94 patients with iron deficiency anemia. They were 58 females and 36 males. Their ages range from 6 years to 12 years with mean age of 8.4 years. In the period between October 2018 and January 2019. Each child was submitted to full history taking, complete clinical examination and laboratory investigations including complete blood count, Serum ferritin, serum iron and total iron binding capacity.Results: oral administration of bovine lactoferrin (BLf) significantly increases the number of red blood cells, hemoglobin, serum ferritin and total iron after thirty days of the treatment. BLf is a more effective and safe alternative than elemental iron for treating iron deficiency and iron deficiency anemia.Conclusion: lactoferrin is a better substitute for elementary iron in treatment of iron deficiency.

The impact of probiotics and lactoferrin supplementation on piglet gastrointestinal microbial communities.

Probiotics and lactoferrin are currently being used in neonatal intensive care units in the hopes of reducing rates of sepsis and necrotizing enterocolitis (NEC). While studies have shown that these measures can be clinically beneficial to premature babies, and there are ongoing trials to measure their impact on NEC and sepsis rates, little is known about how they may impact microbiota development. We thus employed a newborn piglet model to assess the impact of feeding probiotics or a combination of probiotics and lactoferrin on development of the gastrointestinal microbiota. Healthy full-term piglets were fed either probiotics alone or probiotics and a bovine lactoferrin supplement over the first weeks of life, and their microbiota profiles were compared with unsupplemented controls. We found that both probiotic and probiotic plus lactoferrin treatments impacted the microbial composition within the gastrointestinal tract, with differing impacts on various regions within the gut. In addition, the impact of probiotics was often reversed by the presence of lactoferrin and both feeding interventions altered the microbiota's genetic propensity to use ferric versus ferrous ions. These results suggest that iron availability may be a key factor to consider when designing feeding interventions that target the microbiome.

A study on efficacy of oral administration of colostrum fortified lactoferrin in the weight gain of low birth weight infants

Background: Low birth weight babies is the result of being small for gestational age (i.e. under 10th percentile of the reference population) and preterm (i.e. before 37 weeks of gestation. Preterm infants have higher protein, calorie requirement, which cannot be met with unfortified breast milk feeds.Methods: This study was conducted prospectively in the Department of Pediatrics, Rajah Muthiah Medical College and Hospital, Chidambaram from October 2016 to April 2018. 20 low birth weight babies were selected by randomization technique and they were administered with 2 grams of oral colostrum fortified lactoferrin daily for 4 weeks. The rate of weight gain, length gain and head circumference gain were assessed prospectively for a period of 4 weeks. They were analysed statistically by ANOVA and tabulated. Babies weighing less than 2.5 kg and on exclusive breast feeding, were included. Babies more than 2.5kg and less than 1kg, at risk for neonatal sepsis, congenital heart disease, necrotizing enterocolitis were excluded from the study.Results: In the present study, 20 low birth weight babies were included. 11 maternal risk factors were identified. Out of which anemia stands as a single risk factor. The rate of weight gain in oral colostrum fortified lactoferrin, is 320 grams with P value of 0.703 which is not statistically significant. The rate of length gain is 3.3cm, p value is 0.093 which is statistically insignificant. The rate of head circumference gain in oral colostrum fortified lactoferrin is 2.8cm, with the p-value of 0.001 which is statistically significant.Conclusions: The rate of weight and length gain was normal, but the rate of head circumference gain is significantly increased in oral colostrum fortified lactoferrin supplementation.

Lactoferrin stimulates the expression of vitamin D receptor in vitamin D deficient mice

Abstract Vitamin D deficiency, a growing public health problem, is associated with elevated serum pro-inflammatory cytokines and gut microbial dysbiosis. Lactoferrin (LF), a strongly cationic glycoprotein, is an multifunctional components of milk. We explored the effects of oral administratation with LF (100 mg/kg and 1000 mg/kg) on intestine of vitamin D deficient mice. Our results showed that LF reduced the abundance of Oscillibacter, increased the proportion of Lachnospiraceae, Faecalibaculum and Lactobacillus. In addition, LF alleviated the elevated serum LBP, TNF-α, IL-6 and TGF-β induced by vitamin D deficiency. Notably, we found the expression of vitamin D receptor significantly increased after LF supplement in colon of vitamin D deficient mice. At the same time, LF reduced the expression of TLR-4, inhibited the activity of NF-κB P65 and enhanced the expression of intestinal barrier proteins, including ZO-1, occludin, claudin-1 as well as E-cadherin in the colon of vitamin D deficient mice.

Nutritional Intervention for Developmental Brain Damage: Effects of Lactoferrin Supplementation in Hypocaloric Induced Intrauterine Growth Restriction Rat Pups.

Introduction: Intrauterine Growth Restriction (IUGR) refers to an impaired development of the fetus and hence results in adverse neurodevelopmental and psychiatric consequences later in life. Lactoferrin (Lf) is a glycoprotein present in milk that has already shown neuroprotective effects through its anti-inflammatory and antioxidant properties on impaired developing brains. The aim of this study was to characterize a rat model of IUGR and assess the neuroprotective effect of a nutritional supplementation with bovine Lf during pregnancy and lactation on this model.Methods: A model of 50% gestational caloric restriction (CR) was used. Three groups were designed, and pregnant rats had either ad libitum access to food (control group, CTL) or 50% of the controls' intake (restricted group, IUGR). The diet was isocaloric and supplemented with bovine Lf for the caloric restricted dams (restricted-Lf, IUGR_Lf). At postnatal day 7 and 21, advanced ex-vivo diffusion MRI techniques at 9.4T were used to investigate brain cortical and white matter microstructure. Further, genes and proteins involved in structure (synaptophysin, MBP), microglia (Iba-1), metabolism (MCT2, βCaMKII) and apoptosis (Bcl-2) were analyzed in the cortex and striatum. In the cortex, the number of parvalbumin immunoreactive interneurons and their perineuronal nets were quantified. Behavioral tests were performed at P31.Results: Effects of the CR were significant in the cortex and striatum with reduction of synaptophysin (marker of synaptogenesis) at P7 and MBP (marker of myelin) at P21 in the cortex. Indeed, MCT2 (energy metabolism), Bcl-2 (anti-apoptotic protein) and βCaMKII (synapse activity) expressions were reduced in IUGR groups at P7. In the striatum NG2 (marker of oligodendrocyte precursor cells) and Bcl-2 at P7 as well as βCaMKII at P21 were decreased following IUGR and restored by Lf. Cortical microstructure was impaired following CR with partial effect of Lf. Lf prevented oxidative stress induced parvalbumin interneurons impairments whereas striatum and external capsule showed alterations in microstructure depicted by diffusion MRI, which were also partially reversed by Lf.Discussion and Conclusion: The model of 50% caloric restriction induced mild impairment partially reversed by nutritional intervention using Lf during pregnancy and lactation.

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).

Supplementing 2 g per day bovine lactoferrin from late gestation until weaning did not improve lactation performance of mixed parity sows

Context Lactoferrin is a non-haem binding protein that possesses antimicrobial, antioxidant and anti-inflammatory properties. A previous study showed lactoferrin supplementation from early gestation to weaning improved lactation performance in primiparous sows; however, it is unknown whether the supplementation within a more specified duration (from late gestation to weaning) can improve lactation performance in multiparous sows, which limits its commercial application. Aims This experiment investigated the effects of 2 g/day bovine lactoferrin supplementation from late gestation to weaning on lactation performance in mixed parity sows. Methods Forty-seven primiparous sows and 167 multiparous sows (up to parity 5; Large White × Landrace, PrimeGro Genetics, Corowa, NSW) were allocated to either a Control diet (2 g/day casein) or Lactoferrin supplement diet (2 g/day lactoferrin) when entering the farrowing house in late gestation (101 ± 4.6 days, mean ± s.d.) balanced by parity (2.4 ± 1.80, mean ± s.d.). Sows were housed individually in farrowing crates and fed the experimental diets until weaning (26 ± 2.5 days, mean ± s.d.). Farrowing outcomes and lactation performance were recorded. Key results Lactoferrin supplementation did not affect the number of piglets born alive, number of stillborn piglets, number of mummified fetuses, the percentage of born-light piglets (≤1.1 kg) or piglet pre-fostering survival rate. Cross-fostering within the first 48 h standardised the litter size and litter weight between dietary treatments. Piglet pre-weaning survival rate, litter weight gain, average daily gain of piglets, or coefficient of variation of piglet growth rate was not affected by lactoferrin supplementation. Daily feed intake during lactation, bodyweight and backfat thickness of sows at weaning were similar between the dietary treatments. Conclusions Two grams per day lactoferrin supplementation from late gestation to weaning did not affect lactation performance in mixed parity sows. Implications The effectiveness of lactoferrin supplementation may depend upon the duration of supplementation, which should be optimised in future studies.

A pilot study on serum lactoferrin in patients with mild versus severe acne in correlation with disease duration

Background Acne vulgaris (AV) is a chronic inflammatory disease of the pilosebaceous units. Lactoferrin (LF) is an iron-binding glycoprotein, which is known to have a role in decreasing inflammation and microbial infection. A few studies have reported that many of the patients with acne had acceptable therapeutic response to LF supplementation. However, no studies have directly assessed serum LF level in patients with acne. Objective To evaluate serum LF level in patients with severe versus mild acne in comparison with healthy controls. Patients and methods Serum LF was assessed using enzyme-linked immunosorbent assay in 40 AV patients comprising two subgroups; 20 mild and 20 severe cases, versus 20 healthy controls. Levels were correlated with disease duration. Results Mean serum LF levels were significantly higher in patients with AV than in healthy controls (P Conclusion Serum LF is directly related to acne severity, being elevated in severe rather than mild cases. Therefore, it could be of prognostic value. Serum LF level is higher in acute stages rather than chronic cases, denoting its possible role as a compensatory acute-phase reactant, to overcome the detrimental effects of acute inflammation.

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.

Lactoferrin: A Critical Player in Neonatal Host Defense.

Newborn infants are at a high risk for infection due to an under-developed immune system, and human milk has been shown to exhibit substantial anti-infective properties that serve to bolster neonatal defenses against multiple infections. Lactoferrin is the dominant whey protein in human milk and has been demonstrated to perform a wide array of antimicrobial and immunomodulatory functions and play a critical role in protecting the newborn infant from infection. This review summarizes data describing the structure and important functions performed by lactoferrin in protecting the neonate from infection and contributing to the maturation of the newborn innate and adaptive immune systems. We also briefly discuss clinical trials examining the utility of lactoferrin supplementation in the prevention of sepsis and necrotizing enterocolitis in newborn infants. The data reviewed provide rationale for the continuation of studies to examine the effects of lactoferrin administration on the prevention of sepsis in the neonate.

Bioavailability of a Novel Form of Microencapsulated Bovine Lactoferrin and Its Effect on Inflammatory Markers and the Gut Microbiome: A Pilot Study.

Bovine lactoferrin, extracted from milk or whey, is used in a range of products to enhance immunity and support digestive health, iron absorption, and homeostasis. This study examined the absorption and effect of Progel (Brisbane, Queensland, Australia) microencapsulated bovine lactoferrin (InferrinTM, Bega Bionutrients, Victoria, Australia) on immune markers and the microbiome. A double-blind randomised, cross-over trial was conducted with 12 healthy males randomised to one of two doses, equivalent to 200 mg or 600 mg lactoferrin, for two four-week supplementation arms, with a two-week washout period. Subjects received either standard bovine lactoferrin or InferrinTM for each arm. Baseline and post each trial arm, CD69+ activation on CD4+ and CD8+ cells was analysed, bovine and human lactoferrin contents of faecal and serum samples were reported, and the gut microbiome was analysed using 16S sequencing and metagenomic sequencing. The mean level of CD69+ activation on the CD4+ cells was lower after supplementation regardless of the form or dose of lactoferrin. This was statistically significant for the 200 mg dose. A higher level of bovine lactoferrin was found post-supplementation in those taking InferrinTM, although this was not statistically significant. Changes in phylum-level microbial community profiling were detected post-supplementation in the second trial arm, particularly in those receiving InferrinTM. Metagenomic sequencing showed changes in the volumes of the top 100 species of bacteria present before and after all treatment arms. Results suggest that lactoferrin supplementation may have beneficial effects on the microbiome and immune system, and that the use of InferrinTM improves absorption. Larger detailed studies are needed to ascertain the potential positive effects of bovine lactoferrin supplementation.

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.

Effect of enteral bovine lactoferrin on neonatal iron status

Background All infants experience a decrease in hemoglobin (Hb) soon after birth, which results in varying degrees of anemia. Oral bovine lactoferrin (LF) supplementation, an iron-binding glycoprotein, is a promising therapy for iron-deficiency anemia. Objectives To evaluate the effect of enteral LF supplementation on the levels of Hb, hematocrit, and serum ferritin in infants admitted in the neonatal intensive care units. This was an interventional double-blind trial conducted on 52 neonates who were randomized into LF group (n=26) and placebo group (n=26). LF was administered at a dose of 100 mg/day once by enteral route starting from birth to 30th day of life. Complete blood count and serum ferritin were assessed in patients at 7th and 30th day of life. Results There were no significant differences between both the studied groups as regards serum ferritin, Hb, hematocrit, mean corpuscular volume, red cell distribution width, platelet count, and total leukocytic count on day 7. There were statistically significant higher serum ferritin, Hb, hematocrit, and mean corpuscular volume, and lower red cell distribution width and total leukocytic count in the LF group than the placebo group on day 30. The placebo group had significantly higher mortality than LF group (19.2% vs. zero; P=0.051). Conclusion Bovine LF is an effective and safe therapy to prevent anemia in neonates.

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.

Exposure to Gastric Acid Inhibitors Increases the Risk of Infection in Preterm Very Low Birth Weight Infants but Concomitant Administration of Lactoferrin Counteracts This Effect

To investigate whether exposure to inhibitors of gastric acidity, such as H2 blockers or proton pump inhibitors, can independently increase the risk of infections in very low birth weight (VLBW) preterm infants in the neonatal intensive care unit. This is a secondary analysis of prospectively collected data from a multicenter, randomized controlled trial of bovine lactoferrin (BLF) supplementation (with or without the probiotic Lactobacillus rhamnosus GG) vs placebo in prevention of late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in preterm infants. Inhibitors of gastric acidity were used at the recommended dosages/schedules based on the clinical judgment of attending physicians. The distribution of days of inhibitors of gastric acidity exposure between infants with and without LOS/NEC was assessed. The mutually adjusted effects of birth weight, gestational age, duration of inhibitors of gastric acidity treatment, and exposure to BLF were controlled through multivariable logistic regression. Interaction between inhibitors of gastric acidity and BLF was tested; the effects of any day of inhibitors of gastric acidity exposure were then computed for BLF-treated vs -untreated infants. Two hundred thirty-five of 743 infants underwent treatment with inhibitors of gastric acidity, and 86 LOS episodes occurred. After multivariate analysis, exposure to inhibitors of gastric acidity remained significantly and independently associated with LOS (OR, 1.03; 95% CI, 1.008-1.067; P = .01); each day of inhibitors of gastric acidity exposure conferred an additional 3.7% odds of developing LOS. Risk was significant for Gram-negative (P < .001) and fungal (P = .001) pathogens, but not for Gram-positive pathogens (P = .97). On the test for interaction, 1 additional day of exposure to inhibitors of gastric acidity conferred an additional 7.7% risk for LOS (P = .003) in BLF-untreated infants, compared with 1.2% (P = .58) in BLF-treated infants. Exposure to inhibitors of gastric acidity is significantly associated with the occurrence of LOS in preterm VLBW infants. Concomitant administration of BLF counteracts this selective disadvantage. isrctn.org: ISRCTN53107700.

Growth Performance, Hemato-Immunological Responses, and Digestive Enzyme Activities in Silvery-Black Porgy (Sparidentex hasta) Fed Dietary Bovine Lactoferrin.

An 8-week study was conducted to evaluate three different diets supplemented with bovine lactoferrin (LF) at 0 (control), 800, and 1200mg LFkg-1 diet on somatic growth, hemato-immunological parameters, antioxidant status, and digestive enzyme activities in silvery-black porgy (Sparidentex hasta) juveniles. Fish fed the 800mg LFkg-1 diet had higher growth performance and feed utilization parameters than the other groups. Hematological and liver antioxidant parameters were not affected by dietary LF supplementation. Fish fed the 800mg LFkg-1 diet had higher plasma lysozyme activity values than the other groups. Total protease activity was higher in fish fed LF-supplemented diets than the control group. Results indicated that diet supplemented with 800mgkg-1 for 8weeks enhanced somatic growth performance, lysozyme activity, and proteolytic digestive enzyme activities in S. hasta, as well as improving feed efficiency parameters like the protein efficiency and feed conversion ratios.

Dietary lactoferrin supplementation to gilts during gestation and lactation improves pig production and immunity.

Lactoferrin (LF), a sialylated iron-binding glycoprotein, performs multiple beneficial functions including modulating immunity and improves neurodevelopment, health and growth performance. Maternal LF intervention for gilts (first parity sows) on the performance of gilts and their offspring remains unknown. In the current study gilts were fed with a commercial pig feed supplemented with 1g LF /day (treatment group) or 1g milk casein/day (control group) from day 1 post mating throughout pregnancy and lactation for about 135 days. The milk production and body weight gain was monitored. The immunoglobulin concentrations in the serum of gilts and piglets were measured using ELISA. Our study showed that maternal LF supplementation to the gilt (1) significantly increased milk production at different time points (day 1, 3, 7 and 19) of lactation compared to the control (p<0.001); (2) significantly increased body weight gain of their piglets during the first 19 days of life compared to the control group (p<0.05); (3) tended to increase pregnancy rate, litter size and birth weight, number of piglets born alive, and decrease the number of dead and intrauterine growth restriction (IUGR) piglets; (4) significantly increased the concentration of serum IgA in gilt and serum sIgA in piglet (p<0.05). In summary, maternal Lf intervention in gilts can improve milk production, pig production and serum IgA and sIgA levels, and therefore plays a key role in shaping the performance of their progeny.

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.