lactoferrin and Enterocolitis--Necrotizing

The network meta-analysis (NMA) investigated the efficacy of six food supplements, namely glutamine, arginine, lactoferrin, prebiotics, synbiotics, and probiotics, in preventing necrotizing enterocolitis in premature infants.. MEDLINE, Embase, and Cochrane Library were searched. Randomized controlled trials comparing different food supplements for premature infants were included.. Probiotics (OR, 0.47; 95% CrI, 0.33-0.63), arginine (OR, 0.38; 95% CrI, 0.14-0.98), glutamine (OR, 0.30; 95% CrI, 0.079-0.90), and synbiotics (OR, 0.13; 95% CrI, 0.037-0.37). were associated with a decreased incidence of NEC. Only probiotics (OR, 0.81; 95% CrI, 0.69-0.95) and lactoferrin (OR, 0.74; 95% CrI, 0.54-0.92) achieved lower risk of sepsis. Probiotics (OR, 0.58; 95% CrI, 0.40-0.79), prebiotics (OR, 0.23; 95% CrI, 0.043-0.86), and synbiotics (OR, 0.15; 95% CrI, 0.035-0.50) were associated with lower odds of mortality. Probiotics (MD, -2.3; 95% CrI: -3.7- -0.63) appeared to have earlier age of attainment of full feeding.. Based on this NMA, probiotics and synbiotics had the potential to be the top two preferable food supplements.

Topics: Arginine; Enterocolitis, Necrotizing; Glutamine; Humans; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature; Lactoferrin; Network Meta-Analysis; Probiotics

Early adverse fetal environments can significantly disturb central nervous system (CNS) development and subsequently alter brain maturation. Nutritional status is a major variable to be considered during development and increasing evidence links neonate and preterm infant impaired brain growth with neurological and psychiatric diseases in adulthood. Breastfeeding is one of the main components required for healthy newborn development due to the many "constitutive" elements breastmilk contains. Maternal intake of specific nutrients during lactation may alter milk composition, thus affecting newborn nutrition and, potentially, brain development. Lactoferrin (Lf) is a major protein present in colostrum and the main protein in human milk, which plays an important role in the benefits of breastfeeding during postnatal development. It has been demonstrated that Lf has antimicrobial, as well as anti-inflammatory properties, and is potentially able to reduce the incidence of sepsis and necrotizing enterocolitis (NEC), which are particularly frequent in premature births. The anti-inflammatory effects of Lf can reduce birth-related pathologies by decreasing the release of pro-inflammatory factors and inhibiting premature cervix maturation (also related to commensal microbiome abnormalities) that could contribute to disrupting brain development. Pre-clinical evidence shows that Lf protects the developing brain from neuronal injury, enhances brain connectivity and neurotrophin production, and decreases inflammation in models of perinatal inflammatory challenge, intrauterine growth restriction (IUGR) and neonatal hypoxia-ischemia (HI). In this context, Lf can provide nutritional support for brain development and cognition and prevent the origin of neuropsychiatric diseases later in life. In this narrative review, we consider the role of certain nutrients during neurodevelopment linking to the latest research on lactoferrin with respect to neonatology. We also discuss new evidence indicating that early neuroprotective pathways modulated by Lf could prevent neurodegeneration through anti-inflammatory and immunomodulatory processes.

Topics: Adult; Brain; Enterocolitis, Necrotizing; Female; Humans; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature; Lactoferrin; Longevity; Milk, Human; Pregnancy; Premature Birth

This study aimed to systematically review and meta-analyze the role of lactoferrin supplementation to prevent late-onset sepsis (LOS) in preterm infants.. Database search include PubMed, Web of Science, and Cochrane central for randomized clinical trial (RCTs). The Cochrane Grading of Recommendations Assessment, Development, and Evaluation methodology was used for summarizing the results.. Ten RCTs involving 3,679 infants were included. Lactoferrin supplementation with or without probiotics decreased all LOS (relative risk [RR]: 0.56; 95% confidence interval [CI]: 0.36-0.86;. Low to moderate quality evidence suggests that lactoferrin supplementation reduces LOS in preterm infants. Further research is needed to improve the certainty in the evidence.

Topics: Administration, Oral; Age of Onset; Bronchopulmonary Dysplasia; Cause of Death; Enteral Nutrition; Enterocolitis, Necrotizing; Humans; Infant; Infant Mortality; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lactoferrin; Mycoses; Probiotics; Randomized Controlled Trials as Topic; Retinopathy of Prematurity; Sepsis

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.

Topics: Enterocolitis, Necrotizing; Female; Gastrointestinal Microbiome; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lactoferrin; Milk, Human; Sepsis

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.

Topics: Administration, Oral; Bacterial Infections; Cause of Death; Chronic Disease; Enteral Nutrition; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lacticaseibacillus rhamnosus; Lactoferrin; Lung Diseases; Mycoses; Numbers Needed To Treat; Probiotics; Randomized Controlled Trials as Topic; Retinopathy of Prematurity; Sepsis

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.

Topics: Anti-Bacterial Agents; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Lactoferrin; Neonatal Sepsis; Probiotics; Randomized Controlled Trials as Topic; Treatment Outcome

Currently, prophylactic use of drugs to promote a healthy gut microbiota and immune system in preterm infants is hot debated, among which lactoferrin is a promising supplementation. However, the effect and safety of lactoferrin to prevent late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in preterm infants remains controversial.. Databases including Medline, Ovid-Embase, The Cochrane Library, CBM, CNKI, and VIP database of Chinese Journal were searched to collect randomized controlled trials (RCTs) about lactoferrin for preventing LOS and NEC in preterm infants. Languages of included RCTs were restricted to English and Chinese. Meta-analysis was conducted by Rev Man 5.3 software. The Mantel-Haenszel method with random-effects model was used to calculate pooled relative risks (RRs) and 95% confidence intervals (CIs).. A total of 9 RCTs, involving 1834 patients, were included. Pooled analysis showed that prophylactic lactoferrin could significantly reduce the incidence all culture-proven LOS (41/629 [6.5%] vs 96/659 [15.3%]; RR 0.47; 95% CI 0.33-0.67; P < .01) and NEC (stage II or more) (9/448 [2.0%] vs 26/462 [5.6%]; RR 0.40; 95% CI 0.18-0.86; P < .01). Lactoferrin was also associated with a significantly decreased hospital-acquired infection (16/139 [11.5%] vs 35/140 [25%]; RR 0.47; 95% CI 0.27-0.80; P < .01); and infection-related mortality (4/474 [0.8%] vs 25/505 [4.9%]; RR 0.24; 95% CI 0.04-1.32; P < .01, I = 53%). Lactoferrin could shorten time to reach full enteral feeding (weighted mean difference [WMD] = -2.11, 95% CI -3.12 to -1.10; P < .01) and showed a decreasing trend of duration of hospitalization (WMD = -1.69, 95% CI -6.87 to 3.50; P < .01; I = 95%). Lactoferrin did not have a significant effect on all-cause mortality (22/625 [3.5%] vs 35/647 [5.4%]; RR 0.70; 95% CI 0.38-1.30; P = .16; I = 13%). None of the included trials reported any confirmed adverse effects caused by the supplemented lactoferrin or probiotics.. Current evidence indicates that lactoferrin could significantly reduce the incidence of NEC and LOS, and decrease the risk of hospital-acquired infection and infection-related mortality in premature infants without obvious adverse effects.

Topics: Anti-Infective Agents; Cross Infection; Enterocolitis, Necrotizing; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lactoferrin; Male; Sepsis; Treatment Outcome

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.

Topics: Anti-Infective Agents; Dietary Supplements; Enterocolitis, Necrotizing; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Immunologic Factors; Infant, Newborn; Infant, Newborn, Diseases; Lactoferrin; Milk, Human; Sepsis

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.

Topics: Administration, Oral; Bacterial Infections; Cause of Death; Chronic Disease; Enteral Nutrition; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lacticaseibacillus rhamnosus; Lactoferrin; Lung Diseases; Mycoses; Numbers Needed To Treat; Probiotics; Randomized Controlled Trials as Topic; Retinopathy of Prematurity; Sepsis

Neonatal sepsis and necrotizing enterocolitis (NEC) are two most important neonatal problems in nursery which constitute the bulk of neonatal mortality and morbidity. Inflammatory mediators secondary to sepsis and NEC increases morbidity, by affecting various system of body like lung, brain and eye, thus causing long term implications. Lactoferrin (LF) is a component of breast milk and multiple actions that includes antimicrobial, antiviral, anti-fungal and anti-cancer and various other actions. Few studies have been completed and a number of them are in progress for evaluation of efficacy and safety of LF in the prevention of neonatal sepsis and NEC in field of neonatology. In future, LF prophylaxis and therapy may have a significant impact in improving clinical outcomes of vulnerable preterm neonates. This review analyse the role of lactoferrin in prevention of neonatal sepsis and NEC, with emphasis on mechanism of action, recent studies and current studies going on around the globe.

Topics: Anti-Infective Agents; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature, Diseases; Lactoferrin; Neonatology; Sepsis

The early postnatal period is a critical time for gastrointestinal (GI) and immune development. Neonates fed mother's milk have more rapid GI and immune development than fed-formula infants. In addition, clinical and epidemiologic data provide strong evidence that breastfeeding reduces the incidence and/or severity of infectious diseases. Lactoferrin is a 77 kDa, iron-binding glycoprotein that is present at high concentration in human milk compared with bovine milk and infant formula. It is a multifunctional protein that mediates many of the physiological processes in which breastfed infants have advantages over their formula-fed peers, including promoting GI and immune development, protection from infections, and improved cognitive development. Feeding bovine lactoferrin or recombinant human lactoferrin was well tolerated and stimulated intestinal cell proliferation and increased villus length and crypt depth in piglets. Lactoferrin also influenced both systemic and GI immune development by stimulating a balanced T-helper-1/T-helper-2 cytokine immune response. Further, there was a tendency for immune cells to secrete more anti-inflammatory cytokines in an unstimulated state, while being primed for a robust pro-inflammatory response when presented with a bacterial trigger in piglets fed lactoferrin. These findings support clinical studies demonstrating benefits of dietary lactoferrin in the prevention of infections, late onset sepsis, and necrotizing enterocolitis.

Topics: Animals; Breast Feeding; Cattle; Enterocolitis, Necrotizing; Gastrointestinal Tract; Humans; Immune System; Infant; Infant Formula; Infant Nutritional Physiological Phenomena; Infant, Newborn; Lactoferrin; Milk; Models, Animal; Sepsis; Swine; Translational Research, Biomedical

To discuss the potential clinical benefits of lactoferrin in preterm and term infants, as well as in young children and to review information on the burden of neonatal sepsis. Current evidence on the mechanisms that explain the role of human milk in the neonatal and infant anti-infective responses will be briefly reviewed and preclinical research data on the potential mechanisms of action by which lactoferrin may impact infant gut health, gut immune development and functions, including the lactoferrin effects on the neonatal microbiome, will be examined. Finally, updated translational research on lactoferrin will be presented and discussed and the current evidence from prospective randomized controlled trials in neonates, infants, and toddlers will be analyzed. These randomized controlled trials demonstrate that lactoferrin has a clinically significant impact on feeding, the microbiome, and clinical outcomes in neonates and infants.

Topics: Anti-Infective Agents; Candidiasis; Child, Preschool; Enterocolitis, Necrotizing; Gastrointestinal Tract; Humans; Infant; Infant Nutritional Physiological Phenomena; Infant, Newborn; Intensive Care, Neonatal; Lactoferrin; Microbiota; Milk, Human; Sepsis

Necrotizing enterocolitis (NEC) is the most common acquired disease of the gastrointestinal tract (GIT) in premature infants and newborns. It is defined as an ulcerative inflammation of the intestinal wall. The clinical signs of incipient NEC are often very discrete, and range from localized intestinal symptoms to generalized signs of sepsis. NEC is classified depending on its severity into disease states according to the modified Bell's Classification. Treatment of NEC ranges, depending on its severity, from a conservative therapeutic approach to surgery with resection of the affected parts of the intestine. Mortality is considerably high in extremely small preterm infants reaching up to 42% of the affected children. Measures such as breastfeeding or alternatively nutrition with pasteurized human donor milk from a milk bank, administration of probiotics, avoidance of histamine type II receptor antagonists, and restrictive antibiotic treatment should be considered early on for prevention of NEC.

Topics: Breast Feeding; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infusions, Parenteral; Lactoferrin; Probiotics; Risk Factors; Sepsis

Sepsis and necrotizing enterocolitis (NEC) cause significant morbidity and mortality in the newborn. Their ill effects persist in spite of appropriate and effective antibiotic therapy. Lactoferrin as an adjunct to antibiotics in the treatment of sepsis or NEC in the newborn may improve the clinical outcomes by enhancing the host defense and modulating the inflammatory response. This review focuses on the various aspects of lactoferrin use in the newborn.

Topics: Anti-Bacterial Agents; Antifungal Agents; Antiviral Agents; Child Development; Enterocolitis, Necrotizing; Fetal Organ Maturity; Humans; Immunologic Factors; Infant, Newborn; Infant, Premature, Diseases; Lactoferrin; Sepsis

Lactoferrin, a normal component of human colostrum and milk, can enhance host defense and may be effective in the prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates.. Primary objective To assess the safety and effectiveness of oral lactoferrin in the prevention of sepsis and NEC in preterm neonates. Secondary objectives1. To determine the effects of oral lactoferrin used 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 later.2. To determine the adverse effects of oral lactoferrin in the prophylaxis of neonatal sepsis and/or NEC.When data were available, we analyzed the following subgroups.1. Gestational age < 32 weeks and 32 to 36 weeks.2. 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.. We used the search strategy of the Cochrane Neonatal Review Group (CNRG) and updated our search in July 2014. 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 trials 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.. Four RCTs are included in this review. Oral lactoferrin supplementation decreased late-onset sepsis (typical risk ratio (RR) 0.49, 95% confidence interval (CI) 0.32 to 0.73; typical risk difference (RD) -0.09, 95% CI -0.14 to -0.04; number needed to treat for an additional beneficial outcome (NNTB) 11, 95% CI 7 to 25; four trials, 678 participants, moderate-quality evidence), NEC stage II or greater (typical RR 0.30, 95% CI 0.12 to 0.76; typical RD -0.05, 95% CI -0.08 to -0.01; NNTB 20, 95% CI 12.5 to 100; two studies, 505 participants, low-quality evidence), and "all-cause mortality" (typical RR 0.30, 95% CI 0.12 to 0.75; typical RD -0.05, 95% CI -0.08 to -0.01; NNTB 20, 95% CI 12.5 to 100; two studies, 505 participants, low-quality evidence).Oral lactoferrin supplementation with a probiotic 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 greater (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."Oral lactoferrin with or without probiotics decreased fungal sepsis but not chronic lung disease or length of hospital stay (from one study, low-quality evidence). No adverse effects were reported. Long-term neurological outcomes or periventricular leukomalacia was not evaluated.. Evidence of moderate to low quality suggests that oral lactoferrin prophylaxis with or without probiotics decreases late-onset sepsis and NEC stage II or greater in preterm infants without adverse effects. Completion of ongoing trials will provide evidence from more than 6000 preterm neonates and may enhance the quality of the evidence. Clarifications regarding optimum dosing regimens, type of lactoferrin (human or bovine), and long-term outcomes are still needed.

Topics: Administration, Oral; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lacticaseibacillus rhamnosus; Lactoferrin; Probiotics; Randomized Controlled Trials as Topic; Sepsis

There is an intense interest among neonatal caregivers as to whether lactoferrin given enterally may reduce the incidence of necrotizing enterocolitis in preterm infants. This review presents scientific and clinical evidence that lactoferrin alleviates or prevents this life-threatening disease.. Preclinical studies in neonatal rats showed that lactoferrin given orally before enteral infection with pathogenic Escherichia coli reduced bacteremia and mortality. A multicentered clinical trial found that very low-birth weight preterm infants given bovine lactoferrin had a significant reduction in late-onset sepsis; there was also a trend towards a diminished incidence of necrotizing enterocolitis. Although multicentered trials of lactoferrin use in preterm infants are near completion, regulatory burdens required to bring lactoferrin to the bedside may limit its availability.. Extremely preterm infants should receive colostrum, a natural lactoferrin concentrate, immediately after birth and, ideally, continue on breast milk throughout the hospital stay. This practice appears well tolerated, but additional experience will tell us whether this practice reduces the prevalence of necrotizing enterocolitis.

Topics: Animals; Colostrum; Enteral Nutrition; Enterocolitis, Necrotizing; Gastrointestinal Tract; Humans; Immunity, Innate; Incidence; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Inflammation; Lactoferrin; Randomized Controlled Trials as Topic; Sepsis

Recent advances in perinatal and neonatal intensive care have resulted in significant improvements in the survival of preterm extremely low-birthweight (PELBW) infants; however, extrauterine growth restriction (EUGR) and undernutrition occur frequently during hospitalization and are associated with adverse outcomes, including bronchopulmonary dysplasia, sepsis, and neurodevelopmental impairment. Early optimal parenteral nutrition with adequate amino acids and lipids, especially long-chain polyunsaturated fatty acids, has been shown to decrease the incidence of EUGR, bronchopulmonary dysplasia, necrotizing enterocolitis, sepsis, and retinopathy of prematurity in animal models and clinical trials. In PELBW infants, breast milk and probiotics have been shown to reduce the incidence of necrotizing enterocolitis, and lactoferrin has been demonstrated to prevent late-onset sepsis. Thus, early administration of optimal postnatal parenteral and enteral nutrients can help prevent neurodevelopmental impairment caused by EUGR, necrotizing enterocolitis, sepsis, bronchopulmonary dysplasia, and retinopathy of prematurity, and recent evidence indicates such treatment is feasible.

Topics: Animals; Child Development; Diet; Enterocolitis, Necrotizing; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Lactoferrin; Malnutrition; Milk, Human; Parenteral Nutrition; Probiotics

Lactoferrin (LF) is a multifunctional protein and a member of the transferrin family. LF and lysozyme in breast milk kill bacteria. In the stomach, pepsin digests and releases a potent peptide antibiotic called lactoferricin from native LF. The antimicrobial characteristics of LF may facilitate a healthy intestinal microbiome. LF is the major whey in human milk; its highest concentration is in colostrum. This fact highlights early feeding of colostrum and also fresh mature milk as a way to prevent necrotizing enterocolitis.

Topics: Animals; Colostrum; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Intestine, Small; Lactoferrin; Metagenome; Milk; Milk, Human; Muramidase

Neonatal sepsis and necrotizing enterocolitis (NEC) are associated with significant mortality and morbidity. Inflammation secondary to sepsis and NEC increases morbidity, especially those related to the lung, brain and eye. Therapeutic strategies that target inflammation and decrease the emergence of antibiotic resistance are urgently needed. Lactoferrin (Lf) is a multifunctional protein that modulates inflammation, cell growth and differentiation and has broad antimicrobial activity. Studies evaluating the efficacy and safety of Lf in the prevention of neonatal sepsis and NEC are currently in progress, and one completed study shows significant promise. In this article, the functions of this multifunctional molecule and current clinical evidence for its use in the newborn are reviewed. Lf prophylaxis and therapy may have a significant impact in improving clinical outcomes of vulnerable preterm neonates.

Topics: Animals; Anti-Infective Agents; Clinical Trials as Topic; Enterocolitis, Necrotizing; Humans; Immunomodulation; Infant, Newborn; Lactoferrin; Mice; Sepsis; Treatment Outcome

Topics: Clinical Trials as Topic; Enteral Nutrition; Enterocolitis, Necrotizing; Female; Humans; Immunity, Innate; Infant Nutritional Physiological Phenomena; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Lactoferrin; Milk, Human; Multicenter Studies as Topic

Sepsis-related morbidity and mortality is an increasing concern in all neonatal ICUs (NICUs). Sepsis occurs in 20-40% of all preterm patients, and although much is known on the origin, the incidence is reported to be constantly increasing. Many risk factors account for the increased risk of sepsis in preterms, including use of broad-spectrum antibiotics selecting resistant microflora and pathogenic gut colonization, parenteral nutrition, acid inhibitors and steroids, as well as the systematic and long-lasting use of invasive management and in-dwelling lines. As treatment does not prevent severe long-term neurodevelopmental impairment and sequelae in septic premature neonates, the best strategy is to avoid infections rather than to treat them.. Published results from several recent randomized controlled trials currently show a level I evidence that fluconazole for prevention of fungal sepsis, probiotics for prevention of necrotizing enterocolitis, and bovine lactoferrin for prevention of bacterial sepsis should be considered as preventive strategies in NICUs.. In this article, the current evidence in favour of lactoferrin use in preterm neonates will be reviewed and the areas of further research and future improvements will be discussed in order to illustrate the implications of the recent findings for clinical practice or research.

Topics: Anti-Infective Agents; Chemoprevention; Enterocolitis, Necrotizing; Fluconazole; Humans; Infant, Newborn; Lactoferrin; Premature Birth; Probiotics; Randomized Controlled Trials as Topic; Sepsis

Lactoferrin, a normal component of human colostrum, milk, tears and saliva can enhance host defence and may be effective in the prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates.. To assess the safety and effectiveness of oral lactoferrin in the prevention of sepsis and NEC in preterm neonates.. We used the search strategy of the Cochrane Neonatal Review Group (CNRG) including searches of CENTRAL (The Cochrane Library), MEDLINE and PREMEDLINE, EMBASE and CINAHL. We also searched trials registries and the conference proceedings of Pediatric Academic Society. Searches updated in July 2011.. Randomized or quasi-randomized controlled trials evaluating oral lactoferrin at any dose or duration for the prophylaxis of sepsis or NEC in preterm neonates.. Data collection and analysis were performed according to the standard methods of the CNRG.. One trial (Manzoni 2008) that randomized 472 very low birth weight infants was eligible. A statistically significant reduction in late-onset sepsis was observed in the groups that received either lactoferrin alone (RR 0.34, 95% CI 0.17 to 0.70) or in combination with Lactobacillus rhamnosus GG (RR 0.27, 95% CI 0.12 to 0.60).In subgroup analyses, infants weighing less than 1000 g and those fed exclusively on maternal milk had a significant reduction in late-onset sepsis after oral lactoferrin supplementation alone. In the group supplemented with oral lactoferrin and Lactobacillus rhamnosus, infants weighing less than 1000 g had a significant reduction in late-onset sepsis, a result not seen in infants fed maternal milk exclusively.Prophylaxis with oral lactoferrin alone did not reduce the incidence of NEC (RR 0.33, 95% CI 0.09 to 1.17), but a significant reduction in NEC with a combination of lactoferrin and Lactobacillus rhamnosus GG was noted (RR 0.05, 95% CI 0.00 to 0.90).No adverse effects due to lactoferrin were observed in this study. Long-term neurological outcomes were not assessed in this trial.. Oral lactoferrin prophylaxis reduces the incidence of late-onset sepsis in infants weighing less than 1500 g and most effective in infants weighing less than 1000 g. There is no evidence of efficacy of oral lactoferrin (given alone) in the prevention of NEC in preterm neonates.Well designed, randomized trials should address dosing, duration, type of lactoferrin (bovine or human) prophylaxis in prevention of sepsis and NEC. The effect of exclusive maternal milk feeding should be clarified.

Topics: Administration, Oral; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lacticaseibacillus rhamnosus; Lactoferrin; Sepsis

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.. 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.. 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: www.clinicaltrials.gov and www.controlled-trials.com, 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.. 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).. 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.. We did not identify any eligible neonatal trial evaluating lactoferrin for treatment of neonatal sepsis or NEC.. 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.. 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.

Topics: Administration, Oral; Anti-Bacterial Agents; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Lactoferrin; Sepsis

Lactoferrin, a normal component of human colostrum, milk, tears and saliva can enhance host defence and may be effective in the prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates.. To assess the safety and effectiveness of oral lactoferrin in the prevention of sepsis and NEC in preterm neonates.. The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE and PREMEDLINE (1966 to Oct 2009), EMBASE (1980 to Oct 2009) and CINAHL (1982 to Oct 2009) were searched. Ongoing trials at www.clinicaltrials.gov and www.controlled-trials.com were searched. Conference proceedings of Pediatric Academic Societies (American Pediatric Society, Society for Pediatric Research and European Society for Pediatric Research) were searched for abstracts 1990 from the journal 'Pediatric Research' and 'Abstracts Online'.. Randomized or quasi-randomized controlled trials evaluating oral lactoferrin at any dose or duration for the prophylaxis of sepsis or NEC in preterm neonates.. Data collection and analysis were performed according to the standard methods of the CNRG.. One trial (Manzoni 2008) that randomized 472 very low birth weight infants was eligible. A statistically significant reduction in late-onset sepsis was observed in the groups that received either lactoferrin alone (RR 0.34, 95% CI 0.17, 0.70; RD -0.11, 95% CI -0.18, -0.05; NNT 9, 95% CI 5, 20) or in combination with Lactobacillus rhamnosus GG (RR 0.27, 95% CI 0.12, 0.60; RD -0.13, 95% CI -0.19, -0.06; NNT 8, 95% CI 5, 17).In subgroup analyses, infants weighing less than 1000 g and those fed exclusively on maternal milk had significant reduction in late-onset sepsis after oral lactoferrin supplementation alone. In the group supplemented with oral lactoferrin and Lactobacillus rhamnosus, infants weighing less than 1000 g had a significant reduction in late-onset sepsis, but not exclusively maternal milk fed infants.Prophylaxis with oral lactoferrin alone did not reduce the incidence of NEC (RR 0.33, 95% CI 0.09, 1.17; RD -0.04, 95% CI -0.08, 0.00), but a significant reduction in NEC with combination of lactoferrin with Lactobacillus rhamnosus GG was noted (RR 0.05, 95% CI 0.00, 0.90; RD -0.06, 95% CI -0.10, -0.02; NNT17, 95% CI 10, 50).No adverse effects due to lactoferrin were observed in this study. Long-term neurological outcomes were not assessed in this trial.. Oral lactoferrin prophylaxis reduces the incidence of late-onset sepsis in infants weighing less than 1500 g and most effective in infants weighing less than 1000 g. There is no evidence of efficacy of oral lactoferrin (given alone) in the prevention of NEC in preterm neonates.Well designed, randomized trials should address dosing, duration, type of lactoferrin (bovine or human) prophylaxis in prevention of sepsis and NEC. The effect of exclusive maternal milk feeding should be clarified.

Topics: Administration, Oral; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lacticaseibacillus rhamnosus; Lactoferrin; Probiotics; Sepsis

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.. 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.. Relevant trials in any language were searched in June 2008 in the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE (1966 - June 2008), PREMEDLINE, EMBASE (1980 - June 2008), CINAHL (1982 - June 2008), web sites: www.clinicaltrials.gov and www.controlled-trials.com, abstracts from the annual meeting of Pediatric Academic Societies (1990- June 2008), by contacting authors who have published in this field, from the reference lists of identified clinical trials and in the reviewer's personal files.. 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).. 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.. Our search strategy did not identify any eligible trials or potentially eligible ongoing neonatal trials. One trial was excluded and three ongoing or soon to be started adult trials using lactoferrin for the treatment of infections were identified.. 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.. The safety and efficacy of different preparations and doses of lactoferrin needs 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 (e.g. mortality).

Topics: Administration, Oral; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Lactoferrin; Sepsis

Despite the use of potent antimicrobials, neonatal sepsis and necrotizing enterocolitis are associated with significant mortality and morbidity. The emergence of microbial antibiotic resistance is a grave concern. Inflammation secondary to sepsis and necrotizing enterocolitis increases pulmonary and cerebral morbidity. New strategies that target inflammation and reduce the emergence of antibiotic resistance are urgently needed. Lactoferrin has broad-spectrum antimicrobial and immunomodulatory activities. In animal models of colitis, lactoferrin reduces inflammatory injury. Lactoferrin also induces the receptor-mediated proliferation and differentiation of intestinal cells. A randomized, controlled trial of lactoferrin in premature neonates to prevent late-onset sepsis is currently in progress. Lactoferrin is a promising agent in the prevention of neonatal sepsis and necrotizing enterocolitis but needs further evaluation to confirm its safety, tolerability and efficacy.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Enterocolitis, Necrotizing; Humans; Immunologic Factors; Infant, Newborn; Infant, Premature; Inflammation; Lactoferrin; Sepsis

Results from previous studies have suggested that supplemental bovine lactoferrin (BLF) given to preterm infants (<32 weeks 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;

Topics: Administration, Oral; Double-Blind Method; Enterocolitis, Necrotizing; Humans; Infant; Infant, Newborn; Infant, Premature; Lactoferrin; Sepsis; United Kingdom

In Canada alone, almost 3000 VLBW infants are born and treated annually with almost 1200 going onto death or survival with severe brain injury, chronic lung disorders, aggressive retinopathy of prematurity, late-onset sepsis, or significant necrotizing enterocolitis. Lactoferrin is an antimicrobial, antioxidant, anti-inflammatory iron-carrying, bifidogenic glycoprotein found in all vertebrates and in mammalian milk, leukocytes and exocrine secretions. Lactoferrin aids in creating an environment for growth of beneficial bacteria in the gut, thus reducing colonization with pathogenic bacteria. It is hypothesized that oral bovine lactoferrin (bLF), through its antimicrobial, antioxidant and anti-inflammatory properties, will reduce the rate of mortality or major morbidity in very low birth weight preterm infants.. Lactoferrin Infant Feeding Trial_Canada (LIFT_Canada) is a multi-centre, double-masked, randomized controlled trial with the aim to enroll 500 infants whose data will be combined with the data of the 1542 infants enrolled from Lactoferrin Infant Feeding Trial_Australia/New Zealand (LIFT_ANZ) in a pooled intention-to-treat analysis. Eligible infants will be randomized and allocated to one of two treatment groups: 1) a daily dose of 200 mg/kg bLF in breast/donor human milk or formula milk until 34 weeks corrected gestation or for a minimum of 2 weeks, whichever is longer, or until discharge home or transfer, if earlier; 2) no bLF with daily feeds. The primary outcome will be determined at 36 weeks corrected gestation for the presence of neonatal morbidity and at discharge for survival and treated retinopathy of prematurity. The duration of the trial is expected to be 36 months.. Currently, there continues to be no clear answer related to the benefit of bLF in reducing mortality or any or all of the significant neonatal morbidities in very low birth weight infants. LIFT_Canada is designed with the hope that the pooled results from Australia, New Zealand, and Canada may help to clarify the situation.. Clinical Trials.Gov, Identifier: NCT03367013, Registered December 8, 2017.

Topics: Anti-Infective Agents; Brain Injuries; Canada; Cerebral Palsy; Double-Blind Method; Enteral Nutrition; Enterocolitis, Necrotizing; Female; Hospital Mortality; Humans; Infant Formula; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Intention to Treat Analysis; Lactoferrin; Male; Milk, Human; Sepsis

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.

Topics: Administration, Oral; Dietary Supplements; Enterocolitis, Necrotizing; Gastric Acid; Histamine H2 Antagonists; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Intensive Care Units, Neonatal; Italy; Lacticaseibacillus rhamnosus; Lactoferrin; New Zealand; Probiotics; Proton Pump Inhibitors; Risk Factors; Sepsis

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.

Topics: Bronchopulmonary Dysplasia; Child, Preschool; Cost-Benefit Analysis; Developmental Disabilities; Dietary Supplements; Enteral Nutrition; Enterocolitis, Necrotizing; Female; Gestational Age; Humans; Infant; Infant Mortality; Infant, Extremely Premature; Infant, Newborn; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Lactoferrin; Male; Multicenter Studies as Topic; Randomized Controlled Trials as Topic

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

Topics: Animals; Cattle; Enteral Nutrition; Enterocolitis, Necrotizing; Female; Gestational Age; Humans; Infant, Extremely Premature; Infant, Premature, Diseases; Infections; Lactoferrin; Male

To determine tolerability of bovine lactoferrin (bLF) in very preterm infants, and whether the intervention can be adequately masked.. In a single-center masked pilot trial infants under 31 weeks gestation were randomized before 48 h of age to receive milk with 100 mg per day of bLF or control. The primary outcome was feeding tolerance, defined as time to achieve full feeds (140 ml kg(-1) per day). Parents answered a short questionnaire regarding acceptability of the intervention.. Seventy-nine infants were enrolled and analyzed according to intention to treat. There was no effect of bLF on the primary outcome. In addition, mortality, late onset sepsis and other complications of prematurity were no different. Equal numbers of parents in both groups believed their infant received bLF.. We demonstrated that bLF is well tolerated, easy to administer and its presence in prepared milk is not evident. Trial registration number ISRCTN66482337.

Topics: Animals; Canada; Cattle; Double-Blind Method; Enterocolitis, Necrotizing; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Lactoferrin; Male; Neonatal Sepsis; Pilot Projects

To evaluate the safety and explore the efficacy of recombinant human lactoferrin (talactoferrin [TLf]) to reduce infection.. We conducted a randomized, double blind, placebo-controlled trial in infants with birth weight of 750-1500 g. Infants received enteral TLf (n = 60) or placebo (n = 60) on days 1 through 28 of life; the TLf dose was 150 mg/kg every 12 hours. Primary outcomes were bacteremia, pneumonia, urinary tract infection, meningitis, and necrotizing enterocolitis (NEC). Secondary outcomes were sepsis syndrome and suspected NEC. We recorded clinical, laboratory, and radiologic findings, along with diseases and adverse events, in a database used for statistical analyses.. Demographic data were similar in the 2 groups of infants. We attributed no enteral or organ-specific adverse events to TLf. There were 2 deaths in the TLf group (1 each due to posterior fossa hemorrhage and postdischarge sudden infant death), and 1 death in the placebo group, due to NEC. The rate of hospital-acquired infections was 50% lower in the TLf group compared with the placebo group (P < .04), including fewer blood or line infections, urinary tract infections, and pneumonia. Fourteen infants in the TLf group weighing <1 kg at birth had no gram-negative infections, compared with only 3 of 14 such infants in the placebo group. Noninfectious outcomes were not statistically significantly different between the 2 groups, and there were no between-group differences in growth or neurodevelopment over a 1-year posthospitalization period.. We found no clinical or laboratory toxicity and a trend toward less infectious morbidity in the infants treated with TLf.. ClinicalTrials.gov: NCT00854633.

Topics: Administration, Oral; Bacteremia; Cross Infection; Double-Blind Method; Enterocolitis, Necrotizing; Female; Follow-Up Studies; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lactoferrin; Male; Meningitis; Pneumonia; Protective Agents; Sepsis; Treatment Outcome; Urinary Tract Infections

NEC is a common and severe complication in premature neonates, particularly those with very-low-birth-weight (VLBW, <1500 g at birth). Probiotics including lactobacillus rhamnosus GG (LGG) proved effective in preventing NEC in preterm infants in several RCTs.. Lactoferrin, a mammalian milk glycoprotein involved in innate immune host defences, can reduce the incidence of NEC in animal models, and its action is enhanced by LGG. We tried to assess whether bovine lactoferrin (BLF), alone or with the probiotic LGG, has a similar effect in human infants, something that has not yet been studied.. An international, multicenter, randomized, double-blind, placebo-controlled trial conducted from October 1st, 2007 through July 31st, 2010.. Thirteen Italian and New Zealand tertiary neonatal intensive care units.. 743 VLBW neonates were assessed until discharge for development of NEC.. Infants were randomly assigned to receive orally either BLF (100 mg/day) alone (group LF; n = 247) or with LGG (at 6×10(9) CFU/day; group BLF + LGG; n = 238), or placebo (Control group; n = 258) from birth until day 30 of life (45 for neonates <1000 g at birth).. ≥ stage 2 NEC; death-and/or-≥ stage 2 NEC prior to discharge.. Demographics, clinical and management characteristics of the 3 groups were similar, including type of feeding and maternal milk intakes. NEC incidence was significantly lower in groups BLF and BLF + LGG [5/247 (2.0%)] and 0/238 (0%), respectively] than in controls [14/258 (5.4%)] (RR = 0.37; 95% CI: 0.136-1.005; p = 0.055 for BLF vs. control; RR = 0.00; p < 0.001 for BLF + LGG vs. control). The incidence of death-and/or-NEC was significantly lower in both treatment groups (4.0% and 3.8% in BLF and BLF + LGG vs. 10.1% in control; RR = 0.39; 95% CI: 0.19-0.80; p = 0.008. RR = 0.37; 95% CI: 0.18-0.77; p = 0.006, respectively). No adverse effects or intolerances to treatment occurred.. Compared with placebo, BLF supplementation alone or in combination with LGG reduced the incidence of ≥ stage 2 NEC and of death-and/or ≥ stage 2 NEC in VLBW neonates. BLF might be a promising strategy to prevent NEC in NICU settings. Further data on larger sample sizes are warranted before BLF can be widespreadly used in clinical settings.. ISRCTN53107700-http://www.controlled-_trials.com/ISRCTN53107700.

Topics: Animals; Anti-Infective Agents; Cattle; Enterocolitis, Necrotizing; Female; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Lactoferrin; Male

Lactoferrin (LF) is effective in the prevention of sepsis in very low birth weight (VLBW) neonates. T-regulatory cells (Tregs) are important subsets of T lymphocytes that control pathogen-specific immune responses and are essential for intestinal immune homoeostasis. The aim of the present study is to determine whether oral LF at a dosage of 200 mg/d reduces nosocomial sepsis episodes and necrotizing enterocolitis (NEC) in premature infants and to evaluate the possible effects of LF on Treg levels.. In this prospective, placebo-controlled, double-blind, randomized trial, infants either VLBW or born before 32 weeks were assigned to receive either placebo (n = 25), or 200 mg LF (n = 25) daily throughout hospitalization. Episodes of culture proven nosocomial sepsis and NEC were recorded. The level of FOXP3 + CD4 + CD25hi lymphocytes was studied by flow cytometry at birth and discharge. A third comparison was made with healthy term neonates (n = 16).. Fewer sepsis episodes were observed in LF-treated infants (4.4 vs. 17.3/1,000 patient days, p = 0.007) with none developing NEC, without statistical significance. Treg levels at birth and discharge were similar, while preterm infants showed significantly lower levels than term controls. However, individual increases in Treg levels were higher in the LF group.. LF prophylaxis reduced nosocomial sepsis episodes. Treg levels in preterm infants were lower than in term infants and an increase of Treg levels under LF prophylaxis was observed. Increase in Treg levels can be the mechanism for protective effects of LF on nosocomial sepsis.

Topics: Administration, Oral; Anti-Infective Agents; Cross Infection; Double-Blind Method; Enterocolitis, Necrotizing; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Lactoferrin; Lymphocyte Count; Male; Prospective Studies; Sepsis; T-Lymphocytes, Regulatory

While endotoxin (lipopolysaccharide) can be harmful and contribute to morbidity and mortality with Gram-negative sepsis or necrotizing enterocolitis in preterm infants, non-toxic amounts are produced as part of the neonatal microbiome and may be present in enteral nutrition and medications administered. The United States Food and Drug Administration has given guidance for endotoxin concentration limits for intravenous medications and fluids of 5 endotoxin units/kg/hour (120 endotoxin units/kg/day), but no guidance for amounts of endotoxin in enteral products. To determine baseline exposure to infants in the neonatal intensive care unit, we examined endotoxin content of enteral formulas and fortification used for preterm infants, as well as bovine lactoferrin products. We also examined endotoxin exposure and outcomes in very low birth weight infants. Endotoxin content was measured using kinetic chromogenic limulus amebocyte lysate analysis. Daily endotoxin exposure from enteral formulas ranged between < 75 to 7110 endotoxin units/kg and from lactoferrin products from 7 to 3720 endotoxin units/kg. In examining neonatal outcomes from a bovine lactoferrin product studied at three different escalating doses (100, 200, and 300 mg/kg/day), we measured endotoxin in the lactoferrin product and daily exposure was 1089 (N = 10), 2178 (N = 10) and 3287 (N = 11) endotoxin units/kg, respectively. There were no cases of necrotizing enterocolitis or mortality and no lactoferrin-related adverse effects in these patients. Enteral endotoxin daily exposures from lactoferrin products are similar to amounts in preterm enteral nutrition and appear safe and not associated with patient harm. Testing enteral products and establishing safety limits may improve care of high risk patients.

Topics: Endotoxins; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Lactoferrin; United States

Modulation of intestinal microbiome by administering probiotics, prebiotics, or both may prevent morbidity and mortality in premature infants.. To assess the comparative effectiveness of alternative prophylactic strategies through a network meta-analysis (NMA) of randomized clinical trials.. MEDLINE, EMBASE, Science Citation Index Expanded, CINAHL, Scopus, Cochrane CENTRAL, and Google Scholar from inception until May 10, 2023.. Eligible trials tested probiotics, prebiotics, lactoferrin, and combination products for prevention of morbidity or mortality in preterm infants.. A frequentist random-effects model was used for the NMA, and the certainty of evidence and inferences regarding relative effectiveness were assessed using the GRADE approach.. All-cause mortality, severe necrotizing enterocolitis, culture-proven sepsis, feeding intolerance, time to reach full enteral feeding, and duration of hospitalization.. A total of 106 trials involving 25 840 preterm infants were included. Only multiple-strain probiotics were associated with reduced all-cause mortality compared with placebo (risk ratio [RR], 0.69; 95% CI, 0.56 to 0.86; risk difference [RD], -1.7%; 95% CI, -2.4% to -0.8%). Multiple-strain probiotics alone (vs placebo: RR, 0.38; 95% CI, 0.30 to 0.50; RD, -3.7%; 95% CI, -4.1% to -2.9%) or in combination with oligosaccharides (vs placebo: RR, 0.13; 95% CI, 0.05 to 0.37; RD, -5.1%; 95% CI, -5.6% to -3.7%) were among the most effective interventions reducing severe necrotizing enterocolitis. Single-strain probiotics in combination with lactoferrin (vs placebo RR, 0.33; 95% CI, 0.14 to 0.78; RD, -10.7%; 95% CI, -13.7% to -3.5%) were the most effective intervention for reducing sepsis. Multiple-strain probiotics alone (RR, 0.61; 95% CI, 0.46 to 0.80; RD, -10.0%; 95% CI, -13.9% to -5.1%) or in combination with oligosaccharides (RR, 0.45; 95% CI, 0.29 to 0.67; RD, -14.1%; 95% CI, -18.3% to -8.5%) and single-strain probiotics (RR, 0.61; 95% CI, 0.51 to 0.72; RD, -10.0%; 95% CI, -12.6% to -7.2%) proved of best effectiveness in reduction of feeding intolerance vs placebo. Single-strain probiotics (MD, -1.94 days; 95% CI, -2.96 to -0.92) and multistrain probiotics (MD, -2.03 days; 95% CI, -3.04 to -1.02) proved the most effective in reducing the time to reach full enteral feeding compared with placebo. Only single-strain and multistrain probiotics were associated with greater effectiveness compared with placebo in reducing duration of hospitalization (MD, -3.31 days; 95% CI, -5.05 to -1.58; and MD, -2.20 days; 95% CI, -4.08 to -0.31, respectively).. In this systematic review and NMA, moderate- to high-certainty evidence demonstrated an association between multistrain probiotics and reduction in all-cause mortality; these interventions were also associated with the best effectiveness for other key outcomes. Combination products, including single- and multiple-strain probiotics combined with prebiotics or lactoferrin, were associated with the largest reduction in morbidity and mortality.

Topics: Enterocolitis, Necrotizing; Humans; Infant; Infant, Newborn; Infant, Premature; Lactoferrin; Morbidity; Network Meta-Analysis; Oligosaccharides; Prebiotics; Probiotics; Sepsis

Lactoferrin as a nutritional enteral supplement has emerged as a novel preventative therapy against serious infections in preterm infants, although neonatal studies have demonstrated variable results, in part due to the lack of pharmacokinetic data and differences in the products tested. We conducted a prospective, dose escalation (100, 200, and 300 mg·kg

Topics: Animals; Birth Weight; Cattle; Dietary Supplements; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Lactoferrin; Prospective Studies; Urinary Tract Infections

Topics: Dietary Supplements; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Lactoferrin; Sepsis

Topics: Dietary Supplements; Enterocolitis, Necrotizing; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lactoferrin

Lactoferrin (LF) is a protective protein present in milk with anti-infective and immune-modulating properties.. The aim of this study was to determine the association of maternal LF intake and mother's own milk intake in the first 10 days of life on the prevention of late-onset sepsis (LOS), necrotizing enterocolitis (NEC), or death in the first 8 weeks of life in newborns with a birth weight <2,000 g.. A retrospective cohort study was conducted, with the exposure being the consumption of mother's own LF and mother's own milk in the first 10 days of life, and the outcome being LOS, NEC, or death during days 11 and 56 of life, analyzed by Cox regression.. Two hundred and ninety-nine infants were enrolled, including 240 with human LF intake information. The average daily human LF intake over days 4-10 of life was 283 mg/kg/day (IQR 114-606 mg/kg/day). The hazard ratio (HR) of mother's own milk LF intake ≥100 mg/kg/day in days 4-10 for LOS, NEC, or death was 0.297 (95% CI 0.156-0.568, p < 0.001); the adjusted HR was 0.752 (95% CI 0.301-1.877, p = 0.541). The adjusted HR of mother's own milk cumulative intake (days 4-10) of 54-344 mL/kg (25-75 quartiles) for LOS, NEC, or death was 0.414 (95% CI 0.196-0.873, p = 0.02). Infants who developed an event (LOS, NEC, or death) had significantly less median daily human LF intake than those that did not (89 vs. 334 mg/kg/day, respectively, p < 0.0001).. Consumption of higher amounts of mother's own milk in the first days of life is associated with less infection, NEC, and death. Early human milk intake should be strongly encouraged in all newborns.

Topics: Enterocolitis, Necrotizing; Female; Humans; Infant; Infant, Newborn; Lactoferrin; Milk, Human; Mothers; Neonatal Sepsis; Retrospective Studies; Sepsis

Inflammation plays a critical role in the development of severe neonatal morbidities. Myeloid-derived suppressor cells (MDSCs) were recently implicated in the regulation of immune responses in newborns. Here, we report that the presence of MDSCs and their functional activity in infants are closely associated with the maturity of newborns and the presence of lactoferrin (LF) in serum. Low amounts of MDSCs at birth predicted the development of severe pathology in preterm infants - necrotizing enterocolitis (NEC). In vitro treatment of newborn neutrophils and monocytes with LF converted these cells to MDSCs via the LRP2 receptor and activation of the NF-κB transcription factor. Decrease in the expression of LRP2 was responsible for the loss of sensitivity of adult myeloid cells to LF. LF-induced MDSCs (LF-MDSCs) were effective in the treatment of newborn mice with NEC, acting by blocking inflammation, resulting in increased survival. LF-MDSCs were more effective than treatment with LF protein alone. In addition to affecting NEC, LF-MDSCs demonstrated potent ability to control ovalbumin-induced (OVA-induced) lung inflammation, dextran sulfate sodium-induced (DSS-induced) colitis, and concanavalin A-induced (ConA-induced) hepatitis. These results suggest that cell therapy with LF-MDSCs may provide potent therapeutic benefits in infants with various pathological conditions associated with dysregulated inflammation.

Topics: Adult; Animals; Animals, Newborn; Cell- and Tissue-Based Therapy; Disease Models, Animal; Enterocolitis, Necrotizing; Female; Humans; In Vitro Techniques; Infant, Newborn; Infant, Premature; Inflammation; Lactoferrin; Low Density Lipoprotein Receptor-Related Protein-2; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Myeloid-Derived Suppressor Cells; NF-kappa B

Myeloid-derived suppressor cells (MDSCs) are pathologically activated and relatively immature myeloid cells that have been implicated in the immunological regulation of many pathologic conditions. Phenotypically and morphologically, MDSCs are similar to neutrophils (PMN-MDSCs) and monocytes (M-MDSCs). However, they have potent suppressive activity and distinct gene expression profiles and biochemical characteristics. No or very few MDSCs are observed in steady-state physiological conditions. Therefore, until recently, accumulation of MDSCs was considered a consequence of pathological processes or pregnancy. Here, we report that MDSCs with a potent ability to suppress T cells are present during the first weeks of life in mice and humans. MDSC suppressive activity was triggered by lactoferrin and mediated by nitric oxide, PGE2, and S100A9 and S100A8 proteins. MDSCs from newborns had a transcriptome similar to that of tumor MDSCs, but with strong upregulation of an antimicrobial gene network, and had potent antibacterial activity. MDSCs played a critical role in control of experimental necrotizing enterocolitis (NEC) in newborn mice. MDSCs in infants with very low weight, who are prone to NEC, had lower MDSC levels and suppressive activity than did infants with normal weight. Thus, the transitory presence of MDSCs may be critical for regulation of inflammation in newborns.

Topics: Animals; Animals, Newborn; Calgranulin A; Calgranulin B; Dinoprostone; Enterocolitis, Necrotizing; Gene Expression Regulation; Humans; Infant, Very Low Birth Weight; Inflammation; Lactoferrin; Mice; Myeloid-Derived Suppressor Cells; Nitric Oxide

Topics: Adult; Asthma; Bifidobacterium; Breast Feeding; Child, Preschool; Diabetes Mellitus; Dietary Supplements; Enterocolitis, Necrotizing; Female; Gastrointestinal Microbiome; Health; Humans; Infant; Infant, Newborn; Lactobacillus; Lactoferrin; Microbiota; Milk, Human; Neonatology; Oligosaccharides; Parturition; Pregnancy; Probiotics; Proteobacteria

Preterm infants remain at high risk of adverse outcomes following necrotizing enterocolitis (NEC) and late onset sepsis (LOS). Meta-analysis of randomized trials has indicated a reduction in severe NEC following use of probiotics and bovine lactoferrin (LF). Overall, however, uncertainty remains over which probiotic, or combination to use. The aim of this study was to compare the incidence of severe NEC and LOS before and after routine supplementation with Lactobacillus GG (LGG) and LF.. In this retrospective cohort study, infants <32 weeks or <1500 g routinely received LGG and 100 mg lactoferrin daily from 2011 -2015 were compared with similar infants born from 2004-2008. Cases of NEC were Bell stage 2 or greater and LOS was blood or spinal fluid culture positive after 48 hrs of age.. We noted a marked decline in the incidence of NEC from 3% to 1% with a RR of 0.29 (CI 0.1-0.9) and a number needed to benefit of 50. The cost of preventing one case of NEC was estimated to be NZ $2800, considerably lower than the cost of treatment. LOS rates were not significantly different. There was a decrease in retinopathy treatment rates. During the period there was one case of LGG sepsis in a 23 week gestation infant with abdominal pathology and one infant developed NEC after stopping prophylaxis.. The rates of severe NEC was markedly reduced following prophylaxis. The case of LGG sepsis indicates caution is required in extremely preterm infants.

Topics: Animals; Case-Control Studies; Cattle; Cohort Studies; Dietary Supplements; Enterocolitis, Necrotizing; Female; Humans; Infant, Extremely Low Birth Weight; Infant, Extremely Premature; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Lacticaseibacillus rhamnosus; Lactoferrin; Male; Neonatal Sepsis; New Zealand; Probiotics; Retrospective Studies; Severity of Illness Index

Necrotizing enterocolitis (NEC) is a severe disease of mostly premature infants with high morbidity and mortality rates. There is no reliable biomarker for detecting newborns at risk for NEC development. We aimed to investigate small intestinal lactoferrin (LF) and calprotectin (CAL) levels as predictors and indicators of disease severity in an experimental newborn rat model.. Newborn pups were randomly divided into two groups, NEC and control. The NEC group pups were decapitated on the second, third and fourth days of the experiment for an assessment of the different stages of NEC. In the study group, hypoxia-reoxygenation model used to induce NEC. As biochemical parameters, small intestinal LF and CAL levels were measured with an enzyme-linked immunosorbent assay technique and intestinal injury scoring was evaluated as a pathologic parameter.. Small intestinal levels of both LF and CAL increased in the second and the third day groups, but began to decrease by the fourth day. The first, second and third day levels of LF and CAL were higher than controls. The intestinal injury scores of all NEC groups were significantly higher than the control group.. Small intestinal lactoferrin and calprotectin were good markers for demonstrating NEC. However, instead of spot testing, monitoring the levels of these markers may be more informative.

Topics: Animals; Animals, Newborn; Biomarkers; Enterocolitis, Necrotizing; Enzyme-Linked Immunosorbent Assay; Lactoferrin; Leukocyte L1 Antigen Complex; Rats

Bioactive milk proteins may be important in protecting preterm infants from developing inflammation and necrotising enterocolitis (NEC). A preterm pig model was used to investigate the protective effects of enteral bovine lactoferrin (bLF) against NEC development and inflammation. Caesarean-delivered preterm pigs were fed parenteral and minimal enteral nutrition for the first 2 d followed by 2 d of total enteral nutrition before euthanasia. Pigs were stratified into two groups and fed with either a control formula (CON, n 15) or a 10 g/l of bLF-enriched formula (LF, n 13). NEC incidence, gut functions and inflammatory cytokines were analysed. NEC incidence and nutrient absorption were similar between the two groups. In pigs that developed NEC, disease outcome was more severe in the colon accompanied by increased intestinal permeability in LF pigs. In contrary, the LF pigs had a lowered IL-1β level in the proximal small intestine. Dose-dependent effects of bLF on cell proliferation, intracellular signalling and cytokine secretion were tested in porcine intestinal epithelial cells (PsIc1) in vitro. Low doses (0·1-1 g/l) increased cell proliferation via extracellular signal-regulated kinase (ERK), limited IL-8 secretion and prevented NF-κB and hypoxia-inducible factor-1α (HIF-1α) activation, suggesting anti-inflammatory effects. In contrast, at a higher dose (10 g/l), bLF exerted adverse effects by reducing cell proliferation, stimulating IL-8 release, inhibiting ERK activation and up-regulating NF-κB and HIF-1α activation. Overall, at a dose of 10 g/l, bLF exacerbated disease severity in pigs that developed NEC, while the in vitro studies indicated the positive effects of bLF at low doses (0·1-1 g/l). Supplementation of infant formulas with bLF should therefore be optimised carefully.

Topics: Animals; Blood Glucose; Cattle; Cell Proliferation; Cytokines; Enterocolitis, Necrotizing; Female; Gene Expression Regulation; Insulin; Intestinal Mucosa; Intestines; Lactoferrin; Lipopolysaccharides; Pregnancy; Premature Birth; Swine

Topics: Blood Banks; Bronchopulmonary Dysplasia; Child Development; Chromosomes, Human, Pair 18; Enterocolitis, Necrotizing; Fetal Blood; Hematinics; Humans; Hypoxia, Brain; Infant; Infant, Newborn; Lactoferrin; Sepsis; Trisomy; Trisomy 18 Syndrome

Lactoferrin (Lf) is an iron-binding glycoprotein present in high concentration in human milk. It is a pleiotropic protein and is involved in diverse bioactivities, such as stimulation of cell proliferation and differentiation, immune competence, antimicrobial activities, anti-infection, and anticancer activities. Lf has been shown to be partly resistant to proteolysis in the gastrointestinal tract and may thus play important roles in the intestine and liver during infancy. Talactoferrin alfa (TLf) is a recombinant human Lf shown to protect against sepsis and necrotizing enterocolitis as well as cancer. Because bovine Lf (bLf) and human Lf have different amino acid composition and all 3 Lfs differ in glycosylation, they may have different functions/potency. The objective of the present study was to investigate and compare bioactivities of TLf and Lfs from human and bovine milk and thus to provide a better understanding of the bioactivities of different forms of Lf and their potential applications.. In the present study, Caco-2 and C3A cells were used as intestine and liver models to evaluate internalization of Lfs by intestine and liver cells, effects of Lfs on cell proliferation and differentiation, growth of enteropathogenic Escherichia coli (EPEC), chemokine (C-C motif) ligand 20 (CCL20) secretion, and transforming growth factor (TGF)-β1 expression. In addition, HT-29 cells were used as a colon cancer cell model to examine the effects of Lfs on apoptosis.. All Lfs significantly enhanced cell proliferation and differentiation, apoptosis, CCL20 secretion, and TGF-β1 expression. They also markedly suppressed growth of EPEC. Compared with bLf, TLf showed stronger effects on suppression of EPEC growth and enhancement of TGF-β1 secretion, whereas bLf exhibited more potent effects on cell differentiation, apoptosis, and CCL20 secretion.. Our results demonstrate that TLf has several bioactivities similar to human Lf and bLf from milk and may play critical roles in immune and intestinal development in infants as well as having anti-cancer activities in adults. TLf and bLf may be used for different applications owing to their various potencies. TLf may preferentially be used for anti-bacterial applications, whereas bLf may be used for cancer therapy because it exhibits stronger effects on CCL20 secretion, cell differentiation, and apoptosis.

Topics: Animals; Apoptosis; Caco-2 Cells; Cattle; Cell Proliferation; Chemokine CCL20; Colonic Neoplasms; Enterocolitis, Necrotizing; Escherichia coli; HT29 Cells; Humans; Intestinal Mucosa; Intestines; Lactoferrin; Liver; Milk; Milk, Human; Transforming Growth Factor beta1

Topics: Administration, Oral; Anti-Infective Agents; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature, Diseases; Infection Control; Lactoferrin; Sepsis

Early detection of necrotizing enterocolitis can improve the prognosis, however, there is not a reliable laboratory test to detect either newborns at risk for necrotizing enterocolitis development or those at early stages of the disease. Since fecal lactoferrin and fecal calprotectin are inflammatory markers of gastrointestinal diseases, it was hypothesized that both these biomarkers could be successfully used in the diagnosis of necrotizing enterocolitis.. In a prospective study, fecal lactoferrin and fecal calprotectin concentrations of 14 newborns with necrotizing enterocolitis and consecutively admitted 40 healthy preterm, and 23 healthy full-term newborns were measured with enzyme-linked immunosorbent assay technique.. Mean fecal lactoferrin and fecal calprotectin were not different between preterm and full-term newborns (p = .235 and p = .845, respectively), or those who were diagnosed with necrotizing enterocolitis or not (p = .545 and p = .968, respectively). Prevalence of necrotizing enterocolitis was 1.51% (14 of 2734). Stage of the disease did not have a statistical effect on mean levels (p = .694 and p = .267, respectively). Mean fecal lactoferrin and fecal calprotectin levels were not different in the case of breastfeeding (p = .623 and p = .792, respectively).. Neither fecal lactoferrin nor fecal calprotectin has a role in the identification of necrotizing enterocolitis, especially in early stages of the disease. Further studies on wider necrotizing enterocolitis series are needed for a more definite conclusion.

Topics: Biomarkers; Enterocolitis, Necrotizing; Enzyme-Linked Immunosorbent Assay; Feces; Humans; Infant, Newborn; Infant, Premature; Lactoferrin; Leukocyte L1 Antigen Complex; Prospective Studies

Enteral nutrition with human milk lowers the incidence of necrotizing enterocolitis in preterm human infants. Lactoferrin, the major whey protein in human milk, has many functions related to host defense against bacterial infection. Here, we hypothesize that lactoferrin also helps terminate bacterial invasion of enterocytes via a detachment-induced apoptosis called anoikis. Death of infected epithelia by anoikis prevents local spread of bacterial pathogens because the bacteria are trapped within the cell. Such infected, apoptotic and sloughed epithelia also cannot infect the lower gastrointestinal tract, and the epithelia exit the body in the stool. Currently, anoikis is a phenomenon related to the renewal of enterocytes, and it is not recognized as an anti-bacterial host defense. We suggest that anoikis of infected enterocytes is a process in which lactoferrin plays an important role. In a pilot study in which neonatal rats were pre-treated with intra-gastric recombinant human lactoferrin, we found evidence of epithelia with anoikis in ileal fluid after enteric infection. This finding was rarely seen in infected neonatal rats without pre-treatment with lactoferrin. Quantitative analysis of intestinal lavage specimens and quantitative stereology of apoptotic epithelia in this model will be required to verify the theory. We propose that oral use of recombinant human lactoferrin might have these hypothesized and other anti-bacterial effects in preterm infants, and hence, this protein might prevent necrotizing enterocolitis in preterm infants who cannot take human milk.

Topics: Animals; Animals, Newborn; Anoikis; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Lactoferrin