title: Efficacy of Bovine Lactoferrin Supplementation in Preventing Late-onset Sepsis in low Birth Weight Neonates: A Randomized Placebo-Controlled Clinical Trial. Prophylaxis with lactoferrin, a novel antimicrobial agent, in a neonatal rat model of coinfection Phase I trial of oral talactoferrin alfa in refractory solid tumors Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial. Very Low Birth Weight Preterm Infants With Early Onset Neonatal Sepsis: The Predominance of Gram-Negative Infections Continues in the National Institute of Child Health and Human Development Neonatal Research Network, 2002–2003 Lactoferrin Inhibits Hepatitis C Virus Viremia in Patients with Chronic Hepatitis C: A Pilot Study Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. Bovine Lactoferrin Prevents Invasive Fungal Infections in Very Low Birth Weight Infants: A Randomized Controlled Trial Oral lactoferrin to prevent nosocomial sepsis and necrotizing enterocolitis of premature neonates and effect on T-regulatory cells. Randomized double-blind controlled trial of bovine lactoferrin for prevention of diarrhea in children. Reduction in necrotizing enterocolitis and improved outcomes in preterm infants following routine supplementation with Lactobacillus GG in combination with bovine lactoferrin. The Lacuna Trial: a double-blind randomized controlled pilot trial of lactoferrin supplementation in the very preterm infant Bovine lactoferrin supplementation for prevention of necrotizing enterocolitis in very-low-birth-weight neonates: a randomized clinical trial. National Institute of Child Health and Human Development Randomized Controlled Trial of Lactoferrin for Prevention of Sepsis in Peruvian Neonates Less than 2500 g Randomized Controlled Trial of Talactoferrin Oral Solution in Preterm Infants. A Double-Blind, Placebo-Controlled, Pilot Study of Bovine Lactoferrin Supplementation in Bottle-fed Infants
abstract: OBJECTIVES To evaluate the efficacy of bovine lactoferrin ( BLF ) in preventing first episode of late-onset sepsis ( LOS ) in low birth weight ( LBW ) neonates . METHODS In this study conducted from May 2012 to July 2013 in the neonatal intensive care unit ( NICU ) of a tertiary care hospital , inborn asymptomatic neonates , < 2000 g , admitted to NICU in first 12 h of birth with no maternal risk factors for sepsis were r and omized to receive BLF or placebo from 1st to 28th day of life . The incidence of culture-proven sepsis and sepsis-attributable mortality after 72 h of life was recorded . Increasing doses of BLF were used with higher birth weights . RESULTS Incidence of first episode of culture-proven LOS was significantly lower in the BLF group vs. placebo [ 2/63 ( 3.2 % ) vs. 9/67(13.4 % ) ; risk ratio , 0.211 ; 95 % CI , 0.044 - 1.019 ; p = 0.036 ] . Statistically significant reduction in the sepsis-attributable mortality was also seen after use of prophylactic BLF [ 0/63 ( 0 % ) vs. 5/67 ( 7.5 % ) ; p = 0.027 ] . CONCLUSION BLF  supplementation in LBW neonates reduced the incidence of first episode of LOS Lactoferrin has broad-spectrum antimicrobial activity , and the authors hypothesized that recombinant human lactoferrin ( Talactoferrin alfa [ TLF ] ) would reduce mortality and morbidity in a coinfection model . The MIC50 ( minimum inhibitory concentration required to inhibit the growth of 50 % of organisms ) of TLF againstC and ida albicans and Staphylococcus epidermidis was determined . Neonatal Wistar rats were infected withCalbicans orS epidermidis or both , at doses of 2 × 108 colony-forming units ( CFUs ) given subcutaneously . Rat pups in each group were r and omly given TLF intraperitoneally at 40 mg/kg/dose or 300 mg/kg/dose , or saline in 0.2 mL , once a day for 4 d and were monitored for mortality , weight gain , and blood culture positivity . Trough serum levels of TLF were measured at 24 , 48 , 72 , 96 , and 144 h. MIC50 of TLF was 30 μg/mL and 500 μg/mL forC albicans and Sepidermidis , respectively . TLF prophylaxis significantly improved survival in the coinfection group at 40 mg/kg/dose ( by 16.1 % ; P=.019 ) and at 300 mg/kg/dose ( by 15.1 % ; P=.027 ) and in the Sepidermidis group at a dose of 40 mg/kg/dose ( by 1 8.6 % ; P=.04 ) . Weight gain was not affected by TLF prophylaxis . Serum trough levels of TLF were 1000-fold lower than in vitro MIC50 . The authors conclude that lactoferrin prophylaxis significantly enhanced survival in coinfection and in the subgroupof S epidermidis infection ( 40 mg/kg/dose ) through indirect mechanisms Summary Background : Lactoferrin is an iron-binding glycoprotein first identified in breast milk as a protein product of mammary epithelial cells . Its immunomodulatory functions include activation of NK and lymphokine-activated killer cells and enhancement of PMN and macrophage cytotoxicity . Studies in animal models have shown promising anti-cancer activity . The purpose of the present study was to evaluate the safety and tolerability of talactoferrin alfa ( talactoferrin ; TLF ) in humans , as well as pharmacokinetics and pharmacodynamics . Methods : Ten adult patients with progressive advanced solid tumors who had failed conventional chemotherapy  were administered oral TLF at doses from 1.5 to 9 g/day , using a 2 weeks on , 2 weeks off schedule . Patients were evaluated for drug toxicity , tumor growth rate , talactoferrin pharmacokinetics and cytokine markers . Results : Talactoferrin was very well tolerated . No hematological , hepatic , or renal toxicities were reported . A single patient had Grade 2 diarrhea , and there were no Grade 3 or 4 toxicities . Following oral administration , significant levels of talactoferrin  were undetectable in circulation , but a statistically significant increase in circulating IL-18 , a pharmacodynamic indicator of talactoferrin activity , was observed . Of the eight patients who were radiologically evaluable , five ( 63 % ) had stable disease by RECIST criteria two months after start of therapy , including one patient with a minor response . Seven patients ( 88 % ) had a decrease in their tumor growth rate . The three patients with non-small cell lung cancer ( NSCLC ) all survived for at least one year following the start of talactoferrin monotherapy . Conclusions : Talactoferrin is a promising , well-tolerated new agent that should be evaluated further in patients with refractory metastatic cancer CONTEXT Sepsis is a common and severe complication in premature neonates , particularly those with very low birth weight ( VLBW ) ( < 1500 g ) . Whether lactoferrin , a mammalian milk glycoprotein involved in innate immune host defenses , can reduce the incidence of sepsis is unknown . In animal models , the probiotic Lactobacillus rhamnosus GG ( LGG ) enhances the activity of lactoferrin but has not been studied in human infants . OBJECTIVE To establish whether bovine lactoferrin ( BLF ) , alone or in combination with LGG , reduces the incidence of late-onset sepsis in VLBW neonates . DESIGN , SETTING , AND PATIENTS Prospect i ve , multicenter , double-blind , placebo-controlled , r and omized trial conducted in 11 Italian tertiary neonatal intensive care units . Patients were 472 VLBW infants enrolled from October 1 , 2007 , through July 31 , 2008 , and assessed until discharge for development of sepsis . INTERVENTION Infants were r and omly assigned to receive orally administered BLF ( 100 mg/d ) alone ( n = 153 ) , BLF plus LGG ( 6 x 10(9 ) colony-forming units/d ) ( n = 151 ) , or placebo ( n = 168 ) from birth until day 30 of life ( day 45 for neonates < 1000 g at birth ) . MAIN OUTCOME MEASURE First episode of late-onset sepsis , ie , sepsis occurring more than 72 hours after birth with isolation of any pathogen from blood or from peritoneal or cerebrospinal fluid . RESULTS Demographic , clinical , and management characteristics of the 3 groups were similar , including type of feeding and intake of maternal milk . Incidence of late-onset sepsis was significantly lower in the BLF and BLF plus LGG groups ( 9/153 [ 5.9 % ] and 7/151 [ 4.6 % ] , respectively ) than in the control group receiving placebo ( 29/168 [ 17.3 % ] ) ( risk ratio , 0.34 ; 95 % confidence interval , 0.17 - 0.70 ; P = .002 for BLF vs control and risk ratio , 0.27 ; 95 % confidence interval , 0.12 - 0.60 ; P < .001 for BLF plus LGG vs control ) . The decrease occurred for both bacterial and fungal sepsis . No adverse effects or intolerances to treatment occurred . CONCLUSION Compared with placebo , BLF supplementation alone or in combination with LGG reduced the incidence of a first episode of late-onset sepsis in VLBW neonates . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N53107700 Background : Early onset neonatal sepsis ( EOS , occurring in the first 72 hours of life ) remains an important cause of illness and death among very low birth weight ( VLBW ) preterm infants . We previously reported a change in the distribution of pathogens associated with EOS from predominantly Gram-positive to primarily Gram-negative organisms . Objective : To compare rates of EOS and pathogens associated with infection among VLBW infants born at centers of the National Institute of Child Health and Human Development ( NICHD ) Neonatal Research Network during 3 time periods : 1991–1993 ; 1998–2000 ; and 2002–2003 . Study Design : Prospect ively collected data from the NICHD Neonatal Research Network VLBW registry were retrospectively review ed . Rates of blood culture confirmed EOS , selected maternal and infant variables and pathogens associated with infection were compared between 2002–2003 and 2 previously published cohorts . Results : During the past 13 years , overall rates of EOS have remained stable ( 15–19 per 1000 live births of infants 401–1500 g ) . More than one-half of early infections in the 2002–2003 cohort were caused by Gram-negative organisms ( 53 % ) , with Escherichia coli the most common organism ( 41 % ) . Rates of group B streptococcal infections remain low ( 1.8 per 1000 live births ) . Between 1991–1993 and 1998–2000 , there was a significant increase in rates of E. coli infections ; but in 2002–2003 , there was no significant change ( 7.0 per 1000 live births ) . Infants with EOS continue to be at significantly increased risk for death compared with uninfected infants . Conclusion : EOS remains an uncommon but important cause of morbidity and mortality among VLBW infants . Gram-negative organisms continue to be the predominant pathogens associated with EOS Hepatitis C virus ( HCV ) is associated with the development of cirrhosis and hepatocellular carcinoma . We recently found that bovine lactoferrin , a milk protein belonging to the iron transporter family , effectively prevented HCV infection in cultured human hepatocytes ( PH5CH8 ) . We tested the hypothesis that lactoferrin inhibits HCV viremia in patients with chronic hepatitis C. Eleven patients with chronic hepatitis C received an 8‐week course of bovine lactoferrin ( 1.8 or 3.6 g/day ) . At the end of lactoferrin treatment , a decrease in serum alanine transaminase and HCV RNA concentrations was apparent in 3 ( 75 % ) of 4 patients with low pretreatment serum concentrations of HCV RNA . However , 7 patients with high pretreatment concentrations showed no significant changes in these indices . This pilot study suggests that lactoferrin is one potential c and i date as an anti‐HCV reagent that may be effective for the treatment of patients with chronic hepatitis OBJECTIVE Late-onset sepsis ( occurring after 3 days of age ) is an important problem in very low birth weight ( VLBW ) infants . To determine the current incidence of late-onset sepsis , risk factors for disease , and the impact of late-onset sepsis on subsequent hospital course , we evaluated a cohort of 6956 VLBW ( 401 - 1500 g ) neonates admitted to the clinical centers of the National Institute of Child Health and Human Development Neonatal Research Network over a 2-year period ( 1998 - 2000 ) . METHODS The National Institute of Child Health and Human Development Neonatal Research Network maintains a prospect i ve registry of all VLBW neonates admitted to participating centers within 14 days of birth . Exp and ed infection surveillance was added in 1998 . RESULTS Of 6215 infants who survived beyond 3 days , 1313 ( 21 % ) had 1 or more episodes of blood culture-proven late-onset sepsis . The vast majority of infections ( 70 % ) were caused by Gram-positive organisms , with coagulase-negative staphylococci accounting for 48 % of infections . Rate of infection was inversely related to birth weight and gestational age . Complications of prematurity associated with an increased rate of late-onset sepsis included patent ductus arteriosus , prolonged ventilation , prolonged intravascular access , bronchopulmonary dysplasia , and necrotizing enterocolitis . Infants who developed late-onset sepsis had a significantly prolonged hospital stay ( mean length of stay : 79 vs 60 days ) . They were significantly more likely to die than those who were uninfected ( 18 % vs 7 % ) , especially if they were infected with Gram-negative organisms ( 36 % ) or fungi ( 32 % ) . CONCLUSIONS Late-onset sepsis remains an important risk factor for death among VLBW preterm infants and for prolonged hospital stay among VLBW survivors . Strategies to reduce late-onset sepsis and its medical , social , and economic toll need to be addressed urgently CONTEXT Neonatal infections are frequent complications of extremely low-birth-weight ( ELBW ) infants receiving intensive care . OBJECTIVE To determine if neonatal infections in ELBW infants are associated with increased risks of adverse neurodevelopmental and growth sequelae in early childhood . DESIGN , SETTING , AND PARTICIPANTS Infants weighing 401 to 1000 g at birth ( born in 1993 - 2001 ) were enrolled in a prospect ively collected very low-birth-weight registry at academic medical centers participating in the National Institute of Child Health and Human Development Neonatal Research Network .  Neurodevelopmental and growth outcomes were assessed at a comprehensive follow-up visit at 18 to 22 months of corrected gestational age and compared by infection group . Eighty percent of survivors completed the follow-up visit and 6093 infants were studied . Registry data were used to classify infants by type of infection : uninfected ( n = 2161 ) , clinical infection alone ( n = 1538 ) , sepsis ( n = 1922 ) , sepsis and necrotizing enterocolitis ( n = 279 ) , or meningitis with or without sepsis ( n = 193 ) . MAIN OUTCOME MEASURES Cognitive and neuromotor development , neurologic status , vision and hearing , and growth ( weight , length , and head circumference ) were assessed at follow-up . RESULTS The majority of ELBW survivors ( 65 % ) had at least 1 infection during their hospitalization after birth . Compared with uninfected infants , those in each of the 4 infection groups were significantly more likely to have adverse neurodevelopmental outcomes at follow-up , including cerebral palsy ( range of significant odds ratios [ ORs ] , 1.4 - 1.7 ) , low Bayley Scales of Infant Development II scores on the mental development index ( ORs , 1.3 - 1.6 ) and psychomotor development index ( ORs , 1.5 - 2.4 ) , and vision impairment ( ORs , 1.3 - 2.2 ) . Infection in the neonatal period was also associated with impaired head growth , a known predictor of poor neurodevelopmental outcome . CONCLUSIONS This large cohort study suggests that neonatal infections among ELBW infants are associated with poor neurodevelopmental and growth outcomes in early childhood . Additional studies are needed to eluci date the pathogenesis of brain injury in infants with infection so that novel interventions to improve these outcomes can be explored Background : Lactoferrin is a mammalian milk glycoprotein involved in innate immunity . Recent data show that bovine lactoferrin ( bLF ) prevents late-onset sepsis in preterm very low birth weight ( VLBW ) neonates . Methods : This is a secondary analysis of data from a multicenter r and omized controlled trial where preterm VLBW neonates r and omly received bLF ( 100 mg/day ; group A1 ) , bLF + Lactobacillus rhamnosus GG ( 106 colony-forming units per day ; group A2 ) , or placebo ( group B ) for 6 weeks . Here we analyze the incidence rates of fungal colonization , invasive fungal infection ( IFI ) , and rate of progression from colonization to infection in all groups . Results : This study included 472 neonates whose clinical , nutritional , and demographical characteristics were similar . Overall , the incidence of fungal colonization was comparable ( 17.6 % , 16.6 % , and 18.5 % in A1 , A2 , and B , respectively ; P = .89 [ A1 ] and .77 [ A2 ] ) . In contrast , IFIs were significantly decreased in A1 and A2 ( 0.7 % and 2.0 % , respectively ) compared with B ( 7.7 % ; P = .002 [ A1 ] and .02 [ A2 ] ) , and this was significantly true both in < 1000 g ( 0.9 % [ A1 ] and 5.6 % [ A2 ] , vs 15.0 % ) and in 1001 to 1500 g infants ( 0 % and 0 % vs 3.7 % ) . The progression rate colonization-infection was significantly lower in the bLF groups : 3.7 % ( A1 ) and 12 % ( A2 ) , vs 41.9 % ; P < .001 ( A1 ) and P = .02 ( A2 ) . No IFI-attributable deaths occurred in the treatment groups , versus 2 in placebo . No adverse effects or intolerances occurred . Conclusions : Prophylactic oral administration of bLF reduces the incidence of IFI in preterm VLBW neonates . No effect is seen on colonization . The protective effect on IFI is likely due to limitation of ability of fungal colonies to progress toward invasion and systemic disease in colonized infants OBJECTIVE 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 . STUDY DESIGN In this prospect i ve , placebo-controlled , double-blind , r and omized 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 ) . RESULTS 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 . CONCLUSION 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 OBJECTIVE To determine the effect of bovine lactoferrin ( bLF ) on prevention of diarrhea in children . STUDY DESIGN We conducted a community-based r and omized double-blind placebo controlled trial comparing supplementation with bLF vs placebo .  Previously weaned children were enrolled at 12 - 18 months and followed for 6 months with daily home visits for data collection and supplement administration . Anthropometric measures were done monthly . RESULTS Five hundred fifty-five children were r and omized : 277 to bLF and 278 to placebo ; 65 dropped out ; 147 894 doses were administered ( 92 % compliance ) . Overall there were 91 446 child-days of observation and 1235 diarrhea episodes lasting 6219 days . The main pathogens isolated during diarrheal episodes were norovirus ( 35.0 % ) , enteropathogenic E coli ( 11.4 % ) , Campylobacter ( 10.6 % ) , enteroaggregative E coli ( 8.4 % ) , enterotoxigenic E coli ( 6.9 % ) , and Shigella ( 6.6 % ) . The diarrhea incidence was not different between groups : 5.4 vs 5.2 episodes/child/year for bLF and placebo , respectively ( P = .375 ) . However , the diarrhea longitudinal prevalence was lower in the bLF group vs placebo ( 6.6 % vs 7.0 % , P = .017 ) , as well as the median duration of episodes ( 4.8 vs 5.3 days , P = .046 ) , proportion of episodes with moderate or severe dehydration ( 1.0 % vs 2.6 % , P = .045 ) , and liquid stools load ( 95.0 vs 98.6 ) liquid stools/child/year , P < .001 ) . There were no adverse events related to the intervention . CONCLUSIONS Although there was no decrease in diarrhea incidence , longitudinal prevalence and severity were decreased with LF BACKGROUND Preterm infants remain at high risk of adverse outcomes following necrotizing enterocolitis  ( NEC ) and late onset sepsis ( LOS ) . Meta- analysis of r and omized 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 . METHODS 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 . RESULTS 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 . CONCLUSION The rates of severe NEC was markedly reduced following prophylaxis . The case of LGG sepsis indicates caution is required in extremely preterm infants Objective : To determine tolerability of bovine lactoferrin ( bLF ) in very preterm infants , and whether the intervention can be adequately masked . Study Design : In a single-center masked pilot trial infants under 31 weeks gestation were r and omized 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 question naire regarding acceptability of the intervention . Results : 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 . Conclusion : We demonstrated that bLF is well tolerated , easy to administer and its presence in prepared milk is not evident . Trial registration number IS RCT N66482337 IMPORTANCE 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 . OBJECTIVE 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 . DESIGN An international , multicenter , r and omized , double-blind , placebo-controlled trial conducted from October 1st , 2007 through July 31st , 2010 . SETTING Thirteen Italian and New Zeal and tertiary neonatal intensive care units . PARTICIPANTS 743 VLBW neonates were assessed until discharge for development of NEC . INTERVENTION Infants were r and omly 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 ) . MAIN OUTCOME MEASURES ≥ stage 2 NEC ; death- and /or-≥ stage 2 NEC prior to discharge . RESULTS 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 . CONCLUSIONS AND RELEVANCE 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 setting s. Further data on larger sample sizes are warranted before BLF can be widespreadly used in clinical setting s. TRIAL REGISTRATION IS RCT N53107700-http://www.controlled-_trials.com/IS RCT N53107700 The National Institute of Child Health and Human Development conducts and supports research on all stages of human development from preconception to adulthood in order to better underst and the health of children , youths , adults , families , and communities . Health and human development information is made easily available on the site with a simple A to Z list , along with clinical trials and health education campaign information . Links to clinical trials , news releases , publications , and related web sites are also available , as well as information on research being conducted at present and supported by the National Institute of Child Health and Human Development Background : Lactoferrin ( LF ) is a broad-spectrum antimicrobial and immunomodulatory milk glycoprotein . Objective : To determine the effect of bovine LF on the prevention of the first episode of late-onset sepsis in Peruvian infants . Methods : We conducted a pilot r and omized placebo-controlled double blind study in infants with a birth weight ( BW ) less than 2500 g in 3 Neonatal Units in Lima . Patients were r and omized to receive bovine LF 200mg/kg/d or placebo for 4 weeks . Results : One hundred and ninety neonates with a BW of 1591 ± 408 g and a gestational age of 32.1 ± 2.6 weeks were enrolled . Overall , 33 clinical ly defined first late-onset sepsis events occurred . The cumulative sepsis incidence in the LF group was 12/95 ( 12.6 % ) versus 21/95 ( 22.1 % ) in the placebo group , and 20 % ( 8/40 ) versus 37.5 % ( 15/40 ) for infants less than or equal to 1500 g. The hazard ratio of LF , after adjustment by BW , was 0.507 ( 95 % CI : 0.249–1.034 ) . There were 4 episodes of culture-proven sepsis in the LF group versus 4 in the placebo group . Considering that children did not received the intervention until the start of oral or tube feeding , we ran a secondary exploratory analysis using time since the start of the treatment ; in this model , LF achieved significance . There were no serious adverse events attributable to the intervention . Conclusions : Overall sepsis occurred less frequently in the LF group than in the control group . Although the primary outcome did not reach statistical significance , the confidence interval is suggestive of an effect that justifies a larger trial OBJECTIVE To evaluate the safety and explore the efficacy of recombinant human lactoferrin ( talactoferrin [ TLf ] ) to reduce infection . STUDY DESIGN We conducted a r and omized , 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 data base used for statistical analyses . RESULTS 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 . CONCLUSION We found no clinical or laboratory toxicity and a trend toward less infectious morbidity in the infants treated with TLf . TRIAL REGISTRATION Clinical Trials.gov : NCT00854633 Background : Lactoferrin has an array of biological activities that include growth , immune modulation , and antimicrobial effects . The aim of this r and omized , placebo-controlled , double-blind study was to examine the impact of bovine lactoferrin supplementation in infants . Patients and Methods : Healthy , formula-fed infants , ≥34 weeks ' gestation and ≤4 weeks of age , enrolled in a pediatric clinic . Infants received either formula supplemented with lactoferrin ( 850 mg/L ) or commercial cow milk – based formula ( 102 mg/L ) for 12 months . Growth parameters and information on gastrointestinal , respiratory , and colic illnesses were collected for the infants ' first year . Antibodies to immunizations and hematologic parameters were measured at 9 and 12 months . Results : The lactoferrin-enhanced formula was well tolerated . There were significantly fewer lower respiratory tract illnesses , primarily wheezing , in the 26 lactoferrin-fed ( 0.15 episodes/y ) compared with the 26 regular formula-fed ( 0.5 episodes/y ) infants ( P < 0.05 ) . Significantly higher hematocrit levels at 9 months ( 37.1 % vs 35.4 % ; P < 0.05 ) occurred in the lactoferrin-supplemented group compared with the control formula group . Conclusions : Lactoferrin supplementation was associated with potentially beneficial outcomes such as significantly fewer lower respiratory tract illnesses and higher hematocrits . Larger , more focused studies in infants are warranted
target: 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 .
background: BACKGROUND Lactoferrin , a normal component of human colostrum and milk , can enhance host defenses and may be effective for prevention of sepsis and necrotizing enterocolitis ( NEC ) in preterm neonates .
  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 .
  Type of feeding : breast milk versus formula milk SEARCH METHODS : We used the search strategy of the Cochrane Neonatal Review Group ( CNRG ) to up date our search in December 2016 .