Enteral lactoferrin to prevent infection for very preterm infants: the ELFIN RCT. Reduction in necrotizing enterocolitis and improved outcomes in preterm infants following routine supplementation with Lactobacillus GG in combination with bovine lactoferrin. Randomized Trial of Donor Human Milk Versus Preterm Formula as Substitutes for Mothers' Own Milk in the Feeding of Extremely Premature Infants Bovine lactoferrin supplementation for prevention of necrotizing enterocolitis in very-low-birth-weight neonates: a randomized clinical trial. Lactobacillus Reuteri for the prevention of necrotising enterocolitis in very low birthweight infants: a randomised controlled trial Oral Probiotics Prevent Necrotizing Enterocolitis in Very Low Birth Weight Preterm Infants: A Multicenter, Randomized, Controlled Trial The Effect of Neutral Oligosaccharides on Reducing the Incidence of Necrotizing Enterocolitis in Preterm infants: A Randomized Clinical Trial Effect of oral probiotics supplementation in the prevention of necrotizing enterocolitis among very low birth weight preterm infants. Oral lactoferrin to prevent nosocomial sepsis and necrotizing enterocolitis of premature neonates and effect on T-regulatory cells. Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial Does fortification of pasteurized donor human milk increase the incidence of necrotizing enterocolitis among preterm neonates? A randomized controlled trial Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial. Efficacy of Probiotics Versus Placebo in the Prevention of Necrotizing Enterocolitis in Preterm Very Low Birth Weight Infants: A Double-Blind Randomized Controlled Trial. Is Lactoferrin More Effective in Reducing Late-Onset Sepsis in Preterm Neonates Fed Formula Than in Those Receiving Mother's Own Milk? Secondary Analyses of Two Multicenter Randomized Controlled Trials. Probiotics Feeding in Prevention of Urinary Tract Infection, Bacterial Sepsis and Necrotizing Enterocolitis in Preterm Infants Necrotizing enterocolitis - classification and two initial steps towards prevention. Oral probiotics: Lactobacillus sporogenes for prevention of necrotizing enterocolitis in very low-birth weight infants: a randomized, controlled trial
BACKGROUND Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants . Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin , an antimicrobial protein processed from cow 's milk , prevents infections and associated complications . OBJECTIVE To determine whether or not enteral supplementation with bovine lactoferrin ( The Tatua Cooperative Dairy Company Ltd , Morrinsville , New Zeal and ) reduces the risk of late-onset infection ( acquired > 72 hours after birth ) and other morbidity and mortality in very preterm infants . DESIGN R and omised , placebo-controlled , parallel-group trial . R and omisation was via a web-based portal and used an algorithm that minimised for recruitment site , weeks of gestation , sex and single versus multiple births . SETTING UK neonatal units between May 2014 and September 2017 . PARTICIPANTS Infants born at < 32 weeks ' gestation and aged < 72 hours at trial enrolment . INTERVENTIONS 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 . OUTCOMES Primary outcome - microbiologically confirmed or clinical ly 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 setting s. RESULTS 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 setting s. There were 16 reports of serious adverse events for infants in the lactoferrin group and 10 for infants in the sucrose group . CONCLUSIONS Enteral supplementation with bovine lactoferrin does not reduce the incidence of infection , mortality or other morbidity in very preterm infants . FUTURE WORK 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 . TRIAL REGISTRATION Current Controlled Trials IS RCT N88261002 . FUNDING This project was funded by the National Institute for Health Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol . 22 , No. 74 . See the NIHR Journals Library website for further project information . This trial was also sponsored by the University of Oxford , Oxford , UK . The funder provided advice and support and monitored study progress but did not have a role in study design or data collection , analysis and interpretation 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 . Compared with preterm formula ( PF ) , mother 's milk ( MM ) is associated with lower rates of late-onset sepsis ( LOS ) and necrotizing enterocolitis ( NEC ) among premature infants . Because not all mothers of premature infants produce sufficient milk to supply their infants throughout hospitalization , we reasoned that pasteurized donor human milk ( DM ) would be a suitable alternative . Methods . Extremely premature infants ( < 30 weeks of gestation ) whose mothers intended to breastfeed were assigned r and omly to receive either pasteurized DM or PF if the supply of their own MM became insufficient during the study ( birth to 90 days of age or hospital discharge ) . Infection-related events ( LOS , NEC , meningitis , presumed sepsis , or urinary tract infection ) that occurred after the attainment of a milk intake of 50 mL/kg , dietary intake , growth , skin-to-skin contact , and duration of hospital stay were compared . The primary analysis compared groups DM and PF on an intent-to-treat basis . If no differences were noted , then these groups were combined and compared with the reference group , group MM . If differences were noted , then the subsequent analyses compared each group with group MM . Results . Of 243 infants , 70 ( 29 % ) received only MM ; group DM included 81 infants and group PF included 92 infants . Because of poor weight gain , 17 infants ( 21 % ) , all in group DM , were switched to PF . There were no differences in birth weight , gestational age , multiple births , and age at attainment of feeding of 50 mL/kg among groups . There were no differences between group DM and group PF in LOS and /or NEC , other infection-related events , hospital stay , or number of deaths . Group DM received a greater intake of milk and more nutritional supplements but had a slower rate of weight gain , compared with group PF . Compared with groups DM and PF , group MM had fewer episodes of LOS and /or NEC and total infection-related events and a shorter duration of hospital stay . Group MM also had fewer Gram-negative organisms isolated from blood cultures than did the other groups . Conclusions . In this r and omized , blinded trial of feeding of extremely premature infants , we found that , as a substitute for MM , DM offered little observed short-term advantage over PF for feeding extremely premature infants . Advantages to an exclusive diet of MM were observed in terms of fewer infection-related events and shorter hospital stays 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 Objective To evaluate the effect of oral Lactobacillus reuteri ( L reuteri ) first on the incidence and severity of Necrotising enterocolitis ( NEC ) and second on sepsis . Design Prospect i ve r and omised controlled study . Setting Tertiary neonatal intensive care unit . Patients and interventions Preterm infants with a gestational age of ≤32 weeks and a birth weight of ≤1500 g were included ( n=400 ) . Infants in the first group were given 100 million CFU/day ( 5 drops ) of lyophilised L reuteri ( DSM 17938 ) mixed in breast milk or formula , starting from first feeding until discharge . Participants in the control group were given a placebo . Main outcome measures To determine and compare the frequency of NEC and /or death after 7 days , frequency of proven sepsis , rates of feeding intolerance and duration of hospital stay . Results There was no statistically significant difference between groups in terms of frequency of NEC stage ≥2 ( 4 % vs 5 % ; p=0.63 ) or overall NEC or mortality rates ( 10 % vs 13.5 % ; p=0.27 ) . Frequency of proven sepsis was significantly lower in the probiotic group compared to the control group ( 6.5 % vs 12.5 % ; p=0.041 ) . A significant difference was also observed with regard to rates of feeding intolerance ( 28 % vs 39.5 % ; p=0.015 ) and duration of hospital stay ( 38 ( 10–131 ) vs 46 ( 10–180 ) days ; p=0.022 ) . Conclusions Our results show that oral L reuteri does not seem to affect the overall rates of NEC and /or death in preterm infants followed up in the neonatal intensive care unit , and significant reductions were observed in the frequency of proven sepsis , rates of feeding intolerance and duration of hospital stay . Trial registration number NCT01531179 OBJECTIVE . The goal was to investigate the efficacy of orally administered probiotics in preventing necrotizing enterocolitis for very low birth weight preterm infants . METHODS . A prospect i ve , blinded , r and omized , multicenter controlled trial was conducted at 7 NICUs in Taiwan , to evaluate the beneficial effects of probiotics in necrotizing enterocolitis among very low birth weight infants ( birth weight : < 1500 g ) . Very low birth weight infants who survived to start enteral feeding were eligible and were assigned r and omly to 2 groups after parental informed consent was obtained . Infants in the study group were given Bifidobacterium bifidum and Lactobacillus acidophilus , added to breast milk or mixed feeding ( breast milk and formula ) , twice daily for 6 weeks . Infants in the control group were fed with breast milk or mixed feeding . The clinicians caring for the infants were blinded to the group assignment . The primary outcome measurement was death or necrotizing enterocolitis ( Bell 's stage ≥2 ) . RESULTS . Four hundred thirty-four infants were enrolled , 217 in the study group and 217 in the control group . The incidence of death or necrotizing enterocolitis ( stage ≥2 ) was significantly lower in the study group ( 4 of 217 infants vs 20 of 217 infants ) . The incidence of necrotizing enterocolitis ( stage ≥2 ) was lower in the study group , compared with the control group ( 4 of 217 infants vs 14 of 217 infants ) . No adverse effect , such as sepsis , flatulence , or diarrhea , was noted . CONCLUSION . Probiotics , in the form of Bifidobacterium and Lactobacillus , fed enterally to very low birth weight preterm infants for 6 weeks reduced the incidence of death or necrotizing enterocolitis Background : Necrotizing enterocolitis ( NEC ) is one of the most destructive diseases associated with conditions of neonatal prematurity . Supplementation with enteral prebiotics may reduce the incidence of NEC , especially in infants who fed exclusively with breast-milk . Therefore , we compared the efficacy and safety of enteral supplementation of a prebiotic mixture ( short chain galacto-oligosaccharides/long chain fructo-oligosaccharides [ SCGOS/LCFOS ] ) versus no intervention on incidence of NEC in preterm infants . Methods : In a single-center r and omized control trial 75 preterm infants ( birth weight [ BW ] ≤1500 g , gestational age ≤34 weeks and were not fed with formula ) on 30 ml/kg/day volume of breast-milk were r and omly allocated to have enteral supplementation with a prebiotic mixture ( SCGOS/LCFOS ; 9:1 ) or not receive any prebiotic . The incidence of suspected NEC , feeding intolerance , time to full enteral feeds , duration of hospitalization were investigated . Results : Differences in demographic characteristics were not statistically important . SCGOS/LCFOS mixture significantly reduced the incidence of suspected NEC , ( 1 [ 4.0 % ] vs. 11 [ 22.0 % ] ; hazard ratio : 0.49 [ 95 % confidence interval : 0.29 - 0.84 ] ; P = 0.002 ) , and time to full enteral feeds ( 11 [ 7 - 21 ] vs. 14 [ 8 - 36 ] days ; P - 0.02 ] . Also duration of hospitalization was meaningfully shorter in the prebiotic group ( 16 [ 9 - 45 ] vs. 25 [ 11 - 80 ] ; P - 0.004 ] . Prebiotic oligosaccharides were well tolerated by very low BW ( VLBW ) infants . Conclusions : Enteral supplementation with prebiotic significantly reduced the incidence of NEC in VLBW infants who were fed exclusively breast-milk . This finding suggests that it might have been the complete removal of formula which caused a synergistic effect between nonhuman neutral oligosaccharides ( prebiotic ) and human oligosaccharides BACKGROUND Necrotizing enterocolitis ( NEC ) is the most serious gastrointestinal problem in very low birth weight preterm infants . Multiple risk factors activate the inflammatory cascade leading to high expressions of pro-inflammatory mediators causing bowel injury in NEC . The anti-inflammatory effect of probiotics is due to the inhibition and reduction of inflammatory signal in intestinal epithelium . OBJECTIVE To evaluate the efficacy of probiotics supplementation in the prevention of NEC among very low birth weight preterm infants . STUDY DESIGN A prospect i ve r and omized controlled trial . MATERIAL AND METHOD All preterm infants with gestational age less than or equal to 34 weeks and birth weight less than or equal to 1,500 grams admitted in neonatal care unit , Queen Sirikit National Institute of Child Health during June 1st , 2012 and January 31th , 2013 were enrolled in this study . They were r and omized into two groups , study and control group . Infants in the study group were fed Infloran ( Lactobacillus acidophilus 1 x 10(9 ) and Bifidobacterium bifidum 1 x 10(9 ) organisms ) dose 125 mg/kg/dose twice a day with breast milk or premature formula from the start of feeding until 6 weeks or discharge . Infants in the control group were fed with either breast milk or premature formula alone . The primary outcome was NEC stage ≥ 2 . RESULTS Sixty infants completed the study , 31 infants in the study group and 29 infants in the control group . The baseline characteristic data of infants were similar except for more males in the present study group . Incidence of NEC stage ≥ 2 were similar in both the groups , 3.2 vs. 3.4 % ( p = 0.74 ) . There were no deaths during the study period . Days to reach full feeding , 150 ml/kg/day , were no differences between the two groups , 12.03 ± 5.49 days vs. 13.76 ± 8.25 days ( p = 0.31 ) . No adverse effects such as sepsis , flatulence or diarrhea were noted . CONCLUSION In this study , there was no difference in incidence of NEC stage ≥ 2 between the two groups . No adverse effects of probiotics supplementation were observed 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 Summary Background Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants . Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin , an antimicrobial protein processed from cow 's milk , prevents infections and associated complications . The aim of this large r and omised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice . Methods In this r and omised placebo-controlled trial , we recruited very preterm infants born before 32 weeks ' gestation in 37 UK hospitals and younger than 72 h at r and omisation . Exclusion criteria were presence of a severe congenital anomaly , anticipated enteral fasting for longer than 14 days , or no realistic prospect of survival . Eligible infants were r and omly assigned ( 1:1 ) to receive either enteral bovine lactoferrin ( 150 mg/kg per day ; maximum 300 mg/day ; lactoferrin group ) or sucrose ( same dose ; control group ) once daily until 34 weeks ' postmenstrual age . Web-based r and omisation minimised for recruitment site , gestation ( completed weeks ) , sex , and single versus multifetal pregnancy . Parents , caregivers , and outcome assessors were unaware of group assignment . The primary outcome was microbiologically confirmed or clinical ly suspected late-onset infection ( occurring > 72 h after birth ) , which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95 % CI between the two groups . The trial is registered with the International St and ard R and omised Controlled Trial Number 88261002 . Findings We recruited 2203 participants between May 7 , 2014 , and Sept 28 , 2017 , of whom 1099 were assigned to the lactoferrin group and 1104 to the control group . Four infants had consent withdrawn or unconfirmed , leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group . Primary outcome data for 2182 infants ( 1093 [ 99·5 % ] of 1098 in the lactoferrin group and 1089 [ 99·0 ] of 1101 in the control group ) were available for inclusion in the modified intention-to-treat analyses . 316 ( 29 % ) of 1093 infants in the intervention group acquired a late-onset infection versus 334 ( 31 % ) of 1089 in the control group . The risk ratio adjusted for minimisation factors was 0·95 ( 95 % CI 0·86–1·04 ; p=0·233 ) . During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group . Two events in the lactoferrin group ( one case of blood in stool and one death after intestinal perforation ) were assessed as being possibly related to the trial intervention . Interpretation Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants . These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants . Funding UK National Institute for Health Research Health Technology Assessment programme ( 10/57/49 ) Abstract Objective : To compare the effect of fortified pasteurized donor human milk ( PDHM ) versus unfortified PDHM on the incidence of necrotizing enterocolitis ( NEC ) and immediate outcome among preterm neonates . Methods : This r and omized controlled trial ( RCT ) conducted in a tertiary care teaching hospital , south India included 80 healthy preterm neonates r and omized to two groups ( Group A and B ) . Neonates in Group A and B were fed with fortified PDHM and unfortified PDHM , respectively . Neonates in both groups were managed uniformly as per st and ard NICU protocol . The primary outcome was the incidence of NEC and the secondary outcomes included severity of NEC , incidence of sepsis , mortality , duration of hospital stay , number of days to reach full enteral feeds and weight gain . Neonates were followed up for 28 days or discharge whichever was earlier . Results : The baseline maternal and neonatal characteristics in both groups were comparable . There was no increase in incidence of NEC in fortified PDHM group compared to unfortified PDHM group ( 2.5 versus 7.5 % , p = .31 ) . Severity of NEC , incidence of sepsis , mortality , duration of hospital stay , number of days to reach full enteral feeds and weight gain were also similar in both groups . Conclusions : St and ard fortification of PDHM does not increase the incidence of NEC among preterm neonates 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 OBJECTIVE To evaluate the efficacy of orally administered probiotics in preventing necrotizing enterocolitis ( NEC ) in preterm very low birth weight ( VLBW ) infants . STUDY DESIGN Ar and omized double blind controlled trial . PLACE AND DURATION OF STUDY The Paediatrics Department of Sylhet M.A.G. Osmani Medical College Hospital , Sylhet Bangladesh , from July 2012 to June 2015 . METHODOLOGY Preterm ( 28 - 33 weeks gestation ) VLBW ( birth weight 1000 - 1499 g ) neonates were enrolled . The study group was fed with probiotics once daily with breast milk from first feeding , and the control group with only breast milk without the addition of probiotics . Both the groups received other st and ard care . The primary outcome was the development of NEC ( stage II and III ) , categorized by modified Bell 's classification . RESULTS In 108 neonates , development of NEC was significantly lower in the study group than that of control group [ 1 ( 1.9 % ) vs. 6 ( 11.5 % ) ; p=0.044 ] . Age of achievement of full oral feeding was significantly earlier in the study group than that in the control group ( 14.88 ±3.15 and 18.80 ±4.32 days ; p < 0.001 ) . Duration of hospital stay was significantly short in the study group compared to the control group ( 15.82 ±2.94 days vs. 19.57 ±4.26 days ; p < 0.001 ) . CONCLUSION Probiotic supplementation reduces the frequency of necrotising enterocolitis in preterm neonates with very low birth weight . It is also associated with faster achievement of full oral feeding and short duration of hospital stay BACKGROUND Lactoferrin is the major antimicrobial protein in human milk . In our r and omized controlled trial ( RCT ) of bovine lactoferrin ( BLF ) supplementation in preterm neonates , BLF reduced  late-onset sepsis ( LOS ) .  Mother 's own milk ( MM ) contains higher concentrations of lactoferrin than donor milk or formula , but whether BLF is more effective in infants who receive formula or donor milk is uncertain . AIM To evaluate the incidence of LOS in preterm infants fed MM and in those fed formula and /or donor milk . STUDY DESIGN This is a ( A ) post hoc subgroup analysis , in our RCT of BLF , of its effects in preterm infants fed MM , with or without formula , versus those fed formula and /or donor milk ( no-MM ) and ( B ) post hoc meta- analysis , in our RCT of BLF and in the ELFIN ( Enteral Lactoferrin in Neonates ) RCT , of the effect of BLF in subgroups not exclusively fed MM . RESULTS ( A ) Of 472 infants in our RCT , 168 were r and omized to placebo and 304 were r and omized to BLF . Among MM infants , LOS occurred in 22/133 ( 16.5 % ) infants r and omized to placebo and in 14/250 ( 5.6 % ) r and omized to BLF ( relative risk or risk ratio ( RR ) : 0.34 ; relative risk reduction ( RRR ) : 0.66 ; 95 % confidence interval ( 95 % CI ) for RR : 0.18 - 0.64 ; p < 0.0008 ) . Among no-MM infants , LOS occurred in 7/35 ( 20.0 % ) r and omized to placebo and in 2/54 ( 3.7 % ) r and omized to BLF ( RR : 0.19 ; RRR : 0.81 ; 95 % CI for RR : 0.16 - 0.96 ; p = 0.026 ) . In multivariable logistic regression analysis , there was no interaction between BLF treatment effect and type of feeding ( p = 0.628 ) . ( B ) In 1,891 infants not exclusively fed MM in our RCT of BLF and in the ELFIN RCT , BLF reduced the RR of LOS by 18 % ( RR : 0.82 ; 95 % CI : 0.71 - 0.96 ; p = 0.01 ) . CONCLUSION Adequately powered studies should address the hypothesis that BLF is more effective in infants fed formula or donor milk than those fed MM . Such studies should evaluate whether a specific threshold of total lactoferrin intake can be identified to protect such patients from LOS Background : It has been suggested that probiotics can reduce the overgrowth of pathogens in the bowels of preterm infants and contribute to the reduction of the incidence of nosocomial infections in neonatal intensive care units ( NICUs ) . The purpose of this study was to evaluate the effectiveness of Lactobacillus GG supplementation in reducing the incidence of urinary tract infections ( UTIs ) , bacterial sepsis and necrotizing enterocolitis ( NEC ) in preterm infants . Methods : A double-blind study was conducted in 12 Italian NICUs . Newborn infants with a gestational age <33 weeks or birthweight < 1,500 g were r and omized to receive st and ard milk feed supplemented with Lactobacillus GG ( Dicoflor ® , Dicofarm , Rome , Italy ) in a dose of 6 × 109 colony-forming units ( cfu ) once a day until discharge , starting with the first feed or placebo . Results : Five hundred eighty-five patients were studied . The probiotics group ( n = 295 ) and the placebo group ( n = 290 ) exhibited similar clinical characteristics . The duration  of Lactobacillus GG and placebo supplementation was 47.3 ± 26.0 and 48.2 ± 24.3 days , respectively . Although UTIs ( 3.4 vs. 5.8 % ) and NEC ( 1.4 vs. 2.7 % ) were found less frequently in the probiotic group compared to the control group , these differences were not significant . Bacterial sepsis was more frequent in the probiotics group ( 4.4 % , n = 11 ) than in the placebo group ( 3.8 % , n = 9 ) , but the difference was not significant . Conclusion : Seven days of Lactobacillus GG supplementation starting with the first feed is not effective in reducing the incidence of UTIs , NEC and sepsis in preterm infants . Further studies are required to confirm our results in lower birthweight population The premature infant suffers from immaturity of all organ systems , one of them being the gastrointestinal tract . When the infant is born , the immature gastrointestinal tract is exposed to milk and simultaneously colonized by high densities of bacteria . The combination of milk , microbiota and an immature gut , leaves the infant vulnerable to developing the dreaded intestinal emergency necrotizing enterocolitis ( NEC ) . NEC is often very aggressive and no cure exists , which means that prevention is an utmost important topic to research ers , physicians , parents - and infants . Despite immense research during the last decades , no specific test to determine if an infant suffers from NEC exists . Most neonatal units use Bell 's staging criteria , which are based on clinical and radiographic findings , as a diagnostic tool ; however the diagnosis given according to Bell 's stages has not been vali date d. In study I , we aim ed to determine the validity of the NEC diagnosis given at discharge . An expert panel consisting of a neonatologist , a paediatric surgeon and a paediatric radiologist served as the golden st and ard . We found that the diagnosis given at discharge had a poor validity which significantly affected the reported incidence of NEC in the neonatal department at Rigshospitalet , Denmark . The validity of the NEC diagnosis was worse than the validity of most other paediatric diagnoses that had been investigated . In studies II and III , we aim ed to explore possible means of NEC prevention . The role of nutrition in NEC development is well established with mother 's milk as the best option to avoid NEC in the preterm infant . Maternal milk is , however , most often not available in sufficient amounts during the first days of life , and preterm infant formula or human donor milk is used in its absence . Studies in preterm piglets showed that bovine colostrum equally to human donor milk protected against NEC compared to infant formula . Furthermore , bovine colostrum was superior to human donor milk in stimulating gut immunity and digestive functions . Hence , in study II we aim ed to design a pilot study of bovine colostrum used as a supplement to maternal milk in the first days of life and to determine if the study was feasible . In the paper , we present the protocol and the results of the first two phases of the Precolos study in which 12 infants were included and received pasteurized , spray-dried and reconstituted bovine colostrum during the first days of life as the first infants in the world . We found that the infants tolerated bovine colostrum without clinical adverse effects , but we also observed a transient hypertyrosinemia on day seven of life in five infants . The results were evaluated by a safety management board which encouraged us to continue the pilot study with the last phase , which was a r and omized controlled trial of 20 + 20 infants comparing supplementation with bovine colostrum to supplementation with st and ard nutrition . The r and omized trial has just finished recruitment . At last , we wanted to shed light on a possible microbiological angle of NEC prevention . Dysbiosis and bacterial translocation are believed to play a crucial role in the development of NEC as intestinal pneumatosis , which occurs when bacteria produce gas inside the intestinal wall , is a pathognomonic radiographic finding . In a quality improvement study from the US published in 2014 , NEC incidence was significantly reduced after the implementation of several quality improvement interventions . St and ardized weekly exchange of nasogastric feeding tubes was suggested as one of the potential NEC-reducing interventions . In the neonatal unit at Rigshospitalet , Denmark , preterm infants are fed 8 - 12 times daily through a resident nasogastric feeding tube which is exposed to body temperature , contains milk residuals from the last meal and is h and led by both parents and personnel . Since bacterial pollution of milk given through the nasogastric feeding tube might be NEC-inducing , we aim ed in study III to determine the bacterial load given to the infants when feeding them through a tube . We collected 92 used nasogastric feeding tubes and flushed them with one ml saline each to imitate a meal given through them . Eighty-nine percent of the tubes contaminated the meals with more than 1000 colony-forming units of bacteria and fifty-five percent contaminated the meals with the possible pathogens Enterobacteriaceae or Staphylococcus aureus . The concentration of bacteria in the saline flushed through the tubes was as high as 109 colony-forming units per ml ; however , neither the risk of contamination nor the concentration of bacteria in the flush was associated with the duration of use . Implementation of st and ardized weekly exchange of feeding tubes would therefore not prevent the contamination of meals . In conclusion , the studies included in this thesis serve as a base for future studies investigating the prevention of NEC . We found a poor validity of the NEC diagnosis given at discharge . This should be kept in mind when conducting epidemiological studies of NEC and especially when conducting interventional trials with NEC as an outcome . If the findings of the r and omized part of the Precolos study indicate a positive effect of bovine colostrum and do not give rise to concerns regarding feasibility , safety or tolerability , a large-scale r and omized controlled study with NEC as the primary outcome will be planned . Based on the high concentrations of bacteria found in the nasogastric feeding tubes , a r and omized controlled trial investigating whether the frequency of feeding tube exchange affects the early colonization has been commenced in the neonatal department at Rigshospitalet . Hopefully , the results of these studies will bring us closer to preventing NEC in the future Background / Objective : The identification of probiotic species involved in gut homeostasis and their potential therapeutic benefits have led to an interest in their use for preventing necrotizing enterocolitis ( NEC ) . Although bifidobacterium and lactobacilli sp. have been used to reduce the incidence of NEC in clinical trials . Lactobacillus sporogenes has not been used in the prevention of NEC in very low-birth weight infants yet . The objective of this study was to evaluate the efficacy of orally administered L sporogenes in reducing the incidence and severity of NEC in very low-birth weight ( VLBW ) infants . Subjects/ Methods : A prospect i ve , blinded , r and omized controlled trial was conducted in preterm infants with a gestational age of <33 weeks or birth weight of < 1500 g. VLBW infants who survived to start enteral feeding were r and omized into two groups The infants in the study group were given L. sporogenes with a dose of 350 000 000 c.f.u . added to breast milk or formula , once a day , starting with the first feed until discharged . The infants in the control group were fed without L. sporogenes supplementation . The primary outcome measurement was death or NEC ( Bell 's stage ⩾2 ) . Results : A total of 221 infants were studied : 110 in the study group and 111 in the control group . There was no significant difference in the incidence of death or NEC between the groups . Feeding intolerance was significantly lower in the probiotics group than in the control group ( 44.5 % ( n : 49 ) vs 63.1 % ( n : 70 ) , respectively ; P=0.006 ) . Conclusions : L. sporogenes supplementation at the dose of 350 000 000 c.f.u/day is not effective in reducing the incidence of death or NEC in VLBW infants , however , it could improve the feeding tolerance
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 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 .