title: Randomized trial of exclusive human milk versus preterm formula diets in extremely premature infants. Dietary Supplementation With Medium-Chain Triglycerides Reduces Candida Gastrointestinal Colonization in Preterm Infants Pasteurization of Mother’s Own Milk for Preterm Infants Does Not Reduce the Incidence of Late-Onset Sepsis Zinc supplementation reduces morbidity and mortality in very-low-birth-weight preterm neonates: a hospital-based randomized, placebo-controlled trial in an industrialized country. An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. Oral supplementation with Lactobacillus casei subspecies rhamnosus prevents enteric colonization by Candida species in preterm neonates: a randomized study. Arginine supplementation prevents necrotizing enterocolitis in the premature infant. The propre-save study: effects of probiotics and prebiotics alone or combined on necrotizing enterocolitis in very low birth weight infants. Randomized Controlled Trial of Talactoferrin Oral Solution in Preterm Infants. The effects of lactulose supplementation to enteral feedings in premature infants: a pilot study. Nutrient enrichment of human milk with human and bovine milk-based fortifiers for infants born weighing <1250 g: a randomized clinical trial. Enteral lactoferrin to prevent infection for very preterm infants: the ELFIN RCT. Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-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.
abstract: OBJECTIVE To compare the duration of parenteral nutrition , growth , and morbidity in extremely premature infants fed exclusive diets of either bovine milk-based preterm formula ( BOV ) or donor human milk and human milk-based human milk fortifier ( HUM )  , in a r and omized trial of formula vs human milk . STUDY DESIGN Multicenter r and omized controlled trial . The authors studied extremely preterm infants whose mothers did not provide their milk . Infants were fed either BOV or an exclusive human milk diet of pasteurized donor human milk and HUM . The major outcome was duration of parenteral nutrition . Secondary outcomes were growth , respiratory support , and necrotizing enterocolitis ( NEC ) . RESULTS Birth weight ( 983 vs 996 g ) and  gestational age ( 27.5 vs 27.7 wk ) , in BOV and HUM , respectively , were similar . There was a significant difference in median parenteral nutrition days : 36 vs 27 , in BOV vs HUM , respectively ( P = .04 ) . The incidence of NEC in BOV was 21 % ( 5 cases ) vs 3 % in HUM ( 1 case ) , P = .08 ; surgical NEC was significantly higher in BOV ( 4 cases ) than HUM ( 0 cases ) , P = .04 . CONCLUSIONS In extremely preterm infants given exclusive diets of preterm formula vs human milk , there was a significantly greater duration of parenteral nutrition and higher rate of surgical NEC in infants receiving preterm formula . This trial supports the use of an exclusive human milk diet to nourish extremely preterm infants in the neonatal intensive care unit Background : C and ida is an important cause of infections in premature infants . Gastrointestinal colonization with C and ida is a common site of entry for disseminated disease . The objective of this study was to determine whether a dietary supplement of medium-chain triglycerides ( MCTs ) reduces C and ida colonization in preterm infants . Methods : Preterm infants with C and ida colonization ( n = 12 ) receiving enteral feedings of either infant formula ( n = 5 ) or breast milk ( n = 7 ) were r and omized to MCT supplementation ( n = 8) or no supplementation ( n = 4 ) . Daily stool sample s were collected to determine fungal burden during a 3-week study period . Infants in the MCT group received supplementation during 1 week of the study period . The primary outcome was fungal burden during the supplementation period as compared with the periods before and after supplementation . Results : Supplementation of MCT led to a marked increase in MCT intake relative to unsupplemented breast milk or formula as measured by capric acid content . In the treatment group , there was a significant reduction in fungal burden during the supplementation period as compared with the period before supplementation ( rate ratio , 0.15 ; P = 0.02 ) , with a significant increase after supplementation was stopped ( rate ratio , 61 ; P < 0.001 ) . Fungal burden in the control group did not show similar changes . Conclusions : Dietary supplementation with MCT may be an effective method to reduce C and ida colonization in preterm infants Background : Feeding preterm infants human  milk has a beneficial effect on the risk of late-onset sepsis ( LOS ) . Due to lack of microbiological st and ards , practice s such as pasteurization of mother ’s own milk differ widely among neonatal intensive care units worldwide . Objectives : To investigate whether pasteurization of mother ’s own milk for very-low-birth-weight ( VLBW ) infants influences the incidence and severity of infection-related outcomes . Methods : In this r and omized controlled trial , preterm infants ( gestational age < 32 weeks and /or birth weight < 1,500 g ) received either raw or pasteurized mother ’s own milk during the first 8 weeks of life . The primary outcome was the incidence of proven LOS . A dose-response relation was verified , i.e. the dependence of the risk of sepsis on the actual and cumulative quantities of mother ’s own milk . Results : This study included 303 VLBW infants ( mean birth weight : 1,276 g ; mean gestational age : 29 weeks ) whose baseline and nutritional characteristics were similar . The incidence of laboratory-confirmed sepsis was not statistically different in infants fed raw milk compared to infants who received pasteurized milk : 22/151 ( 0.15 , CI : 0.08–0.20 ) and 31/152 ( 0.20 , CI : 0.14–0.27 ) , respectively ( RR : 0.71 ; 95 % CI : 0.43–1.17 ) . A significant dose-response relation was observed between the adjusted quantity of enteral feeding and the risk of LOS , regardless of the type of feeding . Conclusion : For preterm infants , pasteurization of mother ’s own milk shows a trend towards an increase in infectious morbidity , although no statistical significance was reached . Practice s should focus on collection , storage and labeling procedures to ensure the safety and quality of expressed milk BACKGROUND Zinc plays a pivotal role in the pathogenesis of many diseases and in body growth . Preterm neonates have high zinc requirements . OBJECTIVE The objective of the study was to investigate the efficacy of zinc supplementation in reducing morbidity and mortality in preterm neonates and to promote growth . DESIGN This was a prospect i ve , double-blind , r and omized controlled study of very-low-birth-weight preterm neonates r and omly allocated on the seventh day of life to receive ( zinc group ) or not receive ( control group ) oral zinc supplementation . Total prescribed zinc intake ranged from 9.7 to 10.7 mg/d in the zinc group and from 1.3 to 1.4 mg/d in the placebo control group . The main endpoint was the rate of neonates with ≥ 1 of the following morbidities : late-onset sepsis , necrotizing enterocolitis , bronchopulmonary dysplasia , periventricular leucomalacia , and retinopathy of prematurity . Secondary outcomes were mortality and body growth . RESULTS We enrolled 97 neonates in the zinc group and 96 in the control group .  Morbidities were significantly lower in the zinc group ( 26.8 % compared with 41.7 % ; P = 0.030 ) . The occurrence of necrotizing enterocolitis was significantly higher in the control group ( 6.3 % compared with 0 % ; P = 0.014 ) . Mortality risk was higher in the placebo control group ( RR : 2.37 ; 95 % CI : 1.08 , 5.18 ; P = 0.006 ) . Daily weight gain was similar in the zinc ( 18.2 ± 5.6 g · kg⁻¹ · d⁻¹ ) and control ( 17.0 ± 8.7 g · kg⁻¹ · d⁻¹ ) groups ( P = 0.478 ) . CONCLUSION Oral zinc supplementation given at high doses reduces morbidities and mortality in preterm neonates . This trial was registered in the Australian New Zeal and Clinical Trial Register as ACTRN12612000823875 OBJECTIVE To evaluate the health benefits of an exclusively human milk-based diet compared with a diet of both human milk and bovine milk-based products in extremely premature infants . STUDY DESIGN Infants fed their own mothers ' milk were r and omized to 1 of 3 study groups . Groups HM100 and HM40 received pasteurized donor human milk-based human milk fortifier when the enteral intake was 100 and 40 mL/kg/d , respectively , and both groups received pasteurized donor human milk if no mother 's milk was available . Group BOV received bovine milk-based human milk fortifier when the enteral intake was 100 mL/kg/d and preterm formula if no mother 's milk was available . Outcomes included duration of parenteral nutrition , morbidity , and growth . RESULTS The 3 groups ( total n = 207 infants ) had similar baseline demographic variables , duration of parenteral nutrition , rates of late-onset sepsis , and growth . The groups receiving an exclusively human milk diet had significantly lower rates of necrotizing enterocolitis ( NEC ; P = .02 ) and NEC requiring surgical intervention ( P = .007 ) . CONCLUSIONS For extremely premature infants , an exclusively human milk-based diet is associated with significantly lower rates of NEC and surgical NEC when compared with a mother 's milk-based diet that also includes bovine milk-based products BACKGROUND Colonization by C and ida species is the most important predictor of the development of invasive fungal disease in preterm neonates , and the enteric reservoir is a major site of colonization . We evaluated the effectiveness of an orally supplemented probiotic ( Lactobacillus casei subspecies rhamnosus ; Dicoflor [ Dicofarm spa ] ; 6 x 10(9 ) cfu/day ) in the prevention of gastrointestinal colonization by C and ida species in preterm , very low birth weight ( i.e. , < 1500-g ) neonates during their stay in a neonatal intensive care unit . METHODS Over a 12-month period , a prospect i ve , r and omized , blind , clinical trial that involved 80 preterm neonates with a very low birth weight was conducted in a large tertiary neonatal intensive care unit . During the first 3 days of life , the neonates were r and omly assigned to receive either an oral probiotic added to human ( maternal or pooled donors ' ) milk ( group A ) or human milk alone ( group B ) for 6 weeks or until discharge from the NICU , if the neonate was discharged before 6 weeks . On a weekly basis , specimens obtained from various sites ( i.e. , oropharyngeal , stool , gastric aspirate , and rectal specimens ) were collected from all patients for surveillance culture , to assess the occurrence and intensity of fungal colonization in the gastrointestinal tract . RESULTS The incidence of fungal enteric colonization ( with colonization defined as at least 1 positive culture result for specimens obtained from at least 1 site ) was significantly lower in group A than in group B ( 23.1 % vs. 48.8 % ; relative risk , 0.315 [ 95 % confidence interval , 0.120 - 0.826 ] ; P = .01 ) . The numbers of fungal isolates obtained from each neonate ( P = .005 ) and from each colonized patient ( P = .005 ) were also lower in group A than in group B. L. casei subspecies rhamnosus was more effective in the subgroup of neonates with a birth weight of 1001 - 1500 g. There were no changes in the relative proportions of the different C and ida strains . No adverse effects potentially associated with the probiotic were recorded . CONCLUSIONS Orally administered L. casei subspecies rhamnosus significantly reduces the incidence and the intensity of enteric colonization by C and ida species among very low birth weight neonates OBJECTIVES To determine whether supplementation with L -arginine reduces the incidence of all stages of necrotizing enterocolitis ( NEC ) in premature infants with birth weight < or = 1250 g and gestational age < or = 32 weeks . STUDY DESIGN In a r and omized , double-blind , placebo-controlled study , 152 premature infants were prospect ively , r and omly assigned to receive either supplemental L -arginine ( 1.5 mmol/kg per day ; n = 75 [ group A ] ) or placebo ( control group ; n = 77 [ group B ] ) with oral feeds/parenteral nutrition during the first 28 days of life . Nutrient intake , plasma ammonia , arginine , and amino acid concentrations were measured in all infants at days 3 , 14 , and 28 and at the time of diagnosis of NEC . RESULTS NEC developed in 5 infants in group A compared with 21 infants in group B ( P < .001 ) . Arginine intake and plasma arginine concentrations were similar in both groups at study entry and ( as expected ) increased in group A at days 14 and 28 . Plasma arginine concentrations were lower in both groups at time of diagnosis of NEC . No significant differences in maternal and neonatal demographics , nutrient intake , plasma ammonia and total and essential amino acid concentrations were present between the two groups . CONCLUSIONS Arginine supplementation ( 1.5 mmol/kg per day ) in premature infants reduces the incidence of all stages of NEC OBJECTIVE To test the efficacy of probiotic and prebiotic , alone or combined ( synbiotic ) , on the prevention of necrotizing enterocolitis ( NEC ) in very low birth weight ( VLBW ) infants . STUDY DESIGN A prospect i ve , r and omized , controlled trial was conducted at 5 neonatal intensive care units in Turkey . VLBW infants ( n = 400 ) were assigned to a control group and 3 study groups that were given probiotic ( Bifidobacterium lactis ) , prebiotic ( inulin ) , or synbiotic ( Bifidobacterium lactis plus inulin ) added to breastmilk or formula for a maximum of 8 weeks before discharge or death . The primary outcome was NEC ( Bell stage ≥2 ) . RESULTS The rate of NEC was lower in probiotic ( 2.0 % ) and synbiotic ( 4.0 % ) groups compared with prebiotic ( 12.0 % ) and placebo ( 18.0 % ) groups ( P < .001 ) . The times to reach full enteral feeding were faster ( P < .001 ) , the rates of clinical nosocomial sepsis were lower ( P = .004 ) , stays in the neonatal intensive care unit were shorter , ( P = .002 ) , and mortality rates were lower ( P = .003 ) for infants receiving probiotics , prebiotics , or synbiotic than controls . The use of antenatal steroid ( OR 0.5 , 95 % CI 0.3 - 0.9 ) and postnatal probiotic ( alone or in synbiotic ) ( OR 0.5 , 95 % CI 0.2 - 0.8 ) decreased the risk of NEC , and maternal antibiotic exposure increased this risk ( OR 1.9 , 95 % CI 1.1 - 3.6 ) . CONCLUSIONS In VLBW infants  , probiotic ( Bifidobacterium lactis ) and synbiotic ( Bifidobacterium lactis plus inulin ) but not prebiotic ( inulin ) alone decrease NEC 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 OBJECTIVE To assess the safety and prebiotic effects of lactulose in preterm infants . STUDY DESIGN This was a prospect i ve , double-blinded , placebo-controlled , single-center study in 23- to 34-weeks premature infants . The study group received 1 % lactulose , and control infants received 1 % dextrose in all feeds ( human milk or formula ) . RESULTS Twenty-eight infants participated ( 15 lactulose , 13 placebo ) . Small doses of lactulose appeared to be safe and did not cause diarrhea .  Premature infants on lactulose had more Lactobacilli-positive stool cultures that appeared earlier with larger number of colonies . The lactulose group tended to have less intolerance to enteral feedings , to reach full oral feeds earlier , and to be discharged home earlier . They also tended to have fewer episodes of late-onset sepsis , lower Bell stage necrotizing enterocolitis , and their nutritional laboratory indices were better , especially calcium and total protein . CONCLUSIONS This pilot study supports the safety of supplementing preterm infants ' feeds with low doses of lactulose . It also demonstrated trends that may suggest positive prebiotic effects Background Human milk-based fortifiers ( HMBFs ) are being adopted in neonatal care to enrich the nutrients in human milk for very low birth weight ( VLBW ) infants despite being costly and there being limited efficacy data . No r and omized clinical trial has evaluated the use of HMBF compared with bovine milk-based fortifiers ( BMBFs ) in the absence of formula feeding . Objective To determine if HMBF compared with BMBF for routine nutrient enrichment of human milk improves feeding tolerance , reduces morbidity , reduces fecal calprotectin ( a measure of gut inflammation ) , and supports the growth of infants < 1250 g. Design In this blinded r and omized clinical trial , infants born weighing < 1250 g were recruited from neonatal units in Ontario , Canada between August 2014 and November 2015 . The infants were fed mother 's milk and donor milk as required . Fortification commenced at 100 mL/kg per day of HMBF ( 0.81 kcal/mL ) or BMBF ( 0.72 kcal/mL ) and advanced at 140 mL/kg per day to 0.88 and 0.78 kcal/mL , respectively . The primary outcome was percentage of infants with a feeding interruption for ≥12 h or a > 50 % reduction in feeding volume . Secondary outcomes included a dichotomous mortality and morbidity index ( i.e. , affirmative for any one of death , late-onset sepsis , necrotizing enterocolitis , chronic lung disease , or severe retinopathy of prematurity ) , fecal calprotectin , and growth . Results Of 232 eligible infants , 127 ( 54.7 % ) were r and omized ( n = 64 HMBF , n = 63 BMBF ) . Mean ± SD birth weight and gestational age of infants were 888 ± 201 g and 27.7 ± 2.5 wk , respectively . No statistically significant differences were identified in feeding interruptions [ 17/64 HMBF , 20/61 BMBF ; unadjusted risk difference : -6.2 % ( 95 % CI : -22.2 % , 9.8 % ) ] . There was no statistically significant difference in the mortality and morbidity index ( 48.4 % HMBF , 49.2 % BMBF , adjusted P = 0.76 ) , changes in fecal calprotectin , or growth z scores . Conclusions Among infants born weighing < 1250 g and exclusively fed human milk , the use of HMBF did not improve feeding tolerance or reduce mortality and morbidity compared with BMBF . This trial was registered at clinical trials.gov as NCT02137473 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 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 ) 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
target: In RCTs , pasteurized human donor milk , as opposed to formula , reduced NEC but not infections or mortality .
  Pooled data of small trials and a recent large RCT suggested that bovine lactoferrin reduced rates of fungal sepsis without impact on other infections , NEC , or mortality .
  Pooled data of RCTs assessing the use of prebiotic oligosaccharides found reduced infection but not mortality .
  A meta- analysis sensitivity approach found multiple-strain ( but not single-strain ) probiotics to be highly effective in reducing NEC and mortality .
  Thus , selected food components may help to improve outcomes in preterm infants
background: Observational studies demonstrating reduced rates of infections , necrotizing enterocolitis ( NEC ) , and mortality in preterm infants fed their own mother ’s milk , as opposed to formula , have prompted endeavors to achieve similar effects with the right choice of food and food additives .
  In a systematic review of meta-analyses and r and omized controlled trials ( RCTs ) , we considered nutritional interventions aim ed at reducing the rates of infections , NEC , or mortality in very preterm infants .