Reduction in necrotizing enterocolitis and improved outcomes in preterm infants following routine supplementation with Lactobacillus GG in combination with bovine lactoferrin. Probiotic Effects on Late-onset Sepsis in Very Preterm Infants: A Randomized Controlled Trial The politics of probiotics: probiotics, necrotizing enterocolitis and the ethics of neonatal research Probiotics Feeding in Prevention of Urinary Tract Infection, Bacterial Sepsis and Necrotizing Enterocolitis in Preterm Infants Efficacy of Saccharomyces boulardii on necrotizing enterocolitis or sepsis in very low birth weight infants: a randomised controlled trial. Delayed Cord Clamping in Very Preterm Infants Reduces the Incidence of Intraventricular Hemorrhage and Late-Onset Sepsis: A Randomized, Controlled Trial Bacillus clausii for Prevention of Late-onset Sepsis in Preterm Infants: A Randomized Controlled Trial. Bronchopulmonary dysplasia: incidence, risk factors and resource utilization in a population of South American very low birth weight infants. Effect of oral probiotics supplementation in the prevention of necrotizing enterocolitis among very low birth weight preterm infants. Late-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network. Comparison between killed and living probiotic usage versus placebo for the prevention of necrotizing enterocolitis and sepsis in neonates. Double-blind, randomised clinical assay to evaluate the efficacy of probiotics in preterm newborns weighing less than 1500 g in the prevention of necrotising enterocolitis Efficacy of Bifidobacterium breve and Lactobacillus casei oral supplementation on necrotizing enterocolitis in very-low-birth-weight preterm infants: a double-blind, randomized, controlled trial. Enteral lactoferrin to prevent infection for very preterm infants: the ELFIN RCT. Oral probiotics prevent necrotizing enterocolitis in very low birth weight neonates.
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 BACKGROUND AND OBJECTIVE : Late-onset sepsis frequently complicates prematurity , contributing to morbidity and mortality . Probiotics may reduce mortality and necrotizing enterocolitis ( NEC ) in preterm infants , with unclear effect on late-onset sepsis . This study aim ed to determine the effect of administering a specific combination of probiotics to very preterm infants on culture-proven late-onset  sepsis . METHODS : A prospect i ve multicenter , double-blinded , placebo-controlled , r and omized trial compared daily administration of a probiotic combination ( Bifidobacterium infantis , Streptococcus thermophilus , and Bifidobacterium lactis , containing 1 × 109 total organisms ) with placebo ( maltodextrin ) in infants born before 32 completed weeks ’ gestation weighing < 1500 g. The primary outcome was at least 1 episode of definite late-onset sepsis . RESULTS : Between October 2007 and November 2011 , 1099 very preterm infants from Australia and New Zeal and were r and omized . Rates of definite late-onset sepsis ( 16.2 % ) , NEC of Bell stage 2 or more ( 4.4 % ) , and mortality ( 5.1 % ) were low in controls , with high breast milk feeding rates ( 96.9 % ) . No significant difference in definite late-onset sepsis or all-cause mortality was found , but this probiotic combination reduced NEC of Bell stage 2 or more ( 2.0 % versus 4.4 % ; relative risk 0.46 , 95 % confidence interval 0.23 to 0.93 , P = .03 ; number needed to treat 43 , 95 % confidence interval 23 to 333 ) . CONCLUSIONS : The probiotics B infantis , S thermophilus , and B lactis significantly reduced NEC of Bell stage 2 or more in very preterm infants , but not definite late-onset sepsis or mortality . Treatment with this combination of probiotics appears to be safe There have been over twenty prospect i ve , r and omized trials of the use of probiotics to prevent  necrotizing enterocolitis ( NEC ) in premature babies . A Cochrane meta- analysis of 16 of the studies ( 1 ) including 2842 preterm infants , reported that ‘ enteral probiotics supplementation significantly reduced the incidence of severe NEC ( stage II or more ) ( typical RR , 0.35 ; 95 % CI , 0.24–0.52 ) and mortality ( typical RR , 0.40 ; 95 % CI , 0.27–0.60 ) with no evidence of harm . They concluded , ‘ Enteral supplementation of probiotics prevents severe NEC and all-cause mortality in preterm infants ’ . In a sensitivity analysis , including only the 4 highest quality studies , the results and conclusions were unchanged . For neonates born at < 32 weeks of gestation , the number needed to treat in order to prevent one NEC or one death is twenty . The risks of probiotics are minimal . A more recently published systematic review included several additional r and omized controlled trials , mostly published in the Chinese literature , and analysed a total of 20 publications and over 3800 preterm infants ; it came to similar conclusions as the Cochrane meta- analysis ( 2 ) . Probiotics are used in many European units but only rarely in North-America . In spite of the evidence , this safe and effective treatment for one of the most serious complications of prematurity has never been studied in the United States and perhaps never will . Probiotics will probably never be approved by the U.S. Food and Drug Administration ( FDA ) . Instead , they will remain in regulatory purgatory , neither approved nor unapproved , an evidence -based treatment that can not become the st and ard of care , a safe and effective treatment that is not on hospital formularies in the United States . Probiotics fall into a peculiar lacuna of the regulatory system . Most innovative treatments are either drugs or devices , and the regulatory pathways for evaluating and approving them are fairly well defined by federal law . The FDA has jurisdiction over both drugs and devices . Probiotics are neither drugs nor devices , and they are made by companies that generally market health products to the general public . In contrast , in Canada , probiotics are under the jurisdiction of the Natural Health Products Directorate ( NHPD ) which has rigorous requirements for quality control and detailed labelling . But the NHPD does not evaluate overtly medical cl aims made about a product . It has little experience dealing with either a product that could actually decrease major complications or save lives in a particularly fragile population where mortality is rather common . Probiotics are quite inexpensive to manufacture . People can even make them at home . They are in most yogurts . For pennies , some parents buy them for their preterm infants in health food stores . Some mothers have started adding probiotics to their breast milk . In these cases , the medical team can either be unaware a preterm infant is in fact receiving probiotics or tacitly not interfere with these parental initiatives . Given the low cost of probiotics and Articles in the series A Different View are edited by William Meadow ( wlm1@uchicago.edu ) . We encourage you to offer your own different view either in response to A Different View you do not fully agree with , or on an unrelated topic . Send your article to Dr. Meadow ( wlm1@uchicago.edu ) 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 BACKGROUND Probiotics have strain specific effects and the effects of fungi in preventing diseases in preterm infants have been investigated poorly . Saccharomyces boulardii is a yeast which acts both as a probiotic and a polyamine producer . AIM The objective of this study was to investigate the efficacy of S. boulardii in preventing necrotizing enterocolitis ( NEC ) or sepsis in very low birth weight infants . STUDY DESIGN AND SUBJECTS A prospect i ve , double blind , placebo controlled trial was conducted in preterm infants ( ≤ 32 GWs , ≤ 1500 g birth weight ) . They were r and omized either to receive feeding supplementation with S. boulardii 50 mg/kg every 12 h or placebo , starting with the first feed until discharged . OUTCOME MEASURES Necrotizing enterocolitis ( NEC ) or sepsis and NEC or death . RESULTS Birth weight and gestational age of the study ( n = 104 ) and the control ( n = 104 ) groups were 1126 ± 232 vs 1162 ± 216 g and 28.8 ± 2.2 vs 28.7 ± 2.1 weeks , respectively . Neither the incidence of stage ≥ 2 NEC or death nor stage ≥ 2 NEC or late onset culture proven sepsis was significantly lower in the study group when compared with the control group ( 9.6 % vs 7.7 % , p = 0.62 ; 28.8 % vs 23 % , p = 0.34 ) . Time to reach 100 mL/kg/day of enteral feeding ( 11.9 ± 7 vs 12.6 ± 7 days , p = 0.37 ) was not different between the groups . CONCLUSIONS Saccharomyces boulardii did not decrease the incidence of NEC or sepsis OBJECTIVE . This study compared the effects of immediate ( ICC ) and delayed ( DCC ) cord clamping on very low birth weight ( VLBW ) infants on 2 primary variables : bronchopulmonary dysplasia ( BPD ) and suspected necrotizing enterocolitis ( SNEC ) . Other outcome variables were late-onset sepsis ( LOS ) and intraventricular hemorrhage ( IVH ) . STUDY DESIGN . This was a r and omized , controlled unmasked trial in which women in labor with singleton fetuses < 32 weeks ’ gestation were r and omly assigned to ICC ( cord clamped at 5–10 seconds ) or DCC ( 30–45 seconds ) groups . Women were excluded for the following reasons : their obstetrician refused to participate , major congenital anomalies , multiple gestations , intent to withhold care , severe maternal illnesses , placenta abruption or previa , or rapid delivery after admission . RESULTS . Seventy-two mother/infant pairs were r and omized . Infants in the ICC and DCC groups weighed 1151 and 1175 g , and mean gestational ages were 28.2 and 28.3 weeks , respectively . Analyses revealed no difference in maternal and infant demographic , clinical , and safety variables . There were no differences in the incidence of our primary outcomes ( BPD and suspected NEC ) . However , significant differences were found between the ICC and DCC groups in the rates of IVH and LOS . Two of the 23 male infants in the  DCC group had IVH versus 8 of the 19 in the ICC group . No cases of sepsis occurred in the 23 boys in the DCC group , whereas 6 of the 19 boys in the ICC group had confirmed sepsis . There was a trend toward higher initial hematocrit in the infants in the DCC group . CONCLUSIONS . Delayed cord clamping seems to protect VLBW infants from IVH and LOS , especially for male infants BACKGROUND OF THE STUDY Preterm infants are managed with antibiotics for sepsis , including suspected or probable sepsis . This leads to a delayed and abnormal colonization of the gut with potentially pathogenic organisms and a microbiome , which lacks biodiversity and increases the risk for late-onset sepsis ( LOS ) . Probiotics have been proven to reduce the risk for necrotizing enterocolitis , but evidence for prevention of LOS is inconclusive . Probiotic effect depends also on the strain used , dose and indication for use . This study evaluated Bacillus clausii probiotic administered prophylactically to preterm neonates for prevention of LOS . OBJECTIVES To study B.clausii given prophylactically to preterm neonates for prevention of LOS . DESIGN Double-blinded , placebo-controlled , r and omized trial . SETTING S Tertiary care neonatal unit in India . PARTICIPANTS Consecutive preterm neonates < 34 weeks , admitted from 1 March 2012 to 28 February 2014 were stratified as extreme preterm and very preterm . INTERVENTION R and omized to receive either probiotic or placebo for 6 weeks , discharge from hospital , death or occurrence of sepsis , whichever was earlier . PRIMARY OUTCOME Incidence of definite and probable LOS in probiotic group compared with placebo . RESULTS Of 326 eligible preterm infants , 244 were enrolled and 82 were excluded . Of these , 120 were stratified as extreme preterm and r and omized to receive placebo ( n = 59 ) and probiotic ( n = 61 ) . Of 124 babies stratified as very preterm , an equal number was r and omized to receive placebo ( n = 62 ) and probiotic ( n = 62 ) . There was no significant difference in the incidence of LOS between the two arms in the extreme preterm group [ 29 % vs. 23 % ; relative risk ( RR ) 1.27 ; 95 % confidence interval ( CI ) 0.88 - 1.66 ; p = 0.36 ] and the very preterm group ( 13 % vs. 10 % ; RR 1.33 ; 95 % CI 0.96 - 1.70 ; p = 0.32 ) . Full feeds were achieved significantly faster in the probiotic group in both the extreme preterm ( RR 0.82 ; 95 % CI 0.74 - 0.88 ) and the very preterm ( RR 0.67 ; 95 % 0.32 - 0.77 ) . CONCLUSIONS Prophylactic administration of B.clausii to preterm neonates did not result in a significant difference in the incidence of LOS as compared with placebo OBJECTIVE To determine the incidence of bronchopulmonary dysplasia , its risk factors and re source utilization in a large South American population of very low birth weight infants . METHODS Prospect ively collected data in infants weighing 500 to 1,500 g born at 16 NEOCOSUR Network centers from 10/2000 through 12/2003 . Multivariate relative risk and 95 % confidence intervals were estimated by Poisson regression with robust error variance to find factors that affected the risk of bronchopulmonary dysplasia . RESULTS 1,825 very low birth weight infants survivors were analyzed . Mean birth weight and gestational age were 1085+/-279 g and 29+/-3 weeks respectively . Bronchopulmonary dysplasia incidence averaged 24.4 % and survival without bronchopulmonary dysplasia augmented with increasing gestational age . A higher birth weight and gestational age and a female gender all decreased the risk for bronchopulmonary dysplasia . Factors that independently increased that risk were surfactant requirement , mechanical ventilation , airleak , patent ductus arteriosus , late onset sepsis and necrotizing enterocolitis . Bronchopulmonary dysplasia infants had more days of hospitalization ( 91+/-27 vs. 51+/-19 ) , of mechanical ventilation ( 19+/-20 vs. 4+/-7 ) and  oxygen therapy  ( 72+/-30 vs. 8+/-14 ) in comparison with non BPD infants . CONCLUSIONS Bronchopulmonary dysplasia incidence was 24.4 % in a large South American population and is related to greater re source utilization . Risk factors for bronchopulmonary dysplasia in this study were : surfactant requirement , mechanical ventilation , airleak , patent ductus arteriosus , late onset sepsis and necrotizing enterocolitis . These studies may provide useful information in the design of effective preventive perinatal strategies 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 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 7861 VLBW ( 401 to 1500 gm ) neonates admitted to the 12 National Institute of Child Health and Human Development ( NICHD ) Neonatal Research Network centers during a 32-month period ( 1991 to 1993 ) . METHODS The NICHD Neonatal Research Network maintains a prospect ively collected registry of all VLBW neonates cared for at participating centers . Data from this registry were analyzed retrospectively . RESULTS Of 6911 infants who survived beyond 3 days , 1696 ( 25 % ) had one or more episodes of blood culture-proven sepsis .  The vast majority of infection ( 73 % ) were caused by gram-positive organisms , with coagulase-negative staphylococci accounting for 55 % of all infections . Rate of infection was inversely related to birth weight and gestational age . Complications of prematurity associated with an increased rate of infection included intubation , respiratory distress syndrome , prolonged ventilation , bronchopulmonary dysplasia , patent ductus arteriosus , severe intraventricular hemorrhage , and necrotizing enterocolitis . Among infants with bronchopulmonary dysplasia , those with late-onset sepsis had a significantly longer duration of mechanical ventilation ( 45 vs 33 days ; p < 0.01 ) . Late-onset sepsis prolonged hospital stay : the mean number of days in the hospital for VLBW neonates with and without late-onset sepsis was 86 and 61 days , respectively ( p < 0.001 ) . Even after adjustment for other complications of prematurity , including intraventricular hemorrhage , necrotizing enterocolitis , and bronchopulmonary dysplasia , infants with late-onset sepsis had a significantly longer hospitalization ( p < 0.001 ) . Moreover , neonates in whom late-onset sepsis developed were significantly more likely to die than those who were uninfected ( 17 % vs 7 % ; p < 0.000 1 ) , especially if they were infected with gram-negative organisms ( 40 % ) or fungi ( 28 % ) . Deaths attributed to infection increased with increasing chronologic age . Whereas only 4 % of deaths in the first 3 days of life were attributed to infection , 45 % of deaths after 2 weeks were related to infection . CONCLUSIONS Late-onset sepsis is a frequent and important problem among VLBW preterm infants . Successful strategies to decrease late-onset sepsis should decrease VLBW mortality rates , shorten hospital stay , and reduce costs UNLABELLED The aim of the study is to compare the role of killed ( KP ) Lactobacillus acidophilus with living ( LP ) in reducing incidence of sepsis ( NS ) and necrotizing enterocolitis ( NEC ) in neonates . R and omized double blind placebo study , included 150 neonates admitted to NICU at day 1 , sixty received oral ( LP ) and 60 received ( KP ) and 30 received placebo .  One gram of stools was collected on admission , at day 7 , at end of the study , as well as on suspected NEC or NS and was sent for culture . RESULTS LP and KP were preventive factors for NEC with absolute risk reduction ( AAR ) 16 , 15 % , respectively and 18 % for NS compared to placebo .  Incidence of NEC and NS did not differ significantly between neonates supplemented with LP and those with KP . Preterm neonates supplemented with KP showed significantly lower incidence of NEC compared to placebo , while incidence of NS showed no significant difference between both groups . There is significant reduction in NS and NEC among neonates with positive Lactobacillus colonization of gut compared to those none colonized at day 7 ( 27.9 vs. 85.9 % , 0 vs. 7.8 % ) and at day 14 ( 48.7 vs. 91.7 % for NS and 0 vs. 20.8 % for NEC ) . Overall comparison between the three groups showed statistical significant reduction in the incidence of NEC . Present conclusions are that early gut colonization with beneficial bacteria lowers the incidence of NEC and NS . KP retained similar benefits to live bacteria Background A r and omised , double-blind clinical trial was undertaken in order to assess the effectiveness of probiotics in the prevention of  necrotising enterocolitis ( NEC ) in newborns weighing < 1500 g. Methods We studied a group of 150 patients who were r and omised in two groups after parental consent was obtained , to receive either a daily feeding supplementation with a multispecies probiotic ( Lactobacillus acidophilus , Lactobacillus rhamnosus , Lactobacillus casei , Lactobacillus plantarum , Bifidobacteruim infantis , Streptococcus thermophillus ) 1 g per day plus their regular feedings or to receive their regular feedings with nothing added ( control group ) , over the period of January 2007 through June 2010 . Clinicians in care of the infants were blinded to the group assignment . Results The primary outcome was the development of NEC . Both groups were comparable , with no differences during hospitalisation , including the type of nutrition received . Blood cultures obtained from cases that developed sepsis did not reveal lactobacillus or Bifidobacteria growth . No differences were detected in terms of NEC risk reduction ( RR : 0.54 , 95 % CI 0.21 to 1.39 ) although we did observe a clear trend in the reduction of NEC frequency in the studied cases : 6 ( 8 % ) versus 12 ( 16 % ) in the control group . When the combined risk of NEC or death was calculated as a post hoc analysis , we found a significantly lower risk ( RR : 0.39 , 95 % CI 0.17 to 0.87 ) for the study group . Conclusions Probiotics may offer potential benefits for premature infants and are a promising strategy in the reduction of the risk of NEC in preterm newborns BACKGROUND Probiotics are used for the prevention of necrotizing enterocolitis ( NEC ) because of their positive effects on intestinal motor function , modulation of inflammatory response , and mucosal barrier function . OBJECTIVE The objective was to assess whether the combined use of Lactobacillus casei and Bifidobacterium breve may prevent the occurrence of NEC stage ≥ 2 by the criteria of Bell in very-low-birth-weight preterm infants . DESIGN A double-blind , r and omized , controlled clinical trial was conducted in 231 preterm infants weighing from 750 to 1499 g at birth . The intervention group was composed of 119 infants who received human milk with probiotic supplementation ( B. breve and L. casei )  and a control group of 112 infants who received human milk containing no probiotics .  The primary outcome was the occurrence of NEC stage ≥ 2 as defined by Bell 's modified criteria . RESULTS Four confirmed cases of NEC stage ≥ 2 by Bell 's criteria occurred only in the control group . CONCLUSIONS Oral supplementation of B. breve and L. casei reduced the occurrence of NEC ( Bell 's stage ≥ 2 ) . It was considered that an improvement in intestinal motility might have contributed to this result . This trial was registered at www.is rct in.org as number 67165178 ( International St and ard R and omized 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 OBJECTIVE To test the hypothesis that normalizing the intestinal flora by administration of prophylactic probiotics would provide a natural defense , thereby reducing both the incidence and severity of  necrotizing enterocolitis ( NEC ) in preterm neonates . STUDY DESIGN Neonates < or = 1500 g birth weight were r and omized to either receive a daily feeding supplementation with a probiotic mixture ( Bifidobacteria infantis , Streptococcus thermophilus , and Bifidobacteria bifidus ; Solgar , Israel ) of 10(9 ) colony forming units (CFU)/day or to not receive feed supplements .  NEC was grade d according to Bell 's criteria . RESULTS For 72 study and 73 control infants , respectively , birth weight ( 1152 + /- 262 g vs 1111 + /- 278 g ) , gestational age ( 30 + /- 3 weeks vs 29 + /- 4 weeks ) , and time to reach full feeds  ( 14.6 + /- 8.7 days vs 17.5 + /- 13.6 days ) were not different . The incidence of NEC was reduced in the study group ( 4 % vs 16.4 % ; P=.03 ) . NEC was less severe in the probiotic-supplemented infants ( Bell 's criteria 2.3 + /- 0.5 vs 1.3 + /- 0.5 ; P=.005 ) . Three of 15 babies who developed NEC died , and all NEC-related deaths occurred in control infants . CONCLUSION Probiotic supplementation reduced both the incidence and severity of NEC in our premature neonatal population
Meta-regression did not show any significant association between the RR for NEC or LOS and the RR for BPD .
In conclusion , our results suggest that NEC and LOS prevention by probiotics does not affect the risk of developing BPD in preterm infants
Probiotic supplementation reduces the risk of necrotizing enterocolitis ( NEC ) and late-onset sepsis ( LOS )  in preterm infants , but it remains to be determined whether this reduction translates into a reduction of other complications .
We conducted a systematic review and meta- analysis to evaluate the possible role of probiotics in altering the risk of bronchopulmonary dysplasia ( BPD ) .