Efficacy Of Probiotics Versus Placebo In The Prevention Of .
ORIGINAL ARTICLEEfficacy of Probiotics Versus Placebo in the Prevention ofNecrotizing Enterocolitis in Preterm Very Low Birth Weight Infants:A Double-Blind Randomized Controlled TrialTanjina Chowdhury1, Muhammad Manajjir Ali1, Muhammad Monir Hossain1, Jugindra Singh1,Abu Noyeem Muhammad Yousuf2, Fatema Yasmin1 and Fazle Rabbi Chowdhury3ABSTRACTObjective: To evaluate the efficacy of orally administered probiotics in preventing necrotizing enterocolitis (NEC) inpreterm very low birth weight (VLBW) infants.Study Design: A randomized double blind controlled trial.Place and Duration of Study: The Paediatrics Department of Sylhet M.A.G. Osmani Medical College Hospital, SylhetBangladesh, from July 2012 to June 2015.Methodology: Preterm (28 - 33 weeks gestation) VLBW (birth weight 1000 - 1499 g) neonates were enrolled. The studygroup was fed with probiotics once daily with breast milk from first feeding, and the control group with only breast milkwithout the addition of probiotics. Both the groups received other standard care. The primary outcome was thedevelopment 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 thanthat in the control group (14.88 3.15 and 18.80 4.32 days; p 0.001). Duration of hospital stay was significantly shortin 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 verylow birth weight. It is also associated with faster achievement of full oral feeding and short duration of hospital stay.Key Words: Necrotizing enterocolitis. Probiotics. Very low birth weight.INTRODUCTIONNecrotizing enterocolitis (NEC) is a serious conditionrelated to the digestive tract in preterm infants.1 NEC isa worldwide problem in very low birth weight infants, withhighly variable incidence affecting 2.6% to 28%, andcausing 1% to 5% of admissions to the neonatalintensive care unit (NICU).2,3 The most frequent riskfactors associated with NEC include prematurity and lowbirth weight. Over 90% of neonates who develop NECare preterm.4 NEC is reported to be 1 - 5% of the livebirths globally.5 In Pakistan, the incidence of NEC isaround 14% with a mortality rate of 39.28%.6 Theprecise pathogenesis of NEC is unknown but is widelyconsidered as a multifactorial disease. Gastrointestinalimmaturity, enteral feeding (especially formula feeding),presence of bacteria, and inflammation in thegastrointestinal tract may all contribute to the13Department of Paediatrics / Ophthalmology2, Sylhet MAGOsmani Medical College, Sylhet, Bangladesh.Nuffield Department of Medicine, Centre for TropicalMedicine and Global Health, University of Oxford, UK.Correspondence: Dr. Fazle Rabbi Chowdhury, NuffieldDepartment of Medicine, Centre for Tropical Medicine andGlobal Health, University of Oxford, UK.E-mail: fazle.chowdhury@ndm.ox.ac.ukReceived: February 01, 2016; Accepted: August 30, 2016.770development of NEC.3 Host-pathogen interactionstrigger inflammation in the gut that result in bowel injury,which may contribute to the pathogenesis of thedisease.7,8It significantly increases mortality (attributable mortalityof 15% to 30%) and morbidity (including surgery in 20%to 40% of infants and delayed neurodevelopment),despite the use of potent antimicrobial agents. Buteffective preventive strategies are lacking.9,10 Hence,the agents that modulate inflammation and enhancehost defences may improve the outcome of infants withneonatal sepsis or NEC.11,12 Researchers in differentsettings are trying number of preventive strategies likeprobiotics, exclusive breast milk feedings, steroids,platelet activating factor and their receptor antagonistetc.7Probiotics are live exogenous micro-organism deliveredenterally that improve mucosal defences of thegastrointestinal tract and potentially provide benefit tothe host.13 The most frequently used probiotics areLactobacillus and Bifidobacterium. There is increasinginterest in the potential health benefits of protectivecolonization of the gastrointestinal tract of preterminfants.14 However, the limited number of clinical trialslimits the definition of optimal strains, timing, dosage,and duration of probiotics administered to VLBWpreterm infants; and these issues need to be evaluatedJournal of the College of Physicians and Surgeons Pakistan 2016, Vol. 26 (9): 770-774
Efficacy of probiotics versus placebo in the prevention of necrotizing enterocolitis in preterm very low birth weight infantsin small and large trials. Two previous studies done inBangladesh showed significant efficacy of probiotics inthe prevention of NEC.15,16 But those studies did notspecify the dose, count of organism, and exact durationof treatment. Regional studies on this issue is alsolacking. So the primary objective of this study was todetermine the efficacy of oral probiotics in the preventionof necrotizing enterocolitis in preterm VLBW infants.METHODOLOGYThis randomized double-blind control trial was carriedout in the neonatal unit of Sylhet MAG Osmani MedicalCollege Hospital (SOMCH), Sylhet, Bangladesh, fromJuly 2012 to June 2015. Neonates with diagnosis ofpreterm ( 33 weeks gestation) VLBW (birth weight 1500g) and fulfilling the inclusion criteria (able totolerate oral feed and survive beyond 48 hours) wereenrolled in this study. The ethical permission for thisstudy was taken from SOMCH ethical committee(reference number: 2773). Babies with suspicion ofclinical sepsis, presence of perinatal asphyxia, majorcongenital anomaly, and babies who expired due toother neonatal illness were excluded. Gestation wasassessed from history of last menstrual period and afterbirth by new Ballard scores. Sample was calculated byusing Guilford and Frucher's formula, considering 5%level of significance, and 5% precision level (marginalerror). Infants were selected by convenient sampling, i.e.every second case was enrolled. Informed writtenconsent was taken from the parents or guardians afterdetailed explanation of the purpose of study. Groupallocation was done to Group A and Group B (Figure I).Coding was done by a faculty of another departmentwho was not related to this study. Group A was the casegroup (preterm VLBW) which received probiotics alongwith regular breast feeding and standard care; andGroup B was the control group (preterm VLBW) whichonly received regular breast feeding and standard care.First case was selected to one group by lottery methodand subsequent group was continued accordingly.Participants and investigators were not known groupallocation.The study group was fed with probiotics at a dose of3x109 CFU/day. (Cap TS6 probiotic containingBifidobacterium spp., Lactobacillus at 6 x 109 CFU 6billion CFU, manufactured by Tensall Bio-tech Co. Ltd.Taiwan, distributed by Century Health Care, Bangladesh))dissolved with 6 ml of breast milk then given 3 ml (3billion probiotics) once daily from first feeding (aftertrophic feeding) through nasogastric tube untildischarged (continued for at least 10 days). Probioticswas added to breast milk by registrar or assistantregistrar of the corresponding unit before feeding.Probiotics was given after two hours of givingintravenous antibiotic.Feeding was started when the infants have stable vitalsigns, active bowel sound without abdominal distension,no bile or blood from the nasogastric tube. A strictfeeding protocol was followed for all study infants. Iftrophic feedings were tolerated for 24 hours, gradualadvancement of feeding volume was continued. Trophicfeedings were not mixed with probiotics. The amount offeeding was advanced slowly at approximately 10 - 20ml/kg/day. Feeding was stopped if there was any sign offeeding intolerance (defined as the presence of gastricaspirate in the amount more than half of the previousfeeding, with abdominal distension). An oral intake of150 ml/kg/day was defined as complete enteral feeding.The research assistant and the principal investigatorswere in charge of the care of the infants during theirhospital stay. There was no modifications in the hospitalmanagement protocols, clinical practices, equipment,and infrastructure in the unit during the study periodexcept the addition of probiotics to the study group. NEC(stage II or more) was diagnosed clinically in any infantpresenting with the triad of feeding intolerance,abdominal distension, and grossly bloody stool. NECwas categorized according to the modified Bell'sclassification. To exclude mild and doubtful cases, onlycases of NEC (stage II and III) were considered.Figure 1: Flow diagram showing the steps and enrolment of the study.Abdominal X-rays and ultrasound were performed todiagnose and determine progression of NEC.Laboratory values such as complete blood count withdifferential, arterial blood gas measurements, andelectrolytes were measured. Thrombocytopenia, persistentJournal of the College of Physicians and Surgeons Pakistan 2016, Vol. 26 (9): 770-774771
Tanjina Chowdhury, Muhammad Manajjir Ali, Muhammad Monir Hossain, Jugindra Singh, Abu Noyeem Muhammad Yousuf, Fatema Yeasmin et al.metabolic acidosis and hyponatremia constitute themost common triad of signs and help to confirm thediagnosis. The primary outcome was the occurrence ofNEC (stage II and III) by modified Bell's classification.Secondary outcome measures were days to achieve fullenteral feeding and length of hospital stay. After datacollection decoding was done by guide.Data were analysed with SPSS (statistical package forsocial sciences) version 21.0. Quantitative data wereexpressed as mean and standard deviation andcomparison was done by unpaired 't' test. Qualitativedata was expressed as frequency and percentage andcomparison was carried by Chi-square (X2) test.A probability value (p) of less than 0.05 was consideredstatistically significant.RESULTSFifty-two (86.6%) patients were finally enrolled to theGroup-A (Study group) and 50 (83.3%) patients inGroup-B (Control group). There were total 69 (67.6%)male and 33 (32.3%) female neonates (Table I). Male:female ratio was 2.1:1. There were no significantdifferences in mean age, sex, gestational age, weight,and age at initiation of feeding of the patients betweenthe study group and control group. Baselinecharacteristics between the study group and controlgroup showed age in median and IQR which is 2.0(1.0 - 11.0) hours vs. 2.0 (1.0 - 8.25) hours; MannWhitney U test (p 0.970); gender [33 (63.5%) male vs.36 (72.0%) female; x2 0.849; p 0.357]; gestational age(31.38 0.93 weeks vs. 31.68 0.84 weeks; t 1.676;p 0.097); weight (1310.6 110.4 gm vs. 1338.0 97.71gm; t 1.326; p 0.188) and age at initiation of feeding(3.33 0.58 days vs. 3.42 0.88 days; t 0.630;p 0.530).Table II showed the distribution of the patients bydevelopment of NEC (stage II or III). NEC developed in1 (1.9%) neonates in study group and 6 (11.5%)neonates in control group. Development of NEC wassignificantly less in study group than that of controlgroup (χ2 4.050; p 0.044).Table III showed the distribution of the patients by age ofachievement of full oral feeding (an oral intake of 150ml/kg/day) and total duration of hospital stay in days.The mean age of achievement of full feeding in studyand control groups were 14.88 3.15 days and 18.80 4.32 days, respectively. Age of achievement of fullfeeding was significantly earlier in study group than thatof control group (t -5.090; p 0.001). The mean durationof hospital stays in study and control groups were 15.82 2.94 days and 19.57 4.26 days, respectively (Table II).Duration of hospital stay was significantly shorter instudy group than that of control group (t -5.037;p 0.001).772Table I: Baseline characteristics of infants in study and control group.BaselineStudy subjectsp-valuecharacteristicsCase (n 52)Control (n 50)(median; IQR)2.0 (1.0-11.0)2.0 (1.0-8.25)*p 0.970Age in hoursGestational-age(wks; SD)Weight (gram, SD)SexMaleFemaleAge at initiation offeeding (days; SD)1310.6 110.4131.38 0.931338.0 97.7131.68 0.84†p 0.09733 (63.5%)36 (72.0%)‡p 0.3573.333.42†p 0.53019 (36.5%)14 (28.0%)SD Standard deviation† Unpaired t-test; ‡ Chi-Square (χ2) testP 0.05 Significant.†p 0.188Table II: Primary outcome of infants in case and control group.Development of NECYesNoTotalX2 4.050*Chi-Square (χ2) testP 0.05-Significant.Study subjectsCase (n 52)Control (n 50)51 (98.1%)44 (88.5%)1 (1.9%)52 (100.0)6 (11.5%)p-value*P 0.04450 (100.0)Table III: Comparison of secondary outcomes in case versus control.Outcome parameterAge of achievement offull feeding (days)Length of hospital stay(days)Study subjectsp-valueCase (n 52)Control (n 44)14.88 [ 3.15]18.80 [ 4.32]*P 0.000115.82 [ 2.94]19.57 [ 4.26]*P 0.0001Data were presented as Mean Standard deviation*Unpaired t-test.P 0.05 Significant.DISCUSSIONProbiotics may protect high-risk neonates and infantsfrom developing necrotizing enterocolitis in many ways.There may be an increased barrier for migration ofbacteria and their products across the mucosa,competitive exclusion of potential pathogens, modificationof host response to microbial products, augmentation ofIgA mucosal responses, and/or enhancement of enteralnutrition that inhibits the growth of pathogens andupregulation of immune responses.14,17 Development ofNEC was significantly less in number in our study groupthan that of control group (p 0.05). Similar observationswere seen in studies done at home and abroad. Studydone by Mannan et al. at Dhaka found similar result (6%vs. 18.3%) with the use of probiotics.15 Lin et al. reporteda lower incidence of NEC in the probiotics group (1.1%vs. 5.3%; p 0.04) compared to control group.18 Bin-Nunet al. found a significantly lower incidence of all cases ofNEC in the probiotics group (4% vs. 16.6%; p 0.031).17In a meta-analysis of 20 randomized, controlled trials,Wang et al. found probiotics supplement was associatedwith a significantly decreased risk of NEC in pretermVLBW infants (RR 0.33; 95% confidence interval [CI],Journal of the College of Physicians and Surgeons Pakistan 2016, Vol. 26 (9): 770-774
Efficacy of probiotics versus placebo in the prevention of necrotizing enterocolitis in preterm very low birth weight infants0.24-0.46; p 0.001).19 In another meta-analysis of11 randomized, controlled trials Deshpande et al. founda higher proportion of neonates in the no probiotics(control group) developed definite NEC compared withthe probiotics group (71 [6.56%] vs. 26 [2.37%]) andestimated a lower risk (RR: 0.35 [CI: 0.23-0.55];p 0.001) of NEC in the probiotic group.20 Mihatsch et al.found only two cases of NEC (Bell 2) in the probioticsgroup and 4 in the placebo group of their study whichwas statistically insignificant.21 Sari et al. also did notfind any significant difference in the incidence of NECbetween the study and control groups (5.8 vs. 9%,respectively; p 0.447).22 The possible explanation ofboth the findings are: they used single strain ofprobiotics whereas we used multiple strain.21,22In this study, the mean age of achievement of full oralfeeding was significantly earlier in probiotics treatedgroup than that of control group (p 0.001). This resultwas similar to the study of Deshpande et al., where thetime to full oral feeds was significantly shorter in theprobiotic group (weighted mean difference -2.74 days,95% CI -4.98 to -0.51) than in controls.23 Bin Nun et al.did not find any difference between the study and controlgroup in terms of early oral feeding (p 0.13).17 Severalother studies also reported no significant difference inreaching full oral feeds.18,21In this study, the mean duration of hospital stays wassignificantly shorter in study group compared to controlgroup (p 0.001). This result was similar to that of thestudy by Samanta et al. where the duration of hospitalstay was significantly shorter in probiotic group than thatof control group (17.17 3.23) days versus 24.07 4.00days.24 Though, Lin et al. did not find any significantdifference in the hospital stay between case (46.7 27.1days) and control (46.5 26.1 days) in his study.18 Lin etal. set 34 weeks (not less than that) as preterm and 1500grams as low birth weight which might produce theprobable result.18 In this study, infants (both case andcontrol) need to stay in the hospital for longer periodthan usual, probably because of the prematurity andsepsis (in some cases). It requires extended research tofind out the exact reasons behind this. A very recentstudy also showed that probiotics can reduce theincidence of sepsis in LBW infants.25 This might beanother area of further research.CONCLUSIONProbiotic supplementation reduced the frequency ofnecrotising enterocolitis (NEC) in preterm neonates withvery low birth weight. It was also associated with fasterachievement of full oral feeding and shorter duration ofhospital stay.REFERENCES1. Braga TD, da Silva GAP, de Lira PIC, de Carvalho ML. Efficacyof bifidobacterium breve and lactobacillus casei oralsupplementation on necrotizing enterocolitis in very-low-birth-weight preterm infants: A double-blind, randomized, controlledtrial. Am J Clin Nutr 2011; 93:81-6.2. Kafetzis DA, Skevaki C, Costalos C. Neonatal necrotizingenterocolitis: An overview. Cur Opin Infect Dis 2003; 16:349-55.3. Lin PW, Stoll BJ. Necrotizing enterocolitis. Lancet 2006; 368:1271-83.4. Srinivasan PS, Brandler MD, D'Souza A. Necrotizing enterocolitis.Clin Perinatol 2008; 35:251-72.5. Gane B, Bhat BV, Adhisivam B, Joy R, Prasadkumar P,Femitha P, et al. Risk factors and outcome in neonatalnecrotising enterocolitis. Indian J Pediatr 2014; 81:425-8.6. Shah SS, Saleem M, Mehmood T, Ahmed T. Frequency andoutcome of necrotizing enterocolitis in preterm neonates.J Ayub Med Coll Abbottabad 2015; 27:85-7.7. Schnabl KL, van Aerde JE, Thomson AB, Clandinin MT.Necrotizing enterocolitis: A multifactorial disease with no cure.World J Gastroenterol 2008; 14:2142-61.8. Pammi M, Abrams SA. Oral lactoferrin for the prevention ofsepsis and necrotizing enterocolitis in preterm infants.Cochrane Database Syst Rev 2010; 5:CD007137.9. Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR,Vohr B, et al. Neurodevelopmental and growth impairmentamong extremely low-birth-weight infants with neonatalinfection. JAMA 2004; 292:2357-65.10. Alfaleh K, Anabrees J, Bassler D, Al-Kharfi T. Probiotics forprevention of necrotizing enterocolitis in preterm infants.Cochrane Database Syst Rev 2011; 3:CD005496.11. Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA,Ehrenkranz RA, et al. Late-onset sepsis in very low birthweight neonates: The experience of the NICHD NeonatalResearch Network. Pediatrics 2002; 110 (2 pt 1): 285-91.12. Millar M, Wilks M, Costeloe K. Probiotics for preterm infants?Arch Dis Child Fetal Neonatal Ed 2003; 88:354-58.13. Neu SJ, Walker WA. Necrotizing enterocolitis. N Engl J Med2011; 364:255-64.14. Lin CH, Su BH, Chen AC, Lin TW, Tsai CH, Yeh TF, et al. Oralprobiotics reduce the incidence and severity of necrotizingenterocolitis in very low birth weight infants. Pediatrics 2005;115:1-4.15. Mannan MA, Shahidullah M, Barua CC, Nahar Z, Barua S.Effect of probiotics on necrotizing enterocolitis in very low birthweight infants. JCMCTA 2010; 21:30-3.16. Moni SC, Mannan MA, Dey SK, Dey AC, Saha D, Shahidullah M,et al. Probiotic supplementation and effects on weight and feedtolerance in preterm low birth weight new-borns: A clinical trial.Bangladesh J Child Health 2015; 39(2).17. Bin-Nun A, Bromiker R, Wilschanski M, Kaplan M, Rudensky B,Caplan M, et al. Oral probiotics prevent necrotizing enterocolitisin very low birth weight neonates. J Pediatr 2005; 147:192-6.18. Lin HC, Hsu CH, Chen HL, Chung MY, Hsu JF, Lien RI, et al.Oral probiotics prevent necrotizing enterocolitis in very lowb
billion probiotics) once daily from first feeding (after trophic feeding) through nasogastric tube until discharged (continued for at least 10 days). Probiotics was added to breast milk by registrar or assistant registrar of the corresponding unit before feeding. Probiotics was given after two hours of giving intravenous antibiotic.
probiotics. There was insufficient evidence from one RCT to comment on the effect of probiotics versus antibiotics. P L A I N L A N G U A G E S U M M A R Y Probiotics for preventing urinary tract infections in adults and children Background Urinary tract infections (UTIs) occur in kidneys, ureters, urethra or bladder.
The aim of this study was to assess the efficacy and safety of DDEA 1.16% gel compared with placebo gel in acute NP. Methods: In a randomized, double-blind, placebo-controlled study, patients with acute NP (n 72) were treated with DDEA 1.16% gel (2 g, 4x/day, for 5 days) or placebo. Efficacy assessments included pain-on-movement (POM),
and Christian Gluud1 Abstract Background: The evidence on selective serotonin reuptake inhibitors (SSRIs) for major depressive disorder is unclear. Methods: Our objective was to conduct a systematic review assessing the effects of SSRIs versus placebo, ‘active’ placebo, or no intervention in adult part
Change in lipid profile in volunteers treated with ForsLean and placebo. There is a significant positive change (p 0.05) in the concentration of HDL. 40 50 16 0 10 20 30 Placebo Forslean Placebo Forslean Placebo Forslean HDL (mg/dL) Total HDL/LDL Ratio VLDL (mg/ml) 0 week 12 week Bhagwat et al (2004) 60 subject study, CPBRC Bombay, India
The Prophylactic Use of Probiotics in the Prevention of Radiation Therapy-Induced Diarrhea At a Glance F Radiation therapy (RT) to the abdominal and pelvic region can cause RT enteritis, a gastrointestinal tract inflammatory process that leads to severe diarrhea. F Probiotics such as VSL #3 and Lactobacillus casei DN-114
of probiotics.23–27 Therefore, interpretation of recom-mendations must be made cautiously. One study not included in these systematic reviews from China re-ported that prophylactic use of probiotics in VLBW in-fants was not associated with growth, neurodevelop-mental delay, or sensory impairment in children 3 years
Prophylactic v Therapeutic Use of Probiotics by Hatchery Scale –Central AP 2018 15.11/kg 51.11/kg 14.47/kg 17.10/kg - 2017 probiotic-use: L 100%, M 88%, S 36% - Small greater propensity for therapeutic use & lower recurrent historic use rate - All probiotics applied to water (no in-feed app.)
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