The Efficacy and Mechanisms of Oral Probiotics in Preventing Necrotizing Enterocolitis

NCT02552706 — Not applicable, Unknown, 270 participants, Shenzhen Bao'an Maternal and Child Health Hospital
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The Efficacy and Mechanisms of Oral Probiotics in Preventing Necrotizing Enterocolitis Among Very Low Birth Weight Infants With Formula-feeding

RegistryNCT02552706
StatusUnknown
PhaseNot applicable
Study typeInterventional; randomized, parallel, masking: double, prevention
Enrollment270 (Estimated)
SponsorShenzhen Bao'an Maternal and Child Health Hospital (Other); collaborators: China Medical University Hospital, Shenzhen People's Hospital, Shenzhen Sixth People's Hospital, Longhua Hospital Of Baoan District, Shenzhen
ConditionsNecrotizing Enterocolitis, Death
Interventionsprobiotics, glucose solution (Dietary supplement)
Datesstart 2014-09-01, primary completion 2017-01-01 (estimated), completion 2017-09-01 (estimated), first posted 2015-09-17, last updated 2016-03-29
Locations4 sites in China

Related Papers Related Patents Related Grants Related Experts
All trials for Necrotizing Enterocolitis All trials for Death All trials of probiotics All trials of glucose solution

-Summary

The purpose of this study is to investigate the efficacy and its mechanisms of oral mixture probiotics in preventing necrotizing enterocolitis among the preterm very low birth weight infants.

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+Detailed description

Necrotizing enterocolitis (NEC) remains the most catastrophic gastrointestinal emergencies in preterm very low birth weight (VLBW) infants.Although study showed it is a multifactorial disease, its pathogenesis is still not yet unclear currently. Prematurity and formula feeding is considered as the main risk factors.Gut microbiota disturbance and immature immune system is associated with NEC. A lot of studies had showed that oral probiotics can alter gut microbiota flora colonization and reduce the incidence of NEC,but the exact mechanism remains unclear.The aim of this study is to elucidate the clinical efficacy and possible molecular mechanism of oral mixture probiotics in preventing NEC among preterm VLBW infants.

Patient Registry procedures: First,randomized numbers was generated by the computer and sent to the principal investigator(PI) at each center when an infant was eligible for enrollment.Second, patient will be assigned randomly to experimental group or control group by PI.Finally,the PI at each center will be responsible for the accuracy,completeness or representativeness of medical records, registry forms,data collection.

Sample size determination: The incidence of death and NEC was around 20% recently.To reduce the incidence of NEC and death to 10% at discharge would require a 50% improvement.At 80% power at P = 0.05 (two-sided),the loss rate of 0.2, this would require 135 subjects per arm.

Statistical analysis:The two groups were compared by a Χ2-test for categorical variables,Mann-Whitney U Test were used when reporting medians.A P value of <0.05 was considered statistically significant.

+Arms and interventions

ArmTypeInterventionsDescription
probiotics groupExperimentalDietary Supplement: probioticsAdministration of probiotics 500mg begins by mouth within 4 hours of life with 1-3 consecutive doses; the frequency depends on the feeding times. Study is continuous until preterm infants grow up to 36 weeks post menstrual age.
control groupPlacebo comparatorDietary Supplement: glucose solutioncontrol group received 1 mL of a 5% glucose solution. Administration of control group begins by mouth within 4 hours of life with 1-3 consecutive doses; the frequency depends on the feeding times. Study is also continuous until preterm infants grow up to 36 weeks post menstrual age.
  • probiotics (Dietary supplement): Administration of mixture probiotics 500mg by mouth, one time or divided into 2-4 times depends on the feeding volume until to 36 weeks post menstrual age.
  • glucose solution (Dietary supplement): Administration of 1 mL of a 5% glucose solution by mouth, one time or divided into 2-4 times depends on the feeding volume until to 36 weeks post menstrual age.

+Outcome measures

Primary outcomes

  • the incidence of combined death and necrotizing enterocolitis [at 36 weeks correct gestational age]

Secondary outcomes

  • the incidence of sepsis,intraventricular hemorrhage(IVH)(grade 3-4),feeding intolerance(FI),bronchopulmonary dysplasia(BPD),parenteral nutrition associated liver disease(PNALD)and retinopathyof prematurity(ROP). [participants will be followed for the duration of hospital stay, an expected average of 8 weeks]

Other outcomes

  • the influence of oral probiotics on gut microbiota and immunomodulatory [at birth, 2 and 4 weeks of life, 36 week correct gestational age.]: test fecal microbiota via high throughput sequencing and blood toll like receptor(TLR)2,TLR4,neclear factor kappa B(NF-KB)were detected using flow cytomtry.Inflammatory factors of blood were tested via Cytometric Bead Array(CBA).All above samples were obtained only from Shenzhen Bao'an Maternal and Child Health Hospital.The fecal DNA were first extracted at centre laboratory in aboved hospital and sent them to Beijing Genomics Institute(BGI) for further sequenceing ,if necessary, quantitative polymerase chain reaction(qPCR)of gut dominant bacterias related to late onset sepsis(LOS) will be tested for assessing the effect of oral probiotics on gut microbiota and underlying the mechanism. Flow cytometry analysis of TLR2,TLR4 and NF-KB were made by the senior laboratorian of our department and resposible for the accuracy of experimental result. CBA of inflammatory factors will be made by senting the blood samples to Beijing JIAMAY BIOLAB.

+Eligibility

Sex: All, ages: any to 3 Days

Inclusion Criteria:

* Preterm infants ≦ 34 weeks gestational age and birth weight below 1500 gm and who survive to NICU are eligible for the trial.

Exclusion Criteria:

* severe asphyxia (stage III),
* fetal chromosomal anomalies,
* cyanotic congenital heart disease,
* congenital intestinal atresia, gastroschisis, omphalocele, active upper gastric intestinal bleeding,
* lacking/refused of parental consent,
* those who are fasted for >3 weeks during the study period.

+Locations (4)

FacilityCityCountryStatus
Longhua People's Hospital of ShenzhenShenzhen, GuangdongChinaActive not recruiting
Shenzhen Bao'an Maternal and Child Health HospitalShenzhen, GuangdongChinaRecruiting
Shenzhen People's HospitalShenzhen, GuangdongChinaRecruiting
Shenzhen Sixth People's HospitalShenzhen, GuangdongChinaActive not recruiting

+Publications

  • Lin HC, Hsu CH, Chen HL, Chung MY, Hsu JF, Lien RI, Tsao LY, Chen CH, Su BH. Oral probiotics prevent necrotizing enterocolitis in very low birth weight preterm infants: a multicenter, randomized, controlled trial. Pediatrics. 2008 Oct;122(4):693-700. doi: 10.1542/peds.2007-3007. PMID 18829790
  • Results publication: Genzel-Boroviczeny O, MacWilliams S, Von Poblotzki M, Zoppelli L. Mortality and major morbidity in premature infants less than 31 weeks gestational age in the decade after introduction of surfactant. Acta Obstet Gynecol Scand. 2006;85(1):68-73. doi: 10.1080/00016340500290947. PMID 16521683
  • Results publication: Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Narwal R, Adler A, Vera Garcia C, Rohde S, Say L, Lawn JE. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet. 2012 Jun 9;379(9832):2162-72. doi: 10.1016/S0140-6736(12)60820-4. PMID 22682464
  • Results publication: Rees CM, Pierro A, Eaton S. Neurodevelopmental outcomes of neonates with medically and surgically treated necrotizing enterocolitis. Arch Dis Child Fetal Neonatal Ed. 2007 May;92(3):F193-8. doi: 10.1136/adc.2006.099929. Epub 2006 Sep 19. PMID 16984980
  • Results publication: Huda S, Chaudhery S, Ibrahim H, Pramanik A. Neonatal necrotizing enterocolitis: Clinical challenges, pathophysiology and management. Pathophysiology. 2014 Feb;21(1):3-12. doi: 10.1016/j.pathophys.2013.11.009. Epub 2014 Feb 11. PMID 24525171
  • Results publication: Hall NJ, Eaton S, Pierro A. Royal Australasia of Surgeons Guest Lecture. Necrotizing enterocolitis: prevention, treatment, and outcome. J Pediatr Surg. 2013 Dec;48(12):2359-67. doi: 10.1016/j.jpedsurg.2013.08.006. PMID 24314171
  • Results publication: Quigley MA, Henderson G, Anthony MY, McGuire W. Formula milk versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD002971. doi: 10.1002/14651858.CD002971.pub2. PMID 17943776
  • Results publication: Mshvildadze M, Neu J, Mai V. Intestinal microbiota development in the premature neonate: establishment of a lasting commensal relationship? Nutr Rev. 2008 Nov;66(11):658-63. doi: 10.1111/j.1753-4887.2008.00119.x. PMID 19019028
  • Results publication: Sharma R, Tepas JJ 3rd, Hudak ML, Mollitt DL, Wludyka PS, Teng RJ, Premachandra BR. Neonatal gut barrier and multiple organ failure: role of endotoxin and proinflammatory cytokines in sepsis and necrotizing enterocolitis. J Pediatr Surg. 2007 Mar;42(3):454-61. doi: 10.1016/j.jpedsurg.2006.10.038. PMID 17336180
  • Results publication: Nair V, Soraisham AS. Probiotics and prebiotics: role in prevention of nosocomial sepsis in preterm infants. Int J Pediatr. 2013;2013:874726. doi: 10.1155/2013/874726. Epub 2013 Jan 14. PMID 23401695
  • Results publication: Sarowska J, Choroszy-Krol I, Regulska-Ilow B, Frej-Madrzak M, Jama-Kmiecik A. The therapeutic effect of probiotic bacteria on gastrointestinal diseases. Adv Clin Exp Med. 2013 Sep-Oct;22(5):759-66. PMID 24285463
  • Results publication: Di Gioia D, Aloisio I, Mazzola G, Biavati B. Bifidobacteria: their impact on gut microbiota composition and their applications as probiotics in infants. Appl Microbiol Biotechnol. 2014 Jan;98(2):563-77. doi: 10.1007/s00253-013-5405-9. Epub 2013 Nov 28. PMID 24287935
  • Results publication: Liu Y, Fatheree NY, Mangalat N, Rhoads JM. Lactobacillus reuteri strains reduce incidence and severity of experimental necrotizing enterocolitis via modulation of TLR4 and NF-kappaB signaling in the intestine. Am J Physiol Gastrointest Liver Physiol. 2012 Mar 15;302(6):G608-17. doi: 10.1152/ajpgi.00266.2011. Epub 2011 Dec 29. PMID 22207578
  • Results publication: Deshpande G, Rao S, Patole S, Bulsara M. Updated meta-analysis of probiotics for preventing necrotizing enterocolitis in preterm neonates. Pediatrics. 2010 May;125(5):921-30. doi: 10.1542/peds.2009-1301. Epub 2010 Apr 19. PMID 20403939
  • Results publication: Lu P, Sodhi CP, Hackam DJ. Toll-like receptor regulation of intestinal development and inflammation in the pathogenesis of necrotizing enterocolitis. Pathophysiology. 2014 Feb;21(1):81-93. doi: 10.1016/j.pathophys.2013.11.007. Epub 2013 Dec 22. PMID 24365655
  • Results publication: Hackam DJ, Afrazi A, Good M, Sodhi CP. Innate immune signaling in the pathogenesis of necrotizing enterocolitis. Clin Dev Immunol. 2013;2013:475415. doi: 10.1155/2013/475415. Epub 2013 May 23. PMID 23762089
  • Results publication: Ganguli K, Meng D, Rautava S, Lu L, Walker WA, Nanthakumar N. Probiotics prevent necrotizing enterocolitis by modulating enterocyte genes that regulate innate immune-mediated inflammation. Am J Physiol Gastrointest Liver Physiol. 2013 Jan 15;304(2):G132-41. doi: 10.1152/ajpgi.00142.2012. Epub 2012 Nov 8. PMID 23139215
  • Results publication: Sharif S, Meader N, Oddie SJ, Rojas-Reyes MX, McGuire W. Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants. Cochrane Database Syst Rev. 2023 Jul 26;7(7):CD005496. doi: 10.1002/14651858.CD005496.pub6. PMID 37493095
  • Results publication: Sharif S, Meader N, Oddie SJ, Rojas-Reyes MX, McGuire W. Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants. Cochrane Database Syst Rev. 2020 Oct 15;10(10):CD005496. doi: 10.1002/14651858.CD005496.pub5. PMID 33058137

+Investigators