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Probiotics and the Prevention of Necrotizing Enterocolitis , - PowerPoint PPT Presentation

Probiotics and the Prevention of Necrotizing Enterocolitis , Death , and Sepsis S ave the dates Monday, March 11 at 12pmET Experiences of Centers Routinely Using Probiotics - University of Utah - Kaiser Permanente, Northern California


  1. Probiotics and the Prevention of Necrotizing Enterocolitis , Death , and Sepsis

  2. S ave the dates  Monday, March 11 at 12pmET Experiences of Centers Routinely Using Probiotics - University of Utah - Kaiser Permanente, Northern California - Kaiser Permanente, Southern California   Monday, May 6 at 12pmET Practical Considerations and Consent - Emory University - UC Davis - Patient-family perspective

  3. Disclaimer This an educational webinar series. The NEC Society and invited speakers are not marketing any probiotic products, which are not currently FDA approved for the prevention of necrotizing enterocolitis or other neonatal diseases.

  4.  Jennifer Canvasser with son, Micah  Founder, Director of NEC Society  Vision: create a world without NEC  Jennifer@ NECsociety.org

  5. Today’s speakers Jennifer Canvasser, MS W Founder, Director NEC S ociety Mark Underwood, MD, MAS Professor of Pediatrics UC Davis, CA S cientific Advisor, NEC S ociety Ravi Patel, MD, MS c Associate Professor of Pediatrics Emory University, Atlanta, GA S cientific Advisor, NEC S ociety

  6. Overview of today’s webinar  History and mechanisms  Mark Underwood, MD, MAS  Review of clinical trials to date  Ravi Patel, MD, MS c  Product choices and quality considerations  Mark Underwood, MD, MAS  Patient-family perspective  Jennifer Canvasser, MS W

  7. 222 registrants from 15 countries

  8. Probiotics History and mechanisms of action Mark Underwood MD UC Davis Disclosures: Abbott (speakers bureau) Avexegen (advisory board) IBT (chair DSMB) Evolve (support for clinical trial) Probiotics are not approved by the FDA for the treatment, mitigation or prevention of any disease

  9. History  1899 Henri Tissier: Y shaped bacteria dominate the feces of healthy breast fed infants  1907 Elie Metchnikoff proposed consumption of lactic acid producing bacteria to improve health  1917 Alfred Nissle isolated a dominant strain of E coli from a healthy soldier and fed it to soldiers with dysentery  With the discovery of antibiotics, probiotics moved to the fringes

  10. History  1999 Angela Hoyos: first probiotic cohort study. 25 bed NICU in Bogota. Treatment year (1994-1995): all patients received Infloran (250M B. inf ant is and 250M L. acidophilus) once daily from admit to discharge. N=1237 Comparison year (1993-1994): no probiotic administration. N=1282 Hoyos AB, 1999 Int J Infect Dis

  11. History  1999 Michael Caplan: first NEC animal study of probiotics and NEC Control Probiotic Caplan MS , Gastroenterology 1999

  12. Mechanisms  Alter the composition of the gut microbiota  Decrease pro-inflammatory response  Decrease intestinal permeability and bacterial translocation  Effects of bacterial metabolites

  13. Gut Microbiota 922 samples from 58 preemies La Rosa, PNAS 2014 16,669 infants < 33 weeks Yee WH, Pediatrics 2012

  14. Meta-analysis of 8 studies of fecal samples prior to NEC • 106 infants with NEC • 278 control infants • 2944 samples Bacteroidetes Proteobacteria Firmicutes Control NEC Control NEC Control NEC Pammi M, Microbiome, 2017

  15. Mechanisms for changing the microbiota Bacteriocins Competition for human milk oligosaccharides Anaerobic vs aerobic conditions Competition for iron?

  16. Is it possible to change the fecal microbiota? Underwood 2013 J Pediatrics

  17. B. breve M16V Underwood, 2017 JPGN

  18. Decrease pro-inflammatory response LPS TLR4 PMN TNF alpha, TOLLIP/SIGIRR recruitment IL1beta, IL6, IL8, IL23 Lymphocyte NFKB recruitment B infantis B bifidum B breve B lactis L acidophilus L reuteri L rhamnosus

  19. Decrease intestinal permeability Prematurity: Increased apoptosis, Barrier decreased mucin production, absent Paneth failure cell function B infantis B bifidum B breve B lactis L acidophilus L reuteri L rhamnosus

  20. Bacterial metabolites  Lactate and short chain fatty acids  B vitamins  S econdary bile acids  Tri-methyl amine oxide

  21. Disclosure: Probiotics Probiotics: are not approved by the US Food and Drug Administration Review of for the prevention of NEC or other diseases in preterm infants. clinical trials This webinar is intended to to date be educational in nature only. Ravi Mangal Patel, MD, MS c Associate Professor of Pediatrics Emory University and Children’s Healthcare of Atlanta rmpatel@ emory.edu @ ravimpatelmd #preventNEC

  22. Deaths caused by NEC Causes of death for 6075 deaths among 22,248 live births at 22-28 weeks’ gestation at 25 US academic centers within the NICHD Neonatal Research Network Percent of all deaths caused by NEC 100 90 80 70 60 50 40 30 20 10 0 Postnatal age #preventNEC Patel RM, et al. N Engl J Med. 2015

  23. Trends in NEC incidence ~7% Under 5% #preventNEC Horbar et al. JAMA Pediat r. 2017

  24. Prevention of NEC Drivers Non-human milk feeding Aim Inconsistent feeding Prevent NEC Dysbiosis Abnormal intestinal oxygenation Prematurity #preventNEC

  25. Prevention of NEC Drivers Non-human milk feeding Aim Inconsistent feeding Prevent NEC Dysbiosis Abnormal intestinal oxygenation Prematurity #preventNEC

  26. Probiotic trials to date: 46 RCTs enrolling 12,185 preterm infants Risk ratio of on NEC: 0.5 (95% CI 0.4 - 0.6) Risk difference: -0.03 (95% CI -0.03 to -0.02) #preventNEC

  27. Probiotic trials to date: #preventNEC

  28. Probiotic PiPs Trial trials to date: ProPrems Trial #preventNEC

  29. ProPrems Trial #preventNEC Jacobs S E et al. Pediat rics. 2013

  30. ProPrems Trial *Secondary outcome of trial; primary outcome late-onset sepsis #preventNEC Jacobs S E et al. Pediat rics. 2013

  31. PiPS Trial • Phase 3, multicenter trial of infants born between 23 to 30 weeks gestation in 24 UK hospitals. • Intervention started as soon as possible after randomization, regardless of feeding. Costeloe et al. Lancet . 2016 #preventNEC

  32. PiPS Trial Costeloe et al. Lancet . 2016 #preventNEC

  33. Costeloe et al. Lancet . 2016 #preventNEC

  34. Cumulative meta-analysis #preventNEC Patel and Underwood. S em Ped S urg. 2018

  35. Summary of meta-analysis #preventNEC Patel and Underwood. S em Ped S urg. 2018

  36. Summary of meta-analysis #preventNEC Patel and Underwood. S em Ped S urg. 2018

  37. Current use of probiotics in US Based on a 2015 survey, 70 (14%) US NICUs were supplementing probiotics to very low birth weight infants #preventNEC Viswanathan et al. J Perinat ol. 2016

  38. Use of probiotics worldwide Germany Canada UK 68% of NICUs 21% of infants 12% of NICUs Denkel et al. Duffield & Clarke. <29 weeks’ GA US PLoS One. 2016 Arch Dis Child Fetal Singh et. al. 14% of NICUs Neonatal Ed. 2018 Pediatrics. 2019 Viswanathan et. al. J Perinatol. 2016 #preventNEC

  39. Differences by strain Effect on risk of NEC Stage II+ by strain: • Lactobacillus : RR 0.45 (0.27-0.75) • Bifidobacterium : RR 0.48 (0.16-1.47) • Sacchromyces boulardii : RR 0.72 (0.34-1.55) • Combination (2 or more): RR 0.37 (0.25-0.54) Test for subgroup differences: P=0.48 #preventNEC Alfaleh et al. Cochrane Dat abase. 2014

  40. Conclusions • The cumulative evidence from meta-analyses of randomized trials demonstrates probiotics effectively reduce the risks of NEC, sepsis and mortality in preterm infants. • Subgroup analyses do not show consistent differences between treatment effects of combination vs. single strain preparations. • However, some individual trial data provide conflicting results, potentially from differences in preparations used. #preventNEC

  41. Probiotics Product choices and quality considerations Mark Underwood MD UC Davis Disclosures: Abbott (speakers bureau) Avexegen (advisory board) IBT (chair DSMB) Evolve (support for clinical trial) Probiotics are not approved by the FDA for the treatment, mitigation or prevention of any disease

  42. How to choose a probiotic  S ingle organism vs combination?  Include a prebiotic glycan?  Purity and viability?

  43. Single strain or combination?  8 RCTs of a Bif idobact erium plus a Lact obacillus +/ - a S t rept ococcus strain: RR 0.41 (0.25, 0.66)  5 RCTs of a Lact obacillus species alone: RR 0.63 (0.39, 1.03)  5 RCTs of a Bif idobact erium species alone: RR 0.53 (0.22, 1.26)  Comparisons of a multi-strain and a single-strain probiotic would be valuable Thomas JP , Acta Paediatr 2017

  44. Prebiotics  Galacto-oligosaccharide  Fructo-oligosaccharide  Inulin  Lactulose  Human milk oligosaccharides  S tudies to date of prebiotics alone have not shown decrease in NEC or death  Many of the probiotic trials have shown better NEC reduction with the combination of probiotic + human milk

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