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
Monday, March 11 at 12pmET
Monday, May 6 at 12pmET
Jennifer Canvasser
Founder, Director of
Vision: create a world
Jennifer@
NECsociety.org
Jennifer Canvasser, MS W Founder, Director NEC S
Mark Underwood, MD, MAS Professor of Pediatrics UC Davis, CA S cientific Advisor, NEC S
Ravi Patel, MD, MS c Associate Professor of Pediatrics Emory University, Atlanta, GA S cientific Advisor, NEC S
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
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
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
1999 Angela Hoyos: first probiotic cohort
Hoyos AB, 1999 Int J Infect Dis
1999 Michael Caplan: first NEC animal study of
probiotics and NEC
Control Probiotic Caplan MS , Gastroenterology 1999
Alter the composition of the gut microbiota Decrease pro-inflammatory response Decrease intestinal permeability and bacterial
translocation
Effects of bacterial metabolites
922 samples from 58 preemies La Rosa, PNAS 2014 16,669 infants < 33 weeks Yee WH, Pediatrics 2012
Proteobacteria Firmicutes Bacteroidetes Control NEC Control NEC Control NEC Pammi M, Microbiome, 2017
Bacteriocins Competition for human milk oligosaccharides Anaerobic vs aerobic conditions Competition for iron?
Is it possible to change the fecal microbiota?
Underwood 2013 J Pediatrics
Underwood, 2017 JPGN
PMN recruitment Lymphocyte recruitment TOLLIP/SIGIRR B infantis B bifidum B breve B lactis L acidophilus L reuteri L rhamnosus
Barrier failure Prematurity: Increased apoptosis, decreased mucin production, absent Paneth cell function B infantis B bifidum B breve B lactis L acidophilus L reuteri L rhamnosus
Lactate and short chain fatty acids B vitamins S
econdary bile acids
Tri-methyl amine oxide
Ravi Mangal Patel, MD, MS c Associate Professor of Pediatrics Emory University and Children’s Healthcare of Atlanta rmpatel@ emory.edu @ ravimpatelmd
#preventNEC Disclosure: Probiotics are not approved by the US Food and Drug Administration for the prevention of NEC or
infants. This webinar is intended to be educational in nature only.
10 20 30 40 50 60 70 80 90 100
Percent of all deaths caused by NEC Postnatal age
Patel RM, et al. N Engl J Med. 2015
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
#preventNEC
Horbar et al. JAMA Pediat r. 2017
~7% Under 5%
#preventNEC
Dysbiosis
Prematurity
Abnormal intestinal oxygenation Inconsistent feeding Non-human milk feeding
Drivers Aim
#preventNEC
Dysbiosis
Prematurity
Abnormal intestinal oxygenation Inconsistent feeding Non-human milk feeding
Drivers Aim
#preventNEC
#preventNEC
#preventNEC
#preventNEC PiPs Trial ProPrems Trial
#preventNEC
Jacobs S E et al. Pediat rics. 2013
#preventNEC
Jacobs S E et al. Pediat rics. 2013
*Secondary outcome of trial; primary outcome late-onset sepsis
#preventNEC
Costeloe et al. Lancet . 2016
30 weeks gestation in 24 UK hospitals.
randomization, regardless of feeding.
#preventNEC
Costeloe et al. Lancet . 2016
#preventNEC
Costeloe et al. Lancet . 2016
Patel and Underwood. S em Ped S
#preventNEC
Patel and Underwood. S em Ped S
#preventNEC
Patel and Underwood. S em Ped S
#preventNEC
#preventNEC
Viswanathan et al. J Perinat ol. 2016
#preventNEC US 14%
Viswanathan et. al. J Perinatol. 2016
Canada 21%
<29 weeks’ GA
Singh et. al.
UK 12%
Duffield & Clarke. Arch Dis Child Fetal Neonatal Ed. 2018
Germany 68%
Denkel et al. PLoS One. 2016
#preventNEC
Alfaleh et al. Cochrane Dat abase. 2014
#preventNEC
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
S
ingle organism vs combination?
Include a prebiotic glycan? Purity and viability?
8 RCTs of a Bif idobact erium plus a Lact obacillus +/ - a
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
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
S
everal studies have shown significant concerns about both purity and viability
Only 1 product of 14 tested contained the exact species stated on the
microorganisms that were specified on the label, but had additional microbial constituents as well. 5 of the products were missing 1 species claimed on the label. -Marcobal A, JPGN 2008
Only 1 of the 16 products tested exactly matched the bifidobacterial species claims on the label in every sample tested. S
not internally consistent as both pill-to-pill and lot-to-lot variation were observed. -Lewis ZT , Pediatr Research 2016
Currently B. infant is plus L. acidophilus
RCTs
Lin 2005, 367 infants: Probiotic 1.1% Placebo 5.3%
Lin 2008, 434 infants: Probiotic 1.8% Placebo 6.5%
Cohort studies
Hoyos 1999, 2510 infants: Probiotic 2.7% Control 6.6%
Hartel 2014, 5351 infants: Probiotic 3.1% Control 4.9%
Repa 2015, 463 infants: Probiotic 7.0% Control 10.3%
Guthmann 2016, 1224 infants: Probiotic 1.4% Control 2.1%
Denkel 2016, 10,890 infants: Probiotic 1.7% Control 3.4%
S amuels 2016, 1961 infants: Probiotic 5.1% Control 7.8%
Raj put 2017, 252 infants: Probiotic 0% Control 1.6%
Escribano 2018, 516 infants: Probiotic 13.3% Control 5.9%
Currently B. breve, B. bif idum, B. longum, B.
Produced under good manufacturing practice
(GMP) in Canada
Cohort studies
Janvier 2014, 611 infants: Probiotic 5.4%Control 9.8% S
ingh 2019, 2956 infants: NEC [aOR 0.52 (0.31, 0.87)], mortality [aOR 0.34 (0.20, 0.56)], and composite outcome
Currently B. bif idum, B. inf ant is, and S
RCTs
Bin-Nun 2005, 144 infants: Probiotic 1.4% Placebo 13.9% Jacobs 2013, 1099 infants: Probiotic 2.0% Placebo 4.4%
This product was taken off the market
following a death from a fungal contaminant, but is now available again
Produces a variety of bacteriocins
Decreases gut inflammation
Improves gut motility
Meta-analysis of 6 RCTs (1778 preterm infants): significant improvement in time to full feeds, length of NICU stay, and late-onset sepsis, trends towards decreased NEC and death
2 cohort studies (665 preterm infants): decreased NEC
Probiotics in the U.S . containing pure L. reut eri
Biogaia Protectis (meets GMP requirements in Canada) Gerber S
Infant Bacterial Therapeutics has completed a phase 2 multi- center trial of a strain of L. reut eri under IND oversight by the FDA (they are looking for sites for the phase 3 trial) Athalye-Jape G, 2016, JPEN
Large amount of research in adult diseases RCTs
Dani 2002, 585 infants: Probiotic 1.4% Placebo 2.8% Manzoni 2006, 80 infants: Probiotic 2.6% Placebo 7.3% Awad 2010, 90 infants: Probiotic 0% Placebo 16.7%
Cohort studies
Luoto 2010, 2318 infants: 4.5% Control 3.2% Dang 2015, 263 infants: Probiotic 1.6% Control 5.9% Kane 2018, 640 infants: Probiotic 16.8% Control 10.2%
Consumes all structures of human milk
Decreases NEC in animal studies S
uppresses inflammation
Decreases gut permeability Probiotics in the U.S
. containing pure B. inf ant is
Natren Life S
tart
Evivo
No clinical trials or RCTs of B. infant is alone in
preemies
Found in many combination products
RCT trial in term breast fed infants S tart S top Frese S A, 2017 mS phere
RCTs
Wang 2007, 66 infants: Probiotic 0% Placebo 0% Patole 2014, 159 infants: Probiotic 0% Placebo 1.2%
Cohort studies
Y
amashiro 2010, 564 infants: Probiotic 0% Control 2.7%
Patole 2016, 1755 infants: Probiotic 1.3% Control 3.0%
RCT
Costeloe 2015, 1310 infants: Probiotic 9.5% Placebo 10%
More studies of combination probiotics have shown benefit than single organism probiotics, head to head comparisons are needed
“ No intervention comes close to probiotics when it comes to significant reduction in death, NEC, LOS and feeding intolerance at a cost of less than a dollar a day irrespective of the setting and baseline incidence of NEC” -Athalye-Jape, 2019 Microb Biotechnol
and the Perspectives of
Lack of information Views, concerns, and questions
“Why didn’t probiotics even
come up in conversation? My friend’s baby at a different hospital received probiotics.”
“If they aren’t telling me
about probiotics, what else aren’t they telling me?”
Lack of FDA approval Lack of dosing/ usage
guidelines
Variable product quality “How do you know
probiotics won’t hurt my baby?”
Inequitable S
tifling
Unacceptable “If this can help
“I wanted to be part of my baby’s
Build trust and rapport Empathetic
communication
Multimedia
communication
Provide rationale More information as
early as possible
“I wanted to be part of the decision- making process. I knew I would live with the consequences of these decisions for a lifetime.”
NEC Prevention Through Collaboration
Probiotics & Human Milk
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