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Probioticsand the
Prevention of
Necrotizing Enterocolitis,
Death, and Sepsis
Save the dates
Monday, March 11 at 12pmETExperiences 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
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.
Jennifer Canvasserwith son, Micah
Founder, Director of NEC Society
Vision: create a world without NEC
Today’s speakersJennifer Canvasser, MSWFounder, DirectorNEC Society
Mark Underwood, MD, MASProfessor of PediatricsUC Davis, CAScientific Advisor, NEC Society
Ravi Patel, MD, MScAssociate Professor of PediatricsEmory University, Atlanta, GAScientific Advisor, NEC Society
Overview of today’s webinar
History and mechanisms Mark Underwood, MD, MAS
Review of clinical trials to date Ravi Patel, MD, MSc
Product choices and quality considerations Mark Underwood, MD, MAS
Patient-family perspective Jennifer Canvasser, MSW
222 registrants from 15 countries
ProbioticsHistory and mechanisms of action
Mark Underwood MDUC 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
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
History 1999 Angela Hoyos: first probiotic cohort
study. 25 bed NICU in Bogota. Treatment year (1994-1995): all patients received Infloran (250M B. infantis 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
History
1999 Michael Caplan: first NEC animal study of probiotics and NEC
Control
Probiotic
Caplan MS, Gastroenterology 1999
Mechanisms
Alter the composition of the gut microbiota
Decrease pro-inflammatory response
Decrease intestinal permeability and bacterial translocation
Effects of bacterial metabolites
Gut
Mic
robi
ota 922 samples from
58 preemiesLa Rosa, PNAS 2014
16,669 infants < 33 weeksYee WH, Pediatrics 2012
Proteobacteria Firmicutes Bacteroidetes
Control NEC Control NEC Control NEC
Pammi M, Microbiome, 2017
Meta-analysis of 8 studies of fecal samples prior to NEC• 106 infants with NEC• 278 control infants• 2944 samples
Mechanisms for changing the microbiota
BacteriocinsCompetition for human milk oligosaccharidesAnaerobic vs aerobic conditionsCompetition for iron?
Is it possible to change the fecal microbiota?
Underwood 2013J Pediatrics
B. breve M16V
Underwood, 2017 JPGN
Decrease pro-inflammatory response
TLR4LPS
NFKB
TNF alpha, IL1beta, IL6,
IL8, IL23
PMN recruitment
Lymphocyte recruitment
TOLLIP/SIGIRR
B infantisB bifidumB breveB lactisL acidophilusL reuteriL rhamnosus
Decrease intestinal permeability
Barrier failure
Prematurity: Increased apoptosis, decreased mucin production, absent Paneth
cell function
B infantisB bifidumB breveB lactisL acidophilusL reuteriL rhamnosus
Bacterial metabolites
Lactate and short chain fatty acids
B vitamins
Secondary bile acids
Tri-methyl amine oxide
Probiotics:Review of clinical trials to date
Ravi Mangal Patel, MD, MScAssociate Professor of PediatricsEmory University andChildren’s Healthcare of Atlanta
[email protected]@ravimpatelmd
#preventNEC
Disclosure: Probioticsare not approved by the USFood and Drug Administrationfor the prevention of NEC orother diseases in preterm infants.
This webinar is intended to be educational in nature only.
Deaths caused by NEC
0
10
20
30
40
50
60
70
80
90
100
Perc
ent o
f all
deat
hs c
ause
d by
NEC
Postnatal agePatel RM, et al. N Engl J Med. 2015
Causes of death for 6075 deaths among 22,248 live births at 22-28 weeks’ gestationat 25 US academic centers within the NICHD Neonatal Research Network
#preventNEC
Trends in NEC incidence
Horbar et al. JAMA Pediatr. 2017
~7%
Under 5%
#preventNEC
Prevention of NEC
Prevent NECDysbiosis
Prematurity
Abnormal intestinal oxygenation
Inconsistent feeding
Non-human milk feeding
Drivers
Aim
#preventNEC
Prevention of NEC
Prevent NECDysbiosis
Prematurity
Abnormal intestinal oxygenation
Inconsistent feeding
Non-human milk feeding
Drivers
Aim
#preventNEC
Probiotictrials to date:
#preventNEC
46 RCTs enrolling 12,185 preterm infantsRisk ratio of on NEC: 0.5 (95% CI 0.4 - 0.6)
Risk difference: -0.03 (95% CI -0.03 to -0.02)
#preventNEC
Probiotictrials to date:
#preventNEC
PiPs Trial
ProPrems Trial
Probiotictrials to date:
#preventNEC Jacobs SE et al. Pediatrics. 2013
ProPrems Trial
ProPrems Trial
#preventNEC Jacobs SE et al. Pediatrics. 2013
*Secondary outcome of trial; primary outcome late-onset sepsis
PiPS Trial
#preventNEC Costeloe et al. Lancet. 2016
• 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.
#preventNEC Costeloe et al. Lancet. 2016
PiPS Trial
#preventNEC Costeloe et al. Lancet. 2016
Cumulative meta-analysis
Patel and Underwood. Sem Ped Surg. 2018#preventNEC
Summary of meta-analysis
Patel and Underwood. Sem Ped Surg. 2018#preventNEC
Summary of meta-analysis
Patel and Underwood. Sem Ped Surg. 2018#preventNEC
Current use of probiotics in US
#preventNEC
Based on a 2015 survey, 70 (14%) US NICUs were supplementing probiotics to
very low birth weight infants
Viswanathan et al. J Perinatol. 2016
Use of probiotics worldwide
#preventNEC
US14% of NICUsViswanathan et. al.J Perinatol. 2016
Canada21% of infants<29 weeks’ GA
Singh et. al.Pediatrics. 2019
UK12% of NICUsDuffield & Clarke.
Arch Dis Child Fetal Neonatal Ed. 2018
Germany68% of NICUs
Denkel et al.PLoS One. 2016
Differences by strain
#preventNEC Alfaleh et al. Cochrane Database. 2014
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
Conclusions
#preventNEC
• 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.
ProbioticsProduct choices and quality considerations
Mark Underwood MDUC 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
How to choose a probiotic
Single organism vs combination?
Include a prebiotic glycan?
Purity and viability?
Single strain or combination?
8 RCTs of a Bifidobacterium plus a Lactobacillus +/- a Streptococcus strain: RR 0.41 (0.25, 0.66)
5 RCTs of a Lactobacillus species alone: RR 0.63(0.39, 1.03)
5 RCTs of a Bifidobacterium 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
Prebiotics
Galacto-oligosaccharide
Fructo-oligosaccharide
Inulin
Lactulose
Human milk oligosaccharides
Studies 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
Purity and viability
Several studies have shown significant concerns about both purity and viability
Only 1 product of 14 tested contained the exact species stated on the label. 7 of the probiotic combinations contained all of 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 bifidobacterialspecies claims on the label in every sample tested. Some products were not internally consistent as both pill-to-pill and lot-to-lot variation were observed. -Lewis ZT, Pediatr Research 2016
Combination products: Infloran
Currently B. infantis 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%
Samuels 2016, 1961 infants: Probiotic 5.1% Control 7.8%
Rajput 2017, 252 infants: Probiotic 0% Control 1.6%
Escribano 2018, 516 infants: Probiotic 13.3% Control 5.9%
Combination products: Ultimate Flora Baby
Currently B. breve, B. bifidum, B. longum, B. infantis and L. rhamnosus
Produced under good manufacturing practice (GMP) in Canada
Cohort studies Janvier 2014, 611 infants: Probiotic 5.4% Control 9.8%
Singh 2019, 2956 infants: NEC [aOR 0.52 (0.31, 0.87)], mortality [aOR 0.34 (0.20, 0.56)], and composite outcome of NEC or mortality [aOR 0.34 (0.22, 0.52)]
Combination products: ABC Dophilus
Currently B. bifidum, B. infantis, and S. thermophilus
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
Single organism probiotics: L reuteri 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. reuteri
Biogaia Protectis (meets GMP requirements in Canada) Gerber Soothe
Infant Bacterial Therapeutics has completed a phase 2 multi-center trial of a strain of L. reuteri under IND oversight by the FDA (they are looking for sites for the phase 3 trial)
Athalye-Jape G, 2016, JPEN
Single organism probiotics: L. rhamnosus GG
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%
Single organism probiotics: B. infantis
Consumes all structures of human milk oligosaccharides (best colonizer)
Decreases NEC in animal studies Suppresses inflammation Decreases gut permeability Probiotics in the U.S. containing pure B. infantis
Natren Life Start
Evivo
No clinical trials or RCTs of B. infantis alone in preemies
Found in many combination products
Single organism probiotics: B. infantis
RCT trial in term breast fed infants
Start Stop
Frese SA, 2017 mSphere
Single organism probiotics: B. breve
B. breve M16V
RCTs
Wang 2007, 66 infants: Probiotic 0% Placebo 0%
Patole 2014, 159 infants: Probiotic 0% Placebo 1.2%
Cohort studies
Yamashiro 2010, 564 infants: Probiotic 0% Control 2.7%
Patole 2016, 1755 infants: Probiotic 1.3% Control 3.0%
B. breve BBG-001
RCT
Costeloe 2015, 1310 infants: Probiotic 9.5% Placebo 10%
Conclusion
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
Probioticsand the Perspectives of Parents
Variability in care Lack of information
Views, concerns, and questions often disregarded
“Why didn’t probiotics even come up in conversation? My friend’s baby at a different hospital received probiotics.”
“If they aren’t telling meabout probiotics, what else aren’t they telling me?”
Are probiotics safe? Lack of FDA approval
Lack of dosing/usage guidelines
Variable product quality
“How do you know probiotics won’t hurt my baby?”
Access to interventions Inequitable
Stifling
Unacceptable
“If this can help protect my baby’s health, why aren’t we using it?”
“Parents need more information.
More information prepares us
for our journey ahead and
enables us to better care for
our baby.”
Empower parents
More information
Mentor families
“I wanted to be part of my baby’scare team, but I didn’t know how.”
Engagement strategies 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 Society Resources
NEC Prevention Through Collaboration
NEC Society Resources
Probiotics & Human Milk
