and the Prevention of Necrotizing Enterocolitis …...Necrotizing Enterocolitis, Death, and Sepsis Save the dates Monday, March 11 at 12pmET Experiences of Centers Routinely Using

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

Jennifer@NECsociety.org

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

rmpatel@emory.edu@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

Questions & Discussion Please use the chat box

Follow up:

Jennifer@NECsociety.org