Maryland Patient Safety Center
Perinatal/Neonatal Learning Network
June 11, 2015
The Role of Probiotics in
Preventing NEC: Should This
Therapy be Standard of Care?
Ravi Mangal Patel, MD, MSc
Assistant Professor of Pediatrics
Division of Neonatology
rmpatel@emory.edu
Disclosure statement
• I will be discussing the use of various probiotic
preparations, none of which have been approved by
the Food and Drug Administration for use in preterm
infants and none of which I am specifically endorsing.
• I have no other relevant conflicts of interest.
Children’s Healthcare of Atlanta | Emory University
Hypothetical case
• You are caring for a 27 week gestation female infant,
who is currently 4 weeks old.
• She initially needed mechanical ventilation, but is
currently in room air doing well. She is receiving
enteral feedings by a feeding tube.
• The parents are encouraged by the progress their
daughter has made in the NICU.
Children’s Healthcare of Atlanta | Emory University
Hypothetical case
• The following day, the baby develops emesis, bloody
stools and abdominal distention.
Children’s Healthcare of Atlanta | Emory University
Hypothetical case
• An abdominal radiograph shows NEC with portal gas.
Children’s Healthcare of Atlanta | Emory University
Hypothetical case
• An exploratory laparotomy is performed and 45cm of
affected small bowel is resected.
• Short gut syndrome discussed with the family
Neu and Walker, NEJM. 2011
Children’s Healthcare of Atlanta | Emory University
The parents search the internet and find
some studies that show probiotic therapy
reduces NEC.
They ask you why their daughter did not
receive this therapy?
Learning objectives
At the end of this talk, you should know:
• The current evidence regarding the risks and benefits
of probiotic therapy in preterm infants including:
– Probiotic effects on NEC and mortality
– Probiotic effects on sepsis
– Differences in effect between various probiotic strains
• Strategies for implementation, including:
– Selection of appropriate probiotic, including dose/duration
– Considerations before implementation
– Use of quality improvement principles
Children’s Healthcare of Atlanta | Emory University
Necrotizing enterocolitis (NEC)
• Characterized by intestinal inflammation and
necrosis although the exact pathogenesis is unknown
• Leading cause of mortality in very low birth weight
infants with case fatality rates of 20-30%
• Up to 50% of infants requiring surgery die
• Deaths from NEC have increased among extremely
preterm infants from 2000 to 2011
Lin PW and Stoll BJ, Lancet. 2006
Patel RM et al. NEJM. 2015
Children’s Healthcare of Atlanta | Emory University
Pathophysiology of NEC multifactorial
Premature birth
- Propensity towards gut inflammation
- Impaired intestinal barrier function
- Decreased intestinal motility
Abnormal
intestinal
microbiota
NEC
Other
potential
factors
- Abnormal gut
vascular regulation
- RBC transfusion
- Anemia
- Decreased commensal flora
- Increased pathogenic bacteria
- Prolonged antibiotic therapy
- Acid suppression medications
Enteral feeding
- Formula feeding
Patel RM and Denning PW.
Pediatric Research, 2015
Children’s Healthcare of Atlanta | Emory University
Pathophysiology of NEC multifactorial
Premature birth
- Propensity towards gut inflammation
- Impaired intestinal barrier function
- Decreased intestinal motility
Abnormal
intestinal
microbiota
NEC
Other
potential
factors
- Abnormal gut
vascular regulation
- RBC transfusion
- Anemia
- Decreased commensal flora
- Increased pathogenic bacteria
- Prolonged antibiotic therapy
- Acid suppression medications
Enteral feeding
- Formula feeding
Patel RM and Denning PW.
Pediatric Research, 2015
Children’s Healthcare of Atlanta | Emory University
Abnormal bacterial colonization
Patel RM and Denning PW.
Clinics in Perinatology, 2013
Children’s Healthcare of Atlanta | Emory University
Probiotics: How do they work?
Patel and Denning. Clinics in Perinatology, 2013
Children’s Healthcare of Atlanta | Emory University
Probiotics: What is the evidence?
AlFaleh K, Anabrees J. Probiotics for prevention of
necrotizing enterocolitis in preterm infants. Cochrane
Database of Systematic Reviews 2014, Issue 4.
Twenty of 24 randomized trials evaluated
Total of 5529 infants studied
Children’s Healthcare of Atlanta | Emory University
Effect of probiotics on definite NEC
(Bell’s Stage 2-3)
Probiotics significantly decrease the risk of NEC
Pooled relative risk – definite NEC = 0.43 [0.33, 0.56]
Analysis limited to <1500g infants = 0.41 [0.31, 0.56]
<1500g
AlFaleh K, Anabrees J. Cochrane Database of Systematic Reviews 2014.
Effect of probiotics on mortality
Probiotics significantly decrease mortality
Pooled relative risk – all cause mortality = 0.65 [0.52, 0.81]
Pooled relative risk – NEC-related mortality = 0.39 [0.18, 0.82]
NEC-related mortality
AlFaleh K, Anabrees J. Cochrane Database of Systematic Reviews 2014.
What about the risks of sepsis?
Probiotics do not increase or decrease the risk of sepsis
(however, more heterogeneity among studies)
Pooled relative risk = 0.92 [0.81, 1.04]
AlFaleh K, Anabrees J. Cochrane Database of Systematic Reviews 2014.
What about the risk of sepsis in the
smallest infants <1000g?
Although of potential concern, there is no clear
Lin HC, et al. Pediatrics. 2008
evidence that the risk of sepsis from probiotic
therapy is increased among infants <1000g at birth
Culture proven sepsis <1000g
AlFaleh K, Anabrees J. Cochrane Database of Systematic Reviews 2014.
Do benefits vary by strain of probiotics?
Is a combination better than a single strain?
Differences by strain (genus)
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
AlFaleh K, Anabrees J. Cochrane Database of Systematic Reviews 2014.
Children’s Healthcare of Atlanta | Emory University
Differences by strain
Wang et al. J Pediatr Surg, 2012
Patel and Denning. Clinics in Perinatology, 2013
Children’s Healthcare of Atlanta | Emory University
What is the external validity of the
probiotic trials?
(i.e. have the benefits of probiotics been
demonstrated in routine clinical practice)
Cohort study in Canada
• All infants <32wk GA treated with first feeding and
continued until 34wk postmenstrual age
• Florababy (combination probiotic) 0.5g in 1ml daily
P<0.05
P<0.02
No difference between groups among infants <1000g at birth
NEC: pre=17% vs. post=10%
Sepsis: pre=35% vs post=30%
Janvier et al. J Peds 2014
OR (95% CI)
adjusted for GA, SGA, female
Children’s Healthcare of Atlanta | Emory University
Cohort study in Germany
• Study of VLBW at 46 German NICUs (n=5351)
• Infloran (Lactobacillus acidophilus/ Bifidobacterium
infantis) equivalent of 1 capsule per day
Hartel et al. J Peds 2014
Children’s Healthcare of Atlanta | Emory University
Are probiotics ready for primetime?
Should we start using routinely?
5-10 years ago
• Animal data supports
biologic plausibility
• Several small single
center RCTs in foreign
countries
• Lack of a large, multicenter RCTs
• Lack of implementation cohort studies
• Insufficient evidence regarding
optimal strain
• Concerns for sepsis amongst the
smallest infants
• No FDA-approved preparation
• Manufacturer quality control
• Other strategies to reduce NEC risk
For probiotics
Against probiotics
Today
• Multiple RCTs with >5000 infants
including the ProPrems trial shows
consistent benefit in reducing NEC
• Subgroup analyses by strains shows
similar treatment effects
• 2+ implementation cohort studies
• Meta-analysis for <1000g shows no
increase in risk of sepsis
• NEC remains a major cause of death
• Lack of FDA approved preparation
• Manufacturer quality control
• No long-term follow-up studies
Against probiotics
For probiotics
Local NEC incidence may influence
overall risk:benefit ratio at a center
• For units with NEC incidence <5%, number needed to
treat (NNT) to prevent 1 case of NEC may be too high
NEC
NNT
0.0%
--Compared to VON:
2.5%
67
Median NEC incidence
in 2013 was 3.8%
5.0%
35
(Q1, Q3: 0.0%, 7.1%)
Probiotic use in infants
7.5%
23
for 2013 was 10.5%
(Q1, Q3: 0.0%, 1.8%)
10.0%
18
15.0%
12
NNT estimates based on point-estimate of relative risk 0.43 for
Bell’s 2+ NEC (probiotic vs. control) from Cochrane analysis
Children’s Healthcare of Atlanta | Emory University
Which probiotic do I choose
and how do I obtain it?
Brand Name Made in
Type
Strains
Cost per
dose
Culturelle
Denmark
Single-dose packet
Lactobacillus rhamnosus GG
$
0.81
FloraBaby
USA
Multi-dose container Bifidobacterium & Lactobacillus & FOS
$
0.38
ProBiota
USA
Multi-dose container Bifidobacterium & Lactobacillus
$
0.50
FloraTummys USA
Singe-dose packet
Bifidobacterium & Lactobacillus
$
1.00
FlorastorKids USA
Singe-dose packet
Sacchromyces boulardii
$
0.78
VSL#3 Junior USA
Singe-dose packet
Bifidobacterium & Lactobacillus &
Streptococcus
$
2.56
ABC Dophilus USA
Multi-dose container Bifidobacterium and Streptococcus
$
0.48
Infloran*
Switzerland Single-dose capsule
Probiotics used in prior studies:
Data from amazon.com 11/20/13
Bifidobacterium & Lactobacillus
ProPrems trail (Au/NZ): ABC Dophilus
Janvier et al. (Canada): FloraBaby
Manzoni et al (Italy). LGG (similar to Culturelle)
Hartel et al. (Germany): Infloran
*Minimal data on Infloran available
ABC Dophilus – FDA Recall
Children’s Healthcare of Atlanta | Emory University
36
Lactobacillus reuteri
• Some studies suggest benefit in reducing colic
• Large recent negative trial for NEC
– Randomized trial of 400 infants
– No difference in NEC, lower risk of sepsis
Oncel MY et al. Arch Dis Child Fetal Neonatal Ed 2014
Children’s Healthcare of Atlanta | Emory University
Bifidobacterium breve
• PiPS trial: large multicenter trial in the UK
• Enrolled 1315 infants less than 31 weeks gestation
• Results not yet published but preliminary report
suggests no benefit
Costeloe KL et al. Arch Dis Child 2014;99(Suppl 2):A1–A620
https://www.npeu.ox.ac.uk/pips
Children’s Healthcare of Atlanta | Emory University
What dose per day?
How long do we treat?
Significant variability in dose and duration of treatment.
Most studies initiate therapy within the first 24-72hr or with
initial feed and treat for at least 28 days, a few until discharge
Desphande et al. Pediatrics 2010
Dose depends on preparation
Most studies use a dose range of
1 - 5 x 109 CFU per day
Patel and Denning. Clinics in Perinatology, 2013
Who should receive treatment?
Summary of inclusion criteria
Majority of studies included infants <1500g,
Several added a gestational age inclusion (<30-35wk)
Patel and Denning. Clinics in Perinatology, 2013
Children’s Healthcare of Atlanta | Emory University
How do you start?
Pharmacy
Infectious
disease
expertise
NNPs
Nursing
educators
Parents?
Nursing
leadership
Nutrition
Physicians
microbiology
Our protocol
Children’s Healthcare of Atlanta | Emory University
Our protocol
Children’s Healthcare of Atlanta | Emory University
Apply QI principles
• “N of 1” tests-of-change before broad implementation
• Things to consider?
– Where will the probiotic powder be prepared?
– Does it need to be approved by your P&T committee?
• If so, will it be dispensed or prepared by pharmacy?
• If not, will it be prepared by nursing staff or nutrition?
– Staff education regarding handling, preparation
• Hand hygiene, CLABSI, clogging of feeding tubes
– Dosing frequency - CLABSI tradeoff
– Approach for sepsis evaluation
• Type of culture medium, addition of empiric Ampicillin, genotyping
– Tracking of process and outcome data
Children’s Healthcare of Atlanta | Emory University
Apply QI principles
• Key outcome measures (NEC, sepsis) will have some
lag time and may have substantial common cause
variation if measuring on monthly or even quarterly
intervals
– consider looking at number of cases as opposed to
proportion
• Focus on process measures
– What proportion of eligible infants are receiving probiotic
treatment?
– What proportion of eligible infants receive probiotics within
24 hours of initiating feeding?
Children’s Healthcare of Atlanta | Emory University
Should we obtain parental consent?
Parental consent vs. opt-in/opt-out
vs. informing parents
•
Information sheet adapted from Sesham et al. Arch Dis
Child Fetal Neonatal Ed. 2014
Children’s Healthcare of Atlanta | Emory University
What if I want to wait for an
FDA-approved preparation?
Clinical trial in US ongoing
• Estimated Phase Ib/IIa completion in December 2017
• Study plans to enroll 400 infants at 6 US hospitals
Children’s Healthcare of Atlanta | Emory University
Thank you.
Questions?
rmpatel@emory.edu