1. 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

2. 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.

3. 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.

4. Hypothetical case
The following day, the baby develops emesis, bloody stools and abdominal distention.

5. Hypothetical case
An abdominal radiograph shows NEC with portal gas.

6. 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

7. 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?

8. 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

9. 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

10. Pathophysiology of NEC multifactorial
Premature birth
Other potential factors
Enteral feeding
Abnormal intestinal microbiota
- Propensity towards gut inflammation
- Impaired intestinal barrier function
- Decreased intestinal motility
NEC
- Decreased commensal flora
- Increased pathogenic bacteria
- Prolonged antibiotic therapy
- Acid suppression medications
- Abnormal gut vascular regulation
- RBC transfusion
- Anemia
State we can’t predict which infants will develop NEC
- Formula feeding
Patel RM and Denning PW.
Pediatric Research, 2015

11. Pathophysiology of NEC multifactorial
Premature birth
Other potential factors
Enteral feeding
Abnormal intestinal microbiota
- Propensity towards gut inflammation
- Impaired intestinal barrier function
- Decreased intestinal motility
NEC
- Decreased commensal flora
- Increased pathogenic bacteria
- Prolonged antibiotic therapy
- Acid suppression medications
- Abnormal gut vascular regulation
- RBC transfusion
- Anemia
State we can’t predict which infants will develop NEC
- Formula feeding
Patel RM and Denning PW.
Pediatric Research, 2015

12. Abnormal bacterial colonization
State we can’t predict which infants will develop NEC
Patel RM and Denning PW.
Clinics in Perinatology, 2013

13. Probiotics: How do they work?
Patel and Denning. Clinics in Perinatology, 2013

14. 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

15. Effect of probiotics on definite NEC
(Bell’s Stage 2-3)

16. 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.

17. Effect of probiotics on mortality

18. 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.

19. What about the risks of sepsis?

20. 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.

21. What about the risk of sepsis in the smallest infants <1000g?

22. Although of potential concern, there is no clear evidence that the risk of sepsis from probiotic therapy is increased among infants <1000g at birth
Lin HC, et al. Pediatrics. 2008
A prospective, blinded, randomized, multicenter controlled trial was conducted at 7 NICUs in Taiwan, to evaluate the beneficial effects of probiotics in necrotizing enterocolitis among very low birth weight infants (birth weight: <1500 g). Very low birth weight infants who survived to start enteral feeding were eligible and were assigned randomly to 2 groups after parental informed consent was obtained. Infants in the study group were given Bifidobacterium bifidum and Lactobacillus acidophilus, added to breast milk or mixed feeding (breast milk and formula), twice daily for 6 weeks. Infants in the control group were fed with breast milk or mixed feeding. Four hundred thirty-four infants were enrolled, 217 in the study group and 217 in the control group. The incidence of death or necrotizing enterocolitis (stage >or=2) was significantly lower in the study group (4 of 217 infants vs 20 of 217 infants). The incidence of necrotizing enterocolitis (stage >or=2) was lower in the study group, compared with the control group (4 of 217 infants vs 14 of 217 infants). No adverse effect, such as sepsis, flatulence, or diarrhea, was noted.
Culture proven sepsis <1000g
AlFaleh K, Anabrees J. Cochrane Database of Systematic Reviews 2014.

23. Do benefits vary by strain of probiotics?
Is a combination better than a single strain?

24. Differences by strain (genus)
Effect on risk of NEC Stage II+ by strain:
Lactobacillus: RR 0.45 ( )
Bifidobacterium: RR 0.48 ( )
Sacchromyces boulardii: RR 0.72 ( )
Combination (2 or more): RR 0.37 ( )
Test for subgroup differences: P=0.48
AlFaleh K, Anabrees J. Cochrane Database of Systematic Reviews 2014.

25. Differences by strain Wang et al. J Pediatr Surg, 2012
Patel and Denning. Clinics in Perinatology, 2013

26. What is the external validity of the probiotic trials?
(i.e. have the benefits of probiotics been demonstrated in routine clinical practice)

27. adjusted for GA, SGA, female
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
OR (95% CI)
adjusted for GA, SGA, female
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

28. 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

29. Are probiotics ready for primetime? Should we start using routinely?

31. 5-10 years ago For probiotics Against probiotics
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
Animal data supports biologic plausibility
Several small single center RCTs in foreign countries
For probiotics
Against probiotics

32. Today Against probiotics For probiotics
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

33. 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% ---
2.5% 67
5.0% 35
7.5% 23
10.0% 18
15.0% 12
Compared to VON:
Median NEC incidence in 2013 was 3.8%
(Q1, Q3: 0.0%, 7.1%)
Probiotic use in infants for 2013 was 10.5% (Q1, Q3: 0.0%, 1.8%)
NNT estimates based on point-estimate of relative risk 0.43 for Bell’s 2+ NEC (probiotic vs. control) from Cochrane analysis

34. Which probiotic do I choose
and how do I obtain it?

35. Probiotics used in prior studies: ProPrems trail (Au/NZ): ABC Dophilus
Brand Name
Made in
Type
Strains
Cost per
dose
Culturelle
Denmark
Single-dose packet
Lactobacillus rhamnosus GG $
FloraBaby
USA
Multi-dose container
Bifidobacterium & Lactobacillus & FOS $
ProBiota
Bifidobacterium & Lactobacillus $
FloraTummys
Singe-dose packet $
FlorastorKids
Sacchromyces boulardii $
VSL#3 Junior
Bifidobacterium & Lactobacillus & Streptococcus $
ABC Dophilus
Bifidobacterium and Streptococcus $
Infloran*
Switzerland
Single-dose capsule
Probiotics used in prior studies: ProPrems trail (Au/NZ): ABC Dophilus
Janvier et al. (Canada): FloraBaby
Manzoni et al (Italy). LGG (similar to Culturelle)
Hartel et al. (Germany): Infloran
Data from amazon.com 11/20/13
*Minimal data on Infloran available

36. ABC Dophilus – FDA Recall

37. 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

38. 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

39. What dose per day?
How long do we treat?

40. 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

41. 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

42. Who should receive treatment?

43. 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

44. How do you start?

46. Infectious disease expertise
Parents?
Nursing leadership
Pharmacy
NNPs
Nutrition
Nursing educators
Physicians
microbiology

47. Our protocol

48. Our protocol

49. 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

50. 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?

51. Should we obtain parental consent?

52. Parental consent vs. opt-in/opt-out vs. informing parents
Information sheet adapted from Sesham et al. Arch Dis Child Fetal Neonatal Ed. 2014

53. What if I want to wait for an FDA-approved preparation?

54. Clinical trial in US ongoing
Estimated Phase Ib/IIa completion in December 2017
Study plans to enroll 400 infants at 6 US hospitals

55. Thank you. Questions? rmpatel@emory.edu