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.

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.

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

Hypothetical case An abdominal radiograph shows NEC with portal gas.

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

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

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

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

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

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

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

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

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 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.

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.

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

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

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

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

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

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

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

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

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

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 $ 0.81 FloraBaby USA Multi-dose container Bifidobacterium & Lactobacillus & FOS $ 0.38 ProBiota Bifidobacterium & Lactobacillus $ 0.50 FloraTummys Singe-dose packet $ 1.00 FlorastorKids Sacchromyces boulardii $ 0.78 VSL#3 Junior Bifidobacterium & Lactobacillus & Streptococcus $ 2.56 ABC Dophilus Bifidobacterium and Streptococcus $ 0.48 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

ABC Dophilus – FDA Recall

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

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

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

How do you start?

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

Our protocol

Our protocol

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

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?

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

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

Thank you. Questions? rmpatel@emory.edu