1. Introducing a new practice on the NICU: Probiotics A James 1 H Tranter 2 A Davies 1 S Cherian 2 Royal Gwent Hospital 1 & University Hospital of Wales 2

2. Background Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in preterm infants Affects 6-7% of VLBW infants Economic burden of NEC is significant Probiotics are live micro-organisms when administered in adequate amounts confer a health benefit on the host – Improved gut barrier – Enhanced mucosal IgA response – Increased production of antiinflammatory cytokines

3. Reducing the risk of NEC and death in preterm infants Shlomai NO et al Neonatology 2014

4. Probiotics for infants < 1500 g: Preventing severe NEC (stage II-III) NNT 25 AlFaleh et al Cochrane Reviews 2014

5. Probiotics for infants < 1500 g: Reducing mortality NNT 33 AlFaleh et al Cochrane Reviews 2014

6. Species of probiotic: Prevention of severe NEC

7. Probiotic species: Reducing mortality

8. Infloran Contains Lactobacillus acidophilus and Bifidobacterium bifidus The most widely studied product Babies receive a daily dose of 10 9 of each live bacterial species Not licensed as a medicine, categorised as a supplement in UK Low cost intervention- approx £1 per treatment per day per baby

9. Introducing change Literature review, discussions within units Microbiology: Drug samples obtained, cultured Public Health, IPCNG: discussions, review Pharmacy, Medicines group: discussions, review Presented to Directorate Clinical Governance Business case, presented to Trust Finance Guidelines prepared, PIL prepared Staff education

10. Cost of Infloran Estimated number of infants: 70 Estimated median duration:7 weeks Cost per capsule: £0.90 Cost per patient: £44.10 Cost per year: £3087

11. Cost of treating NEC Increased direct hospital cost: ‘Medical’ NEC: $ 14,000 ‘Surgical NEC’: $23,000 Estimated 5cases/year/unit: $80,000/£50,000 NB: 2009 CPI, USA Johnson T et al J Pediatrics 2013

12. Collaboration PINC UK: Probiotics In Newborns Collaboration Newcastle, Bradford, Norfolk & Norwich Eligible infants: <32 weeks gestation <1500g birth weight < 7 days old if outborn, no NEC

13. PINC UK Study period: 01/05/2013- 30/04/2014 Control period: 01/05/2012-30/04/2013

14. Infloran prescription Infloran: 10 9 bacilli LBA and BBB in 250mg Dose is 125mg twice daily Quality control data available MHRA no objection to use in a hospital setting Prescribed as drug for quality control and safety reasons Pharmacy procures, maintains cold chain

15. Preparation & administration Preparation in designated area in milk kitchen Capsule contents dissolved in 1ml water, 0.5ml administered as a bolus Can be started when feeds of 0.5ml tolerated Not to be administered if on continuous feeds Consider stopping if unwell, feeds stopped Safe to administer if on steroids

16. Results: Eligible infants Study groupControl group Number164170 Gestation median (full range) weeks30 (23-37)29 (23-39) Birth weight median (full range) grams1270 (420-2370)1223 (520-2170)

17. Study group Probiotics received130 Age at start (Median)5 days Age at start (Min)1 day Age at start (Max)58 days

18. Study group Duration of administration of probiotics: Median17 days Min1 day Max65 days

19. Outcomes Study group (n=164)Control group (n=170) Probiotics given1300 NEC ≥ stage2*1413 Deaths (all causes)*1715 Positive blood cultures*2634 *Fishers exact test NS

20. Reason for non-administration Died before starting feeds8 Transferred out before feeds started4 >34 weeks when feeds started9 >34 weeks on 01/05/20133 Missed10

21. Cause of death Study Extensive NEC6 Sepsis2 Complications of prematurity7 Congenital anomalies1 Twin to twin transfusion1 Control Extensive NEC 4 Sepsis 1 Complications of prematurity10

22. Newport, Cardiff: Study group Newport (n=93)Cardiff (n=71) Probiotics given8050 NEC ≥ stage2113 Deaths (all causes)710

23. Reducing the risk of NEC and death in preterm infants Shlomai NO et al Neonatology 2014 ✓ ✓ ✓

24. Confounding factors Newport (%)Cardiff (%)VON Network(%) Antenatal steroids86.386.682.9 Any human milk on discharge43.347.557.3 Only human milk on discharge2012.511.7 Ibuprofen for PDA221.68.1 Major congenital anomalies1.710.44.4 Small for gestational age30.535.824.7 NEC13.91.64.5 2013 VON Annual reports for Newport and Cardiff ? Differences in population, microbiome

25. NEC in Japan Incidence 0.2%-1.6%: ? reason Exclusive breast milk <28 w infants Full feeds in 7 days Avoid UVC insertion Early use of PIC lines Probiotics Minimal handling Use antibiotics only if certain of infections Isayama T et al Pediatrics 2012 Lee SK at SIGNEC 2014

26. EPIQ Canada Evidence Based Practice for Improving Quality All tertiary NICUs in Canada Included all infants <29w gestation For reducing NEC: practice changes implemented – Standardised feeding guidelines – Early feeding – Use of donor milk – Colostrum & enhanced breast milk feeds – Early TPN – Hold enteral feeds during blood transfusions Lee SK CMAJ 2014

27. EPIQ Canada NEC reduced significantly Pre: Post intervention: 10% vs 8%, OR 0.73 (.52-.98) Effective practices were: – Standardised feeding guidelines – Early feeding – Use of donor milk – Colostrum & enhanced breast milk feeds – Early TPN – Hold enteral feeds during blood transfusions Lee SK CMAJ 2014

28. Conclusions Introduced routine probiotic use on 2 NICUs Safe: No sepsis with probiotic organism No difference in NEC, sepsis or death Small numbers Need to improve breast feeding both centers ? Consider holding enteral feeds during transfusions at Cardiff (TANEC audit)