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

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

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

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

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

Species of probiotic: Prevention of severe NEC

Probiotic species: Reducing mortality

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

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

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

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

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

PINC UK Study period: 01/05/ /04/2014 Control period: 01/05/ /04/2013

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

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

Results: Eligible infants Study groupControl group Number Gestation median (full range) weeks30 (23-37)29 (23-39) Birth weight median (full range) grams1270 ( )1223 ( )

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

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

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

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

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

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

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

Confounding factors Newport (%)Cardiff (%)VON Network(%) Antenatal steroids Any human milk on discharge Only human milk on discharge Ibuprofen for PDA Major congenital anomalies Small for gestational age NEC VON Annual reports for Newport and Cardiff ? Differences in population, microbiome

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

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

EPIQ Canada NEC reduced significantly Pre: Post intervention: 10% vs 8%, OR 0.73 ( ) 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

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)