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Trust Guideline for the use of probiotics in high-risk preterm infants to prevent necrotizing enterocolitis A clinical guideline recommended for use For use in: The Neonatal Intensive Care Unit (NICU) By: Doctors, nurses, and dieticians on the neonatal unit For: Preterm neonates at high risk of necrotising entercolitis Division responsible Division 3 for document: Probiotics, Necrotising enterocolitis, Lactobacillus, Key words: Bifidobacterium, prevention, Name of document Dr Paul Clarke author: Job title of document Consultant Neonatologist author: Name of document David Booth author’s Line Manager: Job title of document Consultant Neonatologist and Clinical Director of Paediatrics author’s Line Manager: Drs MP Dyke, R Roy, P Muthukumar, H O‟Reilly, F Walston (Consultant Neonatologists); Dr D Booth (Consultant Neonatologist and Clinical Director for Paediatrics) Drs MA Morris & G Briars (Consultant Paediatric Gastroenterologists); Dr Supported by: C Tremlett (Consultant Microbiologist), Sara Pullan (Specialist Paediatric Dietician); Ros Howe (Clinical Pharmacist); Luisa Lyons (Infant Feeding Co-ordinator); Mr Milind Kulkarni (Consultant Paediatric Surgeon); Assessed and Clinical Guidelines Assessment Panel (CGAP) approved by: Date of approval: 24 November 2015 Reported as approved Clinical Effectiveness Committee to the: Clinical Governance Committee To be reviewed before: 24 November 2018 To be reviewed by: Dr Paul Clarke Reference and/or ID No: 8689 Trustdocs ID No: Version No: 2.1 Description of New front page & footers changes: Compliance links: None If Yes – does the strategy/policy deviate from the N/a recommendations of NICE? If so, why? This guideline has been approved by the Trust's Clinical Guidelines Assessment Panel as an aid to the diagnosis and management of relevant patients and clinical circumstances. Not every patient or situation fits neatly into a standard guideline scenario and the guideline must be interpreted and applied in practice in the light of prevailing clinical circumstances, the diagnostic and treatment options available and the professional judgement, knowledge and expertise of relevant clinicians. It is advised that the rationale for any departure from relevant guidance should be documented in the patient's case notes. The Trust's guidelines are made publicly available as part of the collective endeavour to continuously improve the quality of healthcare through sharing medical experience and knowledge. The Trust accepts no responsibility for any misunderstanding or misapplication of this document. Clinical Guideline for: Use of Probiotics in high-risk preterm infants to prevent necrotizing enterocolitis Author/s: Paul Clarke Author/s title: Consultant Neonatologist Approved by: CGAP Date approved: 24/11/2015 Review date: 24/11/2018 Available via Trust Docs Version: 2.1 Trust Docs ID:8689 Page 1 of 13 Trust Guideline for the use of probiotics in high-risk preterm infants to prevent necrotizing enterocolitis Quick reference Eligible for Infloran® probiotics: <32 weeks‟ gestation, or <1500g birthweight and <37 weeks‟ gestation Speak to parents before or as soon as possible after birth Give approved Parent Information Sheet (Appendix) Document discussions in infant‟s casenotes Start Infloran® ideally on postnatal day 1 (unless considered ineligible for enteral feeding) Prescribe Infloran® dose on NICU drug chart: 125 mg twice daily Refer to Infloran® „drug‟ information sheet in NICU formulary folder for full guidance on preparation/ administration ® For every infant treated, record Infloran use daily in SEND („Drugs Given‟, daily data) Continue daily Infloran® supplementation until 34 weeks‟ post menstrual age or transfer Continue daily Infloran® supplementation until discharge in very low birth weight babies born at 32-36 weeks‟ gestation Clinical Guideline for: Use of Probiotics in high-risk preterm infants to prevent necrotizing enterocolitis Author/s: Paul Clarke Author/s title: Consultant Neonatologist Approved by: CGAP Date approved: 24/11/2015 Review date: 24/11/2018 Available via Trust Docs Version: 2.1 Trust Docs ID:8689 Page 2 of 13 Trust Guideline for the use of probiotics in high-risk preterm infants to prevent necrotizing enterocolitis Objectives The purpose of this guideline is to guide the routine use of probiotics for the prevention of necrotizing enterocolitis (NEC) in high risk neonates admitted to the Norfolk and Norwich University Hospital NICU. Summary Probiotics are gram positive non-pathogenic and non-toxigenic live microbes which, when administered enterally, have been shown to successfully colonise the gut of preterm infants. Probiotic products such as Infloran® contain lactobacilli and bifidobacteria, the predominant organisms found in the gastro-intestinal tract of healthy breastfed infants. Colonisation with these organisms is thought to protect the gut from colonisation by more pathogenic species. Successive systematic reviews have shown that oral probiotics very significantly reduce the risk of necrotizing enterocolitis (NEC) and the risk of death in preterm infants when given in early postnatal life (1)(2)(3). With the addition of recent published studies, there are now over 5000 babies in the latest update to the Cochrane review (3). This latest published meta-analysis shows that enteral probiotic supplementation significantly reduced the incidence of severe NEC (stage II or more) (typical relative risk (RR) 0.43, 95% confidence interval (CI) 0.33 to 0.56; 20 studies, 5529 infants) (Fig 1) and mortality (typical RR 0.65, 95% CI 0.52 to 0.81; 17 studies, 5112 infants). The included trials reported no systemic infection with the supplemental probiotic organism/s. Probiotic preparations containing either lactobacillus alone or in combination with bifidobacterium were found to be effective. The review authors‟ conclusions were that enteral supplementation of probiotics prevents severe NEC and all-cause mortality in preterm infants and that the available evidence strongly supports a change in practice towards use routine use of probiotics. Long term follow-up data are presently scant(3) but probiotic use does not appear to be associated with significant side-effects. Our NICU introduced routine probiotics for high-risk neonates under this Trust Guideline in January 2013. To date (October 2015) our experience has been very positive. We have treated over 350 babies, have seen fewer cases of definite NEC (4) (local audit, ongoing, Dr Clarke), and have had no case of sepsis due to a supplemented probiotic organism. Parental feedback has also been very positive.(5) Clinical Guideline for: Use of Probiotics in high-risk preterm infants to prevent necrotizing enterocolitis Author/s: Paul Clarke Author/s title: Consultant Neonatologist Approved by: CGAP Date approved: 24/11/2015 Review date: 24/11/2018 Available via Trust Docs Version: 2.1 Trust Docs ID:8689 Page 3 of 13 Trust Guideline for the use of probiotics in high-risk preterm infants to prevent necrotizing enterocolitis Fig 1 Cochrane plot for definite NEC from AlFaleh 2014 (3) Clinical Guideline for: Use of Probiotics in high-risk preterm infants to prevent necrotizing enterocolitis Author/s: Paul Clarke Author/s title: Consultant Neonatologist Approved by: CGAP Date approved: 24/11/2015 Review date: 24/11/2018 Available via Trust Docs Version: 2.1 Trust Docs ID:8689 Page 4 of 13 Trust Guideline for the use of probiotics in high-risk preterm infants to prevent necrotizing enterocolitis Since the first version of this Trust Guideline was published (2012) an important study of probiotics in neonates has concluded, the UK PiPS trial (https://www.npeu.ox.ac.uk/pips). The PiPS trial is to date the largest and best conducted multi-centre study of probiotics in neonates. This high-quality study randomised over 1300 babies to placebo or to a single species probiotic (a Bifidobacterium Breve, single strain BBG). The primary outcomes were blood stream infection with any organism other than a skin commensal after 72 hours after birth, necrotising enterocolitis Bell Stage 2 or 3, and death. The results showed that NEC stage 2 or worse occurred in similar incidence in treated babies and controls (9.4 % vs. 10% respectively). To date (October 2015) these data have been presented only in abstract form.(6) Others have already speculated as to the apparent lack of benefit of probiotics in the PiPS trial. “Among the possibilities, this study avoided biases that exaggerated the benefits in other studies; this study suffered from biases that reduced the benefits; the organism chosen was less effective for this purpose (or less effective at colonising the infants’ intestines); random variation in efficacy across numerous studies. The 95% CI of the relative risk from this individual trial are from 0.68 to 1.27. Which means that although this was a high quality trial, it cannot with confidence exclude a substantial benefit (or indeed harm) for probiotics”.(7) Another possible reason for the null result of the PiPS study is that the B. breve strain used does not normally have the genetic and enzymatic capabilities to utilise oligosaccharides present in human breast milk (in contrast to the case with other bifidobacterial species, such as those contained in Infloran®) and thus would be expected to have only limited colonisation and effectiveness as a strain in prevention of NEC. Unlike the PiPS study, our experience has been with Infloran® which not only contains a different Bifidobacterium but also contains a lactobacillus species in combination. It is entirely plausible that lactobacilli form an important component, or indeed that the combination with bifidobacteria is important for efficacy. Being as yet unpublished, the PiPS study does not yet feature in any published metaanalysis. Nevertheless inclusion of the PiPS study in an ad hoc meta-analysis has been done (see: https://neonatalresearch.files.wordpress.com/2015/03/forestplot.png) and, as expected, leaves the overall positive effect of probiotics to prevent NEC in neonates unchanged. While the PiPS study is certainly not the first study to indicate a null effect for probiotics,(3) being the largest study to date it does highlight the need for ongoing research and the need for ongoing local audit of our own use of probiotics and NEC rates.(7) The optimal product (or combination of products), timing and duration remain to be determined. Meanwhile on the neonatal unit in Norwich we will continue to use the product studied most widely in neonates (Infloran®) and will continue to offer routine supplementation with it to those infants at greatest risk of NEC. Clinical Guideline for: Use of Probiotics in high-risk preterm infants to prevent necrotizing enterocolitis Author/s: Paul Clarke Author/s title: Consultant Neonatologist Approved by: CGAP Date approved: 24/11/2015 Review date: 24/11/2018 Available via Trust Docs Version: 2.1 Trust Docs ID:8689 Page 5 of 13 Trust Guideline for the use of probiotics in high-risk preterm infants to prevent necrotizing enterocolitis Our practice, summarised below, uses the published evidence-base for guiding our use of probiotics in preterm neonates.(3)(8) Key practice points 1. Give Infloran® to any baby born <32 weeks and to any very low birth weight preterm baby (ie <1500 g and <37 weeks‟ gestation). 2. Speak to parents (even before birth where possible) and offer them written information (parent information sheet – see appendix) and document in the infant‟s casenotes that this has been done. 3. Aim to start Infloran® as soon as enteral feeds are being commenced (this will usually be on day 1 postnatal). If EBM is unavailable or likely to be delayed then probiotics should still be administered on day 1 providing that the baby is considered eligible for enteral feeding. 4. Emphasise the vital role of early and frequent breast milk expression for optimal early infant nutrition and maternal lactation. 5. Prescribe Infloran® 125 mg twice daily (half a capsule twice daily) on the NICU Drug Prescription Chart. 6. Mix the contents of one full capsule (250 mg) with 2 mL expressed breast milk (EBM) and/or sterile water. Use breast milk when available, but where EBM is unavailable or the amount of available breast milk is <2 mL then make up the difference wholly or partly with sterile water. 7. Using a syringe, draw up and give half the resulting volume (1 mL: containing 125 mg Infloran®) as a bolus via the nasogastric tube (NGT). Discard the remainder. It is safe to provide this 1 mL bolus twice daily as an additional volume, even in babies on as little as 0.5 mL/kg/hour. 8. Continue with supplementation until ~34 weeks corrected age, providing the baby has been tolerating enteral feeds for a full 2-week period by this time (stop earlier or discontinue later at consultant discretion). Continue until discharge in very low birth weight babies born at 32-36 weeks‟ gestation. 9. Consider withholding in any baby who is seriously unwell, septicaemic, and those with suspected NEC. 10. Discuss with consultant before starting or restarting in a baby who has had proven NEC. 11. Ensure that each baby‟s treatment with „Infloran®‟ is entered in BadgerNet (in the baby‟s daily data entry for “Drugs given” search for and select „Infloran®‟ from drugs menu). Background and Rationale Preterm babies experience delayed and abnormal colonisation of their gut, and continue to be exposed to sterile environments and antibiotics. There is increasing evidence that this is one of the key factors in the development of NEC. Many trials have shown that oral probiotics (live micro-organisms given by capsule) improve Clinical Guideline for: Use of Probiotics in high-risk preterm infants to prevent necrotizing enterocolitis Author/s: Paul Clarke Author/s title: Consultant Neonatologist Approved by: CGAP Date approved: 24/11/2015 Review date: 24/11/2018 Available via Trust Docs Version: 2.1 Trust Docs ID:8689 Page 6 of 13 Trust Guideline for the use of probiotics in high-risk preterm infants to prevent necrotizing enterocolitis patterns of gut colonisation, and decrease the risk of both NEC and death.(3) Probiotics appear to be both safe and effective. Although long term effects (if any) remain unclear, the overall evidence that they reduce death appears so convincing that any as-yet-unknown potential long term effects are outweighed by their immediate effects on reduction in mortality. While in the UK probiotics are not currently in widespread use outside of clinical trials, some other countries (such as Ireland, Italy, Denmark, and the Scandinavian countries) and are increasingly reporting their routine use. A number of other UK neonatal units are currently practising routine probiotic supplementation of high-risk infants, with parental assent.(4) We believe that the data available to clinicians worldwide are compelling, showing the safety and efficacy of probiotics in small preterm infants to prevent NEC. We believe that parents of preterm babies also have a right to be informed of these data. Parents also believe that they themselves have a right to be informed about these data.(4) We believe that the devastating disease burden of necrotizing enterocolitis and the relative safety of probiotics make continued delays in routine administration of probiotics increasingly difficult to justify. Choice of product We use Infloran® (Desma Healthcare, Chiasso, Switzerland). Infloran® is the most studied(3)(4)(5)(9)(10) and most widely available probiotic product. It contains Lactobacillus acidophilus and Bifidobacterium bifidum (providing 109 colony-forming units of each of these bacteria per day). This probiotic combination was reviewed and approved by the Trust‟s Drug, Therapeutics & Medicines Management Committee in July 2012. It is included in the Trust‟s formulary for the indication of prevention of necrotizing enterocolitis in high-risk preterm babies. Regulatory considerations Infloran® is not licensed as a medicine in the UK but is categorised as a food product. Therefore in the UK it is in the same regulatory group as breast milk fortifiers. The Medicines and Healthcare products Regulatory Agency (MHRA) has no objection to the import of this product for use in a hospital setting under a physician‟s discretion/responsibility. Use of probiotics in babies on the neonatal unit may therefore be considered analogous to use of other non-drug agents such as human milk fortifiers or feed thickeners. However it is worth noting that in some other European countries (e.g. Italy, Switzerland, Austria, Spain) the product Infloran® is classed as a medicine, and consequently its production and quality control therefore meets the more stringent requirements applied for drug products. Infloran® is the only probiotic containing L. acidophilus and B. bifidum that is registered as a drug. The Infloran® manufacturing site where both active ingredient and finished product are made are authorised by Italian health authorities for pharmaceutical production, with certified inspections every two years, assuring that manufacturing is compliant with the practice requirements referred to in EC Directive 2003/94/EC („The principles and guidelines of Good Manufacturing Practice‟). Clinical Guideline for: Use of Probiotics in high-risk preterm infants to prevent necrotizing enterocolitis Author/s: Paul Clarke Author/s title: Consultant Neonatologist Approved by: CGAP Date approved: 24/11/2015 Review date: 24/11/2018 Available via Trust Docs Version: 2.1 Trust Docs ID:8689 Page 7 of 13 Trust Guideline for the use of probiotics in high-risk preterm infants to prevent necrotizing enterocolitis Eligible population Infloran® will continue to be offered to those at highest risk of NEC. At present we still consider this group as being comprised of babies born at <32 weeks‟ gestation or of birth weight <1500g and preterm. Occasional other babies may merit probiotics based on individual needs (e.g. short gut syndrome), after appropriate discussion between consultant neonatologists, gastroenterologists, and surgeons, and in conjunction with parents. Prescribing probiotics on our NICU Although not licensed as a medicine, to ensure appropriate delivery, dosage, and governance on the neonatal unit, Infloran® is prescribed on the neonatal drug prescription chart and is administered after checking by two nurses in the same way as for a drug. It is given by mixing with EBM and/or sterile water, via a NGT. Expressed breast milk should be promoted and used when available. Where the amount of available breast milk is <2 mL (or the baby is receiving formula) then make up the difference with sterile water. The dose is 125 mg twice daily and should be given soon after birth unless there are any contraindications to enteral feeding. Continue until ~34 weeks post-menstrual age, or until discharge or transfer if this occurs sooner. Probiotic prescription for very low birth weight babies born at 32-36 weeks‟ gestation may continue until their discharge. Higher doses can be given to specific infants (e.g. larger babies with short gut etc.) Infloran® comes as a capsule containing 250 mg of probiotic granules – the capsule will be added to 2 mL of milk (and/or sterile water) and approximately half the contents given. It is not necessary to give exactly half the capsule – a rough approximation will suffice. It should be given as a 1 mL bolus. It is safe to give this size of bolus even in babies on only 0.5 mL/kg/hr. Risks of using probiotics There is a very small risk of infection with the probiotic bacteria themselves. Sepsis associated with probiotic treatment is not new: there have been reports of lactobacilli sepsis in both paediatric and adult patients (11). Case in neonates seem to be very rare (there were no cases in >5000 babies studied in the randomised trials) but there have nevertheless been several recent cases reported with Infloran® use (12) (13) so vigilance and an awareness of the possibility is necessary. The affected babies reported to date have ranged in gestational age from 26 to 30 weeks.(12) (13) As no sepsis cases have so far been reported in any lower gestation premature infants (2325 weeks) who received supplementation, the risk of probiotic sepsis may not be inversely related to gestational age. The sporadic reported cases of babies with probiotic-associated infection have had infections that were relatively minor and easy to treat. Current antibiotic regimes are adequate, but as with current practice, any seriously unwell baby should be discussed with neonatal consultants and microbiology advice sought if there are specific concerns. The risk of gut translocation may be increased when babies are unwell. (8) Just as we would usually discontinue enteral feeds in an unwell baby, consider stopping Infloran® if the baby is very unwell, septic or has signs of evolving NEC. Only give Infloran® to babies considered eligible to receive milk or already tolerating milk. Clinical Guideline for: Use of Probiotics in high-risk preterm infants to prevent necrotizing enterocolitis Author/s: Paul Clarke Author/s title: Consultant Neonatologist Approved by: CGAP Date approved: 24/11/2015 Review date: 24/11/2018 Available via Trust Docs Version: 2.1 Trust Docs ID:8689 Page 8 of 13 Trust Guideline for the use of probiotics in high-risk preterm infants to prevent necrotizing enterocolitis Information for parents We have a short parent information leaflet (appended, and available at Admission to NICU id=1317 that explains our current approach to probiotics and why we provide probiotics as a routine supplement to specific babies. We do not ask for written parental consent, but adopt a similar approach to that we utilise for blood transfusion, or introduction of breast milk fortifiers/multivitamin/iron supplements. We aim to include a short entry in the infant‟s casenotes recording that discussion with parents has taken place, that the information sheet has been given, and that the parents agree with the plan. Nursing or medical staff can have the discussion, and make the notes entry. If parents prefer or request their baby not to receive probiotics then we will: i) document their wishes and ii) advise the consultant responsible in case further discussion may be needed. Clinical audit standards and Governance We routinely record which infants receive probiotics and their key outcomes (NEC, sepsis, mortality) In 2014 we presented nationally an audit of our probiotic use and outcomes.(5) We continue to audit our probiotic use and NEC rates on an ongoing basis. Summary of development and consultation process undertaken before registration and dissemination The original guideline was drafted in 2012 by Dr Paul Clarke on behalf of the Neonatal Department. It was circulated for comments to consultant neonatologists, consultant paediatric surgeons, specialist registrars, trainees and ANNPs in neonatal medicine, and it was discussed at the Neonatal Departmental Guidelines meeting where amendments were made to incorporate suggestions and comments. The neonatal unit pharmacist and dietician also reviewed and approved it, and it was supported by the Jenny Lind Nutritional Support Team, by Dr Tremlett, consultant microbiologist, and by the Infant Feeding coordinators. The author reviewed the published literature to date in October 2015 in support of this updated guideline and circulated the revised draft widely within the department for comments before finalisation. The cited references are available from the author on request. The final version has been endorsed by the Clinical Guidelines Assessment Panel. The parent information was reviewed by parents of infants on the NICU in September 2012 and their suggestions/comments were incorporated into the version first approved in October 2012 by the Trust‟s Patient Information Forum. During the update of this guideline, several minor updates were made to the parent information leaflet. Acknowledgments The author wishes to acknowledge the support of Mr Milind Kulkarni, former Clinical Director for Paediatrics, and Colin Green and Dr Tarnya Marshall for the Trust‟s Clinical Guideline for: Use of Probiotics in high-risk preterm infants to prevent necrotizing enterocolitis Author/s: Paul Clarke Author/s title: Consultant Neonatologist Approved by: CGAP Date approved: 24/11/2015 Review date: 24/11/2018 Available via Trust Docs Version: 2.1 Trust Docs ID:8689 Page 9 of 13 Trust Guideline for the use of probiotics in high-risk preterm infants to prevent necrotizing enterocolitis Drug, Therapeutics & Medicines Management Committee, and also Drs Nick Embleton, Consultant Neonatologist with Newcastle Neonatal Service, and Sam Oddie, Consultant Neonatologist, Bradford Royal Hospital for their kind support and advice. We also thank Dr Lindsay Hall, Senior Lecturer and Research Leader in Gastrointestinal Sciences, UEA/Institute of Food Research, Norwich, for collaboration and kind assistance with internal microbiological QC of our probiotic batches. Distribution list/ dissemination method Hospital intranet; Neonatal Unit. Abbreviations EBM, expressed breast milk NEC, necrotizing enterocolitis NGT, nasogastric tube NICU, neonatal intensive care unit SEND, standardised electronic neonatal database References 1. Deshpande G, Rao S, Patole S, Bulsara M. Updated meta-anlysis of probiotics for preventing NEC in preterm neonates. Pediatrics 2010;125(5):921-30. 2. Wang Q, Dong J, Zhu Y. Probiotic supplement reduces risk of necrotizing enterocolitis and mortality in preterm very low-birth-weight infants: an updated meta-analysis of 20 randomized, controlled trials. J Pediatr Surg 2012; 47(1):241-248. Available at: http://www.sciencedirect.com/science/article/pii/S0022346811008360 3. AlFaleh K, Bassler D. Probiotics for prevention of necrotizing enterocolitis in preterm infants (updated 2013). Cochrane Database Syst Rev 2014, Issue 2. Art. No.: CD005496. doi: 10.1002/14651858. CD005496.pub4. Available at: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD005496.pub4/epdf 4. Sesham R, Oddie S, Embleton ND, Clarke P. Probiotics for preterm neonates: parents' perspectives and present prevalence. Arch Dis Child Fetal Neonatal Ed. 2014 Jul;99(4):F345. 5. Balain M, Oddie S, Banait N, Embleton N, Sesham R, Clarke P. PINC UK (Probiotics in Neonatal Collaboration in UK). [Abstract]. Arch Dis Child Fetal Neonatal Ed. 2014 Jun;99 Suppl 1:A70. Data presented at Perinatal Medicine Congress, Harrogate, 2014. Conference poster available at: https://www.researchgate.net/publication/263899903_PC.99_PINC_UK_(Probi otics_in_Neonatal_Collaboration_in_UK) 6. Costeloe KL, Wilks M, Hardy P, Nelis C, Millar MR. Early Bifidobacterium Breve Bbg-001 To Prevent Necrotising Enterocolitis, Late-onset Sepsis And Death: The Pips Trial. [Abstract] Arch Dis Child 2014;99:A23-A24. doi:10.1136/archdischild-2014-307384.75 Clinical Guideline for: Use of Probiotics in high-risk preterm infants to prevent necrotizing enterocolitis Author/s: Paul Clarke Author/s title: Consultant Neonatologist Approved by: CGAP Date approved: 24/11/2015 Review date: 24/11/2018 Available via Trust Docs Version: 2.1 Trust Docs ID:8689 Page 10 of 13 Trust Guideline for the use of probiotics in high-risk preterm infants to prevent necrotizing enterocolitis 7. Barrington K. What is the news about probiotics? Neonatal Research website, 9th March 2015. Available at: http://neonatalresearch.org/2015/03/09/what-isthe-news-about-probiotics/ 8. Deshpande GC, Rao SC, Keil AD, Patole SK. Evidence-based guidelines for use of probiotics in preterm neonates. BMC Med. 2011 Aug 2;9:92. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163616/pdf/1741-7015-992.pdf 9. Lin H-C, Hsu C-H, Chen H-L, et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight preterm infants: A multicenter, randomized, controlled trial. Pediatrics 2008; 122; 693-700. http://pediatrics.aappublications.org/cgi/content/abstract/122/4/693 10. Lin H-C, Su B-H, Chen A-C, et al. Oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants. Pediatrics 2005; 115; 1-4. 11. Land MH, Rouster-Stevens K, Woods CR, Cannon ML, Cnota J, Shetty AK. Lactobacillus sepsis associated with probiotic therapy. Pediatrics. 2005 Jan;115:178-81. 12. Zbinden A, Zbinden R, Berger C, Arlettaz R. Case series of Bifidobacterium longum bacteremia in three preterm infants on probiotic therapy. Neonatology. 2015;107:56-9. doi: 10.1159/000367985. 13. Bertelli C, Pillonel T, Torregrossa A, Prod'hom G, Fischer CJ, Greub G, Giannoni E. Bifidobacterium longum bacteremia in preterm infants receiving probiotics. Clin Infect Dis. 2015 Mar 15;60:924-7. doi: 10.1093/cid/ciu946. Clinical Guideline for: Use of Probiotics in high-risk preterm infants to prevent necrotizing enterocolitis Author/s: Paul Clarke Author/s title: Consultant Neonatologist Approved by: CGAP Date approved: 24/11/2015 Review date: 24/11/2018 Available via Trust Docs Version: 2.1 Trust Docs ID:8689 Page 11 of 13 Trust Guideline for the use of probiotics in high-risk preterm infants to prevent necrotizing enterocolitis For a copy of the patient information leaflet -Trust docs id 8565 click here Probiotics - Information for parents ‘Getting the right gut bacteria from the start’ We understand that having a premature baby is difficult and stressful. Your views are most important and we want to keep you fully informed about how we plan to care for your baby. Here we explain some important feeding issues in premature babies. We wish to inform you that we plan to use a probiotic product, Infloran ®, with the aim of protecting your baby and improving feeding outcomes. What is different about feeding premature babies? We know that premature babies tolerate milk best if it is introduced gradually. Until they are able to tolerate enough milk, we feed most premature babies with a special intravenous liquid feed called Parenteral Nutrition (“PN”). This liquid feed contains protein, energy, fat, vitamins and minerals to help your baby to grow. Some babies find digesting milk difficult and take longer than others to manage this. Most babies remain very well, but around 5-10% of premature babies become unwell with a condition called „NEC‟ (Necrotising EnteroColitis) in which there is inflammation of the gut. Most babies who get NEC recover fully, but it can sometimes be serious, sometimes needs an operation, and can occasionally be life-threatening. What can we do to try and prevent NEC? Your choice in how you will feed your baby is one important factor. Breast milk is the best milk for your baby. It reduces the risks of bowel problems including NEC. Even small amounts of breast milk are important for your baby. Early expression of breast milk starting as soon as possible after birth and ongoing frequent expression of breast milk are important for optimal early nutrition of your baby and successful lactation. We will support and encourage you if you choose to express breast milk. If you are unable to or choose not to express breast milk we will advise on the most suitable alternatives. Probiotics There is now very good evidence that giving preterm babies small amounts of „healthy‟ bacteria in their milk (like those bacteria found in live yoghurts and probiotic drinks that are now available in our supermarkets) reduces the risk of NEC, including in babies fed breast milk. Some neonatal units in the UK now give probiotics routinely to preterm babies, though it is not yet widespread practice in all units. Studies are still taking place, but already there is good scientific evidence to show that probiotics prevent some babies getting NEC. We consider it important to share this information with you. What do we know about probiotics and preterm babies? Probiotics to prevent NEC have now been studied in over 5000 preterm babies. The accumulated evidence clearly shows that probiotic bacteria (specifically bifidobacteria and lactobacilli) are effective in reducing the incidence of NEC by more than 50%, Clinical Guideline for: Use of Probiotics in high-risk preterm infants to prevent necrotizing enterocolitis Author/s: Paul Clarke Author/s title: Consultant Neonatologist Approved by: CGAP Date approved: 24/11/2015 Review date: 24/11/2018 Available via Trust Docs Version: 2.1 Trust Docs ID:8689 Page 12 of 13 Trust Guideline for the use of probiotics in high-risk preterm infants to prevent necrotizing enterocolitis and so reduce mortality. This means that probiotics appear to protect babies against NEC and improve their survival chances. Babies who got probiotics developed serious NEC half as often as those not given probiotics. Of all premature babies studied so far, no serious side effects have been seen with probiotics. Are there any risks of getting probiotics? There is a very small risk that a baby may actually get an infection from the probiotic bacteria. While occasional cases have been reported rarely, there were no cases among any of the 5000+ babies studied in the clinical trials. Also there have been no cases to date in our own unit‟s experience of giving probiotics to several hundred babies since January 2013. In the unlikely event that an infection happened we have antibiotics available that kill probiotic bacteria. Rare cases of blood stream infection reported so far were relatively minor and easy to treat. Are there any risks from not getting probiotics? If your baby does not get probiotics, current evidence suggests that, on average, he/she may be at an increased risk of developing NEC compared to a baby of similar size/gestational age that is given probiotics. However, most premature babies do not get NEC even without probiotics, and giving probiotics will not prevent all cases of NEC. What is being offered? We believe your baby may benefit from probiotics. We plan to start giving your baby probiotics as soon as they are ready to receive their first milk feeds unless you tell us that you do not want us to do this. We will normally carry on giving the probiotics twice daily with the milk feeds until your baby reaches around 34 weeks corrected age, or until their discharge/transfer, whichever is sooner. If your baby is transferred back to another hospital before 34 weeks corrected age, because probiotics are not yet widely used in all other UK neonatal units, it is possible that ongoing probiotic treatment will not be available after transfer. Although probiotics are classed as food supplements in the UK, the production and quality control of the probiotic we will give to your baby („Infloran®‟) meets the highest standards as used in the manufacture of drug products. Please let the doctor or nurse looking after your baby know if you do not want your baby to be given probiotics. If you are unsure, or wish to discuss this with a senior doctor, please let the nurse caring for your baby know. What if I want more information or have any questions? Please tell the nurse or doctor looking after your baby that you would like more information. Thank you for reading this leaflet. Neonatal Unit nurses and doctors. Neonatal Unit Norfolk & Norwich University Hospital Tel: 01603 286868 Clinical Guideline for: Use of Probiotics in high-risk preterm infants to prevent necrotizing enterocolitis Author/s: Paul Clarke Author/s title: Consultant Neonatologist Approved by: CGAP Date approved: 24/11/2015 Review date: 24/11/2018 Available via Trust Docs Version: 2.1 Trust Docs ID:8689 Page 13 of 13