Download Probiotics in high-risk preterm infants to prevent necrotizing

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