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Incidence of necrotising enterocolitis before and after introducing routine prophylactic Lactobacillus and Bifidobacterium probiotics
  1. Claire Robertson1,2,
  2. George M Savva3,
  3. Raducu Clapuci1,
  4. Jacqueline Jones1,
  5. Hassan Maimouni4,
  6. Eleanor Brown1,
  7. Ashish Minocha5,
  8. Lindsay J Hall2,
  9. Paul Clarke1,4
  1. 1 Neonatal Unit, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK
  2. 2 Gut Microbes and Health, Quadram Institute Bioscience, Norwich, UK
  3. 3 Core Science Resources, Quadram Institute Bioscience, Norwich, UK
  4. 4 Norwich Medical School, University of East Anglia, Norwich, UK
  5. 5 Paediatric and Neonatal Surgery, Jenny Lind Children's Hospital, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK
  1. Correspondence to Prof Paul Clarke, Neonatal Unit, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK; paul.clarke{at}


Objective To compare rates of necrotising enterocolitis (NEC), late-onset sepsis, and mortality in 5-year epochs before and after implementation of routine daily multistrain probiotics administration in high-risk neonates.

Design Single-centre retrospective observational study over the 10-year period from 1 January 2008 to 31 December 2017.

Setting Level 3 neonatal intensive care unit (NICU) of the Norfolk and Norwich University Hospital, UK.

Patients Preterm neonates at high risk of NEC: admitted to NICU within 3 days of birth at <32 weeks’ gestation or at 32–36 weeks’ gestation and of birth weight <1500 g.

Intervention Prior to 1 January 2013 probiotics were not used. Thereafter, dual-species Lactobacillus acidophilus and Bifidobacterium bifidum combination probiotics were routinely administered daily to high-risk neonates; from April 2016 triple-species probiotics (L. acidophilus, B. bifidum, and B. longum subspecies infantis) were used.

Main outcome measures Incidence of NEC (modified Bell’s stage 2a or greater), late-onset sepsis, and mortality.

Results Rates of NEC fell from 7.5% (35/469 neonates) in the pre-implementation epoch to 3.1% (16/513 neonates) in the routine probiotics epoch (adjusted sub-hazard ratio=0.44, 95% CI 0.23 to 0.85, p=0.014). The more than halving of NEC rates after probiotics introduction was independent of any measured covariates, including breast milk feeding rates. Cases of late-onset sepsis fell from 106/469 (22.6%) to 59/513 (11.5%) (p<0.0001), and there was no episode of sepsis due to Lactobacillus or Bifidobacterium. All-cause mortality also fell in the routine probiotics epoch, from 67/469 (14.3%) to 47/513 (9.2%), although this was not statistically significant after multivariable adjustment (adjusted sub-hazard ratio=0.74, 95% CI 0.49 to 1.12, p=0.155).

Conclusions Administration of multispecies Lactobacillus and Bifidobacterium probiotics has been associated with a significantly decreased risk of NEC and late-onset sepsis in our neonatal unit, and no safety issues. Our data are consistent with routine use of Lactobacillus and Bifidobacterium combination probiotics having a beneficial effect on NEC prevention in very preterm neonates.

  • Late-onset sepsis
  • microbiota
  • necrotizing enterocolitis
  • preterm
  • very low birth weight

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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  • Presented at These data were previously presented in abstract form at the autumn meeting of the Neonatal Society, London, November 2018, and at the 7th Congress of the European Academy of Paediatric Societies (EAPS), Paris, France, November 2018.

  • Contributors PC devised the study. CR, JJ, RC, HM, EB and PC collected the data. CR, PC and AM adjudicated NEC cases. GMS provided statistical expertise and analysed the data. CR, GMS, LJH and PC wrote the first manuscript draft and PC wrote the final draft. LJH provided intellectual input. All authors contributed to manuscript revisions and approved the final version. PC is guarantor.

  • Funding This work was part funded by: a Wellcome Trust Investigator award to LJH (100974/C/13/Z); a BBSRC ISP grant for Gut Health and Food Safety to LJH (BB/J004529/1); BBSRC ISP grants for Gut Microbes and Health BB/R012490/1 and its constituent project(s) (BBS/E/F/000PR10353 and BBS/E/F/000PR10355) to LJH. GMS was supported by the BBSRC Core Capability Grant BB/CCG1860/1. CR received a Bliss travel bursary sponsored by Chiesi, which supported conference presentation of data from this study.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval This project was a registered clinical audit/service evaluation. It was reviewed by the R+D Services Manager of the Norfolk and Norwich University Hospitals NHS Foundation Trust and was considered exempt from requiring formal research ethics service approval.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available on reasonable request.

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