Meeting of the Special Interest Group in Necrotizing Enterocolitis, London 2017
Day Two: Clinical research and improvements in practice
Turning loss into light: The Necrotizing Enterocolitis Society’s commitment to advocacy, prevention and diverse collaboration.
Turning loss into light
NEC and parents: Putting babies’ best interests first.
Caroline Lee-Davey, Chief Executive of Bliss, the leading UK charity for babies born premature or sick, gave a presentation about ensuring that babies’ interests are always at the heart of decision-making. This covered two main issues:
– Neonatal transport services: in particular highlighting the findings of Bliss’ 2016 report on neonatal transport across the UK , and the importance of ensuring that every neonatal network has sufficient resources and protocols in place to deliver timely in-utero and postnatal transfers, both to ensure that babies are born in the right place and also to ensure swift escalation of care where needed.
– Putting family-centred care at the heart of all neonatal care provision: in particular emphasising the importance of parental involvement in all aspects of neonatal decision-making and care from the point of admission onwards, and the key role this plays in enabling parents to flag early signs of deterioration in their baby which may indicate NEC – and, importantly, to be listened to by the clinical team and thus for these concerns to be acted upon swiftly.
Finally, Caroline let delegates know that Bliss has parent information on NEC which can be found here.
NEC and parents: Putting babies’ best interests first
Transfers of babies with NEC.
Dr Andy Leslie from CenTre Neonatal Transport offered an overview of the organisation of neonatal transport in the UK as well as discussion of the place of transfers for actual or suspected NEC. Andy pointed-out that “suspected” NEC is an important distinction for transport services as for many infants the definitive diagnosis is not established until after transfer to a surgical centre. In the first 6 months of 2017, CenTre undertook 902 neonatal transfers of which 346 were for uplift of care and of these just 27 transfers were of infants in whom NEC was suspected. Andy and Dr Arthi Mistry have looked at a whole year of CenTre’s possible-NEC transfers (April 2016 – March 2017) and traced their final diagnoses. Of 55 infants transferred in whom NEC was considered 31 had a diagnosis of NEC made and the remaining 24 either had other abdominal diagnoses (meconium ileus x 1, ileal perforation x 1) or were investigated without yielding a firm diagnosis.
Andy also discussed the UK readiness for responding to NEC transfers, pointing out that the trend in neonatal transport has been for ever-larger transport services and a concentration of transport resources. There are now 15 neonatal transport services in the UK of whom 13 have dedicated vehicles, 8 have 24 hour Consultant availability to attend transfers if needed and 11 can conference their calls.
Transfers of babies with NEC
Single Immunoglobulin Interleukin-1 Related Receptor in NEC
Genetic susceptibility to NEC – Myth or Truth
Studies in infants with NEC and experimental animal data suggest that abnormal activation of the intestinal immune system is important for the pathogenesis of NEC. However, why the intestinal immune system responds abnormally to gut bacteria causing NEC selectively in certain babies is unknown. Our laboratory has identified mutations in a key gene SIGIRR, that can cause an exaggerated intestinal response to gut bacteria resulting in NEC. Using genomic sequencing, we identified mutations in SIGIRR that are enriched in premature infants who develop NEC but not in preterm infants without NEC. Studies in intestinal epithelial cells suggest that these mutations increase bacteria-mediated intestinal inflammation and cellular injury. Using experimental mouse models of NEC, we show that SIGIRR is developmentally regulated in the intestine and is a major inhibitor of intestinal inflammation. Further, mice carrying a SIGIRR mutation discovered in human NEC have spontaneous activation of immune pathways implicated in NEC. Future studies will focus on the contribution of SIGIRR mutations to NEC, and understand how SIGIRR prevents abnormal bacteria-intestinal interactions that cause NEC in premature infants. (Please note that this presentation given by Dr Sampath on Day One is not available for public dissemination.)
Several risk factors have been identified for NEC including use of formula milk, bowel ischemia, abnormal gut microbial colonization, and immature intestinal immune responses. However, infants who have these risk factors do not necessarily develop NEC and severe NEC can develop in infants who do not have these risk factors. This suggests that there might be inherent predisposition of certain premature infants to develop NEC when exposed to clinical and environmental risk factors. In the last decade, several researchers have attempted to identify genetic risk factors for NEC in premature infants.
Predominantly, research has focused on genetic variants in immune genes that recognize bacterial components, genes that decrease oxidative stress, cytokine genes that contribute to inflammation, and genes that regulate blood vessel growth and function. Most of these studies have been small studies that have not had clearly identified any genetic risk factors. Some of the more well-done studies have identified that genetic variants in NOD2, a gene involved in intracellular anti-bacterial immunity, may increase vulnerability to NEC in premature infants. Further, very preliminary studies indicate that mutations in genes that inhibit exaggerated innate immune responses such as SIGIRR may contribute to increased risk of NEC. There is an increasing need for large scale studies incorporating state of art sequencing technology to identify genomic markers for NEC vulnerability in premature infants. Identification of robust genetic risk factors will inform the use of targeted therapy in high-risk infants to prevent this devastating disease in premature infants.
Genetic predisposition to NEC: Myth or Truth?
Overview of the nationwide surveys for neonates with necrotizing enterocolitis in Japan.
Professor Tomoaki Taguchi MD PhD FACS
Professor and Chairman
Department of Pediatric Surgery
Director, Children’s Medical Centre
Kyushu University Hospital
Congress Chairman, Japanese Society of Pediatric Surgeons 2016
NEC incidence, risk factors, and prognosis were examined by using data from two national surveys in Japan. The first survey was Neonatal Research Network Japan (NRNJ). In NRNJ, more than 40000 neonates, whose birthweight were less than 1500g, had been prospectively accumulated. In NRNJ, the incidence of NEC children whose gestational age were 28 weeks or less was 2.8 %, which was the lower than any published data from other networks. Multivariate analyses revealed that the risk factors for NEC were PDA, lower gestational age, small head circumference, HFO, PPHN, not using indomethacin, and cord blood transfusion. While, as prognostic factors, NEC had correlated with cerebral hemorrhage, neurological dysfunction, motor dysfunction, and death. The second survey was multi-center study, which retrospectively accumulated laparotomy confirmed NEC cases (n=51) and FIP cases (n=63), whose birthweight were less than 1500g. In this survey, two matched control for each case had been also selected and surveyed. As a result of multivariate analysis, the NEC onset had correlated with RDS, PDA, and male sex. While NEC mortality had correlated with preoperative high CRP and late surgery date. Survival time analyses showed NEC survival was significantly poorer than their matched control, while FIP survival was not.
In these two surveys, poor prognosis of NEC had been confirmed, which emphasizes importance of its prevention. PDA is well known risk factor for NEC and was shared in these two surveys, but its treatment also known to vary in countries and regions. In NRNJ, indomethacin administration had been chosen for up to 95% of symptomatic PDA patient, and only less than 5% had chosen observation. For current NRNJ analysis had shown that indomethacin administration suppresses NEC development, this lower rate of observation therapy for PDA patients might have correlation with the lower incidence of NEC in Japan. Another possibility of low incidence of NEC in Japan is the slow speed of increasing milk feed. Our speed was lower than that of UK which was shown in literature.
Overview of surveys of necrotizing enterocolitis in Japan
Professor Taguchi's publications
MAGPIE: Mechanisms affecting the guts of preterm infants in enteral feeding trials.
Dr Nicholas Embleton BSc MBBS MD FRCPCH
Consultant Neonatal Paediatrician
Newcastle Hospitals NHS Foundation Trust
Honorary Reader in Neonatal Medicine, Newcastle University
Newcastle upon Tyne, UK
The MAGPIE study (Mechanisms Affecting the Gut of Preterm Infants in Enteral feeding trials) is funded by the UK NIHR Efficacy and Mechanistic Evaluation programme. It successfully completed recruitment of 474 preterm infants who were enrolled in SIFT or ELFIN . A further 134 infants who were also enrolled in SIFT or ELFIN, and whose samples form part of our recently established, and unique, Great North Neonatal Biobank in Newcastle will also contribute to the analyses. We hypothesise that trial interventions involve effects on gut microbial diversity and types of taxa, metabolites (e.g. short-chain fatty acids) and aspects of host immune function. Whilst current data suggest that NEC and/or LOS are due to a dysregulated immune system in the context of gut dysbiosis, mechanisms have not been systematically studied within large RCTs.
Microbiomic analysis will use next generation sequencing and metabolites will be assessed by mass spectrometry to detect volatile organic and other compounds, and we will explore differences between disease cases and controls, as well as exploring the actions of trial interventions. Impacts of this research are multiple: translation of knowledge of mechanisms promoting gut health may explain outcomes or suggest alternate strategies to improve health. Results may identify new non-invasive diagnostic or monitoring techniques, preventative or treatment strategies for NEC or LOS, or provide data useful for risk stratification in future studies. Mechanistic evaluation might be especially informative where there are not clear effects on the primary outcome. (ISRCTN 12554594) A copy of the full protocol is available as open access.
MAGPIE: Mechanisms affecting the gut of preterm infants in enteral feeding trials
Development of a tissue engineered intestine.
Gail E. Besner MD
H. William Clatworthy Professor of Pediatric Surgery
Chief, Department of Pediatric Surgery
Principal Investigator, Center for Perinatal Research
Nationwide Children’s Hospital
Development of a tissue engineered intestine
New insights into the epidemiology of NEC: role of anemia and cytomegalovirus.
New insights into the epidemiology of NEC: role of anemia and cytomegalovirus
Management and outcomes of surgical NEC: A UK wide cohort study.
Amit Gupta MD FRCPCH PGCertMEd
Oxford University Hospitals NHS FT
Honorary Senior Lecturer, University of Oxford
Associate Dean – Oxford Deanery