Necrotising Enterocolitis: Population approaches 4/19/2017 Necrotising Enterocolitis: Population approaches This final talk of the day will focus on how the data collected by you provides population-based data which can be used to further our understanding of devastating diseases such as NEC. I will describe some of challenges in conducting NEC-related research and how the data you contribute may help resolve some these issues in the UKNC- NEC study . Cheryl Battersby Clinical Research Fellow Neonatal Data Analysis Unit

Necrotising Enterocolitis Infant mortality in UK: Overall ↓ NEC associated ↑ (Rees et al 2008) Affects up to 10% of low birth weight babies, 30-50% mortality (Lin and Stoll 2006) Long-term complications (Stoll et al 2004) Limited preventive and treatment strategies Limited knowledge of risk factors beyond low gestational age and birth weight With improving survival of preterm infants, the population of babies at risk of developing NEC is increasing Therefore although overall infant mortality in the UK is falling, NEC associated mortality is on the rise. It Approximately affects up to... Although the exact uK figures are unknown Longterm complications include neurodevelopmental delay, gastrointestinal PN-associated cholestasis, liver failure, and short bowel syndrome Despite rising incidence there are limited preventive and treatment strategies are known . And little is known about specific risk factors beyond prematurity and low birth weight

Enteral feeding: A common dilemma Enteral feeding is widely believed to influence the susceptibility to NEC A common dilemma on daily ward rounds are about feeding –whether we should feed today, what milk if mums milk is not available, how fast to advance….. yet the optimum feeding strategy remains unknown. This systematic review highlights the need for further research as most randomised controlled trials performed have been inadequately powered to look at the outcome of NEC

First step: A population approach To provide: A case-definition used consistently Sample sizes needed for future studies Current feeding practices Baseline incidence and systematic surveillance However, before we embark on further interventional randomised CT a few fundamental first steps need to be taken in an observational study- Using a population approach This will provide data to develop a case-definition for NEC which is currently lacking,, Variations in case definition across studies invalidates comparative analyses , makes it difficult to pool data, and to use “NEC” as an outcome in clinical trials. It will also inform us about sample sizes needed , current enteral feeding practices across a geographically –defined area.as Im sure you appreciate this can differ widely across the country , Estimate the baseline incidence rate of NEC and systematic surveillance

NEC Surveillance: Practical challenges History tells us that using questionnaires to conduct NEC surveillance studies to estimate incidence of NEC is challenging. These 2 studies both used different case-definitions for NEC , one performed in the 1980s and another in 2010 were both limited by a Poor response rate of 50-60%.

Observational studies: A novel approach The Challenges What is needed Low incidence and small sample sizes Collaboration   An evidence-based case-definition   Variations in use of case-definitions Paucity of population-based data Population-based incidence and systematic surveillance   SO we do need further observational studies but a different approach is required to resolve some of the challenges. Because of the relatively low incidence of NEC in individual units , it is difficult to achieve sample sizes required to power studies. What we need is collaboration between many neonatal units nationally and perhaps internationally. We need to develop an evidence-based case-defintion and apply it consistently across studies. There is a paucity of population-based data and even large databases worldwide often limit data to those from the very low birth weight / this data is therefore not/ generalisable. And does not tell us population incidence . What we need is data from all babies at risk of NEC in a population and monitor temporal trends Majority of studies have been retrospective case-control studies from single institutions – with its own limitations What we need is the capture of data PROSPECTIVELY as part of routine clinical care Retrospectively collected data Prospectively collected routine data  

UK Neonatal Collaborative NEC STUDY NIHR funded Medicines for Neonates Programme CRN portfolio adopted study 140 (86%) neonatal units: 41 level 3, 61 level 2, 38 level 1 Many of you will be involved in the UKNC-NEC STUDY . NIHR funded study which is part of the Medicines for Neonates Programme, and has been adopted into the Clinical research network portfolio 86% of neonatal units in England are participating in the study including the majority of tertiary units . Including 10 complete networks Thank you to all of you who have joined the UKNC-NEC study Group, committed to entering high quality electronic data which will help fulfill the aims of this study. WHICH ARE......

Aims To determine the population incidence of NEC in England To establish an objective case-definition for NEC 3) To identify enteral-feed related factors that precede onset of NEC in order to inform the design of future interventional randomised controlled trials

Method Analyse data collected from all babies admitted to participating neonatal units over an 18 month period November 2011- May 2013 Dependent on the quality of data Interim analyses on data completeness will be performed and fed back to units Data collected by you over an 18 month period will be analysed

Data Analysis Report by network using established case-definition AIM 1: To determine the population incidence of NEC in England Report by network using established case-definition AIM 2: To establish an objective case-definition for NEC Which best predicts the "gold-standard" confirmatory evidence of NEC: “NEC on histology of resected bowel OR visual inspection at laparotomy OR visual inspection at post mortem examination” The population incidence will be reported by network and therefore complete network participation is encouraged. Cases of NEC will be identified using a case-defintiion developed as part of this study, which .... Best predicts..... Which is limited to...

Abdominal x-ray performed ad-hoc form You will be familiar with this simple way of capturing the clinical signs, x-ray appearances and outcomes, These will contribute to establishing a case definition and to estimating the incidence of NEC .

AIM 3: Enteral-feed related antecedents of NEC Hypothesis: “There is an association between enteral-feed related factors and NEC” Method: Comparing the outcome (NEC or no NEC) between groups of patients with different enteral-feed exposures Statistical analysis: A selection of statistical methods to adjust for confounding factors For the third aim, The outcome of NEC or no NEC will be compared between groups of patients with diff enteral-feed explosures using the case-definition A selection of statistical methods including propensity score will be ..

Enteral-feed related exposures Days (from birth) to first feed Type of first feed (Maternal Expressed Breast Milk, Human Donor Milk, Formula) Days to reach 120ml/kg/day Summary measure of type of feed up to development of NEC: 1) Exclusive maternal breast milk 2) Maternal breast milk with breast milk fortifier 3) Exclusive human donor milk 4) Human donor milk with breast milk fortifier 5) Exclusive formula 6) Mixed human (maternal or donor) milk 7) Mixed human (maternal or donor) milk and formula 8) Nil by mouth   The different enteral-feed exposures include days to first feed, type of first feed, rate of advancement of feeds and summary measure of type of feed up to development of NEC

Daily feeding data: Time of first feed , Type, Volume You will be familiar with this simple way of capturing this data through the daily feeding data form A drop down menu for the name of formula , and the volume ml given to a baby in 24 hours

Summary Population-based data Integrating clinical and research processes UKNC-NEC study – a stepping stone for future collaborative studies In summary, collaborative efforts in collecting high quality routine data can provide population-based data , which can be used for research purposes as well as your day-to day clinical uses. Integrating both clinical and research processes. Many of you have embraced the uKNC NEC studyd and seen it as an opportunity for it to be a stepping stone for future collaborative studies. we have been approached by neonatal surgeons and neonatologists to address surgical related issues We are currently collaborating with the East of England network to evaluate the effect of a care bundle designed to reduce NEC. The routine electronic data is being used for analysis and data agreement studies are being conducted We look forward future collaborations.

Acknowledgements- THANK YOU Supervisors: Professors Neena Modi and Kate Costeloe UKNC–NEC Study Group: All neonatal units contributing data NDAU Team NDAU Steering Board Jane Abbott (BLISS) Jacquie Kemp Prof. Peter Brocklehurst Prof. Azeem Majeed Prof. Kate Costeloe Prof. Neena Modi Prof. Liz Draper Prof. Andrew Wilkinson