BMJ Open: first published as 10.1136/bmjopen-2019-030452 on 3 September 2019. Downloaded from BMJ Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available. When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to. The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript. BMJ Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay-per-view fees (http://bmjopen.bmj.com). If you have any questions on BMJ Open’s open peer review process please email [email protected] http://bmjopen.bmj.com/ on September 23, 2021 by guest. Protected copyright. BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-030452 on 3 September 2019. Downloaded from Management and Outcomes of Congenital Anomalies in Low-, Middle- and High-Income Countries: Protocol for a Multi-Centre, International, Prospective Cohort Study ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2019-030452 Article Type: Protocol Date Submitted by the 14-Mar-2019 Author: Complete List of Authors: Wright, Naomi; King's College London, King's Centre for Global Health and Health Partnerships, School of Population Health and Environmental Sciences PAEDIATRIC SURGERY, Paediatric anaesthesia < ANAESTHETICS, Paediatric intensive & critical care < INTENSIVE & CRITICAL CARE, Keywords: NEONATOLOGY, PAEDIATRICS, Neonatal intensive & critical care < INTENSIVE & CRITICAL CARE http://bmjopen.bmj.com/ on September 23, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 23 BMJ Open 1 2 3 Management and Outcomes of Congenital Anomalies in Low-, BMJ Open: first published as 10.1136/bmjopen-2019-030452 on 3 September 2019. Downloaded from 4 5 Middle- and High-Income Countries: Protocol for a Multi-Centre, 6 International, Prospective Cohort Study 7 8 9 10 11 Global PaedSurg Research Collaboration 12 13 Correspondence to: Naomi J. Wright, King’s Centre for Global Health and Health Partnerships, 14 School of Population Health and Environmental Sciences, King’s College London, Denmark Hill, SE5 15 9RJ, UK. Email: [email protected] 16 17 18 For peer review only 19 ABSTRACT 20 21 Introduction 22 23 th 24 Congenital anomalies are the 5 leading cause of death in children under 5-years of age globally, contributing an estimated half a million deaths per year. Very limited literature exists from low- and 25 middle-income countries (LMICs) where most of these deaths occur. The Global PaedSurg Research 26 Collaboration aims to undertake the first multi-centre, international, prospective cohort study of a 27 selection of common congenital anomalies, comparing management and outcomes between low-, 28 middle- and high-income countries (HICs) globally. 29 30 Methods and Analysis 31 32 33 The Global PaedSurg Research Collaboration consists of surgeons, paediatricians, anaesthetists and 34 allied healthcare professionals involved in the surgical care of children globally. Collaborators will prospectively collect observational data on consecutive patients presenting for the first time, with one 35 of seven common congenital anomalies (oesophageal atresia, congenital diaphragmatic hernia, 36 intestinal atresia, gastroschisis, exomphalos, anorectal malformation and Hirschsprung's disease). 37 http://bmjopen.bmj.com/ 38 39 Data collection will be for a minimum of one month from October 2018 to April 2019 with a 30-day post-primary intervention follow-up period. Anonymous data will be collected on patient 40 demographics, clinical status, interventions and outcomes using REDCap. Collaborators will complete 41 a survey regarding the resources and facilities for neonatal and paediatric surgery at their centre. 42 43 44 The primary outcome is all-cause in-hospital mortality. Secondary outcomes include the occurrence of post-operative complications. Chi-squared analysis will be used to compare mortality between LMICs 45 on September 23, 2021 by guest. Protected copyright. and HICs. Multilevel, multivariate logistic regression analysis will be undertaken to identify patient 46 level and hospital level factors affecting outcomes with adjustment for confounding factors. 47 48 49 Ethics and Dissemination 50 51 At the host centre this study is classified as an audit not requiring ethical approval. Participating 52 collaborators must gain local approval in accordance to their institutional ethical regulations. All 53 collaborators will be encouraged to present the results locally, nationally and internationally. The 54 results will be submitted for open access publication in a peer reviewed journal. 55 56 Registration Details 57 58 This study has been registered with ClinicalTrials.Gov, identifier: NCT03666767. The registration is 59 available to view via: https://goo.gl/ffXNMH 60 1 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 23 1 2 3 Strengths and Limitations of this Study BMJ Open: first published as 10.1136/bmjopen-2019-030452 on 3 September 2019. Downloaded from 4 5 This will be the first large-series, geographically comprehensive, multi-centre, international, 6 prospective cohort study to define the management and outcomes of a selection of common 7 congenital anomalies in low-, middle- and high-income countries across the globe. 8 The collaborative approach for this study allows a large series of high-quality data to be collected 9 in a timely manner without overburdening high-volume, low-resource centres. 10 11 The seven study conditions constitute a selection of the commonest life-threatening congenital 12 anomalies requiring emergency surgical care in the neonatal period (Box 1). 13 We recognise that some children may not reach a facility capable of providing acute paediatric 14 surgical care and hence the results obtained may be an underestimation of true morbidity and 15 mortality, especially in LMICs. 16 This study will only report on acute management and outcomes as follow up will be limited to 30- 17 days post-primary intervention. 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 23, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 23 BMJ Open 1 2 3 INTRODUCTION BMJ Open: first published as 10.1136/bmjopen-2019-030452 on 3 September 2019. Downloaded from 4 5 In 2015, the Global Burden of Disease study concluded congenital anomalies to be the 5th leading 6 cause of death in children under 5-years of age globally.1 This equates to approximately half a million 7 deaths from congenital anomalies each year, 97% of which occur in low- and middle-income countries 8 (LMICs) where the incidence and prevalence is higher compared to high-income countries (HICs).2,3 9 Indeed, this is likely to be an underestimation of the actual number of deaths due to under-diagnosis 10 of neonates with congenital anomalies who die in the community and a lack of death certification in 11 many LMICs.4 There is limited research and a lack of congenital anomaly registries in LMICs and 12 hence they have received very little global attention.5 13 14 The conditions forming the focus of this study (Box 1) constitute a selection of the most common life- 15 threatening congenital anomalies, which involve the gastrointestinal tract. They each have an 16 incidence of 1/2000 – 1/5000, they collectively form up to 40% of emergency neonatal surgery and 17 associated mortality can be in excess of 50% in many LMICs.6-9 Disparities in outcomes globally can 18 be stark; for exampleFor the mortality peer from gastroschisis review is 75-100% only in many LMICs compared to 4% or 12-14 19 less in HICs. Reasons for poor outcomes include a lack of antenatal diagnosis, delayed 20 presentation, limited neonatal transport and in-hospital resources, a dearth of trained support 9,15,16 21 personnel and a lack of intensive care and parenteral nutrition for neonates. In Uganda, it was 8 22 calculated that only 3.5% of the need for neonatal surgery was met by the healthcare system. 23 24 25 Box 1. Congenital Anomalies in the Global PaedSurg Study 26 27 Oesophageal atresia (OA) +/- tracheo-oesophageal fistula (TOF) 28 Congenital diaphragmatic hernia (CDH) 29 Intestinal atresia (IA) 30 Gastroschisis 31 Exomphalos 32 Anorectal malformation (ARM) 33 Hirschsprung’s disease 34 35 36 37 In 2010, the World Health Assembly passed a resolution recommending ‘prevention whenever http://bmjopen.bmj.com/ 38 possible, to implement screening programmes and to provide care and ongoing support to children 39 with birth defects and their families’.2 Prevention is paramount, however this is not yet possible for 40 many congenital anomalies and hence a focus on improving postnatal care and outcomes is vital. The 41 Sustainable Development Goal 3.2 aims to end preventable deaths of newborns and children under 6, 10,11 42 the age of 5-years by 2030. With a third of infant deaths being attributed to congenital 43 anomalies, clearly this will not be achievable without an accelerated effort towards the provision of 44 surgical care for children. It is estimated that two-thirds of deaths and disability from congenital anomalies can be avoided with the provision of neonatal and paediatric surgical care.6 Indeed, studies 45 on September 23, 2021 by guest.