HEALTH TECHNOLOGY ASSESSMENT

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1 HEALTH TECHNOLOGY ASSESSMENT VOLUME 17 ISSUE 59 DECEMBER 2013 ISSN The Percutaneous shunting in Lower Urinary Tract Obstruction (PLUTO) study and randomised controed tria: evauation of the effectiveness, cost-effectiveness and acceptabiity of percutaneous vesicoamniotic shunting for ower urinary tract obstruction RK Morris, GL Main, E Quinan-Jones, LJ Middeton, L Diwakar, K Hemming, D Burke, J Danies, E Denny, P Barton, TE Roberts, KS Khan, JJ Deeks and MD Kiby on behaf of the PLUTO Coaborative Group DOI /hta17590

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3 The Percutaneous shunting in Lower Urinary Tract Obstruction (PLUTO) study and randomised controed tria: evauation of the effectiveness, cost-effectiveness and acceptabiity of percutaneous vesicoamniotic shunting for ower urinary tract obstruction RK Morris, 1,2 GL Main, 1 E Quinan-Jones, 1 LJ Middeton, 3 L Diwakar, 4 K Hemming, 5 D Burke, 5 J Danies, 3 E Denny, 6 P Barton, 4 TE Roberts, 4 KS Khan, 1 JJ Deeks 3,5 and MD Kiby 1,2 * on behaf of the PLUTO Coaborative Group 1 Schoo of Cinica and Experimenta Medicine, Coege of Medica and Denta Sciences, University of Birmingham, Birmingham, UK 2 Feta Medicine Centre, Birmingham Women s Hospita NHS Foundation Trust, Edgbaston, Birmingham, UK 3 Birmingham Cinica Trias Unit, University of Birmingham, Birmingham, UK 4 Heath Economics Unit, Schoo of Heath and Popuation Sciences, Coege of Medica and Denta Sciences, University of Birmingham, Birmingham, UK 5 Pubic Heath, Epidemioogy and Biostatistics, Schoo of Heath and Popuation Sciences, Coege of Medica and Denta Sciences, University of Birmingham, Birmingham, UK 6 Centre for Heath and Socia Care Research, Facuty of Heath, Birmingham City University, Edgbaston, Birmingham, UK *Corresponding author

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5 Decared competing interests of authors: Dr Hemming carried out paid peer-review work for statistica review, as statistica editor, of papers submitted to BJOG and she is the parent of a baby born with a ower urinary tract obstruction. Before the start of this project Dr Danies was a co-investigator on a project grant from Webeing of Women to initiate the PLUTO tria. Professor Denny has received royaties for three academic textbooks on heath socioogy. Professor Khan provides expert reports in medica negigence cases for which a fee is paid by instructing soicitors. In addition, Professor Khan has received grants from pubic bodies and pharmaceutica companies in the UK and EU. Money was paid to Professor Khan and his institution from Ferring Pharmaceuticas and various universities and societies and he has received honoraria for speaking at meetings. Professor Khan has aso received royaties for his books from pubishers Hodder Arnod and Huber and payment for advice on media research, and he and his institution have received sponsorship from Ferring Pharmaceuticas, Leo-Pharma, Aere, Ethicon, Hoogic, Viforpharma and Pregem/ Quinties for organising educationa meetings. Before the start of this project Professor Khan was a co-investigator on a project grant from Webeing of Women to initiate the PLUTO tria. Before the start of this project Professor Kiby received a project grant from Webeing of Women to initiate the PLUTO tria. He aso received a $750 honorarium for air trave to a debate in the USA on the roe of feta vesicoamniotic shunting at the Society of Materna and Feta Medicine, San Francisco, CA, USA in February He wi be the Visiting Professor at the University of Deft and Leiden in June This wi be to ead a joint meeting between feta medicine subspeciaists and paediatric uroogists on congenita badder neck obstructions. He wi be paid traveing expenses and subsistence ony. Professor Kiby aso provides expert witness statements for medica negigence caims for which a fee is paid by instructing soicitors. A other authors decared no competing interests. Pubished December 2013 DOI: /hta17590 This report shoud be referenced as foows: Morris RK, Main GL, Quinan-Jones E, Middeton LJ, Diwakar L, Hemming K, et a. The Percutaneous shunting in Lower Urinary Tract Obstruction (PLUTO) study and randomised controed tria: evauation of the effectiveness, cost-effectiveness and acceptabiity of percutaneous vesicoamniotic shunting for ower urinary tract obstruction. Heath Techno Assess 2013;17(59). Heath Technoogy Assessment is indexed and abstracted in Index Medicus/MEDLINE, Excerpta Medica/EMBASE, Science Citation Index Expanded (SciSearch ) and Current Contents / Cinica Medicine.

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7 Heath Technoogy Assessment HTA/HTA TAR ISSN (Print) ISSN (Onine) Five-year impact factor: Heath Technoogy Assessment is indexed in MEDLINE, CINAHL, EMBASE, The Cochrane Library and the ISI Science Citation Index and is assessed for incusion in the Database of Abstracts of Reviews of Effects. This journa is a member of and subscribes to the principes of the Committee on Pubication Ethics (COPE) ( Editoria contact: nihredit@southampton.ac.uk The fu HTA archive is freey avaiabe to view onine at Print-on-demand copies can be purchased from the report pages of the NIHR Journas Library website: Criteria for incusion in the Heath Technoogy Assessment journa Reports are pubished in Heath Technoogy Assessment (HTA) if (1) they have resuted from work for the HTA programme, and (2) they are of a sufficienty high scientific quaity as assessed by the reviewers and editors. Reviews in Heath Technoogy Assessment are termed systematic when the account of the search appraisa and synthesis methods (to minimise biases and random errors) woud, in theory, permit the repication of the review by others. HTA programme The HTA programme, part of the Nationa Institute for Heath Research (NIHR), was set up in It produces high-quaity research information on the effectiveness, costs and broader impact of heath technoogies for those who use, manage and provide care in the NHS. Heath technoogies are broady defined as a interventions used to promote heath, prevent and treat disease, and improve rehabiitation and ong-term care. The journa is indexed in NHS Evidence via its abstracts incuded in MEDLINE and its Technoogy Assessment Reports inform Nationa Institute for Heath and Care Exceence (NICE) guidance. HTA research is aso an important source of evidence for Nationa Screening Committee (NSC) poicy decisions. For more information about the HTA programme pease visit the website: This report The research reported in this issue of the journa was funded by the HTA programme as project number 07/01/44. The contractua start date was in September The draft report began editoria review in October 2012 and was accepted for pubication in February The authors have been whoy responsibe for a data coection, anaysis and interpretation, and for writing up their work. The HTA editors and pubisher have tried to ensure the accuracy of the authors report and woud ike to thank the reviewers for their constructive comments on the draft document. However, they do not accept iabiity for damages or osses arising from materia pubished in this report. This report presents independent research funded by the Nationa Institute for Heath Research (NIHR). The views and opinions expressed by authors in this pubication are those of the authors and do not necessariy refect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Heath. If there are verbatim quotations incuded in this pubication the views and opinions expressed by the interviewees are those of the interviewees and do not necessariy refect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Heath. Queen s Printer and Controer of HMSO This work was produced by Morris et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. Pubished by the NIHR Journas Library ( produced by Prepress Projects Ltd, Perth, Scotand (

8 Editor-in-Chief of Heath Technoogy Assessment and NIHR Journas Library Professor Tom Waey Director, NIHR Evauation, Trias and Studies and Director of the HTA Programme, UK NIHR Journas Library Editors Professor Ken Stein Chair of HTA Editoria Board and Professor of Pubic Heath, University of Exeter Medica Schoo, UK Professor Andree Le May Chair of NIHR Journas Library Editoria Group (EME, HS&DR, PGfAR, PHR journas) Dr Martin Ashton-Key Consutant in Pubic Heath Medicine/Consutant Advisor, NETSCC, UK Professor Matthias Beck Chair in Pubic Sector Management and Subject Leader (Management Group), Queen s University Management Schoo, Queen s University Befast, UK Professor Aieen Carke Professor of Heath Sciences, Warwick Medica Schoo, University of Warwick, UK Dr Tessa Criy Director, Crysta Bue Consuting Ltd, UK Dr Peter Davidson Director of NETSCC, HTA, UK Ms Tara Lamont Scientific Advisor, NETSCC, UK Professor Eaine McCo Director, Newcaste Cinica Trias Unit, Institute of Heath and Society, Newcaste University, UK Professor Wiiam McGuire Professor of Chid Heath, Hu York Medica Schoo, University of York, UK Professor Geoffrey Meads Honorary Professor, Business Schoo, Winchester University and Medica Schoo, University of Warwick, UK Professor Jane Norman Professor of Materna and Feta Heath, University of Edinburgh, UK Professor John Powe Consutant Cinica Adviser, Nationa Institute for Heath and Care Exceence (NICE), UK Professor James Raftery Professor of Heath Technoogy Assessment, Wessex Institute, Facuty of Medicine, University of Southampton, UK Dr Rob Riemsma Reviews Manager, Keijnen Systematic Reviews Ltd, UK Professor Heen Roberts Professoria Research Associate, University Coege London, UK Professor Heen Snooks Professor of Heath Services Research, Institute of Life Science, Coege of Medicine, Swansea University, UK Pease visit the website for a ist of members of the NIHR Journas Library Board: Editoria contact: nihredit@southampton.ac.uk NIHR Journas Library

9 DOI: /hta17590 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 59 Abstract The Percutaneous shunting in Lower Urinary Tract Obstruction (PLUTO) study and randomised controed tria: evauation of the effectiveness, cost-effectiveness and acceptabiity of percutaneous vesicoamniotic shunting for ower urinary tract obstruction RK Morris, 1,2 GL Main, 1 E Quinan-Jones, 1 LJ Middeton, 3 L Diwakar, 4 K Hemming, 5 D Burke, 5 J Danies, 3 E Denny, 6 P Barton, 4 TE Roberts, 4 KS Khan, 1 JJ Deeks 3,5 and MD Kiby 1,2 * on behaf of the PLUTO Coaborative Group 1 Schoo of Cinica and Experimenta Medicine, Coege of Medica and Denta Sciences, University of Birmingham, Birmingham, UK 2 Feta Medicine Centre, Birmingham Women s Hospita NHS Foundation Trust, Edgbaston, Birmingham, UK 3 Birmingham Cinica Trias Unit, University of Birmingham, Birmingham, UK 4 Heath Economics Unit, Schoo of Heath and Popuation Sciences, Coege of Medica and Denta Sciences, University of Birmingham, Birmingham, UK 5 Pubic Heath, Epidemioogy and Biostatistics, Schoo of Heath and Popuation Sciences, Coege of Medica and Denta Sciences, University of Birmingham, Birmingham, UK 6 Centre for Heath and Socia Care Research, Facuty of Heath, Birmingham City University, Edgbaston, Birmingham, UK *Corresponding author m.d.kiby@bham.ac.uk Background: Congenita ower urinary tract obstruction (LUTO) is a disease associated with high perinata mortaity and chidhood morbidity. Feta vesicoamniotic shunting (VAS) bypasses the obstruction with the potentia to improve outcome. Objective: To determine the effectiveness, cost-effectiveness and patient acceptabiity of VAS for feta LUTO. Design: A muticentre, randomised controed tria incorporating a prospective registry, decision-anaytic heath economic mode and prepanned Bayesian anaysis using eicited opinions. Patient acceptabiity was evauated by interview in a quaitative study. Setting: Feta medicine departments in the UK, Ireand and the Netherands. Participants: Pregnant women with a mae singeton fetus with LUTO. Interventions: In utero percutaneous VAS compared with conservative care. Main outcome measures: The primary outcome was surviva to 28 days. Secondary outcome measures were surviva and rena function at 1 year of age, cost of care and cost per additiona ife-year and per disabiity-free surviva at the end of 1 year. Queen s Printer and Controer of HMSO This work was produced by Morris et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. vii

10 ABSTRACT Resuts: The tria stopped eary with 31 women randomised because of difficuties in recruitment. Of those randomised to VAS and conservative management, 3/16 (19%) and 2/15 (13%), respectivey, did not receive their aocated intervention. Based on intention-to-treat anaysis, surviva at 28 days was higher if aocated VAS (50%) than conservative management (27%) [reative risk (RR) 1.88, 95% confidence interva (CI) 0.71 to 4.96, p = 0.27]. At 12 months surviva was 44% in the VAS arm and 20% in the conservative arm (RR 2.19, 95% CI 0.69 to 6.94, p = 0.25). Neither difference was statisticay significant. Of survivors at 1 year, two in the VAS arm had no evidence of rena impairment and four in the VAS arm and two in the conservative arm required medica management. One baby in the conservative arm had end-stage rena faiure at 1 year. VAS was more expensive because of additiona surgery and intensive care. VAS cost 15,500 per survivor at 1 year and 43,900 per disabiity-free year. Eicited expert opinions showed uncertainty in the effect of VAS at 28 days. In a Bayesian anaysis combining eicited opinion with the resuts, uncertainty of the benefit of VAS remained (RR 1.31, 95% credibe interva 0.84 to 2.18). The acceptabiity study identified visuaisation of the fetus during utrasound scanning, perceiving a persona benefit, and atruism as positive infuences on recruitment. Fear of the VAS procedure and the perceived severity of LUTO infuenced non-participation. The need for more detaied information about the condition and its impications during pregnancy and foowing deivery was a further important finding of this research. Recruitment was hampered by ogistica and reguatory difficuties, a ower incidence of LUTO and ower antenata diagnosis rate [estimated to be 3.34 (95% CI 2.95 to 3.72) per 10,000 tota births and 47%, respectivey, in an associated epidemioogica study] and high termination of pregnancy rates. In the registry women aso demonstrated a cear preference for conservative management. Concusions: Surviva to 28 days and 1 year appears to be higher with VAS than with conservative management, but it is not possibe to prove benefit beyond reasonabe doubt. Notaby, prognosis in both arms for surviva and rena function is poor. VAS was substantiay more costy and unikey to be regarded as cost-effective based on the 1-year data. Parents shoud be counseed about the risks of pregnancy oss with or without VAS insertion. The Nationa Institute for Heath and Care Exceence interventiona procedures guidance (IPG 202) shoud be updated to refect this new evidence. Babies in the PLUTO tria shoud be foowed up ong term for the different outcomes. Tria registration: ISRCTN Funding: This project was funded by the NIHR Heath Technoogy Assessment programme and wi be pubished in fu in Heath Technoogy Assessment ; Vo. 17, No. 59. See the NIHR Journas Library website for further project information. viii NIHR Journas Library

11 DOI: /hta17590 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 59 Contents List of abbreviations....xi Scientific summary...xiii Chapter 1 Introduction 1 Feta badder obstruction and its treatment 1 Definition of ower urinary tract obstruction 1 Evidence of the need for a randomised controed tria 2 Systematic reviews performed during the PLUTO study 3 Evidence on ong-term outcomes and assessment measures in chidren affected by ower urinary tract obstruction 11 Evidence of experts prior beiefs for the effectiveness of vesicoamniotic shunting and evidence for Bayesian anaysis 11 Evidence for cost-effectiveness 12 Evidence for patient acceptabiity 12 Chapter 2 Objectives 13 Outine of the report 13 Chapter 3 A popuation-based epidemioogica study 15 Introduction 15 Objectives 15 Methods 16 Resuts 17 Discussion 22 Concusion 25 Chapter 4 Methods of the randomised controed tria and the registry 27 Objectives 27 Study design 27 Chapter 5 Findings of the randomised controed tria 37 Recruitment and participants 37 Surviva outcomes (incuding primary outcome of surviva to 28 days) 40 Other outcomes 43 Discussion 45 Chapter 6 Findings of the registry and termination of pregnancy register 49 Recruitment and participants 49 Surviva outcomes (incuding primary outcome of surviva to 28 days) 49 Other outcomes 49 Combined ogistic regression anaysis of randomised and registry data focusing on predictors of surviva to 28 days 55 Termination of pregnancy register 58 Discussion 59 Queen s Printer and Controer of HMSO This work was produced by Morris et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. ix

12 CONTENTS Chapter 7 Bayesian anaysis of the randomised controed tria 61 Introduction 61 Methods 61 Combining prior distributions with PLUTO tria data to obtain posterior distributions 65 Resuts 68 Discussion 96 Chapter 8 Economic anaysis 101 Introduction 101 Methods 101 Resuts 114 Discussion 120 Chapter 9 Patient acceptabiity and experience of the PLUTO study 123 Introduction 123 Methods 123 Resuts 125 Discussion 131 Chapter 10 Discussion 135 Evidence of cinica effectiveness and cost-effectiveness 135 Why was it hard to recruit to the tria? 137 Impications for practice 137 Recommendations for research 138 Acknowedgements 139 References 143 Appendix 1 Search terms for the epidemioogica study 153 Appendix 2 List of a centres (randomised and registry) and principa investigators 155 Appendix 3 Participant information sheet for the randomised controed tria and registry 157 Appendix 4 Consent form for the randomised controed tria and registry 163 Appendix 5 Randomisation and registry notepad 165 Appendix 6 The PLUTO study protoco 167 Appendix 7 Revised proposa for the PLUTO study 207 Appendix 8 PLUTO tria Bayesian priors cinician questionnaire 215 Appendix 9 WinBUGS code for perinata surviva 221 Appendix 10 WinBUGS code for surviva anaysis for proportiona hazards assumption and uninformative prior distribution 229 Appendix 11 Participation in an interventiona tria requiring an invasive procedure during pregnancy: infuences on women s decision-making 231 x NIHR Journas Library

13 DOI: /hta17590 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 59 List of abbreviations AT as treated NICU neonata intensive care unit BCTU BINOCAR Birmingham Cinica Trias Unit British Ises Network of Congenita Anomay Registers NIHR NNT Nationa Institute for Heath Research number needed to treat BME back and minority ethnic ONS Office for Nationa Statistics CI confidence interva OR odds ratio CINAHL Cumuative Index to Nursing and Aied Heath Literature PARCA Parent Report of Chidren s Abiities Cr DMEC DSA EVPI credibe interva data monitoring and ethics committee deterministic sensitivity anaysis expected vaue of perfect information PedsQL PLUTO PSA PUV Pediatric Quaity of Life Inventory Percutaneous shunting in Lower Urinary Tract Obstruction probabiistic sensitivity anaysis posterior urethra vave HR hazard ratio QALY quaity-adjusted ife-year HRG Heathcare Resource Group R&D research and deveopment HTA ICD-10 Heath Technoogy Assessment Internationa Cassification of Diseases, 10th Edition RCOG RCT Roya Coege of Obstetrics and Gynaecoogy randomised controed tria ICER IMD IPG IQR incrementa cost-effectiveness ratio Index of Mutipe Deprivation interventiona procedures guidance interquartie range RR SD SIGLE SROM reative risk standard deviation System for Information on Grey Literature in Europe spontaneous rupture of membranes ITT IUD LR LUTO MCUG MeSH MPD MRC MREC NICE intention to treat intrauterine death ikeihood ratio ower urinary tract obstruction micturating cystourethrogram medica subject headings maximum poo depth Medica Research Counci muticentre research ethics committee Nationa Institute for Heath and Care Exceence STROBE TOP TSC VAS WHO WMCAR WoW WTP Strengthening the Reporting of Observationa Studies in Epidemioogy termination of pregnancy tria steering committee vesicoamniotic shunting Word Heath Organization West Midands Congenita Anomay Register Webeing of Women wiingness to pay Queen s Printer and Controer of HMSO This work was produced by Morris et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xi

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15 DOI: /hta17590 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 59 Scientific summary Background Congenita ower urinary tract obstruction (LUTO) may be identified using prenata utrasound and is associated with a high perinata mortaity and high infant and chidhood morbidity because of the prevaence of chronic rena impairment. Utrasound-directed, in utero, vesicoamniotic shunting (VAS) bypasses the congenita urethra obstruction to potentiay improve feta outcome. Objectives The Percutaneous shunting in Lower Urinary Tract Obstruction (PLUTO) study aimed to determine the effectiveness, cost-effectiveness and patient acceptabiity of VAS for feta LUTO. The primary objective of the study was to determine whether intrauterine VAS to treat LUTO improves perinata and neonata mortaity (surviva to 28 days) and rena function compared with conservative, non-interventiona care. Secondary objectives incuded cost-effectiveness of VAS compared with conservative management; effects of VAS on short-term morbidity; surviva and deveopment of chronic rena faiure at 1 year of age; identifying prognostic markers of outcome; determining cinicians prior beiefs about the effectiveness of VAS; and assessing infuences on women s decision-making with respect to opting for termination of pregnancy (TOP), randomisation and the acceptabiity of the intervention. We aso studied the epidemioogy of this condition using popuation-based methodoogy. Methods Randomised controed tria and registry A muticentre, internationa randomised controed tria (RCT) was undertaken, suppemented by a register of pregnancies with LUTO not recruited to the RCT because of patient or cinician preference and an anonymous register of TOPs associated with this congenita anomay. Expert opinions on the reative benefits of VAS and conventiona treatment were eicited from feta medicine speciaists, paediatric nephroogists and paediatric uroogists for use in a Bayesian anaysis. The panned sampe size of the tria was 150 but recruitment was abandoned after 31 women were randomised. Setting Feta medicine departments across Engand, Scotand, Ireand and the Netherands. Popuation Pregnant women with a singeton, mae fetus with isoated LUTO. Intervention Randomisation was to either insertion of a VAS or conservative management. Insertion of the VAS was under continuous utrasound examination of the fetus. During pregnancy both groups were foowed with reguar utrasound scans. Queen s Printer and Controer of HMSO This work was produced by Morris et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xiii

16 SCIENTIFIC SUMMARY Outcome measures The primary outcome measure was surviva to 28 days with secondary outcome measures being 1-year surviva and rena function at 28 days and 12 months measured using serum creatinine, rena utrasound and evidence of rena impairment. Prospective foow-up was arranged at 28 days and 12 months by paediatric nephroogists/uroogists to assess these secondary outcomes. Anaysis An intention-to-treat (ITT) approach was foowed, suppemented by anaysis comparing groups according to the intervention received (as treated). Intrauterine deaths and TOPs were incuded, cassed as a death in the first instance, athough a sensitivity anaysis was performed excuding non-treatment-reated TOP. The reationship between gestationa age at diagnosis, iquor voume at diagnosis, materna age and surviva to 28 days was assessed in a ogistic regression anaysis using combined data from randomised and registry patients. Bayesian anaysis for the randomised controed tria Expert opinions on the reative benefits of VAS and conventiona treatment were eicited from feta medicine speciaists, paediatric nephroogists and paediatric uroogists. Bayesian modes were used to estimate the effectiveness of VAS at 28 days (a ogistic mode) and surviva to 1 year of age (a Cox regression mode). Bayesian prior distributions utiising evidence eicited from experts in the fied and enthusiastic, sceptica and uninformative priors were used. The same priors were incorporated into the Cox proportiona hazards regression anaysis, excuding the eicited priors as these were obtained for perinata surviva ony. Economic anaysis for the randomised controed tria A mode-based economic evauation, based on a decision tree utiising data inputs on resource use and outcomes from the RCT, assessed the cost-effectiveness of VAS compared with standard conservative management. Unit costs from routine sources were appied to resource use. The mode adopted a time horizon of 1 year. A anayses took the perspective of the NHS and resuts are presented in terms of cost per additiona survivor at 28 days, cost per survivor at 1 year and cost of disabiity-free surviva. We conducted deterministic and probabiistic sensitivity anayses to expore data uncertainty and the robustness of the resuts. Patient acceptabiity study A patient acceptabiity study using a phenomenoogica approach was used to expore the ways in which women make sense of their experiences and to eicit their motivations for participation in the RCT. A series of semistructured interviews were undertaken with a purposive sampe of RCT and registry patients to eicit the ived experience of women. Epidemioogica study A retrospective study identified a popuation of fetuses affected by LUTO deivering between 1995 and 2007 and recorded in the West Midands Congenita Anomay Register (WMCAR). Cases were seected using Internationa Cassification of Diseases, 10th Edition (ICD-10) codes and keyword terms and diagnoses were vaidated using additiona data sets from regiona feta medicine, perinata pathoogy and paediatric services. Outcome measures were incidence, prenata diagnosis rates and mortaity. Resuts Resuts of the randomised controed tria and registry study A tota of 31 women from seven centres were randomised between October 2006 and October Of those randomised to VAS, 3/16 (19%) did not receive the intervention and, of those randomised to xiv NIHR Journas Library

17 DOI: /hta17590 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 59 conservative management, 2/15 (13%) received a VAS. There were 12 ive births in each arm [12/16 (75%) for VAS vs. 12/15 (80%) for conservative management]. Eight out of 16 (50%) of the babies randomised to VAS survived to 28 days compared with 4/15 (27%) of those randomised to conservative management, giving an ITT anaysis reative risk (RR) of 1.88 [95% confidence interva (CI) 0.71 to 4.96] in the direction of benefit with VAS. One baby in each arm died after 28 days giving a RR of 2.19 (95% CI 0.69 to 6.94) at 1 year, again in the direction of benefit with VAS but not excuding harm. Of those babies who survived to 1 year, ony two had no evidence of rena impairment (VAS arm), with four in the VAS arm and two in the conservative arm requiring medica management. One baby in the conservative arm had end-stage rena faiure at 1 year. A tota of 45 women were entered onto the registry of whom the majority (78%) had conservative management. Those women who entered the study registry and had conservative management were more ikey to have a norma iquor voume at diagnosis (greater than the fifth centie) than those receiving VAS (p = 0.07) or those randomised (p = 0.05). There was aso a higher proportion with gestationa age at diagnosis of 24 weeks among these women than among those randomised (p = 0.003). These variabes were strongy associated with improved surviva to 28 days in a mutivariabe ogistic regression anaysis. Over the period of recruitment 68 TOPs for LUTO were notified to the tria office. Resuts of the Bayesian anaysis In tota, 52 experts provided information on their beiefs about change in perinata mortaity as a resut of intrauterine VAS. The eicited opinions combined over a experts gave a prior odds ratio (OR) of 1.22 [95% credibe interva (Cr) 0.52 to 2.92] for surviva to 28 days with VAS, which, when compared with the tria resuts in a Bayesian anaysis, yieded a RR of 1.31 (95% 0.84 to 2.18), sighty increasing the average and focusing the range of vaues that can be considered as ikey estimates of effect. The possibiity that VAS may have a harmfu effect coud not be rued out. Combining the tria data and the eicited priors gave a probabiity of 25% that VAS had a arge cinicay important effect (a reative increase in surviva of 55% or more). The anaysis of surviva to 1 year showed VAS to have an effect in the direction of harm [hazard ratio (HR) > 1 favours treatment] from randomisation to birth (36.5 weeks) (HR 0.90, 95% Cr 0.25 to 3.04) and in the direction of benefit between birth and 1 year (HR 1.75, 95% Cr 0.51 to 6.84). Resuts of the heath economic anaysis The use of VAS was more expensive. In the ITT anaysis insertion of VAS incurred an additiona cost of approximatey 15,500 per survivor at 1 year. The additiona cost of VAS per disabiity-free surviva at the end of 1 year was much higher, at about 43,900. Resuts of the patient acceptabiity study The acceptabiity study found that various factors were infuentia to women when they were deciding whether to take part in research during pregnancy. Positive infuences were visuaisation of the fetus during utrasound scanning and perceiving a benefit from the tria, but women were simiary motivated to participate for atruistic reasons. Fear of VAS and the perceived severity of LUTO in the baby tended to resut in non-participation in the study. The need for more detaied information about the condition and its impications during pregnancy and foowing deivery was a further important finding of this research. Resuts of the epidemioogica study There were 284 LUTO cases among 851,419 tota births in the West Midands region from 1 January 1995 to 31 December 1997, giving an incidence of 3.34 (95% CI 2.95 to 3.72) per 10,000 tota births, which was observed to be stabe over time. The incidence of LUTO was significanty higher in back and minority ethnic groups and was associated with area-based deprivation measures (p < 0.01). Of the 284 cases, 221 (77.8%) were isoated and the remainder were associated with other structura or chromosoma anomaies. There were 211 (74.3%) cases of isoated, non-femae, singeton foetuses, which woud fit the Queen s Printer and Controer of HMSO This work was produced by Morris et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xv

18 SCIENTIFIC SUMMARY tria eigibiity criteria, but ony 46.9% (99/211) had been diagnosed prenatay and thus woud be suitabe for incusion in the tria. Concusions The PLUTO tria stopped eary because of poor recruitment. The concusions that can be drawn from the study concerning the reative effectiveness of VAS are uncertain as they are based on ony 31 participants. Surviva to 28 days and 1 year appeared to be higher with VAS but the uncertainty in the direction and magnitude of the effect is high and it is not possibe to concude benefit. However, prognosis in both arms (conservative and VAS) at 12 months is poor, with ony two babies overa surviving to 1 year of age with no rena impairment. This finding reinforces the natura pathogenesis of this feta disease as one of severe and significant mortaity and morbidity independent of treatment and suggests that, even if perinata surviva is increased, VAS may not have a ong-term benefit. A high number of women did not receive the treatment aocated because of cinician choice or a changing cinica picture. Reativey few women were wiing to consider randomisation and opted instead for either entry onto the registry or TOP. The anaysis of expert opinion concerning the vaue of VAS for 28-day mortaity showed that experts have uncertainty of its vaue. Combining expert opinion with the tria data suggests that the data shoud persuade experts to hod a more positive view, but not to rue out the possibiity of harm. Data from the whoe cohort (RCT and registry) demonstrated that norma iquor voume (greater than the fifth centie) and age at diagnosis of 24 weeks are associated with increased probabiity of surviva at 28 days in fetuses with a confirmed diagnosis of LUTO. Patients in the VAS arm accrued more expenses than those in the conservative management arm, mainy because of costs associated with additiona surgery and intensive care. The observed increase in surviva at 28 days and 1 year, if rea, needs to be considered in reation to this increase in cost. The cost-effectiveness anaysis suggested that these costs are ikey to be very high for the benefits observed up to 1 year. Long-term foow-up data are needed to compete this anaysis. Why was it difficut to recruit? Infuences on women s participation in the RCT were perceived benefit, atruism and to increase scientific knowedge and understanding. Fear of the shunting procedure, persona faith and perceived extent of the condition were reasons suggested as infuentia in non-participation in the RCT. The abiity to have open, detaied and ongoing communication with a heath professiona dedicated to the study appeared to be a positive infuence on participation in this research. The finding that the expert cinicians who took part in the Bayesian eicitation exercise were quite pessimistic suggests that many cinicians may not have referred patients for incusion in the PLUTO tria because of preconceived opinions that the intervention was not beneficia. The epidemioogica study aso noted the incidence of LUTO to be ower than previousy reported, with a high percentage of cases not detected antenatay and thus unabe to be incuded in the tria. Parenta choice of TOP was not insignificant in this cohort (and indeed in those pregnancies with apparenty isoated LUTO). Bureaucratic barriers and deays were aso experienced, reated to governance, insurance and approvas for an internationa tria in this fied. Impications for heath care The resuts of the RCT suggest that VAS may improve overa perinata surviva compared with conservative management but that the ong-term prognosis for these babies into infant ife is poor (with high rates of mortaity and morbidity). Athough VAS may increase surviva compare with conservative management, it is xvi NIHR Journas Library

19 DOI: /hta17590 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 59 unikey to be a cost-effective option. Parents shoud be counseed about the risks of pregnancy oss with or without VAS insertion. The Nationa Institute for Heath and Care Exceence (NICE) interventiona procedures guidance (IPG 202) shoud be updated to refect this new evidence. Women (and their famiies) faced with a difficut diagnosis in pregnancy shoud be appropriatey counseed (by professionas from different discipines/speciaties) and supported and, when considering entry into research studies, the recruitment process shoud ideay use an individuaised approach with a dedicated research midwife/cinician. Recommendations for future research Ideay, a arger RCT woud be performed but it is unikey that this woud be funded or deivered. Thus, it is imperative that the babies recruited into the PLUTO tria are prospectivey foowed up throughout chidhood to determine the effects of VAS on outcomes such as rena function, incontinence, cognitive deveopment and quaity of ife. Further research shoud ook at ways to overcome the barriers to recruitment identified within this study, namey the methodoogy of RCTs in rare diseases (especiay reating to pregnancy). Higher education institutions and funders must work hard to resove the issue of indemnity and sponsorship to aow internationa coaboration in the research into rare diseases. The factors that appear to infuence decision-making with regard to participation in an RCT may be used to taior future research designs to meet the needs of pregnant women and address the issues of importance to them around this difficut time. Tria registration This tria is registered as ISRCTN Funding Funding for this study was provided by the Heath Technoogy Assessment programme of the Nationa Institute for Heath Research. Queen s Printer and Controer of HMSO This work was produced by Morris et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xvii

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