Title: NIHR Global Health Research Group on PReterm bIrth prevention and manageMEnt (PRIME) at The University of Sheffield.
Funder: Department of Health and Social Care

Abstract: a) The University of Sheffield (UoS) has an internationalisation “think global” initiative that seeks to promote research and innovation offering real solutions to global issues: one aspect of this objective is to develop transformational change in healthcare through multidisciplinary and multi-country research collaborations. This proposal brings together leading researchers in the Social Sciences, Reproductive Medicine, Health Economics, Public Health, Immunology and Pathology, Engineering, and Evidence Synthesis. This presents an ideal opportunity to combine their skills and expertise to address health challenges in LMICs. The UoS approach is underpinned by our global reputation in bioimpedance and health services research, strengths which are brought together in this bid. b) We are global leaders in bioimpedance research, having developed the clinical application of electrical impedance spectroscopy (EIS) to the detection of cervical (1, 2) and oral (3) cancer, and more recently to assess pre-labour cervical remodeling (4-6) and PTB prediction (7). A CE-marked cervical cancer screening device (the ZedScan™) is now marketed globally through a spin-out company affiliated to the UoS. DA’s group is a global research leader of EIS technologies for predicting PTB, holding two related international patent filings (PCT/GB2016/054013 and PCT/GB2016/054008, (8, 9)). We have reported, for the first time globally, that a panel of metabolites in cervicovaginal secretions (10-12) are predictive of PTB. If funded, we will undertake pilot studies of vaginal metabolites for predicting PTB in LMICs and engage stakeholders to prioritise what research is most likely to improve PTB care in LMIC settings. c) The research track record of the University’s School of Health and Related Research (ScHARR) is internationally recognised in applied public health and health services research. In the 2014 Research Excellence Framework, ScHARR was ranked 4th in the UK for the metric which combines research quality and volume. ScHARR has a critical mass of world-leading expertise in three core areas of applied public health research: health economics & modelling (SD); development & evaluation of complex public health interventions (SS, JB); and getting research into practice (FC, SS). These strengths are now being applied to global health issues, with the aspiration to build collaborations of global significance. UoS ORGANISATIONAL SUPPORT FOR THE PROJECT IF FUNDED: Two funded PhD studentships Two scholarships on the Masters in Public Health or the Health Technology Assessment Distance Learning course run by ScHARR Home/EU fees for an MSc programme in the Faculty of Medicine Office space and laboratory experience for PRIME Group visitors to Sheffield. d) Working with all partners, research priorities for the Group will be developed through a series of activities as outlined below: 1. Evidence synthesis a Mapping review and mixed methods systematic review to synthesise current knowledge and define the evidence gap in LMICs regarding the prevalence, pattern, and perinatal management of PTB, addressing the following questions: what is the true magnitude and impact of PTB, what prenatal care philosophies, guidelines, and outcome data exist, what infections contribute to PTB in LMICs, what is the evidence of effectiveness of PTB care interventions in LMICs? b Network Research Events (NREs): these will adopt a holistic health systems approach to explore factors that shape approaches and access to care, and the processes operating within families, communities, at the patient-provider interface, and within the health workforce and organization in LMICs. The NREs will focus on understanding differential access, experiences and outcomes in advantaged and deprived populations. They will be held in a minimum of two sites in each LMIC, one of which will capture slum areas and “underprivileged” communities. c The findings from the mapping exercise and systematic reviews will inform a Stakeholder-led Research Prioritisation Exercise (SRPE) which will determine a research agenda (immediate, medium-, and long-term) relevant to each LMIC, to be developed/implemented during the remainder of the project and post-project. 2. Guidelines development To set standards for future evaluation and research, we will develop prenatal and postnatal evidencebased multi-professional guidelines for perinatal care for PTB, which will be informed by standards from the National Institute for Health and Care Excellence (NICE) and the WHO, the findings of our systematic review and views captured from NREs. The guidelines, aimed at healthcare providers, healthcare professionals and policymakers will also identify aspects of PTB care for which primary research evidence from LMICs is lacking and will benchmark care quality for PTB in LMICs. 3. Infection and inflammation-induced preterm birth in LMICs Given the higher prevalence of PTB, and of several infections (HIV, malaria, syphilis, herpes virus, cytomegalovirus and other “TORCH” organisms) which cause a placentitis associated with PTB in LMICs, we propose pilot studies on term and preterm placentas to improve understanding of the contribution of these specific, often endemic, infections in LMICs to PTB. This will inform new research priorities around prevention of identified infections, screening for these infection during pregnancy, prophylaxis, and prompt treatment of affected mothers, given that effective treatment and prophylaxis is available and affordable for the majority of likely causative infections. 4. PTB Screening in LMICs a We propose to consider new approaches to assessing the risk of PTB, developed in Sheffield, for future study and adoption in LMICs contexts. Funded by the MRC through a Developmental Pathways Scheme (DPFS) award (ECCLIPPx studies), we developed: o A vaginal swab test measuring cervico-vaginal fluid metabolites during pregnancy that is predictive of PTB (10-12). o An electrical impedance spectroscopy (EIS) device for cervical assessment (The Sheffield Mark V device) that is predictive of PTB (7, 13, 14) (NIHR website 27/02/2017 https://www.nihr.ac.uk/news/new-device-could-help-doctors-reliably-predict-the-risk-ofpretermbirth/ 5652; The Telegraph http://www.telegraph.co.uk/news/2017/02/25/premature-babiessmart- pen-save-nhs-1bn-yearrevolutionising, manuscripts in preparation) b With predictive accuracies for PTB with a sensitivity of ~80% and a specificity of ~80% for each of these two approaches (and when combined between ~90-95%) we will: a) carry out vaginal swab studies in partner LMICs and b) explore at the SRPEs whether future studies of cervical EIS would be feasible, practical and acceptable in LMICs contexts. Although group partners from LMICs deem developing cost-effective screening approaches for predicting PTB in LMICs crucially important to inform prenatal care, and have strongly expressed an interest in exploring cervical EIS, this approach must first be endorsed at the SRPE events. If it is, we will then seek to understand the ethics procedures and device regulatory requirements in individual partner LMICs, to inform a future research programme of multi-centre studies post-project. In response to a recent RCT showing that extrapolating PTB treatments employed in high-income countries to LMIC contexts without local primary research evidence of efficacy could, in fact, be harmful, a recent Cochrane commentary highlighted a gap in primary research evidence generated in LMICs regarding PTB to inform care (15). 5. Patient Public Involvement (PPI) in PRIME Research. As detailed in the entire project proposal, every work package of the project will involve the direct engagement/participation of key stakeholders. As shown in the Organogram a PPI Advisory group comprising selected members from Sheffield, Bangladesh (Ba) and South Africa (SA) will work directly with the Project Management Group to provide PPI input into all project matter.

Lay abstract: Preterm birth (PTB) affects 15 million babies annually, with over 1 million deaths occurring as a direct consequence. It is the leading cause of under-5 deaths (50% of all neonatal deaths are due to preterm birth), particularly in Low and Middle-Income Countries (LMICs). Common infections in some LMICs such as malaria, kidney infections and HIV/AIDS, as well as others found in the placenta after delivery, probably contribute to high PTB rates. Reducing under-5 and newborn deaths is a key goal of the United Nations. In LMICs, health-promoting behaviours that may reduce PTB risk are not always supported, women often register late for prenatal care, pregnancy is often inaccurately dated, and the risk of PTB seldom assessed. Women who develop preterm labour often deliver at home or in inadequately resourced facilities. We will address the challenges posed by PTB in LMICs through innovative and sustainable research of its causes, consequences, prevention and care. We are a group of established researchers who will work closely with service-users, healthcare policymakers and administrators in partner LMICs to address key challenges of PTB care, focusing on underprivileged communities. We will: a) search the literature, interview women, healthcare professionals and policymakers to develop culturally and context appropriate approaches to determine the risk and manage PTB in LMICs, b) develop care guidelines, a kit comprising essential material for looking after a premature baby at home, and training packages for frontline carers involved in managing PTB, and c) work with stakeholders to prioritise research needed in LMICs regarding PTB. Furthermore, we will investigate the possibility of screening pregnant women for PTB in LMICs. In Sheffield, we recently concluded a large study (ECCLIPPx™, funded by the Medical Research Council) that showed that taking a swab of vaginal fluid and measuring substances in it called “metabolites” can predict PTB. The main study also found that a new device can be used to assess the cervix of women at 20 weeks of pregnancy, to predict or rule out subsequent premature births. The device is small, can be employed by the bedside, requires limited training to use, and cheaper, making it suitable for LMICs. We will explore whether women and healthcare providers and planners in our partner LMICs consider these tests to be culturally and economically acceptable for predicting PTB. These tests could also help to improve management of PTB. There is evidence that the pattern of vaginal bacteria and metabolites differs with race and background so we aim to understand such variations by carrying out the initial swab studies we propose in specific LMICs. Infections that may contribute to the higher rates of PTB in LMICs have rarely been investigated. Understanding which of these infections cause PTB can enable them to be prevented and treated promptly during pregnancy. We therefore plan, for the first time, to study features of infection in the placentas of women who experience PTB (in Sheffield and SA, assess acceptability in Ba) to clarify which infections contribute to high rates of PTB in LMICs and how we can prevent, detect or treat them during pregnancy. Working with professionals in SA and Ba we will develop PTB care guidance and training for healthcare staff. We will strengthen links with Nigeria (by recruiting more skilled researchers) and explore further collaborations in LMICs where partnership members have existing research links.

Research activity codes: 3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH