Title: FERN: Intervention or Expectant Management for Early Onset Selective Fetal Growth Restriction in Monochorionic Twin Pregnancy
Funder: Department of Health and Social Care

Abstract: The UK has approximately 11,000 twin pregnancies per year with a third of these sharing a placenta (the afterbirth), called monochorionic (MC) twins. MC twin pregnancy poses extra risks to both the mother and her babies, with some babies dying during pregnancy or shortly after birth. Often this can be due to complications of MC twin pregnancy such as; (1) selective Fetal Growth Restriction (sFGR) where one twin is smaller than the other or (2) twin-to twin transfusion syndrome. _x000D_ _x000D_ sFGR affects one in seven MC twin pregnancies in the UK although we know less about pregnancies where this happens early (before 24 weeks of pregnancy). sFGR in MC twins poses some unique risks; if the smaller twin dies, its death may harm the other twin, causing either death or brain damage. _x000D_ _x000D_ There are three main ways of managing twin pregnancies with sFGR. Firstly, a watch and wait approach (also called expectant management). The difficulty with this approach is that the smaller twin could die in the womb, which can lead to death or brain damage to the other twin. Secondly, a procedure can be performed which blocks the umbilical cord from the smaller twin to the placenta and as a consequence the smaller twin dies (also known as selective termination). This allows the larger twin to continue growing and gaining maturity, hopefully delivering at a normal gestation. Finally, a laser can be used to completely separate the twins’ circulations. This method protects the larger twin in the event of the death of the smaller twin, but increases the risk of losing the smaller twin._x000D_ _x000D_ We do not have good evidence on the best way of managing sFGR in twin pregnancies, so women and their partners are offered different management options depending upon where they live and who they see. It is also clear that there are gaps in what we know about sFGR. We have already set up a UK national registry of complicated twin pregnancies to collect information about pregnancy outcomes. There is an urgent need for more research to see if a study comparing different management options is possible. Before running such a study, we need to understand things like how many twin pregnancies would be needed to run the study and whether women and clinicians would be willing to take part. We also need to work out which management options would be best to use and what outcomes would be important._x000D_ _x000D_ We will set up 3 work packages (WP) which will help us to define the current situation and design a future study that will tell us how best to manage sFGR in MC twins. In WP1 we will recruit women (120) with sFGR in MC twin pregnancies from 15 UK fetal medicine units over 18 months. In WP2, we will perform interviews with parents (25) and doctors (25) to get their views about whether a bigger trial is possible and what the different types of management should be. WP3 will develop a consensus about what is most important by seeking agreement between clinicians, parents, patient groups and funders to design the best possible study to answer ‘what is the best way to manage MC twin pregnancies with sFGR’._x000D_ _x000D_ We anticipate that we will determine the current UK practice and number of cases/year, natural history of sFGR in MC twins, pregnancy outcomes, women’s preference, clinicians’ preference, ethical dilemmas, whether it is feasible to conduct a trial of active intervention versus expectant management in sFGR in MC twins and the key elements of a potential future trial design.

Lay abstract: Research question_x000D_ Is it feasible to conduct an RCT of active intervention versus expectant management in monochorionic (MC) twin pregnancies with selective fetal growth restriction (sFGR)?_x000D_ _x000D_ Background_x000D_ sFGR in MC twin pregnancy is associated with stillbirth and neurological disability. It also poses the unique risk of co-twin demise (40%) or neurological handicap (30%). Early delivery to prevent death of the sFGR twin may expose the larger twin to prematurity, with associated risks of neurodisability, such as cerebral palsy. _x000D_ There are 3 management options for sFGR: (1) Expectant: carries a risk of intrauterine demise of the sFGR twin. (2) Selective termination of the sFGR twin (3) Selective placental laser photocoagulation of connecting vessels: technically challenging and may worsen outcomes for the sFGR twin. _x000D_ _x000D_ Our recent survey of 29 UK fetal medicine clinicians from 13 units demonstrates equipoise and need for high quality evidence to guide management. There are many challenges for a potential RCT, including a low incidence of the condition, uncertainty whether women will agree to participate and be randomised to expectant management or active fetal intervention._x000D_ _x000D_ Aims_x000D_ To determine:_x000D_ 1. Whether it is feasible to conduct a trial of active intervention versus expectant management in sFGR in MC twins_x000D_ 2. Women’s preference _x000D_ 3. Clinicians’ preference_x000D_ 4. Ethical dilemmas_x000D_ 5. Current UK practice and number of cases/year_x000D_ 6. Natural history of sFGR_x000D_ 7. Key elements of a potential future trial design_x000D_ _x000D_ Methods_x000D_ A mixed methods study of 3 work packages (WPs)._x000D_ We will build on our experience from our recent survey of practice and the TAMBA supported TTTS registry to collect prospective data on the management and clinical outcomes from MC pregnancies complicated by sFGR (WP1). 15 UK fetal medicine units will recruit 120 women to this study which will focus on sFGR <24 weeks in MC twin pregnancy. We will assess management strategies and clinical outcomes from routine practice. This will determine the natural history of sFGR, distribution of interventions and pregnancy outcomes._x000D_ We will assess 25 parents and 25 clinician preferences via interviews to identify ethical concerns and barriers to randomization to management options (WP2). This information will be critically important in building into WP3._x000D_ We will utilise the information provided in WP1 and WP2 to develop a consensus on a future definitive study. We will use the Delphi methodology involving all stakeholder groups (patients, clinicians, funders and charities) to reach a consensus over two rounds. If appropriate, we will then be able to propose a trial of intervention vs non-intervention for sFGR in MC twin pregnancy (WP3). _x000D_ _x000D_ Setting_x000D_ UK fetal medicine units_x000D_ _x000D_ Outcomes _x000D_ Recommend whether RCT of intervention vs expectant management of sFGR in MC twin pregnancy is feasible, women’s preference, clinicians’ preference, current practice and equipoise; numbers of cases; elements of a potential future trial design_x000D_ _x000D_ Timelines for delivery_x000D_ 27 months (6 months set up, 18 months recruitment/data collection, 6 months Delphi consensus, 3 months analysis and reporting)_x000D_ _x000D_ Impact and dissemination _x000D_ Improved management of sFGR in MC twin pregnancies may result in a reduction in both stillbirth and cerebral palsy. Findings will be communicated to patients, stakeholders and funders via newsletters, study website, peer reviewed publications, national and international conferences.

Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH