Title: Development of microCT for human fetal post-mortem imaging
Funder: Health Education England

Abstract: Background The main barrier to investigating childhood deaths in the UK is parents declining a post-mortem examination: only 40% of bereaved parents agree to a traditional invasive post-mortem. However, over 90% of bereaved parents find less-invasive autopsy or post-mortems (LIA) a more acceptable alternative. LIA involving imaging and small needle biopsies should provide the same diagnostic information but with less trauma to the body. By developing a range of approaches, including less invasive methods, each family will be able to decide on the best choice for them when given appropriate counselling, giving them the best chance of finding out why their baby died and whether those factors will affect future children. A successful, least-invasive approach should appeal to more parents and thus increase uptake, improving the current NHS standard of care. Our team at GOSH have pioneered non-invasive post-mortem imaging of human fetal specimens as an acceptable alternative to conventional invasive post-mortem. This has been shown to be particularly useful for the fetal heart, however current clinical imaging techniques lack image resolution to allow for diagnoses in very small specimens. Micro computed tomography (microCT) is now being trialled in human organ imaging, and the first reports of its use in fetal post-mortem cardiac imaging have been published by the team at GOSH. I have outlined a series of experiments including tissue preparation optimisation, image acquisition optimisation, histopathological confirmation and diagnostic accuracy trials required to establish the true diagnostic utility of microCT for fetal organ imaging and whole body non-invasive fetal post-mortem imaging. By comparing microCT with existing techniques we would be able to assess the diagnostic accuracy of this technique in early fetal death and develop this approach for clinical use. Aims Four work packages are proposed to achieve these aims (Figure 1): 1. Development and optimisation of microCT of single extracted organs to determine best protocol. 2. Diagnostic accuracy assessment of microCT against histopathological evaluation. 3. Development and optimisation of microCT for human fetal post-mortem to determine best protocol. 4. Diagnostic accuracy assessment of whole body fetal post mortem microCT against histopathological evaluation. Plan (PICOT): Population: All patients referred for fetal post-mortem. Investigation: Following optimisation, fetuses will undergo a series of post-mortem investigations: post-mortem imaging including microCT and then the parents' choice of either key-hole (laparoscopic) or full post-mortem. Comparator: The primary comparator will be microCT vs histopathology for clinical acceptability. The secondary comparator will be whether microCT accuracy varies according to gestation or body weight. Outcomes: Diagnostic accuracy statistics for microCT which will allow us to establish microCT's anticipated clinical utility. Time: An estimated sample size of 120 patients is required for the diagnostic accuracy trial, which is achieveable over the proposed time scale from a single centre. Benefits 1. Evaluating the diagnostic yield of microCT will allow us to define where the service best fits within the evolving perinatal post-mortem clinical service. 2. Improving the parent experience at this difficult time should improve short and long-term parental experience. 3. Providing high resolution imaging as part of a post-mortem service following miscarriage will significantly reduce the psychological burden of early pregnancy loss on the NHS. This body of work will allow clinicians & bereaved parents to make a fully informed, evidence-based choice regarding perinatal post-mortem.

Lay abstract: Background: Following a miscarriage or stillbirth, many parents want to know why their baby died, but do not want a post-mortem that involves cutting into the body. But if a post-mortem is not carried out, parents and clinicians miss out on valuable information about why their baby died, future pregnancies and whether future children might be at increased risk of dying. There may also be religious reasons why a post-mortem is unacceptable. Recent work: Our research work demonstrates that imaging can provide much of the information that a post-mortem would provide, and is acceptable to more parents. Three-dimensional imaging techniques (computed tomography (CT) and magnetic resonance imaging (MRI)) have been developed to be carried out as part of a less-invasive post-mortem', together with keyhole surgery to take samples of specific organs and provide information about the cause of death. This type of post-mortem gives the same information as a standard post-mortem for nine out of ten babies, and is more acceptable to parents than current techniques. Why do we need this research? Ideally parents would have a range of choices for the investigation after death, from less invasive techniques to the standard invasive post-mortem, and reliable information about the likelihood of getting helpful information about their baby with each option. One area where current imaging techniques are not able to give helpful information is for fetuses lost in the first part of pregnancy (between 8 18 weeks). This project is testing a new imaging technique that should be able to provide useful information about fetal organs in these circumstances. How are we going to do it? A new imaging technique called Micro Computed Tomography (microCT) has become available which can take clear images of very small organs and body parts. This project will test how well microCT can provide useful images of tiny areas of organs in babies who have died from different medical causes, when we know our other ways of taking images do not work. MicroCT images will be compared with CT, MRI images and tissue obtained at a post-mortem, to see which method gives the most useful information. This will allow a how to do it' guide to be written so that other NHS centres can provide the same choice to parents. Why is this important for parents and how will they be approached? Many parents say they can't bear the thought of their baby being cut open', but don't mind non-invasive tests being carried out, such as imaging and a keyhole post-mortem. If the same answers can be obtained with less disturbance to the body than in a traditional post-mortem, this will be welcomed by parents. In this particular study, parents will be approached by their doctor, bereavement midwife (or equivalent) to discuss the choices available including minimally invasive autopsy. Parents can choose to be referred to our institution to undergo MicroCT and other imaging tests according to their expressed preference. This well-established consent pathway enables patients from all backgrounds to access a range of specialist examinations, including participating in this trial. Why is this important to the NHS? Parents state that they want the minimum necessary' disturbance to their baby's body in a post-mortem. Developing new techniques such as microCT should mean the most suitable tests for individual babies can be offered. Families will have more choice, supported by appropriate counselling, giving them the best chance of finding out why their baby has died and whether future children might be affected. If microCT is shown to be helpful in this project, it could become the standard imaging technique offered to parents who have suffered a miscarriage, because there is no other technique that can provide this diagnostic information. This may avoid the need for standard post-mortem, change the way that pregnancy loss is dealt with in the NHS, and help counsel parents for possible future pregnancies. These are key priority areas for the NHS' 5-year forward view, and the Department of Health. Patient & Public Involvement (PPI) summary: PPI is a core element of this project and we have a well-established less-invasive autopsy external advisory panel. This group consists of bereaved parents, several charities and other organisations, and meet regularly to influence our on-going research projects. The group helped to put this project application together, and will actively influence the project. PPI involvement ensures that our work is highly relevant and accessible, in particular through raising awareness in the most relevant patient groups.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH