Title: Next generation perinatal autopsy: changing death investigation through imaging-based less invasive autopsy.
Funder: Department of Health and Social Care

Abstract: Parental rejection of traditional invasive autopsy procedures is the main barrier to investigating childhood deaths in the UK: only 40% of bereaved parents agree to an autopsy. However, over 90% of bereaved parents find less-invasive autopsy (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. A successful, least-invasive approach should appeal to more parents and thus increase uptake, improving the current NHS standard of care.Prevalence The current uptake of autopsy is around 40% of the 7500 fetal & childhood UK deaths each year, thus around 4500 cases go unexamined. If only 75% of these parents would agree to less invasive autopsy, we would potentially improve care for 3375 cases per year across the UK, i.e. over 16,000 families, with siblings and affected relatives, during the 5 years of this proposed fellowship.Aims There are 4 synergistic, parallel aims: 1. Evaluate diagnostic accuracy of post-mortem ultrasound (compared to MRI). If it is as good as MRI, ultrasound would be an easier technique to roll-out to other centres as it is cheap and widely available. 2. Evaluate image-guided biopsy in perinatal autopsy, compared to current tissue sampling techniques. If needle biopsy is as good as invasive tests then invasive autopsy may no longer be necessary. 3. Evaluate the additional diagnostic yield of PM imaging relative to antenatal imaging. In particular, in which circumstances does post-mortem imaging most refine or add to a presumptive antenatal diagnosis? 4. Establish best-practice clinical pathways for perinatal PM imaging, with implementation across the UK with a solid governance framework.Plan Population: All patients referred for perinatal autopsy, up to 6 months of age (400 per year). Investigation: All subjects will undergo the following series of post mortem tests in the PRACTICAL trial (PeRinatal Autopsy Conducted with Targeted Imaging Core-Biopsy triAL): post mortem ultrasound (PMUS), post-mortem MRI, image-guided needle tissue biopsy, then parents' choice of either key-hole (laparoscopic) or full autopsy. Comparator: The key comparators will be (1) PMUS vs PM MRI for initial diagnosis, and (2) image-guided biopsy vs autopsy for tissue sampling, as MRI already plays a key role in LIA (figure 1). Outcome: By comparing diagnostic parameters, we will develop clinical guidelines regarding the least invasive post-mortem imaging and tissue sampling technique. With the addition of retrospective antenatal imaging data, we can model which type of autopsy approach is likely to be most effective according to patient subgroup. We will provide training for other centres, with an emphasis on local acquisition and clinical governance infrastructure. Time: An estimated sample size of 350 patients is required, achievable over a 3 year period from a single centre.Benefits Establishing comprehensive evidence-based clinical guidelines for post-mortem imaging and tissue sampling techniques will allow the NHS to offer the least invasive, most diagnostically effective technique. Offering this service will meet the need of parents who currently decline conventional autopsy. Improving the patient experience at this difficult time should improve short and long-term parental experience. Developing a network of other UK centres willing and able to provide this NHS service will allow the UK to continue to lead in this area. This body of work allows clinicians & bereaved parents to make a fully informed, evidence-based choice regarding perinatal autopsy. This research will feed into the next phase of analysis: an economic evaluation of these techniques taking into account their diagnostic effectiveness and parental acceptability. In turn, this will underpin future clinical training for pathologists, radiologists and fetal medicine specialists and help them better understand individualised patient care following perinatal death.

Lay abstract: Background Following the death of their baby or child, many parents do not agree to an autopsy (also known as a post-mortem) which involves incisions (cuts through the skin) to the body, as they feel that their child has suffered enough. In refusing a post-mortem, both parents and clinicians miss out on valuable information regarding why their child died and whether their future children are also at increased risk of dying.Recent workAs a response to these problems with invasive autopsy, my team has pioneered a new, less invasive method. This uses a combination of detailed 3D magnetic resonance imaging (MRI) and key-hole surgery exploration to provide information about the cause of death. Research already shows this gives the same answer as an invasive autopsy in more than 90% of cases. It is also more acceptable to parents, who are overwhelmingly supportive of alternative service, particularly in the Jewish and Muslim communities. However, this approach may be refined further through the use of needle sampling.Why do we need this research? Radiologists (doctors who specialise in X-rays) often taken samples of body organs in live patients using a fine needle (such as a liver or kidney biopsy), which gives enough tissue for a diagnosis and leaves only a tiny mark on the skin. We think this needle sampling (biopsy) approach would be even better than key-hole surgery during an autopsy examination: if we can get the same answers with even less disturbance to the body, parents should find this even more acceptable. Given the technology that is available to the living when trying to understand cause of disease, it seems only fair to offer the same technology to parents trying to understand the cause of death of their baby or child.How are we going to do it? This project will test how good needle biopsies are compared to the current autopsy being offered, as it should give the same diagnostic information whilst making fewer and smaller marks to the skin. To test this, parents consenting to autopsy will be offered a series of imaging tests and less invasive needle biopsies, so that we can compare the results to key-hole or full autopsy.Why is this important to a parent? Parents tell us: As this is non-invasive, I think it is acceptable for me; I couldn't bear the thought of my baby being cut open however I was more than happy for them to carry out any non-invasive tests. Current research indicates that in most cases, parents prefer the key-hole surgery approach to a full autopsy because it is less invasive. We therefore anticipate that using a small needle will become even more acceptable, and so we will be able to help an increasing number of parents.Why is this important to the NHS?As parents tells us that they want the minimum necessary approach to autopsy at a very sensitive and difficult time for them, new approaches such as these will allow the right test to be offered in the right situation. By developing a range of approaches, each family can be counselled appropriately, to allow them to decide on the best possible manner of finding out why their baby died and whether those factors will affect future children.Currently not all centres in the UK are able to offer this choice to parents, which means there is a lack of fairness in the system. By helping to make this service available in other NHS hospitals, we hope to set the foundations of a new NHS autopsy service. We see a future where instead of a traditional autopsy when a baby dies, the NHS will offer an evidence-based appropriate investigation of death.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH