Written evidence from Peter Fleming, Professor of Infant Health and Developmental Physiology, University of Bristol, on behalf of the Expert Group reviewing unexpected child deaths on behalf of NHS England during the COVID19 pandemic
Membership of the Group (in alphabetical order)
Ian Arrow, HM Senior Coroner for Plymouth and South Devon,
Peter Blair, Professor of Epidemiology and Statistics, University of Bristol,
Marta Cohen, Professor of Perinatal and Paediatric Pathology, University of Sheffield,
Karen Luyt, Reader in Neonatal Medicine, University of Bristol,
Tamas Marton, Consultant Perinatal Pathologist, Birmingham Women’s Hospital,
Neil Sebire, Professor of Paediatric Pathology, University College, London,
Vicky Sleap, Manager, National Child Mortality Database, University of Bristol
Jan Till, Consultant Paediatric Cardiologist, Royal Brompton Hospital Trust
Sudden unexpected death in infancy and childhood is the result of interactions between underlying genetic vulnerabilities and environmental risk factors. In the UK, for more than 200 infants and children who die suddenly and unexpectedly each year, no sufficient explanation is found, meeting the definition of Sudden Infant death Syndrome (SIDS) or Sudden unexplained death in Childhood (SUDC)1.
The Kennedy report established agreed guidelines for multiagency investigation in all sudden unexpected infant or child deaths. The report was the result of a working group jointly convened by The Royal College of Pathologists and the Royal College of Paediatrics and Child Health, chaired by Helena, Baroness Kennedy QC. First published in 2004, the guidelines covered the investigation of sudden unexpected death in infants and up to 2 years of age.
The recommendations of the Report were adapted to include the unexpected deaths of older children (up to and including those aged 17years) and were incorporated into the Statutory Guidance to the Children Act 2004. They thus achieved statutory authority in England from 2008. The protocol was updated in 20162 and was explicitly included in the updated Statutory Guidance to the Children Act 2004 issued in July 20183.
The Kennedy guidelines reinforced the minimum tissue samples and ancillary investigations to be conducted in non-suspicious infant and child deaths investigated by paediatric pathologists. The guidelines recognised that genetic testing, including whole-genome sequencing (WGS), is likely to become increasingly possible in the future, and may provide additional likely causes of death in some cases (for example cardiac ion channelopathies).
Sudden Infant Death Syndrome (SIDS) and Sudden Unexplained Death in Childhood (SUDC) are diagnostic categories reached after all known diseases and conditions have been excluded (they are more a categorisation, than a diagnosis as they constitute a “diagnosis by exclusion”). Paediatric pathologists sometimes refer to such investigations as “negative post-mortem”, as there are no external, internal, or histological findings found at postmortem that can fully explain the death. Therefore, paediatric pathologists heavily rely on results obtained through ancillary investigations.
The change of practice that took place in 2004, by which the SIDS and SUDC post mortems were mostly conducted by paediatric pathologists, assisted where appropriate by Forensic (Home Office) Pathologists has been found to work well, as the post-mortem results became more informative with the routine addition of virology, microbiology, metabolic and toxicological investigations. This change in the investigatory process increased the identification of deaths secondary to infections, malformations, and metabolic diseases.
Genetic analysis is not yet part of the routine investigations conducted in all SIDS and SUDC cases. However, research studies have shown that genes known to be associated with cardiac channelopathy susceptibility (causing arrhythmias) and cardiomyopathy susceptibility (hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy) have been reported to be present in a small but significant percentage of cases. About 13% of SIDS cases host one or more “potentially informative” genetic variants regarded as having a significant probability of being part of the chain of causality for the infant’s sudden death and having potential clinical utility for assessing a family for genetic risk. These novel research studies used Whole Exome Sequencing (WES). The exome is the best studied and most well understood part of the genome (the total genetic material contained on the chromosomes and mitochondria), and is where the vast majority of known disease-casing variants are found. Thus, sequencing the whole exome makes it possible to screen for a wide variety of disease-associated genetic variants in a single test.
NHS England has recently implemented Whole Genome Sequencing (WGS) through the NHS Genomic Medicine Service (GMS), available for the diagnosis of rare diseases for critically ill babies and children and cancer patients, but this group of patients (SUDIC and SUDC has not yet been targeted).
The GMS is the result of the 100,000 Genomes Project, set up by the NHS England Board in 2017 with the aim to develop a national genomic laboratory service through a network of Genomic Laboratory Hubs, a new National Genomic Test Directory to underpin the genomic laboratory network and a clinical genomics medicine service. The project envisaged that the systematic application of genomic technologies had the potential to transform patients’ lives by enabling a quicker diagnosis for patients with a rare disease.
Causation of SIDS and SUDC remains elusive, and it is our opinion that the identification of genetic variants of clinical significance should be incorporated into the routine investigation of these tragic deaths.
The finding of informative or potentially informative gene variants will not only contribute to the identification of the cause of death (or mechanisms behind it) of the deceased infant or child, but will also allow identification of family members at risk of sudden death.
When an infant or child dies suddenly and unexpectedly, a careful postmortem following the current Kennedy protocol of investigation will still leave a high number of cases unsolved (cause of death unknown: “SIDS /SUDC”). In recent UK case series at least 40-50% of such deaths remain unexplained.
The great majority of unexpected infant and child deaths are from natural causes – very few have significant forensic implications, thus it is appropriate that part of the investigations for the majority of such deaths should be addressed (and funded) by the health service rather than the local authority.
Currently funding for investigations conducted after unexpected child deaths are funded via the Coroners service by the local authority, not the health service.
The implications of identifying possible genetically determined causes of such deaths are predominantly in the provision of appropriate investigation and advice to relatives of the deceased and thus potentially the prevention of further deaths or illness in subsequent children or other family members.
Currently families who have lost their babies and children to SIDS or SUDC cannot access genetic analysis for rare diseases that is provided for living patients through NHS Genomic Medicine Service.
We propose that genomic sequencing by the NHS Genomic medicine service with appropriate genetic follow up and counselling by the NHS Clinical Genetics service where appropriate should become a routine part of all postmortem examinations conducted after unexpected child deaths.
The UK is at the forefront of the study and investigation of SIDS and SUDC, and implementation of Next Generation Sequencing Analysis (Whole Exome Sequencing, WES, and Whole Genome Sequencing, WGS) is envisaged as the necessary next step in this process. The guideline of the Autopsy protocol into SUDIC by the RCPath is currently under review, and we strongly advise that this recommendation should be addressed.
Support for this proposal would be extremely helpful.