CURRENT INITIATIVES AND RESEARCH

The NIH has been the primary federal resource for research on sudden unexplained death of infants since the Sudden Infant Death Syndrome Act of 1974 was passed. The NIH supports research on sudden unexpected death in the young via the SUID and SDY Case Registry and its associated research grants. The SDY portion of the SUID and SDY Case Registry was initiated as a $20 million (2014–2019) collaboration between CDC and two NIH institutes, the National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke; it was recently funded for another five years. The SUID and SDY Registry’s purpose is to foster study of sudden unexpected deaths in infants, children, and young adults up to age 20 years (1) with the aim to determine the incidence of sudden deaths in this population and to understand underlying causes, risk factors, and opportunities for prevention. To date, data are only available for a small number of cases of sudden unexplained child deaths since the incidence of unexplained child death is far lower than the incidence of unexplained infant death.

Beyond its contribution to supporting the SUID and SDY Case Registry, the NIH has supported $16–20 million per year in basic and translational research projects on unexplained infant deaths. Some of the funded research programs examine and promote safe sleep practices. Other NIH-funded studies seek to understand genetic susceptibilities, physiologic mechanisms, and environmental exposures that may place infants and children at risk of sudden death.

Activities at the CDC focus on strengthening mortality and risk factor surveillance for sudden unexpected infant deaths to accurately report incidence, predictors, and trends. The CDC’s main surveillance sources include data from national mortality files (2), the SUID and SDY Case Registry (3), and the Pregnancy Risk Assessment Monitoring System (4). These data sources identify populations with highest mortality rates and the greatest prevalence of unsafe sleep practices – important targets for interventions. The SUID and SDY Case Registry builds on existing Child Death Review programs to establish population-based surveillance. These multidisciplinary teams review the circumstances of death, autopsy findings, and medical and social histories for all relevant cases in their respective populations and enter data into a centralized data system (5, 6).

Private foundations also fund basic and translational research (Table 15.1) of unexplained pediatric deaths; however, there are few organizations that sponsor research specific to unexplained deaths of older children. The SUDC Foundation is one of the few nonprofit organizations dedicated to promoting awareness, advocating for research, and supporting those affected by sudden unexpected or unexplained death in children after one year of age. With the support of the SUDC Foundation, the New York University School of Medicine (NYU) launched the SUDC Registry and Research Collaborative (7), a multi-institutional study to assess risk factors and pathophysiologic mechanisms leading to sudden death, with the aim of documenting research findings that will improve understanding of the underlying etiologies, find methods for prevention, and improve the processes and systems involved in investigating these tragedies. The SUDC Registry and Research Collaborative collects extensive phenotypic data, investigative and autopsy reports, decedent biospecimens, and DNA from the deceased and their biological parents and siblings. Robert’s Program at Boston Children’s Hospital is a clinical program offered to families living in Massachusetts who have experienced the sudden and unexpected death of a child under age three years; this program seeks to understand the cause of the child’s death while providing bereavement support to the families. Robert’s Program also has a research program that accepts cases from outside of Massachusetts. National nonprofit organizations dedicated to prevention, education, research, and bereavement support include the American SIDS Institute, CJ Foundation for SIDS, and First Candle.

Table 15.1

Organizations for Parental Support and Research Studies.

Registries and foundations striving to understand the epidemiology and risk factors of sudden death in infants and children may improve surveillance when standardized definitions and criteria for classification are implemented. The SUID and SDY Case Registry developed standard definitions and classification systems that may be a foundation for future efforts to improve surveillance, identify risk factors, and create targeted prevention efforts (1, 3, 6).

RESEARCH TO INFORM BEST PRACTICES FOR MEDICOLEGAL INVESTIGATION

Research may improve surveillance and understanding of unexplained pediatric deaths by identifying recurring data collection gaps, sources of error, and barriers to uniformity in investigation, autopsy, and reporting practices. Professional organizations and leaders in death investigation practice can identify common gaps in the investigative process and update and/or create practice guidelines accordingly (8). Data from the SUID and SDY Case Registry highlight common gaps in death investigation practices such as incomplete scene information (especially lack of doll reenactments), limited description of threats to the infant’s airway, and absence of metabolic and genetic testing (9). Investigators conducting etiologic research found similar gaps in records of death investigations (9). Due to unique complexities and challenges that present during a death investigation, there may be appropriate or unavoidable reasons for absent data elements or specific tests in an individual case. On a system level, characterization of recurring gaps may aid in appropriately directing resources to the medicolegal death investigation system.

One issue that affects our ability to define the limitations of current data is the difficulty in knowing whether the original cause of death or a registry determination based on secondary review is most accurate in individual cases. The SUDC Registry and Research Collaborative performed detailed data extraction and blinded pathologic review by two forensic pathologists in 96 cases, leading 3% of “unexplained” cases to be recategorized as explained, and 19% of “explained” cases to be recategorized as unexplained (10). Considerable skill, judgement, and interprofessional coordination are needed to conduct a thorough investigation, perform an autopsy, choose relevant ancillary tests, and interpret and integrate all the resulting data. Each death presents unique difficulties and subtleties that may or may not be successfully captured in the written investigative documents, which can alter the course of investigation and influence the final determination of cause of death. Secondary reviews may both benefit from and be limited by algorithms and classification criteria.

Research to identify potential sources of variation and error in investigation, autopsy performance and interpretation may improve diagnostic reliability. For example, morphometric data such as body weight and height are assumed to be reliable, but body weight at autopsy varied by an average of 11% from premortem findings and led to false normal heart weights in 4% of autopsies in one study (11). Interinstitutional review of slides for forensic pathology revealed significant discrepancies that were greatest for pulmonary slides (12). There is great variability in how sudden, unexpected deaths in children are investigated and certified in different jurisdictions (9, 13). Developing methods to measure this variability, on local, regional, or national levels, may allow us to determine what effect implementation of policies or guidelines has on data quality. There is a dire need for research to better understand the current barriers to conducting adequate and complete death investigations in children. Are variations in causes and manners of death due to lack of resources or differences in attitudes, education, training, or experience of death investigators and pathologists, and/or policies of the office performing the autopsy?

Additional research is needed to evaluate the sensitivity and specificity of current autopsy ancillary tests in detecting entities of concern in sudden, unexpected pediatric deaths. Research is also needed to define the diagnostic criteria for establishing various etiologies as either mechanisms or causes of death. For example, which criteria must be met to conclude that a myocarditis or bronchopneumonia was a mechanism of death? Is identification of brainstem gliosis reproducible between pathologists and is it informative for cause of death? Finally, there is a need for more validated and consistent methodologies to recognize or exclude asphyxia and identify purposefully inflicted injuries.

Research to develop and validate new methods to identify underlying etiologies is also needed. As research identifies more underlying causes of sudden pediatric death, new diagnostic tools, and the resources to implement their use, should be incorporated into the forensic evaluation. There is an escalating shortage of forensic pathologists and medicolegal death investigation systems rarely have all the resources needed to manage their public health responsibilities (14). Most medicolegal death investigation systems are restricted from participating in research or have substantial hurdles to participating with consistency. Academic researchers can work closely and collaboratively with medical examiner and coroner offices to exchange ideas and increase research opportunities. One example of cooperation between researchers and investigative teams is the collection and use of postmortem DNA biospecimens to identify genetic variants implicated in impaired cardiovascular, respiratory or neurologic function, metabolic disease, and other disorders (15–17). It is hoped that such research will explain a larger subset of sudden unexpected pediatric deaths and aid in the identification of surviving family members at risk.

THE ROLE OF MULTIDISCIPLINARY TEAMS

Sudden, unexplained pediatric deaths do not fall completely under any one medical, public health, or research focus. Medical examiners and coroners are the common point for identification of unexplained pediatric deaths and thus play a central role in multidisciplinary review teams that are commonly comprised of members representing various fields of medicine, public health, legal and judicial systems, and child advocacy. Participation in multidisciplinary review fosters use of common nomenclatures and adherence to standards that may ultimately advance research and surveillance. The SUID and SDY Case Registry developed a multidisciplinary model that involves critical partnerships between medical examiners/coroners, public health offices, vital statistics staff, child death review teams, clinicians, genetic counselors, researchers, and families. Such a model could be leveraged, expanded, and enhanced to promote national, multinational, and international collaborations that would improve capture of geographic, racial, and socioeconomic data and facilitate further integration of research efforts and harmonization of data capture.

The SUDC Registry & Research Collaborative (SUDCRRC) is an excellent example of a multidisciplinary collaboration. The SUDCRRC is based at NYU Langone Medical Center and involves multiple medical centers and medical examiner and coroner offices across the United States. The purpose of the SUDCRRC is to increase the understanding of the characteristics, circumstances surrounding death, medical histories, and pathologies of children from ages 11 months through 18 years who have died suddenly and unexpectedly, and in some instances, without explanation. The SUDCRRC provides the following services: 1) review of the child’s death, medical, and family history by study pathologists (including forensic, pediatric, cardiac, and neuropathologists) to determine whether a possible, probable, or definite cause of death can be identified and whether additional studies would be helpful in determining a specific cause of death; 2) cardiac and neuropathology consultations for cases that are open/active; and 3) access to genetic analysis (whole exome sequencing) for those cases confirmed to be unexplained after review (when viable samples are available). Additional genetic analysis opportunities for biological parents and some family members may be available.

BIOSPECIMENS IN RESEARCH

Advancing our understanding of sudden pediatric death will require more systematic study of known causes (e.g., de novo and inherited cardiac conditions), suspected mechanisms (e.g., febrile seizures), and pathologies which we still do not fully understand (e.g., functional brainstem disorders). All are reliant on the accessibility of biospecimens from decedents. However, the retention of organs and tissues at autopsy for the sole purpose of research presents ethical and, potentially, legal dilemmas. The Human Tissues Act 2004 was enacted in Britain in 2006, in large part, because of publicity surrounding retention of organs without family consent in pediatric autopsies. Since enactment of this law, other laws have been passed to regulate use of postmortem biospecimens for research purposes. In the United States, regulations regarding retention of organs and biospecimens for research varies by state and jurisdiction. Most state and county statutes only allow autopsy specimens to be retained for further investigation into cause and manner of death.

The primary barrier to conducting research using postmortem tissues from forensic autopsies of children is family consent. From an ethical standpoint, most forensic pathologists will not retain specimens purely for research purposes without family consent. However, in some jurisdictions, it may be permissible to conduct research on autopsy tissues previously taken for diagnostic purposes, as long as the data is anonymized. There are many initiatives, such as brain and tissue banks, that utilize postmortem donations, but many, if not all, require informed patient or family consent prior to donation. Obtaining family consent between notification of death and autopsy can be challenging due to time constraints and the delicate nature of discussing research in the early stages of investigation and at a chaotic and traumatic time for families.

For example, there is a law in California permitting retention of organs in cases of sudden infant death for subsequent research without consent, if anonymized (18). In New Jersey, there are laws that permit use of any organs or tissues retained at autopsy for diagnostic purposes and that are destined to be destroyed (e.g., stock tissue, whole organs examined after fixation), to be used for research without consent, if anonymized. New Jersey also has a statute that allows autopsy specimens from sudden pediatric deaths (under three years of age) to be retained for preapproved research projects without consent, contingent on family consent being obtained prior to their transfer to the researcher (19).

Study of postmortem tissue would greatly enhance basic research into the mechanisms of sudden, unexpected pediatric death. Genetic studies are already providing insight into heritable conditions that may cause sudden death, but much further research is needed. Epigenetic, cellular, or tissue level studies might similarly uncover pathological processes that cause or contribute to sudden death. Further research and resources can ensure that postmortem samples are consistently collected from sudden, unexplained pediatric deaths and stored in a way that preserves DNA integrity for the longest possible time. Collection and storage of samples for purposes of DNA testing are discussed in detail in Chapter 9 Evaluation for Genetic and Metabolic Disorders.

While collection, storage and accessibility of biospecimens is critical, lack of easy access to the decedents’ medical records limits research use of the specimen. In some countries (e.g., Sweden, Switzerland), medical examiners/coroners can access the complete electronic medical records of decedents, making death investigation more efficient and complete. However, the US healthcare system does not have universal access for death investigators for medical records across physician offices, diagnostic laboratories, outpatient surgical centers, urgent care centers, hospitals, and health systems. Improving the quality and timeliness of data available to medical examiners/coroners will make cause of death determinations more accurate and improve subsequent use of death investigation records and specimens for research (20).

GENETIC MECHANISM RESEARCH

Genetic studies have greatly advanced our understanding of cardiac causes of sudden death, especially cardiac channelopathies. For optimal genetic analysis in cases of sudden pediatric and young adult death, DNA is needed from the decedent and both biological parents. Testing this trio makes it possible to identify de novo genetic mutations. While many genetic variants contain a single altered amino acid (i.e., missense mutations), the functional significance (i.e., pathogenicity) of such variants is often unknown. Various algorithms can be used to predict the potential pathogenicity of a genetic variant (e.g., based on conservation of the amino acid in evolution, change in charge or protein structure, critical core component of a channel protein), but such tools often provide ambiguous results. Also, use of different algorithms occasionally leads to different predictions. If such a missense mutation is present in a cardiac (or epilepsy gene) and is not present in either parent (i.e., a de novo mutation is present), it is much more likely to be pathogenic and contribute to sudden death than if it was inherited from a parent with no history of cardiac, metabolic, or neurological disease.

Application of new technologies, often adopted from other disciplines, has been a leading source of discoveries. For example, retrospective analysis of cardiac studies (e.g., identifying an unrecognized prolonged QT interval on the electrocardiogram [21]) and use of cardiac gene panels have enabled identi fication of cardiac arrhythmias as the probable cause of death in 5–10% of sudden unexplained deaths in infancy and childhood (22–25). The application of whole exome sequencing has also increased recognition of rare genetic causes of infant or childhood deaths. For example, parental mosaicism, in which only a portion of a healthy parent’s cells express a mutation, can explain inherited cases in which one parent expresses low levels (i.e., <50%) of a pathogenic variant while their deceased child expresses 50% of a pathogenic variant in SCN1A. This was recently documented in a child with a history of febrile seizures who died suddenly at age 20.5 months (26). A younger sibling with the same variant was subsequently diagnosed with Dravet syndrome. The decedent had the same disorder, but since no afebrile seizures had occurred before death, had not been diagnosed. More widespread use of whole exome sequencing of decedent and parents, together with larger and accurately curated datasets of specific ethnic groups to distinguish benign and pathogenic variants, will all greatly enhance our ability to correctly interpret genetic variants and their potential role in sudden infant and childhood deaths. We can now use formalin fixed, paraffin-embedded tissue derived from organs (e.g., autopsy and surgical pathology specimens more than a decade old) to perform whole exome sequencing and identify pathogenic variants (16).

Future advances will allow assessment of novel risk factors and mechanisms of death using molecular, cellular, and animal studies, and prospective and case-control series. Some potential examples of novel factors include: 1) role of environment as detected in biospecimens (e.g., toxins, antibodies, viral genomes); 2) decedent’s environment (e.g., pollutants, allergens); and 3) biological markers, including a) whole genome sequencing (which can identify critical regulatory elements that modify gene expression), b) transcriptome profiling (RNA-Seq) as is a proxy for protein expression, c) small RNA (e.g., microRNA) that regulates DNA expression, d) methylation profiling of DNA to assess epigenetic changes, e) whole exome sequencing of blood versus organ (e.g., heart, brain) to identify somatic mutations, and f) many others. Finally, genetic discoveries are often driven by large sample sizes and therefore large-scale national and international collaborations are needed. Such collaborations provide greater power to identify rare pathogenic variants and to identify variants that occur in the population (common variants) but still contribute to risk of sudden death. As resources become more widely available and costs are reduced, genetic testing (from targeted panels to whole exome sequencing to whole genome sequencing) should be considered in all pediatric sudden deaths that are not clearly explained.

Most research in the area of sudden unexplained death has focused on infants and adults, and much more is needed regarding older children. Areas of active research and controversy include the development of best practices in screening, risk stratification approaches, standardization of postmortem evaluation, and identification of modifiable barriers to providing better outcomes (27). At present, the cost of routine genetic testing exceeds the resources of most medical examiner/coroner offices. In this case, the family may choose to pay themselves, participate in a research project, or attempt to get coverage from their health insurance carrier (which do not typically cover decedent testing). Identification of a possible index case warrants referral of the family for comprehensive genetic counseling and additional testing. When DNA analysis is not possible due to cost or other factors, DNA banking for potential use in future clinical or research studies may be an interim solution for the family. Many families deeply regret that they were not given the opportunity to participate in research that might help explain the cause of their child’s death or prevent the deaths of other children (28). There are several ethical and legal arguments that need to be addressed regarding access to, and payment for, genetic testing of the deceased victim, counselling of relatives before testing, and counselling for relatives who tested positive for mutations of serious and preventable diseases (29).

FUTURE NEEDS AND CHALLENGES/BARRIERS TO RESEARCH

Effective collaboration and communication across medical examiner and coroner jurisdictions, within the United States and internationally, would provide a critical resource for disease surveillance and understanding pathogenesis of disease. However, the culture and underpinnings for medicolegal death investigation in the US would need to shift to improve research. As reported by the Scienti fic Working Group on Medicolegal Death Investigation, these systems are mandated by states to determine cause and manner of death at the individual case level (30). Office accreditation, by the National Association of Medical Examiners, International Association of Coroners and Medical Examiners, or American National Standards Institute, is voluntary and thus varies across jurisdictions and type of office, which impacts standardization. In addition, medical examiner participation in research may be prohibited by state or local statutes and regulations in some jurisdictions (31). Further, the current strain on the limited resources of US medical examiner/coroner systems hinders research participation. Collaboration with academic, private foundation, or other national researchers (Table 15.1) could help bridge this research gap. Inter-medical examiner/coroner office collaborations could include quality assurance, improved diagnostic criteria, databases to inform public health studies, scientific research into potential causes and risk factors, and collection of biospecimens to advance research. Addressing barriers to research participation, particularly biospecimen collection, could facilitate a broad shift toward increased research in medicolegal death investigation systems.

SUMMARY: IMPROVING RESEARCH OF SUDDEN PEDIATRIC DEATHS

Advancing our understanding of why children die suddenly yet have no clear cause of death will require more systematic study of known causes (e.g., de novo and inherited cardiac conditions), suspected mechanisms (e.g., febrile seizures, systemic inflammatory response to infection), and pathologies which we still do not fully understand (e.g., functional brain disorders, hippocampal anomalies). This will entail funding basic and translational research in sudden unexplained death in both infants and children.

Additional resources for medical examiner/coroner offices may improve consistent standardized and comprehensive investigations, pathologic examinations, and genetic evaluation of sudden unexplained pediatric deaths. Resources are also needed to enable routine collection, storage, and release of high-quality postmortem biospecimens needed for diagnostic and research genetic testing.

Addressing barriers to research participation, particularly biospecimen collection, could facilitate a broad shift toward increased research participation by medicolegal death investigation systems and families affected.

Additional research is needed to inform diagnosis of heritable cardiac conduction and seizure disorders as cause of death and identify and clinically evaluate family members at risk.

Consensus guidelines/recommendations are needed to define a comprehensive postmortem genetic investigation and appropriate genetic investigations for surviving first-degree relatives (32, 33).

Additional research is needed to understand the etiology of febrile seizures and the mechanisms through which seizures cause death (33). There is also a need to develop markers (including genetic) to identify which patients with febrile seizures are at risk for sudden death and to provide guidance for physicians to counsel these families and treat identified children (34).

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*

The views expressed in this manuscript are those of the authors and do not reflect official positions of the National Institutes of Health or the Centers for Disease Control and Prevention