Introduction

Sudden infant death syndrome (SIDS) is defined as the sudden death of an infant less than 1 year of age that remains unexplained after a complete autopsy and death scene investigation (1). Typically, SIDS is associated with a sleep period and with risk factors in the sleep environment — for example, prone/face-down sleep, bed sharing, soft bedding, and over-bundling (2-4). Despite national safe sleep campaigns, SIDS remains the leading cause of post-neonatal infant mortality in the United States, with an overall rate of 0.40 SIDS deaths per 1,000 live births (5).

SIDS is a complex heterogeneous disorder that presents in seemingly healthy infants as death — sudden and unexplained. For the family, it comes without warning, devastating all of those in and surrounding the family. For the medical examiner, it comes with the challenge of distinguishing the SIDS death from other sudden and unexpected deaths in infancy, those associated with accidental asphyxia (e.g. accidental suffocation while bed sharing), unidentified infection, or trauma. An ultimate goal in SIDS research is to identify specific biomarkers of SIDS risk which can be used to prevent a SIDS death from occurring (via successful intervention), thus alleviating the burden to the family; or, if the death does occur, to identify a readily accessible biomarker of SIDS death, thus alleviating the burden of the medical examiner adjudicating the death. In this chapter we will address the concept of biomarkers of SIDS, biomarkers of a SIDS death, and biomarkers of SIDS risk.

Biomarkers, defined as objective indicators of a pathologic process, medical condition, or medical state, can be presented in many different forms or types of measurements. They can be biochemical biomarkers with a distinct signature of a single metabolite or group of metabolites specific to a disease process, genomic biomarkers defined as a DNA or RNA characteristic associated with a pathogenic process, or biomarkers which utilize physiological tests (e.g. heart rate and blood pressure) to identify or predict a disease state or disease risk. There have been several studies reporting physiological biomarkers (apnea, cardiac rate abnormalities, and arousal deficits) in infants who subsequently died of SIDS (6-10). Likewise, there have been genetic studies reporting on the potential association of genetic alterations with SIDS death (11-25).

Introduction

Global childhood mortality rates in the under-5s were 44 per 1,000 live births in 2013, ranging from 2.3 in Singapore to 152.5 in Guinea-Bissau (Western sub-Saharan Africa), with rates of 4.9 per 1,000 live births in the United Kingdom (UK) (1). In England and Wales there are >5,000 deaths annually in children aged 0-19 years (2) from an estimated population of 12.9 million in this age group (3). Around 3,000 of these deaths are in infants (less than 1 year) with the majority having known serious medical conditions; such deaths are hence “expected”. Most are due to perinatal and immaturityrelated conditions, which account for around 40% of cases, followed by congenital anomalies. Many of these deaths occur in the early (less than 7 days) or late neonatal (7 to 27 days) period (2). The next most commonly affected age group is adolescents, who account for around 1,000 deaths annually, with more than half being due to external, non-natural causes (2).

Unexpected death occurring in an apparently healthy infant is termed “sudden unexpected death in infancy (SUDI)” and refers to such a presentation in an infant 7-365 days of age. According to most definitions, unexpected deaths in infants under 7 days of age are excluded from the SUDI category, and instead have been termed “sudden unexpected early neonatal death (SUEND)”. All cases of SUDI and SUEND require investigation to determine the cause of death. In England and Wales such cases are referred to Her Majesty's Coroner (HMC), who will direct a post-mortem examination by a specialist pediatric pathologist. The primary rationale of the postmortem examination, including its components and ancillary investigations, is to diagnose or exclude those natural (and non-natural) causes of death which are identifiable and to allow a specific cause of death to be provided (the specific details of the autopsy procedure are detailed in Chapter 24). Whilst many cases will subsequently be found to have died from previously unrecognized medical conditions, such as congenital anomalies or acquired natural diseases, a significant number will remain unexplained despite a complete autopsy including ancillary investigations (microbiology, virology, radiology, and metabolic studies).

Introduction

South Africa, at the southern tip of the African continent, is often referred to as “a world in one country” — a multicultural, biodiverse country with a vibrant economy. It is home to eight World Heritage Sites and seven different biomes. The country is divided into nine provinces, each with its own legislature, premier, and executive council. Eleven official languages are recognized (1).

The country covers some 1,219,602 km2 and is home to around 55.91 million people, of which close to 11% are under 4 years of age. The infant mortality rate is estimated at 33.7 per 1,000 live births (2016), a figure which has seen a steady decline from around 48.2 per 1,000 live births in 2002. Similarly, the under-5 mortality rate declined from 70.8 child deaths per 1,000 live births to 44.4 child deaths per 1,000 live births between 2002 and 2016 (2). Despite the decline in these rates over the years, South Africa is still faced with an immense challenge if it wishes to decrease the high death rate in infants. Investigation into unexpected deaths in children are complicated by multiple factors, however, including a significant variation in population density in different regions of the country, a lack of standardized national death investigation protocols, language and culture barriers, and a paucity of resources and funding for medico-legal death investigation and qualified forensic pathologists, especially in the rural regions of the country.

It is nearly impossible to understand the medico-legal death investigation process in South Africa without being mindful of the political history and development of the country, specifically the most recent 100 years or so. The South African political arena is most significantly marked by the process of segregation and the ideology of apartheid, which was consolidated after the 1948 general election, won by the National Party. Government regulated the job market, often with only the white minority being allowed skilled work opportunities. Legislation culminated in the Natives (Urban Areas) Act 1923, entrenching urban segregation. Pass laws controlled African mobility.

Introduction

Emerging evidence in the 1980s of a link between infants positioned to sleep on their front (prone) and sudden infant death syndrome (SIDS) eventually led to a national “Back to Sleep” campaign in England and Wales in November 1991 (1-6). The SIDS rate dramatically fell by two-thirds (67%) in just four years, from a peak of 1,597 SIDS deaths in 1988 to 531 deaths by 1992 (7). To monitor the characteristic profile of this reduced number of deaths, and identify further potential risk factors associated with SIDS, a case-control study was commissioned as part of a Confidential Enquiry into Stillbirths and Deaths in Infancy (CESDI) and conducted via the University of Bristol between 1993 and 1996 across a third of England (8, 9). A similar study in a smaller geographical area, the South West Infant Sleep Scene Study (SWISS), collecting additional details surrounding the infant sleeping environment, was conducted 10 years later between 2003 and 2006 by the same team (10). Both studies have been instrumental in providing the evidence base for SIDS risk reduction campaigns worldwide and reducing these deaths nationally by a further 60% to 212 SIDS deaths in 2014. This is a review of the main findings, the changes in risk profile over time, and what can be learnt from combining the data from these two studies.

The Optimal Study Design

Despite SIDS being one of the leading causes of post-neonatal infant death, it is a relatively rare event and thus the optimal study design is the observational case-control study. With this design, rare events can be captured as they happen (cases) and compared to suitable controls, although it is often difficult to establish whether significant associations are causal or whether the observations collected are subject to bias. With SIDS investigations in particular, the importance of the final sleeping environment and lack of an immediate causal explanation means recall and misclassification bias can be problematic.

Introduction

In Chapter 1 the various definitions of sudden infant death syndrome (SIDS) were discussed, with the one common theme being the lack of diagnostic features. In a way, pathology represents the weak link in the SIDS chain, as there have never been consistent and reproducible diagnostic tissue markers (1, 2). Thus, current definitions of SIDS are generally of exclusion, which means that the term “SIDS” can only be used for an infant death once other causes of sudden death have been excluded. This requires very careful interpretation of the autopsy findings to determine whether tissue changes are causative or coincidental, or whether they are merely epiphenomena. Other problems also involve the history and circumstances, which may be typical but are also not diagnostic (3, 4).

As there are no pathognomonic markers at autopsy in SIDS deaths, there is a danger that the “diagnosis” will be used inappropriately for natural deaths, accidents, and homicides — John Emery's “diagnostic dustbin” (5, 6). The degree of certainly with which alternative diagnoses can be made varies and the Avon system grades this from Ia for completely unexplained deaths, to grade III when a definite cause can be established (7).

Another issue which has arisen many times is the lack of a control population with which to compare the findings in SIDS autopsies. Examples of this include the reported changes in the heart in SIDS infants which were subsequently considered to be part of normal growth and development of an immature organ, and the ubiquitous finding of minor inflammatory infiltrates in various organs that are often more common in controls and do not, therefore, indicate significant lethal occult infection (8, 9).

Despite recommendations for decades that autopsies are a mandatory part of the work-up of SIDS cases, they have not always been performed in cases that have still been classified as “SIDS”. For example, in publications from the 1990s the autopsy rate was less than 25% in Belgium (10) and autopsies occurred in only 50 to 60% of infants in the Netherlands (11).

Introduction

In the 1980s, sudden infant death syndrome (SIDS) in Norway made up half of all post-neonatal deaths, and more than 80% of all sudden unexpected deaths during the first year after birth. As in most Western countries, the rate of SIDS in Scandinavian countries dropped dramatically after 1990 (the era of safe sleep campaigns). Before 1990 the police attended the death scene following a sudden death in an infant, as in all other cases of sudden unexpected deaths, regardless of age. Due to massive criticisms from parents who felt incriminated, the Prosecutor General in 1991 withdrew the police from the scene of death in infants. Since the diagnosis of SIDS requires performance of a death scene investigation, an initiative was necessary. This chapter discusses SIDS in Scandinavia and the issues faced regarding death scene investigations.

SIDS Epidemic

Of the Scandinavian countries, Norway and Denmark were most severely hit by the SIDS epidemic in the 1980s (1). In Sweden and Finland the epidemic was less dramatic (1). As in all Western countries, the “this side up” campaign led to a dramatic drop in the SIDS rate. In Norway the SIDS rate has dropped from 2.4 per 1,000 live-born to 0.15 per 1,000 live-born in 2016 (Figure 20.1).

The SIDS epidemic: Real or due to a diagnostic shift?

The question as to whether the dramatic reduction in SIDS rate might partly be due to a change in diagnostic practice has been ruled out in Norway. Looking at the total post-neonatal mortality, there was an increase during the 1980s and a decline during the 1990s, in parallel with the drop in SIDS rates (Figure 20.2).

The SIDS Diagnosis

Since SIDS is a diagnosis of exclusion (2), it is necessary to perform an extensive autopsy, including comprehensive histology, microbiology, X-ray examination, toxicology, genetic testing, and metabolic screening before concluding that SIDS is the cause of death. It is also mandatory to perform a death scene investigation. In Norway all of these diagnostic tools, in addition to a CT scan, are included. Full metabolic screening is not yet operative. We do, however, perform testing for medium-chain acyl-CoA dehydrogenase deficiency (MCAD) mutation, and plan to add full metabolic screening in the future. The result of the autopsy is discussed in an interdisciplinary case conference and the final diagnosis given. The case conference also discusses whether the death could have been prevented.

Introduction

The identification of risk factors associated with sudden infant death syndrome (SIDS) has led to significant advances in the prevention of this tragic outcome. The discovery of the prone sleeping position and smoking as two of the major risk factors (1-5) led to worldwide awareness campaigns, such as, for example, the “Back to Sleep” campaign launched in the United States in 1996, and various smoking cessation campaigns (6, 7). These initiatives resulted in a dramatic reduction in the number of children succumbing to SIDS (5, 8). Unfortunately, SIDS still remains the number-one cause of death in infants under 1 year of age in many countries, despite epidemiological and pathological studies that continue to identify additional risk factors, such as hearing deficiencies, or various genetic alterations associated with SIDS (9-11, 12, 13). To parents and families, as well as some health professionals and researchers, the sheer number of suggested risk factors and gene mutations can also be bewildering.

The Triple Risk hypothesis by Dr Hannah Kinney and collaborators (14) can partly resolve this confusion. This hypothesis states that SIDS is caused by an incident in which not just one but three risk factors come together to bring an infant into a situation that leads to the sudden death. Specifically, it was proposed that those factors include [1] a vulnerable infant; [2] a critical period of development in homeostatic control; and [3] an exogenous stressor (14, 15). In other words, in the presence of two risk factors, namely being a vulnerable infant in a critical period of development, a third risk factor (e.g. an exogenous stressor) can become the ultimate cause that triggers an irreversible cascade of events leading to the sudden death.

The Triple Risk hypothesis also has important practical implications. The awareness campaigns have shown that it is possible to significantly reduce the risk of an infant being exposed to exogenous stressors. A potentially more challenging task is to identify the infant who is particularly vulnerable, which is clearly one of the major tasks for research. A better understanding of the characteristics of a vulnerable infant would facilitate the development of strategies that target a specific vulnerability.

Introduction

Back in the early 2000s, when I was a junior pediatrician, this was the typical advice that I would receive from my seniors when I was dealing with a case of sudden unexpected death in infancy (SUDI) in the Emergency Department; it was considered appropriate for junior staff to manage SUDI without direct consultant support. Parents would usually be offered an outpatient appointment with a consultant pediatrician some weeks later to discuss the results of the post-mortem examination, but few families attended as they had never met the consultant beforehand. Bereaved parents described saying goodbye to their dead infant in the Emergency Department, leaving the hospital, and never receiving any further information from medical staff about the possible reasons for the death. As a junior doctor, I felt that this process was wrong and that families deserved better care; thankfully, during the next few years the management of SUDI changed dramatically in England.

In 2008, a new joint agency approach (JAA) to investigating SUDI was introduced in England (1); this approach aimed to establish the complete causes for death, including any risk factors, and to address the needs of the family, including the need to safeguard other children. Professionals therefore have to balance the need to forensically investigate the cause of death and offer appropriate support to bereaved families (2). The JAA has been described in detail in Chapter 5, but is summarized here. Police, health, and social care jointly investigate deaths following national statutory guidance (2). The investigation is led by experienced pediatricians and the police response is provided by specialist teams with particular expertise in managing child death and child safeguarding enquiries. Key elements include taking the deceased infant to an Emergency Department, a pediatrician (possibly accompanied by the police) taking a detailed medical history from the parents, a joint examination of the scene of death by police and pediatrician, and follow-up for the parents. There is inter-agency communication throughout the JAA with a case conference to discuss the full causes of death. The process of the JAA is shown in Figure 7.1. Despite statutory guidance, the practice of joint police and pediatric examination of the scene of death is still variable, and often police examine death scenes alone.

Introduction

Sudden infant death syndrome (SIDS) rates have declined significantly in the United States (US) as a result of the “Back to Sleep” campaign. Despite this and many state and local risk reduction campaigns, rates still remain high in the African American and American Indian/Alaska Native populations. The American Academy of Pediatrics (AAP) recently released (2016) updated guidelines and recommendations for a safe sleep environment (12). However, certain recommendations, especially the advice against infant bed sharing, continue to be controversial and are not followed by some groups. Further research on the reasons for non-adherence and identification of culturally acceptable and safe alternatives that address parental concerns are needed to help in targeting educational interventions in high-risk populations. In this chapter, we will address SIDS from a US perspective, covering rates and trends, interventions to reduce risk, the bed-sharing controversy, and current laws and regulations in the US.

SIDS Rates in the US

Sudden unexpected infant death (SUID), also known as sudden unexpected death in infancy (SUDI), is defined as the sudden and unexpected death of an infant regardless of cause (1). The largest proportion of SUID deaths among all racial/ethnic groups is attributed to sudden infant death syndrome (SIDS). SIDS, a subset of SUID, is defined as “the sudden and unexpected death of an infant under 12 months of age that remains unexplained after a review of the clinical history, complete autopsy and death scene investigation” (1) (p. 681). In 2014, there were approximately 3,500 SUID deaths in the US, and 44% of them (1,500 deaths) were attributed to SIDS (2). Despite continued efforts to promote safe sleep, the SIDS mortality rates in the US have plateaued.

Trends

In 1994, in response to studies from Europe and Australia, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) initiated the “Back to Sleep” campaign to help educate millions of caregivers in the US on ways to reduce the risk of SIDS (3). The campaign promoted placing babies on their back to sleep. In 2012, the NICHD expanded the campaign to emphasize safe sleep environments and back sleeping as ways to reduce SIDS and other sleep-related deaths, renaming it the “Safe to Sleep” campaign.

Sudden Unexplained Death in Childhood Defined

Although many sudden deaths are unexpected, deaths that remain unexplained intensify anguish among family, friends, and the community at large, especially when the decedent is an infant or child. Sudden infant death syndrome (SIDS) and sudden unexplained death in childhood (SUDC) are assigned as “causes” of death after the exclusion of any other known reason (1). There are two main differences between SIDS and SUDC: [1] SIDS is much more common, with a rate of 38.7 deaths per 100,000 live births; this compares to the SUDC rate of 1.0-1.4 deaths per 100,000 of the population; and [2] SIDS affects infants up to the age of 1 year, and SUDC affects mostly toddlers, aged greater than 1 year (highest incidence in 1-4-year-olds). Also, risk factors for SIDS (tobacco smoke exposure, placed prone for sleep, bed sharing) have not been shown to be risk factors for SUDC. These deaths deserve extensive investigation and merit dedicated research in an attempt to uncover any potential cause(s) of death in the young child. In 2005, Krous and colleagues (2) provided the working definition of SUDC: “[t]he sudden and unexpected death of a child over the age of 1 year that remains unexplained after a review of the clinical history and circumstances of death and performance of a complete autopsy with appropriate ancillary testing”. For the purposes of this chapter, discussion is limited to deaths that occurred during a sleep period.

Global Perspective

Only one-third of 55 million global deaths per year are tracked in an established civil registry (3), and only one-quarter of the global population lives in a country that registers at least 90% of births and deaths (4). Globally speaking, performance of a complete autopsy, especially when supplemented by ancillary studies, is uncommon. The United Nations (UN) and World Health Organization (WHO) are proponents of Sample Vital Registration with Verbal Autopsy (SAVVY) (5) for most countries attempting to develop a system of Vital Records. A substantial amount of information available for mortality for children aged less than 5 years is based on the collection of birth histories, verbal autopsy, disease modeling, and other strategies in absence of a civil registration system.

There has been a great need for a text such as this for some time now, with the last general book on sudden infant death syndrome (SIDS) published over a decade and a half ago, in 2001. Since that time many significant developments have occurred in our understanding of sudden and unexplained deaths in pediatrics, ranging from updated definitions with increased emphasis on mandatory death scene investigations to highquality scientific work examining the role of neurotransmitter abnormalities in the brain. The issue of sudden death in toddlers over a year of age (SUDC) has also become an area of study, with a clearer understanding of the usefulness of the more general term sudden and unexpected death in infancy (SUDI). The Triple Risk Model has stood the test of time and has facilitated the integration of laboratory-based work with epidemiological risk factors. Many fringe theories have fortunately finally fallen into well-deserved historical obscurity along with odd entities such as status thymicolymphaticus.

As the reader will quickly realise, the text is an extremely eclectic mix of chapters written by experts in their respective fields. Important chapters deal with the history of SIDS, the role of parent organizations in promoting bereavement support, the very raw issue of parental grief, and research into the underlying mechanisms associated with SUDI. The later chapters focus variably on processes and locations, particularly within the brain, the roles of which in SUDI are being more clearly teased out and understood.

Of necessity there is some repetition in chapters, as SIDS and SUDI in general are a heterogeneous mix of mechanisms and processes that cannot be boxed into discrete areas. While this has sometimes led to different authors taking somewhat contradictory positions on certain subjects, it merely reflects the complexity and reality of the SIDS/SUDI arena today.

The editors hope that this text will have enabled experts from a variety of backgrounds to explain and elaborate on their particular areas of study and investigation. It will also serve as a summary of SIDS, SUDI, and SUDC as we know them today, and will lay the foundation for further exciting discoveries. As such, hopefully this book will provide an invaluable resource for individuals across many arenas, including parents, clinicians, medical examiners, and researchers. We are very close to understanding why SIDS/ SUDI occurs: our next challenge is to prevent these tragic deaths from ever happening.

Introduction

Both experimental and observational studies provide evidence indicating that infection and inflammation might play a role in sudden infant death syndrome (SIDS). Indeed, as early as 1889, Paltauf demonstrated mild inflammatory changes in the walls of the bronchioles in SIDS cases (1). In the 1950s the notion of minimal inflammation of the airways in SIDS was again noted, and since then several studies have reported that a large proportion of SIDS victims have signs of infection prior to death (2-5). Several of the factors associated with susceptibility to infection and inflammation have also proven to be risks for SIDS. A mild upper respiratory infection has been reported in about half of SIDS cases in the last days prior to death (6).

Signs of slight infection are often found by microscopic investigations, just as markers of infections and inflammation are often found at autopsy in SIDS. There are several studies indicating that the mucosal immune system is activated in SIDS (7-9). A higher number of IgM immunocytes in the tracheal wall, as well as a higher number of IgA immunocytes in the duodenal mucosa, have been reported in SIDS cases compared to controls (7). It has also been shown that SIDS victims have higher IgG and IgA immunocyte density in the palatine tonsillar compartments than controls (8). Furthermore, a higher number of CD45+ stromal leucocytes, as well as intensified epithelial expression of human leukocyte antigen—antigen D related (HLA-DR) and secretory component, and an increased expression of HLA class I and II have been reported in the salivary glands in SIDS (9). These observations confirm that the immune system is activated in SIDS, probably with release of certain cytokines that are known to up-regulate epithelia expression of HLA-DR and secretory component.

There are a vast number of studies reporting findings of bacteria in SIDS (4, 5, 10-14). It has been reported that there is a higher prevalence of S. aureus in nasopharyngeal flora from SIDS, and samples from the intestinal tract in SIDS have shown that S. aureus and staphylococcal endotoxins were more prevalent in SIDS compared to samples of feces from healthy controls (10-12). It is suggested that the toxins from S. aureus might contribute to SIDS via synergistic interactions with other colonizing species, in particular E. coli (4).

Introduction

Upper airway obstruction causing sudden death is well recognized. Examples include food aspiration, infectious disease such as diphtheria, and intentional or accidental suffocation.

Obstructive sleep apnea (OSA) has often been suggested as a cause of sudden and unexpected infant death (SUID). The fact that sudden infant death syndrome (SIDS)/SUID is believed to occur during sleep lends support for this theory. The cause of death in such a case would not be evident at post-mortem examination and so would be consistent with a SUID death. The severity of OSA increases with viral infections of the upper airway which increase nasal resistance. Additionally, epidemiological studies have found that a family history of OSA is a risk factor for SUID (1). However, were OSA to be a major cause of infant deaths, it would not explain the beneficial effect of back sleeping in reducing SUID/SIDS deaths. Significantly, brief episodes of upper airway obstruction during sleep are more common in infants who ultimately died of SIDS/SUID than in infants who survived (2).

The Role of Upper Airway Infection, Laryngeal Chemoreflex, Apnea, and Brain Cytokines in SUID/SIDS

It has been suggested that prolonged apnea, associated with the normally airwayprotective laryngeal chemoreflex (LCR) reflexes, might be causal in SIDS/SUID (3-6). The LCR combined responses are initiated when low chloride or acidic liquids stimulate intra-epithelial receptors in the inter-arytenoid space of the larynx (5, 7, 8). Such stimulation results in swallowing, apnea, vocal cord constriction, cough, and arousal from sleep (4, 8, 10). The apnea component of the LCR is particularly prominent in preterm infants, and later diminishes with maturation (8, 11). Stimulation of the LCR by introducing a drop of water onto the larynx can cause prolonged apnea, especially in preterm infants (12, 13).

The interaction between the LCR, infection, and circulating cytokines is particularly relevant to SIDS causal theories. Hypothetically, upper airway infection, particularly with respiratory syncytial virus (RSV), can result in a fatal course of events that leads to SIDS/SUID. Like the apnea caused by introducing water into an infant's larynx, RSV-related prolonged apnea is characterized by central apnea associated with obstructed inspiratory efforts, as with LCR apnea or prolonged central apnea during periodic breathing (14). Infants between 2 and 4 months of age are at highest risk for SIDS and normally have transient “physiologic” anemia. This is usually more prominent in preterm than in term infants.

Introduction

When a child dies suddenly and unexpectedly, we, as professionals, have a wide range of duties and obligations that must be fulfilled. Statutory requirements may place constraints on what we can do, when we need to do it, and how we can go about it. At the heart of it all, however, there remains a bereaved family, for whom the worst thing imaginable has just happened. As one bereaved mother put it: “Words may hurt me or make me angry, but I have lost my child, so don't flatter yourself — nothing that you say will actually make the situation worse”.

Nevertheless, as the quotes at the start of this chapter highlight, parents’ experiences following the death of their child vary enormously, and the way we respond to them can make a considerable difference. The way we respond can make a difference also to the outcome of an investigation. Identifying an unusual medical cause of death, or uncovering the circumstances of a tragic accident or a case of intentional filicide is more likely with a thorough, systematic investigation, conducted with sensitivity and respect, than with one carried out carelessly or in a haphazard or aggressive manner.

In most jurisdictions, the sudden unexpected death of an infant or child requires the case to be referred to a coroner, medical examiner, or procurator fiscal. In England, for example, a coroner is obliged to conduct an investigation into violent or unnatural deaths, deaths where the cause is unknown, and deaths which occur in custody or otherwise in state detention (1). Coroner's officers, or police officers acting on behalf of the coroner, will need to carry out an investigation into the causes and circumstances of the death.

Introduction

Three research areas derived from human studies of epidemiology, pathology, and sleep in infants have made contributions to our understanding of sudden infant death syndrome (SIDS). Epidemiological studies of infants who died of SIDS have identified a variety of risk factors associated with increased and decreased risk of SIDS (1-7), including prone sleeping position (8, 9), maternal cigarette smoking during pregnancy, and heat stress in the infant, often related to overheated environments, excessive bed clothing, or other unsafe sleeping practices (8, 10, 11). Additional risk factors include a recent upper respiratory tract infection, bed sharing, prematurity, and intrauterine and/or postnatal hypoxic stress.

Similar progress in understanding the origins of SIDS has been made by pathologists analysing the brains of infants who died and were classified as SIDS. Analyses of brain tissue from these infants have consistently revealed a high prevalence of abnormalities in the brainstem serotoninergic system including an increased number of serotonergic neurons, a higher proportion of serotonergic neurons displaying immature morphology, decreased tissue levels of serotonin (5-HT) and its synthetic enzyme, tryptophan hydroxylase 2 (TPH2), and decreased 5-HT receptor binding intensity both in serotonergic nuclei themselves and in several nuclei that are important in cardiorespiratory control (9, 12-16). Similar serotonin system deficits have been described in infants who died of asphyxia (17). There has been persistent speculation that infants who died of SIDS suffered from hypoxia (i.e. low oxygen levels) at some time preceding death (18-22), and hypoxia appeared to delay maturation of the brain in infants who died of SIDS (19-21, 23, 24).

Finally, sleep studies in the infants who subsequently died of SIDS have revealed a sequence of repetitive episodes of hypoxia preceding, or following, apnea and/or bradycardia, followed by autoresuscitative efforts to restore normal breathing and arouse from sleep (25-28). Death occurred when the autoresuscitation or arousal following prolonged apnea failed to restore regular breathing and adequate oxygenation. Many infants experienced sequences of multiple hypoxic apneic events from which they recovered, only to succumb to a final event in which autoresuscitation and/or arousal failed.