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.

Worldwide (6), the main causes of death of children under the age of 5 in 2015 included preterm birth complications (18%), pneumonia (16%), intrapartum-related complications (12%), diarrhea (9%), and sepsis/meningitis (9%). Importantly, almost half of all deaths in children under 5 are attributable to undernutrition (7). These causes of death account for essentially 100% of child deaths, underscoring the rarity of SUDC around the globe.

Even in the United States, with a well-established vital records registry, standards vary widely among the 2,300 medical examiner and coroner jurisdictions regarding which deceased individuals will be examined post-mortem, who performs the autopsy, concomitant toxicology and other ancillary testing, organ sampling, tissue retention, and duration of storage.

The National Center for Health Statistics (NCHS) through the Office of Analysis and Epidemiology (OAE) at the Centers for Disease Control and Prevention (CDC) produces statistics on a wide range of factors (birth, disease prevalence, morbidity, and mortality incidence). The CDC has compiled data from death certificates since 1968, using International Classification of Disease (ICD) codes and ICD-10-CM (version 10 Clinical Modification, simplified and condensed for purposes of morbidity). The CDC categorizes children by age groups: the 1-4-year age group is most relevant for this overview. Using unexplained death codes from ICD-9 (798.1 and .2 and .9 as well as 799.9) and ICD-10-CM (R95-99), rates of sudden and unexplained death in the 1-4-year age group have ranged from 1.0-2.0/100,000 population for the nation, roughly 224 deaths per year (Figure 3.1) (8).

Figure 3.1:

Rates of SUDC compiled from CDC. X-axis represents year; y-axis represents rate.

Review of the Literature

At the time of the initial publication of Krous et al. on SUDC in 2005, there was a lack of literature on negative-autopsy deaths in children over 1 year of age. Molander (9), in 1982, published his review of 43 cases of sudden unexpected natural death (SUND) in a series of 389 child and adolescent (through age 20 years) deaths over a six-year period in Sweden. Molander found that some sudden deaths were nonetheless not unexpected due to chronic heart disease, or epilepsy, for example. In his cohort, there were only four cases for which the cause of death was unknown, a rate of 0.007 per 1,000 live births, substantially less than that of SIDS, which was 0.6 per 1,000 live births in Sweden at that time.

In 1985, Neuspiel and Kuller (10) reviewed 207 cases of SUND over nine years. The ages of their population were 1-21 years; ultimately, 15 of 62 deaths in the 1-4-year age group remained unexplained, and they found that “referral for medicolegal evaluation was inconsistent”. Siboni and Simonsen (11) reviewed 1920 medicolegal autopsies of children and young adults (age range 2-30 years) over a 10.5-year period. SUND accounted for 78 (4%) of deaths and ultimately only one case (a 22-year-old female) was unexplained.

In 1987, Southall et al. (12) published their findings of SUD (sudden unexpected death) in a cohort of 9,856 infants followed from birth. They subsequently published their findings on cot death (death occurring in an infant while in a cot or crib during a sleep period) in this prospective study in a separate article in 1983 (13). There were 15 deaths between the ages of 1 and 5 years. Of these, five (33%) remained unexplained after post-mortem examination.

Hoffman et al. (14) published an article with their findings from a case-control study examining SIDS risk factors. The study population was aged 2 weeks through 2 years of age; 16 deaths occurred among toddlers between the ages of 52 and 103 weeks, that were classified as “definitely” or “probably” SIDS (the investigators used 103 weeks as the upper age limit for SIDS deaths). Eleven cases of unexplained death were found in an investigation by Keeling et al. (15) of SUND over a 20-year period. The cases ranged from 2 to 20 years; 169 out of 1,012 (17%) cases were SUND.

Since these publications and that of Krous et al. (2), multiple investigators from various countries have published their findings upon researching the phenomenon of sudden and unexplained death in childhood. Within the last five years, almost 200 different articles have addressed sudden death in childhood, although a majority focus on sudden cardiac death or sudden unexplained death in epilepsy (SUDEP).

Regarding unexplained deaths, researchers in New Zealand (16) published their results in 2011 from a prospective, population-based study constructed on a nationwide protocol of molecular autopsy when someone aged 1-40 years dies suddenly, with a negative post-mortem examination. Genetic investigation after autopsy confirmed that 15% of deaths were due to Long QT Syndrome, i.e. LQTS, an acquired or inherited condition affecting the heart rhythm, characterized by a prolonged QT interval on an electrocardiogram (17); while another 15% of subjects had a probable cause of death established due to the information gained from cardiac screening of family members of the proband (e.g. arrhythmogenic right ventricular cardiomyopathy). The study had four subjects aged 5 years and younger; all four were male, an 18-month-old, a 25-month-old and a 28-month-old were all asleep at the time of death; the 5-year-old child was “vomiting”. Interestingly, although this study included ages up to 40 years, 55% of the study population were asleep when they died.

In June 2012, McGarvey et al. published a review of SUDC cases, along with a comparison to SIDS, in Ireland (18). This research supported findings of Kinney et al. (19) with male predominance, a high incidence of febrile seizures, and being found prone after a sleep period. Unlike SIDS in Ireland, maternal smoking was not associated with increased post-infancy risk of dying suddenly without explanation.

In December 2012, researchers in Denmark published their findings (20) of 44 cases of sudden unexplained death (subjects aged 1-35 years) with DNA available for cardiogenetic testing. Given that previous estimates of sudden cardiac death accounted for one-third of cases referred for testing in Denmark, the authors wanted to investigate the incidence of genes associated with LQTS and sudden cardiac death in a cohort from 2000 to 2006. They found that genopositive results explained death in only 11% of cases.

In March 2013, researchers in Ireland published their conclusions from an ambitious audit of SUDC cases autopsied in Ireland (21), utilizing a modified Rushton Scoring Method (22) (see Table 3.1). Using a Minimal Acceptable Score (MAS), chosen somewhat arbitrarily and representing 60% of total possible points, 300/500 points, they compared SUDC (defined as deaths ranging from 52-152 weeks of age) autopsies with SIDS autopsies, and found that the proportion reaching the MAS was 67% for SIDS cases and 58% for SUDC autopsies. When they analysed data by site, 19/21 (95%) of SUDC cases referred to a Specialist Center and autopsied by a pediatric pathologist achieved the MAS. Reasonably, they recommended that all cases of SUDC should be referred to specialist centers and that guidelines for investigation should meet the same protocols as followed in a SIDS investigation.

Researchers from Sydney, Australia, published their findings in 2014 of a comparison of conventional autopsy to magnetic resonance (MRI) and computer tomography (CT) imaging in sudden death cases up to age 35 years at death (23). Only three children less than 6 years of age at death met study criteria. All were male, two were found deceased in bed (the 5-year-old with intracranial tumor and 18-month-old with a history of “febrile convulsions” and unexplained death). A 4-year-old with gastrointestinal upset was taken to hospital but deteriorated. MRI and autopsy did not explain the cause of death; the CT diagnosis was intra-abdominal hemorrhage.

Table 3.1:

Rushton Modified Scoring Method. (Reproduced with permission from Dr A Treacy.).

Developments

San Diego SUDC Research Project, phase II

Following Krous’s retirement in 2012, his longtime collaborator and member of the SUDC team of investigators, Hannah Kinney, with Boston Children’s Hospital, took over as Principal Investigator of the study. Kinney and her colleagues undertook a new review of all the cases in the San Diego SUDC research project dataset, the result of which led to a few cases having the cause of death assigned as SUDEP, given the personal and/or family seizure history. She also limited the dataset to children less than 7 years of age at the time of death.

Under Kinney’s supervision, Hefti et al. distilled all the information and study findings from the cases into two manuscripts (33, 34). Part I summarized the pathological, phenotypic, and socioeconomic variables. The most salient observations included a statistically significant association with SUDC, and a personal and/or family history of febrile seizures and SUDC, and being found dead during a sleep period; hippocampal abnormalities were the most common neuropathologic finding in SUDC cases (almost 50% of those cases with neuropathological tissue available).

The companion manuscript, Part II, delineated the range of neuropathology discoveries among the cases for whom neuropathologic tissue was available to review. Not surprisingly, a hippocampal abnormality was more often found with an increase in number of microscopic slides of brain tissue available to review. Given that 55% of 83 cases with neuropathologic tissue available had an abnormality, one wonders about the brains of deceased children that were not sufficiently sectioned to determine a cause of death. This manuscript proposes a new category of SUDC: hippocampal malformation associated with sudden death (HMASD). Neuropathological defects were largely confined to the temporal lobe in this study population, excepting the commonality of hyper-eosinophilic acutely ischemic neurons found in all categories of cause of death.

Autopsy audits

The author is grateful to her colleague Dr Jane Cryan and fellow researchers (specifically Dr Ann Treacy) for permission to reproduce their modified Rushton scale to audit Krous’s SUDC cases. Of 151 SUDC cases, 139 autopsy reports of children under 5 years of age were available to review. The original Rushton total maximum score is 500 points, with a Minimal Accepted Score of 300 points (60%) (Table 3.1). Measures of central tendency for the Krous cohort of SUDC cases include a mean of 330 ± 85.5 points, with a median of 325 and a mode of 270 (n=7) points. The range of scores was 142-490. Almost half (58 cases, i.e. 42%) of the autopsies did not attain the MAS of 300 points. The item missed most often was expected organ weights for the major organs. Figure 3.2 indicates the percentage fulfilling each criterion, except for microbiology, which shows the proportion of cases reaching at least 30 of 50 possible points.

Figure 3.2:

Results of audit of autopsies from the San Diego SUDC Research Project. (Format borrowed with permission from Jane Cryan and Ann Treacy.).

Because these cases accumulated from around the globe, the specialty (or non-specialty) of the prosecting pathologist was often not readily discernible from the available paperwork, so comparisons cannot be made between the quality of autopsies by pathologists holding board certification in forensics and other prosecting physicians.

Current Status

Future Possibilities

The aim for future research and clinical efforts is to avert these tragic deaths in children, perhaps through early detection of genetic defects in utero or chromosomal analysis proceeding from a family member’s heart condition, or prompted by a history of seizures in the family. Determining a cause of death may have implications for future pregnancy plans or siblings, or for both.

Globally expanded routine newborn screening

Metabolic screening

Screening infants at birth for inherited and treatable disorders of hemoglobin (e.g. sickle cell), endocrinology (e.g. congenital adrenal hyperplasia), and metabolism (e.g. phenylketonuria (PKU)) is effective in the US because >98% of infants are born at a birthing center or hospital (42). In some developing countries, up to 80% of infants are not born in hospitals. Also, in some countries (e.g. the Philippines) newborn screening is not free (43). Screening at birth is crucial in preventing irreversible brain damage and other physical problems stemming from disrupted metabolism or hormonal disorders.

Although few of the cases reviewed in the SUDC research project were posthumously diagnosed with an inborn error of metabolism, increased screening for these and other disorders would undoubtedly save lives. In 1967, Guthrie (44) (a physician and also a microbiologist) was working with bacterial inhibition assays, which led to the invention of a card of filter paper and desiccant to enable collection of blood spots on newborns to screen for PKU (his niece was diagnosed with PKU). He also had a son with “mental retardation” and he was intent in finding ways to prevent the same condition in other children. He went on to develop a test for maple syrup urine disease and galactosemia.

The use of the newborn screening test became widespread in the United States in 1969-70 (45). Nationally, the Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) is charged with monitoring the Recommended Uniform Screening Panel (RUSP) of 31 core disorders and 26 secondary disorders for newborn screening tests. The recommendations are merely suggestions, and are not enforceable. Although there is a panel of standard tests suggested by the federal government, each state independently decides which diseases or disorders to test for based on the state budget, the established infrastructure for testing and follow-up of positive results, the prevalence of the disorder in the state, as well as treatment availability for the disease or condition being tested. Advances in polymerase chain reaction (PCR) have enabled additional tests to be done, using the same quantity of blood from a heel stick.

California currently screens for 58 conditions. Parents in California also have the option of signing a form to request that the state incinerate their child’s blood spot after screening is completed. As another example, Alaska (46) partners with Northwest Regional Newborn Screening Program at the Oregon Public Health Laboratory (OPHL) and Oregon Health Sciences University (OHSU) for their newborn blood spot tests. In 2002, OHSU used a new technology (tandem mass spectrometry) that allowed additional screening tests for organic acid disorders, fatty acid oxidation disorders, and amino acid and urea cycle disorders but without the need for additional blood or heel sticks. Alaska agreed to test newborns for the OHSU expanded panel of metabolic diseases beginning in 2003. Table 3.2 has a list by state of tests in addition the RUSP.

Table 3.2:

Newborn screening tests by American state. (Reproduced with permission from Dr Brad Therrell, Director, National Newborn Screening and Global Resource Center (NNSGRC).).

Ireland has the highest prevalence of cystic fibrosis (CF) (47) of any country in the world but it was not until July 2011 that screening for CFAND carrier status was implemented. In addition to CF, Ireland also tests for PKU, congenital hypothyroidism, maple syrup urine disease, classical galactosemia, and homosystinuria. 2M Associates, Inc. is associated with the University of Colorado Health Sciences Center, and provides expanded newborn screening in the United States, India, the United Arab Emirates, and several other countries.

Critical congenital heart defect screening

In 2011, the United States Secretary of Health and Human Services recommended adding pulse oximetry to the RUSP. Given that heart defects often lead to hypoxia, oximetry is a noninvasive way of ensuring that a newborn’s blood is sufficiently oxygenated. The seven main disorders screened for with pulse oximetry are hypoplastic left heart syndrome, pulmonary atresia, tetralogy of Fallot, total anomalous pulmonary venous return, transposition of the great arteries, tricuspid atresia, and truncus arteriosus. Some birthing hospitals in the United States have already initiated screening for congenital heart defects via pulse oximetry (48). Pulse oximetry is more cost-effective with larger populations because of a greater yield of true positive results, and necessitates referral to a pediatric cardiologist for abnormal findings. The future may include routine MRIs or digital echocardiograms to ensure congenital heart and lung defects are diagnosed prior to the infant leaving the hospital.

Conclusions

In summary, this is an exciting and rewarding time to be researching causes of sudden death in childhood. Surveillance efforts in the United States are expanding; there is an established online support community for bereaved families; and DNA sampling technology is widespread and becoming more common, easier and affordable. There are also effective treatments for known disorders screened at birth. The sudden death of a child is always tragic, and grief is compounded when a cause of death cannot be ascertained. With an increase in successful determination of cause and manner of death, whether through genetic testing, advances in forensic science, or scientifically tenable prevention efforts, we can hope for a future with fewer deaths among toddlers.

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Footnotes

1

See http://sudc​.org for more information.

2

See http://pubmed​.gov for more information.

3

Marzen v Department of Health and Human Services, 825 F.2d 1148 (7^th Cir, 1987); New York Times Co. v NASA, 782 F. Supp. 628 (DDC, 1991).