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Duncan JR, Byard RW, editors. SIDS Sudden Infant and Early Childhood Death: The Past, the Present and the Future. Adelaide (AU): University of Adelaide Press; 2018 May.

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SIDS Sudden Infant and Early Childhood Death: The Past, the Present and the Future.

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Chapter 3Sudden Unexplained Death in Childhood: An Overview

, MPH.

Author Information and Affiliations

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.

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.).

Table 3.1:

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


San Diego SUDC Research Project

As cited above, Krous et al. were the first to define SUDC (2) and they were also the first to accrue a large series of cases, albeit retrospectively. Krous began studying sudden infant death early in his career and authored nearly 100 articles on SIDS and other sudden unexpected deaths in infancy. Following an invited presentation on “post-infancy SIDS” at the 1999 SIDS Alliance Annual Conference, Krous was approached by several parents of toddlers who had died suddenly and unexpectedly, all with either a negative autopsy, or with questionably lethal findings (mild bronchiolitis, interstitial pneumonitis). He offered these families a second-opinion review of their child’s case. From that point, the case load of families wanting a second review grew and two bereaved mothers founded the non-profit Sudden Unexplained Death in Childhood Foundation in 2001. The SUDC Foundation continues to this day with both a research component and an element offering family support, outreach, and fundraising.1

The individual consult appeals were the foundation for what would become the San Diego SUDC Research Project, an expansion of the San Diego SIDS Research Project based at Rady Children’s Hospital. Krous accrued cases via the SUDC Foundation website, word-of-mouth among parents, and, occasionally, directly from coroners and medical examiners. The San Diego SUDC Research Project evolved over time with additional cases and collaborators, resulting in 11 articles published in peer reviewed medical journals, along with increasingly detailed and specific pathology findings, and the emergence of a phenotype.

A major weakness of the SUDC research population is that it was self-selected. Due to the rarity of sudden unexpected death in children, especially among toddlers, and the novelty of concerted investigation into these deaths when the San Diego SUDC Research Project was founded, there were no surveillance efforts, nor was there an organized community of afflicted families at that time. The fledgling project relied on families to self-enroll, and the resulting study population was predominantly white (82%), and college-educated (88% of mothers and 84.5% of fathers). The demographic homogeneity is striking, given that cases came from foreign countries (Australia, Canada, England, Germany, Ireland, New Zealand, Russia, and Scotland) as well as from 36 states and the District of Columbia. More than half (51%) of the San Diego SUDC research parent population had pregnancy complications and/or difficulty in conceiving. A number (16%) had conceived with the aid of fertility drugs; 38% had a history of miscarriage/stillbirth; and, with the SUDC child, many (36%) had complications prenatally (e.g. pre-eclampsia, gestational hypertension, gestational diabetes, vaginal bleeding, and premature labor).

While there are no legally mandated federal or international autopsy standards in such cases, some counties, states, and foreign countries have established guidelines for autopsy. A requirement for study participation was that microscopic slides from autopsy were available for review, and this resulted in a wide range of the number of organs sampled for histologic evaluation as well as considerable variation in the number and type of post-mortem ancillary studies. All available hospital and clinic medical records were obtained and reviewed, along with a lengthy family survey completed by the child’s primary caretaker. None of the cases were being litigated in civil or criminal court. After review of all available materials, a study cause and manner of death was established for each case.

San Diego SUDC Research Project publications

The initial publication of the San Diego SUDC Research Project was in 2005; it summarized the findings from the first 50 cases reviewed, 36 of which remained unexplained (2). Perhaps not surprisingly, aside from age, certain aspects of these cases’ phenotype mirrored that of SIDS: male predominance and being found dead, prone, and face-down during an apparent sleep period. An unexpected and important observation was the association of SUDC with a personal and/or family history of seizures, especially those that were febrile, either in the toddler (32%), his/her immediate family (31%), or both (21%). The high incidence of febrile seizures was well in excess of the 2-5% incidence found among toddlers in the general population (24).

The next manuscript was published in 2007 (25) and included pediatric neuropathologist Hannah Kinney’s observations of hippocampal gross asymmetry and a variety of microdysgenetic abnormalities among a subset of five unexplained toddler deaths. The abstract suggested a “potential entity” of microdysgenetic hippocampal and temporal lobe findings somehow associated with sudden death during a sleep period.

In a 2009 publication from the San Diego SUDC Research Project (19), Kinney et al. elaborated on the new entity of the 2007 publication and included stronger association with febrile seizures and the observation that some cases of SUDC resembled SUDEP via an unwitnessed seizure precipitating sudden death. An article from 2012 (26) examined potential genetic inheritance of sudden death among toddlers among three generations of family related to the toddler, which showed autosomal dominance in two-thirds (although in one family there was variable expression).

Case reports of explained sudden unexpected deaths in toddlers and childhood

Among the individual cases of sudden death in childhood, some novel pathologic findings were noted, which led to publication of five case reports. In 2005, a case of sudden unexpected death in a 13-year-old male with meningioangiomatosis detected at autopsy was summarized (27). The adolescent was found dead in bed, prone, with no medical history of any significance except for being medicated with methylphenidate for an attention deficit disorder. He had no seizure history and there was no family history of meningioangiomatosis.

In 2007, a case report of a unique expression of tuberous sclerosis in a 9-year-old female who died suddenly and unexpectedly was published. Autopsy findings were significant for a cardiac rhabdomyoma, cardiomegaly, involuting adrenal ganglioneuroma, and megalencephaly. The cause of death was assigned as a lethal cardiac arrhythmia arising from the tumor in the subendocardial conduction fibers on the right side of the posterior ventricular septum (28).

Another case report published in 2007 (29) presented two toddlers dying suddenly and unexpectedly with viral meningitis, leading to massive cerebral edema, neurogenic pulmonary edema, and hemorrhage. In 2008, a report of the sudden and unexpected death in a toddler with Williams syndrome was published (30). The final case report from the SUDC Research Project population was published in 2009 — a toddler death associated with laryngeotracheitis caused by human parainfluenza virus-1 (31).

NORD webpage

With the co-operation of the SUDC Foundation website, SUDC was added to the list of uncommon diseases and disorders provided by the National Organization for Rare Disorders (32).

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.).

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

Sudden unexplained death in pediatrics (SUDP)

As the San Diego SUDC Research Project could not transition to Boston Children’s Hospital, Kinney and Goldstein continue research into SUDC and other unexplained pediatric deaths with a new program currently limited to families residing in Massachusetts. A comprehensive team of investigators with Harvard and Boston Children’s Hospital collaborate with the Massachusetts Office of the Chief Medical Examiner (OCME) as well as the Massachusetts Center for Sudden Infant Death Syndrome and the Massachusetts Infant and Child Death Bereavement Program. In 2016, Kinney et al. (35) published a comprehensive review of their neuropathological findings and sudden death across all pediatric life stages.

CDC Sudden death in the young

On 24 October 2013, the National Institutes of Health (NIH) (37) and the CDC announced an expansion of the registry for sudden unexpected infant deaths (up to age 1 year). The expanded Sudden Death in the Young Case Registry (SDY-CR) includes deaths under age 19 years and excludes deaths from homicide, suicide, or trauma. This effort formalizes surveillance of SUDEP and sudden cardiac death (SCD). Seven states (Delaware, Georgia, Minnesota, New Hampshire, New Jersey, Nevada and Tennessee) and three jurisdictions (San Francisco; Tidewater, Virginia; and selected counties in Wisconsin) applied for, and received, funding for their epidemiologic efforts in 2014. Deaths occurring in 2015 are the first to be included. Data collection began in April 2016. The SDY-CR provides autopsy guidelines, an autopsy summary document, a field guide, and family interview questions. The Registry includes a biorepository at the University of Michigan, which will store de-identified blood specimens indefinitely.

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.

Molecular autopsy

Molecular autopsies do not replace traditional autopsies, but are helpful after a negative gross autopsy with no conclusive findings from histology, microbiology, and toxicology studies. In 1997, the CDC established an Office of Public Health Genomics (OPHG), tasked with “identifying, evaluating, and implementing evidence-based genomics practices to prevent and control the country’s leading chronic, infectious, environmental, and occupational diseases”. As of 30 November 2016, there are 1495 publications from this office. The CDC examines the sensitivity and specificity of tests, the costs, extent of ease or invasiveness to obtain testing material, along with the disease or disorder incidence and prevalence in the population to be studied. They have established evidence-based guidelines on which genetic tests are useful and appropriate for specific populations.

According to the US National Library of Medicine National Institutes of Health website, PubMed2, one of the first English-language articles in which genetics gave insight into autopsy findings was in 1987 by Tanzi, who described mapping a gene for β amyloid peptide precursor to chromosome 21 in an Alzheimer patient (38). In 2001, Ackerman published an account of determination of the cause of death following the negative autopsy of a 17-year-old male found dead in bed (39). An epinephrine challenge of the boy’s mother indicated a defect encoded in the KVLQT1 gene. Ackerman was subsequently able to recover molecular material from the boy’s paraffin-embedded heart tissue which revealed a 5-base pair deletion in the same gene as the mother. Importantly, he was able to establish a likely cause of death and demonstrate that necropsy tissue is viable for DNA investigations. To date, Ackerman has gone on to publish 16 articles on molecular autopsy, cardiomyopathy, and channelopathies.

Since then, several countries/states/institutions have published their findings with this approach to unexplained death. Whole exome sequencing (WES) is increasingly available, and at decreasing cost. Rady Children’s Hospital, San Diego, unveiled their Institute for Genomic Medicine in 2016; at the time of this writing, they held the Guinness Book of Records for the fastest genetic diagnosis, by successfully diagnosing critically ill newborns in just 26 hours. The initial candidates at Rady are patients in the Neonatal Intensive Care Unit and Pediatric Intensive Care Unit, some acutely ill with an unknown cause. This institute will also incorporate epigenomics, proteomics, and metabolomics.

The office of the San Diego County Medical Examiner has partnered with Scripps Translational Science Institute (STSI) since 2014. This partnership offers no-cost genetic testing for suddenly deceased individuals less than 45 years of age at death with no obvious anatomic explanation for their death. STSI provides a report looking at whether the decedent was positive or negative for any genetic variants that may explain a sudden death. The range of positive findings includes “Likely Causal DNA Variants” and “Plausible Causal DNA Variants”.

Routine cardiogenetic testing

Genetic testing is not currently routine at autopsy. The cost would be prohibitive, and public health tenets mandate that effective screening tests account for prevalence of the disease (or gene) being studied, and also that prevention or treatment is available and affordable, concomitant with infrastructure to notify and follow up with the families of individuals with genopositive results.

The New York Office of the Chief Medical Examiner (40), however, has had its own molecular genetic laboratory since 2008. Since then, autopsy-negative SUD (sudden unexplained death) cases have been screened for the six genes most often associated with a cardiac channelopathy (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and RyR2). The results from testing a series of 274 ethnically diverse SUD cases revealed that 13.5% of infants and 19.5% of non-infants were positive for a total of 22 previously classified channelopathy-associated variants, along with 24 novel channelopathy variants. The SCN5A gene accounted for 68% of infant and 50% of non-infant positive results. The researchers concluded that molecular testing is valuable, especially for establishing a cause of death, and for providing potentially life-saving information to family members of the decedent.

Researchers in Australia (41) evaluated screening of autopsy-negative sudden arrhythmic death syndrome (SADS) and unexplained cardiac arrest (UCA). The targeted genetic testing of more than 100 SADS families had a diagnostic yield of 18%, while the yield of UCA families was 62%. The majority findings in both groups were LQTS and Brugada syndrome.

A literature search on PubMed reveals that the future of life-saving interventions is at the molecular level. In addition to the increasingly popularity of looking for a genetic link to LQTS, Short QT intervals have been noted to be perilous as well. Previously, family members of a decedent with putative cardiac cause would be subjected to exercise or epinephrine stress tests, wearing a heart monitor for 24 hours (or more), echocardiogram, and MRI for cardiac anatomical defects. Now, given the future in genomic medicine, those families may be able to obtain answers upon submitting a cheek swab.

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).).

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.

Infrastructure concerns

While it is encouraging that viable DNA can be obtained from either fresh-frozen or paraffin-embedded tissue, there are substantial system issues to be addressed to ensure that material is available for genetic testing. In some jurisdictions, the system for retaining and storing specimens and tissue blocks is chaotic and disorganized. Older medical examiner and coroner facilities are often smaller and may have outgrown their storage capacity. Local and state governments likely do not have funds available to hire an employee trained and dedicated to shipping specimens in compliance with United States federal guidelines. Some offices lack even a basic inventory of shipping supplies — for example, appropriately sized, insulated shipping containers, packing tape, and Dry Ice UN 1845 adhesive labels. Most medical examiner and coroner offices do not have dry ice for shipping frozen specimens because it is not a part of a daily forensic practice. Ideally, medical examiner and coroner offices would have a designated -40 °F (or colder) freezer for specimen storage. Another important component of sending specimens is that the freezer is sufficiently organized to enable retrieval of a specific case.

Ethical considerations

In California, as in most of the United States, there is no right to privacy after death. With the United States Privacy Act, an individual’s right to privacy terminates at death (49). However, under the United States Freedom of Information Act (FOIA), the privacy of a decedent’s survivors may be considered and, in some landmark cases, families have prevailed (Marzen v HHS in 1987; New York Times Co. v NASA in 19913). Also, as in other jurisdictions, death certificates, autopsy, and investigative reports are part of the public record in California, unless sealed by law enforcement. Scientists in Houston, Texas, (50) have addressed ethical considerations of molecular autopsies, customarily done by a medical examiner or coroner without additional consent from next-of-kin in their purview to determine a cause and manner of death. Their recommendations include that genetic testing results should be treated as an “unwarranted invasion of privacy” and that the genetic results are exempt from disclosure and discovery under the FOIA. Other recommendations include guidelines for disclosure of results to first-degree relatives and the importance of underscoring the limitation of current knowledge in the case of negative findings for a genetic cause of death. Families of a decedent with a positive genetic finding associated with a sudden death should be referred to genetic counselors and specialists in the clinical condition accounting for death.


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

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