Search

Sudden infant death syndrome (SIDS) "gray zone" or borderline cases are those in which it is challenging to define whether the pathological findings are sufficiently severe to lead to death. We report a case of a 17-day old male newborn who came to our attention for unexplained death. A complete autopsy was performed, including close examination of the cardiac conduction system. Lungs presented diffuse alveolar damage and interstitial inflammation, the cardiac conduction system showed fetal dispersion, resorptive degeneration, junctional tissue islands and cartilaginous hypermetaplasia of the central fibrous body. The final cause of death was a "gray zone" SIDS. This case report will highlight the intersection of SIDS and pneumonia in newborns, exploring the challenges and controversies surrounding the diagnosis and management of this complex condition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

We conducted an autopsy on a 3-month-old boy in whom Kawasaki disease (KD) was strongly suspected based on the autopsy findings. The infant had a fever and was brought to a nearby clinic, where he was prescribed antipyretics and kept under observation. However, 15 days after onset of the fever, he suddenly died in bed. He exhibited no obvious redness of the lips, tongue, or conjunctiva. Membranous desquamation was present on his distal fingers. Vasculitis was observed in the coronary arteries, renal artery, splenic artery, and pulmonary vein. In addition, coronary artery aneurysms were present in the right coronary artery and left anterior descending artery. Thrombotic occlusion was observed in one aneurysm in the right coronary artery, resulting in acute myocardial infarction. The coronary artery wall showed infiltration of numerous macrophages and neutrophils. This case was classified as incomplete KD because the coronary artery aneurysm could not be demonstrated before death and was only recognized at autopsy. Pathologists and forensic scientists need to be aware that there are cases in which KD goes undiagnosed and untreated, leading to coronary artery aneurysm formation and sudden death., (© 2024 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Objective: To evaluate in the Netherlands the national outcomes in providing cause of and insights into sudden and unexplained child deaths among children via the Postmortem Evaluation of Sudden Unexplained Death in Youth (PESUDY) procedure., Study Design: Children aged 0-18 years in the Netherlands who died suddenly were included in the PESUDY procedure if their death was unexplained and their parents gave consent. The PESUDY procedure consists of pediatric and forensic examination, biochemical, and microbiological tests; radiologic imaging; autopsy; and multidisciplinary discussion. Data on history, modifiable factors, previous symptoms, performed diagnostics, and cause of death were collected between October 2016 and December 2021., Results: In total, 212 cases (median age 11 months, 56% boys, 33% comorbidity) were included. Microbiological, toxicological, and metabolic testing was performed in 93%, 34%, and 32% of cases. In 95% a computed tomography scan or magnetic resonance imaging was done and in 62% an autopsy was performed. The cause of death was explained in 58% of cases and a plausible cause was identified in an additional 13%. Most children died from infectious diseases. Noninfectious cardiac causes were the second leading cause of death found. Modifiable factors were identified in 24% of non-sudden infant death syndrome/unclassified sudden infant death cases and mostly involved overlooked alarming symptoms., Conclusions: The PESUDY procedure is valuable and effective for determining the cause of death in children with sudden unexplained deaths and for providing answers to grieving parents and involved health care professionals., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

In the past, histological diagnosis of (post-)viral myocarditis was based on the so-called Dallas criteria, which have been criticized because of high interobserver variability and sampling error. Immunohistochemical qualification and quantification of interstitial intramyocardial leucocytes was established and standard values concerning adults were published. Fatal casualties due to a viral myocarditis are rare as far as babies and children are concerned (sudden unexpected death in infancy; SUDI). Cases of sudden unexpected death in the first year of life are frequently regarded as sudden infant death syndrome (SIDS). To diagnose myocarditis when there are only single focal lymphocytic infiltrates in the myocardium, the number of samples taken by autopsy is relevant. But even in babies, immunohistochemical qualification and quantification of interstitial lymphocytes and macrophages can lead to standard values allowing diagnosis of myocarditis. Depending on the course of a viral infection, molecular pathological detection of viral genome in the myocardium is possible to support the diagnosis. Using the mentioned methods gradually, there are more cases of suspected SIDS, which are in fact cases of virus-induced myocarditis as cause of death. Primary enteroviruses (coxsackie viruses) and adenoviruses were found but also Epstein-Barr virus and PVB-19., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Infection is an important cause of death during infancy worldwide and is a frequent etiology of sudden unexpected death in infancy (SUDI). Procalcitonin (PCT) is a useful marker to diagnose infection in patients, and several studies report the stability of PCT after death. The added value of a biological marker, such as the PCT level in the blood, remains controversial in investigating SUDI. The aim of this study was to determine if PCT can help clinicians determine whether infection caused SUDI. We conducted a retrospective, multicenter study with the French SUDI registry (Observatoire National des Morts Inattendues du Nourrisson; OMIN). We collected data from this registry on children who died between May 2015 and June 2021. The levels of PCT in the blood of 540 SUDI patients were measured. We compared PCT and other biological tests performed in terms of infection status, autopsy results, and cause of death using clinical and biological data compiled by pediatricians at the SUDI referral center. PCT levels were significantly higher in the children who died from infection than in those who did not (0.12 µg/L vs. 0.08 µg/L, p < 0.001). A PCT blood level exceeding 0.2 µg/L was more frequently observed when infection was present than in the absence of infection (44.3% vs. 15.4%, p < 0.001). The same data were obtained with a 0.5 µg/L cut-off (36.1% with infection vs. 9.2% without, p < 0.001).  Conclusions: PCT is a sensitive biomarker for detecting infections postmortem; thus, additional samples may be necessary during autopsy. What is known: • PCT is a stable marker postmortem and increases earlier than CRP, i.e., 2-4 h after the beginning of an infection vs. 6 h. • PCT can be measured up to 140 h after death. What is new: • PCT is a sensitive marker for detecting infection in SUDI patients postmortem. • This test can reveal an infection from non-standardized samples obtained during autopsy if such an infection was not determined before death., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: As it is now 20 years since the San Diego definition of sudden infant death syndrome (SIDS) was proposed, it is timely to examine the impact of this consensus statement., Results: Concerns at the time were expressed that 'death scene' had been replaced by circumstances of death and so it may have been more useful to have a more inclusive statement of 'death scene, including circumstances of death'. The category of unclassified sudden infant deaths (USID) that was proposed has not been widely adopted. More disturbing, however, is the increasing failure to use either the San Diego or earlier definitions in published research, with recent studies showing that almost two-thirds of peer-reviewed SIDS publications (2019-2021) did not quote or reference internationally accepted definitions. This is a decrease of 33% from the 68% of papers that correctly used SIDS definitions in 2011. The definition is therefore not being uniformly applied and in addition, diagnostic shift is occurring, with more pathologists favouring 'undetermined' over a designation of SIDS., Conclusions: Given these developments, how can we correctly interpret conclusions relating to SIDS research, and can we accurately monitor trends in SIDS mortality? The authors would suggest that unfortunately, at present we cannot with any precision., (© 2023 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Aim: To determine whether there has been a change in the incidence and type of conditions causing sudden and unexpected natural death in infants and young children in recent years., Methods: A search was undertaken of pathology records at Forensic Science SA in Adelaide, Australia for all cases of sudden and unexpected natural death in children aged less than 10 years at the time of death over two time periods: 1994-1998 and 2014-2018., Results: Overall, 136 cases were identified consisting of 81 boys and 55 girls (M:F = 16:11; age range 0-9 years). No difference was shown in the numbers of sudden unexplained deaths in infants and young children between the two time periods (80 vs. 56; p = 0.18). A trend was shown for a prominent decrease in SIDS cases (55 vs. 12) with an increase in undetermined cases, <1 year (5 vs. 18). However, when the two categories were combined there was no statistical difference between the two periods (60/80 vs. 30/56) (p = 0.26), although a decrease in numbers had occurred., Conclusion: Analysis of numbers of fatalities reported from medicolegal institutes should be undertaken with an awareness of the potential effect of diagnostic shift., (© 2023 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Competing Interests: Competing interests: None declared.

Sudden unexpected infant death (SUDI) is reported to be an extraordinarily high burden in sub-Saharan Africa, with the incidence rate in South Africa among the highest in the world. It is common for the cause of many such infant deaths to remain unexplained even after a full medico-legal death investigation, and then to be categorised as a sudden unexplained infant death (SUID). Fortunately, advances in molecular-based diagnostics allow researchers to identify numerous underlying inherited cardiac arrhythmogenic disorders in many SUDI cases, with a predominance of variants identified in the SCN5A gene. Such cardiac arrhythmogenic-related sudden deaths generally present with no structural alterations of the heart that are macroscopically identifiable at autopsy, therefore highlighting the importance of post mortem genetic testing. We report on a significant genetic finding that was made on a SUDI case in which the cause was ascribed to an acute bacterial pneumonia but it was still subjected to post mortem genetic testing of the SCN5A gene. The literature shows that many SUDI cases diagnosed with inherited cardiac arrhythmogenic disorders have demonstrated a viral prodrome within days of their death. It is therefore not uncommon for these cardiac disorders in infants to be mistaken for flu, viral upper respiratory tract infection or pneumonia, and without the incorporation of post mortem genetic testing, any other contributory causes of these deaths are often disregarded. This study highlights the need for research reporting on the genetics of inherited cardiac disorders in Africa.

Competing Interests: Declaration of interests EM receives funding from a Clinical Academic Research Partnership from the MRC/NIHR. EM received an honorarium from Lupin pharmaceuticals in Feb 2022 to attend an advisory board meeting regarding the diagnosis and management of children with myotonic disorders and was appointed as an output assessor for the UK REF 2021 process Sub-panel 4: Psychology, Psychiatry and Neuroscience.

Sudden death of an infant can be from numerous causes. The leading cardiac causes include major congenital heart disease, myocarditis, cardiomyopathies, and channelopathies. There are new approaches to evaluating these patients and surviving family members. Pediatricians are a key component in support of the family, investigation of other at-risk family members, and coordination of subspecialty consultation. [Ped Ann. 2022;51(6):e228-e233.] .

Background: Autonomic dysfunction has been implicated in the pathophysiology of the Sudden Infant Death Syndrome (SIDS). Butyrylcholinesterase (BChE) is an enzyme of the cholinergic system, a major branch of the autonomic system, and may provide a measure of autonomic (dys)function. This study was undertaken to evaluate BChE activity in infants and young children who had died from Sudden Infant Death or Sudden Unexpected Death., Methods: In this case-control study we measured BChE activity and total protein in the eluate of 5μL spots punched from the dried blood spots taken at birth as part of the newborn screening program. Results for each of 67 sudden unexpected deaths classified by the coroner (aged 1 week-104 weeks) = Cases, were compared to 10 date of birth - and gender-matched surviving controls (Controls), with five cases reclassified to meet criteria for SIDS, including the criterion of age 3 weeks to 1 year., Findings: Conditional logistic regression showed that in groups where cases were reported as "SIDS death" there was strong evidence that lower BChE specific activity (BChEsa) was associated with death (OR=0·73 per U/mg, 95% CI 0·60-0·89, P=0·0014), whereas in groups with a "Non-SIDS death" as the case there was no evidence of a linear association between BChEsa and death (OR=1·001 per U/mg, 95% CI 0·89-1·13, P=0·99)., Interpretation: BChEsa, measured in dried blood spots taken 2-3 days after birth, was lower in babies who subsequently died of SIDS compared to surviving controls and other Non-SIDS deaths. We conclude that a previously unidentified cholinergic deficit, identifiable by abnormal -BChEsa, is present at birth in SIDS babies and represents a measurable, specific vulnerability prior to their death., Funding: All funding provided by a crowd funding campaign https://www.mycause.com.au/p/184401/damiens-legacy., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Sudden unexpected infant death (SUID) remains the leading cause of postnatal mortality in many countries. French and international guidelines recommend a thorough examination with toxicology studies., Objectives: The main objective was to determine the prevalence of toxic detection and positive analyses. The secondary objectives were to describe the different toxics and compare children with positive (Tox+) and negative results (Tox-) with other SUID risk factors., Design and Methods: We used the data registered from May 2015 to December 2018 by the French national SUID registry (OMIN). It collects data for all SUID cases admitted to any of the 35 participating French SUID referral centers., Results: Of the 624 SUID cases registered in the OMIN, a post-mortem toxicological analysis was performed in 398 infants. Thirty-six patients (9%) were positives for expected (Etox+ ( n  = 19 [53%], e.g., resuscitation drugs, regular treatments) and unexpected (UTox+) ( n  = 17 [47%]) toxics. The unexpected toxics were opioids ( n  = 8), cannabis ( n  = 4), cocaine ( n  = 3), cotinine ( n  = 2), carbon monoxide ( n  = 2), caffeine ( n  = 2), alcohol ( n  = 1) and GHB ( n  = 1). UTox + infants had a different seasonal distribution ( p  = .03), a higher incidence of inappropriate sleeping position and bedding at the time of death (respectively OR 3.8, p  = .037 - OR 5.4, p  = .026); inadequate body hygiene (OR 10.6, p  = .0005), a younger maternal age ( p  = .045) and a higher rate of maternal drug abuse (OR 21.9, p  = .0008)., Conclusion: The high rate of positive results warrants routine toxicology testing. The imputability of identified molecules is complicated by the presence of other known risk factors for SUID.

Sudden infant death syndrome (SIDS) is one of the primary causes of death of infants in the first year of life. According to the WHO's data, the global infant mortality rate is 0.64-2 per 1,000 live-born children. Molecular and cellular aspects of SIDS development have not been identified so far. The purpose of this paper is to verify and analyze the expression of melatonin 1 and 2 receptors, serotonin (as a melatonin precursor), and CD34 molecules (as hematopoietic and endothelial markers of cardiovascular damage) in the medulla, heart, and aorta in infants who died from SIDS. An immunohistochemical method was used to investigate samples of medulla, heart, and aorta tissues of infants 3 to 9 months of age who died from SIDS. The control group included children who died from accidents. It has been shown that the expression of melatonin receptors as well as serotonin and CD34 angiogenesis markers in tissues of the medulla, heart, and aorta of infants who died from SIDS is statistically lower as compared with their expression in the same tissues in children who died from accidents. The obtained data help to clarify in detail the role of melatonin and such signaling molecules as serotonin and CD34 in SIDS pathogenesis, which can open new prospects for devising novel methods for predictive diagnosis of development and targeted prophylaxis of SIDS., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Sudden unexpected death in infancy (SUDI) represents the commonest presentation of postneonatal death. We explored whether machine learning could be used to derive data driven insights for prediction of infant autopsy outcome., Methods: A paediatric autopsy database containing >7,000 cases, with >300 variables, was analysed by examination stage and autopsy outcome classified as 'explained (medical cause of death identified)' or 'unexplained'. Decision tree, random forest, and gradient boosting models were iteratively trained and evaluated., Results: Data from 3,100 infant and young child (<2 years) autopsies were included. Naïve decision tree using external examination data had performance of 68% for predicting an explained death. Core data items were identified using model feature importance. The most effective model was XG Boost, with overall predictive performance of 80%, demonstrating age at death, and cardiovascular and respiratory histological findings as the most important variables associated with determining medical cause of death., Conclusion: This study demonstrates feasibility of using machine-learning to evaluate component importance of complex medical procedures (paediatric autopsy) and highlights value of collecting routine clinical data according to defined standards. This approach can be applied to a range of clinical and operational healthcare scenarios.

Background: Genetic predispositions in cases suffering sudden unexpected infant death have been a research focus worldwide during the past decade. Despite large efforts, there is still uncertainty concerning the molecular pathogenesis of these deaths. With genetic technology in constant development, the possibility of an alternative approach into this research field has become available, like mRNA expression studies., Methods: In this study, we investigated mRNA gene expression in 14 cases who died suddenly and unexpectedly from infection without a history of severe illness prior to death. The control group included eight accidents, two cases of natural death, one undetermined, one case of medical malpractice, and two homicides. The study included tissue from liver, heart, and brain using Illumina whole-genome gene expression assay., Results: From the array, 19 genes showed altered expression in the infectious deaths compared to controls. Tissue from the heart showed 15 genes with altered mRNA expression compared to the control group., Conclusions: Downregulation of KCNE5 in heart tissue from cases of infectious death was of particular interest. Variants of KCNE5 are associated with Brugada syndrome and sudden death and could be responsible for the fatal outcome in the group of infectious death., Impact: KCNE5 is downregulated in tissue from the heart in cases of infectious death in infancy. This study provides knowledge about the gene expression profile in cases of infectious death. Variants of a gene known to give increased risk of cardiac arrhythmia is downregulated in cases of infectious death in infancy. The results could give us better knowledge as to why some infants do not survive an infection. This study provides a candidate gene for future studies.

Objective: To study recent epidemiologic trends of sudden unexpected death in infancy (SUDI) in Western Europe., Study Design: Annual national statistics of death causes for 14 Western European countries from 2005 to 2015 were analyzed. SUDI cases were defined as infants younger than 1 year with the underlying cause of death classified as "sudden infant death syndrome," "unknown/unattended/unspecified cause," or "accidental threats to breathing." Poisson regression models were used to study temporal trends of SUDI rates and source of variation., Results: From 2005 to 2015, SUDI accounted for 15 617 deaths, for an SUDI rate of 34.9 per 100 000 live births. SUDI was the second most common cause of death after the neonatal period (22.2%) except in Belgium, Finland, France, and the UK, where it ranked first. The overall SUDI rate significantly decreased from 40.2 to 29.9 per 100 000, with a significant rate reduction experienced for 6 countries, no significant evolution for 7 countries, and a significant increase for Denmark. The sudden infant death syndrome/SUDI ratio was 56.7%, with a significant decrease from 64.9% to 49.7% during the study period, and ranged from 6.1% in Portugal to 97.8% in Ireland. We observed between-country variations in SUDI and sudden infant death syndrome sex ratios., Conclusions: In studied countries, SUDI decreased during the study period but remained a major cause of infant deaths, with marked between-country variations in rates, trends, and components. Standardization is needed to allow for comparing data to improve the implementation of risk-reduction strategies., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Sudden unexpected infant death (SUID) is a major cause of death in infants < 1 year of age. Sudden infant death syndrome (SIDS) is a SUID still unexplained after post-mortem examination. In 2014, a protocol of post-mortem investigation was introduced to assess both the prevalence and the etiopathogenesis of SUID. Our aim was to compare SUID data before and after the application of a standardized autopsy protocol of investigation. In the time interval 2004-2018, SUID cases occurring in the Veneto Region, North-East Italy, were referred to our Core Lab. Since 2014, a complete autopsy was performed, including gross and histological study with toxicologic and molecular analysis carried out at the referral center. A total of 36 SUIDs (22 M, mean age 95.5 ± 80 days), 17 before (group A) and 19 after (group B) 2014, were collected. In group A, only 1 (6%) resulted as explained SUID, due to lymphocytic myocarditis and 16 (94%) were SIDS. In group B, 8 were SIDS (42%) and 11 (58%) explained SUID cases (p < 0.01), consisting of interstitial pneumonia and bronchiolitis in 9 and lymphocytic myocarditis in 2 cases. Molecular analysis was positive for viruses in 8 of them (73%). In conclusion, since the application of a standardized protocol of post-mortem investigation, inflammatory, mostly infective, cardio-pulmonary diseases have been identified as the most common cause of SUID, with SIDS falling from 94 to 42% of SUID. Efforts must be made to implement a uniform autopsy protocol to provide reliable epidemiological data on SIDS.

Background: The Sudden Unexpected Infant Death Syndrome (SUID) is one of the leading causes of mortality in the first year of life. The aim of this work was the retrospective evaluation of the incidence of SUID and the effectiveness of the multiagency approach to this phenomenon in the Tuscany Region., Methods: Data were obtained from the regional registry of SUID cases in the period 2009-2019. The registry contains both sudden unexpected deaths in the first week of life (Sudden Unexpected Early Neonatal Deaths - SUEND), and those occurring after the first week up to 1 year of age (SUID)., Results: In this timeframe a total of 73 sudden unexpected deaths occurred in our region; 32 were Unexplained (i.e. Sudden Infant Death Syndrome - SIDS), 24 Explained, 10 Undetermined, and 7 SUEND. Autopsies were performed in 91% of cases, and in 95% of these by three groups of selected pathologists according to our protocol. We found a low incidence of SUID (0.21 ‰), and SIDS deaths accounted for 0.1‰ of live births (48% of cases) with a high prevalence of infants of non-Italian ethnicity (38% of cases). Bereaved families were able to receive psychological support from mental health professionals and have contact with the family association, Seeds for SIDS. Audits were organized when post-mortem examinations were not carried out or carried out incorrectly in procedural terms, and when the diagnosis was particularly uncertain., Conclusions: This paper first provides data on SUID mortality based on complete post-mortems in an Italian region. According to these findings we can state that our approach is effective both in terms of correctly performed autopsies and support for bereaved families. Future efforts are necessary to further reduce the incidence of SUID especially among non- Italian infants. An improvement action is also recommended for ensuring a more accurate and consistent picture of the circumstances of death. The final approval of the National Protocol for the management of SUID cases is therefore strongly advocated in order to improve surveillance in this specific field and abolish disparities among the Italian regions.

Despite being widely used, few studies have assessed the utility of the San Diego definition of sudden infant death syndrome (SIDS). The purpose of this study was to evaluate pathologists' application of the San Diego definition in all cases of sudden unexpected death in infancy (SUDI) that occurred in Queensland, Australia, between 2010 and 2014. Key coronial documents of 228 cases of SUDI were reviewed independently by three reviewers and classified according to the San Diego definition. Clear guidance regarding the evidentiary threshold for classification and interpretation of the San Diego definition was provided. All reviewers classified cases identically in 202 cases (88.6%). Consensus was achieved on the classification of the remaining 26 deaths following case discussion. After review, 79 cases were classified as SIDS, a one third reduction compared with the original classification, mainly due to a high probability of accidental asphyxia. The number of cases classified as undetermined (USID) almost doubled (75/228, 32.9%), and there was more than a fivefold increase in cases classified as asphyxia (43/228, 18.9%). Natural conditions decreased by approximately one third (21/228, 9.2%). This study demonstrates that with clear guidelines for interpretation, the San Diego definition can be applied reliably, with discrepancies resolved through a process of peer review.

Objectives: To describe infant deaths where a u-shaped pillow was under or around an infant and to describe cases classified as Explained Suffocation., Methods: We examined demographics and circumstances of 141 infant deaths during 2004-2015 in the US National Fatality Review Case Reporting System with u-shaped pillows in the sleep environment., Results: Most infants were < 6 months old (92%), male (58%), non-Hispanic White (53%), and of the nine explained suffocation deaths, four occurred when the u-shaped pillow obstructed the infant's airway; five occurred when the infant rolled off the pillow and their airway was obstructed by another object., Conclusions for Practice: Although infrequent, infant deaths with u-shaped pillows have occurred. Health care providers may include discussion of the importance of caregivers following infant product packaging precautions and warning labels for commonly used consumer products, such as u-shaped pillows in their advice to caregivers.

When a healthy infant dies suddenly and unexpectedly, it is critical to correctly determine if the death was caused by child abuse or neglect. Sudden unexpected infant deaths should be comprehensively investigated, ancillary tests and forensic procedures should be used to more-accurately identify the cause of death, and parents deserve to be approached in a nonaccusatory manner during the investigation. Missing a child abuse death can place other children at risk, and inappropriately approaching a sleep-related death as maltreatment can result in inappropriate criminal and protective services investigations. Communities can learn from these deaths by using multidisciplinary child death reviews. Pediatricians can support families during investigation, advocate for and support state policies that require autopsies and scene investigation, and advocate for establishing comprehensive and fully funded child death investigation and reviews at the local and state levels. Additional funding is also needed for research to advance our ability to prevent these deaths., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

We aimed to investigate the pathogenicity of cardiac ion channel variants previously associated with SIDS. We reviewed SIDS-associated variants previously reported in databases and the literature in three large population-based cohorts; The ExAC database, the Inter99 study, and the UK Biobank (UKBB). Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Of the 92 SIDS-associated variants, 59 (64%) were present in ExAC, 18 (20%) in Inter99, and 24 (26%) in UKBB. Using the Inter99 cohort, we found no difference in J-point amplitude and QTc-interval between carriers and non-carriers for 14/18 variants. There was no difference in the risk of syncope (P = 0.32), malignant ventricular arrhythmia (P = 0.96), and all-cause mortality (P = 0.59) between carriers and non-carriers. The ACMG guidelines reclassified 75% of all variants as variant-of-uncertain significance, likely benign, and benign. We identified ~2/3 of variants previously associated with SIDS and found no significant associations with electrocardiographic traits, syncope, malignant ventricular arrhythmia, or all-cause mortality. These data indicate that many of these variants are not highly penetrant, monogenic causes of SIDS and underline the importance of frequent reappraisal of genetic variants to avoid future misdiagnosis.

Sensing properties of chemical sensors based on ternary hydroxyapatite-graphene-multiwalled carbon nanotube (HA-GN-MWCNT) nanocomposite in the detection of chemical substances representing risk factors for sudden infant death syndrome (SIDS), have been evaluated. Characterization data of the synthesized composite have shown that the graphene-MWCNT network serves as a matrix to uniformly disperse the hydroxyapatite nanoparticles and provide suitable electrical properties required for developing novel electrochemical and conductometric sensors. A HA-GN-MWCNT composite-modified glassy carbon electrode (HA-GN-MWCNT/GCE) has been fabricated and tested for the simultaneous monitoring of nicotine and caffeine by cyclic voltammetry (CV) and square wave voltammetry (SWV), whereas a HA-GN-MWCNT conductive gas sensor has been tested for the detection of CO 2 in ambient air. Reported results suggest that the synergic combination of the chemical properties of HA and electrical/electrochemical characteristics of the mixed graphene-MWCNT network play a prominent role in enhancing the electrochemical and gas sensing behavior of the ternary HA-GN-MWCNT hybrid nanostructure. The high performances of the developed sensors make them suitable for monitoring unhealthy actions (e. g. smoking, drinking coffee) in breastfeeding women and environmental factors (bad air quality), which are associated with an enhanced risk for SIDS., Competing Interests: The authors declare no conflict of interest.

Background and Objectives: The American Academy of Pediatrics published guidelines for evaluation and management of lower-risk infants for a brief resolved unexplained event (BRUE). The guideline identified gaps in knowledge related to caregiver satisfaction, anxiety, and family-centered educational strategies to improve caregiver experience and patient outcomes. The objective of this study was to understand caregivers' experience with hospitalization for infants with BRUE, including their perception of the hospital stay, the diagnosis of BRUE, and their feelings toward the upcoming discharge from the hospital., Methods: We conducted a qualitative study using semistructured interviews with caregivers of infants aged 0 to 12 months who were admitted to a quaternary care children's hospital for a BRUE. Interviews were conducted within 24 hours of discharge. Two investigators coded transcripts and identified themes using consensus., Results: Eighteen caregivers of 13 infants were interviewed. No infants met criteria for being low risk according to the American Academy of Pediatrics guidelines. The coding scheme produced 3 major themes. First, parents felt reassured by hospital monitoring, diagnostic evaluation, and staff support in the hospital. Second, parents felt unsettled by the uncertainty of the child's condition and whether BRUE's "unexplainable" quality is understood as being part of normal infant behavior. Third, these themes manifested as conflicting emotions about caregivers' readiness for discharge., Conclusions: Although hospital monitoring may provide reassurance for some caregivers, they continue to struggle with the uncertainty of the diagnosis. Caregiver perspectives can inform physicians' strategies to improve hospital experience and discharge readiness., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Introduction: Infant mortality comprises deaths among infants younger than one year old. The proportion of sudden unexpected death in infancy (SUDI) varies by country and based on the cause of death., Objective: To describe the spatial and temporal variation of SUDI in Argentina between 1991 and 2014 according to the International Classification of Diseases, tenth revision., Materials and Methods: Based on infant death data (provided by the Health Statistics and Information Department), we estimated the percentage of SUDI over the total number of infant deaths and the frequency of causes of death at a provincial, regional, and national level. The risk for death and the secular trend were estimated using a Poisson regression. The SaTScan software, v9.1.1, was used to detect clusters of districts where the percentage of SUDI was significantly different from the national percentage., Results: In Argentina, between 1991 and 2014, 267 552 infants younger than 1 year died; 7 % corresponded to SUDI; the secular trend of causes was negative and statistically significant; the risk for SUDI was 0.86, and a great spatial heterogeneity was observed. At a national level, the most common cause was sudden infant death syndrome, with inter-regional differences. In nine district clusters, the risk for SUDI ranged between 4.36 and 1.24, which is significantly different from the rest of the country., Conclusions: The proportion of SUDI and its causes show inter-regional heterogeneity; codes related to inaccurate diagnoses predominated in more unfavorable regions, while sudden infant death syndrome was prevalent in the more developed regions., Competing Interests: The authors report no conflicts of interest in this work., (Sociedad Argentina de Pediatría.)

The aim of this paper was to highlight the importance of a multidisciplinary and multiprofessional management of SIDS for a complete approach to this tragic event. Both biomedical and psychosocial aspects are evaluated, focusing on the impact of SIDS diagnosis on the family. The paper describes the organization of our team, composed of a network of specialists involved in both prevention and management of SIDS. A protocol is proposed to improve SIDS diagnosis and management. In our team, the clinical pediatrician is the coordinator of specialists and the mediator between the family and the other specialists, thanks to his direct relationship with parents.

Primary cardiac tumors are rare in children with a low incidence varying from 0.0017 to 0.28% in autopsy studies. Approximately 90% of the reported primary cardiac tumors in the pediatric population are benign and the most common subtype is rhabdomyomas accounting for approximately 60%, while hemangiomas are rare primary tumors with a 5% incidence. Hypoplastic left heart syndrome is abnormal development of the left-sided cardiac structures, leading to obstruction of blood flow from the left ventricle out-flow tract. Here we report a case of tricuspid hemangioma in association with hypoplastic left heart syndrome, a rare association not previously reported in the literature.

Background: Sudden Infant Death Syndrome (SIDS) mechanisms of death remains obscured. SIDS' Triple Risk Model assumed coexistence of individual subtle vulnerability, critical developmental period and stressors. Prone sleeping is a major risk factor but provide no clues regarding the mechanism of death. The leading assumed mechanisms of death are either an acute respiratory crisis or arrhythmias but neither one is supported with evidence, hence both are eventually speculations. Postmortem findings do exist but are inconclusive to identify the mechanism of death. WHAT DOES THE PROPOSED HYPOTHESIS BASED ON?: 1. The stressors (suggested by the triple risk model) share a unified compensatory physiological response of decrease in systemic vascular resistant (SVR) to facilitate a compensatory increase in cardiac output (CO). 2. The cardiovascular/cardiorespiratory control of the vulnerable infant during a critical developmental period may be impaired. 3. A severe decrease in SVR is associated with hyper-dynamic state, high output failure and distributive shock., The Hypothesis: Infant who is exposed to one or more stressors responds normally by decrease in SVR which increases CO. In normal circumstances once the needs are met both SVR and CO are stabilized on a new steady state. The incompetent cardiovascular control of the vulnerable infant fails to stabilize SVR which decreases in an uncontrolled manner. Accordingly CO increases above the needs to hyper-dynamic state, high output heart failure and hyper-dynamic shock., Conclusions: The proposed hypothesis provides an appropriate alternative to either respiratory crises or arrhythmia though both speculations cannot be entirely excluded., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A 2-month-old girl with normal development and no previous physical illnesses was resuscitated having been found lifeless on her back at home. On admission to Paediatric Intensive Care, she had severe metabolic disturbance, associated with an extremely troubling neurological signs. She died 2 hours later. A full body CT scan did not reveal injury and her parents declined an autopsy. Peripheral blood and cerebrospinal fluid samples were sterile. However, a broad-range PCR coupled with electrospray-ionisation mass spectrometry onto the PLEX-ID automat of peripheral blood revealed the presence of varicella zoster virus. There was a specific viral load in whole blood of 20 542 copies/ml. It is presumed that Varicella myocarditis was the likely cause of death. Our case illustrates the potential usefulness of a broad range PCR strategy in determining infectious causes of death in sudden infant death. Varicella is a potential cause of sudden infant death., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Infants who die within the first weeks to months of life may have genetic disorders, though many die without a confirmed diagnosis. Non-genetic conditions may also be responsible for unexplained infant deaths, and the diagnosis may be reliant upon studies performed in the peri-mortem period. Neonatologists, obstetricians, or pediatricians caring for these children and their families may be unsure of which investigations can and should be performed in the setting of a newborn or infant who is dying or has died. Recent advances in genomic sequencing technology may provide additional diagnostic options, though the interpretation of genetic variants discovered by this technique may be contingent upon clinical phenotype information that is obtained peri-mortem or upon autopsy. We have reviewed the current literature concerning the evaluation of an unexplained neonatal or infantile demise and synthesized a diagnostic approach, with a focus on the contribution of new and emerging genomic technologies.

Background: Heterologous functional validation studies of putative long-QT syndrome subtype 2-associated variants clarify their pathological potential and identify disease mechanism(s) for most variants studied. The purpose of this study is to clarify the pathological potential for rare nonsynonymous KCNH2 variants seemingly associated with sudden infant death syndrome., Methods: Genetic testing of 292 sudden infant death syndrome cases identified 9 KCNH2 variants: E90K, R181Q, A190T, G294V, R791W, P967L, R1005W, R1047L, and Q1068R. Previous studies show R181Q-, P967L-, and R1047L-Kv11.1 channels function similar to wild-type Kv11.1 channels, whereas Q1068R-Kv11.1 channels accelerate inactivation gating. We studied the biochemical and biophysical properties for E90K-, G294V-, R791W-, and R1005W-Kv11.1 channels expressed in human embryonic kidney 293 cells; examined the electronic health records of patients who were genotype positive for the sudden infant death syndrome-linked KCNH2 variants; and simulated their functional impact using computational models of the human ventricular action potential., Results: Western blot and voltage-clamping analyses of cells expressing E90K-, G294V-, R791W-, and R1005W-Kv11.1 channels demonstrated these variants express and generate peak Kv11.1 current levels similar to cells expressing wild-type-Kv11.1 channels, but R791W- and R1005W-Kv11.1 channels accelerated deactivation and activation gating, respectively. Electronic health records of patients with the sudden infant death syndrome-linked KCNH2 variants showed that the patients had median heart rate-corrected QT intervals <480 ms and none had been diagnosed with long-QT syndrome or experienced cardiac arrest. Simulating the impact of dysfunctional gating variants predicted that they have little impact on ventricular action potential duration., Conclusions: We conclude that these rare Kv11.1 missense variants are not long-QT syndrome subtype 2-causative variants and therefore do not represent the pathogenic substrate for sudden infant death syndrome in the variant-positive infants., (© 2018 American Heart Association, Inc.)

According to the French High Authority for Health, sudden unexpected death in infants (SUDI) is defined as "a sudden death that occurs in an infant, whereas nothing in its known history could have predicted it". This is an exclusion diagnosis. There are great interregional disparities despite the professional recommendations established in February 2007. For the examination of the brain, instructions are not adapted to current and research practice. The role of the pathologist, like anyone involved in SUDI, is to eliminate an abuse head trauma and to determine the cause of death. Major neuropathological lesions by definition do not exist. Lesions of hypoxia/ischemia are the most frequent but not specific. The accessibility of anti-APP immunoblotting has highlighted the role of anoxia in the development of axonal diffuse damages. Many studies are looking for a neurological substratum of the SUDI (neuropathological and/or neurobiochinic). This article aims to define a detailed sampling protocol based on foreign consensus and current data of science in order to assist pathologists and to promote a homogeneous data bank in France., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

We identified SCN1A variants in 2 infants who died of sudden infant death syndrome (SIDS) with hippocampal abnormalities from an exome sequencing study of 10 cases of SIDS but no history of seizures. One harbored SCN1A G682V, and the other had 2 SCN1A variants in cis: L1296M and E1308D, a variant previously associated with epilepsy. Functional evaluation in a heterologous expression system demonstrated partial loss of function for both G682V and the compound variant L1296M/E1308D. Our cases represent a novel association between SCN1A and SIDS, extending the SCN1A spectrum from epilepsy to SIDS. Our findings provide insights into SIDS and support genetic evaluation focused on epilepsy genes in SIDS., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

The analysis of proteomics data can be significantly challenging. Beyond the technical challenges of accurately identifying and quantifying peptides, identifying the most biologically coherent set of biomarkers can be a particularly daunting step. In this chapter, we will review a series of methods implemented in the software AltAnalyze that can be used to normalize proteomics peptide counts, identify a minimal set of the most distinguishing morbidity-associated biomarkers, and connect up these results to known pathways and interacting protein and regulatory networks. Here, we will apply this workflow to two examples that highlight different benefits of an integrated analysis workflow: (1) urine proteomics samples from patients with distinct kidney transplantation morbidities and (2) sudden infant death syndrome. By the end of this chapter, the reader should be able to apply a similar workflow to their own datasets to identify biologically significant protein markers and relevant networks.

Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant mortality in developed countries, characterized by the death of infants for no obvious reason and without prior warning. The complex interaction of multiple factors in the pathogenesis of SIDS is illustrated by the 'triple risk hypothesis', which proposed that SIDS results from a convergence of three overlapping risk factors: a critical developmental period, an exogenous stressor, and underlying genetic and/or nongenetic vulnerability in the infant. Rare variants in genes associated with inherited arrhythmia syndromes and cardiomyopathies have been proposed as the substrate for an infant's critical vulnerability in a small subset of SIDS cases. Given the potential risk of inherited cardiac disease, current guidelines recommend post-mortem genetic testing (molecular autopsy) and cardiological investigation of the surviving family, complemented by targeted genetic testing if appropriate. In this Review, we highlight the latest developments in understanding the spectrum and prevalence of cardiac-mediated SIDS, and discuss the clinical implications of SIDS in the surviving family and the general population.

Context: Sudden infant death syndrome (SIDS) is a leading cause of postneonatal infant mortality. Our previous meta-analyses showed that any breastfeeding is protective against SIDS with exclusive breastfeeding conferring a stronger effect.The duration of breastfeeding required to confer a protective effect is unknown., Objective: To assess the associations between breastfeeding duration and SIDS., Data Sources: Individual-level data from 8 case-control studies., Study Selection: Case-control SIDS studies with breastfeeding data., Data Extraction: Breastfeeding variables, demographic factors, and other potential confounders were identified. Individual-study and pooled analyses were performed., Results: A total of 2267 SIDS cases and 6837 control infants were included. In multivariable pooled analysis, breastfeeding for <2 months was not protective (adjusted odds ratio [aOR]: 0.91, 95% confidence interval [CI]: 0.68-1.22). Any breastfeeding ≥2 months was protective, with greater protection seen with increased duration (2-4 months: aOR: 0.60, 95% CI: 0.44-0.82; 4-6 months: aOR: 0.40, 95% CI: 0.26-0.63; and >6 months: aOR: 0.36, 95% CI: 0.22-0.61). Although exclusive breastfeeding for <2 months was not protective (aOR: 0.82, 95% CI: 0.59-1.14), longer periods were protective (2-4 months: aOR: 0.61, 95% CI: 0.42-0.87; 4-6 months: aOR: 0.46, 95% CI: 0.29-0.74)., Limitations: The variables collected in each study varied slightly, limiting our ability to include all studies in the analysis and control for all confounders., Conclusions: Breastfeeding duration of at least 2 months was associated with half the risk of SIDS. Breastfeeding does not need to be exclusive to confer this protection., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2017 by the American Academy of Pediatrics.)

Background: Virtual autopsies by computer tomography (CT) or magnetic resonance imaging can be valuable in cases of unexplained infant death. The radiologist must be familiar with the normal appearance of all the segments of the thoracic aorta in normal and deceased children. A thorough review of the literature revealed no prior articles describing CT changes in the ascending aorta or the aortic arch in pediatric virtual autopsies., Objectives: To compare the CT appearance of the thoracic aorta in deceased children and in those younger than 3 years of age., Methods: Hospital registries were searched for cases of unexpected deaths in children younger than 3 years old, with a postmortem CT available, as well as for clinically indicated chest CT in children of the same age during a 5 year period. The ascending aorta (AA), aortic arch (arch), and the descending aorta (DA) diameters were measured. Student's t-tests and Mann-Whitney U-tests were used to compare the two groups., Results: A total of 64 scans were reviewed: 35 postmortem and 29 performed on living patients. The differences in the diameter and the ratios of the diameter between the AA and the arch, as well as between the arch and the DA in the postmortem and living groups were statistically significant (P < 0.05)., Conclusions: On postmortem CT scans, we found focal tapering of the aortic caliber at the level of the arch between the origin of the brachiocephalic artery and left subclavian artery. This finding should not be misinterpreted as a hypoplastic aortic arch.

This review article describes the role of the medicolegal death investigator and medical examiner or coroner (MEC) in the investigations of a sudden unexpected infant death (SUID) beginning with an introduction into the case types that should be investigated and how infant deaths fit into that legal framework. The article also provides an overview of the history of the Centers for Disease Control and Prevention SUID investigation guidelines and process. The article concludes with a description of how the MEC correlates the scene investigation with autopsy findings, as well as the role of the MEC in cause of death determinations. There is also a brief discussion on how infant mortality data are captured and subsequently used to decrease infant mortality. [Pediatr Ann. 2017;46(8):e297-e302.]., (Copyright 2017, SLACK Incorporated.)

Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

Currently little is known about the underlying pathophysiology associated with SIDS, and no objective biomarkers exist for the accurate identification of those at greatest risk of dying from SIDS. Using targeted metabolomics, we aim to profile the medulla oblongata of infants who have died from SIDS (n = 16) and directly compare their biochemical profile with age matched controls. Combining data acquired using 1 H NMR and targeted DI-LC-MS/MS, we have identified fatty acid oxidation as a pivotal biochemical pathway perturbed in the brains of those infants who have from SIDS (p = 0.0016). Further we have identified a potential central biomarker with an AUC (95% CI) = 0.933 (0.845-1.000) having high sensitivity (0.933) and specificity (0.875) values for discriminating between control and SIDS brains. This is the first reported study to use targeted metabolomics for the study of PM brain from infants who have died from SIDS. We have identified pathways associated with the disease and central biomarkers for early screening/diagnosis.

Objectives: To quantify and describe variation in cause-of-death certification of sudden unexpected infant deaths (SUIDs) among US medical examiners and coroners., Methods: From January to November 2014, we conducted a nationally representative survey of US medical examiners and coroners who certify infant deaths. Two-stage unequal probability sampling with replacement was used. Medical examiners and coroners were asked to classify SUIDs based on hypothetical scenarios and to describe the evidence considered and investigative procedures used for cause-of-death determination. Frequencies and weighted percentages were calculated., Results: Of the 801 surveys mailed, 60% were returned, and 377 were deemed eligible and complete. Medical examiners and coroners classification of infant deaths varied by scenario. For 3 scenarios portraying potential airway obstruction and negative autopsy findings, 61% to 69% classified the death as suffocation/asphyxia. In the last scenario, which portrayed a healthy infant in a safe sleep environment with negative autopsy findings, medical examiners and coroners classified the death as sudden infant death syndrome (38%) and SUID (30%). Reliance on investigative procedures to determine cause varied, but 94% indicated using death scene investigations, 88% full autopsy, 85% toxicology analyses, and 82% medical history review., Conclusions: US medical examiners and coroners apply variable practices to classify and investigate SUID, and thus, they certify the same deaths differently. This variability influences surveillance and research, impacts true understanding of infant mortality causes, and inhibits our ability to accurately monitor and ultimately prevent future deaths. Findings may inform future strategies for promoting standardized practices for SUID classification., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2017 by the American Academy of Pediatrics.)

Sudden infant death syndrome (SIDS) is described as the sudden and unexplained death of an apparently healthy infant younger than one year of age. Genetic studies indicate that up to 35% of SIDS cases might be explained by familial or genetic diseases such as cardiomyopathies, ion channelopathies or metabolic disorders that remained undetected during conventional forensic autopsy procedures. Post-mortem genetic testing by using massive parallel sequencing (MPS) approaches represents an efficient and rapid tool to further investigate unexplained death cases and might help to elucidate pathogenic genetic variants and mechanisms in cases without a conclusive cause of death. In this study, we performed whole-exome sequencing (WES) in 161 European SIDS infants with focus on 192 genes associated with cardiovascular and metabolic diseases. Potentially causative variants were detected in 20% of the SIDS cases. The majority of infants had variants with likely functional effects in genes associated with channelopathies (9%), followed by cardiomyopathies (7%) and metabolic diseases (1%). Although lethal arrhythmia represents the most plausible and likely cause of death, the majority of SIDS cases still remains elusive and might be explained by a multifactorial etiology, triggered by a combination of different genetic and environmental risk factors. As WES is not substantially more expensive than a targeted sequencing approach, it represents an unbiased screening of the exome, which could help to investigate different pathogenic mechanisms within the genetically heterogeneous SIDS cohort. Additionally, re-analysis of the datasets provides the basis to identify new candidate genes in sudden infant death.