Dysregulation of platelet serotonin, 14-3-3, and GPIX in sudden infant death syndrome.

Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant mortality, but the underlying cause(s) are unclear. A subset of SIDS infants has abnormalities in the neurotransmitter, serotonin (5-hydroxytryptamine [5-HT]) and the adaptor molecule, 14-3-3 pathways in regions of the brain involved in gasping, response to hypoxia, and arousal. To evaluate our hypothesis that SIDS is, at least in part, a multi-organ dysregulation of 5-HT, we examined whether blood platelets, which have 5-HT and 14-3-3 signaling pathways similar to brain neurons, are abnormal in SIDS. We also studied platelet surface glycoprotein IX (GPIX), a cell adhesion receptor which is physically linked to 14-3-3. In infants dying of SIDS compared to infants dying of known causes, we found significantly higher intra-platelet 5-HT and 14-3-3 and lower platelet surface GPIX. Serum and plasma 5-HT were also elevated in SIDS compared to controls. The presence in SIDS of both platelet and brainstem 5-HT and 14-3-3 abnormalities suggests a global dysregulation of these pathways and the potential for platelets to be used as a model system to study 5-HT and 14-3-3 interactions in SIDS. Platelet and serum biomarkers may aid in the forensic determination of SIDS and have the potential to be predictive of SIDS risk in living infants.

Sudden Unexpected Postnatal Collapse: Review and Management.

Sudden unexpected postnatal collapse (SUPC) of healthy newborns is a catastrophic event caused by cardiorespiratory collapse in a healthy newborn. The most common cause of SUPC is poor positioning of the newborn during skin-to-skin contact or breastfeeding when the newborn is not being observed by a health professional, attentive parent, or caretaker. Maternal/newborn health care professionals need to know about the essential information, definitions, incidence, risk factors, clinical presentation, outcomes, and prevention and management strategies to minimize the occurrence and impact of SUPC. A sample SUPC hospital policy is included in the manuscript.

Sudden Infant Death Syndrome (SIDS): State of the Art and Future Directions.

Sudden infant death syndrome (SIDS) is a type of death that occurs suddenly and without any apparent explanation, affecting infants between 28 days of life and up to a year. Recognition of this entity includes performing an autopsy to determine if there is another explanation for the event and performing both an external and internal examination of the different tissues to search for possible histopathological findings. Despite the relative success of awareness campaigns and the implementation of prevention measures, SIDS still represents one of the leading causes of death among infants worldwide. In addition, although the development of different techniques has made it possible to make significant progress in the characterization of the etiopathogenic mechanisms underlying SIDS, there are still many unknowns to be resolved in this regard and the integrative consideration of this syndrome represents an enormous challenge to face both from a point of view scientific and medical view as humanitarian. For all these reasons, this paper aims to summarize the most relevant current knowledge of SIDS, exploring from the base the characterization and recognition of this condition, its forensic findings, its risk factors, and the main prevention measures to be implemented. Likewise, an attempt will be made to analyze the causes and pathological mechanisms associated with SIDS, as well as potential approaches and future paths that must be followed to reduce the impact of this condition.

Prenatal and postnatal factors associated with sudden infant death syndrome: an umbrella review of meta-analyses.

BACKGROUND: Comprehensive quantitative evidence on the risk and protective factors for sudden infant death syndrome (SIDS) effects is lacking. We investigated the risk and protective factors related to SIDS. METHODS: We conducted an umbrella review of meta-analyses of observational and interventional studies assessing SIDS-related factors. PubMed/MEDLINE, Embase, EBSCO, and Google Scholar were searched from inception until January 18, 2023. Data extraction, quality assessment, and certainty of evidence were assessed by using A Measurement Tool Assessment Systematic Reviews 2 following PRISMA guidelines. According to observational evidence, credibility was graded and classified by class and quality of evidence (CE; convincing, highly suggestive, suggestive, weak, or not significant). Our study protocol was registered with PROSPERO (CRD42023458696). The risk and protective factors related to SIDS are presented as equivalent odds ratios (eORs). RESULTS: We identified eight original meta-analyses, including 152 original articles, covering 12 unique risk and protective factors for SIDS across 21 countries/regions and five continents. Several risk factors, including prenatal drug exposure [eOR = 7.84 (95% CI = 4.81-12.79), CE = highly suggestive], prenatal opioid exposure [9.55 (95% CI = 4.87-18.72), CE = suggestive], prenatal methadone exposure [9.52 (95% CI = 3.34-27.10), CE = weak], prenatal cocaine exposure [4.38 (95% CI = 1.95-9.86), CE = weak], prenatal maternal smoking [2.25 (95% CI = 1.95-2.60), CE = highly suggestive], postnatal maternal smoking [1.97 (95% CI = 1.75-2.22), CE = weak], bed sharing [2.89 (95% CI = 1.81-4.60), CE = weak], and infants found with heads covered by bedclothes after last sleep [11.01 (95% CI = 5.40-22.45), CE = suggestive], were identified. On the other hand, three protective factors, namely, breastfeeding [0.57 (95% CI = 0.39-0.83), CE = non-significant], supine sleeping position [0.48 (95% CI = 0.37-0.63), CE = suggestive], and pacifier use [0.44 (95% CI = 0.30-0.65), CE = weak], were also identified. CONCLUSIONS: Based on the evidence, we propose several risk and protective factors for SIDS. This study suggests the need for further studies on SIDS-related factors supported by weak credibility, no association, or a lack of adequate research.

Correlation of gestational age and age at death in sudden infant death syndrome: another pointer to the role of critical developmental period?

BACKGROUND: Filiano and Kinney proposed a triple-risk model for the sudden infant death syndrome (SIDS) that involves the intersection of three risks: (1) a vulnerable infant, (2) a critical developmental period in homeostatic control, and (3) an exogenous stressor(s). The primary evidence for the role of a critical developmental period in SIDS etiology is the peak of cases around the third month of life. Independently, several studies pointed to correlation between gestational age and age at death in SIDS, but used that to assess the SIDS risk for preterm infants, ignoring further ramifications. METHODS: We did a detailed analysis of CDC data spanning over two decades (1983-2011). We focused not only on the correlation between two age variables (gestational and age at death), but also on the possibility of misdiagnosis. Also, we attempted to account for potential biases in the data induced by the ICD-9/ICD-190 transition or the "Back to Sleep" campaign. RESULTS: The peak of deaths in the third month of life, that was the main argument for the role of the critical development period, wasn't unique to SIDS. However, we confirmed an almost linear and negative correlation between gestational age and the week of death due to SIDS. This pattern (slope of correlation < 0 and significance of correlation p < 0.05) is characteristic of SIDS among all diseases analyzed in the study. CONCLUSIONS: We interpret the results as the evidence of the role of the critical development period in SIDS etiology. Possibly more attention in the future research should be put to theories that are based on homeostatic control.

Sudden Infant Death Associated with Rhinovirus Infection.

A less than one-month-old infant with symptoms of rhinitis died unexpectedly in his sleep. He was not born prematurely and had no known underlying disease. Cerebrospinal fluid, nasopharyngeal and lung samples, and rectal swab were found to be positive for subgroup A rhinovirus, while the blood was negative. This case highlights the important finding that the rhinovirus, a common pathogen associated with upper respiratory tract infections, can sometimes, as the only pathogen, lead to complications such as a cerebrospinal infection and be involved in the sudden infant death syndrome (SIDS). Vigilance is necessary in case of viral infections in the infant's environment, and measures of hygiene and protection must be encouraged in order to reduce the risk of the SIDS.

Identifying infants at risk of sudden unexpected death with an automated predictive risk model.

BACKGROUND/OBJECTIVE: Sudden unexpected infant death (SUID) is a common cause of infant death. We evaluated whether a predictive risk model (PRM) - Hello Baby - which was developed to stratify children by risk of entry into foster care could also identify infants at highest risk of SUID and non-fatal unsafe sleep events. PARTICIPANTS AND SETTING: Cases: Infants with SUID or an unsafe sleep event over 5½ years in a single county. CONTROLS: All births in the same county. METHODS: Retrospective case-control study. Demographic and clinical data were collected and a Hello Baby PRM score was assigned. Descriptive statistics and the predictive value of a PRM score of 20 were calculated. RESULTS: Infants with SUID (n = 62) or an unsafe sleep event (n = 37) (cases) were compared with 23,366 births (controls). Cases and controls were similar for all demographic and clinical data except that infants with unsafe sleep events were older. Median PRM score for cases was higher than controls (17.5 vs. 10, p < 0.001); 50 % of cases had a PRM score 17-20 vs. 16 % of controls (p < 0.001). CONCLUSIONS: The Hello Baby PRM can identify newborns at high risk of SUID and non-fatal unsafe sleep events. The ability to identify high-risk newborns prior to a negative outcome allows for individualized evaluation of high-risk families for modifiable risk factors which are potentially amenable to intervention. This approach is limited by the fact that not all counties can calculate a PRM or similar score automatically.

Risk factors for unexpected infant death among very premature infants in France.

BACKGROUND: Prematurity is one of the risk factors for sudden unexpected infant death (SUID), a phenomenon that remains poorly explained. MATERIALS AND METHODS: The analysis of specific factors associated with SUID among very premature infants (VPI) was performed through a retrospective review of data collected in the French SUID registry from May 2015 to December 2018. The factors associated with SUID among VPI were compared with those observed among full-term infants (FTI). Results are expressed as means (standard deviation [SD]) or medians (interquartile range [IQR)]. RESULTS: During the study period, 719 cases of SUID were included in the registry, 36 (incidence: 0.60 ‰) of which involved VPI (gestational age: 29.2 [2] weeks, 1157 [364]) g] and 313 (0.18 ‰) involved FTI (gestational age: 40 [0.8] weeks, 3298 [452] g). The infants' postnatal age at the time of death was similar in the two groups: 15.5 (12.2-21.8) vs. 14.5 (7.1-23.4) weeks. We observed low breastfeeding rates and a high proportion of fathers with no occupation or unemployment status among the VPI compared to the FTI group (31% vs. 55 %, p = 0.01 and 32% vs. 13 %, p = 0.05, respectively). Among the VPI, only 52 % were in supine position, and 29 % were lying prone at the time of the SUID (compared to 63 % and 17 %, respectively, in the FTI group). CONCLUSION: This study confirms prematurity as a risk factor for SUID with no difference in the SUID-specific risk factors studied except for breastfeeding and socioeconomic status of the fathers. VPI and FTI died at similar chronological ages with a high proportion of infants dying in prone position. These results argue for reinforcement of prevention strategies in cases of prematurity.

Sudden death with cardiac involvement in a neonate with carnitine-acylcarnitine translocase deficiency.

A female neonate born with normal Apgar scores at 38+2 weeks of gestational age unexpectedly passed away within less than 30 hours after birth. The situation mirrored her brother's earlier demise within 24 hours post-delivery, suggesting a possible genetic disorder. Gross examination revealed widespread cyanosis and distinct yellowish changes on the cardiac ventricles. Histopathological examination disclosed lipid accumulation in the liver, heart, and kidneys. Tandem mass spectrometry detected elevated levels of 10 amino acids and 14 carnitines in cardiac blood. Trio-whole genome sequencing (Trio-WGS) identified the SLC25A20 c.199-10T>G mutation associated with carnitine-acylcarnitine translocase disease (CACTD), a type of fatty acid oxidation disorders (FAODs) with a potential for sudden death. Further validation of gene expression confirmed the functional deficiency of SLC25A20, ultimately diagnosing CACTD as the underlying cause of the neonate's demise. This case highlights the importance of prenatal metabolic and genetic screening for prospective parents and emphasizes the need for forensic doctors to integrate metabolomic and genomic investigations into autopsies for suspected inherited metabolic diseases.

Infant death from accidental suffocation and strangulation in bed in England and Wales: rare or unrecognised events?

BACKGROUND: Mandatory joint police and healthcare investigations of sudden unexpected death in infancy (SUDI) have been in place since 2008 in England. These include death scene examination with cause of death determined at multiprofessional case conference. Detailed evidence on sleep arrangements is available for most cases potentially leading to more being identified as due to accidental suffocation. SUDI remaining unexplained following investigation are classified as SIDS (sudden infant death syndrome) or unspecified deaths.Our objective was to determine whether detailed SUDI investigation has led to an increase in deaths classified as accidental suffocation or strangulation in bed (ASSB)? METHODS: We obtained official mortality data for England and Wales for infants dying aged 0-364 days for International Statistical Classification of Diseases and Related Health Problems, 10th revision codes R95 (SIDS), R96, R98, R99 (unspecified causes of mortality) and W75 (ASSB) for the years 2000-2019.We calculated the mortality rate for ASSB, SIDS and unspecified causes based on total live births each year. RESULTS: Unexplained SUDI decreased from 353 in 2000 to 175 in 2019, with the mortality rate falling from 0.58 to 0.29 per 1000 live births. The total postneonatal mortality rate fell during this time from 1.9 to 0.9 per 1000 live births suggesting this is a genuine fall. SIDS accounted for 70% of unexplained SUDI in 2000 falling to 49% in 2020 with a corresponding increase in R99 unspecified deaths.Few deaths were recorded as ASSB (W75), ranging between 4 in 2010 and 24 in 2001. The rate for ASSB ranged from 0.6 to 4.0 per 100000 live births. CONCLUSIONS: There is a shift away from SIDS (R95) towards unspecified causes of death (R96, R98, R99). Improved investigation of deaths has not led to increased numbers of death identified as due to ASSB. There needs to be clear guidelines on accurate classification of deaths from ASSB to facilitate learning from deaths and inform prevention efforts.

Diagnostic challenges and forensic implications in a case of infantile fatal myocarditis.

We present the case of a 23-month-old child who died less than 24 h after the onset of cardiac symptoms, despite being admitted to the hospital 72 h earlier. Autopsy revealed no significant macroscopic changes, and histologic examination revealed focal lymphocytic myocarditis with myocyte disruption, diffuse alveolar damage in the exudative phase, and generalized lymphocytic immune activation in other organs. Ante-mortem and post-mortem microbiological exams did not clearly prove a causative role of infectious agents. The peculiarity of this case was characterized by the contrast between the severe clinical features and the mild cardiac histological findings. This discrepancy, coupled with the suspicion of a viral causative role based on both ante-mortem and post-mortem microbiological examinations, presented significant challenges in reaching an etiological diagnosis. This case also confirms that the diagnosis of myocarditis in children cannot be made solely on the basis of histological cut-offs or microbiological results. Using abductive reasoning, various diagnostic hypotheses were formulated and evaluated to arrive at the final diagnosis of fatal myocarditis of viral or post-viral origin. Data from post-mortem examination are often the only source of information that is available to the experts, especially in cases of sudden infant death syndrome. In such cases, the forensic pathologists should accurately evaluate findings that may appear to indicate a different etiology, and, in the absence of clinical or radiological data, interpret post-mortem data in a logically correct manner. The autopsy is the first essential step to evaluate the cause of death and must be integrated with the results of ante- and post-mortem diagnostic tests in a holistic approach, which is crucial to allow forensic pathologists to provide an appropriate and relevant opinion.

Understanding the immune profile of sudden infant death syndrome - proteomic perspectives.

AIM: The aim of this study was to investigate a panel of immune proteins in cases of sudden infant death syndrome (SIDS). It was hypothesised that, in at least a subset of SIDS, a dysregulated immune response may be a contributing factor leading to death. METHODS: The subjects included 46 SIDS cases and 41 controls autopsied at the Department of Forensic Sciences, Norway. The causes of death in the controls were accidents/trauma. Samples of cerebrospinal fluid (CSF) were analysed quantitatively by Proximity Extension Assay (PEA). RESULTS: Initial results revealed that normalised protein expression differed in 35 proteins. For the purposes of this report five proteins that are involved in immune system were selected for analysis: IFNLR1 (p = 0.003), IL10 (p = 0.007), IRAK4 (p < 0.001) and IL6 (p = 0.035); all had lower protein concentrations in SIDS cases compared to controls except for CD28 (p = 0.024) which had higher protein concentrations in SIDS cases. CONCLUSION: The results confirm previous studies indicating that a dysregulation of the immune system may be a predisposing factor for SIDS. The results may indicate that these aberrant protein concentrations could lead to an inadequate response to immune triggers and uncontrolled defence mechanisms towards the common cold or other non-fatal infections.

A Systematic Approach to Evaluate Sudden Unexplained Death in Children.

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.

Actualización de las recomendaciones sobre sueño seguro / Update on safe sleep recommendatios

La muerte súbita de un lactante puede ser de causa explicada, indeterminada ­si no se investigó en forma suficiente­ o inexplicada ­cuando una investigación completa no permite determinar su causa­. La muerte súbita inexplicada, o síndrome de muerte súbita infantil, afecta en particular a las poblaciones más vulnerables. La muerte de estos niños que nacen con alteraciones del neurodesarrollo es la parte visible de una problemática que se origina en el embarazo. Disminuir la cantidad de niños vulnerables depende de políticas de salud y, sobre todo, de lograr mejorar las condiciones de vida de la población. Son acciones a largo plazo. Conocer a fondo los factores de riesgo que pueden desencadenar la muerte inesperada es lo que se puede hacer ya. La actualización de las recomendaciones sobre sueño seguro refleja nuevos conocimientos basados en la evidencia científica y un enfoque integral de los aspectos socioculturales relacionados con esta problemática.

Sudden unexpected infant death may be explained, cause by an etiology, unexplained but insufficiently investigated, or unexplained when a full investigation fails to determine the cause. Unexplained sudden death in infancy or sudden infant death syndrome particularly affects the most vulnerable populations. The death of these children who are born with alterations in their neurodevelopment is the visible part of a problem that originates in pregnancy. Reducing the number of vulnerable children depends on health policies and, above all, on improving the living conditions of the population. These are long-term actions. Knowing in depth the risk factors that can trigger unexpected death is what can be done now. The update of the recommendations on safe sleep reflects new knowledge based on scientific evidence and a comprehensive approach to the sociocultural aspects related to this problem.

Changes in background characteristics and risk factors among SIDS infants in England: cohort comparisons from 1993 to 2020.

OBJECTIVES: Using the National Child Mortality Database, this work aims to investigate background characteristics and risk factors in the sleeping environment associated with sudden infant death syndrome (SIDS) and compare the prevalence with previous English SIDS case-control studies. DESIGN: Cohort of SIDS in 2020 compared with a combined analysis of two case-control studies conducted in 1993-1996 and 2003-2006. SETTING: England, UK PARTICIPANTS: 138 SIDS deaths in 2020 compared with 402 SIDS deaths and 1387 age-equivalent surviving controls, combined from previous studies. RESULTS: The increased vulnerability of SIDS infants identified in previous studies has become more marked. The infants who died in 2020 were younger (median=66 days (IQR: 34-118) vs 86 days (IQR: 52-148), p=0.003) with an increased prevalence of low birth weight (30.5% vs 21.6%, p=0.04) and preterm births (29.6% vs 19.3%, p=0.012). The excess of socioeconomically deprived families, male infants and high levels of maternal smoking during pregnancy were still evident. Among recent deaths, fewer infants were put down or found on their side; however, there was no significant change in the proportion of infants who were put down (15.6% vs 14.6%, p=0.81) and found prone (40.4% vs 35.3%, p=0.37), despite population wide risk reduction advice over three decades. The proportional increase observed in 2003-2006 of half the deaths occurring while sleeping next to an adult was maintained in 2020, and for the vast majority (90%), this was in hazardous circumstances (adult had consumed alcohol, smoked, slept on a sofa, or the infant was premature or low birth weight and less than 3 months old). More deaths also occurred when there was a disruption in infant care routine compared with previous observations (52.6% vs 20.7%, p<0.001). CONCLUSIONS: A more targeted approach is needed with vulnerable families emphasising the importance of sleeping infants on their back and proactive planning infant sleep when there are disruptions to the normal routine, in particular to avoid hazardous co-sleeping.

[Update on safe sleep recommendatios]. / Actualización de las recomendaciones sobre sueño seguro.

Sudden unexpected infant death may be explained, cause by an etiology, unexplained but insufficiently investigated, or unexplained when a full investigation fails to determine the cause. Unexplained sudden death in infancy or sudden infant death syndrome particularly affects the most vulnerable populations. The death of these children who are born with alterations in their neurodevelopment is the visible part of a problem that originates in pregnancy. Reducing the number of vulnerable children depends on health policies and, above all, on improving the living conditions of the population. These are long-term actions. Knowing in depth the risk factors that can trigger unexpected death is what can be done now. The update of the recommendations on safe sleep reflects new knowledge based on scientific evidence and a comprehensive approach to the sociocultural aspects related to this problem.

La muerte súbita de un lactante puede ser de causa explicada, indeterminada ­si no se investigó en forma suficiente­ o inexplicada ­cuando una investigación completa no permite determinar su causa­. La muerte súbita inexplicada, o síndrome de muerte súbita infantil, afecta en particular a las poblaciones más vulnerables. La muerte de estos niños que nacen con alteraciones del neurodesarrollo es la parte visible de una problemática que se origina en el embarazo. Disminuir la cantidad de niños vulnerables depende de políticas de salud y, sobre todo, de lograr mejorar las condiciones de vida de la población. Son acciones a largo plazo. Conocer a fondo los factores de riesgo que pueden desencadenar la muerte inesperada es lo que se puede hacer ya. La actualización de las recomendaciones sobre sueño seguro refleja nuevos conocimientos basados en la evidencia científica y un enfoque integral de los aspectos socioculturales relacionados con esta problemática.