An audit of the use of definitions of sudden infant death syndrome (SIDS)

Given that there are a number of contradictions in the SIDS literature and that the definition of SIDS that was relied upon to authenticate cases in reports is not always specified, an audit of publications was undertaken. Fifty papers dealing with SIDS that were published in 2005 were reviewed. The majority (58%) of reports had either not specified a definition of SIDS, or had used non-standard or idiosyncratic definitions. Of the papers that had documented a definition: 30% used the 1989 NICHD definition, 10% used the 2004 San Diego definition, and 2% used the 1969 Seattle definition. Failure to use standard published definitions of SIDS and/or to clearly specify the definition that has been followed may severely hamper the evaluation of SIDS research.     

Hemoglobin F in sudden infant death syndrome: a San Diego SIDS/SUDC Research Project report

Whether levels of fetal hemoglobin (HbF), a possible marker of antecedent hypoxemia, are increased in sudden infant death syndrome (SIDS) compared to controls is unresolved. Our aims are to: (1) Compare percent fetal hemoglobin (%HbF) levels in SIDS and control cases, and (2) compare our findings with those reported in previous studies. Using Triton-acid-urea gel electrophoresis and quantitative densitometry, %HbF was determined in whole blood specimens obtained at autopsy from SIDS and control cases accessioned into the San Diego SIDS/SUDC Research Project database. The SIDS and control cases were not different with respect to mean age, gender, gestational age, method of delivery, birth weight, or mean autopsy interval; %HbF levels in SIDS and control cases were not significantly different. Given that our results were obtained using optimal methods in well-defined SIDS and control cases, we concur with others that %HbF is not elevated in SIDS.     

The pathology of the adrenal glands in Sudden Infant Death Syndrome (SIDS)

Summary The sudden infant death syndrome (SIDS) is at present based on unknown pathogenetical mechanisms but in industrial nations is the most common cause of death in infancy after the perinatal period. Studies of a large number of adrenal glands in this syndrome have not been reported. Therefore, we evaluated 146 SIDS cases (85 males, 61 females, aged 14–465 days) and 24 control cases (17 males, 7 females, aged 18–623 days) by light microscopy, morphometry and immunocytochemistry (anti-chromogranin A and anti-S 100 protein). Our data revealed a normal maturation of the adrenal glands in SIDS cases. Necroses, extensive hemorrhages or inflammation were not found. A focal lipid depletion of the zona fasciculata was seen in 92% of the adrenal glands of the SIDS and control cases. We found a siderosis (in 33% of the SIDS cases and 4% of the control cases) and calcium deposits (13% and 12% respectively) due to hyperemic involution of the fetal zone. The medulla, including the sustentacular cells (S 100 protein-positive cells) and chromaffin cells (chromogranin A-positive cells) was unchanged. Our results indicate that the few morphological alterations of the adrenal glands in SIDS cases are the effect of the underlying disease and not the cause of the sudden death.Dedicated to Prof. Dr. J. Kracht on the occasion of his 70th birthday     

Unnatural causes of sudden unexpected deaths initially thought to be sudden infant death syndrome

The aim of this clinicopathological study was to determine the frequency of infant deaths due to unnatural causes among cases of sudden and unexpected infant death. Nine institutes of legal medicine in Germany that took part in the German study on Sudden Infant Death Syndrome (GeSID), representing 35% of the German territory, investigated in a 3-year period (from 1998 to 2001) 339 cases of infant death that were not expected to be due to unnatural causes from the first external examination. All cases were investigated by complete, standardised, post-mortem examination including death scene investigation, autopsy, histology, toxicology and neuropathology. The frequency of unnatural deaths was 5.0% (n=17). The causes of death were head injury (n=7), suffocation (n=5), poisoning (n=2), neglect (n=2) and septicaemia due to aspiration of a foreign body (n=1). Two deaths were unsuspected accidents and 12 were due to infanticide. In 3 cases, it was not possible to differentiate between accidental death and infanticide. A complete postmortem examination including an analysis of the clinical history, death scene investigation, autopsy, histology, toxicology, and neuropathology is mandatory to differentiate sudden and unexpected deaths due to natural causes (e.g. SIDS) and cases of unnatural death.Contributors at Institutes of Legal Medicine: U. Deml, Friedrich-Alexander-University, Erlangen; A. Freislederer, University Duisburg-Essen, Essen; S. Heide, Martin-Luther-University, Halle; H.-J. Kaatsch, S. Ritz-Timme, Christian-Albrechts-University, Kiel; K.-P. Larsch, A. Fiegut, Medizinische Hochschule Hannover, Hannover; H.W. Leukel, Johann-Wolfgang-Goethe-University, Frankfurt am Main; C. Ortmann, Friedrich-Schiller-University, Jena; R. Penning, Ludwig-Maximilians-University, Munich.     

Morphology, immunohistochemistry and morphometry of pancreatic islets in cases of sudden infant death syndrome (SIDS)

The pancreatic islets from 112 infants (66 males and 46 females) who died of SIDS during the years 1990– 1992 have been studied. The control group consisted of endocrine pancreas tissue from 19 infants who died of a clear cause of death (pneumonia, drowning, sepsis, etc.). The mean age of the SIDS group was 5.1 months. We found histologically normally developed organs in all the SIDS cases. By evaluating the relative endocrine cell area of the pancreas by immunohistochemical investigations, A-cells were found to make up 10–30%, B-cells 30–60%, D-cells 10–30% and pancreatic polypeptide cells less than 10% in the SIDS group and in the controls with a small increase in glucagon and insulin cells among SIDS cases. The morphometric evaluation revealed that cell enlargement and cytoplasm shrinking occurred slightly more often in the SIDS group than in the control group. The diameter of the islets was normal and the maximal volume was not enlarged. The results did not show significant differences so that a relationship between alterations of the endocrine pancreas and sudden infant death syndrome could not be demonstrated.     

Nicotine and cotinine in infants dying from sudden infant death syndrome

The aim of this component of the German Study on Sudden Infant Death was to determine (1) nicotine concentrations in hair (NCH), as a marker of long standing exposure to tobacco, (2) cotinine concentrations in pericardial fluid (CCP) and (3) cotinine concentrations in liquor cerebrospinalis (CCL), the latter measures being markers of recent exposure to tobacco in the last few hours of life. The results obtained were compared with data on parental smoking revealed from interviews. In 100 cases of sudden infant death syndrome, material was taken at autopsy to determine NCH. In 41 cases, NCH and CCP, and in 70 cases, NCH and CCL were determined. Infants of mothers who stated having smoked during pregnancy had higher NCH than infants of non-smoking mothers (p = 0.008). Furthermore, there was a weak but statistically significant relationship between NCH's and the daily cigarette consumption of the mother during pregnancy (n = 64, r = 0.24, p = 0.05). In 43% of infants, nicotine could be detected in their hair, although the mothers had said at the interview that they did not smoke during pregnancy. On the other hand, in 33% of infants whose mother stated they had smoked during pregnancy nicotine was not detectable in the infant's hair. CCP's were strongly correlated with CCL's (r = 0.62, p = 0.0027). For this reason, both parameters were treated as equivalent for the detection of tobacco smoke exposure in the last hours before death. The influence of breast-feeding was evaluated by comparison of the nicotine concentrations in breast fed and non-breast-fed infants from smokers and non-smokers. Fivefold higher nicotine concentrations were determined in non-breast-fed infants of parents who smoked as compared to all other groups. It can be concluded that nicotine intake by passive smoking is much more important than by breast-feeding. We conclude that both interview data and biochemical measures should be sought to understand the true exposure to tobacco smoke.     

Morphology,immunohistochemistry and morphometry of the thyroid gland in cases of sudden infant death syndrome (SIDS)

The thyroid glands of 107 SIDS victims (sudden infant death syndrome) have been studied. Controls consisted of 20 thyroid glands from infants who died of other causes (accidents, pneumonia etc.). The thyroid glands were investigated histologically, immunohistologically and morphometrically. Immunohistochemistry (S100 protein and calcitonin) and morphometry showed no significant results. Histologically, hyperemia (severe: 34 cases = 31.8%; mild: 23 cases = 21.5%), and fibrosis (45 cases = 42.1%; mild: 26 cases = 24.3%) were found. A large number of cases showed depleted follicles (87 cases 81.3%), little colloid (little: 37 cases = 34.6%; none: 9 cases = 8.4%) and desquamation (severe: 21 cases = 19.6%; abundant: 20 cases = 18.7%). Only fibrosis and depleted follicles were found more often in SIDS than in the controls (conditional logistic regression: rise of incidence for SIDS 2.9 times,P = 0.028, and 1.2 times,P = 0.051, respectively), a commoner occurrence of hyperemia in SIDS was of limited significance (P = 0.105). The alterations found can be taken as stress reactions to current or recurrent hypoxemia and the mild fibrosis indicates recurrent hypoxemia. All alterations indicate that the victims had previously suffered near death episodes. Even though the glands were handled with care, artefacts and autolysis must be taken into consideration. Neither the histological, immunohistological nor morphometrical studies of the thyroid gland gave an explanation as to the cause of death or showed any changes providing explicit help in diagnosing SIDS.     

Basement membrane thickness of the vocal cord in cases of sudden infant death

In 1991, 1994 and 1997 Shatz et al. reported on a specific and pathognomonic basement membrane (BM) thickening of the vocal cord in cases of sudden infant death syndrome (SIDS). In 40 cases of sudden and unexpected infant death the histological examination of the larynx was performed to identify possible differences between SID (n = 26) and non-SID (n = 14) cases. The dissection technique of Hohmann (1963) and Maxeiner (1986) was modified for the infant’s larynx. Since the normal range of the BM thickness of the vocal cord for the age group younger than 1 year had not yet been exactly defined, a reference interval had to be established (0.5 μm–2.0 μm). In 2 SID and 1 non-SID cases a mean BM thickness (BMT) of more than 2.0 μm could be estimated (2.38 μm–2.95 μm). The BMT in these cases appeared to be highly variable and not harmonically thickened. None of the investigated regions of the BM (cranial to caudal thirds, ventral to dorsal areas) seemed to be prefered thickened. There was no statistically significant difference between the two groups. A specific thickening of the BM of the vocal cord in SID cases could not be confirmed. Therefore, BMT cannot be used as a diagnostic postmortem marker for SID. Received: 10 June 1998 / Received in revised form: 21 August 1998     

A re-audit of the use of definitions of sudden infant death syndrome (SIDS) in peer-reviewed literature

The use of different definitions of sudden infant death syndrome (SIDS) may make comparison of data among studies difficult. Fifty randomly selected papers dealing with SIDS that were published between 2010 and 2011 in peer-reviewed journals were reviewed to determine whether one of three internationally accepted definitions of SIDS had been either written in the text or referenced. A significant improvement in the use of definitions has occurred since 2005, with the percentage of papers either quoting or referencing a standard definition increasing by 26%, from 42 to 68%. The 1989 NICHD definition remained the most commonly used definition (35.1%) followed by the 2004 San Diego definition (26.3%). Although the percentage of papers where either no definition was provided or where an idiosyncratic or mis-cited definition was used fell 26%, from 58 to 32%, nearly one in three papers published on SIDS in peer-reviewed journals that were included in this study still did not cite a standard definition.     

A sudden infant death associated with atrial septal aneurysm and abnormality of the connecting site between the inferior vena cava and right atrium

An atrial septal aneurysm (ASA) is a rare cardiac anomaly characterized by varicose bulging of the atrial septum (oval fossa) into the left or right atrium. Pathogenesis and clinical significance of ASA are controversial. We report an autopsy case of a huge undiagnosed ASA with abnormality of the connecting site between the inferior vena cava and the right atrial ostium in a 2-month-old Japanese female who died suddenly and unexpectedly. She was born at 36 weeks 4 days (body weight 3,110 g). No abnormality was detected during pregnancy or delivery. The postnatal growth was normal with no cardiac problem detected at the 1-month checkup. The ASA bulged off in a mass to the left atrium (width, 0.8 cm; excursion ratio, 53%), reaching close to the inflow site of the right pulmonary vein, with dilation of the pulmonary vein. The connecting site between the inferior vena cava and the right atrium was atypically located 1.6 cm away from the atrioventricular groove. Although most cases of ASA in an infant resolve physiologically as the infant grows, the infant in the present case is thought to have had an exceptional pathological ASA, possibly causing supraventricular arrhythmia. The abnormality of the connecting site between the inferior vena cava and the right atrium might have affected the development and continuation of the ASA.     

Sudden infant death syndrome and long QT syndrome: an epidemiological and genetic study

Sudden infant death syndrome (SIDS) is a frequent cause of death among infants. The etiology of SIDS is unknown and several theories, including fatal ventricular arrhythmias, have been suggested. We performed an epidemiological and genetic investigation of SIDS victims to estimate the presence of inherited long QT syndrome (LQTS) as a contributor for SIDS. Forty-one consecutively collected and unrelated SIDS cases were characterized by clinical and epidemiological criteria. We performed a comprehensive gene mutation screening with single-strand conformation polymorphism analysis and sequencing techniques of the most relevant LQTS genes to assess mutation frequencies. In vitro characterization of identified mutants was subsequently performed by heterologous expression experiments in Chinese hamster ovary cells and in Xenopus laevis oocytes. A positive family history for LQTS was suspected by mild prolonged Q-T interval in family members in 2 of the 41 SIDS cases (5%). In neither case, a family history of sudden cardiac death was present nor a mutation could be identified after thorough investigation. In another SIDS case, a heterozygous missense mutation (H105L) was identified in the N-terminal region of the KCNQ1 (LQTS 1) gene. Despite absence of this mutation in the general population and a high conservational degree of the residue H105 during evolution, electrophysiological investigations failed to show a significant difference between wild-type and KCNQ1_H105L/minK-mediated I_Ks currents. Our data suggest that a molecular diagnosis of SIDS related to LQTS genes is rare and that, even when an ion channel mutation is identified, this should be regarded with caution unless a pathophysiological relationship between SIDS and the electrophysiological characterization of the mutated ion channel has been demonstrated.H. Wedekind, T. Bajanowski and P. Friederich contributed equally to this study.     

The story of the internal carotid artery of mammals: from Galen to sudden infant death syndrome

Some anatomical aspects of the blood supply of the brains of mammals have been examined to illuminate their functions. A fundamental explanation of sudden infant death syndrome (cot death) is suggested following experimental¹ observations. Speculative contributions have been made to comparative physiological ideas concerning mammals of pronograde and erect habitus, their vascular pressure adaptations and temperature management. Neuro- and interventional radiologists may make some significant future applications of these ideas. Of immediate practical interest is the possibility of influencing the well-being of human embryos' neural tube development in utero by a comprehensive study of their temperature environment. Received: 3 March 1998 Accepted: 7 March 1998     

A common FMO3 polymorphism may amplify the effect of nicotine exposure in sudden infant death syndrome (SIDS)

Smoking during pregnancy has been identified as one of the major modifiable risk factors of sudden infant death syndrome (SIDS). It has been demonstrated that the risk of SIDS increases with increasing cigarette consumption. A variety of hypotheses have been proposed for explanation, including a genetic predisposition. The flavin-monooxygenase 3 (FMO3) is one of the enzymes metabolising nicotine, and several polymorphisms have already been described in this gene. Here, we studied variations in the exons and introns of the FMO3 gene by direct sequencing analysis and minisequencing in 159 SIDS cases and 170 controls. The three common variants G472A (E158K), G769A (V257M) and A923G (E308G) in the exons of the FMO3 gene were identified. The homozygote 472AA genotype occurred more frequently in SIDS cases than in controls (p = 0.0054) and was more frequent in those SIDS cases for which the mothers reported heavy smoking (p = 0.0084). This study is the first to demonstrate a gene–environment interaction in SIDS. The findings suggest that the common polymorphism G472A of FMO3 could act as an additional genetic SIDS risk factor in children whose mothers smoke. Parents who could pass on the 472A allele should be informed of the increased risk associated with smoking. Smoking mothers should be strongly advised to give up smoking during pregnancy and for at least the first year of the child’s life.     

German study on sudden infant death (GeSID): design,epidemiological and pathological profile

The German study on sudden infant death (GeSID) is a multi-centre case-control study aiming at the assessment of etiological factors and risk factors of SIDS. This report describes the study design and the methods applied and presents some general findings. Between 1998 and 2001, 455 cases of sudden and unexpected death of infants aged between 8 and 365 days were recruited into the study. The study comprised at least 11 out of the 16 German states with 18 centres involved. In 1999 and 2000, 75% of all SIDS cases registered with the Federal Office of Statistics (ICD 10/R95, n=384) in the study area were recruited into the study (n=286). A standardised autopsy including extended histology, microbiology, virology, toxicology and neuropathology investigations was carried out. Of the parents 82% (n=373) agreed to fill in an extensive questionnaire containing 120 questions reflecting all important aspects of the infants development. For each SIDS case, the parents of three living control infants were interviewed. These controls were matched for age, gender and region (n=1,118). The response rate of the controls was 58.7%. Data were linked with medical records obtained from obstetrics departments, the childrens hospitals, and general practitioners. Death scene investigation was performed in 4 study areas (cases: n=64, controls: n=191). All cases were classified into one of 4 categories using defined criteria: 7.3% of the children were assigned to category 1 (no pathological findings: SIDS), 61.1% to category 2 (minor findings: SIDS+), 20.4% to category 3 (severe findings: SIDS+) and 11.2% to category 4 (findings which explained the death: non-SIDS). In case conferences the previous history and circumstantial factors were included and an extended category (E-cat.) was defined. The consideration of these factors for the final classification is of great importance in the causal explanation of some cases. An analysis of 18 main variables in cases of categories 1–3 (SIDS) compared to the cases of category 4 (non-SIDS) showed significant differences for the sleeping position, coughing the day before death and breast-feeding indicating that the cases of both groups should be separated for further analyses.Electronic Supplementary Material Supplementary material is available in the online version of this article at A list of the collaborating authors and institutes is given in the appendix.     

Histiocytoid cardiomyopathy and ventricular non-compaction in a case of sudden death in a female infant

A case of sudden infant death with histiocytoid cardiomyopathy and ventricular non-compaction was investigated with immunohistochemical methods. Histiocytoid cardiomyopathy is thought to be a developmental defect of the cardiomyocytes of the conduction system. In contrast to mature cardiomyocytes, the histiocytoid cells showed only weak reactions to desmin and myosin antibodies. They lacked cross-striation but reacted strongly to enolase and myoglobin antibodies. The protein Pax-7, seen only in cells undergoing differentiation, and the proliferation marker Ki-67 were not expressed in the histiocytoid cells. In areas of altered myocardium, clusters of CD4-, CD8-, and CD68-positive inflammatory cells were seen as well an abundance of mast cells. With the TUNEL method, it was found that many of the histiocytoid cells were undergoing apoptosis. Our results confirm that the histiocytoid cells are defective cardiomyocytes. The apoptotic and inflammatory changes point to a degenerative process rather than defective maturation of cardiomyocytes as has been suggested in some earlier studies. Ventricular non-compaction is a developmental defect of the subendocardial tissue with hypertrabeculation and weak development of the papillary muscles. Only one case combined with histiocytoid cardiomyopathy has been described previously. A causal connection between the two conditions cannot be established until more cases have been analyzed.     

Maternal smoking and increased risk of sudden infant death syndrome: A meta-analysis

Maternal smoking is detrimental to the development of fetuses and neonates. This meta-analysis was performed to measure the accumulated association of sudden infant death syndrome (SIDS) risk with both prenatal and postnatal maternal smoking. The odds ratio (OR) corresponding to the 95% confidence interval (CI) was used to assess the associations between maternal smoking and SIDS risk. The statistical heterogeneity among studies was assessed with the Q-test and I² statistics. The data for this meta-analysis were available from 35 case-control studies. The prenatal and postnatal maternal smoking was associated with a significantly increased risk of SIDS (OR = 2.25, 95% CI = 2.03–2.50 for prenatal maternal smoking analysis, and OR = 1.97, 95% CI = 1.77–2.19 for postnatal maternal smoking analysis, respectively) by random effects model. After stratified analyses, regardless of prenatal or postnatal smoking, heavy cigarette consumption increased the risk of SIDS and significantly elevated SIDS risk was found to be associated with co-sleeping with postnatal smoking mothers. Our results suggested that maternal smoking were associated with elevated SIDS risk, the effects were dose-dependent. In addition, SIDS risk was significantly increased in infants co-sleeping with postnatal smoking mothers.     

Forensic issues and possible mechanisms of sudden death in Rett syndrome

A 20-year-old female with an established diagnosis of Rett syndrome was found dead in bed. There had been no history of recent deterioration in health and at autopsy no acute lesions were found. There was no evidence of trauma. Toxicological analysis of blood revealed therapeutic levels of carbamazepine and clonazepam. Death was attributed to the complications of Rett syndrome, an uncommon developmental disorder characterized by autistic type behaviour, hypotonia, stereotyped movements, seizures and growth failure, caused by mutations in the MECP2 gene on the X chromosome. Establishing the precise cause of sudden death in individuals with Rett syndrome may be difficult as epilepsy, defective autonomic nervous system control and cardiac arrhythmias may relate more to functional problems rather than to defects that can be demonstrated at autopsy. Thus, although there are a variety of well-documented underlying mechanisms that may cause sudden death in this condition, determining the exact sequence of events in an unwitnessed death may be more by inference and elimination, given the absence of pathognomonic and acute lethal lesions that are able to be found histopathologically. 'Complications of Rett syndrome' may, therefore, be the most accurate designation when individuals with this condition are found unexpectedly dead and no anatomical cause of death can be identified at autopsy.