Nicotinic Receptors in the Brainstem Ascending Arousal System in SIDS With Analysis of Pre-natal Exposures to Maternal Smoking and Alcohol in High-Risk Populations of the Safe Passage Study.

Pre-natal exposures to nicotine and alcohol are known risk factors for sudden infant death syndrome (SIDS), the leading cause of post-neonatal infant mortality. Here, we present data on nicotinic receptor binding, as determined by 125I-epibatidine receptor autoradiography, in the brainstems of infants dying of SIDS and of other known causes of death collected from the Safe Passage Study, a prospective, multicenter study with clinical sites in Cape Town, South Africa and 5 United States sites, including 2 American Indian Reservations. We examined 15 pons and medulla regions related to cardiovascular control and arousal in infants dying of SIDS (n = 12) and infants dying from known causes (n = 20, 10 pre-discharge from time of birth, 10 post-discharge). Overall, there was a developmental decrease in 125I-epibatidine binding with increasing postconceptional age in 5 medullary sites [raphe obscurus, gigantocellularis, paragigantocellularis, centralis, and dorsal accessory olive (p = 0.0002-0.03)], three of which are nuclei containing serotonin cells. Comparing SIDS with post-discharge known cause of death (post-KCOD) controls, we found significant decreased binding in SIDS in the nucleus pontis oralis (p = 0.02), a critical component of the cholinergic ascending arousal system of the rostral pons (post-KCOD, 12.1 ± 0.9 fmol/mg and SIDS, 9.1 ± 0.78 fmol/mg). In addition, we found an effect of maternal smoking in SIDS (n = 11) combined with post-KCOD controls (n = 8) on the raphe obscurus (p = 0.01), gigantocellularis (p = 0.02), and the paragigantocellularis (p = 0.002), three medullary sites found in this study to have decreased binding with age and found in previous studies to have abnormal indices of serotonin neurotransmission in SIDS infants. At these sites, 125I-epibatidine binding increased with increasing cigarettes per week. We found no effect of maternal drinking on 125I-epibatidine binding at any site measured. Taken together, these data support changes in nicotinic receptor binding related to development, cause of death, and exposure to maternal cigarette smoking. These data present new evidence in a prospective study supporting the roles of developmental factors, as well as adverse exposure on nicotinic receptors, in serotonergic nuclei of the rostral medulla-a finding that highlights the interwoven and complex relationship between acetylcholine (via nicotinic receptors) and serotonergic neurotransmission in the medulla.

Concurrent prenatal drinking and smoking increases risk for SIDS: Safe Passage Study report.

BACKGROUND: Sudden infant death syndrome (SIDS) is the leading cause of postneonatal mortality. Although the rate has plateaued, any unexpected death of an infant is a family tragedy thus finding causes and contributors to risk remains a major public health concern. The primary objective of this investigation was to determine patterns of drinking and smoking during pregnancy that increase risk of SIDS. METHODS: The Safe Passage Study was a prospective, multi-center, observational study with 10,088 women, 11,892 pregnancies, and 12,029 fetuses, followed to 1-year post delivery. Subjects were from two sites in Cape Town, South Africa and five United States sites, including two American Indian Reservations. Group-based trajectory modeling was utilized to categorize patterns of drinking and smoking exposure during pregnancy. FINDINGS: One-year outcome was ascertained in 94·2% infants, with 28 SIDS (2·43/1000) and 38 known causes of death (3·30/1000). The increase in relative risk for SIDS, adjusted for key demographic and clinical characteristics, was 11·79 (98·3% CI: 2·59-53·7, p < 0·001) in infants whose mothers reported both prenatal drinking and smoking beyond the first trimester, 3.95 (98·3% CI: 0·44-35·83, p = 0·14), for drinking only beyond the first trimester and 4·86 (95% CI: 0·97-24·27, p = 0·02) for smoking only beyond the first trimester as compared to those unexposed or reported quitting early in pregnancy. INTERPRETATION: Infants prenatally exposed to both alcohol and cigarettes continuing beyond the first trimester have a substantially higher risk for SIDS compared to those unexposed, exposed to alcohol or cigarettes alone, or when mother reported quitting early in pregnancy. Given that prenatal drinking and smoking are modifiable risk factors, these results address a major global public health problem. FUNDING: National Institute on Alcohol Abuse and Alcoholism, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute on Deafness and Other Communication Disorders.

The Institution of a Standardized Investigation Protocol for Sudden Infant Death in the Eastern Metropole, Cape Town, South Africa,.

The rate for the sudden infant death syndrome (SIDS) in Cape Town, South Africa, is estimated to be among the highest in the world (3.41/1000 live births). In several of these areas, including those of extreme poverty, only sporadic, nonstandardized infant autopsy, and death scene investigation (DSI) occurred. In this report, we detail a feasibility project comprising 18 autopsied infants with sudden and unexpected death whose causes of death were adjudicated according to the 1991 NICHD definitions (SIDS, n = 7; known cause of death, n = 7; and unclassified, n = 4). We instituted a standardized autopsy and infant DSI through a collaborative effort of local forensic pathology officers and clinical providers. The high standard of forensic investigation met international standards, identified preventable disease, and allowed for incorporation of research. We conclude that an effective infant autopsy and DSI protocol can be established in areas with both high sudden unexpected infant death, and elsewhere. (SUID)/SIDS risk and infrastructure challenges.

Serotonin Receptors in the Medulla Oblongata of the Human Fetus and Infant: The Analytic Approach of the International Safe Passage Study.

The Safe Passage Study is an international, prospective study of approximately 12 000 pregnancies to determine the effects of prenatal alcohol exposure (PAE) upon stillbirth and the sudden infant death syndrome (SIDS). A key objective of the study is to elucidate adverse effects of PAE upon binding to serotonin (5-HT) 1A receptors in brainstem homeostatic networks postulated to be abnormal in unexplained stillbirth and/or SIDS. We undertook a feasibility assessment of 5-HT1A receptor binding using autoradiography in the medulla oblongata (6 nuclei in 27 cases). 5-HT1A binding was compared to a reference dataset from the San Diego medical examiner's system. There was no adverse effect of postmortem interval ≤100 h. The distribution and quantitated values of 5-HT1A binding in Safe Passage Study cases were essentially identical to those in the reference dataset, and virtually identical between stillbirths and live born fetal cases in grossly non-macerated tissues. The pattern of binding was present at mid-gestation with dramatic changes in binding levels in the medullary 5-HT nuclei over the second half of gestation; there was a plateau at lower levels in the neonatal period and into infancy. This study demonstrates feasibility of 5-HT1A binding analysis in the medulla in the Safe Passage Study.

Progressive primary pulmonary tuberculosis presenting as the sudden unexpected death in infancy: a case report.

The classification of an unexpected infant death as the sudden infant death syndrome (SIDS) depends upon a complete autopsy and death scene investigation to exclude known causes of death. Here we report the death of a 4-month-old infant in a tuberculosis endemic area that presented as a sudden unexpected death in infancy (SUDI) with no apparent explanation based on the death scene characteristics. The autopsy, however, revealed progressive primary pulmonary tuberculosis with intrathoracicadenopathy, compression of the tracheobronchial tree and miliary lesions in the liver. This case underscores the clinical difficulties in the diagnosis of infantile tuberculosis, as well as the possibility of sudden death as part of its protean manifestations. The pathology and clinical progression of tuberculosis in infants differ from older children and adults due to the immature immune response in infants. This case dramatically highlights the need for complete autopsies in all sudden and unexpected infant deaths, as well as the public health issues in a sentinel infant tuberculosis diagnosis.

Hepatic hemangioendothelioma presenting as sudden unexpected death in infancy: a case report.

The classification of an unexpected infant death as sudden infant death syndrome (SIDS) depends upon a complete autopsy, death scene investigation, and review of medical history to exclude known causes of death. Death from occult neoplastic disease in infancy is extremely rare but is within the broad differential diagnosis of SIDS. We report the sudden and unexpected death of a 1-month-old infant from a hepatic (infantile) hemangioendothelioma. The physiologic mechanism of death was likely cardiac failure induced by the circulatory demands of this large vascular tumor and respiratory compromise from diaphragmatic thoracic incursion. The clinical progression and pathology of these relatively common tumors of infant livers are extremely variable. This case dramatically illustrates the potential for fatal outcome of this tumor, as well as the need for autopsy to determine the cause of sudden and unexpected death in an infant.

Neurologic outcome after penetrating extracranial arterial trauma.

PURPOSE: We undertook this study to determine factors that adversely affect outcome in patients with penetrating injury to the extracranial cerebral vasculature. Patients and methods Medical records were reviewed for all patients who had undergone surgical intervention to treat penetrating injury to the extracranial cerebral arteries between January 1989 and December 1999. Forensic autopsy findings were also reviewed for all patients who died as a result of their injury. RESULTS: One hundred fifty-one patients with injury to the brachiocephalic artery (n = 21), common carotid artery (n = 98), or internal carotid artery (n = 32) were identified. Overall mortality was 21.2%, and stroke rate in surviving patients was 15.1%. Twenty-five of 32 deaths (78.1%) were stroke-related. Brachiocephalic artery injury was associated with the highest mortality (38.1%), and survivor stroke rate was highest in patients with internal carotid injuries (22.7%). Hemodynamic instability at presentation led to both higher mortality (30.7%) and stroke rate (19.2%). Preoperative angiography did not influence mortality or stroke rate in hemodynamically stable patients. Procedural mortality associated with arterial ligation was 45% (9 of 20 patients), and no surviving patient experienced a change in pre-ligation neurologic state. Nine patients remained neurologically intact after ligation, and 2 patients with preoperative localized neurologic deficit were unchanged postoperatively. In 131 patients, mortality after arterial repair was 17.6%, and in 5 surviving patients (5.4%) an ischemic neurologic deficit developed. Twelve of 15 surviving patients (80%) with preoperative neurologic deficit who underwent arterial repair had improved neurologic status. Cerebral infarcts were confirmed at autopsy in 23 patients; 18 infarcts were ischemic (10, repair; 8, ligation), and 5 infarcts were hemorrhagic (all, repair). No factor was identified that was predictive of ischemic versus hemorrhagic infarction in patients undergoing repair. CONCLUSIONS: The presence of hypovolemic shock, internal carotid artery injury, complete vessel transection, and arterial ligation are associated with unfavorable outcome. Penetrating injury to the brachiocephalic, common carotid, or internal carotid artery should be repaired rather than ligated when technically possible. Subsequent ischemic or hemorrhagic cerebral infarction is unpredictable, but overall outcome is superior to that with ligation of the injured artery.