Sudden infant death syndrome "gray zone" disclosed only by a study of the brain stem on serial sections

Sudden infant death syndrome (SIDS) "gray zone" or borderline cases are defined as those cases in which it is difficult to establish whether the pathological findings are sufficiently severe to have caused the death. Examination of the brainstem in 103 cases of SIDS disclosed five SIDS "gray zone" cases in which only further investigations of serial sections successfully identified anatomico-pathological findings that likely represent the morphological substrates for a sudden reflexogenic death. A complete autopsy was performed, including close examination of the brainstem and cardiac conduction system, according to our guidelines. Our five cases are consistent with the triple-risk model of SIDS, a hypothesis postulating an underlying biological vulnerability to exogenous stressors or triggering factors in a critical developmental period. Inflammatory infiltrates (cases 1 and 2), necrotic focus of the solitary tract (case 3), hemangioendothelioma (case 4) and mild pneumonia (case 5) alone might or might not have accounted for the sudden deaths, if it had not been for the location and/or concomitant presence of brainstem abnormalities that could have had a triggering role in causing the sudden death of these babies.     

Sudden fetal and infant deaths: shared characteristics and distinctive features

Recent evidence suggests sudden infant death syndrome (SIDS) infants have a diminished capacity to respond to autonomic challenges during a vulnerable developmental period. We speculate that a dysfunction or altered trajectory in the development of the autonomic nervous system may be detected in utero and also may play a role in the pathogenesis of unexplained late stillbirth. Some fetuses, as well as infants, may be more vulnerable than others to autonomic challenges during periods of autonomic instability. Investigation of potential shared underlying mechanisms in both SIDS and unexplained stillbirth will require expanded epidemiological investigation of genetic and environmental correlates along with a systematic study of developmental physiology and neuropathology. As with SIDS, there are likely important interactions between genetic susceptibility and environmental exposures occurring during gestation, which lead to infants who have altered trajectories or deficits in autonomic function and who need to be identified before they enter the periods of greatest risk.     

Totgeburt und plötzlicher Kindstod

During the last 30 years the rate of stillbirths in industrial countries has remained nearly identical, while neonatal mortality und the incidence of the sudden infant death syndrome (SIDS) has declined significantly. This observation is in contrast to the decline of stillbirths due to placental insufficiency, maternal diabetes mellitus, preeclampsia, rhesus incompatibility and fetal aneuploidy. However, the incidence of unexplained stillbirths has increased. The decrease of the incidence of the sudden infant death syndrome proves that prevention of diseases of unknown origin is possible. Smoking, obesity and an excessive increase in body weight before pregnancy are modifiable risk factors for intrauterine stillbirth. The detection and treatment of diabetes mellitus, gestational diabetes and arterial hypertension are effective measures in pregnancy to reduce the risk for stillbirth. The induction of labor at term is also effective in the reduction of stillbirths, however, the burden of elective induction with all of the possible negative effects has to be balanced against the benefit of avoiding intrauterine deaths as approximately 300 labor inductions with the corresponding disadvantages, would be necessary to avoid 1 stillbirth.     

The significance of ante- and perinatal periods for formation of risk of sudden infant death syndrome

The results of the research, which are carried out according to two international programs on studying and prevention of the sudden infant death syndrome (SIDS), are submitted in the article. The features of ante- and perinatal periods, characteristics of obstetric history of the mothers of deceased babies are analyzed, the relative risk of SIDS development is estimated at the influence of a complex of factors. High parity, young age of mother at the time of delivery, poor antenatal care, preterm delivery, intrauterine fetal growth retardation, fast delivery, alcohol and coffee abuse by a mother, smoking during pregnancy, early change of the child's feeding from breast to bottle are referred to the most significant risk factors of SIDS stipulated by the unfavorable course of pregnancy and delivery. The practical recommendations directed on elimination of the risk factors of SIDS in ante- and perinatal periods are offered.     

The effectiveness of antenatal care programmes to reduce infant mortality and preterm birth in socially disadvantaged and vulnerable women in high-income countries: a systematic review

Background

Infant mortality has shown a steady decline in recent years but a marked socioeconomic gradient persists. Antenatal care is generally thought to be an effective method of improving pregnancy outcomes, but the effectiveness of specific antenatal care programmes as a means of reducing infant mortality in socioeconomically disadvantaged and vulnerable groups of women has not been rigorously evaluated.

Methods

We conducted a systematic review, focusing on evidence from high income countries, to evaluate the effectiveness of alternative models of organising or delivering antenatal care to disadvantaged and vulnerable groups of women vs. standard antenatal care. We searched Medline, Embase, Cinahl, PsychINFO, HMIC, CENTRAL, DARE, MIDIRS and a number of online resources to identify relevant randomised and observational studies. We assessed effects on infant mortality and its major medical causes (preterm birth, congenital anomalies and sudden infant death syndrome (SIDS))

Results

We identified 36 distinct eligible studies covering a wide range of interventions, including group antenatal care, clinic-based augmented care, teenage clinics, prenatal substance abuse programmes, home visiting programmes, maternal care coordination and nutritional programmes. Fifteen studies had adequate internal validity: of these, only one was considered to demonstrate a beneficial effect on an outcome of interest. Six interventions were considered 'promising'.

Conclusions

There was insufficient evidence of adequate quality to recommend routine implementation of any of the programmes as a means of reducing infant mortality in disadvantaged/vulnerable women. Several interventions merit further more rigorous evaluation.     

Epidemiology of the sudden infant death syndrome: maternal, neonatal, and postneonatal risk factors.

Infants dying of sudden infant death syndrome (SIDS) constitute the single largest component of postneonatal infant mortality. Many different scientific approaches and hypotheses have been pursued in research studies over the past two decades. The field of epidemiology provides a comprehensive view of risk factors for SIDS with which theories of underlying physiologic defects or other putative causes should conform. Epidemiologic research has a vital role to play in assessing hypotheses derived from other types of studies.     

The role of breastfeeding in sudden infant death syndrome.

The objective of this article is to review the literature regarding the risk of sudden infant death syndrome (SIDS) in bottle-fed infants compared to those that are breastfed. A meta-analysis and qualitative literature review were performed. Cohort and case-control studies were included if they met a minimum SIDS definition and presented data allowing calculation of an odds ratio (OR). Twenty-three studies were included in the meta-analysis. The studies were heterogeneous, and a majority (14) were of "fair" or "poor" quality. Crude ORs from 19 individual studies favored breastfeeding as protective against SIDS. The combined analysis indicated that bottle-fed infants were twice as likely to die from SIDS (pooled OR = 2.11; 95% CI 1.66-2.68). The results of the analysis show that there is an association between bottle-feeding and SIDS, but this may be related to confounding variables.     

Sudden unexpected death of a term fetus in an anticardiolipin-positive mother

A term male fetus suddenly and unexpectedly died in utero at the 40th week of gestation. The mother had a regular and unremarkable pregnancy except for an anticardiolipin antibodies positivity. The histological examination of the cardiac conduction system showed islands of conduction tissue in the central fibrous body, known as persistent fetal dispersion. The brainstem examination revealed a severe bilateral hypoplasia of the arcuate nucleus. This morphological finding has been described in more than 35% of our stillborn as well as sudden infant death syndrome (SIDS) cases, independently from the presence of anticardiolipin antibodies. Some authors have given emphasis to the possible lethal association of maternal autoantibodies and QT prolongation. Our findings emphasize the need of an accurate postmortem examination including the study of brainstem and cardiac conduction system in every case of unexpected late intrauterine death, following the same standardized autopsy protocol adopted in SIDS cases.     

Impaired arousal from sleep: relationship to sudden infant death syndrome

There is a relationship between deficient sleep arousal response to asphyxia, the presence of symptomatic apnea, and the risk for recurrent episodes of life-threatening sleep apnea. This documented abnormality in arousal responsiveness, which could result in the inability to respond to apnea-induced asphyxia, is the only respiratory control deficit that could result in sudden death. Inability to arouse from sleep in response to asphyxia may also be the underlying abnormality explaining numerous other behavioral deficits reported in infant groups with symptomatic apnea or otherwise thought to be at increased risk for sudden infant death syndrome (SIDS), including awake behavioral differences in temperament. An arousal response deficit to asphyxia may thus be a critically important and fundamental pathophysiological component of the essential defect necessary for the occurrence of sudden death during sleep. As with any other observed abnormality, however, it has not yet been possible to design an asphyxic arousal response test with sufficient accuracy and sensitivity to identify prospectively those infants otherwise destined to die of SIDS. Although an impairment in arousal responsiveness may be necessary for SIDS to occur such a deficit may not be sufficient to cause SIDS unless or until another factor(s) occurs that can cause sleep-related asphyxia. Although impaired respiratory control appears to be the likely precipitating cause of sleep-related asphyxia, it is also possible that factors unrelated to respiratory control are important in causing asphyxia; superimposed on an underlying arousal deficit, these could result in SIDS.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sleeping position for preterm infants

Supine sleeping is recommended to prevent the sudden infant death syndrome (SIDS). Low birth weight infants are at increased risk for SIDS, which is increased further if they are placed prone. Prone sleeping, however, also has advantages for preterm infants, such as a reduced apnoea rate, an increased lung volume and more quiet sleep. In their first weeks of life, these infants are usually on a monitor and under continuous observation. SIDS is extremely unlikely under these circumstances. Because of the aforementioned advantages, these infants may be placed prone during their first few weeks of life in the hospital. One week before discharge, however, they should be changed to back sleeping and the parents be explained that their baby is now nearing discharge and should thus be placed as it should also sleep at home: on its back and in a sleeping sack. We do not prescribe home monitors for SIDS prevention, but occasionally use pulse oximeters at home for a few weeks if an infant continues to exhibit apnoea of prematurity.     

Placental pathology is not predictive for sudden infant death syndrome (SIDS)

A previous report has suggested an increased incidence of chorioamnionitis in the placentae of sudden infant death syndrome (SIDS) victims. To further evaluate placental pathology in SIDS, 27 cases were identified from coroner's records and matched to two control groups. Both control groups were matched for birthweight, gestational age, and season, with the second also matched for maternal race, infant sex, blood type B, and maternal parity. No significant increase in chorioamnionitis or other placental abnormalities were found in SIDS victims when controlling for prematurity, which is a factor related to chorioamnionitis. An increased incidence of vaginal bleeding (P less than 0.04) and possibly substance abuse or anemia at delivery was found in SIDS mothers. There were more premature and black infants found in the SIDS group compared with the general birth population, and also lower five-minute Apgar scores (P less than 0.02) compared to matched controls. Analysis of the second control group match, including infant Apgar scores, maternal hematocrit, maternal age, and complications of pregnancy and delivery, did not influence any of our conclusions. The data suggests that matching for prematurity may be important in identifying the strength of additional risk factors for SIDS, since the risk factors for SIDS and premature delivery are similar.     

Guidelines for Investigating Stillbirths: An Update of a Systematic Review

ObjectiveTo identify formal, publicly available guidelines for stillbirth investigation and to identify the most appropriate clinical practice guideline (or component of a guideline) for use in Alberta.MethodsA systematic literature search was conducted to identify primary and secondary research studies published between January 1985 and August 2006 and formal, publicly available guidelines on the subject of stillbirth investigation. The Cochrane Library, PubMed, EMBASE, CINAHL, HealthSTAR, Science Citation Index, BIOSIS, and the NHS and CRD databases were searched. The methodological quality of the selected primary research studies was assessed according to specific criteria.ResultsAll six of the publicly available clinical practice guidelines selected for this review outlined similar steps in the stillbirth investigation but differed about which tests to include and which components should be core or additional investigations. They agreed on including several elements for routine investigation, such as complete autopsy and detailed examination of the cord and placenta.Of 61 retrieved primary research studies, only seven met the inclusion criteria. No studies compared the value of specific guidelines. Although reviewed evidence highlights the value of fetal autopsy and placental examinations as integral components of stillbirth investigation, the value of other components is still not clear.ConclusionsNo firm scientific judgement could be made about which clinical practice guideline for stillbirth investigation is the most appropriate or which components are essential. Currently there is no generally accepted reference guideline for stillbirth investigation. Fetal autopsy and placental examination remain important components, assuming the postmortem examination is of high quality. These data may be helpful in counselling parents who are considering whether or not to consent to a postmortem examination.     

Population trends in sudden infant death syndrome

This review documents and assesses recent trends in sudden infant death syndrome. We review medical literature, Internet resources, and national governmental data. A striking reduction in SIDS incidence of more than 50% has been observed in various countries after interventions, particularly during the early 1990s, to reduce the prevalence of prone infant sleeping. A reduction in postneonatal mortality has accompanied these lower rates. Evaluation studies from several countries indicate that the SIDS rate drop is largely attributable to a decline in the proportion of babies sleeping prone. Within countries, the SIDS rate decline has not occurred to the same extent for different ethnic and socio-economic groups. Future public health activities must aim to address this issue. In the post-intervention era, the relative importance of the risk factors of side compared to supine sleeping and soft bedding near the infant's airway have become more evident. Recent death scene data indicate that a substantial proportion of the remaining SIDS deaths could be avoided by supine sleeping and by providing a safe sleeping environment for all infants.     

Sudden infant death syndrome among twin births: United States, 1995-1998.

OBJECTIVES: To compare the incidence and risk factors for sudden infant death syndrome (SIDS) in twin and singleton births and to estimate the concordance of SIDS in twins. STUDY DESIGN: A cohort analysis using the National Center for Health Statistics Linked Birth and Infant Death files (1995-1998). RESULTS: Twins had higher SIDS rate (1.3/1000 live births) compared to singletons (0.7/1000 live births), relative risk: 1.9, 95% confidence interval: 1.68, 2.01. Male and small- for-gestational age infants as well as infants of black, unmarried, and smoking mothers were at increased risk for SIDS in both twins and singletons. Placental abnormalities also were associated with SIDS in singletons and twins, although this association failed to achieve statistical significance in twins. There is a higher rate of SIDS in the second twin after a first twin SIDS. CONCLUSIONS: Twins are at higher risk of SIDS than are singletons. Overall, the epidemiology of SIDS in twins is quite similar to that seen in singletons.     

Thiamine Deficiency – A Neglected Problem of Infants and Mothers – Possible Relationships to Sudden Infant Death Syndrome

An unexpectedly high incidence of biochemical thiamine deficiency (erythrocyte transketolase) was found in groups of mothers and infants, selected for apparent health from a westernized Caucasian community in Australia. Deficiency was common in mothers at term but not their infants, and in apparently healthy older infants but not their mothers. These findings can be explained by preferential delivery of thiamine to the fetus, at the expense of the pregnant mother; after delivery the mother recovers, and the infant becomes depleted. The incidence of thiamine deficiency was high in 'near-miss' sudden infant death syndrome (SIDS) infants and their mothers, and in siblings of SIDS. The thiamine deficient infants had a high familial incidence of SIDS deaths. These 'high risk families' might reflect poor nutrition or genetic defects of thiamine uptake and metabolism. Since apparently thriving infants with thiamine deficiency can sometimes die unexpectedly, thiamine status deserves more attention in clinical practice and research.     

Stillbirth: tissue findings with environmental and genetic links

This article discusses stillbirth from a pathologist's perspective. Stillbirth may be caused by many different mechanisms. There are specific maternal and fetal disorders leading to stillbirth, and some of these have genetic and environmental associations. Frequently, an autopsy examination may determine the specific cause of the fetal death. We illustrate tissue findings in stillbirth to put individual faces on this condition.     

New brain stem and bone marrow abnormalities in victims of sudden infant death syndrome

The study looked for new abnormalities in 31 victims of sudden infant death syndrome (SIDS). The focus was on respiratory control centers in the brain stem, because some SIDS victims have had abnormalities in respiratory control during sleep. A major respiratory control area (lateral reticular nucleus) of the medulla was hypomyelinated in 9 of the 31 SIDS victims. In a second study, the size of the 12th cranial nerve nucleus and its neuronal composition were analyzed because this nucleus regulates tongue movements, and the tongue has been postulated to help obstruct the airway in some SIDS victims. The 12th nucleus was found to have a neuronal deficit in more than two thirds of the SIDS victims. Finally, the SIDS victims were found to have a normoblastic hyperplasia in their bone marrows, a presumed response to chronic hypoxemia during sleep.     

The project to understand and research preterm pregnancy outcomes and stillbirths in South Asia (PURPOSe): a protocol of a prospective,cohort study of causes of mortality among preterm births and stillbirths

Background

In South Asia, where most stillbirths and neonatal deaths occur, much remains unknown about the causes of these deaths. About one-third of neonatal deaths are attributed to prematurity, yet the specific conditions which cause these deaths are often unclear as is the etiology of stillbirths. In low-resource settings, most women are not routinely tested for infections and autopsy is rare.

Methods

This prospective, cohort study will be conducted in hospitals in Davengere, India and Karachi, Pakistan. All women who deliver either a stillbirth or a preterm birth at one of the hospitals will be eligible for enrollment. With consent, the participant and, when applicable, her offspring, will be followed to 28-days post-delivery. A series of research tests will be conducted to determine infection and presence of other conditions which may contribute to the death. In addition, all routine clinical investigations will be documented. For both stillbirths and preterm neonates who die ≤ 28 days, with consent, a standard autopsy as well as minimally invasive tissue sampling will be conducted. Finally, an expert panel will review all available data for stillbirths and neonatal deaths to determine the primary and contributing causes of death using pre-specified guidance.

Conclusion

This will be among the first studies to prospectively obtain detailed information on causes of stillbirth and preterm neonatal death in low-resource settings in Asia. Determining the primary causes of death will be important to inform strategies most likely to reduce the high mortality rates in South Asia.

Trial registration

Clinicaltrials.gov (NCT03438110) Clinical Trial Registry of India (CTRI/2018/03/012281).