Risk Factors For Sudden Infant Death Syndrome Research Articles

Heat stress and sudden infant death syndrome—Stress gene expression after exposure to moderate heat stress

The aim of the present study was to investigate stress gene expression in cultured primary fibroblasts established from Achilles tendons collected during autopsies from sudden infant death syndrome (SIDS) cases, and age-matched controls (infants dying in a traumatic event). Expression of 4 stress responsive genes, HSPA1B, HSPD1, HMOX1, and SOD2, was studied by quantitative reverse transcriptase PCR analysis of RNA purified from cells cultured under standard or various thermal stress conditions. The expression of all 4 genes was highly influenced by thermal stress in both SIDS and control cells. High interpersonal variance found in the SIDS group indicated that they represented a more heterogeneous group than controls. The SIDS group responded to thermal stress with a higher expression of the HSPA1B and HSPD1 genes compared to the control group, whereas no significant difference was observed in the expression of SOD2 and HMOX1 between the two groups. The differences were related to the heat shock treatment as none of the genes were expressed significantly different in SIDS at base levels at 37°C. SOD2 and HMOX1 were up regulated in both groups, for SOD2 though the expression was lower in SIDS at all time points measured, and may be less related to heat stress. Being found dead in the prone position (a known risk factor for SIDS) was related to a lower HSPA1B up-regulation in SIDS compared to SIDS found on their side or back.The study demonstrates the potential usefulness of gene expression studies using cultured fibroblasts established from deceased individuals as a tool for molecular and pathological investigations in forensic and biomedical sciences.

The male excess in sudden infant deaths

The peak age at which sudden infant death syndrome (SIDS) occurs corresponds to the developmental period in which infants are dependent on their innate responses to infection. There is a growing body of evidence indicating that dysregulation of inflammatory responses might contribute to the physiological changes leading to these sudden deaths. This study examined the effects of three important risk factors for SIDS on inflammatory responses: cigarette smoke, virus infection and male sex. Cytokine responses of peripheral monocytic blood cells of healthy, non-smoking males and females to endotoxin were measured. Surrogates for virus infection or cigarette smoke were assessed using IFN-γ or water-soluble cigarette smoke extract (CSE). For most conditions, cells from males had lower pro-inflammatory cytokine responses than those of females. An opposite trend was observed for IL-10. Significantly lower levels of some cytokines were noted for cells from male donors exposed to CSE. In females, there were significant correlations between testosterone levels and levels of pro-inflammatory cytokines, but none for males. Testosterone levels in females correspond to those among male infants in the age range at greatest risk of SIDS. The effects of the testosterone surge in male infants need to be examined in relation to changes in cortisol levels that occur during the same period of infant development.

Hypophosphatemia as a key factor in sudden infant death syndrome (SIDS)?

Dear Sir, Sudden Infant Death Syndrome or SIDS remains an important cause of mortality in infants. The 2011 publication of Siren and Siren (1) and the subsequent letter to the editor (2) focus on critical diaphragm failure as a possible cause and provide plausible evidence. However, these articles do not explore the metabolic basis for this critical diaphragm failure. Several authors, including Aubier et al. (3) and Fiaccadori et al. (4) have described that the diaphragm is extremely susceptible to hypophosphatemia, and this may be the origin of the symptoms reported by Siren and Siren. Hence, it may well be the yet unexplored underlying mechanism responsible for SIDS. A reason for suspecting hypophosphatemia as the cause for SIDS is because neonates are extremely prone to developing hypophosphatemia as shown in numerous publications (e.g. (5-8)). A very brief period of stress, like separation from the mother or a brief period of illness, can result in phosphaturia severe enough to result in the loss of 50% of the free phosphate pool within 24 hours. This results in an immediate drop in blood phosphate levels. Worse, this hypophosphatemia can subsequently become aggravated over the course of 1–2 weeks without obvious visible symptoms and despite resumption of normal eating behavior, something not reported in older subjects. In infants with risk factors for SIDS like intrauterine growth retardation, exposure to cigarette smoke, male sex, and heat stress, this phosphaturetic stress response is enhanced possibly through augmented or longer-lasting sympathetic activity (9,10), and, hence, they are more prone to develop severe hypophosphatemia and ATP deficiency. Hypophosphatemia not only affects contraction of the diaphragm, but it is also involved in the formation of 2,3-diphosphoglycerate (2,3-DPG; more correctly referred to as 2,3-bisphosphoglycerate) in erythrocytes. This 2,3-DPG regulates the release of oxygen from hemoglobin. Tissues with a high metabolic activity result in high levels of 2,3-DPG in the blood causing the liberation of oxygen (11-13). Hypophosphatemia impedes the formation of 2,3-DPG, which subsequently prevents the release of oxygen from hemoglobin and, in effect, suffocates the tissue. Thus, severe hypophosphatemia results in signs of asphyxiation despite adequate access to free air (14), either through inducing an ATP deficiency affecting the diaphragm or through inhibiting oxygen release from hemoglobin. For example, in briefly stressed subjects, in parallel with the drop in plasma phosphate, a doubling of the ratio of pCO2/pO2, an increase in SpO2, and lactic acidosis were observed but without obvious visible signs of distress. If severe enough, this could lead to death from inner suffocation (SIDS). The presence of fetal hemoglobin may also play a role in SIDS. Fetal hemoglobin purportedly has a higher binding affinity for oxygen (15) and thus could predispose an infant to SIDS when 2,3-DPG is compromised. Other symptoms of SIDS can also be explained by hypophosphatemia. Hypophosphatemia can lead to petechiae: minor hemorrhages caused by platelet dysfunction (16,17) and often seen postmortem in SIDS victims. Similarly, pulmonary edema (18) has been linked to hypophosphatemia, as have cardiac arrhythmias (19,20). Hypophosphatemia is also implicated in the morbidity and mortality associated with refeeding syndrome (21) and in hypophosphatemic rickets, which is more prevalent in boys (22) in line with a higher incidence of SIDS in boys. Siren and Siren's (1) comment that REM sleep inhibits intercostal muscles compounded by diurnal rhythms in blood phosphate could explain why SIDS strikes during night-time REM sleep. Also, phosphate has a seasonal rhythm with lows in the winter which could explain a higher prevalence of SIDS in this season, and 2,3-DPG is lower in infants exposed to cigarette smoke which could explain a higher incidence of SIDS in houses of smokers (23,24). In summary, both the etiology as well as the symptoms of SIDS can be explained by hypophosphatemia. A brief stressor can induce hypophosphatemia in infants, particularly in those with SIDS risk factors, and aggravate it despite resumption of normal food intake. This since the urinary loss of phosphate induced by stress or a large drop in metabolic rate and the subsequent enhanced phosphate demand for re-started anabolic processes cannot be quickly compensated by normal dietary intake. This hypophosphatemia can aggravate to the point of affecting O2 release from red blood cells through a depletion of 2,3-DPG or affect diaphragm contractility through ATP deficiency, either one which leads to death from apparent suffocation: SIDS.

Sudden twin infant death on the same day: a case report and review of the literature

Sudden infant death syndrome (SIDS) is a major contributor to infant mortality. The cause of death is unknown: suggested possibilities include cardiovascular disease, anaphylactic shock, and suffocation. The occurrence of simultaneous sudden infant death syndrome is uncommon, such cases being extremely rare in forensic pathologic practice. We report two 10-week-old male twins who appeared well at the time of their evening feeding, yet died while sleeping on their backs. Both infants had petechial hemorrhages on the visceral pleura, epicardial surface of the heart, and thymus gland. Microscopic examination revealed pulmonary edema, intra-alveolar hemorrhage, and minor lymphocytic infiltration, again in both infants. In this report, we discuss the risk factors for SIDS, which should be considered individually or in combination as possible causes of death.

Maternal Alcohol Use and Sudden Infant Death Syndrome and Infant Mortality Excluding SIDS

Improvements in the rate of infant mortality (death in first year of life) have not occurred in recent years. This study investigates the association between maternal alcohol-use disorder and sudden infant death syndrome (SIDS) and infant mortality not classified as SIDS using linked, population-based health and mortality data. Exposed mothers were identified through the presence of an International Classification of Diseases 9/10 alcohol diagnosis, a proxy for alcohol-use disorder, recorded on health, mental health, and/or drug and alcohol datasets (1983-2005). Comparison mothers without an alcohol diagnosis were frequency matched to exposed mothers on maternal age within maternal race and year of birth of their children. All offspring with their birth recorded on the Midwives Notification System compose the exposed (n = 21 841) and comparison (n = 56 054) cohorts. Cases of SIDS (n = 303) and infant mortality excluding SIDS (n = 598) were identified through linkage with the Western Australian Mortality Register. Analyses were conducted by using Cox regression and results presented as adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). The highest risk of SIDS occurred when a maternal alcohol diagnosis was recorded during pregnancy (aHR 6.92, 95% CI 4.02-11.90) or within 1 year postpregnancy (aHR 8.61, 95% CI 5.04-14.69). An alcohol diagnosis recorded during pregnancy more than doubled the risk of infant deaths (excluding SIDS) (aHR 2.35, 95% CI 1.45-3.83). Maternal alcohol-use disorder is attributable for at least 16.41% (95% CI 9.73%-23.69%) of SIDS and 3.40% (95% CI 2.28%-4.67%) of infant deaths not classified as SIDS. Maternal alcohol-use disorder is a significant risk factor for SIDS and infant mortality excluding SIDS.

Sudden Infant Death Syndrome in Twins and Singletons in Japan, 1995-2008

Objective: To compare the infant mortality rate (IMR) due to sudden infant death syndrome (SIDS) in twins and singletons and consider the risk factors of SIDS. Materials and methods: The IMR due to SIDS was analyzed among twins and singletons from 1995 to 2008 using the Japanese Vital Statistics. Results and discussion: The IMR for both twins and singletons decreased (1/3-1/4) significantly during 1995- 2008 and was significantly higher among twins than in singletons during 1995-2000 and 2003-2004. The relative risks of SIDS for maternal age groups between <25 years and 30–34 years were 9-fold for twins and 3-fold for singletons. The IMR increased with parity for both 1st- and 2nd-twin born. Seasonal variations were observed in IMRs for twins and singletons. The time of death from 4 a.m. to 7 a.m. was a risk factor for SIDS in twins and singletons. Conclusion: The relative risks for SIDS in twins and singletons decreased after 2005. The SIDS IMR was lower in Japan than in the US, the UK, and Canada which related to lower percentage of prone and facedown sleeps position in Japan. The concordance rate of SIDS was uncommon in twins. Younger maternal age is a risk factor for both twins and singletons.

Sudden Infant Death Syndrome in Korea: A Retrospective Analysis of Autopsy-Diagnosed Cases

This study aimed to elucidate the demographic and sleeping environmental factors associated with sudden infant death syndrome (SIDS) in Korea. The autopsy reports of all SIDS cases reported to the National Forensic Service and Seoul National University College of Medicine between 1996 and 2008 were reviewed for data collection and analysis to identify the risk factors for SIDS. Analysis of the 355 SIDS cases reported within the study period revealed that of the 168 (47.3%) cases for which sleeping position before death had been reported, 75 (44.7%) cases had occurred after placement in prone or side position. Of the 204 (57.5%) cases for which bed-sharing situation had been reported, 121 (59.3%) deaths had occurred during bed-sharing, of which 54 (44.6%) infants were under 3 months of age, a significantly younger age than that of the non-bed-sharing cases (P = 0.0279). Analysis of the results indicated no tendency toward an increase or decrease in the use of a prone or side position. Rather, there was a statistically significant increasing trend for bed-sharing over the study period (OR, 1.087; 95% CI, 1.004-1.177; P = 0.04). These findings indicate the need for nationwide educational programs promoting a safe sleeping environment to enhance SIDS prevention.

Sociodemographic and meteorological correlates of sudden infant death in Taiwan

This study was designed, using three national datasets including the Taiwan Death Registry, Taiwan Birth Registry, and National Meteorological Dataset, to examine the sociodemographic, geographic and meteorological correlates of sudden infant death syndrome (SIDS). One thousand, six hundred and seventy-one cases of SIDS occurring between 1994 and 2003, and 8355 matched controls were included in this nested case-control study. Over the study period, the annual rate of SIDS declined only slightly, with an average annual rate of 57.9/10(5) . Male infants (adjusted odds ratio [AOR], 1.19; 95% confidence interval [CI]: 1.06-1.33), preterm births (AOR, 1.69; 95%CI: 1.33-2.13), low birthweight (AOR, 2.87; 95%CI: 2.30-3.59), and birth order ≥3 (AOR, 1.62; 95%CI: 1.37-1.92) were the demographic risk factors for SIDS. Additionally, paternal age <25 years (AOR, 1.37; 95%CI: 1.09-1.71), urbanization (AOR, 1.46; 95%CI: 1.20-1.78), lower paternal education (elementary and less; AOR, 1.28; 95%CI: 1.01-1.64), and parental age difference >10 years (AOR, 1.72; 95%CI: 1.24-2.39) were also associated with increased risk of SIDS. It was also noted that daily average temperature ranging from 9.2°C to 14.2°C (AOR, 2.10; 95%CI: 1.67-2.64) was associated with the most increased risk, while temperature ≥26.4°C (AOR 0.60, 0.61) was significantly associated with the most reduced risk. Sociodemographic, geographic and meteorological data can be used to identify families in greater need of early guidance and to promote various prevention measures to avoid the occurrence of SIDS.

Maternal and perinatal risk factors for SIDS: a novel analysis utilizing pregnancy outcome data

A number of maternal and perinatal factors to increase an infant's risk of sudden infant death syndrome (SIDS) have been found in past investigations. We analysed data for potential SIDS risk factors including the presence of complications or conditions considered as detrimental to the infant's or mother's health. The data for 118 SIDS cases and 227 matched controls were obtained from a state pregnancy outcome unit. SIDS was found to be significantly more common in cases where the infant's mother was not in a relationship (i.e. divorced, separated or never married) (p = 0.005), if the infant was not the first born (p = 0.0001) and when the mother resided in a socioeconomically disadvantaged area (p = 0.03). Overall, this SIDS cohort appears to display classical SIDS associations, and our findings are consistent with those from other regions. This novel epidemiological tool opens the way for a national Australia-wide study using pregnancy outcome data collected by the individual states and could be helpful in assessing maternal and fetal risk factors for other paediatric medical conditions.

The high burden of infant deaths in rural Burkina Faso: a prospective community-based cohort study

BackgroundInfant mortality rates (IMR) remain high in many sub-Saharan African countries, especially in rural settings where access to health services may be limited. Studies in such communities can provide relevant data on the burden of and risk factors for infant death. We measured IMR and explored risk factors for infant death in a cohort of children born in Banfora Health District, a rural area in South-West Burkina Faso.MethodsA prospective community-based cohort study was nested within the PROMISE-EBF trial (NCT00397150) in 24 villages of the study area. Maternal and infant baseline characteristics were collected at recruitment and after birth, respectively. Home visits were conducted at weeks 3, 6, 12, 24 and 52 after birth. Descriptive statistics were calculated using robust standard errors to account for cluster sampling. Cox multivariable regression was used to investigate potential risk factors for infant death.ResultsAmong the 866 live born children included in the study there were 98 infant deaths, yielding an IMR of 113 per 1000 live births (95% CI: 89–143). Over 75% of infant deaths had occurred by 6 months of age and the post neonatal infant mortality rate was 67 per 1000 live births (95% CI: 51–88). Infections (35%) and preterm births complications (23%) were the most common probable causes of death by 6 months. Multivariable analyses identified maternal history of child death, polygyny, twin births and poor anthropometric z-scores at week-3 as factors associated with increased risk of infant death.ConclusionsWe observed a very high IMR in a rural area of Burkina Faso, a country where 75% of the population lives in rural settings. Community-based health interventions targeting mothers and children at high risk are urgently needed to reduce the high burden of infant deaths in these areas.

Abstract 223: A Case for Hypoxia and Long QT Syndrome in Sudden Infant Death Syndrome

INTRODUCTION: Long QT syndrome is considered an important factor in the pathogenesis of Sudden Infant Death Syndrome (SIDS). Prolonged QTc intervals (c=corrected for heart rate) in SIDS are sometimes caused by mutations in genes encoding ion channels. Other causes remain largely idiopathic. HYPOTHESIS: Risk factors for SIDS, including maternal bed sharing, head covering and high altitude, are associated with a reduced oxygen environment. Our studies investigate a link between hypoxia and long QT syndrome in the neonate. METHODS: We characterised, for the first time, changes in the murine neonatal electrocardiogram (ECG) at: 0, 1, 3, 6, 12, 24 hours (n=12) and 2, 6 and 10 days (n=25) after birth. We investigated whether birth into hypoxia 10% O2 (n=16) and genetically elevating cardiac hypoxic signalling in neonatal mice alters the course of changes in ECG morphology (n=14). We analysed the ECG for heart rate and parameters associated with dysrrhythmia and sudden death, including the QTc interval. RESULTS: In the hours and days following birth, we observed a steady increase in heart rate (p&lt;0.0001) and decrease in QTc interval (p&lt;0.05). When neonates were raised in hypoxia for 24 hours, the trends in heart rate (p&lt;0.001) and QTc interval (p&lt;0.0001) were abolished and risk of neonatal death was 52% (17 out of 33) over 24 hours. In transgenic neonatal mice with elevated cardiac hypoxic signalling, we observed a significant bradycardia (p&lt;0.0001) and elongated QTc interval (p&lt;0.0001) compared to controls at ten days after birth, with death occurring pre-weaning. &gt;CONCLUSIONS: Following birth there are significant changes in ECG morphology, including an increase in heart rate and decrease in QTc interval. Hypoxia diminishes these changes resulting in bradycardia and elongated QTc intervals. We hypothesise that the increase in ambient oxygen concentration after birth drives the maturation of cardiac electrical conduction, failure of which predisposes to dysrhythmia and sudden death. This is consistent with known risk factors of SIDS and provides a link between neonatal hypoxia and ECG repolarisation abnormalities.

Apparent Life-Threatening Events

Apparent Life-Threatening Events

All sudden unexplained infant respiratory deaths may result from the same underlying mechanism

All sudden unexplained infant respiratory deaths may result from the same underlying mechanism The Sudden Infant Death Syndrome (SIDS) was defined in 1969 by Beckwith as sudden death of an infant or young child, unexpected by medical history, remaining unexplained after thorough autopsy/death-scene investigation. Recently researchers have used the general terms Sudden Unexplained Death in Infancy (SUDI) and Sudden Unexpected Infant Death (SUID) as "umbrella-terms" covering unexplained deaths (SIDS); sudden deaths for which SIDS risk factors present but insufficient cause is found; and sudden deaths for which sufficient cause is found. A characteristic feature of such deaths is that, 24-hours before death (or unexpected collapse that led to death), the caregivers were unaware that the baby was at increased risk of dying. The explainable cases include deaths from several recognized causes including infection, metabolic conditions, accidental and non-accidental injury, and various genetic or cardiac conditions as well as "Accidental Suffocation and Strangulation in Bed (ASSB)." SIDS is characterized by a ~50% male excess common to all respiratory infant deaths and a 4-parameter lognormal age distribution - thought to be unique and SIDS main distinguishing characteristic. In this article we model these data for age and/or gender distributions of SUDI/SUID and SIDS reported from the U.K., U.S., Norway and Germany. When pooled together with SIDS, these explained SUDI/SUID data on infant ages and gender have the same distributions as SIDS, indicating that the final mode of death for all SUDI or SUID may be a consequence of different paths to the same biological phenomena as for SIDS, though the mechanism of death remains unclear.

Sudden Infant Death Syndrome: An Update

Sudden Infant Death Syndrome: An Update

Changing infant death rates: diagnostic shift, success story, or both?

Over the past 20 years there have been remarkable and gratifying falls in the rates of infant deaths in many Western countries due to declining numbers of cases attributed to sudden infant death syndrome (SIDS). This reduction in unexpected infant fatalities has been due in large part to the effects of the ‘‘Reduce the Risks’’ campaigns where community awareness programs were undertaken by local and national SIDS organizations to warn parents and carers of the potential dangers of prone sleeping, cigarette smoke exposure, head covering and overheating [1]. However, in the late 1970s changes in infant mortality had also been noted in a number of jurisdictions which were not due to a real reduction in lethal events, but were due instead to pathologists reassigning causes of death—in this instance from respiratory infections to SIDS [2]. This was termed a diagnostic shift and was clearly identified by a lack of change in overall infant mortality figures. Diagnostic shift was regarded as an unfortunate event which had the potential to influence the recording of mortality figures. Concerns were expressed that the fall in infant death rates in the early 1990s might be due to a similar diagnostic shift distorting mortality data [3, 4]. In this instance, however, studies revealed that the fall in numbers of SIDS deaths was matched by an associated fall in overall infant mortality, and that other causes of infant death had not significantly increased [4]. Thus, changing diagnostic practice by pathologists was not thought to be a factor in the initial change in patterns of infant death. In addition to identifying risk factors for SIDS, the 1990s was also characterized by moves to improve infant death investigations with the establishment of standardized protocols for both death scene and autopsy examinations [5, 6]. These protocols were aimed at improving diagnostic accuracy by providing additional information to enable more accurate determination of causes of death and to facilitate more meaningful comparisons of infant death rates between populations. In addition it was hoped that international guidelines would improve research in this area and further reduce infant death rates. The International Standardized Autopsy Protocol (ISAP) and Sudden Unexplained Infant Death Investigation Report Form (SUIDIRF) were subsequently formulated, endorsed by professional bodies, and published [5, 6]. Trends in infant deaths and diagnostic practices continued to be monitored throughout the 1990s and this subsequently showed that changes in diagnoses were occurring; i.e. the concerns that a diagnostic shift was present were realized. Pathologists had been identifying more cases of accidental asphyxia from dangerous sleeping environments [7, 8], in addition to detecting rarer forms of sudden death involving underlying metabolic and genetic conditions [9]. Although this was initially considered to be a problem, representing again a possible arbitrary reclassification of deaths, it was soon realized that this was in fact a positive finding. Changes in diagnoses in this instance endorsed the usefulness of protocols by demonstrating that they were providing useful information to help pathologists to identify conditions that would previously have been included under the umbrella of ‘‘SIDS.’’ In other words, protocols were allowing more cases of unexpected infant death to be removed from the ‘‘diagnostic dustbin’’ of SIDS [10]. As is often the case, however, improvements in medicine are often accompanied by opposing trends. In this case R. W. Byard (&) Discipline of Anatomy and Pathology, Level 3 Medical School North Building, The University of Adelaide, Frome Road, Adelaide 5005, Australia e-mail: roger.byard@sa.gov.au

Epidemiology of Infant Death Among Black and White Non-Hispanic Populations in Hampton Roads, Virginia

To evaluate the presence of racial disparities in infant mortality rates and assess risk factors for infant death among black and white populations in Hampton Roads, Virginia. A retrospective study with secondary analyses of linked birth/death certificate data was conducted using a sample of 201,610 live-born infants and 1659 infant deaths identified between January 1, 1999 and December 31, 2008 in Hampton Roads. Infant, neonatal, and postneonatal mortality rates were significantly (P < 0.0001) higher among black compared with white populations. Racial disparities were noted whereby black infants were significantly (P < 0.0001) more likely to die of conditions originating in the perinatal period, whereas white infants were significantly more likely to die of congenital malformations, deformations, and chromosomal abnormalities (P < 0.0001) or neoplasms (P = 0.03). Multivariable logistic modeling suggested significantly higher odds of black infants dying in the first year of life than white infants. Among blacks, the odds of infant death were inversely related to maternal education. Among whites, the odds of infant death declined with increasing parity. Among black and white populations, history of child death, presence of maternal morbidities and the Kotelchuck Maternal Utilization of Prenatal Care Index were key determinants of infant death. Black infants are at higher odds of dying compared with white infants in Hampton Roads, Virginia. Continued efforts should target prenatal care, preterm delivery, and low-birth-weight infants and neonates to reduce infant mortality rates.

How Risk Factors for SIDS Have Changed Since the Back-to-Sleep Campaign

Although the rate of sudden infant death syndrome (SIDS) in the U.S. has declined more than 50% since the start of the 1994 Back-to-Sleep campaign, the

Systemic administration of Interleukin‐1beta enhances thermal prolongation of the laryngeal chemoreflex in decerebrate piglets—implications for Sudden Infant Death Syndrome

The laryngeal chemoreflex (LCR) causes apnea and may initiate the process leading to the Sudden Infant Death Syndrome (SIDS). Recent upper respiratory tract infection (URI) and thermal stress are risk factors for SIDS, and elevating body temperature in decerebrate piglets prolongs the duration of LCR apnea. We tested the hypothesis that administering interleukin‐1beta (IL‐1b), a cytokine that is elevated by URIs and in turn elevates body temperature, would enhance thermal prolongation of the LCR. Decerebrate piglets (P4 to P13) were tracheostomized, paralyzed and ventilated, and 0.1 ml of water was introduced into the larynx to elicit the LCR. We recorded the duration of phrenic apnea and respiratory disruption associated with the LCR at normal body temperature and when body temperature was elevated by 2 degrees C. Pretreatment by intraperitoneal (IP) administration of IL‐1b (3 microgm/Kg) enhanced thermal prolongation of the LCR compared to control animals treated simultaneously with 10 mg/Kg IP indomethacin and IL‐1b. We conclude that IL‐1b enhances thermal prolongation of the LCR through a mechanism that requires synthesis of additional inflammatory mediators.Support: grants 36379 &amp; 42707 from the NICHD

A mouse model to study the link between hypoxia, long QT interval and sudden infant death syndrome

SUMMARYThe pathology of sudden infant death syndrome (SIDS) is poorly understood. Many risk factors, including hypoxia, have been identified. Prolongation of the ECG QTc interval is associated with elevated risk of SIDS but its aetiology in most cases remains unknown. We have characterised ECG changes in the newborn mouse in the hours and days following birth. There was a steady increase in heart rate alongside significant decreases in QTc interval, QRS duration and QTc dispersion over the first 10 postnatal days. Birth into hypoxia (10% FiO2) prevented electrocardiac maturation, downregulated cardiac ion-channel expression and led to neonatal death. We found that risk of death decreased with increasing age of exposure to hypoxia. Genetic elevation of cardiac hypoxia-signalling after birth in αMHC-Cre::VHLfl/fl mice also prevented electrocardiographic maturation, leading to arrhythmia and death before weaning. Immunohistochemistry and western blotting revealed internalisation and dephosphorylation of Connexin43. We conclude that increased ambient oxygen concentration after birth drives maturation of the cardiac electrical conduction system, failure of which leads to aberrant ion channel and Connexin43 expression and predisposes to arrhythmia and sudden death. This is consistent with known risk factors of SIDS and provides a link between neonatal hypoxia, ECG abnormalities and sudden death.

Nicotine Delays the Development of Cardiac Conduction System: Leading to Sudden Infant Death Syndrome

More than 50% of newborns death is due to the sudden infant death syndrome (SIDS). Exposure to cigarette smoke represents the highest risk factor for SIDS. Cardiac bradycardias are observed in most cases. The cardiac conduction system is molded by a resorptive degeneration process (apoptosis). Nicotine is known to possess anti-apoptotic effects. Therefore, we hypothesized that nicotine disrupts the maturation of the sinoatrial (SAN) and auriculoventricular (AVN) nodes, which in return can cause arrhythmias leading to SIDS.Osmotic pumps delivering nicotine were implanted in rabbits at their second week of pregnancy. We characterized the level of apoptosis in SAN of newborn rabbits exposed or not to nicotine. Moreover, we did patch clamp techniques to evaluate the effects of nicotine on adrenergic responses. Finally, using quantitative PCR, we quantified the expression of sodium channels in the atria of the rabbits’ hearts at 0, 7, 14 and 30 days postnatal.Nicotine decreased apoptosis at 7 days postnatal, thus preventing the early development of SAN. At 14 and 30 days when serum nicotine levels reached 0 ng/ml, apoptosis reached levels similar to unexposed rabbit at 7 days. Nicotine inverted the expression pattern of SCN1A and SCN5A in the SAN of rabbits at 0 day postnatal and increased the expression of SCN5A by 70 times in the right atrium at 30 days postnatal. Expression of SCN1A and SCN4A increased by 4 fold in the 0 day old treated rabbit in the atria. Finally, nicotine suppresses the effect of isoproterenol on sodium channels.In conclusion, our study demonstrates that nicotine disturbed the resorptive degeneration process, delays the development of the SAN and regionally perturbed the expression of SCN1A, SCN4A and SCN5A. These changes might explain the conduction disturbances observed in SIDS.