Higher Incidence Of Sudden Infant Death Syndrome Research Articles

Association between Temperature and Sudden Infant Death Syndrome in the US

Introduction: Sudden infant death syndrome (SIDS) is the most common cause of post-neonatal infant death. Studies have attributed higher incidence of SIDS in the cold season to overwrapping infants...

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.

Another new theory explaining the cause of SIDS

A great number of theories explaining the cause of the Sudden Infant Death Syndrome (SIDS) have been published during the last decades, many in so-called `high-impact' journals. In fact, few diseases in paediatrics have inspired so many scientists in various fields to solve the enigma why apparently healthy infants suddenly die. A new study was recently published in JAMA by Paterson et al. (1). The authors reported that victims of SIDS have a decreased binding of serotonin in some important brain nuclei involved in sleep and respiration. The reduced receptor binding density was particularly seen in the male SIDS cases. This finding confirms a previous observation by Ozawa et al. (2). Furthermore, Paterson et al. found a significantly higher serotonin neuron density in medullary nuclei involved in homeostatic function. These findings are very thought-provoking and also fit into the well-established finding that sleeping in prone position increases the risk. Infants who lie with the face down towards the mattress may develop desaturation and carbon dioxide retention. Normally, this should result in arousal and awakening of the infant, but deficiencies involving serotonin containing nuclei may hazard this mechanism. It is interesting that serotonin has been proposed to play a crucial role in the CO2-sensitivity (3). The finding of more marked disturbances of the serotonin system in the male SIDS cases also fit with the higher incidence of SIDS among boys. Furthermore, Weese-Mayer et al. have demonstrated that victims of SIDS often has a mutation of the PHOX2b gene, which is involved in the encoding of the serotonin synthesizing enzymes (4). This was mainly found in Afro-American infants who have a high risk of dying of SIDS. The findings are novel and of considerable interest to understand the mechanisms causing SIDS. However, the limitations of this study have also been pointed out in an Editorial in JAMA (5). The size of the study group is relatively small, with only 31 index infants and 10 control cases. The main problem is that one third of the index cases were ex-preterm infants. Although prematurity is a well-known risk factor for SIDS it cannot be excluded that the differences between the SIDS victims and the controls may be due to immaturity. Only one of the ten controls was born preterm. The finding that the expression of neurotransmitters and their receptors may be disturbed in SIDS victims is not new. The same research group has earlier reported changes of muscarinic receptors (6). Neuropeptides like substance P have also been found to be different in SIDS victims (7). Furthermore, nicotinic receptors may also be involved, since maternal smoking is one of the most important risk factors causing SIDS (8). The current findings were published in a high-impact journal and aroused a lot of media attention and were presented in the CNN news nearly every hour on the day they were published, like many other new hypotheses on SIDS (Fig. 1). This can be compared with the first reports suggesting the importance of putting the baby in a back position instead of a prone position (9-11). It took some time before they attracted attention, resulting in the most successful prevention of SIDS. Some theories on the cause of SIDS published in the New England Journal of Medicine.

Interleukin-10 and sudden infant death syndrome

Uncontrolled pro-inflammatory responses to infections or bacterial toxins have been suggested to play a role in triggering the physiological events leading to sudden infant death syndrome (SIDS). We tested the hypothesis that these uncontrolled responses might be due to interactions between the gene polymorphisms inducing low levels of IL-10 and exposure to cigarette smoke. In vitro, the IL-10 (G-1082A) polymorphism was associated with low IL-10 levels and the –1082G allele was associated with high levels. The first objective was to assess the distribution of this polymorphism among SIDS infants, parents of SIDS infants and controls, and two ethnic groups: Aboriginal Australians who have a high incidence of SIDS; and Bangladeshis who in Britain have a low incidence of SIDS compared with Europeans. The second objective was to assess effects of human recombinant IL-10 on interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) responses of human leukocytes to staphylococcal toxins implicated in SIDS. The third objective was to assess IL-10 responses to endotoxin and toxic shock syndrome toxin (TSST) from leukocytes of smokers and non-smokers in relation to the IL-10 (G-1082A) polymorphism. There were major differences in the distributions of these polymorphisms between Europeans and Bangladeshis ( p=0.00) and between Europeans and Aboriginal Australians ( p=0.00); however, they were similar for the Bangladeshi and Aboriginal Australian subjects. There were no significant differences in the distribution of these polymorphisms among SIDS infants or parents of SIDS infants compared to control groups. IL-10 significantly reduced IL-6 and TNF-α responses to TSST and staphylococcal enterotoxins A and C. At 50 ng ml −1, IL-10 significantly increased TNF-α but not IL-6 responses to TSST and enterotoxin A. Although IL-10 responses to endotoxin were lower from leukocytes of smokers who were homozygous for the G allele, the differences were not significant; however, significantly lower IL-10 responses were found for smokers who were homozygous for the A allele ( p=0.01) and heterozygotes ( p=0.04). The pooled data found smokers had significantly lower levels of IL-10 responses to TSST, but there were no significant differences for smokers compared with non-smokers for the three genotypes. The high incidence of SIDS and serious respiratory infections among Aboriginal Australian infants and the low incidence of these conditions among Bangladeshi infants might be explained in part by our findings of differences in IL-10 responses between smokers and non-smokers. The lowest levels of IL-10 responses were observed among smokers who were homozygous for the A allele which is most prevalent among the Aboriginal Australians (83%) and Bangladeshis (84%). The major difference between the risk factors for SIDS in these two groups is the level of exposure of infants to cigarette smoke associated with maternal smoking.

Interleukin 1-β responses to bacterial toxins and sudden infant death syndrome

We tested the hypothesis that significantly higher IL-1β responses to toxic shock syndrome toxin (TSST) noted for parents of sudden infant death syndrome (SIDS) infants might be due in part to genetic factors such as the IL-1β (C-511T) and IL-1RN (T + 2018C) single nucleotide polymorphisms (SNP). The first objective was to assess the distribution of these polymorphisms among SIDS infants, parents of SIDS infants and controls, and two ethnic groups: Aboriginal Australians who have a high incidence of SIDS; and Bangladeshis who in Britain have a low incidence of SIDS compared with Europeans. The second objective was to assess IL-1β responses to endotoxin and toxic shock syndrome toxin (TSST) from leukocytes of smokers and non-smokers in relation to these polymorphisms. There were major differences in the distributions of the IL-1β (C-511T) SNP between Europeans and Bangladeshis ( p=0.00) and between Europeans and Aboriginal Australians ( p=0.00); however, they were similar for the Bangladeshi and Aboriginal Australian subjects. The allele frequency distribution of the IL-1RN (T + 2018C) SNP for the Aboriginal Australians was statistically different from the European group ( p=0.00), but it was not different from the Bangladeshi group ( p=0.09). Compared with controls of European origin, there were no significant differences in the distribution of these polymorphisms among SIDS infants or parents of SIDS infants. For the IL-1β (C-511T) SNP, the highest IL-1β responses to endotoxin were obtained with leukocytes of non-smokers with the heterozygous CT genotype. Smokers had significantly lower levels of IL-1β in response to endotoxin ( p=0.01) and these differences were significant for donors with the wild type CC ( p=0.00) and CT ( p=0.03) genotypes. Similar patterns were observed for IL-1β responses to TSST, but the differences were not significant. For the IL-1RN (T + 2018C) SNP, the highest IL-1β responses to endotoxin were obtained with leukocytes from non-smoker donors with the wildtype TT genotype and significantly lower responses were found with leukocytes from donors with the TC genotype ( p=0.02). The responses of smokers were lower but the differences were significant only for donors with the TT genotype ( p=0.00). Similar patterns were observed for IL-1β responses to TSST, but the differences were not significant. IL-1β responses to both endotoxin and TSST were increased for the small number of smokers with the TT genotype of the IL-1β (C-511T) SNP. The TT genotype of the IL-1β (C-511T) was found predominantly among Aboriginal Australian and Bangladeshi individuals but only a small proportion of Europeans. Smokers with the AA genotype of the IL-10 (G-1082A) SNP which is found predominantly among these two groups had significantly lower levels of IL-10 responses. If cigarette smoke enhances pro-inflammatory responses and reduces anti-inflammatory responses in individuals with these genotypes, this might partly explain the increased susceptibility of Aboriginal Australian infants to infections and SIDS.

Higher incidence of SIDS at weekends, especially in younger infants

Background: An increased incidence of sudden infant death syndrome (SIDS) at weekends has been previously noted, although it has not been found in all studies. Where a weekend effect has...

Back to Sleep for Preterm Infants to Reduce the Risk of SIDS

After completing this article, readers should be able to: 1. Compare the prevalence of sudden infant death syndrome (SIDS) among preterm and term infants. 2. Delineate the developmental period at which there is a high incidence of SIDS. 3. Compare the age associated with the highest incidence of SIDS in preterm and term infants. 4. List the most important factor associated with SIDS. 5. List other factors contributing to SIDS. Most SIDS deaths occur during a narrow developmental window of 1 to 4 months postnatal age, a period when significant changes occur in sleep and circadian rhythms organization and in the modulation of brainstem and cortical centers involved in cardiovascular/respiratory and arousal state control. There is consensus that SIDS typically occurs during sleep periods, but it is unclear whether SIDS occurs during sleep itself, within transitions between sleep and waking, or between sleep states. Nevertheless, the link between the peak occurrence of SIDS and the period of major sleep developmental changes suggests that SIDS is state-related and involves abnormal interactions between the state-modulated arousal threshold and central regulatory mechanisms of cardiovascular/respiratory control. It also is generally agreed that infants who are at risk for SIDS may have central nervous system abnormalities at birth that may be too subtle to detect clinically. Most of the SIDS pathology data show abnormalities in the brainstem and hypothalamus, areas involved in sleep, arousal, central cardiovascular/respiratory control, and circadian rhythms. Among the most notable changes in sleep and circadian rhythms occurring between 1 and 4 months of age, both in term and preterm (corrected age) infants, are: 1) an increase in the percentage and episode length of quiet sleep (QS), 2) sleep onset changes from rapid eye movement or …

A competing risk model of sudden infant death syndrome incidence in two US birth cohorts

Objectives: To compare changing incidence and changing risk factors associated with sudden infant death syndrome (SIDS) in the 1989 and 1996 US birth cohorts. Study design: All available singleton births over 500 g from the 1989 linked birth–infant death file and the 1996 and 1997 Perinatal Mortality files were examined. A log-logistic survival model was used to explicitly account for declining competing risks among low birth weight infants. Results: Controlling for maternal prenatal smoking and other confounders, SIDS incidence declined by >33% between the 2 survey years (adjusted odds ratio = 0.628 with 95% CI [0.598, 0.660]). Self-reported declines in maternal prenatal smoking were also associated with significant declines in SIDS incidence. African American infants and infants born weighing <1000 g experienced increased relative risk compared with non-Hispanic white infants born weighing >2500 g. Hispanic/Latino infants had significantly lower SIDS risk than non-Hispanic white infants in both years. Accounting for declining competing risks and other factors, relative SIDS risks among infants born between 500 and 1000 g increased over the study period. Conclusions: SIDS incidence sharply declined between 1989 and 1996. High incidence of SIDS in African Americans and increased relative SIDS risk for infants born weighing <1000 g require increased attention from clinicians and public health policy makers. (J Pediatr 2001;138:661-7)

The role of infection in sudden infant death syndrome.

Studies on the potential role of infectious agents in sudden infant death syndrome (SIDS) have been published over the years in a variety of journals. The aim of this special issue of FEMS Immunology and Medical Microbiology is to bring together a group of the most recent studies from Europe, Australia and Canada which cover epidemiology and laboratory studies examining hypotheses relating to infection and inflammation in SIDS. The articles in this issue examine evidence for the involvement of specific micro-organisms in SIDS and the problems relating to experimental studies on infection in relation to the underlying pathology of these deaths. There is an update on the evidence for the common bacterial hypothesis proposed in 1987 examining risk factors identified in epidemiological studies, particularly how the prone sleeping position could affect bacterial colonisation or induction of toxins. Evidence for induction of inflammatory responses in SIDS infants is reviewed and the relation of these responses to mechanisms proposed as causes of death assessed. Factors found to be associated with reduction of the risk of SIDS (breast feeding and immunisation) are examined in relation to some of the toxigenic bacteria implicated in these deaths. Finally, the high incidence of SIDS in some ethnic groups is examined as a potential model to investigate the contributions of genetic, environmental and cultural differences to susceptibility of infants not only to SIDS but to serious respiratory tract infections.

The role of infection in sudden infant death syndrome

Studies on the potential role of infectious agents in sudden infant death syndrome (SIDS) have been published over the years in a variety of journals. The aim of this special issue of FEMS Immunology and Medical Microbiology is to bring together a group of the most recent studies from Europe, Australia and Canada which cover epidemiology and laboratory studies examining hypotheses relating to infection and inflammation in SIDS. The articles in this issue examine evidence for the involvement of specific micro-organisms in SIDS and the problems relating to experimental studies on infection in relation to the underlying pathology of these deaths. There is an update on the evidence for the common bacterial hypothesis proposed in 1987 examining risk factors identified in epidemiological studies, particularly how the prone sleeping position could affect bacterial colonisation or induction of toxins. Evidence for induction of inflammatory responses in SIDS infants is reviewed and the relation of these responses to mechanisms proposed as causes of death assessed. Factors found to be associated with reduction of the risk of SIDS (breast feeding and immunisation) are examined in relation to some of the toxigenic bacteria implicated in these deaths. Finally, the high incidence of SIDS in some ethnic groups is examined as a potential model to investigate the contributions of genetic, environmental and cultural differences to susceptibility of infants not only to SIDS but to serious respiratory tract infections.

Screening for SIDS: A neonatal perspective.

* Abbreviations: SIDS = : sudden infant death syndrome • ECG = : electrocardiogram The good news is that the incidence of sudden infant death syndrome (SIDS) is steadily decreasing. Preliminary available US data reveal a SIDS rate of 0.74 per 1000 live births in 1996, down from a rate of 1.5 per 1000 live births over the last 20 years.1 In low and very low birth weight infants the SIDS rate has consistently been three- to fourfold higher than that in term infants.2 Whether this low birth weight population is exhibiting a similar decline in SIDS rate is unclear. Therefore, neonatologists who spend most of their time taking care of preterm infants remain wary about the high-risk status of this population, especially because the mechanism underlying the high incidence of SIDS in preterm infants is unclear. Any rational way to screen such infants (and others) for SIDS risk status would be very welcome. Historically, neonatal apnea screening via diagnostic pneumograms seemed a good place to begin. Persistence of …

The role of infection in sudden infant death syndrome

Studies on the potential role of infectious agents in sudden infant death syndrome (SIDS) have been published over the years in a variety of journals. The aim of this special issue of FEMS Immunology and Medical Microbiology is to bring together a group of the most recent studies from Europe, Australia and Canada which cover epidemiology and laboratory studies examining hypotheses relating to infection and inflammation in SIDS. The articles in this issue examine evidence for the involvement of specific micro-organisms in SIDS and the problems relating to experimental studies on infection in relation to the underlying pathology of these deaths. There is an update on the evidence for the common bacterial hypothesis proposed in 1987 examining risk factors identified in epidemiological studies, particularly how the prone sleeping position could affect bacterial colonisation or induction of toxins. Evidence for induction of inflammatory responses in SIDS infants is reviewed and the relation of these responses to mechanisms proposed as causes of death assessed. Factors found to be associated with reduction of the risk of SIDS (breast feeding and immunisation) are examined in relation to some of the toxigenic bacteria implicated in these deaths. Finally, the high incidence of SIDS in some ethnic groups is examined as a potential model to investigate the contributions of genetic, environmental and cultural differences to susceptibility of infants not only to SIDS but to serious respiratory tract infections.

PHYSIOLOGICAL STUDIES OF GASTRO‐OESOPHAGEAL REFLUX AND AIRWAY PROTECTIVE RESPONSES IN THE YOUNG ANIMAL AND HUMAN INFANT

1. The mechanisms that underlie the Sudden Infant Death Syndrome (SIDS) must explain its two unique features; age at death and death during apparent sleep. 2. The occurrence of gastro-oesophageal reflux (GOR) during active sleep in infants presenting with apparent life threatening episodes (ALTE) and their similar age distribution to SIDS infants, suggested that reflux could be a cause of asphyxia. 3. Sleep related GOR was found to be a physiological and not a pathological event in normal, healthy term infants. 4. In healthy term infants, those infants that were formula-fed (who have a higher incidence of SIDS) had significantly longer oesophageal clearance times for acid reflux and significantly more active sleep compared with breast fed infants. 5. In very preterm infants (who are at increased risk for SIDS), both the frequency and duration of reflux during active sleep was significantly less at term equivalent age compared with healthy term infants, suggesting additional factors must operate to promote an ALTE. 6. One mechanism which may explain the pathogenesis of GOR could be that the reflux reaches the level of the pharynx and this, in turn, stimulates laryngeal receptors to produce apnoea. 7. Simulated reflux to the level of the pharynx in the sleeping piglet evoked airway protective responses, namely swallow, arousal and occasionally expectoration, but neither apnoea nor oxygen desaturation. 8. In the same piglets treated with pentobarbitone sodium, swallowing was impaired and arousal depressed. Simulated reflux to the pharynx produced significant apnoea and oxygen desaturation and death in two of five piglets.(ABSTRACT TRUNCATED AT 250 WORDS)

Sudden infant death syndrome in infants of substance-abusing mothers

A population-based study was performed to determine whether substance abuse during the perinatal period may be a risk factor for sudden infant death syndrome (SIDS). The incidence of SIDS was studied in 2143 infants of substance-abusing mothers (ISAM) born in Los Angeles County during 1986 and 1987 who were reported to the Los Angeles County Department of Health Services because of a history of drug exposure or positive urine test results in the mother, infant, or both. By comparing the ISAM birth reports with records of autopsy-proven SIDS in Los Angeles County, we found 19 SIDS cases in the population of 2143 ISAM, a SIDS rate of 8.87 cases per 1000 ISAM (95% confidence interval 5.3 to 13.8). This was significantly higher than the SIDS rate for the non-ISAM general population: 396 SIDS deaths among 325,372 live births, an incidence rate of 1.22 cases per 1000 births, p less than 0.00001. The age of ISAM at death was 99 +/- 63 (mean +/- SD) days compared with 91 +/- 52 days for the non-ISAM population (not significant). The incidence of SIDS was significantly greater in male infants, during the winter months, in black infants, and in non-Hispanic white infants in the non-ISAM population. Such differences were not observed in the ISAM group. A greater incidence of symptomatic apnea was reported before SIDS for the ISAM than for the non-ISAM population (22% vs 5.4%, p = 0.022). We conclude that ISAM have a higher incidence of SIDS than the non-ISAM general population. However, it was not possible to separate maternal substance abuse from other confounding variables that may also have had an impact on SIDS risk in the ISAM group.