Iron, infection and sudden infant death

Three risk factors for sudden infant death syndrome are well established: maternal smoking, prone sleeping position and non-breast feeding. Two additional risk factors have been proposed: microbial infection in the gastrointestinal or respiratory tracts and iron loading. This review endeavors to integrate these five disparate factors into a unifying concept.     

Generalized view of the origins of the sudden infant death syndrome

A hypothesis is present that explains Sudden Infant Death Syndrome (SIDS) as an outcome of biological immaturity. This hypothesis fits the known characteristics of SIDS and does not conflict with other possible explanations of its genesis.     

Sudden infant death syndrome associated with rotavirus infection

Rotavirus was detected in the stools of five children stricken with sudden infant death syndrome (SIDS) over a three-week period. While none of the children had acute gastroenteritis, four of the five had acute upper respiratory infections. Rotavirus was also identified in tracheal aspirates from two of the infants. Extensive investigations failed to reveal the presence of any other viruses or toxins in specimens obtained from the five children with SIDS. Rotavirus was not found in the stool specimens obtained from a control group of 36 infants including six who died of causes other than SIDS. Future attempts at the prevention of rotavirus infections should be directed at populations susceptible to sudden infant death syndrome.     

IL-10 gene polymorphisms are associated with infectious cause of sudden infant death

Cytokines are involved in regulating the intensity and duration of the immune response, and cytokine production is carefully regulated. With regard to sudden infant death, interleukin-10 (IL-10) is of special interest. This is an immunregulatory cytokine that plays an important role in the development of infectious disease. The purpose of this study was to elucidate the relationship between polymorphisms in the promoter region of the IL-10 gene and sudden infant death due to either sudden infant death syndrome (SIDS) or infection. The polymorphisms investigated include the SNPs in base pairs (bp) -1082, -819, -592, and the two microsatellites IL-10G and IL-10R. The main finding is an association between the ATA haplotype and the ATA/ATA genotype and infectious death. The group of infectious deaths also had a higher percentage of the genotypes G21/G22 and G21/G23, compared with the SIDS patients. In addition, G21/G22 was found in a higher percentage of the SIDS patients than in the controls. These findings lead us to speculate that, in some situations, an infant with an unfavorable IL-10 genotype may exhibit aberrant IL-10 production, which in turn leads to an imbalance in the immune response and renders the infant unable to cope with the infection.     

The role of infection and inflammation in sudden infant death syndrome

Sudden Infant Death Syndrome (SIDS) is the most common cause of post-neonatal mortality in the developed world. The exact cause of SIDS is likely to be multifactorial involving a critical developmental period, a vulnerable infant, and one or more triggers. Many SIDS infants have a history of viral illness preceding death. Prone sleep position, one of the leading risk factors, can increase airway temperature, as well as stimulate bacterial colonization and bacterial toxin production. Markers of infection and inflammation are often found on autopsy along with microbial isolates. Although the causal link between infection and SIDS is not conclusive, there is evidence that an infectious insult could be a likely trigger of SIDS in some infants.     

IL6 G-174C associated with sudden infant death syndrome in a Caucasian Australian cohort

The aims of this study were to analyze IL6 G-174C in relation to high interleukin (IL)-6 concentrations found in some sudden infant death syndrome (SIDS) infants, and to assess the effects of IL6 G-174C, smoking status, and gender on IL-6 responses. SIDS infants, parents of SIDS infants, and populations with high (Aboriginal Australian), medium (Caucasian) or low (Bangladeshi) SIDS incidences were genotyped. Leukocytes were stimulated in vitro with endotoxin and IL-6 responses were assessed in relation to IL6 G-174C genotype, smoking status, and gender. The study findings showed that GG genotype, associated with high IL-6 responses, was predominant among Australian SIDS infants (58%) compared with control subjects (38%, p = 0.02), as well as Bangladeshis (94%) and Aboriginal Australians (88%) compared with Caucasians (42%, p < 0.01). GC smokers had higher median IL-6 responses (8.4 ng/ml(-1)) than GG (3.5 ng/ml(-1), p = 0.01) or CC smokers (2.4 ng/ml(-1), p < 0.01). GG nonsmokers had higher median IL-6 responses (4.9 ng/ml(-1)) than GG smokers (p < 0.05). Gender did not affect IL-6 responses. In conclusion, an association between IL6 G-174C and Australian SIDS infants was observed. IL6 G-174C alone cannot explain observed differences in the incidence of SIDS in the Bangladeshi and Aboriginal Australian populations. Further investigations are needed on interactions between smoking and gene polymorphisms in relation to proinflammatory responses implicated in SIDS.     

Exchange transfusions for extreme hypertriglyceridemia in a 7-week-old infant with multi-organ failure

Severe hypertriglyceridemia is the third most common cause of acute pancreatitis and is strongly associated with an increased risk of cardiovascular disease. In infants, the most common cause of severe hypertriglyceridemia is lipoprotein lipase deficiency. We describe a 7-week-old infant with severe hypertriglyceridemia, who presented with frequent gastrointestinal bleeding, respiratory distress, a decreased level of consciousness and lipemia retinalis. Triglycerides were reduced from 734 to 2 mmol/L (64,956–177 mg/dL), by exchange transfusions. The infant made a remarkable recovery with no sequelae. This case highlights atypical, protean presentations and a potential treatment when established therapies are unavailable.     

Death-scene investigation in sudden infant death

We conducted death-scene investigations in 26 consecutive cases in which a presumptive diagnosis of sudden infant death syndrome (SIDS) was made and the infants were brought to the emergency room of the Kings County Hospital Center between October 1983 and January 1985. In six cases, we observed strong circumstantial evidence of accidental death. In 18 other cases, we discovered various possible causes of death other than SIDS, including accidental asphyxiation by an object in the crib or bassinet, smothering by overlying while sharing a bed, hyperthermia, and shaken baby syndrome. This study suggests that many sudden deaths of infants have a definable cause that can be revealed by careful investigation of the death scene and that the extremely high rate of SIDS (4.2 per 1000 live births) reported in the population of low socioeconomic status served by Kings County Hospital Center should be questioned.     

Myocarditis and sudden infant death syndrome

This is a retrospective survey of findings of myocarditis in 437 infants under the age of 1 year who died suddenly and unexpectedly between 1982 and 1999, and were investigated at the Department of Forensic Medicine in Stockholm, Sweden. Myocarditis was diagnosed in 69/410 infants who died naturally (16.8%) and in 2/27 violent deaths (7.4%). In 43/410 natural deaths (10.5%) the myocarditis was an isolated finding and the only explanation for cause of death and in 26 (6.3%) there were additional possible causes of death. The myocarditis was acute in 45/69 and chronic in 24/69 natural deaths, and was found to occur as early as at a few weeks of age. No specific risk factors were found when reviewing critical time of year, age, gender, previous symptoms, sleeping position, aspiration of gastric contents and environmental factors in infant deaths with finding of myocarditis compared to 313 deaths due to sudden infant death syndrome. Myocarditis was found in 13 of 37 deaths where cultures for cytomegalovirus were positive. More than 50% of the foci of the isolated myocarditis were located in the upper part of the interventricular septum and the adjacent part of the right atrium, areas including parts of the conduction system. This localisation is significant for the cause of death when comparing deaths with myocarditis as an isolated finding to deaths with other possible causes.     

Isolated cardiac amyloidosis associated with sudden death

An unusual case of localized cardiac amyloidosis was associated with sudden death in the absence of prior symptoms of heart disease. Autopsy studies showed amyloid deposition in the ventricular myocardium and conduction system; there were no deposits in other viscera, and evidence of a plasma cell dyscrasia was lacking. Thus, it appears that isolated involvement of the heart by amyloidosis may cause death, even in patients who do not have a history of congestive heart failure or arrhythmia.     

Association of IL-10 genotype with sudden infant death syndrome

Sudden infant death syndrome (SIDS) is a major cause of infant death of unknown etiology. We propose that SIDS results from a genetically determined imbalance in the production of inflammatory and anti-inflammatory cytokines in response to the infant’s microbial flora. We were especially interested to know the relationship between SIDS and genetically determined higher or lower production of IL-10, an anti-inflammatory cytokine. Biallelic polymorphisms in the promoter region of the IL-10 gene associated with higher or lower production of IL-10 were determined in a SIDS and in a control group using a sequence-specific oligonucleotide approach. One particular allele of the IL-10 gene, the IL-10-592*A allele, was significantly associated with SIDS. Indeed, 70% of the SIDS babies carried the IL-10-592*A allele (p = 0.007 compared with control). In addition, there was a significant reduction in the frequency of homozygosity for the allele IL-10-592*C (p = 0.001 compared with control). Carrying the A allele (either A/A or A/C) had an odds ratio of 3.3 (95% confidence interval 1.4–8.0). In the same patients there was no association with other IL-10 gene polymorphisms nor with other cytokine (TNF-, TGF-β1) genotypes, emphasizing the particular relationship between SIDS and the IL-10-592*A allele.     

TNF-alpha promoter polymorphisms in sudden infant death

Several studies indicate that the immune system is stimulated in sudden infant death syndrome (SIDS). Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that strongly affects the cytokine cascade. A genetic variant associated with high production of TNF-alpha may thus be of significance in the pathogenesis of SIDS. The purpose of the current study was to investigate possible relationships among the promoter polymorphisms -1031T/C, -857C/T, -308G/A, -244G/A, and -238G/A in the TNF-alpha gene and SIDS. The subjects investigated consisted of 148 SIDS cases, 56 borderline SIDS cases, 41 cases of infectious death, and 131 adult controls. When investigating each single nuclear polymorphism (SNP) separately, associations between -238GG and SIDS (p=0.022) and between -308GA and borderline SIDS (p=0.005) were found. There were no associations between any of the other SNPs investigated. Furthermore, a SNP profile was constructed by creating a genotype pattern from the investigated SNPs. Fifteen gene combinations were obtained, and 4 profiles had significantly different frequencies in SIDS cases and controls. The two SNP profiles -1031CT, -238GG, -857CC, -308GG and -1031TT, -238GG, -857CC, -308AA were found more often in SIDS and may thus be unfavorable. The findings add evidence to the theory that an unfavorable genetic profile in the TNF-alpha gene may be involved in SIDS by exposing the infant to both a high level of and prolonged exposure to TNF-alpha.     

Budd-Chiari syndrome presenting as sudden infant death

Budd-Chiari syndrome rarely occurs in infants. We report a case of a 1-month-old female infant who presented as a sudden infant death and was found at autopsy to have thrombi occluding both hepatic veins. Microscopically the liver showed perivenular fibrosis extending into the lobule and central venous congestion consistent with Budd-Chiari syndrome.     

Intrauterine hypoxia and sudden infant death syndrome

Sudden infant death syndrome (SIDS) or crib or cot death are synonyms for the sudden, unexpected and unexplained death of an infant. The incidence of SIDS has been estimated to be from 1-2% to 3%. Protracted intrauterine hypoxia or recurrent hypoxic insults during fetal life undoubtedly influence the development of the central nervous structures as a tissue most susceptible to hypoxia, although well developed mechanisms of defense against hypoxia exist during the fetal life. The mechanisms underlying SIDS include neurologically compromised infants who are deprived of compensatory mechanisms during sleep, sustaining a hypoxic insult with alterations in neurotransmitter receptors within the regions involved in chemoreception and cardiovascular control. Changes in the brain result from perinatal prolonged hypoxia (persistent reticular pathways in the pons and medulla, astroglia in the brainstem, gliosis of brain nerve nuclei, defects in neurotransmitter receptors, neuronal apoptosis, microthrombosis, and hypoxic ischemic lesion). Hypoxic perinatal risk factors for SIDS included passive and active exposure to cigarette smoking in pregnancy, abuse of drugs, alcohol, coffee and medication in pregnancy, intrauterine growth retardation, perinatal hypoxia with or without resuscitation, preeclampsia, anemia in pregnancy, prematurity, multiparity, multiple pregnancy, pregnant women aged < 20 years and > 35 years, cardiocirculatory, pulmonary and endocrine diseases in pregnancy, and short time interval between two pregnancies. As cigarette smoking has been demonstrated to lead to fetoplacental insufficiency, which result in fetal hypoxia, it is concluded that hypoxia is a precondition for the occurrence of SIDS. Prenatal exposure to cigarette smoke decreases maternal red blood cell count, and concentrations of tyrosine and selenium, reduces fetal and neonatal cerebral blood flow, and increases maternal MCV, leukocytosis, especially neutrophils, monocytes and lymphocytes, maternal and fetal heart rate, systolic and diastolic blood pressure, resistance index in umbilical artery, fetal hemoglobin, cytokine, serotonine, dopamine, catecholamine, hypoxanthine, endorphin and interleukin-6. Pregnancy at a risk of hypoxia, especially in heavy smokers, is a major risk factor for SIDS, and such pregnancy requires close and intensive antenatal monitoring.     

Allergy and the risk of sudden infant death syndrome

Background and Objective There are several sources that suggest that there is a link between allergy and sudden infant death syndrome. We endevavoured to look for evidence of an association between allergic disease and the risk of sudden infant death syndrome (SIDS). Methods A nationwide case-control study covering a region with 78% of all births in New Zealand during 1987–90. Interviews were completed with the parents of 393 (81.0% of total) infants who died from the sudden infant death syndrome (SIDS), and 1592 (88.4% of total) control families who were a representative sample of all hospital births in the study region. Results Eczema was reported in 13.9% control infants compared with only 8.0% of the SIDS infants, univariate odds ratio for this in terms of risk for SIDS was 0.56 (95% confidence interval 0.37, 0.84) for infants with eczema compared with those without. This lesser risk for SIDS was unchanged when adjusted for potential confounding factors. The risk of SIDS was not associated with reported cow's milk reactions or a family history of allergic symptoms once adjustments were made for possible confounding factors. Conclusion Infants with skin disorders identified by their parents as eczema had a low risk for SIDS. Families can be reassured that atopy is not a risk factor for SIDS.