Sudden infant death syndrome (SIDS) in African Americans: polymorphisms in the gene encoding the stress peptide pituitary adenylate cyclase-activating polypeptide (PACAP)

Aims: Mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP) are prone to sudden death in the second post-natal week, having respiratory and metabolic disturbances reminiscent of the human Sudden Infant Death Syndrome (SIDS). Here we test the hypothesis that the human PACAP gene is a site of genetic variance associated with SIDS in a cohort of 92 victims and 92 matched controls.
Methods: Using polymerase chain reaction and sequencing, we examined the PACAP gene in 92 SIDS cases (46 Caucasians and 46 African Americans) and 92 race- and gender-matched controls.
Results: We found no significant associations between PACAP and SIDS in Caucasians. However, in the African Americans, a non-synonymous single nucleotide polymorphism (i.e. an aspartic acid/glycine coding variant, rs2856966) within exon 2 of PACAP was significantly associated with SIDS (p = 0.004), as were haplotypes containing this polymorphism (p < 0.0001). Glycine was three times more likely at this location in the African-American SIDS victims (17 cases) than African-American controls (5 cases).
Conclusion: These data are the first to suggest an association between a variant within the coding region of the PACAP gene and SIDS. Based on these findings, further investigations are warranted into the functional importance of PACAP signaling in neonatal survival and the role of PACAP-signaling abnormalities in SIDS.     

Home monitoring of infants considered at risk for the sudden infant death syndrome

From 1977 to 1981, 500 infants had been referred to evaluate their risk for the sudden infant death syndrome (SIDS). These included 186 infants who had presented an event (prolonged apnea, hypotonia, pallor or cyanosis) initated while asleep, 133 siblings and 181 controls. All-night polygraphic recordings were performed in all infants, and if indicated by the history of the infants, complementary clinical investigations were done. These procedures led to the identification of 50 infants considered at risk for SIDS (10% of all referrals): 30 near-misses for SIDS, 10 siblings and 10 infants with a minor incident during sleep but with abnormal polygraphic recordings. These 50 infants (group I) were monitored at home during sleep with the help of a cardiac and respiratory monitor. Eight infants not considered at risk were monitored similarly at the request of their parents (group II). Forty of the 50 infants in group I presented with repetitive sleep apneas and bradycardias, and required stimulation by their parents to regain normal cardiorespiratory rhythm. Twelve had to be resuscitated at least once for a life-threatening event. None of the infants in group II showed alarms during sleep. Monitoring could be discontinued after a mean length of 7.2 months for the infants in group I, 4.1 months in group II. It is concluded that if identified in time through adequate investigations, some infants may be protected against SIDS through home monitoring. This approach requires expensive and well trained teams, ready, at any time, to cope with the problems that may arise in the homes of the monitored infants.     

Serotonin transporter gene variation in sudden infant death syndrome

AIM: To investigate polymorphisms in the serotonin transporter (5-HTT) gene in cases of sudden infant death syndrome (SIDS) and controls, and further to elucidate a possible relationship between 5-HTT genotypes and external risk factors for SIDS. METHOD: The subjects investigated consist of 163 SIDS cases and 243 controls. Polymorphisms in both the promoter and intron 2 of the 5-HTT gene were investigated, and the genotypes were determined using polymerase chain reaction (PCR) and gel electrophoresis. RESULTS: In the promoter, there was a tendency for the L allele and L/L genotype to be found more often in the SIDS cases than in the controls (p=0.05 and p=0.07, respectively). Regarding the intron 2 polymorphism, there were no differences between the groups, and the SIDS cases were not found to have a higher frequency of either the L/L-12/12 genotype or the L-12 haplotype than the controls. When investigating possible correlations between genotype and risk factors for SIDS, there was a tendency towards different distribution of the promoter genotypes in cases found dead prone compared to cases found dead in other sleeping positions (p=0.06). CONCLUSION: Polymorphisms in the promoter of the 5-HTT gene may be of importance with regard to SIDS.     

Cholinergic and oxidative stress mechanisms in sudden infant death syndrome

Aim:  To determine whether biochemical parameters of cholinergic and oxidative stress function including red cell acetylcholinesterase (AChE), serum/plasma thyroglobulin, selenium, iron, ferritin, vitamins C, E, and A affect risk in apparent life-threatening event (ALTE), sudden infant death syndrome (SIDS), and sudden unexpected death in infancy (SUDI). To assess these biochemical parameters as a function of age; and for influence of pharmacology and epidemiology, including infant health, care, and feeding practices.
Methods:  A multicentre, case–control study with blood samples from 34 ALTE and 67 non-ALTE (control) infants matched for age, and 30 SIDS/SUDI and four non-SIDS/non-SUDI (post-mortem control) infants.
Results:  Levels/activity of the biochemical parameters were not significantly different in ALTE vs. control infants, with the exception of higher vitamin C levels in the ALTE group (p = 0.009). In ALTE and control groups, AChE and thyroglobulin levels increased and decreased respectively from birth to attain normal adult levels from 6 months. Levels of iron and ferritin were higher in the first 6 month period for all infant groups studied, intersecting with vitamin C levels peaking around 4 months of age.
Conclusion:  Lower AChE levels and higher combined levels of iron and vitamin C in the first 6 months of life may augment cholinergic and oxidative stress effect, particularly at the age when SIDS is most prevalent. This may contribute to risk of ALTE and SIDS/SUDI events during infancy.     

Sinus tachycardia in term infants preceding sudden infant death

The quantities of sinus tachycardia in 24-h recordings of the electrocardiogram from 16 full-term infants (37 weeks gestation) who were subsequently victims of the sudden infant death syndrome (SIDS), from 230 randomly selected age-matched full-term survivors and from 64 full-term survivors matched for age and birth weight were measured by computer and manual analysis techniques. Of 16 infants dying of SIDS, 7 had elevated levels of sinus tachycardia (>95th centile in controls) (P<0.01). Although high levels of sinus tachycardia might be of value in identifying infants at high risk of SIDS, these encouraging findings must first be validated by further prospective studies.Abbreviations IHR instantaneous heart rate - SIDS sudden infant death syndrome - ECG electrocardiogram     

脑干功能障碍与婴儿突然死亡综合征

目的　 探讨婴儿突然死亡综合征 (SIDS)的病理机制。 方法 　SIDS和对照组各 16例脑标本 ,通过常规神经病理检查、胶原纤维酸性蛋白 ( glialfibrillaryacidicprotein ,GFAP)、酪氨酸羟化酶 (tyrosinehydorxylase ,TH)免疫组织化学染色 ,观察脑组织病理变化、胶质细胞增生和脑干TH活性的改变。 结果 　 16例SIDS中 7例可见白质软化坏死 ,白质区GFAP阳性胶质细胞增生明显 ,与对照组比较差别显著。在SIDS组 ,桥脑滑车神经核、延髓迷走神经核和腹外侧网状结构GFAP阳性胶质细胞明显增加 ,与对照组比较差别显著 ;中脑黑质GFAP阳性胶质细胞虽然也增加 ,但与对照组比较 ,差别不显著。迷走神经核和腹外侧网状结构中或强阳性TH免疫反应在SIDS组明显低于对照组 ,但在中脑黑质和滑车神经核 ,两组间差别不显著。 结论 　慢性缺氧或缺血可能引起脑干儿茶酚胺神经元的改变 ,从而导致睡眠时呼吸或循环中枢调节功能障碍 ,成为SIDS的一个重要促发因素。     

Association between sudden infant death syndrome and diphtheria-tetanus-pertussis immunisation: an ecological study

Background

Sudden infant death syndrome (SIDS) continues to be one of the main causes of infant mortality in the United States. The objective of this study was to analyse the association between diphtheria-tetanus-pertussis (DTP) immunisation and SIDS over time.

Methods

The Centers for Disease Control and Prevention provided the number of cases of SIDS and live births per year (1968–2009), allowing the calculation of SIDS mortality rates. Immunisation coverage was based on (1) the United States Immunization Survey (1968–1985), (2) the National Health Interview Survey (1991–1993), and (3) the National Immunization Survey (1994–2009). We used sleep position data from the National Infant Sleep Position Survey. To determine the time points at which significant changes occurred and to estimate the annual percentage change in mortality rates, we performed joinpoint regression analyses. We fitted a Poisson regression model to determine the association between SIDS mortality rates and DTP immunisation coverage (1975–2009).

Results

SIDS mortality rates increased significantly from 1968 to 1971 (+27% annually), from 1971 to 1974 (+47%), and from 1974 to 1979 (+3%). They decreased from 1979 to 1991 (−1%) and from 1991 to 2001 (−8%). After 2001, mortality rates remained constant. DTP immunisation coverage was inversely associated with SIDS mortality rates. We observed an incidence rate ratio of 0.92 (95% confidence interval: 0.87 to 0.97) per 10% increase in DTP immunisation coverage after adjusting for infant sleep position.

Conclusions

Increased DTP immunisation coverage is associated with decreased SIDS mortality. Current recommendations on timely DTP immunisation should be emphasised to prevent not only specific infectious diseases but also potentially SIDS.     

Home monitoring for infants at risk of the sudden infant death syndrome

Abstract This study evaluates the effectiveness and social implications of home monitoring of 31 infants at risk of sudden infant death syndrome (SIDS). Thirteen siblings of children dying of SIDS, nine near miss SIDS infants and nine preterm infants with apnoea persisting beyond 40 weeks post conceptual age were monitored from a mean age of 15 days to a mean of 10 months. Chest movement detection monitors were used in 27 and thoracic impedance monitors in four. Genuine apnoeic episodes were reported by 21 families, and 13 infants required resuscitation. Apnoeic episodes occurred in all nine preterm infants but in only five (38%) of the siblings of SIDS (P<0.05). Troublesome false alarms were a major problem occurring with 61% of the infants and were more common with the preterm infants than the siblings of SIDS. All but two couples stated that the monitor decreased anxiety and improved their quality of life. Most parents accepted that the social restrictions imposed by the monitor were part of the caring process but four couples were highly resentful of the changes imposed on their lifestyle.
The monitors used were far from ideal with malfunction occurring in 17, necessitating replacement in six, repair in six and cessation of monitoring in three. The parents became ingenious in modifying the monitors to their own individual requirements
Although none of these 31 'at risk' infants died the study sample was far too small to conclude whether home monitoring prevented any cases of SIDS.     

Incidence and significance of primary abnormalities of cardiac rhythm in infants at high risk for sudden infant death syndrome

Summary The exact relationship between cardiac arrhythmias and sudden infant death syndrome (SIDS) is uncertain. Several reports have implicated both ventricular and supraventricular arrhythmias in isolated cases, but there have been no studies of the incidence or type of arrhythmias that occur in populations at risk for SIDS. Of 1699 infants at high risk for SIDS, 60 (4%) were found to have a primary cardiac arrhythmia (i.e., not associated with disordered respiration or apnea). The incidence of atrial and ventricular premature beats, supraventricular tachycardia, and Wolff-Parkinson-White syndrome was similar to the incidence found in normal infants. Primary bradycardia (defined as a heart rate less than 60 for greater than 10 s not associated with abnormal respiration) was the most common arrhythmia, occurring with a frequency and severity not seen in normal infants. Thirty-two infants experienced periodic bradycardia. In 19 of these latter infants, there were symptoms associated with these bradyarrhythmias that necessitated treatment. Heart rates as low as 20 beats/min were recorded. One infant presented with an episode of ventricular fibrillation and on further evaluation was noted to have recurrent bradyarrhythmias. In no infant was there abnormal prolongation of the QT interval. Primary bradyarrhythmias are seen at an increased incidence in infants at high risk for SIDS and may play a causal role in this syndrome. Most symptomatic infants can be adequately controlled with sympathomimetic or parasympatholytic therapy. Other cardiac arrhythmias occur at a rate similar to that in normal infants and are therefore unlikely to play a major role in SIDS.     

Serum testosterone and estradiol in sudden infant death

OBJECTIVE: To test the hypothesis that among infants who die unexpectedly, testosterone and/or estradiol levels are elevated in those diagnosed with SIDS versus those with known causes of death (controls). STUDY DESIGN: Postmortem blood was collected and coded from infant autopsies, and serum was prepared and frozen until assayed for total testosterone and estradiol by fluoroimmunoassay. Subject information was then collected from the medical examiner's report. RESULTS: Testosterone, but not estradiol, was significantly higher in 127 SIDS cases versus 42 controls for both males (4.8 +/- 0.4 vs 2.2 +/- 0.4 nmol, respectively; P < .005) and females (2.4 +/- 0.2 vs 1.6 +/- 0.2 nmol, respectively; P < 0.03). CONCLUSIONS: Higher testosterone levels in infant victims of unexpected, unexplained death may indicate a role for testosterone or related steroids in SIDS. Further research is needed to understand the potential utility of testosterone as an indicator of SIDS risk.     

Apolipoprotein E e4 and its prevalence in early childhood death due to sudden infant death syndrome or to recognised causes

BACKGROUND:: Specific genetic polymorphisms have been shown to be more common in unexplained infant death. The APOE genotype exhibits opposite effects at the extremes of age with protective effects of e4 on perinatal mortality but detrimental effects as age progresses. OBJECTIVE:: To determine whether the APOE e4 allele is associated with early childhood (1 week-2 years) unexplained death ('sudden infant death syndrome', SIDS) or with recognised causes (non-SIDS) and to compare these cohorts with published perinatal and adult data. METHODS:: DNA was extracted from spleen tissue of children dying in South East Scotland between 1990 and 2002. APOE alleles (e2, e3, e4) were determined using PCR. Comparisons of allele frequencies between groups were made. RESULTS:: There were 167 SIDS cases and 117 non-SIDS cases. Allele distributions of SIDS cases were similar to healthy newborns. Allele distributions of non-SIDS cases were more similar to adults than to healthy newborns. The percentage of children with at least one e4 allele was significantly lower in non-SIDS compared to SIDS (p=0.016). Non-SIDS cases had a higher frequency of e3 compared to SIDS cases (p=0.01) and to healthy newborns (0.005). CONCLUSIONS:: Children dying from identified causes have different APOE allele distributions from SIDS cases, but are similar to adults. Children dying from SIDS have an allele distribution comparable to healthy newborns. The prevalence of e4 in SIDS is not of an order to contribute significantly to the age-related decline in e4.     

Renal glomerular size in infants with congenital heart disease and in cases of sudden infant death syndrome

Recurrent apnoea and chronic hypoventilation have been implicated in the pathogenesis of the sudden infant death syndrome (SIDS) and markers of chronic hypoxaemia have been reported in such infants at post mortem examination. Markers of chronic hypoxaemia are common in cyanotic congenital heart disease. Glomerular enlargement in congenital heart disease is said to be related to hypoxaemia although the precise mechanism whereby this occurs is not clear.We have established a normal range of glomerular size for the postperinatal period and confirmed glomerular enlargement to be a common finding in children with congenital heart disease of similar age. In contrast glomerular size in SIDS is not different from controls. The results question the role of significant chronic hypoxaemia being involved in these deaths.Abbreviations SIDS sudden infant death syndrome - VSD ventricular septal defect - ASD atrial septal defect     

Altered placental development in pregnancies resulting in sudden infant death syndrome (SIDS)

Background

Sudden infant death syndrome (SIDS) is postulated to be a developmental disorder originating during fetal life in utero. Knowledge regarding the intrauterine environment in which SIDS infants develop is, however, inadequate and how the placenta develops prior to a SIDS event has not been studied.

Aim

To investigate the morphological development of the placenta obtained from full-term infants who subsequently succumbed to SIDS.

Study design

To estimate the percentage and total volumes of the chorionic villi and villous trophoblast membrane using stereological techniques.

Subjects

Placentas were obtained retrospectively from normal birthweight (SIDS-NBW n = 18) and small-for-gestational age (SIDS-SGA, n = 14) infants who had succumbed to SIDS, and compared to either control (n = 8) or SGA placentas (n = 7), respectively.

Results

SIDS-NBW placentas displayed evidence of augmented villous growth shown by significantly greater volumes of placental chorionic villi (gas-exchanging (GE) villi) in comparison to controls; this was not observed for SIDS-SGA placentas. However, both SIDS-NBW and SIDS-SGA placentas displayed significantly greater volumes of the cytotrophoblast (CT) (SIDS-NBW only), syncytiotrophoblast (SIDS-SGA only) and syncytial knots (SCT-K) and those displaying apoptotic syncytial nuclei (AP SCT-K). In contrast, SGA placentas displayed significantly reduced volumes of chorionic villi, GE villi and the villous trophoblast indicating a SIDS-specific effect associated with augmented placental growth.

Conclusions

Our findings provide initial evidence that placental abnormality, although not necessarily causative, may precede a subset of SIDS cases supporting the hypothesis that the origins of SIDS begin during fetal life in utero.     

Previous breastfeeding does not alter thymic size in infants dying of sudden infant death syndrome

The relationship between thymic weights and previous feeding histories was examined in 294 infants of 37 wk gestation or more dying of sudden infant death syndrome (SIDS). One hundred and sixty-five infants had been breastfed exclusively, 89 had been partially breastfed and 40 had never been breastfed. We found no relationship between thymic weight and type of previous feeding. The difference between these findings in SIDS and the substantially greater thymic size previously reported in 4-mo-old breastfed living infants deserves further study.