Sudden infant death syndrome: exposure to cigarette smoke leads to hypomethylation upstream of the growth factor independent 1 (GFI1) gene promoter.

PURPOSE: Smoking during pregnancy has long been known as an important risk factor for sudden infant death syndrome (SIDS). However, the precise relationship between the smoking behavior of the mother and SIDS still remains unclear. In this study, the influence of prenatal smoking exposure on the childrens' DNA methylation state of a CpG island located upstream of the promoter of the growth factor independent 1 (GFI1) gene was analyzed. METHODS: Blood samples of well-defined SIDS cases with non-smoking mothers (n = 11), SIDS cases with smoking mothers during pregnancy (n = 11), and non-SIDS cases (n = 6) were obtained from a previous study and methylation states were determined by bisulfite sequencing. RESULTS: Significant hypomethylation was observed in this CpG island in SIDS cases with cigarette smoke exposure compared to non-exposed cases. The strongest effect in this CpG island was observed for 49 CpG sites located within a transcription factor binding site. Coding for a transcriptional repressor, GFI1 plays an important role in various developmental processes. Alterations in the GFI1 expression might be linked to various conditions that are known to be associated with SIDS, such as dysregulated hematopoiesis and excessive inflammatory response. CONCLUSION: Data obtained in this study show that analysis of methylation states in cases of sudden infant death syndrome might provide a further important piece of knowledge toward understanding SIDS, and should be investigated in further studies.

Candidate gene variants of the immune system and sudden infant death syndrome.

BACKGROUND: Sudden infant death syndrome (SIDS) causes early infant death with an incidence between 0.5 and 2.5 cases among 1000 live births. Besides central sleep apnea and thermal dysregulation, infections have been repeatedly suggested to be implicated in SIDS etiology. METHODS: To test the risk contribution of common genetic variants related to infection, we genotyped 40 single-nucleotide polymorphisms (SNPs) from 15 candidate genes for association with SIDS in a total of 579 cases and 1124 controls from Germany and the UK in a two-stage case control design. RESULTS: The discovery-stage series (267 SIDS cases and 303 controls) revealed nominally significant associations for variants in interleukin 6 (IL6) (rs1880243), interleukin 10 (IL10) (rs1800871, rs1800872), and mannose-binding lectin 2 (MBL2) (rs930506), and for several other variants in subgroups. Meta-analyses were then performed in adding genotype information from a genome-wide association study of another 312 European SIDS cases and 821 controls. Overall associations were observed for two independent variants in MBL2: rs930506 in a co-dominant model (odds ratio (OR) = 0.82, p = 0.04) and rs1838065 in a dominant model (OR = 1.27, p = 0.03). CONCLUSION: Our study did not replicate published associations of IL10 variants with SIDS. However, the evidence for two independent MBL2 variants in the combined analysis of two large series seems consistent with the hypothesis that infection may play a role in SIDS pathogenesis.

International comparison of sudden unexpected death in infancy rates using a newly proposed set of cause-of-death codes.

BACKGROUND: Comparing rates of sudden unexpected death in infancy (SUDI) in different countries and over time is difficult, as these deaths are certified differently in different countries, and, even within the same jurisdiction, changes in this death certification process have occurred over time. AIMS: To identify if International Classification of Diseases-10 (ICD-10) codes are being applied differently in different countries, and to develop a more robust tool for international comparison of these types of deaths. METHODS: Usage of six ICD-10 codes, which code for the majority of SUDI, was compared for the years 2002-2010 in eight high-income countries. RESULTS: There was a great variability in how each country codes SUDI. For example, the proportion of SUDI coded as sudden infant death syndrome (R95) ranged from 32.6% in Japan to 72.5% in Germany. The proportion of deaths coded as accidental suffocation and strangulation in bed (W75) ranged from 1.1% in Germany to 31.7% in New Zealand. Japan was the only country to consistently use the R96 code, with 44.8% of SUDI attributed to that code. The lowest, overall, SUDI rate was seen in the Netherlands (0.19/1000 live births (LB)), and the highest in New Zealand (1.00/1000 LB). SUDI accounted for one-third to half of postneonatal mortality in 2002-2010 for all of the countries except for the Netherlands. CONCLUSIONS: The proposed set of ICD-10 codes encompasses the codes used in different countries for most SUDI cases. Use of these codes will allow for better international comparisons and tracking of trends over time.

That's not it, either-neither polymorphisms in PHOX2B nor in MIF are involved in sudden infant death syndrome (SIDS).

The occurrence of sudden infant death syndrome (SIDS) has been linked to several genetic risk factors, e.g. genes involved in the neuroadrenergic system, variations in serotonin reporter genes or mutations in long-QT syndrome genes. Additionally, polymorphisms in genes with impact in sleep disorder syndromes have been proposed to be of importance as genetic risk factors for SIDS. In this study, we investigated the polyalanine length variation of PHOX2B and the -794 CATT repeat in the MIF promoter region as well as single nucleotide polymorphisms (rs28462174, rs28727473, rs16853571, rs755622, rs12485058, rs12485068, rs4822444, rs4822445, rs4822446, rs4822447 and rs2012124) in both genes in 278 SIDS cases and 240 controls. No significant differences were found in allele distribution of neither length polymorphisms nor single nucleotide polymorphisms between SIDS cases or controls. Therefore, an importance of these variations for the occurrence of SIDS could be ruled out.

Sudden infant death syndrome (SIDS) and polymorphisms in Monoamine oxidase A gene (MAOA): a revisit.

Literature describes multiple possible links between genetic variations in the neuroadrenergic system and the occurrence of sudden infant death syndrome. The X-chromosomal Monoamine oxidase A (MAOA) is one of the genes with regulatory activity in the noradrenergic and serotonergic neuronal systems and a polymorphism of the promoter which affects the activity of this gene has been proclaimed to contribute significantly to the prevalence of sudden infant death syndrome (SIDS) in three studies from 2009, 2012 and 2013. However, these studies described different significant correlations regarding gender or age of children. Since several studies, suggesting associations between genetic variations and SIDS, were disproved by follow-up analysis, this study was conducted to take a closer look at the MAOA gene and its polymorphisms. The functional MAOA promoter length polymorphism was investigated in 261 SIDS cases and 93 control subjects. Moreover, the allele distribution of 12 coding and non-coding single nucleotide polymorphisms (SNPs) of the MAOA gene was examined in 285 SIDS cases and 93 controls by a minisequencing technique. In contrast to prior studies with fewer individuals, no significant correlations between the occurrence of SIDS and the frequency of allele variants of the promoter polymorphism could be demonstrated, even including the results from the abovementioned previous studies. Regarding the SNPs, three statistically significant associations were observed which had not been described before. This study clearly disproves interactions between MAOA promoter polymorphisms and SIDS, even if variations in single nucleotide polymorphisms of MAOA should be subjected to further analysis to clarify their impact on SIDS.

Bed sharing when parents do not smoke: is there a risk of SIDS? An individual level analysis of five major case-control studies.

OBJECTIVE: To resolve uncertainty as to the risk of Sudden Infant Death Syndrome (SIDS) associated with sleeping in bed with your baby if neither parent smokes and the baby is breastfed. DESIGN: Bed sharing was defined as sleeping with a baby in the parents' bed; room sharing as baby sleeping in the parents' room. Frequency of bed sharing during last sleep was compared between babies who died of SIDS and living control infants. Five large SIDS case-control datasets were combined. Missing data were imputed. Random effects logistic regression controlled for confounding factors. SETTING: Home sleeping arrangements of infants in 19 studies across the UK, Europe and Australasia. PARTICIPANTS: 1472 SIDS cases, and 4679 controls. Each study effectively included all cases, by standard criteria. Controls were randomly selected normal infants of similar age, time and place. RESULTS: In the combined dataset, 22.2% of cases and 9.6% of controls were bed sharing, adjusted OR (AOR) for all ages 2.7; 95% CI (1.4 to 5.3). Bed sharing risk decreased with increasing infant age. When neither parent smoked, and the baby was less than 3 months, breastfed and had no other risk factors, the AOR for bed sharing versus room sharing was 5.1 (2.3 to 11.4) and estimated absolute risk for these room sharing infants was very low (0.08 (0.05 to 0.14)/1000 live-births). This increased to 0.23 (0.11 to 0.43)/1000 when bed sharing. Smoking and alcohol use greatly increased bed sharing risk. CONCLUSIONS: Bed sharing for sleep when the parents do not smoke or take alcohol or drugs increases the risk of SIDS. Risks associated with bed sharing are greatly increased when combined with parental smoking, maternal alcohol consumption and/or drug use. A substantial reduction of SIDS rates could be achieved if parents avoided bed sharing.

Examination of (suspected) neonaticides in Germany: a critical report on a comparative study.

In cooperation with the Crime Investigation Agency (Landeskriminalamt) of North Rhine-Westphalia, we carried out a study of 150 cases of (suspected) neonaticide dating from 1993 to 2007 from all over Germany. The autopsy reports and additional expert opinions (if performed) were evaluated for a minimum of 78 variables. Emphasis was placed on the application of special preparation techniques and other special questions arising during the examination of a deceased newborn child. Forty-five percent of the cases remained unsolved, which means that the mother could not be identified. Twenty-seven percent of the corpses were in a state of such severe putrefaction that forensic examination was limited. The main causes of death were all forms of suffocation. The signs of maturity (such as length, weight, and fingernails) were recorded in more than 95 % of the cases. Hydrostatic test of the lung was performed in 96 %, and that of the gastrointestinal tract in 84 %. Given the results of the study, standard protocols and checklists are recommended to facilitate comparability and to ensure the completeness of findings. Full-body X-rays or CT scans should be used to complete viability examinations.

Reanalyses of case-control studies examining the temporal association between sudden infant death syndrome and vaccination.

In this paper we examine different time periods after vaccinations and investigate whether the risk of sudden infant death is different during the post-vaccination period than at other times. Three already published case-control studies are re-examined in this context. Several evaluation approaches are presented. The recently developed self-controled case series (SCCS) method for terminal events, which only takes the cases into account, is used in addition. There is no increased or reduced risk of sudden infant death during the period after the vaccination. The previously reported protective effect seen in case contol studies is based on the inclusion of unvaccinated cases. The results of the case-control analysis of one study is affected by two confounders. The SCCS method for terminal events, in which all time-independent confounders are eliminated, is an alternative to case-control analysis when it comes to the temporal association between exposed time periods and SIDS after vaccination.

Bed sharing and the risk of sudden infant death syndrome: can we resolve the debate?

OBJECTIVE: To conduct a meta-analysis on the relationship between bed sharing and sudden infant death syndrome (SIDS) risk. STUDY DESIGN: Data from PubMed and Medline were searched for studies published after Jan 1, 1970. The search strategy included articles with the terms "sudden infant death syndrome," "sudden unexpected death," and "cot death" with "bed sharing" or "co-sleeping." To further specify the potential risk of bed sharing and SIDS, subgroup analyses were performed. RESULTS: Eleven studies met inclusion criteria and were included in the final meta-analysis. The combined OR for SIDS in all bed sharing versus non-bed sharing infants was 2.89 (95% CI, 1.99-4.18). The risk was highest for infants of smoking mothers (OR, 6.27; 95% CI, 3.94-9.99), and infants <12 weeks old (OR, 10.37; 95% CI, 4.44-24.21). CONCLUSIONS: Bed sharing is a risk factor for SIDS and is especially enhanced in smoking parents and in very young infants.

Cytokines and sudden infant death.

BACKGROUND: It has been hypothesised that inflammatory reactions could play an important role in the pathway(s) leading to sudden and unexpected death in infancy. On a molecular level, these reactions are regulated by various cytokines. METHODS: To characterise the role of IL-1ß, IL-6 and TNFα more precisely, the concentrations of these cytokines were determined quantitatively using specific ELISA techniques in serum and cerebrospinal fluid (CSF) in 119 cases of sudden infant death. The infants were grouped into four categories (SIDS, SIDS with infection, natural death due to infection and unnatural death). RESULTS: A good correlation was found between CSF and serum for IL-6 (Spearman correlation coefficients (SCC), 0.73) and also for TNFα (SCC, 0.57), although the CSF concentrations were lower than that from the serum. There were no significant differences between the categories of death for any of the serum or CSF cytokines. Compared with normal values, increased serum concentrations of IL-1ß, IL-6 and TNFα were found in 70%, 69% and 38% of the cases respectively, indicating possible agonal or post-mortem changes of cytokine concentrations. In three cases very high cytokine concentrations were found (mainly for IL-6). This may have contributed to the mechanism of death (cytokine storm) in two of the cases. CONCLUSIONS: In a small group of patients, very high cytokine concentrations are a possible explanation for the cause of death ("cytokine storm").

Breastfeeding and reduced risk of sudden infant death syndrome: a meta-analysis.

CONTEXT: Benefits of breastfeeding include lower risk of postneonatal mortality. However, it is unclear whether breastfeeding specifically lowers sudden infant death syndrome (SIDS) risk, because study results have been conflicting. OBJECTIVE: To perform a meta-analysis to measure the association between breastfeeding and SIDS. METHODS: We identified 288 studies with data on breastfeeding and SIDS through a Medline search (1966-2009), review articles, and meta-analyses. Twenty-four original case-control studies were identified that provided data on the relationship between breastfeeding and SIDS risk. Two teams of 2 reviewers evaluated study quality according to preset criteria; 6 studies were excluded, which resulted in 18 studies for analysis. Univariable and multivariable odds ratios were extracted. A summary odds ratio (SOR) was calculated for the odds ratios by using the fixed-effect and random-effect inverse-variance methods of meta-analysis. The Breslow-Day test for heterogeneity was performed. RESULTS: For infants who received any amount of breast milk for any duration, the univariable SOR was 0.40 (95% confidence interval [CI]: 0.35-0.44), and the multivariable SOR was 0.55 (95% CI: 0.44-0.69). For any breastfeeding at 2 months of age or older, the univariable SOR was 0.38 (95% CI: 0.27-0.54). The univariable SOR for exclusive breastfeeding of any duration was 0.27 (95% CI: 0.24-0.31). CONCLUSIONS: Breastfeeding is protective against SIDS, and this effect is stronger when breastfeeding is exclusive. The recommendation to breastfeed infants should be included with other SIDS risk-reduction messages to both reduce the risk of SIDS and promote breastfeeding for its many other infant and maternal health benefits.

A modified self-controlled case series method to examine association between multidose vaccinations and death.

The self-controlled case series method (SCCS) was developed to analyze the association between a time-varying exposure and an outcome event. We consider penta- or hexavalent vaccination as the exposure and unexplained sudden unexpected death (uSUD) as the event. The special situation of multiple exposures and a terminal event requires adaptation of the standard SCCS method. This paper proposes a new adaptation, in which observation periods are truncated according to the vaccination schedule. The new method exploits known minimum spacings between successive vaccine doses. Its advantage is that it is very much simpler to apply than the method for censored, perturbed or curtailed post-event exposures recently introduced. This paper presents a comparison of these two SCCS methods by simulation studies and an application to a real data set. In the simulation studies, the age distribution and the assumed vaccination schedule were based on real data. Only small differences between the two SCCS methods were observed, although 50 per cent of cases could not be included in the analysis with the SCCS method with truncated observation periods. By means of a study including 300 uSUD, a 16-fold risk increase after the 4th dose could be detected with a power of at least 90 per cent. A general 2-fold risk increase after vaccination could be detected with a power of 80 per cent. Reanalysis of data from cases of the German case-control study on sudden infant death (GeSID) resulted in slightly higher point estimates using the SCCS methods than the odds ratio obtained by the case-control analysis.

Association between lifestyle factors and headache.

Modification of lifestyle habits is a key preventive strategy for many diseases. The role of lifestyle for the onset of headache in general and for specific headache types, such as migraine and tension-type headache (TTH), has been discussed for many years. Most results, however, were inconsistent and data on the association between lifestyle factors and probable headache forms are completely lacking. We evaluated the cross-sectional association between different lifestyle factors and headache subtypes using data from three different German cohorts. Information was assessed by standardized face-to-face interviews. Lifestyle factors included alcohol consumption, smoking status, physical activity and body mass index. According to the 2004 diagnostic criteria, we distinguished the following headache types: migraine, TTH and their probable forms. Regional variations of lifestyle factors were observed. In the age- and gender-adjusted logistic regression models, none of the lifestyle factors was statistically significant associated with migraine, TTH, and their probable headache forms. In addition, we found no association between headache subtypes and the health index representing the sum of individual lifestyle factors. The lifestyle factors such as alcohol consumption, smoking, physical activity and overweight seem to be unrelated to migraine and TTH prevalence. For a judgement on their role in the onset of new or first attacks of migraine or TTH (incident cases), prospective cohort studies are required.

Petechial bleedings in sudden infant death.

The autopsy reports of 484 cases of deceased infants (201 females, 283 males) were analysed retrospectively for the existence of external and internal petechial bleedings (PET). The cases were divided into five groups on the basis of the cause of death (sudden infant death syndrome, sepsis, airway infections, asphyxia and trauma). Internal PET (pleural, pericardial, epicardial, thymic and peritoneal) were observed in each group with a lower prevalence in cases of trauma. The highest prevalence of external (cutaneous and conjunctival) PET was detected in cases of asphyxia (38% and 31%, respectively). However, even if with low prevalence, such bleedings were detected in every group. Factors like sex, age, cardiopulmonary resuscitation and its duration did not influence the presence of PET. The detection of external PET at autopsy is a suspicious finding that suggests asphyxia. Because of the possible natural origin of these bleedings, the medicolegal investigation has to be as complete as possible and has to include histology as mandatory.

A common FMO3 polymorphism may amplify the effect of nicotine exposure in sudden infant death syndrome (SIDS).

Smoking during pregnancy has been identified as one of the major modifiable risk factors of sudden infant death syndrome (SIDS). It has been demonstrated that the risk of SIDS increases with increasing cigarette consumption. A variety of hypotheses have been proposed for explanation, including a genetic predisposition. The flavin-monooxygenase 3 (FMO3) is one of the enzymes metabolising nicotine, and several polymorphisms have already been described in this gene. Here, we studied variations in the exons and introns of the FMO3 gene by direct sequencing analysis and minisequencing in 159 SIDS cases and 170 controls. The three common variants G472A (E158K), G769A (V257M) and A923G (E308G) in the exons of the FMO3 gene were identified. The homozygote 472AA genotype occurred more frequently in SIDS cases than in controls (p = 0.0054) and was more frequent in those SIDS cases for which the mothers reported heavy smoking (p = 0.0084). This study is the first to demonstrate a gene-environment interaction in SIDS. The findings suggest that the common polymorphism G472A of FMO3 could act as an additional genetic SIDS risk factor in children whose mothers smoke. Parents who could pass on the 472A allele should be informed of the increased risk associated with smoking. Smoking mothers should be strongly advised to give up smoking during pregnancy and for at least the first year of the child's life.

Amniotic fluid aspiration in cases of SIDS.

The scope of this study was to evaluate the incidence and the eventual consequences of amniotic fluid aspiration (AFA) in cases of sudden infant death. Cases of sudden infant death syndrome (SIDS; n = 113: 39 females, 74 males; mean age 4.6 months) were compared to a control group of 39 cases of explained death (14 females, 25 males; mean age 5.6 months). In each case, sections of the lung stained with hematoxylin and eosin and with the immunohistochemical reaction 34BE12 specific for cytokeratins were available. The microscope slides were observed at x200 magnification and semi-quantitatively classified into four categories(-, +, ++, and +++). In both groups, rests of amniotic fluid could be observed up to the fourth month of life. The comparison between the two groups did not show any significant difference. In the SIDS group, immunohistochemical reactions with the antibodies CD68, MRP8, MRP14, 27E10, 25F9, CD3, CD20Cy, and CD45R0 were available for the lungs. Twelve cases with AFA were compared to a group of SIDS cases without AFA with similar age and pathological distribution to evaluate whether the presence of amniotic remnants induced inflammatory changes in the lungs. No differences emerged. This study shows that AFA is not a rare event. Even moderate to severe AFA does not necessary cause death. A correlation between AFA and SIDS could not be shown.

Impact of sodium/proton exchanger 3 gene variants on sudden infant death syndrome.

OBJECTIVE: To determine the contribution of variations in the sodium/proton exchanger 3 (NHE3) gene in sudden infant death syndrome (SIDS). STUDY DESIGN: Variations in the exons and promoter of the NHE3 gene were analyzed with direct sequencing analysis and mini sequencing (SNaPshot analysis) in 251 cases of SIDS, plus 50 infant control subjects who had died of other causes, and 170 healthy adults. RESULTS: The C2405T variant (exon 16) and 2 polymorphisms in the promoter (G1131A and C1197T) were encountered significantly more frequently in cases of SIDS than in control subjects. At least 1 of these 3 variants was detected in 49% of SIDS cases, but only in 30% of control subjects. CONCLUSIONS: Our findings suggest the involvement of polymorphisms in the NHE3 gene and promoter in cases of SIDS, which may result in an overexpression of NHE3 in the medulla oblongata and which possibly leads to a disturbance in breathing control. Furthermore, our results underline the heterogeneous character of SIDS.

Organ weights in cases of sudden infant death syndrome: a German study.

Despite its decreasing incidence, sudden infant death syndrome (SIDS) still remains an important cause of death in infancy. Since Felix Platter described the case of a child suffocated because of a massive goiter (Platter E. Suffocatio a struma interna abscondita, circa iugulum. Observationum in hominis affectibus plerisque corpori et animo, functionum lesione, dolore, aliave molestia et vitio incommodantibus. Libris tres, Part IX. Basel: König and Brandmylieri; 1614), many authors have attempted to verify the existence of a correlation between the dimensions of organs of infants and SIDS. The lack of recent published norms and the difficulty in finding a suitable control group by which to compare the cases of SIDS shows the importance of this study.This article presents the organ weights of 209 male and 132 female babies whose cause of death was SIDS. The data have been collected from 2 different studies: the Westphalian Cot Death Study from 1990 to 1994 and the German National Study on SIDS from 1998 to 2001. The organ weights increased from month to month during the first year of life showing a tendency towards higher weights in males compared with females (these are, however, not statistically significant). No significant differences compared with the recently published data of Thompson and Cohle, J Forensic Sci. 2004;49:575-585 were found.The heart weights were compared with a control group of 47 babies (21 females, 26 males) died because of both natural and unnatural causes. The weight of the organs that presented macro-microscopical pathologic changes was excluded.The weights of the heart were also compared with those published by Schulz and Giordano, Arch Pathol. 1962;74:464-471 and Kelmanson, Eur J Pediatr. 1996;155:440-444. This comparison showed minor differences which are discussed in the article. We suggest that organ weights obtained in SIDS cases can be used as norms in the first year of life.

Sleep environment risk factors for sudden infant death syndrome: the German Sudden Infant Death Syndrome Study.

OBJECTIVE: Our goal was to investigate the risk factors for sudden infant death syndrome in the infants' sleep environment for a population in which few infants sleep prone as a result of education campaigns. METHODS: This was a population-based sudden infant death syndrome case-control study over 3 years (1998-2001) in Germany. RESULTS: There were 333 sudden infant death syndrome cases and 998 matched controls. Although only 4.1% of the infants were placed prone to sleep, those infants were at a high risk of sudden infant death syndrome. Those who were unaccustomed to sleeping prone were at very high risk, as were those who turned to prone. Bed sharing (especially for infants younger than 13 weeks); duvets; sleeping prone on a sheepskin; sleeping in the house of a friend or a relative (compared with sleeping in the parental home); and sleeping in the living room (compared with sleeping in the parental bedroom) increased the risk for sudden infant death syndrome; pacifier use during the last sleep was associated with a significantly reduced risk of sudden infant death syndrome. CONCLUSIONS: This study has clarified the risk factors for sudden infant death syndrome in a population where few infants sleep prone. This study supports the current recommendations of the American Academy of Pediatrics. This study has identified several novel risk factors for sudden infant death syndrome: an increased risk if the infants sleeps outside the parental home, death in the living room, and the high risk when sleeping prone on a sheepskin; however, because the numbers of cases in these groups are small, additional studies are needed to confirm these findings.

Leptomeningeal neurons are a common finding in infants and are increased in sudden infant death syndrome.

Developmental abnormalities of the brain, in particular, the brainstem potentially affecting centers for breathing, circulation and sleep regulation, are thought to be involved in the etiology of sudden infant death syndrome (SIDS). In order to investigate whether leptomeningeal neurons could serve as morphological indicators for a developmental failure or retardation in cerebral maturation, we evaluated the density of isolated leptomeningeal neurons (without associated glia) in 15 brain regions of 24 SIDS and 8 control cases, representing part of the German Study on sudden infant death. Leptomeningeal neurons were encountered in 79% of SIDS and 68% of control cases. More leptomeningeal neurons in SIDS versus control cases were found in lower pons (p = 0.002), upper pons (p = 0.016), cerebellar hemispheres (p = 0.012), lower medulla oblongata (p = 0.039), and temporal lobe (p = 0.041). Summarizing the data according to gross anatomical region of origin (i.e., brainstem, cerebellum or cerebrum), higher numbers of leptomeningeal neurons in SIDS cases were only found in the brainstem (p = 0.006 vs. 0.13 and 0.19, respectively). Our data show that single leptomeningeal neurons are present in most normal infantile brains. The age-dependent increase of leptomeningeal neurons among SIDS cases may either (a) represent a delayed maturation or retardation, i.e., a later or slower reduction of neurons or a delayed peak in occurrence (shift toward an older age), or (b) may be interpreted as a generally increased occurrence of leptomeningeal neurons among SIDS cases as a result of a diffuse developmental abnormality during central nervous system maturation.