SBS-SUDDEN INFANT DEATH STUDY

SBS/Sudden Infant Death

http://ajrccm.atsjournals.org/cgi/content/full/164/3/346

Am. J. Respir. Crit. Care Med., Volume 164, Number 3, August 2001, 346-357
Sudden Infant Death Syndrome and Other Causes of Infant Mortality
Diagnosis, Mechanisms, and Risk for Recurrence in Siblings

CARL E. HUNT
Department of Pediatrics, Medical College of Ohio, and Mercy Children's Hospital, Toledo, Ohio

CONTENTS
SUDDEN, UNEXPECTED DEATH IN...
RECURRENT INFANT MORTALITY IN...
OBSTRUCTIVE SLEEP APNEA...
PHYSIOLOGICAL STUDIES
IMPLICATIONS
REFERENCES

Introduction

Sudden, Unexpected Death in Infancy

Explained by Autopsy

Unexplained by Autopsy

Summary

Recurrent Infant Mortality in Siblings

Explained Causes

Unexplained Causes

Summary and Critique

Obstructive Sleep Apnea Syndrome

Family Studies

Summary and Critique

Physiological Studies

Siblings of a Previous SIDS Victim

Parents of SIDS Victims

Summary and Critique

Implications

The risk of sudden infant death syndrome (SIDS) recurring in siblings of SIDS victims is controversial. The mortality studies of recurrent SIDS have been considered inconclusive and criticized on methodological grounds, and the family studies in siblings and parents of SIDS have yielded inconsistent results. How often intentional suffocation has been misdiagnosed as (recurrent) SIDS is unknown because there are no objective diagnostic criteria. Some health professionals have stated that only homicide runs in families and that all second cases of SIDS in a family should be investigated for intentional suffocation (1).

The purpose of this report is to review the evidence and possible mechanisms for sudden unexpected infant death and SIDS in siblings. Relevant data were obtained from published articles about SIDS and electronic searches for infant mortality, child abuse, infant homicide (filicide), Munchausen syndrome by proxy, sleep, and genetics. Exclusions included SIDS deaths at younger than 1 wk or older than 1 yr of age, studies published before 1970 or not published in English, and reports without a control group.

SUDDEN, UNEXPECTED DEATH IN INFANCY

CONTENTS
SUDDEN, UNEXPECTED DEATH IN...
RECURRENT INFANT MORTALITY IN...
OBSTRUCTIVE SLEEP APNEA...
PHYSIOLOGICAL STUDIES
IMPLICATIONS
REFERENCES

Explained by Autopsy

Natural. In a cohort of sudden unexpected deaths including unintentional (accidental) deaths, 18% were explained by a "thorough case investigation" (4) compared with 20% explained among sudden unexpected deaths excluding unintentional deaths (5). Infections were the most frequent natural cause (Table 1).

TABLE 1

DIFFERENTIAL DIAGNOSIS OF SUDDEN UNEXPECTED DEATH IN INFANCY*

Unintentional. These deaths are typically identified by the history and autopsy findings. Unintentional deaths accounted for 15% of all explained causes of sudden unexpected death in infancy in a population-based case-control study (4).

Traumatic child abuse (Filicide). Male caretakers are usually the perpetrators. Also called "shaken baby syndrome," typical autopsy findings include multiple fractures and intracranial hemorrhage (6). Traumatic filicide accounted for 13-24% of all explained sudden unexpected deaths.

Unexplained by Autopsy

Sudden infant death syndrome (SIDS). Pathophysiology. SIDS is defined as the sudden death of an infant younger than 1 year of age that remains unexplained after a thorough case investigation that includes a complete autopsy, examination of the death scene, and review of the clinical history (11) (Table 1). This definition was established in 1969 and revised in 1989 to include scene investigation and clinical history review. Among sudden unexpected infant deaths, 80-82% were diagnosed as SIDS (4, 5). Accounting for 2,529 deaths in 1998 in the United States (12), SIDS is the third leading cause of infant mortality (8.9%) after congenital anomalies (22%) and short gestation/ low birth weight (14%).

There is no autopsy finding pathognomonic of SIDS and no finding required for the diagnosis. There are, however, some common findings (13, 14). Petechial hemorrhages are found in more than 70-90% of cases. Pulmonary edema is often present and may be substantial. Due to lack of uniform criteria among pathologists, some unexpected deaths may be "misdiagnosed" as pneumonia or other natural causes based on minimal findings at autopsy insufficient to explain sudden death.

No single mechanism has been established. It is likely that a number of distinct pathophysiologies may be related to SIDS. A brain stem abnormality related to neuroregulation of cardiorespiratory or other autonomic functions appears to be the most compelling hypothesis (15, 16). Autopsy studies indicating preexisting, chronic low-grade hypoxemia attributed to sleep-related hypoventilation support this hypothesis. The autopsy evidence for chronic hypoxemia includes (a) persistence of adrenal brown fat, hepatic erythropoiesis, brain stem gliosis and other structural abnormalities (13), and (b) multiple neurotransmitter abnormalities in brain stem regions relevant to neural cardiorespiratory regulation (17, 18).

These postmortem studies of neurotransmitter and receptors have identified reduced binding to kainate receptors in the arcuate nucleus, a region of the human ventral medullary surface involved in chemosensitivity to CO2 in experimental animals (17). SIDS victims also have been observed to have decreased binding of serotonin in the nucleus raphe obscurus, a brain structure linked to the arcuate nucleus, and in four other brain regions (18, 19). These brain regions have their origin in a part of the rhombic lip, a region later giving rise to key structures in the brain stem and thought to play a crucial role in regulating arousal responsiveness from sleep, as well as breathing, heart rate, and body temperature.

Deficient kainate binding in the arcuate nucleus and deficient serotonergic receptor binding in the brain stem may be indicative of genetic alterations of normal prenatal development of the brain stem. It is possible, however, that these apparent brain stem abnormalities are secondary to an "upstream" deficit as yet undefined. It is also possible and indeed likely, as discussed later, that these neurotransmitter abnormalities represent interaction(s) between environmental risk factors and susceptibility genes associated with autonomic dysregulation.

Deficient inflammatory responsiveness to infection and allergic reactions have also been hypothesized to be a cause of SIDS (20). SIDS victims with mild upper respiratory infections are more likely to have deletions of either complement C4A or the C4B gene than control subjects (21). Partial deletions in the C4 genes may thus contribute to the link between upper respiratory infection and SIDS (16). Mast cell degranulation has been reported in SIDS victims, implying degranulation in the immediate hours before death and hence consistent with anaphylaxis (22, 23). Family members of some SIDS victims also have increased mast cell hyperreleasability and degranulation (24), further supporting anaphylaxis and allergic mediators as a possible cause for SIDS and indicating a genetic mechanism.

Additional insights into the pathophysiology of SIDS are suggested by physiological studies of groups considered to be at increased risk for SIDS, including infants with idiopathic apparent life-threatening events (ALTE) and premature infants (15, 16). The abnormalities observed in these infants, a few of whom later died of SIDS, include frequent/prolonged apnea, diminished chemoreceptor sensitivity to hypercarbia or hypoxia, impaired control of heart and respiratory rate, abnormal heart rate variability and vagal tone, deficient or absent arousal responses from sleep, metabolic abnormalities, infection, and impaired inflammatory response to infectious agents (16, 24).

Genetic susceptibility. Sequencing the 3 billion base pairs containing the 80,000 genes in the human genome will lead to fundamental changes in the way we think about health and disease, including the role of specific gene products in facilitating or permitting adverse pathophysiological responses (25). Achieving consensus on the role of genetic susceptibility in SIDS is not yet possible because there is no consensus as to which pathophysiologies are directly linked to SIDS. To the extent that impaired neural control of breathing is relevant to SIDS, however, data are rapidly accumulating that link gene function in the brain stem to breathing control (26). Adaptation to an environmental risk such as hypoxia, for example, involves complex regulation of gene expression in precise brain stem sites, and normal postnatal cardiorespiratory control at rest depends on genes controlling prenatal development.

Neural control of breathing and sleep are closely integrated, and abnormalities in regulation of sleep and circadian rhythmicity can thus result in impaired cardiorespiratory integration and arousal responsiveness from sleep (27). Circadian rhythmicity has been extensively studied in animals, and homologous counterparts of essential circadian clock genes isolated in Drosophila have been identified in mammals (28). Because the sleep-wake cycle is under control of the circadian clock, these circadian master genes as well other sleep-related genes likely influence sleep regulation (29).

Targeted gene inactivation studies in animals have identified several genes involved with prenatal brain stem development of respiratory control including arousal responsiveness. During embryogenesis, for example, neurotrophins regulate the survival of specific cellular populations composing the respiratory neuronal network (30). The neurotrophins are a multigene family of growth factors encoding closely homologous peptides, and the diversity of neurotrophins is complemented by similar heterogeneity in neurotrophin receptors. Brain-derived neurotrophic factor is required for development of normal breathing behavior in mice and newborn mice lacking functional brain-derived neurotrophic factor exhibit ventilatory depression associated with apparent loss of peripheral chemoafferent input (30, 31). Ventilation is depressed and hypoxic ventilatory drive is deficient or absent (31).

Krox-20, a homeobox gene important for hindbrain morphogenesis, also appears to be required for normal development of the respiratory central pattern generator (26, 32). Krox-20-null mutants exhibit an abnormally slow respiratory rhythm and increased incidence of respiratory pauses, and this respiratory depression can be further modulated by endogenous enkephalins (32). Inactivation of Krox-20 may result in the absence of a rhythm-promoting reticular neuron group localized in the caudal pons and could thus be a cause of life-threatening apnea.

Brain stem muscarinic cholinergic pathways are important in ventilatory responsiveness to CO2. The muscarinic system develops from the neural crest, and the ret protooncogene is important for this development (33). Ret knockout mice have a depressed ventilatory response to hypercarbia, implicating absence of the ret gene as a cause of impaired hypercarbic responsiveness and hence relevant to SIDS (15, 16). Diminished ventilatory responsiveness to hypercarbia has also been demonstrated in male newborn mice heterozygous for Mash-1 (34). There is a molecular link between ret and Mash-1, and the latter is expressed in embryonic neurons before the former in vagal neural crest derivatives and in brain stem locus coeruleus neurons (35), an area involved with arousal responsiveness. Mash-1 thus appears to be involved in respiratory control development via mechanisms linked to the X chromosome. Abnormality of this gene identifies one possible genetic basis for the increased frequency of SIDS in males (36) and for the impaired arousal responsiveness thought to be critically important in the pathophysiology of SIDS (15, 16, 27).

Genetic-environmental interactions. There are abundant data indicating multiple and robust associations between environmental factors and SIDS (4, 16, 36). These associations do not, however, preclude important polygenic mechanisms in which multiple genes interacting in different environments increase or decrease risk for that disorder.

A theoretical analysis of familial aggregation of disease among siblings concluded that such aggregation was generally related to genetic factors as clustering of most environmental risk factors with a relative risk (RR) =< 10 among relatives would lead to only slight and often unmeasurable excess aggregation of disease (39). Considering the many well-established examples of clinical conditions with dynamic interactions between genetic susceptibility and environmental influences, however, it is likely more accurate to consider genetic-environmental interactions as the most important mechanism. In regard to congenital defects, the combined RR for having the same defect in the second as in the first sibling in a population-based study was 7.6 (95% confidence interval [CI] 6.5-8.8) and subanalyses indicated strong indirect evidence of contributions from environmental factors (40). A significant genetic role is also suggested, however, by an increased RR for recurrence of the same congenital defect in offspring as in the mother, when common environmental influences would be less likely (41).

There are many examples of interactions between genetic susceptibility and environmental factors. Asthma, for example, shows polygenic inheritance and genetic heterogeneity (Table 2) (42). Multiple independent segregating genes are required for phenotypic expression and different combinations of gene variants can contribute to the phenotype in different families. Causal genetic and environmental interactions have also been identified for other common clinical entities (46).

TABLE 2

ASTHMA AND SUDDEN INFANT DEATH SYNDROME (SIDS)*

TABLE 6

SUMMARY OF DATA PROVIDING DIRECT OR INDIRECT EVIDENCE FOR GENETIC SUSCEPTIBILITY TO SUDDEN INFANT DEATH SYNDROME (SIDS)*

In regard to SIDS, there are putative interactions between sleep position, soft bedding and blankets, and impaired cardiorespiratory control, especially impaired ventilatory and arousal responsiveness (55). Facedown sleeping occasionally occurs in healthy full-term infants sleeping prone and can result in transient episodes of airway obstruction and asphyxia, but these healthy infants were able to arouse (56). Infants with insufficient arousal responsiveness to asphyxia, however, would be at risk for fatal asphyxia (55). Risk for life-threatening asphyxia from rebreathing can also be increased with soft bedding. Hypercarbia and hypoxemia when sleeping prone have each been observed in studies relating rebreathing or upper airway obstruction to prone sleeping (57).

There also appear to be interactions between sleep position and impaired thermoregulation (60). Facedown sleeping can cause clinically significant thermal stress, which could further compromise infants with deficient cardiorespiratory control or autonomic control, especially with genetic susceptibility to impaired thermoregulation.

Fetal and postnatal exposure to cigarette smoke in animal and human studies is a major risk factor for SIDS (16, 37, 61- 65), especially if associated with polygenic susceptibility. Both lambs and infants demonstrate impaired ventilatory and arousal responsiveness to hypoxia associated with fetal exposure (61, 62, 64), and postnatal nicotine exposure in piglets may interfere with normal autoresuscitation after apnea (68). In addition, fetal rat exposure to maternal smoking reduces protein kinase C within the dorsocaudal brain stem (62), which would impair respiratory control.

Intentional suffocation. The mother is typically the perpetrator, in contrast to traumatic child abuse. Intentional suffocation may be suspected from the case history and scene investigation and may be alleged because of prior sudden and unexpected infant death(s) in the family, but there are no pathognomonic findings at autopsy (Table 1). Like SIDS, therefore, the diagnosis can neither be confirmed nor excluded at autopsy. A moderate degree (>= 5%) of pulmonary hemorrhage has been proposed as an indicator of prolonged airway obstruction from overlying or intentional smothering (69). However, alveolar hemorrhage appears to be a characteristic of sudden unexpected death in a young infant, regardless of cause of the unexplained death, and hence appears neither necessary nor sufficient for diagnosis of suffocation (70).

Intentional suffocation may be a form of Munchausen syndrome by proxy in which the abuse is premeditated and may be associated with maternal psychiatric disturbance (71, 72). Intentional suffocation has been documented as a cause of ALTE by covert video surveillance (73, 74) but cannot be diagnosed with certainty in sudden unexpected death unless the perpetrator confesses. A behavioral profile developed for perpetrators of Munchausen syndrome by proxy does seem to be common in mothers guilty of intentional suffocation but the profile is not specific (73).

The incidence of intentional suffocation is unknown (Table 1). In a retrospective and selective referral group of 27 families with 57 sudden unexpected infant deaths (24 families with two, three with three deaths) studied by confidential inquiry, 55% of the deaths were attributed to intentional suffocation, 31% to explained causes including unintentional, 9% to SIDS, and 5% undetermined (75). Among 39 children thought to be victims of life-threatening abuse, covert video surveillance documented abuse in 33 including intentional suffocation in 30 (77%) (74). Among 41 siblings of these 39 children, there were 12 previous sudden unexpected infant deaths; investigations prompted by the video surveillance results led to four parental confessions of eight intentional suffocation and one conviction for deliberate salt poisoning. The population-based incidence of intentional suffocation has been estimated to be as high as 10% of sudden unexpected infant deaths, but is more likely < 5% and may be as low as 2% (6).

Summary

A thorough case investigation including autopsy should identify all explainable causes of unexpected infant death. Fatal child abuse comprises two distinct subgroups: traumatic child abuse explained by postmortem examination and intentional suffocation that cannot be differentiated from SIDS by autopsy.

Missed cases of intentional suffocation notwithstanding, SIDS cases constitute the majority of sudden unexpected deaths in infancy. Extensive pathological and physiological data implicate impaired cardiorespiratory control, especially deficits in arousal from sleep. These neural control systems appear to depend at least in part on genes controlling prenatal development of thebrain stem. There are likely important interactions between genetic susceptibility and environmental exposures occurring during fetal development (e.g., cigarette smoking) and postnatal (e.g., prone sleep position, soft bedding, passive smoking).

RECURRENT INFANT MORTALITY IN SIBLINGS

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SUDDEN, UNEXPECTED DEATH IN...
RECURRENT INFANT MORTALITY IN...
OBSTRUCTIVE SLEEP APNEA...
PHYSIOLOGICAL STUDIES
IMPLICATIONS
REFERENCES

Explained Causes

The next siblings of first-born infants dying of SIDS are at increased risk for birth-related deaths (76) (Table 3). When considering the specific cause of death in a subsequent sibling, the RR for same cause of death was 9.1 compared with 1.6 for a different cause of death. Among sibling pairs with recurrence of the same cause of death, the RR was significantly increased for all causes except infection. An expert panel reviewed all sudden unexpected infant deaths, but autopsy rates in the index cases were only 50-70%.

TABLE 3

RECURRENT INFANT MORTALITY IN SIBLINGS DUE TO SUDDEN INFANT DEATH SYNDROME (SIDS) AND NON-SIDS CAUSES

Autopsy rates were higher in a second study of recurrent infant mortality, 90% in the first and 100% in the next sibling death (77). The results, however, were similar to the first study (76). The RR for postperinatal infant mortality from the same general cause was significantly increased in the next-born and all subsequent siblings for explained causes. This observed increase in RR for recurrent infant mortality related to prematurity is consistent with the observed increased risk of prematurity in second-born siblings when the first-born sibling was premature (78).

In a population-based case-control study of all sudden unexpected infant deaths among 473,000 live births in 1993-1996 (UK) (37), infants with explained deaths were significantly more likely than control subjects to have had a previous sibling death in infancy (OR 5.96, CI 1.29-27.63), but not of having a previous stillbirth. Although scene investigations were not done, this study is strengthened by a 100% autopsy rate among the 456 sudden unexpected deaths, two later home visits by trained interviewers for data collection, a local multidisciplinary case review, and review by a multidisciplinary regional confidential inquiry committee. The inquiry included clinical history, psychosocial factors, gross pathology, histopathology, biochemistry, microbiology, virology, and radiology.

Unexplained Causes

Ten mortality studies have quantified the risk of recurrent SIDS when a prior sibling has died suddenly and unexpectedly (37, 76, 77, 79). The RR for recurrent SIDS in siblings is increased from 3.7 to 10.0 (all differences significant), which is similar to increased risk for recurrence of non-SIDS causes of infant mortality (37, 76, 77). The risk for recurrent SIDS in one study was no longer increased after adjusting for maternal age and birth rank (81), but the study then had insufficient power to detect a difference less than 4-fold.

Increasing parity is associated with higher risk for SIDS, with an odds ratio (OR) of 1.8 and 1.7 for all U.S. births in 1990 and 1996, respectively (CDC, unpublished data). The observed RR for recurrent SIDS, however (Table 3), was 4.6 times greater than expected by the effect of parity alone (76). The recurrence risk for all subsequent siblings is increased to a similar and significant extent as for the next sibling (76, 80, 81). The RR for risk of SIDS was also similar when analyzed for prior siblings (83).

The risk for recurrent SIDS in the twin of a SIDS victim was observed to be six of 625 in one region of South Australia, a rate ratio of 9.6/1,000 twin births (84). In a later cohort of all U.S. births in 1987-1991 with autopsy in all deaths, however, the rate ratio was only 0.004/1,000 twin births, corresponding to an RR of 8.2 (CI 1.2-56.7) for SIDS in the twin of a SIDS victim (85).

Summary and Critique

Subsequent siblings appear to be at increased risk for the same natural cause of infant mortality as the first sibling, except possibly infections. This relationship exists for both expected and unexpected causes of infant death and, among the latter, exists for explained causes and for SIDS. The risk of recurrent SIDS in surviving twins is also increased, but not to any greater extent than in nontwin siblings.

The early mortality studies of sudden unexpected infant deaths have deficits that limit general acceptance of the results, including missing or incomplete autopsy data. The autopsy rate was not provided for index cases in three instances (80) and for subsequent sibling deaths in one instance (80). Further, the rate in index cases was as low as 50% and never > 90%. Of note, however, the autopsy rate in subsequent siblings in four SIDS studies was 100% (77, 79, 81, 82) with results similar to the other studies.

The case-control study of deaths from five regions in England included thorough case investigations for the index death but information regarding prior infant deaths in the family was based on family reports (37). Although not designed as a study of recurrence risk for SIDS in siblings, the results may provide a useful perspective as the thorough investigation of all index cases of sudden unexpected infant death should reduce the number of missed cases of intentional suffocation to the lowest possible level. It is thus noteworthy (Table 3) that SIDS infants were significantly more likely than control infants to have had a previous sibling death during infancy, similar to the studies from Norway and Oregon of recurrent SIDS in siblings (76, 77). In addition, SIDS infants were again more likely than control infants to have had a prior stillbirth.

Another limitation of the mortality studies is that with one exception (37), no prevalence data for epidemiological risk factors associated with SIDS are included (69). It is therefore not possible to determine the extent to which risk for recurrent sudden unexpected death in infancy including SIDS might be related to common environmental risk factors. This is especially relevant now because overall SIDS rates have decreased substantially since the back-to-sleep campaigns and the relative impact of epidemiological factors on risk for SIDS and recurrent SIDS is changing (37, 86, 87).

OBSTRUCTIVE SLEEP APNEA SYNDROME

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SUDDEN, UNEXPECTED DEATH IN...
RECURRENT INFANT MORTALITY IN...
OBSTRUCTIVE SLEEP APNEA...
PHYSIOLOGICAL STUDIES
IMPLICATIONS
REFERENCES

Family Cohort Studies

Studies of obstructive sleep apnea syndrome or sleep-disordered breathing in families provide another perspective regarding genetic susceptibility to breathing control problems. Because these studies also suggest an increased risk for SIDS when obstructive sleep apnea aggregates in families, these data may also provide important insight regarding one possible pathophysiological mechanism for SIDS (88). The high percentage of adult children of patients with obstructive sleep apnea syndrome also having obstructive sleep apnea suggests that it may be an inherited syndrome (88). Obstructive sleep apnea syndrome appears to significantly aggregate within families and the risk appears to increase progressively with increasing numbers of affected relatives. This familial aggregation is not explained entirely by similarities in body mass index or neck circumference, suggesting the importance of other familial factors in increasing genetic susceptibility (90). As adults, children of patients with obstructive sleep apnea syndrome appear to have inherited subtle defects that reduce their ability to compensate for increased loads and maintain upper airway patency during sleep (89). Familial sleep-disordered breathing may be based partly on a familial abnormality in ventilatory control associated with blunting of the hypoxic ventilatory response. The greater increase in impedance during inspiratory loading in members of affected families also suggests a propensity for dynamic airway narrowing (89). Among Japanese men with obstructive sleep apnea syndrome, the frequency of HLA-A2 and HLA-B39 is increased, again suggesting an important role for genetic susceptibility (94).

A genetic contribution to the etiology of obstructive sleep apnea syndrome is further suggested by the associated craniofacial dysmorphism (93,95). Adults with obstructive sleep apnea syndrome having a relative with SIDS or ALTE were more likely than affected adults having no relative with SIDS or ALTE to have brachycephaly (p = 0.05), smaller mean posterior nasal spine-basion distance (p = 0.0001), and smaller ratio of anterior mandibular/anterior maxillary dental height (p < 0.05) (92). In this same study of children of index adults with obstructive sleep apnea syndrome and first-second-degree relatives, there was a trend toward higher incidence of SIDS/ALTE in the sleep apnea syndrome index families (10.8% versus 3.2%, p = 0.11) and all 10 SIDS/ALTE events occurred in families with at least one obstructive sleep apnea syndrome (p = 0.03) (Table 5).

TABLE 5

SUMMARY OF THE PHYSIOLOGICAL STUDIES PERFORMED IN PARENTS OF SUDDEN INFANT DEATH SYNDROME (SIDS) VICTIMS AND A FAMILY COHORT STUDY OF OBSTRUCTIVE SLEEP APNEA SYNDROME, SIDS, AND APPARENT LIFE-THREATENING EVENTS (ALTE)*

In further support of a genetic link between SIDS and upper airway compromise, SIDS victims have been reported to have retroposition of the maxilla (96), and morphometric analyses indicate that tongues of SIDS victims are heavier, wider, and thicker than control infants, unrelated to differences in fluid content (97). These differences were postulated to be genetic and to have developed prenatal because tongue weight was already increased in the youngest SIDS infants. Tongue weights were also significantly greater in males than in females.

Summary and Critique

Familial aggregation of obstructive sleep apnea syndrome, HLA abnormalities in affected men, and presence of deficient control of upper airway patency and hypoxic responsiveness in asymptomatic adult family members are all suggestive of genetic susceptibility factors. Because the relationship of ALTE to SIDS is unclear, however (15, 16), interpretation of analyses based on their combined frequency in these family cohorts is difficult. Among families with and without aggregation of obstructive sleep apnea syndrome, studies of nasopharyngeal airway dimensions are needed in SIDS victims and separately in ALTE patients. Pending a more defined relationship between SIDS and ALTE, population-based cohort studies need to be sufficiently large to analyze SIDS and ALTE rates as independent outcomes.

PHYSIOLOGICAL STUDIES

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SUDDEN, UNEXPECTED DEATH IN...
RECURRENT INFANT MORTALITY IN...
OBSTRUCTIVE SLEEP APNEA...
PHYSIOLOGICAL STUDIES
IMPLICATIONS
REFERENCES

Siblings of a Previous SIDS Victim

Physiological studies in siblings of prior SIDS victims (SIDS siblings) are a potentially useful strategy to identify intermediate phenotypes relevant to SIDS (see "SIDS Pathophysiology") (Table 4). Thirty-one publications evaluate brain stem regulation of cardiorespiratory or other autonomic control systems in SIDS siblings and matched controls (98). Siblings were specifically identified as asymptomatic in half of the studies. In a study of control of breathing in SIDS siblings, one subject had a history of idiopathic ALTE (117), but the results were comparable to the asymptomatic siblings. Although health status is unknown in the remaining publications, clinical assessment usually began before symptoms related to ALTE would be likely. In 12 studies, for example, all SIDS siblings were younger than 1 mo of age.

TABLE 4

SUMMARY OF THE PHYSIOLOGICAL STUDIES PERFORMED IN SIBLINGS OF PRIOR SUDDEN INFANT DEATH SYNDROME (SIDS) VICTIMS*

Most siblings studied had only one prior sibling death from SIDS. A study of overnight cardiorespiratory recordings in 78 siblings included seven families with two SIDS and one family with three SIDS, but these eight siblings did not appear to have differences in apnea or bradycardia patterns compared with the other 70 siblings and siblings did not differ from controls (112). In the 11 publications derived from the same group of 35 subsequent siblings, infants with more than one prior SIDS sibling were excluded (99, 100, 102, 103, 105-107, 113- 116). Only 19 of 31 publications stated that the diagnosis of SIDS was confirmed by autopsy and only 13 of 19 specifically stated that the autopsy rate was 100%.

Brain stem abnormalities in respiratory control. Respiratory pattern was evaluated in nine studies. SIDS siblings were significantly more likely to have central and obstructive apnea and periodic breathing (98), and two other studies reported increased periodic breathing and more central apnea 5-14.9 s (108, 109). In another study, infants with a well-defined ALTE or family history of SIDS were divided into those with (a) family history of multiple SIDS, ALTE, or obstructive sleep apnea syndrome and (b) those without obstructive sleep apnea syndrome and only one SIDS or ALTE (129). Infants with a family history of multiple SIDS, ALTE, or obstructive sleep apnea syndrome were more likely to have mixed and obstructive apnea (p < 0.05) and these apneas occurred more frequently.

In contrast, SIDS siblings did not have an increased frequency of obstructive apnea in another study (107), and periodic breathing and central apnea frequency did not differ from control subjects in three other studies (110). In one study, the number of 2-5 s apneas at 3-4 mo of age, 6-9 s apneas at 1-6 mo of age, and apneas > 9 s during the first week of life were all actually significantly less in SIDS siblings compared with control subjects (103).

Ventilatory responses to hypercarbia or hypoxia were assessed in five publications (117). SIDS siblings had a normal ventilatory response to 4% CO2 but responded to mild hypoxia (17% O2) with decreased respiratory rate, increased total duration of apneas > 3 s, increased periodic breathing, and increased time spent in apnea compared with control subjects (117). Ventilatory response to hypercarbia was significantly less than control subjects in one study using the P0.1 occlusion technique (120), but another study found no diminished ventilatory response to 2-4% CO2 even though resting minute ventilation was significantly less than control subjects (119). There were no significant differences in the estimated ventilatory response to 2% CO2 or in resting transcutaneous PCO2 and PO2 (118). Older siblings of a previous SIDS had no apparent diminished ventilatory response to hypercarbia or hypoxia (121).

Arousal responses were reported in six publications and included analyses of both spontaneous electroencephalogram (EEG)-based and stimulus-based arousal responsiveness. SIDS siblings had significantly increased intervals between active sleep epochs at certain times during the night as newborns, and a reduced tendency to enter short waking periods at 2-3 mo of age compared with control subjects (113). The latter was interpreted as an increased tendency to remain asleep or a relative failure to arouse from sleep. A study of temporal patterning of slow-wave sleep (114) observed significantly increased delta amplitude in the early morning at 3-4 mo of age, consistent with higher arousal thresholds. SIDS siblings were significantly more likely to stay asleep longer and to proceed from AS to QS than to AW (115). Arousal responsiveness to partial nasal obstruction at 1 wk to 6 mo of age was significantly decreased during quiet sleep (122). At 3 mo, there was decreased movement associated with obstructive apnea (107). The number of SIDS siblings arousing to 4% CO2 was not decreased compared with control subjects, but there was a trend toward fewer arousals to 17% O2 (0 of 16 versus 3 of 13 in controls, p < 0.08) (117).

Increased brain stem auditory conduction times are indicative of delayed or deficient maturation of neural processing in the brain stem (130, 131). Brain stem conduction times were prolonged in 26 siblings compared with 67 control subjects (123). Brain stem auditory evoked responses did not differ from control subjects in another study, but only nine siblings and 11 control subjects were studied (124). In a single study of increased beta -endorphin levels as a marker for diminished ventilatory drive in SIDS siblings, beta -endorphin levels in spinal fluid were significantly higher in SIDS siblings (127).

Other abnormalities in brain stem autonomic regulation. Sleep maturation has been assessed utilizing EEG power spectral analysis (116). Whereas abnormal sleep maturation might be associated with cardiorespiratory control abnormalities such as observed in some SIDS siblings, this study indicated accelerated sleep maturation compared with control subjects, resulting in a 1-mo advance in normal sequencing. They speculated that this acceleration might be a postnatal adaptive response to a stimulus such as hypoxia, but the actual stimulus is unknown and the clinical significance of this observation is hence also unknown.

Bradycardia and diminished heart rate variability have been implicated as autonomic abnormalities potentially associated with SIDS and tachycardia has been observed in infants later dying of SIDS (15, 16). During an overnight polysomnogram, heart rate was increased overall in SIDS siblings compared with control subjects (99), but fetal heart rate studied intrapartum or during home sleep recordings did not differ between the two groups (101, 102). SIDS siblings studied in utero at 36 wk gestation showed a trend toward more bradycardia > 10 min in duration (100). SIDS siblings have not been reported as having decreased heart rate variability, and the results have been similar to control subjects when studied postnatal (99, 101, 102). When studied in utero at 36 wk gestation, heart rate variability was increased (100), an observation of unknown clinical significance.

A prolonged Q-T interval (> 440-450 ms) has been implicated as a cause of SIDS (132). Among SIDS parents in whom at least one member had a prolonged Q-T interval, the Q-T interval was prolonged in 9 of 23 siblings of SIDS victims versus 0 of 18 siblings from the SIDS families with normal parental Q-T intervals (p < 0.01) (128). Although direct comparisons in siblings of prior SIDS victims with controls are needed, this study does indirectly support prolonged Q-T interval as one potential cause of SIDS and hence another genetic mechanism for SIDS (133).

Abnormalities in respiratory rate have not been associated with SIDS, except insofar as related to increased frequency or severity of apnea (15, 16). Although of uncertain clinical significance, the respiratory rate was increased in SIDS siblings in two studies (103, 105). In other studies, however, the respiratory rate was either lower than control subjects (104) or was similar (118).

Skin temperature in SIDS siblings was significantly increased during sleep, suggesting differences in temperature regulation (105). Although excessive sweating during sleep has been reported in SIDS victims, SIDS siblings do not have excessive sweating as determined by transepidermal water loss during sleep (125). Disordered autonomic function has also been hypothesized to be a mechanism for SIDS. When assessed by blood pressure and heart rate responses during sleep to postural change from supine to upright sitting, however, autonomic function was not different in SIDS siblings versus control subjects (126).

Parents of SIDS Victims

In addition to family studies of obstructive sleep apnea syndrome already discussed, these studies include ventilatory responses to hypercarbia and/or hypoxia (134) and sleep state regulation (100, 134) (Table 5). The autopsy rate was 100% in seven studies (100, 134) and not mentioned in one (140). Two studies specified inclusion of only families with a single SIDS (137, 138). One negative study of ventilatory chemosensitivity included two fathers with two SIDS children each (139), and one study showing reduced ventilatory response to hypoxia included a couple with two SIDS children (140). Mothers of two infant SIDS victims (80) had significantly fewer siblings than did their husbands and the parents of a single SIDS (p < 0.001).

Brain stem abnormalities in respiratory control. There was a trend toward diminished ventilatory responses to 5% CO2 in SIDS parents (135). In response to 4% CO2, however, there were no changes in respiratory rate, tidal volume, inspiratory time, arterial blood gases, or ventilation compared with control subjects (136). Using a single vital capacity breath of 13% CO2, parents did not differ from control subjects in regard to tidal or minute volume, tidal volume/inspiratory time, or inspiratory time/respiratory cycle time (137).

Measuring ventilatory responses to hypercarbia or hypoxia using increased airway resistance may be a more sensitive test for detecting differences between SIDS parents and control subjects. In two studies of ventilatory responsiveness to 5-7% CO2 with inspiratory loading, lower ventilatory drive was observed in parents of SIDS, with and without inspiratory flow resistance (138). At a lower inspiratory flow resistance, however, the response to hypercarbia was not decreased (139).

Ventilatory responsiveness to hypoxia was studied in four reports. One study documented a lower ventilatory response to progressive isocapnic hypoxia in parents of SIDS (expired PO2 = 50 mm Hg) (140). Three other studies (134, 136, 139), however, observed no difference in responsiveness even though the hypoxic stimulus was greater (expired PO2 = 40 mm Hg).

Sleep. Sleep state regulation and breathing control regulation are closely related. Mothers of SIDS victims studied at 36 wk gestation during the next pregnancy had less REM sleep and decreased Stage IV quiet sleep than control subjects (100), but the clinical significance of this difference is unclear. In fathers and nonpregnant mothers, there were no differences in sleep characteristics (134).

Summary and Critique

The physiological studies in siblings of prior SIDS victims and parents of SIDS investigate multiple putative cardiorespiratory control and other brain stem autonomic abnormalities related to SIDS. Approximately half of the studies in SIDS siblings and a somewhat lesser percentage in parents of SIDS identified abnormalities. Although no contradictory results were observed in parental studies, fetal heart rate variability was increased in siblings of prior SIDS whereas it is decreased in infants later dying of SIDS (15). One study of apnea and periodic breathing reported fewer rather than more apnea at some ages, but these overnight recordings were performed in a sleep laboratory rather than at home and the results may not be interchangeable.

Deficient arousal responsiveness was the most consistent abnormality in SIDS siblings and the most compelling in regard to increased mortality risk (27,55). Unfortunately, arousal responsiveness has not been studied in parents of SIDS. Generalizability of these arousal response deficits is enhanced by the consistency of results despite using three different assessment strategies in three separate subject groups at multiple ages.

Some of the results in siblings and parents of prior SIDS, including obstructive sleep apnea cohorts, are consistent with incomplete phenotypes having increased susceptibility to SIDS. Most of the negative physiological studies were small, and power to detect a significant difference was likely insufficient considering the high intragroup variability. It is possible that larger study populations might have identified a broader scope of brain stem autonomic deficits. A meta-analysis of these multiple small studies was not performed due to the general lack of standardization in methodology and analysis.

Other limitations in the physiologic studies may also be pertinent. First, 11 of the studies in SIDS siblings were based on a single group of about 35 siblings (99, 100, 102, 103, 105, 113) who may not be representative of all subsequent siblings. Second, most of the other sibling studies of apnea did not utilize breath-detection methods capable of identifying obstructed breaths and included few if any extreme apnea/bradycardia events most likely to be of clinical significance (Table 4) (141). Third, no information is available regarding presence of epidemiological risk factors that might contribute to the differences observed. Fourth, many of the studies do not specify the extent to which analyses were conducted blind to group identity of the subjects. Fifth, we cannot exclude the possibility that cause of death in some of the index siblings was intentional suffocation rather than SIDS and that some of the siblings of presumed SIDS were intentionally being intermittently suffocated to cause the observed physiological differences. Inclusion of cases of intentional suffocation misdiagnosed as SIDS, however, would not explain the differences observed in parental studies, and would not explain some of the differences observed in the sibling studies, especially at the youngest ages. These limitations notwithstanding, the physiological data are in the aggregate consistent with the hypothesis that deficiencies in cardiorespiratory control and arousal from sleep are present in some SIDS siblings and may contribute to increased susceptibility to SIDS in these families.

IMPLICATIONS

CONTENTS
SUDDEN, UNEXPECTED DEATH IN...
RECURRENT INFANT MORTALITY IN...
OBSTRUCTIVE SLEEP APNEA...
PHYSIOLOGICAL STUDIES
IMPLICATIONS
REFERENCES

Studies indicate multiple genetic influences on developmental maturation of brain stem autonomic control mechanisms including cardiorespiratory control and arousal (Table 6). To the extent that phenotypes with impairment in such mechanisms are indeed at increased risk for SIDS, genetic susceptibility is most likely related, as in other complex conditions, to polygenic abnormalities with incomplete penetrance (63). Susceptibility conferred by alleles at one locus would hence also depend on alleles at other independently segregating loci interacting with environmental influences. Polygenic susceptibility to recurrent infant mortality notwithstanding, therefore, genetic susceptibility may be most relevant when confronted with sufficient environmental influence(s).

There have been multiple barriers to acceptance of a genetic role in pathophysiology of SIDS. These barriers have included a desire to minimize potential for parental guilt or blame and the misperception that acknowledging a genetic role implies a single gene disease or existence of discrete genotypes causing SIDS unrelated to environmental risks. Another barrier has been an assumption that SIDS does not adhere to usual patterns of disease associated with other natural causes of infant mortality in which genetic and environmental interactions are well accepted. To the extent that some cases of SIDS are associated with cardiorespiratory, arousal, or other autonomic deficits, our increasing knowledge of related genetic mechanisms suggests that the question is no longer whether there is a genetic defect but rather "how strong is the genetic component and what genes are involved?" (142).

There are no new strategies for "diagnosing" intentional suffocation and quantifying its contribution to sudden unexpected infant mortality. It is therefore impossible to calculate extent of familial aggregation of SIDS using measures such as the recurrence risk ratio (143). Failure to diagnose infant suffocation, however, does not explain the increased mortality rate in subsequent siblings from explained natural causes or the physiological abnormalities observed in some parents of SIDS, and likely does not explain the physiological abnormalities observed in younger siblings of SIDS. Although no studies reviewed exclude substantial environmental influences, these studies document increased recurrent mortality rates in subsequent siblings from explained natural causes.

A major potential impact of these hypothesized links among genetic susceptibility, SIDS, and recurrent infant mortality in siblings may be inclusion of genetic susceptibility in future explorations of mechanisms for SIDS and relationship to other clinical entities (142). Notwithstanding the evidence for recurrent SIDS in siblings of SIDS victims, recurrent SIDS is nevertheless an uncommon occurrence. Assuming an incidence of SIDS of 0.7 deaths/1,000 live births for the first sibling and RR = 5 for recurrence, SIDS parents considering another pregnancy can be reassured that depending on magnitude of environmental risk factors, 99.65% or more of siblings may survive infancy.

Footnotes

Correspondence and requests for reprints should be addressed to Carl E. Hunt, Director, National Center on Sleep Disorders Research, National Heart, Lung, and Blood Institute, Two Rockledge Centre, Room 10038, 6701 Rockledge Drive, MSC 7920, Bethesda, MD 20892-7920. E-mail: huntc@nhlbi.nih.gov

(Received in original form October 13, 2000 and in revised form January 5, 2001).

Acknowledgments: The author wishes to thank Marian Willinger, Ph.D. (Special Assistant for SIDS, Pregnancy and Perinatology Branch, Center for Research for Mothers and Children, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD) and George Lister, M.D. (Professor of Pediatrics, Yale University School of Medicine, New Haven, CT) for their critical review of this manuscript.
References

CONTENTS
SUDDEN, UNEXPECTED DEATH IN...
RECURRENT INFANT MORTALITY IN...
OBSTRUCTIVE SLEEP APNEA...
PHYSIOLOGICAL STUDIES
IMPLICATIONS

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