{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:00:48Z","timestamp":1791896448093,"version":"4.3.4"},"reference-count":34,"publisher":"American Academy of Pediatrics (AAP)","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2002,11,1]]},"abstract":"<jats:p>Sudden infant death syndrome (SIDS) victims were regarded as normal as a matter of definition (Beckwith 1970) until 1952 when Kinney and colleagues argued for elimination of the clause, \u201cunexpected by history.\u201d They argued that \u201cnot all SIDS victims were normal,\u201d and referred to their hypothesis that SIDS results from brain abnormalities, which they postulated \u201cto originate in utero and lead to sudden death during a vulnerable postnatal period.\u201d Bergman (1970) argued that SIDS did not depend on any \u201csingle characteristic that ordains a infant for death,\u201d but on an interaction of risk factors with variable probabilities. Wedgwood (1972) agreed and grouped risk factors into the first \u201ctriple risk hypothesis\u201d consisting of general vulnerability, age-specific risks, and precipitating factors. Raring (1975), based on a bell-shaped curve of age of death (log-transformed), concluded that SIDS was a random process with multifactorial causation. Rognum and Saugstad (1993) developed a \u201cfatal triangle\u201d in 1993, with groupings similar to those of Wedgwood, but included mucosal immunity under a vulnerable developmental stage of the infant. Filiano and Kinney (1994) presented the best known triple risk hypothesis and emphasized prenatal injury of the brainstem. They added a qualifier, \u201cin at least a subset of SIDS,\u201d but, the National Institute of Child Health and Development SIDS Strategic Plan 2000, quoting Kinney\u2019s work, states unequivocally that \u201cSIDS is a developmental disorder. Its origins are during fetal development.\u201d Except for the emphasis on prenatal origin, all 3 triple risk hypotheses are similar.<\/jats:p>\n               <jats:p>Interest in the brainstem of SIDS victims began with Naeye\u2019s 1976 report of astrogliosis in 50% of all victims. He concluded that these changes were caused by hypoxia and were not the cause of SIDS. He noted an absence of astrogliosis in some older SIDS victims, compatible with a single, terminal episode of hypoxia without previous hypoxic episodes, prenatal or postnatal.<\/jats:p>\n               <jats:p>Kinney and colleagues (1983) reported gliosis in 22% of their SIDS victims. Subsequently, they instituted studies of neurotransmitter systems in the brainstem, particularly the muscarinic (1995) and serotenergic systems (2001). The major issue is when did the brainstem abnormalities, astrogliosis, or neurotransmitter changes occur and whether either is specific to SIDS. There is no published method known to us of determining the time of origin of these markers except that the injury causing astrogliosis must have occurred at least 4 days before death (Del Bigio and Becker, 1994). Because the changes in neurotransmitter systems found in the arcuate nucleus in SIDS victims were also found in the chronic controls with known hypoxia, specificity of these markers for SIDS has not been established. It seems likely that the \u201cacute control\u201d group of Kinney et al (1995) died too quickly to develop gliosis or severe depletion of the neurotransmitter systems. We can conclude that the acute controls had no previous episodes of severe hypoxia, unlike SIDS or their \u201cchronic controls.\u201d Although the average muscarinic cholinergic receptor level in the SIDS victim was significantly less than in the acute controls, the difference was only 27%, and only 21 of 41 SIDS victims had values below the mean of the acute controls. The study of the medullary serotonergic network by Kinney et al (2001) revealed greater reductions in the SIDS victims than in acute controls, but the questions of cause versus effect of the abnormalities, and whether they occurred prenatally or postnatally, remain unanswered.<\/jats:p>\n               <jats:p>Hypoplasia of the arcuate nucleus was stated to occur in 5% of their SIDS cases by Kinney et al (2001), but this is a \u201cprimary developmental defect\u201d according to Matturri et al (2002) with a larger series, many of whom were stillbirths. These cases should not be included under the rubric of SIDS, by definition.<\/jats:p>\n               <jats:p>There are difficulties with Filiano and Kinney\u2019s (1994) explanation of the age at death distribution of SIDS. They postulate that the period between 1 and 6 months represents an unstable time for virtually all physiologic systems. However, this period demonstrates much less instability than does the neonatal period, when most deaths from congenital defects and severe maternal anemia occur. We present data for infants born to mothers who were likely to have suffered severe anemia as a consequence of placenta previa, abruptio placentae, and excessive bleeding during pregnancy; these infants presumably are at increased risk of hypoxia and brainstem injury. The total neonatal mortality rate in these 3 groups of infants is 4 times greater than the respective postneonatal mortality, and in the postneonatal period the non-SIDS mortality rate is between 14 and 22 times greater than the postneonatal SIDS rate in these 3 groups. A preponderance of deaths in the neonatal period is also found for congenital anomalies, a category that logically should include infants who experienced prenatal hypoxia or ischemia; this distribution of age of death is very different from that for SIDS, which mostly spares the first month and peaks between 2 and 3 months of age.<\/jats:p>\n               <jats:p>Finally, evidence inconsistent with prenatal injury as a frequent cause of SIDS comes from prospective studies of ventilatory control in neonates who subsequently died of SIDS; no significant respiratory abnormalities in these infants have been found (Waggener et al 1990; Schectman et al 1991).<\/jats:p>\n               <jats:p>We conclude that none of the triple risk hypotheses presented so far have significantly improved our understanding of the cause of SIDS. Bergman\u2019s and Raring\u2019s concepts of multifactorial causation with interaction of risk factors with variable probabilities is less restrictive and more in keeping with the large number of demonstrated risk factors and their varying prevalence. If prenatal hypoxic damage of the brainstem occurred, it seems likely that the infant so afflicted would be at risk for SIDS, but it is even more likely that their death would occur in the neonatal period, as we have demonstrated in infants who have known maternal risk factors that involve severe anemia. This is in contrast to the delay until the postneonatal period of most SIDS deaths. A categorical statement that the origin of SIDS is prenatal is unwarranted by the evidence. Brainstem abnormalities have not been shown to cause SIDS, but are more likely a nonspecific effect of hypoxia.<\/jats:p>","DOI":"10.1542\/peds.110.5.e64","type":"journal-article","created":{"date-parts":[[2004,8,14]],"date-time":"2004-08-14T00:17:55Z","timestamp":1092442675000},"page":"e64-e64","source":"Crossref","is-referenced-by-count":155,"title":["The Triple Risk Hypotheses in Sudden Infant Death Syndrome"],"prefix":"10.1542","volume":"110","author":[{"given":"Warren G.","family":"Guntheroth","sequence":"first","affiliation":[{"name":"From the Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip S.","family":"Spiers","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"417","published-online":{"date-parts":[[2002,11,1]]},"reference":[{"key":"2022121213554392300_R1","unstructured":"Beckwith JB. 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