Etiology

Etiology is currently unknown. Indeed, the identification of a specific etiology/acute process in an infant as a cause of death is sufficient to eliminate the diagnosis of SIDS.

The frequent autopsy finding of mild upper airway inflammation in suspected cases of SIDS raises the possibility that intercurrent respiratory tract infections have a role in SIDS, particularly in combination with over-bundling.[12]

Associations with other modifiable risk factors, such as sleeping position, sleeping surface, sleeping arrangements, smoke exposure, not breast-feeding, and non-use of a pacifier have been well established, although direct causative roles have yet to be determined.[13]​ One Cochrane Database systematic review in 2017 found no randomized controlled trial evidence on which to support or refute the use of pacifiers in SIDS and another one in 2022 similarly found no randomized controlled trial evidence on which to make recommendations about the safety or danger of bed-sharing.[14][15]​​ However, it should be noted that, because of ethical considerations, no randomized controlled trials have been conducted to establish risk factors for SIDS; instead, case-control data are used.

Genetic differences between infants with SIDS and those dying from other causes have been reported.[16][17][18][19][20][21][22][23] Candidate genes with possible roles in susceptibility to SIDS include those related to and/or involved in dysrhythmias, development of autonomic control, inflammatory response mechanisms, and production of neurotransmitters.

The mechanisms for how genetic differences contribute to SIDS susceptibility have yet to be elucidated. Mutations in genes encoding for Na+ or K+ channels linked to long QT syndrome have been reported in 5% to 29% of SIDS victims. Although this percentage is significantly higher than that observed in the general population, dysrhythmias appear to account for only 5% to 10% of deaths from SIDS.[16][17]​ Regulation of brainstem serotonin concentration may also have an important role in determining susceptibility to SIDS. Differences in genes regulating serotonin concentration in nerve endings and serotonin transporter expression have been found between infants whose deaths have been attributed to SIDS and matched, non-SIDS controls.[18][19][20]​ Genetic differences in pathways involved in regulating proinflammatory responses (i.e., interleukin-6, complement) have also been reported in small numbers of SIDS victims.[22][23]

Pathophysiology

While the pathophysiology of SIDS remains incompletely defined, it is increasingly understood that it is multifactorial and that the presence of any 1 risk factor is probably insufficient in itself to lead to a fatal event. First described more than 15 years ago, the most commonly utilized model to explain SIDS is the “Triple-Risk” hypothesis, wherein 3 categories of factors converge to result in infant death.[24] These 3 key risk categories/factors are:

  • A vulnerable infant (e.g., prematurity, low birth weight, disordered autonomic regulation)

  • A critical period during homeostatic control development (e.g., cardiorespiratory regulatory mechanism maturation)

  • An exogenous stressor (e.g., smoke exposure, sleep environment, overheating).

In infants succumbing to SIDS, the final common pathway appears to involve abnormal cardiorespiratory control, specifically an inadequate/incomplete ability to arouse from sleep.[25] Children dying from SIDS may have a different hypoxic gasping pattern, which is associated with ineffective autoresuscitation (increases in heart rate and respirations) compared with otherwise healthy infants or those dying of non-SIDS causes.[26]

Brainstem abnormalities involving the medullary serotonergic (5-HT) system have been found in up to 70% of SIDS infants.[27][28][29][30] Serotonin is important in coordinating many respiratory, arousal, and autonomic functions, and it is believed that functional serotonin is critical in the normal protective responses to stressors that commonly occur during sleep. Pathologic brainstem changes that appear unique to SIDS victims include increased apoptotic and gliotic changes in the medulla oblongata, which have been associated with obstructive apnea events in SIDS victims.[31][32][33] Changes consistent with chronic medullary hypoxic-ischemic injury have also been noted in SIDS victims, which suggests that SIDS may not always be the result of a discrete, single event but rather the culmination of multiple, subtle brainstem perturbations occurring over hours or even days.[34]

Mechanisms linking risk factors to cardiorespiratory dysregulation are being increasingly understood and provide valuable pathophysiologic insights.[35][36]

  • Prematurity: these infants have relative immaturity of central respiratory regulation compared with term infants. However, this must be differentiated from apnea of prematurity, which, as a discrete entity, is not an independent risk factor for SIDS.

  • Smoke exposure: prenatal smoke exposure alters heart rate variability during stress.[37] Additionally, nicotine has neuroteratogenic effects that affect, among other things, arousal to hypoxic stress.[38]

  • Exhaled gas rebreathing: while evidence is still conflicting, it remains postulated that prone positioning, soft compressible sleep surfaces, soft bedding, and head covering during sleep promote CO2 rebreathing, with implications for sleep arousal.[39][40][41][42][43][44]

  • Proinflammatory cytokines: an overactive inflammatory response has been implicated as a risk factor for SIDS and may act by altering cardiorespiratory regulation.[22] Prone position and viral upper respiratory infections increase nasopharyngeal temperature and contribute to production and release of proinflammatory cytokines by nasopharyngeal colonizing bacteria.[45] Related to this, nighttime cortisol production, which decreases inflammatory cytokine levels, is lowest in infants between 2 and 4 months of age.[46]

Classification

SIDS - standardized investigations and classification: recommendations[5]

There is no formal classification system. In 2007, an expert panel proposed a stratification of SIDS diagnoses based on demographic, clinical, and autopsy findings.[5] However, this classification system has not been universally accepted, including the criterion regarding the possible association between onset of fatal event and sleep.

Category IA SIDS

  • History: age >21 days and <9 months; noncontributory clinical history; full-term gestation (37 weeks or later); normal growth and development; and no similar deaths in siblings/relatives.

  • Circumstances of death: scene investigation performed, no explanation of death provided; no evidence of accident; and safe sleeping environment.

  • Autopsy: no lethal pathologic findings; no unexplained trauma/abuse/neglect; no substantial thymic stress; and negative toxicology, microbiology, radiology, vitreous chemistry, and metabolic screening.

Category IB SIDS

  • History: age >21 days and <9 months; noncontributory clinical history; full-term gestation (37 weeks or later); normal growth and development; and no similar deaths in siblings/relatives.

  • Circumstances of death: scene not investigated by forensics team.

  • Autopsy: no lethal pathologic findings; no unexplained trauma/abuse/neglect; no substantial thymic stress; negative toxicology, microbiology, radiology, vitreous chemistry, and metabolic screening; and 1 or more of these tests not carried out.

Category II SIDS

  • History: age 0 to 21 days or >9 months; neonatal/perinatal conditions that had resolved by time of death; and similar death(s) in siblings/relatives.

  • Circumstances of death: mechanical asphyxia or suffocation by overlaying not determined with certainty.

  • Autopsy: no lethal pathologic findings; no unexplained trauma/abuse/neglect; no substantial thymic stress; negative toxicology, microbiology, radiology, vitreous chemistry, and metabolic screening; abnormal growth/development not thought to have contributed; and more marked inflammatory changes or abnormalities that alone are insufficient to have caused death.

Unclassified sudden infant death

  • History: criteria for category I or II SIDS not fulfilled.

  • Circumstances of death: alternative diagnoses of natural or unnatural death equivocal.

  • Autopsy: not performed.

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