Which factor is associated with an increased occurrence of sudden infant death syndrome?

Although multiple hypotheses have been proposed as the pathophysiologic mechanisms responsible for SIDS, none have been proven. The triple-risk model, proposed by Filiano and Kinney, suggests that SIDS represents an intersection of factors, including the following [15] :

• A vulnerable infant possessing intrinsic abnormalities in cardiorespiratory control

• A critical period in the development of homeostatic control mechanisms

• Exogenous extrinsic stressors (triggering factors)

SIDS rarely occurs in infants who are risk free or those who have only one risk factor. Ostfeld et al (2010) report that in one study, 96.3% of decedents had 1 to 7 risk factors, with 78.3% having 2 to 7. [16] In another report, 57% of SIDS infants had one intrinsic risk factor and 2 extrinsic factors. [17]

Death occurs when vulnerable infants are subjected to stressors at times when normal defense mechanisms may be structurally, functionally, or developmentally deficient.

The triple-risk model allows for the possibility of multiple stressors and for heterogeneous underlying vulnerabilities that manifest as SUID. Epidemiologic data suggest that genetic factors play a role, and many studies have attempted to identify SIDS-associated genes. [18] A copious literature implicates various genes, encoded proteins, and signaling pathways in the pathogenesis of SIDS, including central nervous system (CNS) pathways, cardiac channelopathies, immune dysfunction, metabolic pathways, and nicotine responses.

QT interval hypothesis

Although both prolongation of the QT interval (long QT syndrome [LQTS]) and shortening of the QT interval (short QT syndrome [SQTS]) are associated with increased risk of cardiac arrhythmia and sudden death, it is QT prolongation that has received the greatest attention in SIDS. [19] Clinically, these dysrhythmias may present as syncope, seizures, or sudden cardiac death. According to conservative estimates, 30-35% of infants who subsequently die of SIDS have prolongation of the QT interval in the first week of life.

The QT interval is heart rate−dependent and is calculated according to Bazett’s formula. Prolongation of the corrected QT interval (QTc) is a marker of reduced cardiac electrical stability and is strongly associated with SIDS. Some clinicians consider the QTc to be prolonged when it exceeds 440 msec; others consider it to be prolonged when it exceeds 450-475 msec.

The QTc increases during the second month of life but returns to values recorded at birth by the sixth month. These findings are derived from a large prospective study of infants born over a 19-year period, and another study, which together examined more than 40,000 infants. The odds ratio for SIDS among all infants with prolonged QTc was 41:1; for boys, the odds ratio was approximately 47:1.

Prolongation of the QTc may act as an arrhythmogenic substrate that requires other postnatal factors to trigger development of life-threatening arrhythmias. The trigger is usually a sudden increase in sympathetic activity, which, during the first year of life, may have a number of causes, including sudden noise, apnea leading to a chemoreceptive reflex, exposure to cold, and rapid eye movement (REM) sleep and arousal.

Developmental alteration in cardiac sympathetic innervation is one hypothesis proposed to explain QTc prolongation. Such innervation continues after birth for approximately 6 months. Occasionally, right and left sympathetic nerves develop at different rates, creating a temporary neural imbalance. During this stage, a sudden increase in sympathetic activity may cause a lethal arrhythmia in these electrically unstable hearts. This is most commonly the torsades de pointes variant of ventricular tachycardia, due to early after-depolarizations.

A second hypothesis proposes a variant of congenital LQTS. Patients with this syndrome are at high risk for sudden death, especially under conditions of stress, but also during sleep.

Congenital LQTS has several distinct genetic forms or may arise as a spontaneous mutation. An autosomal dominant form (Romano-Ward) and an autosomal recessive form (Jervell and Lange-Nielsen) are recognized. The latter is associated with sensorineural deafness. LQTS may also occur sporadically. The genes encoding ion-channel proteins regulating sodium and potassium ion flux have been described. Multiple mutations involving 8 genes on 5 separate chromosomes have been identified to date. [20, 21, 22, 23, 24]

A long-term prospective study, involving 34,442 newborns over an 18-year period, explored the relation of QTc prolongation to SIDS. [25] Within this large cohort, 24 infant deaths occurred that were attributed to SIDS. Twelve of the 24 infants exhibited prolongation of the QT interval on their newborn electrocardiogram (ECG). The authors suggested that these deaths might have been preventable with medications (beta-blockers) known to suppress the development of the fatal dysrhythmias associated with QTc prolongation.

Although other traditional SIDS risk factors (eg, prone sleeping position, maternal smoking, and bed sharing) have odds ratios markedly lower than that observed with QTc prolongation, the American Academy of Pediatrics considers it unlikely that this electrical irregularity explains more than a small minority of SIDS cases. Future studies will help to determine whether targeted or population-based screening for QTc prolongation among newborns is the best evidence-based strategy.

Hypoxia/apnea hypothesis

Apnea (cessation of respiratory airflow) can be manifested in several different forms, including the following:

• Periodic breathing

• Pathologic apnea

• Apnea of infancy

Definitions of these terms (see below) are based on those promulgated by the National Institutes of Health Consensus Development Conference on Infantile Apnea and Home Monitoring, supplemented as noted.

A BRUE (previously called apparent life-threatening event) is frightening to observe and is characterized by some combination of apnea (central, occasionally obstructive), color change (usually cyanotic or pallid, occasionally erythematous or plethoric), marked change in muscle tone (usually limpness), choking, or gagging. In some cases, observers fear the infant has died. BRUE survivors share many risk factors for SIDS and are at increased risk for the syndrome; however, debate exists as to whether BRUEs are interrupted SIDS events, separate phenomena, or SIDS-related events.

The estimated frequency of BRUE among healthy term infants is 1-3%. A potential relation between SUID and BRUE is suggested by the observation that the risk of subsequent death among infants experiencing a BRUE is 1-2%. The risk increases to 4% for infants whose BRUE is associated with respiratory syncytial virus (RSV) infection and rises to 8-10% for infants who experience BRUE during sleep or require some form of cardiopulmonary resuscitation (CPR). Among infants with SIDS, only 5% have a history of a BRUE preceding the death.

Approximately 25-30% of BRUEs remain unexplained even after a thorough evaluation. The most conditions commonly associated with BRUE include gastroesophageal reflux disease (GERD), lower respiratory tract infection (bronchiolitis), pertussis, urinary tract infection (UTI), respiratory control disorder, and seizure. Less common causes include cardiac dysrhythmia (LQTS), anemia, structural CNS anomaly, and cardiac or airway anomaly.

Periodic breathing is a breathing pattern in which 3 or more respiratory pauses of more than 3 seconds’ duration are separated by less than 20 seconds of respiration between pauses. This breathing pattern can be normal.

Pathologic apnea involves an abnormal pause in respiration. A respiratory pause is abnormal if it is prolonged (>20 sec) or if it is associated with cyanosis; abrupt, marked pallor; hypotonia; or bradycardia.

Apnea of prematurity is characterized by periodic breathing with pathologic apnea in a premature infant. Apnea of prematurity usually ceases by 37 weeks’ gestation (postmenstrual dating) but occasionally persists for several weeks past term.

Apnea of infancy is characterized by an unexplained episode of cessation of breathing for 20 seconds or longer or by a briefer respiratory pause associated with cyanosis, pallor, marked hypotonia, or bradycardia. This term is generally applied to infants who are older than 37 weeks’ gestational age at the onset of pathologic apnea. Typically, their BRUEs are idiopathic but are considered to be related to apnea. Accordingly, the apnea of infancy classification is generally reserved for those infants for whom no specific BRUE cause can be identified.

Several anatomic and physiologic findings support the role of apnea in SIDS. SIDS, despite its name, is not always sudden.

Meny et al reviewed data from 6 infants who died while on home monitors. [26] Of the 6 deaths, 3 were ascribed to SIDS. All SIDS patients had bradycardia that preceded (n = 2) or occurred simultaneously with (n = 1) central apnea; 1 had tachycardia before bradycardia. The monitor printout of 1 patient showed a slow decrease in heart rate for about 2 hours before death. One infant who had rapid CPR could not be revived, which suggested that myocardial depression secondary to hypoxemia may have preceded the bradycardia.

Other evidence also implicates hypoxia (acute and chronic) in SIDS. Hypoxanthine, a marker of tissue hypoxia, is elevated in the vitreous humor of patients who die of SIDS as compared with control subjects who die suddenly. This adds biochemical support to the concept that in some cases, SIDS is a relatively slow process. In addition, a number of infants who die of SIDS manifest necropathologic evidence of chronic hypoxia, including changes in the bronchiolar walls, pulmonary neuroendocrine cells in the lungs, and elevated fetal hemoglobin levels.

Alveolar hypoxia stimulates pulmonary vasoconstriction and, eventually, pulmonary vascular smooth muscle cell hyperplasia. Muscularity of the pulmonary vasculature causes pulmonary vasoconstriction, increased right ventricular afterload, and heart failure with more tissue hypoxia. Arterial hypoxemia and ischemia result in astrogliosis of the brainstem, which promotes hypoventilation and further astrogliosis.

Another significant autopsy finding is pleural petechiae, whose formation reflects acute hypoxia in a physiologically intact infant. Hypoxic asphyxia in newborns occurs in the following well-defined stages:

• Stage 1 - Tachypnea for 60-90 seconds followed by apparent loss of consciousness, passage of urine, and no respiratory effort

• Stage II - Deep, gasping respiratory efforts separated by 10-second periods of respiratory silence

• Stage III - Formation of pleural petechiae, ultimately resulting in cessation of gasping

• Stage IV – Death, if resuscitation is not initiated

The latter stages of asphyxia are triggered when arterial oxygen tension (PaO2) falls toward zero. Asphyxia may occur with the airway open, partially occluded, or closed.

Although SIDS autopsies often demonstrate no pathologic findings, most infants who die of SIDS have an extremely large number of petechiae. Their presence suggests that repeated episodes of asphyxia occurred in a period of hours to days before death, causing recurrent gasping episodes with associated petechiae formation. Studies in newborn animals have shown that metabolic recovery from asphyxia takes hours. Thus, repeated asphyxia episodes that were previously self-limited by arousal and autoresuscitation might eventually prove fatal.

In general, apnea may be classified into the following 3 basic types:

• Central or diaphragmatic (ie, no respiratory effort)

• Obstructive (usually due to upper airway obstruction)

• Mixed

Whereas short central apnea (< 15 sec) can be normal at all ages, prolonged apnea that disrupts physiologic function is never normal. Some pathologic evidence and ample theoretical evidence support central apnea as a cause of SIDS and obstructive apnea as playing an associated, if not key, role in some infants. Expiratory apnea (lung collapse) also has been proposed as a cause of SIDS; however, necropathologic evidence of its presence is found in only a small minority of cases.

Obstructive apnea

Developing infants have normal sites of anatomic and physiologic vulnerability that, alone or combined, may transiently predispose to airway obstruction. Among these vulnerabilities are the following:

• Shallow hypopharynx

• Cephalad position of the tongue and epiglottis

• More compliant rib cage

Positioning may predispose the newborn to upper airway obstruction as well. Although infants with anatomic anomalies are at particular risk, obstruction may also occur in those with normal anatomy. Most infants are obligate nasal breathers for the first few months of life. The nares flare anteriorly, with the nose forming no protrusion. Four to 6 months represents the period of cardinal transition from nose breathing to mouth breathing. [27]

Hypoxemia of sufficient severity to produce electroencephalographic (EEG) evidence of cerebral hypoxia does not begin until 60-70 seconds after the onset of obstruction. Although infants placed in the prone position on a level sleeping surface may turn their faces to maintain oxygen flow, respiratory obstruction with compression of the nose and backward displacement of the mobile mandible has been implicated as a cause of asphyxia in the prone position.

Gastroesophageal reflux (GER) may play a role in obstructive apnea as well. Regurgitation increases mucosal adhesive forces, a development of particular significance with the more pliable airways of infants. The occurrence of this phenomenon in infants who have laryngeal inflammation secondary to chronic regurgitation increases the risk of obstructive apnea.

Central apnea

Unlike older children and adults, normal neonates and infants may exhibit a reflexlike apneic response to a number of physiologic and pathophysiologic conditions, such as hypoxia, hypoglycemia, intracranial bleeding, infection, some toxins, and stimulation of the upper larynx.

Studies of the cry characteristics of SIDS siblings demonstrate hyperadductional vibratory behavior of the vocal fold. [28] The acid regurgitated in GER may affect a putative laryngochemoreceptor, causing respiratory pause, airway closure, and swallowing. This may result in an awake apneic event, which is not uncommonly reported by parents.

Such apneic responses are probably due to incomplete development of the CNS, increased vagal tone, and decreased respiratory muscle reserve. Although no statistical association has been established between such episodes of apnea and SIDS, the potential for the immature nervous system to interrupt its respiratory cycle easily may be a critical precondition for SIDS shared by all normal infants.

Infants with subclinical dysfunction of the autonomic nervous system or those undergoing physiologic stress may be predisposed to fatal evolution of an otherwise benign episode of apnea. Hypoxia, hypercarbia, and other noxious stimuli normally cause arousal and generalized alertness of the musculoskeletal and nervous systems, in addition to tachypnea and gasping. This development is followed by cycles of apnea alternating with a gasp.

SIDS is rare during the first month of life, perhaps in part because neonates have better aerobic capacity than older infants and a gasp may raise their PaO2 to over 20 mm Hg and allow them to continue breathing. If such is not the case, each gasp becomes weaker than the preceding one, until terminal apnea and death occur. Indirect evidence suggests that slowly progressive hypoxia inhibits protective ventilatory reflexes in normal infants. When these infants are acutely rechallenged, hypoventilation and apnea result, rather than a tachypneic response.

Acquired ventilatory dysfunction may explain the chronic tissue hypoxia seen in many infants who die of SIDS. Several, but not all, studies suggest that at-risk infants have subclinical ventilatory impairment that is midway between normal infants and those with central hypoventilation syndrome. Infants who demonstrate diminished ventilatory response to hypoxia and hypercapnia have significantly diminished arousal response. Such diminished arousal response is correlated with future episodes of apnea that require resuscitation.

Death may result during abnormal sleep, from dysfunction of the brainstem, or during normal sleep, when a pathophysiologic setting incites a lethal cascade of events. Diminished arousal response has been identified in newborns who subsequently suffer a BRUE, as well as in asymptomatic siblings of infants who died of SIDS, which suggests that some cases are congenital. Such diminished arousal also may be seen in some healthy infants (who do not have impaired ventilation).

Prone sleeping results in hypoxemia and hypercarbia, findings that attach special significance to these abnormal responses to subclinical hypoxemia and hypercarbia and their possible relation to SIDS.

Infants at risk have a relative inability to awaken and remain awake from all stages of sleep. Term infants have more episodes of nonperiodic apnea during rapid-eye-movement (REM) sleep, which is autonomically active, than during quiet sleep.

Relaxation of respiratory and accessory muscles has been documented in conjunction with skeletal muscle relaxation during REM sleep. Infants who subsequently died of SIDS had significantly more REM-associated obstructive breathing events; however, sleep-related airway obstruction did not occur in high-risk infants as long as there was arousal. Increased respiratory effort, occasionally with transient obstructive apnea, has been noted during quiet, non-REM sleep.

Critical diaphragm failure

Siren and Siren (2011) propose a critical diaphragm failure theory of SIDS (SIDS-CDF), [29] and present the following rationale:

• Prone sleeping significantly increases the workload on the diaphragm

• Infants younger than 6 months have undeveloped respiratory muscles that are susceptible to CDF. At approximately age 6 months, the infant diaphragm achieves the same fiber composition and pressure-generating capacity as the adult diaphragm

• The younger the infant, the smaller the oxidative capacity of the respiratory muscles, and consequently a greater risk of respiratory muscle fatigue (low-birth-weight infants or premature infants have a 4 times greater risk of SIDS than do full-term infants)

• Systemic infection can induce significant reduction in the adenosine triphosphate (ATP)–generating capacity of diaphragmatic muscle tissue, and even minor infections can significantly decrease diaphragmatic strength

• Intercostal muscles show both phasic and tonic inhibition during REM sleep that renders them largely or totally inactive; while incapacitation of the intercostal muscles is usually not lethal, bilateral diaphragmatic paralysis usually eventuates in respiratory failure; off further significance, a 3-month-old spends 38% of sleep time in REM phase, whereas a premature infant spends 80%

A study by Männikkö et al reported that four (1·4%) of the 278 infants in the SIDS cohort had a rare functionally disruptive SCN4A variant compared with none (0%) of 729 ethnically matched controls (p=0·0057). [30]

Other hypotheses

Behavioral disability

Developmental disability of infantile neurorespiratory control is posited, occurring during the transition period when protective subcortical reflexes are no longer present and voluntary defensive responses mediated via the cortex (ie, those that allow reestablishment of ventilation when it has been compromised) have not yet been sufficiently learned.

This hypothesis proposes that infants so affected manifest global passivity from ill-defined constitutional, arousal, or behavioral disabilities. Those infants, in turn, have less opportunity to respond, learn, and benefit from experience, including early exposure to normal (partial or brief) airway obstructions.

Primary autonomic nervous system instability

This theory proposes that apnea and bradycardia are the result of primary autonomic dysfunction or sympathetic imbalance.

Defective neuronal development, receptor deficiency, and genetic polymorphism

Numerous structural and functional nerve cell abnormalities have been described in infants with SIDS. Evidence suggesting delayed development of the brain stem has been demonstrated in 2 studies in which elevated dendritic spine counts were noted among infants who have died of SIDS. [31, 32] Reductions in the degree of myelination of specific brain regions of infants with SIDS provide further evidence of defective neuronal development.

Several studies have demonstrated neurotransmitter abnormalities in infants with SIDS. [33, 34, 35, 36] Studies of brainstem nuclei taken from babies who died of SIDS have revealed deficiencies in muscarinic receptors (whose neurotransmitter is acetylcholine), kainite receptors (whose neurotransmitter is glutamate), and lysergic acid receptors (whose neurotransmitter is serotonin). [12]

The receptor deficiencies were found to be concentrated in nuclei that control cardiorespiratory response to a variety of stimuli. [12] These receptor deficiencies were noted much more frequently in SIDS victims than in babies dying of other causes. For example, 60-70% of SIDS babies had serotonin receptor defects. It is unlikely that any single defect is solely responsible for SIDS.

The medullary serotonin system (5-HT) is thought to play a key role in autonomic nervous system regulation of cardiorespiratory control, the sleep-wake cycle, and thermoregulation. [37, 38, 39] Autopsy-derived data and animal model studies have helped to identify key structural and functional components of these pathways and their potential relationships to SIDS. [14, 40, 41, 42, 43, 44, 45, 12]

Genetic polymorphisms have been described in association with defects in components of serotonin-binding neural pathways. [46, 47] Polymorphisms in the serotonin transporter promoter genes were identified more often in SIDS patients than in control subjects. [48]

Harrington et al found that the activity of butyrylcholinesterase (BChE), which plays a role in autonomic function, was significantly decreased in infants who died of SIDS, compared with living infants and those who died of other causes. BChE activity was measured in dried blood spots obtained shortly after birth. [49]

Ten cardiac channelopathy susceptibility genes are implicated in SIDS. [50] At least 1 in 5 SIDS victims carries a mutation in a cardiac ion channel–related gene, of which the majority are a malignant phenotype. [24] It has been postulated that latent functional defects may only become malignant in the presence of certain conditions, such as acidosis or high temperature. For example, several immunologic polymorphisms that facilitate uncontrolled inflammatory responses are more frequently found in SIDS victims versus controls. One hypothesis is that pathogenic toxins may give rise to an overwhelming proinflammatory cytokine response that then causes the altered physiology resulting in death. Altered cytokine response has also been suggested as a pathophysiologic mechanism by which cigarette smoke can contribute to SIDS.

Mutations in genes responsible for encoding the cardiac potassium channels can cause LQTS or SQTS, either of which may result in increased risk for ventricular arrhythmias and sudden cardiac death. [19] Such genetic mutations are found in 5-10% of SIDS cases.

In addition to LQTS, other heritable cardiac arrhythmia syndromes (eg, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia) account for 10-15% of SIDS cases. Most SIDS-related mutations occur in the cardiac sodium channel. [51] The polymorphism S1103Y-SCN5A is associated with increased susceptibility to ventricular arrhythmia and has a prevalence of 13% among African Americans (who have the second highest rate of SIDS in the US). Infants homozygous for Y1103 were found to have a 24-fold increased risk of SIDS.

The sodium proton exchanger subtype 3 system (NHE3) plays a role in controlling breathing. [52] Animal studies showed that alveolar ventilation during wakefulness is inversely correlated with expression of NHE3 mRNA in the brainstem; thus, NHE3 expression seems to be related to the set point of normal breathing. This set point is one of the keys to the stability of respiration during sleep. A study of the brainstems of infants who died of SIDS revealed elevated NHE3 expression, suggesting that this might be a causative factor in SIDS.

Vertebral artery compression

Anatomic dissections have demonstrated that the vertebral arteries of infants are vulnerable to compression on neck extension or rotation. The structural factors productive of such compression are as follows:

• The lateral mass on the superior surface of C1 is small and does not provide a good means of preventing downward compression of the vertebral arteries

• The arch of the atlas is smaller than the foramen magnum and may invert up into the foramen magnum during neck extension, with resultant compression of the vertebral arteries

• The ligamentous support for the atlanto-occipital junction is poorly formed, with greater mobility in infants than in adults

• The vertebral artery lies exposed on the surface of C1 and not in a bony groove as in adults

• The posterior atlanto-occipital membrane is often thick and compresses the vertebral artery during extension because of its position immediately above the vertebral artery

In approximately 40% of infants, flow in one vertebral artery is less than half that in the contralateral vessel; thus, if the larger vessel is occluded, the brainstem is jeopardized much more than it would be if flow were bilaterally equal. If both vertebral arteries are compressed, flow continues, given normal anatomy, via the posterior communicating arteries of the internal carotids. However, flow through the posterior communicating arteries in infants is only 13% of basilar artery flow, and the brainstem is thereby placed at risk.

Immunopathogenesis

The peak incidence of SIDS is during the second to fourth months of life. Around the third month, a decrease is seen in the passive immunity conferred by the mother, as the infant’s immune system is activated. Early active immunity triggers localized immunologic responses to several substances, including respiratory irritants and infectious agents, with the potential for bronchospasm, pulmonary edema, and cytokine-mediated effects (eg, fever).

Raised concentrations of immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA) have been recovered from infants who died of SIDS but not from infants who died from explained causes.

Infection

The peak incidence of SIDS coincides with critical periods in the development of the immune system; at such a time, the infant might be transiently vulnerable to lethal infection. SIDS incidence increases in the winter, during viral epidemics in a community, and 2 weeks after viral infection.

Compared with healthy control infants and infants who died of known causes, infants who died of SIDS are more likely to harbor toxigenic bacteria, such as Escherichia coli, Staphylococcus aureus, and Clostridium difficile, as well as influenza virus and respiratory syncytial virus (RSV). Most strongly implicated is RSV, which is well known for its association with central apnea. Approximately 70% of infants with SIDS have a history of recent mild upper respiratory or gastrointestinal (GI) tract illness in the days preceding death.

Elevated interleukin (IL)-6 levels have been identified in the cerebrospinal fluid (CSF) of SIDS infants. [53] Abnormal IL-6 receptor expression on serotonin-binding neurons within the arcuate nucleus of the medulla (a region involved in carbon dioxide sensing and in the mediation of responses of heart rate, respiration, blood pressure, and arousal to changes in carbon dioxide) has been noted. [54] These findings suggest a role for infection in modifying life-sustaining responses to asphyxial stressors in the sleep microenvironment. [13]

Defects of fatty acid beta-oxidation

Severe fatty change in the liver is noted at autopsy in a small proportion of SUID cases. Such change may be observed in various conditions, including severe dehydration associated with an enterocolitis, systemic sepsis, or inherited metabolic disorders. Previously, as many as 10% of SIDS deaths were thought to be due to definable inherited metabolic diseases.

In the fed state, glucose is the primary substrate for energy metabolism. In the fasted state, fat replaces glucose as a source of fuel. Long-chain fatty acids are mobilized from adipose tissue and are metabolized within the mitochondrion by progressive beta-oxidation. The first steps in the processing of fats are facilitated by acyl-CoA dehydrogenases. Three distinct acyl-CoA dehydrogenases have been identified, with varying affinities for long-, medium-, and short-chain fatty acids. Inherited defects of all 3 dehydrogenases are now recognized.

The most common disorder of fatty acid beta-oxidation is medium-chain acyl-CoA dehydrogenase deficiency (MCADD). MCADD is an autosomal recessive disorder. Studies of its molecular basis have demonstrated that in approximately 90% of those affected, the condition is caused by a single point mutation (G-985). [55] Use of polymerase chain reaction (PCR) techniques to determine the frequency of the G-985 mutation in SIDS and control populations has failed to demonstrate the homozygous condition in SIDS.

Affected children typically present within the first 2 years of life with altered mental status and hypoglycemia brought on by periods of reduced nutritional intake associated with acute viral respiratory or GI illnesses. Previously, as many as 25% of children affected with MCADD were estimated to have presented with sudden unexpected death.

In most US centers and many centers worldwide, MCADD testing has been incorporated into expanded newborn metabolic screening programs. Tandem mass spectrometry blood spot screening established an incidence of MCADD of 1:14,600 (95% confidence interval [CI], 1:13,500-1:15,900) in 8.2 million newborns worldwide. Other prospective screening studies identified the prevalence of 1:8930 [56] and 1:12,000. [57] Most children identified by newborn screening do well, but adverse outcomes have not been entirely avoided. [58]

Defects in fatty acid beta-oxidation should be considered in instances of sudden death associated with fatty change of the liver on autopsy or in situations of SIDS with atypical features (eg, early neonatal death, death in children older than 1 year, or a history of SIDS within a family).

Unstable homeostatic control

It has been proposed that SIDS results from a developmental malfunction of brainstem centers that control respiratory or cardiac functions during sleep. This malfunction occurs as the body’s thermostats change from fetal to mature mode, usually during the second to third months of life.

At some point, in healthy infants aged 8-16 weeks, 2 sleep-related temperature patterns emerge: a precipitous drop in rectal temperature amounting to several tenths of a degree Celsius, followed by hourly oscillations throughout sleep. These temperature fluctuations are thought to herald maturation of the brainstem during months 2-4 of life (which is also the peak period for the occurrence of SIDS).

Temperature maturation occurs earlier (closer to 8 weeks than 16 weeks) in infants who are breastfed and firstborn, who sleep in a lateral or supine position, whose mothers are older, and who are born into more affluent families (all factors associated with decreased incidence of SIDS). Oyen et al posit that preterm babies probably have a delay in their vulnerable period, because they die later than term infants do (mean ages at death, 19.6 weeks and 15 weeks, respectively). [59]

As the baby grows, heightened metabolism and increasing body fat prompt a shift from the neonate’s susceptibility to cold stress to the infant’s increased vulnerability to heat stress. The shift occurs at about the same time as the highest risk for SIDS. This hyperthermic response may be aggravated by the increased metabolism seen during the early stages of a viral infection, as well as via IL-mediated vasoconstriction. Thus, even small elevations in body temperature can profoundly affect the respiratory rate, resulting in hypoventilation and apnea.

Triggering factors

Vulnerable periods in brainstem maturation may be critical when associated with the prone sleeping position. In this position, infants often sleep with the face down, especially in response to cold stimulus to the face.

Healthy infants aged 6 months or younger were studied as they slept in the prone position on soft and firm bedding. Even though all of the infants were able to turn their heads from this position, they slept face down an average of 14% of total sleep time on hard bedding and 35% on soft bedding. Babies aged 13-24 weeks (the time of peak risk for SIDS) are more mobile than younger infants are; however, they may not have the motor ability to extricate themselves from dangerous positions (eg, face down on soft bedding). [59]

A study of infants aged 3-37 weeks who never slept on their stomachs found that the infants did not learn the behaviors that could reduce their risk of SIDS if they were prone. When the researchers placed a comforter over a foam rubber mattress directly under the babies’ faces, all babies awoke after about 5 minutes and sought fresher air. Those experienced in sleeping prone lifted and turned their heads to the side; however, those inexperienced in sleeping prone only nuzzled the bedding or briefly lifted their heads and then resumed sleeping face down.

An infant sleeping prone, surrounded by a soft mattress, blankets, or other bedding—and possibly sleeping in the same bed with adults and compressed by or between large bodies—is in an environment that predisposes to progressive increase in carbon dioxide-rich, oxygen-poor air. The normal responses to rebreathing expired air are increased ventilation and arousal. Repetitive exposure to hypoxia causes a blunting of arousal and autonomic response [60] ; with normal responses blunted, hypoxia and hypercarbia may proceed unchecked.

A study using the cadavers of infants aged 6-9 weeks who were found dead in their cribs measured resistance to airflow pumped through the upper respiratory tract. When the body was placed face down on a pillow on various types of bedding, respiratory resistance increased 30- to 40-fold. Moisture of respiration, regurgitated milk, and mucus from the nostrils may dampen bedding material, increasing the obstructive effect when this material is compressed against the mouth and nose. When the pillow was damp, mean pressure increased by 235%.

Thermal stress and rebreathing of carbon dioxide may be interrelated as contributors to SIDS. Hyperpnea secondary to rebreathing increases the production of heat; rebreathing of warmed, expired air reduces respiratory heat exchange and enhances thermal stress; heat stress is presumably associated with an increased production of carbon dioxide, which could increase the risk of suffocation.

Sleeping in a hyperthermic environment also may alter the response to hypoxia or hypercarbia. An inadequate response to a critical incident may precipitate SIDS in a vulnerable infant who has acquired deficits in arousal or other physiologic aberrations in utero that are enhanced during postnatal development.

The dangers of prone sleeping also may stem from more episodes of quiet sleep, sleep for longer periods with fewer arousals, and decreased ability to lose heat, which is a phenomenon that may be enhanced by a heated room, excessive wrapping, fever, or illness.

In view of the relationship between the risk of SIDS and increased temperature, it is reasonable to ask, Why does the incidence of SIDS increase in cold temperature? Evidence suggests that autonomic dysfunction in at-risk infants is greatest at the lowest ambient temperature, even though body temperature remains normal. This cold-induced autonomic dysfunction may explain the association between SIDS and the cold ambient temperatures of winter.

An interesting correlation between several of the factors discussed above and the possibility of vertebral artery compression has been suggested. For example, in the prone sleeping position, infants who have the ability to do so will attempt to clear their nose from bedding by extending or rotating their head. These are the exact neck positions potentially productive of vertebral artery compression with resultant brainstem ischemia.

During the first months of life, the infant brainstem is particularly vulnerable to ischemia as a result of blood flow lagging behind the rapidly growing brainstem. SIDS is not common before the age of 1 month or after the age of 6 months. In the first month of life, infants may lack both the strength and the coordination to rotate or extend their heads to the degree required for compression of the vertebral artery. By age 6 months, however, the adverse anatomy that may predispose to arterial compression has begun to resolve.

The vertebral arteries arise from the subclavian arteries; thus, the vertebrobasilar circulation is in competition with the vascular beds of the upper extremities for flow. Heating of the limbs has the potential to increase blood flow to the upper extremities by 4-5 times the norm, thus potentially diverting blood flow that would otherwise go to the vertebral arteries and necessitating vasodilation of the vertebrobasilar system to maintain constant flow to the posterior fossa.

Passive smoking has been found to impair vasodilatation in young adults. Should a similar mechanism be operative in infants, the vertebral arteries may lack the ability to dilate adequately to prevent subclavian steal resulting from overheating.

Synthesis of pathogenetic hypotheses

SIDS is probably caused by maldevelopment, or delayed maturation, of the neural network in the brainstem that operates to affect arousal and physiologic responses to life-threatening events during sleep. [61]

Most cases of SIDS probably result from a lethal sequence of events initiated by a temporary defect in neural control of either respiratory or cardiac function during vulnerable periods in the maturation of respiratory control, sleep-wake development, and thermoregulation. Cardiorespiratory function, arousal and gasp reflexes, autonomic mechanisms, chemoreceptor sensitivity, thermoregulation, and sleep control are all controlled by the medullary and related structures of the brainstem.

Autopsy examinations of the brainstems of infants with a diagnosis of SIDS have demonstrated hypoplasia or decreased neurotransmitter binding of the arcuate nucleus, the region of the brain believed to be involved with hypercapnic ventilatory response, chemosensitivity, and blood pressure responses.

The exact nature of the possible brainstem dysfunction is unknown. One hypothesis involves exaggeration of the postulated developmental lag between loss of infantile protective neuroreflexes and development of mature integrative connections in the brainstem. Another proposes that brainstem dysfunction may be congenital or may be the result of arrested maturation of the otherwise normal brain by an internal or external agent. If this hypothesis is true, SIDS is an acquired, and therefore potentially preventable, cause of death.

Yet another hypothesis is that SIDS is the result of a transient physiologically vulnerable period during maturation of a normal CNS, in which the coincidence of several risk factors may cause apnea and death.

Regardless of the exact mechanism or mechanisms responsible, it can be theorized that the infant responds to a range of stimuli, insults, and risk factors with prolonged apnea, bradycardia, and death. This theory sets the stage for a spectrum of brainstem pathologies that include the following:

• Infants with normally functioning brainstems who are at no risk for SIDS, no matter the nature or the quantity of risk factors

• Infants with relatively minor brainstem dysfunction who will develop prolonged apnea and die only in the presence of multiple risk factors

• Infants with greater brainstem dysfunction who require only 1 additional risk factor (eg, additional warmth and decreased air circulation resulting from an extra blanket or benign viral infection that causes a relatively minor subglottic airway obstruction)

• Infants at the far end of the continuum whose brainstems are so dysfunctional that they will have virtually unprovoked SIDS

This theory can incorporate other proposed SIDS mechanisms, such as abnormal infantile respiratory patterns leading to apnea, exaggerated vagal response to GER, sleep disorders, and autonomic dysfunction. It also can account for the variable epidemiologic and pathophysiologic findings and the frequent lack of demonstrable pathology at autopsy.

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