Your Family Physician

Introduction

Background

The National Institute of Child Health and Human Development defines sudden infant death syndrome (SIDS) as:

The sudden death of an infant younger than 1 year of age that remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and a review of the clinical history.

The sudden demise of an infant, thankfully, is not a common occurrence. While the unexpected death of an infant may result from a number of processes, the leading postneonatal cause is a syndrome with an etiology that has not been fully elucidated.

The diagnosis of SIDS is one of exclusion and, thus, should be demystified, with the specific evidence in each infant death subject to careful and complete examination.

In its Policy on Distinguishing Sudden Infant Death Syndrome from Child Abuse Fatalities, the Committee on Child Abuse and Neglect of the AmericanAcademy of Pediatrics states that the death of an infant may be attributed to SIDS when all of the following are true:

• A complete autopsy is performed, including cranium and cranial contents, and autopsy findings are compatible with SIDS;
• no gross or microscopic evidence of trauma or significant disease process is present;
• no evidence of trauma exists on skeletal survey;
• other causes of death are adequately ruled out, including meningitis, sepsis, aspiration, pneumonia, myocarditis, abdominal trauma, dehydration, fluid and electrolyte imbalance, significant congenital lesions, inborn metabolic disorders, carbon monoxide asphyxia, drowning, or burns;
• no evidence of current alcohol, drug, or toxic exposure is present;
• thorough death scene investigation and review of the clinical history are negative.

Although death from SIDS is much more common than death from child abuse, the possibility of homicide, nevertheless, is an omnipresent etiologic overlay. Presentation of an infant with a life-threatening event thus creates many unique challenges for emergency physicians and has a high potential for producing cognitive dissonance.

Elicitation of the history of present illness, vital to every workup, may reveal inconsistencies that raise suspicions for human agency as the underlying cause of the infant's condition. Physical examination directed toward the identification of medical problems may reveal evidence of intentional trauma.

Treatment of physiologic instability must be conducted simultaneously with attention to identification and preservation of potential physical evidence. Even emotional support of the parents, integral to comprehensive medical management and compassionate medical practice, should be carried out in a manner that does not compromise possible subsequent legal proceedings.

Informing parents of the death of a child is cited as the most stressful experience physicians confront in emergency medicine. These events often are compounded by feelings of guilt and inadequacy, which are experienced by many emergency physicians following an unsuccessful pediatric resuscitation. These reactions may be markedly different, qualitatively and quantitatively, from the emotions generally experienced by emergency physicians when confronting other crises.

Pathophysiology

This section begins with a discussion of the triple-risk model of sudden infant death syndrome (SIDS), followed by specific examination of each of the proposed elements. A synthesis of these theories concludes the section.

Although multiple hypotheses have been proposed as the pathophysiologic mechanisms responsible for SIDS, none have been proven. The triple-risk model of SIDS proposes that the cause of SIDS is multifactorial, and that the sudden death of an infant may occur when a predisposed infant is in an unstable period of homeostatic control and is exposed to triggering factors.

QT interval hypothesis

Although both prolongation of the QT interval (long QT syndrome, or LQTS) and shortening of the QT interval (short QT syndrome, or SQTS) are associated with increased risk of cardiac arrhythmia and sudden death, it is QT prolongation that has received the greatest attention in SIDS.¹ QTc prolongation of more than 440 milliseconds is a marker of reduced cardiac electrical stability and is strongly associated with SIDS. 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 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.

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

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

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.

Although the authors of these studies indicate that other traditional SIDS risk factors (eg, prone sleeping position, maternal smoking, bed sharing) have odds ratios markedly lower than that observed with QT prolongation, the American Academy of Pediatrics states it is unlikely that this electrical irregularity explains more than a small minority of SIDS cases.

Apnea hypothesis

Terms used throughout this article are defined below, together with a differential list for some conditions. These definitions are based upon those promulgated by the National Institutes of Health Consensus Development Conference on Infantile Apnea and Home Monitoring, supplemented as cited.

• Apparent life-threatening event (ALTE): This is a frightening episode to observe. ALTE 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. Survivors of an ALTE share many risk factors for SIDS and are at a statistically increased risk for the syndrome; however, debate exists as to whether ALTEs are interrupted SIDS events, separate phenomena, or events related to SIDS.
• Periodic breathing: This 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: A respiratory pause is abnormal if it is prolonged (>20 seconds) or associated with cyanosis; abrupt, marked pallor; hypotonia; or bradycardia.
• Apnea of prematurity: This type of apnea 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: This type of apnea is characterized by an unexplained episode of cessation of breathing for 20 seconds or more, or a briefer respiratory pause associated with cyanosis, pallor, marked hypotonia, or bradycardia. This term generally refers to infants who are older than 37 weeks' gestational age at onset of pathologic apnea. These infants' ALTEs were idiopathic but were considered to be related to apnea. Accordingly, the apnea of infancy classification is reserved for those infants for whom no specific ALTE cause can be identified.

Several anatomic and physiologic findings support the role of apnea in SIDS. SIDS, despite the apparent contradiction, is not always sudden. Meny et al reviewed data from 6 infants who died while on home monitors.² Of these deaths, 3 were ascribed to SIDS. All SIDS patients had a bradycardia that preceded (2 cases) or occurred simultaneously with (1 case) central apnea. One of the patients had tachycardia prior to bradycardia. The monitor printout of 1 patient showed a slow decrease in heart rate for approximately 2 hours prior to death. One infant who had rapid cardiopulmonary resuscitation (CPR) could not be revived, suggesting that myocardial depression secondary to hypoxemia may have preceded the bradycardia.

Other evidence also suggests hypoxia (acute and chronic) as causal of SIDS. Hypoxanthine, a marker for tissue hypoxia, is elevated in the vitreous humor of patients who die from SIDS compared to controls who die suddenly. This evidence adds biochemical support to the concept that, in some patients, SIDS is a relatively slow process. In addition, a substantial number of infants who die from 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 the cessation of gasping
• Stage IV – Death, if resuscitation is not initiated

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

Although a significant number of SIDS autopsies do not demonstrate any pathological 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 prior to death, causing recurrent episodes of gasping with associated petechiae formation. Studies in newborn animals have shown that it takes hours to recover metabolically from asphyxia. Repeated episodes of asphyxia that were previously self-limited by arousal and autoresuscitation, therefore, might eventually prove fatal.

Cessation of respiratory airflow (apnea) may be central or diaphragmatic (ie, no respiratory effort), obstructive (usually due to upper airway obstruction), or mixed. While short central apnea (<15>

Obstructive apnea

Developing infants have normal sites of anatomic and physiologic vulnerability that, alone or combined, may transiently dispose an infant to airway obstruction. Among these vulnerabilities are the shallow hypopharynx, the cephalad position of the tongue and epiglottis, and the more compliant rib cage.

Positioning may predispose the newborn to upper airway obstruction as well. While infants with anatomic anomalies are particularly at risk, obstruction may 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. Hypoxemia of sufficient severity to produce 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 while in the prone position.

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

Central apnea

Unlike older children and adults, normal neonates and infants may suffer 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.³ GER's acid reflux may affect a putative laryngo-chemoreceptor, 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. While there is no statistical association between such episodes of apnea and SIDS, the potential for the immature nervous system to easily interrupt its respiratory cycle 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 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 a 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 supports the hypothesis that slowly progressive hypoxia inhibits protective ventilatory reflexes in normal infants. When these infants are acutely rechallenged, the result is hypoventilation and apnea, rather than a tachypneic response.

Acquired ventilatory dysfunction could explain the chronic tissue hypoxia seen in many infants who die from SIDS. Several, but not all, studies suggest that at-risk infants have subclinical impairment in ventilation 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 responses are 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 an ALTE as well as asymptomatic siblings of infants who died from SIDS, suggesting 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 relationship 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 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.

For further information on apnea, see Sleep Apnea and Pediatrics, Apnea.

Other hypotheses

Behavioral theory

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. The thesis 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.

Receptor deficiencies and genetic polymorphism

These two related, but distinct, conditions are the focus of increasing research focus.

Leiter and Bohm report that 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).⁴ The receptor deficiencies were found to be concentrated in nuclei that control cardiorespiratory response to a variety of stimuli. 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.⁵ Postmortem studies of the brains of infants who died of SIDS reveal abnormalities in the development and function of the 5-HT system, specifically increased effectiveness of the serotonin transporter, resulting in decreased availability of serotonin in the synapse and extracellular space.⁴

Mutations in genes responsible for encoding the cardiac potassium channels can cause long QT syndrome or short QT syndrome, either of which may result in increased risk for ventricular arrhythmias and sudden cardiac death.¹ Such genetic mutations are found in 5-10% of SIDS cases.

In addition to long QT syndrome, other heritable cardiac arrhythmia syndromes such as Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia are thought to account for 10-15% of SIDS cases. The majority of SIDS-related mutations occur in the cardiac sodium channel.⁶ The polymorphism S1103Y-SCN5A is associated with increased susceptibility for 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) has a role in the control of breathing.⁷ Animal studies have shown 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, together with the gain of respiratory controller, is a key to the stability of respiration during sleep. A study of the brainstems of infants who died of SIDS revealed elevated NHE3 expression, suggesting such might be a causative factor in SIDS.

Vertebral artery compression theory

Anatomical 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 (1) 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; (2) 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; (3) the ligamentous support for the atlantooccipital junction is poorly formed, with greater mobility in infants than in adults; (4) the vertebral artery lies exposed on the surface of C1 and not in a bony groove as in adults; and (5) the posterior atlantooccipital 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 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 theory

The peak incidence of SIDS occurs 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 such as fever. Raised concentrations of immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA) have been recovered from infants who have died of SIDS but not from infants who have died from explained causes.

Infections and SIDS

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, many infants who died of SIDS have toxigenic bacteria, such as Escherichia coli, Staphylococcus aureus, and Clostridium difficile, as well as influenza and respiratory syncytial virus (RSV). Most strongly implicated is RSV, which is well known for its association with central apnea.

Unstable homeostatic control

SIDS has been proposed to be the result of a developmental malfunction of brain stem centers that control respiratory and/or cardiac functions during sleep. This 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 the second to fourth months of life. The second through fourth months are also the peak time for occurrence of SIDS. Temperature maturation occurs earlier (closer to 8 wk than 16 wk) 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 do term infants (mean ages of 19.6 wk and 15 wk, respectively).⁸

As the baby grows, its heightened metabolism and increasing body fat prompt a shift from the neonate's susceptibility to cold stress toward increased vulnerability to heat stress in infancy. This 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 interleukin-mediated vasoconstriction. The available evidence suggests that even small elevations in body temperature can have profound effects upon the respiratory rate, resulting in hypoventilation and apnea.

Triggering factors

Vulnerable periods in maturation of the brain stem may be critical when associated with the prone sleeping position. When sleeping prone, infants frequently assume a facedown position, especially in response to cold stimulus to the face. Healthy infants, aged to 6 months, were studied as they slept in the prone position on soft and firm bedding. Despite the fact that all 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. The PaCO₂ rose in all infants from rebreathing while face down, with inspired carbon dioxide higher in those on soft bedding.

Babies aged 13-24 weeks (the time of peak risk for SIDS) are more mobile than are younger infants; however, Oyen et al opined that they may not have the motor ability to extricate themselves from dangerous positions, such as facedown on soft bedding.⁸ In another study of infants aged 3-37 weeks who never slept on their stomach, it was found that they do not learn the behaviors that may reduce their risk of SIDS if they are prone. In this study, researchers placed a comforter over a foam rubber mattress directly under the babies' faces. All babies awoke after approximately 5 minutes and sought fresher air. The babies with prone sleeping experience lifted and turned their heads to the side; however, the babies inexperienced in sleeping prone only nuzzled the bedding or briefly lifted their heads and then resumed sleeping facedown.

An infant sleeping prone, surrounded by a soft mattress, blankets, or other bedding, and possibly co-bedding 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 response to rebreathing expired air is increased ventilation and arousal, but with these 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 by a factor of 30- to 40-fold. Moisture of respiration, regurgitated milk, and mucus from the nostrils may dampen bedding material, with increased obstructive effect when that wet material is compressed against the mouth and nose. In fact, when the pillow was damp, the mean increase in pressure was 235%.

Thermal stress and rebreathing carbon dioxide may share an interrelationship as contributors to SIDS. Hyperpnea secondary to rebreathing increases the production of heat; rebreathing 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.

Given the interrelationship between the risk of SIDS and increased temperature, 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 remained 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 advanced.

With regard to the prone sleeping position, infants having the ability to do so will attempt to clear their nose from bedding by extending or rotating their head, 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 age 1 month or after age 6 months. Before the second month, infants may lack both the strength and coordination to rotate or extend their heads to the degree required for compression of the vertebral artery. By age 6 months, 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.

Smoking is a risk factor for SIDS. 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, as discussed above.

Synthesis

SIDS is probably caused by maldevelopment, or delayed maturation, of the neural network in the brainstem that operates to affect arousal and physiological responses to life-threatening events during sleep.⁹ 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 involved with hypercapnic ventilatory response, chemosensitivity, and blood pressure responses.

While the exact nature of possible brainstem dysfunction is unknown, hypotheses include exaggeration of the postulated developmental lag between loss of infantile protective neuroreflexes and the development of mature integrative connections in the brainstem. Alternatively, it has been proposed that brainstem dysfunction may be congenital, or they 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.

Irrespective of the exact mechanism, the infant responds to a range of stimuli, insults, and risk factors with prolonged apnea, bradycardia, and death. Such a theory sets the stage for a spectrum of brainstem pathologies that include the following:

• Infants with normally functioning brainstems at no risk for SIDS, no matter the nature or 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, 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. This theory also can account for the variable epidemiologic and pathophysiologic findings and the frequent lack of demonstrable pathology at autopsy.

Frequency

United States

In 2004, 2,246 deaths were certified as sudden infant death syndrome (SIDS), accounting for 8% of infant deaths.¹⁰ SIDS is the most common cause of death in infants aged 1 month to 1 year, although its incidence has shown a progressive decline since 1992. In that year, the incidence of SIDS was 1.2 cases per 1000 live births; in 2004, the incidence had dropped to 0.51.⁴

As this decrease in the SIDS rate occurred, postneonatal mortality rates of a number of other causes of sudden unexpected death have shown a significant increase, particularly since 1999.⁹ It is postulated that some deaths previously classified as SIDS are now being more correctly categorized¹¹ and that the true SIDS rate since 1999 may be static.⁹ In this regard, a survey of medical examiners and coroners in 6 jurisdictions found that most used to certify many more deaths as SIDS than they do now.¹²

While cases of true SIDS are decreasing, concern exists that the proportion of unexplained infant deaths resulting from child abuse may be increasing. Notably, the AmericanAcademy of Pediatrics estimates that the incidence of infanticide among cases designated as SIDS ranges from less than 1% to 5%.

International

The incidence per 1000 live births in many Asian countries is 0.04. Japan has a rate of 0.09,¹² and Hong Kong has a rate of approximately 0.2. Some Scandinavian countries have rates in the range of 0.1¹² (the Netherlands) to 0.6. In Italy, the incidence is 0.7. Prior to recommendation of the supine sleeping position, the United Kingdom had an incidence of 3.5 cases per 1000 live births (now reduced to 0.41¹² ), and New Zealand had an incidence of approximately 4.5 (now 0.8¹² ).

Race

Risk among racial groups in the United States varies substantially. In 2003, the last year for which complete data are available, sudden infant death syndrome (SIDS) rates were highest for American Indian/Alaskan Native and non-Hispanic black mothers, 2.5 and 2.2 times more, respectively, than the rate for non-Hispanic white mothers. Of note, African Americans are twice as likely to place infants prone for sleep, and they are also twice as likely to bedshare than are other racial groups.¹² Contrasted with that was the SIDS rate for Mexican mothers, which was 51% lower, and Central American and South American mothers who had a SIDS rate 62% lower, than the rate for non-Hispanic white mothers.¹³ Further data as to rates by race, per 1000 live births, are as follows:

• Central Americans and South Americans - 0.20 cases
• Asian/Pacific Islanders - 0.28 cases
• Mexicans - 0.24 cases
• Puerto Ricans - 0.53 cases
• Whites - 0.51 cases
• African Americans - 1.08 cases
• American Indian - 1.24 cases

Sex

Approximately 60-70% of SIDS deaths occur in males.

Age

• Approximately 80% of SIDS deaths occur in infants younger than 5 months, with a peak incidence in infants aged 2-4 months. Only 1% of deaths occur in neonates. The remainder of deaths are noted after the sixth month of life.
• Slightly higher proportions of deaths certified as SIDS occurring in the neonatal period and after 6 months of age were reported in 2001 as compared with 1992.⁹
• Prior to adoption of the current case definition, 3% of SIDS deaths were reported after the first year of life.

Clinical

History

• The classic presentation of sudden infant death syndrome (SIDS) begins with an infant who is put to bed, typically after breastfeeding or bottle-feeding.
• Checks of the baby at varying intervals are unremarkable, but the baby is found dead, usually in the position in which he or she had been placed at bedtime or naptime.
• Although most of infants are apparently healthy, many parents of infants who died of SIDS state that their babies "were not themselves" in the hours before death.
• Diarrhea, vomiting, and listlessness have been reported in the 2 weeks prior to death.
• Observations most commonly reported with apparent life-threatening events (ALTEs) are cyanosis (50-60%), breathing difficulties (50%), and abnormal limb movements (35%). Antecedent events may provide an indication regarding etiology, particularly the relationship of the ALTE to feeding or descriptions suggestive of seizure.
• After calming the parents, it is important to determine the exact sequence before and during the event by taking a detailed history.
• Did the infant have a foreign body, trauma, or ingestion?
• Does the infant have a history of apnea?
• What activity did the infant exhibit prior to the event?
• Apnea following paroxysmal cough, in an infant with upper respiratory infection, suggests pertussis.
• Arching with apnea after feeding—with or without milk or formula in the oronasal passages—suggests GER.
• What was the time and amount of the last meal? (Parents may misinterpret postprandial regurgitation as a life-threatening event.)
• Was the baby asleep or awake? GER may occur in an awake infant following feeding.
• What was the child's position?
• What was observed first? Chest wall movement and effort in respiration, in the absence of airflow, indicates obstructive apnea, whereas the absence of chest wall movement, respiratory effort, and airflow is consistent with central apnea.
• What was the period of apnea in seconds? Most healthy babies momentarily stop breathing when they are asleep.
• Did the infant change color?
• If the patient turned blue, ask "how blue," inquire as to lighting in the room, and ascertain the location of the cyanosis.
• A number of healthy babies appear to turn blue around the mouth when crying.
• Acrocyanosis or color changes during defecation may be misinterpreted as life-threatening events.
• What was the baby's tone (eg, limp, stiff, shaking)? Stiffening or clonic movement followed by apnea suggests postictal apnea.
• What was the duration of the event?
• What was done and how (eg, CPR)?
• Carefully question parents or other witnesses about their efforts to revive the baby.
• No need for resuscitative effort is consistent with a benign cause, whereas the need for respiratory resuscitation or CPR directs attention to serious pathology.
• Children are poorly served if abuse is not considered in the differential diagnosis of infants with ALTEs.
• Autopsy cannot distinguish death due to sudden infant death syndrome (SIDS) from death by suffocation. Certain elements of the history, however, may raise suspicion as to abuse, although none is pathognomonic.
• History surrounding death
• Consistent with SIDS - Apparently healthy infant, fed, put to bed, found lifeless, silent death, Emergency Medical Services (EMS) resuscitation unsuccessful
• Suspicious for child abuse - History atypical for SIDS, discrepant history, unclear history, prolonged interval between bedtime and death
• Age at death
• Consistent with SIDS - Peak in infants aged 2-4 months, 90% younger than 7 months
• Suspicious for child abuse - 6 months or older at the time of death
• History of pregnancy, delivery, and infancy
• Consistent with SIDS - Prenatal care was minimal to maximal. Frequently, a history of cigarette use during pregnancy as well as a premature delivery or low birth weight is reported. Subtle defects in feeding, crying, and neurological status (eg, hypotonia, lethargy, irritability) may have been present. Other factors include diminished postneonatal height and weight gain, twins, triplets, thrush, pneumonia, spitting, GER, tachypnea, tachycardia, and cyanosis. In one study, infants who died suddenly were 3 times as likely to have previously been admitted to a hospital compared to control infants matched for age (16% vs 5.4%). Signs of antecedent difficulty usually are not present.
• Suspicious factors for child abuse - Unwanted pregnancy, little or no prenatal care, late arrival for delivery, birth outside of hospital, no well-baby care or few visits, no immunizations, use of alcohol and/or other drugs during and after pregnancy, infant described as hard to care for or discipline, deviant feeding practices, previous unexplained medical disorders (eg, seizures), and previous episodes of apnea in the presence of the same person
• Previous infant deaths in family
• Consistent with SIDS - First, unexplained, and unexpected infant death
• Suspicious for child abuse - The threshold expressed by Reese is more than 1 previous unexplained or unexpected infant death, whereas the Committee on Child Abuse and Neglect finds suspicious the previous unexpected or unexplained death(s) of 1 or more siblings while under the care of the same unrelated person. According to some reports, the siblings of an infant who died of SIDS are themselves at higher risk for SIDS, although a history of any other infant deaths in the family raises the possibility of inborn errors of metabolism and child abuse.
• Previous involvement of law enforcement or child protective services
• Consistent with SIDS - None
• Suspicious for child abuse - Two or more times, 1 or more family member(s) arrested for violent behavior

Physical

• Clinical assessment following an apparent life-threatening event (ALTE)
  • Following an ALTE, many patients present to the ED in no acute distress. In 50% of these infants, physical examination is entirely normal. Pyrexia is documented in 25% of patients presenting to the ED; infection is noted in 25%.
  • The literature has varying recommendations concerning the extensiveness of the ED workup of an apparently healthy infant who presents following an ALTE.
  • Agreement does exist regarding elicitation of a detailed history and performance of a thorough physical examination.
  • Findings from the history and physical examination should enable the physician to determine if the child had an ALTE and whether the apneic episode was central, obstructive, or mixed.
  • Examine the patient after all clothing has been removed.
  • Direct the physical examination at identifying congenital anomalies of the heart or CNS and to recognizing dysmorphic features indicative of a congenital syndrome.
  • Findings of poor muscle tone or irregular respirations indicate a true ALTE.
• Truncal bruising
  • Most accidental bruising occurs over bony prominences. Contusions in "soft" sites (eg, cheeks, trunk) suggest abuse. An examination of babies with accidental bruises revealed no infant with a contusion measuring more than 10 mm in any diameter; some infants did have more than 1 contusion.
  • Development of a contusion is determined by a number of factors, including the amount of blunt force applied to the skin, tissue density, vascularity of the tissue, fragility of blood vessels, and the amount of blood escaping into surrounding tissues.
  • Bruises on one person, of identical age and cause, may not appear as the same color and may not change at the same rate.
    • Red, blue, purple, or black may occur at any time between 1 hour after the causal trauma and resolution of the contusion. The presence of red coloration therefore has no bearing on the age of the bruise.
    • A bruise with any yellow must be older than 18 hours.
    • Other than describing bruises that are yellow, brown, or green as older, further specification of age is difficult.
• Pinch or human bite marks
• Wounds in different stages of healing
• Scalds or burns, including those caused by cigarettes
• Fractures, particularly if of different ages
• Pupillary changes
• Retinal hemorrhages
  • Retinal hemorrhages, while strongly associated with inflicted head injury (shaken-impact syndrome), are not specific for that diagnosis.
  • Retinal hemorrhages may be seen in accidental trauma, subarachnoid hemorrhage, sepsis, coagulopathy, severe hypertension, galactosemia (rarely), following resuscitation, in conjunction with papilledema, and in up to 40% of vaginally delivered newborns, with resolution taking up to 1 month after birth.
• Oronasal hemorrhage: Southall et al noted frank bleeding from the nose and/or mouth in 11 of 38 suspected child abuse cases, but in none of the control group of 46 children with recurrent ALTE attributable to natural medical cause.¹⁴
• Contribution of the clinical examination to death investigation
  • In the case of a deceased infant, the National Association of Medical Examiners makes it very clear that "medical examiners and coroners have the sole legal authority to investigate deaths that are sudden, unexpected, unexplained, and potentially due to external causes such as injury," and that "examination or manipulation of the deceased body by child maltreatment experts without proper statutory authority or family permission may constitute a tort or be a violation of criminal law."
  • If an infant arrives in cardiopulmonary arrest, relevant findings from a clinical examination conducted during the course of a resuscitation-attempt should be carefully documented in the chart and will complement the autopsy and other components of the death investigation.
  • The examination should address many of the same elements indicated for assessment of an ALTE, modified as appropriate to the unresponsive patient.
• In addition to the abnormalities previously presented, the following physical findings suggest death from SIDS versus findings that increase suspicion of infanticide:
  • Consistent with SIDS
    • Serosanguineous watery, frothy, or mucoid discharge from mouth and/or nose is present.
    • The infant's face and dependent portions of the body may have reddish-blue mottling from postmortem lividity.
    • Pressure points of the body may have marks.
    • The infant appears well cared for and there is no significant skin trauma.
  • Suspicious for child abuse
    • Malnutrition, neglect, cutaneous injuries, traumatic lesions, or abnormalities of the head or body (eg, conjunctiva, fundi, scalp, intraoral, ears, neck, trunk, anogenital, extremities, including fractures)
    • Suspicions are increased with distribution of hypostasis indicative that a child was in a different position than that stated or in the presence of pressure ischemia over the nose and mouth.
• Absence of physical stigmata does not necessarily mean the death was natural.
  • So-called gentle battering occurs when a physical act leaves no mark, such as when a hand or pillow is placed over the face or when the infant is placed face down on a pillow or soft mattress, occasionally without any criminal intent (eg, to stifle a cry).
  • Physical examination of SIDS infants may reveal evidence of terminal motor activity such as clenched fists.
• Do not misinterpret postmortem changes or physical findings often seen in deaths from SIDS, (eg, confusing postmortem lividity or anal dilatation with trauma secondary to abuse).

Causes

Over 70 different theories of sudden infant death syndrome (SIDS) have been proposed, and the literature is frequently contradictory as to the relative risk (or absence thereof) posed by disparate conditions.

• Several authors classify risk factors into groups such as maternal (eg, drug use during pregnancy, unmarried, anemia during pregnancy, weight gain <20>
• Infants at increased risk of SIDS include term infants who have had an apparent life-threatening event (ALTE), premature infants of low birth weight, infants of substance-abusing mothers, and infants with apnea of infancy.
• ALTE
• One to 3% of infants in the general population experience an ALTE. Of all infants who die of SIDS, 5-7% have an ALTE history.¹⁵
• A large study that reviewed all types of ALTEs found a 1% risk of subsequent SIDS. These data should be interpreted within the context that most studies of ALTEs and SIDS have excluded infants with a history of prematurity, chronic lung disease, or congenital heart disease.
• The mortality rate is 4% for infants suffering an apneic episode secondary to infection with RSV.
• Strong data associate "serious" ALTEs (infants experiencing an ALTE during sleep and/or those who required vigorous stimulation or CPR) and SIDS. Such infants have an 8-10% risk of SIDS. Infants with a history of more than 1 serious ALTE have a 28% risk of SIDS despite use of home monitoring.
• Among the causes of ALTEs are infection (5-40%, depending on the season), laryngeal chemoreceptor stimulation secondary to GER (20%), and seizures and other neurologic disorders (15-20%). Cardiac dysrhythmias and abuse (including Munchausen syndrome by proxy) also should be included in the differential. Cyanotic congenital heart disease generally presents in the first few weeks of life, with difficulty feeding, poor weight gain, and diaphoresis.
• Despite extensive workup, no definitive cause can be found for more than 50% of ALTEs.
• Anecdotal, pathologic, physiologic, and epidemiologic data suggest that apnea of infancy is a risk factor for SIDS, although there is no conclusive evidence.
• Patients with apnea of infancy have a mortality rate in the range of 2-6%.
• The rate climbs to 10% for infants who manifest apnea during sleep on 1-2 occasions; the risk of death triples if there are more than 2 incidents.
• Only 2-4% of infants who die from SIDS have a record of apnea of prematurity.
• Regurgitation of gastric contents with acidic pH can cause reflexive apnea with resultant hypoxia. While autoresuscitation might be possible in the absence of regurgitation, it is not possible when regurgitation has occurred.¹⁶
• Berkowitz reports a higher incidence of SIDS in infants with residual bronchopulmonary dysplasia (11% of premature infants in 1 study)¹⁷ ; however, Gausche maintains that infants with bronchopulmonary dysplasia are not at increased risk for SIDS.¹⁸
• A study from New Zealand suggests that infants who are not breastfed are at increased risk for SIDS. Other studies, conducted in countries with a low incidence of SIDS, have failed to demonstrate a similar correlation.
• The incidence of SIDS is higher in multiple births, with twins or triplets having a rate 2.5 times that of singleton babies. Gausche cites an incidence for triplets of 8.3 cases per 1000 infants.¹⁸
• Gausche further states that siblings of an infant who dies from SIDS are not at increased for SIDS.¹⁸ Reece supports this view and reports that, when comparing families matched for maternal age and birth rank, there is no statistically significant difference in SIDS rates or in total infant mortality in families with a history of SIDS and those families without a history of SIDS.¹⁹
• Other authors, however, indicate that siblings of infants who have succumbed to SIDS are at higher risk as addressed below.
• Many of the epidemiologic risk factors for sudden infant death syndrome (SIDS) and other causes of infant mortality are identical.
• Some studies have found that siblings of an infant who dies from SIDS have about a 5-fold increased risk of death from SIDS and a 6-fold increase in risk of death from other causes, although it should be noted that the research design of these studies has been criticized. The theory advanced is that genetic factors and the environmental milieu that may have contributed to the death of the first infant would effect siblings.²⁰
• To identify which risk factors are specific for SIDS, rather than characteristic of postneonatal deaths in general, data were reviewed on 11,734 infants, of which 649 deaths had been attributed to SIDS and 1221 postneonatal deaths were from other causes.
• Factors such as black race, very low birth weight (<1500>
• Perinatal and sociodemographic risk factors were not independently associated with SIDS.
• Of the risk factors examined, only maternal smoking during pregnancy was independently associated with SIDS.
• Gilbert-Barness and Barness maintain that unequivocal evidence shows that a substantial number of deaths from SIDS are preventable by avoiding the prone sleeping position, particularly on any type of soft bedding.²¹ Lazoff and Kauffman, however, point out that prone sleeping is common in Hong Kong and Sweden, both of which have a very low incidence of SIDS.²²
• Subsequent to strong warnings against the nonsupine sleeping position, dramatic changes were noted in several Scandinavian countries. Oyen et al reported that the combined effect of nonsupine sleeping and other prenatal and maternal risk factors (ie, preterm birth, intrauterine growth retardation, any signs of illness during the first week of life, maternal smoking during pregnancy, maternal age <25>8
• The combination of prone sleeping and birth weight less than 2500 grams was far greater than the sum of the risk from each risk alone.
• In infants aged 13-24 weeks, the combined effect of nonsupine sleeping and lower birth weight carried the highest risk for SIDS.
• Ackerman and Gilbert-Barness reported a related issue concerning 15 fatalities in which infants aged 3 months or younger were placed face down in a level, suspended rocking cradle.²³
• In 14 of the cases, a locking pin to prevent cradle movement was not used.
• The typical position in which the infants were found was lying in the dependent end of the cradle, with their head pressed against the cradle mesh (with or without obstruction of the nose and mouth); thus, the cradle was either set in motion or infants shifted to one end of the cradle during normal sleep movements.
• Wedging the head in the corner of a tilted cradle or positioning the head against gravity, increases the difficulty in moving or turning the head.
• The rocking cradles involved in these deaths have been removed from the market in the US. These cradles, nevertheless, frequently are passed on from one baby to the next or are bought secondhand. Accordingly, they constitute a potentially lethal sleeping environment unless the locking mechanism is used.
• Co-sleeping (parent with infant) and sleeping on a soft surface or polystyrene-filled cushion also have been implicated as risk factors for SIDS.
• Cigarette smoking during pregnancy is highly significant as a risk factor in the pathogenesis of SIDS, and studies continue to lend weight to the mounting evidence of a causal mechanism between SIDS and maternal smoking. As previously indicated, only maternal smoking during pregnancy was independently associated with SIDS and, in fact, was significantly more prevalent in the SIDS cohort than in infants dying of other causes. In the 1980s, the smoking rate among SIDS mothers was reported to be 70%, whereas it decreased to 42% in the 1990s.²⁴
• The incidence of SIDS is 7 times higher among infants whose mothers smoked more than 1 pack per day during pregnancy.
• Early neuropathologic changes in autonomic pathways are noted with prenatal exposure to maternal smoking.¹²
• Research implicates prenatal exposure to nicotine in the alteration of the infant's arousal mechanism, a possible explanation for the increased risk for SIDS associated with prone sleeping position.
• Decreased volume and compliance of the lung, and decreased heart rate variability in response to stress, are also reported.¹²
• Data indicate that if women refrained from smoking (a completely modifiable risk factor) during pregnancy, up to 30% of SIDS deaths might be prevented.
• A risk factor independent of prenatal exposure to tobacco is the chronic exposure to cigarette smoke that infants experience when parents smoke.
• Infants so exposed demonstrate a modest increase in SIDS.
• Abuse of drugs other than nicotine is less strongly associated with SIDS.
• Prenatal exposure to cocaine may cause cocaine-induced maturational delay.
• Term newborns exposed to cocaine prenatally have respiratory instability similar to that seen in preterm infants not exposed to cocaine.
• Risks posed by heroin, or particularly the synthetic narcotic, methadone, are higher than that conferred by cocaine.
• A study of 2964 infants revealed 44% who tested positive for drugs: 30.5% for cocaine, 20.2% for opiates, and 11.4% for cannabinoids.
• Over a third (34.4%) of infants whose mothers denied a history of illegal drug use screened positive for drugs.
• While high perinatal morbidity was seen in infants who were drug positive (with significantly lower birth weight, head circumference, and length), there was no associated increase in overall mortality during the first 2 years of life.
• Of particular note, SIDS incidence was not significantly higher among infants who were drug positive, in contrast to other reports.
• Low birth weight and prematurity, both known consequences of drug use during pregnancy, are important determinants of infant mortality and morbidity.
• Most infants with low birth weight (£ 2500 g) tested positive for drugs (often in combination), with 20.5% testing positive for cocaine and 18.7% testing positive for morphine versus 13.6% of infants who tested negative.
• A significantly higher mortality rate was observed among babies with low birth weight who were exposed to both cocaine and opioids.
• Forty percent of 43 infants who died when younger than 2 days and whose autopsy failed to identify an obvious anatomic cause of death had toxicologic evidence of cocaine exposure.
• A second review of 600 infant deaths found evidence of cocaine exposure in 2.7% of infants younger than 8 months who died suddenly and unexpectedly.
• Research reported in 2007 by Kahlert, Rudin, Kind and the Swiss HIV Cohort Study and the Swiss Mother & Child HIV Cohort Study found a greatly increased risk for SIDS of infants born to HIV-infected mothers who used opioids during pregnancy.²⁵ The SIDS rate of 14.9 per 1000 live births did not appear to be mediated by the known SIDS risk factors of prematurity or low birth weight, nor by perinatal HIV infection or antiretroviral drug exposure. Kahlert et al note that QT-interval prolongation has been observed in methadone maintenance patients, raising the possibility that a similar phenomenon may have been operative in these SIDS deaths.²⁵
• No evidence suggests that maternal alcohol use during pregnancy increases the risk for SIDS.
• Ford et al first reported an association between caffeine intake in pregnancy and SIDS.²⁶ They found heavy caffeine consumption throughout pregnancy in 14% of control mothers and in 28% of mothers whose infants died from SIDS.
• Caffeine is a stimulant that can cross the placental barrier, thereby exposing the fetus, an effect potentiated in the last trimester when caffeine elimination from the mother is reduced about 3-fold.
• Some studies have found an association between caffeine intake and low birth weight and spontaneous abortion.
• Withdrawal from caffeine at birth can induce apnea in newborns.
• Even though caffeine has a respiratory stimulant effect, maternal caffeine use during pregnancy has been associated with central apnea in infants.
• This raises the possibility that the fetal respiratory center may be altered in the presence of high caffeine concentrations, only to be left with an inadequate respiratory drive when exposed to stressors in the absence of caffeine.
• The pathophysiologic mechanism may lie in adenosine receptor sites in the brainstem.
• Long-term caffeine exposure causes an increase in the number of adenosine receptors, with caffeine serving as a competitive antagonist.
• Adenosine, which can induce respiratory depression in newborn animals, is produced during episodes of severe hypoxia.
• Prior in utero exposure to caffeine may increase the vulnerability of an infant who is exposed to episodes of hypoxia after birth.
• After adjusting for confounding variables (eg, maternal smoking), the relative risk of SIDS for infants born to mothers with heavy caffeine use (consuming >400 mg/d, as in 4 cups of coffee or 10 cups of tea or glasses of cola) was 1.30 for the first trimester, 1.46 for the third trimester, and 1.65 for heavy caffeine use throughout pregnancy.
• Increased apoptosis in the brainstem of SIDS infants has been found to be affected by postconceptional age, male gender, prone sleep position, and exposure to cigarette smoke.²⁷ The increased cell death in the dorsal column nuclei could result in dampening or loss in relay of touch and proprioception, creating difficulty when an infant in the prone position attempts to turn into the supine position.
• In one study reported by Esani et al, the mothers of SIDS infants were more likely to be young (11% were 18 or younger) compared to mothers of infants who experienced an ALTE (5% of whom were 18 or younger).¹⁵
• Three studies have found a link between SIDS and maternal psychiatric disorders.²⁸ Two of the studies reported a link with postnatal depression, and one found an association between a history of depression in the year before birth, and a trend (not reaching statistical significance) for an association between SIDS and depression after birth.
• At the time of death, 30-50% of otherwise healthy infants have an acute infection such as gastroenteritis, otitis media and, particularly, upper respiratory tract infection.
• Infantile botulism may be the cause of 5-10% of sudden infant deaths.
• Of particular note, RSV is associated with life-threatening apneic episodes, particularly in premature infants and those with a history of apnea. During RSV season, the virus is reportedly causative of up to 40% of ALTEs.
• An apparent association exists for infection and SIDS in older males.
• Approximately 65% of SIDS deaths occur in autumn and winter; infection may play a role in these deaths.
• Lazoff and Kauffman state that SIDS is not associated with changes in core body temperature, although that view is not universal.²²
• Incidence of SIDS increases with colder outdoor temperature and warmer indoor (room) temperature.
• Estimates indicate that 73.7% of all SIDS deaths could be prevented if all infants slept in the supine position.
• Elimination of maternal smoking during pregnancy could reduce the number of SIDS deaths by 46.7%.
• Prevention of low birth weight could avoid 16.2% of SIDS deaths. As reported by Esani et al, 9% of infants with an ALTE were small for gestational age, versus 19% who died of SIDS.¹⁵
• One in 5 infants dying of SIDS is premature.¹⁵
• Low birth weight infants, whether the result of premature birth or other causes, have a maturational delay in the ability to turn their head to the face down position. While the face down position is not desired, turning out of the face down position is a skill that is perfected only after development of the ability to turn face down.²⁹
• Two in three infants are in nonparental child care for varying periods of time: 50% are cared for by relatives, 10% by an in-home baby sitter, and 40% in organized child care. The reduction in SIDS deaths already noted has not been reflected in the incidence of SIDS occurring in child care. It is thought this may be a function of infants still being placed prone by a nonparental caregiver. This carries great potential for risk, because when an infant is placed in a prone sleep position to which he or she is not accustomed, the risk of SIDS increases by as much as 18 times.⁹
• Lazoff and Kauffman indicate that 10-25% of apparent SIDS cases are actually homicides.²² They also state that human agency is causal in up to 33% of infant deaths in families with multiple cases of apparent SIDS.³⁰
• Samuels and Southall report that child abuse was the cause of ALTEs in 33% of patients who received cardiopulmonary resuscitation.³¹
• Failure to diagnose factitious or induced illness leaves the child and any siblings at risk for death, results in continued suffering (perhaps for the lifetime of the victim), and creates the potential that he or she will become an abuser as an adult.
• In their landmark study, Southall et al used covert video recordings to study 39 infants with a median age of 9 months (range, 2-44 months), most of whom were referred for evaluation of an ALTE.¹⁴
• Of the 39 suspected cases, 33 involved abuse.
• Intentional suffocation was documented in 30 cases, with poisonings (disinfectant or anticonvulsant), deliberate fracture, and other emotional and physical abuse identified in the remainder.
• The first ALTE occurred at a median age of 3.6 months (corrected for expected date of delivery).
• Of 41 siblings of the suspect patients, 12 deaths had occurred, with 11 of the deaths attributed to SIDS.
• When parents were confronted with video surveillance evidence, 4 of them admitted the deliberate suffocation of 8 of the children.
• In comparison, there were 52 siblings of the 46 controls, of whom 2 died, with SIDS listed as the cause of 1 death.
• The high number of deaths in siblings evidences the long-term risk posed to children in severely dysfunctional families.
• The circumstances surrounding the mistreatment of a child may range from a sudden isolated loss of control by a parent, to long-standing premeditated acts intended to harm the child.
• Multiple personal, familial, and environmental pressures may accumulate to push parents or other caregivers beyond the thresholds of restraint.
• While no parent had a psychotic mental illness, Munchausen syndrome by proxy was present in some.

Source : http://emedicine.medscape.com/article/804412-overview