Sudden Infant Death Syndrome (SIDS)

SIDS is a disease of unknown cause. The National Institute of Child Health and Human Development defines SIDS as "the sudden death of an infant under 1 year of age which remains

unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of the clinical history."[91] An aspect of SIDS

that is not stressed in the definition is that the infant usually dies while asleep, hence the pseudonyms of crib death or cot death.

Epidemiology.

As infantile deaths owing to nutritional problems and microbiologic infections have come under control in countries with higher standards of living, SIDS has assumed greater importance

in many countries, including the United States. SIDS is the leading cause of death between age 1 month and 1 year in this country and the third leading cause of death overall in infancy,

after congenital anomalies and diseases of prematurity and low birth weight. Due largely to nationwide SIDS awareness campaigns by organizations such as the American Academy of

Pediatrics, there has been a significant drop in SIDS-related mortality in the past decade, from over 5000 annual deaths in 1990 to approximately 2600 deaths in 1999. Worldwide, in

countries where unexpected infant deaths are diagnosed as SIDS only after postmortem examination, the death rates from SIDS (20 to 100/100,000 live births) are comparable to death

rates in the United States (77/100,000 live births).

Approximately 90% of all SIDS deaths occur during the first 6 months of life, most between ages 2 and 4 months. This narrow window of peak susceptibility is a unique characteristic that

is independent of other risk factors (to be described) and the geographic locale. Most infants who die of SIDS, die at home, usually during the night after a period of sleep. Only rarely is

the catastrophic event observed, but even when seen, it is reported that the apparently healthy infant suddenly turns blue, stops breathing, and becomes limp without emitting a cry or

struggling. Most infants have had minor manifestations of an upper respiratory infection preceding the fatal event. The term apparent life-threatening event (ALTE) has been applied to

those infants who could be resuscitated after such an episode. [92] Infants with ALTE are often siblings of SIDS victims and harbor a range of physiologic abnormalities such as frequent or

prolonged apnea, diminished chemoreceptor sensitivity to hypercarbia and hypoxia, and impaired control of heart, respiratory rate, and vagal tone.[92] Some of these infants later succumb

to SIDS.

Morphology.

At autopsy, a variety of findings have been reported. They are usually subtle and of uncertain significance and are not present in all cases. Multiple petechiaeare the most common finding

in the typical SIDS autopsy (~80% of cases); these are usually present on the thymus, visceral and parietal pleura, and epicardium. Grossly, the lungs are usually congested, and vascular

engorgementwith or without pulmonary edemais demonstrable microscopically in the majority of cases. These changes possibly represent agonal events, since they are found with

comparable frequencies in explained sudden deaths in infancy. Within the upper respiratory system (larynx and trachea), there may be some histologic evidence of recent infection

(correlating with the clinical symptoms), although the changes are not sufficiently severe to account for death and should not detract from the diagnosis of SIDS. The central nervous

system demonstrates astrogliosisof the brain stem and cerebellum. Sophisticated morphometric studies have revealed quantitative brainstem abnormalities such as hypoplasia of the

arcuate nucleusor a subtle decrease in brain stem neuronal populations in several cases;[93] [94] these observations are not uniform, however, and not amenable to most "routine" autopsy

procedures. Nonspecific findings include frequent persistence of hepatic extramedullary hematopoiesisand periadrenal brown fat; it is tempting to speculate that these latter findings

relate to chronic hypoxemia, retardation of normal development, and chronic stress. Thus, autopsy usually fails to provide a clear cause of death, and this may well be related to the

etiologic heterogeneity of SIDS. The importance of a postmortem examination rests in identifying other causes of sudden unexpected death in infancy, such as unsuspected infection,

congenital anomaly, or a genetic disorder ( Table 10-8 ), the presence of any of which would exclude a diagnosis of SIDS, and in ruling out the unfortunate possibility of traumatic child

abuse.

Pathogenesis.

The circumstances surrounding SIDS have been explored in great detail, and it is generally accepted that

TABLE 10-8-- Risk Factors and Postmortem Findings Associated with Sudden Infant Death Syndrome

Parental

Young maternal age (age <20 years)

Maternal smoking during pregnancy

Drug abuse in either parent, specifically paternal marijuana and maternal opiate, cocaine use

Short intergestational intervals

Late or no prenatal care

Low socioeconomic group

African American and American Indian ethnicity (? socioeconomic factors)

Infant

Brain stem abnormalities, associated defective arousal, and cardiorespiratory control

Prematurity and/or low birth weight

Male sex

Product of a multiple birth

SIDS in a prior sibling

Antecedent respiratory infections

? Gastroesophageal reflux

Environment

Prone sleep position

Sleeping on a soft surface

Hyperthermia

Postnatal passive smoking

Postmortem Abnormalities Detected in Cases of Sudden Unexpected Infant Death *

Infections

• Viral myocarditis

• Bronchopneumonia

Unsuspected congenital anomaly

• Congenital aortic stenosis

• Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA)

Traumatic child abuse

• Intentional suffocation (filicide)

Genetic and metabolic defects

• Long QT syndrome (SCN5A and KCNQ1 mutations)

• Fatty acid oxidation disorders (MCAD, LCHAD, SCHAD mutations)

• Histiocytoid cardiomyopathy (MTCYB mutations)

• Abnormal inflammatory responsiveness (partial deletions in C4a and C4b)

*SIDS is not the only cause of sudden unexpected death in infancy but rather is a diagnosis of exclusion. Therefore, performance of an autopsy may often reveal findings that would

explain the cause of sudden unexpected death. These cases should not, strictly speaking, be labeled as "SIDS." SCN5A, sodium channel, voltage-gated, type V, alpha polypeptide; KCNQ1,

potassium voltage-gated channel, KQT-like subfamily, member 1; MCAD, medium-chain acyl coenzyme A dehydrogenase; LCHAD, long-chain 3-hydroxyacyl coenzyme A

dehydrogenase; SCHAD, short-chain 3-hydroxyacyl coenzyme A dehydrogenase; MTCYB, mitochondrial cytochrome b; C4, complement component 4.

it is a multifactorial condition, with a variable mixture of contributing factors. A "triple risk" model of SIDS has been proposed, which postulates the intersection of three overlapping

factors: (1) a vulnerable infant, (2) a critical developmental period in homeostatic control, and (3) an exogenous stressor(s). [95] According to this model, several factors make the infant

vulnerable to sudden death during the critical developmental period (i.e., age 1 month to 1 year). These vulnerability factors may be attributable to the parents or the infant, while the

exogenous stressor(s) is attributable to the environment ( Table 10-8 ).

While numerous factors have been proposed to account for a vulnerable infant, the most compelling hypothesis is that SIDS reflects a delayed development of arousal and

cardiorespiratory control.[96] Regions of the brain stem, particularly the arcuate nucleus, located in the ventral medullary surface, play a critical role in the body's "arousal" response to

noxious stimuli such as hypercarbia, hypoxia, and thermal stress encountered during sleep. In addition, these areas regulate breathing, heart rate, and body temperature. In certain infants,

for yet unexplained reasons, there may be a maldevelopment or delay in maturation of this region, compromising the arousal response to noxious stimuli. This physiologic impairment is

compounded by other factors, such as sleeping position or infection (see below). Support of this hypothesis comes from postmortem studies in SIDS victims demonstrating both

quantitative abnormalities (e.g., arcuate hypoplasia and decrease in neuronal density) as well as qualitative abnormalities (e.g., reduced serotonergic and muscarinic receptor binding) in the

brain stem.[93] [97] [98] Whether these changes are primary or merely the manifestation of a more "upstream" deficit remains to be elucidated. Recently, some candidate genes have been

identified from experimental animal models, which may provide a genetic basis to abnormal neural regulation in the brainstem. For example, Krox20, a homeobox gene, appears to be

required for hindbrain segmentation and myelination. Mouse models lacking Krox20 function exhibit abnormally slow respiratory rhythm and prolonged apnea.[99] Similarly, brain-derived

neurotrophic factor (BDNF) is required for normal development of the central respiratory rhythm, including the stabilization of central respiratory output that occurs after birth. Loss of one

or both BDNF alleles results in an approximately 50% depression of central respiratory frequency compared with wild-type controls, while hypoxic ventilatory drive is deficient or absent.

[100] Whether knowledge gleamed from these animal models of central respiratory dysfunction will be applicable to humans remains to be seen.

Epidemiologic studies of infant deaths have found additional risk factors for SIDS ( Table 10-8 ). Infants who are born before term or who are low birth weight are at increased risk, and

risk increases with decreasing gestational age or birth weight. Male sex is associated with a slightly greater incidence of SIDS. SIDS in a prior sibling is associated with a fivefold relative

risk of recurrence, underscoring the importance of a genetic and/or shared environmental predisposition; traumatic child abuse needs to be carefully excluded under these circumstances.

Most SIDS babies have an immediate prior history of a mild respiratory tract infection, but no single causative organism has been isolated. These infections may predispose an already

vulnerable infant to even greater impairment of cardiorespiratory control and delayed arousal. In this context, laryngeal chemoreceptors have emerged as a putative "missing link" between

upper respiratory tract infections, the prone position (see below), and SIDS. When stimulated, these laryngeal chemoreceptors elicit an apneic and bradycardic reflex.[101] Stimulation of

the chemoreceptors is augmented by respiratory tract infections, which increase the volume of secretions, and by the prone position, which impairs swallowing and clearing of the airways

even in healthy infants. In a previously vulnerable infant with impaired arousal, the apneic and bradycardic reflex may prove fatal.

Maternal smoking during pregnancy has consistently emerged as a risk factor in epidemiologic studies of SIDS, with children exposed to in utero nicotine having more than double the risk

of SIDS compared to children born to nonsmokers. [102] Young maternal age, frequent childbirths, and inadequate prenatal care are all risk factors associated with increased incidence of

SIDS in the offspring. African Americans and American Indians have significantly higher rates of SIDS deaths than Caucasians. It is not obvious whether these ethnic trends represent the

effects of genetic make up or the effects of lower socioeconomic status, which by itself is a risk factor for SIDS.

Among the potential environmental factors, prone sleeping position, sleeping on soft surfaces, and thermal stress are possibly the most important modifiable risk factors for SIDS.[103] The

prone position predisposes an infant to one or more recognized noxious stimuli (hypoxia, hypercarbia, and thermal stress) during sleep. In addition, the prone position is also associated

with decreased arousal responsiveness compared to the supine position. Results of studies from Europe, Australia, New Zealand, and the United States showed clearly increased risk for

SIDS in infants who sleep in a prone position, prompting the American Academy of Pediatrics to recommend placing healthy infants on their back when laying them down to sleep. This

"Back To Sleep" campaign has resulted in substantial decreases in SIDS-related deaths since its inception in 1994.[104]

It should be noted that SIDS is not the only cause of sudden unexpected deaths in infancy. In fact, SIDS is a diagnosis of exclusion, requiring careful examination of the death scene and a

complete postmortem examination. The latter can reveal an unsuspected cause of sudden death in up to 20% or more of "SIDS" babies ( Table 10-8 ). Infections (e.g., viral myocarditis or

bronchopneumonia) are the most common causes of sudden "unexpected" death, followed by an unsuspected congenital anomaly. In part due to advancements in molecular diagnostics and

knowledge of the human genome, several genetic causes of sudden "unexpected" infant death have emerged. For example, fatty acid oxidation disorders, characterized by defects in

mitochondrial fatty acid oxidative enzymes, may be responsible for up to 5% of sudden death in infancy; of these, a deficiency in medium-chain acyl-coenzyme A dehydrogenase is the

most common.[105] Retrospective analyses of SIDS cases have also revealed mutations of cardiac sodium and potassium channels, which result in a form of cardiac arrhythmia

characterized by prolonged QT intervals; these account for no more than 1% of SIDS deaths.[106] Other newly emerging genetic causes of explained sudden death are listed in Table 10-8 .

Date: 2016-04-22; view: 731