From Kliegman RM, Greenbaum LA, Lye PS: Practical strategies in pediatric diagnosis and therapy, ed 2, Philadelphia, 2004, Elsevier Saunders, p 101.

Epidemiology

SIDS is the 3rd leading cause of infant mortality in the USA, accounting for 8% of all infant deaths. It is the most common cause of postneonatal infant mortality, accounting for 40-50% of all deaths between 1 mo and 1 yr of age. The annual rate of SIDS in the USA was stable at 1.3-1.4/1,000 live births (about 7,000 infants/yr) before 1992, when the American Academy of Pediatrics (AAP) recommended that infants sleep nonprone as a way to reduce risk for SIDS. Since then, particularly after initiation of the national Back to Sleep campaign in 1994, the rate of SIDS progressively declined and then leveled off in 2001 at 0.55/1,000 live births (2,234 infants). The rates have remained stagnant since that time; in 2006 it was 0.55/1,000 live births (2,323 infants). The decline in the number of SIDS deaths in the USA and other countries has been attributed to the increasing use of the supine position for sleep. In 1992, 82% of sampled infants in the USA were placed prone for sleep. Several other countries have decreased prone sleeping prevalence to ≤2%, but in the USA in 2008, 15% of infants were still being placed prone for sleeping.

Pathology

There are no autopsy findings pathognomonic for SIDS and no findings required for the diagnosis, although there are some common findings. Petechial hemorrhages are found in 68-95% of cases and are more extensive than in explained causes of infant mortality. Pulmonary edema is often present and may be substantial. The reasons for these findings are unknown.

SIDS victims have several identifiable changes in the lungs and other organs and in brainstem structure and function. Nearly 65% of SIDS victims have structural evidence of pre-existing, chronic low-grade asphyxia, and other studies have identified biochemical markers of asphyxia. SIDS victims have higher levels of vascular endothelial growth factor (VEGF) in the cerebrospinal fluid (CSF). These increases may be related to VEGF polymorphisms (see Genetic Risk Factors) or might indicate recent hypoxemic events, because VEGF is upregulated by hypoxia. Brainstem findings include a persistent increase of dendritic spines and delayed maturation of synapses in the medullary respiratory centers, and decreased tyrosine hydroxylase immunoreactivity and catecholaminergic neurons. Decreases in serotonin 1A (5-HT_1A) and 5-HT_2A receptor immunoreactivity have been observed in the dorsal nucleus of the vagus, solitary nucleus, and ventrolateral medulla, whereas increases are present in periaqueductal gray matter of the midbrain. The decreased immunoreactivity of receptors is accompanied by brainstem gliosis, and it is therefore unclear whether the decreases are secondary to hypoxia or ischemia or whether they reflect primary alterations in 5-HT metabolism or transport (see Genetic Risk Factors) (Table 367-4).

Table 367-4 IDENTIFIED GENES FOR WHICH THE DISTRIBUTION OF POLYMORPHISMS DIFFERS IN SUDDEN INFANT DEATH SYNDROME INFANTS COMPARED TO CONTROL INFANTS

CARDIA CHANNELOPATHIES (7)

Sodium ion channel gene (SCN5A) (long QT syndrome 3, Brugada syndrome)

Potassium ion channel genes (KCNE2, KCNH2, KCNQ1)

CAV3 (long QT syndrome 9)

GPD1-L (Brugada syndrome)

RyR2 (catecholaminergic polymorphic ventricular tachycardia)

SEROTONIN (5-HT) (3)

5-HT transporter protein (5-HTT)

Intron 2 of SLC6A4 (variable numer tandem repeat [VNTR] polymorphism)

5-HT FEV gene

GENES PERTINENT TO DEVELOPMENT OF AUTONOMIC NERVOUS SYSTEM (8)

Paired-like homeobox 2a (PHOX2A)

PHOX2B

Rearranged during transfection factor (RET)

Endothelin converting enzyme-1 (ECE1)

T-cell leukemia homeobox (TLX3)

Engrailed-1 (EN1)

Tyrosine hydroxylase (THO1)

Monamine oxidase A (MAOA)

INFECTION AND INFLAMMATION (6)

Complement C4A

Complement C4B

Interleukin-10 (IL-10)

Interleukin-6 (IL-6) (pro-inflammatory)

Vascular endothelial growth factor (VEGF) (pro-inflammatory)

Tumor necrosis factor (TNF)-α (pro-inflammatory)

ENERGY PRODUCTION (1)

Mitochondrial DNA (mtDNA) polymorphisms

Adapted from Hunt CE, Hauck FR: Sudden infant death syndrome: gene-environment interactions. In Brugada R, Brugada J, Brugada P, editors: Clinical care in inherited cardiac syndromes, Guildford, UK, 2009, Springer-Verlag London.

The ventral medulla has been a particular focus for studies in SIDS victims. It is an integrative area for vital autonomic functions including breathing, arousal, and chemosensory function. Quantitative 3-dimensional (3D) anatomic studies indicate that some SIDS infants have hypoplasia of the arcuate nucleus and up to 60% have histopathologic evidence of less extensive bilateral or unilateral hypoplasia. Considering the apparent overlap between putative mechanisms for SIDS and unexpected late fetal deaths, ∼30% of late unexpected and unexplained stillbirths also have hypoplasia of the arcuate nucleus.

Neurotransmitter studies of the arcuate nucleus have also identified receptor abnormalities in some SIDS infants that involve several receptor types relevant to state-dependent autonomic control overall and to ventilatory and arousal responsiveness in particular. These deficits include significant decreases in binding to kainate, muscarinic cholinergic, and 5-HT receptors. Studies of the ventral medulla have identified morphologic and biochemical deficits in 5-HT neurons. Immunohistochemical analyses have revealed an increased number of 5-HT neurons and an increase in the fraction of 5-HT neurons showing an immature morphology, suggesting a failure or delay in the maturation of these neurons. It is not known whether such deficits in ventral medullary 5-HT neurons are sufficient to result in fatal autonomic dysfunction. High neuronal levels of interleukin 1β (IL-1β) are present in the arcuate and dorsal vagal nuclei in SIDS victims compared to controls, perhaps contributing to molecular interactions affecting cardiorespiratory and arousal responses.

The neuropathologic data provide compelling evidence for altered 5-HT homeostasis, creating an underlying vulnerability contributing to SIDS. 5-HT is an important neurotransmitter and the 5-HT neurons in the medulla project extensively to neurons in the brainstem and spinal cord that influence respiratory drive and arousal, cardiovascular control including blood pressure, circadian regulation and non-REM sleep, thermoregulation, and upper airway reflexes. Medullary 5-HT neurons may be respiratory chemosensors and may be involved with respiratory responses to intermittent hypoxia and respiratory rhythm generation. Decreases in 5-HT_1A and 5-HT_2A receptor immunoreactivity have been observed in the dorsal nucleus of the vagus, solitary nucleus, and ventrolateral medulla. There are extensive serotoninergic brainstem abnormalities in SIDS infants, including increased 5-HT neuronal count, a lower density of 5-HT_1A receptor-binding sites in regions of the medulla involved in homeostatic function, and a lower ratio of 5-HT transporter (5-HTT) binding density to 5-HT neuronal count in the medulla. Male SIDS infants have lower receptor-binding density than female SIDS infants. These findings suggest that the synthesis and availability of 5-HT is altered within 5-HT pathways and hence alters neuronal firing. These neuropathologic data could be explained by an increased number of 5-HT neurons, leading to an excess of extracellular 5-HT and secondary down-regulation of 5-HT_1A receptors. It is also possible that 5-HT synthesis and/or release may be deficient, leading to a deficiency of extracellular 5-HT despite a compensatory overabundance of 5-HT neurons. Although the neuropathologic data thus do not clarify whether medullary 5-HT levels are increased or decreased in SIDS infants, the 5-HTT polymorphism data are consistent with decreased extracellular or synaptic 5-HT concentrations.

Environmental Risk Factors

Declines of 50% or more in rates of SIDS in the USA and around the world have occurred in the past decade, at least in part as a result of national education campaigns directed at reducing risk factors associated with SIDS. The reductions in risk appear to be related primarily to decreases in placing infants prone for sleep and increases in placing them supine. A number of other risk factors also have significant associations with SIDS (Table 367-5); although many are nonmodifiable and most of the modifiable factors have not changed appreciably, self-reported maternal smoking prevalence during pregnancy has decreased by 25% in the past decade.

Table 367-5 ENVIRONMENTAL FACTORS ASSOCIATED WITH INCREASED RISK FOR SUDDEN INFANT DEATH SYNDROME

MATERNAL AND ANTENATAL RISK FACTORS

Elevated 2nd trimester serum α-fetoprotein

Smoking

Alcohol use

Drug use (cocaine, heroin)

Nutritional deficiency

Inadequate prenatal care

Low socioeconomic status

Younger age

Lower education

Single marital status

Shorter interpregnancy interval

Intrauterine hypoxia

Fetal growth restriction

INFANT RISK FACTORS:

Age (peak 2-4 mo, but may be decreasing)

Male gender

Race and ethnicity (African-American and Native American)

Prone and side sleep position

Recent febrile illness (mild infections)

Inadequate immunizations

Smoking exposure (prenatal and postnatal)

Soft sleeping surface, soft bedding

Bed sharing with parent(s) or other children

Thermal stress, overheating

Colder season, no central heating

Nonmodifiable Risk Factors

Although SIDS affects infants from all social strata, lower socioeconomic status is consistently associated with higher risk. In the USA, African-American, Native American, and Alaskan Native infants are 2 to 3 times more likely than white infants to die of SIDS, whereas Asian, Pacific Islander, and Hispanic infants have the lowest incidence. Some of this disparity may be related to the higher concentration of poverty and other adverse environmental factors found within the communities with higher incidence.

Infants are at greatest risk of SIDS at 2-4 months of age, with most deaths having occurred by 6 months. This characteristic age has decreased in some countries as the SIDS incidence has declined, with deaths occurring at earlier ages and with a flattening of the peak incidence. Similarly, the commonly found winter seasonal predominance of SIDS has declined or disappeared in some countries as prone prevalence has decreased, supporting prior findings of an interaction between sleep position and factors more common in colder months (overheating, infection). Male infants are 30-50% more likely to be affected than female infants.

Modifiable Risk Factors

Pregnancy-Related Factors

An increased SIDS risk is associated with numerous obstetric factors, suggesting that the in utero environment of future SIDS victims is suboptimal. SIDS infants are more commonly of higher birth order, independent of maternal age, and of gestations after shorter interpregnancy intervals. Mothers of SIDS infants generally receive less prenatal care and initiate care later in pregnancy. Additionally, low birthweight, preterm birth, and slower intrauterine and postnatal growth rates are risk factors.

Cigarette Smoking

There is a major association between intrauterine exposure to cigarette smoking and risk for SIDS. The incidence of SIDS is about 3 times greater among infants of mothers who smoke in studies conducted before SIDS risk-reduction campaigns and 5 times higher in studies after implementation of risk-reduction campaigns. The risk of death is progressively greater as daily cigarette use increases. The effects of smoking by the father and other household members are more difficult to interpret because they are highly correlated with maternal smoking. There appears to be a small independent effect of paternal smoking, but data on other household members have been inconsistent.

It is very difficult to assess the independent effect of infant exposure to environmental tobacco smoke (ETS) because parental smoking behavior during and after pregnancy are also highly correlated. An increased risk of SIDS is also found for infants exposed to only postnatal maternal ETS. There is a dose response for the number of household smokers, number of people smoking in the same room as the infant, and the number of cigarettes smoked. These data suggest that keeping the infant free of ETS can further reduce an infant’s risk of SIDS.

Drug and Alcohol Use

Most studies link maternal prenatal drug use, especially opiates, with an increased risk of SIDS, ranging from 2-15-fold increased risk. Most studies have not found an association between maternal alcohol use prenatally or postnatally and SIDS. However, in one study of Northern Plains Indians, periconceptional alcohol use and binge drinking in the 1st trimester were associated with a 6-fold and an 8-fold increased risk of SIDS, respectively. A Danish cohort study found that mothers admitted to the hospital at any time before or after the birth of their infants for an alcohol- or drug-related disorder had a 3-times higher risk of their infant dying from SIDS, and a Dutch study reported that maternal alcohol consumption in the 24 hr before the infant died carried a 2-8-fold increased risk of SIDS. Siblings of infants with fetal alcohol syndrome have a 10-fold increased risk of SIDS compared to controls.

Infant Sleep Environment

Sleeping prone has consistently been shown to increase the risk of SIDS. As rates of prone positioning have decreased in the general population, the odds ratios for SIDS in infants still sleeping prone have increased. The highest risk of SIDS might occur in infants who are usually placed nonprone but placed prone for last sleep (“unaccustomed prone”) or found prone (“secondary prone”). The “unaccustomed prone” position is more likely to occur in daycare or other settings outside the home and highlights the need for all infant caretakers to be educated about appropriate sleep positioning.

The initial SIDS risk-reduction campaign recommendations considered side sleeping to be nearly equivalent to the supine position in reducing the risk of SIDS. Subsequent studies have indicated that although it is safer than the prone position, side-sleeping infants are twice as likely to die of SIDS as infants sleeping supine. This increased risk might relate to the relative instability of the position, with some infants placed on the side rolling to the prone position. The current recommendations call for supine position for sleeping for all infants except those few with specific medical conditions for which recommending a different position may be justified.

Many parents and health care providers were initially concerned that supine sleeping would be associated with an increase in adverse consequences, such as difficulty sleeping, vomiting, or aspiration. Evidence suggests that the risk of regurgitation and choking is highest for prone-sleeping infants. Some newborn nursery staff still tend to favor side positioning, which models inappropriate infant care practice to parents. Infants sleeping on their backs do not have more episodes of cyanosis or apnea; reports of apparent life-threatening events decreased in Scandinavia after increased use of the supine position. Among infants in the USA who maintained the same sleep position at 1, 3, and 6 mo of age, no clinical symptoms or reasons for outpatient visits (including fever, cough, wheezing, trouble breathing or sleeping, vomiting, diarrhea, or respiratory illness) are more common in infants sleeping supine or on their sides compared with infants sleeping prone. Three symptoms are actually less common in infants sleeping supine or on their sides: fever at 1 month, stuffy nose at 6 months, and trouble sleeping at 6 months. Outpatient visits for ear infection are less common at 3 and 6 months for infants sleeping supine and also less common at 3 months for infants sleeping on their sides. These results provide reassurance for parents and health care providers and should contribute to universal acceptance of supine as the safest and optimal sleep position for infants.

Soft sleep surfaces or bedding, such as comforters, pillows, sheepskins, polystyrene bean pillows, and older or softer mattresses are associated with increased risk of SIDS. Head and face covering by loose bedding, particularly heavy comforters, is also associated with increased risk. Overheating has been associated with increased risk for SIDS based on indicators such as higher room temperature, high body temperature, sweating, and excessive clothing or bedding. Some studies have identified an interaction between overheating and prone sleeping, with overheating increasing the risk of SIDS only when infants are sleeping prone. Higher external environmental temperatures have not been associated with increased SIDS incidence in the USA.

Several studies have implicated bed sharing as a risk factor for SIDS. Bed sharing is particularly hazardous when other children are in the same bed, when the parent is sleeping with an infant on a couch or other soft or confining sleeping surface, and when the mother smokes. Infants <4 mo of age are at increased risk even when mothers are nonsmokers. Risk is also increased with longer duration of bed sharing during the night; returning the infant to his or her own crib is not associated with increased risk. Room sharing without bed sharing is associated with lower SIDS rates; the safest place for an infant to sleep may be in his or her own crib in the parents’ room.

One study found that having a fan on in the room during sleep was associated with a reduced risk of SIDS. This effect was more pronounced in adverse sleep environments. Other studies will need to confirm this finding before recommendations can be made about this factor.

Infant-Feeding Care Practices and Exposures

A number of studies have demonstrated a protective effect of breast-feeding, but others have found that this protective effect is not present after adjusting for potentially confounding factors. A large study from Germany found a reduced risk of SIDS among breast-fed infants, even after adjusting for socioeconomic and other confounding factors. This study and several others now provide strong evidence of benefit from breast-feeding.

Pacifier (dummy) use lowers the risk of SIDS in the majority of studies when used for last or reference sleep. Although it is not known if this is a direct effect of the pacifier itself or from associated infant or parental behavior, there is increasing evidence that pacifier use and dislodgment can increase the arousability of infants during sleep. Concerns have been expressed about recommending pacifiers as a means of reducing the risk of SIDS for fear of adverse consequences, particularly interference with breast-feeding. Well-designed studies have found no association between pacifiers and breast-feeding duration. A small increased incidence of otitis media and of respiratory and gastrointestinal illness has been reported for pacifier users compared with nonusers. The Netherlands (for bottle-fed babies) and Germany have recommended pacifier use as a potential way to reduce the risk of SIDS. The most recent AAP guidelines recommend pacifier use for all infants, delaying introduction for nursing infants until after breast-feeding has been well established.

Upper respiratory tract infections have generally not been found to be an independent risk factor for SIDS. These and other minor infections might play a role in the pathogenesis of SIDS. Risk for SIDS has been found to be increased after illness among prone sleepers, those who were heavily wrapped, and those whose heads were covered during sleep.

No adverse association between immunizations and SIDS has been found. SIDS infants are less likely to be immunized than control infants; in immunized infants, no temporal relationship between vaccine administration and death has been identified. In a meta-analysis of case-control studies that adjusted for potentially confounding factors, the risk of SIDS for infants immunized with diphtheria, tetanus, and pertussis was half that for nonimmunized infants.

SIDS rates remain higher among Native Americans, Alaskan Natives, and African-Americans. This may be due, in part, to group differences in adopting supine sleeping or other risk-reduction practices. Greater efforts are needed to address this persistent disparity and to ensure that SIDS risk-reduction education reaches all parents and all other care providers, including other family members and personnel at daycare centers.

Genetic Risk Factors

As shown in Table 367-4, there are numerous genetic differences identified among healthy infants, infants dying from other causes, and SIDS infants. Polymorphisms occurring at higher incidence in SIDS compared to controls have been identified for 7 cardiac ion channelopathy genes that are proarrhythmic, 3 5-HT genes, 8 autonomic nervous system (ANS) development genes, 6 genes related to infection and inflammation that are pro-inflammatory, and 1 gene related to energy production.

Long Q-T syndrome (LQTS) is a known cause of sudden unexpected death in adults and children, due to a prolonged cardiac action potential by either increasing depolarization or decreasing repolarization current. The first evidence supporting a causal role for LQTS in SIDS was a large Italian study in which having a corrected QT interval >440 ms on an electrocardiogram performed on day 3-4 of life was associated with a 41.3 odds ratio for SIDS. Several case reports have provided proof-of-concept that cardiac channelopathy polymorphisms are associated with SIDS. LQTS has been associated with polymorphisms related to mainly gain-of-function mutations in the sodium channel gene (SCN5A) that encode critical channel pore-forming alpha subunits or essential channel interacting proteins. LQTS has also been associated with mainly loss-of-function polymorphisms in 3 potassium channel genes (KCNE2, KCNH2, KCNQ1). The mechanism by which potassium channel variants can contribute to SIDS is thought to be mediated at least in part through increased sympathetic activity during sleep, including REM sleep, and associated sleep-related hypoxemia and chemoreceptive reflexes. Short QTS (SQTS) is more recently recognized as another cause of life-threatening arrhythmia or sudden death, often during rest or sleep. Gain-of-function mutations in genes including KCNH2 and KCNQ1 have been causally linked to SQTS, and some of these deaths have occurred in infants, suggesting that SQTS may also be causally linked to SIDS.

Both LQTS and SQTS are pro-arrhythmic and associated with cardiac arrest and sudden death. However, some of these polymorphisms are associated with concealed phenotypes in which perturbation by a stressor such as acidosis, hypoxemia, or adrenergic stress is required to elicit electrocardiographic evidence of the pro-arrhythmic dysfunction. The other cardiac ion-related channelopathy polymorphisms are also pro-arrhythmic, including Brugada syndrome (BrS1, BrS2), and catecholaminergic paroxysmal ventricular tachycardia (CPVT1). Collectively, these mutations in cardiac ion channels provide a lethal arrhythmogenic substrate in some infants at risk for SIDS (Fig. 367-1) and might account for as many as 10% of SIDS.

Figure 367-1 An arrhythmogenic pathogenetic pathway for sudden infant death syndrome (SIDS) from patient genotype to clinical phenotype, with environmental influences noted. The genetic abnormality—in this instance, a polymorphism in the cardiac Na⁺ channel SCN5A—causes a molecular phenotype of increased late Na⁺ current (I_Na) under the influence of environmental factors such as acidosis. Interacting with other ion currents that may themselves be altered by genetic and environmental factors, the late Na⁺ current causes a cellular phenotype of prolonged action potential duration as well as early after-depolarizations. Prolonged action potential in the cells of the ventricular myocardium and further interaction with environmental factors such as autonomic innervation, which, in turn, may be affected by genetic factors, produce a tissue-organ phenotype of a prolonged Q-T interval on the electrocardiogram (ECG) and torsades de pointes arrhythmia in the whole heart. If this is sustained or degenerates to ventricular fibrillation, the clinical phenotype of SIDS results. Environmental and multiple genetic factors can interact at many different levels to produce the characteristic phenotypes at the molecular, cellular, tissue, organ, and clinical levels

(From Makielski JC: SIDS: genetic and environmental influences may cause arrhythmia in this silent killer, J Clin Invest 116:297–299, 2006.)

Many genes are involved in the control of 5-HT synthesis, storage, membrane uptake, and metabolism. Polymorphisms have been identified in the promotor region of the 5-HT transporter (5-HTT) protein gene located on chromosome 17 that occur in greater frequency in SIDS than control infants. The long “L” allele increases effectiveness of the promotor and reduces extracellular 5-HT concentrations at nerve endings compared to the short “S” allele. White, African-American, and Japanese SIDS infants are more likely than controls to have the “L” (long) allele. There is also a negative association between SIDS and the S/S genotype. The L/L genotype is associated with increased serotonin transporters on neuroimaging and postmortem binding studies.

An association has also been observed between SIDS and a 5-HTT intron 2 polymorphism, which differentially regulates 5-HTT expression. There are positive associations between SIDS and the intron 2 genotype distributions in African-American infants compared to African-American controls. The human fifth Ewing variant (FEV) gene is specifically expressed in central 5-HT neurons in the brain, with a predicted role in specification and maintenance of the serotoninergic neuronal phenotype. An insertion mutation has been identified in intron 2 of the FEV gene, and the distribution of this mutation differs significantly in SIDS compared to control infants.

Molecular genetic studies in SIDS victims have also identified mutations pertinent to early embryologic development of the autonomic nervous system (ANS). The relevant genes include mammalian achaete-scute homolog-1 (MASH1), bone morphogenic protein-2 (BMP2), paired-like homeobox 2a (PHOX2a), PHOX 2b, rearranged during transfection factor (RET), endothelin converting enzyme-1 (ECE 1), T-cell leukemia homeobox (TLX3), engrailed-1 (EN1), tyrosine hydroxylase (THO1), and monamine oxidase A (MAOA). Eleven protein-changing rare mutations have been identified in 14/92 SIDS cases among the PHOX 2a, RET, ECE1, TLX3, and EN1 genes. Only one of these mutations (TLX3) was found in 2/92 controls. African-American infants accounted for 10/11 mutations in SIDS infants and in both affected controls with protein-changing mutations. Eight polymorphisms in the PHOX2B gene occurred significantly more frequently in SIDS compared to control infants.

Genetic differences in SIDS infants compared to control infants have been reported for 2 complement C4 genes. Among SIDS infants, infant deaths attributed to infection, and healthy infant controls, SIDS infants with mild upper respiratory infection prior to death are more likely to have deletion of either the C4A or the C4B gene compared to SIDS victims without infection or to living controls. Among living infants, there are no differences in the C4 gene in those with versus without an upper respiratory infection. These data suggest that partial deletions of C4 in combination with a mild upper respiratory infection place these relatively hypoimmune infants at increased risk for sudden unexpected death. Some SIDS infants have loss-of-function polymorphisms in the gene promoter region for interleukin-10 (IL-10), another anti-inflammatory cytokine. Among SIDS infants compared to living controls, sudden infant death is strongly associated with the IL-10 polymorphism. These IL-10 polymorphisms are associated with decreased IL-10 levels and hence could contribute to SIDS by delaying initiation of protective antibody production or reducing capacity to inhibit inflammatory cytokine production. A larger study did not find differences in IL-10 genes in SIDS compared to control infants, but it did identify an association with the ATA haplotype in sudden and unexpected infant deaths classified as resulting from infection.

Significant associations with SIDS have been reported for polymorphisms in vascular endothelial growth factor (VEGF), IL-6, and tumor necrosis factor-α (TNF-α). These 3 cytokines are pro-inflammatory, and these gain-of-function polymorphisms would result in increased inflammatory response to infectious or inflammatory stimuli and hence contribute to an imbalance between pro-inflammatory and anti-inflammatory cytokines. As apparent proof of principle, elevated levels of IL-6 and VEGF have been reported from cerebrospinal fluid in SIDS infants. There were no group differences in the IL6-174G/C polymorphism in a Norwegian SIDS study, but the aggregate evidence nevertheless suggests an activated immune system in SIDS and thus implicates genes involved in the immune system.

Several studies of mtDNA in SIDS infants have demonstrated significant differences in mutations compared to control infants, including a high substitution rate in the HVR-1 region of the D-loop and an association between a high number of these substitutions and mutations in coding areas of mtDNA. Another study of mitochondrial tRNA genes and flanking regions did not demonstrate an association between a specific mitochondrial tRNA gene mutation and SIDS, or a higher mtDNA mutation frequency in SIDS versus control infants. Cardiac arrhythmias, including prolonged QT intervals, have been observed in families with mitochondrial disease. Although the mtDNA polymorphism T3394C that is associated with cardiac arrhythmia has not been observed to occur with greater frequency in SIDS compared to control infants, it is nevertheless possible that mtDNA mutations such as T3394C may be genetic variants that when combined with environmental risk factors not present in healthy infants could predispose to sudden death.

Gene-and-Environment Interactions

Interactions between genetic and environmental risk factors determine the actual risk for SIDS in individual infants (Fig. 367-2). There appears to be an interaction between prone sleep position and impaired ventilatory and arousal responsiveness. Facedown or nearly facedown sleeping does occasionally occur in prone-sleeping infants and can result in episodes of airway obstruction and asphyxia in healthy full-term infants. Healthy infants arouse before such episodes become life-threatening, but infants with insufficient arousal responsiveness to asphyxia may be at risk for sudden death. There may also be links between modifiable risk factors such as soft bedding, prone sleep position and thermal stress, and links between genetic risk factors such as ventilatory and arousal abnormalities and temperature or metabolic regulation deficits. Cardiorespiratory control deficits could be related to 5-HTT polymorphisms, for example, or to polymorphisms in genes pertinent to ANS development. Affected infants could be at increased risk for sleep-related hypoxemia and hence more susceptible to adverse effects associated with unsafe sleep position or bedding. Infants at increased risk for sleep-related hypoxemia could also be at greater risk for fatal arrhythmias in the presence of a cardiac ion channelopathy polymorphism.

Figure 367-2 Schematic illustration of potential interactions between representative environmental and genetic risk factors for sudden unexpected death in infancy (SUDI) and sudden infant death syndrome (SIDS). ANS, autonomic nervous system; 5-HTT, serotonin (5-HT) transporter.

(Adapted from Hunt CE, Hauck FR: Sudden infant death syndrome: gene-environment interactions. In Brugada R, Brugada J, Brugada P, editors: Clinical care in inherited cardiac syndromes, Guildford, UK, 2009, Springer-Verlag London.)

In >50% of SIDS victims, recent febrile illnesses, often related to upper respiratory infection, have been documented (see Table 367-5). Otherwise benign infections might increase risk for SIDS if interacting with genetically determined impaired immune responses including those due to partial deletions in the complement C4 gene or to interleukin polymorphisms (see Table 367-4). Deficient inflammatory responsiveness can also occur due to mast cell degranulation, which has been reported in SIDS infants; this is consistent with an anaphylactic reaction to a bacterial toxin, and some family members of SIDS infants also have mast cell hyper-releasability and degranulation, suggesting that increased susceptibility to an anaphylactic reaction is another genetic factor influencing fatal outcomes to otherwise minor infections in infants. Interactions between upper respiratory infections or other minor illnesses and other factors such as prone sleeping might also play a role in the pathogenesis of SIDS.

The increased risk for SIDS associated with fetal and postnatal exposure to cigarette smoke may be related at least in part to genetic or epigenetic factors, including those affecting brainstem autonomic control. Although no genetic studies have yet identified any polymorphism affecting nicotine or tobacco metabolism, both animal and human infant studies document decreased ventilatory and arousal responsiveness to hypoxia following fetal nicotine exposure, and impaired autoresuscitation after apnea has been associated with postnatal nicotine exposure. Decreased brain stem immunoreactivity to selected protein kinase C and neuronal nitric oxide synthase isoforms occurs in rats exposed to cigarette smoke prenatally, another potential cause of impaired hypoxic responsiveness. Smoking exposure also increases susceptibility to viral and bacterial infections and increases bacterial binding after passive coating of mucosal surfaces with smoke components, implicating interactions between smoking, cardiorespiratory control, and immune status.

In infants with a cardiac ion channelopathy, risk for a fatal arrhythmia during sleep may be substantially enhanced by predisposing perturbations that increase electrical instability. These perturbations could include REM sleep with bursts of vagal and sympathetic activation, minor respiratory infections, or any other cause of sleep-related hypoxemia or hypercarbia, especially those resulting in acidosis. The prone sleeping position is associated with increased sympathetic activity.

Infant Groups at Increased Risk for Sids

Unexplained Apparent Life-Threatening Events

Infants with an unexplained apparent life-threatening event (ALTE) are at increased risk for SIDS. A history of an unexplained ALTE is reported in 5-9% of SIDS victims, and the risk of SIDS appears to be higher with 2 or more unexplained events, but no definitive incidence rates are available. Compared with healthy control infants, the risk for SIDS may be as much as 3 to 5 times greater in infants having experienced an ALTE. Although most studies of ALTE have not specified gestational age, 30% of ALTE infants in the Collaborative Home Infant Monitoring Evaluation were ≤37 wk gestation at birth.

Subsequent Siblings of a SIDS Victim

The next-born siblings of first-born infants dying of any noninfectious natural cause are at significantly increased risk for infant death from the same cause, including SIDS. The relative risk is 9.1 for the same cause of recurrent death vs 1.6 for a different cause of death. The relative risk for recurrent SIDS (range, 5.4-5.8) is similar to the relative risk for non-SIDS causes of recurrent death (range, 4.6-12.5). The risk for recurrent infant mortality from the same cause as in the index sibling thus appears to be increased to a similar degree in subsequent siblings for both explained causes and for SIDS. This increased risk in SIDS families is consistent with genetic risk factors interacting with environmental risk factors (Table 367-5 and Fig. 367-2).

Controversy as to the extent to which risk for SIDS may be increased in subsequent siblings prevails as a result of uncertainty about the frequency with which intentional suffocation is misclassified as SIDS and continued limits of understanding of the role of genetic risk factors. Clarification of the role of intentional suffocation has been impaired by the lack of objective criteria for diagnosis. Although some health professionals have in the past stated that all subsequent cases of sudden unexpected infant deaths in a family should be investigated for possible homicide, there are substantial data in support of genetic and environmental factors leading to increased natural risk for recurrent SIDS in some families. In addition to genetic evidence consistent with increased risk for SIDS in subsequent siblings, epidemiologic data from the United Kingdom confirm that 2nd infant deaths in families are not rare and that at least 80-90% are natural. The proportion of recurrent infant death from SIDS in subsequent siblings was 5.9 times greater than the proportion of probable homicides.

Prematurity

There is an inverse relationship between risk for SIDS and gestational age. The environmental risk factors associated with SIDS in preterm infants are not substantially different from those observed in full-term infants, including prone and side sleeping. The postnatal age of preterm infants dying of SIDS is 5-7 wk older than that of full-term infants, and the postconceptional age is 4-6 wk younger than that of full-term infants. Compared with infants with birthweight >2,500 g, infants with birthweight of 1,000-1,499 g and 1,500-2,499 g are approximately 4 and 3 times more likely to die of SIDS, respectively.

Physiologic Studies

Physiologic studies have been performed on healthy infants in early infancy, a few of whom later died of SIDS. Physiologic studies have also been performed on infant groups at increased risk for SIDS, especially those with ALTE and subsequent siblings of SIDS. In the aggregate, these studies indicate brainstem abnormalities in neuroregulation of cardiorespiratory control or other autonomic functions and are consistent with the autopsy findings and genetic studies in SIDS victims (see the “Pathology” and “Genetic Risk Factors” sections).

Brainstem muscarinic cholinergic pathways develop from the neural crest and are important in ventilatory responsiveness to CO_2. The muscarinic system develops from the neural crest, and the RET gene is important for this development. RET knockout mice have a depressed ventilatory response to hypercarbia. In addition to chemoreceptor sensitivity, these observed physiologic abnormalities also affect respiratory patterns, control of heart and respiratory rate or variability, and asphyxic arousal responsiveness. A deficit in arousal responsiveness may be a necessary prerequisite for SIDS to occur but may be insufficient to cause SIDS in the absence of other genetic or environmental risk factors. Autoresuscitation (gasping) is a critical component of the asphyxic arousal response, and a failure of autoresuscitation in SIDS infants may be the final and most devastating physiologic failure. Most full-term infants <9 wk of age arouse in response to mild hypoxia, but only 10-15% of normal infants >9 wk of age arouse. These data thus suggest that as infants mature, their ability to arouse to mild to moderate hypoxic stimuli diminishes as they reach the age range of greatest risk for SIDS.

The ability to shorten the QT interval as heart rate increases appears to be impaired in some SIDS victims, suggesting that such infants may be predisposed to ventricular arrhythmia. This is consistent with the observations of cardiac ion channel gene polymorphisms in other SIDS victims (Table 367-4), but there are no antemortem QT interval data in the SIDS infants having postmortem channelopathy polymorphisms. Infants studied physiologically and dying of SIDS a few weeks later have higher heart rates in all sleep-wake states, diminished heart rate variability during wakefulness, and significantly lower heart rate variability at the respiratory frequency across all sleep-wake cycles. Also, these SIDS infants have longer QT intervals than control infants in both REM and non-REM sleep, especially in the late hours of the night when most SIDS likely occurs. In only 1 of these SIDS infants, however, did the QT interval exceed 440 ms.

Part of the decreased heart rate variability and increased heart rate observed in infants who later die of SIDS may be related to decreased vagal tone. This decreased tone appears, at least in part, to be related to vagal neuropathy or to brainstem damage in areas responsible for parasympathetic cardiac control. In a comparison of heart rate power spectra before and after obstructive apneas in infants, future SIDS infants do not have the decreases in low-frequency to high-frequency power ratios observed in control infants. Some future SIDS victims thus have different autonomic responsiveness to obstructive apnea, perhaps indicating impaired ANS control associated with higher vulnerability to external or endogenous stress factors and hence to reduced electrical stability of the heart.

Sweating during sleep has been observed in some infants with an unexplained ALTE or SIDS. Although overheating may be the cause of this sweating, it might also be caused by hypoventilation and secondary asphyxia or by autonomic dysfunction as part of a more generalized deficiency in brainstem function.

Home cardiorespiratory monitors with memory capability have recorded the terminal events in some SIDS victims. These recordings have not included pulse oximetry and do not permit identification of obstructed breaths due to reliance on transthoracic impedance for breath detection. In most instances, there has been sudden and rapid progression of severe bradycardia that is either unassociated with central apnea or appears to occur too soon to be explained by the central apnea. These observations are consistent with an abnormality in autonomic control of heart rate variability, or with obstructed breaths and associated bradycardia or hypoxemia.