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).

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.

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