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Sudden Infant Death Syndrome
Sudden infant death syndrome (SIDS) is defined as the sudden, unexpected death of an infant that is unexplained by a thorough postmortem examination, which includes a complete autopsy, investigation of the scene of death, and review of the medical history. An autopsy is essential to identify possible natural explanations for sudden unexpected death such as congenital anomalies or infection and to diagnose traumatic child abuse ( Tables 402.1 to 402.3 ; see Chapter 16 ). The autopsy typically cannot distinguish between SIDS and intentional suffocation, but the scene investigation and medical history may be of help if inconsistencies are evident. Sudden unexpected infant death (SUID) is a term that generally encompasses all SUIDs that occur during sleep, including SIDS (ICD-10 R95), accidental suffocation and strangulation in bed (ICD-10 W75), and ill-defined deaths, also known as undetermined (ICD-10 R99).
Table 402.1
Differential Diagnosis of Sudden Unexpected Infant Death
Modified from Hunt CE: Sudden infant death syndrome and other causes of infant mortality: diagnosis, mechanisms and risk for recurrence in siblings, Am J Respir Crit Care Med 164(3):346–357, 2001.
| CAUSE OF DEATH | PRIMARY DIAGNOSTIC CRITERIA | POTENTIAL CONFOUNDING DIAGNOSES | FREQUENCY DISTRIBUTION (%) |
|---|---|---|---|
| EXPLAINED AT AUTOPSY | |||
| Natural | 18–20 * | ||
| Infections | History, autopsy, and cultures | If minimal findings: SIDS | 35–46 † |
| Congenital anomaly | History and autopsy | If minimal findings: SIDS | 14–24 † |
| Unintentional injury | History, scene investigation, autopsy | Traumatic child abuse | 15 * |
| Traumatic child abuse | Autopsy and scene investigation | Unintentional injury | 13–24 * |
| Other natural causes | History and autopsy | If minimal findings: SIDS, or intentional suffocation | 12–17 * |
| UNEXPLAINED AT AUTOPSY | |||
| SIDS | History, scene investigation, absence of explainable cause at autopsy | Intentional suffocation | 80–82 |
| Intentional suffocation (filicide) | Perpetrator confession, absence of explainable cause at autopsy | SIDS | Unknown, but <5% of all SUID |
| Accidental suffocation or strangulation in bed (ASSB) | History and scene investigation, ideally including doll re-enactment | Assigned to ICD-10 code (SIDS) for US vital statistics database Unexplained Undetermined |
Varies with individual medical examiners and coroners |
| Genetic mutations | SCN5A , SCN1B-4B , SCN4A, long QT syndromes, plus Table 402.4 | May have negative family history secondary to recessive mutations, de novo mutation, or incomplete penetrance | Unknown, perhaps <10% |
ICD-10, International Classification of Diseases, Version 10; SIDS, sudden infant death syndrome; SUID, sudden unexpected infant death.
* As a percentage of all sudden unexpected infant deaths explained at autopsy.
† As a percentage of all natural causes of sudden unexpected infant deaths explained at autopsy.
Table 402.2
Conditions That Can Cause Apparent Life-Threatening Events * or Sudden Unexpected Infant Death
From Kliegman RM, Greenbaum LA, Lye PS: Practical strategies in pediatric diagnosis and therapy , ed 2, Philadelphia, 2004, Elsevier Saunders, p. 98.
| CENTRAL NERVOUS SYSTEM |
| Arteriovenous malformation |
| Subdural hematoma |
| Seizures |
| Congenital central hypoventilation |
| Neuromuscular disorders (Werdnig-Hoffmann disease) |
| Chiari crisis |
| Leigh syndrome |
| CARDIAC |
| Subendocardial fibroelastosis |
| Aortic stenosis |
| Anomalous coronary artery |
| Myocarditis |
| Cardiomyopathy |
| Arrhythmias (prolonged QT syndrome, Wolff-Parkinson-White syndrome, congenital heart block) |
| PULMONARY |
| Pulmonary hypertension |
| Vocal cord paralysis |
| Aspiration |
| Laryngotracheal disease |
| GASTROINTESTINAL |
| Diarrhea and/or dehydration |
| Gastroesophageal reflux |
| Volvulus |
| ENDOCRINE–METABOLIC |
| Congenital adrenal hyperplasia |
| Malignant hyperpyrexia |
| Long- or medium-chain acyl coenzyme A deficiency |
| Hyperammonemias (urea cycle enzyme deficiencies) |
| Glutaric aciduria |
| Carnitine deficiency (systemic or secondary) |
| Glycogen storage disease type I |
| Maple syrup urine disease |
| Congenital lactic acidosis |
| Biotinidase deficiency |
| INFECTION |
| Sepsis |
| Meningitis |
| Encephalitis |
| Brain abscess |
| Pyelonephritis |
| Bronchiolitis (respiratory syncytial virus) |
| Infant botulism |
| Pertussis |
| TRAUMA |
| Child abuse |
| Accidental or intentional suffocation |
| Physical trauma |
| Factitious syndrome (formerly Munchausen syndrome) by proxy |
| POISONING (INTENTIONAL OR UNINTENTIONAL) |
| Boric acid |
| Carbon monoxide |
| Salicylates |
| Barbiturates |
| Ipecac |
| Cocaine |
| Insulin |
| Others |
* Recommended terminology now is “brief resolved unexplained events.”
Table 402.3
Differential Diagnosis of Recurrent Sudden Infant Death in a Sibling
From Kliegman RM, Greenbaum LA, Lye PS: Practical strategies in pediatric diagnosis and therapy , ed 2, Philadelphia, 2004, Elsevier Saunders, p 101.
| IDIOPATHIC |
| Recurrent sudden infant death syndrome |
| CENTRAL NERVOUS SYSTEM |
| Congenital central hypoventilation |
| Neuromuscular disorders |
| Leigh syndrome |
| CARDIAC |
| Endocardial fibroelastosis |
| Wolff-Parkinson-White syndrome |
| Prolonged QT syndrome or other cardiac channelopathy |
| Congenital heart block |
| PULMONARY |
| Pulmonary hypertension |
| ENDOCRINE–METABOLIC |
| See Table 402.2 |
| INFECTION |
| Disorders of immune host defense |
| CHILD ABUSE |
| Filicide or infanticide |
| Factitious syndrome (formerly Munchausen syndrome) by proxy |
Epidemiology
SIDS is the 3rd leading cause of infant mortality in the United States, accounting for approximately 7% of all infant deaths. It is the most common cause of postneonatal infant mortality, accounting for 21% of all deaths between 1 mo and 1 yr of age. The annual rate of SIDS in the United States was stable at 1.3-1.4 per 1,000 live births (approximately 7,000 infants per year) before 1992, when it was recommended that infants sleep nonprone as a way to reduce the 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 per 1,000 live births (2,234 infants). There has been a slower rate of decline since that time; in 2015 the rate was 0.39 per 1,000 live births (1,568 infants). The decline in the number of SIDS deaths in the United States and other countries has been attributed to increasing use of the supine position for sleep. In 1992, 82% of sampled infants in the United States were placed prone for sleep. Although several other countries have decreased prone sleeping prevalence to ≤2%, in the United States in 2010 (the last year for which these data were collected by the National Infant Sleep Position study), 13.5% of infants were still being placed prone for sleep and 11.9% were being placed in the side position. Among black infants, these rates were even higher: 27.6% prone and 16.1% side in 2010.
There is increasing evidence that infant deaths previously classified as SIDS are now being classified by medical examiners and coroners as due to other causes, notably accidental suffocation and strangulation in bed and ill-defined deaths . Between 1994 and 2013, there has been a 7-fold increase in the rate of accidental suffocation and strangulation in bed, from 0.03 to 0.21 deaths per 1,000 live births. There has also been an increase in the rate of ill-defined deaths between 1995 and 2013, from 0.21 to 0.28 deaths per 1,000 live births. These sudden and unexpected infant deaths are primarily associated with unsafe sleeping environments, including prone positioning, sharing a sleep surface with others, and soft bedding in the sleep environment. Based on these trends and the commonality of many of the sleep environment risk factors that are associated with both SIDS and other sleep-related SUID, risk reduction measures that will be later described are applicable to all sleep-related SUID.
Pathology
Although there are no autopsy findings pathognomonic for SIDS and no findings are required for the diagnosis, there are some that are commonly seen on postmortem examination. Petechial hemorrhages are found in 68–95% of infants who died of SIDS 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. Infants who died of SIDS have higher levels of vascular endothelial growth factor (VEGF) in the cerebrospinal fluid. These increases may be related to VEGF polymorphisms (see “Genetic Risk Factors” later and Table 402.4 ) or might indicate recent hypoxemic events because VEGF is upregulated by hypoxia.
Table 402.4
Identified Genes for Which the Distribution of Polymorphisms Differs in Sudden Infant Death Syndrome Infants Compared With Control Infants
Modified 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.
| CARDIAC CHANNELOPATHIES |
| Potassium ion channel genes (KCNE2, KCNH2, KCNQ1, KCNJ8) |
| Sodium ion channel gene (SCN5A) (long QT syndrome 3, Brugada syndrome) |
| GPD1-L-encoded connexin43 (Brugada syndrome) |
| SCN3B (Brugada syndrome) |
| CAV3 (long QT syndrome 9) |
| SCN4B (long QT syndrome 10) |
| SNTA-1 (long QT syndrome 11) |
| RyR2 (catecholaminergic polymorphic ventricular tachycardia) |
| SEROTONIN (5-HT) |
| 5-HT transporter protein (5-HTT) |
| Intron 2 of SLC6A4 (variable number tandem repeat [VNTR] polymorphism) |
| 5-HT fifth Ewing variant (FEV) gene |
| GENES PERTINENT TO DEVELOPMENT OF AUTONOMIC NERVOUS SYSTEM |
| 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) |
| Sodium/proton exchanger 3 (NHE3) (medullary respiratory control) |
| INFECTION AND INFLAMMATION |
| Complement C4A |
| Complement C4B |
| Interleukin-1RN (gene encoding IL-1 receptor antagonist [ra]; proinflammatory) |
| Interleukin-6 (IL-6; proinflammatory) |
| Interleukin-8 (IL-8; proinflammatory; associated with prone sleeping position) |
| Interleukin-10 (IL-10) |
| Vascular endothelial growth factor (VEGF) (proinflammatory) |
| Tumor necrosis factor (TNF)- α (proinflammatory) |
| OTHER |
| Mitochondrial DNA (mtDNA) polymorphisms (energy production) |
| Flavin-monooxygenase 3 (FMO3) (enzyme metabolizes nicotine; risk factor with smoking mothers) |
| Aquaporin-4 (T allele and CT/TT genotype associated with maternal smoking and with increased brain/body weight ratio in SIDS infants) |
| SCN4A (nondystrophic myotonia, laryngospasm) |
SIDS infants have several identifiable changes in the lungs and other organs. Nearly 65% of these infants have structural evidence of preexisting, chronic, low-grade asphyxia, and other studies have identified biochemical markers of asphyxia. Some studies have shown carotid body abnormalities, consistent with a role for impaired peripheral arterial chemoreceptor function in SIDS. Numerous studies have shown brain abnormalities that could cause or contribute to an impaired autonomic response to an exogenous stressor, including in the hippocampus and brainstem, the latter being the major area responsible for respiratory and autonomic regulation. The affected brainstem nuclei include the retrotrapezoid nucleus and the dorsal motor nucleus of the vagus, primary sites of central chemoreception and respiratory drive. Abnormalities in both the structure and expression of the PHOX2B gene, which is involved in neuronal maturation, have also been reported in significantly more SIDS infants than controls.
The ventral medulla has been a particular focus for studies in infants who died of SIDS. It is an integrative area for vital autonomic functions including breathing, arousal, and chemosensory function. Some SIDS infants have hypoplasia of the arcuate nucleus and up to 60% have histopathologic evidence of less-extensive bilateral or unilateral hypoplasia. Consistent with the apparent overlap between putative mechanisms for SIDS and for unexpected late fetal deaths, approximately 30% of sudden intrauterine unexplained deaths also have hypoplasia of the arcuate nucleus. Imaging mass spectroscopy of postmortem medullary tissue has identified abnormal expression of 41 peptides, especially in the raphe, hypoglossal, and pyramidal nuclei that include components for developmental neuronal/glial/axonal growth, cell metabolism, cytoarchitecture, and apoptosis. These findings suggest that SIDS infants have abnormal neurologic development contributing to pathogenesis, with the impairments suggesting delayed neurologic maturation.
Neurotransmitter studies of the arcuate nucleus have also identified several receptor abnormalities 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 serotonin (5-HT) receptors. Studies of the ventral medulla have identified morphologic and biochemical deficits in 5-HT neurons and decreased γ-aminobutyric acid receptor A receptor binding in the medullary serotonergic system. Immunohistochemical analyses reveal 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. High neuronal levels of interleukin (IL)-1β are present in the arcuate and dorsal vagal nuclei in SIDS infants compared with 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–rapid eye movement (REM) sleep, thermoregulation, and upper airway reflexes. 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 do female SIDS infants. Overall, these 5-HT–related studies suggest that the synthesis and availability of 5-HT are decreased within 5-HT pathways, and medullary tissue levels of 5-HT and its primary biosynthetic enzyme (tryptophan hydroxylase) are lower in SIDS infants compared with age-matched controls.
Environmental Risk Factors
Declines of 50% or more in rates of SIDS in the United States and around the world have occurred following national education campaigns directed at reducing risk factors associated with SIDS ( Table 402.5 ). Although many risk factors 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 in the United States.
Table 402.5
Risk Factors Associated With 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 1-4 mo) |
| Male gender |
| Race and ethnicity (African American, American Indian, Alaska Native, other minorities) |
| Growth failure |
| No breastfeeding |
| No pacifier (dummy) |
| Prematurity |
| 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 Environmental Risk Factors
Lower socioeconomic status has consistently been associated with higher risk, although SIDS affects infants from all social strata. In the United States, African-American, American Indian, and Alaska Native infants are 2-3 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 some, but not all, of the communities with higher incidence.
Infants are at greatest risk of SIDS at 1-4 mo of age, with most deaths having occurred by 6 mo. 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 age incidence. Similarly, the commonly observed 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 as a consequence of elevated interior temperatures or bundling with blankets and heavy clothing, or infection). Male infants are 30–50% more likely to be affected by SIDS than are female infants.
Modifiable Environmental Risk Factors
Pregnancy-Related Factors
An increased SIDS risk is associated with numerous obstetric factors, suggesting that the in utero environment of future SIDS infants 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. In addition, 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 was 2-3 times greater among infants of mothers who smoked in studies conducted before SIDS risk-reduction campaigns and 4 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 infant's 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. The effect of prenatal smoking on SIDS risk is not believed to be caused by lower birthweight, which is often found among infants of smoking mothers.
It is very difficult to assess the independent effect of infant exposure to environmental tobacco smoke because parental smoking behaviors during and after pregnancy are also highly correlated. However, a 2-fold increased risk of SIDS is found for infants exposed only to postnatal maternal environmental tobacco smoke. 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 environmental tobacco smoke 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 a 2- to 15-fold increased risk. Studies looking at the association between maternal alcohol use prenatally or postnatally and SIDS have conflicting results. 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 for an alcohol- or a drug-related disorder at any time before or after the birth of their infants had a 3-time 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 an 8-fold increased risk of SIDS. Siblings of infants with fetal alcohol syndrome have a 10-fold increased risk of SIDS compared with controls. Although there are conflicting reports of illicit drug use and SIDS overall, prenatal drug use, especially opiates, is associated with an increased risk of SIDS, ranging from 2- to 15-fold. Data on cannabis use and SIDS are extremely limited, with only one study from New Zealand reporting results for postpartum maternal use. This study found that nighttime cannabis use was associated with a 2-fold increased risk of SIDS, whereas daytime use was not associated with increased risk.
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 occurs in infants who are usually placed nonprone but placed prone for last sleep (“unaccustomed prone”) or found prone (“secondary prone”). The “unaccustomed prone” position may be 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.
Side-Sleeping: Significant Risk Factor
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 documented that side-sleeping infants were twice as likely to die of SIDS as infants sleeping supine. This increased risk may be related to the relative instability of the position. Infants who are placed on their side and roll to prone are at exceptional risk, with one study finding they are almost 9 times more likely to die of SIDS than those placed supine. Although the majority of SIDS occurrences are still associated with infants being found prone, a higher proportion of SIDS is now attributed to being placed on the side for sleeping than for being placed prone. 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, in infants with anatomic or functional upper airway compromise.
Many parents and healthcare providers were initially concerned that supine sleeping would be associated with an increase in adverse consequences, such as difficulty sleeping, vomiting, or aspiration. However, 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, and reports of apparent life-threatening events actually decreased in Scandinavia after increased use of the supine position. Among infants in the United States 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) were more common in infants sleeping supine or on their sides compared with infants sleeping prone. Three symptoms were actually less common in infants sleeping supine or on their sides: fever at 1 mo, stuffy nose at 6 mo, and trouble sleeping at 6 mo. Outpatient visits for ear infection were less common at 3 and 6 mo for infants sleeping supine and also less common at 3 mo for infants sleeping on their side. These results provide reassurance for parents and healthcare providers and should contribute to universal acceptance of supine as the safest and optimal sleep position for infants.
Soft Sleep Surfaces and Soft or Loose Bedding
Soft sleep surfaces and soft or loose bedding , including comforters, pillows, bumper pads, stuffed animals, mattress toppers, pillow-top mattresses, sheepskins, polystyrene bean pillows, and old or soft mattresses, are associated with increased risk of SIDS. Infant sleep positioners, including pillows and wedges, which are often marketed to hold infants on their side or at an angle to help with reflux, are also not recommended. Based on available research, swaddling infants , or wrapping them in a blanket, is not recommended as a strategy to reduce SIDS. Infants who roll to the prone position while swaddled are at particularly high risk of SIDS. Wearable blankets, which may have a built-in swaddle, are an acceptable alternative.
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