Sudden infant death syndrome

Sleep Disorders

Updated 05.08.2022
Released 02.13.1995
Expires For CME 05.08.2025

Sudden infant death syndrome

Authors: Lourdes M DelRosso MD PhD, Michelle Y Sobremonte-King MD

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Editor: Antonio Culebras MD FAAN FAHA FAASM

Sudden infant death syndrome

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Introduction

Overview

Sudden infant death syndrome (SIDS) is the sudden, unexpected death of an infant (< 1 year old) that is unexplained by careful review of history, autopsy, and death scene investigation. SIDS is a subcategory of sudden unexpected infant death (SUID), a term used to designate any unexpected death without an obvious cause that occurs in children before 1 year of age. Besides SIDS, SUID includes other conditions such as asphyxia, arrhythmias, and accidental trauma. SIDS is a leading cause of death in infants younger than 1 year of age. Ninety percent of SIDS cases occur before 6 months of age. The exact etiology of SIDS is not known, but generally the triple-risk model is the most accepted hypothesis. This model proposes that SIDS is caused by the interplay between risk factors from 3 areas: 1) a specific and/or critical period of development, 2) an infant’s underlying vulnerability, and 3) an environmental trigger. Accordingly, risk factors and protective factors have been identified and contribute to the current recommendations directed at prevention of SIDS. In this article, the authors discuss the clinical presentation, pathophysiology, diagnostic workup, and current recommendations for SIDS (68).

Key points

	• By definition, sudden infant death syndrome (SIDS) is of unknown cause and is a diagnosis of exclusion (unexplained after review of history, autopsy, and death scene investigation); if evidence of a specific cause of death is found, then it is not SIDS.
	• Sudden unexpected infant death (SUID) is a term that includes unexpected deaths in infants younger than 1 year of age that fit various categories (eg, SIDS, asphyxia, arrhythmias, accidental trauma).
	• SIDS affects infants less than 12 months of age, peaks between 2 to 4 months, and is less common after 6 months of age. SIDS is more common in boys and African Americans.
	• The etiology of SIDS is unknown but is thought to be associated with autonomic nervous system dysregulation and impaired arousal mechanisms.
	• Preventative measures include sleeping on the back; sleeping on a firm surface without extraneous soft bedding, clothing, toys, or positioning devices; breastfeeding; room sharing with parents, but not bed sharing; avoiding excessive room heat; avoiding exposure to cigarette smoke, alcohol, and drugs during pregnancy and after birth; and the use of pacifiers.

Historical note and terminology

Sudden infant death syndrome (SIDS) has been postulated to have existed from prehistoric times (40). The first recorded case that could be considered SIDS appears to have been an infant in the Old Testament (Bible: 1 Kings 3:19), though the infant’s death was attributed to suffocation from overlying by its mother. To this day, distinguishing between accidental or intentional suffocation and SIDS in the absence of overt signs of physical violence proves difficult. In 19th-century Germany, pathologists invented an explanation that would defend mothers and nursemaids from accusations of either overlying or infanticide. Initially, they blamed enlargement of the thymus for directly suffocating the infant, failing to recognize that the thymus is typically large in infancy (39). Later pathologists theorized that sudden death was caused by status thymicolymphaticus, a fictional constitutional disorder associated with alleged hyperplasia of the thymus, but did not specify any measurements.

At the Second International Conference on Causes of Sudden Death in Infants in 1969, a definition of SIDS was proposed by Beckwith as “the sudden death of any infant or young child which is unexpected by history, and in which a thorough postmortem examination fails to demonstrate an adequate cause of death” (07). This definition was further refined in 1989 by an expert panel with the National Institute of Child Health and Human Development to specify age less than 1 year old and include death scene investigation. Some have recommended exclusion of the diagnosis of SIDS if the death scene has not been visited, but that alone should not exclude the diagnosis of SIDS because it would exclude half of all probable cases (45). A new definition of SIDS, “the San Diego classification,” was proposed in 2004 and introduced subcategories for SIDS cases; however, it has not been universally accepted, and adjustment of the definition has been suggested (51). The necessity of a universally accepted definition is evident when considering the results of a national survey of medical examiners and coroners, in which they did not universally agree on the classification of death when given 4 different case scenarios of SIDS (89).

The term “sudden unexpected infant death” (SUID) has emerged to include all cases of unexplained sudden and unexpected deaths in infants younger than 1 year old. This is an umbrella term that encompasses SIDS, suffocation, trauma, asphyxia, entrapment, arrhythmia, and metabolic conditions, among other causes of death (68).

For years, “apparent life-threatening event” (ALTE) was used to describe events that were frightening to the observer, which typically included presentation of apnea, color change, and marked change in muscle tone. In ALTE, the observer frequently feared that the infant could die or had died. In the past, ALTE was termed “near-miss SIDS.” However, evidence supports that fact that ALTE and SIDS are different and that ALTE does not increase the risk for SIDS. As such, the near-miss SIDS term is no longer used. Furthermore, children presenting with ALTE were ultimately found to have an underlying condition in 50% of cases. It is important to remember that ALTE is a subjective observer-experienced event (18).

In 2016, the term “brief resolved unexplained event” (BRUE) was introduced and recommended to be used instead of ALTE in infants with no explanation for the event after a history and physical exam, thereby adding the objective clinical exam to the definition. BRUE is defined as an episode occurring in an infant younger than 12 months and reported by the observer as brief (less than 1 minute) and now resolved (infant back to baseline), with normal vital signs, history, and physical examination at the time of assessment by a medical provider. If the observed episode does not fit the criteria for this definition, the guideline recommends further investigation. Infants with BRUE need to be risk stratified into low risk and high risk. The following characteristics identify low risk according to published guidelines: infants older than 60 days, gestational age more than 32 weeks, and postconceptional age more than 45 weeks; no history of prior BRUE; event duration of less than 1 minute; CPR was not required; and no concerning history or physical exam findings. High-risk infants with BRUE include infants younger than 2 months with recurrent episodes, unstable vital signs, abnormal history or physical exam findings, and a prolonged event or event requiring cardiopulmonary resuscitation (102).

Clinical manifestations

Presentation and course

	• There are no warning signs or symptoms for SIDS.
	• ALTE and BRUE have not been associated with SIDS.
	• High-risk BRUE infants should be identified in order to be appropriately treated.

Most SIDS victims appear to be healthy, free from significant health concerns, and are asymptomatic prior to death. Minor respiratory and gastrointestinal symptoms, as well as impaired cardiovascular control, have been reported in some cases, but are not thought to be causative of death. Hence, SIDS remains a diagnosis of exclusion in the sudden and unexpected death of an infant. Although specific identifiers cannot predict SIDS, there has been great focus on risk factors. Risk factors have been identified in relationship to the mother, the infant, and the environment. Maternal risk factors include young age, low socioeconomic status, higher parity, and smoking. Infant-associated risk factors include genetics (sibling of an infant who died of SIDS), prematurity, gender (increased in males), size at birth (small for gestational age), and sleep position (prone or lateral decubitus). Environmental risk factors include sleeping in car seats, soft bedding, bed sharing, and overheating.

Early autopsy findings in victims of SIDS have been documented in the medical literature, but none of these have been demonstrated on a consistent enough basis to be considered specific to SIDS. On autopsy, several features have been described that include intrathoracic petechia (08); thyromegaly, encephalomegaly, microcardia, light kidneys (Kelmanson 1992); and intracardiac unclotted blood, empty bladder, and mild fatty liver (10). Intrathoracic petechiae are present in approximately three-fourths of victims. Although some pathologists have concluded that petechiae are specific to airway obstruction, that speculation is not supported by a majority of pathologists.

Histologic investigation in SIDS cases should include the central nervous system (to distinguish non-specific changes such as hyperemia and edema from other findings leading to diagnosis of meningitis, trauma, or malformations), respiratory system (non-specific changes such as congestion and pleural hemorrhages or evidence of minor respiratory infection), and myocardium (ie, to rule out myocarditis or other cause of death) (05). Specifically, over 50% of SIDS cases have associated respiratory infections (04). A separate review of 200 cases for alternate histologic findings showed that approximately 10% of cases had alternative causes of death, including pneumonia, aspiration, metabolic disorders, sepsis, and meningitis (59).

Prognosis and complications

Most SIDS cases occur during the first 6 months of life without warning or alerting symptoms. There is no cure for SIDS as death is part of the syndrome. Some risk factors and protective factors have been identified. ALTE or BRUE have not been associated with SIDS. The main challenge for physicians is to decide when a child with BRUE requires further work up or hospitalization or is at risk of complications or recurrent events. Although most infants with ALTE or BRUE will have a benign course without any complications, 12% will require admission for further evaluation, and up to 24% will have a recurrent episode (09).

Fifty percent of children with ALTE have an underlying condition, with gastroesophageal reflux being the most common; other important conditions include seizures and respiratory infections (35).

The current guidelines recommend that parents of infants with low-risk BRUE undergo education and training in cardiopulmonary resuscitation and have scheduled follow-up visits. Infants can be discharged after brief monitoring. In some instances, electroencephalography and testing for pertussis can be indicated. High-risk infants with BRUE should be admitted for evaluation or treatment of the underlying condition (71).

Clinical vignette

A stable family was enjoying their second-born son who was full term and now eating well, gaining weight appropriately, and in overall good health. A few days earlier, he was seen by his pediatrician and found to be a healthy 3 month old. The pediatrician recommended that both parents quit smoking. One evening, the baby took his bottle of formula and was placed supine with a small stuffed toy to sleep for the night in his crib, per his usual routine. The parents slept well, but were surprised that he hadn't cried that night. When the mother came in to feed him, she was horrified to find him blue, cold, and not breathing. The mother started administering mouth to nose respirations to the baby while the father called the paramedics, who arrived within 5 minutes. Unfortunately, the first responders were unable to resuscitate the infant. The infant was then taken to the nearest hospital for an autopsy, which was unremarkable except for the demonstration of some petechiae on his thymus and pericardium. Based on these findings, a diagnosis of SIDS was made.

The hospital put the family in contact with a local SIDS parents' group, who counseled and comforted them as much as possible. They were told that it is impossible to predict SIDS, but that it was unlikely to recur in future babies. The parents later received the final autopsy report, which showed no inherited disease and no serious infection; the unexplained and unexpected death was, therefore, deemed SIDS. Their recovery from the grief of this tragedy was prolonged and difficult. Their physician advised them not to rush into another pregnancy to allow for their physical and emotional recovery.

Biological basis

Etiology and pathogenesis

	• The triple-risk hypothesis is commonly accepted.
	• The pathophysiology of SIDS is unknown.
	• Various pathophysiologic mechanisms have been postulated: respiratory, cardiac, and neurologic dysfunction.

Many theories regarding the mechanism of death in SIDS have evolved over the years.

The triple-risk hypothesis, a popular theory proposed in 1994 by Filiano and Kinney, suggests that SIDS can be attributed to a combination of the following:

	• An underlying vulnerability intrinsic to the infant based on potential abnormalities in serotonergic signals, arousal mechanisms, or cardiovascular reflexes
	• Age-related risk specific to a period of the child’s development based on known critical changes in cardiovascular response between the ages of 2 and 4 months
	• Environmental stressors based on studies and findings with overheating, bed clothing, and sleep position

Various physiology mechanisms have been studied and proposed to explain infant deaths.

Respiratory control of breathing dysfunction. The normal hypoxic ventilatory response in infants demonstrates a biphasic curve with an initial period of augmentation in ventilation followed by a sustained reduction in ventilation similar to or below normoxic ventilation. The response is sustained in infants up to 6 months of age. Based on the hypothesis of the critical period during development in which external exposures (ie, abnormal oxygen levels, smoke) can permanently alter the final responses of the system, 2 to 4 months of age represents a critical period for ventilatory control. Abrupt changes in multiple neurotransmitters over short periods of time can also result in temporary overall instability in the ventilatory control system (61). Regulation of breathing is controlled by respiratory centers in the brainstem. Studies have shown that during the first months of life, infants demonstrate increased numbers of central apneas (average index of 10 events per hour), which may represent immaturity of the respiratory centers. In fact, Lavezzi and associates have hypothesized that the expression of the pontine Kölliker-Fuse nucleus (KFN), which plays a critical role in breathing control and sleep-wake transition, is defective and, thus, contributes to sudden infant death (57).

One study has shown that healthy infants have an increased index of apneas and hypopneas (mean 14.9 per hour) during the first month of age (25) and nadir oxyhemoglobin saturations of 84.4%. This demonstrates that although infants could have apneas secondary to immature respiratory centers, it is still within expected and not associated with SIDS; further, it resolves quickly during the first months of life. It has also been hypothesized that the arousal response after the apnea, not the apnea itself, may be responsible for SIDS. Apneas are usually terminated by an arousal or a gasp. The arousal results in restoration of physiological parameters to levels of wakefulness or a lighter stage of sleep. A higher arousal threshold has been postulated as a possible contributor to SIDS. In particular, protective factors of SIDS, such as pacifier use and breastfeeding, are known to lower the arousal threshold. Cigarette smoking, high ambient temperatures, and infection are known to increase the arousal threshold, potentially prolonging the apnea and the associated gas exchange abnormality.

Cardiovascular dysregulation. Arrhythmias and cardiovascular disease have been suggested as potential causes of SIDS. Very early studies reviewed electrocardiac information from first-degree relatives of SIDS victims and found QT prolongation in 11 of 42 sets of parents (66), suggesting a heritable and long QT-associated cause of SIDS. The first direct electrocardiac evidence of long QT in SIDS victims was a study in 1998 by Schwartz and colleagues, which found 12 of 24 SIDS victims with prolonged QTc (> 440ms) in a cohort of 33,034 infants with 1-year follow-up data (87). Multiple studies have investigated and have found variable mutations with and without functional significance in genes related to long QT syndrome, sodium channels, and potassium channels, which are nicely detailed in a review by Wilders (100). However, a functional gene study of one such mutation in hERG channels in a family with recurrent SIDS found that the mutation did not result in a significant change in channel expression and function (88). This study brings into light the implications of misdiagnosis based on the finding of a mutation without consideration of its effect on function, as well as variability and penetrance of a genetic mutation.

Other causes of sudden death proposed by Wilders include short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT) such that “the prevalence of malignant cardiac ion channel-related mutations among SIDS victims may actually be close to 20%” (100). This concept is supported by a Danish study that suggested that up to 7.5% in a SIDS cohort (5/66) demonstrated genetic variations in sodium channel complex genes (101). A review by Evans and colleagues, however, shows no change in incidence when looking at possible cardiac ion channel mutations that have been implicated in SIDS (32). Additionally, Andreasen and colleagues found that many previously associated gene channelopathy variants were highly prevalent in the general population when looking at whole exome data (03).

One group of researchers demonstrated genetic variants in sarcomere genes in children with sudden unexplained death based on parallel sequencing of DNA and suggested the possibility of a correlation between SIDS and cardiomyopathy, but this link has not been definitively established (83).

In 2019, a study revealed that hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase subunit A (HADHA, tri-functional protein alpha) is required for fatty acid beta-oxidation and cardiolipin remodeling and is essential for functional mitochondria in human cardiomyocytes. Deficiency in this enzyme resulted in MTP-deficient newborns who presented with SIDS and can manifest after birth, once the child begins nursing on lipid-rich breast-milk (69).

Central nervous system dysfunction. A small study investigating cerebellar microvessel length as a marker of chronic hypoxia found no difference between SIDS cases and controls (72). A study showing cytoarchitectural alterations in both the auditory and respiratory centers of SIDS cases suggested a potential link in their development. Additional abnormalities of the brainstem described delayed loss of dendritic spines in the reticular substance, subtle abnormalities of neurotensin binding sites in the brainstem, abnormalities in vagal nuclei, and decreased muscarinic receptor binding in the arcuate nucleus. However, Duncan and colleagues reported what they regarded as specific deficiencies in medullary serotonin (31), but failed to consider that these deficiencies could have been caused by increased serotonin consumption associated with trying to survive. Support for this is the presence of breakdown products from serotonin in the spinal fluid of victims (17). Others found no correlation between pathologic data on serotonin and earlier physiologic studies of these infants who subsequently died of SIDS (84). Evidence that the changes in the vital serotoninergic system are simply depletion resulting from attempts to survive the hypoxic injury may be seen in the increase of interleukin-6 in the cerebrospinal fluid in SIDS victims and in the arcuate nucleus of the medullary 5-HT system (81). Also, serotoninergic system abnormalities in SIDS infants are associated with clinical risk factors, including smoking, bed sharing, and sleep position (60) as opposed to a prenatal cause as suggested by Paterson and colleagues (78). Guntheroth and colleagues concluded that it was not possible to prove or disprove that these abnormalities originated before birth and that the epidemiologic evidence favors a postnatal origin (43; 44; 85).

Age at death versus mortality for congenital anomalies and sudden infant death syndrome

Age at death in days versus mortality per 10,000 live births for congenital anomalies (open circles) and sudden infant death syndrome (closed circles). If sudden infant death syndrome were due to a prenatal origin, it would likely...

In addition, studies of infants who subsequently died of SIDS demonstrated no defects in ventilatory responsiveness during the first week of life (96); if the brainstem abnormalities had occurred before birth, this neonatal testing should have revealed abnormal responsiveness during the first week of life rather than a couple of months later.

Neurotransmitter abnormalities. The serotonin deficiency theory has been popular as an explanation of SIDS. Kinney’s work ties together the features of impaired autonomic function and respiratory control through the medullary serotonergic system (Kinney and Filiano 2001; 54). Others, however, suggest that the deficiency is more likely to represent consumption of serotonin in the process of trying to autoresuscitate (44; 91). Some studies have found no significant differences in serotonin transporter gene encoding or expression, or in serotonin breakdown products, when comparing SIDS cases and controls (75; 82). Although a clear connection between SIDS and serotonin has not been made, the essential role of the 5-HT2A receptor in carbon dioxide–induced arousals described in an article illustrates why the field has maintained its interest in this pathway (15; 47).

An additional study by Huang and colleagues evaluated the expression of pituitary adenylate cyclase activating polypeptide (PACAP) and its complementary pituitary adenylate cyclase activating polypeptide type 1 receptor (PAC1) in the brainstem, as they are known to function in central respiratory control (50). They found that in non-SIDS- versus SIDS-related deaths, there was decreased expression of the PAC1 receptor in the arcuate nucleus of the rostral medulla. One of the functions of the arcuate nucleus is in sensing carbon dioxide levels in the blood. Lower expression of PAC1 may, therefore, contribute to a defective response to hypercapnia stresses in SIDS infants.

Additionally, the neuropeptide substance P, which is implicated in functions of respiratory rhythm generation and reflex response to hypoxia, has been studied in relation to SIDS. Bright and colleagues noted decreased neurokinin-1 receptor binding of substance P in SIDS cases as compared to non-SIDS controls (14). Dysregulation of this mechanism is thought to affect both respiratory regulation and arousal responses to contribute to the incidence of SIDS. However, this study was limited by small sample size. Findings should be replicated in other studies to better understand the significance of these findings.

Impaired function of the orexin system has been hypothesized as a possible contributor for SIDS. Although the exact mechanism has not yet been mapped, a study conducted by Dergacheva and colleagues showed continued hypoxia- and hypercapnia-induced hyperpolarization, accompanied by rapid depression, and then cessation of firing activity in orexin neurons. This type of orexin neuron depression has been seen in individuals with obstructive sleep apnea and SIDS (30).

Altered immune response. Histologic evidence of minor respiratory infection is present in a majority of SIDS autopsies, and viral isolates can be obtained at a rate several times higher than that seen in living controls. The role of infection and an enlarged thymus have been revised in a study comparing the weight of the thymus of infant victims of SIDS with the weight of the thymus of controls who died of trauma (38).

Several studies have found an association between the anti-inflammatory cytokine interleukin-10 and SIDS (27), suggesting that these victims may have an inadequate inflammatory response to infection. The genetic pathway to this cytokine has been examined, but no association with SIDS has been found (24).

Studies from Norway and Germany investigated the C4 gene in victims of SIDS. However, neither was able to detect any differences between SIDS and control cases with regards to gene frequencies. In contrast, both studies showed an association between mild infection before death and partial deletions of either the C4A or C4B gene, suggesting that this combination can increase the risk of SIDS (86; 76). Partial deletions of the C4 gene are fairly common and are found in up to 20% of the Caucasian population (74).

Because minor infectious diseases are associated with SIDS, keeping the routine vaccination schedule is recommended for all infants. In fact, a meta-analysis showed that immunizations are actually associated with a halving of the risk of SIDS (95).

Skeletal muscle abnormalities. There is evidence implicating sodium channelopathies in skeletal muscle in SIDS cases. Researchers have found rare mutations in the SCN4A gene, which encodes the NaV1.4 voltage gated skeletal muscle sodium channel, in SIDS cases that were not found in matched controls (65). Both gain-of-function and loss-of-function mutations in the SCN4A gene have previously been implicated in neurologic disorders such as myotonia and congenital myasthenic syndrome. The NaV1.4 channel is thought to be crucial to the function of fast twitch respiratory muscles, particularly in situations such as hypoxia, which place increased demand on these muscles. Although Mannikko and colleagues conducted functional gene studies and noted that there was decreased current density in the mutated gene, these studies were only conducted in vitro and will need to be further studied for clinical significance.

Genetic abnormalities. The possibility of polygenic or polymorphic contributions to SIDS cannot be dismissed, given the 50% excess of males for SIDS and in deaths from respiratory illnesses and congenital heart disorders that result in severe hypoxia. Mage and Donner hypothesize the common factor as terminal hypoxia with failure to protect against cerebral anoxia arising from a dominant allele on the X-linked gene (62). Their model also predicts the 25% male excess for all infant and child mortality for the first 5 years of life. But from the perspective of Mendelian inheritance, there is no evidence that SIDS is familial, considering the recurrence rate of only 1.3% (41), which suggests a stronger role for de novo mutations. Based on epidemiology and pathologic findings, genetic studies have focused on the serotonergic system, nicotinic system (based on the link with tobacco smoke exposure), the autonomic nervous system related to impairment in cardiorespiratory function, including cardiac channelopathies (SCN5A being most prevalent), and inflammation. Ferrante and colleagues further support a possible genetic mutation link in SIDS cases (33). Their findings indicate that as compared to controls, SIDS cases exhibit altered expression of a number of genes that are involved in the inflammatory process.

Epidemiology

	• The rate of SIDS has declined with the implementation of prevention measures.
	• There are increased risk factors for SIDS.
	• There are preventive factors for SIDS.

SIDS rates have declined considerably from 130.3 deaths per 100,000 live births in 1990 to 35.2 deaths per 100,000 live births in 2018. This decline is largely due to the “back to sleep” campaign, which focuses on the prevention of SIDS by recommending that parents put infants to sleep on their backs. Although the incidence is typically considered to be less than 1 per 1000 live births, it is on average 2 to 3 times higher in African-American and American Indian/Alaskan natives. The rate has also been found to be disproportionately higher in childcare settings (15% to 20% of cases) and is more common in boys (odds ratio 1.49). The occurrence of SIDS peaks between 2 to 4 months of age and diminishes rapidly thereafter. SIDS is uncommon after 6 months.

Different risk factors in sleep environment have been found in the younger, 0- to 3-month population (bed sharing, sleeping in an adult bed) and the 4 month and older population (objects present in the sleeping environment) (23). By consensus, 12 months of age is regarded as the upper limit for inclusion.

On average, the victims are smaller than normal infants and prematurely born; however, small-for-gestational-age infants are at increased risk of SIDS, but only slightly. Other residual abnormalities resulting from prematurity create 2.5 times greater risk of SIDS, with the increase primarily in preterm infants born between 24 and 28 weeks (64; 63).

The risk of SIDS is strongly affected by the sleep position of the infant: the highest risk is for the prone position, and the lowest risk is for the supine (28; 42). Prone sleeping increases the amount of time sleeping, particularly in quiet sleep, and reduces spontaneous arousal and arousal to a variety of stimuli (49). Moreover, a study from Tasmania showed that the risk of SIDS associated with prone sleep increased 10-fold when there was a concurrent infection (99). A Nordic study also showed a 29-fold increase in risk due to prone plus infection (48; 26).

In addition to sleep position, sleep location has also been noted to be associated with SIDS. Rechtman and colleagues demonstrated that 12.9% of a SIDS cohort was noted to be sleeping on a sofa and that these deaths were also associated with additional SIDS risks: prenatal tobacco smoke exposure, sleep surface sharing, and a new sleep location (79). Altitude has also been associated with an increased risk of SIDS (OR 2.3; 95% CI 1.01-5.24) (52).

Maternal smoking is associated with a doubling of the risk for sudden infant death. A meta-analysis found that the risk is associated with pre- and postnatal maternal smoking and appears to be dose dependent (103). A potential pathway for this finding is suggested by a study showing impaired chemoreception in neonatal rats with cigarette smoke exposure, though this effect was only noted with under acidotic conditions (58). The risk associated with prenatal cigarette smoke exposure, as with the risk associated with alcohol or drug use, is further increased when associated with bed sharing (20). Infants of substance-abusing mothers are also at substantial risk. The infants of women on methadone programs have an increased risk of SIDS, particularly if the mother smokes (16). Along these same lines, hypoxic challenges in neonates demonstrated alterations in change in minute volume in children with either cigarette smoke exposure or substance abuse (02). A study showed that 12/32 (37.5%) of a SIDS cohort were born to mothers who used methadone and/or other drugs of abuse during pregnancy (21). The presence of additional SIDS risk factors in these cases, however, made it difficult to know how much of an impact the drug exposure had. This highlights the importance of identifying and educating parents who use drugs about how to limit additional risk factors in their high-risk infants.

Infants that die of SIDS tend to be formula-fed rather than breast-fed. A large meta-analysis across 8 countries studying 2267 SIDS cases and 6837 controls suggested a minimum requirement of 2 months breastfeeding for protective effects against SIDS (93).

The great majority of victims of SIDS are asleep at the time of death. Two exceptions are infants with gastroesophageal reflux and those with seizure disorders, which typically produce prolonged apnea. Sedatives or tranquilizers in cough suppressants have been found to increase the risk of SIDS, presumably by depressing arousal (80).

Heat stress has been implicated in several studies (67). The head is a major heat exchanger, and covering the head produces a remarkably high odds ratio for sudden infant death (34).

Bed sharing has been implicated in infant deaths for centuries; the inference has usually been that the infant suffocated from being overlain. Sofa sharing is a particularly risky form of bed sharing (67), which is made worse by alcohol or drug use before co-sleeping (11). It is additionally postulated that the mechanism of death is different in co-sleeping infants as compared to alone sleepers due to higher levels of medullary astrogliosis in alone sleepers (90). Astrogliosis is a marker of injury that builds up over time and suggests that the mechanism of death in these infants, such as accidental suffocation, is a rapid process and does not allow time for reactive astrogliosis.

Prevention

	• Infants must sleep on their back.
	• The sleeping environment must include room sharing but not bed sharing, use of a firm sleep surface, and no loose bedding.
	• Breastfeeding is recommended.
	• No smoking, alcohol, or drugs are allowed during pregnancy and after birth.
	• Offer the infant a pacifier at naptime and bedtime.
	• Avoid overheating.
	• Seek prenatal care.
	• Immunize the infant according to American Academy of Pediatrics recommendations.

Several epidemiologic studies indicate risk factors for SIDS, many of which are amenable to intervention, and a full list of recommendations is found in alphabetical order in Table 1. The American Academy of Pediatrics released an updated policy statement in 2016 reaffirming many of these recommendations (71).

Judging by the dramatic decrease in SIDS rates in most countries that have mounted "Back to Sleep" campaigns, prone sleeping is the single most important risk factor that is amenable to intervention. Although overall incidence of SIDS has significantly decreased with the “Back to Sleep” campaign, there continue to be racial disparities in SIDS incidences: the higher rates found in American Indian/Alaska Native populations, followed by non-Hispanic blacks, and Hispanics; the lowest rates are found in Asians/Pacific Islanders (77). Similar campaigns related to sleep location, rather than position, have been far less successful, likely related to social and cultural differences (06).

Another preventive factor is the use of a pacifier, particularly for formula-fed infants (70). How pacifiers reduce the risk for SIDS has not been agreed on, but a New Zealand study found that pacifiers produce a small but significant forward displacement of the jaw that may protect the upper airway in a manner similar to mouthpieces used for obstructive airway disorders in adult sleep apnea (94).

The American Academy of Pediatrics recommends against the use of home cardiorespiratory monitors in infants. They have not shown to decrease the incidence of SIDS. Routine in-hospital cardiorespiratory monitoring before discharge also has not been shown to detect infants at risk for SIDS. There are no data supporting the use of any commercial devices designed to monitor infant vital signs to reduce the risk of SIDS.

Smartphone integrated consumer baby monitors that measure vital signs are not regulated by the FDA. A study from 2017 measured the accuracy of pulse oximetry-based consumer baby monitors by comparing it with an FDA-cleared oximeter (13). They studied two of these consumer baby monitors that use pulse oximetry in infants 0 to 6 months hospitalized in general pediatrics and the cardiology service who were born after 34 weeks of gestation, not critically ill, not anemic, not febrile, and with stable vital signs. The first monitor detected hypoxemia (sensitivity and specificity of 88.8% and 85.7%, respectively) but performed inconsistently, and the other monitor never detected hypoxemia and also displayed falsely low pulse rates (sensitivity and specificity for hypoxemia were 0.0% and 100.0%, respectively, and for bradycardia were 0.0% and 82.3%, respectively) (13).

Another important intervention to prevent SIDS is education via preventive campaigns. The campaigns on “back to sleep” have proven to be very effective. Pediatricians and other healthcare professionals, beginning with staff in newborn nurseries and Neonatal Intensive Care Units, should educate parents on the recommendations listed in Table 1 (92).

Table 1. Risk Factors Potentially Amenable to Intervention in SIDS

Risk factor	Intervention suggested
Arousal depressed in infant	Avoid sedatives, sleep deprivation
Bed sharing	Crib for infant in room with adult
Cigarette smoking	Smoking cessation
Failure to recognize illness or cyanosis	Baby sleeps supine in crib located in parents’ bedroom
Formula feeding	Breastfeeding*
Hypoxia in premature infants	Oxygen supplement for low saturations at home
Immunization failure	Immunize infants*
Infections, particularly febrile	Identification and treatment of underlying cause
Maternal depression	Diagnosis and treatment*
Not using pacifiers	Consider use of pacifiers
Pillows, stuffed animals, positioning devices, or heavy blankets in bed	Avoid
Poverty, uneducated mothers	Addressing disparities, maternal education*
Prenatal care absent or late	Early care (direct effect)*
Prolonged apnea	Work-up including EEG, polysomnography, evaluation for gastroesophageal reflux
Prone or side sleep position, especially if novel for the infant	Supine sleep position, always
Short inter-pregnancy interval	Pregnancy interval greater than 6 months*
Sleep	Avoid sleep disruption or deprivation, and encourage a regular infant sleep schedule
Substance abuse, maternal	Avoidance, counseling*
Thermal stress: excess insulation, heated room, head covered	Avoid
Young, unwed, multiparous mother	Contraception, sex education
* Designates interventions that reduce all infant mortality

Management

Outcomes

	• There is no treatment for SIDS.
	• Management is aimed toward care and support of the family.
	• Education of caregivers and healthcare workers is important for the prevention of SIDS.
	• Future research is needed.

There is no treatment for SIDS as death is the outcome. The main focus is care and support of the family who have lost a child, as the grief that follows can be prolonged and difficult. For most, support from health care professionals and relatives is sufficient to help families during this time of grief (12). However, approximately 10% to 15% of parents can experience a serious disruption in emotional stability, which can lead to poor physical and psychosocial outcomes (73; 98).

A review in 2020 identified 5 overarching components in bereavement interventions: 1) acknowledgement of parenthood and the child’s life, 2) establishing keepsakes, 3) follow-up contact, 4) education and information, and 5) remembrance activities (56). The limitation is that although these studies described the methodology, experience, and specific intervention, there are no data to describe efficacy. Because most interventions lacked empirical evidence, they were evaluated against key concepts, which showed that all the components of intervention had a theoretical basis. The group concluded that interventions should focus on the continuous transition process parents experience in readjusting to a new reality (56).

A study in 2020 showed that 98.6% of bereaved mothers who lost their child from SIDS reported having transitional objects of grief, such as saved objects of their deceased child (37). Mothers diagnosed with prolonged grief disorder visited these transitional objects more frequently and had more distress, especially when visited privately. However, mothers with prolonged grief disorder who felt comforted by the objects had lower risk of either finding life meaningless or finding discussion about the infant intolerable. As such, more research is needed to understand the potential therapeutic use of transitional objects in promoting bereavement adjustment (37).

In order to prevent SIDS, multiple attempts have been made to educate medical personnel and parents about infant safe sleep practices. Some of these attempts included providing educational videos and brochures, modeling safe sleep practices in the hospital, enforcing hospital safe sleep policies, computer-based training, and written and visual instructions for parents and healthcare workers (97). However, even with these specific interventions, a survey of 3297 mothers from 32 U.S. hospitals in 2017 still report having received either no advice or incorrect advice regarding safe sleep practices (22). In addition, none of these studies included trained participants who were tasked to arrange a completely safe sleep environment or a predetermined performance criterion to objectively assess their knowledge (97).

Indirect measures such as self-report or questionnaires were used instead to assess the effectiveness of interventions, which can be problematic because participants may report increased knowledge or adherence to safe sleep practices without being able to demonstrate this in real life (01). Therefore, direct measurement of behavior seems to be a better strategy for the evaluation of effectiveness of interventions.

To address this issue, researchers presented behavioral skills training (BST) as a possible strategy. This is an evidenced based teaching strategy that involves instructions, modeling, rehearsal, and feedback. To enhance the applicability of behavioral skills training, a simulation environment may also be used to approximate a naturalistic setting. The use of behavioral skills training has also demonstrated more robust outcomes compared to traditional educational approaches (36). In a study from 2020, behavioral skills training significantly improved appropriate arrangement of a safe sleep environment for 8 infants (19). Notably, however, the participants were students, rather than parents or caregivers, and the small sample size limits the generalizability of these results. Regardless, these represent insightful data that warrant further investigation in a larger group of participants.

Lastly, future research on SIDS remains important in our continued learning and can help support recommendations, better educate parents and healthcare workers, and focus efforts into strategic action. The Global Action and Prioritization of Sudden Infant Death Project was an international consensus that aimed to guide future research. The three main themes among priorities identified are: 1) better understanding of mechanisms underlying sudden unexpected infant death (SUID); 2) ensuring best practice in data collection, management, and sharing; and 3) a better understanding of target populations and more effective communication of risk (46).

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All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Lourdes M DelRosso MD PhD

Dr. DelRosso University of Washington School of Medicine has no relevant financial relationships to disclose.
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Michelle Y Sobremonte-King MD

Dr. Sobremonte-King of the University of Washington School of Medicine has no relevant financial relationships to disclose.
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Editor

Antonio Culebras MD FAAN FAHA FAASM

Dr. Culebras of SUNY Upstate Medical University at Syracuse has no relevant financial relationships to disclose.
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Former Authors

Philip S Spiers PhD, Warren G Guntheroth MD (deceased), Pallavi P Patwari MD, Ryan Coates MD, Darius A Loghmanee MD, Matthew Balog MPH, and Usha S Appalaneni MD

Patient Profile

Age range of presentation: 0 to 12 months
Sex preponderance: male>female, >1:1, excess of 50% (Mage and Donner 2004)
Heredity: none
Population groups selectively affected: African Americans

Native Americans
Occupation groups selectively affected: none selectively affected

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Sudden infant death syndrome

Associated Disorders

Autonomic dysregulation

Differential Diagnosis

suffocation
infection
arrhythmia
trauma
metabolic disease
- entrapment
- asphyxia
- cystic fibrosis
- hepatitis
- encephalitis
- arteriovenous malformation with hemorrhage
- congenital adrenal hyperplasia
- pulmonary hypertension
- congenital heart disease
- myocarditis
- sepsis
- bronchiolitis
- pneumonia
- meningitis
- enterocolitis
- metabolic diseases
- child abuse

	• The diagnostic workup in the evaluation of victims of SIDS includes a full clinical history.
	• The full report from first responders provides valuable information about the environment and circumstances of the infant’s death.
	• Autopsy, including laboratory work up, is mandatory.

Sudden infant death syndrome

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Table 1. Risk Factors Potentially Amenable to Intervention in SIDS

Differential diagnosis

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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