Pediatric Potpourri: State of the Art 1996 University Children's Medical Group
Maui, Hawaii / February 18, 1996

Sudden Infant Death Syndrome

Thomas G. Keens, M.D.
Childrens Hospital Los Angeles

Reprinted with permission

"And this woman's son died in the night because she lay on it." 1 Kings 3: 19.

INTRODUCTION.

For nearly 3,000 years, it has been recognized that apparently healthy infants could die suddenly and unexpectedly, usually during their sleep. Throughout most of history, it was believed that these infants somehow suffocated, either by maternal overlaying or by strangling in bedclothes. Although these explanations have been discarded, two per thousand infants continue to die suddenly and unexpectedly.

Sudden infant death syndrome (SIDS) is the sudden death of an infant under one-year of age which remains unexplained after performance of a complete postmortem investigation, including an autopsy, examination of the death scene, and review of the case history 1.. SIDS is the most common cause of death in infants between the ages of one-week and one-year, affecting about one out of every 500-600 live births 2,3.. This accounts for 6,000 to 10,000 deaths in the United States per year, or 20 to 30 per day. In California from 1974-88, the mean SIDS rate was 1.54^6^1^0.10 [SD] per 1000 live births (Table 1) 4.. Unfortunately, SIDS is not a rare occurrence in the general population. The peak incidence is between 2 and 4 months of age. Approximately 95% of SIDS deaths occur before the age of 6-months, but SIDS deaths can occur until one-year of age 2,3..

A typical clinical course for a SIDS death is that the parents or caregivers leave the infant to go to sleep, either at night or during a daytime nap 2,3.. They return at some later time to find that the infant has died unexpectedly. Usually, these infants were healthy prior to death, although some had evidence of a mild upper respiratory infection, or recently had some other physical stress prior to death.

SIDS deaths have occurred when parents or caregivers have placed their infants down for a nap, have been within hearing distance of the infant the entire time, and have returned as briefly as 20-30 minutes later to find that their infant has died. Yet, these parents report hearing no signs of a struggle. Thus, SIDS deaths appear to occur swiftly and silently.

ONE CAUSE OR MANY?

Does SIDS have one cause or many causes? By definition, the etiology of SIDS is not known 1,2,3.. In approximately 15%-20% of infants who die suddenly and unexpectedly, a conventionally accepted cause for the death is found at postmortem examination. These infants are not said to have died from SIDS, but rather from the cause of death found. This leaves 80%-85% of infants who died suddenly and unexpectedly in whom no cause of death can be found at postmortem examination. These infants comprise the group called SIDS. Unfortunately, it is not known if this group is homogeneous 2,3..

SIDS has often been referred to as a diagnosis of exclusion. That is, the pathologist looks for identifiable causes of death. If none are found, then, by exclusion, the diagnosis of SIDS is made. This would imply that there may be many causes of sudden death in infants which go unexplained, and thus SIDS may have many causes 3.. On the other hand, there are some unique and characteristic features about most SIDS deaths which suggest that most babies dying from SIDS die from the same final common mechanism or final common pathway of death 2.. These unique features include:

1. A unique age distribution. The peak incidence of SIDS is between 2 and 4 months of age. Infants are relatively spared in the first few months of life, and 95% of SIDS deaths occur before 6 months of age. This is contrary to other natural causes of infant mortality where the rate is highest near birth, and decreases thereafter 2,3..

2. A unique seasonal distribution. SIDS is more common in winter months and less common in the summer. Other natural causes of infant death do not share this unique seasonal distribution 2,3..

3. SIDS victims are generally healthy infants. There is usually no evidence of chronic disease 2,3..

4. Usually, the post-mortem examination reveals characteristic autopsy findings. While these findings are not present in all SIDS victims, and they do not provide an explanation for the cause of death, they are observed in a high proportion 2..

There is not a consensus on the question of whether SIDS represents one final common mechanism of death, or many. We believe that epidemiologic evidence favors the hypothesis that the majority of SIDS victims died from a single common mechanism of death, although many "causes" may have led an infant into that final common pathway.

EPIDEMIOLOGIC STUDIES.

Epidemiologic studies have been performed in an attempt to identify risk factors for SIDS 2,3.. SIDS deaths are more frequent in winter months. There is a unique age distribution. SIDS is more common in lower socioeconomic groups.

Maternal factors associated with a statistically increased risk for SIDS include: cigarette smoking or substance abuse (specifically opiates or cocaine) during pregnancy 5., teen-aged and older mothers, short inter-pregnancy intervals, delay in initiating prenatal care, low blood pressure during the third trimester of pregnancy, and high or low hemoglobin during late gestation. Although these studies do not point to a specific etiology, they suggest that infants who had a suboptimal intrauterine environment may be at a higher risk of dying from SIDS.

Infant factors which are associated with a statistically increased risk for SIDS include: preterm infants 6., low birthweight infants 6., slower or delayed growth during infancy, and multiple gestation (twins, triplets, etc.) 7,8,9.. Not uncommonly, SIDS deaths are temporally associated with viral respiratory infections 2,3..

POST-MORTEM EXAMINATION IN SIDS.

By definition, an identifiable cause of death is not found at post-mortem examination 1,2,3.. The autopsy of a SIDS victim shows the absence of other serious illness which could contribute to the death, no signs of severe illness, and no signs of significant stress. However, common post-mortem findings in the SIDS victim are: intrathoracic petechiae; pulmonary congestion and edema; minor airway inflammation; minimal stress effects in the thymus and adrenal glands; normal nutrition and development; fluid blood; and an empty urinary bladder 2.. The significance of most of the latter four of these findings is that these infants were generally healthy prior to death. The autopsy should be performed by a qualified pathologist.

Using research techniques, Naeye and others have found tissue markers in many SIDS victims suggesting that they may have been chronically hypoxic or hypoxemic prior to death 10,11,12,13.. Some of these findings have been confirmed by other laboratories, but many have not been confirmed. Whether or not these actually are present in a majority of SIDS victims remains controversial, and the object of continued study. Kinney and others have found gliosis and subtle changes in brainstem centers responsible for control of breathing and control of sleep/wakefulness cycles 12,14,15.. These findings suggest that the origins of SIDS may lie in abnormal control of breathing or abnormalities in regulation of sleep/wakefulness 3..

A common finding in SIDS victims is the presence of intrathoracic petechiae on the thymus, lungs, pleural surfaces, and occasionally the heart 2,16,17.. Extrathoracic portions of the thymus do not show petechiae. These intrathoracic petechiae may have been formed by the generation of highly negative intrathoracic pressures, as might occur when an infant attempts to breathe against upper airway obstruction 17.. Intrathoracic petechiae suggest that obstructive apnea may be involved in the final mechanism of SIDS deaths 17..

It must be emphasized the neither epidemiologic studies nor the post-mortem findings have resulted in a generally accepted cause for SIDS. The cause remains unknown 1,2,3., though current research efforts are making advances in our knowledge which may ultimately lead to this answer. WHY DO SIDS VICTIMS DIE?

In SIDS victims, there are only a few theoretical mechanisms of death, including:

1. Cardiac causes (cardiac arrhythmia).

2. Respiratory causes (central or obstructive apnea).

3. Other physiologic or metabolic crises.

EVIDENCE FOR CARDIAC CAUSES OF SIDS.

When one thinks of sudden death, the heart is often the first focus of attention. Cardiac arrhythmia can cause sudden death, but are not likely to be detected at post-mortem examination 3.. The Long Q-T Interval Syndrome can cause intermittent lethal ventricular fibrillation, though it remains controversial whether this is an important cause of SIDS. Recently, physiologic recordings of death have become available form infants who had apnea-bradycardia monitors at the time of a SIDS death. These suggest an abrupt bradycardia as the cause of death in these infants 18.. However, there is some debate over the interpretation of these tracings. Finally, studies have shown decreased beat-to-beat heart rate variability in infant at high risk for SIDS, and in infants who have died from SIDS 19,20. However, these results are interpreted as abnormal autonomic nervous function controlling heart rate variability, rather than a primary cardiac abnormality. Research into the potential role of the heart in SIDS continues. However, there is not a lot of evidence favoring primary cardiac causes of SIDS.

EVIDENCE FOR RESPIRATORY CAUSES OF SIDS.

The infant respiratory system is developmentally immature and rapidly changing. From an engineering perspective, a rapidly changing system is intrinsically unstable. Neurologic control of breathing is abnormal. Ventilation is depressed by hypoxia, and immature reflexes cause apnea. Immaturity of the lungs predisposes to atelectasis, airway obstruction, pulmonary hypertension, and edema. The upper airway is predisposed to collapse, causing obstructive apnea during sleep. Chest wall instability causes decreased lung volume and increased work of breathing. Ventilatory muscle strength and endurance are decreased, resulting in ventilatory muscle fatigue. Thus, normal infants, without increased risk for SIDS, can have apneas up to 15-seconds duration during sleep.

Cessation of breathing (apnea) can cause sudden death, which may not be detected at post-mortem examination. Infants with unexplained apnea have an increased risk of dying from SIDS 21,22,23,24,25.. Tissue markers of chronic hypoxia and hypoxemia have been described in many SIDS victims by some investigators 10,11,12,13.. Brainstem lesions have been seen in areas controlling respiration and sleep/wakefulness in many SIDS victims 16,18,19.. Many infants at high risk for SIDS have respiratory control disorders 21,22,26,27.. While these findings do not prove that SIDS is due to a respiratory disorder, there is considerable circumstantial evidence suggesting that SIDS may involve central or obstructive apnea during sleep 3..

The circumstantial evidence in favor of respiratory causes for SIDS prompted many investigators to formulate the apnea hypothesis of SIDS. The simplistic version of this hypothesis says:

1) SIDS occurs when infants stop breathing during sleep 3,21,22,23,24,25,26..

2) One can test infants to see if they have apneas.

3) Infants with increased apnea during sleep are at high risk for SIDS and should be treated or protected 21,22.. Home apnea-bradycardia monitoring, which sounds an alarm to summon trained parents when an infant has a prolonged apnea or bradycardia, has been advocated as the preferred method to protect these infants 22..

However, relatively few SIDS victims had any previous apneas observed prior to death 28,29.. Prospective studies of the sleeping ventilatory pattern do not predict SIDS or death in infants 24,30,31.. Home apnea-bradycardia monitoring and infant apnea evaluations have not substantially decreased the SIDS rates for the general population. Thus, the simplistic approach to treating apnea in infants has not resulted in decreases in SIDS. However, it is still possible that SIDS involves a respiratory disorder.

THE AROUSAL DISORDER HYPOTHESIS OF SIDS.

Arousal from sleep is an important defense mechanism against danger-signaling stimuli during sleep. The inability to arouse from sleep in response to an apnea or hypoxia could prevent the infant from terminating an apnea, resulting in death 27.. The process of changing from sleep to wakefulness (arousal) is associated with many changes in respiratory system which improve breathing. Thus, arousal is a logical defense mechanism to protect breathing during sleep.

Preliminary evidence suggested that infants at high risk for SIDS had abnormal arousal responses to low oxygen (hypoxia) 27,32.. These same infants also had alterations in their catecholamine metabolism 33.. However, recent studies show that normal control infants often fail to arouse in response to hypoxia 34.. Normal infants arouse frequently under 9 weeks of age, but not between 9 weeks and 6 months of age 34.. This corresponds to the age distribution for SIDS. It is possible that infants are born with a protective brainstem hypoxic arousal response which is inhibited by increasing cortical influences after 2 months of age. However, this is all quite preliminary and theoretical, and a great deal more work is required to establish a link between these altered arousal patterns and SIDS 27,32,33,34,35..

VULNERABILITY TO SIDS.

If SIDS were as simple as one abnormality in one system, the major research thrust directed toward solving the mystery of SIDS would likely have answered the question by now. Thus, SIDS must be more complex than a single abnormality in a single physiologic system. This has major implications for determining the vulnerability of individual infants to SIDS. There are three possible ways to view vulnerability of individual infants to SIDS:

1. Some infants are vulnerable and some are not.

2. All infants are vulnerable, but some they are more vulnerable at specific ages.

3. All infants are vulnerable, but some infants are more vulnerable than others.

The mechanism of SIDS remains unknown. Until recently, the most common research hypotheses about SIDS were that certain infants were abnormal, and thus predisposed to die from SIDS; i.e., some infants were vulnerable and some were not. Vulnerable infants, then, were destined to die regardless of what happened to them. Recent data suggest that the environment, age, and differences between infants may all play a role in SIDS. This has fundamentally changed the way we view SIDS, and what now becomes important is the interaction of at least three factors:

1) Development: SIDS is most common between the ages of 2-4 months. Thus, all infants may face a developmental window of increased vulnerability for SIDS during this age. It would take less of an environmental stress to cause SIDS in an infant during this age than if the infant was younger or older.

2) Infant Physiologic Responses: All infants have physiologic responses to various stresses or challenges. For example, infants increase breathing in response to low oxygen. However, some infants will increase breathing more than other infants. Infants increase heart rate in response to exercise or work. However, some infants will increase heart rate more than other infants. Although all infants have these responses, the magnitude of these responses differs between infants. Those infants with brisker responses may be able to tolerate greater environmental stresses or challenges than those with lesser responses. These differences do not define normal compared to abnormal responses. However, differences in some responses may mean that all infants are vulnerable to SIDS, but some infants are more vulnerable than others.

3) Environmental Factors: Infants are constantly challenged by changes in their environment to which they must respond. For some infants, prone sleeping may cause sufficient compromise that SIDS can occur, especially if it occurs during the 2-4 month age. For other infants, prone sleeping would pose little danger, especially over 6-months of age. Respiratory infections, overheating, swaddling, sleeping prone in soft bedding, and other stresses are variable environmental challenges which may cause SIDS in some infants, but not in others.

Thus, SIDS is likely to be a multifactorial problem requiring the interaction of many components to cause death. For example, SIDS may start with a more vulnerable infant with subtle decreases in physiologic responses. Then, the infant may need to be at an age when infants are increasingly vulnerable, such as three months of age when the respiratory system is unstable in all infants. Then, SIDS may require an environmental stress, such as an upper respiratory infection. Sleeping position may be an additional contributing factor to such an infant, even if it makes no difference to breathing in an otherwise healthy infant at a younger or older age.

REDUCING THE RISKS OF SUDDEN INFANT DEATH SYNDROME.

It is important to emphasize that SIDS can not, based on current knowledge, be prevented. However, it is possible that the risks for SIDS can be reduced in individual infants, although there is no consensus on whether this can occur. SIDS clearly has not been completely prevented, even in countries where interventions have reduced the risk in some infants. Possible ways to reduce the risk of SIDS would be to intervene in one or more of the three interacting components:

1. Development: In order to reach the age of one-year, all infants must pass through 2-4 months of age. Thus, the age of highest risk can not be avoided. However, it is conceivable that one would concentrate potential interventions in this high risk age range.

2) Infant Physiologic Responses: Some infants may be at higher risk for SIDS because of variations their physiologic responses, even if these responses are not abnormal. Thus, potential interventions might target infants identified as being at higher risk. To date, no test or group of tests accurately predicts which infants will die from SIDS. Therefore, it is not possible to accurately target the highest risk infants. Some groups of infants with relatively high risks which do receive diagnostic testing and/or management include: apnea of infancy, preterm infants, and siblings of SIDS victims.

3) Environmental Factors: Some environmental factors may increase the risk of SIDS for some infants. Currently, there is no consensus on how much reduction in the SIDS rate is possible by eliminating or reducing certain environmental factors. However, it may be prudent to introduce promising interventions which have little risk, such as infant sleeping position (see below). It is likely that no intervention will be uniformly effective in all infants, but some may have differential effects at different ages or in infants with differing risks.

INFANT SLEEPING POSITION AND SIDS.

Since 1985, investigators from around the world have suggested that infants who sleep on their stomachs (prone) may have a higher risk of dying from SIDS than those who sleep on their sides or their backs. In response to these reports, some countries, notably Australia, England, and the Netherlands, initiated public education campaigns designed to change the sleeping practices of infants in order to reduce the SIDS rate. These campaigns include four recommendations to reduce infants' risk for SIDS:

1. Put your baby to sleep on the back or side.

2. Do not let your baby get too hot.

3. Keep your baby in a [cigarette] smoke-free environment.

4. Breastfeed your baby.

Decreases in SIDS rates were observed in response to these campaigns. In April, 1992, the American Academy of Pediatrics recommended that healthy infants be encouraged to sleep on their backs or sides because of evidence that it might reduce the risk of SIDS in infants.

Many babies have died from SIDS while sleeping on their backs, and most infants who sleep on their stomachs will not die from SIDS. Thus, the prone position does not always result in SIDS, and sleeping supine does not totally prevent SIDS. However, the suggestion that the risk for SIDS is increased in infants who sleep prone should not be ignored either. Further research in this area is needed, especially to find out how the data from other countries relate to the U.S.

How might sleeping prone allow SIDS to occur more frequently? A recent epidemiologic study from Tasmania explored what factors increased the risk for SIDS when accompanied by prone sleeping 36.. There were four factors which markedly increased the risk of SIDS in infants who slept prone:

1) Sleeping on thick wool or natural fiber bedding.

2) Swaddling.

3) A recent respiratory infection.

4) A heater in the room.

These findings suggest two possible ways that prone sleeping can cause SIDS:

1) A swaddled infant whose face is buried in thick bedding or natural fiber bedding may not be able to move, and thus could theoretically suffocate from direct occlusion of the infant's airway. Alternatively, infants may rebreathe air from a pocket formed in soft bedding, couches, comforters, or bunched up sheets 37. It is not clear if infants would arouse from sleep in response to this obstruction in order to rescue themselves. However, thick wool or natural fiber bedding is rarely placed under infants in the U.S., so this may not be as relevant for U.S. infants.

2) A heater in the room, swaddling, and a recent infection (with fever) could cause infants to overheat. Overheating has been suggested as a mechanism for SIDS, and could disrupt normal neurologic control of sleep and breathing or cause fatal overheating. The temperature of the infant ("local" temperature) is likely to be more important than the room temperature alone.

Thus, there are possible mechanisms by which sleeping prone could increase the likelihood of SIDS. However, none of these are proved, and more research into them is required.

Can SIDS be prevented? There is no evidence that SIDS can be entirely prevented at present. However, one may be able to reduce the risk of SIDS occurring. At present, one can not alter infant physiologic responses, nor even detect which types of physiologic responses might pose an increased risk for SIDS. Certainly all infants must pass through the 2-4 month age if they ever hope to be one-year of age. The only remaining way to try and reduce the SIDS risk is to address environmental factors.

A goal of SIDS research is to prevent SIDS. Although we can not totally prevent SIDS, data on sleeping position suggests that we may be able to reduce the risk for SIDS in some settings. Although we do not know the cause of SIDS, this should not prevent us from taking some actions to try and reduce SIDS, if they may be beneficial. The following approach in response to the current information available on sleeping position and SIDS is recommended:

1. Many infants who do not sleep prone have still died from SIDS. Most infants who sleep prone will not die from SIDS. Thus, sleeping prone is not the only cause of SIDS, and having all infants sleep supine will not completely prevent SIDS.

2. A reduction in SIDS has been reported by some countries by reducing prone sleeping. There appears to be no harm to normal infants from sleeping on their backs. Therefore, based on available data, it would seem prudent to endorse the recommendation for infants to sleep on their sides or backs, when possible, because of the possibility that it may reduce their risk of SIDS. However, it should be emphasized that SIDS will not be entirely eliminated by this practice.

3. There is no know risk of supine sleeping in healthy infants. The possible benefits of reducing SIDS, even though we do not understand why, would favor recommending that infants sleep on their backs or sides. Infants with birth defects affecting the nose, mouth, or throat; and infants with significant problems spitting up may be asked by their pediatrician to sleep prone.

4. Since SIDS is not caused by sleeping prone alone, it is important to emphasize that SIDS parents did not cause their babies to die if they slept prone. Similarly, it is possible that their infants would still have died even if they slept supine. Based on current knowledge, there is still nothing that SIDS parents did to cause their babies' deaths, and nothing they could have done to prevent them.

5. More research is needed on this important question. More rigorous epidemiologic studies need to be conducted as well as scientific studies of the possible impact on sleep, breathing, and temperature control in the prone vs. supine sleeping positions. While it is not likely that a better understanding sleeping position will totally explain the cause of SIDS, it is possible that such research may add important clues to our understanding of SIDS. Therefore, this research should be encouraged.

6. These recent findings must be put into perspective. Often in the past, when there has been increased interest in SIDS in a particular region or country, the SIDS rates have fallen due to nonspecific reasons. The recent flurry of SIDS interest centering around sleeping position is, nevertheless, an increased interest in SIDS. Other epidemiologic factors, which may appear hidden to the investigators, may also be important, and may, at least in part, explain the apparent reduction in SIDS which has been attributed to a change in sleeping position. This issue can only be answered with more research.

In summary, the issue of sleeping position and SIDS remains unanswered, and further investigation to clarify the role of sleeping position in SIDS is required. However, until more definitive answers become available, recommending that normal, healthy babies sleep on their backs or sides is harmless and may have some benefit. It should also be emphasized that sleeping on the back or side may be associated with a decreased risk for SIDS, but the practice has not totally prevented SIDS in any country where recommendations have been followed.

SIDS AND GRIEF.

The parents and families of a SIDS victim are no less the victims of this tragedy than the baby 2,38.. Although the death of any child is painful, SIDS deaths have some unique characteristics. SIDS deaths are unexpected, so parents have not had the opportunity to plan the death or say "good-bye" to their child. Perhaps the most important issue is that, at the present time, SIDS deaths are unexplained. Medical professionals can not tell parents how their baby died. Thus, parents search the pregnancy and child's life for things that they (the parents) did or did not do, which caused the death, at least in their own minds. The guilt generated by a SIDS death in the parents is tremendous, and is generally more than in other infant deaths because the cause is unknown.

For most families of SIDS victims, the single best and most important resource is a SIDS Parent Support Group 2,38.. The National Sudden Infant Death Syndrome Alliance is a national SIDS parent support organization, which has parent support counselors who are available to speak with SIDS parents at any time. While the immediate impact of the SIDS death is devastating to families, the ability to talk with someone who has been through it, who understands it, and who has survived it is reassuring. SIDS parent support groups are the best resource for SIDS parents available, and it is extremely important to get new SIDS parents in touch with their local organization.

When dealing with families of SIDS victims, the role of the health professional is to educate the family about SIDS and reassure them that they did not cause the death of their baby, either by something they did or by something they did not do. It is important to emphasize that SIDS can not be prevented, and there is nothing they or anyone else could have done to prevent their child's death. Many families of SIDS victims report that they are tremendously reassured to hear this from a health professional (an expert).

SUBSEQUENT SIBLINGS OF SUDDEN INFANT DEATH SYNDROME VICTIMS.

Sudden infant death syndrome (SIDS) is not thought to be hereditary. However, subsequent siblings of SIDS victims may be at increased risk of dying from SIDS 24,39,40,41,42,43,44,45,46.. This statement is based on nine studies (Table 3). All of these studies suggest that the SIDS rate for subsequent siblings of SIDS victims is increased over that of the general population (Relative Risk >1). However, they are all based on relatively small numbers of actual SIDS recurrences in families with a previous SIDS death. Thus, in each study, a difference of only one or two SIDS deaths could have resulted in marked differences in the estimations of SIDS risk. The incidence of SIDS deaths in subsequent siblings of SIDS victims has not been adequately studied. The current studies suggest that the risk for these infants is probably increased over that of the general population. However, when proper controlled studies are performed, the risk for SIDS siblings is no greater than for infants born to non-SIDS parents of similar age, birth order, etc., in one study 41.. Another study showed that SIDS rates were elevated, and that the infant death rate from all causes (both SIDS and non-SIDS) was 2%, which is not trivial 43.. However, this was similar to the infant death rate for siblings of infants dying from causes other than SIDS 43.. Thus, a family history of SIDS per se does not seem to confer a substantially increased risk over infants born into similar non-SIDS families 41,43.. It is possible, however, that death rates are elevated slightly for the sibling of one previous SIDS victim.

It is not currently possible to give a more exact or precise estimate of the SIDS recurrence risk for siblings of SIDS victims. Because the recurrence risk is not markedly increased, current recommendations are that SIDS siblings do not require study or treatment 29,48.. However, some SIDS parents may be sufficiently anxious about their subsequent child that home apnea-bradycardia monitoring will reduce anxiety and improve parenting skills. This is an acceptable indication for the use of home apnea-bradycardia monitoring 29,48..

SUMMARY.

Sudden infant death syndrome (SIDS) is the most common cause of death between the ages of 1-week and 1-year. It affects 1 out of every 500-600 live births. The etiology of SIDS is unknown. There are no tests currently available which predict the infant who will die from SIDS. SIDS can not be prevented.

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