Sudden Infant Death Syndrome

Disease Overview

Sudden infant death syndrome (SIDS) is the sudden death of an infant under the age of 1 year that remains unexplained after careful review of the history, death scene investigation, and thorough autopsy. In 2008, the most recent published data from the National Vital Statistics System indicated that SIDS was listed as the third leading cause of death in infants in the United States. Causes of SIDS are considered to be multifactorial. The triple risk hypothesis describes the presence of three risk factors that, when overlapping, predispose a baby to SIDS. These include an environmental trigger/stress, a critical developmental period, and an underlying vulnerability. Physician-scientists and scientists are studying neuropathological tissue and genetic material from SIDS victims to ascertain factors that might be responsible for heightening an infant’s vulnerability to SIDS. Others are performing physiologic studies on infants known to have an increased risk for SIDS. Basic scientists are studying animal models that might provide insight into mechanisms responsible for SIDS. Current clinical management targets improving education for families and caregivers regarding known modifiable environmental stressors (risk factors) (see below).

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Synonyms

• cot death
• crib death
• SIDS

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Signs & Symptoms

There are typically no symptoms prior to a SIDS death. Though SIDS occurs during sleep, the deaths may occur during day or night time sleep. Existing literature does not indicate any evidence for suffering by the infant in the moments preceding the sudden death.

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Causes

By definition, the cause of SIDS is unknown. Therefore, the existing research addresses modifiable environmental risk factors, neuropathological and genetic factors that may predispose to SIDS, potential physiologic markers in at-risk infants, and animal modeling.

The American Academy of Pediatrics summarizes modifiable environmental factors with current recommendations for reducing the risk of SIDS. The focus is on modification of sleep position, sleep environment, and nicotine exposure. Infants should be placed to sleep in the supine position (on her or his back). The “Back to Sleep” NICHD campaign in 1994 encouraged parents to place their infant to sleep on their back or side, then the AAP campaign in 1996 recommendation that “back is best” (no side sleeping) led to a significant decrease in SIDS. The risks of supine sleep are positional plagiocephaly (malformation of the skull related to position) which can be decreased by giving the infant “tummy time” while awake, avoiding prolonged periods of time in car seats or bouncy chairs, and encouraging upright “cuddle time.” Modifications of sleep environment include placing the infant to sleep on a firm surface without soft bedding, blankets or toys, placing the infant to sleep in the same room as the parent without bed-sharing, and in a bedroom with temperature that is comfortable for a lightly clothed adult. If an additional blanket is to be used, it should be placed on the infant so that the sheet reaches only to the infant’s chest and is tucked in around the crib mattress to prevent it from covering the baby’s face. The rationale is that these actions may reduce the chance of suffocation and overheating for the infant. Offering a pacifier at the onset of sleep is associated with decreased SIDS risk, but pacifier use should be delayed until after 1 month of age if the baby is breastfeeding and should not be reintroduced into the baby’s mouth after (s)he falls asleep. Smoking or second hand exposure for the pregnant woman, new mother, and baby should be avoided to reduce SIDS risk and for many other health reasons.

Though the cause for SIDS is unknown, there has been much investigation into the pathophysiology (functional changes due to disease) and neuropathology (study of brain disease and diseases of the nervous system) of SIDS with many thoughts regarding the underlying problems that may make an infant vulnerable. Considering this, the etiology of SIDS is thought to include, but is not limited to, serotonergic system dysfunction, autonomic nervous system dysfunction, and impaired arousal mechanisms. All of these are inter-related in the baby’s developing nervous system. Serotonin is a neurotransmitter (brain chemical involved in neuron-cell signaling) that has influence over a broad range of functions such as the sleep-wake cycle, thermoregulation, cardiovascular control, and modulation of motor activity. Neuropathological studies have found a decrease in serotonergic receptor binding in the medulla (area of the brain important for homeostatic function) of SIDS victims. Further, the serotonergic system has been found to be abnormal in 50% of SIDS cases. These findings have led to candidate gene studies, primarily based on clues from the neuropathological findings in SIDS victims and the limited clinical information documented before the sudden death; thus far, findings in the serotonergic system and genes expressed in the early embryology of the autonomic nervous system have not identified variations strongly associated with SIDS risk. Testing of additional genes, in larger cohorts, is currently under way.

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Affected populations

SIDS can affect all infants under 1 year of age. Most deaths occur less than 6 months of age with the peak affected age between 2 and 4 months. Gender, ethnic and racial differences also exist. For example, boys are at greater risk for SIDS than girls. Also, the SIDS rate in African American infants is 2.7 times greater than the Caucasian rate in the US. Likewise, SIDS rates are increased in the American Indians and Alaskan natives as compared to Caucasians. These differences may reflect both cultural practices and genetic variations.

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Disorders with Similar Symptoms

There is not necessarily a definitive relationship between the following disorders and SIDS. They are often considered in the same context because of the similarity in terms of life threatening events and/or sudden death.

Congenital central hypoventilation syndrome (CCHS) is a disorder of the autonomic nervous system (automatic body regulation) that is caused by a genetic mutation in the Paired-Like Homeobox gene, PHOX2B. Individuals with CCHS typically present in the newborn period, though cases are now being identified in later infancy, childhood, and adulthood. The hallmark of CCHS is alveolar hypoventilation (shallow breathing) during sleep with failure to respond to the resultant low oxygen and high carbon dioxide levels. In severe cases, individuals have hypoventilation during sleep and wakefulness. The phenotype of CCHS includes additional symptoms of autonomic nervous system dysregulation including abnormalities of heart rate and rhythm, constipation, abnormal sweating, altered temperature regulation, pupillary abnormalities, decreased perception of pain, anxiety, and more. Other associated problems include Hirschsprung Disease and tumors of neural crest origin, such as neuroblastoma, ganglioneuromas, and ganglioneuroblastomas. It is quite possible that a subset of infants dying in the first year of life and diagnosed as “SIDS” or dying after the first year of life and diagnosed as Sudden Unexpected Death of Childhood (SUDC) actually have CCHS. The definitive assessment includes performing the PHOX2B Screening Test and if negative the PHOX2B Sequencing Test. (For more information about this disorder, choose “CCHS” as your search term in Rare Disease Database.)

Apparent life threatening events (ALTE) refers to a frightening episode witnessed by a caregiver where the infant has apnea (cessation of breathing), color change, limpness, and/or choking. ALTE is not a diagnosis and is only a description of the presenting event. It has multiple possible causes that can originate from any of the body systems. A short list of possible causes include gastroesophageal reflux, seizures, CCHS, respiratory infection, laryngomalacia (floppy airway that causes noisy breathing), congenital heart defect, heart rhythm problem, sepsis (overwhelming body infection), and child abuse. A baby that has been evaluated for ALTE is not at increased risk for SIDS and to date no association has been made.

Long QT syndrome (LQTS) is a genetic channelopathy that causes a change in the electrical signal in the heart and can result in syncope (fainting), arrhythmia (abnormal hearth rhythm), or even sudden death. This is an inherited condition that affects the channels of the heart involved with ion transport. Individuals with Long QT Syndrome can have episodes of fainting, palpitations, or no symptoms at all. Initial evaluation requires obtaining an ECG (measurement of the electrical rhythm of the heart) and patients are often referred to a Cardiologist for further assessment. Genetic testing for known Long QT mutations will confirm the diagnosis. Studies in regard to SIDS have shown that a prolonged QT interval in the first week of life is a major risk factor for sudden death. Likely 10-15% of SIDS deaths are due to Long QT Syndrome. If identified early, medication can be provided to prevent the ECG abnormalities and sudden death.

Apnea of infancy is the cessation of breathing in an infant less than 1 year of age for longer then 20 seconds which may or may not be associated with color change. Apnea of infancy can be considered central (impaired signal from the brain to breath), obstructive (problem with the airway that does not allow adequate air flow to the lungs), or mixed (combination of central and obstructive) and can be secondary to multiple medical conditions. The causes are similar in scope to those for ALTE.

Sudden unexpected death of childhood (SUDC) is very rare and is the sudden death of a child older than one year of age which remains unexplained after thorough investigation. Deaths occur most often during sleep, but also include childhood deaths when awake. (For more information about this disorder, choose “SUDC” as your search term in Rare Disease Database.)

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Diagnosis

SIDS is a diagnosis of exclusion which means that it is only determined as the cause of death after thorough investigation of clinical history, scene of death, and autopsy reveal no other cause.

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Standard Therapies

Treatment

Apnea or cardiac monitors have not been found to be useful in preventing SIDS. They serve to alert a caregiver to a potentially life threatening event. However, an infant can experience significant hypoxemia (reduced oxygen content) or abrupt bradycardia (slow heart rate) before the alarm is activated.

Because the diagnosis of SIDS is made after death, there is no treatment. The current recommendations are aimed at reducing risk factors that are associated with SIDS.

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Clinical Trials and Studies

SIDS parents have the opportunity to contribute tissue to the NICHD-funded University of Maryland Brain and Tissue Bank. Parents are encouraged to donate tissue within 24 hours of death. For further information, please go to: www.BTBankFamily.org

The aim of the genetic and neuropathological studies is to design intervention strategies to avert the sudden death of these seemingly normal infants.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

For more information on SIDS, congenital central hypoventilation syndrome, and/or PHOX2B testing, please contact:

Pallavi P. Patwari, M.D.

Assistant Professor of Pediatrics at Northwestern University Feinberg School of Medicine

Center for Autonomic Medicine in Pediatrics (C.A.M.P.)

Ann & Robert H. Lurie Children’s Hospital of Chicago

225 East Chicago Avenue, Box 165, Chicago, Illinois 60611-2605

Chicago, Illinois 60611-2605

phone: 312-227-3300

fax: 312-227-9606

e-mail: PPatwari@LurieChildrens.org

web address: https://www.luriechildrens.org/en-us/care-services/conditions-treatments/autonomic-medicine/Pages/basics/basics.aspx

Casey M. Rand, B.S.

Senior Project Coordinator

Ann & Robert H. Lurie Children’s Hospital of Chicago

225 East Chicago Avenue, Box 165, Chicago, Illinois 60611-2605

Chicago, Illinois 60611-2605

phone: 312-227-3300

fax: 312-227-9606

e-mail: CRand@LurieChildrens.org

web address: https://www.luriechildrens.org/en-us/care-services/conditions-treatments/autonomic-medicine/Pages/basics/basics.aspx

Debra E. Weese-Mayer, M.D.

Professor of Pediatrics at Northwestern University Feinberg School of Medicine

Director, Center for Autonomic Medicine in Pediatrics (C.A.M.P.)

Ann & Robert H. Lurie Children’s Hospital of Chicago

225 East Chicago Avenue, Box 165, Chicago, Illinois 60611-2605

Chicago, Illinois 60611-2605

phone: 312-227-3300

fax: 312-227-9606

e-mail: DWeese-Mayer@ LurieChildrens.org

web address: https://www.luriechildrens.org/en-us/care-services/conditions-treatments/autonomic-medicine/Pages/basics/basics.aspx

web information on CCHS: www.genetests.org

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References

JOURNAL ARTICLES

Klaver E.C., Versluijs G.M., Wilders R. Cardiac ion channel mutations in the sudden infant death syndrome. Int J Cardiol. 2011;152:162-170.

Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Trang H. An official American Thoracic Society clinical policy statement: Congenital central hypoventilation syndrome: Genetic basis, diagnosis, and management. Am J Respir Crit Care Med. 2010;181:626-644.

Kinney H.C. Brainstem mechanisms underlying the sudden infant death syndrome: evidence from human pathologic studies. Dev Psychobiol. 2009;51:223-233.

Franco P, Groswasser J, Scaillet S, et al. QT Interval Prolongation in Future SIDS Victims: A polysomnographic study. Sleep 2008; 31(12):1691-1699.

Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Rand CM. Congenital central hypoventilation syndrome (CCHS) and sudden infant death syndrome (SIDS): Kindred disorders of autonomic regulation. Respir Physiol & Neurobiol. 2008;164:38-48.

Martin JA, Kung HC, Mathews TJ, et al. Annual Summary of Vital Statistics: 2006. Pediatrics. 2008;121(4):788-801.

Weese-Mayer DE, Ackerman MJ, Marazita ML, Berry-Kravis EM. Sudden infant death syndrome: Review of implicated genetic factors. Am J Med Genet. 2007;143A:771-788.

Paterson DS, Trachtenbert FL, Thompson EG, et al. Multiple serotonergic brainstem abnormalities in the Sudden Infant Death Syndrome. JAMA. 2006;296:2124-2132.

Hoyert DL, Heron MP, Murphy SL, Kung HC. Deaths: Final Data for 2003. Natl Vital Stat Rep. 2006;54(13): 1-120.

Tomashek KM, Qin C, Hsia J, et al. Infant Mortality trends and differences between American Indian/Alaskan Native infants and white infants in the United States, 1989-1991 and 1998-2000. Am J Public Health. 2006;96:2222-2227.

Krous HF, Chadwick AE, Crandall L, Nadeau-Manning JM. Sudden unexpected death in childhood: A report of 50 cases. Pediatr & Devel Pathol. 2005;8:307-319.

American Academy of Pediatrics Task Force on Sudden Infant Death Syndrome. The Changing Concept of Sudden Infant Death Syndrome: Diagnostic Coding Shifts, Controversies Regarding the Sleeping Environment, and New Variables to Consider in Reducing Risk. Pediatrics. 2005;116(5):1245-1255.

Kinney HC, Randall LL, Sleeper LA, et al. Serotonergic brainstem abnormalities in Northern Plains Indians with the sudden infant death syndrome. J Neuropathol Exp Neurol. 2003;62:1178-1191.

Ozawa Y, Okado N. Alterations of serotonergic receptors in the brainstems of human patients with respiratory disorders. Neuropediatrics. 2002;33:142-149.

Panigrahy A, Filiano J, Sleeper LA, et al. Decreased serotonergic receptor binding in rhombic lip-derived regions of the medulla oblongata in the sudden infant death syndrome. J Neuropathol Exp Neurol. 2000;59:377-384.

Schwartz PJ, Stramba-Badiale M, Segantini A, et al. Prolongation of the QT interval and the sudden infant death syndrome. NEJM. 1998;338:1709-1714.

Filiano JJ, Kinney HC. A perspective on neuropathologic findings in victims of sudden infant death syndrome: the triple-risk model. Biol Neonate. 1994;65(3-4):194-197.

Jacobs BL, Azmitia EC. Structure and Function of the Brain Serotonin System. Physiol Rev. 1992;72(1):165-229.

Willinger M, James LS, Catz C. Defining the sudden infant death syndrome (SIDS): deliberations of an expert panel convened by the National Institute of Child Health and Human Development. Pediatr Pathol. 1991;11(5):677-684.

INTERNET

Weese-Mayer DE, Marazita ML, Berry-Kravis EM, Patwari PP. (Updated November 10, 2011). Congenital Central Hypoventilation Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2012. Available at https://www.genetests.org. Accessed July 9, 2012.

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