1. SUDDEN INFANT DEATH SYNDROME Michael Klufas, MS III

2. INTRODUCTION Sudden Infant Death Syndrome (SIDS) continues to be the most common cause of postneonatal infant death 25% of all deaths between 1 month and 1 year of age SIDS is a complex, multifactorial disorder of which the cause is not fully understood Some environmental risk factors are modifiable Reducing exposure to modifiable risk factors has lowered the incidence of SIDS New research indicates genetic risk factors Actual risk of SIDS may depend on interaction of environmental and genetic risk factors

3. DEFINTION Sudden death of an infant under 1 year old that is unexpected by history and unexplained after a thorough postmortem examination Investigation includes: Complete autopsy Investigation of the scene of death Review of medical history

4. EPIDEMIOLOGY SIDS rate in United States 1990 – 1.3 per 1000 live births 2002 – 0.6 per 1000 live births ~ 3000 SIDS deaths/yr Changes in classification of sudden unexpected deaths in infants from SIDS to categories of asphyxia and “unknown” has occurred in recent years May be falsely reducing SIDS rates while overall death rate from unexpected infant deaths remains the same

5. DEMOGRAPHICS less frequently in 1 st month of life Peaks 2-4 month of age 90% in first 6 months of life Boys 30-50% more likely to be affected than girls Racial and ethnic disparities 2-3x risk for African American, Native American or Alaska Native (irrespective of socioeconomic status) ‏ African Americans twice as likely to place infants prone to for sleep & twice as likely to bedshare High rates of smoke exposure and bedsharing among Native Americans and Alaskan Natives Asian, South Pacific, Hispanic infants lowest incidence Winter seasonal predominance has declined or disappeared

6. PATHOPHYSIOLOGY Multifactorial in origin Triple Risk Hypothesis Vulnerable infant Critical developmental period in homeostatic control Exogenous stressors Final pathway believed to involve immature cardiorespiratory and autonomic control along with failure of arousal responsiveness from sleep

7. AUTONOMIC CONTROL AND AROUSAL SIDS infants higher baseline heart rates, lower heart rate variability, prolonged QT indexes, lower parasympathetic tone and/or high sympathovagal balance Abnormalities of arousal Kato and colleagues report infants who died of SIDS had fewer spontaneous arousals from sleep and immature sleep patterns Prone sleeping Increases total time infants spend asleep particularly time spent in quiet sleep, a state of reduced arousability Also decreased spontaneous arousability, induced arousability and fewer full cortical arousals Associated with altered autonomic control manifest by raised heart rates, decreased heart rate variability and increased sympathetic tone Infants exposed to smoking in utero have decreased spontaneous and stimulus-induced arousal from sleep

8. AUTOPSY FINDINGS No pathognomonic findings Common findings: Petechial hemorrhages of thymus gland, visceral pleura in 68- 95% Pulmonary congestion (89%) and edema (63%) indicative of terminal left ventricular failure Oronasal secretions that are typically frothy, mucoid and pink or bloody 2/3 structural evidence of pre-existing, chronic low-grade asphyxia Study identified increased VEGF in CSF of SIDS infants, 308 versus 85 pg/dL in controls Hypoxia frequently precedes death in SIDS One study of 20 SIDS infants found 50% had levels of IL-6 in CSF equivalent to those found in infants who died of infectious diseases Staphylococcus aureus may have role in infection as 56% of healthy infants and 86% of SIDS infants had these bacteria in the respiratory tract

9. NEUROANATOMICAL FINDINGS Structural and neurotransmitter alterations in brainstem consistent with autonomic dysregulation Increase in dendritic spines (marker of delayed neuronal maturation) and delayed maturation of synapes in medullary respiratory centers Decreased tyrosine hydroxylase immunoreactivity in catecholaminergic neurons Increased number and density of 5-HT neurons with decreased serotonin 1A and 2A receptor Serotonin affects various autonomic functions including cardiorespiratory and circadian rhythms

10. NEUROANATOMICAL FINDINGS 60% SIDS cases hypoplasia of arcuate nucleus Vital area of autonomic control and integration Receptor abnormalities relevant to autonomic control Decreases in binding to kainate, muscarinic cholinergic and 5-HT receptors Lavezzi showed alterations of the cerebellum 62% of SIDS compared to 10% controls showed neuronal immaturity, altered apoptotic programs, negative expression somatostatin and EN2 gene, intense c-fos expression and astrogliosis in cortex and dentate nucleus Water reported increased neuronal apoptosis in hippocampus and brainstem Neuronal loss in regions sensitive to hypoxia and regions associated with sensation in the face

11. RISK FACTORS

12. PREGNANCY RELATED FACTORS Increased risk with: Lower socioeconomic status Younger maternal age Lower maternal education Single marital status Mothers of SIDS infants: Less prenatal care Care initiated later in pregnancy Low birth weight Preterm birth IUGR Shorter intervals between pregnancies (< 18 mo) More often 2 nd or higher order birth child SOCIAL FACTORS

13. SUBSTANCE USE Major association between intrauterine exposure to cigarette smoking and risk of SIDS Risk of death is progressively greater with increased smoking May be small independent effect of paternal smoking An independent effect of postnatal exposure to tobacco smoke has been found in a small number of studies as well as dose-response effect with number of household smokers Evidence linking prenatal illegal drug is conflicting Opiates increase risk of SIDS 2-15 fold Alcohol not clearly linked, but siblings of infants with FAS 20 fold increased risk of SIDS compared to controls

14. INFANT SLEEP PRACTICES & ENVIRONMENT Prone sleeping consistently shown to increase risk of SIDS Highest risk when usually placed in another sleeping position but were placed on stomach for last sleep, “unaccustomed prone”, more likely to occur outside the home such as day care centers Also risk of choking highest in prone position Placing infant on side still places risk twice as likely to die of SIDS compared to sleeping supine Exceptions may be made with certain medical conditions Soft sleeping surfaces 2 to 3 fold increase risk of SIDS Prone sleeping + soft bedding  20 fold increase Overheating with increased room temperature, high body temperature, sweating or excessive clothing increase incidence No increase with high external environment temperature No protective effect from bed sharing Advocates of this practice typically promoters of breast feeding 1/3 reduction with sleeping in parent’s bedroom in separate crib

15. BABY IN A SAFE CRIB

16. INFANT FEEDING PRACTICES & EXPOSURES Association between breast-feeding and SIDS inconclusive Recent study showed breast-feeding associated with decreased risk of postneonatal deaths overall but not decreased risk of SIDS Decreased risk with pacifier use Not known whether direct effect or associated infant or parental behaviors Pacifier use and dislodgement may enhance arousability No association between pacifier use and breast-feeding duration Small increased in otitis media, respiratory tract and GI tract illnesses Must use consistently, one study showed increased risk of SIDS if pacifier was not used before last sleep AAP recommends pacifier use once breast-feeding has been established

17. OTHER CONCERNS Upper respiratory tract infection has not been found to be independent risk factor for SIDS However, these and other minor infections may play a role in the pathogenesis if SIDS For instance, if in prone position, heavily wrapped or head covered during sleep there was increased risk of SIDS with infection Parents should be reassured that immunization does not present a risk for SIDS No temporal relation between vaccine administration and death Not caused by vomiting or choking

18. GENETICS No specific genotypic differences in infants who died of SIDS, but several gene polymorphisms identified Generally involving entities in cardiorespiratory, immune function and arousal Triple risk model suggests gene polymorphisms may make certain infants more vulnerable to SIDS This vulnerability manifests when there is an environment challenge (prone sleeping, tobacco exposure) ‏

19. GENE ENVIRONMENT INTERACTIONS

20. GENETIC RISK FACTORS Sodium (SCN5A) and Potassium channel polymorphisms associated with long QT syndrome 5-10% of SIDS cases associated with defective cardiac ion channel with increased potential for lethal arrhythmia Polymorphisms in serotonin transporter (5-HTT) gene Increased in transporter activity, reducing 5-HT concentrations at nerve endings Autonomic nervous system development genes (PHOX2A, RET, ECE1, TLX3, EN1) ‏ Polymorphisms in promoter of anti-inflammatory cytokine IL-10  decreased antibody production and increased inflammatory cytokines SIDS infants w/mild respiratory infections before death were more likely than SIDS infants without infection and controls to have deficient complement C4 gene (C4A, C4B) ‏

21. DIAGNOSIS By definition, SIDS is a diagnosis of exclusion Protocols for standardized autopsies and death scene investigations have been published However, wide variability in protocols in both content and frequency with which they are implemented across jurisdictions, within countries and across different countries Cause of death can be difficult to diagnose from autopsy alone Examination of circumstances present immediately before death including detailed description of sleep environment have been increasingly emphasized in recent years Surveys of medical examiners and coroners have reflected how much more complicated, confusing and time consuming SIDS case have become Most also noted they used to label many more infant death cases as SIDS than they do now This may be an effect of confusing risk factors for SIDS Reaching consensus internationally on a classification scheme is essential to accurately monitor trends and direct future research

22. AAP SIDS RISK REDUCTION RECOMMENDATIONS 2005

23. RISK REDUCTION Campaign to reduce risk of SIDS began in 1994 in the United States Largely focused on reducing prone sleeping and promoting supine positioning Some campaigns also included messages to reduce smoking during pregnancy No significant changes in these behaviors and reduced SIDS rates mostly attributed to avoidance of prone sleeping Breast-feeding advocates have opposed discouraging bed sharing as they worry these measures will reduce breast- feeding frequency and duration and prevent families from enjoying the experience and benefits of bed sharing

24. MANAGEMENT AND SUPPORT Loss of infant is devastating for everyone concerned In addition to loss of infant, families face could face police investigation, long wait for autopsy results and continued uncertainty leading to prolonged emotional distress consequently affecting the grieving process Physician can play active role by advocating for an autopsy, discussing autopsy results with the family and providing emotional support Surviving siblings and other family members need age appropriate emotional support If appropriate refer family for genetic counseling and/or metabolic testing Direct family to local counseling and support groups which are available in most communities

25. FUTURE DIRECTIONS Despite decrease in prevalence of SIDS, more work is needed Elucidation of risk and protective factors with appropriately targeted and implemented interventions leading to increased adoption by families Unlikely disorder is completely eliminated or reduced to lowest possible rates until specific causative mechanisms are more fully understood Need studies with larger sample sizes and infants from highest risk groups Investigations of still births and sudden unexplained deaths in children over 1 year of age might provide additional insights Surveillance of trends in rates of SIDS comparisons across jurisdictions and internationally according to a universal, standardized classification protocol Will require multidisciplinary and collaborative effort to understand more

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