SUDDEN INFANT DEATH SYNDROMEMichael Klufas, MS III

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

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

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

DEMOGRAPHICS less frequently in 1st 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

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

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

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

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

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

RISK FACTORS

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 2nd or higher order birth child

SOCIAL FACTORS

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

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

BABY IN A SAFE CRIB

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

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

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)

GENE ENVIRONMENT INTERACTIONS

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)

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

AAP SIDS RISK REDUCTION RECOMMENDATIONS 2005

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

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

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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Gurbutt D, Gurbutt R. Risk reduction and sudden infant death syndrome. Community Pract. Jan 2007;80(1):24-27.

Fleming P, Blair PS. Sudden Infant Death Syndrome and parental smoking. Early Hum Dev. Nov 2007;83(11):721-725.

Damato EG. Safe sleep: can pacifiers reduce SIDS risk? Nurs Womens Health. Feb 2007;11(1):72-76.

Haycock G. Recent research in sudden infant death syndrome. J Fam Health Care. 2007;17(5):149-151.