SUDDEN INFANT DEATH SYNDROME

R M Harper, The David Geffen School of Medicine at

UCLA, Los Angeles, CA, USA
& 2006 Elsevier Ltd. All rights reserved.
Abstract
The sudden infant death syndrome (SIDS) occurs during sleep
from unknown causes between the rst and ninth month of age;
victims show no pathological signs at autopsy which are suf-
cient to cause death. The prevalence ranges between 0.5 per
1000 and 6.0 per 1000 live births in different countries and
ethnic groups, is higher in males, aboriginal and AfricanAmer-
ican populations, and in lower socioeconomic groups. The
prone sleeping position is a substantial risk factor, as is maternal
smoking prior to and following birth. Current hypotheses of
pathogenesis include a failure to arouse from, or adequately
process an airway obstruction, CO
2
or hypoxic challenge, or to
compensate for a sudden loss in blood pressure. These failures
possibly result from decient serotonergic or other neurotrans-
mitter binding in brainstem areas mediating cardiovascular and
respiratory control. Multiple polymorphisms, related to se-
rotonin transporter and autonomic nervous system target genes,
have been identied in SIDS victims, and may contribute to risk.
Introduction
Sudden infant death syndrome (SIDS) is dened as
the sudden and unexpected death of an infant under
one year of age, with onset of the lethal episode ap-
parently occurring during sleep, that remains un-
explained after a thorough investigation including
performance of a complete autopsy, and review of
the circumstances of death and the clinical history.
The reference to sleep was added in 2004 to incor-
porate recent ndings. The new SIDS definition con-
tains three subcategories which include the classic
definition, but recognizes variations in autopsy in-
formation, death scene data, age, developmental
characteristics, and similarity of deaths of close rel-
atives. An unclassied sudden infant death category
includes cases not meeting classic criteria, but for
which alterative diagnoses of natural or unnatural
conditions are unclear, or in which no autopsy was
performed.
Approximately 92% of cases occur within 21 and
270 days of life. The mechanisms by which sparing
occurs very early in life, and after 270 days, are un-
known.
Etiology
The origins of SIDS have roots in fetal life, because
certain prenatal exposures, such as maternal tobacco
use during pregnancy, markedly affect risk for the
syndrome. Other indications that infants who suc-
cumb are compromised well before the fatal event
include disordered sleep-state organization, reduced
respiratory inuences on heart rate variation, altered
numbers of arousals from sleep, a higher incidence of
obstructed respiratory events, periods of tachycardia,
and relatively xed respiratory rates. Thus, infants
who succumb are vulnerable from birth, and die dur-
ing a critical developmental period, likely from expo-
sure to an exogenous stressor. No simple genetic
mechanism has been associated with the syndrome;
however, several genes have been identied for which
the distribution of polymorphisms differs in a
high proportion of SIDS victims over control infants.
Some of the polymorphisms relate to the serotonin
transporter protein gene (5-HTT); others relate to
development of the autonomic nervous system; the
proportion of mutations may differ in particular eth-
nic groups. These polymorphisms may contribute to
risk, which, combined with particular stress circum-
stances and age of the infant, result in a fatal outcome.
Pathology/Epidemiology
The incidence varies widely internationally; the prev-
alence is rarer in Asian populations and more com-
mon in aboriginal populations in several countries
and AfricanAmerican groups. A male preponder-
ance in deaths (60%) exists, and socioeconomic is-
sues contribute in a major way, as does a higher risk
for infants of younger mothers. The incidence has
declined remarkably since the early 1990s, when ed-
ucational campaigns urging parents to place infants
down to sleep in the supine, rather than prone po-
sition, were initiated. Over the past 15 years, deaths
declined from 2 per 1000 live births to less than 0.5
in regions within the UK (2004); however, the rate
currently is 5.5 in aboriginal tribes in New Zealand.
A comparable declining pattern has emerged in the
USA since initiation of a Back to Sleep campaign;
however, substantial variance in incidence rate stems
from ethnic and socioeconomic issues.
Clinical Features
SIDS cases typically are found following a period in
which the infant was sleeping. In addition to the
face-down sleeping position, a nding of an environ-
ment inducing high body temperature is common,
132 SUDDEN INFANT DEATH SYNDROME
either from head or body covering or from room in-
terior heat. No pathology sufcient to cause death is
found at autopsy, that is, the diagnosis is one of ex-
clusion. Indications of mild respiratory infections are
common, but these signs are also insufcient for a
fatal outcome. Frothy, mucous, or pink uid may be
present in oral and nasal passages. The presence of
blood in the oralnasal uid may be indicative of
accidental or intentional asphyxiation, and thus does
not lie within the classication of SIDS. Pulmonary
congestion and edema are commonly found. In over
8090% of cases, petechial hemorrhages involving
the thymus, epicardium, and visceral pleural surfaces
are present, and may be increased after cardiopul-
monary resuscitation and with increasing age of the
victim. The distribution of petechiae (supradia-
phragmatic, but not on facial or conjunctival areas,
or on external surfaces of the thoracic wall) is char-
acteristic, but not diagnostic for SIDS, and, in some
cases, is not found.
Pathogenesis
The mechanisms underlying the fatal event remain
unknown. Since breathing cessation or cardiovascu-
lar collapse occurs during sleep, some state-related
process contributes to failure. That process may be a
failure to arouse, thus losing protective forebrain and
other brain inuences on breathing or blood pressure
control. The reorganization of neural processes con-
trolling vital functions that occurs normally during
sleep may depend on structures that are decient in
SIDS victims.
A prevalent hypothesis (current in the mid-1970s),
that periods of central apnea precede the event long
before death, is not supported by current evidence.
One research focus has been the possibility of inad-
equate sensing of increased CO
2
or hypoxia, or a
failure of transduction of these chemoreceptor
signals to signal appropriate breathing output. The
demonstration in SIDS victims of defects in neuro-
transmitter receptors in brain areas involved with
chemoreceptor and cardiovascular regulation, espe-
cially serotonergic receptor binding in the caudal
raphe and ventral medulla, has added support to this
hypothesis. A fatal cardiac arrhythmia, with pro-
longed QT syndrome a primary suspect, has also
been proposed. A third possibility is a blood pressure
collapse, in a shock-like process, with blood pressure
loss triggered by deep visceral pain, infection, upper
airway stimulation from foreign uid or regurgitate,
or occurring spontaneously during rapid eye move-
ment sleep. The occasional report of reduced neck
muscle tone in later SIDS victims, a characteristic of
reduced blood pressure, suggests the potential for
underlying inadequate blood pressure control. The
conditions surrounding the fatal event, including
profuse sweating prior to the fatal sequence, and
indications of profound bradycardia in recordings
during some events, together with evidence of
neuropathologic damage in blood pressure control
areas, provide evidence for possible failure to com-
pensate for loss of blood pressure. Other support for
the hypotensive hypothesis includes the possibility
that elevated body temperature found in some SIDS
victims has led to vasodilatation, and thus lowered
blood pressure, and that altered vestibular input
in the prone body position impedes compensatory
blood pressure recovery.
The developmental expression of the syndrome
corresponds with substantial changes in sleep-waking
state organization, with an increasing proportion of
quiet sleep during the rst 6 months over the high
prevalence of the rapid eye movement state in the
newborn period. Rapid eye movement sleep is ac-
companied by major neural control changes in cardio-
vascular and respiratory muscle actions, as well as in
sensory processing associated with that control. The
neuropathologic ndings in SIDS include excessive
apoptosis of vestibular nuclei and maldevelopment of
inferior olive areas which project to cerebellar cortex
and deep nuclei. Cortical cerebellar structures show
delayed maturation in SIDS cases and play critical
roles in breathing and blood pressure control.
Animal Models
No adequate animal model exists for SIDS. However,
numerous examinations of prenatal exposure to
nicotine, compromised fetal circulation and other
developmental insults, as well as sleep effects on
physiology have beneted from animal studies.
Management and Current Therapy
Interventions to reduce the incidence of SIDS begin
with prenatal counseling against the use of tobacco-
related products, since overwhelming evidence dem-
onstrates that maternal smoking during pregnancy
increases the risk of SIDS nearly vefold. The evi-
dence for postnatal tobacco exposure inuence on
risk is less clear, but that inuence appears also to
be substantial. Educational efforts to switch from
prone sleeping to the supine position have substan-
tially reduced the risk for SIDS in every country
where those efforts have begun; an intermediate po-
sition, that is, placing the infant on its side to sleep,
doubles the risk for SIDS, possibly because the in-
fants may turn prone during sleep time. Placing an
infant who routinely sleeps supine into the prone
SUDDEN INFANT DEATH SYNDROME 133
position (a circumstance that can easily occur when
the infant is placed in the hands of a novel caregiver,
e.g., a day care center) puts the infant at exception-
ally high risk. The mechanisms underlying reduced
risk from supine sleeping are unclear, but may relate
to ensuring adequate airow, temperature reduction
(since heat dissipates rapidly from the face), or vesti-
bular inuences, because the prone position dampens
vestibular inuences on protective heart rate and
breathing responses to blood pressure loss.
Breastfeeding is usually associated with protection
against SIDS, although this association is confounded
with other issues, including socioeconomic factors.
Pacier use also reduces risk for SIDS, possibly as a
consequence of exercising brain areas controlling
upper airway muscle action or initiating blood pres-
sure changes that accompany suckling, thus provid-
ing the brain practice for recovery from sudden
blood pressure falls.
A continuing concern has been the possibility that
vaccinations, typically administered at peak risk pe-
riods for SIDS, may enhance the predisposition for
risk; no evidence for such an association has been
demonstrated, and some data suggest a small pro-
tective inuence in favor of vaccinations.
Attention should be directed to assuring a safe
sleep environment by use of rm mattresses and care
in selection of bedding materials; a high proportion
of infants found dead have had their heads covered
so the use of soft materials with the potential to cover
the head, leading to elevated temperatures or im-
peded air exchange, should be discouraged.
Electronic monitors that detect apnea, brady-
cardia, or oxygen saturation are fraught with dif-
culties in false positive and negative indications of
breathing or cardiovascular dysfunction, particularly
when an infant is ill from other causes. Monitors
have a disconcerting history of failure to perform or
inadequacy to alert a caregiver during events that
result in fatalities. False triggering of alarms from
inadequate placement of physiological sensors or
from arousals associated with mild illnesses often
prompt disuse on occasions when the necessity for
monitoring may be especially warranted. Monitors,
however, can supply solace to concerned parents, and
substantial progress in technology may emerge in the
near future. Monitors that supply recordings of
physiological signals during near-fatal or fatal events
have provided invaluable information on potential
mechanisms in SIDS.
See also: Breathing: Breathing in the Newborn. Infant
Respiratory Distress Syndrome. Neurophysiology:
Neuroanatomy. Sleep Apnea: Genetics of Sleep Apnea.
Further Reading
Byard RW and Krous HF (2003) Sudden infant death syndrome:
overview and update. Pediatric and Developmental Pathology
6(2): 112127.
Byard RW and Krous HF (eds.) (2004) Sudden Infant Death Syn-
drome: Problems Progress and Possibilities. London: Arnold.
Fleming P, Blair P, Bacon C, and Berry J (eds.) (2000) Sudden
Unexpected Deaths in Infancy: The Cesdi Sudi Studies. London:
The Stationery Ofce.
Gaultier C, Amiel J, Dauger S, et al. (2004) Genetics and early
disturbances of breathing control. Pediatric Research 55(5):
729733.
Harper RM (2000) Sudden infant death syndrome: a failure of
compensatory cerebellar mechanisms? Pediatric Research 48:
140142.
Harper RM and Hoffman HJ (eds.) (1988) Sudden Infant Death
Syndrome: Risk Factors and Basic Mechanisms. New York:
PMA Publishing.
Harper RM, Kinney HC, Fleming PJ, and Thach BT (2000) Sleep
inuences on homeostatic functions: implications for sudden
infant death syndrome. Respiratory Physiology 119(23): 123
132.
Kinney HC, Filiano JJ, and Harper RM (1992) The neuropatho-
logy of the sudden infant death syndrome. Journal of Neuro-
pathology and Experimental Neurology 51(2): 115126.
Krous HF, Beckwith JB, Byard RW, et al. (2004) Sudden infant
death syndrome and unclassied sudden infant deaths: a deni-
tional and diagnostic approach. Pediatrics 114(1): 234238.
Mitchell EA (2000) SIDS: facts and controversies. Medical Journal
of Australia 173(4): 175176.
Weese-Mayer DE, Berry-Kravis EM, Maher BS, Silvestri JM, Cur-
ran ME, and Marazita ML (2003) Sudden infant death syn-
drome: association with a promoter polymorphism of the
serotonin transporter gene. American Journal of Medical
Genetics 117A: 268274.
Weese-Mayer DE, Berry-Kravis EM, Zhou L, et al. (2004) Sudden
infant death syndrome: case-control frequency differences at
genes pertinent to early autonomic nervous system embryologic
development. Pediatric Research 56(3): 391395.
Willinger M, James LS, and Catz C (1991) Dening the sudden
infant death syndrome (SIDS): deliberations of an expert panel
convened by The National Institute of Child Health and Human
Development. Pediatric Pathology 11: 677684.
Surface Mechanics see Alveolar Surface Mechanics.
134 SUDDEN INFANT DEATH SYNDROME