Manifestation and Pathogenesis of Sudden Infant Death Syndrome: A Review
Jasndeep Kaler, Azhar Hussain
Abstract
Historically known as ‘cot death,’ or more commonly ‘crib death,’ sudden infant death syndrome (SIDS) is one of
the leading causes of postnatal death in infants. According to the Centers of Disease Control and Prevention, in 2010,
more than 2,000 U.S. infants died from SIDS. Sudden infant death syndrome is a referred to as a postnatal
complication that results in the unexplainable death of an infant, less than one year old, that is otherwise healthy.
SIDS, a concept that was first coined in 1969, SIDS typically presents in infants under the age of one year, with a
peak incidence between the age of 2-4 months of age. Death by SIDS is typically more prevalent in the winter
months due to the association with the higher frequency of respiratory infections, making the infant vulnerable.
Despite witness a significant decrease in deaths by SIDS due to medical advancements and awareness, SIDS
continues to remain as the leading cause of infant mortality in the Western countries, accounting for half of all
postnatal deaths. Through this paper, there will be an increased focus on the environmental factors, physiological
factors and genetic factors that cause an infant to be increasingly more susceptible to SIDS. There is a multiple
contingency hypothesis – triple risk hypothesis – that states an increase in risk of SIDS increases in situations where
there is an overlap of three or more factors. The presence of three or more factors is considered to exceed the infant’s
threshold for survival. Deaths by SIDS has declined considerably from 130.3 deaths per 100,000 live births in 1998
to 38.7 deaths per 100,000 live births in 2014. Despite the decrease in deaths by SIDS, it still remains to be one of
the largest postnatal causes of death, globally
Introduction
Often referred to as ‘crib death,’ sudden infant death syndrome (SIDS) is defined as the unexplainable death of an
infant, less than one year old, that is otherwise healthy. Once referred to as ‘cot death,’ death by SIDS is visibly more
common in winter months. According to Peterson (1988), the association with incidence of SIDS higher in the winter
months can be correlated to the respiratory infections that are seen occurring at a higher frequency in the colder and
darker months. SIDS was a term that was coined first in the 1969 by Beckwith (1970) as an applicable diagnosis for
an infant that dies suddenly, without any other identifiable cause (Dwyer, 1996). Sudden infant death syndrome is a
post-natal complication that presents with a peak incidence between 2-4 months of age, with the incidence
decreasing afterwards (Dwyer, 1995). Sudden infant death syndrome is a complication of infancy that cannot be
predicted. The largest issue with terming a death as SIDS is that, till date, there are no diagnostic features that can be
attributed to a SIDS death and therefore, the application of the term relies solely on a process of elimination
(Duncan, 2018). When no other cause can be attributed to the death of an infant, even after an autopsy has been
conducted, the death of an infant will be labelled as SIDS.
Campaigns, such as Safe to Sleep or Back to Sleep, provided insight to the public about the various etiological
factors that could lead to SIDS, leading to the reduction of infant deaths. According to Duncan (2018), there has been
a reduction in the SIDS rate by 30-83%. The incidence rates of deaths by SIDS were at a peak in the 1970s and
1980s. From then, the rate of deaths by SIDS has declined considerably from 130.3 deaths per 100,000 live births in
1998 to 38.7 deaths per 100,000 live births in 2014 (CDC). According to Duncan (2018), there has been an overall
decline in the number of SIDS victims during the last century and this can largely be attributed to awareness, medical
advancements and increased standards of living. Despite the medical advancements and the awareness, SIDS
continues to remain as the leading cause of infant mortality in the Western countries, accounting for half of all post-
neonatal deaths (Carpenter, 2004).
The high incidence of SIDS can be explained by a concept that was first expanded upon by Wedgwood in 1972
(Duncan, 2018). Wedgewood expanded on a multiple contingency hypothesis through which he suggested that the
risk of SIDS was increased in situations where there was an overlap of three or more factors. These factors were [1]
general, such as prematurity, sex, overcrowding, poverty; [2] developmental; and [3] physiological. Wedgewood
reinforced that there needed to be an overlap of a variety of risk factors, instead of the presence of just one in
isolation. Duncan (2018) also mentions that Wedgewood stated death by SIDS would only occur in cases where the
combination of multiple factors would exceed the infant’s threshold for survival. Wedgewood’s hypothesis provides
a rather sinister explanation for the role of the various risk factors in leading to death by SIDS. It has been estimated
by Red Nose that, on average, at least 60 people are impacted by a child’s death to SIDS (Duncan, 2018).
When looking at SIDS victims, there appears to be a male predominance with boys accounting for 60% of the SIDS
deaths, but the exact reason for this gender dominance remains unknown (Esani, 2008). Some studies suggest that
the male vulnerability is due to the influence of sex differences in genetic and biological makeup (Duncan, 2018).
Male infants being victims of SIDS at a larger scale may simply just be a reflection of the fact that male infants tend
to be more vulnerable to illnesses and disease than females. Furthermore, male vulnerability by SIDS is further
exacerbated by the fact that males tend to have, overall, a greater mortality rate. Prematurity and low birth weight
also tend to increase the risk for SIDS fourfold and the most likely reason for this is the associated vulnerability in
premature or low birthweight infants due to an immature autonomic system (Duncan, 2018). Mothers of SIDS
victims tend to be less than 20 years of age, overweight, drug users (Akopian…). Though there is not much study in
regard to this, Duncan (2018) states that the pregnant women less than the age of 20 years an increased risk for SIDS.
Although the exact cause of SIDS is unknown, there are several factors that make the infant much more vulnerable,
but these risk factor this vary from infant to infant.
Wedgewood (1972) introduced a “triple risk hypothesis,’ that which consisted of focusing on general vulnerability of
the infant age-specific factors and precipitating factors. Rognum and Saugstad (1993) followed a similar perspective
to that of Wedgewood (1972), developing a “fatal triangle” in 1993, with groupings similar to those of Wedgewood.
Following the introduction of the “triple risk hypothesis,” several researchers corroborated the multi-factorial nature
of SIDS and the perspective that the combination of the various factors is what essentially causes an infant to become
a victim to SIDS. Despite being a multi-factorial syndrome, the risk factors for SIDS can be generalized into intrinsic
risk factors and extrinsic risk factors and be further broken down such as, environmental/physical risk factors, parent
risk factors, and infant risk factors. Within the categorization of the risk factors, there are a few factors that can be
deemed to be more important than the others. Through this paper, we will be discussing the categorization of the risk
factors in SIDS, and further investigating the more common risk factors within the categories.
RESEARCH POSTER PRESENTATION DESIGN © 2012
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Xavier University School of Medicine
Discussion
Prior to focusing on the various factors that can cause death by SIDS, it is important Duncan
(2018) states that any risk factor, alone, is not sufficient in causing SIDS – rather, an interaction
amongst a combination of factors is what results in death. there is an interaction amongst the
various risk factors that increases the vulnerability of an infant to become a victim to SIDS. When
looking at the intrinsic, or extrinsic, factors that could lead to SIDS death, it is important to note
that neither intrinsic nor extrinsic factors are exclusively visible in cases with SIDS. In 90% of all
SIDS cases, at least one extrinsic factor, sometimes more, is present.
Some studies have reported differences in the expression of up to 17 genes in SIDS infants,
including 3 genes involved in mediating inflammatory response (Ferrante, 2016). There have also
been some reports of polymorphism in the promotor region of the serotonin transporter gene, that
could result in altered serotonin uptake and regulation, supporting pathological and neurochemical
studies that report the serotonergic dysfunction in SIDS infants (Duncan, 2010). Both Narita et al.
(2001) and Weese-Meyer et al. (2003) report an increase in the ‘L’ allele in SIDS cases across
different ethnic groups. The L allele is responsible for increasing the effectiveness of the promotor
region in the serotonin transporter gene and therefore, an increased expression should essentially
lead to reduced serotonin concentrations .
Duncan (2018) suggests serotonergic abnormalities in the medullary network that may play a key
role in SIDS. The correlation between the serotonergic system and SIDS stems from role of the
serotonergic pathway in virtually all homeostatic processes (Duncan, 2018). SIDS infants have
also been associated with a reduced tryptophan hydroxylase2 activity. Tryptophan hydroxylase2 is
a key enzyme that is required for serotonin production. A reduction in the tryptophan hydroxylase2
activity suggests that SIDS infants may not be able to produce adequate levels of serotonin
(Duncan, 2018). There has been an association with SIDS and an increased brain weight that is not
associated with any type of edema or other cerebral anomalies. Periventricular and subcortical
white matter changes (Horne, 2005) and brainstem gliosis in the nucleus of the solitary tract and
inferior olive (Viemari, 2013) have both been reported in SIDS victims.
Thermal stress is a known risk factor of SIDS that is used to explain why bed sharing may put
infants at an increased risk (McGarvey, 2006). The implication being that the body heat from the
adjacent adults sharing the bed might contribute to SIDS through overheating of the infant or
rebreathing of expired air (McGarvey, 2006). Tappin (2005) suggests that all types of bed sharing
should be avoided, especially in cases where parents are smokers, alcoholics, drug users, or
excessively tired. In events where the adults are less aware of their surroundings while they are
asleep, co-sleeping with an infant could be proven to be a much more significant risk as accidental
smothering or suffocation of the infant could occur. It should be noted that when McGarvey (2006)
refers to bedsharing, it is the practice of co-sleeping.
Breakdown of Sudden Unexpected Infant Death by Cause, 2017
25%
Su d de n Infa n tDe ath S yn d rom e (SIDS)
39%
Un kn own Ca us es
Acci d en tal Su ffoc ati on an d S tran gu al ti on n
i Be d
36%
Figure 1
Multi-factorial causation of SIDS
Environmental Factors
Genetic SIDS Physiological
Factors Factors
External Stressors
Figure 2
Conclusion
Through this paper, we intended to not only provide insight into the complex nature of the factors
that increase susceptibility of an infant to SIDS, but to also explain the various implicit
mechanisms that may be occurring within the physiology of the infant as well. It is imperative to
understand that the infant’s internal homeostasis and reflexes to maintain the homeostatic
equilibrium are yet to be fully developed and because of that, even the slightest external stressor
could prove to be detrimental for the infant before the age of 1 year. With the ability of the trachea
to collapse while in prone sleeping position, or decreased baroreceptor sensitivity, slight internal
imbalances become difficult for the infant to counteract and with the presence of 3 or more
stressors, the infant suffers as the stressors become much stronger than the reflexes and receptors
within the infant. It is crucial that to ensure that the number of extrinsic risk factors and external
stressors are kept at a minimum to ensure the number of risk factors present are as less as possible,
further reducing the number of SIDS victims. It is important to understand that there have also
been factors that have been considered to decrease the risk of SIDS, but just like with the factors
associated with increased risk of SIDS, there is a lack of subsequent research that reinforces
whether or not such practices truly reduce the likelihood of SIDS. All factors listed: physiological
factors, environmental factors and genetic, are factors that produce a collaborative effect of SIDS.
None of the factors alone are strong enough to be causing SIDS. Like with Wedgewood (1972)
stated with his triple risk hypothesis, it at least three factors must be present in order for the
causation of SIDS and this is largely due to the strength of the factors being greater than the
infant’s threshold for survival. The accumulation of several factors causes a maximum amount of
stress for the infant that he/she is unable to withstand, and therefore, becoming a victim of SIDS.
References
Beckwith, B.J. (1970). Observations on the pathological anatomy of the sudden infant death syndrome. In
International Conference on Causes of Sudden Death in Infants, 1970 (pp. 88-139). University of Washington Press.
Bell, H. J., & Haouzi, P. (2009). Acetazolamide suppresses the prevalence of augmented breaths during exposure to
hypoxia. American Journal of Physiology-Regulatory, Integrative and Compartive Physiology, 297(2), R370-R381.
Blackwell, C., Moscovis, S., Hall, S., Burns, C., & Scott, R. J. (2015). Exploring the risk factors for sudden infant
deaths and their role inflammatory responses to infection. Frontiers in immunology. 6, 44.
Blair, P. S., Sidebotham, P., Pease, A., & Fleming, P. J. (2014). Bed-sharing in the absence of hazardous
circumstances: is there a risk of sudden infant death syndrome? An analysis from two case-control studies conducted
in the UK. PLoS One, 9(9), e107799.
Byard, R. W., Bright, F., & Vink, R. (2018). Why is a prone sleeping position dangerous for certain infants? Forensic
Science, Medicine and Pathology, 14(1), 114-116.
Carpenter, R. G., Irgens, L. M., Blair, P. S., England, P.D., Fleming, P., Huber, J., … & Schreuder, P. (2004). Sudden
unexplained infant death in 20 regions in Europe: case control study. The Lancet, 363(9404), 185-191.
Duncan, J. R., & Byard, R. W. (Eds). (2018). SIDS Sudden infant and early childhood death: The past, the present
and the future. University of Adelaide Press.
Duncan, J. R., & Paterson, D. S., Hoffman, J. M., Mokler, D. J., Borenstein, N. S., Belliveau, R. A., … &
Trachtenberg, F. L. (2010). Brainstem serotonergic deficiency in sudden infant death syndrome. Jama 303(5), 430-
437.
Dwyer, T., & Ponsonby, A. L. (1995). SIDS epidemiology and incidence. Pediatric annals 24(7), 350-356.
Dwyer, T. & Ponsonby, A. L. (1996). The decline of SIDS: a success story for epidemiology. Epidemiology, 323-325.
Esani, N., Hodgman, J. E., Ehsani, N., & Hoppenbrouwers, T. (2008). Apparent life-threatening events and sudden
infant death syndrome: comparison of risk factors. The Journal of pediatrics, 152(3), 365-370.
Ferrante, L., Rognum, T. O., Vege, A., Nygård, S., & Opdal, S. H. (2016). Altered gene expression and possible
immunodeficiency in cases of sudden infant death syndrome. Pediatric Research, 80(1), 77.
Fleming, P., Blair P., & Pease, A. (2017). Why or how does the prone sleep position increase the risk of unexpected
and unexplained infant death?
Franco, P., Lipshutz, W., Valente, F., Adams, S., Scaillet, S., & Kahn, A. (2002). Decreased arousals in faints who
sleep with the face covered by bedclothes. Pediatrics, 109(6), 1112-1117.
Heininger, U., Kleemann, W. J., & Cherry, J. D. (2004). A controlled study of the relationship between Bordetella
pertussis infections and sudden unexpected deaths among German infants. Pediatrics, 114(1), e9-e15.
Horne, R. S., Sly, D. J., Cranage, S.M., Chau, B., & Adamson, T. M. (2000). Effects of prematurity on arousal from
sleep in the newborn infant. Pediatric research, 47(4), 468.
Horne, R. S., Ferens, D., Watts, A. M., Vitkovic, J., Lacey, B., Andrew, S., … & Adamson, T. M. (2001). The prone
sleeping position impairs arousability in term infants. The Journal of pediatrics, 138(6), 811-816.
Horne, R.S., Parslow, P.M., & Harding, R. (2005). Postnatal development of ventilatory and arousal responses to
hypoxia in human infants. Respiratory physiology and neurobiology 149(1-3). 257-271.
Li, P., Janczewski, W. A., Yackle, K., Kam, K., Pagliardini, S., Krasnow, M. A., & Feldman, J. L. (2016). The
peptidergic control circuit for sighing. Nature, 530(7590), 293.
McGarvy, C., McDonnell, M., Hamilton, K., O’Regan, M., & Matthews, T. (2006). An 8 year study of risk factors
for SIDS: bed-sharing versus non-bed-sharing. Archives of diseases in childhood, 91(4), 318-323.