It is currently believed that SIDS is not due to a single factor but is multifactorial in origin. Over the past four decades several models have been proposed to explain the multifactorial nature of SIDS, including the three interrelated causal spheres of influence model (21), the Quadruple Risk Model (22) and the Triple Risk Model (23). The most widely accepted model is the Triple Risk Model for SIDS, which provides useful means for organizing SIDS knowledge. This model proposes that SIDS occurs when three factors occur simultaneously: [1] a vulnerable infant; [2] a critical developmental period for homeostatic control; and [3] an exogenous stressor (23) ().
In an attempt to understand how the Triple Risk Hypothesis is related to infant cardiorespiratory physiology, many researchers have examined how the known risk and protective factors for SIDS alter infant physiology and arousal, particularly during sleep. The remainder of this chapter discusses the association between the three components of the Triple Risk Hypothesis and major risk factors for SIDS, such as prone sleeping and maternal smoking, together with three “protective” factors and cardiovascular control and arousability from sleep in infants, along with their potential involvement in SIDS.
Vulnerable infant
Neuropathologic findings from SIDS victims show significant deficits in brainstem and cerebellar structures involved in the regulation of both respiratory drive, cardiovascular control, sleep/wake transition, and arousal from sleep (25-32). Furthermore, genetic polymorphisms have been identified in SIDS victims which affect genes involved in autonomic function, neurotransmission, energy metabolism, and the response to infection (33-37). Infants with certain genetic polymorphisms are believed to be more vulnerable to SIDS, particularly when these are associated with challenges caused by suspected suboptimal intrauterine and postnatal environments (24).
Exposure to cigarette smoke, alcohol, and illicit drugs
Prenatal and/or postnatal exposure to cigarette smoke is one factor which increases infant vulnerability to SIDS (38, 39), with over 40 studies showing a positive association with risk ratios of between 0.7 and 4.85 (40-43). This increased SIDS risk is likely to be due to the effects of nicotine exposure on autonomic control and arousal (32, 44-48). In support of this idea, Duncan and colleagues (49) found that chronic exposure to nicotine in the prenatal baboon fetus altered serotonergic and nicotinic acetylcholine receptor binding in regions of the medulla, critical to cardiorespiratory control. Furthermore, they identified that these alterations were associated with abnormalities in fetal heart rate variability, indicating altered cardiovascular control (49). Studies in infants exposed to maternal smoking have demonstrated altered heart rate and blood pressure control compared with control infants (50-56). Maternal tobacco smoking also decreases both total arousability and the proportion of cortical arousals. Arousal impairment was observed for both spontaneous arousals from sleep and responses induced by various stimuli (57-63). Few mothers change their smoking behavior postpartum (64); it is therefore difficult to ascertain whether these physiological effects are caused by prenatal or postnatal smoke exposure. Environmental smoke (in the same room) independently increases the risk of SIDS (65, 66). Importantly, it has been shown that before discharge from hospital, preterm infants of smoking mothers already exhibited disruptions in sleep patterns prior to any postnatal smoke exposure (67).
Exposure to alcohol is also a risk for SIDS (68, 69). Animal studies have shown that arousal latency to hypoxia is increased when rat pups were exposed to prenatal alcohol (70). Furthermore, a number of studies have identified that prenatal exposure to illicit drugs also increases the risk for SIDS (71-73). Studies have shown that infants exposed to illicit drugs had an impaired response to a hypoxic challenge at the peak age for SIDS (74). However, another study found no differences in arousal responses to auditory stimuli in methamphetamine-exposed infants; however, infants in both groups were also exposed to maternal smoking (75).
In summary, there is considerable evidence from both animal and human studies suggesting that prenatal exposure to cigarette smoke, alcohol, and illicit drugs has deleterious effects on the developing brain and cardiorespiratory system. It is suggested that these effects increase infant vulnerability to SIDS.
Preterm birth
Maternal smoking may also be a confounding risk factor for SIDS due to its association with other risk factors, such as preterm birth and intrauterine growth restriction (IUGR) (76-79), which likely result from suboptimal intrauterine environments. Regardless of prenatal exposure to maternal smoking, infants born both preterm and IUGR are at increased risk for SIDS (80-87). The proportion of infants who die suddenly and unexpectedly and who are preterm is approximately four times as great as those born at term (20% compared to 5%). These proportional differences have remained unchanged since the introduction of public campaigns for reducing the risks, and the risk factors for preterm infants are similar to those born at term (84, 85). Despite more than halving the rate for preterm infant deaths attributed to SIDS over the last 20 years, the risk for SIDS deaths among preterm infants compared with infants born at term remains elevated (87).
The risk for SIDS in preterm infants has also been shown to be inversely related to gestational age (88-95), with one study demonstrating that the incidence of SIDS in infants born at 24-28 weeks, 29-32 weeks, 33-36 weeks, and more than 37 weeks was 3.52, 3.01, 2.27, and 1.06 deaths per 1,000 live births respectively (83).
Impaired heart rate control, manifesting as shorter cardiac R-R intervals and higher resting sympathetic tone, has been reported in term-born IUGR infants when compared with infants of appropriate size for gestational age (96, 97). Similarly, preterm infants demonstrated impaired autonomic control compared with term infants studied at, or before, term-equivalent age, and this pattern was inversely related to gestational age at birth (98-103). Longitudinal studies after term-equivalent age have identified that preterm infants exhibited lower blood pressure, delayed blood pressure recovery following head-up tilting, and impaired baroreflex control of blood pressure and heart rate across the first six months corrected age, when compared with age-matched term infants (104-108). Furthermore, maturation of baroreflex control of blood pressure is affected by gestational age at birth, with infants born very preterm (<32 weeks of gestation) having reduced increases in baroreflex sensitivity compared to both preterm and term infants (109). Recently, studies have also identified that cerebral oxygenation is also lower in preterm, compared to term, infants across the first six months corrected age (110) and that cerebrovascular control after a head-up tilt is more variable (111), indicating immature or impaired control.
When compared with term infants at matched conceptional ages, preterm infants also exhibit decreased frequencies and durations of spontaneous arousals from sleep (112-114), together with decreased heart rate responses following arousal (115). Furthermore, preterm infants exhibited longer arousal latencies after exposure to mild hypoxia (15% inspired O2), reaching significantly lower oxygen saturations than term infants (116). Cardiorespiratory complications commonly associated with prematurity, apnea and bradycardia, have also been shown to suppress total arousability when these infants were compared to preterm infants with no history of apnea (117).
In summary, infants born preterm and growth-restricted are at increased risk for SIDS, and alterations in cardiorespiratory control and arousability during sleep likely underpin this vulnerability. Such physiological disturbances may be further exacerbated during a critical developmental period within infancy and by exposure to exogenous stressors.
Critical developmental period
Approximately 90% of SIDS deaths occur in infants aged less than 6 months (24, 118). During this period, the central nervous system undergoes dramatic maturational changes which are reflected in extensive alterations to sleep architecture, EEG characteristics, and autonomic cardiorespiratory control. The 2- to 4-month period, in particular, has been described as a “developmental window of vulnerability” (119, 120), and coincides with the age where a distinct peak in SIDS incidence occurs (24, 118). The age of peak SIDS incidence has been reported to have remained constant at 2 to 4 months of age following the introduction of safe sleeping campaigns in some studies (118, 121). However, other studies have reported that the peak SIDS incidence may now occur at an earlier age (122), with a decrease in the median peak age from 80 to 64 days in Sweden (123) and 91 to 66 days in South West England (124) since the initiation of “Back to Sleep” campaigns.
Autonomic control
Autonomic function increases with gestational age in the fetus during pregnancy (125, 126). Both parasympathetic and sympathetic activities increase during gestation, but not in the same manner. The largest increase in parasympathetic activity occurs during the last trimester, while the largest increase in sympathetic activity occurs early on, with smaller changes occurring during the last trimester (127). After birth at term, heart rate increases initially over the first month of life before declining gradually, as a result of an increase in parasympathetic dominance of autonomic control of heart rate (18, 128). Studies of the maturation of heart rate control using HRV have shown an increasing dominance of parasympathetic control across the first six months of life (17). Preterm birth has been associated with immaturity of autonomic nervous system control of the cardiovascular system. This manifests as higher heart rates (98, 99), reduced heart rate variability (99, 129, 130), and decreased baroreflex sensitivity compared to infants born at term (131, 132). Longitudinal studies examining the maturation of blood pressure and its control during sleep in healthy term infants are limited, primarily because of the difficulty of measuring blood pressure continuously and non-invasively. From large studies using intermittent blood pressure measurements, it has been identified that during the first six weeks after birth, systolic blood pressure rises rapidly to reach a steady level which is maintained during infancy (133). Diastolic blood pressure has been shown to fall after birth, reaching a nadir at approximately 2 months of age, followed by a gradual increase until 1 year of life (133).
A number of significant developmental factors may make an infant more vulnerable to a cardiorespiratory challenge during this critical developmental period from birth to 6 months of age, and particularly between 2 to 4 months when the risk of SIDS peaks. Studies in both preterm (105, 110) and term (18) infants have identified a nadir in basal blood pressure during sleep at 2 to 4 months of age, when compared to both earlier (2 to 4 weeks) and later (5 to 6 months) ages studied; a nadir in physiological anemia also occurs at this age. Blood pressure responses to a cardiovascular challenge (head-up tilting) are also impaired at 2 to 4 months compared to younger (2 to 4 weeks) and older (5 to 6 months) ages (134). Studies have also shown that there is a maturational reduction in cerebral oxygenation, which is most marked between 2 to 4 weeks and 2 to 4 months of age, which may be due to limited or inadequate flow-metabolism coupling at this age (135). Thus, the 2- to 4-month age could represent a critical time period when effects of low blood pressure could accentuate decrements in oxygen-carrying capacity and delivery to critical organs (18).
There are even fewer studies of maturation of blood pressure variability (BPV) in infants. BPV decreases with increasing gestational age until term, suggesting a reduction in sympathetic modulation to term-equivalent age (136). BPV continues to decrease with postnatal age after term (137). Taken together these findings suggest that, while sympathetic vascular control is predominant in the newborn period, there is a shift to that of predominantly parasympathetic control with increasing postnatal age, with critical maturational changes occurring when the risk of SIDS is greatest.
The arterial baroreflex is the most important autonomic regulatory mechanism for the short-term control of blood pressure, heart rate, and cardiac contractility. This reflex minimizes changes in blood pressure primarily by altering heart rate and arterial vascular tone. Thus, when there is an increase in blood pressure, it is countered by a decrease in both heart rate and arterial vascular tone. The responses of heart rate and vascular tone are mediated by the efferent parasympathetic and sympathetic limb of the baroreflex respectively. As both systems are involved, studies of the baroreflex provide information on the sympathovagal balance of control of the autonomic nervous system. The baroreflex is present and functional from early fetal life and undergoes significant maturation in utero. The effectiveness of the baroreflex, termed baroreflex sensitivity, increases significantly with postnatal age from 5 to 6 ms/mmHg at 2 to 4 weeks of age to 11-16 ms/mmHg at 5 to 6 months of age, a value similar to that reported in adults (138). Whilst immature, infants may be at increased vulnerability to hypotensive or hypertensive events.
Effects of postnatal age on respiratory control
In order to maintain blood oxygen levels, adult humans exposed to lowered oxygen levels experience a prompt increase in ventilation that peaks within 3 to 5 minutes. This period of hyperventilation is sustained for approximately 15 to 30 minutes before a subsequent decline to pre-hypoxic baseline values. This response is referred to as the hypoxic ventilatory response (HVR). The HVR in infants is quite different to that of adults. Following exposure to low oxygen levels, infants exhibit a “biphasic” HVR response which typically consists of a transient hyperventilation (within the first 2 minutes) termed the augmented phase, followed by a sustained reduction in ventilation towards or below normoxic levels, termed the depressive phase. This biphasic HVR has been demonstrated in term and preterm infants during both wakefulness and sleep and some studies have observed the immature HVR in human infants up to two months after birth (139, 140), while others have shown that it remains immature up to 6 months of age (141).
Arousal responses
Infant arousal responses are also affected by postnatal age, although these maturational effects are sleep-state-dependent. Previous studies have demonstrated that in response to respiratory (mild hypoxia), tactile (nasal air-jet) and auditory stimulation, total arousability is reduced with increasing age during quiet sleep, whilst remaining unchanged in active sleep (142-144). Following the introduction of standard scoring criteria for sub-cortical activation and cortical arousal as separate entities, a recent study noted that spontaneous sub-cortical activations decreased with increasing postnatal age, whilst cortical arousals increased (145). Conversely, another study analyzed both spontaneous and nasal air-jet induced arousability during supine sleep, and found no change in the percentage of cortical arousals (from total responses) throughout the first six months of life (146). Interestingly, when the same infants slept in the prone position, an increased propensity of cortical arousal was identified at 2 to 3 months, the age when SIDS is most common (63, 146). This increase in cortical arousals may reflect an innate protective response to ensure an appropriate level of arousal for restoring homeostasis, not only during a vulnerable period of development, but also in the presence of an exogenous stressor (e.g. the prone sleeping position).
In summary, a large body of work has demonstrated that both autonomic control of the cardiovascular system and arousal responses from sleep are maximally affected by the major risk factors for SIDS, at 2 to 4 months of age when SIDS risk is greatest.
Exogenous stressor(s)
An exogenous stressor constitutes the third aspect of the Triple Risk Model for SIDS. Epidemiological studies have identified numerous factors common to SIDS victims, such as the prone sleeping position, overheating, and recent infection, which may disrupt homeostasis (24, 33, 147, 148).
Prone sleeping
The prone sleeping position has long been considered the major risk factor for SIDS (78, 149-152), with some studies suggesting a causal relation between prone sleep and SIDS (153, 154). Several physiological changes ensue when infants sleep prone, including increased peripheral skin temperature and baseline heart rate, together with decreased heart rate variability (18, 155-163). In an effort to identify changes in autonomic cardiovascular control with sleeping position, studies examining heart rate responses to auditory and nasal air-jet stimuli have suggested an increase in sympathetic, and a decrease in parasympathetic, tone in the prone sleeping position (164, 165). Furthermore, sympathetic effects on blood pressure and vasomotor tone are decreased in the prone sleeping position. Lower resting blood pressure and altered cardiovascular responses to head-up tilting have also been identified in term infants when sleeping in the prone position, compared with the supine position (18, 134). Cerebral oxygenation is reduced and cerebrovascular control impaired in the prone position in both term (135, 166) and preterm infants (110, 167). In addition, prone sleeping infants exhibit reduced cardiac and respiratory responses when arousing from sleep, when compared to sleeping in the supine position (164, 165).
Previous studies of both term and preterm infants have consistently identified increases in sleep time, with significant reductions in spontaneous arousability associated with prone sleeping when compared with the supine position (168-171). Furthermore, in other studies the prone sleeping position depressed arousal responses provoked by postural change (155), auditory (172), and somatosensory challenges (62, 156, 173). It has been demonstrated that both spontaneous and induced arousal responses are similarly affected by sleep state and SIDS risk factors, suggesting that they are mediated through the same pathways (174). Despite this well-documented decrease in total arousability, examining subcortical and cortical responses separately has produced conflicting results. Although one study reported a decreased frequency of spontaneous cortical arousals in the prone position (171), more recent studies have found an increased proportion of cortical arousals (of total responses) in both infants not exposed to cigarette smoke and those exposed to cigarette smoke when sleeping prone (63, 146). This apparent promotion of full cortical arousal, demonstrated for both spontaneous and stimulus-induced responses, may protectively compensate against the threat of altered autonomic control and the already blunted total arousability imposed by the prone position.
The prone sleeping position also potentiates the risk of overheating, by reducing the exposed surface area available for radiant heat loss and reducing respiratory heat loss when the infants face is covered (175). Both physiological studies in healthy infants and theoretical model studies of heat balance have observed a decreased ability to lose heat when in the prone position (176-178). Early studies observed decreased variation in behavior and respiratory pattern, increased heart rate, and increased peripheral skin temperature during prone, compared with supine, sleep (177). These studies suggest that infants are less able to maintain adequate respiratory and metabolic homeostasis when sleeping prone.
Increased sweating occurs in SIDS victims, regardless of whether infants slept prone or supine; these cases were predominantly associated with a covered face (118, 179). A history of profuse sweating in SIDS victims has been postulated to be a phenomenon representing an abnormality of function of the autonomic nervous system (180). The involvement of thermal stress with SIDS is further supported by the finding of similar odds ratios for both too much and too little bedding (181), and the suggestion that future SIDS victims may have had atypical temperature regulation (182). Infant arousability is also affected by body and room temperature: decreased sleep continuity and increased body movements have been associated with exposure to cooler temperatures (183), whilst infants sleeping in warmer environments (28 °C vs 24 °C) exhibited increased arousal thresholds to auditory stimuli (184). Furthermore, based on studies assessing blood pressure control in infants (157, 162), it has been suggested that in response to the increased peripheral skin temperature when infants sleep prone, thermoregulatory vasodilatation of the peripheral microvasculature occurs, resulting in a decrease in blood pressure and a reduction in vasomotor tone. Recent studies in preterm infants have shown that increased ambient temperature led to significant changes in autonomic control with elevated heart rate and lower heart rate variability compared to thermoneutral or cooler temperature (185).
Head covering
Head covering has been identified as a major risk for SIDS, with between 16-28% of SIDS infants found with their heads covered. Although a causal relationship with SIDS has not been established (186, 187), it appears likely that rebreathing and impaired arousal are involved. It has been suggested that the increased SIDS risk associated with head covering may result from hypoxia and hypercapnia via rebreathing of expired air (186, 188). Head covering in healthy infants has profound effects on autonomic control during sleep (189). Franco and colleagues (189) found that infants sleeping supine with their head covered by a bedsheet exhibited decreased parasympathetic activity, increased sympathetic activity, and increased body temperature when compared with head-uncovered periods. In addition, arousal responses in active sleep were also depressed when the head was covered (190).
Bed sharing
Bed sharing or co-sleeping has also been reported to significantly increase the risk of SIDS, particularly when the mother smokes (118, 124, 191, 192), with more than 50% of SIDS deaths occurring in this situation between 1997 and 2006 (193, 194). There have been few studies investigating the physiology behind this risk factor. In infants from non-smoking families who were studied on successive bed-sharing and solitary-sleeping nights, bed sharing was associated with increased awakenings and transient arousals during slow-wave sleep compared to solitary nights (195). In contrast, another study found that bed-sharing infants spent less time moving and were more likely to have their heads partially or fully covered by bedding than cot-sleeping infants (196). Thus more studies are required to identify the exact physiological changes which occur during bed sharing.
Swaddling
Swaddling, or firm wrapping, is a traditional infant care practice which, according to an extensive historical review, has been used in some form or another by various cultures since medieval times (197). Low incidences of SIDS in populations where swaddling is common has led to the proposal that swaddling may be protective (198, 199) and on this basis a number of SIDS prevention organizations recommend it. Several studies have documented a “tranquil” behavioral state with longer sleep periods in swaddled infants. Therefore, despite a disparity between studies on the risk for SIDS (124, 200, 201), swaddling has become increasingly popular as a soothing technique throughout the world (202, 203).
Swaddling is a common practice in infants throughout the first six months of life, during the period of increased SIDS risk. The duration of swaddling and the age of initiation of the practice vary widely. The average duration of swaddling has been reported to be 35 days in infants in Yunnan Province in China (204) and to be for the entire first year of life in rural Turkish children (205). The age of initiation of swaddling also varies, with reports of commencing swaddling in the first month of life in Mongolia (206) and immediately after birth in Russia (207). Currently it is unclear if swaddling is protective against SIDS or if it is indeed a risk. In the United Kingdom during the mid-1990s, swaddling during the last sleep was more common amongst SIDS infants than age-matched controls (14% vs. 9%); furthermore, a more recent study showed that this difference has since become more marked (19% vs. 6%) (124). However, a recent meta-analysis has concluded that swaddling was not protective and that placing an infant prone when swaddled significantly increased the risk of death (208). That there is no evidence to recommend swaddling as a strategy to reduce the risk of SIDS has now been endorsed by the American Academy of Pediatrics (209).
Studies investigating the effect of swaddling on cardiovascular control are limited. Swaddling elicits a mild increase in respiratory frequency, most likely due to restricted tidal volumes imposed by the firm wrapping (210-212). No significant effects have been documented on baseline heart rate, skin temperature, or oxygen saturation in term infants when swaddled during sleep (211, 213). Studies which compared infants who were routinely swaddled to those who were unused to this practice found that sleep time and heart rate variability were only altered in those infants naïve to swaddling (214). Several studies investigated the effects of swaddling in relation to infant arousability; however, divergent results have been published. The commonly observed decreases in spontaneous movements and startle responses with swaddling are in contrast to effects of other protective factors for SIDS (197, 215). One study reported that when infants were swaddled, fewer startle responses progressed to a full awakening, indicating an inhibition of the cortical arousal process (216). More recent studies reported that swaddled infants exhibited increased arousal thresholds in response to nasal air-jet stimulation. Furthermore, a decreased frequency of full cortical arousals was observed primarily in infants who were unaccustomed to being swaddled, at 3 months of age (211). Spontaneous cortical arousals were also decreased in those infants unaccustomed to being swaddled, at 3 months of age (214).
These arousal differences between routinely swaddled and naïve-to-swaddling infants, only at this age of peak SIDS risk, may explain the contradictory findings of another group which found decreased auditory arousal thresholds in swaddled infants when compared to infants who were free to move (213). The authors attributed these effects of swaddling on arousal to the greater autonomic changes found after auditory stimulation in swaddled conditions (217). As with the other risk factors discussed above, the mechanisms whereby swaddling may increase the risk for SIDS remain unclear, and further research is required.
Other external stressors
Other external stressors, such as infection, fever, and minor respiratory and gastrointestinal illnesses, commonly occur in the days to weeks preceding death of SIDS victims (218-220). Although not identified as an independent risk factor for SIDS, minor infections have been associated with an increased likelihood of SIDS when combined with head covering or prone sleeping (122, 200). In the prone sleeping position, minor infection, in combination with fever, could further exacerbate thermoregulatory effects on peripheral vasculature, which could increase the susceptibility of a hypotensive episode. Thus, hypotension, in combination with a decreased ability to arouse from sleep, which has been documented in term infants immediately following an infection (221), could potentially further impair an infant’s ability to appropriately respond to a life-threatening challenge such as circulatory failure or an asphyxial insult.
In summary, numerous studies have shown that exposure to exogenous stressors which have been associated with increased SIDS risk, such as prone sleeping and head covering, impair autonomic cardiorespiratory control and infant arousal responses from sleep. The mechanism of increased risk for other factors, such as bed sharing and swaddling, is less clear and further research is required.
![Figure 22.2:. Triple Risk Model for SIDS, illustrating the three overlapping factors: [1] a vulnerable infant; [2] a critical developmental period; and [3] an exogenous stress. (Adapted from (23).).](/books/NBK513398/bin/9781925261677_fig22_2.gif)