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Plasma progesterone levels, infant temperament, arousals from sleep, and the Sudden Infant Death Syndrome
Medical
Hypotheses
9:
215-222,
1982
PLASMA PROGESTERONE LEVELS, INFANT TEMPERAMENT, AND THE SUDDEN INFANT DEATH SYNDROME
AROUSALS
FROM SLEEP,
Marc Weissbluth, M.D., Div. Ambulatory Services, Children's Hospital, 2300 Children's Plaza, Chicago, Illinois.
Memorial
ABSTRACT Endogenous plasma progesterone levels may influence relationships between infant temperament, sleep patterns, and respiratory control Elevated progesterone levels may account for the lethargic deficits. temperament observed among victims of Sudden Infant Death Syndrome. INTRODUCTION Infantile colic and the sudden infant death syndrome (SIDS) have similar In contrast, the temperament characteristics of high natural histories. activity and high intensity among infants with colic are dramatically opposite from the low activity and low intensity ratings among SIDS victims. A previous study of infants with the near-miss sudden infant death syndrome (N-M SIDS) suggested that arousals from sleep may represent a protective mechanism in infants with sleep-related respiratory control deficits (1). Plasma progesterone levels may influence arousals from sleep, sleep patterns, respiratory control during sleep, and infant temperement characteristics. A feedback control relationship might exist between endogenous plasma progesterone levels and hypoxia or hypercarbia resulting from Severe respiratory control deficits respiratory dysrhythmias during sleep. might produce elevated plasma progesterone levels to stimulate respiratory In addition to respiratory stimulation, high progesterone levels effort. However, the high might modulate sleep patterns and awake behavior. progesterone levels might have the undesirable and possibly lethal effect of diminishing or abolishing the protective arousal responses to asphyxic apneic episodes during sleep.
215
PROGESTERONE Pharmacologic doses of progesterone and its metabolite pregnanedione have been shown to induce sleep and anesthesia (2). Newborn animals are unusually sensitive to steroid anesthetics in comparison to conventional anesthetics. Experimental studies with mammalian brain tissue showed that progesterone may be readily converted to pregnanedione by endogenous enzymatic activity (3). Thus, in infants, it is possible that endogenous plasma progesterone levels may influence sleep-wake control mechanisms. In contrast to the central nervous system depressor effects of steroid anesthetics, progesterone and its analogues have respiratory stimulating properties (4-6). Pharmacologic doses of progesterone analogues have been utilized successfully to treat adults with respiratory control disorders. Progesterone may also affect behavior directly. Behavioral effects of other sex hormones have been well documented (7). For example, young animals are susceptible to sex hormones which imprint sexually dimorphic mating patterns. Thus, in addition to being unusually sensitive to steroid anesthetics, newborn animals are particularly susceptible to the behavioral effects of sex hormones. In infants, a progesterone analogue, ethisterone, was used to successfully treat colic (8). In that study, the authors postulated that infantile colic was due 'to progesterone deficiency. A recent study showed that plasma progesterone levels were not significantly lower among infants with colic (9). However, that study did show that low levels of plasma progesterone were significantly associated with the related conditions of difficult infant temperament and low sensory threshold. INFANT TEMPERAMENT Infant temperament characteristics appear to represent congenital differences (10). Genetic factors as well as prenatal and postnatal environmental factors may contribute to the development of infant temperament characteristics. It is possible that a single neuropathologic process produces specific awake behavioral styles and respiratory control deficits during sleep. Alternatively, congenitally distinct infant temperament characteristics may be subsequently modulated directly by abnormal sleep patterns or indirectly by parental response to brief and interrupted infant sleep patterns. The difficult infant temperament diagnosis describes a particular clinical Infants with a difficult and statistical clustering of characteristics. temperament are irregular, withdrawing, slowly adaptable, intense, and negative in mood. Parent ratings greater than the mean in four of these five temperament characteristics with two ratings greater than one standard deviation above the mean are published diagnostic criteria (11). Intensity ratings greater than the mean must be one of the four high temperament ratings needed to establish this diagnosis.
216
As reported previously
(l), there are several separate older studies suggesting a relationship between infantile colic, difficult temperament, low sensory threshold (12), and frequent night awakenings (13). Recent studies have supported the association betweyn difficult temperament, frequent night awakenings (141, and brief sleep durations (10,lS). Brief sleep durations were also observed in a group in infants with symptomatic sleep apnea (N-M SIDS) (16). In that study, high activity and high intensity ratings were associated with less apnea. Also, in that study, low sensory threshold was associated with less apnea. An expected physiologic protective response to sleep apnea would be partial or complete arousals from sleep (17). AROUSALS
FROM SLEEP
Arousal from sleep may be a naturally occurring protective physiologic response to abort sleep-related pathologic events such as apneic asphyxia (1,18). Among N-M SIDS infats, impaired behavioral awakenings from sleep or diminished arousal responses to hypercarbia and hypoxia have been reported recently (19). In contrast, an increased frequency of night awakenings has been reported in normal infants with a low sensory threshold (13). A low sensory threshold in normal infants has also been reported to be associated with colic (12) and low plasma progesterone levels (9). Finally, among N-M SIDS infants, those with a low sensory threshold had less sleep apnea (16). Thus, there appears to be a parallel relationship between chemosensitivity mediated arousal from sleep and sensitivity to external stimulation when awake. Infants who awaken from sleep easily are also sensitive to external stimulation when awake and may tend to have colicky behavior, difficult temperaments, and low plasma progesterone levels. SUDDEN INFANT DEATH SYNDROME Pathologic studies of SIDS victims and physiologic studies of N-M SIDS infants suggest that these disorders may result from sleep-related respiratory control deficits (20). Documented respiratory deficits among N-M SIDS infants include diminished ventilatory and arousal responses to hypoxia and/or hypercarbia, prolonged sleep apnea, and increased frequency of periodic breathing. Recent studies suggest that the arousal response is mediated by the carotid body chemoreceptors (21,22). This paper hypothesizes an additional pathophysiologic process due to elevated endogenous plasma progesterone levels (Figure). Initially, congenital respiratory control deficits might lead to increased plasma progesterone to stimulate respiration during sleep and an increased frequency of protective arousals from sleep. Parents would note an apparent difficulty in maintaining long sleep durations or unusual Typically, infants with colic behave in this wakefulness in such infants. sleepless fashion (23). As would be expected among infants selected for N-M SIDS, a significantly increased prevalence of colic was reported (1).
217
FIGURE
PROGESTERONE, PATTERNS AND
SLEEP
Congenital
Frequent octrtial or complete Irregular sleep patter&,
SLEEP APNEA, INFANT TEMPERAMENT
Respiratory -
Control
Deficits
Elevated
orousals (awakening)
endogenous
progesterone
levels
Respiratory stimul&ion plus increased central nervous system depression
brief sleep periods
1 Colic occurs if infants have high lirf8nsity (dlffkull femperomenfl or low sensory threshold
1 Colic disappears
I Brief total and night sleep durations 1 negative Difficult
mood
temperameni occurs if infants have nigh intensity
Arousal response deficit occurs from sleep fragmentation?, abnormol sleep state periodicity?, Otr high plasma progesterone levels? Outcome
determined
1
by balance between
congenital
temperament
Low sensory threshold Lower progesterone levels Blunted arousals present Brief sleep durations Less symptomatic sleep apnea
Low activity, low intensity ( easy 1 High sensory threshold Higher progesterone levels Arousals absent Long sleep durations More symptomatic sleep apnea
+ N-M SIDS
+ SIDS
High activity,
high
intensity
fdifficuff)
218
The interrupted durations which sleep durations affect the mood
sleep pattern might lead to the brief ni ht sleep also were observed for N-M SIDS infants 4 16). Brief might directly produce a negative mood or indirectly of the infant by altering parental response to the infant.
Infants with the congenital temperament of low intensity and/or mild respiratory control deficits might have less sleep pattern disruption. These infants would be expected to not have colic or the difficult temperament. The hypothesis that sleep related respiratory control deficits may influence behavior when awake by disrupting sleep is consistent with recent observations in children with obstructive sleep apnea (24). In that study, behavioral and developmental deficits were observed to be reversible after successful treatment. The rapidity of improvement following treatment suggests that sleep deprivation or sleep fragmentation directly produces behavioral changes when awake. Although arousal response deficits may be congenital in origin, they also may be experimentally induced in dogs by interrupting sleep for as brief a time as two days (25). Therefore, the initially protective arousals from sleep might also severely disrupt sleep patterns. Subsequently, cumulative effects of fragmented sleep might lead to an acquired arousal response deficit. Presumably, the acquired arousal response deficit could be mediated by increased plasma progesterone levels producing increased control nervous system depression. As a result of sleep deprivation or central nervous system depression, lethargic awake behavioral patterns would be expected to occur. This type of behavior was observed in the experimental sleep fragmentation study. The dogs were listless, less spontaneously active, and participated only lazily in exercise routines. The observation that colic disappeared before the victims of SIDS died (1) could also be attributed to increasing plasma progesterone levels which might suppress the fretful, restless and irritable colicky spells. Additionally, plasma progesterone levels might fluctuate over a 24 hour period. It appears that the time of highest risk for impaired arousals among N-M SIDS infants is between 0100 and 0600 hours (26). Further, recent studies of N-M SIDS infants suggest that the periodicity of their sleep states is abnormal (27). Therefore, the relationship between sleep fragmentation, acquired arousal deficits and high progesterone levels might not be due to absolute high progesterone levels but rather to a developmental asynchrony between circadian rhythms controlling sleep states and plasma progesterone levels. Thus, inappropriately high progesterone levels occurring during a particularly vulnerable sleep-state or time period might block protective arousals from sleep. Whether N-M SIDS or SIDS occurs in infants with congenital respiratory control deficits might be determined by a balance between congenital temperament factors, the severity of the respiratory control deficit and plasma progesterone levles. Infants who survive symptomatic sleep apneic
219
episodes (N-M SIDS) might have more mild respiratory control deficits and/ or more vigorous temperaments (high activity, high intensity, low sensory threshold). Progesterone levels would be expected to be lower in this group compared to the SIDS victims. The SIDS victims might have more severe respiratory control deficits and/or more lethargic temperaments (low activity, low intensity, and high sensory threshold). This hypothesis is consistent with a retrospective study of SIDS victims which showed that they had low activity and low intensity (28). The hypothetical association between sleep patterns, sleep apnea, progesterone, and infant temperament is based on several separate studies of normal infants, SIDS victims, siblings of SIDS victims, and N-M SIDS A consistent relationship is present among these study groups. infants. However, because of the diversity of groups studied, generalizations cannot be made whether the behavioral changes when awake (intensity, activity, threshold, colic) are caused by the primary pathophysiology (sleep-related respiratory control deficit) or they are secondary to disordered sleep patterns or altered parental response. CONCLUSION
In response to congenital sleep-related respiratory control deficits, plasma progesterone levels may rise to stimulate respiration. In severely affected infants, elevated progesterone levels produce a central nervous system depression which tends to blunt or abolish protecBehavioral changes accompanying or caused by tive arousals from sleep. the disturbed sleep and/or elevated progesterone levels include low activity, low intensity, a high sensory threshold, and the absence or disappearance of colic. Because colicky behavior or the difficult temperament may result from several unrelated factors (9), it should not be concluded that all infants with colic or difficult temperament have a respiratory control deficit. ACKNOWLEDGEMENT I wish to thank Mrs. Yvonne Shy for secretarial
assistance.
REFERENCES Infantile colic and near-miss M. Medical Hypothesis 7:1193, 1981.
sudden infant death
1.
Weissbluth syndrome.
2.
Gyermerk 1975.
3.
Kawahara FS, Berman ML, Green OC. Conversion of progesterone-1-2'H to 5 6 -Pregnane-3, 20-Dione by brain tissue. Steroids 25:459, 1975.
4.
Skatrud JB, Dempsey JA, Kaiser DG. Ventilatory response to medroxyprogesterone acetate in normal subjects. Journal of Applied Physiology 44:939, 1978.
5.
Sutton DF, Zwillich CW, Creagh CE, Pierson DJ, terone for outpatient treatment of Pickwickian Internal Medicine 83:476, 1975.
L and Soyka LF.
Steroid anesthetics.
220
Anesthesiology
42:331,
and Weill JV. Progessyndrome. Annals of
6.
Hensley MJ, Saunders NA, and Strohl KP. Medroxyprogesterone ment of obstructive sleep apnea. Sleep 3:441, 1980.
treat-
7.
Harris GW. Sex hormones, brain development, Endocrinology 75:627, 1964.
8.
Clark RL, Ganis FM, Bradford WL. A study of the possible Pediatrics 31:65, 1963. ship of progesterone to colic.
9.
Weissbluth M and Green OC. Plasma progesterone levels, infant temperament, and sleep duration. Journal of Pediatrics, February, 1982 (submitted).
and brain function. relation-
10.
Weissbluth M. Chinese-American infant temperament and sleep durations. Journal of Behavioral Child Development, February, 1982 (in press).
11.
Carey WB and McDevitt SC. questionnaire. Pediatrics
12.
Carey WB. Clinical applications of infant temperament Journal of Pediatrics 81:823, 1972.
13.
Carey WB. Pediatrics
14.
Snow ME, Jacklin CN, Maccoby EE. Crying episodes and sleep-wakefulness transitions in the first 26 months of life. Infant Behavior and Child Development 3:387, 1980.
15.
Weissbluth Pediatrics
16.
Weissbluth M, Brouillette RT, Liu K, Hunt CE. Sleep apnea, sleep Journal of Pediatrics, 1982 (in duration and infant temperament. press).
17.
Phillipson EA, Sullivan CE. Arousal: The forgotten response to respiratory stimuli. American Review of Respiratory Disease 118:807, 1978.
18.
Guilleminault C, Tilkian A, Dement WC. The sleep apnea syndromes. Annual Review of Medicine 24:471, 1976.
19.
Hunt CE. Abnormal miss SIDS infants.
hypercarbic and hypoxic arousal responses Pediatric Research 15:1462, 1981.
20.
Valdes-Dapena MA. medical literature
Sudden infant death syndrome: A review of the 1974-1979. Pediatrics 66:597, 1980.
21.
Bowes G, Townsend ER, Bromley SM, Kozar LF, Phillipson EA. Role of the carotid body and of afferent vagal stimulation in the arousal American Review of response to airway occlusion in sleeping dogs. Respiratory Disease 123:644, 1981.
22.
Cole S, Lindenberg LB, Galioto FM, Howe PE, DeGraff AC, Davis JM, Lubka R, Cross EM. Ultrastructure abnormalities of the carotid body Pediatrics 63:13, 1979. in sudden infant death syndrome.
23.
Sundrell
24.
Brouillette RT, Fernbach SK, Hunt CE. Obstructive sleep apnea in infants and children. Journal of Pediatrics 100:31, 1982.
Revision of the infant temperament 61:735, 1978.
Night waking and temperament 84:756, 1974.
in infancy.
M. Sleep duration and infant temperament. 99:817, 1981.
CE.
Sleeplessness
in infants.
221
Practitioner
measurements.
Journal of
Journal of
in near-
109:89, 1922.
25.
Bowes G, Wolf GM, Sullivan CE, Phillipson EA. Effect of sleep fragmentation on ventilatory and arousal response of sleep dogs to resAmerican Review of Respiratory Disease 122:899, 1980. piratory stimuli.
26.
Guilleminault C, Ariagno R, Korobkin R, Coons S, Owen-Boeddiker M, Baldwin R. Sleep parameters and respiratory variables in 'near-miss' sudden infant death syndrome infants. Pediatrics 68:354, 1981.
27.
Harper RM, Leake B, Hoffman H, Walter DO, Hoppenbrouwers T, Hodgman J, Sterman MD. Periodicity of sleep states is altered in infants at risk for the sudden infant death syndrome. Science 213:1030, 1981.
28.
Naeye RL, Messner J, Specht T, Merritt TA. Sudden infant death syndrome temperament before death. Journal of Pediatrics 88:511, 1976.
222
Hypotheses
9:
215-222,
1982
PLASMA PROGESTERONE LEVELS, INFANT TEMPERAMENT, AND THE SUDDEN INFANT DEATH SYNDROME
AROUSALS
FROM SLEEP,
Marc Weissbluth, M.D., Div. Ambulatory Services, Children's Hospital, 2300 Children's Plaza, Chicago, Illinois.
Memorial
ABSTRACT Endogenous plasma progesterone levels may influence relationships between infant temperament, sleep patterns, and respiratory control Elevated progesterone levels may account for the lethargic deficits. temperament observed among victims of Sudden Infant Death Syndrome. INTRODUCTION Infantile colic and the sudden infant death syndrome (SIDS) have similar In contrast, the temperament characteristics of high natural histories. activity and high intensity among infants with colic are dramatically opposite from the low activity and low intensity ratings among SIDS victims. A previous study of infants with the near-miss sudden infant death syndrome (N-M SIDS) suggested that arousals from sleep may represent a protective mechanism in infants with sleep-related respiratory control deficits (1). Plasma progesterone levels may influence arousals from sleep, sleep patterns, respiratory control during sleep, and infant temperement characteristics. A feedback control relationship might exist between endogenous plasma progesterone levels and hypoxia or hypercarbia resulting from Severe respiratory control deficits respiratory dysrhythmias during sleep. might produce elevated plasma progesterone levels to stimulate respiratory In addition to respiratory stimulation, high progesterone levels effort. However, the high might modulate sleep patterns and awake behavior. progesterone levels might have the undesirable and possibly lethal effect of diminishing or abolishing the protective arousal responses to asphyxic apneic episodes during sleep.
215
PROGESTERONE Pharmacologic doses of progesterone and its metabolite pregnanedione have been shown to induce sleep and anesthesia (2). Newborn animals are unusually sensitive to steroid anesthetics in comparison to conventional anesthetics. Experimental studies with mammalian brain tissue showed that progesterone may be readily converted to pregnanedione by endogenous enzymatic activity (3). Thus, in infants, it is possible that endogenous plasma progesterone levels may influence sleep-wake control mechanisms. In contrast to the central nervous system depressor effects of steroid anesthetics, progesterone and its analogues have respiratory stimulating properties (4-6). Pharmacologic doses of progesterone analogues have been utilized successfully to treat adults with respiratory control disorders. Progesterone may also affect behavior directly. Behavioral effects of other sex hormones have been well documented (7). For example, young animals are susceptible to sex hormones which imprint sexually dimorphic mating patterns. Thus, in addition to being unusually sensitive to steroid anesthetics, newborn animals are particularly susceptible to the behavioral effects of sex hormones. In infants, a progesterone analogue, ethisterone, was used to successfully treat colic (8). In that study, the authors postulated that infantile colic was due 'to progesterone deficiency. A recent study showed that plasma progesterone levels were not significantly lower among infants with colic (9). However, that study did show that low levels of plasma progesterone were significantly associated with the related conditions of difficult infant temperament and low sensory threshold. INFANT TEMPERAMENT Infant temperament characteristics appear to represent congenital differences (10). Genetic factors as well as prenatal and postnatal environmental factors may contribute to the development of infant temperament characteristics. It is possible that a single neuropathologic process produces specific awake behavioral styles and respiratory control deficits during sleep. Alternatively, congenitally distinct infant temperament characteristics may be subsequently modulated directly by abnormal sleep patterns or indirectly by parental response to brief and interrupted infant sleep patterns. The difficult infant temperament diagnosis describes a particular clinical Infants with a difficult and statistical clustering of characteristics. temperament are irregular, withdrawing, slowly adaptable, intense, and negative in mood. Parent ratings greater than the mean in four of these five temperament characteristics with two ratings greater than one standard deviation above the mean are published diagnostic criteria (11). Intensity ratings greater than the mean must be one of the four high temperament ratings needed to establish this diagnosis.
216
As reported previously
(l), there are several separate older studies suggesting a relationship between infantile colic, difficult temperament, low sensory threshold (12), and frequent night awakenings (13). Recent studies have supported the association betweyn difficult temperament, frequent night awakenings (141, and brief sleep durations (10,lS). Brief sleep durations were also observed in a group in infants with symptomatic sleep apnea (N-M SIDS) (16). In that study, high activity and high intensity ratings were associated with less apnea. Also, in that study, low sensory threshold was associated with less apnea. An expected physiologic protective response to sleep apnea would be partial or complete arousals from sleep (17). AROUSALS
FROM SLEEP
Arousal from sleep may be a naturally occurring protective physiologic response to abort sleep-related pathologic events such as apneic asphyxia (1,18). Among N-M SIDS infats, impaired behavioral awakenings from sleep or diminished arousal responses to hypercarbia and hypoxia have been reported recently (19). In contrast, an increased frequency of night awakenings has been reported in normal infants with a low sensory threshold (13). A low sensory threshold in normal infants has also been reported to be associated with colic (12) and low plasma progesterone levels (9). Finally, among N-M SIDS infants, those with a low sensory threshold had less sleep apnea (16). Thus, there appears to be a parallel relationship between chemosensitivity mediated arousal from sleep and sensitivity to external stimulation when awake. Infants who awaken from sleep easily are also sensitive to external stimulation when awake and may tend to have colicky behavior, difficult temperaments, and low plasma progesterone levels. SUDDEN INFANT DEATH SYNDROME Pathologic studies of SIDS victims and physiologic studies of N-M SIDS infants suggest that these disorders may result from sleep-related respiratory control deficits (20). Documented respiratory deficits among N-M SIDS infants include diminished ventilatory and arousal responses to hypoxia and/or hypercarbia, prolonged sleep apnea, and increased frequency of periodic breathing. Recent studies suggest that the arousal response is mediated by the carotid body chemoreceptors (21,22). This paper hypothesizes an additional pathophysiologic process due to elevated endogenous plasma progesterone levels (Figure). Initially, congenital respiratory control deficits might lead to increased plasma progesterone to stimulate respiration during sleep and an increased frequency of protective arousals from sleep. Parents would note an apparent difficulty in maintaining long sleep durations or unusual Typically, infants with colic behave in this wakefulness in such infants. sleepless fashion (23). As would be expected among infants selected for N-M SIDS, a significantly increased prevalence of colic was reported (1).
217
FIGURE
PROGESTERONE, PATTERNS AND
SLEEP
Congenital
Frequent octrtial or complete Irregular sleep patter&,
SLEEP APNEA, INFANT TEMPERAMENT
Respiratory -
Control
Deficits
Elevated
orousals (awakening)
endogenous
progesterone
levels
Respiratory stimul&ion plus increased central nervous system depression
brief sleep periods
1 Colic occurs if infants have high lirf8nsity (dlffkull femperomenfl or low sensory threshold
1 Colic disappears
I Brief total and night sleep durations 1 negative Difficult
mood
temperameni occurs if infants have nigh intensity
Arousal response deficit occurs from sleep fragmentation?, abnormol sleep state periodicity?, Otr high plasma progesterone levels? Outcome
determined
1
by balance between
congenital
temperament
Low sensory threshold Lower progesterone levels Blunted arousals present Brief sleep durations Less symptomatic sleep apnea
Low activity, low intensity ( easy 1 High sensory threshold Higher progesterone levels Arousals absent Long sleep durations More symptomatic sleep apnea
+ N-M SIDS
+ SIDS
High activity,
high
intensity
fdifficuff)
218
The interrupted durations which sleep durations affect the mood
sleep pattern might lead to the brief ni ht sleep also were observed for N-M SIDS infants 4 16). Brief might directly produce a negative mood or indirectly of the infant by altering parental response to the infant.
Infants with the congenital temperament of low intensity and/or mild respiratory control deficits might have less sleep pattern disruption. These infants would be expected to not have colic or the difficult temperament. The hypothesis that sleep related respiratory control deficits may influence behavior when awake by disrupting sleep is consistent with recent observations in children with obstructive sleep apnea (24). In that study, behavioral and developmental deficits were observed to be reversible after successful treatment. The rapidity of improvement following treatment suggests that sleep deprivation or sleep fragmentation directly produces behavioral changes when awake. Although arousal response deficits may be congenital in origin, they also may be experimentally induced in dogs by interrupting sleep for as brief a time as two days (25). Therefore, the initially protective arousals from sleep might also severely disrupt sleep patterns. Subsequently, cumulative effects of fragmented sleep might lead to an acquired arousal response deficit. Presumably, the acquired arousal response deficit could be mediated by increased plasma progesterone levels producing increased control nervous system depression. As a result of sleep deprivation or central nervous system depression, lethargic awake behavioral patterns would be expected to occur. This type of behavior was observed in the experimental sleep fragmentation study. The dogs were listless, less spontaneously active, and participated only lazily in exercise routines. The observation that colic disappeared before the victims of SIDS died (1) could also be attributed to increasing plasma progesterone levels which might suppress the fretful, restless and irritable colicky spells. Additionally, plasma progesterone levels might fluctuate over a 24 hour period. It appears that the time of highest risk for impaired arousals among N-M SIDS infants is between 0100 and 0600 hours (26). Further, recent studies of N-M SIDS infants suggest that the periodicity of their sleep states is abnormal (27). Therefore, the relationship between sleep fragmentation, acquired arousal deficits and high progesterone levels might not be due to absolute high progesterone levels but rather to a developmental asynchrony between circadian rhythms controlling sleep states and plasma progesterone levels. Thus, inappropriately high progesterone levels occurring during a particularly vulnerable sleep-state or time period might block protective arousals from sleep. Whether N-M SIDS or SIDS occurs in infants with congenital respiratory control deficits might be determined by a balance between congenital temperament factors, the severity of the respiratory control deficit and plasma progesterone levles. Infants who survive symptomatic sleep apneic
219
episodes (N-M SIDS) might have more mild respiratory control deficits and/ or more vigorous temperaments (high activity, high intensity, low sensory threshold). Progesterone levels would be expected to be lower in this group compared to the SIDS victims. The SIDS victims might have more severe respiratory control deficits and/or more lethargic temperaments (low activity, low intensity, and high sensory threshold). This hypothesis is consistent with a retrospective study of SIDS victims which showed that they had low activity and low intensity (28). The hypothetical association between sleep patterns, sleep apnea, progesterone, and infant temperament is based on several separate studies of normal infants, SIDS victims, siblings of SIDS victims, and N-M SIDS A consistent relationship is present among these study groups. infants. However, because of the diversity of groups studied, generalizations cannot be made whether the behavioral changes when awake (intensity, activity, threshold, colic) are caused by the primary pathophysiology (sleep-related respiratory control deficit) or they are secondary to disordered sleep patterns or altered parental response. CONCLUSION
In response to congenital sleep-related respiratory control deficits, plasma progesterone levels may rise to stimulate respiration. In severely affected infants, elevated progesterone levels produce a central nervous system depression which tends to blunt or abolish protecBehavioral changes accompanying or caused by tive arousals from sleep. the disturbed sleep and/or elevated progesterone levels include low activity, low intensity, a high sensory threshold, and the absence or disappearance of colic. Because colicky behavior or the difficult temperament may result from several unrelated factors (9), it should not be concluded that all infants with colic or difficult temperament have a respiratory control deficit. ACKNOWLEDGEMENT I wish to thank Mrs. Yvonne Shy for secretarial
assistance.
REFERENCES Infantile colic and near-miss M. Medical Hypothesis 7:1193, 1981.
sudden infant death
1.
Weissbluth syndrome.
2.
Gyermerk 1975.
3.
Kawahara FS, Berman ML, Green OC. Conversion of progesterone-1-2'H to 5 6 -Pregnane-3, 20-Dione by brain tissue. Steroids 25:459, 1975.
4.
Skatrud JB, Dempsey JA, Kaiser DG. Ventilatory response to medroxyprogesterone acetate in normal subjects. Journal of Applied Physiology 44:939, 1978.
5.
Sutton DF, Zwillich CW, Creagh CE, Pierson DJ, terone for outpatient treatment of Pickwickian Internal Medicine 83:476, 1975.
L and Soyka LF.
Steroid anesthetics.
220
Anesthesiology
42:331,
and Weill JV. Progessyndrome. Annals of
6.
Hensley MJ, Saunders NA, and Strohl KP. Medroxyprogesterone ment of obstructive sleep apnea. Sleep 3:441, 1980.
treat-
7.
Harris GW. Sex hormones, brain development, Endocrinology 75:627, 1964.
8.
Clark RL, Ganis FM, Bradford WL. A study of the possible Pediatrics 31:65, 1963. ship of progesterone to colic.
9.
Weissbluth M and Green OC. Plasma progesterone levels, infant temperament, and sleep duration. Journal of Pediatrics, February, 1982 (submitted).
and brain function. relation-
10.
Weissbluth M. Chinese-American infant temperament and sleep durations. Journal of Behavioral Child Development, February, 1982 (in press).
11.
Carey WB and McDevitt SC. questionnaire. Pediatrics
12.
Carey WB. Clinical applications of infant temperament Journal of Pediatrics 81:823, 1972.
13.
Carey WB. Pediatrics
14.
Snow ME, Jacklin CN, Maccoby EE. Crying episodes and sleep-wakefulness transitions in the first 26 months of life. Infant Behavior and Child Development 3:387, 1980.
15.
Weissbluth Pediatrics
16.
Weissbluth M, Brouillette RT, Liu K, Hunt CE. Sleep apnea, sleep Journal of Pediatrics, 1982 (in duration and infant temperament. press).
17.
Phillipson EA, Sullivan CE. Arousal: The forgotten response to respiratory stimuli. American Review of Respiratory Disease 118:807, 1978.
18.
Guilleminault C, Tilkian A, Dement WC. The sleep apnea syndromes. Annual Review of Medicine 24:471, 1976.
19.
Hunt CE. Abnormal miss SIDS infants.
hypercarbic and hypoxic arousal responses Pediatric Research 15:1462, 1981.
20.
Valdes-Dapena MA. medical literature
Sudden infant death syndrome: A review of the 1974-1979. Pediatrics 66:597, 1980.
21.
Bowes G, Townsend ER, Bromley SM, Kozar LF, Phillipson EA. Role of the carotid body and of afferent vagal stimulation in the arousal American Review of response to airway occlusion in sleeping dogs. Respiratory Disease 123:644, 1981.
22.
Cole S, Lindenberg LB, Galioto FM, Howe PE, DeGraff AC, Davis JM, Lubka R, Cross EM. Ultrastructure abnormalities of the carotid body Pediatrics 63:13, 1979. in sudden infant death syndrome.
23.
Sundrell
24.
Brouillette RT, Fernbach SK, Hunt CE. Obstructive sleep apnea in infants and children. Journal of Pediatrics 100:31, 1982.
Revision of the infant temperament 61:735, 1978.
Night waking and temperament 84:756, 1974.
in infancy.
M. Sleep duration and infant temperament. 99:817, 1981.
CE.
Sleeplessness
in infants.
221
Practitioner
measurements.
Journal of
Journal of
in near-
109:89, 1922.
25.
Bowes G, Wolf GM, Sullivan CE, Phillipson EA. Effect of sleep fragmentation on ventilatory and arousal response of sleep dogs to resAmerican Review of Respiratory Disease 122:899, 1980. piratory stimuli.
26.
Guilleminault C, Ariagno R, Korobkin R, Coons S, Owen-Boeddiker M, Baldwin R. Sleep parameters and respiratory variables in 'near-miss' sudden infant death syndrome infants. Pediatrics 68:354, 1981.
27.
Harper RM, Leake B, Hoffman H, Walter DO, Hoppenbrouwers T, Hodgman J, Sterman MD. Periodicity of sleep states is altered in infants at risk for the sudden infant death syndrome. Science 213:1030, 1981.
28.
Naeye RL, Messner J, Specht T, Merritt TA. Sudden infant death syndrome temperament before death. Journal of Pediatrics 88:511, 1976.
222