Circadian Rhythms in Infants

Abstract

After completing this article, readers should be able to: Circadian rhythms are endogenously generated rhythms that have a period length of about 24 hours. Evidence gathered over the past decade indicates that the circadian timing system develops prenatally, with the suprachiasmatic nuclei (SCN) in the anterior hypothalamus, the site of a circadian clock, present by mid-gestation in primates. Recent evidence also shows that the circadian system of primate infants is responsive to light at very early stages (as early as 25 to 28 weeks’ gestation in humans) and that low-intensity lighting can regulate the developing clock. After birth, circadian system outputs mature progressively, with rhythms in sleep-wake cycles, body temperature, and hormone production generally developing between 1 and 3 months of age. The importance of light in regulation of circadian rhythm in infants is highlighted by the early establishment of rest-activity patterns that are in phase with the 24-hour light-dark cycle in preterm infants exposed to low-intensity cycled lighting. With the continued elucidation of circadian system development and influences on human physiology and illness, it is anticipated that consideration of circadian biology will become an increasingly important component of neonatal care.Notable examples of circadian rhythms include the sleep-wake cycle and daily rhythms in body temperature and hormone production. Circadian rhythms are also involved in the pathogenesis of illnesses, such as reactive airway disease (eg, asthma) and myocardial infarction.The system responsible for the generation and regulation of circadian rhythms is the circadian timing system. This neural system consists of a biologic clock, input pathways, and output pathways (Fig. 1). The paired SCN in the anterior hypothalamus are the site of a biologic clock. The SCN exhibit endogenous rhythmicity and have a period of oscillation of close to 24 hours.Because SCN oscillations are not exactly 24 hours, the circadian pacemaker must be reset each day. Otherwise, endogenous clock oscillations will drift (or free-run) out of phase with the external light-dark cycle. Input pathways relay photic information from the retina to the SCN to synchronize (or entrain) the oscillations of the clock to the 24-hour solar cycle. The pathway that relays photic information from the retina to the SCN is the retinohypothalamic tract (RHT), which has been shown to be both necessary and sufficient for photic entrainment. This pathway is independent from the visual pathway. The ganglion cells in the retina carry information about the level of illumination in the environment to the biologic clock. This pathway is not involved in object recognition and visual cortical processing. Indeed, blind children who have an intact RHT can entrain to a 24-hour light-dark cycle.Output pathways are responsible for the overt expression of circadian rhythms. Several discrete neural pathways projecting from the SCN to hypothalamic and nonhypothalamic sites have been defined. It is via these pathways that the circadian system influences the rhythmic production of several hormones, including melatonin and cortisol, respiratory and cardiac function, sleep-wake, the level of alertness, and body temperature.The human SCN are located above the optic chiasm at the base of the third ventricle. In contrast to rodents, human SCN cells are not densely clustered, making the nuclei less visually apparent. However, using probes to label melatonin receptors and SCN peptides, these nuclei can be identified (Fig. 2). Supporting the concept that the SCN are the site of the human circadian pacemaker, tumors and congenital lesions in the SCN region result in the loss of circadian rhythms, including temperature and sleep-wake rhythms.The human RHT has been identified in studies of postmortem specimens using techniques that label degenerating retinal axons. Thus, entrainment pathways are similar in humans and animals. Although it was suggested that cutaneous light exposure could influence circadian function, there is little support for the hypothesis of extraretinal photoreception in mammals. Investigators also have failed to reproduce phase-shifting effects of cutaneous light exposure.Outputs of the primate circadian system have been widely characterized in human clinical studies. Notable examples of circadian rhythms include the sleep-wake cycle and the level of alertness, daily rhythms in body temperature, and day-night rhythms in cortisol and melatonin production. Day-night differences in gonadotropin, testosterone, growth hormone, and thyrotropin secretion are also present.Based on human and nonhuman primates studies, it appears that the SCN neurons form early in gestation (Fig. 3). It is not currently known exactly when the primate SCN initially are apparent morphologically. Using probes to label the nuclei, the human SCN have been detected at 18 weeks’ gestation. Functional studies in prematurely born baboons show that the primate SCN oscillate prenatally.The RHT has been identified in a 36-week gestation human newborn. However, because of human study limitations, it has not been possible to determine if the circadian clock of human infants is functionally responsive to light at birth. Studies of nonhuman primates suggest that the retina functionally innervates the SCN at stages equivalent to 25 weeks postconception human infants.Increasing evidence indicates that the circadian timing system is a fundamental homeostatic system that potently influences human behavior and physiology throughout development. After birth, there is progressive maturation of the circadian system, with day-night rhythms in sleep-wake patterns and hormone secretion developing between 1 and 3 months of age. Recent evidence shows that the circadian systems of primate infants are responsive to light at very premature stages and that low-intensity lighting can regulate the developing clock. As the relationship between the circadian system development and its influences on human physiology and illness become clearer, circadian biology should become an increasingly important component of clinical neonatal care.Circadian rhythm development originates during the fetal period. A fetal biologic clock responsive to maternal entraining signals is already oscillating by the last trimester of gestation in primates. A clear day-night rhythm of fetal heart rate synchronized with maternal rest-activity, heart rate, cortisol, melatonin, and body temperature rhythms is found in humans. We have recorded 24-hour fetal heart rates in a discordant anencephaly twin pregnancy and compared these data with three normal twin pregnancies. Although circadian rhythm was present in the intact fetus and all other twin pregnancy fetal heart rate recordings, no circadian rhythm was found in the anencephalic fetus despite day-night rhythm in the maternal heart rate. The lack of circadian rhythmicity in the anencephalic fetus despite the presence of this rhythm both in the mother and in the intact twin fetus supports the concept that the fetal brain (most probably the fetal biologic clock) is necessary for this endogenous rhythm to appear. These observations also support the hypothesis that the mother entrains the developing circadian rhythm of the infant to the light-dark cycle during fetal life and long before birth. Consolidated periods of activity and rest in the infant generally are not observed until after the first or second postnatal month. Activity plots of human newborns reveal that sleep is generally distributed over the 24-hour day during the first few weeks after birth. At 6 weeks of age, infants are awake more during the day than at night. Although consolidated periods of rest and activity are not usually apparent until more than 1 to 2 months after birth, day-night differences in activity can be detected as early as 1 week after birth in some babies. At the age when day-night differences in infant activity become clearly apparent, day-night rhythms in hormone production also are observed. Day-night rhythms in melatonin production can be detected at 12 weeks of age. Circadian variation in cortisol levels appears between 3 and 6 months of age. With advancing age, circadian rhythms have been detected for a variety of other hormones and circulating factors.Over the past decade, studies of patterns of infant activity, heart rate, temperature, and sleep state in preterm infants have flourished. When temperature and heart rate are studied beginning at a postmenstrual age (PMA) of 24 to 29 weeks, circadian rhythmicity is generally not apparent even at 17 weeks after birth. Studies of preterm infants at 32 weeks PMA have failed to detect day-night differences in sleep patterns, although some differences are noted in term infants. Analyses of temperature, heart rate, and activity patterns at 36 weeks PMA have revealed ultradian (2 to 6 h) rhythms. Because feeding and physical contact influence infant temperature, heart rates, and activity patterns, it is likely that infant care schedules drive the ultradian rhythms seen in preterm infants. It is also possible that these interventions may mask the detection of circadian rhythms.We have studied the development of circadian rhythms in a group of 40 preterm infants born at a mean gestational age of 30 weeks (birthweight range, 751 to 2,280 g). Rectal temperature was recorded continuously over 1 to 3 days as an endogenous marker of circadian rhythm. We have recorded rhythms in these infants at 36 weeks PMA (before discharge from nursery) and at 1 and 3 months corrected age at home. The amplitude of the circadian rhythm was determined by calculating the magnitude of body temperature change (maximum minus minimum) for each infant at each age. These longitudinal studies in preterm infants showed a significant maturation in circadian rhythm of body temperature (Fig. 4). The amplitude of the rhythm increased by 3 months of age to a level very similar to that seen in 6-month or older children.Another result of circadian rhythm development is the consolidation of sleep and wakefulness over the 24-hour day. Using a movement-sensitive mattress, 12 preterm infants were continuously recorded for 2 consecutive days at 36 weeks PMA (before discharge) and at 3 months corrected age. At 36 weeks PMA, the infants slept as much during the day (65%) as during the night (71%), but by 3 months of age the same infants showed a clear day-night rhythm of sleep. At 3 months of age, the percentage of recording time asleep during the day was 18±12% versus a more consolidated 65±11% sleep at night (P<.001).Following the Hoa and Rivkee discovery that the primate circadian clock is responsive to light in very preterm infant baboons, we began examining the effects of photic entrainment on human preterm infants. The development of rest-activity patterns was examined in human preterm infants (32 to 34 weeks’ gestation) exposed to continuous dim lighting or low-intensity cycled lighting before discharge.Day-night differences in rest and activity were not apparent in hospitalized infants exposed to continuous dim light or cycled lighting. Over the first 10 days at home, distinct day-night differences in activity were not seen in the dim-light group, but infants exposed to cycled lighting were more active during the day than at night. It was not until 21 to 30 days after discharge that day-night activity ratios in infants exposed to dim light matched those seen in infants exposed to cycled lighting shortly after discharge (Figs. 5 and 6). Despite the differences in rest-activity patterns between the groups, no differences in weight gain or head circumference were seen.These observations suggest that exposure of preterm infants to low-intensity cycled lighting for 10 days before discharge induces distinct patterns of rest-activity in preterm infants that are in synchrony with the light-dark cycle that they will encounter at home. In contrast, the appearance of rest-activity patterns in synchrony with the light-dark cycle is delayed in infants who have been reared in continuous dim lighting before discharge from hospital to home.A nocturnal trough of body temperature, which is a good marker of human circadian rhythms, is already present at 6 to 12 weeks of age in term infants. Many factors, including feeding (scheduled versus on demand, human milk versus formula), environmental lighting (indoor versus outdoor, regular versus irregular light-dark cycle), and age of the infant, influence the experimental outcome. For example, some infants show circadian rhythm of body temperature as early as 8 weeks and others not until 16 weeks. Breastfed infants, girls, and first-born infants show earlier rhythm development. Recio and associates have discussed a number of important issues influencing the development of circadian rhythm, especially during the first 3 months of postnatal life. They indicated that newborns are often kept in a dark room during the day so they can sleep and may be exposed to bright light during nightly feeding periods. This unusual environmental light-dark cycle may conflict with the infant’s endogenous rhythm. Additionally, the change from human milk, which contains melatonin, to commercial milk may affect melatonin levels in the infant. Furthermore, mothers usually provide human milk that has been pumped during the day and, therefore, would also lack melatonin for night-time feedings. In both cases, the newborn is deprived of the maternal melatonin signal because the melatonin peak in maternal milk is between midnight and 4 am.Recently, McGraw and colleagues carefully studied a term infant from the moment of birth, recording hourly body temperature, daily sleep-wake patterns, and weekly 24-hour melatonin levels. The infant was fed only on demand and left undisturbed by the mother, the first author. Careful attention was paid to having outdoor daytime lighting and dim light at night. Even during feeding at night, no extra lighting was used to avoid disturbing the circadian rhythm of the infant. These investigators found a clear circadian rhythm in body temperature 1 week after birth. Circadian rhythms of sleep-wake and melatonin emerged by 6 weeks of age. Their study clearly demonstrates that the results from earlier circadian research in human infancy were confounded by maternal/environmental factors as well as by only recording sleep-wake or rest-activity cycles. These results are in accordance with several other investigations demonstrating that the inherent functional fetal biologic clock can continue oscillating after birth if not disturbed by interfering ex utero environmental factors (including scheduled feeding every 2 to 4 h and nighttime bright light). Kennaway found no evidence of circadian rhythm in melatonin before 9 to 12 weeks of age in term infants as well as a delay of 2 to 3 weeks in the development of melatonin circadian rhythm in preterm (corrected for age) versus term infants.Many investigators have documented individual differences in the development of circadian rhythms in infants. The extent to which these individual differences are the results of differences in prenatal circadian rhythms or postnatal environmental conditions is yet to be studied. For example, in the Stanford studies of preterm infants before discharge from the nursery, although no day-night differences were present in body temperature at fewer than 14 days postnatal age, a small but significant rhythm of body temperature emerged in infants older than 14 days of age. The presence or absence of circadian rhythms in preterm infants also is influenced by intrauterine growth. Although we were not able to find significant differences in the presence of fetal heart rate between intrauterine growth-retarded fetuses and controls, postnatal studies showed that the percentage of preterm infants who had circadian rhythms of body temperature and heart rate was significantly greater in the appropriate-for-gestational age group compared with the small-for-gestational age infants. PMA (maturational effect) is important to consider in the development of circadian rhythms. In our postnatal studies at Stanford, 35 to 37 weeks PMA preterm infants had much higher amplitudes of body temperature rhythm than 32 to 34 weeks PMA infants.An important function of maternal entrainment during the perinatal development may be to prepare the fetus’ circadian timing system for later independent adaptation to the light-dark cycle. It is possible that the postnatal development of human circadian rhythms may be hampered by maternal, fetal, or perinatal disturbances. This is observed clinically when the intimate mother-fetus relationship is dramatically altered by preterm birth or maternal illness. Furthermore, preterm infants are exposed to continuous or irregular light illumination for several weeks or months in the neonatal intensive care unit (NICU) and intermediate care nursery. Preterm infants are deprived of several potentially important maternal entrainment factors. This lack of maternal entrainment and irregular extrauterine lighting and care in the nursery may induce disturbances in sleep, body temperature, feeding, and other rhythms in preterm infants. For example, Mann and colleagues reported increased sleep and growth in preterm infants subjected to a regular light-dark cycle in the nursery, although this finding was not evident until 6 weeks after discharge. Others found some beneficial effect of a light-dark cycle in the nursery on the development of circadian rhythms of heart rate and skin temperature in preterm infants before discharge. Kennaway also found that the delayed development of the melatonin rhythm in some preterm infants could be advanced by home cycled light.In most nurseries in the United States, infants are not cared for in an environment that has regular light-dark cycles; rather, infants are exposed to irregular light or continuous darkness. This is similar to living in a cave or other settings without time cues. In the absence of time cues, circadian phase will not be in synchrony with the regular day-night cycle. Thus, when expressed rhythmicity develops, infants may be more active at night when parents are sleeping and less active and alert during the day when parents desire to interact with their children. Based on studies in animals, desynchronous circadian phase may result in disturbed parent-child interactions.Although continuous dim lighting is the norm in many nurseries, it is not clear how this practice evolved and became accepted. There is little scientific justification for this type of lighting exposure. More than a decade ago, it was suggested that ambient lighting might contribute to eye disease in preterm infants, but rigorous clinical studies have failed to show adverse effects of low-intensity lighting on preterm infants.Investigators who propose a NIDCAP (Neonatal Individualized Developmental Care Assessment Program) have suggested that because the womb is dark, preterm infants should be cared for in the dark. Yet, this approach overlooks the fact that the fetus is exposed to maternal circadian rhythms that synchronize the fetal clock with the external light-dark cycle. Keeping preterm infants in the dark during their stay in the neonatal nursery deprives these babies of the time-of-day information that they would have received throughout gestation. Data also suggest that the NIDCAP approach and dark rearing does not improve developmental outcome or sleep of preterm infants. The concerns about the potential adverse effects of light on retinal development have been addressed in The National Institutes of Health study (LIGHT-ROP Cooperative Group). In this large multicenter trial, the effect of a severe reduction of nursery lighting was compared with nonorganized environmental lighting. The study showed no difference in the incidence of retinopathy of prematurity, blindness, or other major visual defects between infants exposed to continuous dim or regular lighting.Despite widespread discussion about optimizing infant lighting conditions, potential influences of cycled lighting on preterm infants have been the subject of only a few previous studies. Mann and coworkers found that exposing preterm infants to light-dark cycles before discharge resulted in better weight gain and more sleep over the 24-hour day than did chaotic lighting patterns. These effects were seen no sooner than 6 weeks after discharge. It has been suggested that the observed effects were not a direct result of circadian rhythm modulation, as measured by a 24-hour sleep log from the mother. The distribution of sleep was throughout the 24 hours in both groups rather than greater night time sleep, as would be expected with circadian organization. More recently, Brandon and associates suggested that exposing infants to light-dark cycles improves the in-hospital growth of babies if exposure occurs before 36 weeks of age. Yet, it is not clear that the treatment groups in this study were comparable. Considering that it is difficult to detect circadian rhythms in humoral factors in preterm infants, the potential mechanisms by which lighting could directly influence the growth of preterm infants is not clear.Recently at Stanford, we collected retrospective follow-up (4 mo corrected age) clinical outcome measures for 109 low-birthweight preterm infants discharged from our cycled and continuous dim lighting nurseries. There were no significant differences in demographic measures, including birthweight, gestational age, Apgar score, clinical risk index for babies (CRIB), score for neonatal acute physiology (SNAP II), and score for neonatal acute physiology, perinatal extension, version 2 (SNAPPE), between the two groups prior to the intervention. However, by 4 months of age, there was a significant increase in body weight, head circumference, and lengths of infants discharged from the cycled room compared with the dim room. Infants exposed to cycled light during the stay in the nursery were an average of 500 g heavier and 2 cm longer and had an average 1-cm larger head circumference (Table). There are no data or rationale to support the use of a constant dim or continuous chaotic lighting environmental approach in the neonatal nursery for the care of preterm infants. Lack of circadian rhythmicity, not only in light but also in the pattern of noise and parental care, may subject the infant’s developing circadian rhythm to conflicting temporal cues. Furthermore, if the SCN (biologic clock) is responsive as early as 25 to 28 weeks’ gestation, cycled light at this time until discharge home may influence circadian organization. Introducing a regular day-night cycle into the NICU and intermediate nursery has been recommended in the recent Guidelines for Perinatal Care by the American Academy of Pediatrics and The American College of Obstetricians and Gynecologists. Continuing such regular day-night rhythm at home as well as maximizing the day-night differences by minimizing nighttime caregiver intervention (including feeding and light) should benefit the development of preterm and term infants. Achievement of such a regimen would also have great practical implications for mothers of young infants, especially working mothers, who would benefit from the early development of day-night organization of their infant.