Circadian rhythm development in preterm infants. The role of postnatal versus postmenstrual age

Background, Aims: Circadian rhythm maturation may be disturbed in premature infants undergoing neonatal intensive care. We used continuous heart rate recordings across the entire neonatal intensive care period to study circadian rhythm development in preterm infants and to evaluate the roles of postmenstrual (PMA) versus postnatal age (PNA). Materials and methods: The circadian rhythm was calculated using a cosine fit of heart rate. The circadian rhythm amplitudes were averaged weekly and studied relative to PMA and PNA using the linear mixed effects models, adjusting for clinical variables that could affect the heart rate. The daily circadian rhythms were used to create grand averages for PMA groups: <= 31, 32-35, and > 35 weeks, and for PNA groups: <= 30, 31-60, and > 60 days. Results: Sixty-six infants were evaluated as part of an ongoing prospective study with gestational ages between 23 and 36 weeks. The PMA (1.47 x 10(-2) beats per minute (bpm)/week, P = 2.07 x 10(-8)) and PNA (1.87 x 10(-2) bpm/day; P = 1.86 x 10(-6)) were significantly associated with the circadian rhythm amplitude independent of covariates. Infants <= 31 weeks' PMA and <= 30 days PNA, the phase of circadian rhythm amplitude grand averages showed a peak at night and a nadir during the day. Hereafter the circadian rhythm phase reversed to that established for mature individuals. The highest circadian rhythm amplitudes present >35 weeks' PMA and > 60 days PNA. Conclusions: Our results indicate circadian rhythm matures with advancing gestation. The reversed circadian rhythm phase during the early postnatal period could be due to premature exposure to the ex-utero environment and warrant further study.