Noninvasive surrogate markers for plasma cortisol in newborn infants: utility of urine and saliva samples and caution for venipuncture blood samples.

CONTEXT: Hypothalamus-pituitary-adrenal function is associated with important physiological/pathological events in neonates. Plasma/serum cortisol levels have been used to assess hypothalamus-pituitary-adrenal function. Several noninvasive surrogate markers have been used without sufficient validation. OBJECTIVE: The objectives of the study were to investigate whether plasma cortisol levels are correlated with those in saliva and urine and whether these correlations are affected by procedural pain at blood sampling. DESIGN, SETTING, AND PATIENTS: Fifty neonates were recruited from a tertiary neonatal intensive care unit. Saliva and urine samples were collected shortly before routine clinical blood sampling. MAIN OUTCOME MEASURES: Cortisol levels were compared between plasma and noninvasive samples using a linear regression analysis for the entire study population and groups, whose blood was obtained via indwelling arterial catheters (group A) or by venipuncture (group V). Predictive values of salivary/urinary cortisol for low plasma cortisol levels less than 2.0 µg/dL were evaluated by receiver-operating characteristic analysis. RESULTS: Plasma cortisol showed linear correlations with salivary and urinary cortisol for the entire study population and patients in group A (all P < .0002) but not in group V. Areas under the curves of salivary and urinary cortisol to predict low plasma cortisol levels were 0.87 (95% confidence interval 0.78-0.97) and 0.84 (95% confidence interval 0.74-0.95), respectively. CONCLUSIONS: Cortisol levels from saliva or urine samples were shown to be useful surrogate markers for plasma cortisol levels in neonates. Caution is required in interpreting the findings of plasma cortisol levels in young patients when blood samples are obtained by venipuncture because procedural pain may induce alteration of cortisol levels.

Diurnal cortisol changes in newborn infants suggesting entrainment of peripheral circadian clock in utero and at birth.

BACKGROUND: In the rodent and human fetus, a diurnal cortisol rhythm is observed that is entrained in antiphase to the maternal rhythm. However, after birth, the adrenal circadian rhythm becomes unsynchronized with the clock time, and an adult-type, 24-h rhythm is observed only after a few months. Little is known about when and how the fetal adrenal circadian rhythm is synchronized with the day-night cycle. METHODS: To investigate the function of adrenal circadian clock in the newborn infant, eight serial saliva samples were collected every 3 h over 24 h (starting at 0900 h) in 27 newborn infants. RESULTS: Cortisol levels were higher during the period 1500 to earlier than 2100 h than during 0900 to earlier than 1500 h and 0300 to earlier than 0900 h (both P < 0.05). Salivary cortisol levels collected during 0 to <6, 6 to <12, and 12 to <18 hours after the clock time at birth (birth time) were higher than those collected during 18 to <24 hours after the birth time (P < 0.005, 0.05, and 0.05, respectively). The acrophase of salivary cortisol was linearly correlated with the birth time within the first 5 d of life (P < 0.005) but not thereafter. CONCLUSION: In the newborn infant, diurnal increase in cortisol was observed in the late afternoon and in correspondence with the birth time. The adrenal circadian rhythm acquired in utero may be reentrained by endocrinological events at birth. Such complex regulation of the adrenal circadian clock may inhibit a swift synchronization of the circadian clock to the day-night rhythm.