Development of 24-Hour Rhythms in Cortisol Secretion Across Infancy: A Systematic Review and Meta-Analysis of Individual Participant Data

Context: In adults, cortisol levels show a pronounced 24-hour rhythm with a peak in the early morning. It is unknown at what age this early-morning peak in cortisol emerges during infancy, hampering the establishment of optimal dosing regimens for hydrocortisone replacement therapy in infants with an inborn form of adrenal insufficiency. Objective: We aimed to characterize daily variation in salivary cortisol concentration across the first year of life. Methods: We conducted a systematic review followed by an individual participant data meta-analysis of studies reporting on spontaneous (ie, not stress-induced) salivary cortisol concentrations in healthy infants aged 0-1 year. A one-stage approach using linear mixed-effects modeling was used to determine the interaction between age and time of day on cortisol concentrations. Results: Through the systematic review, 54 eligible publications were identified, reporting on 29 177 cortisol observations. Individual participant data were obtained from 15 study cohorts, combining 17 079 cortisol measurements from 1904 infants. The morning/evening cortisol ratio increased significantly from 1.7 (95% CI: 1.3-2.1) at birth to 3.7 (95% CI: 3.0-4.5) at 6 to 9 months (P <. 0001). Cosinor analysis using all available data revealed the gradual emergence of a 24-hour rhythm during infancy. Conclusion: The early-morning peak in cortisol secretion gradually emerges from birth onwards to form a stable morning/evening ratio from age 6 to 9 months. This might have implications for hydrocortisone replacement therapy in infants with an inborn form of adrenal insufficiency.