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The hypothalamic-pituitary-adrenal (HPA) axis is essential for maintaining homeostasis in the fetus and newborn. A proportion of extremely preterm infants suffer from transient adrenocortical insufficiency of prematurity. Although these infants have suboptimal adrenocortical response to stress in the first week of life, the HPA axis adapts rapidly, and most exhibit an adequate response by day 14. An attenuated cortisol response in preterm infants might be protective against intracranial bleeding. Severe hypoxic-ischemic encephalopathy is a potent stimulus to the HPA axis. Chronic intrauterine hypoxemia can up-regulate the setpoint of the HPA axis and augments adrenal steroidogenic production, resulting in sustained elevation of circulating cortisol levels.