Background: Many very preterm (i.e., <32 weeks of gestation) newborns fail to mount an adequate adrenocortical response to stress or illness, termed relative adrenal insufficiency. Conversely, later in life these infants show features of increased glucocorticoid bioactivity, such as abdominal adiposity, insulin resistance, raised blood pressure, shorter stature and internalizing problem behavior. Summary: Studies suggested that very preterm newborns have impairments along multiple levels of the hypothalamus-pituitary-adrenal (HPA) axis. Among the impairment were defects in: (1) the pituitary responsiveness to exogenous corticotropin-releasing hormone, (2) 11β-hydroxylase activity, and (3) the interconversion between cortisol and inert cortisone. There is some evidence suggesting that later in life these infants have an increased basal secretion rate of cortisol and adrenal hyperandrogenism. However, the response to acute (psychosocial) stress was blunted rather than enhanced in them. The mechanisms explaining this switch in HPA axis activity are complex and not yet fully understood. Key Messages: Very preterm newborns have several impairments along the HPA axis that could impede an adequate adrenocortical response to stress or illness. Later in life, these infants are predisposed to increased HPA axis activity, which could partially explain their phenotype.

Although the incidence of adverse growth patterns decreased between the cohorts, possibly indicating improvements in care over time, the impact of these growth patterns on neurodevelopmental outcomes was not significantly different. Achieving adequate early-life growth may be crucial for improving neurodevelopmental outcomes, especially for preterms born SGA.

Preterm-born children are at risk for later neurodevelopmental problems and cardiometabolic diseases; early-life growth restriction and suboptimal neonatal nutrition have been recognized as risk factors. Prevention of these long-term sequelae has been the focus of intervention studies. High supplies of protein and energy during the first weeks of life (i.e., energy > 100 kcal kg−1 day−1 and a protein-to-energy ratio > 3 g/100 kcal) were found to improve both early growth and later neurodevelopmental outcome. Discontinuation of this high-energy diet is advised beyond 32–34 weeks postconceptional age to prevent excess fat mass and possible later cardiometabolic diseases. After discharge, nutrition with a higher protein-to-energy ratio (i.e., > 2.5–3.0 g/100 kcal) may improve growth and body composition in the short term.Conclusion: Preterm infants in their first weeks of life require a high-protein high-energy diet, starting shortly after birth. Subsequent adjustments in nutritional composition, aimed at achieving optimal body composition and minimizing the long-term cardiometabolic risks without jeopardizing the developing brain, should be guided by the growth pattern. The long-term impact of this strategy needs to be studied. What is Known:• Preterm infants are at risk for nutritional deficiencies and extrauterine growth restriction.• Extrauterine growth restriction and suboptimal nutrition are risk factors for neurodevelopmental problems and cardiometabolic disease in later life. What is New:• Postnatally, a shorter duration of high-energy nutrition may prevent excess fat mass accretion and its associated cardiometabolic risks and an early switch to a protein-enriched diet should be considered from 32-34 weeks postconceptional age.• In case of formula feeding, re-evaluate the need for the continuation of a protein-enriched diet, based on the infant’s growth pattern.

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