# Stress exposure, stress responses, and short-term outcomes in very preterm neonates: a national cohort study

## TL;DR

This study explores how stress in preterm infants affects their cortisol levels and health outcomes, finding that gestational age influences these responses.

## Contribution

The study reveals gestational age-dependent effects of stress exposure on cortisol levels in very preterm neonates.

## Key findings

- High cortisol levels were associated with neonatal morbidity and mortality.
- Cortisol levels varied with gestational age and stress exposure over time.
- Stress exposure impacts the development of the HPA axis in preterm infants.

## Abstract

Very preterm neonates admitted to the neonatal intensive care unit (NICU) face daily stressors that activate their hypothalamic–pituitary–adrenal (HPA) axis, triggering cortisol release and potentially affecting their outcomes. We examined the relationship between NICU stressors, urinary cortisol levels, and short-term outcomes in very preterm neonates. This study was part of a multicenter cohort study (HIPPO) including 446 neonates (gestational age < 29 weeks) across all Dutch NICUs. Data on daily stress exposure for the first 28 days and outcomes were prospectively collected, along with urine samples on postnatal days 8 (T1) and 28 (T2) to determine cortisol levels as markers of the stress response. Urinary samples were available for 391 (88%) neonates. In general, the most preterm born neonates had the highest cortisol levels, though highly variable with similar stress exposure. At T1, cortisol levels rose with increasing stress exposure in neonates born after gestational ages ≥ 27 weeks but decreased in the most preterm. At T2, cortisol levels tended to rise with stress exposure across all gestational ages. Though cortisol levels were higher in neonates that died or developed intraventricular hemorrhage, bronchopulmonary dysplasia or retinopathy of prematurity, cortisol was not independently associated with any of these outcomes.

Conclusion: High cortisol levels are linked to neonatal morbidity and mortality, but not independently, since urinary cortisol levels are moderated by gestational age. To protect preterm infants’ future, it is key to understand their responses to stress in order to develop and evaluate stress protection strategies.
What is known:• Very preterm neonates in the neonatal intensive care unit (NICU) are exposed to high levels of stress on a daily basis.• Stress exposure and altered cortisol responses in very preterm neonates have both been linked to adverse outcomes.What is new:• This study reveals gestational age-dependent effects of stress exposure on very preterm neonates’ cortisol levels.• In general, high cortisol was associated with morbidity and mortality.• This study provides insight in hypothalamic–pituitary–adrenal axis development and highlights the importance of reducing stress.

What is known:

• Very preterm neonates in the neonatal intensive care unit (NICU) are exposed to high levels of stress on a daily basis.

• Stress exposure and altered cortisol responses in very preterm neonates have both been linked to adverse outcomes.

What is new:

• This study reveals gestational age-dependent effects of stress exposure on very preterm neonates’ cortisol levels.

• In general, high cortisol was associated with morbidity and mortality.

• This study provides insight in hypothalamic–pituitary–adrenal axis development and highlights the importance of reducing stress.

The online version contains supplementary material available at 10.1007/s00431-026-06765-1.