Cortisol levels are related to neonatal pain exposure in children born very preterm at age 18 months in two independent cohorts

Abstract

Exposure to pain‐related stress from frequent invasive procedures in the neonatal intensive care unit (NICU) has been associated with altered physiological stress regulation, neurodevelopment, and behavior in children born very preterm (≤32 weeks gestation). Previously, in a cohort born 2003–2006 (Cohort 1), we found that, at 18 months corrected age (CA), children born extremely low gestational age (ELGA; 24–28 weeks) and very low gestational age (VLGA; 29–32 weeks), had higher pre‐test cortisol levels and a different pattern of cortisol output across a developmental assessment involving cognitive challenge compared to children born full‐term (FT; 39–41 weeks). Also, greater neonatal pain‐related stress exposure among the preterm children was related to higher pre‐test cortisol levels. Given the adverse long‐term effects of neonatal pain in preterm infants and the ensuing rise in clinical concerns to appropriately manage pain in the NICU in recent years, we aimed to examine whether our findings from Cohort 1 would still be evident in an independent cohort (Cohort 2) born 2006–2011 and recruited from the same tertiary NICU in Vancouver, Canada. We also compared the cortisol patterns, clinical and socio‐demographic factors, and their interrelationships between the two cohorts. In Cohort 2, our findings using multi‐level modeling support and extend our earlier findings in Cohort 1, demonstrating that children born ELGA display higher pre‐test cortisol levels than FT. As well, greater cortisol output across assessment was related to more anxiety/depressive behaviors in children born VLGA. Importantly, children born ELGA were exposed to less neonatal pain/stress, mechanical ventilation, and morphine in Cohort 2 than Cohort 1. In both cohorts, however, cortisol levels and patterns were related to neonatal pain/stress and clinical factors (days on mechanical ventilation, overall morphine exposure). Despite less exposure to pain/stress and adverse clinical factors in Cohort 2 compared to Cohort 1, cortisol levels and patterns across cognitive challenge in preterm children at 18‐month CA were consistent across the two independent cohorts. These findings highlight that, despite improvements to neonatal care, children born extremely preterm continue to display altered HPA axis activity, which is associated with their poorer neurodevelopmental and behavioral outcomes.

Repetitive neonatal procedural pain affects stress‐induced plasma corticosterone increase in young adult females but not in male rats

“…Unfortunately, clinical studies did not include possible gender differences in their analysis. Altogether, our results and previous clinical and preclinical studies suggest an age-and sex-dependent effect of repetitive neonatal procedural pain on the HPA axis (Brummelte et al, 2015;Chen et al, 2016;Grunau et al, 2004;Lowe et al, 2023;McLean et al, 2023;Mooney-Leber & Brummelte, 2020;Olszewska et al, 2022). Given that many studies did not include longitudinal and gendered effects, conclusions must be taken with precaution and additional longitudinal research including gender-related aspects is required.…”

“…Furthermore, the HPA axis response depends on negative feedback from glucocorticoids on the glucocorticoid receptors (GR) and the mineralocorticoid receptors (MR), an adaptive response under the influence of sex hormones and epigenetically sensitive to early-life events (De Kloet et al, 1998;Goel et al, 2011;Keller-Wood & Dallman, 1984;Nicolaides et al, 2015). Early-life adversities, including repetitive neonatal procedural pain, promote continued increase of glucocorticoids levels in rodents and human alike (Grunau et al, 2004;McLean et al, 2023;Mooney-Leber et al, 2018;Olszewska et al, 2022;Victoria, Karom, et al, 2013). Rodent females may be more sensitive to the heightened glucocorticoids levels as suggested by their higher ACTH response at P8 following ether inhalation (Hary & Dupouy Isabelle Grégoire, 1986).…”

“…Clinical studies have shown that continued neonatal procedural pain shifts the level of the main stress hormone cortisol in former NICU patients (Brummelte et al, 2015;Grunau et al, 2004Grunau et al, , 2005McLean et al, 2023;Mörelius et al, 2016;Olszewska et al, 2022;Stoye et al, 2022). Nevertheless, the long-term effects of repetitive neonatal procedural pain on the HPA axis are still unclear and the directionality of this effect seems to depend on exposure intensity in combination with gender and age (Grunau, 2013;LaPrairie & Murphy, 2010;Matthews, 2002).…”