Inflammatory Mediators of Stress Exposure and Neurodevelopment in Very Preterm Infants

Background: Preterm birth is an increasing global health concern. Survivors of preterm birth are at risk for poor neurodevelopmental outcomes, including impairments in cognition, motor performance, sensory processing, and socio-emotional functioning. Stress exposure during the initial period of hospitalization has been linked to poorer neurodevelopment. Determining the important mediators of stress exposure and neurodevelopment is critical to the development of targeted interventions to improve long-term outcomes. Inflammation may be one such mediator, as elevated inflammatory biomarkers during the neonatal period are associated with brain injury and impaired neurodevelopment in preterm infants.

Purpose: The overarching purpose of this study is to determine the relationships among stress exposure, inflammation, and neurodevelopment in very preterm infants. This study will accomplish the following specific aims: (1) determine the relationships among stress exposure, inflammation, and neurodevelopment and determine the mediated effect, (2) determine the effect of stress exposure on weekly changes in inflammatory and anti-inflammatory cytokines from one week of age until 35 weeks post-menstrual age (PMA), and (3) examine the correlation between a published scale of neonatal stress exposure and chronic stress response in very preterm infants.

Theoretical/Scientific Premise: The “Biological Embedding of Childhood Adversity Model” provides the theoretical framework for this study. The model posits that early life stressors affect biological processes to produce a pro-inflammatory phenotype, resulting in poorer adult health outcomes. The model has been previously adapted for the study of preterm infant stress exposure and long-term immune and hypothalamic-pituitary-adrenal (HPA) axis functioning and has been further adapted for the current study. Preterm infant stress exposure affects neurodevelopmental outcomes and this relationship is partially mediated by inflammation. The intensity of the inflammatory response is dependent upon the reciprocal regulation of pro-inflammatory and anti-inflammatory factors.

Method: A non-experimental, repeated measures design will be used to determine the relationships among stress exposure, inflammation, and neurodevelopment. Cumulative stress will be measured using the Neonatal Infant Stressor Scale (NISS) and hair cortisol concentration (HCC). NISS scores will be calculated for each day of hospitalization until 35 weeks PMA to determine a cumulative stress score. A hair sample will be collected at 35 weeks PMA to measure chronic stress responses. Inflammation will be measured by a panel of urinary and plasma cytokines, quantified by multiplex assay. Plasma and urine samples will be collected weekly for the measurement of cytokines. Neurodevelopment will be assessed using the Neurobehavioral Assessment of the Preterm Infant (NAPI) at 35 weeks PMA.

Data Analysis: Multiple linear regression, correlation, and linear mixed effects models will be used to determine the relationships among the primary variables. Mediation/moderation analysis with bias-corrected bootstrap confidence intervals will be used to determine the indirect effect. Linear mixed effect models will be used to examine the effect of cytokine trends on neurodevelopment.

Funding: Funding for this study has been provided by the National Institutes of Nursing Research (F31 NR017321; PI: Nist); Sigma Theta Tau International; Midwest Nursing Research Society 2018 Founders’ Circle Endowment Fund Grant; Association of Women’s Health, Obstetric, and Neonatal Nurses and Kimberly-Clark; The Ohio State University Alumni Grants for Graduate Research and Scholarship; and The Ohio State University Critical Difference for Women.