An Integrative Review of Cytokine/Chemokine Predictors of Neurodevelopment in Preterm Infants

Abstract

Preterm infants are at risk of brain injury and poor neurodevelopmental outcomes including impairments in cognition, behavioral functioning, sensory perception, and motor performance. Systemic inflammation has been identified as an important, potentially modifiable precursor of neurologic and neurodevelopmental impairments. Inflammation is typically measured by quantifying circulating cytokines and chemokines. However, it is unclear which specific cytokines/chemokines most consistently predict neurodevelopment in preterm infants. In this integrative review, we evaluated and analyzed the literature ( N = 37 publications) to determine the cytokines/chemokines most predictive of neurodevelopment in preterm infants, the optimal timing for these measurements, and the ideal source for collecting cytokines/chemokines. Synthesis of the findings of these studies revealed that interleukin (IL)-6, IL-1β, IL-8, and tumor necrosis factor (TNF)-α collected during the first 3 weeks of life are most predictive of subsequent neurodevelopment. Methodological variation among studies hinders more specific analysis, including the evaluation of cytokine thresholds and meta-analyses, that would allow for the use of cytokines/chemokines to predict neurodevelopment. Future research should focus on identifying explicit cytokine values, specifically for IL-6, IL-1β, IL-8, and TNF-α, that are most predictive for identifying preterm infants most at risk of impairment, keeping in mind that longitudinal measures of cytokines/chemokines may be more predictive of future outcomes than single-time point measures.

Inflammatory mediators of stress exposure and neurodevelopment in very preterm infants: Protocol for the stress neuro‐immune study

“…The Stress Neuro‐Immune Study integrates knowledge from interdisciplinary research on stress exposure, inflammation, and neurodevelopment into a theory‐guided study that allows for the relationships among these concepts to be more thoroughly explored. Many investigators have studied the effect of stress exposure in the NICU on neurodevelopment in preterm infants (Grunau et al, ; Valeri et al, ) or the relationship between neonatal inflammatory markers on neurodevelopment (, in press). A limited number of studies have included investigation of the effect of stress exposure on neonatal immune function, and most studies have used animal models (Pinheiro et al, ; Roque, Ochoa‐Zarzosa, & Torner, ).…”

Placental programming, perinatal inflammation, and neurodevelopment impairment among those born extremely preterm

“…47 In a metaanalysis of 37 studies, the protein biomarkers most consistently predictive of neurodevelopmental impairments were IL-6, IL-8, and, to a lesser extent, TNF-α and IL-1β. 48 In the ELGAN Study, elevated levels in neonatal blood of multiple inflammation biomarkers, most prominently IL-8, were associated with neonatal brain ultrasound indicators of white matter damage, 49 cognitive impairment, 50 cerebral palsy, 51 autism spectrum disorder, 52 and attention deficit hyperactivity disorder symptoms, 53 as well as decreased cortical and deep gray matter, cerebellar, and brainstem volumes as measured with magnetic resonance at 10 years of age. 54 A detailed description of the cellular and molecular events that could explain a causal relationship between perinatal inflammation and neurodevelopmental impairments is beyond the scope of this review, and the interested reader is referred to several excellent reviews of this topic.…”

Regulation of glutamate transport and neuroinflammation in a term newborn rat model of hypoxic–ischaemic brain injury

“…Emerging evidence indicates that hypoxia–ischaemia causes an inflammatory response in the brain, with activation of microglia by the excitotoxically injured neurons and infiltration of peripheral immune cells via the disrupted blood–brain barrier ( Algra et al, 2013 ; Hagberg et al, 2015 ; Winerdal et al, 2012 ; Yong and Marks, 2010 ). Levels of pro-inflammatory cytokines tumour necrosis factor alpha (TNFα), interleukin (IL)1β and IL6 have been shown to predict neurodevelopmental impairment in at-risk newborns ( Magalhães et al, 2019 ; Nist and Pickler, 2019 ).…”