Preterm Brain Injury, Antenatal Triggers, and Therapeutics: Timing Is Key

Abstract

With a worldwide incidence of 15 million cases, preterm birth is a major contributor to neonatal mortality and morbidity, and concomitant social and economic burden Preterm infants are predisposed to life-long neurological disorders due to the immaturity of the brain. The risks are inversely proportional to maturity at birth. In the majority of extremely preterm infants (<28 weeks' gestation), perinatal brain injury is associated with exposure to multiple inflammatory perinatal triggers that include antenatal infection (i.e., chorioamnionitis), hypoxia-ischemia, and various postnatal injurious triggers (i.e., oxidative stress, sepsis, mechanical ventilation, hemodynamic instability). These perinatal insults cause a self-perpetuating cascade of peripheral and cerebral inflammation that plays a critical role in the etiology of diffuse white and grey matter injuries that underlies a spectrum of connectivity deficits in survivors from extremely preterm birth. This review focuses on chorioamnionitis and hypoxia-ischemia, which are two important antenatal risk factors for preterm brain injury, and highlights the latest insights on its pathophysiology, potential treatment, and future perspectives to narrow the translational gap between preclinical research and clinical applications.

Keywords: annexin A1; biomarkers; chorioamnionitis; erythropoietin; hypoxia-ischemia; preterm brain injury; stem cells; therapeutic hypothermia; timing.

Figure 1

Annexin A1 (ANXA1) expression over time in response to intra-amniotic lipopolysaccharide (LPS) exposure in the vasculature of the fetal brain parenchyma and the choroid plexus. (A) Integrated density (mean grey value of stained area*percentage of the stained area) of ANXA1 immunoreactivity in the cerebrovasculature. (B) The integrated density of ANXA1 expression within the vasculature of the choroid plexus. (C) Representative picture of ANXA1 expression within the blood vessels within the brain parenchyma of coronal sections containing the hippocampus; 200× magnification, scale bar 50 µm. (D) Representative picture of ANXA1 within the blood vessels of the choroid plexus; 400× magnification, scale bar 50 µm. Data are presented as mean/standard error of the mean and the Kruskal–Wallis test was performed: p < 0.05 = *, p < 0.1 = #.