Preventing Brain Injury in the Preterm Infant—Current Controversies and Potential Therapies

Abstract

Preterm birth is associated with a high risk of morbidity and mortality including brain damage and cerebral palsy. The development of brain injury in the preterm infant may be influenced by many factors including perinatal asphyxia, infection/inflammation, chronic hypoxia and exposure to treatments such as mechanical ventilation and corticosteroids. There are currently very limited treatment options available. In clinical trials, magnesium sulfate has been associated with a small, significant reduction in the risk of cerebral palsy and gross motor dysfunction in early childhood but no effect on the combined outcome of death or disability, and longer-term follow up to date has not shown improved neurological outcomes in school-age children. Recombinant erythropoietin has shown neuroprotective potential in preclinical studies but two large randomized trials, in extremely preterm infants, of treatment started within 24 or 48 h of birth showed no effect on the risk of severe neurodevelopmental impairment or death at 2 years of age. Preclinical studies have highlighted a number of promising neuroprotective treatments, such as therapeutic hypothermia, melatonin, human amnion epithelial cells, umbilical cord blood and vitamin D supplementation, which may be useful at reducing brain damage in preterm infants. Moreover, refinements of clinical care of preterm infants have the potential to influence later neurological outcomes, including the administration of antenatal and postnatal corticosteroids and more accurate identification and targeted treatment of seizures.

Stem Cell Therapy for Neonatal Hypoxic-Ischemic Encephalopathy: A Systematic Review of Preclinical Studies

“…However, in newborns diagnosed with severe HIE, TH does not improve the major neurodevelopmental disabilities and neuromotor delays. Currently, TH is not established for preterm neonates presenting HIE due to the peculiarities of this injury when occurring in the preterm brain, and it was reported to be associated with a higher incidence of complications, such as hyperglycemia and coagulopathy, and higher mortality in preterm neonates [19,20]. Therefore, it is essential to uncover therapies that will improve the outcome of newborns diagnosed with HIE, including those classified as severe.…”

Fetal heart rate variability is a biomarker of rapid but not progressive exacerbation of inflammation in preterm fetal sheep

“…Preterm birth accounts for about 11% of deliveries worldwide 1 and is a leading cause of neonatal morbidity and mortality 2 . Perinatal infection and inflammation are associated with approximately 40% of premature deliveries 3 – 7 , and high rates of neurodevelopmental disability 8 , 9 . In recent studies, gram-negative bacteria were predominantly involved in early-onset sepsis amongst preterm neonates, denoting a high rate of gram-negative infection in the immediate perinatal period 10 .…”

Anti-Inflammatory Therapies for Treatment of Inflammation-Related Preterm Brain Injury

“…Although the causes are likely multifactorial, disability in preterm born children is strongly associated with infection and inflammation around the time of birth. Infection is implicated in 25-40% of all preterm births [10,11], while both intrauterine and postnatal infections are highly associated with brain injury and neurological impairment [12][13][14]. Given the apparently causal relationship between inflammation and adverse developmental outcomes in preterm born infants, it is logical to assume that modulation of the inflammatory response would be beneficial.…”