Abstract
Congenital heart defects (CHD), the most common cause of birth defects with increasing birth prevalence, affect nearly 1% of live births worldwide. Cyanotic CHD are characterized by hypoxemia, with subsequent reduced oxygen delivery to the brain, especially critical during brain development, beginning in the fetus and continuing through the neonatal period. Therefore, neonates with CHD carry a high risk for neurological comorbidities, even more frequently when there are associated underlying genetic disorders. We review the currently available knowledge on potential prevention strategies to reduce brain damage induced by hypoxemia during fetal development and immediately after birth, and the role of erythropoietin (EPO) as a potential adjunctive treatment. Maternal hyper-oxygenation had been studied as a potential therapeutic to improve fetal oxygenation. Despite demonstrating some effectiveness, maternal hyper-oxygenation has proven to be impractical for extensive clinical application, thus prompting the investigation of specific pathways for pharmacological intervention. Among those, the role of antioxidant pathways and Hypoxia Inducible Factors (HIF) have been studied for their involvement in the protective response to hypoxic injury. One of the proteins induced by HIF, EPO, has properties of being anti-apoptotic, antioxidant, and protective for neurons, astrocytes, and oligodendrocytes. In human trials, EPO administration in neonates with hypoxic ischemic encephalopathy (HIE) significantly reduced the neurological hypoxemic damages in several reported studies. Currently, it is unknown if the mechanisms of pathophysiology of cyanotic CHD are like HIE. Neonates with cyanotic CHD are exposed to both chronic hypoxemia and episodes of acute ischemia-reperfusion injury when undergo cardiopulmonary bypass surgery requiring aortic cross-clamp and general anesthesia. Our review supports future trials to evaluate the potential efficiency of EPO in reducing the hypoxemic neurologic damages in neonates with CHD. Furthermore, it suggests the need to identify early biomarkers of hypoxia-induced neurological damage, which must be sensitive to the neuroprotective effects of EPO.
Highlights
Improved prenatal and neonatal detection of congenital heart defects (CHD), along with advancements in medical treatments and surgical interventions, has led to improved survival rates among children with complex CHD (Erikssen et al, 2015; Bouma and Mulder, 2017)
Immutable risk factors include underlying genetic conditions associated with neurodevelopmental impairment, chronic hypoxemic state, and acute reoxygenation with ischemia-reperfusion injury related to cardiopulmonary bypass
EPO receptor is present in rats’ oligodendrocytes and astrocytes in culture, and high dose EPO (1, 3, 10 U/ml) markedly enhanced the proliferation of astrocytes. These results suggested that EPO promotes the differentiation and/or maturation in oligodendrocytes, and enhances the proliferation of astrocytes (Sugawa et al, 2002)
Summary
Improved prenatal and neonatal detection of congenital heart defects (CHD), along with advancements in medical treatments and surgical interventions, has led to improved survival rates among children with complex CHD (Erikssen et al, 2015; Bouma and Mulder, 2017). An overexpression of EPO receptor is observed after brain hypoxia, and this high expression is needed for a successful treatment with exogenously administered high doses of rhEPO In this regard nasal administration of lower doses of rhEPO can help to produce neuroprotection without increasing the circulating red blood cells (Merelli et al, 2011a; Merelli et al, 2015). One randomized clinical trial reported that low dose rhEPO intravenous treatment significantly decreased the incidence of retinopathy of prematurity, an effect of preterm hypoxia, in infant boys (Sun et al, 2020), while many other studies focused on demonstrating that such oxidative damage was not related to EPO concentrations. Other forms of EPO, slightly modified to improve delivery through the blood-brain barrier, without the need of administrating high doses of EPO, are under development (Zhang et al, 2010)
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