Prevention, Reduction and Repair of Brain Injury of the Preterm Infant

Abstract

Periventricular-intraventricular hemorrhages (PIVH) and (diffuse) white matter injury (WMI) are the most important acquired brain lesions of the very and extremely prematurely born neonate. Both carry a high risk for death or adverse neurodevelopmental outcome. The first part of the review discusses the standard of care and latest insights with respect to prevention and/or reduction of PIVH and WMI, taking into account their etiopathogenesis which is tightly linked to (functional) immaturity of the cerebral vascular bed and nervous system and commonly encountered inflammation. The second part discusses repair of hemorrhagic- ischemic and post-inflammatory brain lesions as it is an increasingly important topic in newborn medicine. In the near future trials of trophic and (autologous or allogenic) cell-therapy in infants at risk of or demonstrating established PIVH and WMI will be started. The focus of these potential trials will be discussed.

Keywords: brain hemorrhage; neuroprotection; neuroregeneration; prematurity; white matter injury in the preterm infant.

Figure 1

(A) MRI of a preterm infant (gestational age 26 2/7 weeks, birthweight 965 g) with a large IVH and a large left-sided (arrowhead) and small right-sided venous infarct. Post-hemorrhagic ventricular dilatation was treated with CSF removal from a subcutaneous reservoir. T2 weighted coronal image at the age of 8 weeks after birth. (B) MRI of a preterm infant (gestational age 32 2/7 weeks, birthweight 1,670 g) with several lesions in the periventricular white matter (arrowheads). T2 weighted coronal image at the age of 6 days after birth.

Figure 2

Individual values of Carotid blood flow [Qcar (ml/min)], representing global cerebral blood flow, as a function of (mean) carotid blood pressure (MCBP; mm Hg), representing cerebral perfusion pressure, in pretreated with indomethacin (filled circles) and non-treated ventilated preterm sheep fetuses, representing a perinatal lamb model (van Bel et al., 1993,1994,1995). Note the lower Qcar values and better autoregulatory curve in the indomethacin-treated animals. The small black arrow indicates the lower limit of MCBP where cerebral autoregulation is still operative.

Figure 3

Proposed actions of mesenchymal stem cells (MSC) when present in a (previously) hypoxic–ischemic environment: production of vesicles (exosomes) of various growth factors, (anti-inflammatory) cytokines, signaling proteins and mitochondria which give rise to recovery of affected neurons and to proliferation of endogenous paraventricular-situated neural stem cells to form oligodendrocytes, astrocytes and neurons.