Review articleBlocked, delayed, or obstructed: What causes poor white matter development in intrauterine growth restricted infants?
Introduction
Intrauterine growth restriction (IUGR) is a significant health issue worldwide. In developed countries, up to 9% of all pregnancies are complicated by IUGR, which equates to approximately 30 million newborns worldwide. IUGR is defined as the failure of a fetus to reach its genetic growth potential, and is second only to prematurity as a leading cause of perinatal death (Bernstein et al., 2000). It is commonly caused by poor placental function, a condition known as placental insufficiency, which leads to chronic hypoxemia and reduced nutrient supply to the fetus, and ultimately impacts on organogenesis and fetal body growth in general. The placental dysfunction that underlies IUGR is itself not always detectable, and the problem is usually revealed only when the fetus fails to meet the expected growth profile, or the baby is born with asymmetrically small body proportions. Clinical management of an IUGR pregnancy involves fetal monitoring and preterm delivery if indicated, however there is currently no treatment to prevent the placental insufficiency, the restricted fetal growth or the brain injury that ensues.
Surviving IUGR infants have a greatly heightened risk of neurodevelopmental impairment (Geva et al., 2006b) and a 10–30-fold increase in the risk of developing cerebral palsy (Blair and Stanley, 1990, Jacobsson and Hagberg, 2004, MacLennan et al., 2015, McIntyre et al., 2013); indeed, the risk of cerebral palsy is positively correlated with the severity of IUGR (Jacobsson et al., 2008), and IUGR is a greater risk factor for the development of cerebral palsy than is birth asphyxia and inflammation combined (McIntyre et al., 2013). White matter injury and reduced myelination as a consequence of IUGR is more strongly associated with the later development of cerebral palsy than any other neuroimaging finding (e.g. infarction, hypoxic-ischemic brain injury) (Wu et al., 2006b). However, our understanding of the mechanisms that underlie the association between IUGR, cerebral palsy and poor white matter development is incomplete, even though much emphasis is placed on studies of white matter injury induced by hypoxia-ischemia and/or endotoxin-induced fetal inflammation. Recent reviews have discussed the issue of disorders of myelination in relation to preterm birth (van Tilborg et al., 2016) and adult demyelinating disease (Fancy et al., 2011a, Kotter et al., 2011). In this review we specifically focus on the impact of IUGR on the developing white matter, and discuss some of the mechanisms thought to underlie impaired myelination, particularly in relation to IUGR, drawing upon knowledge gained in studies of preterm birth and demyelinating disease in the adult brain. We will propose and discuss putative therapies that could be exploited in future preclinical studies to either prevent poor myelination in the growing brain, or promote its appropriate development.
Section snippets
Neuroanatomical and neuropathological changes
In IUGR infants, the brain is relatively less affected in terms of size compared to the body as a whole, leading to the concept of brain ‘sparing’, but there is clearly an attrition of central nervous system (CNS) development in terms of both structure and function observable even in the fetus. For example, while brain growth in the IUGR baby is “spared” relative to other organs, key neurodevelopmental processes (e.g. myelination) are affected and this can lead to significant neurological
Basic regulation of oligodendrocyte maturation
The oligodendroglial cell lineage has been well characterized, with a number of identified regulators known to be important in driving the full transition from progenitor to the mature oligodendrocyte that synthesizes myelin and lays it down in an ordered structure wherever the oligodendrocyte projection abuts an axon (Fig. 2). OPCs are first generated from multipotent stem cells in the proliferative zones of the brain and spinal cord. Olig2-positive stem cells are present in the germinal
Possible mechanisms of impaired white matter development in IUGR
Relative to studies of adult demyelinating disease, there are considerably fewer studies that have assessed impaired oligodendrocyte development in IUGR. This is despite the growing body of evidence that shows that white matter volume is reduced and myelination has been delayed in infants, children and adults who were born IUGR (Eixarch et al., 2016, Padilla et al., 2011, Ramenghi et al., 2011, Fischi-Gomez et al., 2015). Intrinsic (molecular) and extrinsic (hormonal, growth factor) signals
Putative therapies to promote myelination in IUGR
There are currently no clinically accepted treatments to prevent the poor placental function associated with IUGR. At best, IUGR detected antenatally is managed using fetal surveillance followed by early delivery if concerns arise. Neuroimaging studies indicate that brain injury in the IUGR fetus and neonate occurs during pregnancy (Businelli et al., 2014, Dubois et al., 2008, Ramenghi et al., 2011), not after birth, thus the significant white matter injury has already occurred by the time
Conclusion
During brain development, oligodendrocyte maturation is driven by multiple signals that either promote or inhibit differentiation. A host of transcription factors regulate oligodendrocyte differentiation and maturation that lead to myelination, and the impact of fetal hypoxia and other conditions present in utero leading to IUGR (hypoglycemia, hypercortisolemia, for example) need to be investigated in order to understand why myelination delay often occurs in the neonates from such pregnancies.
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