Intrauterine Growth Restriction and Hyperoxia as a Cause of White Matter Injury

Abstract

Intrauterine growth restriction (IUGR) is estimated to occur in 5% of pregnancies, with placental insufficiency being the most common cause in developed countries. While it is known that white matter injury occurs in premature infants, the extent of IUGR on white matter injury is less defined in term infants. We used a novel murine model that utilizes a thromboxane A₂ (TXA₂) analog (U46619), a potent vasoconstrictor, to induce maternal hypertension and mimic human placental insufficiency-induced IUGR to study the white matter. We also investigated the role of hyperoxia as an additional risk factor for white matter injury, as IUGR infants are at increased risk of respiratory comorbidities leading to increased oxygen exposure. We found that TXA₂ analog-induced IUGR results in white matter injury as demonstrated by altered myelin structure and changes in the oligodendroglial cell/oligodendrocyte population. In addition, our study demonstrates that hyperoxia exposure independently results in white matter perturbation. To our knowledge, this is the first study to report single and combined effects of IUGR with hyperoxia impacting the white matter and motor function. These results draw attention to the need for close monitoring of motor development in IUGR babies following hospital discharge as well as highlighting the importance of limiting, as clinically feasible, the degree of oxygen overexposure to potentially improve motor outcomes in this population of infants.

Intrauterine Growth Restriction Followed by Oxygen Support Uniquely Interferes with Genetic Regulators of Myelination

“…In contrast to transient changes in OL populations in IUGR, IUGR with hyperoxia resulted in sustained OL alterations into adulthood. The combination of IUGR and hyperoxia also led to more pronounced WMI on MRI and gait changes in adult mice (Chang et al, 2018). The different findings seen with these perinatal exposures support a multi-hit hypothesis for WMI and also highlight that different mechanisms may be involved with each exposure.…”

“…Existing animal studies of IUGR demonstrate evidence of oligodendroglial (OL) injury and subsequent WMI (Olivier et al, 2007;Tolcos et al, 2011;Volpe et al, 2011;Reid et al, 2012;Basilious et al, 2015;Rideau Batista Novais et al, 2016), specifically, a decrease in immature/pre-myelinating OLs and total OL population (Chang et al, 2018). This is similar to findings in models of prematurity and hypoxic-ischemic injury where blocked maturation of oligodendrocyte progenitor cells (OPCs) is implicated in impaired white matter development (Chang et al, 2018). Despite these cellular changes, the molecular mechanisms remain incompletely understood.…”

“…A number of population-based cohort studies have shown a 5-7 fold increased risk of developing CP in growth restricted infants (Ahlin et al, 2013;Dahlseng et al, 2014;Blair and Nelson, 2015;Freire et al, 2015;Streja et al, 2015;Mor et al, 2016). Existing animal studies of IUGR demonstrate evidence of oligodendroglial (OL) injury and subsequent WMI (Olivier et al, 2007;Tolcos et al, 2011;Volpe et al, 2011;Reid et al, 2012;Basilious et al, 2015;Rideau Batista Novais et al, 2016), specifically, a decrease in immature/pre-myelinating OLs and total OL population (Chang et al, 2018). This is similar to findings in models of prematurity and hypoxic-ischemic injury where blocked maturation of oligodendrocyte progenitor cells (OPCs) is implicated in impaired white matter development (Chang et al, 2018).…”

“…Recently, the multi-hit hypothesis was tested in a mouse model of IUGR, with and without supplemental oxygen (Chang et al, 2018). Postnatal hyperoxia exposure independently resulted in white matter dysfunction different from that seen in IUGR.…”

Fetal Brain-Sparing, Postnatal Cerebral Oxygenation, and Neurodevelopment at 4 Years of Age Following Fetal Growth Restriction

“…Although Verhagen et al similarly reported poorer cognition at r c SO 2 levels above 83% on day 1, Verhagen et al (20) the inverse relationship between r c SO 2 and PIQ is puzzling. PIQ has, however, been related to motor function, and oxidative stress is known to cause white matter and motor neuron injury, in particular if preceded by hypoxia (36)(37)(38)(39)(40)(41). Additionally, hemodynamic redistribution may occur within the brain from frontal regions to basal ganglia in FGR fetuses with brainsparing and impending cardiac failure, as heralded by abnormal DV waveforms (42)(43)(44).…”