Byline: Julie. Wixey, Stella. Bjorkman
Intrauterine growth restriction (IUGR) occurs when a baby is unable to grow normally due to receiving inadequate nutrients while developing in the womb. IUGR is a leading cause of perinatal death and long-term disability. The fetal brain is particularly vulnerable to IUGR conditions and adverse outcomes range from learning, attention and behavioral difficulties, to cerebral palsy. Due to medical advancements, more IUGR babies now survive, resulting in an even greater burden of disability. Many IUGR children require long-term medical care and support, and their families experience significant emotional stress and challenges. Currently there is no treatment available to protect the IUGR newborn brain and reduce these life-long burdens. While the development of strategies to reduce brain deficits in IUGR newborns have been proposed as in need of urgent research for several years, very few trials have been undertaken. Assessing long-term outcomes and thorough safety profiling of any treatment option is necessary prior to administering therapies to vulnerable newborns.
In IUGR newborns, changes in brain structure that occur during the prenatal period have been shown to persist into adolescence. Such changes alter brain connectivity and have been associated with neurodevelopmental disabilities. Our animal studies have demonstrated altered neuronal and white matter development both in fetal and postnatal brain (Kalanjati et al., 2017), with these alterations being associated with persistent inflammation even after birth (Wixey et al., 2019a, b).
Mechanisms of brain impairment in IUGR newborn: Multiple mechanisms have been shown to mediate cellular impairment in the IUGR brain. These include oxidative stress, excitotoxicity, necrotic and apoptotic degeneration, blood-brain barrier disruption and neuroinflammation. Recently, inflammation has been regarded a key mechanism associated with brain impairment in the IUGR newborn. Inflammation does not cease after the baby has been born and removed from the adverse intrauterine environment. In our large pre-clinical animal model of IUGR, we have shown sustained increases in activated microglia, astrogliosis, and increases in proinflammatory cytokines in the brain up to 4 days after birth (Wixey et al., 2019a). In humans, high concentrations of proinflammatory cytokines have been reported in the blood of preterm IUGR infants 2 weeks after birth (McElrath et al., 2013). Increases in proinflammatory cytokines in the blood have also been shown to correlate with adverse neurological outcomes at 2 years of age in preterm small for gestational age newborns (Leviton et al., 2013) suggesting that therapeutic targeting of inflammation following birth could reduce or even prevent significant ongoing neurological issues in these babies.
Treating the IUGR newborn to reduce neurological disorders: Treating the IUGR fetus in utero is likely to be beneficial, however 40% of IUGR babies are only diagnosed at or around the time of birth, with a much lower detection rate (average 18.7%) for low-risk populations (Gardosi et al., 2018). As our research has shown that inflammation-mediated brain injury in the IUGR newborn is sustained following birth, there is opportunity to treat the IUGR newborn to improve neurological outcomes. Treatments with anti-inflammatory properties such as melatonin, xenon, and erythropoietin...