The pulmonary and neurological effects of glucocorticoid and antioxidant treatment in the growth restricted ovine fetus

Intrauterine growth restriction (IUGR) is associated with increased perinatal mortality and morbidities as well as high rates of preterm birth. IUGR fetuses are therefore likely to be exposed to synthetic glucocorticoids in order to promote fetal lung maturation. However, few studies have isolated the effects of exogenous glucocorticoids in IUGR fetuses. While there is no doubt that antenatal glucocorticoids reduce neonatal mortality and morbidity, glucocorticoids also have adverse effects on the developing brain. Oxidative stress is increased following glucocorticoids and may contribute to these adverse effects. Therefore, the antioxidant melatonin may be able to protect the fetus against any unwanted effects of glucocorticoids. This thesis used an ovine model of IUGR to investigate the pulmonary and neurological effects of betamethasone administration in the IUGR fetus. The potential neuroprotective properties of melatonin and any possible interference it may have with glucocorticoid-induced lung maturation were then investigated. Pregnant ewes carrying twins underwent surgery between 105-110 days (0.7) gestation, in which single umbilical artery ligation (SUAL) was performed to induce IUGR in one twin, with the other twin acting as a control. Half the ewes received betamethasone (11.4mg) on days five and six following surgery. Animals allocated to receive melatonin commenced a maternal infusion of 2mg/hr from 30 minutes prior to the first dose of betamethasone, which continued until post mortem on day seven following surgery (48 hours after betamethasone/melatonin administration). This thesis finds that SUAL-induced IUGR fetuses do indeed benefit from exogenous glucocorticoid administration with improved lung maturation compared to untreated fetuses. This improved maturation included a reduced tissue density and an increase in the surfactant protein (SP) genes SP-A, SP-B and SP-C. While lung maturation was improved in IUGR fetuses following glucocorticoids, both IUGR and control fetuses show altered brain activity in response to glucocorticoids. This altered activity included an increase in overall amplitude and an increase in the number of seizures. Within the fetal brain, glucocorticoids increased apoptotic cell death in all fetuses. IUGR fetuses also respond to glucocorticoid administration with an increase in cerebral blood flow that does not occur in control fetuses. When melatonin was co-administered with glucocorticoids, this cerebral blood flow response was augmented in IUGR fetuses. Melatonin administration prevented the increase in brain activity amplitude in control fetuses as well as reducing both the number and amplitude of transient spikes in all fetuses. Within the fetal brain, melatonin reduced the amount of lipid peroxidation products in all fetuses. Surprisingly, melatonin administration promoted fetal lung maturation with the lowest tissue density seen in fetuses that received both melatonin and glucocorticoids. However this reduction in tissue density was found to be at the expense of cell proliferation and it is unknown what effect this may have on alveolarisation within the lung. Overall, this thesis has shown that both control and SUAL-induced IUGR fetuses respond to glucocorticoid administration with increased lung maturation but altered fetal brain activity and cell death. Melatonin appears to be a safe and effective neuroprotective strategy, acting to decrease brain oxidative stress and may act with glucocorticoids to promote lung maturation. This may provide an opportunity for lowering the dose of glucocorticoids used to promote fetal lung maturation in preparation for preterm delivery.