Perinatal asphyxia and oxidative stress: studies in preterm IUGR pregnancies and term acute asphyxia

Abstract

Pregnancies complicated by intrauterine growth restriction (IUGR), preeclampsia (PE) or HELLP syndrome often have to be terminated prematurely. As a consequence of the early gestational age (GA) at delivery, infants born from these pregnancies are at increased risk of developing respiratory problems. It is unclear, however, whether placental insufficiency and maternal hypertensive disease have independent beneficial or detrimental effects on fetal lung maturation and clinical respiratory outcome. This information may be important for obstetricians who have to decide on whether or not to administer antenatal corticosteroids and on the optimal timing of delivery. The first part of this thesis concentrates on respiratory outcome, fetal lung maturation and underlying pathophysiology of infants born from pregnancies complicated by IUGR and/or PE/HELLP syndrome. Results show that placental insufficiency does not influence clinical respiratory outcome. Contrary to expectation, measures of fetal lung maturation (amniotic fluid L/S ratio) are significantly higher in pregnancies complicated by placental insufficiency, indicating enhanced lung maturation. This apparent contradiction may be due to differences in study design. Interestingly, IUGR fetuses from pregnancies complicated by HELLP syndrome have a significantly poorer neonatal respiratory outcome and lower L/S ratios as compared to IUGR fetuses with otherwise healthy mothers. Furthermore, markers of oxidative stress and inflammation are increased in infants and placentae from mothers with HELLP syndrome as compared to PE. These results indicate that harmful pathophysiological pathways are (more intensely) activated in infants from mothers with HELLP syndrome. These pathways may cause lung damage and surfactant inactivation, providing a possible explanation for the increased RDS incidence in these infants. Despite extensive research on short term outcome of IUGR fetuses, long term outcome has not yet been studied. Previously, GA has been shown to be the most important variable determining short term outcome before 30 weeks of gestation. In this thesis, mortality was shown to decrease with increasing GA, but abnormal neurodevelopment continued to be high. This suggests that delivery of infants born after 30 weeks may be too late in some cases, exposing them too long to continuing undernutrition. So far, this thesis has focused on factors affecting outcome of the preterm IUGR fetus. It would be of great clinical significance if an intrauterine therapeutic approach could be designed. Oxidative stress has been implicated in both IUGR and term asphyxia and reducing oxidative stress may be beneficial in these fetuses. In the second part of this thesis we therefore focused on the first step towards developing an intrauterine approach for reduction of oxidative stress in term fetal asphyxia with allopurinol. We showed that maternal allopurinol treatment reduces cardiac oxidative stress and improves the recovery of umbilical blood flow and fetal survival in a fetal sheep model of acute asphyxia. In humans, maternal allopurinol crosses the placenta during fetal hypoxia although fetal levels are not always within the therapeutic range. In newborns with therapeutic allopurinol concentrations, plasma levels of the brain injury marker protein S-100B appeared to be lower. A larger trial in compromised fetuses at term seems warranted in which the allopurinol dosage must be adjusted and long term neurodevelopmental outcome should be studied.