The effect of intrauterine inflammation on the perinatal cardiovascular system: consequences for renal, cardiopulmonary and neural systems

Preterm birth poses one of the greatest challenges for perinatal medicine. Preterm birth is responsible for up to 70% of perinatal mortality in developed countries, excluding deaths associated with congenital defects. Infants that survive preterm birth are at the greatest risk of suffering from cardio-respiratory problems, mental retardation, cerebral palsy, vision and hearing impairment, when compared to infants born at term. One of the main causes of preterm birth is chorioamnionitis (intrauterine inflammation), which is defined as inflammation, caused by bacterial infection of the chorion, amnion and placenta, which often leads to an inflammatory response within the fetal circulation. Intrauterine inflammation is not only a cause of preterm birth per se, but is also a major cause of neonatal morbidity and mortality. Importantly, the effect of intrauterine inflammation on the perinatal cardiovascular system remains poorly understood. There is a substantial amount of evidence indicating that being born preterm impairs renal development, however the effect of preterm birth caused by intrauterine inflammation, on renal development is poorly understood. The aim of the first experimental study (chapter 2) in this thesis was to determine the effect of intrauterine inflammation during late gestation, on renal development in preterm fetal sheep. To address this aim, a study of the effect of intrauterine inflammation on renal development was undertaken in a well-established sheep model of intrauterine inflammation. This study demonstrated that experimental chorioamnionitis caused a 23 and 18% reduction in glomerular number in singleton and twin LPS-exposed fetuses respectively, which may contribute to impaired renal function in preterm neonates exposed to chorioamnionitis and increase the risk of hypertension and end-stage renal disease in adulthood. Studies in chapters 3 and 4 were designed to investigate the effect of intrauterine inflammation on fetal and neonatal cardiopulmonary and cerebral hemodynamics. The rational for these studies arises from a large amount of clinical and experimental evidence suggesting that preterm infants exposed to chorioamnionitis are more likely to suffer chronic lung disease (defined by long term respiratory support), and brain injury. The aims of these studies were to investigate the effect of intrauterine inflammation on cardiopulmonary and cerebral hemodynamics in fetal sheep during late gestation and after preterm birth. These studies demonstrated that intrauterine inflammation impaired pulmonary blood flow and increased cerebral blood flow in fetal sheep. These hemodynamic changes persisted in the preterm neonate with an added increase in cerebral oxygen delivery. These data have developed our knowledge the pathophysiology underlying the increased incidence of chronic lung disease and brain injury in preterm infants exposed to intrauterine inflammation. Furthermore, they suggest that inflammation induced changes to pulmonary vascular development and cerebral metabolism may be detected in the fetus.