From head to heart;: the effects of fetal growth restriction and preterm birth on the cerebral and systemic circulation

Abstract

Fetal growth restriction (FGR) is the condition where a fetus does not grow according to its genetic growth potential. It is estimated that 3-7% of pregnancies are complicated by FGR. FGR has been associated with many adverse outcomes, including an increased risk of perinatal and neonatal morbidity and mortality, as well as long-term neurodevelopmental and cardiovascular sequelae. However, the pathophysiological mechanisms underpinning these adverse outcomes are not fully understood. FGR is most commonly caused by uteroplacental vascular insufficiency. Under these circumstances of chronic oxygen and nutrient deprivation, the fetus displays typical haemodynamic changes. These include cerebral vasodilation resulting in a preferential shift of the cardiac output toward the brain to maximise oxygen and nutrient supply to this vital organ (‘brain-sparing’). Although these haemodynamic changes seem protective during intrauterine life, knowledge is limited regarding the short- and long-term postnatal consequences. The unfavourable intrauterine environment and prenatal haemodynamic changes may alter neurological and cardiovascular development, which could underpin the increased risk of perinatal and neonatal mortality and neurodevelopmental and cardiovascular sequelae. The overall aim of this thesis was to investigate the effects of FGR on the cerebral circulation and the cardiovascular system in neonates and infants born preterm. Part I of the thesis explored the effects of FGR on cerebral oxygenation and cerebral haemodynamics in preterm neonates. Retrospective analyses were performed on data from a large prospective cohort study on normative cerebral oxygenation values of prematurely born neonates admitted to the neonatal intensive care unit of the Wilhelmina Children’s Hospital, in Utrecht, The Netherlands. In this study, continuous near-infrared spectroscopy (NIRS) recordings of regional cerebral oxygen saturation were performed during the first three days of life. These data were used to compare cerebral oxygenation and haemodynamics between preterm FGR and preterm appropriate-for-gestational-age (AGA) neonates. Part II of this thesis investigated the effects of FGR and prematurity on the developing cardiovascular system. A prospective longitudinal cohort study was performed at The Ritchie Centre, in Melbourne, Australia. This study investigated cardiac morphology and function as well as autonomic cardiovascular control in preterm FGR versus preterm and term AGA infants throughout the first months of life. The results of this thesis suggest that preterm FGR neonates form a distinct high risk population within the neonatal intensive care unit. They display subclinical alterations in cardiac morphology, appear prone to circulatory instability, have altered cerebral haemodynamics and appear more vulnerable to cerebral hypo- and hyper-perfusion, which may increase the risk of brain damage and neurodevelopmental sequelae. These findings suggest that preterm FGR neonates may benefit from tailored monitoring and management strategies and further research in this field is of major importance. The early (subclinical) alterations in cardiac morphology and function appear to persist well into infancy, but tend to show improvement over time. Further studies are needed to examine if and how these early alterations are linked to long-term neurodevelopmental and cardiovascular outcome and whether early life interventions may prevent progression into chronic disease.