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Although survival rates of preterm infants are improving, preterm birth is still associated with significant morbidity.The brain is one of the most vulnerable organs in preterm infants. Neonatal brain injury can have a large impact on the quality of life. Monitoring the immature brain is therefore important. Cerebral oxygenation can be monitored with near-infrared spectroscopy (NIRS), a method which sends near-infrared light (700 – 1000nm) through brain tissue and calculates regional cerebral oxygen saturation, which reflects oxygen supply, and cerebral fractional tissue oxygen extraction, reflecting oxygen utilization. The balance between oxygen supply and utilization provides insight in cerebral (patho-)physiology. In our neonatal intensive care unit, cerebral oxygenation monitoring is standard clinical care, together with the amplitude-integrated electro-encephalogram, cranial ultrasound, magnetic resonance imaging (MRI), and the monitoring of vital parameters. With cerebral NIRS, the neonatologist has a tool to monitor the oxygenation of the brain non-invasively. In this thesis we have analysed several factors that affect cerebral oxygenation, in order to gain a better understanding of the (patho-)physiology of the brain. First of all, it is important to take the type of NIRS device and sensor into account, as differences may exist between neonatal sensors and the adult sensors. Reference values for the first 3 days of life in preterm neonates have now been published for both the adult and the neonatal sensors. These values are based on a large cohort of 999 infants. Additionally, the effects of gender, a patent ductus arteriosus (hsPDA) and birth weight have been analysed. Cerebral oxygenation can be affected by several clinical factors. It can be lower in female neonates than in males, or in case of a hsPDA. A hsPDA can negatively affect cerebral perfusion and oxygenation by the ductal steal effect. Additionally, hypocapnia can induce cerebral vasoconstriction and decrease cerebral oxygenation. Cerebral oxygenation is higher with advancing postnatal age and gestational age, in male neonates, and in infants born small-for-gestation-age (SGA). Even though SGA infants have a higher cerebral oxygenation, presumably due to the brain sparing effect by intrauterine growth retardation, they are more severely affected by the negative effect of a hsPDA. Furthermore, hypercapnia can induce cerebral vasodilation with an increase in cerebral oxygenation. The safe range of regional cerebral oxygen saturation is presumed to be between 55-85%. Prolonged exposure to values outside this range has been associated with cerebral injury: especially low cerebral oxygenation has been associated with poor cognitive outcome at early school age in infants with a hsPDA. Early detection of these deteriorations of cerebral oxygenation with appropriate interventions might avoid situations with unfavourable cerebral homeostasis and prevent injury, thereby improving neurodevelopmental outcome. Awareness of which factors affect cerebral oxygenation, and in what way, is therefore of the utmost importance.

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.

Monitoring the newborn brain during surgery Cerebral monitoring in newborns, who require surgery in the first month of life, is important to protect the brain. The newborn brain is vulnerable during neonatal surgery. Newborn babies with a congenital anomaly requiring surgery in the first month of life, are at risk of neurodevelopmental delay. A systematic literature study confirmed this finding by Stolwijk et al. Therefore, since 2013 the Wilhelmina Childrens Hospital has started with cerebral monitoring during surgery and a postoperative MRI of the brain. Stolwijk et al found a high incidence of postoperative brain injury of 63% in patients with non-cardiac congenital anomalies. Also, they discovered that intact cerebral autoregulation of the perfusion in term neonates disappeared during general anaesthesia. This was studied by measuring the oxygen saturation of the brain (Near Infrared Spectroscopy). A small range in the dose of anaesthesia dose caused a wide variety in depression of the brain activity, monitored by amplitude-integrated EEG. Stolwijk et al discovered that neuromonitoring assists in minimalizing the effect of carbon dioxide during laparoscopic and thoracoscopic procedures on the cerebral perfusion by adjusting ventilation settings. Neuromonitoring helps to identify factors influencing the brain perfusion and activity. It offers the opportunity to keep these factors within normal limits. Next to neuromonitoring, is close collaboration between the anesthesiologist, the paediatric surgeon and the neonatologist crucial to achieve this.