The challenges of fetal life: Asphyxia, infection and clinical treatments

Abstract

This thesis explores the origins of perinatal neurodevelopmental impairment in term and preterm fetuses. The first set of studies investigated how fetuses respond and adapt to two common perinatal complications, asphyxia and infection/inflammation. My first two studies illustrated that fetal inflammation is associated with altered fetal heart rate patterns. An evolving pattern of transient ‘subclinical’ decelerations followed by suppression of fetal heart rate variability was observed, which were strongly associated with arterial hypotension. This may help identify fetuses mounting an acute inflammatory response to intrauterine infection. My next study illustrated that sympathetic control of fetal heart rate variability is suppressed during labour-like asphyxia. Fetal heart rate variability in current practice is often regarded as the most important index of fetal wellbeing, but this finding illustrates that it provides limited information about fetal health during labour. I subsequently dissected the currently accepted mechanisms that mediate fetal heart rate decelerations during labour and found that they are not supported by robust evidence. In contrast, there is strong evidence that the majority of brief intrapartum decelerations must be mediated by the peripheral chemoreflex, secondary to fetal asphyxia. The second set of studies investigated the interactions between antenatal glucocorticoid treatment and asphyxial brain injury. Fetuses at risk of preterm delivery are now almost universally treated with maternal glucocorticoids to improve short-term outcomes. The implications for neurodevelopmental outcomes are poorly understood. The first study revealed that glucocorticoid treatment given after severe asphyxia increased brain injury and was associated with increased brain activity during recovery from asphyxia. Cerebral blood flow was uncoupled from metabolism, leading to exacerbated cerebral hypoxia, which likely underpinned the greater neural injury. The second study showed that treatment with dexamethasone before asphyxia was associated with devastating cystic injury and impaired recovery of brain activity. I further showed that these effects were replicated by the induction of hyperglycaemia before asphyxia. This illustrated that glucose was the key detrimental factor, and in turn challenges previous evidence from postnatal rats that glucose is neuroprotective for the perinatal brain. These findings indicate that antenatal glucocorticoids may not be safe in the setting of perinatal asphyxia.