An adverse intrauterine environment: implications for injury and altered development of the brain

Abnormal development of the brain during fetal life is now thought to contribute to the aetiology of many functional and behavioural disorders that manifest throughout life. Many factors are likely to underlie such abnormal development including genetic makeup and an adverse intrauterine environment. This review will focus on prenatal hypoxic-ischemic injury and inflammatory/infective insults. A range of experimental models have been used to characterise lesions formed in response to these insults and to determine mechanisms of damage resulting from such events. Relatively brief periods of fetal hypoxia result in neuronal death (cerebellum, hippocampus, and cerebral cortex), white matter damage and reduced growth of neural processes. These effects are more profound at mid than late gestation. Chronic mild placental insufficiency can result in fetal growth restriction and deficits in neural connectivity and myelination. Exposure of the preterm fetus to inflammatory agents causes brain damage particularly in the white matter and this is exacerbated by hypoxia. These studies show that the timing, severity and nature of specific insults are critical in determining the pattern of injury and thus the extent to which neurological function will be affected postnatally. Defining the causes, patterns and mechanisms of brain injury is crucial if we are to develop rational neuroprotective strategies to reduce the burden of altered brain growth and poor functional and behavioural outcomes.