THE VULNERABILITY OF THE FETAL SHEEP BRAIN TO HYPOXEMIA AT MIDGESTATION

Our aim was to test the hypothesis that a brief episode of hypoxemia n ear mid-gestation in fetal sheep will result in damage to the fetal br ain with the extent and type of damage in any particular region being related to the developmental processes occurring at the time of the in sult. Hypoxemia was induced, sufficient to reduce arterial O-2 content by approximately 50%, by restricting utero-placental blood flow in 14 chronically catheterised fetuses for 6 h or 12 h at 84 days of gestat ion (term 145-8 days). Age-matched fetuses (n = 14; 4 operated and 10 unoperated) were used as controls. Fetuses were killed 7 days after be ing exposed to hypoxemia, and brains removed for histological analysis at the light and ultrastructural levels. Body weights of hypoxemic fe tuses did not differ significantly from controls but brain weights wer e significantly reduced both in absolute terms and when expressed in r elation to body weight (P < 0.05). Most fetuses exposed to hypoxemia s ustained no gross brain damage. However, in one hypoxemic fetus from a multiple pregnancy there was extensive leucomalacia in the cortical w hite matter; mild focal damage was seen in another 8 hypoxemic fetuses . In the cerebral cortex (frontal lobe) the surface folding index was significantly reduced (P < 0.05) in hypoxemic fetuses compared to cont rols suggesting that gyral formation had been delayed. In these fetuse s there were also degenerating neurons in the deeper cortical layers. In the hippocampus of hypoxemic fetuses there was a delay (P < 0.05), compared to controls, in the migration of cells from the germinal laye r to the pyramidal layer in the CAI region, and decreases (P < 0.05) i n the density (areal) of neurons in the pyramidal layer and in the wid th of stratum oriens. In the cerebellum of hypoxemic fetuses there was a decrease (P < 0.05), compared to controls, in the density (areal) o f mitotic bodies in the external granule cell layer. However, there we re no significant differences in the number of pyknotic cells in this layer, in the density of Purkinje cells, in their somal area, or in th e width of the external granule cell or molecular layers. There was an increase (P < 0.05) in the proportion of the brain parenchyma occupie d by blood vessels in both the hippocampus and cortex of hypoxemic fet uses compared to controls. This study has shown that an hypoxemic insu lt near mid-gestation can result, one week later, in white matter dama ge and in neuronal death in the hippocampus and to a lesser extent in the cerebral cortex and cerebellum. It can also retard neuronal migrat ion and the growth Of neural processes in the hippocampus where develo pment is well established at this age. Such brain damage could result in less than optimal neuronal connectivity and could affect function p ostnatally. (C) 1997 Elsevier Science B.V.