Brief Repeated Umbilical Cord Occlusions Cause Sustained Cytotoxic Cerebral Edema and Focal Infarcts in Near-Term Fetal Lambs

The aim of this study was to determine whether asphyxia induced by clinically relevant, brief repetitive umbilical cord occlusions is associated with cerebral compromise. Chronically instrumented fetal lambs were studied at 126.5 ± 2.8 d of gestation (mean ± SD, term 147 d). Occlusions were performed 1 out of every 2.5 min (group I, n = 7), 2 out of every 5 min (group II, n = 9), or not at all (shams, group III,n = 5), and discontinued at a predetermined threshold of severe or persistent hypotension. After 58 ± 8 and 24 ± 2 occlusions, in groups I and II, respectively, the pH was 6.83 ± 0.09, Pco2 9.52± 1.4 kPa, base excess -23.5 ± 3.7 mM, and lactate 14.1 ± 1.6 mM. Two fetuses (out of group II) did not recover from the final occlusion. Ongoing asphyxia was associated with progressive suppression of the EEG, which occurred faster and with more epileptiform and spike activity in group II. Cortical impedance remained elevated for 15.0 ± 4.0 and 11.5± 4.4 h, for groups I and II, respectively (NS). Focal infarcts occurred in the parasagittal cortex, thalamus, and cerebellum, in 6 out of 14 surviving asphyxiated fetuses. Mild selective neuronal loss was observed in these regions in 13 out of 14 fetuses. Infarction was associated with a longer period of blood pressure below baseline levels, with more epileptiform activity, and with slower normalization of the EEG. In a paradigm mimicking birth asphyxia, histologic damage similar to that observed clinically was found. The results suggest that brief repeated insults interact, leading to cardiac compromise and cumulative cell membrane damage in the fetal cerebrum.