We have shown that 5 days of mild hypoxia has significant effects on fetal ECoG activity, heart rate and blood pressure. We now studied if mild prolonged hypoxemia had an adverse effect on the fetal cardiovascular and neural responses to repeated cord occlusion and on the magnitude of neuronal damage. Fetal and maternal catheters were placed at 120 days' gestation and animals allocated at random to receive intratracheal maternal administration of nitrogen (n=8) or compressed air in controls (n=7). Five days after surgery, nitrogen infusion was adjusted to reduce fetal brachial artery pO(2) by 25%. After 5 days of chronic hypoxemia, the umbilical cord was completely occluded for 5 min every 30 min for a total of four occlusions. Data are presented as mean+/-SEM and were analyzed by two-way ANOVA or two-sample t-test. Nitrogen infusion decreased fetal pO(2) by 26% (20.5+/-1.7 vs. 14.3+/-0.8 mm Hg) without changing fetal pCO(2) or pH. Pre-existing hypoxia fetuses had a greater terminal fall in heart rate in occlusions II, III and IV, and also had a more severe terminal hypotension in the final occlusion. Pre-existing hypoxia was associated with a greater fall in spectral edge frequency during occlusions from 14.4+/-0.9 Hz to 6.9+/-0.4 Hz vs. 13.6+/-1.64 Hz to 10.6+/-0.77 Hz in controls, p<0.05. In addition, during the three-day post-occlusion period, the contribution of theta and alpha band frequencies to total ECoG activity was significantly lower in the pre-existing hypoxia fetuses (p<0.05). These effects were associated with increased neuronal loss in the striatum (p<0.05). In summary, the cardiovascular and neural response indicates a detrimental effect of pre-existing mild hypoxia on fetal outcome following repeated umbilical cord occlusions.