Background— The incidence of perinatal morbidity arising from birth hypoxia or asphyxia has not changed significantly in recent years despite marked improvements in labor management. Perinatal mortality in these circumstances may therefore reflect antenatal compromise and subsequent alteration of the fetal capacity to respond to episodes of hypoxia that may occur during labor. Hence, we have investigated the effects of fetal pre-exposure to a period of adverse intrauterine conditions on the mechanisms mediating the fetal defense response to a subsequent episode of acute hypoxia in sheep. Methods and Results— Sixteen fetal sheep were chronically instrumented at 118±2 days for recording of blood pressure, heart rate, and femoral and umbilical blood flows. In 8 of these fetuses, umbilical blood flow was reduced by 30% for 3 days (between days 125 and 128). The remaining 8 fetuses acted as sham-operated controls. Between 2 and 7 days after umbilical cord/sham compression, all fetuses were exposed to 2 episodes of acute hypoxemia on separate days during infusion with either saline or treatment with a combination of N ^G -nitro- l -arginine methyl ester and sodium nitroprusside. We show that previous fetal exposure to a period of adverse intrauterine conditions, such as that induced by compression of the umbilical cord, elevates nitric oxide activity and results in a markedly diminished cardiovascular defense response to subsequent acute hypoxia. Conclusions— The data imply that pre-exposure to adverse antenatal conditions may render the fetus more susceptible to the acute hypoxia or asphyxia that can accompany relatively uncomplicated labor and delivery.