Red cell mass responses to daily erythropoietin and iron injections in the ovine fetus

OBJECTIVE: Anemic ovine fetuses supplemented with intra-amniotic iron undergo rapid expansion of red cell mass. The present study tested the hypothesis that nonanemic fetuses that were supplemented with daily intra-amniotic iron plus intravascular injections of erythropoietin would experience accelerated erythrocyte production. STUDY DESIGN: Nine late gestation ovine fetuses received 100 to 120 units of erythropoietin intravascularly plus 10 mg of iron intra-amniotically daily for 7 days (low erythropoietin dose group). Four additional fetuses received 1000 units of erythropoietin plus 10 mg iron daily for the same period (high erythropoietin dose group). Responses were compared with 9 nonsupplemented time-control fetuses. Statistical testing was by 3-factor repeated measures analysis of variance. RESULTS: Immediately after erythropoietin injection, plasma erythropoietin concentration was elevated approximately 25- and 250-fold in the low and high erythropoietin dose groups, respectively. Erythropoietin returned to basal levels by 24 hours after the injection. Plasma iron concentration increased in the low erythropoietin dose group but not in the control or high erythropoietin dose groups. Reticulocyte index increased in both erythropoietin supplemented groups but not in control fetuses. Hematocrit level increased above control by day 5 in the low erythropoietin dose group and by day 2 in the high erythropoietin dose group. Red cell mass increased significantly on supplement day 7 in the low erythropoietin dose group and on day 5 in the high erythropoietin dose group. Fetal blood gases and pH were unchanged with time in all 3 groups. CONCLUSION: Although daily combined erythropoietin and iron supplements in nonanemic ovine fetuses significantly increased circulating red cell mass in a dose-dependent manner, this increase was small relative to the rapid expansion of red cell mass previously observed after iron supplementation in fetuses with hemorrhage-induced anemia. We speculate that this difference in response may be due to a combination of rapid fetal clearance of erythropoietin plus a relative insensitivity to erythropoietin caused by the absence of other cytokines, which are elevated during fetal anemia.