Fetal iron and cytochrome c status after intrauterine hypoxemia and erythropoietin administration

Abstract

Chronic fetal hypoxemia stimulates erythropoiesis and may result in a redistribution of fetal iron from plasma into erythrocytes. We studied the response of fetal plasma erythropoietin (Ep) to hypoxemia, the role of Ep in stimulating erythropoiesis in utero, and the effect of augmented erythropoiesis on fetal plasma Ep and iron and tissue cytochrome c concentrations in 19 chronically instrumented late-gestation fetal sheep. The fetuses were stimulated to produce 28 erythropoietic responses after exposure to 1) acute hypoxemia (1-5 days), 2) chronic hypoxemia (greater than 7 days), and/or 3) administration of 1,500 U recombinant human Ep concurrently during normoxemia. Plasma Ep peaked less than 12 h after the onset of hypoxemia or Ep bolus. Plasma iron decreased 24-48 h later and returned to baseline 48-96 h after normalization of Ep levels to baseline. The plasma iron response was directly related to the erythropoietin stimulus (r = 0.79, P less than 0.001) and inversely related to liver iron concentration at death (r = -0.84, P less than 0.001). Nine fetuses with depleted liver iron concentrations at autopsy had significantly lower heart and skeletal muscle iron concentrations compared with animals with 10% of control liver iron remaining. Skeletal muscle and heart iron and cytochrome c concentrations were significantly correlated. Ep has a potent biological effect on fetal erythropoiesis and iron metabolism. Augmented fetal erythropoiesis, mediated by Ep, results in decreased plasma iron, hepatic storage iron, and skeletal and cardiac muscle iron and cytochrome c. The model potentially explains the iron abnormalities found in newborn infants after fetal hypoxia.

Iron Deficiency and Renal Development in the Newborn Rat

“…Although mean tail length, representing linear growth, was slightly shorter in the DF ϩ SS and IDA groups, the ratio of body weight/tail length was similar in all groups. Our findings are consistent with the literature, describing preferential diversion of iron to erythropoiesis (22,23). Compared with DF, our nutritional irondeficiency model exhibited a slightly lower (13%) Hb iron, despite a 46% lower renal iron and 30% lower total body iron.…”

Timing of Fetal Nucleated Red Blood Cell Count Elevation in Response to Acute Hypoxia

“…Our results are consistent with those of prior animal experiments [15][16][17]. Widness et al [16] used sodium nitrite infusion (into the fetal umbilical vein) to cause fetal hypoxia in 115-to 146-day chronically instrumented fetal sheep.…”

“…The fetal erythropoietin levels increased within 12 h of exposure and remained increased as compared with those of the controls until day 7 of exposure, when they decreased to near baseline levels until day 21 of hypoxemia. Finally, Georgieff et al [15] exposed 112-to 130-day late-gestation fetal sheep to hypoxia. These authors measured both plasma erythropoietin and plasma iron Blackwell/Hallak/Hotra/Refuerzo/Hassan/ Sokol/Sorokin concentrations following hypoxia.…”

Umbilical cord nucleated red blood cell counts: normal values and the effect of labor

“…It has been shown that in sheep, acute hypoxemia results in erythopoietin increases after at least 3 h, 10 and the resulting reticulocytosis does not peak until 4 days. 11 However, in rats, acute hypoxia resulted in elevated nRBC sometime after 4-12 h. 12 It has also been suggested that acute hypoxia in humans can be associated with elevated nucleated red blood cells. [13][14][15] In humans, labor has been associated with elevated umbilical cord erythropoietin levels.…”