Novel Red Cell Indices Indicating Reduced Availability of Iron are Associated With High Erythropoietin Concentration and Low pH Level in the Venous Cord Blood of Newborns

Abstract

There is evidence that an elevated erythropoietin (EPO) concentration is associated with signs of iron deficient erythropoiesis. The aim of this study was to evaluate the iron status by means of novel cellular indices and serum iron markers and to determine whether these are associated with EPO and pH in the venous cord blood of 193 full-term newborns. There were positive correlations between EPO and the percentage of hypochromic red blood cells (%HYPOm) and reticulocytes (%HYPOr) [r ϭ 0.45 (p Ͻ 0.001) and r ϭ 0.56 (p Ͻ 0.001), respectively]. %HYPOm and %HYPOr also had negative correlations with pH [r ϭ Ϫ0.53 (p ϭ 0.001) and r ϭ Ϫ0.46 (p ϭ 0.001), respectively]. Newborns who had low pH (pH Յ7.15, n ϭ 16) had significantly higher %HYPOm, %HYPOr, and serum transferrin receptor and transferrin concentrations in their cord blood than newborns with normal pH. Thus, in newborn cord blood, the higher number of red cells and reticulocytes with lower Hb content may have impaired the oxygen carrying capacity that has been a trigger for EPO production. E rythropoietin (EPO) is the principal hormonal stimulator of erythropoiesis, and as a response to hypoxia, EPO synthesis is stimulated via regulation by hypoxia inducible factor 1 (1,2). EPO production occurs in the kidneys in human adults, and in fetal liver. Additionally, placental EPO production has been demonstrated in sheep (3). EPO plays some nonerythropoietic roles as well. It is needed for the normal differentiation, apoptosis and survival of neuronal cells as well as gastrointestinal tract epithelium and vascular endothelial cells (4,5). Recent evidence shows that in hypoxic conditions, EPO production increases to protect brain and other tissues, and there is increasing interest in neuroprotective therapeutical approaches against hypoxic-ischemic injury (6,7). Newborns who have had asphyxia after complicated or uncomplicated pregnancies are at risk for impaired neurodevelopmental outcome if EPO level, reflecting fetal hypoxemia, is increased (8). On the other hand, iron deficiency has been shown to be associated with impaired cognitive development in childhood (9 -11).Modern hematological analyzers and flow cytometric techniques make it possible to measure red blood cell (RBC) and reticulocyte features more accurately than earlier (12-14). Novel cell indices are directly measured parameters in which the size of cells and cellular Hb content are measured on a cell-by-cell analysis of RBC or reticulocyte populations (12,15,16). Based on these measurements, the percentages of hypochromic or microcytic cells can be calculated and then used as markers of iron-deficient erythropoiesis.Despite their potential value in diagnostics, the clinical use of these indices is still uncommon. The percentage of hypochromic RBCs (%HYPOm) and cellular Hb content of reticulocytes (CHr) have been established as indicators of iron status in studies on hemodialysis patients, infants, children, adolescents, blood donors, and premenopausal women (17)(18)(19)(20)(21)(22). In the co...

Early signs of maternal iron deficiency do not influence the iron status of the newborn, but are associated with higher infant birthweight

“…This has also been proposed in earlier studies in which only severe maternal iron‐deficiency anemia has been related to iron deficiency of the newborn (47, 48). However, subtle signs of iron‐deficient erythropoiesis have also been related to impaired oxygen‐carrying capacity (EPO and pH), supporting the clinical significance of iron‐deficient erythropoiesis even in the absence of anemia (38, 39). Hence, it would be beneficial to assess maternal iron status in order to ensure the overall sufficiency of iron for pregnant women and fetuses, and also potentially select those mothers who would benefit from iron supplementation.…”

“…The ethics committee of the Pohjois‐Savo Health Care District approved the study. Detailed descriptions of the enrolling protocol and laboratory measurements are given in earlier publications (22), 37–39. The pregnant women, who had been admitted to the hospital for delivery in the Pohjois‐Savo Health Care district, were collected during a 10‐month period from July 2004 to April 2005.…”

A Review of Cord Blood Concentrations of Iron Status Parameters to Define Reference Ranges for Preterm Infants

“…Sweet et al [25,26] as well as Ervasti et al [27,28,29] used the same study population for more than one publication, and just one of each of these publications [25,27] was listed in the tables. We contacted 22 of 30 corresponding authors of the original publications cited herein.…”

Umbilical Cord Serum Ferritin Concentration is Inversely Associated with Umbilical Cord Hemoglobin in Neonates Born to Adolescents Carrying Singletons and Women Carrying Multiples

“…The positive association between EPO and Hb was unexpected, because low Hb concentrations would be expected to stimulate EPO production as seen in adults (68) and neonates with severe anemia (hemolytic anemia and Rh immunization) (69,70). However, other studies in healthy term neonates also reported a lack of significant direct association between Hb and EPO, although these study cohorts included only non-anemic neonates (71,72). Erythroferrone is a newly identified Fe regulatory hormone, which is stimulated by EPO to reduce hepcidin expression (60).…”