Published online August 1, 2005
PEDIATRICS Vol. 116 No. 2 August 2005, pp. 414-422 (doi:10.1542/peds.2004-1601)
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Erythrocyte Zinc Protoporphyrin Is Elevated With Prematurity and Fetal Hypoxemia

David G. Lott, MD*, M. Bridget Zimmerman, PhD{ddagger}, Robert F. Labbé, PhD§, Pamela J. Kling, MD|| and John A. Widness, MD*

* Department of Pediatrics, College of Medicine
{ddagger} Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, Iowa
§ Department of Laboratory Medicine, University of Washington, Seattle, Washington
|| Steele Memorial Children's Research Center, University of Arizona College of Medicine, Arizona Health Sciences Center, Tucson, Arizona

Objective. To examine the utility of red blood cell (RBC) zinc protoporphyrin/heme ratio (ZnPP/H) as an indicator of fetal iron status, because unfavorable neurodevelopmental outcomes have been associated with poor iron status at birth, as indicated by low serum ferritin, and because few reliable indicators of fetal and early neonatal iron status exist.

Methods. Consecutively studied preterm and term fetuses at delivery included the following groups: (1) control nonhypoxic, (2) fetuses with intrauterine growth retardation (IUGR), and (3) fetuses of insulin-treated mothers (FDM). We hypothesized (1) that rapid growth velocity associated with an accelerated erythropoiesis among normal fetuses will lead to reduced iron delivery to a rapidly expanding RBC mass and higher umbilical cord blood RBC ZnPP/H and (2) that fetuses that are exposed to pathologic hypoxemia will experience an additional increase in erythropoiesis and higher cord ZnPP/H. ZnPP/H was determined on saline-washed cord blood erythrocytes by hematofluorometry and was examined for its relationship with clinical factors and cord blood laboratory measurements indicative of tissue oxygenation (plasma erythropoietin [EPO] and reticulocyte count) and iron status (plasma ferritin and erythrocyte indices). Statistical testing included 1-way analysis of variance, 2-way analysis of variance with covariates, simple linear regression, and multiple regression analysis.

Results. Among control group subjects, gestational age at birth was inversely correlated with RBC ZnPP/H and reticulocyte count and positively correlated with ferritin and EPO. Relative to control subjects, IUGR and FDM fetuses at specified gestational age groupings had higher ZnPP/H, lower plasma ferritin, and higher plasma EPO. Statistical modeling of the relationship between ZnPP/H and plasma ferritin among all study groups demonstrated significant impacts of gestational age, plasma EPO, maternal hypertension, and maternal smoking.

Conclusions. The inverse association of fetal ZnPP/H with gestational age at birth among control subjects is attributable to erythropoietic stimulation likely as a result of increasing growth velocity at the earliest gestational ages. The relatively higher ZnPP/H observed among fetuses in the IUGR and FDM groups likely is attributable to increased erythropoietic activity secondary to pathologic hypoxemia. Decreased placental iron transfer may also have limited iron availability and contributed to elevated ZnPP/H in the IUGR group. These data support the concept that increased erythropoietic activity and/or limited iron transport may place infants of diabetic mothers and infants with growth retardation at risk for developing systemic iron deficiency later in infancy and in early childhood.

Key Words: zinc protoporphyrin • fetus • hypoxemia • iron status • ferritin

Abbreviations: IUGR, intrauterine growth retardation • FDM, fetuses of insulin-treated mothers • RBC, red blood cell • Hb, hemoglobin • ZnPP/H, zinc protoporphyrin/heme ratio • EPO, erythropoietin • CRP, C-reactive protein • MCV, mean corpuscular volume • CH, erythrocyte Hb content • CHCM, erythrocyte Hb concentration • ANOVA, analysis of variance • HBP, hypertension

Accepted Nov 23, 2004.


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