Effects of perinatal zidovudine on hematopoiesis: A comparison of effects on progenitors from human fetuses versus mothers

Objective: To compare the effects of zidovudine (ZDV) on clonal maturation of hematopoietic progenitors obtained from the bone marrow of women of child-bearing age with its effects on progenitors obtained from the marrow, liver and blood of fetuses. We also sought to determine whether the adverse effects of ZDV on fetal hematopoiesis resulted exclusively from an action on progenitors, or also involved the inhibition of the production of hematopoietic growth factors. Participants: Hematopoietic progenitors were obtained from bone-marrow aspirates of seven women of child-bearing age, from the bone marrow and liver of seven midtrimester abortuses, and from the umbilical cord blood of seven term infants. Methods: We added increasing concentrations of ZDV to clonal assays of hematopoietic progenitors, after which we assayed clonal maturation of progenitors, and counted the number of erythrocytes per erythroid clone and the number of neutrophils per granulocytic clone. Light-density cell fractions and enriched CD34+ progenitor fractions were studied. In other studies we determined the effect of increasing concentrations of ZDV on production of granulocyte colony-stimulating factor (G-CSF) protein [enzyme-linked immunosorbent assay (ELISA)] and mRNA by fetal and maternal monocytes, and on production of erythropoietin protein (ELISA) and mRNA by Hep3 B cells. Results: Mature erythroid progenitors were the most sensitive to the adverse effects of ZDV on clonal maturation, and multipotent progenitors were the most resistant. Erythroid progenitors from all fetal and neonatal sources were more sensitive to the effect of ZDV than those from the bone marrow of adult women. The inhibitory effects were explained by an action on CD34+ cells; no effect was observed on production of G-CSF or erythropoietin. Conclusions: We speculate that the low hematocrits of neonates delivered after antenatal ZDV treatment are due to reduced clonal maturation of erythroid progenitors, and that fetal erythroid progenitors are inhibited to a greater extent than maternal progenitors.