In vitro studies have demonstrated that ARV drugs can suppress the erythroid and myeloid cell lineages in bone marrow. Cells cultured in the presence of zidovudine show a concentration‐dependent inhibition of CD34+ progenitor proliferation in both myeloid and erythroid lineages, a decrease in mtDNA, and an increase in lactic acid. In vitro studies of primary peripheral‐blood lymphocyte cultures from individuals without HIV infection who are exposed to zalcitabine, didanosine, or stavudine have shown dose‐ and time‐dependent mtDNA depletion accompanied by decreased cell proliferation, increased lactate production, and morphologic changes in mitochondria.
It is known that NRTIs cross the placenta and achieve cord‐blood levels 50%–100% of those in maternal blood. Hematopoietic progenitor cells from the fetus and neonate may be more sensitive to the myelotoxic effects of drugs. In a study that assessed the effect of zidovudine exposure in vitro, fetal erythroid progenitors were more severely inhibited than those from women of childbearing age, as manifested by a diminution in clone generation and in the number of normoblasts per erythroid clone and neutrophils per granulocyte clone. This effect was secondary to an action on CD34+ progenitor cells, given that no effect was observed on the production of granulocyte colony‐stimulating factor or erythropoietin. The precise mechanism of zidovudine’s action on CD34+ cells is unclear.
Additionally, HIV infection of the mother may by itself affect fetal hematologic precursor cells. Poirier et al. measured mtDNA in cord blood and, at ages 1 and 2 years, peripheral‐blood mononuclear cells in children born to HIV‐uninfected mothers, HIV‐infected mothers who did not receive ARV drugs, and HIV‐infected mothers who had received zidovudine during pregnancy. Infants born to HIV‐infected women who did not receive ARV drugs had significant reductions in mtDNA that persisted up to age 2 years; mtDNA was even further depleted in infants born to HIV‐infected mothers who had received zidovudine. Similarly, a study that compared HIV‐exposed, uninfected infants born before 1994 who did not have perinatal exposure to ARV drugs with 72 infants born to HIV‐uninfected women reported that CD4+ cell counts were persistently lower in HIV‐exposed infants.
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ARV drugs are routinely prescribed during the second trimester, a time in the fetus when hepatic hematopoiesis is active, spleen development is occurring, and active lymphopoiesis, thymic education, and bone‐marrow development are ongoing. The administration of ARVs during the critical window of hematopoiesis and lymphopoiesis may affect the generation of these precursors. The differences in hemoglobin concentrations in our patient population were no longer found in children 6–24 months old, which suggests a reversible insult in a system with ample recovery potential. Likewise, significant differences in neutrophil counts did not persist, which possibly reflects the fact that granulocytes are the last population to appear during development, are not formed in large numbers until after birth, and have brief life spans.