The fetal circulation contains abundant nucleated erythrocytes (NRBCs). The P o2 of fetal blood is an estimated one-third to one-fourth of the P o2 of adult blood, and fetal hypoxemia stimulates fetal erythropoietin production and consequently increases the number of hematopoietic progenitor cells or NRBCs in fetal circulation (1). Severe hypoxia stimulates the proliferation of hematopoietic progenitor cells (2). When neonates are born with abundant NRBCs in their peripheral blood, the number of NRBCs rapidly decreases, and NRBCs become undetectable within 1 week after birth. Together, these facts suggest that differences in oxygen concentration between fetal and maternal blood play an important role in the clearance of NRBCs from maternal circulation. In a previous study, we isolated fetal NRBCs from maternal blood by fluorescence-activated cell sorting (FACS). We used an antibody to the γ-chain of fetal hemoglobin and confirmed the fetal origin of the NRBCs by fluorescence in situ hybridization analysis with chromosome-specific probes (3). Microscopic analysis of these fetal cells by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL), which detects DNA fragmentation, showed that apoptotic changes occurred in 47% of fetal NRBCs circulating in maternal blood (3). This suggests that apoptosis is the mechanism by which fetal cells are cleared from the maternal circulation. Apoptosis is an active, physiologic form of cell death that is mediated by the internal machinery of certain cells. Apoptosis leads to rapid recognition, uptake, and degradation of intact cells by phagocytes, thus preventing the release of noxious contents (4). We speculated that apoptosis in fetal NRBCs may play an important role in preventing immunization of the mother against the fetus. The purpose of the present study was to clarify the mechanism by which apoptotic changes are induced in fetal NRBCs transferred into the maternal circulation. We focused on oxygen concentration as a …