PRENATAL AND POSTNATAL TREATMENT OF THE RHESUS MACAQUE (MACACA-MULATTA) WITH AZIDOTHYMIDINE .1. FETAL STUDIES

Methods for treating noninfected macaque fetuses with azidothymidine ( AZT) in utero were studied in order to determine the potential for tox icity during prenatal life. Multiple routes were investigated includin g direct fetal treatment [intraamniotic (n = 4) or intraperitoneal (IP ) (n = 14) every 10 days, gestational day (GD) 60-160; 20 mg/kg] and m aternal treatment [oral 60 mg/kg/day divided every 8 h (n = 4) or via subcutaneous (SQ) osmotic pumps (Alzet(R)), 1.4 mg/kg/h (n = 4) or 1.1 mg/kg/h (n = 10); GD 60-160]. Ten vehicle controls were included. Pre natal growth was monitored sonographically and fetal (amniotic fluid a nd blood) and maternal (blood and urine) samples were collected period ically to monitor drug levels and hematologic status. Results indicate d an increased incidence of abortion, fetal/neonatal death, and premat ure delivery in all AZT-treated groups with minimal effects (1 abortio n, 1 premature delivery) at 1.1 mg/kg/h SQ. Statistically significant effects on maternal and fetal red cell counts, hemoglobins, and hemato crits were observed with maternal oral and SQ administration but not d irect fetal treatment. Drug levels in maternal (pumps: 0.13 +/- 0.02 m ug/ml; oral: 0.79 +/- 0.08) and fetal plasma (pumps: 0.17 +/- 0.02 mug /ml; oral: 1.02 +/- 0.16) were similar during the course of gestation, with no indication of drug accumulation over time. All neonates were grossly normal at delivery with no significant effects on Apgar scores or overall body size. Chronic treatment via the maternal SQ (pump) ro ute at the lowest dose studied was determined to be the most efficient ; continuous and consistent drug levels were achieved in both the fetu s and dam throughout gestation, although prenatal hematologic toxicity was observed.