Amelioration of zidovudine-induced fetal toxicity in pregnant mice

Abstract

The effects of zidovudine (AZT) on the fetus were investigated in pregnant mice by using parameters such as the number of fetuses, fetal size, and the fetal hepatic cell clonogenic assay. AZT caused dose-dependent toxicity to the fetus upon administration via drinking water to pregnant mice from days 1 to 13 of gestation. At the 0.5-mg/ml dose level, AZT caused a decrease in the number of fetuses to 12 from an average of 16.5 in control animals, and the fetal size (crown-rump length) was reduced from 10.5 to 8.5 mm. The CFU of the erythroid progenitor cell colonies derived from the fetal hepatic cells were decreased to 38% of that of the control, and the hematocrit dropped to 33.5 + 1.7 from a control value of 42.6 ± 2.5. Concomitant administration of erythropoietin, vitamin E, or interleukin-3 to the AZT-treated pregnant mice caused a significant reversal in the AZT-induced toxicity to the fetus and to the mother's bone marrow. The success of therapeutic intervention was demonstrated by (i) restoration of the number of fetuses to the level of untreated controls, (ii) an increase in the size of fetuses to normal values, and (iii) an increase in hematocrit to >40. The results suggest that AZT is toxic to the fetus in a dose-dependent manner and that treatment with erythropoietin, vitamin E, or interleukin-3 can ameliorate the AZT-induced fetal toxicity.Significant dose-related toxicity, primarily anemia and leukopenia associated with the administration of zidovudine (AZT), remains a limiting factor in the clinical management of AIDS (13,20). With an increasing recognition of the heterosexual spread of human immunodeficiency virus (HIV) and a high rate of reproduction reported for HIVpositive women (79% in the reproductive ages), the importance of treating pregnant women with AIDS with anti-HIV drugs is apparent. A recent prospective study of infants born to HIV-seropositive mothers has concluded that approximately one-third of them will have evidence of HIV type 1 infection or AIDS by the age of 18 months (4). Furthermore, the perinatal transmission of HIV type 1 exerts a major adverse effect on the survival of the infant (21), indicating that effective antiretroviral therapy during gestation and in the perinatal period could potentially be very useful in the management of maternal transmission of HIV (23). Although AZT has been shown to cross the placental barrier and to achieve therapeutic levels in the body fluid of the infants during the first 36 h of life (7), there are relatively few published reports which describe the toxic effects of AZT on the embryo. An overview report by Ayers (3) indicated that there is no evidence of teratogenicity in the offspring of rats or rabbits given AZT during gestation; however, an increased incidence of late fetal resorption was observed. Another report demonstrated that administration of AZT to rats on day 10 of gestation had no effect on the growth or survival of the offspring (18). (27) indicated that AZT is well tolerated by pregnant women, 3 of the 7 newborns with hem...

Effect of zidovudine on preimplantation murine embryos

“…These findings mirrored those previously noted in retrovirally infected mice which had been exposed to the drug through their drinking water during middle to late gestation; no adverse drug effects were detected in the offspring (13,14). We and others have found, however, that AZT results in death of mouse embryos when exposure occurs in the first half of gestation (7,21). Our experiments presented here demonstrated that the critical period of AZT toxicity toward mouse embryos is between ovulation and implantation.…”

“…Therefore, it is important to investigate the toxicity of intragestational administration of HIV antimetabolites in order to enable rational application to humans. It previously has been demonstrated that AZT at concentrations that are readily achievable with conventional human dosing is lethal to murine embryos during early gestation (7,21). Direct exposure of embryos to AZT in vitro resulted in retarded cell division at 0.1 ,ug/ml and cell death at concentrations of 1 ,ug/ml and above (21).…”

Teratogenic and Embryocidal Effects of Zidovudine (AZT) in Sprague‐Dawley Rats

“…Zidovudine was associated with increased preimplantation mouse embryo loss in several studies, [15][16][17][18] but no congenital abnormalities were detectable. The possible mechanism of embryolethality of zidovudine was thought to be due to retarded cell division.…”

An unusual phenotypic and genotypic expression in F2 generation following one stage zidovudine exposure during pregnancy and lactation- an experiment in mice

“…One milliliter of Zidovir oral solution contained 10 mg of active Zidovudine and a dose of 50 mg/kg ZDV was given daily. The dose of ZDV was standardized to 50 mg/kg body weight from 70 mg/kg as used by Gogu et al (1992).…”