A survey of zidovudine use in pregnant women with human immunodeficiency virus infection

Rs, Sperling; Stratton, Pamela; O'Sullivan, M. J.; Boyer, Pamela; Dh, Watts; Lambert, John S.; Hammill, Hunter; Livingston, EG; Gloeb, D. Jay; Minkoff, Howard; Fox, H.

doi:10.1016/0020-7292(92)90670-e

Cited by 3 publications

(3 citation statements)

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“…Recently, examination of 43 infants who had been exposed to AZT during pregnancy revealed no teratogenic effects, even when fetal exposure occurred during the first trimester (17). 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).…”

Section: Discussionsupporting

confidence: 64%

Effect of zidovudine on preimplantation murine embryos

Toltzis

Mourton

Magnuson

1993

Antimicrob Agents Chemother

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It previously has been demonstrated that zidovudine (AZT) is lethal to early murine embryos. The effect of the drug on pre-and postimplantation embryos was examined to delineate the timing of this toxicity and to investigate its possible mechanisms. Embryos exposed in the whole mouse during preblastocyst development were unable to proceed beyond the blastocyst stage. Similarly, when two-cell embryos harvested from unexposed females were exposed to low-concentration (1 ,uM) AZT in vitro over 24 h, development beyond the blastocyst stage was inhibited. In contrast, drug exposure during in vitro blastocyst and postblastocyst development resulted in little or no morphologic toxicity. Further investigation revealed that preblastocyst AZT exposure resulted in the development of blastocysts with significantly lower cell numbers than control embryos.While embryonic exposure to AZT at the blastocyst and postblastocyst stages also resulted in retarded cell division, the effects were milder than those recorded after preblastocyst exposure. These data demonstrate that the critical period of AZT toxicity toward murine embryos is between ovulation and implantation and indicate that AZT directly suppresses cell division in the preimplantation embryo.As the incidence of human immunodeficiency virus (HIV) infection in women increases, growing numbers will be deliberately or inadvertently exposed to zidovudine (AZT) during pregnancy. Recommendations to treat HIV-infected pregnant women with AZT if their CD4 cell counts fall below 200/pul (11) have been made. Moreover, trials to test whether planned antiviral chemotherapy of all pregnant HIV-infected women can interrupt the transmission of virus from mother to child are under way. Traditionally, therapy during pregnancy with any drug has been approached with extreme caution because of concerns about untoward effects upon the embryo or fetus. 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). Safe administration of AZT during human pregnancy requires that this toxicity be better defined and that its underlying mechanism be determined.The first step in defining the embryo toxicity of AZT is to identify the developmental stage at which this effect occurs. Murine embryonic development is sufficiently accessible to in vitro experimental manipulation that all stages can be examined for their susceptibility to drug toxicity by previously established methods (8, 16). Fertilized murine oocytes can be readily isolated from the dam at the one-to two-cell stage. Two-cell embryos can be cultured in vitro and will develop into blastocysts, the stage immedi...

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Section: Discussionsupporting

confidence: 64%

Effect of zidovudine on preimplantation murine embryos

Toltzis

Mourton

Magnuson

1993

Antimicrob Agents Chemother

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“…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 hemoglobin levels of less than 8.4 mmol/liter were born prematurely, and two cases of intrauterine growth retardation were also observed among 38 infants delivered at term by women treated with AZT (27). Since fetal liver is deficient in glucuronyltransferase activity (the major enzyme used for the metabolism of AZT), the developing fetus would be exposed to a continuous high concentration of AZT, thus increasing the risk of toxicity.…”

mentioning

confidence: 99%

Amelioration of zidovudine-induced fetal toxicity in pregnant mice

Gogu

Beckman

Agrawal

1992

Antimicrob Agents Chemother

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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...

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“…Pregnancy does not affect the course of HIV infection in the asymptomatic individual but women with AIDS are at risk of severe opportunistic infection whilst pregnant [6). Whether these women will benefit from antiretroviral therapy is controversial but foetal malformation, excess prematurity or foetal toxicity have not yet been attributed to the use of this drug [7).…”

Section: F Irst Hivseropositive Individual In India Was Identified Inmentioning

confidence: 99%

Hiv Infection and Obstetric Practice

1994

Medical Journal Armed Forces India

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A survey of zidovudine use in pregnant women with human immunodeficiency virus infection

Cited by 3 publications

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Effect of zidovudine on preimplantation murine embryos

Effect of zidovudine on preimplantation murine embryos

Amelioration of zidovudine-induced fetal toxicity in pregnant mice

Hiv Infection and Obstetric Practice

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