Risk Factor: CM
Class: Anti-infectives/ Antivirals
Fetal Risk Summary
The thymidine analogue zidovudine (AZT) is a nucleoside reverse transcriptase inhibitor (NRTI) that is used for the treatment of human immunodeficiency virus (HIV) disease. Other drugs in this class are abacavir, didanosine, lamivudine, stavudine, and zalcitabine.
AZT was not teratogenic in pregnant rats or rabbits at oral doses up to 500 mg/kg/day (1). These doses resulted in peak plasma concentrations in rats 66226 times, and in rabbits 1287 times, the mean steady-state peak human plasma levels obtained with the recommended human dose (100 mg every 4 hours). At 150 or 450 mg/kg/day (rats) and 500 mg/kg/day (rabbits), embryo/fetal toxicity was observed as evidenced by an increased incidence of fetal resorptions (1). At a dose of 3000 mg/kg/day in rats (near the median lethal dose), marked maternal toxicity and an increased incidence of fetal malformations were observed (1). This dose produced peak plasma concentrations 350 times the peak human plasma levels (1). In an in vitro study, a dose-related reduction in blastocyst formation was noted in fertilized mouse oocytes (1).
A 1991 study in rats compared the in vitro and in vivo toxicity of five virustatic nucleoside analogues in whole-embryo cultures and on the 10th day of gestation (2). Among the agents tested (vidarabine, ganciclovir, zalcitabine, 2,3-dideoxyadenosine [ddA], and AZT), AZT had the lowest teratogenic potential.
In an investigation conducted by the manufacturer, a split-dose regimen of 300 mg/kg on gestational day 10 in rats had no adverse effect on the mothers or offspring (3). The AZT concentration in the embryos was approximately one-third of that in the mother, 21.1 g/g vs. 62.6 g/g, respectively. However, another study administered AZT to pregnant mice from days 1 to 13 of gestation and observed dose-related fetal toxicity (decrease in the number of fetuses and fetal growth) (4). Concomitant treatment with erythropoietin, vitamin E, or interleukin-3 lessened the fetal toxicity. The adverse effects were thought most likely to be caused by a direct toxic effect on fetal cells, although a partial effect of maternal bone marrow depression could not be excluded.
Four studies have confirmed a direct dose-related toxic effect of AZT on preimplantation mouse embryos (5,6,7 and 8). The doses tested ranged from 1 to 20 times the concentrations obtainable with therapeutic human doses. Using an in vitro model, investigators demonstrated that exposure to AZT was highly correlated with failure to develop to the blastocyst stage (5). Similar developmental arrest, possibly caused by inhibition of DNA synthesis in blastomeres, was observed in a second study of preimplantation mouse embryos exposed in vitro to zidovudine (6). During the postimplantation portion of this investigation, no adverse fetal effects were observed with doses up to 300 mg/kg/day through all or part of gestation. A third study demonstrated that, when preimplantation mouse embryos were exposed to AZT either in vivo or in vitro, development was unable to proceed beyond the blastocyst stage (7). Exposure at the blastocyst and postblastocyst stages resulted in a lower degree of retarded cell division, indicating that the critical period of toxicity in mouse embryos is between ovulation and implantation. The comparative mouse embryo cytotoxicity of four antiretroviral nucleosides (AZT, didanosine, stavudine, and zalcitabine) was reported in a 1994 study (8). All of the agents showed dose-related inhibition of blastocyst formation, but AZT was the most toxic of the drugs. Cytotoxicity of the other agents was only evident at concentrations equal to the highest obtainable after therapeutic human doses (stavudine) or much higher (didanosine and zalcitabine).
AZT (1.5 mg/kg/dose every 4 hours) was administered via gastric catheter at least 10 days before and throughout gestation to pigtailed macaques (Macaca nemestrina) (9,10). Mean plasma concentrations (area under the plasma concentration-time curve [AUC]) of the drug were comparable to those obtained in human studies. Twelve pregnancies were brought to term (6 AZT, 6 controls), but significantly more matings (17 vs. 9, p=0.007) were required to achieve pregnancy in the AZT-treated primates. A significant decrease in maternal hemoglobin was observed in the AZT-treated animals, but no differences in the mean hematocrit of the drug-exposed newborns or in fetal growth were found in comparison with controls. Moreover, no adverse effects were discovered in neurologic, perceptual, or motor development during a 9- to 10-month follow-up.
The authors of the above investigation speculated that the retarded macaque fertility may have been related to AZT blockage of progesterone synthesis. However, the following two studies on human trophoblast growth and function indicate that inhibition of cell division before blastocyst formation, as demonstrated in the previously described murine studies (5,6,7 and 8), must also be considered (11,12). Human trophoblasts were isolated from 1st-trimester and term pregnancies and maintained in culture (11). Using relatively high drug concentrations (20 mol/L vs. recommended therapeutic concentrations of 35 mol/L) for prolonged periods (211 days), no significant effects on trophoblast function, as measured by human chorionic gonadotropin secretion, protein synthesis, and glucose consumption, were observed. In one of the five term placentas, AZT exposure resulted in a significant decrease (20% of the control value) in progesterone secretion, but the secretion rate (17.2 ng/hour/106 cells) was still much higher than the control values of the other placentas (3.2615.63 ng/hour/106 cells).
A 1999 study investigated the effects of a single 24-hour exposure of AZT or didanosine (ddI) on human trophoblast cells using a human choriocarcinoma cell line that exhibited many characteristics of the early placenta (12). Two drug concentrations (7.6 mM or 0.076 mM) were studied for their effects on trophoblast cell proliferation and hormone production (human chorionic gonadotropin [hCG], estradiol [E2], and progesterone [P4]). The higher concentrations of AZT or ddI resulted in significant decreases in cell numbers and growth rate (38% and 51% of control values, respectively), but increased production of hCG, E2, and P4. The decrease in trophoblast cell proliferation may have been the mechanism for the increased incidence of rodent embryo loss observed with AZT (12). In contrast, the lower concentrations of AZT and ddI did not cause changes in cell numbers, producing only significant increases in E2 production. Because of these findings, the researchers concluded that high therapeutic doses of either AZT or ddI during early human gestation were potentially embryotoxic (12).
Adverse effects on neurobehavior development in mice offspring resulting from a combination of AZT and lamivudine were described in a 2001 study (13). Pregnant mice received both drugs from day 10 of gestation to delivery. The effects on somatic and sensorimotor development were minor but more marked in exposed offspring than when either drugs was given alone (13). Both development endpoints were delayed with respect to control animals. Further, alterations of social behavior were observed in both sexes of exposed offspring (13).
AZT crosses the placenta to the fetus, both in animals (14,15 and 16) and in humans (1,17,18,19,20,21,22,23,24,25,26 and 27). Placental transfer of the drug is rapid and is by simple diffusion (17,18 and 19). Seven pregnant HIV-seropositive women with gestational lengths between 14 and 26 weeks were scheduled for therapeutic abortions (20). The women were given AZT, 200 mg orally every 4 hours for five doses, 12.75 hours before pregnancy termination. Fetal blood concentrations of the parent compound and its inactive glucuronide metabolite ranged from 100 to 287 ng/mL and from 346 to 963.5 ng/mL, respectively. In six patients (one woman had blood levels below the level of detection), mean AZT concentrations in the maternal blood, amniotic fluid, and fetal blood were 143, 168, and 205 ng/mL, respectively.
In a 1990 study, the pregnancy of an HIV-seropositive woman was terminated at 13 weeks’ gestation (21). She had been taking AZT, 100 mg 4 times daily, for 6 weeks, with her last dose consumed approximately 4 hours before the abortion. Both AZT and the glucuronide metabolite were found in the amniotic fluid and various fetal tissues. The lower limit of detection for the assay was 0.01 mol/L (0.01 nmol/g). The concentrations of the parent compound and the metabolite in maternal plasma were 0.35 and 0.90 mol/L, respectively. In comparison, the fetal concentrations of AZT (corresponding levels of the metabolite are shown in parentheses) were: amniotic fluid, 0.31 mol/L (1.16 mol/L); liver, 0.14 nmol/g (0.16 nmol/g); muscle, 0.26 nmol/g (0.50 nmol/g); and central nervous system, 0.01 nmol/g (0.05 nmol/g). The low levels of AZT in the latter system probably indicate that transplacental passage of the drug, at this dose, may be insufficient to treat HIV infection of the fetal central nervous system (21). The significance of this result is increased by the finding that neurologic and neuropsychologic morbidity in infants exposed to HIV in utero is high (21,28).
A 1989 report described the treatment of a 30-year-old HIV-seropositive woman who was treated before and throughout gestation with AZT, 1200 mg/day (22). IV AZT, 0.12 mg/kg/hour, was infused 24 hours before labor induction at 39 weeks’ gestation. An uncomplicated vaginal delivery occurred resulting in the birth of a normal male infant weighing 3110 g, with a height and head circumference of 48.5 and 35 cm, respectively. The newborn’s renal and hepatic functions were normal, and no other toxicity, such as anemia or macrocytosis, was noted. At birth, concentrations of AZT in the maternal blood, amniotic fluid, and cord blood were 0.28, 3.82, and 0.47 g/mL, respectively. AZT concentrations in the infant’s blood at 6, 24, 36, and 48 hours were 0.46, 0.51, 0.44, and 0.27 g/mL, respectively, indicating that in the first 24 hours elimination of the drug from the newborn was negligible (22). Levels of the inactive metabolite were also determined concurrently; in each sample, the metabolite concentration was higher than that of the parent compound. The infant was doing well and growing normally at 6 months of age.
Two HIV-positive women at 18 and 21 weeks’ gestation were treated with AZT (1000 mg/day) for 3 days before elective abortion (23). The final 200-mg dose was consumed 23 hours before abortion. Both AZT and its metabolite were found in the two women and in amniotic fluid and fetal blood, with fetal:maternal ratios for AZT of 1.10 and 6.00, respectively, and for the metabolite of 0.84 and 3.75, respectively.
Three experimental in vitro models using perfused human placentas to predict the placental transfer of NRTIs (didanosine, stavudine, zalcitabine, and AZT) were described in a 1999 publication (29). For each drug, the predicted fetal:maternal plasma drug concentration ratios at steady state with each of the three models were close to those actually observed in pregnant macaques. Based on these results, the authors concluded that their models would accurately predict the mechanism, relative rate, and extent of in vivo human placental transfer of NRTIs (29).
The pharmacokinetics of AZT during human and nonhuman primate pregnancies have been determined in a number of studies (24,26,27,30,31,32 and 33). AZT was administered to seven HIV-positive women beginning at 2835 weeks’ gestation with a 200-mg IV dose on day 1, followed by 200 mg orally 5 times a day from day 2 until labor (24). The mean maternal plasma concentrations of AZT and its inactive glucuronide metabolite at delivery were 0.29 and 0.87 g/mL, respectively. Similar amounts were measured in umbilical cord venous blood, with mean concentrations of 0.28 and 1.01 g/mL, respectively, suggesting that the fetuses and newborns were unable to metabolize AZT (24). No significant drug-induced adverse effects were observed in the women or their newborns and no congenital malformations were noted. Fetal growth was normal in six and accelerated in one, and the slightly lower than normal hemoglobin values were not considered to be clinically significant (24).
In pregnant macaques or humans, the pharmacokinetics of AZT were not affected by pregnancy (macaques) (30), nor did AZT affect the transplacental pharmacokinetics of didanosine (macaques) (31), lamivudine (humans) (32), or stavudine (macaques) (33). Two other studies involving four women infected with HIV measured peak AZT maternal serum levels and elimination half-lives that were statistically similar to those of nonpregnant adults (26,27). However, in three women, the AUC during pregnancy was significantly less than after pregnancy (4.5 mol/L vs. 6.8 mol/L, p=0.02), and the apparent total body clearance was significantly greater (2.5 L/hour/kg vs. 1.7 L/hour/kg, p=0.05) (26). Moreover, the difference in the apparent volume of distribution during and after pregnancy reached near significance (3.9 L/kg vs. 2.6 L/kg, p=0.07) (26).
The effect of AZT on the transplacental passage of HIV is unknown. A 1990 review of AZT in pregnancy focused on the issue of whether the drug prevented HIV passage to the fetus and concluded that available data were insufficient to provide an answer to this question (22). However, a 1993 study observed that, although AZT is transferred to the fetus relatively intact, the approximately 50% retained by the placenta is extensively metabolized, with one of the metabolites being zidovudine triphosphate, the product responsible for the antiviral activity of the parent drug (34). The effect of this may be a reduction in the risk of HIV transmission to the fetus (34).
Brief descriptions of the treatment and pregnancy outcome of 12 HIV-seropositive women were provided in a 1991 abstract (35). AZT therapy was started before conception in 4 women and between 21 and 34 weeks’ (mean 25 weeks) gestation in 8. The mean duration of therapy was 8 weeks (range 124 weeks). Three of the women who had conceived while taking AZT underwent therapeutic abortions of grossly normal fetuses between 10 and 12 weeks’ gestation. Five women had delivered grossly normal infants with a mean birth weight of 2900 g, and the infants of the remaining four women were undelivered between 24 and 36 weeks. Three other abstracts that appeared in 1992 and 1993 described 46 pregnant women treated with AZT without producing toxic effects or anomalies in their fetuses (36,37 and 38).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 2 newborns had been exposed to AZT during the 1st trimester (F. Rosa, personal communication, FDA, 1993). No major birth defects were observed.
Data on 45 newborns (2 sets of twins) of 43 pregnant women, enrolled in studies conducted by 17 institutions participating in acquired immunodeficiency syndrome (AIDS) Clinical Trial Units and who had been treated with AZT, were described in 1992 (39). AZT dosage ranged from 300 to 1200 mg/day, with 24 of the women taking the drug during at least two trimesters. All the infants were born alive. No congenital abnormalities were observed in 12 infants who had been exposed in utero to AZT during the 1st trimester, although one newborn with elevated 17a-hydroxyprogesterone levels had clitoral enlargement. Normal levels of the hormone were measured in this infant at 4 months of age. Two term infants were growth retarded, but 38 other singleton term infants had a mean birth weight of 3287 g. Seven infants had hemoglobin values less than 13.5 g/dL; three of these were delivered prematurely. The authors concluded that the few cases of anemia and growth retardation may have been, at least partially, caused by maternal AZT therapy (39). Another report involving 29 pregnant patients treated with AZT at government-sponsored AIDS clinical trial centers appeared in 1992, but no data on the outcome of these pregnancies were given (40).
The outcomes of 104 pregnancies in which AZT was used were described in a 1994 report (41). Sixteen of the pregnancies terminated during the 1st trimester8 spontaneous and 8 elective abortions. Among the remaining 88 cases, 8 infants had birth defects, 4 after 1st-trimester exposure and 4 after exposure during the 2nd or 3rd trimesters. None of the defects could be attributed to AZT exposure (41): multiple minor anomalies (low-set ears, retrognathia, hirsutism, triangular face, blue sclera, prominent sacral dimple)*; multiple minor anomalies (type not specified)*; extra digits on both hands, hare lip (central), cleft palate; fetal alcohol syndrome; atrial septal defect (asymptomatic) with pectus excavatum*; microcephaly, chorioretinitis (Toxoplasma gondii infection); pectus excavatum*; and albinism with congenital ptosis, growth retardation, and oligohydramnios (* indicates chromosomal analysis normal).
The Antiretroviral Pregnancy Registry reported, for the period January 1989 through July 2000, prospective data (reported to the Registry before the outcomes were known) involving 526 live births that had been exposed during the 1st trimester to one or more antiretroviral agents (42). Nine of the newborns had congenital defects (1.7%, 95% confidence interval [CI] 0.83.3). There were 25 infants with birth defects among 1,256 live births with exposure anytime during pregnancy (2.0%, 95% CI 1.33.0). The prevalence rates for the two periods did not differ significantly nor did they differ from the rates expected in a nonexposed population (42).
There were 1,207 outcomes exposed to AZT (477 in the 1st trimester and 730 in the 2nd and/or 3rd trimesters) either alone (134 in the 1st trimester and 288 in the 2nd and/or 3rd trimesters) or in combination with other antiretroviral agents (42). There were 24 birth defects in the AZT group, 8 exposed during the 1st trimester and 16 during the 2nd/3rd trimesters. The specific defects and treatments were not specified. In comparing the outcomes of prospectively registered cases to the birth defects among retrospective cases (pregnancies reported after the outcomes were known), the Registry concluded that there was no pattern of anomalies to suggest a common cause (42). (See below for required statement.) The failure of maternal AZT therapy to prevent the transmission of HIV type 1 (HIV-1) infection to one of the mother’s female twins was described in a 1990 report (43). The woman was treated with AZT, 400 mg/day, from 18 weeks’ gestation until delivery. A cesarean section was performed at 27 weeks’ gestation because of premature labor that was not responsive to tocolytic therapy. Twin A was diagnosed with culture-proven HIV-1 and cytomegalovirus infection. At the time of the report, the child was 9 months old with limited sight, severe failure to thrive, and encephalopathy. An HIV-1 culture in twin B was negative, but analysis for HIV-1 antigens continued to be positive through 20 weeks of age. A number of possible explanations were proposed by the authors concerning the failure of AZT to protect twin A from infection. Included among these were passage of the virus before the onset of treatment at 18 weeks’ gestation, intrauterine transfer of the virus via an amniocentesis performed at 14 weeks’ gestation, viral resistance to the drug, low fetal tissue drug levels, maternal noncompliance (doubtful), and acquisition of the virus during birth.
A 1992 review on the treatment of HIV-infected pregnant women stated that most obstetric experts offered AZT therapy in cases of AIDS, AIDS-related complex, or when the CD4+ cell counts were below 200 cells/L (44). Although no fetal toxicity secondary to AZT had been reported, the author recommended caution with 1st-trimester use of the agent and noted the potential for fetal bone marrow depression and resulting anemia.
A clinical trial, the subject of several reviews and editorials (45,46,47,48,49,50 and 51), conducted from 1991 to 1993 and published in 1994, found that the risk of maternal-infant transmission of HIV disease could be decreased by 67.5% by treatment of pregnant women (who had mildly symptomatic HIV disease) with AZT (52). The randomized, double-blind, placebo-controlled trial enrolled untreated HIV-infected pregnant women, at 1434 weeks’ gestation, who had CD4+ T-lymphocyte counts above 200 cells/mm3 and no clinical indications for antenatal antiretroviral therapy. The maternal AZT treatment regimen consisted of antepartum oral therapy (100 mg orally 5 times daily) and intrapartum IV dosing (2 mg/kg for 1 hour, then 1 mg/kg/hour until delivery). The newborns were treated with oral AZT (2 mg/kg every 6 hours) for 6 weeks. A total of 477 women were enrolled, 409 of whom delivered 415 live-born infants during the study period. Among those with known HIV-infection status were 180 infants from the AZT-treated group and 183 placebo-treated controls. The authors of this study used statistical methods to predict the number of infants who would be HIV infected at 18 months of age, thus allowing a faster analysis of their data. They estimated that the number of HIV-infected children would be 8.3% (95% CI 3.9%12.8%) in the AZT group and 25.5% (95% CI 18.4%32.5%) in the placebo group (52). This was a 67.5% (95% CI 40.7%82.1%) reduction in the risk of HIV transmission (p=0.00006). No differences in growth, prematurity, or the number and patterns of major or minor congenital abnormalities were observed between the two groups. Thirty-three live-born infants had congenital defects, 17 of 206 (8.3%) in the treatment group and 16 of 209 (7.7%) in the nontreated controls. Cardiac malformations were observed in 10 infants (5 in each group), central nervous system defects in five (3 in the AZT group, 2 in controls), and 9 unspecified defects in each group. The total incidence of congenital malformations is higher than expected in the general population, but this probably reflects the population studied. The only drug-related adverse effect observed in the newborns was a decrease in hemoglobin concentration in those exposed to AZT in utero. The maximum difference in hemoglobin concentration between the groups, 1 g/dL, occurred at 3 weeks of age, but by 12 weeks of age, the hemoglobin values were similar.
Although AZT appeared to be effective in reducing transmission of HIV-1 to the fetus, some infants became infected despite treatment. Possible reasons proposed for these failures included (a) virus transmission before treatment began, (b) ineffective suppression of maternal viral replication, (c) poor maternal compliance with the drug regimen, and (d) virus resistance to AZT (52).
Recommendations for the treatment of pregnant women infected with HIV were updated by the U.S. Public Health Service in 1998 (53). Although the choice of antiretroviral therapy should be based on the same considerations as used for nonpregnant patients, the inclusion of AZT was considered an important component of all treatment plans. However, waiting to initiate therapy until after 1012 weeks’ gestation was an option. The recommendations also stated that AZT was the only drug that had been demonstrated to reduce the risk of perinatal HIV-1 transmission (53). Because of this, AZT should be given to the mother during the intrapartum period and to the newborn for 6 weeks, regardless of the antepartum antiretroviral regiment (53). (See publication for other specific recommendations.) A series of studies and editorials appeared in 1998 through 2000 that evaluated or discussed the effect of short courses of AZT on the perinatal transmission of HIV in various populations (54,55,56,57,58,59 and 60). The most effective therapy, however, involved starting treatment of the mother at 28 weeks’ gestation, with 6 weeks of treatment in the infant (59,60).
A 2000 review described seven clinical trials that have been effective in reducing perinatal transmission, five with AZT alone, one with AZT plus lamivudine, and one with nevirapine (61). Six of the trials were in less-developed countries. Prolonged use of AZT in the mother and infant was the most effective for preventing vertical transmission of HIV, but also the most expensive. The combination of AZT and lamivudine, consisting of antepartum, intrapartum, and postpartum maternal therapy with continued therapy in the infant for 1 week, may have been as effective as prolonged AZT (61). More data are needed, however, before the efficacy and safety of combined therapy in preventing vertical transmission of HIV to the newborn can be assessed.
A study published in 1999 evaluated the safety, efficacy, and perinatal transmission rates of HIV in 30 pregnant women receiving various combinations of antiretroviral agents (62). Many of the women were substance abusers. AZT was used by 26 women in various combinations that included didanosine, lamivudine, indinavir, nelfinavir, nevirapine, saquinavir, and delavirdine. Antiretroviral therapy was initiated at a median of 14 weeks’ gestation (range preconception to 32 weeks). In spite of previous histories of extensive antiretroviral experience and of vertical transmission of HIV, combination therapy was effective in treating maternal disease and in preventing transmission to the current newborns. The outcomes of the pregnancies included one stillbirth, one case of microcephaly, and five infants with birth weights less than 2500 g, two of which were premature (62).
In another 1999 study, the safety and efficacy of a short-course of nevirapine was compared to AZT for the prevention of perinatal transmission of HIV-1 (63). At the onset of labor, women were randomly assigned to receive either a single dose of nevirapine (200 mg) plus a single dose (2 mg/kg) to their infants within 72 hours of birth (N=310) or AZT (600 mg then 300 mg every 3 hours until delivery) plus 4 mg/kg twice daily for 7 days to their infants (N=308). Nearly all (98.8%) of the women breast fed their infants immediately after birth. Up to age 1416 weeks, significantly fewer infants in the nevirapine group were HIV-1 infected, lowering the risk of infection or death, compared with AZT, by 48% (95% CI 24%65%) (63). The prevalence of maternal and infant adverse effects were similar in the two groups. In an accompanying study, the nevirapine regimen was shown to be cost-effective in various seroprevalence settings (64).
In an unusual case, a woman was exposed to HIV through self-insemination with fresh semen obtained from a man with a high HIV ribonucleic acid viral load (>750,000 copies/mL plasma) (65). Ten days later, she was started on a prophylactic regimen of AZT (600 mg/day), lamivudine (300 mg/day), and indinavir (2400 mg/day). Pregnancy was confirmed 14 days after insemination. The indinavir dose was reduced to 1800 mg/day 4 weeks after the start of therapy because of the development of renal calculi. All antiretroviral therapy was stopped after 9 weeks because of negative tests for HIV. She gave birth at 40 weeks’ gestation to a healthy 3490-g male infant, without evidence of HIV disease, who was developing normally at 2 years of age (65).
A case of life-threatening anemia following in utero exposure to antiretroviral agents was described in 1998 (66). A 30-year-old woman with HIV infection was treated with AZT, didanosine, and trimethoprim/sulfamethoxazole (3 times weekly) during the 1st trimester. Vitamin supplementation was also given. Because of an inadequate response, didanosine was discontinued and lamivudine and zalcitabine were started in the 3rd trimester. Two weeks before delivery the HIV viral load was undetectable. At term, a pale, male infant was delivered who developed respiratory distress shortly after birth. Examination revealed a hyperactive precordium and hepatomegaly without evidence of hydrops. The hematocrit was 11% with a reticulocyte count of zero. An extensive workup of the mother and infant failed to determine the cause of the anemia. Bacterial and viral infections, including HIV, parvovirus B19, cytomegalovirus, and others, were excluded. The infant received a transfusion and was apparently doing well at 10 weeks of age. Because no other cause of the anemia could be found, the authors attributed the condition to bone marrow suppression, most likely to AZT (66). A contribution of the other agents to the condition, however, could not be excluded.
A study of the inhibitory effects of AZT on hematopoiesis was published in 1996 (67). The researchers compared the effect of increasing concentrations of AZT on hematopoietic progenitors from women of childbearing age (from bone marrow aspirates), mid-trimester aborted fetuses (from bone marrow and liver), and term newborns (from cord blood). The inhibitory effect of AZT was more pronounced on fetal and neonatal erythroid progenitors than those from the bone marrow of the women. AZT had no effect on granulocyte colony-stimulating factor or erythropoietin. The authors concluded that neonatal anemia after in utero exposure to AZT was due to reduced clonal maturation of erythroid progenitors (67).
A 1999 report from France described the possible association of AZT and lamivudine (NRTIs) use in pregnancy with mitochondrial dysfunction in the offspring (68). Mitochondrial disease is relatively rare in France (estimated prevalence: 1 in 5,00020,000 children) (68). From an ongoing epidemiologic survey of 1,754 mother-child pairs exposed to AZT and other agents during pregnancy, however, 8 children with possible mitochondrial dysfunction were identified. None of the eight infants were infected with HIV, but all received prophylaxis for up to 6 weeks after birth with the same antiretroviral regimen as given during pregnancy. Four of the cases were exposed to AZT alone and four to a combination of AZT and lamivudine. Two from the combination group died at about 1 year of age. All eight cases had abnormally low respiratory-chain enzyme activities. The authors concluded that their results supported the hypothesis of a causative association between mitochondrial respiratory-chain dysfunction and NRTIs. Moreover, the toxicity may have been potentiated by combination of these agents (68).
In a paper following the above study, investigators noted that NRTIs inhibit DNA polymerase g, the enzyme responsible for mitochondrial DNA replication (69). They then hypothesized that this inhibition would induce depletion of mitochondrial DNA and mitochondrial DNA-encoded mitochondrial enzymes, thus resulting in mitochondrial dysfunction (69). Moreover, they stated that support for their hypothesis was suggested by the closeness of the clinical manifestations of inherited mitochondrial diseases with the adverse effects attributed to NRTIs. These adverse effects included polyneuropathy, myopathy, cardiomyopathy, pancreatitis, bone marrow suppression, and lactic acidosis. They also postulated this mechanism was involved in the development of a lipodystrophy syndrome of peripheral fat wasting and central adiposity, a condition that has been thought to be related to protease inhibitors (69).
A commentary on the above two studies concluded that the evidence for NRTI-induced mitochondrial dysfunction was equivocal (70). First, the clinical presentations in the infants were varied and not suggestive of a single cause; indeed, three of the infants were symptom-free and one had Leigh’s syndrome, a classic mitochondrial disease (70). Second, the clinical features, in some cases, were not suggestive of mitochondrial dysfunction. Although three had neurologic symptoms, none had raised levels of lactate in the cerebrospinal fluid. Moreover, histologic or histochemical features of mitochondrial disease were only found in two cases. Finally, low mitochondrial DNA, that would have been direct evidence of NRTI toxicity, was not found in the three cases in which it was measured (70).
A case of combined transient mitochondrial and peroxisomal b-oxidation dysfunction after exposure to NRTIs (AZT and lamivudine) combined with protease inhibitors (ritonavir and saquinavir) throughout gestation was reported in 2000 (71). A male infant was delivered at 38 weeks’ gestation. He received postnatal prophylaxis with AZT and lamivudine for 4 weeks until the drugs were discontinued because of anemia. Other adverse effects that were observed in the infant (age at onset) were hypocalcemia (shortly after birth), group B streptococcal sepsis, ventricular extrasystoles, prolonged metabolic acidosis, and lactic acidemia (8 weeks), a mild elevation of long-chain fatty acids (9 weeks), and neutropenia (3 months). The metabolic acidosis required treatment until 7 months of age, whereas the elevated plasma lactate resolved over 4 weeks. Cerebrospinal fluid lactate was not determined nor was a muscle biopsy conducted. Both the neutropenia and the cardiac dysfunction had resolved by 1 year of age. The elevated plasma fatty acid level was confirmed in cultured fibroblasts, but other peroxisomal functions (plasmalogen biosynthesis and catalase staining) were normal. Although mitochondrial dysfunction has been linked to NRTI agents, the authors were unable to identify the cause of the combined abnormalities in this case (71). The child was reported to be healthy and developing normally at 26 months of age.
A study involving Erythrocebus patas monkeys exposed in utero to AZT was thought to be relevant to the reports of mitochondrial dysfunction in humans (72). Ten pregnant monkeys in the last half of gestation were given daily oral doses of AZT (1.5 mg/kg/day [N=3] or 6 mg/kg/day [N=3]) or no AZT (controls [N=4]). The doses of AZT were 21% and 86% of the human dose, respectively, based on body weight for a 70-kg pregnant woman. All fetuses were delivered by cesarean section 24 hours after the last AZT dose and 35 days before term. No gross defects were evident in the heart left ventricle tissue or skeletal muscle tissue from AZT-exposed or control fetuses. Mitochondria observed by electron microscopy in the two tissue sites were similar in the AZT low-dose and control groups. In contrast, numerous abnormalities were observed in both heart and muscle tissue mitochondria from fetuses exposed to the AZT high-dose group. Moreover, there were dose-dependent alterations in oxidative phosphorylation enzyme assays, in the specific activities of NADH dehydrogenase (complex I), succinate dehydrogenase (complex II), and cytochrome-c oxidase (complex IV), and a dose-dependent depletion of mitochondrial DNA levels. The data were consistent with AZT-induced cardiac and skeletal muscle mitochondrial myopathy (72).
Based on the findings of the above research, a prospective study of the left ventricular structure and function of 382 noninfected (36 exposed to AZT) and 58 HIV-infected (12 exposed to AZT) infants born to HIV-infected women was published in 2000 (73). The median length of in utero exposure to AZT was 103 days (105 days for those not infected and 68 days for those infected at birth). Echocardiographic studies (mean left ventricular fractional shortening, contractility, end-diastolic dimension, and left ventricular mass) were conducted every 46 months during the first 14 months of life. All echocardiograms were examined without knowledge of the child’s clinical status or medications. No statistical differences were found among the four echocardiographic measures in the four groups of children. The investigators identified at least four limitations of their study, including a small sample size that was unable to estimate the frequency of an uncommon toxic effect, the lack of an assessment of a possible dose-effect, the possibility that the sickest children were missed because they were unable to attend follow-up visits, and the effects of other drug therapy in the HIV-infected subgroup that could obscure the effects of AZT (73). Nonetheless, they concluded that perinatal exposure to AZT was not associated with acute or chronic abnormalities in left ventricular structure or function (73).
A 2000 case report described the adverse pregnancy outcomes, including neural tube defects (NTDs), of two pregnant women with HIV infection who were treated with the anti-infective combination trimethoprim/sulfamethoxazole for prophylaxis against Pneumocystis carinii, concurrently with antiretroviral agents (74). Exposure to AZT occurred in one of these cases. A 32-year-old woman with a 3-year history of HIV and recent diagnosis of AIDS was treated before and throughout gestation with the antiinfective combination plus AZT and zalcitabine. Folic acid 10 mg/day was added after the diagnosis of pregnancy (gestational age not specified). At term, a female infant was delivered by cesarean section without HIV infection, but with a bony mass in the lumbar spine (identified by ultrasound at 32 weeks’ gestation). A diagnostic evaluation revealed that the second lumbar vertebra consisted of hemivertebrae and projected posteriorly into the spinal canal (74). A slightly malformed and displaced first lumbar vertebra was also noted. Surgery was planned to correct the defect. The authors attributed the NTDs in both cases to the antifolate activity of trimethoprim (74).
The case of a 6-month-old male infant who was diagnosed with acute lymphoblastic leukemia (ALL) was described in a 2000 case report (75). His mother had been diagnosed with HIV infection during the 5th month of gestation. She had been treated with oral AZT for the last 3 months of pregnancy. The 3.5-kg infant had been delivered by cesarean section and treated with AZT prophylaxis (2 mg/kg 4 times a day) for 6 weeks. All tests for HIV in the infant were negative. He achieved complete remission after chemotherapy for the ALL and was currently receiving the maintenance phase of chemotherapy at age 16 months. The relationship between AZT exposure and the ALL was unknown (75).
Because of the AZT-induced carcinogenicity observed in animal studies, a 1999 study evaluated the short-term risk for tumors in a total of 727 children who had been exposed in utero (antepartum) and/or during the neonatal period to HIV and AZT (76). The children were participants in one of two multicenter clinical studies: Pediatric AIDS Clinical Trials Group (PACTG) 076/219 (N=115) or the Women and Infants Transmission Study (WITS) (N=612). The mean infant follow-up in the PACTG 076/219 group was 38.3 months (366.9 person-years follow-up) whereas it was 14.5 months (743.7 person-years follow-up) for WITS participants. The range for all children was 1 month to 6 years. No tumors of any nature were reported in the children (relative risk 0, 95% CI 017.6) (76).
The long-term effects of in utero exposure to AZT were the subject of a study published in 1999 (77). HIV-uninfected children (N=234) born to 231 HIV-infected women enrolled in the PACTG 076 were evaluated under the PACTG 219 protocol (122 exposed to AZT, 112 in the placebo group). The main outcome measures included physical growth, immunologic parameters, cognitive/developmental function, tumors, and mortality data. Children were evaluated every 6 months up to 24 months, then yearly thereafter or as clinically indicated. The median age at the time of last follow-up was 4.2 years (range 3.25.6 years). There were no significant differences between those exposed to AZT and those not exposed in terms of the sequential outcome measurements. In addition, there were no deaths or malignancies. In the 137 (59%) children who had at least one ophthalmologic examination, 72 were in the AZT group and 65 were in the placebo group. Although there was no significant difference (p=0.99) between the groups in abnormal ophthalmic findings, astigmatism was noted in two (AZT group), ptosis in one (AZT group), and epicanthal folds in one (placebo group). Two other AZT-exposed children had ophthalmic abnormalities: bilateral thinned vessels; discs look slightly pale in one with normal vision; and one with a fundus reported as copper beaten look that was not thought to be related to metabolic disease (77). One other asymptomatic, healthy 4-year-old child in the AZT group had a mild cardiomyopathy on echocardiogram (77).
New York Medicaid data were used in a study published in 2000 to determine if there was an association between prenatal zidovudine use and congenital anomalies (78). The study cohort included 1,932 liveborn infants delivered from 1993 to 1996 to HIV-infected women in the state of New York, 29.5% of whom were exposed in utero to AZT. The prevalence of any anomaly in the study cohort was 2.76 (95% CI 2.363.17) compared to the general New York state population. When AZT-exposed outcomes were compared to those not exposed, the adjusted odds ratios (OR) for major congenital malformations by trimester of first prescription were: 1.20 (95% CI 0.582.51) (1st trimester), 1.47 (95% CI 0.852.55) (2nd trimester), and 1.84 (95% CI 1.043.25) (3rd trimester). There was an increased unadjusted OR for central nervous system defects when compared to those not exposed to AZT (7.98 [95% CI 1.5637.46]). But this finding was based on only four such defects and must be interpreted cautiously (78).
High semen levels of AZT have been reported (79). Six males with HIV disease were treated with 200 mg of the antiviral agent orally every 46 hours. AZT concentrations in semen 3.04.5 hours after a dose ranged from 1.68 to 6.43 mol/L, representing semen:serum ratios of 1.320.4. The semen levels were above the in vitro minimum inhibitory concentration for HIV-1. A 1994 study reported that AZT reversed the effects of HIV-1 disease progression on semen quality, including ejaculate volume, sperm concentration and total count, and the number of abnormal sperm forms (80). Moreover, AZT therapy significantly reduced the semen white blood cell count, the principal HIV-1 host cells in ejaculates of HIV-1infected males. The researchers concluded that this might explain why infected males treated with AZT have a reduced viral load in their semen and a lower rate of sexual transmission (80).
In summary, AZT is effective for the reduction of maternal-fetal transmission of HIV-1 infection with few, if any, adverse effects in the newborns. However, neonatal anemia, a known toxic effect of AZT, may occur and requires monitoring. Although yet unproven, AZT may be effective in reducing the transmission of HIV-1 from semen, thereby lessening the chance of infection in a woman who, when pregnant, could transmit the virus to her offspring. The drug is not teratogenic in animals, except at very high doses, and the experience in humans shows no pattern of birth defects. Experimental evidence, however, indicates that AZT is toxic to rodent embryos, preventing blastocyst development when administered before implantation. In addition, evidence has also been published that AZT may affect human trophoblast cell growth and function in a dose-related manner. This cytotoxicity may have resulted in the reduced fertility observed in nonhuman primates. Thus, impaired human fertility is a concern if AZT is administered in high therapeutic doses during early pregnancy. Additionally, there are unanswered questions relating to the potential for long-term toxicity, such as mutagenesis, carcinogenesis, liver disease, heart disease, and reproductive system effects. One study cited, however, found no cancer in AZT-exposed children, some of whom were followed up to 6 years of age. Mitochondrial dysfunction in offspring exposed in utero to AZT and other NRTIs has been reported. Moreover, evidence of dose-dependent mitochondrial dysfunction was demonstrated in monkey fetuses whose mothers were given a human-equivalent AZT dose. But a recent study did not find cardiac toxicity in a small sample of children exposed to AZT during the perinatal period. The incidence and clinical significance of mitochondrial dysfunction after in utero exposure to AZT is, therefore, still unknown and requires further study.
Two reviews, one in 1996 and the other in 1997, concluded that all women currently receiving antiretroviral therapy should continue to receive therapy during pregnancy and that treatment of the mother with monotherapy should be considered inadequate therapy (81,82). In 1998, the Centers for Disease Control and Prevention (CDC) made a similar recommendation that antiretroviral therapy should be continued during pregnancy, but discontinuation of all therapy during the 1st trimester was a consideration (53). However, AZT should be given to the mother during the intrapartum period and to the newborn for 6 weeks, regardless of the antepartum antiretroviral regimen (53). If indicated, therefore, the benefits of maternal AZT treatment to the infant outweigh the risks of AZT-induced toxicity (73,77,78,83). Children exposed in utero to AZT should be monitored for long periods to answer these concerns fully.
Required statement: Antiretroviral therapies: The Registry’s analytic approach is to evaluate specific classes of antiretroviral drugs (NRTIs [nucleoside analog reverse transcriptase inhibitor(s)], nnRTIs [non-nucleoside reverse transcriptase inhibitor(s)], and PIs [protease inhibitor(s)]). To date, however, accumulated cases of exposures to the antiretroviral agents followed in the Registry used alone or in combination are insufficient for reaching any reliable and definitive conclusions regarding the risk to pregnant women and their developing fetuses. Zidovudine monotherapy: Currently only the zidovudine monotherapy group is large enough to warrant a separate analysis. As other therapy groups attain a larger enrollment such analyses will occur for those as well. To date, the Registry has not demonstrated an increased prevalence of birth defects among women exposed to zidovudine monotherapy during the first trimester when compared with observed rates for early diagnoses in population-based birth defects surveillance systems. (The rate for first trimester zidovudine monotherapy is 1 live birth outcome with a defect out of 114 live births or 0.9%, (95% confidence interval (CI): 0%,5.5%). The CDC’s population-based birth defects surveillance system reports a total prevalence of birth defects identified among births from 1991 through 1995 was 3.14% (95% CI: 3.07%,3.23%), and the total prevalence of birth defects identified either prior to birth or during the first day of life (early diagnoses) is 2.17%, (95% CI: 2.10%,2.23%). However, the ability to detect an increase in birth defects or a pattern of the observed defects is limited by having only an overall 138 outcomes of pregnancy to women with first trimester zidovudine monotherapy exposures report to the Registry.
Breast Feeding Summary
Only one report describing the excretion of zidovudine (AZT) in breast milk has been located (84). Six HIV-seropositive women were given a single 200-mg dose of AZT, and serum and breast milk samples were collected 1, 2, 4, and 6 hours later. Peak serum and milk concentrations, ranging between 422.1 and 1019.3 ng/mL and 472.1 and 1043.0 ng/mL, respectively, were measured at approximately 12 hours after the dose. The milk:serum ratio (based on AUC) ranged between 1.11 and 1.78. The authors speculated that the milk concentrations were sufficiently high to decrease the viral load in milk, thereby reducing the potential for maternal-infant HIV transmission (84).
Breast feeding is not recommended in women with HIV infection because HIV-1 is transmitted in milk (85,86 and 87) . Until 1999, no studies had been published that examined the effect of any antiretroviral therapy on HIV-1 transmission in milk. In that year, a double-blind placebo-controlled trial investigated the effect of oral AZT in the postpartum period on the transmission of HIV-1 to the breast feeding infant (57). Infants (at 6 months of age) of women who had received an oral AZT regimen of 300 mg twice daily until labor, 600 mg at beginning of labor, then 300 mg twice daily for 7 days postpartum, had a 38% reduction (relative efficacy 0.38, 95% CI 0.050.60; p=0.027) in vertical transmission of HIV-1 infection despite breast feeding when compared to controls. Further, no excess of major adverse biological or clinical events was observed in the AZT group compared to controls (57).
- Product information. Retrovir. Glaxo Wellcome, 2001.
- Klug S, Lewandowski C, Merker H-J, Stahlmann R, Wildi L, Neubert D. In vitro and in vivo studies on the prenatal toxicity of five virustatic nucleoside analogues in comparison to aciclovir. Arch Toxicol 1991;65:28391.
- Greene JA, Ayers KM, De Miranda P, Tucker WE Jr. Postnatal survival in Wistar rats following oral dosage with zidovudine on gestation day 10. Fund Appl Toxicol 1990;15:2016.
- Gogu SR, Beckman BS, Agrawal KC. Amelioration of zidovudine-induced fetal toxicity in pregnant mice. Antimicrob Agents Chemother 1992;36:23704.
- Toltzis P, Marx CM, Kleinman N, Levine EM, Schmidt EV. Zidovudine-associated embryonic toxicity in mice. J Infect Dis 1991;12128.
- Sieh E, Coluzzi ML, Cusella de Angelis MG, Mezzogiorno A, Floridia M, Canipari R, Cossu G, Vella S. The effects of AZT and DDI on pre- and postimplantation mammalian embryos: an in vivo and in vitro study. AIDS Res Hum Retroviruses 1992;8:63949.
- Toltzis P, Mourton T, Magnuson T. Effect of zidovudine on preimplantation murine embryos. Antimicrob Agents Chemother 1993;37:16103.
- Toltzis P, Mourton T, Magnuson T. Comparative embryonic cytotoxicity of antiretroviral nucleosides. J Infect Dis 1994;169:11002.
- Nosbisch C, Ha JC, Sackett GP, Conrad SH, Ruppenthal GC, Unadkat JD. Fetal and infant toxicity of zidovudine in Macaca nemestrina (abstract). Teratology 1994;49:415.
- Ha JC, Nosbisch C, Conrad SH, Ruppenthal GC, Sackett GP, Abkowitz J, Unadkat JD. Fetal toxicity of zidovudine (azidothymidine) in Macaca nemestrina: preliminary observations. J Acquir Immune Defic Synd 1994;7:1547.
- Esterman AL, Rosenberg C, Brown T, Dancis J. The effect of zidovudine and 23-dideoxyinosine on human trophoblast in culture. Pharmacol Toxicol 1995;76:8992.
- Plessinger MA, Miller RK. Effects of zidovudine (AZT) and dideoxyinosine (ddI) on human trophoblast cells. Reprod Toxicol 1999;13:53746.
- Venerosi A, Valanzano A, Alleva E, Calamandrei G. Prenatal exposure to anti-HIV drugs: neurobehavioral effects of zidovudine (AZT) + lamivudine (3TC) treatment in mice. Teratology 2001;63:2637.
- Unadkat JD, Lopez AA, Schuman L. Transplacental transfer and the pharmacokinetics of zidovudine (ZDV) in the near term pregnant macaque. In Program and Abstracts of the Twenty-eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, Los Angeles, October 1988. Los Angeles, CA: American Society for Microbiology, 1988:372. As cited in Hankins GDV, Lowery CL, Scott RT, Morrow WR, Carey KD, Leland MM, Colvin EV. Transplacental transfer of zidovudine in the near-term pregnant baboon. Am J Obstet Gynecol 1990;163:72832.
- Lopez-Anaya A, Unadkat JD, Schumann LA, Smith AL. Pharmacokinetics of zidovudine (azidothymidine). I. Transplacental transfer. J Acquir Immune Defic Synd 1990;3:95964.
- Hankins GDV, Lowery CL Jr, Scott RT, Morrow WR, Carey KD, Leland MM, Colvin EV. Transplacental transfer of zidovudine in the near-term pregnant baboon. Am J Obstet Gynecol 1990;163:72832.
- Liebes L, Mendoza S, Wilson D, Dancis J. Transfer of zidovudine (AZT) by human placenta. J Infect Dis 1990;161:2037.
- Bawdon RE, Sobhi S, Dax J. The transfer of anti-human immunodeficiency virus nucleoside compounds by the term human placenta. Am J Obstet Gynecol 1992;167:15704.
- Schenker S, Johnson RF, King TS, Schenken RS, Henderson GI. Azidothymidine (zidovudine) transport by the human placenta. Am J Med Sci 1990;299:1620.
- Gillet JY, Garraffo R, Abrar D, Bongain A, Lapalus P, Dellamonica P. Fetoplacental passage of zidovudine. Lancet 1989;2:26970.
- Lyman WD, Tanaka KE, Kress Y, Rashbaum WK, Rubinstein A, Soeiro R. Zidovudine concentrations in human fetal tissue: implications for perinatal AIDS. Lancet 1990;335:12801.
- Chavanet P, Diquet B, Waldner A, Portier H. Perinatal pharmacokinetics of zidovudine. N Engl J Med 1989;321:15489.
- Pons JC, Taburet AM, Singlas E, Delfraissy JF, Papiernik E. Placental passage of azathiothymidine (AZT) during the second trimester of pregnancy: study by direct fetal blood sampling under ultrasound. Eur J Obstet Gynecol Reprod Biol 1991;40:22931.
- O’Sullivan MJ, Boyer PJJ, Scott GB, Parks WP, Weller S, Blum MR, Balsley J, Bryson YJ, Zidovudine Collaborative Working Group. The pharmacokinetics and safety of zidovudine in the third trimester of pregnancy for women infected with human immunodeficiency virus and their infants: Phase I Acquired Immunodeficiency Syndrome Clinical Trials group study (protocol 082). Am J Obstet Gynecol 1993;168:15106.
- Unadkat JD, Pereira CM. Maternal-fetal transfer and fetal toxicity of anti-HIV drugs. A review. Trophoblast Res 1994;8:6782.
- Watts DH, Brown ZA, Tartaglione T, Burchett SK, Opheim K, Coombs R, Corey L. Pharmacokinetic disposition of zidovudine during pregnancy. J Infect Dis 1991;163:22632.
- Sperling RS, Roboz J, Dische R, Silides D, Holzman I, Jew E. Zidovudine pharmacokinetics during pregnancy. Am J Perinatol 1992;9:2479.
- Tindall B, Cotton R, Swanson C, Perdices M, Bodsworth N, Imrie A, Cooper DA. Fifth International Conference on the Acquired Immunodeficiency Syndrome. Med J Aust 1990;152:20414.
- Tuntland T, Odinecs A, Pereira CM, Nosbisch C, Unadkat JD. In vitro models to predict the in vivo mechanism, rate, and extent of placental transfer of dideoxynucleoside drugs against human immunodeficiency virus. Am J Obstet Gynecol 1999;180:198206.
- Lopez-Anaya A, Unadkat JD, Schumann LA, Smith AL. Pharmacokinetics of zidovudine (azidothymidine). III. Effect of pregnancy. J Acquir Immune Defic Synd 1991;4:648.
- Pereira CM, Nosbisch C, Baughman WL, Unadkat JD. Effect of zidovudine on transplacental pharmacokinetics of ddI in the pigtailed macaque (Macaca nemestrina). Antimicrob Agents Chemother 1995;39:3435.
- Moodley J, Moodley D, Pillay K, Coovadia H, Saba J, van Leeuwen R, Goodwin C, Harrigan PR, Moore KHP, Stone C, Plumb R, Johnson MA. Pharmacokinetics and antiretroviral activity of lamivudine alone or when coadministered with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring. J Infect Dis 1998;178:132733.
- Odinecs A, Nosbisch C, Unadkat JD. Zidovudine does not affect transplacental transfer or systemic clearance of stavudine (2,3-didehydro-3-deoxythymidine) in the pigtailed macaque (Macaca nemestrina), Antimicrob Agents Chemother 1996;40:156971.
- Liebes L, Mendoza S, Lee JD, Dancis J. Further observations on zidovudine transfer and metabolism by human placenta. AIDS 1993;7:5902.
- Viscarello RR, DeGennaro NJ, Hobbins JC. Preliminary experience with the use of zidovudine (AZT) during pregnancy. Society of Perinatal Obstetricians Abstracts. Am J Obstet Gynecol 1991;164:248.
- Cullen MT, Delke I, Greenhaw J, Viscarello RR, Paryani S, Sanchez-Ramos L. HIV in pregnancy: factors predictive of maternal and fetal outcome. Society of Perinatal Obstetricians Abstracts. Am J Obstet Gynecol 1992;166:386.
- Taylor U, Bardeguez A. Antiretroviral therapy during pregnancy and postpartum. Society of Perinatal Obstetricians Abstracts. Am J Obstet Gynecol 1992;166:390.
- Delke I, Greenhaw J, Sanchez-Ramos L, Roberts W. Antiretroviral therapy during pregnancy. Society of Perinatal Obstetricians Abstracts. Am J Obstet Gynecol 1993;168:424.
- Sperling RS, Stratton P, O’Sullivan MJ, Boyer P, Watts DH, Lambert JS, Hammill H, Livingston EG, Gloeb DJ, Minkoff H, Fox HE. A survey of zidovudine use in pregnant women with human immunodeficiency virus infection. N Engl J Med 1992;326:85761.
- Stratton P, Mofenson LM, Willoughby AD. Human immunodeficiency virus infection in pregnant women under care at AIDS Clinical Trials centers in the United States. Obstet Gynecol 1992;79:3648.
- Kumar RM, Hughes PF, Khurranna A. Zidovudine use in pregnancy: a report of 104 cases and the occurrence of birth defects. J Acquir Immune Defic Synd 1994;7:10349.
- The Antiretroviral Pregnancy Registry for abacavir (Ziagen), amprenavir (Agenerase, APV), delavirdine mesylate (Rescriptor), didanosine (Videx, ddl), efavirenz (Sustiva, Stocrin), indinavir (Crixivan, IDV), lamivudine (Epivir, 3TC), lamivudine/zidovudine (Combivir), nelfinavir (Viracept), nevirapine (Viramune), ritonavir (Norvir), saquinavir (Fortovase, SQV-SGC), saquinavir mesylate (Invirase, SQV-HGC), stavudine (Zerit, d4T), zalcitabine (Hivid, ddC), zidovudine (Retrovir, ZDV). Interim Report. 1 January 1989 through 31 July 2000. 2000(December);11(No. 2):155.
- Barzilai A, Sperling RS, Hyatt AC, Wedgwood JF, Reidenberg BE, Hodes DS. Mother to child transmission of human immunodeficiency virus 1 infection despite zidovudine therapy from 18 weeks of gestation. Pediatr Infect Dis J 1990;9:9313.
- Sperling RS, Stratton P, Obstetric-Gynecologic Working Group of the AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases. Treatment options for human immunodeficiency virus-infected pregnant women. Obstet Gynecol 1992;79:4438.
- Rogers MF, Jaffe HW. Reducing the risk of maternal-infant transmission of HIV: a door is opened. N Engl J Med 1994;331:12223.
- CDC. Zidovudine for the prevention of HIV transmission from mother to infant. MMWR 1994;43:2857.
- CDC. Zidovudine for the prevention of HIV transmission from mother to infant. JAMA 1994;271:1567, 1570.
- Cotton P. Trial halted after drug cuts maternal HIV transmission rate by two thirds. JAMA 1994;271:807.
- Anonymous. Zidovudine for mother, fetus, and child: hope or poison? Lancet 1994;344:2079.
- Spector SA. Pediatric antiretroviral choices. AIDS 1994;4(Suppl 3):S158.
- Murphy R. Clinical aspects of human immunodeficiency virus disease: clinical rationale for treatment. J Infect Dis 1995;171(Suppl 2):S817.
- Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O’Sullivan MJ, VanDyke R, Bey M, Shearer W, Jacobson RL, Jimenez E, O’Neill E, Bazin B, Delfraissy J-F, Culnane M, Coombs R, Elkins M, Moye J, Stratton P, Balsley J, for the Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994;331:117380.
- CDC. Public Health Service Task Force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV-1 transmission in the United States. MMWR 1998;47:No. RR-2.
- Wade NA, Birkhead GS, Warren BL, Charbonneau TT, French PT, Wang L, Baum JB, Tesoriero JM, Savicki R. Abbreviated regimens of zidovudine prophylaxis and perinatal transmission of the human immunodeficiency virus. N Engl J Med 1998;339:140914.
- Shaffer N, Chuachoowong R, Mock PA, Bhadrakom C, Siriwasin W, Young NL, Chotpitayasunondh T, Chearskul S, Roongpisuthipong A, Chinayon P, Karon J, Mastro TD, Simonds RJ, on behalf of the Bangkok Collaborative Perinatal HIV Transmission Study Group. Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: a randomised controlled trial. Lancet 1999;353:77380.
- Wiktor SZ, Ekpini E, Karon JM, Nkengasong J, Maurice C, Severin ST, Roels TH, Kouassi MK, Lackritz EM, Coulibaly IM, Greenberg AE. Short-course oral zidovudine for prevention of mother-to-child transmission of HIV-1 in Abidjan, Cte d’Ivoire: a randomised trial. Lancet 1999;353:7815.
- Dabis F, Msellati P, Meda N, Welffens-Ekra C, You B, Manigart O, Leroy V, Simonon A, Cartoux M, Combe P, Ouangre A, Ramon R, Ky-Zerbo O, Montcho C, Salamon R, Rouzioux C, Van de Perre P, Mandelbrot L, for the DITRAME Study Group. 6-month efficacy, tolerance, and acceptability of a short regimen of oral zidovudine to reduce vertical transmission of HIV in breastfed children in Cte d’Ivoire and Burkina Faso: a double-blind placebo-controlled multicentre trial. Lancet 1999;353:78692.
- Mofenson LM. Short-course zidovudine for prevention of perinatal infection. Lancet 1999;353:7667.
- Lallemant M, Jourdain G, Le Coeur S, Kim S, Koetsawang S, Comeau AM, Phoolcharoen W, Essex M, McIntosh K, Vithayasai V, for the Perinatal HIV Prevention Trial (Thialand) investigators. A trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. N Engl J Med 2000;343:98291.
- Peckham C, Newell ML. Preventing vertical transmission of HIV infection. N Engl J Med 2000;343:10367.
- Mofenson LM, McIntyre JA. Advances and research directions in the prevention of mother-to-child HIV-1 transmission. Lancet 2000;355:223744.
- McGowan JP, Crane M, Wiznia AA, Blum S. Combination antiretroviral therapy in human immunodeficiency virus-infected pregnant women. Obstet Gynecol 1999;94:6416.
- Guay LA, Musoke P, Fleming T, Bagenda D, Allen M, Nakabiito C, Sherman J, Bakaki P, Ducar C, Deseyve M, Emel L, Mirochnick M, Fowler MG, Mofenson L, Miotti P, Dransfield K, Bray D, Mmiro F, Jackson JB. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999;354:795802.
- Marseille E, Kahn JG, Mmiro F, Guay L, Musoke P, Fowler MG, Jackson JB. Cost effectiveness of single-dose nervirapine regimen for mothers and babies to decrease vertical HIV-1 transmission in sub-Saharan Africa. Lancet 1999;354:8039.
- Loch M, Carr A, Vasak E, Cunningham P, Smith D. The use of human immunodeficiency virus postexposure prophylaxis after successful artificial insemination. Am J Obstet Gynecol 1999;181:7601.
- Watson WJ, Stevens TP, Weinberg GA. Profound anemia in a newborn infant of a mother receiving antiretroviral therapy. Pediatr Infect Dis J 1998;17:4356.
- Shah MM, Li Y, Christensen RD. Effects of perinatal zidovudine on hematopoiesis: a comparison of effects on progenitors from human fetuses versus mothers. AIDS 1996;10:123947.
- Blanche S, Tardieu M, Rustin P, Slama A, Barret B, Firtion G, Ciraru-Vigneron N, Lacroix C, Rouzioux C, Mandelbrot L, Desguerre I, Rotig A, Mayaux MJ, Delfraissy JF. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 1999;354:10849.
- Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 1999;354:111215.
- Morris AAM, Carr A. HIV nucleoside analogues: new adverse effects on mitochondria? Lancet 1999;354:10467.
- Stojanov S, Wintergerst U, Belohradsky BH, Rolinski B. Mitochondrial and peroxisomal dysfunction following perinatal exposure to antiretroviral drugs. AIDS 2000;14:1669.
- Gerschenson M, Erhart SW, Paik CY, St.Claire MC, Nagashima K, Skopets B, Harbaugh SW, Harbaugh JW, Quan W, Poirier MC. Fetal mitochondrial heart and skeletal muscle damage in Erythrocebus patas monkeys exposed in utero to 3-azido-3-deoxythymidine. AIDS Res Hum Retroviruses 2000;16:63544.
- Lipshultz SE, Easley KA, Orav EJ, Kaplan S, Starc TJ, Bricker JT, Lai WW, Moodie DS, Sopko G, McIntosh K, Colan SD, for the Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study Group. Absence of cardiac toxicity of zidovudine in infants. N Engl J Med 2000;343:75966.
- Richardson MP, Osrin D, Donaghy S, Brown NA, Hay, Sharland M. Spinal malformations in the fetuses of HIV infected women receiving combination antiretroviral therapy and co-trimoxazole. Eur J Obstet Gynecol Reprod Biol 2000;93:2157.
- Moschovi M, Theodoridou M, Papaevangelou V, Tzortzatou-Stathopoulou F. Acute lymphoblastic leukaemia in an infant exposed to zidovudine in utero and early infancy. AIDS 2000;14:24101.
- Hanson IC, Antonelli TA, Sperling RS, Oleske JM, Cooper E, Culnane M, Fowler MG, Kalish LA, Lee SS, McSherry G, Mofenson L, Shapiro DE. Lack of tumors in infants with perinatal HIV-1 exposure and fetal/neonatal exposure to zidovudine. J Acquir Immune Defic Syndr Hum Retrovirol 1999;20:4637.
- Culnane M, Fowler MG, Lee SS, McSherry G, Brady M, O’Donnell K, Mofenson L, Gortmaker SL, Shapiro DE, Scott G, Jimenez E, Moore EC, Diaz C, Flynn P, Cunningham B, Oleske J, for the Pediatric AIDS Clinical Trials Group Protocol 219/076 Teams. Lack of long-term effects of in utero exposure to zidovudine among uninfected children born to HIV-infected women. JAMA 1999;281:1517.
- Newschaffer CJ, Cocroft J, Anderson CE, Hauck WW, Turner BJ. Prenatal zidovudine use and congenital anomalies in a Medicaid population. J Acquir Immune Defic Syndr 2000;24:24956.
- Henry K, Chinnock BJ, Quinn RP, Fletcher CV, de Miranda P, Balfour HH Jr. Concurrent zidovudine levels in semen and serum determined by radioimmunoassay in patients with AIDS or AIDS-related complex. JAMA 1988;259:30236.
- Politch JA, Mayer KH, Abbott AF, Anderson DJ. The effects of disease progression and zidovudine therapy on semen quality in human immunodeficiency virus type 1 seropositive men. Fertil Steril 1994;61;9228.
- Carpenter CCJ, Fischi MA, Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, Montaner JSG, Richman DD, Saag MS, Schooley RT, Thompson MA, Vella S, Yeni PG, Volberding PA. Antiretroviral therapy for HIV infection in 1996. JAMA 1996;276:14554.
- Minkoff H, Augenbraun M. Antiretroviral therapy for pregnant women. Am J Obstet Gynecol 1997;176:47889.
- Mofenson LM. Perinatal exposure to zidovudinebenefits and risks. N Engl J Med 2000;343:8035.
- Ruff A, Hamzeh, Lietman P, Siberry G, Boulos R, Bell K, McBrien M, Davis H, Coberly J, Joseph D, Halsey N. Excretion of zidovudine (ZDV) in human breast milk. (abstract). Presented at the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Orlando, Florida, October, 1994.
- Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990;33:27689.
- de Martino M, Tovo P-A, Tozzi AE, Pezzotti P, Galli L, Livadiotti S, Caselli D, Massironi E, Ruga E, Fioredda F, Plebani A, Gabiano C, Zuccotti GV. HIV-1 transmission through breast-milk: appraisal of risk according to duration of feeding. AIDS 1992;6:9917.
- Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breast-feeding dilemma. Am J Obstet Gynecol 1995;173:4837.