Antiviral
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo/Fetal Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
The animal and human data suggest that stavudine represents a low risk to the embryo–fetus. Theoretically, exposure to stavudine at the time of implantation could result in impaired fertility because of embryonic cytotoxicity, but this has not been studied in humans. Stavudine peak serum concentrations achievable in humans with therapeutic doses, however, are in the same range that has been found to inhibit postblastocyst development in mice. Mitochondrial dysfunction in offspring exposed in utero or postnatally to nucleoside reverse transcriptase inhibitors (NRTIs) has been reported (see Lamivudine and Zidovudine), but these findings are controversial and require confirmation. If indicated, the drug should not be withheld because of pregnancy.
FETAL RISK SUMMARY
Stavudine (2’,3’-didehydro-3’-deoxythymidine; d4T) inhibits viral reverse transcriptase and DNA synthesis. It is classified as an NRTI used for the treatment of HIV infection. Its mechanism of action is similar to that of five other nucleoside analogs: abacavir, didanosine, lamivudine, zalcitabine, and zidovudine. Stavudine is converted by intracellular enzymes to the active metabolite, stavudine triphosphate (1).
No evidence of teratogenicity was observed in pregnant rats and rabbits exposed to maximum plasma concentrations up to 399 and 183 times, respectively, of those produced by a human dose of 1 mg/kg/day. A dose-related increase in common skeletal variations, postimplantation loss, and early neonatal mortality was observed in one or both species (1).
Antiretroviral nucleosides have been shown to have a direct dose-related cytotoxic effect on preimplantation mouse embryos. A 1994 report compared this toxicity among zidovudine and three newer compounds, stavudine, didanosine, and zalcitabine (2). Whereas significant inhibition of blastocyst formation occurred with a 1 µmol/L concentration of zidovudine, stavudine and zalcitabine toxicity was not detected until 100 µmol/L, and no toxicity was observed with didanosine up to 100 µmol/L. Moreover, postblastocyst development was severely inhibited in those embryos that did survive exposure to 1 µmol/L zidovudine. As for the other compounds, stavudine, at a concentration of 10 µmol/L (2.24 mcg/mL), inhibited postblastocyst development, but no effect was observed with concentrations up to 100 µmol/L of didanosine or zalcitabine. Although there are no human data, the authors of this study concluded that the three newer agents may be safer than zidovudine to use in early pregnancy.
Similar to other nucleoside analogues, stavudine appears to cross the human placenta by simple diffusion (3). The relatively low molecular weight (about 224) is in agreement with this. Stavudine also crosses the placenta in rats, resulting in a fetal:maternal ratio of approximately 0.5 (1). In near-term macaques, the steady-state fetal:maternal plasma ratio was approximately 0.8 (4). A related study found that zidovudine did not affect the placental transfer of stavudine in macaques (5). However, no reports in animals or humans have been located relating to the placental transfer of stavudine triphosphate (the active metabolite) or to the capability of the placenta or the fetus to metabolize stavudine.
Three experimental in vitro models using perfused human placentas to predict the placental transfer of NRTIs (didanosine, stavudine, zalcitabine, and zidovudine) were described in a 1999 publication (6). 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 the extent of in vivo human placental transfer of NRTIs (6).
The Antiretroviral Pregnancy Registry reported, for the period January 1989 through July 2009, prospective data (reported before the outcomes were known) involving 4702 live births that had been exposed during the 1st trimester to one or more antiretroviral agents (7). Congenital defects were noted in 134, a prevalence of 2.8% (95% confidence interval [CI] 2.4–3.4). In the 6100 live births with earliest exposure in the 2nd/3rd trimesters, there were 153 infants with defects (2.5%, 95% CI 2.1–2.9). The prevalence rates for the two periods did not differ significantly. There were 288 infants with birth defects among 10,803 live births with exposure anytime during pregnancy (2.7%, 95% CI 2.4–3.0). The prevalence rate did not differ significantly from the rate expected in a nonexposed population. There were 962 outcomes exposed to stavudine (771 in the 1st trimester and 191 in the 2nd/3rd trimesters) in combination with other antiretroviral agents. There were 25 birth defects (19 in the 1st trimester and 6 in the 2nd/3rd trimesters). In reviewing the birth defects of prospective and retrospective (pregnancies reported after the outcomes were known) registered cases, the Registry concluded that, except for isolated cases of neural tube defects (NTDs) with efavirenz exposure in retrospective reports, there was no other pattern of anomalies (isolated or syndromic) (7). (See Lamivudine for required statement.)
A 2000 case report described the adverse pregnancy outcomes, including 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 (8). Exposure to stavudine occurred in one of these cases. A 31-year-old woman presented at 15 weeks’ gestation. She was receiving trimethoprim/sulfamethoxazole, didanosine, stavudine, nevirapine, and vitamin B supplements (specific vitamins and dosage not given) that had been started before conception. A fetal ultrasound at 19 weeks’ gestation revealed spina bifida and ventriculomegaly. The patient elected to terminate her pregnancy. The fetus did not have HIV infection. Defects observed at autopsy included ventriculomegaly, an Arnold-Chiari malformation, sacral spina bifida, and a lumbo-sacral meningomyelocele. The authors attributed the NTDs in both cases to the antifolate activity of trimethoprim (8).
A 1999 case report described a 26-year-old woman with a 5-year history of HIV infection (9). Two years before her current pregnancy, she had received monotherapy with zidovudine for 19 months, followed by 6 months of monotherapy with zalcitabine. She stopped therapy during the first 19 gestational weeks, then started stavudine and lamivudine that were continued until vaginal delivery at term of a healthy 3560-g female infant. The infant was not infected with HIV and was doing well at 9 months of age.
No data are available on the advisability of treating pregnant women who have been exposed to HIV via occupational exposure, but one author discourages this use (10).
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 (11,12). The same conclusion was reached in a 2003 review with the added admonishment that therapy must be continuous to prevent emergence of resistant viral strains (13). In 2009, the updated U.S. Department of Health and Human Services guidelines for the use of antiretroviral agents in HIV type 1 (HIV-1)-infected patients continued the recommendation that therapy, with the exception of efavirenz, should be continued during pregnancy (14). If indicated, stavudine should not be withheld in pregnancy because the expected benefit to the HIV-positive mother outweighs the unknown risk to the fetus. Updated guidelines for the use of antiretroviral drugs to reduce perinatal HIV-1 transmission also were released in 2010 (15). Women receiving antiretroviral therapy during pregnancy should continue the therapy but, regardless of the regimen, zidovudine administration is recommended during the intrapartum period to prevent vertical transmission of HIV to the newborn (15).
BREASTFEEDING SUMMARY
No reports describing the use of stavudine during lactation have been located. The molecular weight (about 224) suggests that stavudine will be excreted into breast milk. The effect of this exposure on a nursing infant is unknown.
Reports on the use of stavudine during human lactation are unlikely because the antiviral agent is used in the treatment of HIV infection. HIV-1 is transmitted in milk, and in developed countries, breastfeeding is not recommended (11,12,14,16–18). In developing countries, breastfeeding is undertaken, despite the risk, because there are no affordable milk substitutes available. 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 study involving zidovudine was published that measured a 38% reduction in vertical transmission of HIV-1 infection despite breastfeeding when compared with controls (see Zidovudine).
References
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3.Bawdon RE, Kaul S, Sobhi S. The ex vivo transfer of the anti-HIV nucleoside compound d4T in the human placenta. Gynecol Obstet Invest 1994;38:1–4.
4.Odinecs A, Nosbisch C, Keller RD, Baughman WL, Unadkat JD. In vivo maternal-fetal pharmacokinetics of stavudine (2’,3’-didehydro-3’-deoxythymidine) in pigtailed macaques (Macaca nemestrina). Antimicrob Agents Chemother 1996;40:196–202.
5.Odinecs A, Nosbisch C, Unadkat JD. Zidovudine does not affect transplacental transfer or systemic clearance of stavudine (2’,3’-didehydro-3’-doxythymidine) in the pigtailed macaque (Macaca nemestrina). Antimicrob Agents Chemother 1996;40:1569–71.
6.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;180:198–206.
7.Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 July 2009. Wilmington, NC: Registry Coordinating Center; 2009. Available at www.apregistry.com. Accessed May 29, 2010.
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14.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Department of Health and Human Services. December 1, 2009;1–161. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed September 17, 2010:60, 96–8.
15.Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. May 24, 2010:1–117. Available at http://aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf. Accessed September 17, 2010:30, Table 5.
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18.Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breast-feeding dilemma. Am J Obstet Gynecol 1995;173:483–7.