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, however, because the antiviral agent is used in the treatment of HIV infection. HIV-1 is transmitted in milk, and in the United States, breastfeeding is not recommended (13).

Stavudine (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, emtricitabine, lamivudine, and zidovudine. Stavudine is converted by intracellular enzymes to the active metabolite, stavudine triphosphate. It has negligible protein binding and an elimination half-life of about 2.3 hours (1).

Animal Data: No evidence of teratogenicity was observed in pregnant rats and rabbits exposed to maximum plasma concentrations up to 488 and 183 times, respectively, of those produced by a human dose of 1 mg/kg/day (HD). Fetal skeletal variations including increased unossified or incomplete ossification of the sternebra were observed with doses about 488 times the HD administered during organogenesis. A dose-related increase in common skeletal variations, postimplantation loss, and early neonatal mortality was observed in rats receiving doses about 488 times the HD from gestational day 17 to postnatal day 21 (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 (3). 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.

Placental Transfer: Similar to other nucleoside analogs, stavudine appears to cross the human placenta by simple diffusion (4). 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 (5). A related study found that zidovudine did not affect the placental transfer of stavudine in macaques (6). 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 (7). For each drug, the predicted fetal:maternal plasma drug concentration ratios at a 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 (7).

Human Data: The Antiretroviral Pregnancy Registry reported, for the periods January 1989 through January 2019, prospective data (reported before the outcomes were known) involving 10,952 pregnancies with 1st trimester exposure to one or more antiretroviral agents (8). There were 1007 outcomes exposed to stavudine (811 in the 1st trimester and 196 in the 2nd/3rd trimesters) in combination with other antiretroviral agents. When comparing live births with defects after 1st trimester exposure, raltegravir had a 2.6% risk for malformations (19/563) (8). Health care professionals are encouraged to register patients exposed to raltegravir during pregnancy in the Antiviral Pregnancy Registry by calling the toll-free number (800-258-4263). (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 (9). Exposure to stavudine occurred in one of these cases. A 31-year-old woman presented at 15 weeks. 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 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 lumbosacral meningomyelocele. The authors attributed the NTDs in both cases to the antifolate activity of trimethoprim (9).

A 1999 case report described a 26-year-old woman with a 5-year history of HIV infection (10). 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 and 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.

In 2019, the updated U.S. Department of Health and Human Services AIDS Info guidelines for the use of antiretroviral agents in during pregnancy recommend that patients continue their regimen during pregnancy but therapy must be individualized (11). See the guideline for the most update information on continuing, initiating, or switching regimens during pregnancy. If indicated, raltegravir should not be withheld in pregnancy since the expected benefit to the HIV-positive mother outweighs the unknown risk to the fetus. 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 if the HIV RNA is known or suspected to be >1000 copies/mL and may be considered if the HIV RNA is 50-999 copies/mL (12). The guidelines recommend that stavudine is not recommended during pregnancy due to toxicity (2).