Risk Factor: CM
Class: Anti-infectives/ Antivirals
Fetal Risk Summary
Zalcitabine (2,3-dideoxycytidine; ddC) is a reverse transcriptase inhibitor that also inhibits viral DNA synthesis. It is classified as a nucleoside reverse transcriptase inhibitor (NRTI) used for the treatment of human immunodeficiency virus (HIV) infections. Its mechanism of action is similar to that of five other nucleoside analogues: abacavir, didanosine, lamivudine, stavudine, and zidovudine. Zalcitabine is converted in vivo to the active metabolite, dideoxycytidine 5-triphosphate (ddCTP), by cellular enzymes.
Zalcitabine was teratogenic in mice given doses 1,365 and 2,730 times the maximum recommended human dose based on AUC measurements (MRHD) (1). A significant decrease in fetal weight was observed at both doses, and decreased embryo survival occurred at the highest dose. In rats, a dose 485 times the MRHD was not teratogenic, but doses greater than this were associated with reduced embryo survival, and a high incidence of hydrocephalus was observed at 1,071 times the MRHD (1). A significant number of rat offspring also had impaired learning and memory, and longer durations of hyperactivity. These findings were considered to result from extensive damage to or gross underdevelopment of the brain, consistent with hydrocephalus (1). Doses 2,142 times the MRHD were teratogenic in rats and resulted in a significant decrease in fetal weight.
In a 1990 report, pregnant mice were given zalcitabine during gestational days 615 in doses of 0, 200, 400, 1000, and 2000 mg/kg/day (2). The highest doses, 1000 and 2000 mg/kg/day, were significantly associated with a variety of congenital malformations, reduced fetal weight, and increased resorption (reduced embryo survival).
The reproductive toxicity of zalcitabine in rats was compared in a combined in vitro/in vivo experiment with four other nucleoside analogues (vidarabine phosphate, ganciclovir, 2,3-dideoxyadenosine [ddA; unphosphorylated active metabolite of didanosine], and zidovudine), and these results were then compared with previous data obtained under identical conditions with acyclovir (3). Using various concentrations of the drug in a whole-embryo culture system and direct administration to pregnant females (200 mg/kg SC every 4 hours 3 doses) during organogenesis, in vitro vidarabine showed the highest potential to interfere with embryonic development, whereas in vivo acyclovir had the highest teratogenic potential. In this study, the in vitro reproductive toxicity of zalcitabine was less than that of vidarabine and acyclovir, but greater than that of the other three agents. The in vivo toxicity of zalcitabine was less than that of acyclovir, vidarabine, and ganciclovir, and equal to that observed with ddA and zidovudine.
Antiretroviral nucleosides have been shown to have direct dose-related cytotoxic effects on preimplantation mouse embryos. A 1994 report compared this toxicity among zidovudine and three newer compounds, zalcitabine, didanosine, and stavudine (4). Whereas significant inhibition of blastocyst formation occurred with a 1-mol/L concentration of zidovudine, zalcitabine and stavudine toxicity was not detected until 100 mol/L, and no toxicity was observed with didanosine up to 100 mol/L. Moreover, postblastocyst development was severely inhibited in those embryos that did survive exposure to 1 mol/L zidovudine. As for the other compounds, stavudine, at a concentration of 10 mol/L, inhibited postblastocyst development, but no effect was observed with concentrations up to 100 mol/L of zalcitabine or didanosine. 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.
Zalcitabine crosses the placenta to the fetus (5,6,7 and 8). Using a perfused term human placenta, investigators concluded in a 1992 publication that the placental transfer of zalcitabine was most likely a result of simple diffusion (5). In near-term rhesus monkeys, a single IV bolus (0.6 mg/kg) of zalcitabine produced ratios of fetal:maternal area under the plasma concentration-time curves from 0 to 3 hours of 0.5 (6) and 0.32 (7). Concentrations of zalcitabine in the fetal brain were 20% of those in the fetal plasma by 3 hours (6,7). However, only very small amounts of the inactive monophosphorylated metabolite of zalcitabine (ddCMP), and none of the active triphosphate metabolite (ddCTP), were detected in fetal tissues (7).
Simple diffusion of zalcitabine across the placenta of near-term pigtailed macaques (Macaca nemestrina) was reported in a 1994 abstract (8). A continuous IV infusion (1.28 g/minute/kg) resulted in a mean fetal:maternal plasma concentration at steady state of 0.58.
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 (9). 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 (9).
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 (10). 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 (10).
There were 40 outcomes exposed to zalcitabine (38 in the 1st trimester and in the 2nd and/or 3rd trimesters) either alone (7 in the 1st trimester) or in combination with other antiretroviral agents (10). There was one birth defect among those exposed during the 1st trimester, but the specific defect and treatment were not identified. 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 (10). (See Lamivudine for required statement.) A case of life-threatening anemia following in utero exposure to antiretroviral agents was described in 1998 (11). A 30-year-old woman with HIV infection was treated with zidovudine, 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 zidovudine (11). A contribution of the other agents to the condition, however, could not be excluded.
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 (12). Exposure to zalcitabine occurred in one of these cases. A 32-year-old woman with a 3-year history of HIV and recent diagnosis of acquired immunodeficiency syndrome was treated before and throughout gestation with the anti-infective combination plus zidovudine 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 (12). 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 (12).
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 (13).
In summary, although the limited human data do not allow an assessment as to the safety of zalcitabine during pregnancy, the reproductive toxicity observed in animals is a concern. Theoretically, exposure to zalcitabine at the time of implantation could result in impaired fertility due to embryonic cytotoxicity, but this has not been studied in humans. Mitochondrial dysfunction in offspring exposed in utero or postnatally to NRTIs has been reported (see Lamivudine and Zidovudine), but these findings are controversial and require confirmation.
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 (14,15). 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 (16). If indicated, therefore, zalcitabine should not be withheld in pregnancy (with the possible exception of the 1st trimester) because the expected benefit to the HIV-positive mother probably outweighs the unknown risk to the fetus. The efficacy and safety of combined therapy in preventing vertical transmission of HIV to the newborn, however, are unknown, and zidovudine remains the only antiretroviral agent recommended for this purpose (14,15).
Breast Feeding Summary
No reports describing the use of zalcitabine during lactation have been located. The relatively low molecular weight (about 211) is low enough that excretion into milk should be expected.
Reports on the use of zalcitabine during human lactation are unlikely because the antiviral agent is used in the treatment of HIV infections. HIV-1 is transmitted in milk, and in developed countries, breast feeding is not recommended (14,15,17,18 and 19). In developing countries, breast feeding 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 in spite of breast feeding when compared to controls (see Zidovudine).
- Product information. Hivid. Roche Laboratories, 2001.
- Lindstrom P, Harris M, Hoberman AM, Dunnick JK, Morrissey RE. Developmental toxicity of orally administered 2,3-dideoxycytidine in mice. Teratology 1990;42:1316.
- 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.
- Toltzis P, Mourton T, Magnuson T. Comparative embryonic cytotoxicity of antiretroviral nucleosides. J Infect Dis 1994;169:11002.
- 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.
- Slikker W Jr, Lipe G, Parker W, Rose L, Ali S, Schmued L, Scallet A, Binienda Z. Disposition of 3H-ddC in the pregnant rhesus monkey (abstract). Placenta 1992;13:A.59.
- Sandberg JA, Binienda Z, Lipe G, Rose LM, Parker WB, Ali SF, Slikker W Jr. Placental transfer and fetal disposition of 2,3-dideoxycytidine and 2,3-dideoxyinosine in the rhesus monkey. Drug Metab Dispos 1995;23:8814.
- Tuntland T, Nosbisch C, Baughman WL, Pereira CM, Unadkat JD. The transplacental transfer of dideoxycytidine is passive in Macaca nemestrina (abstract). Teratology 1994;49:415.
- 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.
- 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.
- 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.
- 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.
- Gerberding JL. Management of occupational exposures to blood-borne viruses. N Engl J Med 1995;332:44451.
- 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;14654.
- Minkoff H, Augenbraun M. Antiretroviral therapy for pregnant women. Am J Obstet Gynecol 1997;176:47889.
- 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.
- 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.