Risk Factor: BM
Class: Anti-infectives/ Antivirals
Fetal Risk Summary
Didanosine (2′,3′-dideoxyinosine; ddI) inhibits viral reverse transcriptase and 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, lamivudine, stavudine, zalcitabine, and zidovudine. Didanosine is converted by intracellular enzymes to the active metabolite, dideoxyadenosine triphosphate (ddATP).
No evidence of teratogenicity or toxicity was observed in pregnant rats and rabbits administered doses of didanosine up to 12 and 14.2 times the human dose, respectively (1). In another report, didanosine was given to pregnant mice in doses ranging from 10300 mg/kg/day, through all or part of gestation, without resulting in teratogenic effects or other toxicity (2).
The reproductive toxicity of 2′,3′-dideoxyadenosine (ddA; the unphosphorylated active metabolite of didanosine) in rats was compared in a combined in vitro/in vivo experiment with four other nucleoside analogues (vidarabine-phosphate, ganciclovir, zalcitabine, and zidovudine), and these results were then compared to previous data obtained under identical conditions with acyclovir (3). Utilizing various concentrations of the drug in a whole-embryo culture system and direct administration to pregnant females (200 mg/kg subcutaneously every 4 hours for three 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 ddA was less than that of the other agents, except for zidovudine. The in vivo toxicity was less than that of acyclovir, vidarabine, and ganciclovir, and equal to that observed with zalcitabine and zidovudine.
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, didanosine, stavudine, and zalcitabine (4). Whereas significant inhibition of blastocyst formation occurred with a 1 mol/L concentration of zidovudine, stavudine and zalcitabine 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 (2.24 g/mL), inhibited postblastocyst development, but no effect was observed with concentrations up to 100 mol/L of didanosine or zalcitabine. An earlier study found no cytotoxicity in preimplantation mouse embryos exposed to didanosine concentrations up to 500 mol/L (2). Although there are no human data, the authors of the 1994 study concluded that the three newer agents may be safer than zidovudine to use in early pregnancy (4).
A 1995 report described the effect of exposure to a relatively high concentration of didanosine (20 mol/L vs. recommended therapeutic concentrations of 35 mol/L) for prolonged periods (211 days) on trophloblasts from term and 1st-trimester placentas (5). No significant effects on trophoblast function, as measured by human chorionic gonadotropin secretion, protein synthesis, progesterone synthesis, and glucose consumption, were observed.
A 1999 study also investigated the effects of a single 24-hour exposure of zidovudine (AZT) or didanosine on human trophoblast cells using a human choriocarcinoma cell line that exhibited many characteristics of the early placenta (6). 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 (6). 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 embryo toxic (6).
Didanosine crosses the placenta to the fetus in both animals and humans (1,7,8,9,10,11,12 and 13). In pregnant macaques (Macaca nemestrina), didanosine was administered by constant infusion at a dose of either 42.5 g/minute/kg or 425 g/minute/kg (7). The compound crossed the placenta by simple diffusion, resulting in fetal:maternal concentration ratios for both doses of approximately 0.5. In near-term rhesus monkeys, a single IV bolus (2.0 mg/kg) of didanosine resulted in mean fetal concentrations of unmetabolized drug of 33% of the maternal plasma concentrations (8). Concentrations of didanosine were 20% of those in the fetal plasma by 3 hours. However, ddATP was not found in any fetal tissue.
Using a perfused term human placenta, investigators concluded in a 1992 publication that the placental transfer of didanosine was most likely due to passive diffusion (9). Two other studies, again using perfused human placenta, found that only about 50% of the drug would be passively transferred to the fetal circulation (10), and at approximately half the rate of zidovudine (11). In contrast to zidovudine (see Zidovudine), no metabolite was detected in the placenta (10).
Two HIV-positive women, at 21 and 24 weeks’ gestation, respectively, were given a single 375-mg oral dose of didanosine immediately prior to pregnancy termination (12). Drug concentrations in the maternal blood, fetal blood, and amniotic fluid at slightly more than 1 hour after the dose were 295, 42, and
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 (14). 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 (14).
The pharmacokinetics of IV (1.6 mg/kg/hr) and oral (200 mg twice daily) didanosine have been studied in pregnant women with HIV infection at 31 weeks’ gestation, during labor, and 6 weeks postpartum (15). This study also described the pharmacokinetics of oral didanosine (60 mg/m2) in infants at day 1 and at week 6 after birth.
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 (16). 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 (16).
There were 95 outcomes exposed to didanosine (64 in the 1st trimester and 31 in the 2nd and/or 3rd trimesters) either alone (4 in the 1st trimester) or in combination with other antiretroviral agents (16). There were two birth defects among those exposed during the 1st trimester, but the specific defects and treatments 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 (16). (See Lamivudine for required statement.) A case of life-threatening anemia following in utero exposure to antiretroviral agents was described in 1998 (17). A 30-year-old woman with HIV infection was treated with zidovudine, didanosine, and trimethoprim/sulfamethoxazole (three 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 morrow suppression, most likely to zidovudine (17). 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 antiinfective combination, trimethoprim/sulfamethoxazole, for prophylaxis against Pneumocystsis carinii, concurrently with antiretroviral agents (18). Exposure to didanosine 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 (18).
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 (19).
In summary, although the limited human data does not allow an assessment as to the safety of didanosine during pregnancy, the animal data and the human experience with other similar antiretroviral agents suggests that didanosine is a low risk to the developing fetus. Theoretically, exposure to didanosine 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).
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 (20,21). 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 (22). If indicated, therefore, didanosine 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 (20,21).
Breast Feeding Summary
No reports describing the use of didanosine during lactation have been located. The molecular weight (about 236) is low enough that excretion into milk should be expected. Both didanosine and its metabolites are excreted into the milk of lactating rats (1).
Reports on the use of didanosine during human lactation are unlikely because the antiviral agent is used in the treatment of human immunodeficiency virus (HIV) infections. HIV-1 is transmitted in milk, and in developed countries, breast feeding is not recommended (20,21,23,24 and 25). 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 despite breast feeding when compared to controls (see Zidovudine).
- Product information. Videx. Bristol-Myers Squibb, 2001.
- 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.
- 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.
- Esterman AL, Rosenberg C, Brown T, Dancis J. The effect of zidovudine and 2’3′-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.
- Pereira CM, Nosbisch C, Winter HR, Baughman WL, Unadkat JD. Transplacental pharmacokinetics of dideoxyinosine in pigtailed macaques. Antimicrob Agents Chemother 1994;38:7816.
- 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.
- 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.
- Dancis J, Lee JD, Mendoza S, Liebes L. Transfer and metabolism of dideoxyinosine by the perfused human placenta. J Acquir Immune Defic Syndr 1993;6:26.
- Henderson GI, Perez AB, Yang Y, Hamby RL, Schenken RS, Schenker S. Transfer of dideoxyinosine across the human isolated placenta. Br J Clin Pharmacol 1994;38:23742.
- Pons JC, Boubon MC, Taburet AM, Singlas E, Chambrin V, Frydman R, Papiernik E, Delfraissy JF. Fetoplacental passage of 2′,3′-dideoxyinosine. Lancet 1991;337:732.
- Dalton JT, Au JL-S. 2’3′-Dideoxyinosine is not metabolized in human placenta. Drug Metab Dispos 1993;21:5446.
- 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.
- Wang Y, Livingston E, Patil S, McKinney RE, Bardeguez AD, Gandia J, O’Sullivan MJ, Clax P, Huang S, Unadkat JD. Pharmacokinetics of didanosine in antepartum and postpartum human immunodeficiency virus-infected pregnant women and their neonates: an AIDS Clinical Trials Group study. J Infect Dis 1999;180:153641.
- 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.
- Centers for Disease Control and Prevention. 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.