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. The effect on a nursing infant is unknown.

Reports on the use of didanosine 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, breastfeeding is not recommended (9, 10, 12, 14, 15, 16). 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).

Didanosine (2',3'-dideoxyinosine; ddI) inhibits viral reverse transcriptase and DNA synthesis (1). It is classified as an NRTI used for the treatment of HIV infections. Its mechanism of action is similar to that of five other nucleoside analogs: abacavir, lamivudine, stavudine, zalcitabine, and zidovudine. Didanosine is converted by intracellular enzymes to the active metabolite, dideoxyadenosine triphosphate (ddATP) (1).

Animal Data: 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 10 to 300 mg/kg/day, through all or part of gestation, without resulting in teratogenic effects or other toxicity (2).

Placental Transfer: Didanosine crosses the placenta to the fetus in humans (1, 3, 4). 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 (3). Drug concentrations in the maternal blood, fetal blood, and amniotic fluid at slightly more than 1 hour after the dose were 295, 42, and <5 ng/mL, respectively, in the first patient, and 629, 121, and 135 ng/mL, respectively, in the second woman. The fetal:maternal blood ratios were 0.14 and 0.19, respectively (3). Although single drug level determinations are difficult to interpret, a study published in 1993 found that human placental first-pass metabolism was not the reason for these low fetal and amniotic fluid levels (4).

Human Data: The Antiretroviral Pregnancy Registry reported, for 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 (5). Congenital defects were noted in 134 (2.8%). In the 6100 live births with earliest exposure in the 2nd/3rd trimesters, there were 153 infants with defects (2.5%). The prevalence rates for the two periods did not differ significantly. There were 288 (2.7%) infants with birth defects among 10,803 live births with exposure anytime during pregnancy. The prevalence rate did not differ significantly from the rate expected in a nonexposed population. There were 627 outcomes exposed to didanosine (370 in the 1st trimester and 257 in the 2nd/3rd trimesters) in combination with other antiretroviral agents. There were 22 birth defects (17 in the 1st trimester and 5 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 with efavirenz exposure in retrospective reports, there was no other pattern of anomalies (isolated or syndromic) (5) (see Lamivudine for required statement).

A case of life-threatening anemia following in utero exposure to antiretroviral agents was described in 1998 (6). 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 morrow suppression, most likely to zidovudine. A contribution of the other agents to the condition, however, could not be excluded (6).

A 2000 case report described the adverse pregnancy outcomes, including NTD, 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 (7). 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 lumbosacral meningomyelocele. The authors attributed the NTDs in both cases to the antifolate activity of trimethoprim (7).

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 (8).

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 (9, 10). 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 (11). 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 (12). If indicated, didanosine should not be withheld in pregnancy because the expected benefit to the HIV-positive mother outweighs the unknown risk to the fetus. The updated guidelines for the use of antiretroviral drugs to reduce perinatal HIV-1 transmission also were released in 2010 (13). 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 (13).