(Last updated: August 6, 2015; last reviewed: August 6, 2015)
Tenofovir disoproxil fumarate, the orally bioavailable form of tenofovir, is classified as Food and Drug Administration Pregnancy Category B.
Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose, respectively, based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus associated with tenofovir. There were also no effects on fertility, mating performance, or early embryonic development when tenofovir was administered to male rats (600 mg/kg/day; equivalent to 10 times the human dose based on body surface area) for 28 days before mating and to female rats for 15 days before mating through Day 7 of gestation. There was, however, an alteration of the estrous cycle in female rats administered 600 mg/kg/day.
Chronic exposure of fetal monkeys to tenofovir at high doses (exposure equivalent to 25 times the area under the curve (AUC) achieved with therapeutic dosing in humans) resulted in lower fetal circulating insulin-like growth factor (IGF)-1, higher IGF binding protein-3 levels, and lower body weights. A slight reduction in fetal bone porosity was also observed. Effects on these parameters were observed within 2 months of maternal treatment.
Placental and Breast Milk Passage
Intravenous administration of tenofovir to pregnant cynomolgus monkeys resulted in a fetal/maternal concentration of 17%, demonstrating that tenofovir crosses the placenta.1
Human Studies in Pregnancy
In a retrospective population pharmacokinetic study of 46 pregnant women and 156 non-pregnant women receiving combination regimens including tenofovir, pregnant women had a 39% higher apparent clearance of tenofovir compared with non-pregnant women, which decreased slightly but significantly with increasing age.2 In a P1026s study of 19 pregnant women receiving tenofovir-based combination therapy at 30 to 36 weeks’ gestation and 6 to 12 weeks postpartum, the percentage of women with tenofovir AUC exceeding the target of 2 μg*hour/mL (the 10th percentile in non-pregnant adults) was lower in the third trimester (74%, 14 of 19 women) than postpartum (86%, 12 of 14 women) (P = 0.02); however, trough levels were similar in the two groups.3 In another study of 34 women receiving tenofovir plus emtricitabine in the third trimester and postpartum, tenofovir AUC, peak, and trough were all about 25% lower in pregnant women compared to postpartum women, but these decreased exposures were not associated with virologic failure.4 Standard dosing during pregnancy continues to be recommended.
Placental and Breast Milk Passage
In studies of pregnant women on chronic tenofovir, the cord-to-maternal-blood ratio ranged from 0.60 to 1.03, indicating high placental transfer.3-6 In studies of pregnant women receiving single-dose tenofovir (with and without emtricitabine) in labor, the drugs were well tolerated and the median tenofovir cord-to-maternal-blood ratio at delivery ranged from 0.55 to 0.73.7,8 Intracellular tenofovir concentrations were detected in the peripheral blood mononuclear cells from cord blood in all infants after a single maternal dose of 600 mg tenofovir with 400 mg emtricitabine, but intracellular tenofovir diphosphate was detectable in only 2 (5.5%) of 36 infants.9
Sixteen breast milk samples were obtained from five women who received 600 mg tenofovir at the start of labor followed by 300 mg daily for 7 days. Tenofovir levels in breast milk ranged from 5.8 to 16.3 ng/mL, resulting in nursing infants ingesting an estimated daily amount of tenofovir that corresponds to 0.03% of the proposed oral dose of tenofovir for neonates.10 Because the form of tenofovir in breastmilk is expected to have lower bioavailability than tenofovir, these exposures are likely overestimates. No studies have measured tenofovir blood levels in infants breastfed by women taking tenofovir.
A retrospective analysis of 7,275 women (1,199 receiving tenofovir-based combination antiretroviral therapy) demonstrated a slight reduction in pregnancy rates, but the findings were limited by the observational nature of the data and additional studies are needed for confirmation.11
In a study of 431 pregnancies occurring during an HIV pre-exposure prophylaxis trial in which HIV-uninfected women were randomized to placebo, tenofovir, or tenofovir plus emtricitabine, there was no difference in risk of congenital anomalies between the tenofovir-containing and placebo arms.12 No association was seen between maternal tenofovir and offspring birth defects in three large U.S. cohorts: PACT 219/219C (n = 2,202 with 214 first-trimester tenofovir exposures), P1025 (n = 1,112 with 138 first-trimester tenofovir exposures),13,14 and Pediatric HIV AIDS Cohort Study (n = 2,580 with 431 first-trimester tenofovir exposures).15 In the French Perinatal Cohort, no association was found between birth defects and tenofovir with a power of 70% for an odds ratio of 1.5 (n = 13,124 with 823 first-trimester tenofovir exposures).16 Finally, in the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to tenofovir in humans have been monitored to be able to detect at least a 1.5-fold increased risk of overall birth defects. No increase in birth defects has been observed with tenofovir. Among cases of first-trimester tenofovir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.2% (47 of 2,141 births; 95% confidence interval [CI], 1.6% to 2.9%), compared with a 2.7% total prevalence in the U.S. population, based on Centers for Disease Control and Prevention surveillance.17
Other Safety Data
Among 382 pregnancies occurring in 302 women in Uganda and Zimbabwe participating in the DART trial—approximately two-thirds of whom received tenofovir through more than 90% of their pregnancies—there were no differences noted in mortality, birth defects, or growth.18 In the Pediatric HIV/AIDS Cohort Study from the United States, 449 (21%) of the 2,029 HIV-exposed but uninfected infants had in utero exposure to tenofovir, and there was no difference at birth between those exposed to combination drug regimens with or without tenofovir in low birthweight, small-for-gestational-age, and newborn length-for-age and head circumference-for-age z-scores (LAZ and HCAZ, respectively). However, at age 1 year, infants exposed to combination regimens with tenofovir had a slight but significantly lower adjusted mean LAZ and HCAZ than those without tenofovir exposure (LAZ: -0.17 vs. -0.03, P = 0.04; HCAZ: 0.17 vs. 0.42, P = 0.02), but no difference in weight-for-age z-score (WAZ). There were no significant differences between those with and without tenofovir exposure at age 1 year when defining low LAZ or HCAZ as ≤1.5 z-score. Thus, these slightly lower mean LAZ and HCAZ scores are of uncertain significance.19 In a different U.S. study (P1025), maternal tenofovir use was similarly not associated with differences in body size parameters at birth; however, among the 1,496 infants followed for 6 months, tenofovir exposure after the first trimester, relative to no exposure, was associated with being underweight (WAZ <5%) at age 6 months (OR [95% CI]: 2.06 [1.01, 3.95], P = 0.04).20