(Last updated: August 6, 2015; last reviewed: August 6, 2015)
Lamivudine is classified as Food and Drug Administration Pregnancy Category C.
Lamivudine has weak mutagenic activity in one in vitro assay but no evidence of in vivo genotoxicity in rats at 35 to 45 times human exposure. Long-term animal carcinogenicity screening studies at 10 and 58 times human exposure have been negative in mice and rats, respectively.1
Lamivudine administered to rats at doses up to 4000 mg/kg/day, producing plasma levels 47 to 70 times those in humans, revealed no evidence of impaired fertility and no effect on the offspring’s survival, growth, and development up to the time of weaning.1
There is no evidence of lamivudine-induced teratogenicity at 35 times human plasma levels in rats and rabbits.
Early embryolethality was seen in rabbits at doses similar to human therapeutic exposure but not in rats at 35 times the human exposure level.1
Human Studies in Pregnancy
Pregnancy does not significantly affect lamivudine pharmacokinetic parameters, as reported in two separate studies.2,3 This was confirmed in a larger analysis of 114 pregnant women, 123 women in labor, and 47 non-pregnant women, in which all received standard once- or twice-daily lamivudine doses.4 Pregnant women had a 22% higher apparent clearance than non-pregnant and postpartum women, but this increase did not lead to sub-therapeutic exposure. The level of lamivudine exposure in pregnant women, although lower than exposure in non-pregnant and parturient women, was relatively close to data reported previously for non-pregnant adults.4 Thus, no dose adjustment in pregnancy is necessary.
Placental and Breast Milk Passage
Lamivudine readily crosses the placenta in humans, achieving comparable cord blood and maternal concentrations.3 In a study of 123 mother/infant pairs, the placental transfer expressed as fetal-to-maternal area under the curve (AUC) ratio was 0.86, and the lamivudine amniotic fluid accumulation, expressed as the amniotic fluid-to-fetal AUC ratio, was 2.9.4 Other studies have also noted accumulation of lamivudine in amniotic fluid due to urinary excretion of lamivudine by the fetus into amniotic fluid.2
Lamivudine is excreted into human breast milk. In a study in Kenya of 67 HIV-infected nursing mothers receiving a combination regimen of zidovudine, lamivudine, and nevirapine, the median breast milk lamivudine concentration was 1,214 ng/mL and the median ratio of lamivudine concentration in breast milk to that in plasma was 2.56.5 In infants who were exposed to lamivudine only via breast milk, median plasma lamivudine concentration was 23 ng/mL (IC50 of lamivudine against wild-type HIV = 0.6–21 ng/mL).
In a large French cohort, lamivudine exposure in the first trimester was associated with an increased risk of overall birth defects (adjusted odds ratio = 1.37, 95% CI 1.06-1.73) but there was no organ system or specific birth defect that predominated.6 However, in the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to lamivudine in humans have been monitored to detect at least a 1.5-fold increase in risk of overall birth defects and a 2-fold increase in the most commonly occurring birth defects, such as defects of the cardiovascular and genitourinary systems. No such increase in birth defects has been observed with lamivudine. Among cases of first-trimester lamivudine exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 3.1% (137 of 4,418 births; 95% CI, 2.6% to 3.7%) compared with a 2.7% total prevalence in the U.S. population, based on Centers for Disease Control and Prevention surveillance.7