Lamivudine is excreted into breast milk. In 10 women on lamivudine monotherapy (300 mg/day), the mean drug concentrations in maternal serum and breast milk were 0.55 and 1.22 mcg/mL, respectively (6). The infants were not allowed to breastfeed.

Reports on the use of lamivudine for HIV during human lactation are unlikely, however, because the antiviral agent is used in the treatment of HIV infection. HIV-1 is transmitted in milk, and in the United States, breastfeeding is not recommended (21).

The CDC states that breastfeeding is compatible in mothers with current hepatitis B infections. Good nipple care is recommended to help prevent cracking and bleeding (22).

Several studies from developing countries have reported the use of lamivudine in HIV patients while breastfeeding (23, 24, 25, 26, 27). In a 2005 study, 20 lactating HIV patients took lamivudine 150 mg twice daily, nevirapine, and either zidovudine or stavudine (23). Patients were either 2 or 5 months postpartum. Milk samples were obtained at a mean of 40 minutes after a dose. Median lamivudine levels were 678 ng/mL in maternal serum, 1828 ng/mL in milk, and 28 ng/mL in infant serum. The milk:plasma ratio was 3.34 (23). In a 2008 study, milk samples were taken at 0-24 weeks after delivery at 2-10 hours postdose from 67 mother-infant pairs (24). No difference was found in levels between the weeks of samples. Lamivudine levels were 508 ng/mL in maternal plasma and 1.213 ng/mL in milk. The milk:plasma ratio was 2.56 (24). In a 2014 study, samples were obtained at 6-24 weeks postpartum in 30 mother-infant pairs (25). Milk levels of lamivudine were 21% higher compared to maternal plasma (0.944 vs. 0.717 mcg/mL), but infant serum levels were 98% lower than milk levels (0.018 mcg/mL). The milk:plasma ratio was 1.21 (25).

A 2015 study evaluated lamivudine levels in 30 mothers coinfected with HIV and hepatitis B while breastfeeding (26). Lamivudine median levels were 1070 ng/mL in maternal serum and 684 ng/mL in milk. A 2014 study of 97 HIV-positive mothers taking the same medication combination as above during lactation compared infant developmental outcomes to 103 controls (27). No difference was observed in the clinical adaptive test (CAT) development quotient, clinical linguistic and auditory milestone scale (CLAMS) development quotient, and full-scale development quotient in infants at a mean age of 22-24 months.

The most common adverse reactions observed in adults are headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough (1). If a woman is receiving this drug while breastfeeding, her nursing infant should be monitored for these effects.

Lamivudine, an antiviral agent structurally similar to zalcitabine, is a nucleoside analogue reverse transcriptase inhibitor. It is indicated for the treatment of chronic hepatitis B virus infection associated with evidence of hepatitis B viral replication and active liver inflammation (2,3). In higher doses, it is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection (3). It is <35% bound to plasma proteins and has an elimination half-life of about 5-7 hours (3).

Animal Data: No teratogenic effects were observed in rats administered lamivudine up to approximately 35 times, respectively, the usual human adult dose. Early embryo lethality was observed in rabbits at doses close to those used in humans and above. This effect was not observed in rats given 35 times the usual human dose (2).

Adverse effects on neurobehavior development in mice offspring resulting from a combination of lamivudine and zidovudine were described in a 2001 study (4). Pregnant mice received both drugs from day 10 of gestation to delivery. The effects on somatic and sensorimotor development were minor but more marked in exposed offspring than when either drug was given alone (2). Both developmental endpoints were delayed with respect to control animals. Further, alterations of social behavior were observed in both sexes of exposed offspring (4).

It was not carcinogenic in mice and rats. Multiple assays for mutagenicity were negative. It did not impair fertility in male and female rats (3).

Placental Transfer: The low molecular weight (about 229) of lamivudine suggests that it will cross the placenta. A study published in 1997 described the human placental transfer of lamivudine using an ex vivo single cotyledon perfusion system (5). Lamivudine crossed the placenta to the fetal side by simple diffusion. Transfer did not appear to be affected by the presence of zidovudine. Confirming this, a 1998 study found that combination therapy with zidovudine did not affect the pharmacokinetics of lamivudine (6). Lamivudine freely crossed the placenta when given near term with nearly equivalent drug levels in the mother, cord blood, and newborn.

Human Data: The Antiretroviral Pregnancy Registry reported, for the period January 1989 through January 2019, prospective data (reported before the outcomes were known) involving 10,952 pregnancies with 1st trimester exposure to one or more antiretroviral agents (7).There were 13,157 outcomes exposed to lamivudine (5694 in the 1st trimester, 5604 in the 2nd trimester, and 1815 in the 3rd trimester as the earliest exposure) in combination with other antiretroviral agents. There were 61 cases with birth defects (8 with periconception, 1 later 1st trimester, and 14 2nd/3rd trimester exposures). When comparing live births with defects after 1st trimester exposure, lamivudine had a 3.1% risk for malformations (161/5209) (7). Health care professionals are encouraged to register patients exposed to lamivudine during pregnancy in the Antiviral Pregnancy Registry by calling the toll-free number (800-258-4263). (See required statement below.)

Required statement: “In reviewing all reported defects from the prospective registry, informed by clinical studies and retrospective reports of antiretroviral exposure, the Registry finds no significant increases in frequency of birth defects with 1st trimester exposures compared to exposures starting later in pregnancy and no pattern to suggest a common cause. While the Registry population exposed and monitored to date is not sufficient to detect an increase in the risk of relatively rare defects, these findings should provide some assurance when counseling patients. However, potential limitations of registries such as this should be recognized. The Registry is ongoing. Because of the data from an observational study in Botswana, the Registry continues to closely monitor cases of neural tube defects with periconception exposures to dolutegravir and other integrase inhibitors (see page 13). Given the use of new therapies about which data are still insufficient, health care providers are strongly encouraged to report eligible patients to the Registry at SM_APR@APRegistry.com via the data forms available at www.APRegistry.com (7).”

A study published in 1999 evaluated the safety, efficacy, and perinatal transmission rates of HIV in 30 pregnant women receiving various combinations of antiretroviral agents (8). Many of the women were substance abusers. Lamivudine was taken by 29 women in various combinations that included zidovudine, nelfinavir, indinavir, stavudine, nevirapine, and saquinavir. Antiretroviral therapy was initiated at a median of 14 weeks (range preconception to 32 weeks). In spite of previous histories of extensive antiretroviral experience and of vertical transmission of HIV, combination therapy was effective in treating maternal disease and in preventing transmission to the current newborns. The outcomes of the pregnancies included one stillbirth, one case of microcephaly, and five infants with birth weights <2500 g, two of whom were premature (8).

In an unusual case, a woman was exposed to HIV through self-insemination with fresh semen obtained from a man with a high HIV ribonucleic acid viral load (>750,000 copies/mL plasma) (9). Ten days later, she was started on a prophylactic regimen of lamivudine (300 mg/day), zidovudine (600 mg/day), and indinavir (2400 mg/day). Pregnancy was confirmed 14 days after insemination. The indinavir dose was reduced to 1800 mg/day, 4 weeks after the start of therapy because of the development of renal calculi. All antiretroviral therapy was stopped after 9 weeks because of negative tests for HIV. She gave birth at 40 weeks to a healthy 3490-g male infant, without evidence of HIV disease, who was developing normally at 2 years of age (9).

Several reports have described the apparent safe use of lamivudine, usually in combination with other agents, during human pregnancy (10, 11, 12, 13). Occasional mild adverse effects were observed in the newborns (e.g., anemia) but no birth defects attributable to drug therapy. In one report, lamivudine concentrations in the newborn were similar to those in the mother (12).

A 1999 report from France described the possible association of zidovudine and lamivudine (NRTIs) use in pregnancy with mitochondrial dysfunction in the offspring (14). Mitochondrial disease is relatively rare in France (estimated prevalence 1 in 5000-20,000 children). From an ongoing epidemiological survey of 1754 mother-child pairs exposed to zidovudine and other agents during pregnancy, however, 8 children with possible mitochondrial dysfunction were identified. None of the eight infants was infected with HIV, but all received prophylaxis for up to 6 weeks after birth with the same antiretroviral regimen as given during pregnancy. Four of the cases were exposed to zidovudine alone and four to a combination of zidovudine and lamivudine. Two from the combination group died at about 1 year of age. All eight cases had abnormally low respiratory chain enzyme activities. The authors concluded that their results supported the hypothesis of a causative association between mitochondrial respiratory-chain dysfunction and NRTIs. Moreover, the toxicity may have been potentiated by combination of these agents (14).

In a paper following the above study, investigators noted that NRTIs inhibit DNA polymerase γ, the enzyme responsible for mitochondrial DNA replication (15). They then hypothesized that this inhibition would induce depletion of mitochondrial DNA and mitochondrial DNA-encoded mitochondrial enzymes, thus resulting in mitochondrial dysfunction. Moreover, they stated that support for their hypothesis was suggested by the closeness of the clinical manifestations of inherited mitochondrial diseases with the adverse effects attributed to NRTIs. These adverse effects included polyneuropathy, myopathy, cardiomyopathy, pancreatitis, bone marrow suppression, and lactic acidosis. They also postulated this mechanism was involved in the development of a lipodystrophy syndrome of peripheral fat wasting and central adiposity, a condition that has been thought to be related to protease inhibitors (15).

A commentary on the above two studies concluded that the evidence for NRTI-induced mitochondrial dysfunction was equivocal (1). First, the clinical presentations in the infants were varied and not suggestive of a single cause; indeed, three of infants were symptom-free and one had Leigh's syndrome, a classic mitochondrial disease. Second, the clinical features, in some cases, were not suggestive of mitochondrial dysfunction. Although three had neurological symptoms, none had raised levels of lactate in the cerebrospinal fluid. Moreover, histological or histochemical features of mitochondrial disease were found in only two cases. Finally, low mitochondrial DNA, which would have been direct evidence of NRTI toxicity, was not found in the three cases in which it was measured (1).

A case of combined transient mitochondrial and peroxisomal β-oxidation dysfunction after exposure to NRTIs (lamivudine and zidovudine) combined with protease inhibitors (ritonavir and saquinavir) throughout gestation was reported in 2000 (16). A male infant was delivered at 38 weeks. He received postnatal prophylaxis with lamivudine and zidovudine for 4 weeks until the agents were discontinued because of anemia. Other adverse effects that were observed in the infant (age at onset) were hypocalcemia (shortly after birth), group B streptococcal sepsis, ventricular extrasystoles, prolonged metabolic acidosis, and lactic acidemia (8 weeks), a mild elevation of long chain fatty acids (9 weeks), and neutropenia (3 months). The metabolic acidosis required treatment until 7 months of age, whereas the elevated plasma lactate resolved over 4 weeks. Cerebrospinal fluid lactate was not determined nor was a muscle biopsy conducted. Both the neutropenia and the cardiac dysfunction had resolved by 1 year of age. The elevated plasma fatty acid level was confirmed in cultured fibroblasts, but other peroxisomal functions (plasmalogen biosynthesis and catalase staining) were normal. Although mitochondrial dysfunction has been linked to NRTIs, the authors were unable to identify the cause of the combined abnormalities in the infant. The child was reported to be healthy and developing normally at 26 months of age (16).

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 (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 (17).

In 2019, the updated U.S. Department of Health and Human Services AIDS Info guidelines for the use of antiretroviral agents in during pregnancy recommend that patients continue their regimen during pregnancy, but therapy must be individualized (18). See the guideline for the most update information on continuing, initiating, or switching regimens during pregnancy. If indicated, lamivudine should not be withheld in pregnancy since the expected benefit to the HIV-positive mother outweighs the unknown risk to the fetus. 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 if the HIV RNA is known or suspected to be >1000 copies/mL and may be considered if the HIV RNA is 50-999 copies/mL (19). The guidelines note that liver transaminases markedly increased in late pregnancy in a case report (HIV) (20).