Animal studies with abacavir (high-dose) have revealed evidence of embryonic and fetal toxicity, including developmental toxicity, fetal anasarca, skeletal malformations, and increased incidence of stillbirth. Animal studies with dolutegravir have failed to reveal evidence of developmental toxicity or teratogenicity; systemic exposures to this component were less than (rabbits) and about 50 times (rats) the exposure in humans at the recommended human dose. Animal studies with lamivudine have failed to reveal evidence of teratogenicity; while early embryolethality was observed in rabbit studies (exposure levels similar to human levels), this effect was not seen in high-dose studies in rats. Moderate and large amounts of data for abacavir and lamivudine (more than 1200 and 5200 outcomes from first trimester exposures, respectively) indicate no malformative toxicity. There are no controlled data in human pregnancy with this combination drug.

Placental transfer to the fetus has been reported as high (cord blood/maternal delivery plasma drug ratio greater than 0.6) with each component.

In 2 clinical trials, maternal, neonatal, and umbilical cord serum lamivudine levels were generally comparable. Amniotic fluid samples collected after natural rupture of membranes from a subset of patients confirmed placental transfer in humans. Amniotic fluid levels of lamivudine were 3.9-fold (1.2- to 12.8-fold) greater than corresponding maternal serum levels, based on limited data at delivery.

To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral therapy, an Antiretroviral Pregnancy Registry (APR) has been established. Health care providers are encouraged to prospectively register patients. For additional information: apregistry.com

The APR has received prospective reports of over 2700 exposures to abacavir-containing regimens (over 1375 exposed in the first trimester; over 1325 exposed in the second/third trimester) resulting in live births; there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in the US reference population. Enough first trimester exposures have been monitored to detect at least a 1.5-fold increase in risk of overall birth defects and a 2-fold increase in risk of cardiovascular and genitourinary defects (the more common classes); no such increases detected. The prevalence of birth defects/live births with first trimester and second/third trimester exposures to abacavir was 3.2% and 3%, respectively.

The APR has received prospective reports of over 1025 exposure to dolutegravir-containing regimens (over 625 exposed in the first trimester; over 400 exposed in the second/third trimester) resulting in live births. There was 1 neural tube defect observed among 539 periconception dolutegravir exposures reported with pregnancy outcome. Enough first-trimester exposures have been monitored to detect at least a 2-fold increased risk of overall birth defects; no such increases detected. The prevalence of birth defects/live births with first trimester and second/third trimester exposures to dolutegravir was 3.3% and 5.1%, respectively; the background birth defect rate was 2.7% in the US reference population.

The APR has received prospective reports of over 12,950 exposures to lamivudine-containing regimens (over 5450 exposed in the first trimester; over 7500 exposed in the second/third trimester) resulting in live births; there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in the US reference population. Enough first trimester exposures have been monitored to detect at least a 1.5-fold increase in risk of overall birth defects and a 2-fold increase in risk of cardiovascular and genitourinary defects (the more common classes); no such increases detected. The prevalence of birth defects/live births with first trimester and second/third trimester exposures to lamivudine was 3.1% and 2.9%, respectively.

In a birth outcome surveillance study in Botswana, 7 cases of neural tube defects were reported out of 3591 deliveries (0.19%) to women taking dolutegravir-containing regimens at time of conception; in comparison, neural tube defect prevalence rates were 0.11% (21/19,361 deliveries) and 0.07% (87/119,630 deliveries) in the non-dolutegravir and HIV-uninfected arms, respectively. The 7 cases reported with dolutegravir included 2 cases of encephalocele, 1 case of anencephaly, 1 case of iniencephaly, and 3 cases of myelomeningocele. In the same study, no increased risk of neural tube defects was detected in women who started dolutegravir during pregnancy; 2 infants out of 4448 (0.04%) deliveries to women who started dolutegravir during pregnancy had a neural tube defect, compared with 5 infants out of 6748 (0.07%) deliveries to women who started non-dolutegravir-containing regimens during pregnancy. The reported risks of neural tube defects by treatment groups were based on interim analyses from the ongoing surveillance study in Botswana; it is unknown if baseline characteristics were balanced between the study treatment groups. The observed trends of association could change as data accumulate.

Most neural tube defects occur within the first 4 weeks of embryonic development after conception (about 6 weeks after last menstrual period). If pregnancy is confirmed in the first trimester while using this drug, the benefits and risks of continuing therapy versus switching to another antiretroviral regimen should be discussed with the patient; gestational age and the critical period of neural tube defect development should be considered.

Data analyzed to date from other sources (including the APR, clinical trials, and postmarketing data) are insufficient to definitively address the risk of neural tube defects with dolutegravir.

Data from the birth outcome surveillance study and postmarketing sources with more than 1000 pregnancy outcomes from second and third trimester exposure in pregnant women indicate no evidence of increased risk of adverse birth outcomes (e.g., fetotoxicity, neonatal toxicity).

According to the Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, dolutegravir is considered a preferred antiretroviral drug for use throughout pregnancy and for women who are trying to conceive. The risks and benefits of using dolutegravir should be discussed with the patient. Current guidelines should be consulted for additional information.

AU TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.

US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

This drug should be used during pregnancy only if the benefit outweighs the risk to the fetus.

AU TGA pregnancy category: B3
US FDA pregnancy category: Not assigned.

Risk summary: Insufficient data available on use of this drug in pregnant women to definitively inform a drug-related risk; data from an ongoing birth outcome surveillance study identified an increased risk of neural tube defects when dolutegravir is used at time of conception.

Comments:
-A pregnancy exposure registry is available.
-Defects related to neural tube closure occur from conception through the first 6 weeks of gestation; embryos exposed to dolutegravir from time of conception through the first 6 weeks of gestation may be at risk.
-Pregnancy testing is recommended in patients of childbearing potential before starting this drug.
-Patients of childbearing potential who are using this drug should be counseled on the consistent use of effective contraception.
-Patients of childbearing potential (including those actively trying to become pregnant) should be apprised of the potential risk of neural tube defects with use of this drug; the risks and benefits of this drug should be assessed and should be discussed with the patient to decide if an alternative regimen should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester.
---A benefit-risk assessment should consider factors such as feasibility of switching to another antiretroviral regimen, tolerability, ability to maintain viral suppression, and risk of HIV-1 transmission to the infant against the risk of neural tube defects associated with in utero exposure to this drug during critical periods of fetal development.
-According to some authorities: Patients of childbearing potential should be advised about the potential risk of neural tube defects with dolutegravir, including consideration of effective contraceptive measures; if pregnancy is planned, the risks and benefits of continuing this drug should be discussed with the patient.

See references

Breastfeeding is not recommended during use of this drug.

Excreted into human milk: Yes

Comments:
-The effects in the nursing infant are unknown; potential for HIV-infected infants developing viral resistance and breastfed infants developing side effects similar to those in adults
-The US CDC, American Academy of Pediatrics, and manufacturer advise HIV-infected women not to breastfeed to avoid postnatal transmission of HIV to a child who may not yet be infected.
-Local guidelines should be consulted if replacement feeding is not an option.

An HIV-infected mother used this combination drug (containing abacavir 600 mg, dolutegravir 50 mg, lamivudine 300 mg) once a day. She exclusively breastfed her infant for about 30 weeks and then partially breastfed for about 20 weeks; the infant showed no obvious side effects.

ABACAVIR:
Abacavir appears in breast milk in small quantities; very little information is available on the safety of its use during breastfeeding.

In a study after abacavir 300 mg orally twice a day (as abacavir/lamivudine/zidovudine), the breast milk to maternal plasma ratio was 0.9.

Breast milk from 15 women and blood samples from 9 of their partially or exclusively breastfed infants were collected about 1 month postpartum; the mothers were using abacavir 300 mg twice a day for 53 to 182 days (with lamivudine and zidovudine). Breast milk was obtained right before a dose; whole breast milk abacavir levels averaged 0.057 mg/L (about 85% of maternal blood levels). Infant blood was obtained 11 to 17 hours after the last maternal dose and about 1 hour (range: 6 minutes to 35 hours) after the last breastfeeding; plasma abacavir levels were undetectable (less than 16 mcg/L) in 8 of 9 infants.

DOLUTEGRAVIR:
Dolutegravir is detectable in maternal milk in low amounts. Elimination by neonates appears prolonged and the drug has been detected in infant plasma during breastfeeding. Dolutegravir has been used safely in HIV-infected mothers during breastfeeding.

An HIV-infected mother used this combination drug once a day. Her breast milk dolutegravir levels (measured periodically over 10 months) averaged about 100 mcg/L at 11 hours after dosing; authors estimated an infant dose of 15 mcg/kg/day. During the period of exclusive nursing (up to about 30 weeks postpartum), her infant had a plasma dolutegravir level of 100 mcg/L; as supplemental food was introduced, plasma levels declined to about 30 mcg/L at 35 weeks and to zero with no nursing after about 50 weeks postpartum.

After taking dolutegravir (dose not provided but presumed 50 mg/day) plus 2 unspecified nonnucleoside reverse transcriptase inhibitors, 2 HIV-infected women donated 2 milk samples each; both women breastfed their infants (extent not provided, but presumed exclusively). At 2 weeks postpartum, steady-state breast milk dolutegravir levels were 154.2 and 40.9 mcg/L at 4 and 24 hours after dosing, respectively, in 1 woman; the plasma levels in 1 infant were 67.8 and 75.5 mcg/L at 4 and 24 hours after maternal dosing, respectively. In the other woman, steady-state breast milk dolutegravir levels were 116.3 and 17.7 mcg/L at 3 and 24 hours after dosing, respectively; the plasma level in the other infant was 16.3 mcg/L at 24 hours after maternal dosing. At 2 and 9 days, respectively, after stopping the drug, breast milk levels were undetectable (less than 10 mcg/L); 2 days after the drug was stopped, 1 infant had a plasma level of 58.6 mcg/L when the maternal plasma level was 103.8 mcg/L.

Of 28 pregnant HIV-infected women randomized to receive an antiretroviral regimen containing dolutegravir (50 mg orally once a day), 17 women underwent extensive postpartum sampling of breast milk and maternal serum, and their breastfed infants had serum levels obtained, at a median of 10 days postpartum; median peak level of dolutegravir in milk was 84.6 mcg/L with a minimum of 22.3 mcg/L while the median peak serum drug level in the infants was 66.7 mcg/L with a minimum of 60.9 mcg/L. Only 1 woman had a milk drug level of 14 mcg/L at 48 hours; all other milk samples were negative for dolutegravir at 48, 72, and 96 hours after discontinuation. After drug discontinuation, levels were detectable in 100%, 80%, and 80% of breastfed infants at 48, 72, and 96 hours after the final maternal dose, respectively; the ratio of paired maternal and infant serum levels was 0.03 and 0.08 at the peak and trough, respectively. Data from this study were used to create a pharmacokinetic model of dolutegravir into milk. Using the model, the level of dolutegravir in breast milk over 24 hours averaged 0.05 mg/L (range: 0.029 to 0.1 mg/L), corresponding to an absolute infant dose of 2.2 mcg/kg/day; this corresponded to a weight-adjusted infant dose of 0.27% of the maternal dose. In 21 of the breastfed infants, 65 serum levels were measured postpartum. In the first 24 hours and over the 96 hours after the last maternal dose, infant serum levels were 4.9% and 11% of maternal plasma level, respectively; the increase indicates slower drug elimination in infants compared to their mothers.

LAMIVUDINE:
Lamivudine has been well studied in HIV-infected breastfeeding patients; it appears to be well tolerated by their nursing infants.

Based on more than 200 mother/child pairs treated for HIV, serum lamivudine levels in breastfed infants of mothers treated for HIV are very low (less than 4% of maternal serum levels) and gradually decrease to undetectable levels by 24 weeks of age.

In studies after lamivudine 150 mg orally twice a day (with zidovudine or as lamivudine-zidovudine or abacavir/lamivudine/zidovudine), the breast milk to maternal plasma ratio ranged between 0.6 and 3.3. Lamivudine infant serum levels ranged between 18 and 28 ng/mL and were undetectable (less than 7 ng/mL) in 1 study.

Milk samples were collected daily before breastfeeding from 2 groups of women using lamivudine, 1 group on monotherapy and the other on combination therapy. In the group using lamivudine 300 mg twice a day (n = 10), milk level averaged 1.2 mg/L (range: less than 0.5 to 6.1 mg/L); in the group using lamivudine 150 mg twice a day plus zidovudine (n=10), milk lamivudine level averaged 0.9 mg/L (range: less than 0.5 to 8.2 mg/L).

Milk samples from 20 women taking lamivudine 150 mg orally twice a day as part of combination antiretroviral therapy (cART) and serum levels from their infants were obtained at 2 or 5 months postpartum, about 4 hours (range: 1 to 8.5 hours) after the last dose. The lamivudine level in breast milk averaged 1.8 mg/L and the infant serum lamivudine level averaged 28 mcg/L (range: less than 14 to 53 mcg/L).

Blood and milk samples were obtained from 40 women on postpartum prophylaxis (with lamivudine, nevirapine, and [zidovudine or stavudine]; doses not provided) once during the first 3 days postpartum and once at 7 days postpartum. Samples were collected after a dose at 5.3 hours (range: 0 to 99 hours) for the first sample and 6 hours (range: 4.3 to 20 hours) for the second sample. Breast milk lamivudine levels averaged 0.4 mg/L (n=9) for the first sample and 0.4 mg/L (n=30) for the second sample; these levels were 2.9 to 3.3 times the coinciding maternal serum levels.

Mothers using lamivudine (dose not provided) as part of cART provided 47 breast milk and serum samples at 6, 12, and 24 weeks postpartum. The breast milk lamivudine levels at about 14 hours after the last dose averaged 510 (17 samples), 387 (17 samples), and 310 mcg/L (13 samples). Milk levels were about 2.6 times (interquartile range [IQR]: 1.1 to 3.5 times) the maternal plasma levels; lamivudine milk to plasma ratio was 2.96 in 49 patients in a related study (same authors). Infant serum lamivudine levels measured about 14 hours after the last maternal dose averaged 13, 10, and 5 mcg/L at 6 (17 samples), 12 (17 samples), and 24 (13 samples) weeks of age, respectively, which was 6% of the maternal serum level.

Serum and breast milk from 58 mothers taking lamivudine 150 mg twice a day (with nevirapine and zidovudine) and serum levels from their 58 infants were analyzed. Mothers started lamivudine at 34 to 36 weeks gestation and continued until 6 months postpartum; they were instructed to exclusively breastfeed for 5.5 months. Breast milk and serum samples were collected within 24 hours after delivery and at 2, 6, 14, and 24 weeks postpartum; breast milk was collected at various times after the prior dose. The breast milk lamivudine level averaged 1214 mcg/L (all visits). The infant dried blood spot lamivudine levels averaged 67 mcg/L at delivery, 32 mcg/L at week 2, 24 mcg/L at week 6, 20 mcg/L at week 14, and were not measurable (less than 16 mcg/L) at week 24 postpartum. According to author estimation, a fully breastfed infant would receive 182 mcg/kg/day of lamivudine.

A total of 206 milk samples were obtained at birth, 1, 3, and/or 6 months postpartum from 66 mothers using lamivudine 150 mg twice a day as part of cART and 64 blood samples from their breastfed infants were analyzed at 1, 3, and/or 6 months postpartum; samples were collected at about 4.5 hours (range: 3.5 to 6 hours) after the prior maternal dose and about 30 minutes (range: 20 to 60 minutes) after nursing. The breast milk lamivudine level averaged 446 mcg/L (range: 269 to 683 mcg/L). The infant plasma lamivudine level averaged 18 mcg/L (range: 7 to 35 mcg/L), which averaged 2% (range: 0 to 4%) of the maternal serum level. In a continuation of this study, 65 breast milk samples (after the same dose at 1, 3, and 6 months postpartum) and 22 blood samples (from 17 breastfed infants [extent not provided] between 1 and 6 months) were collected for lamivudine analysis; lamivudine levels averaged 684 mcg/L in breast milk and 29.2 mcg/L in infant blood. Not clear if some of the same patients from the first study were in the latter study.

Samples of breast milk were obtained right before a dose at about 1 month postpartum from 15 women using lamivudine 150 mg twice a day for 53 to 182 days as part of cART. Whole breast milk levels contained about 0.14 mg/L of lamivudine (about 74% of maternal blood levels). Infant blood was obtained from 24 infants partially or exclusively breastfed by their mothers at about 1 month postpartum, 11 to 18 hours after the last maternal dose and about 1 hour (range: 6 minutes to 35 hours) after the last breastfeeding. Plasma lamivudine levels were undetectable (less than 7 mcg/L) in all infant samples.

Mothers (n=30) starting lamivudine 150 mg orally twice a day (with zidovudine and lopinavir-ritonavir) at delivery provided plasma and breast milk samples at 6, 12, or 24 weeks postpartum (n=10 each time). Maternal plasma and breast milk samples were collected about 14.9 hours after the prior evening dose, before the morning dose, and 2, 4, and 6 hours after the dose. Infant plasma samples were collected before the first maternal dose and at 2, 4, and 6 hours after the maternal dose. Breastfeeding was not restricted during the study. Detectable lamivudine levels (at least 10 mcg/L) were found in 107 of 121 breast milk samples and 107 of 115 infant plasma samples; breast milk level averaged 0.94 mg/L over the 6 hours and infant plasma level averaged 180 mcg/L.

Lamivudine (dose not provided but presumed 300 mg/day), tenofovir, and efavirenz were administered daily (between 6 and 8 p.m.) for prevention of mother-to-child HIV transmission. At 1 month postpartum, milk samples were collected in the morning from 33 women; lamivudine level was 537 mcg/L (IQR: 369 to 768 mcg/L). At 12 months postpartum, milk samples were collected in the morning from 47 women; lamivudine level was 430 mcg/L (IQR: 266 to 531 mcg/L). Blood samples were obtained from 25 of their breastfed infants; the morning infant plasma levels of lamivudine at 6 and 12 months of age were 2.5 mcg/L (IQR: 2.5 to 7.6 mcg/L) and 0 mcg/L, respectively.

In 6 HIV-infected breastfeeding mothers using lamivudine 150 mg twice a day, a peak breast milk level of 994 mcg/L (range: 958 to 1274 mcg/L) was reached at 2 to 4 hours after dosing; 2 of their breastfed infants had detectable lamivudine serum levels (13.2 and 15.6 mcg/L).

Nigerian and Ugandan women (n=39) used lamivudine 150 mg twice a day (n=11) or 300 mg once a day (n=10 [morning]; n=18 [prior evening]) as part of combination HIV therapy. Expressed milk samples were collected before dosing and at 0.5, 1, 2, 4, and 8 hours after the morning dose (150 or 300 mg) or between 12 to 20 hours after the evening dose (300 mg). Using dried breast milk spots, peak breast milk level averaged 908 mcg/L (IQR: 772 to 1015 mcg/L) at about 6 hours (IQR: 4 to 6 hours) after dosing and 663 mcg/L (IQR: 445 to 890 mcg/L) at about 6 hours (IQR: 4 to 8 hours) after dosing in mothers using 150 mg twice a day and 300 mg once a day, respectively. Their exclusively breastfed infants were fed on demand and had blood samples collected at 2 and 8 hours after maternal dosing. Lamivudine was detectable (greater than 16.6 mcg/L) in dried blood spots of 14 of 39 infants (averaged 17.7 mcg/L [IQR: 16.3 to 22.7 mcg/L]); of these, levels were detectable in 7 of 10 infants whose mothers used 300 mg once a day in the morning, in 4 of 18 infants whose mothers had used their dose the prior evening, and in 3 of 11 infants whose mothers used 150 mg twice a day.

At 3-hour intervals before cesarean section, 9 HIV-infected women received 3 doses of lamivudine 50 mg, lopinavir 200 mg, ritonavir 150 mg, zidovudine 300 mg. Breast milk samples were obtained at 25 hours postpartum (mean); milk level of lamivudine averaged 449 mcg/L (range: 143 to 1148 mcg/L) in the 8 women it was quantified.

Of 24 infants breastfed by HIV-infected mothers who developed HIV infection by 6 months of age, 6 infants had a mutation that may have been selected for by subtherapeutic levels of lamivudine in breast milk.

See references