Dolutegravir / lamivudine Pregnancy and Breastfeeding Warnings
Dolutegravir / lamivudine is also known as: Dovato
Medically reviewed by Drugs.com. Last updated on May 14, 2019.
Dolutegravir / lamivudine Pregnancy Warnings
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. 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 both components.
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.
In an ongoing observational study in Botswana, neural tube defects were detected in 4 infants born to 426 women who started a dolutegravir-containing regimen before pregnancy and who were still using it at time of conception (0.94%); in comparison, neural tube defect prevalence rates were 0.12% (14/11,300) and 0.09% (61/66,057) in the non-dolutegravir and HIV-uninfected arms, respectively. The 4 cases reported with dolutegravir included 1 case each of encephalocele, anencephaly, myelomeningocele, and iniencephaly. This study showed no neural tube defects in infants born to 116 women who started a dolutegravir-containing regimen in the first trimester; no neural tube defects were reported in infants born to mothers who started dolutegravir during pregnancy (n = 2812). More data expected from about 600 additional births among pregnant women using a dolutegravir-containing regimen from conception.
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. Encephalocele and iniencephaly (2 of the 4 birth defects reported with dolutegravir), although often called neural tube defects, may occur after neural tube closure, which may be past 6 weeks of gestation (but within the first trimester). Understanding of the reported types of neural tube defects associated with dolutegravir is limited and conception date may not be ascertained with precision. Females of reproductive potential should avoid using this drug at the time of conception through the first trimester due to potential risk of neural tube defects.
The Department of Health and Human Services Antiretroviral Guidelines Panels provide the following interim recommendations regarding use of dolutegravir in adults and adolescents with HIV who are pregnant or of reproductive potential:
-Females not known to be pregnant should have a negative pregnancy test before starting dolutegravir.
-Females currently using a dolutegravir-containing regimen or who wish to be started on dolutegravir should be apprised of the potential risk of neural tube defects when dolutegravir is used near time of conception; neural tube defects occur within the first 28 days after conception or 6 weeks from the last menstrual period.
-Within 8 weeks from last menstrual period, pregnant patients using dolutegravir should consult healthcare providers regarding the risks and benefits of their current regimens; if good alternative options are available, then patients should be switched to a regimen without dolutegravir.
-Pregnant patients at least 8 weeks from last menstrual period may start or continue dolutegravir-containing regimens; stopping such regimens is unlikely to provide any benefits after neural tube formation, and drug changes during pregnancy could increase the risk of viremia and transmission of HIV to the infant.
Current guidelines should be consulted for additional information.
To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral therapy, an Antiretroviral Pregnancy Registry (APR) has been established. Healthcare providers are encouraged to prospectively register patients. For additional information: apregistry.com
The APR has received prospective reports of over 300 exposures to dolutegravir-containing regimens (over 200 exposed in the first trimester; over 100 exposed in the second/third trimester) resulting in live births. Enough first-trimester exposures have been monitored to detect at least a 2-fold increased risk of overall birth defects; no such increases detected. Neural tube defects have not been seen with periconception dolutegravir exposures reported to date. The prevalence of birth defects with first trimester and second/third trimester exposures to dolutegravir was 3.5% and 2.9%, respectively.
The APR has received prospective reports of over 12,300 exposures to lamivudine-containing regimens (over 5000 exposed in the first trimester; over 7300 exposed in the second/third trimester) resulting in live births; there was no difference between lamivudine and overall birth defects 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 increased 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 with first trimester and second/third trimester exposures was 3% and 2.9%, respectively.
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.
Use should be avoided at time of conception through the first trimester of pregnancy; this drug should be used during the second and third trimesters of pregnancy only if the benefit outweighs the risk to the fetus.
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; possible increased risk of neural tube defects when dolutegravir is used at time of conception (compared to non-dolutegravir-containing regimens).
-A pregnancy exposure registry is available.
-If patient plans to become pregnant or if pregnancy is confirmed while using this drug during the first trimester, the patient should be switched to an alternative regimen, if possible.
-Pregnant patients should be apprised of the potential harm to the embryo exposed to this drug from time of conception through the first trimester of pregnancy.
-Females of Reproductive Potential: Pregnancy testing should be performed before starting this drug; patients should be advised to consistently use effective contraception while using this drug.
Dolutegravir / lamivudine Breastfeeding Warnings
Breastfeeding is not recommended during use of this drug. If replacement feeding is not an option, WHO guidelines recommend a triple-drug regimen for HIV-infected women who are nursing; this drug combination is not included in recommended regimens.
Excreted into human milk: Yes
-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 a combination drug (containing dolutegravir 50 mg, lamivudine 300 mg, abacavir 600 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.
Limited published data available regarding use during breastfeeding.
An HIV-infected mother used a combination drug (containing dolutegravir 50 mg, lamivudine 300 mg, abacavir 600 mg) once a day. Her breast milk dolutegravir levels over 10 months averaged about 10 mg/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 10 mg/L; as supplemental food was introduced, plasma levels declined to about 0.3 mg/L at 35 weeks and to zero with no nursing after about 50 weeks postpartum.
Milk samples (2 each) were donated by 2 HIV-infected women using dolutegravir (dose not provided but presumed 50 mg/day) plus 2 unspecified nonnucleoside reverse transcriptase inhibitors; both women breastfed their infants (extent not provided but presumed exclusively). At 2 weeks postpartum, steady-state breast milk dolutegravir levels in 1 woman were 154.2 and 40.9 mcg/L at 4 and 24 hours after dosing, respectively, while plasma levels in her infant were 67.8 and 75.5 mcg/L at 4 and 24 hours after maternal dosing, respectively; 2 days after stopping the drug, breast milk levels were undetectable (less than 10 mcg/L), maternal plasma level was 103.8 mcg/L, and infant plasma level was 58.6 mcg/L. Steady-state breast milk dolutegravir levels in the other woman were 116.3 and 17.7 mcg/L at 3 and 24 hours after dosing, respectively, while plasma level in her infant was 16.3 mcg/L at 24 hours after maternal dosing; 9 days after stopping the drug, breast milk levels were undetectable (less than 10 mcg/L).
In a study that randomized nursing mothers to anti-HIV regimens containing either dolutegravir (n = 29) or efavirenz (n = 31), the regimens were reportedly well tolerated by the infants and no difference in infant side effects were observed between the 2 regimens.
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.
References for pregnancy information
- DHHS AIDSinfo "Recommendations regarding the use of dolutegravir in adults and adolescents with HIV who are pregnant or of child-bearing potential. Available from: URL: https://aidsinfo.nih.gov/news/2109/recommendations-regarding-the-use-of-dolutegravir-in-adults-and-ad" ([2018, May 30]):
- "Product Information. Dovato (dolutegravir-lamivudine)." ViiV Healthcare, Research Triangle Park, NC.
- Panel on treatment of pregnant women with HIV infection and prevention of perinatal transmission "Recommendations for the use of antiretroviral drugs in pregnant women with HIV infection and interventions to reduce perinatal HIV transmission in the United States. Available from: URL: https://aidsinfo.nih.gov/contentfiles/lvguidelines/perinatalgl.pdf." ([2018, Dec 7]):
References for breastfeeding information
- "Product Information. Dovato (dolutegravir-lamivudine)." ViiV Healthcare, Research Triangle Park, NC.
- "Infant feeding and transmission of human immunodeficiency virus in the United States." Pediatrics 131 (2013): 391-6
- United States National Library of Medicine "Toxnet. Toxicology Data Network. Available from: URL: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT." ([cited 2013 -]):
Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.