Animal studies of the components of this drug have failed to reveal evidence of adverse developmental outcomes; exposures were either not maternally toxic (rabbits) or greater than (rats and mice) those in humans at recommended human dose (RHD). For bictegravir, no embryofetal toxicity observed in rats and rabbits at exposures up to about 36 (rats) and 0.6 (rabbits) times the exposure in humans at RHD; spontaneous abortion, increased clinical signs (fecal changes, thin body, cold-to-touch), and decreased body weight observed at maternotoxic dose in rabbits (about 1.4 times higher than human exposure at RHD). For emtricitabine, no significant embryofetal toxicity observed in mice at exposures about 60 times higher and rabbits at about 108 times higher than human exposures at RHD. For tenofovir alafenamide, no adverse embryofetal effects observed in rats at exposures about 2 times higher and rabbits at about 78 times higher than human exposures at RHD. There are no or limited data (less than 300 pregnancy outcomes) from use of bictegravir or tenofovir alafenamide in pregnant women. Data on pregnant women (more than 1000 pregnancy outcomes) showed no malformations, fetotoxicity, or neonatal toxicity with emtricitabine; available data showed no difference in the overall risk of major birth defects for emtricitabine compared with the background rate in the US reference population. There are no controlled data in human pregnancy with this combination drug.

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

Data from an observational study in Botswana showed that dolutegravir (another integrase inhibitor) was associated with increased risk of neural tube defects when administered at time of conception and in early pregnancy. Data available from other sources (including the APR, clinical trials, and postmarketing data) are insufficient to address this risk with bictegravir.

The APR has received an insufficient number of reports to adequately assess the risk of major birth defects associated with bictegravir exposure. The APR has received prospective reports of 3 birth defects among 100 (3%) first trimester exposures to bictegravir-containing regimens resulting in live births; no birth defects were reported among exposures during the second/third trimester.

The APR has received prospective reports of over 5400 exposures to emtricitabine-containing regimens (over 3900 exposed in the first trimester; over 1500 exposed in the second/third trimester) resulting in live births; available APR data show no statistically significant difference in overall risk of major birth defects for emtricitabine compared with the background rate for major birth defects of 2.7% in the US reference population. For emtricitabine, 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 emtricitabine was 2.6% and 2.7%, respectively.

The APR has received prospective reports of over 650 exposures to tenofovir alafenamide-containing regimens (over 525 exposed in the first trimester; over 125 exposed in the second/third trimester) resulting in live births; available APR data show no statistically significant difference in overall risk of major birth defects for tenofovir alafenamide compared with the background rate for major birth defects of 2.7% in the US reference population. For tenofovir alafenamide, enough first-trimester exposures have been monitored to detect at least a 2-fold increase in 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 tenofovir alafenamide was 4.2% and 3%, respectively.

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 inform a drug-related risk.

Comments:
-A pregnancy exposure registry is available.
-Dolutegravir (another integrase inhibitor) has been associated with neural tube defects; insufficient data are available to assess the risk of neural tube defects with bictegravir.
-The benefit-risk of using this drug should be discussed with patients of childbearing potential, especially if pregnancy is planned.

See references

Breastfeeding is not recommended during use of this drug.

Excreted into human milk: Yes (emtricitabine); Unknown (bictegravir, tenofovir alafenamide)
Excreted into animal milk: Yes (bictegravir); Unknown (tenofovir alafenamide)

Comments:
-Tenofovir is present in human breast milk after administration of tenofovir disoproxil fumarate (DF).
-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.

BICTEGRAVIR:
No published data available regarding use during breastfeeding; an alternate agent may be preferred.

EMTRICITABINE:
Emtricitabine has been relatively well studied during breastfeeding; on occasion, it has been used to treat HIV-infected mothers who were breastfeeding. During long-term maternal use of this drug (200 mg/day), breastfed infants usually have undetectable blood levels.

Samples of breast milk obtained from 5 HIV-1-infected women show that emtricitabine is secreted in human milk. Average peak and trough drug levels in breast milk were 679 and 177 mcg/L, respectively. According to author estimation, an exclusively breastfed infant would receive about 2% of the proposed emtricitabine dose for infants and achieve serum levels that may lead to emergence of viral resistance to emtricitabine. Breastfeeding infants whose mothers are treated with emtricitabine may be at risk for developing viral resistance to emtricitabine; other emtricitabine-related risks in such infants are unknown.

During ongoing therapy, emtricitabine was measured after a 300-mg dose to 6 nursing mothers with HIV infection. Peak breast milk level was 872 mcg/L (range: 696 to 1063 mcg/L) at about 3 hours; 1 breastfed infant had detectable emtricitabine serum level of 17.5 mcg/L.

Emtricitabine (200 mg once a day) was part of a combination regimen for HIV in 16 Nigerian women exclusively breastfeeding their infants (on demand). Expressed milk samples were collected before dosing and at 0.5, 1, 2, 4, 8, and 12 hours after dosing; peak breast milk level from dried breast milk spots was 843 mcg/L (interquartile range [IQR]: 702 to 1132 mcg/L) at 4 hours (IQR: 2 to 8 hours) after dosing. Infant blood samples were collected at 2 and 8 hours after maternal dosing; analysis of the dried blood spots showed only 3 samples with quantifiable (greater than 16.6 mcg/L) emtricitabine blood levels of 17.5, 18.8, and 19.4 mcg/L.

TENOFOVIR:
Bioavailability of tenofovir is very poor; it is available in 2 formulations, tenofovir DF (more bioavailable) and tenofovir alafenamide. Tenofovir DF releases tenofovir in the bloodstream while tenofovir alafenamide releases tenofovir after entering cells; both are metabolized intracellularly to tenofovir diphosphate (active metabolite). Although not known, the bioavailabilities of tenofovir and tenofovir diphosphate from breast milk are believed to be very low.

Most published experience is with tenofovir DF in HIV therapy and prophylaxis; exposure of the breastfed infant to tenofovir is trivial in HIV-infected mothers. Some data suggest tenofovir alafenamide produces lower milk levels of tenofovir than tenofovir DF. Among HIV-infected mothers who have breastfed during tenofovir DF therapy, no infant side effects have occurred up to 2 years of age.

See references