Animal studies have failed to reveal evidence of embryofetal toxicity, reproductive toxicity, or teratogenicity. There are no controlled data in human pregnancy; however, emtricitabine-tenofovir DF has been evaluated in a limited number of women during pregnancy and postpartum. Available human data suggest emtricitabine-tenofovir DF does not increase risk of major birth defects overall compared to background rate; data in pregnant women (more than 1000 outcomes) showed no malformations, fetotoxicity, or neonatal toxicity with emtricitabine and tenofovir DF.

Placental transfer to the fetus has been reported as high (cord blood/maternal delivery plasma drug ratio greater than 0.6) with emtricitabine. In studies of pregnant women using emtricitabine, the cord blood-to-maternal plasma ratio ranged from 0.85 to 1.2.

Placental transfer to the fetus has been reported as low (cord blood/maternal delivery plasma drug ratio less than 0.3) with tenofovir alafenamide. In 43 of 44 cord blood samples tested, tenofovir alafenamide was below the assay limit of quantification (less than 3.9 ng/mL); maternal plasma tenofovir alafenamide at delivery was measurable in 4 of 45 paired samples.

Placental transfer to the fetus has been reported as high (cord blood/maternal delivery plasma drug ratio greater than 0.6) with tenofovir DF. In studies of pregnant women using chronic tenofovir DF, the cord blood-to-maternal plasma ratio ranged from 0.6 to 1.03.

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 5750 exposures to emtricitabine-containing regimens (over 4200 exposed in the first trimester; over 1550 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 2.7% and 2.6%, respectively.

The APR has received prospective reports of over 825 exposures to tenofovir alafenamide-containing regimens (over 675 exposed in the first trimester; over 150 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 3.5% and 3.3%, respectively.

The APR has received prospective reports of over 6625 exposures to tenofovir DF-containing regimens (over 4650 exposed in the first trimester; over 1975 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 DF compared with the background rate for major birth defects of 2.7% in the US reference population. For tenofovir DF, 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 tenofovir DF was 2.5% and 2.6%, 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.

Treatment of HIV-1 Infection: This drug should be used during pregnancy only if clearly needed and the benefit outweighs the risk to the fetus.

Preexposure Prophylaxis: If an uninfected patient becomes pregnant while using emtricitabine-tenofovir disoproxil, continued use should be carefully considered, taking into account the potential increased risk of HIV-1 infection during pregnancy.

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

Risk summary:
-Emtricitabine-tenofovir alafenamide: Insufficient data available on use of tenofovir alafenamide in pregnant women to inform a drug-related risk.
-Emtricitabine-tenofovir disoproxil fumarate (DF): Malformative risk with use of this product in pregnant women is unlikely.

Comments:
-A pregnancy exposure registry is available.

See references

EMTRICITABINE-TENOFOVIR DF:
Preexposure prophylaxis, using emtricitabine 200 mg-tenofovir DF 300 mg daily, was administered by directly observed therapy for 10 days to 50 women without HIV infection who were breastfeeding their infants. On days 7 and 10 of therapy, peak and trough milk samples were collected 1 to 2 hours after dosing and 23 to 24 hours after the previous dose, respectively; a single infant blood sample was collected after the mother's 7th dose. Median peak and trough milk emtricitabine levels were 212.5 and 183 mcg/L, respectively; these levels correspond to a daily dose of 27.5 to 31.5 mcg/kg (estimated), which is about 0.5% of the proposed therapeutic dose for infants. Median peak and trough milk tenofovir levels were 3.2 and 3.3 mcg/L, respectively; these levels correspond to a daily dose of 0.47 to 0.49 mcg/kg (estimated), which is less than 0.01% of the proposed therapeutic dose for infants. Of 49 infant blood samples collected, 47 had detectable emtricitabine levels (median plasma level: 13.2 mcg/L) and 46 had undetectable (less than 0.31 mcg/L) tenofovir levels. Emtricitabine plasma levels were 16.6 mcg/L in infants younger than 13 weeks and 10.5 mcg/L in infants at least 13 weeks of age; the 3 detectable tenofovir levels were 0.9, 0.9, and 17.4 mcg/L. Diarrhea lasting 2 to 3 days was reported in 2 of the 50 breastfed infants; no other side effects were reported.

EMTRICITABINE:
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 being treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabine-related risks in such infants are unknown.

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 (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.

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

TENOFOVIR DF:
Bioavailability of tenofovir is very poor; it is available as tenofovir DF (more bioavailable), which is metabolized intracellularly to tenofovir diphosphate (active metabolite). Although unknown, the bioavailabilities of tenofovir and tenofovir diphosphate from breast milk are believed to be very low.

HIV-uninfected nursing mothers using tenofovir as an agent for PrEP appears to present little risk to their breastfed infants and might prevent vertical HIV transmission by preventing maternal infection.

Samples of breast milk obtained from 5 HIV-1-infected mothers show that tenofovir is secreted in human milk. Average peak and trough tenofovir levels in breast milk were 14.1 and 6.8 mcg/L, respectively. According to author estimation, an exclusively breastfed infant would receive about 0.03% of the proposed tenofovir dose for infants and attain trivial infant serum levels. The impact of this exposure in infants breastfed by mothers treated with tenofovir DF is unknown.

In a multicenter study, a single 600 or 900 mg dose of tenofovir was administered to mothers during labor; samples of breast milk were collected at various times postpartum. In 75% of samples obtained from 25 mothers during the first 2 days postpartum, tenofovir was detected (greater than 2.5 mcg/L); levels ranged from 6.3 to 17.8 mcg/L. Only 1 of 21 milk samples had detectable tenofovir level (15.7 mcg/L) at 4 to 6 days postpartum.

Tenofovir (dose not provided; presumed 300 mg/day), lamivudine, 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; tenofovir level was 5 mcg/L (IQR: 0 to 6.1 mcg/L). At 12 months postpartum, milk samples were collected in the morning from 47 women; tenofovir level was 2.5 mcg/L (IQR: 0 to 5.5 mcg/L). Blood samples were obtained from 25 of their breastfed infants; the morning infant plasma level of tenofovir at 6 and 12 months of age was 24 mcg/L (IQR: 0 to 51.6 mcg/L) and 0 mcg/L, respectively.

Tenofovir 300 mg/day was administered to 6 HIV-infected breastfeeding mothers; it was measured after dosing during ongoing therapy. Peak breast milk tenofovir level of 5.9 mcg/L (range: 5.5 to 8 mcg/L) was reached at about 3 hours (range: 1 to 7 hours) after dosing; none of the breastfed infants had detectable tenofovir serum levels.

Nigerian and Ugandan women (n=48) used tenofovir DF 300 mg once a day (either in the morning or evening) as part of combination HIV therapy. Expressed milk samples were collected before dosing and several times during the 12 hours after the morning dose (n=30) or at 12, 16, and 20 hours after the prior evening dose (n=18). Using dried breast milk spots, peak breast milk level averaged 5.98 mcg/L (IQR: 0 to 8.05 mcg/L) at about 4 hours (IQR: 1 to 6 hours) after dosing. Their exclusively breastfed infants were fed on demand and had blood samples collected at 2 and 8 hours after maternal dosing; no infants had measurable (greater than 4.2 mcg/L) tenofovir blood level in dried blood spots.

Serum tenofovir levels were measured in 5 infants exclusively breastfed by 4 mothers using tenofovir 245 mg (presumably tenofovir DF 300 mg) daily; infant age averaged 1.8 months. In 4 infants, serum tenofovir was undetectable (less than 0.005 mg/L); in 1 infant, the serum tenofovir was 0.0055 mg/L. At 4 months of age, no adverse outcomes (on standard developmental parameters) were observed in 2 of the infants exclusively breastfed for 3 months.

In a study of women and their infants using antiretroviral therapy for HIV infection, mothers who used a tenofovir-containing regimen were compared to those who did not. The risk of infant death decreased by 57% in infants breastfed and exposed to tenofovir compared to infants who were not breastfed; no alterations in growth and development were observed in breastfed infants during 2 years of follow-up.

A study of 136 breastfed infants of mothers who used tenofovir, efavirenz, and lamivudine during pregnancy and postpartum measured bone markers at 1, 6, and 12 months of age; markers included bone-specific alkaline phosphatase and C-terminal telopeptide of type I collagen. Although tenofovir is known to affect bone density and bone mineral density in adults, no effects were seen on infants' bone markers in the study.

A prospective cohort study compared growth and development of infants of non-HIV-infected mothers and infants of HIV-infected mothers using tenofovir and efavirenz as part of combination HIV therapy; infants were followed up to 12 months of age. No differences in the groups were found in any growth parameters.

Treatment of HIV-1 Infection: Breastfeeding is not recommended during use of this drug. If replacement feeding is not an option, the WHO recommends a triple-drug regimen for HIV-infected women who are nursing; emtricitabine and tenofovir disoproxil fumarate (DF) are included in the first-choice regimen.

HIV-1 Preexposure Prophylaxis (PrEP): Benefit should outweigh risk.
-According to some authorities: Breastfeeding is not recommended during use of emtricitabine-tenofovir disoproxil.

Emtricitabine-Tenofovir Alafenamide:
-Excreted into human milk: Yes (emtricitabine); Unknown (tenofovir alafenamide)
-Excreted into animal milk: Unknown (tenofovir alafenamide)

Emtricitabine-Tenofovir Disoproxil:
-Excreted into human milk: Yes (emtricitabine, tenofovir)

Comments:
Treatment of HIV-1 Infection:
-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.

HIV-1 PrEP:
-Developmental and health benefits of breastfeeding should be considered as well as the HIV-uninfected mother's clinical need for this product.
-The effects in the nursing infant are unknown; potential side effects in the breastfed child due to this product or the risk of HIV-1 acquisition due to nonadherence and subsequent mother-to-child transmission should be considered.
-Breastfeeding is not recommended if acute HIV-1 infection is suspected due to risk of HIV-1 transmission to the child.

See references