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

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

Risk summary:
-Tenofovir alafenamide: No data available on use of this product in pregnant women to inform a drug-related risk.
-Tenofovir disoproxil fumarate (DF): Malformative risk with use of this drug in pregnant women is unlikely.

Comments:
-A pregnancy exposure registry is available.

Animal studies have failed to reveal evidence of impaired fertility or fetal harm; studies with tenofovir alafenamide were at exposures similar to (rats) and 51-times higher than (rabbits) human exposures at the recommended daily dose and studies with tenofovir DF were at doses up to 14 times (rats) and 19 times (rabbits) the human dose based on body surface area comparisons. Placental transfer of tenofovir DF has been observed in humans. There are no (tenofovir alafenamide) and limited (tenofovir DF) controlled data in human pregnancy; studies have shown no association between maternal use of tenofovir DF and offspring birth defects. Data in pregnant women (more than 1000 pregnancy outcomes) showed no malformations, fetotoxicity, or neonatal toxicity with tenofovir DF.

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 15 of 15 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 2 of the 15 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 on chronic tenofovir DF, the cord-to-maternal-blood ratio of tenofovir ranged from 0.60 to 1.03. After single doses of tenofovir DF (with and without emtricitabine) in pregnant women in labor, the tenofovir cord-to-maternal-blood ratio at delivery averaged 0.55 to 0.73. After a single maternal dose of tenofovir DF 600 mg (with emtricitabine 400 mg), intracellular tenofovir levels were detected in peripheral blood mononuclear cells from cord blood in all infants, but intracellular tenofovir diphosphate was detected in only 2 of 36 infants.

In a preexposure prophylaxis trial in HIV-uninfected women, there was no difference in risk of congenital anomalies between tenofovir DF-containing and placebo arms. In 3 large US cohorts and the French Perinatal Cohort, no association was observed between tenofovir DF and birth defects.

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 not received sufficient numbers of reports regarding exposures to tenofovir alafenamide-containing regimens to estimate rate of birth defects.

The APR has received prospective reports of over 5000 exposures to tenofovir DF-containing regimens (over 3500 exposed in the first trimester; over 1500 exposed in the second/third trimester) resulting in live births; there was no difference between tenofovir DF 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 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 with first trimester and second/third trimester exposures was 2.3% and 2.2%, 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.

See references

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

Data on use of this drug during breastfeeding in HIV-infected mothers and mothers without HIV infection treated for HIV prophylaxis or HBV infection show infant exposure to the drug is trivial. A few infants have been breastfed during maternal use of this drug and no side effects have been observed up to 2 years of age.

An expert review of available data found no rationale at this time for contraindicating the use of this drug for HBV during breastfeeding. No difference in infection rates was observed between breastfed and formula-fed infants born to HBV-infected women, provided hepatitis B immune globulin and hepatitis B vaccine were administered to the infant at birth. After administration of these preventative measures, HBV-infected mothers have been encouraged to breastfeed their infants.

HIV-uninfected nursing mothers using this drug as an agent for preexposure prophylaxis 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 this drug is secreted in human milk. Average peak and trough drug 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 dose for infants and attain trivial infant serum levels that would likely have no adverse outcomes.

In a multicenter study, a single 600 or 900 mg dose of this drug 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 drug 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 (interquartile range [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.

Preexposure prophylaxis, using tenofovir DF 300 mg (and emtricitabine 200 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 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, 46 had undetectable (less than 0.31 mcg/L) tenofovir levels. 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.

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 drug 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, 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.

Starting in the third trimester of pregnancy and continuing postpartum, 5 HBV-infected women were treated with tenofovir DF 300 mg daily. Although instructed not to breastfeed, they all breastfed (extent not provided) their newborn infants. No short-term side effects were observed; the infants' hepatitis B surface antigen (HBsAg) was negative between 28 and 36 weeks of age.

This drug (dose not provided) was used during pregnancy in 14 HBV-infected mothers; 12 started in the first trimester. Three of the women breastfed while using this drug; no adverse outcomes were observed in their breastfed infants up to 1 year of age.

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.

In a long-term study of this drug for chronic hepatitis B, 3 women reportedly breastfed their infants (extent not specified); no infant had any side effects up to 1 year of age.

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.

Hepatitis B Virus (HBV) Infection:
-Tenofovir Alafenamide: Benefit should outweigh risk.
---According to some authorities: Use is not recommended.
-Tenofovir Disoproxil: According to an expert review of available data, there is currently no rationale for contraindicating the use of this drug during breastfeeding; experts have stated that breastfeeding is not contraindicated in patients taking oral HBV antiviral drugs.
---According to some authorities: Use is not recommended.

HIV Infection:
-Tenofovir Disoproxil: 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 is included in the first-choice regimen.

Tenofovir Alafenamide:
-Excreted into human milk: Unknown
-Excreted into animal milk: Unknown

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

Comments:
-The effects of tenofovir alafenamide in the nursing infant are unknown; tenofovir disoproxil has been used without apparent harmful effects in the nursing infant.

For Treatment of HBV Infection:
-Developmental and health benefits of breastfeeding should be considered as well as the mother's clinical need for this drug.
-Potential side effects in the breastfed child due to this drug or the mother's underlying condition should be considered.
-According to some authorities: The manufacturer advises HBV-infected women not to breastfeed to avoid postnatal transmission of HBV to a child who may not yet be infected.

For Treatment of HIV Infection:
-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.

See references