Animal studies with efavirenz have revealed evidence of fetal harm; in cynomolgus monkeys, 3 of 20 fetuses/infants had at least 1 malformation (included anencephaly and unilateral anophthalmia in 1 fetus, microphthalmia in a second, and cleft palate in the third), and in rats, embryofetal toxicity occurred at a dose 10 times less than the human exposure at the recommended clinical human dose (RHD) of efavirenz. Efavirenz crosses the placenta in animals and produces fetal blood levels similar to maternal blood levels. Animal studies with emtricitabine have failed to reveal evidence of embryofetal toxicity; no adverse developmental effects observed at emtricitabine exposures (AUC) about 60 times (mice) and about 120 times (rabbits) higher than human exposures at the RHD. Animal studies with tenofovir disoproxil fumarate (DF) have failed to reveal evidence of embryofetal toxicity; no adverse developmental effects observed when tenofovir DF was administered separately at doses up to 14 times (rats) and up to 19 times (rabbits) the RHD based on body surface area comparisons. Data in pregnant women (more than 1000 pregnancy outcomes) showed no malformations, fetotoxicity, or neonatal toxicity with emtricitabine and tenofovir disoproxil. There are no controlled data in human pregnancy with this combination drug.

Placental transfer to the fetus has been reported as moderate (cord blood/maternal delivery plasma drug ratio 0.3 to 0.6) with efavirenz and high (cord blood/maternal delivery plasma drug ratio greater than 0.6) with emtricitabine and tenofovir DF.

There have been 7 retrospective reports of findings consistent with neural tube defects (including meningomyelocele), all in infants of mothers with first-trimester exposure to efavirenz-containing regimens (not including efavirenz-containing fixed-dose combination tablets). Two cases (1 prospective, 1 retrospective) with findings consistent with neural tube defects were reported with this 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

The APR has received prospective reports of over 1325 exposures to efavirenz-containing regimens (over 1125 exposed in the first-trimester; over 200 exposed in the second/third trimester) resulting in live births; there was no difference between efavirenz and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population. For efavirenz, 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. Detailed monitoring of first trimester exposures to efavirenz for anomalies (including central nervous system defects) did not reveal a pattern. The prevalence of birth defects with first-trimester and second/third trimester exposures to efavirenz was 2.4% and 1.5%, respectively. One of these prospective reports with first-trimester exposure was a neural tube defect. Also, a single case of anophthalmia was prospectively reported with first-trimester efavirenz exposure; however, this case included severe oblique facial clefts and amniotic banding, a known association with anophthalmia.

The APR has received prospective reports of over 5025 exposures to emtricitabine-containing regimens (over 3600 exposed in the first trimester; over 1425 exposed in the second/third trimester) resulting in live births; there was no difference between emtricitabine and overall birth defects compared with the background birth defect rate 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 with first trimester and second/third trimester exposures to emtricitabine was 2.6% and 2.4%, respectively.

The APR has received prospective reports of over 6075 exposures to tenofovir DF-containing regimens (over 4250 exposed in the first trimester; over 1825 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. 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 with first trimester and second/third trimester exposures to tenofovir DF was 2.4% and 2.4%, respectively.

Pregnancy should be avoided during use of this drug and for 12 weeks after discontinuation. Patients of childbearing potential should use effective contraception during therapy and for 12 weeks after stopping this drug. Barrier contraception should always be used in combination with other methods of contraception. Hormonal methods containing progesterone may have decreased efficacy. Patients of childbearing potential should undergo pregnancy testing before starting this drug (due to potential risk of neural tube defects).

According to some experts, use of efavirenz in pregnant women or women planning to become pregnant is not restricted. These experts also recommend continuing efavirenz in pregnant women receiving a virologically suppressive efavirenz-based regimen as antiretroviral drug changes during pregnancy may be associated with loss of viral control and increased risk of perinatal transmission.

AU TGA pregnancy category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.

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 not be used during pregnancy unless there are no alternatives and the benefit outweighs the risk to the fetus.

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

Risk summary: Efavirenz may cause fetal harm when administered to a pregnant woman during the first trimester.

Comments:
-A pregnancy exposure registry is available.
-Effective contraception is recommended during therapy and for 12 weeks after the last dose; local protocol should be consulted regarding contraception timing.
-If this drug is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.

See references

EFAVIRENZ:
Efavirenz is excreted in breast milk and small amounts are found in the serum of some infants. Treatment of HIV-positive mothers with this drug does not appear to affect growth and development of their HIV-negative breastfed infants.

Milk samples from 13 mothers and plasma samples from their breastfed infants were taken 3 to 4 hours after the last dose. The mothers, who averaged 15.8 weeks (range: 6 to 25 weeks) postpartum, used efavirenz 600 mg daily with lamivudine and (zidovudine [n=12] or stavudine [n=1]). Skimmed breast milk efavirenz levels averaged 3.5 mg/L (range: 1.3 to 7.4 mg/L) and infant plasma levels averaged 0.86 mg/L (range: 0.4 to 1.5 mg/L). Infant plasma levels averaged 13% of maternal plasma levels; correlation not statistically significant. Average plasma levels were slightly below the level effective for HIV suppression in adults. No side effects were reported in the infants after 6 months of breastfeeding, none had developed HIV infection, and all were developing normally.

About 146 days after delivery, mid-feed milk samples were collected from 5 mothers at 0.5, 1, 2, 4, 8, 12, and 24 hours after an evening dose; they were using efavirenz 600 mg orally daily (as part of antiretroviral regimen). The peak level averaged 4.5 mg/L at about 4 hours postdose; the trough milk value averaged 2.5 mg/L.

Mothers (n=134) using efavirenz 600 mg at bedtime (as part of antiretroviral regimen) and their infants were studied; during the first part of the trial, women were separated into noncarriers, heterozygotes, and homozygotes for the CYP450 2B6 516TT gene. Random breast milk levels had median values of 1610, 2370, and 4070 mcg/L and random infant serum levels had median values of 124, 164, and 333 mcg/L in the 3 groups, respectively. A subset of mothers and infants underwent extensive plasma and breast milk sampling; in these mothers, peak breast milk levels were 4020, 4540, and 8920 mcg/L, respectively, with corresponding trough milk levels of 1120, 1500, and 2480 mcg/L while in these infants, median plasma levels were 166, 89, and 293 mcg/L at 2 hours after maternal dosing and 134, 86, and 342 mcg/L at 8 hours after maternal dosing, respectively. According to author estimation, average infant dose would be 344, 379, and 1340 mcg/kg/day in the maternal noncarrier, heterozygous, and homozygous groups, respectively.

Efavirenz (dose not proved; presumed 600 mg/day), lamivudine, and tenofovir were administered daily (between 6 and 8 p.m.) for prevention of mother-to-child HIV transmission. At 1 month postpartum, milk samples collected in the morning from 33 women had a median efavirenz level of 1.6 mg/L (interquartile range [IQR]: 0.86 to 2.3 mg/L); at 12 months postpartum, milk samples collected in the morning from 47 women had a median efavirenz level of 1.8 mg/L (IQR: 1 to 4.3 mg/L). Blood samples were obtained from 25 of their breastfed infants; the median morning infant plasma level of efavirenz at 6 months of age was 86.4 mcg/L (IQR: 0 to 329 mcg/L) and was 0 mcg/L at 12 months of age.

Mother-infant pairs were studied among mothers taking efavirenz 600 mg daily (as part of multidrug HIV regimen). Mothers hand-express milk samples 12 to 14 hours after a morning dose at 1, 3, and 6 months postpartum; infants were breastfed (extent not provided) and plasma levels were measured postpartum. At 1, 3, and 6 months, breast milk efavirenz levels averaged 4.66 mg/L (n=22), 4.16 mg/L (n=31), and 3.92 mg/L (n=30), respectively, and infant plasma efavirenz levels averaged 347 mcg/L (n=22), 268 mcg/L (n=30), and 175 mcg/L (n=17), respectively. The weight-adjusted infant dose was calculated as 2.46% at 6 months; the plasma levels ranged from 4.8% to 7.2% of simultaneous maternal plasma levels. Among 32 of their breastfed infants, no side effects were observed by investigators or reported by mothers at 1, 3, and 6 months of age.

Efavirenz was measured in 117 breastfed (90% exclusive) infants whose mothers used efavirenz for HIV infection during pregnancy and postpartum. The drug was detectable in all plasma samples at 0 (mean 1.7 mg/L), 8 (mean 0.3 mg/L), and 12 (mean 0.3 mg/L) weeks postpartum. It was also detectable in all hair samples at 12 weeks postpartum (mean 1.9 ng/mg of hair; range: 0.34 to 11 ng/mg). According to author interpretation, the results suggest infants have substantial exposure to efavirenz during breastfeeding.

A prospective cohort study compared growth and development of infants of non-HIV-infected mothers and infants of HIV-infected mothers using efavirenz and tenofovir for prevention of mother-to-child HIV transmission; infants were followed up to 12 months of age. No differences in the groups were found in any growth parameters.

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-associated 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 (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 DISOPROXIL FUMARATE (DF):
Bioavailability of tenofovir is very poor; tenofovir DF (the more bioavailable of the 2 formulations) releases tenofovir in the bloodstream and is then 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.

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. Among HIV-infected mothers who have breastfed during tenofovir DF therapy, no infant side effects have occurred up to 2 years of age.

Samples of breast milk obtained from 5 HIV-1-infected mothers show that tenofovir 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 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 DF 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 DF (dose not provided; presumed 300 mg/day), efavirenz, and lamivudine were administered daily (between 6 and 8 p.m.) for prevention of mother-to-child HIV transmission. At 1 month postpartum, milk samples collected in the morning from 33 women had a median tenofovir level of 5 mcg/L (IQR: 0 to 6.1 mcg/L); at 12 months postpartum, milk samples collected in the morning from 47 women had a median tenofovir level of 2.5 mcg/L (IQR: 0 to 5.5 mcg/L). Blood samples were obtained from 25 of their breastfed infants; the median morning infant plasma level of tenofovir at 6 months of age was 24 mcg/L (IQR: 0 to 51.6 mcg/L) and was 0 mcg/L at 12 months of age.

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, 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 DF-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 breasted; 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 for prevention of mother-to-child HIV transmission; infants were followed up to 12 months of age. No differences in the groups were found in any growth parameters.

Breastfeeding is not recommended during use of this drug.
-According to some authorities: Use is not recommended.

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.

See references