AU: Use is not recommended.
UK, US: This drug should be used during pregnancy only if the benefit outweighs the risk.

AU TGA pregnancy category: B3
US FDA pregnancy category: C

Comments:
-A pregnancy exposure registry is available.

Animal studies with abacavir (high-dose) have revealed evidence of embryonic and fetal toxicity, including developmental toxicity, fetal anasarca, skeletal malformations, and increased incidence of stillbirth. 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. Animal studies with zidovudine have failed to reveal evidence of teratogenicity; some high-dose studies demonstrated an increased incidence of fetal resorption. Placental transfer of each drug has been observed in humans. Data on pregnant women using abacavir, lamivudine, and zidovudine together as the individual components, abacavir, lamivudine, and zidovudine (more than 300, 600, 3000, and 3000 outcomes from first trimester exposures, respectively; more than 2000 of the 3000 outcomes had exposure to both lamivudine and zidovudine) showed no malformative toxicity. 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

The APR has received prospective reports of over 2000 exposures to abacavir (over 900 exposed in the first trimester), over 11,000 exposures to lamivudine (over 4300 exposed in the first trimester), and over 13,000 exposures to zidovudine (over 4000 exposed in the first trimester) resulting in live births; there was no difference between abacavir, lamivudine, or zidovudine and overall birth defects compared with the background birth defect rate of 2.7% in the reference population. The prevalence of defects in the first trimester was 2.9% for abacavir, 3.1% for lamivudine, and 3.2% for zidovudine. No increased risk of major birth defects observed for these drugs compared to background rate.

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 usually 2 times greater than maternal serum levels, ranging from 1.2 to 2.5 mcg/mL (150 mg twice a day) and 2.1 to 5.2 mcg/mL (300 mg twice a day).

In the trial AIDS Clinical Trial Group (ACTG) 076, perinatal administration of zidovudine was shown to reduce the transmission of HIV-1 from mother to infant by about two-thirds (7.8% compared to 24.9% with placebo; 363 neonates evaluated). Zidovudine had been initiated in HIV-1-infected women with a CD4+ cell count of 200 to 1818 cells/mm3 who had little or no prior exposure to zidovudine. Oral zidovudine was started between 14 and 34 weeks gestation followed by IV zidovudine during labor and delivery. For 6 weeks after birth, infants received oral zidovudine. Zidovudine was well tolerated by mothers and infants; there was no difference in pregnancy-related side effects between the treatment groups. Of 180 infants administered zidovudine during this study, the only fetal or infant toxicity reported was a mean decrease in hemoglobin of less than 1 g/dL, which resolved spontaneously after completion of therapy.

Zidovudine crosses the placenta rapidly, with similar maternal serum and umbilical levels at delivery. Pregnancy does not significantly affect zidovudine pharmacokinetics. Several reports of zidovudine use in pregnancy, including during the first trimester, have not revealed teratogenicity or fetal toxicity, other than reversible anemia. No side effects were observed in HIV-uninfected children with in utero and neonatal exposure to zidovudine followed up for as long as 5.6 years.

One series of 104 cases of intentional or inadvertent use of zidovudine during all stages of pregnancy was unable to demonstrate any specific abnormalities reasonably attributable to zidovudine use. Anomalies reported in infants exposed during the first trimester included low set ears, retrognathia, prominent epicanthal folds, hirsutism, triangular facies with blue sclera, hyperpigmented skin macules, prominent sacral dimple in 1 infant, multiple minor anomalies in 1 infant, and extra digits in 1 infant. Pectus excavatum was reported in 2 infants exposed in the second and third trimesters. An infant exposed during the third trimester exhibited albinism, congenital ptosis, oligohydramnios and intrauterine growth retardation.

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 C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

See references

ABACAVIR:
Breast milk from 15 women and blood samples from 9 of their partially or exclusively breastfed infants were collected about 1 month postpartum; the mothers were using abacavir 300 mg twice a day for 53 to 182 days (with lamivudine and zidovudine). Breast milk was obtained right before a dose; whole breast milk abacavir levels averaged 0.057 mg/L (about 85% of maternal blood levels). Infant blood was obtained 11 to 17 hours after the last maternal dose and about 1 hour (range: 6 minutes to 35 hours) after the last breastfeeding; plasma abacavir levels were undetectable (less than 16 mcg/L) in 8 of 9 infants.

LAMIVUDINE:
Based on more than 200 mother/child pairs treated for HIV, serum lamivudine levels in breastfed infants of mothers treated for HIV are very low (less than 4% of maternal serum levels) and gradually decrease to undetectable levels by 24 weeks of age.

Milk samples were obtained daily before breastfeeding. The milk lamivudine level averaged 1.2 mg/L (range: less than 0.5 to 6.1 mg/L) with 300 mg twice a day (n=10) and 0.9 mg/L (range: less than 0.5 to 8.2 mg/L) with 150 mg twice a day plus zidovudine (n=10).

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 drug 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).

Breast milk from 15 women and blood samples from 24 of their partially or exclusively breastfed infants were collected about 1 month postpartum; the mothers were using lamivudine 150 mg twice a day for 53 to 182 days (with [abacavir or lopinavir-ritonavir] and zidovudine). Breast milk was obtained right before a dose; whole breast milk lamivudine levels averaged 0.14 mg/L (about 74% of maternal blood levels). Infant blood was obtained 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.

Serum and breast milk from 58 mothers using 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. A fully breastfed infant would receive 182 mcg/kg/day of lamivudine (estimated).

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=20) 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: 1.1 to 3.5 times) the maternal plasma levels; milk to plasma ratio was 2.96 in 49 patients in a related study (same authors). Infant serum 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.

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. Breast milk lamivudine level averaged 446 mcg/L (range: 269 to 683 mcg/L). 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 drug analysis; lamivudine levels averaged 684 mcg/L in breast milk and 29.2 mcg/L in infant blood. Unclear if some of the same patients from the first study were in the latter study.

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 at 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.

ZIDOVUDINE:
After administration of a single 200 mg dose to 13 HIV-infected women, the mean zidovudine concentration was similar in human milk and serum.

Milk samples were collected 1, 2, 4, and 6 hours after a single 200 mg oral dose in 6 women. Peak milk zidovudine level averaged 857 mcg/L (range: 472 to 1043 mcg/L) at 1 to 2 hours postdose in 4 women and an hour later in the others.

At either 2 or 5 months postpartum, milk from 18 women using zidovudine 300 mg orally twice a day (as part of cART) and serum levels from their infants were analyzed; the infants were also receiving zidovudine 4 or 6 mg/kg orally 3 times a day (depending on age). Milk and serum samples were collected about 4 hours (range: 1 to 8.5 hours) after the last dose. Zidovudine level averaged 207 mcg/L in breast milk and 123 mcg/L (range: 14 to 3302 mcg/L) in infant serum.

Blood and milk samples were obtained from 40 women on postpartum prophylaxis (with lamivudine, nevirapine, and zidovudine [or stavudine if hemoglobin less than 8 g/dL]; 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 zidovudine levels averaged 130 mcg/L (n=11) for the first sample and 150 mcg/L (n=13) for the second sample; these levels were equal to the coinciding maternal serum levels.

Serum and breast milk from 58 mothers using zidovudine 200 mg twice a day (with lamivudine and nevirapine) and serum levels from their 58 infants were analyzed. Mothers started zidovudine 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 zidovudine level averaged 9 mcg/L (35 selected samples [from all visits]). The infant dried blood spot zidovudine level averaged 24 mcg/L at delivery (16 selected samples; 8 had quantifiable levels); zidovudine levels from 66 samples collected at 2, 6, 14, and 24 weeks postpartum were not measurable (less than 30 mcg/L).

A total of 114 milk samples were obtained at birth, 1, 3, and/or 6 months postpartum from 38 mothers using zidovudine 300 mg twice a day as part of cART and 34 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. Breast milk zidovudine level averaged 33 mcg/L (range: 5 to 117 mcg/L). Infant plasma zidovudine levels ranged from 0 to 2.5 mcg/L, which averaged 2% (range: 0 to 5%) of the maternal serum level.

Breast milk samples from 15 women were collected about 1 month postpartum and blood samples from their partially or exclusively breastfed infants were collected about 1 month (n=24) and 3 months (n=9) postpartum; the mothers were using zidovudine 300 mg twice a day for 53 to 182 days (as part of cART). Breast milk was obtained right before a dose; whole breast milk zidovudine levels averaged 7 mcg/L. Infant blood was obtained at various times after the last maternal dose and about 1 hour (range: 6 minutes to 35 hours) after the last breastfeeding. Serum zidovudine levels were undetectable (less than 45 mcg/L) in all infant samples.

Mothers (n=30) starting zidovudine 300 mg orally twice a day (with lamivudine and lopinavir-ritonavir) at delivery provided plasma and breast milk samples at 6, 12, or 24 weeks postpartum (n=10 at 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 zidovudine levels (at least 10 mcg/L) were found in 98 of 121 breast milk samples and 0 of 115 infant plasma samples; breast milk level averaged 0.2 mg/L over the 6 hours.

In a study to prevent maternal-to-child transmission of HIV infection, pregnant women used zidovudine alone or highly-active antiretroviral therapy (HAART: zidovudine, lamivudine, and nevirapine). After delivery, all infants (some breastfed; others formula fed) received 1 month of zidovudine prophylaxis. At 1 month of age, 15.9% of infants exposed to HAART had neutropenia compared to 3.7% of those not exposed. Hematologic toxicity was transient and asymptomatic. No differences in hematologic toxicity (from 2 to 6 months postpartum) and no statistical difference in hepatic toxicity were observed between the breastfed and formula-fed infants.

In another study for prevention of maternal-to-child transmission of HIV infection, rates of severe anemia were compared in 3 groups of infants who received zidovudine prophylaxis. Through 6 months of age, severe anemia was observed in 7.4% of breastfed infants whose mothers received HAART, 5.3% of breastfed infants whose mothers received only zidovudine, and 2.5% of formula-fed infants. In general, the anemia responded well to iron and multivitamin supplementation and zidovudine discontinuation.

Breastfeeding is not recommended during use of this drug; if replacement feeding is not an option, a different drug may be preferred.

Excreted into human milk: Yes

Comments:
-The effects in the nursing infant are unknown; risk of neutropenia and severe anemia may increase with zidovudine-containing regimens.
-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