Animal studies have revealed evidence of embryofetal toxicity but have failed to reveal evidence of teratogenicity. Pregnant rats given doses (starting 26 days before mating through gestation to postnatal day 21) producing systemic exposures about 33 times higher than exposure at recommended daily human dose showed increased fetal resorption; during oral embryofetal development study, no fetal resorptions observed in rats given doses (gestation day 6 through 15) producing systemic exposure about 117 times higher than exposures at recommended daily human dose. During oral embryofetal development study, increased fetal resorptions observed in rabbits given doses (500 mg/kg/day on gestation day 6 through 18) producing systemic exposure about 108 times higher than exposures at recommended daily human dose; however, no fetal resorptions observed in rabbits at doses up to 150 mg/kg/day which produced systemic exposure about 23 times higher than exposures at recommended daily human dose. No fetal malformations observed in rats and rabbits during oral embryofetal development studies. Data on pregnant women (more than 3000 outcomes from first trimester exposure; more than 3000 outcomes from second/third trimester exposure) showed no malformative toxicity. There are no controlled data in human pregnancy; based on available data, malformative risk unlikely.

Placental transfer of this drug has been observed in humans; placental transfer to the fetus has been reported as high (cord blood/maternal delivery plasma drug ratio greater than 0.6). This drug crosses the human placenta rapidly, reaching cord-to-maternal-blood ratios of about 0.8. Similar maternal serum and umbilical levels have been observed at delivery.

Mild, transient elevations in serum lactate levels/hyperlactatemia (which may be due to mitochondrial dysfunction) have been reported in neonates and infants exposed in utero or peripartum to zidovudine-containing products. Few cases of developmental delay, seizures, and other neurological disease reported. A causal relationship between such events and exposure in utero or peripartum to zidovudine-containing products has not been established; the clinical significance of transient serum lactate elevations is unknown.

In February 1994, early statistical analysis from a study by the AIDS Clinical Trial Group (ACTG 076) revealed that perinatal administration of this drug reduced the transmission of HIV from mother to infant by about two-thirds (8.3% compared to 25.5% with placebo). At this point, the trial was ended and this drug was offered to those participants receiving placebo. This drug had been initiated in HIV-infected women with a CD4 cell count greater than 200/mm3 who had received no antiretroviral therapy during their current pregnancy and were between 14 and 34 weeks gestation. Zidovudine 100 mg orally 5 times a day was given for the duration of pregnancy. During labor, this drug was given IV, beginning with 2 mg/kg over the first hour, followed by 1 mg/kg/hour until delivery. For 6 weeks after birth, infants received 2 mg/kg orally every 6 hours, beginning at 8 to 12 hours of life. This drug was administered to 180 infants 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.

A study was conducted in HIV-1-infected pregnant women to determine the value of this drug for prevention of maternal-fetal HIV-1 transmission. Use of this drug during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% (infants born to placebo-treated mothers) to 7.8% (for infants born to mothers treated with this drug); no differences in pregnancy-related side effects observed between treatment groups. Of 363 neonates evaluated, congenital abnormalities occurred with similar frequency between neonates born to mothers using this drug and neonates born to placebo-treated mothers; observed abnormalities included problems in embryogenesis (before 14 weeks) or were identified on ultrasound before or immediately after starting study drug.

The pharmacokinetics of this drug were not significantly affected by pregnancy. Several reports of 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 this drug followed up for as long as 5.6 years.

A series of 104 cases of intentional or inadvertent use of this drug 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.

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 13,000 exposures to zidovudine-containing regimens (over 4000 exposed in the first trimester; over 9000 exposed in the second/third trimester) resulting in live births; there was no difference in the overall risk of birth defects for this drug 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 increased risk of overall birth defects and a 2-fold increase in 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 3.2% and 2.8%, 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 clearly needed and the benefit outweighs the risk to the fetus.

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

Risk summary: Malformative risk with use of this drug in pregnant women is unlikely.

Comments:
-A pregnancy exposure registry is available.
-Use of this drug in pregnant women (with subsequent treatment of neonates) has shown reduced rate of vertical transmission of HIV.

See references

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; this drug is included in alternative regimens.

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
-Breastfed infants whose mothers use regimens containing this drug have higher rates of neutropenia and severe anemia during the first month and the first 6 months of life, respectively.
-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.

In clinical studies, excretion of drug in breast milk resulted in subtherapeutic infant plasma levels.

After administration of a single 200 mg dose to HIV-infected women, the mean drug level was similar in human milk and serum.

According to some experts, breast milk-to-maternal plasma drug level ratios ranged from 0.44 to 1.35; no drug was detectable in the plasma of nursing infants who received this drug only by breast milk.

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

At either 2 or 5 months postpartum, milk from 18 women using 300 mg orally twice a day (as part of combination antiretroviral therapy [cART]) and serum levels from their infants were analyzed; the infants were also receiving 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. Drug 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 at 5.3 hours (range: 0 to 99 hours) after a dose for the first sample and 6 hours (range: 4.3 to 20 hours) for the second sample. Breast milk drug 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 200 mg twice a day (with lamivudine and nevirapine) and serum levels from their 58 infants were analyzed. Mothers started this drug 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 infant 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 drug level averaged 9 mcg/L (35 selected samples [from all visits]). In infants, the serum level of 16 selected dried blood spot samples averaged 24 mcg/L; at later times postpartum, drug was not detectable (less than 30 mcg/L) in 66 infant dried blood spots.

A total of 114 milk samples were obtained at birth, 1, 3, and/or 6 months postpartum from 38 mothers using 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 drug level averaged 33 mcg/L (range: 5 to 117 mcg/L). Infant plasma drug 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 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 drug 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 drug levels were undetectable (less than 45 mcg/L) in all infant samples.

Mothers (n=30) starting 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 drug 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 this drug alone or highly-active antiretroviral therapy (HAART: zidovudine, lamivudine, and nevirapine). After delivery, all infants (some breastfed; others formula fed) received 1 month of prophylaxis with this drug. 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 prophylaxis with this drug. 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 this drug, and 2.5% of formula-fed infants. In general, the anemia responded well to iron and multivitamin supplementation and discontinuation of this drug.

See references