Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States

Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors

Zidovudine (Retrovir, ZDV)

Summary

• No dose adjustments are required for zidovudine (ZDV) during pregnancy.
• First-trimester exposure to ZDV is not associated with increased risk of congenital anomalies.

Human Studies in Pregnancy

Pharmacokinetics

ZDV pharmacokinetics (PK) are not significantly altered by pregnancy, and standard adult doses are recommended during pregnancy.^1,2 A population PK analysis that evaluated oral and intravenous (IV) ZDV doses during pregnancy and labor found high fetal exposure to ZDV with current IV intrapartum dosing regimens. Simulations suggested that reduced intrapartum ZDV dosing regimens might provide lower, but still adequate, fetal ZDV exposures.³ However, standard dosing of IV ZDV during labor continues to be recommended for people with unknown or elevated viral loads. In pregnant women, as with nonpregnant adults, intracellular ZDV triphosphate concentrations do not vary with plasma concentrations over a wide range of plasma ZDV concentrations.⁴

Placental and Breast Milk Passage

ZDV rapidly crosses the human placenta, achieving cord blood–to–maternal plasma ratios of about 0.80. The ratio of ZDV in amniotic fluid to ZDV in maternal plasma5 is 1.5. ZDV is excreted into human breast milk, with breast milk–to–maternal plasma ZDV concentration ratios ranging from 0.44 to 1.35. No ZDV was detectable in the plasma of nursing infants who were exposed to ZDV only via breast milk.^6-8

Teratogenicity/Adverse Pregnancy Outcomes

In Pediatric AIDS Clinical Trials Group 076 (PACTG 076), the incidence of minor and major congenital abnormalities was similar between groups that received either ZDV or placebo, and no specific patterns of defects were seen.^1,9Similarly, no increase in the incidence of birth defects was detected among infants enrolled in the large observational cohorts PACTG 219/219C and P1025.^10,11 A previous report from the Women and Infants Transmission Study described a 10-fold increase in the risk of hypospadias among infants who were exposed to ZDV, but this finding was not confirmed in a more detailed analysis.^12,13 In the Pediatric HIV/AIDS Cohort Study/Surveillance Monitoring for Antiretroviral Therapy Toxicities (PHACS/SMARTT) study cohort, no association was identified between first-trimester exposure to ZDV and congenital anomalies.¹⁴

In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to ZDV have been monitored to be able to detect at least a 1.5-fold increase in risk of overall birth defects and a twofold increase in risk of defects in the more common classes, including the cardiovascular and genitourinary systems. No such increase in the risk of birth defects has been observed in infants who were exposed to ZDV. With first-trimester ZDV exposure, the prevalence of birth defects was 3.2% (136 of 4,252 births; 95% confidence interval [CI], 2.7% to 3.8%), compared with a total prevalence in the U.S. population of 2.7%, based on Centers for Disease Control and Prevention surveillance.¹⁵ Similarly, a series of 897 infants exposed to HIV born in Spain during 2000 through 2009 reported no increase in the incidence of birth defects among infants with first-trimester ZDV exposure (adjusted odds ratio [aOR] 1.21, 0.56–2.63).¹⁶ A Bayesian analysis that combined a meta-analysis with data from Medicaid Analytic eXtract found no association between ZDV exposure during the first trimester and most congenital malformations.¹⁷

The French Perinatal Cohort reported that first-trimester ZDV exposure was associated with congenital heart defects (1.5% of 3,262 exposures vs. 0.7% of non-exposures; aOR 2.2, 95% CI, 1.5–‍3.2). However, an analysis of cardiac defects among all prenatal ZDV-exposed infants in the Antiretroviral Pregnancy Registry (n = 13,073) reported no difference in the prevalence of ventricular septal defect and congenital heart defects among infants exposed to ZDV-containing regimens (9 of 4,000 infants exposed during the first trimester, rate 0.23; 22 of 9,047 infants with later exposure, rate 0.24, P = 1.00) and regimens that did not contain ZDV (2 of 1,839 infants exposed during the first trimester, rate 0.11; 3 of 538 infants with later exposure, rate 0.56, P = 0.08).¹⁸

In the ANRS 135 PRIMEVA trial, mothers were randomized to receive antepartum treatment with ZDV plus lamivudine plus lopinavir/ritonavir (LPV/r) or LPV/r alone. Female infants of women in the first group had a higher left ventricular shortening fraction at 1 month and increased posterior wall thickness at 1 year—suggestive of myocardial remodeling—when compared with infants whose mothers received LPV/r alone.¹⁹ In a study that performed fetal echocardiography on 42 fetuses who had been exposed to HIV but were not infected and 84 fetuses who had not been exposed to HIV, infants born to mothers who received ZDV were more likely to have thicker myocardial walls and smaller left ventricular cavities than other infants, regardless of HIV exposure. Maternal ZDV treatment was the only factor significantly associated with fetal cardiac changes.²⁰ Another study by the same authors reported the presence of hypertrophic myocardium and signs of increased mitochondrial content in the cord blood of infants who had been exposed to HIV. In this study, both conditions were associated with maternal use of ZDV during pregnancy.²¹ A small follow-up study by the same authors identified hypertension among infants with in utero exposure to ZDV.²²

Cancer has been observed no more frequently among ZDV-exposed infants than among other HIV-exposed or HIV-unexposed infants in a long-term follow-up study for the original PACTG 076 study,²³ in prospective cohort studies,²⁴ and in matches between HIV surveillance and cancer registries.^25,26

Other Safety Information

Mitochondrial dysfunction in mothers and infants exposed to nucleoside reverse transcriptase inhibitors during pregnancy has been described by some, but not all, case reports, case series, prospective cohorts, and surveillance systems. As part of its surveillance for such dysfunction, the PHACS/SMARTT cohort used a “trigger-based design” in which several domains (e.g., metabolic) had predetermined “triggers.” Children meeting the definition of a trigger were further investigated to determine whether they had met the definition of a “case” in that domain. The study found that after adjusting for birth cohort and other factors, ZDV use was associated with an increased risk of meeting the study’s definition of a metabolic case (adjusted relative risk 1.69; 95% CI, 1.08–‍2.64).^27,28

Animal Studies

Carcinogenicity

Late-appearing, non-metastasizing vaginal squamous cell carcinomas were seen in mice and in rats, predominantly among those given the highest dose (approximately 3–24 times the estimated human exposure with a dose of 100 mg every 4 hours).²⁹

With transplacental exposure followed by postnatal exposure in mice (approximately three times the exposure of humans receiving the recommended dose), vaginal tumors were noted.²⁹

One group of authors attributed the vaginal tumors in ZDV-treated mice to vaginal exposure from high urine ZDV concentrations.³⁰

Reproduction/Fertility

ZDV has been shown to have no effect on reproduction or fertility in rodents.²⁹

Teratogenicity/Adverse Pregnancy Outcomes

Embryotoxicity was seen in rats exposed preconceptionally and during gestation (exposure was approximately 33 times higher than that seen in humans receiving the recommended clinical dose), and rabbits exposed gestationally (approximately 108 times the estimated exposure of humans receiving the recommended dose).²⁹

In an additional teratology study in rats, a dose of ZDV 3,000 mg/kg per day (which was very near the median lethal oral dose in rats of 3,683 mg/kg) caused marked maternal toxicity and an increase in the incidence of fetal malformations. This dose resulted in peak ZDV plasma concentrations that were 350 times peak human plasma concentrations (the estimated area under the curve [AUC] in rats at this dose level was 300 times the daily AUC in humans given 600 mg per day). No evidence of teratogenicity was seen in this experiment at doses of ZDV 600 mg/kg per day or less.²⁹

Excerpt from Table 14

Note: When using fixed-dose combination (FDC) tablets, refer to other sections in Appendix B and Table 14 in the Perinatal Guidelines for information about the dosing and safety of individual drug components of the FDC tablet during pregnancy.

References

1. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994;331(18):1173-1180. Available at: https://pubmed.ncbi.nlm.nih.gov/7935654.
2. O' Sullivan MJ, Boyer PJ, Scott GB, et al. The pharmacokinetics and safety of zidovudine in the third trimester of pregnancy for women infected with human immunodeficiency virus and their infants: phase I acquired immunodeficiency syndrome clinical trials group study (protocol 082). Zidovudine Collaborative Working Group. Am J Obstet Gynecol. 1993;168(5):1510-1516. Available at: https://pubmed.ncbi.nlm.nih.gov/8098905/.
3. Fauchet F, Treluyer JM, Valade E, et al. Maternal and fetal zidovudine pharmacokinetics during pregnancy and labour: too high dose infused at labour? Br J Clin Pharmacol. 2014;78(6):1387-1396. Available at: https://pubmed.ncbi.nlm.nih.gov/25040510.
4. Kinai E, Kato S, Hosokawa S, et al. High plasma concentrations of zidovudine (AZT) do not parallel intracellular concentrations of AZT-triphosphates in infants during prevention of mother-to-child HIV-1 transmission. J Acquir Immune Defic Syndr. 2016;72(3):246-253. Available at: https://pubmed.ncbi.nlm.nih.gov/26859826.
5. Bennetto-Hood C, Bryson YJ, Stek A, et al. Zidovudine, lamivudine, and nelfinavir concentrations in amniotic fluid and maternal serum. HIV Clin Trials. 2009;10(1):41-47. Available at: https://pubmed.ncbi.nlm.nih.gov/19362995.
6. Mirochnick M, Thomas T, Capparelli E, et al. Antiretroviral concentrations in breast-feeding infants of mothers receiving highly active antiretroviral therapy. Antimicrob Agents Chemother. 2009;53(3):1170-1176. Available at: https://pubmed.ncbi.nlm.nih.gov/19114673.
7. Palombi L, Pirillo MF, Andreotti M, et al. Antiretroviral prophylaxis for breastfeeding transmission in Malawi: drug concentrations, virological efficacy and safety. Antivir Ther. 2012;17(8):1511-1519. Available at: https://pubmed.ncbi.nlm.nih.gov/22910456.
8. Corbett AH, Kayira D, White NR, et al. Antiretroviral pharmacokinetics in mothers and breastfeeding infants from 6 to 24 weeks post partum: results of the BAN study. Antivir Ther. 2014;19(6):587-595. Available at: https://pubmed.ncbi.nlm.nih.gov/24464632.
9. Sperling RS, Shapiro DE, McSherry GD, et al. Safety of the maternal-infant zidovudine regimen utilized in the Pediatric AIDS Clinical Trial Group 076 study. AIDS. 1998;12(14):1805-1813. Available at: https://pubmed.ncbi.nlm.nih.gov/9792381.
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13. Albano DJ, Sinclair S, Scheuerle D, et al. Zidovudine exposure during pregnancy and hypospadias in infants: An analysis of data from the Antiretroviral Pregnancy Registry, 1989-2014. Clinical Research in HIV/AIDS. 2017. Available at: https://www.jscimedcentral.com/public/assets/articles/HIV-AIDS-4-1033.pdf.
14. Williams PL, Crain M, Yildirim C, et al. Congenital anomalies and in utero antiretroviral exposure in human immunodeficiency virus-exposed uninfected infants. JAMA Pediatr. 2015;169(1):45-55. Available at: https://pubmed.ncbi.nlm.nih.gov/25383770.
15. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 January 1989–31 January 2023. Morrisville, NC: Registry Coordinating Center; 2023.Available at: https://www.apregistry.com.
16. Prieto LM, Gonzalez-Tome MI, Munoz E, et al. Birth defects in a cohort of infants born to HIV-infected women in Spain, 2000-2009. BMC Infect Dis. 2014;14:700. Available at: https://pubmed.ncbi.nlm.nih.gov/25808698.
17. Rough K, Sun JW, Seage GR, 3rd, et al. Zidovudine use in pregnancy and congenital malformations. AIDS. 2017;31(12):1733-1743. Available at: https://pubmed.ncbi.nlm.nih.gov/28537936.
18. Vannappagari V, Albano JD, Koram N, et al. Prenatal exposure to zidovudine and risk for ventricular septal defects and congenital heart defects: data from the antiretroviral pregnancy registry. Eur J Obstet Gynecol Reprod Biol. 2016;197:6-10. Available at: https://pubmed.ncbi.nlm.nih.gov/26687320.
19. Sibiude J, Le Chenadec J, Bonnet D, et al. In utero exposure to zidovudine and heart anomalies in the ANRS French perinatal cohort and the nested PRIMEVA randomized trial. Clin Infect Dis. 2015;61(2):270-280. Available at: https://pubmed.ncbi.nlm.nih.gov/25838291.
20. Garcia-Otero L, Lopez M, Gomez O, et al. Zidovudine treatment in HIV-infected pregnant women is associated with fetal cardiac remodelling. AIDS. 2016;30(9):1393-1401. Available at: https://pubmed.ncbi.nlm.nih.gov/26919731.
21. Garcia-Otero L, Lopez M, Guitart-Mampel M, et al. Cardiac and mitochondrial function in HIV-uninfected fetuses exposed to antiretroviral treatment. PLoS One. 2019;14(3):e0213279. Available at: https://pubmed.ncbi.nlm.nih.gov/30830946.
22. Garcia-Otero L, Lopez M, Gonc EA, et al. Cardiac remodeling and hypertension in HIV uninfected infants exposed in utero to antiretroviral therapy. Clin Infect Dis. 2021. Available at: https://pubmed.ncbi.nlm.nih.gov/33471090.
23. Culnane M, Fowler M, Lee SS, et al. Lack of long-term effects of in utero exposure to zidovudine among uninfected children born to HIV-infected women. Pediatric AIDS Clinical Trials Group Protocol 219/076 Teams. JAMA. 1999;281(2):151-157. Available at: https://pubmed.ncbi.nlm.nih.gov/9917118.
24. Hanson IC, Antonelli TA, Sperling RS, et al. Lack of tumors in infants with perinatal HIV-1 exposure and fetal/neonatal exposure to zidovudine. J Acquir Immune Defic Syndr Hum Retrovirol. 1999;20(5):463-467. Available at: https://pubmed.ncbi.nlm.nih.gov/10225228.
25. Ivy W, 3rd, Nesheim SR, Paul SM, et al. Cancer among children with perinatal exposure to HIV and antiretroviral medications-New Jersey, 1995-2010. J Acquir Immune Defic Syndr. 2015;70(1):62-66. Available at: https://pubmed.ncbi.nlm.nih.gov/26017660.
26. Hankin C, Lyall H, Peckham C, Tookey P. Monitoring death and cancer in children born to HIV-infected women in England and Wales: use of HIV surveillance and national routine data. AIDS. 2007;21(7):867-869. Available at: https://pubmed.ncbi.nlm.nih.gov/17415042.
27. Williams PL, Hazra R, Van Dyke RB, et al. Antiretroviral exposure during pregnancy and adverse outcomes in HIV-exposed uninfected infants and children using a trigger-based design. AIDS. 2016;30(1):133-144. Available at: https://pubmed.ncbi.nlm.nih.gov/26731758.
28. Van Dyke RB, Chadwick EG, Hazra R, et al. The PHACS SMARTT study: assessment of the safety of in utero exposure to antiretroviral drugs. Front Immunol. 2016;7:199. Available at: https://pubmed.ncbi.nlm.nih.gov/27242802.
29. Zidovdine (Retrovir) [package insert]. Food and Drug Administration. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/019655Orig1s059,019910Orig1s046,019951Orig1s037lbl.pdf.
30. Ayers KM, Clive D, Tucker WE, Jr., et al. Nonclinical toxicology studies with zidovudine: genetic toxicity tests and carcinogenicity bioassays in mice and rats. Fundam Appl Toxicol. 1996;32(2):148-158. Available at: https://pubmed.ncbi.nlm.nih.gov/8921318.