• What's New in the Guidelines
• Guidelines Panel Members
• Financial Disclosure
• Introduction
  • Guidelines Development Process
• Lessons From Clinical Trials of Antiretroviral Interventions to Reduce Perinatal Transmission of HIV
  • Overview
  • Mechanisms of Action of Antiretroviral Prophylaxis in Reducing Perinatal Transmission of HIV
  • Lessons from International Clinical Trials of Short-Course Antiretroviral Regimens for Prevention of Perinatal Transmission of HIV
  • Perinatal Transmission of HIV and Maternal HIV RNA Copy Number
• Preconception Counseling and Care for HIV-Infected Women of Childbearing Age
  • Overview
  • Reproductive Options for HIV-Concordant and Serodiscordant Couples
• Antepartum Care
  • General Principles Regarding Use of Antiretroviral Drugs during Pregnancy
  • HIV-Infected Pregnant Women Who Have Never Received Antiretroviral Drugs (Antiretroviral Naive)
  • HIV-Infected Pregnant Women Who Are Currently Receiving Antiretroviral Therapy
  • HIV-Infected Pregnant Women Who Have Previously Received Antiretroviral Treatment or Prophylaxis but Are Not Currently Receiving Any Antiretroviral Medications
  • Special Situations - HIV/Hepatitis B Virus Coinfection
  • Special Situations - HIV/Hepatitis C Virus Coinfection
  • Special Situations - HIV-2 Infection and Pregnancy
  • Special Situations - Acute HIV Infection
  • Special Situations - Stopping Antiretroviral Drugs During Pregnancy
  • Special Situations - Failure of Viral Suppression
  • Monitoring of the Woman and Fetus During Pregnancy
• Special Considerations Regarding the Use of Antiretroviral Drugs by HIV-Infected Pregnant Women and Their Infants
  • Overview
  • Pharmacokinetic Changes
  • Teratogenicity
  • Combination Antiretroviral Drug Regimens and Pregnancy Outcome
  • Nevirapine and Hepatic/Rash Toxicity
  • Nucleoside Reverse Transcriptase Inhibitor Drugs and Mitochondrial Toxicity
  • Protease Inhibitor Therapy and Hyperglycemia
• Antiretroviral Drug Resistance and Resistance Testing in Pregnancy
• Intrapartum Care
  • Intrapartum Antiretroviral Therapy/Prophylaxis
  • Transmission and Mode of Delivery
  • Other Intrapartum Management Considerations
• Postpartum Care
  • Postpartum Follow-Up of HIV-Infected Women
  • Infants Born To Mothers with Unknown HIV Infection Status
  • Infant Antiretroviral Prophylaxis
  • Initial Postnatal Management of the HIV-Exposed Neonate
  • Long-Term Follow-Up of Antiretroviral Drug-Exposed Infants
• Appendix A: Supplement: Safety and Toxicity of Individual Antiretroviral Agents in Pregnancy
  • Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors
    • Abacavir (Ziagen, ABC)
    • Didanosine (Videx, ddI)
    • Emtricitabine (Emtriva, FTC)
    • Lamivudine (Epivir, 3TC)
    • Stavudine (Zerit, d4T)
    • Tenofovir disoproxil fumarate (Viread, TDF)
    • Zalcitabine (HIVID, ddC)
    • Zidovudine (Retrovir, AZT, ZDV)
  • Non-Nucleoside Reverse Transcriptase Inhibitors
    • Delavirdine (Rescriptor, DLV)
    • Efavirenz (Sustiva, EFV)
    • Etravirine (Intelence, ETR)
    • Nevirapine (Viramune, NVP)
    • Rilpivirine (Edurant, RPV)
  • Protease Inhibitors
    • Amprenavir (Agenerase, APV)
    • Atazanavir (Reyataz, ATV)
    • Darunavir (Prezista, DRV)
    • Fosamprenavir (Lexiva, FPV)
    • Indinavir (Crixivan, IDV)
    • Lopinavir + Ritonavir (Kaletra, LPV/r)
    • Nelfinavir (Viracept, NFV)
    • Ritonavir (Norvir, RTV)
    • Saquinavir (Invirase [Hard Gel Capsule], SQV)
    • Tipranavir (Aptivus, TPV)
  • Entry Inhibitors
    • Enfuvirtide (Fuzeon, T-20)
    • Maraviroc (Selzentry, MVC)
  • Integrase Inhibitors
    • Raltegravir (Isentress)
  • Antiretroviral Pregnancy Registry
• Appendix B: Acronyms

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Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States

Early data were conflicting as to whether receipt of combination antiretroviral (ARV) regimens during pregnancy is associated with adverse pregnancy outcomes and, in particular, preterm delivery. The European Collaborative Study and the Swiss Mother + Child HIV Cohort Study investigated the effects of combination ARV regimens in a population of 3,920 mother-child pairs. Adjusting for CD4 T-lymphocyte (CD4-cell) count and intravenous drug use, they found a roughly twofold increase in the odds of preterm delivery for infants exposed to combination regimens with or without protease inhibitors (PIs) compared with no drugs; women receiving combination regimens that had been initiated before pregnancy were twice as likely to deliver prematurely as those who started drugs during the third trimester.¹ However, PI-based combination regimens were received by only 108 (3%) of the women studied; confounding by severity or indication may have biased the results (that is, sicker women may have received PIs more often, but their advanced HIV infection may have actually caused the preterm births). Exposure to nucleoside reverse transcriptase inhibitor (NRTI) single-drug prophylaxis (primarily zidovudine) was not associated with prematurity.

An updated report from the European Collaborative Study, based on an adjusted analysis that included 2,279 mother-child pairs, found a 1.9-fold increased risk of delivery at less than 37 weeks with combination ARV regimens started during pregnancy and a 2.1-fold increased risk with combination ARV regimens started pre-pregnancy compared with mono- or dual-NRTI prophylaxis.² In this report, 767 women received combination ARV regimens during pregnancy, although the proportion receiving PIs was not specified. The risk of delivery before 34 weeks’ gestation was increased by 2.5-fold for those starting combination ARV regimens during pregnancy and 4.4-fold for those entering pregnancy on combination ARV regimens.

In contrast, in an analysis of 7 prospective clinical studies that included 2,123 HIV-infected pregnant women who delivered infants between 1990 and 1998 and had received antenatal ARV regimens and 1,143 women who did not receive antenatal ARV drugs, the use of multiple ARV drugs compared with no drugs or treatment with 1 drug was not associated with increased rates of preterm birth, low birth weight, low Apgar scores, or stillbirth.³ Nor were any significant associations between adverse pregnancy outcome and use of ARV drugs by class or by category (including combination ARV regimens) found in an analysis from the Women and Infants Transmission Study, including 2,543 HIV-infected women (some of whom were included in the previous meta-analysis).⁴

More recent data have continued to be conflicting as to whether preterm delivery is increased with combination ARV regimens. Table 7 reviews results from studies that have evaluated the association of ARV drug use during pregnancy and preterm delivery. Multiple studies have detected small but significant increases (odds ratio [OR] 1.2–1.8 in the largest studies) in preterm birth with PI- or non-PI-based combination ARV regimens as well.^5-8 However, other recent studies that have controlled for maternal and pregnancy characteristics as well as factors related to HIV infection have shown no increase in adverse outcomes including preterm delivery and low birth weight in association with PI-containing drug regimens.^9-11 A meta-analysis of 14 European and American clinical studies found no increase in risk of preterm birth with either any ARV drug receipt compared with no drugs or combination ARV regimens including PIs compared with no drugs.¹² However, a significant but modest increased risk of preterm birth (OR 1.35; 95% confidence interval [CI], 1.08–1.70) was found in women who received combination regimens with PIs compared with combination regimens without PIs. Other reports have found increased rates of preterm birth when combination ARV regimens are compared with dual regimens¹³ and when combination ARV regimens containing non-nucleoside reverse transcriptase inhibitors were compared with other combination ARV regimens.¹⁴

Other variables may confound these observational studies. Some studies have found increased rates of preterm birth if a combination ARV regimen is begun before conception or earlier in pregnancy compared with later during pregnancy, which itself may reflect confounding by severity or indication.^14,15 Recent studies have assessed spontaneous preterm birth only, excluding delivery that was initiated at a preterm gestation because of medical or obstetrical reasons, and found no association between ARV and preterm birth.^16,17 In an analysis of HIV-infected women enrolled in the ANRS French Perinatal Cohort from 1990 to 2009, preterm delivery rates were seen to increase over time, and preterm delivery was associated with combination ARV regimens versus either mono- or dual-ARV regimens and were highest in those who had initiated ARV before pregnancy.¹⁸ A restricted analysis within this cohort of PI-based combination ARV regimens comparing boosted to unboosted PIs showed an association with induced preterm delivery for boosted PI regimens (adjusted odds ratio [AOR] 2.03; 95% CI, 2.06–3.89) that was not seen with spontaneous preterm birth. Boosted PI regimens were also associated with both medical and obstetrical complications, raising the possibility that the association with induced preterm delivery was mediated through these complications.

A secondary analyses of data collected during a randomized, controlled clinical trial conducted in Botswana in women with CD4 T-lymphocyte counts >200 cells/mm³—267 randomized to receive lopinavir/ritonavir/zidovudine/lamivudine (PI group) and 263 randomized to receive abacavir/zidovudine/lamivudine (NRTI group) begun between 26 and 34 weeks’ gestation for prevention of mother-to-child transmission and not for maternal health indications—did show an association between PI-containing ARV regimens and preterm delivery. In logistic regression analysis, use of combination PI-based ARV regimens was the most significant risk factor for preterm delivery (OR 2.03; 95% CI, 1.26–3.27).¹⁹ Those receiving the latest initiation of ARV drugs had the highest preterm delivery rates. However the 20% background rate for preterm delivery in this population was not different from that seen in the PI group, and there was no difference between the 2 groups in neonatal morbidity and mortality. An observational study also from Botswana found that use of combination ARV regimens from before conception was not associated with very preterm delivery (AOR 0.78), which could not be assessed in the controlled clinical trial.²⁰

Clinicians should be aware of a possible increased risk of preterm birth with use of combination ARV drug regimens; however, given the clear benefits for maternal health and reduction in perinatal transmission, these agents should not be withheld because of the possibility of increased risk of preterm delivery. Until more information is known, HIV-infected pregnant women who are receiving combination regimens for treatment of their HIV infection should continue their provider-recommended regimens. They should receive careful, regular monitoring for pregnancy complications and for potential toxicities.

Table 7. Results of Studies Assessing Association Between Antiretroviral Regimens and Preterm Delivery
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References

1. European Collaborative Study, Swiss Mother andChild HIV Cohort Study. Combination antiretroviral therapy and duration of pregnancy. AIDS. Dec 22 2000;14(18):2913-2920. Available at http://www.ncbi.nlm.nih.gov/pubmed/11398741.
2. Thorne C, Patel D, Newell ML. Increased risk of adverse pregnancy outcomes in HIV-infected women treated with highly active antiretroviral therapy in Europe. AIDS. Nov 19 2004;18(17):2337-2339. Available at http://www.ncbi.nlm.nih.gov/pubmed/15577551.
3. Tuomala RE, Shapiro DE, Mofenson LM, et al. Antiretroviral therapy during pregnancy and the risk of an adverse outcome. N Engl J Med. Jun 13 2002;346(24):1863-1870. Available at http://www.ncbi.nlm.nih.gov/pubmed/12063370.
4. Tuomala RE, Watts DH, Li D, et al. Improved obstetric outcomes and few maternal toxicities are associated with antiretroviral therapy, including highly active antiretroviral therapy during pregnancy. J Acquir Immune Defic Syndr. Apr 1 2005;38(4):449-473. Available at http://www.ncbi.nlm.nih.gov/pubmed/15764963.
5. Townsend CL, Cortina-Borja M, Peckham CS, Tookey PA. Antiretroviral therapy and premature delivery in diagnosed HIV-infected women in the United Kingdom and Ireland. AIDS. May 11 2007;21(8):1019-1026. Available at http://www.ncbi.nlm.nih.gov/pubmed/17457096.
6. Schulte J, Dominguez K, Sukalac T, Bohannon B, Fowler MG, Pediatric Spectrum of HIV Disease Consortium. Declines in low birth weight and preterm birth among infants who were born to HIV-infected women during an era of increased use of maternal antiretroviral drugs: Pediatric Spectrum of HIV Disease, 1989-2004. Pediatrics. Apr 2007;119(4):e900-906. Available at http://www.ncbi.nlm.nih.gov/pubmed/17353299.
7. Ravizza M, Martinelli P, Bucceri A, et al. Treatment with protease inhibitors and coinfection with hepatitis C virus are independent predictors of preterm delivery in HIV-infected pregnant women. J Infect Dis. Mar 15 2007;195(6):913-914; author reply 916-917. Available at http://www.ncbi.nlm.nih.gov/pubmed/17299723.
8. Grosch-Woerner I, Puch K, Maier RF, et al. Increased rate of prematurity associated with antenatal antiretroviral therapy in a German/Austrian cohort of HIV-1-infected women. HIV Med. Jan 2008;9(1):6-13. Available at http://www.ncbi.nlm.nih.gov/pubmed/18199167.
9. Dola CP, Khan R, Denicola N, et al. Combination antiretroviral therapy with protease inhibitors in HIV-infected pregnancy. J Perinat Med. Nov 2 2011. Available at http://www.ncbi.nlm.nih.gov/pubmed/22044007.
10. Gonzalez-Tome MI, Cuadrado I, et al. Risk factors of preterm delivery and low birth weight in a multicenter cohort of HIV-infected pregnant women. Paper presented at: 18th Conference on Retroviruses and Opportunistic Infections (CROI); February 27-March 2, 2011; Boston, MA. Abstract 744.
11. Beckerman K, Albano J, et al. Exposure to combination antritretoviral (cARV) regimens containing protease inhibitors (PI) during pregnancy and revalence of low birth weight/preterm delivery (LBS/PTD) among women with low pre-existing risk for LBW/PTD: a astratified analysis of 10,082 pregnancies. Paper presented at: 6th IAS Conference on HIV Pathogenesis and Treatment and Prevention; July 17-20, 2011; Rome, Italy.
12. Kourtis AP, Schmid CH, Jamieson DJ, Lau J. Use of antiretroviral therapy in pregnant HIV-infected women and the risk of premature delivery: a meta-analysis. AIDS. Mar 12 2007;21(5):607-615. Available at http://www.ncbi.nlm.nih.gov/pubmed/17314523.
13. Rudin C, Spaenhauer A, Keiser O, et al. Antiretroviral therapy during pregnancy and premature birth: analysis of Swiss data. HIV Med. Apr 2011;12(4):228-235. Available at http://www.ncbi.nlm.nih.gov/pubmed/20726902.
14. van der Merwe K, Hoffman R, Black V, Chersich M, Coovadia A, Rees H. Birth outcomes in South African women receiving highly active antiretroviral therapy: a retrospective observational study. J Int AIDS Soc. 2011;14:42. Available at http://www.ncbi.nlm.nih.gov/pubmed/21843356.
15. Machado ES, Hofer CB, Costa TT, et al. Pregnancy outcome in women infected with HIV-1 receiving combination antiretroviral therapy before versus after conception. Sex Transm Infect. Apr 2009;85(2):82-87. Available at http://www.ncbi.nlm.nih.gov/pubmed/18987014.
16. Patel K, Shapiro DE, Brogly SB, et al. Prenatal protease inhibitor use and risk of preterm birth among HIV-infected women initiating antiretroviral drugs during pregnancy. J Infect Dis. Apr 1 2010;201(7):1035-1044. Available at http://www.ncbi.nlm.nih.gov/pubmed/20196654.
17. Lopez M, Figueras F, Hernandez S, et al. Association of HIV infection with spontaneous and iatrogenic preterm delivery: effect of HAART. AIDS. Jan 2 2012;26(1):37-43. Available at http://www.ncbi.nlm.nih.gov/pubmed/22008651.
18. Sibiude J, Warszawski J, Tubiana R, et al. Premature delivery in HIV-infected women starting protease inhibitor therapy during pregnancy: role of the ritonavir boost? Clin Infect Dis. May 2012;54(9):1348-1360. Available at http://www.ncbi.nlm.nih.gov/pubmed/22460969.
19. Powis KM, Kitch D, Ogwu A, et al. Increased risk of preterm delivery among HIV-infected women randomized to protease versus nucleoside reverse transcriptase inhibitor-based HAART during pregnancy. J Infect Dis. Aug 15 2011;204(4):506-514. Available at http://www.ncbi.nlm.nih.gov/pubmed/21791651.
20. Parekh N, Ribaudo H, Souda S, et al. Risk factors for very preterm delivery and delivery of very-small-for-gestational-age infants among HIV-exposed and HIV-unexposed infants in Botswana. Int J Gynaecol Obstet. Oct 2011;115(1):20-25. Available at http://www.ncbi.nlm.nih.gov/pubmed/21767835.
21. Cotter AM, Garcia AG, Duthely ML, Luke B, O'Sullivan MJ. Is antiretroviral therapy during pregnancy associated with an increased risk of preterm delivery, low birth weight, or stillbirth? J Infect Dis. May 1 2006;193(9):1195-1201. Available at http://www.ncbi.nlm.nih.gov/pubmed/16586354.
22. Szyld EG, Warley EM, Freimanis L, et al. Maternal antiretroviral drugs during pregnancy and infant low birth weight and preterm birth. AIDS. Nov 28 2006;20(18):2345-2353. Available at http://www.ncbi.nlm.nih.gov/pubmed/17117021.