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
Special Considerations Regarding the Use of Antiretroviral Drugs by HIV-Infected Pregnant Women and their Infants
Combination Antiretroviral Drug Regimens and Pregnancy Outcome
(Last updated:9/14/2011)
Panel’s Recommendation:
• Clinicians should be aware of a possible small increased risk of preterm birth in pregnant women receiving protease inhibitor (PI) based combination antiretroviral (ARV) regimens; however, given the clear benefits of such regimens for both the women’s health and the prevention of mother-to-child transmission, PIs should not be withheld for fear of altering pregnancy outcome (AII). |
Early data were conflicting as to whether receipt of combination 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 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 PIs compared with no drugs; women receiving combination regimens that had been initiated before their 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 (i.e., 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 prepregnancy 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 one drug was not associated with increased rates of preterm labor, 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 (WITS), 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. A prospective cohort study including 681 women from Brazil, Argentina, Mexico, and the Bahamas did not find significant associations between use of combination ARV regimens and preterm birth or low birth weight [5]. A single-center study from Miami including 1,337 women did find a 1.8-fold increased chance of preterm birth among the 134 women in the cohort who received PI-containing combination ARV regimens compared with other combination regimens, after adjustment for possible confounding variables [6]. However, women receiving PI-containing combination ARV regimens uniformly were women with advanced disease or those who had failed other combination drug regimens. The risk of low birth weight and stillbirth were not increased in any drug regimen groups. A recent 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 [7]. However, a significant but modest increased risk of preterm birth (odds ratio [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 studies have detected small but significant increases (OR of 1.2–1.5 in the largest studies) in preterm birth with PI- or non-PI-based combination ARV regimens as well [8-11]. Another variable that may confound these observational studies is the increased rate of preterm birth if the combination ARV regimen is begun before conception compared with later during pregnancy, which itself may reflect confounding by severity or indication [12]. When data from the IMPAACT P1025 observational cohort were examined by multivariable analysis to correct for HIV disease stage, PI-based combination ARV regimens were no more likely than non-PI-based combination ARV regimens to be associated with spontaneous preterm birth (OR 1.22; 95% CI, 0.70–2.12) [13]. A recent combined analysis of three large studies—two from Europe and one from the United States—found heterogeneity in the association between combination ARV regimens and preterm birth, with significant increases in Europe but not the United States. However, increased rates of preterm birth (adjusted OR [AOR] 1.5) were found in all three cohorts when combination ARV regimens were compared with dual regimens. Additional factors found to be associated with preterm birth in all three cohorts included injection drug use and more advanced HIV disease [14]. A similar increase in preterm birth in women receiving combination ARV regimens compared with dual regimens has been reported in the Swiss Mother and Child Cohort as well [15].
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.
References
1. European Collaborative Study, Swiss Mother and Child HIV Cohort Study. Combination antiretroviral therapy and duration of pregnancy. AIDS. 2000 Dec 22;14(18):2913-2920.
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. 2004 Nov 19;18(17):2337-2339.
3. Tuomala RE, Shapiro DE, Mofenson LM, et al. Antiretroviral therapy during pregnancy and the risk of an adverse outcome. N Engl J Med. 2002 Jun 13;346(24):1863-1870.
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. 2005 Apr 1;38(4):449-473.
5. Szyld EG, Warley EM, Freimanis L, et al. Maternal antiretroviral drugs during pregnancy and infant low birth weight and preterm birth. AIDS. 2006 Nov 28;20(18):2345-2353.
6. 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. 2006 May 1;193(9):1195-1201.
7. 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. 2007 Mar 12;21(5):607-615.
8. 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. 2007 May 11;21(8):1019-1026.
9. Schulte J, Dominguez K, Sukalac T, Bohannon B, Fowler MG. 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. 2007 Apr;119(4):e900-906.
10. 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. 2007 Mar 15;195(6):913-914; author reply 916-917.
11. 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. 2008 Jan;9(1):6-13.
12. 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. 2009 Apr;85(2):82-87.
13. 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. 2010 Apr 1;201(7):1035-1044.
14. Townsend C, Schulte J, Thorne C, et al. Antiretroviral therapy and preterm delivery-a pooled analysis of data from the United States and Europe. BJOG. 2010 Oct;117(11):1399-1410.
15. Rudin C, Spaenhauer A, Keiser O, et al. Antiretroviral therapy during pregnancy and premature birth: analysis of Swiss data. HIV Med. 2011 Apr;12(4):228-235.