skip navigation

Skip Nav

Clinical Guidelines Portal

skip navigation

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

General Principles Regarding Use of Antiretroviral Drugs during Pregnancy

Combination Antiretroviral Drug Regimens and Pregnancy Outcome

(Last updated:3/28/2014; last reviewed:3/28/2014)

Panel's Recommendation

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 therapy; however, given the clear benefits of such regimens for both a woman’s health and prevention of perinatal transmission, PIs should not be withheld for fear of altering pregnancy outcome (AII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion

Early data were conflicting as to whether receipt of combination antiretroviral therapy (cART) during pregnancy is associated with adverse pregnancy outcomes and, in particular, preterm delivery. The European Collaborative Study and the Swiss Mother and Child HIV Cohort Study investigated the effects of cART in a population of 3,920 pregnant women who delivered between 1986 and 2000. 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 (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 pregnant women who delivered between 1986 and 2004, found a 1.9-fold increased risk of delivery at less than 37 weeks with cART started during pregnancy and a 2.1-fold increased risk with cART started prior to pregnancy compared with mono- or dual-NRTI prophylaxis.2 In this report, 767 women received cART 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 cART during pregnancy and 4.4-fold for those entering pregnancy on cART.

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 antiretroviral (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 cART) 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 cART. Table 5 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 cART 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 exposure to any ARV drug compared to no drugs or to cART 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 cART without PIs. Other reports have found increased rates of preterm birth when cART is compared with dual regimens13 and when cART regimens containing non-nucleoside reverse transcriptase inhibitors were compared with other forms of cART.14

Other variables may confound these observational studies. Some studies have found increased rates of preterm birth if cART is begun before conception or earlier in pregnancy compared with later in 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 However, a recent U.S. study found an increased risk of spontaneous and overall preterm birth with exposure to PI-containing cART in the first trimester compared to exposure only after the first trimester to PI- or non-PI-containing cART. Exposure to non-PI-containing regimens in the first trimester was not associated with increased risk of preterm birth.18 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 cART versus either mono- or dual-ARV regimens and were highest in those who had initiated ARV drugs before pregnancy.19 A restricted analysis within this cohort of PI-based cART 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 analysis of data collected during a randomized, controlled clinical trial conducted in Botswana in women with CD4 cell 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 perinatal 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).20 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 cART from before conception was not associated with very preterm delivery (AOR 0.78), which could not be assessed in the controlled clinical trial.21

Clinicians should be aware of a possible increased risk of preterm birth with use of cART; 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 cART for their HIV infection should continue their provider-recommended regimens. They should receive careful, regular monitoring for pregnancy complications including preterm delivery22 and for potential toxicities. 

Click here to view this table as an image

Table 5. Results of Studies Assessing Association Between Antiretroviral Regimens and Preterm Delivery
Study
Location(s);
Dates of Study
Total Number of Pregnancies/
Total on
ARV Drugs
Types of ARV Regimens Compared (Numbers) Association Noted Between PI-Containing or Other Multi-ARV Regimens and PTD  Notes
European Collaborative and Swiss Mother and Child HIV Cohort Study;
1986–20001
3,920/896
  • Mono (573)
  • Multi, no PI (215)
  • PI-multi (108)
  • YES (compared with no ARV)
  • Multi: 1.82 (1.13–2.92)
  • PI-multi: 2.60 (1.43–4.7)
  • Increase in PTD if ARV begun before pregnancy versus in third trimester
United States;
1990–19983
3,266/2,123
  • Mono (1,590)
  • Multi (396)
  • PI-multi (137)
  • NO (compared with mono)
  • Multi: 0.95 (0.60–1.48)
  • PI-multi: 1.45 (0.81–2.50)
  • 7 prospective clinical studies
European Collaborative Study;
1986–20042
4,372/2,033
  • Mono (704)
  • Dual (254)
  • Multi (1,075)
  • YES (compared with mono/dual)
  • Multi in pregnancy: 1.88 (1.34–2.65)
  • Multi prepregnancy: 2.05 (1.43–2.95)
 
United States;
1990–20024
2,543/not given Early (<25 weeks):
  • Mono (621)
  • Multi (≥2 without PI or NNRTI) (198)
  • Multi (with PI or NNRTI) (357) 

Late (≥32 weeks):

  • Mono (932)
  • Multi (≥2 without PI or NNRTI) (258)
  • Multi (with PI or NNRTI) (588)
  • NO (compared with mono)
  • No association between any ARV and PTD
  • PTD decreased with ARV compared with no ARV
United States;
1990–200223
1,337/999
  • Mono (492)
  • Multi (373)
  • PI-multi (134)
  • YES (compared with other multi)
  • PI-multi: 1.8 (1.1–3.03)
  • PI-multi reserved for advanced disease, those who failed other multi-ARV regimens
Brazil, Argentina, Mexico, Bahamas;
2002–200524
681/681
  • Mono/dual NRTI (94)
  • Multi-NNRTI (257)
  • Multi-PI (330)
  • NO (compared with mono/dual NRTI)
  • No association between any ARV regimen and PTD
  • All on ARV for at least 28 days during pregnancy
  • Preeclampsia/eclampsia, cesarean delivery, diabetes, low BMI associated with PTD
Meta-analysis, Europe and United States;
1986–200412
11,224/not given
  • Multi-no PI [including dual] or multi-PI (2,556)
  • YES (only comparing PI with multi)
  • PI versus multi-no PI: 1.35 (1.08–1.70)
  • 14 studies, 5 in PTD-ARV comparison.
  • No overall increase in PTD with antepartum ARV.
  • PTD increased in those on ARV pre-pregnancy and in first trimester compared with later use.
Italy;
2001–20067
419/366
  • Multi-PI second trimester (97)
  • Multi-PI third trimester (146)
  • YES
  • Multi-PI second trimester:
    2.24 (1.22–4.12)
  • Multi-PI third trimester:
    2.81 (1.46–5.39)
  • Multivariate association also with hepatitis C
United States;
1989–20046
8,793/6,228
  • Mono (2,621)
  • Dual (1,044)
  • Multi-no PI (1,781)
  • Multi-PI (782)
  • YES (compared with dual)
  • Multi-PI associated with PTD: 1.21 (1.04–1.40)
  • Lack of antepartum ARV also associated with PTD.
  • PTD and low birth weight decreased over time.
United Kingdom, Ireland;
1990–20055
5,009/4,445
  • Mono/dual (1,061)
  • Multi-NNRTI or Multi-PI (3,384)
  • YES (compared with mono/dual)
  • Multi: 1.51 (1.19–1.93)
  • Similar increased risk with PI or no-PI multi.
  • No association with duration of use.
Germany, Austria;
1995–20018
183/183
  • Mono (77)
  • Dual (31)
  • Multi-PI (21)
  • Multi-NNRTI (54)
  • YES (compared with mono)
  • Multi-PI: 3.40 (1.13–10.2)
 
United States;
2002–200716
777/777
  • Mono (6)
  • Dual (11)
  • Multi-no PI (202)
  • Multi-PI (558)
  • NO (compared PI with all non-PI)
  • Multi-PI: 1.22 (0.70–2.12)
  • All started ARV during pregnancy.
  • Analyzed only spontaneous PTD.
Swiss Mother and Child HIV Cohort Study;
1985–200713
1,180/941
  • Mono (94)
  • Dual (53)
  • Multi (PI or no PI) (409)
  • Multi-PI (385)
  • YES (compared with no ARV)
  • Multi: 2.5 (1.4–4.3)
  • No association mono/dual with PTD compared with no ARV.
  • No confounding by duration of ARV or maternal risk factors.
Botswana;
2006–2008
20
530/530
  • Lopinavir/ritonavir plus zidovudine
     plus lamivudine (267)
  • Abacavir
    plus zidovudine
    plus lamivudine (263)
  • YES
  • Multi-PI versus multi-NRTI: 2.03 (1.26–3.27)
  • Secondary analysis of data from randomized, controlled clinical trial of ARV begun 26–34 weeks for prevention of perinatal transmission.
  • All CD4-cell counts >200 cells/mm3.
Botswana;
2007–201021
4,347/3,659
  • ARV, regimen unspecified (70)
  • Mono (2,473)
  • Multi, 91% NNRTI (1,116)
  • NO
  • No association between multi-ART and very PTD (<32 weeks gestation)
  • Observational multi-ART before conception associated with very small for gestational age and maternal hypertension during pregnancy.
Spain;
2000–200810
803/739
  • Mono/dual (32)
  • Multi-no PI (281)
  • Multi-PI (426)
  • NO
  • No association between ARV and PTD
  • Greatest PTD risk if no antepartum ARV received.
Spain;
1986–201017
519/371
  • Mono/dual NRTI (73)
  • All multi (298)
  • Multi-PI (178)
  • NO (compared with no ARV plus mono/dual)
  • Spontaneous PTD not associated with multi-ARV or multi-PI before or during pregnancy
  • Iatrogenic PTD associated with multi-ARV given in second half of pregnancy and prior PTD.
United States; 2007-201018 1,869/1,810
  •  Mono/dual (138)
  • Multi-NRTI (193)
  • Multi-NNRTI (160)
  • Multi-PI (1,319)
  • YES (compared with no ARV in first trimester)
  • Multi-PI in first trimester vs. non in first trimester
  • PTD 1.55 (1.16-2.07); spontaneous PTD 1.59 (1.10-2.30)

NA


Key to Abbreviations
: ARV = antiretroviral; BMI = body mass index; dual = two ARV drugs; mono = single ARV drug; multi = three or more ARV drugs; multi-PI = combination ARV with PI; NNRTI = non-nucleoside analogue reverse transcriptase inhibitor; NRTI = nucleoside analogue reverse transcriptase inhibitor; PI = protease inhibitor; PTD = preterm delivery

References

  1. European Collaborative S, Swiss M, Child HIVCS. Combination antiretroviral therapy and duration of pregnancy. AIDS. 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. 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. 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. 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. 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 HIVDC. 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;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. 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. 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. 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; 2011; Boston, MA.
  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; 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. 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. 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. 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. 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. 2012;26(1):37-43. Available at http://www.ncbi.nlm.nih.gov/pubmed/22008651.
  18. Watts DH, Williams PL, Kacanek D, et al. Combination antiretroviral use and preterm birth. J Infect Dis. 2013;207(4):612-621. Available at http://www.ncbi.nlm.nih.gov/pubmed/23204173.
  19. 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. 2012;54(9):1348-1360. Available at http://www.ncbi.nlm.nih.gov/pubmed/22460969.
  20. 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. 2011;204(4):506-514. Available at http://www.ncbi.nlm.nih.gov/pubmed/21791651.
  21. 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. 2011;115(1):20-25. Available at http://www.ncbi.nlm.nih.gov/pubmed/21767835.
  22. The American College of Obstetricians Gynecologists Committee on Practice Bulletins-Obstetrics. Practice bulletin 130: prediction and prevention of preterm birth. Obstet Gynecol. 2012;120(4):964-973. Available at http://www.ncbi.nlm.nih.gov/pubmed/22996126.
  23. 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;193(9):1195-1201. Available at http://www.ncbi.nlm.nih.gov/pubmed/16586354.
  24. Szyld EG, Warley EM, Freimanis L, et al. Maternal antiretroviral drugs during pregnancy and infant low birth weight and preterm birth. AIDS. 2006;20(18):2345-2353. Available at http://www.ncbi.nlm.nih.gov/pubmed/17117021.