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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

General Principles Regarding Use of Antiretroviral Drugs during Pregnancy

Combination Antiretroviral Drug Regimens and Pregnancy Outcome

(Last updated: August 6, 2015; last reviewed: August 6, 2015)

Panel's Recommendations

Panel's Recommendations

  • 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 the 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

Earlier Studies (Prior to 2005)

Early data are conflicting as to whether receipt of combination antiretroviral therapy (cART) during pregnancy is associated with adverse pregnancy outcomes, specifically, preterm birth (<37 weeks’ gestation). Previous studies were observational and included relatively small numbers of women who had received protease inhibitor (PI)-based cART. Inclusion of data necessary to control for maternal HIV disease stage as well as risk factors for adverse pregnancy outcomes varied, and no studies were able to assess the indication for cART.  

An initial report from the European Collaborative Study and the Swiss Mother and Child HIV Cohort Study on HIV-infected women delivering between 1986 and 2000 demonstrated a roughly 2-fold increase in the odds of preterm birth for infants exposed to cART with or without PIs compared with no antiretroviral (ARV) drugs. Women initiating cART before pregnancy were twice as likely to deliver preterm as those who initiated ARVs during the third trimester (≥28 weeks’ gestation). Exposure to nucleoside reverse transcriptase inhibitor (NRTI) single-drug prophylaxis (primarily zidovudine) was not associated with preterm birth.1

In an updated report from the European Collaborative Study, which included women who delivered from 1986 to 2004, initiation of cART before and during pregnancy was associated with preterm birth, compared to mono- or dual-NRTI ARV regimens. Use of cART before pregnancy was associated with a 2.1-fold increased risk of preterm birth at <37 weeks and a 4.4-fold increased risk of preterm birth at <34 weeks. Initiation of cART during pregnancy was associated with a 1.9-fold increased risk of preterm delivery at <37 weeks and a 2.5-fold risk of preterm birth at <34 weeks.2

In contrast, an analysis of seven prospective clinical studies of women delivering from 1990 to 1998 did not demonstrate an association between ARV regimens and adverse pregnancy outcomes. This analysis accounted for maternal CD4 T lymphocyte (CD4) cell count, HIV disease stage, and history of adverse pregnancy outcomes. Compared to no ARVs or monotherapy, cART with or without PIs was not associated with increased rates of preterm birth, low birth weight, or stillbirth.3 A subsequent analysis of the Women and Infants Transmission Study extended to women delivering through 2002 (some of whom were included in the aforementioned meta-analysis) did not find significant associations between use of ARV drugs by class or by category and adverse pregnancy outcomes.4

Recent Studies (2005–Current)

Results of studies published since 2005 are conflicting with regard to an association between preterm birth and cART use. Multiple observational studies with similar limitations published through 2008 have detected small but significant increases in preterm birth with PI- and non-PI-based cART (odds ratio [OR] 1.2–1.8 in the largest studies).5-8 A meta-analysis of 14 European and American clinical studies demonstrated that use of cART during pregnancy did not increase the overall risk of preterm birth. A subgroup analysis demonstrated a modest increased risk of preterm birth with PI-based cART use compared to non-PI based cART (OR 1.35; 95% confidence interval [CI], 1.08–1.7).9

Subsequent studies that have controlled for maternal characteristics, including HIV disease severity, have not demonstrated an association between PI-based ARV regimens and adverse pregnancy outcomes, including preterm birth and low birth weight.10-12 Other reports have found increased rates of preterm birth when cART is compared with dual-ARV regimens13 and when non-nucleoside reverse transcriptase inhibitor-based cART regimens were compared with other forms of cART.14

Conflicting findings regarding preterm birth and cART use may be influenced by variability in the data available for analysis. For example, some studies have reported increased rates of preterm birth when cART is initiated before or in early pregnancy compared to later in pregnancy. Variables other than prevention of perinatal transmission, such as HIV disease severity, may affect the timing of cART initiation during pregnancy. These variables may be associated with preterm birth independent of cART use.14,15 More recent reports have attempted to assess variables associated with cART initiation. In order to control for medical or obstetrical factors associated with iatrogenic preterm birth, two studies have assessed spontaneous preterm birth alone. One study included women initiating ARV drugs during pregnancy. Neither study reported an association between ARV use and preterm birth.16,17 

A U.S. study of women delivering from 2007 to 2010 found an increased risk of spontaneous and overall preterm birth with exposure to PI-based cART in the first trimester (<14 weeks’ gestation) compared to exposure after the first trimester to PI- or non-PI-based cART (OR 1.59; 95% CI, 1.0–2.30 and OR 1.55; 95% CI, 1.16–2.17, respectively). Exposure to non-PI-based regimens in the first trimester was not associated with increased risk of preterm birth.18 In an analysis of women enrolled in the ANRS French Perinatal Cohort from 1990 to 2009, preterm birth rates increased over time. Preterm birth was associated with cART compared to either mono- or dual-ARV regimens (adjusted odds ratio [AOR] 1.69; 95% CI, 1.38–2.07). Preterm delivery rates were highest in those initiating ARV drugs before pregnancy (AOR 1.31; 95% CI, 1.11–1.55).19 A restricted analysis within this cohort comparing boosted versus non-boosted PI-based cART regimens reported an association with iatrogenic preterm delivery and boosted PI regimens (AOR 2.03; 95% CI, 2.06–3.89). There was no association with spontaneous preterm birth. The use of boosted PI regimens was associated with medical and obstetrical complications, suggesting that the association with iatrogenic preterm delivery was mediated by these complications.

A secondary analysis of a randomized clinical trial conducted in Botswana with pregnant women with CD4 cell counts >200 cells/mm3 found an increased rate of preterm birth in women randomized to a lopinavir/ritonavir PI-based cART regimen compared to a triple nucleoside-based cART regimen (21.4% vs. 11.8%, P = 0.003).20 In a population-based observational study of 33,148 women from 6 sites in Botswana, which included 9,504 HIV-infected women, maternal HIV was significantly associated with increased risk of stillbirth, preterm birth, and small for gestational age (SGA).21 HIV-infected women initiating cART prior to conception compared to all other women were more likely to have preterm birth (AOR 1.2; 95% CI, 1.1–1.4), SGA (AOR 1.8; 95% CI, 1.6–2.1), and stillbirth (AOR 1.5; 95% CI, 1.2–1.8). Among HIV-infected women initiating ARV drugs during pregnancy, use of cART compared to use of zidovudine monotherapy was associated with higher odds of preterm birth (AOR 1.4; 95% CI, 1.2–1.8), SGA (AOR 1.5; 95% CI, 1.2–1.9), and stillbirth (AOR 2.5; 95% CI, 1.6–3.9). However, adverse pregnancy outcomes were also associated with maternal hypertension.

Clinicians should be aware of a possible increased risk of preterm birth with use of cART. Given the clear benefits for maternal health and reduction in perinatal transmission, these agents should not be withheld due to concern for increased risk of preterm delivery. Until more information is available, HIV-infected pregnant women receiving cART should continue their provider-recommended regimens and receive regular monitoring for pregnancy complications, including preterm birth.22 

Table 5. Results of Studies Assessing Associations Between Antiretroviral Regimens and Preterm Delivery
Study
Location(s);
Dates of Study
Total Number of Pregnancies/
Total on
ARV Drugs
Types of the ARV Regimens Compared (Numbers) Association Noted Between PI-Containing or Other Multi-ARV Regimens and PTD  Notes
European Collaborative Study and Swiss Mother and Child HIV Cohort Study;
1986–20001
3,920/896
  • Mono (573)
  • Multi, no PI (215)
  • Multi-PI (108)
  • YES (compared with no ARV)
  • Multi: 1.82 (1.13–2.92)
  • Multi-PI: 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)
  • Multi-PI (137)
  • NO (compared with mono)
  • Multi: 0.95 (0.60–1.48)
  • Multi-PI: 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 pre-pregnancy: 2.05 (1.43–2.95)
 N/A
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)
  • Multi-PI (134)
  • YES (compared with other multi)
  • Multi-PI: 1.8 (1.1–3.03)
  • Multi-PI 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;
1986–20049
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)
 N/A
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 of 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 at 26–34 weeks for prevention of perinatal transmission
  • All CD4 cell counts >200 cells/mm3
Botswana;
2007–201025
4,347/3,659
  • ARV, regimen unspecified (70)
  • Mono (2,473)
  • Multi, 91% NNRTI (1,116)
  • NO
  • No association between multi-cART and very PTD (<32 weeks' gestation)
  • Observational multi-ART before conception associated with very small for gestational age and maternal hypertension during pregnancy
Spain;
2000–200811
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
Botswana; 2009–201121 9,504/7,915
  • Mono (4,625)
  • All multi (3,290)
  • Multi-PI (312)
  • YES (multi-ARV before and during pregnancy compared to mono) 1.2 (1.1–1.4) and 1.4 (1.2–1.8)
  • YES (multi-PI compared to multi-no PI before pregnancy 2.0 (1.1–3.6)
  • cART group classified by initiation before and during pregnancy
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. none in first trimester
  • PTD 1.55 (1.16-2.07); spontaneous PTD 1.59 (1.10-2.30)

N/A

Key to Acronyms: 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 reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; PTD = preterm delivery

References

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