Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States

  •   Table of Contents

Download Guidelines

General Principles Regarding Use of Antiretroviral Drugs during Pregnancy

Combination Antiretroviral Drug Regimens and Maternal and Neonatal Outcomes

Last Updated: November 14, 2017; Last Reviewed: November 14, 2017

Panel's Recommendations Regarding Combination Antiretroviral Drug Regimens and Maternal and Neonatal Outcomes
Panel's Recommendations
  • Clinicians should be aware of a possible small increased risk of preterm delivery in pregnant women receiving antiretroviral therapy; however, given the clear benefits of such regimens for both a woman’s health and the prevention of perinatal transmission, HIV treatment should not be withheld for fear of altering pregnancy outcomes (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

Women taking antiretroviral therapy (ART) may be at increased risk for adverse pregnancy outcomes, including preterm birth or delivery (delivery before 37 weeks’ gestation), low birth weight (LBW) infants (<2,500 g), and small-for-gestational-age (SGA) infants (birth weight <10th percentile expected for gestational age). In this section, we provide a summary of the published data regarding ART and adverse neonatal outcomes. In addition, there are limited data suggesting a potential association between hypertensive disorders of pregnancy and maternal HIV. These data are summarized at the end of this section.

We have reviewed and summarized studies from 1986 to 2017 reporting on obstetric and neonatal outcomes in women with HIV. These studies are conducted in Europe (11), North America (9), sub-Saharan Africa (9), and Latin America (2). Study size and designs vary significantly; the total study participant numbers range from 183 to 10,592. The ART regimens evaluated in these studies differ and may include: 

  • No ART (8)
  • Monotherapy: Single antiretroviral (ARV) drug (19)
  • Dual therapy: Two ARV drugs (13), and
  • Multi-ARVs: At least 3 ARV drugs; protease inhibitor (PI)-based (23) or non-PI-based (27). 

Table 5. Results of Studies Assessing the Association Between Antiretroviral Regimens and Preterm Delivery lists the published, high-quality studies reporting potential effects of ART use on pregnancy outcomes. The studies’ conclusions regarding preterm birth or delivery, LBW, and SGA are provided. These data are weighted heavily regarding preterm birth or delivery (30), and fewer studies report outcomes of LBW (12), SGA (8), and stillbirth (11). 

Pregnancy Outcomes

Preterm Delivery

All the studies reviewed in this section (33) have reported outcomes related to preterm delivery. Among the 19 studies that report an association between ART use and preterm delivery, the relative risks/odds ratios for preterm delivery range from 1.2 to 3.4.1-18 Conflicting findings regarding preterm delivery and ART use may be influenced by variability in the data available for analysis. For example, some studies have reported increased rates of preterm delivery when ART is initiated before or in early pregnancy compared to later in pregnancy. Maternal factors, such as HIV disease severity, may affect the timing of ART initiation during pregnancy. These variables may be associated with preterm delivery independent of ART use.19-21 In order to control for medical or obstetrical factors associated with preterm delivery, two studies have assessed spontaneous preterm delivery alone. One study included women initiating ART during pregnancy. Neither study reported an association between ART use and preterm delivery.22,23 In general, none of the studies reviewed in this section have comprehensively controlled for all potential factors that may be associated with preterm delivery.

Preterm Delivery and Antiretroviral Therapy Exposure Before Pregnancy

Seven of the 31 studies in Table 5 report an association between ART initiation prior to pregnancy and preterm delivery.1 The relative risks and odds ratios reported range from 1.20 to 2.05; the risk is attenuated in multivariate analysis.14 These studies were conducted in Europe (3), Latin America (1), and Africa (3) and included various ART regimens (including single-drug, two-drug, and multidrug regimens). A large meta-analysis of 11,224 women in 14 European and American studies did not demonstrate an increased rate of preterm delivery among women using ART during pregnancy.4

Antiretroviral Therapy Regimens Associated with Preterm Delivery

PI-Based
Fifteen of the 31 studies in Table 5 investigate an associated risk between PI-based ART and preterm delivery. These studies include populations in Europe (4), North America (9), and Africa (3). The risk of preterm delivery ranges from 1.14 to 3.4.1,3-6,8,15,17,18,22,24,25 Five of these studies did not demonstrate a significant association between PI-based ART and preterm delivery.15,22,24-26 The recent PROMISE trial study compared zidovudine-alone to lopinavir/ritonavir ART combined with a dual NRTI backbone of either zidovudine/lamivudine or tenofovir disoproxil fumarate (TDF)/emtricitabine. Compared to women receiving zidovudine-alone, higher rates of extremely preterm delivery were reported in women receiving zidovudine/lamivudine/lopinavir/ritonavir (P < 0.001) but not TDF/emtricitabine/lopinavir/ritonavir (P = 0.77). In contrast, extremely preterm delivery rates were higher among women receiving TDF/emtricitabine/lopinavir/ritonavir than women receiving zidovudine/lamivudine/lopinavir/ritonavir (P = 0.04). These rates of very preterm deliverywere not significantly different compared to women receiving zidovudine-alone (P = 0.10). The use of ritonavir to boost a PI-based regimen may be associated with preterm delivery compared to non-boosted PI regimens. In a small, retrospective Canadian study, women taking non-boosted PI regimens did not have increased rates of preterm delivery.15 A small meta-analysis of 10 studies (8 prospective cohort, 1 randomized controlled trial, and 1 surveillance study) demonstrated an increased risk of preterm birth associated with PI -based ART, aOR 1.32 (CI 1.04-1.6) with an I2 = 47% (moderate heterogeneity). When evaluating the effects of initiating PI-based ART in the first and third trimesters of pregnancy, the pooled effect was non-significant.27

Non-PI-Based
Exposure to NRTI single-drug prophylaxis (primarily zidovudine) was not associated with preterm delivery.1 Other reports have found increased rates of preterm delivery when ART is compared with dual-ARV regimens9 and when non-nucleoside reverse transcriptase inhibitor-based ART regimens were compared with other forms of ART.20

Mechanism for Preterm Delivery

The potential mechanism of action by which PIs may increase a woman’s risk of preterm delivery is unknown. Papp et al. demonstrated in cell culture, mouse models, and in pregnant women with HIV that exposure to PIs (except for darunavir) can decrease plasma progesterone levels. Low levels of plasma progesterone during pregnancy may potentially be associated with fetal loss, preterm delivery, and LBW.28 Papp et al. subsequently demonstrated that pregnant women with HIV exposed to PI-based ART with low serum progesterone have elevated levels of human placental 20-α-hydroxysteroid dehydrogenase levels, an enzyme that inactivates serum progesterone. These women were also noted to have lower prolactin levels in comparison to controls.29

Other Pregnancy Outcomes: Low Birth Weight, Small-for-Gestational-Age, and Stillbirth 

Fewer studies included in Table 5 have evaluated the effects of ART use on outcomes of LBW, SGA, and stillbirth. Reported rates of LBW range from 7.4% to 36%.8,14,16,18,21,24,25,30-33 Of the 15 studies that address effects of ART on birth weight, five demonstrate an association between any ART use and LBW.16,31-34 Seven studies report the rates of SGA, which range from 7.3% to 31%.11,14,16,18,21,26,35,36 When comparing the initiation of monotherapy in pregnancy versus ART initiated before pregnancy and continued during pregnancy, ART was associated with SGA (1.34 [95% CI, 1.05–1.7]).16 Three studies in Botswana report a positive association with ART use (both non-PI-based and PI-based) and SGA.11,18,37 Continuation of ART initiated before pregnancy and initiation of ART during pregnancy may be associated with SGA (1.8 [95% CI, 1.6–2.1] and 1.5 [1.2–1.9]).11 When compared to emtricitabine/TDF/efavirenz ART, both nevirapine-based and lopinavir/ritonavir-based ART were associated with increased SGA18 Ten studies report rates of stillbirth ranging from 0.5% to 11.4%.7,11,12,14,18,21,25,31,33 Two studies have evaluated the association between continuation of ART, both non-PI-based and PI-based, or starting ART during pregnancy and a risk of stillbirth (1.5 [95% CI, 1.2–1.8] and 2.5 [95% CI, 1.6–3.5])11 and (aRR 2.31 [95% CI, 1.64–3.26]).18 In the latter study, zidovudine/lamivudine/nevirapine was associated with a significantly increased rate of stillbirth compared to emtricitabine/TDF/efavirenz.

Maternal Outcomes

Hypertensive Disorders of Pregnancy

Limited data suggest as association of hypertensive disorders of pregnancy and maternal HIV. An earlier meta-analysis38 reported an increased association between maternal HIV and hypertensive disorders of pregnancy, but a more recent meta-analysis39 did not reveal a clear association of maternal HIV with pregnancy-induced hypertension, preeclampsia, or eclampsia. An Italian study demonstrated an increased risk for both early and late-onset preeclampsia (aOR=2.50, 95%CI, 1.51–4.15; aOR=2.64, 95%CI, 1.82–3.85) as well as pre-eclampsia with severe features (aOR=2.03, 95%CI, 1.26–3.28 respectively) when comparing pregnant women living with HIV versus without HIV.40

Few studies have evaluated the effect of combination ART on pre-eclampsia. No studies have evaluated the effect of specific ARV drugs on maternal hypertension. In the NISDI cohort, women exposed to ART in the first trimester had an increased risk of preeclampsia when compared to women who were not exposed to ART (aOR = 2.3, 95% CI, 1.1–4.9)41,42 A secondary analysis of South African data revealed that amongst women with low CD4 T lymphocyte counts (<200 cells/mm3), there was an increased risk of maternal death from hypertensive disorders of pregnancy when comparing those on combination ART vs. those who received no ART during pregnancy (RR = 1.15, 95% CI, 1.02–1.29).43 It is unclear whether this finding reflects the fact that immune reconstitution associated with ART initiation plays a role in increasing inflammatory responses associated with preeclampsia/eclampsia or whether there is a direct effect of ART on this outcome. 

Unknown Effects of Newer Antiretroviral Drugs on Pregnancy Outcomes

Data are insufficient regarding the effects of newer ARV drug classes on adverse pregnancy outcomes. Therefore, potential adverse pregnancy outcomes associated with these drug classes, which include integrase inhibitors, fusion inhibitors, and CCR5 antagonists, are not addressed in this section. 

Summary

Clinicians should be aware of a possible increased risk of preterm delivery with use of ART. 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, pregnant women with HIV receiving ART should continue their provider-recommended regimens and receive regular monitoring for pregnancy complications, including preterm delivery.44

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 ARV Regimens Compared (Numbers) Association Noted Between ARV Regimens and Preterm Delivery 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 preterm delivery if ARV begun before pregnancy versus in third trimester
United States;
1990–199824
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;
1986–200445
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;
1990–200234
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 preterm delivery
  • Preterm delivery decreased with ARV compared with no ARV.
United States;
1990–20023
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;
2002–200530
681/681
  • Mono/dual NRTI (94)
  • Multi-NNRTI (257)
  • Multi-PI (330)
  • NO (compared with mono/dual NRTI)
  • No association between any ARV regimen andpreterm delivery
  • All on ARV for at least 28 days during pregnancy
    Preeclampsia/eclampsia, cesarean delivery, diabetes, low BMI associated with preterm delivery
Meta-Analysis, Europe and United States;
1986–20044
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 preterm-delivery-ARV comparison
  • No overall increase in preterm delivery with antepartum ARV
  • Preterm delivery increased in those on ARV pre-pregnancy and in first trimester compared with later use.
     
Italy;
2001–20065
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 preterm delivery: 1.21 (1.04–1.40)
  • Lack of antepartum ARV also associated with preterm delivery
  • Preterm delivery and LBW decreased over time.
     
United Kingdom, Ireland;
1990–20057
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;
2002–200722
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 preterm delivery
     
Swiss Mother and Child HIV Cohort Study;
1985–20079
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 preterm delivery compared with no ARV
  • No confounding by duration of ARV or maternal risk factors
Botswana;
2006–200810
530/530
  • LPV/r plus ZDV
    plus 3TC (267)
  • ABC
    plus ZDV
    plus 3TC (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;
2007–201037
4,347/3,659
  • ARV, regimen unspecified (70)
  • Mono (2,473)
  • Multi, 91% NNRTI (1,116)
  • NO
  • No association between multi-ART and very preterm delivery (<32 weeks' gestation)
  • Observational; multi-ART before conception associated with very-small-for-gestational-age and maternal hypertension during pregnancy
Spain;
1986–201023
519/371
  • Mono/dual NRTI (73)
  • All multi (298)
  • Multi-PI (178)
  • NO (compared with no ARV plus mono/dual)
  • Spontaneous preterm delivery not associated with multi-ARV or multi-PI before or during pregnancy
  • Preterm delivery associated with multi-ARV given in second half of pregnancy and with prior preterm delivery
Botswana; 2009–201111 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)
  • ART group classified by initiation before and during pregnancy
France; ANRS French Perinatal Cohort
1990–200912
8,696/8,491
  • Mono (950)
  • Dual (590)
  • Multi-PI (2,414)
  • YES (multi-ARV compared to mono) 1.69 (1.38–2.07)
  • YES (before conception compared to during pregnancy) 1.31 (1.11–1.55)
  • Patients on ART before and during pregnancy had increased rates of preterm delivery
United States;
2000–201136
183/183
  • Multi-PI (183)
  • NO (no control group without ART)
  • Rate of preterm delivery 18.6%
  • SGA rate 31.2%
  • NNRTI-based ART less likely to have SGA 0.28 (0.1–0.75)
United States; 2007-201013 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
  • Preterm delivery 1.55 (1.16–2.07); spontaneous preterm delivery 1.59 (1.10–2.30)
     
N/A
Latin America;
2002–201214
1,512/1,446
  • Multi-PI (907)
  • Multi-non-PI (409)
  • Mono/dual (130)
  • No ART or ART <28 days (66)
  • YES (when on ARVs at conception): preterm delivery 1.53 (1.11–2.09)
  • ART for treatment rather than prophylaxis associated with increased rates of LBW (<2,500 g) infants: LBW 1.8 (1.26–2.56)
  • Multi-non-PI associated with decreased risk of LBW (0.33 [0.14–0.74]) and stillbirth (0.11 [0.04-0.34]) 
  • Multi-PI associated with decreased risk of stillbirth: 0.14 (0.05–0.34)
     
Uganda;
2009–201246
356/356
  • Multi-PI, (LPV/r) (179)
  • Multi-non-PI (EFV) (177)
  • NO (no control group without ART)
  • Trend in increased preterm delivery among women starting ART 24–28 week GA was NS: aOR 1.76 (0.96–3.23)
Italy;
1997–201347
158/158
  • Mono/dual (27)
  • Multi-PI (114)
  • Multi-non-PI (17)
  • NO (no control group without ART)
  • Preterm delivery rate was 17% for this cohort, trend towards association with longer duration of ART: 2.82 (0.35–8.09)
Canada;
1988–201115
589/530
  • Multi-non-boosted PI (220)
  • Multi-boosted PI with RTV (144)
  • Multi-non-PI (166)
  • Mono (77)
  • No ART (59)
  • YES (compared to multi-non-boosted PI) 2.01 (1.02–3.97)
  • NO (non-PI compared to non-boosted PI) 0.81 (0.4–1.66)
  • Highest risk of preterm delivery among women not taking ART compared to non-boosted PI group: 2.7 (1.2–6.09)
United Kingdom;
2007–201225
493/493
  • Multi-PI, LPV/r
  • Multi-PI, ATV/r
  • NO (comparing two PI-based regimens) aOR 1.87 (0.93–3.75)
  • Rate of preterm delivery 13% among women who conceived on ART and 14% among women who started ART during pregnancy.
  • In multivariate analysis, a history of preterm delivery was associated with recurrent preterm delivery: aOR 5.23 (1.91–14.34)
     
Republic of the Congo;
2007–201231
188/188
  • Multi-non-PI, EFV-based (31)
  • Multi-non-PI, NVP-based (146)
  • NO (comparing EFV 13% vs NPV 10%)
  • Rate of preterm delivery 11%, no difference between study groups
    LBW increased in EFV group (33% vs 16%, P = 0.04).
  • Stillbirth rate 4% (8/188)
Tanzania;
2004–201116
3,314/2,862
  • Multi (1,094)
  • Mono (1,768)
  • No ART (452-excluded)
  • YES (Multi before pregnancy vs Mono): 1.24 (1.05–1.47)
    Very preterm delivery, YES (Multi before pregnancy vs Mono):1.42 (1.02–1.99)
  • NO (Multi during pregnancy compared to Mono): 0.85 (0.7–1.02)
     
  • Rate of preterm delivery 29%; women who conceived on ART more likely to have preterm delivery compared to women on ZDV monotherapy. 
  • Pregnancy-induced hypertension associated with preterm delivery: 1.25 (1.03–1.51)
     
67 Countries and US Territories, 1989-2013; APR33 14,684/12,780 (ZDV), 1,904 (non-ZDV)
  • Multi
  • ARV with ZDV
  • ARV without ZDV
  • NO (any ZDV-ARV vs non-ZDV-ARV exposure): 1.0 (0.9–1.2)
  • Preterm delivery rate 12%
  • LBW rate 16%, RR of LBW with ZDV-ART vs non-ZDV ART RR: 1.2 (1.0–1.3), P = 0.02
  • Stillbirth rate: 1.5%, RR 0.8 (0.5–1.1)
Texas, United States; 1984–201426
1,004/792
  • Multi, PI ART (597); non-PI ART (230)
  • No ART (177)
 

  • NO (non-PI ART vs PI-ART): 0.9 (0.5–1.5)
  • Rate of preterm delivery: 13% to 21% 
  • Rate of SGA: 19% to 23%, OR 1.3 (0.8–1.9)
 

India, Malawi, South Africa, Tanzania, Uganda, Zambia, Zimbabwe, PROMISE Trial; 2011–201432
3,490/3,096
  • Mono (1,386)
  • All Multi (2,710)
  • ZDV-based (1385)
  • TDF-based (325)
 

  • YES (Multi after 14 weeks vs mono)
  • Rate of preterm delivery: 21% on ZDV-based ART compared to ZDV-mono (P < 0.001).
  • Rate very preterm delivery: 6% in TDF-based ART and 3% in ZDV-based ART (P = 0.04)
  • LBW was more common in ZDV-based ART (23% vs. 12%) in ZDV-alone (P < 0.001) and TDF-based ART (17% vs 9%) in ZDV-alone, (P = 0.004)
 

United States and Puerto Rico; SMARTT 2007–201617
1,864/1,491
  • Multi (1,491)
  • YES: 1.59 (1.2–2.1)

  • PI-based ART exposure in 1st trimester was associated with increased risk of spontaneous preterm delivery compared with no first-trimester ART
South Africa; 2011–201421 3,723/3,547
  • Dual (974)
  • Multi (2,573)
 

  • NO 
  • Dual: 0.2 (0.08–0.5)
  • Multi: 0.3 (0.1–0.9)
 

  • Preterm delivery rate regardless of ART: 22% to 23%
  • LBW rate on ART: 9% to 15%. Risk of LBW: Dual 0.06 (0.02–0.2) and multi 0.12 (0.04–0.4)
  • SGA rate on ART: 7% to 9%. Risk of SGA: Dual 0.37 (0.1 to 1.5) and multi 0.3 (0.07 to 0.9)
  • Stillbirth rate on dual (1.2%) and multi (2.2%). Risk of stillbirth: Dual 0.08 (0.04–0.2) and multi 0.2 (0.1–0.3)
Botswana; 2012–201418
11,932/10,592
  • Multi, PI-based (398)
  • Multi, NNRTI-based (4,597)
 

  • YES
  • Multi PI-based: 1.36 (1.06–1.75)
  • Multi NNRTI-based: 1.14 (1.01–1.29) 
 

  • SGA rates were significantly higher in multi PI-based ART (27.7% and 20.4%) and NVP-based ART (24.9% and 28.2%) compared to EFV-based ART (16.9%).
  • Stillbirth rates were higher in nevirapine-based ART: 2.31 (1.64–3.26). 
 
19 Countries, 5 Continents; 2002–201327
23,490 (meta-analysis 10 studies)
  • Multi, PI-based
  • Multi, PI-sparing 
  • YES
  • Multi-PI based ART: 1.3 (1.04–1.6), I2 =47%

  • 6 of 10 studies demonstrated increased risk of preterm delivery: aOR (1.2–4.14)
Note: The data presented in the column Association Noted between ARV Regimens and Preterm Delivery represent the published results of the study in the corresponding row. Depending on the study designs, these are adjusted and unadjusted odds ratios and relative risks.

Key to Acronyms: 3TC = lamivudine; ABC = abacavir; aOR = adjusted odds ratio; ART = antiretroviral therapy; ARV = antiretroviral; BMI = body mass index; CD4 = CD4 T lymphocyte; dual = two ARV drugs; EFV = efavirenz; GA = gestational age; LBW = low birth weight; mono = single ARV drug; multi = three or more ARV drugs; multi-PI = combination ARV with PI; LPV/r = lopinavir/ritonavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NS = non-significant; OR = odds ratio; PI = protease inhibitor; RR = relative risk; SGA = small for gestational age; TDF = tenofovir disoproxil fumarate; ZDV = zidovudine 

References

  1. European Collaborative Study, Swiss Mother and Child HIV Cohort Study. Combination antiretroviral therapy and duration of pregnancy. AIDS. 2000;14(18):2913-2920. Available at http://www.ncbi.nlm.nih.gov/pubmed/11398741.
  2. European Collaborative Study. Levels and patterns of neutrophil cell counts over the first 8 years of life in children of HIV-1-infected mothers. AIDS. 2004;18(15):2009-2017. Available at http://www.ncbi.nlm.nih.gov/pubmed/15577622.
  3. 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.
  4. 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.
  5. 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.
  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. 2007;119(4):e900-906. Available at http://www.ncbi.nlm.nih.gov/pubmed/17353299.
  7. 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.
  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. 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.
  10. 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.
  11. Chen JY, Ribaudo HJ, Souda S, et al. Highly active antiretroviral therapy and adverse birth outcomes among HIV-infected women in Botswana. J Infect Dis. 2012;206(11):1695-1705. Available at http://www.ncbi.nlm.nih.gov/pubmed/23066160.
  12. 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.
  13. 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.
  14. Kreitchmann R, Li SX, Melo VH, et al. Predictors of adverse pregnancy outcomes in women infected with HIV in Latin America and the Caribbean: a cohort study. BJOG. 2014;121(12):1501-1508. Available at http://www.ncbi.nlm.nih.gov/pubmed/24602102.
  15. Kakkar F, Boucoiran I, Lamarre V, et al. Risk factors for pre-term birth in a Canadian cohort of HIV-positive women: role of ritonavir boosting? J Int AIDS Soc. 2015;18:19933. Available at http://www.ncbi.nlm.nih.gov/pubmed/26051165.
  16. Li N, Sando MM, Spiegelman D, et al. Antiretroviral therapy in relation to birth outcomes among HIV-infected eomen: a cohort study. J Infect Dis. 2015. Available at http://www.ncbi.nlm.nih.gov/pubmed/26265780.
  17. Van Dyke RB, Chadwick EG, Hazra R, Williams PL, Seage GR 3rd. The PHACS SMARTT Study: assessment of the safety of in utero exposure to antiretroviral drugs. Front Immunol. 2016;7:199. Available at https://www.ncbi.nlm.nih.gov/pubmed/27242802.
  18. Zash R, Jacobsen DM, Mayondi G, et al. Dolutegravir/tenofovir/emtricitabine (DTG/TDF/FTC) started in pregnancy is as safe as efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC) in nationwide birth outcomes surveillance in Botswana. Presented at: 9th International AIDS Society Conference. 2017. Paris, France.
  19. 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.
  20. 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.
  21. Moodley T, Moodley D, Sebitloane M, Maharaj N, Sartorius B. Improved pregnancy outcomes with increasing antiretroviral coverage in South Africa. BMC Pregnancy and Childbirth. 2016;16:35. Available at https://www.ncbi.nlm.nih.gov/pubmed/26867536.
  22. 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.
  23. 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.
  24. 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.
  25. Perry M, Taylor GP, Sabin CA, et al. Lopinavir and atazanavir in pregnancy: comparable infant outcomes, virological efficacies and preterm delivery rates. HIV Med. 2015. Available at http://www.ncbi.nlm.nih.gov/pubmed/26200570.
  26. Duryea E, Nicholson F, Cooper S, et al. The use of protease inhibitors in pregnancy: maternal and fetal considerations. Infect Dis Obstet Gynecol. 2015;2015:563727. Available at https://www.ncbi.nlm.nih.gov/pubmed/26617456.
  27. Mesfin YM, Kibret KT, Taye A. Is protease inhibitors based antiretroviral therapy during pregnancy associated with an increased risk of preterm birth? Systematic review and a meta-analysis. Reprod Health. 2016;13:30. Available at https://www.ncbi.nlm.nih.gov/pubmed/27048501.
  28. Papp E, Mohammadi H, Loutfy MR, et al. HIV protease inhibitor use during pregnancy is associated with decreased progesterone levels, suggesting a potential mechanism contributing to fetal growth restriction. J Infect Dis. 2015;211(1):10-18. Available at http://www.ncbi.nlm.nih.gov/pubmed/25030058.
  29. Papp E, Balogun K, Banko N, et al. Low prolactin and high 20-alpha-hydroxysteroid dehydrogenase levels contribute to lower progesterone levels in HIV-infected pregnant women exposed to protease inhibitor-based combination antiretroviral therapy. J Infect Dis. 2016;213(10):1532-1540. Available at http://www.ncbi.nlm.nih.gov/pubmed/26740274.
  30. 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.
  31. Bisio F, Nicco E, Calzi A, et al. Pregnancy outcomes following exposure to efavirenz-based antiretroviral therapy in the Republic of Congo. New Microbiol. 2015;38(2):185-192. Available at http://www.ncbi.nlm.nih.gov/pubmed/25938743.
  32. Fowler MG, Qin M, Fiscus SA, et al. Benefits and risks of antiretroviral therapy for perinatal HIV prevention. N Engl J Med. 2016;375(18):1726-1737. Available at https://www.ncbi.nlm.nih.gov/pubmed/27806243.
  33. Vannappagari V, Koram N, Albano J, Tilson H, Gee C. Association between in utero zidovudine exposure and nondefect adverse birth outcomes: analysis of prospectively collected data from the Antiretroviral Pregnancy Registry. BJOG. 2016;123(6):910-916. Available at https://www.ncbi.nlm.nih.gov/pubmed/26269220.
  34. 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.
  35. Watts DH, Brown ER, Maldonado Y, et al. HIV disease progression in the first year after delivery among African women followed in the HPTN 046 Clinical Trial. J Acquir Immune Defic Syndr. 2013. Available at http://www.ncbi.nlm.nih.gov/pubmed/23846568.
  36. Aaron E, Bonacquisti A, Mathew L, Alleyne G, Bamford LP, Culhane JF. Small-for-gestational-age births in pregnant women with HIV, due to severity of HIV disease, not antiretroviral therapy. Infect Dis Obstet Gynecol. 2012;2012:135030. Available at http://www.ncbi.nlm.nih.gov/pubmed/22778533.
  37. 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.
  38. Calvert C, Ronsmans C. HIV and the risk of direct obstetric complications: a systematic review and meta-analysis. PLoS One. 2013;8(10):e74848. Available at https://www.ncbi.nlm.nih.gov/pubmed/24124458.
  39. Browne JL, Schrier VJ, Grobbee DE, Peters SA, Klipstein-Grobusch K. HIV, antiretroviral therapy, and hypertensive disorders in pregnancy: a systematic review and meta-analysis. J Acquir Immune Defic Syndr. 2015;70(1):91-98. Available at https://www.ncbi.nlm.nih.gov/pubmed/26322669.
  40. Sansone M, Sarno L, Saccone G, et al. Risk of preeclampsia in Human Immunodeficiency Virus-infected pregnant women. Obstet Gynecol. 2016;127(6):1027-1032. Available at https://www.ncbi.nlm.nih.gov/pubmed/27159742.
  41. Machado ES, Krauss MR, Megazzini K, et al. Hypertension, preeclampsia and eclampsia among HIV-infected pregnant women from Latin America and Caribbean countries. J Infect. 2014;68(6):572-580. Available at https://www.ncbi.nlm.nih.gov/pubmed/24462561.
  42. Suy A, Martinez E, Coll O, et al. Increased risk of pre-eclampsia and fetal death in HIV-infected pregnant women receiving highly active antiretroviral therapy. AIDS. 2006;20(1):59-66. Available at https://www.ncbi.nlm.nih.gov/pubmed/16327320.
  43. Sebitloane HM, Moodley J, Sartorius B. Associations between HIV, highly active anti-retroviral therapy, and hypertensive disorders of pregnancy among maternal deaths in South Africa 2011-2013. Int J Gynaecol Obstet. 2017;136(2):195-199. Available at https://www.ncbi.nlm.nih.gov/pubmed/28099739.
  44. The American College of Obstetricians Gynecologists Committee on Practice Bulletins-Obstetrics. Practice bulletin no. 130: prediction and prevention of preterm birth. Obstet Gynecol. 2012;120(4):964-973. Available at http://www.ncbi.nlm.nih.gov/pubmed/22996126.
  45. 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.
  46. Koss CA, Natureeba P, Plenty A, et al. Risk factors for preterm birth among HIV-infected pregnant Ugandan women randomized to lopinavir/ritonavir- or efavirenz-based antiretroviral therapy. J Acquir Immune Defic Syndr. 2014;67(2):128-135. Available at http://www.ncbi.nlm.nih.gov/pubmed/25072616.
  47. d'Arminio Monforte A, Galli L, Lo Caputo S, et al. Pregnancy outcomes among ART-naive and ART-experienced HIV-positive women: data from the ICONA foundation study group, years 1997-2013. J Acquir Immune Defic Syndr. 2014;67(3):258-267. Available at http://www.ncbi.nlm.nih.gov/pubmed/25314248.

Download Guidelines