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Risk Factors for Preterm Birth Among HIV-Infected Pregnant Ugandan Women Randomized to Lopinavir/Ritonavir- or Efavirenz-Based Antiretroviral Therapy

Koss, Catherine A. MD*,†; Natureeba, Paul MBChB; Plenty, Albert MPH†,‡; Luwedde, Flavia MBChB; Mwesigwa, Julia MBChB, MSc; Ades, Veronica MD†,§; Charlebois, Edwin D. MPH, PhD†,‡; Clark, Tamara D. MPH*,†; Achan, Jane MBChB, MMed, PhD†,‖; Ruel, Theodore MD†,¶; Nzarubara, Bridget MBChB, MSc; Kamya, Moses R. MBChB, MMed, MPH, PhD†,#; Havlir, Diane V. MD*,†; Cohan, Deborah MD, MPH†,**

JAIDS Journal of Acquired Immune Deficiency Syndromes: October 1st, 2014 - Volume 67 - Issue 2 - p 128–135
doi: 10.1097/QAI.0000000000000281
Clinical Science
Free

Background: Protease inhibitor–based antiretroviral therapy (ART) has been associated with preterm birth in some studies. We examined risk factors for preterm birth among women randomized to lopinavir/ritonavir (LPV/r)- or efavirenz (EFV)-based ART.

Methods: This was a planned secondary analysis of the PROMOTE-Pregnant Women and Infants Study, an open-label, randomized controlled trial comparing the risk of placental malaria among HIV-infected, ART-naive pregnant Ugandan women assigned to initiate LPV/r- or EFV-based ART at 12–28 weeks gestation. Gestational age was determined based on last menstrual period and ultrasound biometry. All women received bednets and trimethoprim–sulfamethoxazole. Stillbirths, spontaneous abortions, and multiple gestations were excluded from the primary analysis. Potential risk factors for preterm birth (<37 weeks gestation) were evaluated by univariate and multivariate logistic regression.

Results: Three hundred fifty-six women were included in this analysis. At enrollment, median gestational age was 21 weeks and median CD4 cell count was 368 cells per cubic millimeter. 14.7% of deliveries in the EFV arm and 16.2% in the LPV/r arm were preterm. Preterm birth was associated with gestational weight gain below 0.1 kg/week versus 0.1 kg/week or more [odds ratio (OR) = 2.49; 95% confidence interval (CI): 1.38 to 4.47; P = 0.003]. Neither ART regimen of LPV/r versus EFV (OR = 1.12; 95% CI: 0.63 to 2.00; P = 0.69) nor placental malaria (OR = 0.74; 95% CI: 0.38 to 1.44; P = 0.37) was associated with preterm birth.

Conclusions: LPV/r was not associated with an increased risk of preterm birth compared with EFV. However, interventions are needed to address modifiable risk factors for preterm birth, such as nutritional status (ClinicalTrials.gov, NCT00993031).

*HIV/AIDS Division, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, CA;

Makerere University-University of California, San Francisco Research Collaboration, Kampala, Uganda;

Center for AIDS Prevention Studies, Department of Medicine, University of California, San Francisco, San Francisco, CA;

§Department of Obstetrics and Gynecology, New York University, New York, NY;

Medical Research Council Unit, The Gambia;

Division of Infectious Diseases, Department of Pediatrics, University of California, San Francisco, San Francisco, CA;

#Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda; and

**Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA.

Correspondence to: Catherine A. Koss, MD, HIV/AIDS Division, San Francisco General Hospital, University of California, San Francisco, Box 0874, San Francisco, CA 94110 (e-mail: catherine.koss@ucsf.edu).

Supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01 HD059454, D.V.H.) and a training grant from the National Institute of Allergy and Infectious Diseases (T32 AI060530, D.V.H./C.A.K.) at the National Institutes of Health. AbbVie Pharmaceuticals donated lopinavir/ritonavir (Aluvia) for the parent trial. Gilead donates medications for participants in a separate NIH-funded study led by D.V.H. but provides no financial support. All other authors have no conflicts of interest to disclose.

D.C., D.V.H., E.D.C., and M.R.K. designed the study. P.N., F.L., J.M., V.A., B.N., and T.C. contributed significantly to the acquisition of data. C.A.K., A.P., E.D.C., M.R.K., D.V.H., and D.C. analyzed and interpreted the data. C.A.K. and D.V.H. authored the article with input and important revisions from all authors, including P.N., A.P., F.L., J.M., V.A., E.D.C., T.D.C., J.A., T.R., B.N., M.R.K., and D.C.

Presented at the Conference on Retroviruses and Opportunistic Infections, March 6, 2013, Atlanta, GA (Abstract 183LB) and the Conference on Retroviruses and Opportunistic Infections, March 4, 2014, Boston, MA (Abstract 867).

Received March 26, 2014

Accepted May 09, 2014

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INTRODUCTION

Combination antiretroviral therapy (ART) is now recommended for all HIV-infected pregnant and breastfeeding women, regardless of CD4 cell count, for the prevention of mother-to-child transmission of HIV.1 This strategy is also expected to improve women's health and reduce transmission to their partners, particularly if therapy is continued for life.2 With the global scale-up of HIV treatment, large numbers of pregnant women will be starting ART in resource-limited settings. Several previous studies have shown a small, but significant, association between antiretroviral medications (ARVs),3–11 particularly protease inhibitors (PIs),12–16 and preterm birth, whereas others have not.17–19 Preterm birth is the leading cause of neonatal deaths worldwide and is a major cause of developmental disability in surviving children.20 The care of premature infants poses a significant challenge to the existing health care infrastructure in resource-limited settings. In Uganda, the preterm birth rate in the general population ranks 29th in the world at 13.6%, compared with the global preterm birth rate of 11.1%.20,21 Additional studies are needed to evaluate possible risk factors for preterm birth, including ARVs.

Previous observational studies, mainly conducted in Europe and North America, have generated conflicting results regarding the potential association between ARVs and preterm birth. Several studies have shown an increased risk of preterm birth with ART use compared with no ARV exposure or ARV monotherapy or dual therapy,3–11 with some studies showing an association specifically with PIs,12–16 whereas other studies have not demonstrated this association.17–19 Data from Africa are also conflicting. The Mma Bana study, a randomized controlled trial in Botswana, found an increased risk of preterm birth with lopinavir/ritonavir (LPV/r)-based ART compared with a triple NRTI ART regimen.22,23 In contrast, the Kesho Bora study, which randomized women in Burkina Faso, Kenya, and South Africa to LPV/r-based triple ARV prophylaxis versus zidovudine plus single-dose nevirapine (sdNVP), did not find a difference in rates of preterm birth.24

As more HIV-infected pregnant women initiate and continue ART in resource-limited settings, it will be critical to understand risk factors for preterm birth in this population. We sought to evaluate potential risk factors for preterm birth, including ART exposure, among HIV-infected pregnant women at any CD4 cell count who were randomized to receive LPV/r- or efavirenz (EFV)-based ART.

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METHODS

Study Design and Population

We conducted a planned secondary analysis of preterm birth in the PROMOTE-Pregnant Women and Infants Study (ClinicalTrials.gov, NCT00993031). This was an open-label, single-site, randomized trial comparing the risk of placental malaria among HIV-infected, ART-naive pregnant Ugandan women who were randomized at study enrollment to start LPV/r- or EFV-based ART at 12–28 weeks gestation. Women were assigned to a treatment arm and started ART on the date of enrollment. Results of the primary study end point (placental malaria) have been described previously.25

The study was conducted at Tororo District Hospital (TDH) in rural eastern Uganda. Women were recruited from the TDH antenatal clinic and HIV testing service, the AIDS Support Organization (an HIV clinic in Tororo), and other health centers in the surrounding area. Eligible women were aged at least 16 years, infected with HIV-1 with confirmation by 2 assays, and lived within 30 km of the study site. Participants had either never received ART or had received sdNVP or other abbreviated monotherapy or dual therapy for prevention of mother-to-child transmission more than 24 months before enrollment. Women were eligible for enrollment at any CD4 cell count. Women were excluded if they had previous dose-limited toxicity to trimethoprim–sulfamethoxazole (TS) within 14 days, active tuberculosis or other WHO stage 4 disease, cardiac disease, or abnormal laboratory values including hemoglobin <7.5 g/dL, absolute neutrophil count <750 cells per cubic millimeter, platelet count <50,000 cells per cubic millimeter, ALT >225 U/L, AST >225 U/L, total bilirubin ≥2.5 times the upper limit of the normal range, and creatinine ≥1.8 times upper limit of the normal range.

All participants provided written informed consent in their preferred language. The study protocol was approved by the Makerere University Faculty of Medicine's Research and Ethics Committee, the Ugandan National Council of Science and Technology, and the Committee on Human Research at the University of California, San Francisco.

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Study Procedures

At enrollment, all women underwent a history and physical examination and collection of baseline laboratory studies. All women received daily TS and insecticide-treated bednets. Women were also given a basic care package including a safe water vessel, multivitamins, and condoms. Antepartum study visits occurred every 4 weeks until delivery and as needed for any adverse events or health conditions requiring evaluation. Women were encouraged to deliver at TDH. Socioeconomic status was assessed by performing principal component analysis of questions regarding household possessions, as previously described.26

Gestational age at enrollment was determined based on last menstrual period (LMP) and ultrasound measurement of biparietal diameter, head circumference, abdominal circumference, and femur length. Estimated gestational age was based on LMP if the ultrasound was concordant within 7 days before 13 weeks gestation, 14 days at 13–24 weeks gestation, and 21 days at 25 or more weeks of gestation, and was based on ultrasound if LMP and ultrasound did not concur.

Enrollment was stratified at study entry by gravidity (gravida 1 versus gravida 2 or higher) and gestational age at the time of enrollment (less than 24 weeks versus 24 or more weeks). Randomization was performed in permuted blocks of 2 or 4. Participants were randomized 1:1 to receive LPV/r plus lamivudine/zidovudine or EFV plus lamivudine/zidovudine. Women received 2 tablets of LPV/r 200 mg/50 mg twice daily; the dose was increased to 3 tablets twice daily from 30 weeks gestation until delivery, and then reduced to 2 tablets twice daily. The dose of EFV was 600 mg daily. Women in both arms received lamivudine/zidovudine 150 mg/300 mg twice daily. AbbVie Pharmaceuticals (North Chicago, IL) provided LPV/r (Aluvia) for study participants.

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Outcomes

The primary outcome of interest for this analysis was preterm birth, defined as less than 37 weeks gestation. Stillbirths and spontaneous abortions were excluded from the analysis of the primary outcome. Secondary outcomes included very preterm birth (less than 32 weeks gestation) and a composite outcome of preterm birth, stillbirth, and spontaneous abortion. Multiple gestations were excluded from all analyses.

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Statistical Analysis

Baseline characteristics of enrolled patients were compared using the χ2 or Fisher exact test for categorical variables or the Wilcoxon rank-sum test for continuous variables. We used univariate and multivariate logistic regression modeling to evaluate potential risk factors for preterm birth. The multivariate analysis included potential risk factors that were unevenly distributed between study arms at baseline (P < 0.10) or associated with preterm birth on univariate analysis (P < 0.10). Given previous studies suggesting an association between preterm birth with use of PIs, ART regimen was also included in the multivariate model.12–16 Weekly gestational weight gain was defined as the change in weight from study enrollment until the last antenatal weight measurement before delivery, divided by the time from enrollment until that visit. In addition, weight gain within the first 28 days after enrollment was evaluated. This analysis excluded 1 woman with fewer than 28 days of follow-up before delivery. Statistical analysis was performed using Stata software, version 13 (StataCorp, College Station, TX).

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RESULTS

Study Participants

From December 2009 through September 2012, a total of 391 patients were enrolled and randomized to a study arm; 2 were later found to be ineligible for the study, leaving a total of 389 eligible patients who were enrolled (Fig. 1). Analysis of the primary outcome included a total of 356 women who delivered live-born singleton infants; 177 women had been assigned to EFV and 179 women had been assigned to LPV/r. Baseline demographic and clinical characteristics were similar between the ART randomization arms (Table 1), with the exception of time since HIV diagnosis, with more women in the EFV arm than the LPV/r arm diagnosed with HIV in the 3 years before enrollment (P = 0.011). Although time since HIV diagnosis was correlated with previous use of TS, the proportion of women taking TS before enrollment was similar in each study arm (64.4% in the EFV arm and 62.6% in the LPV/r arm). Median maternal age was 30 years [interquartile range (IQR), 26–33] in the EFV arm and 29 years (IQR, 25–33) in the LPV/r arm. Median CD4 cell count was 369 cells per cubic millimeter (IQR, 271–487) in the EFV arm and 368 cells per cubic millimeter (IQR, 281–510) in the LPV/r arm.

FIGURE 1

FIGURE 1

TABLE 1

TABLE 1

All women underwent ultrasound confirmation of dating. Gestational age was determined by LMP for the 1 woman enrolled before 13 weeks gestation, for 152 of 268 (56.7%) women enrolled at 13–24 weeks, and for 55 of 87 (63.2%) women enrolled at 25–28 weeks. Median gestational age at enrollment was 21 weeks in each study arm. Fifty-seven women in the EFV arm and 58 women in the LPV/r arm enrolled between 24 and 28 weeks gestation.

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Gestational Age at Delivery and Relationship of ART to Preterm Birth

Most women delivered between 36 and 41 weeks gestation, with a similar distribution among women taking EFV and LPV/r (Fig. 2). Median gestational age at delivery was 39.1 weeks (IQR, 37.9–40.4) in the EFV arm and 38.6 weeks (IQR, 37.3–39.9) in the LPV/r arm. The prevalence of preterm birth was 15.4% among all live-born singleton infants. In the EFV arm, 26 (14.7%) women delivered preterm, whereas in the LPV/r arm, 29 (16.2%) women delivered preterm. In total, 19 infants were delivered by cesarean section. Five preterm deliveries (3 in the EFV arm and 2 in the LPV/r arm) were cesarean deliveries; the remaining preterm deliveries were spontaneous.

FIGURE 2

FIGURE 2

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Univariate Analysis of Potential Risk Factors for Preterm Birth

Women who gained <0.1 kg/week during the study period versus ≥0.1 kg/week had higher odds of preterm birth [odds ratio (OR) = 2.49; 95% confidence interval (CI): 1.38 to 4.47; P = 0.003] (Table 2). The OR for the association between weight gain within 28 days of enrollment and preterm birth was 0.84 (95% CI: 0.74 to 1.00; P = 0.055). In addition, gestational age of 24–28 weeks at ART initiation was associated with higher odds of preterm birth than ART initiation at 12–23 weeks gestation (OR = 1.95; 95% CI: 1.09 to 3.51; P = 0.03). Neither ART regimen of LPV/r versus EFV (OR = 1.12; 95% CI: 0.63 to 2.00; P = 0.69) nor placental malaria by histopathology was associated with preterm birth (OR = 0.74; 95% CI: 0.38 to 1.44; P = 0.37). There was no association between preterm birth and maternal age, socioeconomic status, gravidity, baseline CD4 cell count, baseline HIV-1 RNA, or anemia.

TABLE 2

TABLE 2

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Multivariate Analysis of Potential Risk Factors for Preterm Birth

In multivariate analysis, maternal gestational weight gain remained significantly associated with preterm birth [adjusted OR (aOR) = 2.37; 95% CI: 1.29 to 4.36; P = 0.006] after adjustment for time since HIV diagnosis (which was unevenly distributed between study arms at baseline) and ART regimen. A trend remained toward higher odds of preterm birth with gestational age at ART initiation of 24–28 weeks versus 12–23 weeks; however, this was no longer statistically significant in the multivariate model (aOR = 1.76; 95% CI: 0.96 to 3.23; P = 0.07).

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Secondary Outcomes

Three infants in each arm (1.7%) were born very preterm. Among all singleton deliveries, 32 of 183 (17.5%) in the EFV arm and 34 of 184 (18.5%) in the LPV/r arm met the criteria for the composite outcome of preterm birth, stillbirth, or spontaneous abortion, with no significant difference between study arms (P = 0.81).

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DISCUSSION

Our study found no difference in rates of preterm birth among HIV-infected pregnant women randomized to receive LPV/r- versus EFV-based ART. We did find an increased risk of preterm birth for women who experienced gestational weight gain <0.1 kg/week during the study period. There was a trend toward an increased risk of preterm birth among women starting ART at 24–28 weeks gestation versus 12–23 weeks gestation. Placental malaria was not associated with preterm birth.

One of the important questions this study addresses is the risk of preterm birth among HIV-infected pregnant women initiating PI- versus NNRTI-based ART. A proposed mechanism for ART leading to an increased risk of preterm birth is that ART may alter Th1 and Th2 cytokine responses.27 During pregnancy, as well as with progressive HIV infection, there is a decrease in Th1 and an increase in Th2 cytokine responses. Fiore et al have hypothesized that ART reverses the normal Th1 to Th2 shift in cytokine response in pregnancy and thus may contribute to preterm delivery.

Previous observational studies have shown conflicting results regarding the risk of preterm birth with ART, with some studies showing an increased risk with ART3–11 or specifically PIs,12–16 and other studies showing no increased risk.17–19 A meta-analysis of European and American studies conducted before 2004 did not show an association between overall use of ART and preterm birth; however, there was a small, but significant, increased risk with PI use.28 In a more recent multicenter US cohort, after adjusting for confounding by ART indication and controlling for baseline CD4 cell count, HIV-1 RNA, and stage of disease, there was no association between PIs and preterm birth.29

The randomized design of PROMOTE permitted us to address the question of the association between PIs and the risk of preterm birth without the bias that may occur in observational studies. To our knowledge, only 2 other randomized trials have been published in which HIV-infected pregnant women were randomized to receive combination ART or triple ARV prophylaxis.22–24 It is interesting that our results contrast with those of the Mma Bana study, which found an increased rate of preterm birth among women on LPV/r-based ART (21.4%) compared with triple NRTI ART (11.8%).22 One notable distinction between the Mma Bana study and PROMOTE is the difference in gestational age at ART initiation. In PROMOTE, women started ART at a gestational age as early as 12 weeks and at a median of 21 weeks, whereas in the Mma Bana study, the gestational age at ART initiation was 26–34 weeks. In addition, the comparison treatment arms were different, with EFV-based ART used in PROMOTE and triple NRTI ART used in Mma Bana. The possibility cannot be excluded that both EFV and LPV/r increase the risk of preterm birth, whereas triple NRTI ART does not, thus accounting for the lack of difference in PROMOTE and an increased risk with LPV/r in Mma Bana. In addition, HIV-infected pregnant women in PROMOTE received TS prophylaxis, which has been associated with a reduced risk of preterm delivery among HIV-infected pregnant women with CD4 cell counts <200 cells per cubic millimeter.30 Similar to our findings, and in contrast to Mma Bana, the Kesho Bora study did not show a difference in rates of preterm birth with LPV/r-based triple ARV prophylaxis (13%) versus zidovudine and sdNVP (11%); however, these findings may have been limited by the later timing of ARV initiation of 28–36 weeks gestation.24 For the first 19 of 39 months of the Kesho Bora Study, women were randomized to initiate an ARV regimen at 34 weeks gestation; after a protocol change, women started ARVs as early as 28 weeks gestation.

In our study, maternal gestational weight gain of <0.1 kg/week was associated with an increased risk of preterm birth. This association remained significant with examination of gestational weight gain as a continuous variable and on multivariate analysis. In additional analyses, gestational weight gain was not associated with age, education level, socioeconomic status, CD4 cell count, viral load at enrollment, clinical malaria, placental malaria, opportunistic infections, or sexually transmitted infections. The poor gestational weight gain among many women in the study is striking. The median weekly weight gain during the study period was 0.19 kg, well below the 0.4–0.5 kg/week gestational weight gain recommended by the Institute of Medicine for women with normal prepregnancy body mass index, although specific guidelines have not been developed for women in East Africa.31 Furthermore, nearly one-fifth of women gained no weight during the study period. These results expand on our previous finding that gestational weight gain was associated with low infant birth weight and adverse birth outcomes.26 These findings are also consistent with those from a previous study of both HIV-infected and HIV-uninfected women in Malawi, in whom gestational weight gain was protective against preterm birth.32 Of note, established measures of gestational weight gain may be subject to bias associated with duration of follow-up time.33 We have attempted to mitigate this by evaluating weight gain within 4 weeks of study enrollment. However, this approach also may not fully reflect weight change over the duration of our study, in which nearly half of women who either lost weight or did not gain weight during pregnancy initially gained weight in the first month of the study. Our findings suggest that maternal nutritional status may be a modifiable risk factor for preterm birth in HIV-infected women, even those who are receiving ART.

Infection with Plasmodium falciparum during pregnancy has also been associated with adverse maternal and infant outcomes, including preterm birth, low birth weight, and infant mortality, with the highest risk of placental malaria occurring among primigravid women.34 HIV-infected women have impaired immune responses to malaria, placing them and their children at increased risk of complications from malaria.35,36 In contrast to previous studies, we did not detect an increased risk of preterm birth among women with placental malaria.34,37 Rates of placental malaria detected by histology in our study may have been lower overall because all subjects received TS, which confers protection against malaria, and because of the high proportion of multigravid women (over 80% were gravida 3 or higher).38 In addition, most women in our study (96%) had WHO stage 1 HIV disease and thus may have had relatively preserved immune responses to malaria compared with previous studies in patients with advanced HIV.

We also found a higher risk of preterm birth on univariate analysis among women starting ART later in pregnancy, at 24–28 weeks gestation versus 12–23 weeks gestation. After adjustment for weight gain and in examining gestational age at ART initiation as a continuous variable, this remained a trend but was no longer statistically significant. Previous studies have shown conflicting results regarding the impact of the timing of ART initiation on preterm birth. Several observational studies have demonstrated an association between preterm birth and continuation of preconception ART or ART exposure in the first trimester compared with later in pregnancy, although timing of ART initiation was variable among studies.11,28,39 In contrast, other studies found an increased risk of preterm birth among women starting ART during pregnancy compared with women continuing preconception ART.7,40 One of the few studies examining this question in Africa, a surveillance study of 6 hospitals in Botswana, found no difference in preterm birth with initiation of ART before 32 weeks gestation versus after 32 weeks gestation, with most women receiving NVP-based ART.3 The authors did note an increased risk of preterm birth among women taking combination ART before conception compared with all other HIV-infected women, and among women initiating combination ART during pregnancy compared with those initiating zidovudine monotherapy.

The main strengths of our study include its randomized design and ultrasound dating. Use of ultrasound improves the accuracy of measurements of gestational age, thereby reducing misclassification of preterm versus term deliveries and preterm infants versus those who are small for gestational age. In addition, we enrolled women as early as 12 weeks gestation and at any CD4 cell count, improving generalizability. One of the ART regimens included EFV, which is considered first line for all HIV-infected adults, including pregnant women, per 2013 WHO Consolidated Guidelines.1 Limitations of our study include that it was a planned secondary analysis and may not have detected a small increase in the risk of preterm birth. We also did not have information for many of the patients on substance abuse, a known risk factor for preterm birth, although based on interviews with a number of our study subjects, we believe that the prevalence of substance abuse was low.

Our study adds to the limited but growing body of literature on randomized trials of ART use in HIV-infected pregnant women. In contrast to previous studies, we did not find an increased risk of preterm birth with LPV/r-based ART. These findings support the use of LPV/r as an option for the treatment of HIV-infected pregnant women. However, preterm birth remains a significant public health problem and interventions are needed to address modifiable risk factors for preterm birth, such as nutritional status, among HIV-infected pregnant women, including those on ART.

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ACKNOWLEDGMENTS

The authors thank the women who participated in the PROMOTE-Pregnant Women and Infants trial, the dedicated PROMOTE study staff, and the practitioners at Tororo District Hospital.

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Keywords:

antiretroviral therapy, highly active; HIV; nutrition during pregnancy; premature birth; prevention of mother-to-child transmission; protease inhibitors

© 2014 by Lippincott Williams & Wilkins