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.
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.
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.
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).
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).
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.
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:© 2014 by Lippincott Williams & Wilkins
antiretroviral therapy, highly active; HIV; nutrition during pregnancy; premature birth; prevention of mother-to-child transmission; protease inhibitors