The Association of ART With Adverse Pregnancy Outcomes Remains Strong After Controlling for Other Well-known Demographic, Clinical, and Obstetrical Risk Factors
In these analyses of data from HIV-positive women in the PROMISE multicountry trial conducted in East and Southern Africa and India, maternal ART effect remained a significant risk factor for LBW/VLBW and PTD/VPTD adverse pregnancy outcomes compared with antenatal ZDV alone, even after adjustment for a number of key demographic/clinical and obstetrical risk factors. These multivariate analyses reinforce the initial antepartum component findings from PROMISE, which found that use of antepartum protease inhibitor (PI)-based ART was associated with increased risk of adverse birth outcomes compared with ZDV alone.
Both ART regimens (TDF/FTC/LPV/r and ZDV/3 TC/LPV/r) were associated with an elevated risk for moderate outcomes of PTD <37 weeks and LBW <2500 g, and the composite outcome (including stillbirths and spontaneous abortions) when compared with antenatal ZDV alone. The TDF-based, but not the ZDV-based, ART regimen had a significantly higher risk for severe outcomes, relative to the ZDV alone arm. Moreover, relative to the TDF-based ART regimen, the ZDV-based regimen was associated with significantly lower risk of the severe outcomes (VPTD and VLBW) but not the moderate outcomes (PTD and LBW). These strong treatment effects, which were evident even after adjustment for various risk factors, could potentially be explained by treatment-associated changes in progesterone levels: several studies report that PI regimens were associated with lowered progesterone levels, which can increase the risk of PTD.[15–18] Given that PIs have poor transplacental transfer, it is unlikely that there is a direct effect on the fetus. Other potential mechanisms may include an independent effect of TDF-FTC, or a TDF-FTC/LPV/r interaction, on hormonal levels as well as possible chronic residual immune activation that is known to occur in patients who are stable and on ART. In addition, specific ART regimens may increase the risk of placental insufficiency, potentially related to placental endothelial damage, which could likewise affect fetal growth and risk of PTD. The fact that the antiretroviral treatment effects remained significant, while controlling for multiple clinical and obstetrical risk factors, suggests that these background risk factors were not the primary biological factors mediating the ARV treatment effects. The results from this analysis are comparable with findings from some, but not all, previous research studies that showed an association between adverse pregnancy outcomes including PTD/LBW and PI-based regimens. These include studies performed in Botswana, where HIV-positive women who were on a PI-based ART regimen had significantly increased risk of preterm births, stillbirths and small for GA infants compared with those on an antenatal NRTI regimen. More recent Botswana surveillance findings reported by Zash et al found a higher risk of adverse pregnancy outcomes for women on ZDV/3 TC/LPV/r ART compared with TDF/FTC/EFV or TDF-FTC/LPV/r ART.
Additional Risk Factors for Adverse Pregnancy Outcomes in PROMISE are Consistent With Findings in General Populations of Pregnant Women
These analyses also found that a number of obstetrical, demographic, and clinical risk factors were related to adverse pregnancy outcomes among PROMISE HIV-infected women; this is consistent with findings from observational studies in non–HIV-infected populations.[24–26] In PROMISE, the demographic/clinical factors associated with LBW and/or PTD included maternal BMI at entry, HIV-RNA at baseline, history of previous PTD outcomes, and study treatment regimen. Obstetric risk factors included several common complications of pregnancy (ie, multiple pregnancy, pregnancy-induced hypertension, chronic hypertension, intrauterine growth restriction, abruptio placentae, oligohydramnios, premature labor, premature rupture of membranes, vaginal bleeding, and GA at entry).
Low maternal BMI at entry (<18.5) was a significant risk factor for PTD, with 9 of 24 low BMI mothers delivering before 37 weeks, where odds ratios were greater than 1.0 for the multivariate analyses but were only statistically significant with the data restricted to participants enrolled in period 2. Univariate analyses revealed a significant association between low BMI and LBW, but this relationship was not statistically significant in multivariate analyses. None of the low BMI mothers delivered before 34 weeks or had infants with birth weight <1500 g; thus, valid odds ratios could not be estimated. By contrast, high BMI was protective against risk of PTD, VPTD, LBW, and VLBW, where the univariate odds ratios were <1.0, but not statistically significant (except for PTD), while the adjusted odds ratios in the multivariate analyses on the full sample were all <1.0 with P values close to 0.02. The association between low maternal BMI and PTD and LBW could potentially be explained by nutritionally deficient diet, strenuous daily life, or medical illness.[27,28]
Maternal baseline HIV-RNA >20,000 copies was not associated with LBW or VLBW but was associated with significantly greater risk for PTD and VPTD in univariate analyses. In multivariate analyses, the odds ratios remained above 1.0 with the P values only remaining marginally statistically significant for PTD, but not for VPTD. This is consistent with a Kenyan study where maternal plasma and cervical HIV-RNA levels were associated with higher chances of preterm births.
GA at study entry was included in the models to adjust for the fact that mothers could be enrolled from 14-week gestation through delivery. Results indicate that those enrolling earlier in gestation were more likely to deliver prematurely and consequently, to have infants with lower birth weight than those enrolling later. However, although this could be the result of longer exposure to study drugs, it could also be a trivial result, indicating that those enrolling early simply had a longer period during which a delivery could be premature, while those enrolling late had either little or no time for this to happen. Thus, the effects of GA at entry should be interpreted with caution, but it is important to control for this variable in the multivariate analyses, since GA at entry may have implications for the effects of the other variables in the models.
In line with previous obstetrical research, multiple gestation was a very strong risk factor for PTD, VPTD, LBW, and VLBW, which remained highly significant across the multivariate analyses, including those with data restricted to participants enrolled during period 2. In the data on the full sample, history of previous preterm births was also a significant risk factor for PTD and LBW, but not for VPTD or VLBW; however, this effect was not present with data restricted to those accrued under period 2. In the general obstetric literature, both of these factors, multiple gestation and previous preterm births, are well-known risk factors for the outcomes of interest.
The effects of country (see Tables S-2 and S-3, Supplemental Digital Content, https://links.lww.com/QAI/B322) seem to be significant and complex. South Africa was chosen as the reference country for the calculation of odds ratios because of its relatively advanced level of medical care. Univariate analyses revealed that, with the exception of Tanzania, all other countries differed significantly from South Africa with respect to PTD, with Malawi, Zambia, and India showing greater risk, while Uganda and Zimbabwe seemed to be protective. Further study may be needed to understand these results.
In PROMISE, the youngest maternal age category at delivery (18 to <21 years) was a significant risk factor for PTD in univariate, but not multivariate analyses. Other studies[29,30] have shown that teenage pregnancy, which is often associated with limited access to prenatal and antenatal care, poor nutrition, and risky behaviors such as smoking and alcohol consumption, is associated with LBW, as well as PTD.
Various obstetric risk factors known to be related to adverse pregnancy outcomes were also included in these analyses. Pregnancy-induced hypertension was significantly associated with PTD, VPTD, LBW, and VLBW in univariate and multivariate analyses that included all data; it remained significant for PTD and LBW but was only marginally significant for VPTD and not significant for VLBW in data restricted to period 2. Chronic hypertension had more complex effects, exhibiting a significant association with VPTD and VLBW, but not PTD and LBW, in univariate analyses, and remaining significant for VPTD and VLBW in multivariate analyses after backward selection. Oligohydramnios was strongly associated with PTD, VPTD, LBW, and VLBW in both univariate and multivariate models. Intrauterine growth restriction was significantly associated with PTD, LBW, and VLBW in both univariate and multivariate analyses, while it was significantly associated with VPTD only in univariate analyses. Premature labor and premature rupture of membranes were each significantly associated with PTD, VPTD, LBW, and VLBW, with these effects persisting in multivariate analyses and in period 2 data. In the data on the full sample, vaginal bleeding was a significant risk factor for LBW in univariate and multivariate analyses but was not significant for the other outcomes. Abruptio placenta, which was a relatively rare event, was a risk factor for PTD, VPTD, LBW, and VLBW where relatively high odds ratios persisted throughout univariate and multivariate analyses. These findings are consistent with literature from general obstetrical observational studies concerning general risk factors associated with LBW and PTD.[24–26]
Strength and Limitations
These analyses had certain limitations. Some potential obstetrical risk factors were too rare events for inclusion in the multivariate analysis. Moreover, the only triple ART regimens were PI-based. Because of limited availability of ultrasound and potential inaccuracies in estimation of last menstrual period, the estimation of GA depended on Ballard assessment. This may have resulted in some misclassification of GA determination at birth.
However, major strengths of the PROMISE trial were that it was a randomized study which reduced the risk of potential bias, that it had a large sample size, and that it was performed at multiple international sites, hence enhancing its validity and generalizability. In addition, the PROMISE study had strong data quality, given the high degree of quality control, quarterly site visits to monitor the trial data, ongoing internal data review and presentations to the external data safety monitoring board.
J Acquir Immune Defic Syndr. 2019;81(5):521-532. © 2019 Lippincott Williams & Wilkins