Risk Factors for Adverse Birth Outcomes in the PROMISE 1077BF/1077FF Trial

Dorothy Sebikari, MBChB, MPH; Mona Farhad, MS; Terry Fenton, EdD; Maxensia Owor, MBChB; Jeffrey S. A. Stringer, MD; Min Qin, PhD; Nahida Chakhtoura, MD; Benjamin H. Chi, MD, MSc; Friday Saidi, MBBS; Neetal Nevrekar, MD; Avy Violari, MD; Tsungai Chipato, MBChB, MCE; James A. McIntyre, MBChB, FRCOG; Dhayendre Moodley, PhD; Taha E. Taha, MBBS, MCM, MPH, PhD; Gerhard Theron, MD; Mary Glenn Fowler, MD, MPH


J Acquir Immune Defic Syndr. 2019;81(5):521-532. 

In This Article

Abstract and Introduction


Background:In the multicountry PROMISE 1077BF/1077FF trial, the risk of low birth weight (LBW; <2500 g) and preterm delivery (PTD; <37 weeks) was significantly higher among women initiating a protease inhibitor–based antiretroviral treatment (ART) regimen than those receiving ZDV alone. Among those assigned to a protease inhibitor regimen, tenofovir/emtricitabine was associated with the more severe outcomes of very LBW (<1500 g) and very PTD (<34 weeks) compared with zidovudine/lamivudine.

Methods:We used multivariate logistic regression to further explore these treatment findings, taking into account demographic baseline clinical and postentry obstetrical factors. We evaluated individual adverse outcomes and composites that included stillbirth and early loss/spontaneous abortion.

Results:Among 3333 women delivering at least 1 live infant, median maternal age at enrollment was 26 years; 661 (20%) were primiparous, and 110 (3.3%) reported at least 1 previous PTD. Seventeen percent of newborns were LBW, 1% were very LBW, 17% had PTD, and 3% had very PTD. Treatment allocation remained strongly associated with multiple adverse outcomes after controlling for other risk factors with both ART regimens exhibiting increased risk relative to ZDV alone. Other risk factors remaining significant in at least one of the multivariate models included the following: country, gestational age at entry, maternal age, maternal body mass index, previous PTD, history of alcohol use, baseline HIV viral titer, multiple gestation, and several obstetric risk factors.

Conclusions:ART effects on adverse pregnancy outcomes reported in the randomized PROMISE trial remained strongly significant even after controlling for demographic, baseline clinical, and obstetrical risk factors, which were also associated with these outcomes.


Among the many diverse elements of the global HIV/AIDS fight, few can compete with the remarkably successful efforts to prevent mother-to-child HIV transmission (PMTCT).[1] Current recommendations include universal HIV testing and counseling in antenatal care, followed by immediate, lifelong antiretroviral therapy (ART) for women found to be HIV seropositive. This approach, known as "Option B+,"[2,3] can reduce the risk of vertical transmission to below 1%.[4] However, exposure to ART in pregnancy may be associated with increased risk of adverse birth outcomes.[5] Studies from a variety of settings have linked antiretroviral drug exposure to a variety of adverse outcomes, including preterm birth, low birth weight (LBW), stillbirth, and neonatal death.[6–10]

The antenatal component of the Promoting Maternal and Infant Survival Everywhere (PROMISE) trial[11] compared the safety and efficacy of 3 PMTCT regimens. It found significantly lower rates of perinatal HIV transmission among women randomized to receive a 3-drug ART combination than was seen in those receiving only zidovudine antenatally with intrapartum nevirapine but also reported higher rates of adverse birth outcomes among those women receiving antepartum combination ART compared with those exposed to zidovudine alone. We sought to further explore these findings in a secondary analysis that considered demographic, baseline clinical, and postentry obstetrical factors that may have mediated any adverse antiretroviral treatment effect or that may have independently increased the probability of adverse birth outcomes.