Adverse pregnancy outcomes and risk factors in the PROMISE trial

New CROI logo 2017

Polly Clayden, HIV i-Base

The multisite, multifactorial PROMISE trial found that antiretroviral therapy (ART) in pregnancy reduced vertical transmission, but also increased the frequency of several adverse birth outcomes compared with antenatal zidovudine (AZT) alone. [1]

PROMISE was conducted at 14 sites in seven countries: India, Malawi, South Africa, Tanzania, Uganda, Zambia and Zimbabwe.

The trial randomised HIV positive women with CD4 counts 350 cells/mm3 or more (not eligible for ART based on local guidelines), who were at least 14 weeks pregnant, but not in labour, to receive one of three antenatal regimens: AZT only (Arm A), AZT plus lamivudine (3TC) plus lopinavir/ritonavir (LPV/r) (Arm B),
or tenofovir DF (TDF) plus emtricitabine (FTC) plus LPV/r (Arm C). Women receiving ART in PROMISE were randomised again to continue or stop their regimen after their first pregnancy.

Three posters at CROI 2017 reported findings from further investigations from the PROMISE trial into risk factors for adverse birth outcomes including in second pregnancies among women remaining on ART. [2, 3, 4]

Higher risk of adverse birth outcomes with lopinavir/ritonavir-based ART

The first poster showed results from an investigation into the association between antiretroviral regimen and adverse birth outcomes. LPV/r-containing ART was associated with a significantly increased risk of such outcomes after controlling for baseline factors and obstetrical complications. For severe birth outcomes, the risk was higher among women receiving TDF/FTC compared with AZT/3TC.

The investigators looked at: preterm delivery (<37 weeks); low birthweight <2500 g; composite outcome (preterm delivery, low birthweight, stillbirth, and spontaneous abortion); very preterm delivery (<34 weeks); very low birthweight (<1500 g); and severe composite outcome (very preterm delivery, very low birthweight, stillbirth, and spontaneous abortion).

They estimated gestational age at delivery by Ballard score. Multivariable models were adjusted for baseline factors: maternal age, BMI, viral load, CD4, alcohol use, country, gestational age at entry and number of previous preterm births and several obstetrical complications.

A total of 3423 women with a median age of 26 years, who enrolled and delivered in PROMISE were included in the analysis: 1507, Arm A; 1497, Arm B; and 419 Arm C.

For outcomes with preterm delivery and/or low birth rate, women receiving AZT+3TC+LPV/r (Arm B) and TDF+FTC+LPV/r (Arm C) each had higher risk for adverse birth outcomes compared with AZT alone (Arm A). When the analysis was restricted to severe outcomes, the risk associated with Arm C remained higher.

When the investigators compared the two ART regimens head-to-head, Arm C had a higher risk of severe adverse birth outcomes: very preterm delivery, AOR 2.56 (95%CI: 1.47 to 4.46) and very low birthweight, AOR 3.37 (95%CI: 1.33 to 8.53).

Several obstetrical and clinical risk factors for low birth weight and preterm delivery

An associated poster further described obstetrical and clinical risk factors for low birthweight and preterm delivery among women in PROMISE. In low-income countries, these conditions are linked to significant mortality and morbidity in newborns. Besides receipt of antenatal LPV/r-based ART, a number of obstetrical risk factors contributed to the adverse birth outcomes.

In the final multivariate models, adjusted for country and gestational age at entry, obstetrical risk factors for low birth weight and/or preterm delivery included several common complications of pregnancy: pregnancy induced hypertension; chronic hypertension; interuterine growth restriction; abruptio placenta; oligohydramnios; premature labour; premature rupture of membranes; and vaginal bleeding (low birthweight only).

Other clinical risk factors were: maternal BMI; multiple gestation; number of previous premature births; maternal age (preterm delivery only) and baseline viral load (preterm delivery only).

Although confidence intervals were very wide, the risk was extremely elevated for several risk factors including: abruptio placenta AOR 20.33 (95%CI: 3.60 to 114.81) and premature rupture AOR 10.8 (95%CI: 4.9 to 23.8) for preterm delivery; and multiple gestation AOR 21.96 (95%CI: 11.05 to 43.64), interuterine growth restriction AOR 49.09 (95%CI: 5.66 to 425.66), oligohydramnios AOR 11.04 (95%CI: 3.49 to 34.90), and premature rupture of membranes AOR 12.79 (95%CI: 5.69 to 28.77), for low birthweight.

Spontaneous abortion and stillbirth more common among women conceiving on ART

A third poster from the PROMISE substudies showed results suggesting that women randomised to continue ART after their first pregnancy who subsequently conceived were more likely to have spontaneous abortion or stillbirth compared to women randomised to stop ART.

Rates of adverse pregnancy outcomes for women who conceive on ART might be increased, but data are conflicting.

Subsequent pregnancies occurred in 277/1652 (17%) women: 144/827 continued ART and 133/825 stopped ART).

A pregnancy outcome was available for 266 women with median age 26 years (IQR 22–30) and median CD4 638 cells/mm3 (IQR 492–833) at estimated conception. At the time of conception 65% of women were virologically suppressed.

Spontaneous abortions were more common in the continue ART arm. There was a significantly higher rate in this arm when spontaneous abortions and stillbirths were combined. See Table 1.

Twelve weeks before pregnancy diagnosis, 86% in the continue ART arm were on a boosted/non-boosted PI regimen vs 6% NNRTI. In the stop ART arm (15%) restarted ART before pregnancy diagnosis. Of these 74% were on a PI regimen vs 26% NNRTI. Among those in the stop ART arm restarting in pregnancy, 53 were on PI vs 27% NNRTI. Use of integrase inhibitors was very rare (<1%) as were regimens with NRTIs only.

Of 113 women in the continue ART arm on a regimen that included a boosted or non-boosted PI, 16% had a spontaneous abortion and 5% a stillbirth. Only 8 women in this arm were on an NNRTI without PI and half of these had a spontaneous abortion and none a stillbirth.

Table 1: Pregnancy outcomes for initial subsequent pregnancy in PROMISE
Continue ART (n=140) Stop ART (n=126) p-value
Live birth 100 (71%) 100 (79%)
Spontaneous abortion 27 (19%) 13 (10%) 0.06
Stillbirth 6 (4%) 2 (2%) 0.29
Spontaneous abortion or stillbirth 33 (24%) 15 (12%) 0.02

Of 113 women in the continue ART arm on a regimen that included a boosted or non-boosted PI, 16% had a spontaneous abortion and 5% a stillbirth. Only 8 women in this arm were on an NNRTI without PI and half of these had a spontaneous abortion and none a stillbirth.

In the continue ART arm 15 women with a subsequent pregnancy were not receiving ART at the time of conception. In this group 27% had a spontaneous abortion.

In the stop ART arm, the majority of women were not receiving ART when they conceived (79%). Of these 12% had a spontaneous abortion and 1% stillbirth.

The investigators noted that pregnancy testing was frequent in PROMISE allowing for early detection of pregnancy and the opportunity to capture early losses that might be missed in clinical practice.


Large randomised trials such as PROMISE provide multiple opportunities to compare outcomes with various strategies and circumstances.

More research is needed to understand the potential mechanisms behind these findings. For the elevated risks with TDF/FTC/LPV/r, these might include an independent effect of TDF/FTC, drug-drug interactions with LPV/r or other biological factors.

Along with optimisation of ART regimens, public health interventions are urgently needed to address obstetrical risk factors. The potential for such factors must be thoroughly evaluated as part of comprehensive antenatal care for HIV positive women. The investigators rightly suggest that this includes educating women about early warning signs of adverse pregnancy so they can seek immediate medical care.

More data are needed to look at pregnancy outcomes on women who conceive on ART and this is particularly important as new regimens are introduced to ART programmes in the era of Treat all.

Observational data from Botswana, presented at CROI 2017, also show notable differences between regimens (among women conceiving on ART) but very high risk of adverse outcomes among HIV positive women receiving ART. [5]


Unless stated otherwise, all references are to the presentations and abstracts from the Conference on Retroviruses and Opportunistic Infections 2017 (CROI 2017), 13–17 February 2017. Seattle, Washington.

  1. Fowler MG et al. Benefits and risks of antiretroviral therapy for perinatal HIV prevention. N Engl J Med 2016; 375:1726-1737.
  2. Chi BH et al. Antenatal antiretroviral therapy and adverse birth outcomes: the PROMISE trial.
 Poster abstract 776. (abstract and poster)
  3. Sebikari D et al. Risk factors for low birth weight and preterm delivery in the PROMISE trial.
 Poster abstract 777. (abstract and poster)
  4. Pilotto JH et al. Subsequent pregnancy outcomes in women during follow-up in PROMISE 1077HS. Poster abstract 772. (abstract and poster)
  5. Zash R et al. Adverse birth outcomes differ by ART regimen from conception in Botswana. CROI 2017. 13–17 February 2017. Seattle, Washington. Oral abstract 25. (abstract) (webcast)

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