Weekly 17 alpha-hydroxyprogesterone caproate to prevent preterm birth among women living with HIV: a randomised, double-blind, placebo-controlled trial

Abstract

Background Women with HIV face an increased risk of preterm birth. 17 alpha-hydroxyprogesterone caproate (17P) has been shown in some trials to reduce early delivery among women with a history of spontaneous preterm birth. We investigated whether 17P would reduce this risk among women with HIV. MethodsWe did a randomised, double-blind, placebo-controlled trial in pregnant women with HIV at the University Teaching Hospital and Kamwala District Health Centre in Lusaka, Zambia. Eligible patients were women aged 18 years or older with confirmed HIV-1 infection, viable intrauterine singleton pregnancy at less than 24 weeks of gestation, and were receiving or intending to commence antiretroviral therapy during pregnancy. Exclusion criteria were major uterine or fetal anomaly; planned or in situ cervical cerclage; evidence of threatened miscarriage, preterm labour, or ruptured membranes at screening; medical contraindication to 17P; previous participation in the trial; or history of spontaneous preterm birth. Eligible participants provided written informed consent and were randomly assigned (1:1) to receive 250 mg intramuscular 17P or placebo once per week, starting between 16 and 24 weeks of gestation until delivery, stillbirth, or reaching term (37 weeks). Participants and study staff were masked to assignment, except for pharmacy staff who did random assignment and prepared injections but did not interact with participants. The primary outcome was a composite of delivery before 37 weeks or stillbirth at any gestational age. Patients attended weekly visits for study drug injections and antenatal care. We estimated the absolute and relative difference in risk of the primary outcome and safety events between treatment groups by intention to treat. This trial is registered with ClinicalTrials.gov, NCT03297216, and is complete.Findings Between Feb 7, 2018 and Jan 13, 2020, we assessed 1042 women for inclusion into the study. 242 women were excluded after additional assessments, and 800 eligible patients were enrolled and randomly assigned to receive intramuscular 17P (n=399) or placebo (n=401). Baseline characteristics were similar between groups. Adherence to study drug injections was 98% in both groups, no patients were lost to follow-up, and the final post-partum visit was on Aug 6, 2020. 36 (9%) of 399 participants assigned to 17P had preterm birth or stillbirth, compared with 36 (9%) of 401 patients assigned to placebo (risk difference 0•1, 95% CI -3•9 to 4•0; relative risk 1•0, 95% CI 0•6 to 1•6; p=0•98). Intervention-related adverse events were reported by 140 (18%) of 800 participants and occurred in similar proportions in both randomisation groups. No serious adverse events were reported.Interpretation Although 17P seems to be safe and acceptable to participants, available data do not support the use of the drug to prevent preterm birth among women whose risk derives solely from HIV infection. The low risk of preterm birth in both randomisation groups warrants further investigation.Funding US National Institutes ...

Adverse perinatal outcomes associated with protease inhibitor-based antiretroviral therapy in pregnant women living with HIV: A systematic review and meta-analysis

“… 73 A potential role for low progesterone as a mediator of adverse outcomes in WLHIV inspired a recent RCT of progesterone supplementation in pregnant WLHIV on ART (mostly NNRTI-ART, only 3% PI-ART). 74 Interestingly, this RCT showed that administration of 17-alpha-hydroxyprogesterone had no effect on the primary outcomes of PTB or stillbirth, but was instead associated with a reduction in the risk of VSGA. 74 In summary, the available mechanistic data are limited and complex, and highlight the need to firmly establish the epidemiological associations between HIV/ART and specific perinatal outcomes before embarking on mechanistic and intervention studies.…”

Risk of Adverse Birth Outcomes in Two Cohorts of Pregnant Women With HIV in Zambia

“…26 However, despite complete data and high adherence, we found that 17P did not reduce the primary outcome of preterm birth or stillbirth at any gestational age in the recent Improving Pregnancy Outcomes with Progesterone (IPOP) randomized trial in Lusaka, Zambia. 27 Combining the IPOP treatment groups, we found a surprisingly low 8% risk of preterm birth, which is among the lowest ever reported among women with HIV. 3 In this study, we investigate the difference in preterm birth and stillbirth in the IPOP trial (treating both study groups as a single cohort) with participants in the Zambian Preterm Birth Prevention Study (ZAPPS study), a prospective pregnancy cohort conducted concurrently and in the same clinics as IPOP.…”

“…In the recently concluded IPOP trial, despite no effect of the intervention, there was a low overall risk of preterm birth and stillbirth among participants with HIV. 27 In this secondary analysis, we compared birth outcomes among participants in the prospective ZAPPS antenatal cohort to those in the IPOP trial (treatment groups combined) by restricting ZAPPS by the same eligibility criteria used in IPOP and then standardizing the ZAPPS cohort to the distribution of key baseline characteristics in the IPOP trial using inverse probability weighting. We found that the initial difference in risk of preterm birth or stillbirth between ZAPPS and IPOP participants was reduced but remained nearly 60% higher in ZAPPS after applying the methods to adjust for confounding.…”

“…We were unable to fully address all exclusion criteria in IPOP, namely presence of cerclage, signs of threatened abortion or preterm labor, planned preterm delivery, and major uterine or fetal anomaly due to incomplete documentation in ZAPPS, although the frequency of these were exceedingly rare reasons for exclusion among women screened for IPOP. 27 We chose not to standardize on all baseline characteristics because some were not associated with the outcome (e.g., anemia, preconceptional ART, viral load, marital status, and electricity), had comparable distribution in IPOP compared to the restricted ZAPPS cohort (e.g., ART regimen), or their prevalence was rare (e.g., smoking and bacteriuria). Additionally, CD4 testing is not part of standard practice in Zambia and thus we were unable to compare immune status between the studies; it is possible that ZAPPS participants with HIV had more advanced disease despite viral suppression being comparable.…”

“…As reported in the primary intent-to-treat analysis, despite very high adherence and retention, the intervention had no effect on the primary outcome: 36 (9%) of 399 participants assigned to 17P had preterm birth or stillbirth, compared to 36 (9%) of 401 participants assigned to placebo. 27 Retention at the delivery visit and ascertainment of the primary composite outcome was 100%. In the ZAPPS cohort, 1,450 women were enrolled, of whom 1,216 (84%) were retained at delivery and 1,208 (83%) had complete gestational age and neonatal vital status information for the primary outcome of interest.…”