A Trial of 17-Hydroxyprogesterone Caproate (17P) to Reduce Preterm Birth Among Women Receiving Antiretroviral Therapy in Pregnancy Preterm birth (PTB) is the most common cause of neonatal death worldwide and the second leading cause of under-5 mortality. Maternal HIV complicates 1.5 million pregnancies per year and increases the risk of PTB. While antiretroviral therapy (ART) in pregnancy can virtually eliminate mother-to-child transmission, it increases the risk of PTB beyond the excess risk attributable to HIV itself. This has led us to the untenable place where, in too many instances, the price of stopping perinatal HIV is prematurity-related neonatal death. Prenatal progesterone reduces the risk of PTB among women diagnosed with shortening of the uterine cervix and among women who have experienced a prior spontaneous PTB. It is standard of care for these indications in the United States. This application has two specific aims.
In Aim 1, we propose a placebo-controlled, double-masked randomized clinical trial of the drug 17-hydroxyprogesterone (17P) to prevent PTB among HIV-infected pregnant women initiating or continuing antiretroviral drug therapy (ART) in Malawi and Zambia. Because stillbirth and preterm birth are competing risks, the trial's primary outcome will be a composite of live birth prior to 37 weeks gestation or stillbirth at any gestational age. The trial is powered to assess whether 17P has the same prophylactic efficacy among HIV-infected women as it does among women with a prior PTB (an indication for which it is FDA approved). Our specific hypothesis is that 17P will reduce the primary outcome by 38% (i.e., from 24% to 15%). The trial will randomly allocate 800 consenting women in a 1:1 ratio to receive weekly intramuscular injections of either active drug or matched placebo. We will follow women through pregnancy and mother-infant pairs to 42 days postpartum.
In Aim 2 of this application, we will study the relationship between timing of ART initiation and the risk of PTB. Our hypothesis is that HIV-infected women who start ART during pregnancy will have higher rates of PTB compared to women who enter antenatal care on ART started prior to conception. This trial will take advantage of longstanding partnerships and robust research infrastructure in Malawi and Zambia. If our primary hypothesis is confirmed ? that 17P works as well among HIV infected women as it does among those with a prior preterm birth ? we will have identified an intervention that could prevent as many as 70,000 preterm births per year worldwide.
Preterm birth and perinatal HIV are among the two biggest risks faced by neonates in many developing countries. We propose a trial of the FDA-approved drug 17-hydroxyprogesterone caproate (17P) to prevent preterm birth among 800 HIV-infected pregnant women in Malawi and Zambia.
