HIV Protease Inhibitor Use During Pregnancy Is Associated With Decreased Progesterone Levels, Suggesting a Potential Mechanism Contributing to Fetal Growth Restriction

Abstract

Background. Protease inhibitor (PI)–based combination antiretroviral therapy (cART) is administered during pregnancy to prevent perinatal human immunodeficiency virus (HIV) transmission. However, PI use has been associated with adverse birth outcomes, including preterm delivery and small-for-gestational-age (SGA) births. The mechanisms underlying these outcomes are unknown. We hypothesized that PIs contribute to these adverse events by altering progesterone levels.Methods. PI effects on trophoblast progesterone production were assessed in vitro. A mouse pregnancy model was used to assess the impact of PI-based cART on pregnancy outcomes and progesterone levels in vivo. Progesterone levels were assessed in plasma specimens from 27 HIV-infected and 17 HIV-uninfected pregnant women.Results. PIs (ritonavir, lopinavir, and atazanavir) but not nucleoside reverse transcriptase inhibitors (NRTIs) or nonnucleoside reverse transcriptase inhibitors reduced trophoblast progesterone production in vitro. In pregnant mice, PI-based cART but not dual-NRTI therapy was associated with significantly lower progesterone levels that directly correlated with fetal weight. Progesterone supplementation resulted in a significant improvement in fetal weight. We observed lower progesterone levels and smaller infants in HIV-infected women receiving PI-based cART, compared with the control group. In HIV-infected women, progesterone levels correlated significantly with birth weight percentile.Conclusions. Our data suggest that PI use in pregnancy may lead to lower progesterone levels that could contribute to adverse birth outcomes.

Benefits and Risks of Antiretroviral Therapy for Perinatal HIV Prevention

“…3,[18][19][20][21] Some studies have shown that protease inhibitors reduce progesterone production in the trophoblast in vitro and that low progesterone levels are associated with preterm delivery. [22][23][24][25] However, other studies have shown that nevirapine-based ART is also associated with a higher rate of preterm delivery than zidovudine plus single-dose nevirapine. 5,6 The PROMISE trial was not designed to compare protease inhibitor-based ART with NNRTI-based ART, and we cannot comment on whether the current WHO-recommended ART regimen of tenofovir, emtricitabine, and efavirenz would be associated with a lower risk of low birth weight or preterm delivery than the ART regimens in the PROMISE trial.…”

Reassuring Birth Outcomes With Tenofovir/Emtricitabine/Efavirenz Used for Prevention of Mother-to-Child Transmission of HIV in Botswana

“…As preterm delivery is the most common cause of neonatal mortality, it is critical to understand the underlying mechanism associating HIV, ART and adverse birth outcomes. Further exploration of current hypotheses linking ART to chronic placental insufficiency [22], decreased progesterone [40,41] and immunomodulatory dysfunction, (particularly Th1/Th2 shift [42]) are needed.…”

Duration of cART Before Delivery and Low Infant Birthweight Among HIV-Infected Women in Lusaka, Zambia

“…(41) Among HIV-uninfected women, low progesterone levels have been associated with lower birthweights. (42, 43) In animal models, PI-based cART regimens have been associated with decreased progesterone levels, which correlated with lower fetal weight.…”

“…(42, 43) In animal models, PI-based cART regimens have been associated with decreased progesterone levels, which correlated with lower fetal weight. (41) Recent findings from the IMPAACT PROMISE study suggest that PI-based cART increases the risk of both LBW and PTB. (44) In Zambia, women initiating treatment during pregnancy start NNRTI-based cART.…”