title: 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.
authors.affiliation: Toronto General Research Institute, University Health Network.
authors.forename: Eszter
authors.initials: E
authors.lastname: Papp
authors.affiliation: Toronto General Research Institute, University Health Network.
authors.forename: Hakimeh
authors.initials: H
authors.lastname: Mohammadi
authors.affiliation: Women's College Research Institute, Women's College Hospital University of Toronto.
authors.forename: Mona R
authors.initials: MR
authors.lastname: Loutfy
authors.affiliation: University of Toronto St. Michael's Hospital.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Yudin
authors.affiliation: University of Toronto Mount Sinai Hospital, Toronto.
authors.forename: Kellie E
authors.initials: KE
authors.lastname: Murphy
authors.affiliation: Toronto General Research Institute, University Health Network University of Toronto.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Walmsley
authors.affiliation: St. Michael's Hospital.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Shah
authors.affiliation: St. Michael's Hospital.
authors.forename: Jay
authors.initials: J
authors.lastname: MacGillivray
authors.affiliation: University of Toronto Lakeridge Health, Rouge Valley Hospital, Ajax, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Silverman
authors.affiliation: Toronto General Research Institute, University Health Network Women's College Research Institute, Women's College Hospital.
authors.forename: Lena
authors.initials: L
authors.lastname: Serghides
mesh_terms: D000328:Adult; D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects; D045744:Cell Line, Tumor; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D005317:Fetal Growth Retardation / Q000139:chemically induced* / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D017320:HIV Protease Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D011256:Pregnancy Outcome; D011374:Progesterone / Q000378:metabolism*; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D011374:Progesterone
keywords: HIV; lopinavir; low birth weight; pregnancy; progesterone; protease inhibitors; small for gestational age