title: Evidence of Subclinical mtDNA Alterations in HIV-Infected Pregnant Women Receiving Combination Antiretroviral Therapy Compared to HIV-Negative Pregnant Women.
abstract: BACKGROUND
  Combination antiretroviral therapy (cART) can effectively prevent vertical transmission of HIV but there is potential risk of adverse maternal, foetal or infant effects. Specifically, the effect of cART use during pregnancy on mitochondrial DNA (mtDNA) content in HIV-positive (HIV+) women is unclear. We sought to characterize subclinical alterations in peripheral blood mtDNA levels in cART-treated HIV+ women during pregnancy and the postpartum period.
  
  
  METHODS
  This prospective longitudinal observational cohort study enrolled both HIV+ and HIV-negative (HIV-) pregnant women. Clinical data and blood samples were collected at three time points in pregnancy (13-<23 weeks, 23-<30 weeks, 30-40 weeks), and at delivery and six weeks post-partum in HIV+ women. Peripheral blood mtDNA to nuclear DNA (nDNA) ratio was measured by qPCR.
  
  
  RESULTS
  Over a four year period, 63 HIV+ and 42 HIV- women were enrolled. HIV+ women showed significantly lower mtDNA/nDNA ratios compared to HIV- women during pregnancy (p = 0.003), after controlling for platelet count and repeated measurements using a multivariable mixed-effects model. Ethnicity, gestational age (GA) and substance use were also significantly associated with mtDNA/nDNA ratio (p≤0.02). Among HIV+ women, higher CD4 nadir was associated with higher mtDNA/nDNA ratios (p<0.0001), and these ratio were significantly lower during pregnancy compared to the postpartum period (p<0.0001).
  
  
  CONCLUSIONS
  In the context of this study, it was not possible to distinguish between mtDNA effects related to HIV infection versus cART therapy. Nevertheless, while mtDNA levels were relatively stable over time in both groups during pregnancy, they were significantly lower in HIV+ women compared to HIV- women. Although no immediate clinical impact was observed on maternal or infant health, lower maternal mtDNA levels may exert long-term effects on women and children and remain a concern. Improved knowledge of such subclinical alterations is another step toward optimizing the safety and efficacy of cART regimens during pregnancy.
authors.affiliation: Department of Obstetrics and Gynaecology, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada; Women's Health Research Institute, BC Women's Hospital and Health Centre, Vancouver, BC, Canada; Oak Tree Clinic, BC Women's Hospital and Health Centre, Vancouver, BC, Canada.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Money
authors.affiliation: Women's Health Research Institute, BC Women's Hospital and Health Centre, Vancouver, BC, Canada.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Wagner
authors.affiliation: Women's Health Research Institute, BC Women's Hospital and Health Centre, Vancouver, BC, Canada; Oak Tree Clinic, BC Women's Hospital and Health Centre, Vancouver, BC, Canada.
authors.forename: Evelyn J
authors.initials: EJ
authors.lastname: Maan
authors.affiliation: Department of Obstetrics and Gynaecology, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Tessa
authors.initials: T
authors.lastname: Chaworth-Musters
authors.affiliation: Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Izabelle
authors.initials: I
authors.lastname: Gadawski
authors.affiliation: Department of Obstetrics and Gynaecology, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada; Women's Health Research Institute, BC Women's Hospital and Health Centre, Vancouver, BC, Canada.
authors.forename: Julie E
authors.initials: JE
authors.lastname: van Schalkwyk
authors.affiliation: Department of Paediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: John C
authors.initials: JC
authors.lastname: Forbes
authors.affiliation: Department of Obstetrics and Gynaecology, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada; Women's Health Research Institute, BC Women's Hospital and Health Centre, Vancouver, BC, Canada.
authors.forename: David R
authors.initials: DR
authors.lastname: Burdge
authors.affiliation: Women's Health Research Institute, BC Women's Hospital and Health Centre, Vancouver, BC, Canada.
authors.forename: Arianne Y K
authors.initials: AY
authors.lastname: Albert
authors.affiliation: Women's Health Research Institute, BC Women's Hospital and Health Centre, Vancouver, BC, Canada.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Lohn
authors.affiliation: Women's Health Research Institute, BC Women's Hospital and Health Centre, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Hélène C F
authors.initials: HC
authors.lastname: Côté
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005865:Gestational Age; D015658:HIV Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000254:growth & development; D006801:Humans; D007231:Infant, Newborn; D008137:Longitudinal Studies; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049590:Postpartum Period; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000473:pathology* / Q000821:virology; D011446:Prospective Studies
chemical_list: D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial