title: In utero exposure to zidovudine and heart anomalies in the ANRS French perinatal cohort and the nested PRIMEVA randomized trial.
abstract: BACKGROUND
  Antiretroviral (ARV) regimens during pregnancy are highly effective in preventing mother-to-child transmission of human immunodeficiency virus (HIV). Congenital heart defects (CHDs) and anomalies in cardiac function have been reported in zidovudine (ZDV)-exposed uninfected children. We explored these associations in a large observational cohort and a randomized clinical trial.
  
  
  METHODS
  Since 1986, the French Perinatal Cohort prospectively enrolled all HIV-infected women in 90 centers and collected follow-up on their children through 2 years of age. All CHDs were reviewed by a specialist blinded to exposures. Additionally, in a randomized trial (PRIMEVA ANRS 135) of 2 ARV regimens during pregnancy, 1 of which was without nucleoside reverse transcriptase inhibitors, infants had a specific follow-up including echocardiography at 1 month and 12 months.
  
  
  RESULTS
  Among 12 888 children included, ZDV exposure in the first trimester was significantly associated with CHD (1.5% vs 0.7%; adjusted odds ratio, 2.2 [95% confidence interval, 1.3-3.7]; P < .001). This association was significant for ventricular septal defects (1.1% vs 0.6%; P = .001) and other CHDs (0.31% vs 0.11%; P = .02). In the randomized trial, among 50 infants, girls (but not boys) exposed in utero to ZDV/lamivudine/ritonavir-boosted lopinavir (LPV/r) had a higher left ventricular shortening fraction at 1 month (40% vs 36%; P = .008), and an increased posterior wall thickness at 1 year (5.4 mm vs 4.4 mm; P = .01) than the LPV/r group.
  
  
  CONCLUSIONS
  This study confirms a specific association between in utero exposure to ZDV and CHDs, and a long-lasting postnatal myocardial remodeling in girls. A potential common mechanism, including the involvement of mitochondrial dysfunction, must be explored, and long-term consequences on cardiac function warrant specific attention.
  
  
  BACKGROUND
  NCT00424814.
authors.affiliation: Department of Obstetrics and Gynecology, Hôpital Louis Mourier, Colombes Department of Epidemiology, Centre de Recherche en Épidémiologie et Santé des Populations, Institut National de la Santé et de la Recherche Médicale (INSERM) U1018, Le Kremlin-Bicêtre.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Sibiude
authors.affiliation: Department of Epidemiology, Centre de Recherche en Épidémiologie et Santé des Populations, Institut National de la Santé et de la Recherche Médicale (INSERM) U1018, Le Kremlin-Bicêtre.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Le Chenadec
authors.affiliation: M3C-Pediatric Cardiology, Assistance Publique, Hôpitaux de Paris (APHP) Hôpital Necker Enfants malades, Université Paris Descartes.
authors.forename: Damien
authors.initials: D
authors.lastname: Bonnet
authors.affiliation: Department of Infectiology, AP-HP, GH Pitié-Salpêtrière, Pierre Louis Institute of Epidemiology and Public Health, Sorbonne University, UPMC, INSERM UMR-S1136.
authors.forename: Roland
authors.initials: R
authors.lastname: Tubiana
authors.affiliation: Department of Pediatrics, AP-HP Hôpital Robert Debré Université Diderot Paris 7.
authors.forename: Albert
authors.initials: A
authors.lastname: Faye
authors.affiliation: Department of Pediatrics AP-HP Hôpital Trousseau.
authors.forename: Catherine
authors.initials: C
authors.lastname: Dollfus
authors.affiliation: Department of Obstetrics and Gynecology, Hôpital Louis Mourier, Colombes Department of Epidemiology, Centre de Recherche en Épidémiologie et Santé des Populations, Institut National de la Santé et de la Recherche Médicale (INSERM) U1018, Le Kremlin-Bicêtre Université Diderot Paris 7.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mandelbrot
authors.affiliation: Department of Epidemiology, Centre de Recherche en Épidémiologie et Santé des Populations, Institut National de la Santé et de la Recherche Médicale (INSERM) U1018, Le Kremlin-Bicêtre.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Delmas
authors.affiliation: INSERM, UMR S953, Université Paris-6.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lelong
authors.affiliation: INSERM, UMR S953, Université Paris-6.
authors.forename: Babak
authors.initials: B
authors.lastname: Khoshnood
authors.affiliation: Department of Epidemiology, Centre de Recherche en Épidémiologie et Santé des Populations, Institut National de la Santé et de la Recherche Médicale (INSERM) U1018, Le Kremlin-Bicêtre Institut National d'études Démographiques, Paris Université Paris Sud, Le Kremlin-Bicêtre.
authors.forename: Josiane
authors.initials: J
authors.lastname: Warszawski
authors.affiliation: Department of Pediatrics, Hôpital Necker EA 7223: Évaluation Thérapeutique et Pharmacologie Périnatale et Pédiatrique, Université Paris Descartes, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blanche
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000627:therapeutic use; D004338:Drug Combinations; D004452:Echocardiography; D005260:Female; D005500:Follow-Up Studies; D005602:France; D015658:HIV Infections / Q000188:drug therapy* / Q000517:prevention & control / Q000635:transmission; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology*; D006345:Heart Septal Defects, Ventricular / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology; D006801:Humans; D007223:Infant; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control*; D019259:Lamivudine / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000188:drug therapy* / Q000821:virology; D011261:Pregnancy Trimester, First; D012737:Sex Factors; D014599:Uterus; D055815:Young Adult; D015215:Zidovudine / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; D004338:Drug Combinations; C109078:lamivudine, zidovudine drug combination; D019259:Lamivudine; D015215:Zidovudine
keywords: PMTCT; congenital heart defects; heart function; randomized trial; zidovudine