In utero exposure to venlafaxine, a serotonin-norepinephrine reuptake inhibitor, increases cardiac anomalies and alters placental and heart serotonin signaling in the rat

Birth Defects Res A Clin Mol Teratol. 2016 Dec;106(12):1044-1055. doi: 10.1002/bdra.23537. Epub 2016 Jul 7.


Background: Human studies are inconsistent with respect to an association between treatment with selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRI/SNRIs) and an increase in the incidence of congenital heart defects. Here we tested the hypothesis that in utero exposure to venlafaxine, a highly prescribed SNRI, increases the incidence of fetal heart defects and alters placental and fetal heart serotonin signaling in the rat.

Methods: Timed-pregnant Sprague Dawley rats were gavaged daily with venlafaxine hydrochloride (0, 3, 10, 30, or 100 mg/kg/day) from gestation day 8 to 20. On gestation day 21, fetuses were examined for external and internal malformations; placentas and fetal hearts were collected for the analysis of gene expression.

Results: Venlafaxine had no effect on the number of live fetuses, fetal body weights, or external morphology in the absence of maternal toxicity. However, venlafaxine significantly increased the placental index (fetal body/placental weight ratio) and the incidence of fetal cardiac anomalies. Venlafaxine exposure decreased placental expression of the serotonin transporter (SERT/Slc6a4) at the transcript and protein levels. In contrast, venlafaxine increased SERT expression in the hearts of female, but not male, fetuses. Expression of the serotonin 2B receptor (5-HT2B /Htr2b) and of fibroblast growth factor 8 was induced in fetal hearts.

Conclusion: In utero venlafaxine exposure altered the placental index and induced fetal cardiac anomalies in rats. We propose that the increased incidence of cardiac anomalies is mediated through alterations in serotonin signaling in the placenta and fetal heart. Birth Defects Research (Part A), 2016. © 2016 Wiley Periodicals, Inc. Birth Defects Research (Part A) 106:1044-1055, 2016. © 2016 Wiley Periodicals, Inc.

Keywords: antidepressants; congenital heart defect; pregnancy; teratogen; ventricular septal defect.

MeSH terms

  • Administration, Oral
  • Animals
  • Female
  • Fetal Weight
  • Fetus
  • Fibroblast Growth Factor 8 / genetics
  • Fibroblast Growth Factor 8 / metabolism
  • Gene Expression / drug effects
  • Heart / drug effects*
  • Heart / physiopathology
  • Heart Defects, Congenital / chemically induced
  • Heart Defects, Congenital / metabolism*
  • Heart Defects, Congenital / pathology
  • Heart Defects, Congenital / physiopathology
  • Litter Size
  • Male
  • Organ Size / drug effects
  • Placenta / drug effects
  • Pregnancy
  • Prenatal Exposure Delayed Effects / chemically induced
  • Prenatal Exposure Delayed Effects / metabolism*
  • Prenatal Exposure Delayed Effects / pathology
  • Prenatal Exposure Delayed Effects / physiopathology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT2B / genetics
  • Receptor, Serotonin, 5-HT2B / metabolism
  • Serotonin / metabolism*
  • Serotonin Plasma Membrane Transport Proteins / genetics
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Serotonin and Noradrenaline Reuptake Inhibitors / adverse effects*
  • Signal Transduction / drug effects
  • Venlafaxine Hydrochloride / adverse effects*


  • Receptor, Serotonin, 5-HT2B
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin and Noradrenaline Reuptake Inhibitors
  • Slc6a4 protein, rat
  • Fibroblast Growth Factor 8
  • Serotonin
  • Venlafaxine Hydrochloride