Adverse placental effects of valproic acid: Studies in perfused human placentas

Miriam Rubinchik-Stern, Miriam Shmuel, Jacob Bar, Michal Kovo*, Sara Eyal

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Objective: In utero exposure to valproic acid (VPA) has been associated with worse pregnancy outcomes compared to all other antiepileptic drugs. We have previously shown that VPA alters the expression of placental transporters for hormones and nutrients in vitro and in pregnant mice. Here, our aim was to characterize the effects of short exposure to VPA on the expression of carriers for compounds essential for fetal development in human placentas ex vivo, under controlled conditions. Methods: Placentas were obtained from cesarean deliveries of women with no known epilepsy. Cotyledons were cannulated and perfused in the absence or the presence of VPA (42, 83, or 166 μg/mL; n = 6/group) in the maternal perfusate over 180 minutes. A customized gene panel array was used to analyze the expression of carrier genes in the perfused cotyledons. We additionally measured in the perfused placentas folic acid concentrations and histone acetylation. Results: VPA significantly altered the mRNA levels of major carriers for folic acid, glucose, choline, thyroid hormones, and serotonin (P <.05) and reduced placental folate concentrations by 25%-35% (P =.059). The effects were observed at therapeutic concentrations sufficient to enhance placental histone acetylation, and some were concentration-dependent. Significance: Our results point to the placenta as a novel target of VPA, implying potential involvement of the placenta in VPA's adverse fetal outcomes.

Original languageAmerican English
Pages (from-to)993-1003
Number of pages11
JournalEpilepsia
Volume59
Issue number5
DOIs
StatePublished - May 2018

Bibliographical note

Funding Information:
We acknowledge the support of the Israel Science Foundation (grant 506/13). We would like to thank Awad Sarur from the Hadassah Medical Center’s laboratories of Clinical Biochemistry for performing tissue folate tests. S.E. is affiliated with the David R. Bloom Center for Pharmacy and Dr. Adolf and Klara Brettler Center for Research in Molecular Pharmacology and Therapeutics at the Hebrew University of Jerusalem, Israel.

Publisher Copyright:
Wiley Periodicals, Inc. © 2018 International League Against Epilepsy

Keywords

  • GLUT1
  • antiepileptic drugs
  • folic acid
  • pregnancy
  • teratogenicity

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