Valproic Acid-Related Adverse Fetal Outcomes May Be Linked to Placental Effects

The effects of short-term VPA exposure on placental compound carrier expression were examined in this study.

Short placental exposure to valproic acid (VPA) is sufficient to generate changes in the expression of carriers for compounds that are essential for fetal growth and development, suggesting a new mechanism for adverse developmental outcomes among VPA-exposed fetuses, according to the results of a study published in Epilepsia.

The investigators sought to explore the effects of short VPA exposure on the expression of compound carriers essential for fetal development, including carrier molecules for folate, glucose, and serotonin.

Using placentas from cesarean section deliveries of woman with no known history of epilepsy, the investigators cannulated and perfused cotyledons with maternal perfusate in the presence or absence of VPA at concentrations of 42, 83, or 166 lg/mL (n=6 per group) for >180 minutes.

The expression of carrier genes in the perfused cotyledons was then analyzed by means of a customized gene panel array. Folic acid concentrations and histone acetylation were also measured in the perfused placenta.

The addition of VPA significantly altered mRNA levels of major carriers for folic acid, glucose, thyroid hormones, choline, and serotonin (P <.05). Moreover, VPA decreased placental folate concentrations by 25% to 35% (P =.059).

All effects were reported at therapeutic levels that are sufficient to enhance placental histone acetylation, some of which were concentration dependent.

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The investigators concluded that the placenta is a novel target for VPA, which is potentially associated with the risk for adverse fetal outcomes. The findings of this study propose a new mechanism for adverse developmental outcomes among VPA-exposed fetuses.


Rubinchik-Stern M, Shmuel M, Bar J, Kovo M, Eyal S. Adverse placental effects of valproic acid: studies in perfused human placentas.  Epilepsia. 2018;59(5):993-1003.