Valproic acid in pregnancy

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Valproic acid in pregnancy

Сообщение Бедолага » Пн мар 30, 2009 4:48 am

Valproic acid in pregnancy: How much are we endangering the embryo and fetus?

Asher Ornoya,

aLaboratory of Teratology, Hebrew University Hadassah Medical School and Israeli Ministry of Health, Jerusalem, Israel

Received 11 October 2008; revised 9 February 2009; accepted 27 February 2009. Available online 13 March 2009.

Valproic acid (VPA) is a known human teratogen. Exposure in pregnancy is associated with approximately three-fold increase in the rate of major anomalies, mainly spina bifida and only rarely anencephaly (NTD), cardiac, craniofacial, skeletal and limb defects and a possible set of dysmorphic features, the “valproate syndrome” with decreased intrauterine growth. This was demonstrated by prospective and retrospective studies. There is also, mainly in the children with the “valproate syndrome”, a significant increase in the rate of developmental problems, manifested by decreased verbal intelligence often with communication problems of the autistic spectrum disorder (ASD). VPA is teratogenic in most animal species tested, but the human embryo seems to be the most susceptible. A daily dose of 1000 mg or more and/or polytherapy are associated with a higher teratogenic risk. It seems that several other AEDs potentiate the teratogenic effects of VPA. Thus, when valproate cannot be avoided in pregnancy, the lowest possible effective dose should be prescribed in 2–3 divided doses, preferably as monotherapy. Women exposed to valproate in pregnancy should be given periconceptional folic acid and followed up in a high risk pregnancy clinic. Appropriate ultrasonographic and other examinations, focusing on the possible different anomalies described with this agent, should be carried out. The specific inhibition by VPA of histone deacetylase and changes in gene expression may explain the teratogenicity of this drug. Other possible explanations are: increased fetal oxidative stress induced by VPA, with the brain being more susceptible to oxidative tress in comparison to other fetal organs, or the folic acid inhibitory action of this drug.

13. Conclusions

Valproic acid seems to be a highly teratogenic antiepileptic drug and therefore, if possible, should be avoided in pregnancy. Because NTD is induced in the third week post fertilization, it may be too late to stop the medication while pregnancy is first diagnosed. Therefore, VPA treated women at childbearing age should use contraceptives and stop the medication before any planned pregnancy. This seems to be possible in most epileptic women and in women taking VPA for any other indication (bipolar disorder or migraine). If there is no alternative for VPA treatment, pregnancies should be considered of high risk and must have the proper follow up including appropriate antenatal diagnosis. It is also suggested that the use of the lowest possible daily dose divided into three doses to minimize fluctuations of serum levels of valproic acid may reduce the risk to the fetus.
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Сообщение Тимур Русланович » Ср апр 01, 2009 7:55 pm

Спасибо. Очень интересная статья. Много важных моментов затронуто.
Врач-невролог центра диагностики и лечения эпилепсии
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Тимур Русланович
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