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Valproic Acid in Pregnancy: How Much Are We Endangering the Embryo and Fetus?

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Valproic Acid in Pregnancy: How Much Are We Endangering the Embryo and Fetus? Reproductive Toxicology 28 (2009) 1–10 Contents lists available at ScienceDirect Reproductive Toxicology journal homepage: www.elsevier.com/locate/reprotox Review Valproic acid in pregnancy: How much are we endangering the embryo and fetus? Asher Ornoy Laboratory of Teratology, Hebrew University Hadassah Medical School and Israeli Ministry of Health, Jerusalem, Israel article info abstract Article history: Valproic acid (VPA) is a known human teratogen. Exposure in pregnancy is associated with approximately Received 11 October 2008 three-fold increase in the rate of major anomalies, mainly spina bifida and only rarely anencephaly (NTD), Received in revised form 9 February 2009 cardiac, craniofacial, skeletal and limb defects and a possible set of dysmorphic features, the “valproate Accepted 27 February 2009 syndrome” with decreased intrauterine growth. This was demonstrated by prospective and retrospective Available online 13 March 2009 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 Keywords: problems of the autistic spectrum disorder (ASD). VPA is teratogenic in most animal species tested, but Valproic acid NTD the human embryo seems to be the most susceptible. A daily dose of 1000 mg or more and/or poly- Verbal intelligence therapy are associated with a higher teratogenic risk. It seems that several other AEDs potentiate the Autistic spectrum disorder 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 preg- nancy 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. © 2009 Elsevier Inc. All rights reserved. Contents 1. Introduction—basic principles in teratology ........................................................................................................... 2 2. Teratogenic effects of antiepileptic drugs—general comments ....................................................................................... 2 3. Effects of valproic acid (VPA) in pregnancy—neural tube defects (NTD) and major congenital anomalies (MCA) ................................... 2 4. Valproic acid syndrome (or AED syndrome)........................................................................................................... 4 5. VPA—neurodevelopmental problems .................................................................................................................. 4 6. VPA and autistic spectrum disorder (ASD)............................................................................................................. 5 7. VPA and folic acid administration ...................................................................................................................... 5 8. VPA-transplacental passage, secretion into milk and into semen ..................................................................................... 5 9. VPA and polytherapy (Tables 1–3)..................................................................................................................... 5 10. Malformations in children of untreated epileptic women ........................................................................................... 6 11. VPA and animal studies ............................................................................................................................... 6 12. Suggested mechanism of teratogenic action of VPA.................................................................................................. 7 12.1. Folic acid deficiency ........................................................................................................................... 7 12.2. Arene oxide intermediates theory ............................................................................................................ 7 12.3. Oxidative stress ............................................................................................................................... 7 12.4. Inhibition of histone deacetylases (HDAC).................................................................................................... 7 13. Conclusions ........................................................................................................................................... 8 Conflict of interest statement.......................................................................................................................... 8 References ............................................................................................................................................. 8 E-mail address: [email protected]. 0890-6238/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.reprotox.2009.02.014 2 A. Ornoy / Reproductive Toxicology 28 (2009) 1–10 1. Introduction—basic principles in teratology The more tratogenic drugs seem to be valproate, phenytoin, phenobarbitone and carbamazepine. Trimethadione and param- The human conceptus undergoes 3 major developmental peri- ethadione seem also to be highly teratogenic, but they are replaced ods: The pre-organogenetic period during the first 2.5 weeks after by newer, more effective drugs. fertilization, active organogenesis from weeks 3 to 8 post fertiliza- For some of the antiepileptic drugs, there is very little infor- tion and afterwards the fetal period. It is commonly accepted that in mation as to their potential hazardous effects on the developing the first period the developing embryo is generally not susceptible embryo and fetus. However, for many, especially the more “clas- to teratogens. If the damage caused by a teratogen is very severe, sic” AEDs that are widely used, there is sufficient human data. the pregnancy may end in a spontaneous abortion or fetal death. Although the main discussion is related to VPA, there will also be Although the most sensitive period to teratogens is during active some reference to the other “classic” AEDs—carbamazepine, pheny- organogenesis, there are some organs (i.e. teeth, external genitalia, toin, phenobarbital and to lamotrigine, but only in relation to co brain) that continue to be very active developmentally beyond that therapy with VPA, a fact that may significantly elevate their overall period and may therefore still be affected by teratogens. Hence, teratogenic potential. teratogens that affect the brain, especially antiepileptic and psy- We searched in Medline prospective and retrospective studies chotropic drugs, may cause damage even if the fetus is exposed on the effects of valproic acid in pregnancy. This is not a complete beyond the first trimester of pregnancy [1–4]. Even in organs that evaluation of the literature because we discuss only the studies continue their development throughout pregnancy, the earlier dur- relevant to the different issues raised in this review. For the evalu- ing embryonic and fetal development the exposure, the larger may ation of the rate of major anomalies or of developmental problems be the damage. Thus, exposure to a teratogen throughout pregnancy we used both retrospective and prospective studies, but only if (i.e. antiepileptic drugs) is usually more dangerous than exposure they describe, among the antiepileptic drugs, also results of val- during a limited time period. In most cases the damage is dose proic acid exposure in pregnancy. Generally we did not evaluate dependent and interacts with the embryonic and fetal genetic back- reviews unless they reported cases not published in other stud- ground [1–5]. ies or they relate to the mechanisms of action of VPA or to the effects of epilepsy on the offspring. The data in the tables had some- 2. Teratogenic effects of antiepileptic drugs—general times to be calculated from the figures and tables of the relevant comments studies. Antiepileptic drugs (AEDs) are used to control various types of convulsive disorders or as mood stabilizers. However, many of these 3. Effects of valproic acid (VPA) in pregnancy—neural tube drugs are teratogenic as their use by the pregnant mother has been defects (NTD) and major congenital anomalies (MCA) associated with an increased risk of major congenital abnormalities in the embryo and fetus [3,5–10]. These anomalies are anatomical VPA is on the market as an anticonvulsant since 1974, and is used and/or functional and may also have neurological, behavioral and in many countries because of its efficiency against several types of cognitive effects. Yet, in the majority of epileptic women planning epilepsy and as a mood stabilizer. One of its main actions is the a pregnancy, antiepileptic drugs cannot be discontinued because of increase in the level of gamma amino butyric acid (GABA) in the the risk of seizures during pregnancy, which can be harmful to both brain. GABA is an important inhibitor of seizures, and reduction of mother and child
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