Is Prenatal Valproate Exposure a Risk Factor for Autism
DOI:
https://doi.org/10.37285/ijpsn.2018.11.2.1Abstract
Sodium valproate (Depakene) and divalproex sodium (Depakote) are two commonly used drugs for epilepsy therapy. Sodium valproate, a first-generation antiepileptic drug, has commonly been used as a treatment for different forms of both epilepsy and psychiatric disorders ever since it was first clinically utilized in 1967. It is a simple 2-chain fatty acid that is believed to affect GABA metabolism, however, the mechanism is still unclear. It has been proven to have adverse side effects, such as neural tube defects if taken in utero during the first trimester of pregnancy and has therefore caused a reservation in the medical community for prescription of this drug in females. However, it is still one of the most commonly prescribed agents in young women of childbearing age with 23.4% of women actively receiving it for non-epileptic disorders, such as psychiatric disorders and 12% of women receiving it as an antiepileptic drug (AED). This may be cause for alarm due to the teratogenic effects that may result from usage of valproate. In this article, the potential of prenatal valproate to cause autism spectrum disorder will be outlined from a nonclinical and clinical perspective, as evident from this basic science report. Overall, valproate is clearly associated with teratogenic risks and hence should not be used in women with epilepsy during reproductive years.
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Keywords:
Antiepileptic, Autism, Epilepsy, Neural tube, Teratogenic, Valproate
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Published
2018-03-31
How to Cite
1.
Reddy DS, Brewer J, Manchi M. Is Prenatal Valproate Exposure a Risk Factor for Autism. Scopus Indexed [Internet]. 2018 Mar. 31 [cited 2024 Nov. 19];11(2):4007-11. Available from: https://ijpsnonline.com/index.php/ijpsn/article/view/357
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Review Articles
References
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Bailey AJ (2012). Autism in adults. Autism Res 5: 1-2.
Baxter P (2014). Valproate and folic acid in pregnancy: Associations with autism. Developmental Medicine and Child Neurology 56: 604-612.
Bojic U, Ehlers K and Ellerbeck U (1998). Studies on the teratogen pharmacophore of valproic acid analogues: evidence of interactions at a hydrophobic centre. Eur J Pharmacol 354: 289-299.
Bromley RL, Mawer GE, Briggs M, C. Cheyne, J. Clayton-Smith, M. García-Fiñana, R. Kneen, S. B. Lucas, R. Shallcross, and Baker GA (2013). The Prevalence of Neurodevelopmental Disorders in Children Prenatally Exposed to Antiepileptic Drugs. National Center for Biotechnology Information. U.S. National Library of Medicine, website Jan 31, 2013.
Chapman AG and Evans MC (1983). Cortical GABA turnover during bicuculline seizures in rats. J Neurochem 41(3): 886-869.
Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, and Vestergaard M (2013). Prenatal valproate exposure and risk of Autism spectrum disorders and childhood autism. JAMA 309: 1696-1698.
Cross JH (2010). Neurodevelopmental effects of antiepileptic drugs. Epilepsy Res 88: 1-10.
Dreifuss FE and Langer DH (1988). Side Effects of Valproate.The American Journal of Medicine 84: 34-41.
Göttlicher M, Minucci S and Zhu P (2001). Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 20(24): 6969-6978.
Horiuchi F, Yasunori Oka, Hiroyuki Uno, Kentaro Kawabe, Fumi Okada, Isao Saito, Takeshi Tanigawa, and Shu-Ichi Ueno (2014). Age- and Gender-related Emotional and Behavioral Problems in Children with Autism Spectrum Disorders: Comparison with Control Children. Psychiatry and Clinical Neurosciences 68: 542-550.
Hrzenjak A, Moinfar F and Kremser ML (2006). Valproate inhibition of histone deacetylase 2 affects differentiation and decreases proliferation of endometrial stromal sarcoma cells. Mol Cancer Ther 5(9): 2203-2210.
Ingram JL, Peckham M, Tisdale B and Rodier PM (2000). Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism. Neurotoxicol Teratol 22: 319-324.
Jägerstad (2012). Folic Acid Fortification Prevents Neural Tube Defects and May also Reduce Cancer Risks. Acta Paediatrica 101: 1007-1012.
James EJ, Gu J, Ramirez-Vizcarrondo CM, Hasan M, Truszkowski TL, Tan Y, Oupravanh PM, Khakhalin AS, and Aizenman CD (2015). Valproate-induced neurodevelopmental deficits in Xenopus laevis tadpoles. J Neurosci 35(7): 3218-3229.
Laegreid L, Kyllerman M, Hedner T, Hagberg B, and Viggedahl G (1993). Benzodiazepine amplification of valproate teratogenic effects in children of mothers with absence epilepsy. Neuropediatrics 24: 88-92.
Manent JB, Jorquera I, Mazzucchelli I, Depaulis A, Perucca E and Ben-Ari Y (2007). Fetal exposure to GABA-acting antiepileptic drugs generates hippocampal and cortical dysplasias. Epilepsia 48: 684-693.
Meador KJ (2006). In Utero Antiepileptic Drug Exposure: Fetal Death and Malformations. Neurology 67: 407-412.
Meador, KJ and Loring DW (2013). Risks of In Utero Exposure to Valproate. Journal of the American Medical Association (JAMA) 309: 1730-731.
Nau H, Tzimas G, Mondry M, Plum C and Spohr HL (1995). Antiepileptic drugs alter endogenous retinoid concentrations: A possible mechanism of teratogenesis of anticonvulsant therapy. Life Sci 57: 53-60.
Parr, JR, Ann Couteur, Gillian Baird, Michael Rutter, Andrew Pickles, Eric Fombonne, and Anthony J. Bailey (2011). Early Developmental Regression in Autism Spectrum Disorder: Evidence from an International Multiplex Sample. Journal of Autism and Developmental Disorders 41: 332-340.
Persico AM and Valerio N (2013). Autism genetics. Behavioural Brain Res 251: 95-112.
Shallcross R, Bromley RL, Irwin B, Bonnett LJ, Morrow J and Baker GA (2011). Child development following in utero exposure: levetiracetam vs sodium valproate. Neurology 76: 383-389.
Rasalam, AH, J. H G Williams JHG, Moore SJ, Turnpenny PD, Lloyd DJ, and Dean JCS (2005). Characteristics of Fetal Anticonvulsant Syndrome Associated Autistic Disorder." Developmental Medicine & Child Neurology 47: 551-55.
Raza S, Harker A, Richards S, Kolb B, and Gibb R (2015). Tactile stimulation improves neuroanatomical pathology but not behavior in rats prenatally exposed to valproic acid. Behavioural Brain Research 282: 25-36.
Reddy DS (2014). Clinical pharmacology of current antiepileptic drugs. Int J Pharma Sci Nanotech 7: 2305-2319.
Reddy DS (2017). Clinical pharmacology of modern antiepileptic drugs. Int J Pharm Sci Nanotech 10: 3875-3890.
Schneider T and Przewłocki R (2005). Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology 30: 80-89
Štefánik P, Olexová L and Kršková L (2015). Increased sociability and gene expression of oxytocin and its receptor in the brains of rats affected prenatally by valproic acid. Pharmacol Biochem Behav 131: 42-50.
Tomson T, Marson A, Boon P, Canevini MP, Covanis A, Gaily E, Kälviäinen R, and Trinka E (2015). Valproate in the treatment of epilepsy in girls and women of childbearing potential. Epilepsia 56(7): 1006-1019.
Umur AS, Selcuki M and Bursali A (2012). Simultaneous folate intake may prevent adverse effect of valproic acid on neurulating nervous system. Childs Nerv Syst 28(5): 729-737.
Vinkers CH, Mirza NR, Olivier B, and Kahn RS (2010). The inhibitory GABA system as a therapeutic target for cognitive symptoms in schizophrenia: investigational agents in the pipeline. Expert Opin Investig Drugs 19(10): 1217-1233.
Williams SCP (2012). Genetics: Searching for answers. Nature 491: S4-S6.
Wisner, KL, Emily Leckman-Westin, Molly Finnerty, and Susan M. Essock (2011). Valproate Prescription Prevalance Among Women of Childbearing Age. Psychiatric Services 62: 218-220.
Younus I and Reddy DS (2017). Epigenetic interventions for epileptogenesis: A new frontier for curing epilepsy. Pharmacol Ther 177:108-122.
Bailey AJ (2012). Autism in adults. Autism Res 5: 1-2.
Baxter P (2014). Valproate and folic acid in pregnancy: Associations with autism. Developmental Medicine and Child Neurology 56: 604-612.
Bojic U, Ehlers K and Ellerbeck U (1998). Studies on the teratogen pharmacophore of valproic acid analogues: evidence of interactions at a hydrophobic centre. Eur J Pharmacol 354: 289-299.
Bromley RL, Mawer GE, Briggs M, C. Cheyne, J. Clayton-Smith, M. García-Fiñana, R. Kneen, S. B. Lucas, R. Shallcross, and Baker GA (2013). The Prevalence of Neurodevelopmental Disorders in Children Prenatally Exposed to Antiepileptic Drugs. National Center for Biotechnology Information. U.S. National Library of Medicine, website Jan 31, 2013.
Chapman AG and Evans MC (1983). Cortical GABA turnover during bicuculline seizures in rats. J Neurochem 41(3): 886-869.
Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, and Vestergaard M (2013). Prenatal valproate exposure and risk of Autism spectrum disorders and childhood autism. JAMA 309: 1696-1698.
Cross JH (2010). Neurodevelopmental effects of antiepileptic drugs. Epilepsy Res 88: 1-10.
Dreifuss FE and Langer DH (1988). Side Effects of Valproate.The American Journal of Medicine 84: 34-41.
Göttlicher M, Minucci S and Zhu P (2001). Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 20(24): 6969-6978.
Horiuchi F, Yasunori Oka, Hiroyuki Uno, Kentaro Kawabe, Fumi Okada, Isao Saito, Takeshi Tanigawa, and Shu-Ichi Ueno (2014). Age- and Gender-related Emotional and Behavioral Problems in Children with Autism Spectrum Disorders: Comparison with Control Children. Psychiatry and Clinical Neurosciences 68: 542-550.
Hrzenjak A, Moinfar F and Kremser ML (2006). Valproate inhibition of histone deacetylase 2 affects differentiation and decreases proliferation of endometrial stromal sarcoma cells. Mol Cancer Ther 5(9): 2203-2210.
Ingram JL, Peckham M, Tisdale B and Rodier PM (2000). Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism. Neurotoxicol Teratol 22: 319-324.
Jägerstad (2012). Folic Acid Fortification Prevents Neural Tube Defects and May also Reduce Cancer Risks. Acta Paediatrica 101: 1007-1012.
James EJ, Gu J, Ramirez-Vizcarrondo CM, Hasan M, Truszkowski TL, Tan Y, Oupravanh PM, Khakhalin AS, and Aizenman CD (2015). Valproate-induced neurodevelopmental deficits in Xenopus laevis tadpoles. J Neurosci 35(7): 3218-3229.
Laegreid L, Kyllerman M, Hedner T, Hagberg B, and Viggedahl G (1993). Benzodiazepine amplification of valproate teratogenic effects in children of mothers with absence epilepsy. Neuropediatrics 24: 88-92.
Manent JB, Jorquera I, Mazzucchelli I, Depaulis A, Perucca E and Ben-Ari Y (2007). Fetal exposure to GABA-acting antiepileptic drugs generates hippocampal and cortical dysplasias. Epilepsia 48: 684-693.
Meador KJ (2006). In Utero Antiepileptic Drug Exposure: Fetal Death and Malformations. Neurology 67: 407-412.
Meador, KJ and Loring DW (2013). Risks of In Utero Exposure to Valproate. Journal of the American Medical Association (JAMA) 309: 1730-731.
Nau H, Tzimas G, Mondry M, Plum C and Spohr HL (1995). Antiepileptic drugs alter endogenous retinoid concentrations: A possible mechanism of teratogenesis of anticonvulsant therapy. Life Sci 57: 53-60.
Parr, JR, Ann Couteur, Gillian Baird, Michael Rutter, Andrew Pickles, Eric Fombonne, and Anthony J. Bailey (2011). Early Developmental Regression in Autism Spectrum Disorder: Evidence from an International Multiplex Sample. Journal of Autism and Developmental Disorders 41: 332-340.
Persico AM and Valerio N (2013). Autism genetics. Behavioural Brain Res 251: 95-112.
Shallcross R, Bromley RL, Irwin B, Bonnett LJ, Morrow J and Baker GA (2011). Child development following in utero exposure: levetiracetam vs sodium valproate. Neurology 76: 383-389.
Rasalam, AH, J. H G Williams JHG, Moore SJ, Turnpenny PD, Lloyd DJ, and Dean JCS (2005). Characteristics of Fetal Anticonvulsant Syndrome Associated Autistic Disorder." Developmental Medicine & Child Neurology 47: 551-55.
Raza S, Harker A, Richards S, Kolb B, and Gibb R (2015). Tactile stimulation improves neuroanatomical pathology but not behavior in rats prenatally exposed to valproic acid. Behavioural Brain Research 282: 25-36.
Reddy DS (2014). Clinical pharmacology of current antiepileptic drugs. Int J Pharma Sci Nanotech 7: 2305-2319.
Reddy DS (2017). Clinical pharmacology of modern antiepileptic drugs. Int J Pharm Sci Nanotech 10: 3875-3890.
Schneider T and Przewłocki R (2005). Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology 30: 80-89
Štefánik P, Olexová L and Kršková L (2015). Increased sociability and gene expression of oxytocin and its receptor in the brains of rats affected prenatally by valproic acid. Pharmacol Biochem Behav 131: 42-50.
Tomson T, Marson A, Boon P, Canevini MP, Covanis A, Gaily E, Kälviäinen R, and Trinka E (2015). Valproate in the treatment of epilepsy in girls and women of childbearing potential. Epilepsia 56(7): 1006-1019.
Umur AS, Selcuki M and Bursali A (2012). Simultaneous folate intake may prevent adverse effect of valproic acid on neurulating nervous system. Childs Nerv Syst 28(5): 729-737.
Vinkers CH, Mirza NR, Olivier B, and Kahn RS (2010). The inhibitory GABA system as a therapeutic target for cognitive symptoms in schizophrenia: investigational agents in the pipeline. Expert Opin Investig Drugs 19(10): 1217-1233.
Williams SCP (2012). Genetics: Searching for answers. Nature 491: S4-S6.
Wisner, KL, Emily Leckman-Westin, Molly Finnerty, and Susan M. Essock (2011). Valproate Prescription Prevalance Among Women of Childbearing Age. Psychiatric Services 62: 218-220.
Younus I and Reddy DS (2017). Epigenetic interventions for epileptogenesis: A new frontier for curing epilepsy. Pharmacol Ther 177:108-122.
