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Restrictions on the use of valproate in female patients of reproductive age: the updated recommendations based on recent clinical data

https://doi.org/10.17749/2077-8333.2019.11.2.110-123

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Abstract

For more than half a century, valproic acid (VA) has been a first-line drug to control seizures in various forms of epilepsy and status epilepticus; VA is also used in bipolar disorders. However, the accumulated clinical evidence indicates negative outcomes of pregnancies in women receiving valproate. Thus, babies born to mothers receiving VA for their epilepsy or bipolar disorder had an increased risk of serious congenital malformations. In addition, VA was found to affect the development of the CNS in a fetus that may result in attention-deficit hyperactivity syndrome (ADHD), autism spectrum disorder (ASD), childhood autism, and other diseases. The data on teratogenic effects of VA have led the regulatory authorities and the manufacturer to adopt restrictive recommendations regarding the use of VA in female patients of reproductive age. The Russian League Against Epilepsy (RLAE) presents this article to inform the medical community about the consequences of using valproic acid in pregnancy and also recommends a number of preventive measures. The article elaborates on the evidence of teratogenic risks associated with VA and reviews documents from the regulatory authorities (EMA, MHRA, Roszdravnadzor of the Russian Federation), which specify the measures needed to prevent the adverse effects of VA during pregnancy. According to these documents, medications containing VA should no longer be used in female patients of childbearing potential, except in cases where other treatments for epilepsy are ineffective or contraindicated. The changes made by the manufacturer in the official instructions for using the reference drug, and the unified instructions of the RF regulatory bodies on the reproduced (generic) drugs containing VA are also presented. The Pregnancy Prevention Program is proposed to minimize individual risks for women using VA. The article also addresses the international clinical practice on the prevention of VA-associated adverse effects during pregnancy and the recommendations of RLAE on alternative anti-epileptic therapy using minimally teratogenic drugs: lamotrigine, levetiracetam, and oxcarbazepine.

About the Authors

G. N. Avakyan
Pirogov Russian National Research Medical University
Russian Federation

Gagik N. Avakyan - MD, PhD, Honored Scientist of Russia, Professor, Department of Neurology, Neurosurgery and Medical Genetics.

1 Ostrovityanova Str., Moscow 117997



D. V. Blinov
Institute of Preventive and Social Medicine; Moscow Haass Medical - Social Institute; Lapino Clinic Hospital, MD Medical Group
Russian Federation

Dmitry V. Blinov - MD, PhD, MBA, Head of Medical and Scientific Affairs, IPSM; Faculty Member, Department of Neurology, Psychiatry and Narcology, MHMSI; Neurologist, Lapino CH, MD Medical Group, Researcher ID: E-8906-2017.

4-10 Sadovaya-Triumfalnaya Str., Moscow; 5 p. 1-1a 2nd Brestskaya Str., Moscow 123056; 1st Uspenskoye Highway, 111, Moscow Region, Odintsovo District, Lapino



G. G. Avakyan
Pirogov Russian National Research Medical University
Russian Federation

Georgii G. Avakyan - MD, PhD, Associate Professor, Department of Neurology, Neurosurgery and Medical Genetics.

1 Ostrovityanova Str., Moscow 117997



E. S. Akarachkova
Sechenov First Moscow State Medical University; International society of stress Stress under control
Russian Federation

Elena S. Akarachkova - MD, PhD, President of International society of stress "Stress under control"; Neurologist, Leading Researcher, Department of Neurology, Sechenov FMNMU.

8-2 Trubetskaya Str., Moscow 119048


S. G. Burd
Pirogov Russian National Research Medical University
Russian Federation

Sergey G. Burd - MD, PhD, Professor at the Department of Neurology, Neurosurgery and Medical Genetics, Faculty of Pediatrics.

1 Ostrovityanova Str., Moscow 117997



P. N. Vlasov
Evdokimov Moscow State University of Medicine and Dentistry
Russian Federation

Pavel N. Vlasov - MD, PhD, Professor of Neurology, Faculty of Medicine.

20-1 Delegatskaya str., Moscow 127473



K. V. Voronkova
Pirogov Russian National Research Medical University
Russian Federation

Kira V. Voronkova - MD, PhD, Professor of Neurology.

1 Ostrovityanova Str., Moscow 117997



V. I. Guzeva
Saint-Petersburg State Pediatric Medical University
Russian Federation

Valentina I. Guzeva - MD, PhD, Professor, Head of the Department of Nervous Diseases, St.PNPMU, Chief Consultant in Pediatric Neurology of the Ministry of Health of the Russian Federation.

Litovskaya Str., 2, Saint Petersburg 194100


I. A. Zhidkova
Evdokimov Moscow State University of Medicine and Dentistry
Russian Federation

Irina A. Zhidkova - MD, PhD, Professor of the Department of Nervous Diseases.

20-1 Delegatskaya str., Moscow 127473



E. A. Katunina
Pirogov Russian National Research Medical University
Russian Federation

Elena A. Katunina - MD, PhD, Professor at the Department of Neurology, Neurosurgery and Medical Genetics.

1 Ostrovityanova Str., Moscow 117997



D. I. Korabelnikov
Moscow Haass Medical - Social Institute
Russian Federation

Daniil I. Korabelnikov - M.D., Ph.D., Professor of The Department of Internal Diseases, General practice, Functional Diagnostics and Infectious Diseases, Rector, RSCI: 7380-7790.

5 p. 1-1a 2nd Brestskaya Str., Moscow 123056



A. V. Lebedeva
Pirogov Russian National Research Medical University
Russian Federation

Anna V. Lebedeva - MD, PhD, Professor at the Department of Neurology, Neurosurgery and Medical Genetics, Faculty of Pediatrics.

1 Ostrovityanova Str., Moscow 117997



L. V. Lipatova
Bechterev National Medical Research Center of Psychiatry and Neurology
Russian Federation

Lyudmila V. Lipatova - MD, PhD, Professor, Scientific Director, Department of Epilepsy.

3 Bekhtereva Str., Saint Petersburg 192019



E. A. Morozova
Kazan State Medical Academy
Russian Federation

Elena A. Morozova - MD, Professor at the Department of Pediatric Neurology, KNMA; Consultant in Pediatric Neurology, Privolzhsky Federal District.

11 Mushtari Str., Kazan 420012



O. M. Oleinikova
Pirogov Russian National Research Medical University
Russian Federation

Olga M. Oleinikova - MD, PhD, Associate Professor at the Department of Neurology, Neurosurgery and Medical Genetics.

1 Ostrovityanova Str., Moscow 117997



I. G. Rudakova
Moscow Regional Research and Clinical Institute (MONIKI)
Russian Federation

Irina G. Rudakova - MD, Professor

61/2 Shchepkina Str., Moscow 129110



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For citation:


Avakyan G.N., Blinov D.V., Avakyan G.G., Akarachkova E.S., Burd S.G., Vlasov P.N., Voronkova K.V., Guzeva V.I., Zhidkova I.A., Katunina E.A., Korabelnikov D.I., Lebedeva A.V., Lipatova L.V., Morozova E.A., Oleinikova O.M., Rudakova I.G. Restrictions on the use of valproate in female patients of reproductive age: the updated recommendations based on recent clinical data. Epilepsy and paroxysmal conditions. 2019;11(2):110-123. (In Russ.) https://doi.org/10.17749/2077-8333.2019.11.2.110-123

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ISSN 2077-8333 (Print)
ISSN 2311-4088 (Online)