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Dose-dependent teratogenicity of valproate in mono- and polytherapy: an observational study. 2015

Torbjörn Tomson, and Dina Battino, and Erminio Bonizzoni, and John Craig, and Dick Lindhout, and Emilio Perucca, and Anne Sabers, and Sanjeev V Thomas, and Frank Vajda, and
From the Department of Clinical Neuroscience (T.T.), Karolinska Institutet, Stockholm, Sweden; Epilepsy Center (D.B.), Department of Neurophysiology and Experimental Epileptology, IRCCS Neurological Institute Carlo Besta Foundation, Milan; Department of Clinical Science and Community (E.B.), Section of Medical Statistics and Biometry G.A. Maccacaro, Faculty of Medicine and Surgery, University of Milan, Italy; Belfast Health and Social Care Trust (J.C.), Belfast, Ireland; Department of Medical Genetics (D.L.), University Medical Center Utrecht; SEIN-Epilepsy Institute in the Netherlands Foundation (D.L.), Hoofddorp, the Netherlands; Department of Internal Medicine and Therapeutics (E.P.), University of Pavia, and Clinical Trial Center, C. Mondino National Neurological Institute, Pavia, Italy; The Epilepsy Clinic (A.S.), Department of Neurology, Rigshospitalet University State Hospital, Copenhagen, Denmark; Department of Neurology (S.V.T.), Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala State, India; and Departments of Medicine and Neurology (F.V.), University of Melbourne, Royal Melbourne Hospital, Australia. torbjorn.tomson@karolinska.se.

OBJECTIVE To assess the risk of major congenital malformations (MCMs) in association with maternal use of valproic acid (VPA) in monotherapy or adjunctive therapy, and its relationship with dose. METHODS The analysis was based on prospectively acquired data from EURAP, a registry enrolling women treated with antiepileptic drugs (AEDs) in early pregnancy, in which the primary outcome is presence of MCMs at 1 year after birth. Exposure was defined as type and dose of AEDs at time of conception. A comparison was made among 3 exposure types: (1) VPA monotherapy (n = 1,224); (2) VPA combined with lamotrigine (LTG) (n = 159); and (3) VPA combined with another AED but not LTG (n = 205). RESULTS The frequency of MCMs at 1 year after birth was 10.0% for VPA monotherapy, 11.3% for exposures to VPA and LTG, and 11.7% for exposures to VPA + another (non-LTG) AED. Regardless of exposure group, the frequency of MCMs increased with dose of VPA, being highest at doses ≥1,500 mg/d (24.0% for monotherapy, 31.0% for VPA + LTG, and 19.2% for VPA + other AEDs), and was similar across treatment groups at the lowest VPA dose level of <700 mg/d (5.9% for monotherapy, 7.0% for VPA + LTG, and 5.4% for VPA + other AEDs). CONCLUSIONS The risk of MCMs associated with VPA exposure increases with increasing VPA dose, both in the presence and in the absence of one concomitant AED, and appears to be related primarily to the dose of VPA.

UI MeSH Term Description Entries
D007231 Infant, Newborn An infant during the first 28 days after birth. Neonate,Newborns,Infants, Newborn,Neonates,Newborn,Newborn Infant,Newborn Infants
D008297 Male Males
D008875 Middle Aged An adult aged 45 - 64 years. Middle Age
D011247 Pregnancy The status during which female mammals carry their developing young (EMBRYOS or FETUSES) in utero before birth, beginning from FERTILIZATION to BIRTH. Gestation,Pregnancies
D011248 Pregnancy Complications Conditions or pathological processes associated with pregnancy. They can occur during or after pregnancy, and range from minor discomforts to serious diseases that require medical interventions. They include diseases in pregnant females, and pregnancies in females with diseases. Adverse Birth Outcomes,Complications, Pregnancy,Adverse Birth Outcome,Birth Outcome, Adverse,Complication, Pregnancy,Outcome, Adverse Birth,Pregnancy Complication
D011446 Prospective Studies Observation of a population for a sufficient number of persons over a sufficient number of years to generate incidence or mortality rates subsequent to the selection of the study group. Prospective Study,Studies, Prospective,Study, Prospective
D012042 Registries The systems and processes involved in the establishment, support, management, and operation of registers, e.g., disease registers. Parish Registers,Population Register,Parish Register,Population Registers,Register, Parish,Register, Population,Registers, Parish,Registers, Population,Registry
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D004359 Drug Therapy, Combination Therapy with two or more separate preparations given for a combined effect. Combination Chemotherapy,Polychemotherapy,Chemotherapy, Combination,Combination Drug Therapy,Drug Polytherapy,Therapy, Combination Drug,Chemotherapies, Combination,Combination Chemotherapies,Combination Drug Therapies,Drug Polytherapies,Drug Therapies, Combination,Polychemotherapies,Polytherapies, Drug,Polytherapy, Drug,Therapies, Combination Drug
D004827 Epilepsy A disorder characterized by recurrent episodes of paroxysmal brain dysfunction due to a sudden, disorderly, and excessive neuronal discharge. Epilepsy classification systems are generally based upon: (1) clinical features of the seizure episodes (e.g., motor seizure), (2) etiology (e.g., post-traumatic), (3) anatomic site of seizure origin (e.g., frontal lobe seizure), (4) tendency to spread to other structures in the brain, and (5) temporal patterns (e.g., nocturnal epilepsy). (From Adams et al., Principles of Neurology, 6th ed, p313) Aura,Awakening Epilepsy,Seizure Disorder,Epilepsy, Cryptogenic,Auras,Cryptogenic Epilepsies,Cryptogenic Epilepsy,Epilepsies,Epilepsies, Cryptogenic,Epilepsy, Awakening,Seizure Disorders

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