Dose-dependent teratogenicity of valproate in mono- and polytherapy: An observational study

Torbjörn Tomson; Dina Battino; Erminio Bonizzoni; John Craig; Dick Lindhout; Emilio Perucca; Anne Sabers; Sanjeev V Thomas; Frank Vajda; EURAP Study Group

doi:10.1212/WNL.0000000000001772

Dose-dependent teratogenicity of valproate in mono- and polytherapy: An observational study

Torbjörn Tomson, Dina Battino, Erminio Bonizzoni, John Craig, Dick Lindhout, Emilio Perucca, Anne Sabers, Sanjeev V Thomas, Frank Vajda, EURAP Study Group

Department of Neurology

133 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Neurology
Volume	85
Issue number	10
Pages (from-to)	866-72
Number of pages	7
ISSN	0028-3878
DOIs	https://doi.org/10.1212/WNL.0000000000001772
Publication status	Published - 8 Sept 2015

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title = "Dose-dependent teratogenicity of valproate in mono- and polytherapy: An observational study",

abstract = "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.",

author = "Torbj{\"o}rn Tomson and Dina Battino and Erminio Bonizzoni and John Craig and Dick Lindhout and Emilio Perucca and Anne Sabers and Thomas, {Sanjeev V} and Frank Vajda and {EURAP Study Group}",

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language = "English",

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TY - JOUR

T1 - Dose-dependent teratogenicity of valproate in mono- and polytherapy

T2 - An observational study

AU - Tomson, Torbjörn

AU - Battino, Dina

AU - Bonizzoni, Erminio

AU - Craig, John

AU - Lindhout, Dick

AU - Perucca, Emilio

AU - Sabers, Anne

AU - Thomas, Sanjeev V

AU - Vajda, Frank

AU - EURAP Study Group

PY - 2015/9/8

Y1 - 2015/9/8

N2 - 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.

AB - 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.

U2 - 10.1212/WNL.0000000000001772

DO - 10.1212/WNL.0000000000001772

M3 - Journal article

C2 - 26085607

SN - 0028-3878

VL - 85

SP - 866

EP - 872

JO - Neurology

JF - Neurology

IS - 10

ER -

Dose-dependent teratogenicity of valproate in mono- and polytherapy: An observational study

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