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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.
GLOSSARY
- AED=
- antiepileptic drug;
- CBZ=
- carbamazepine;
- CI=
- confidence interval;
- EURAP=
- International Registry of Antiepileptic Drugs and Pregnancy;
- LTG=
- lamotrigine;
- MCM=
- major congenital malformation;
- PB=
- phenobarbital;
- VPA=
- valproic acid
Footnotes
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
↵* These authors contributed equally to this work.
EURAP Study Group coinvestigators are listed on the Neurology® Web site at Neurology.org.
Supplemental data at Neurology.org
- Received February 19, 2015.
- Accepted in final form May 11, 2015.
- © 2015 American Academy of Neurology
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