Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy.
OBJECTIVE
To quantify the risks of intrauterine antiepileptic drug (AED) exposure in monotherapy and polytherapy.


METHODS
Data from five prospective European studies totaling 1,379 children were pooled and reanalyzed. Data were available for 1,221 children exposed to AED during pregnancy and for 158 children of unexposed control pregnancies.


RESULTS
Overall, when comparing a subgroup of 192 children exposed to AED with 158 children of matched nonepileptic controls, there was an increased risk of major congenital malformations (MCA) in children exposed to AED during gestation [relative risk (RR) 2.3; 95% confidence interval (CI): 1.2-4.7]. A significant increase in risk was found for children exposed to valproate (VPA) (RR 4.9; 95% CI: 1.6-15.0) or carbamazepine (CBZ) (RR 4.9; 95% CI: 1.3-18.0) in monotherapy. When comparing different AED regimens during all 1,221 pregnancies, risks of MCA were significantly increased for the combination of phenobarbital (PB) and ethosuximide (RR 9.8; 95% CI: 1.4-67.3) and the combination of phenytoin, PB, CBZ, and VPA (RR 11.0; 95% CI: 2.1-57.6). Offspring of mothers using > 1,000 mg VPA/day were at a significantly increased risk of MCA, especially neural tube defects, compared to offspring exposed < or =600 mg VPA/day (RR 6.8; 95% CI: 1.4-32.7). No difference in risk of MCA was found between the offspring exposed to 601-1,000 mg/day and < or =600 mg/day.


CONCLUSIONS
This reanalysis shows that VPA is consistently associated with an increased risk of MCA in babies born to mothers with epilepsy. Significant associations were also observed with CBZ. Larger prospective population-based studies are needed to evaluate the risks of many other less frequently prescribed treatment regimens, including newly marketed AEDs.
Samrén
E B
EB
Department of Clinical Genetics, University Hospital Rotterdam/Dijkzigt, Rotterdam, The Netherlands.
van Duijn
C M
CM
Koch
S
S
Hiilesmaa
V K
VK
Klepel
H
H
Bardy
A H
AH
Mannagetta
G B
GB
Deichl
A W
AW
Gaily
E
E
Granström
M L
ML
Meinardi
H
H
Grobbee
D E
DE
Hofman
A
A
Janz
D
D
Lindhout
D
D
D000014:Abnormalities, Drug-Induced / Q000453:epidemiology* / Q000209:etiology; D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects* / Q000627:therapeutic use; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008431:Maternal-Fetal Exchange; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy*; D011446:Prospective Studies; D012307:Risk Factors
D000927:Anticonvulsants