The teratogenic risk of antiepileptic drug polytherapy.
OBJECTIVE
To compare the risks of fetal malformation during pregnancy associated with antiepileptic drug (AED) polytherapy and monotherapy.


METHODS
Statistical analysis of malformation rate and antiepileptic drug exposure data from the Australian Register of Antiepileptic Drugs in Pregnancy, and from the literature.


RESULTS
The calculated relative risk (RR) value for AED polytherapy compared with monotherapy was below 1.0 in only 3 of 14 literature publications. In the register, at 1 year postnatally there were fetal malformations in 5.32% of 282 AED polytherapy pregnancies, and in 7.84% of 791 AED monotherapy pregnancies, an RR of 0.68 [95% confidence interval (CI) 0.39-1.17). For pregnancies exposed to valproate, the RR of fetal malformation (0.39, 95% CI 0.20-0.89) was lower in polytherapy (7.26%) than in monotherapy (17.9%); the difference did not depend on valproate dosage. The RR values for fetal malformation were not significantly different for AED polytherapy and monotherapy when valproate was not involved. Logistic regression suggested that coadministration of lamotrigine may have reduced the malformation risk from valproate.


CONCLUSIONS
The fetal hazard of AED polytherapy relative to monotherapy may depend more on the degree of exposure to valproate than on the fact of polytherapy per se. Coadministration with lamotrigine may lower the fetal risk of valproate therapy.
Vajda
Frank J E
FJ
Department of Medicine and Neurosciences, Royal Melbourne Hospital and University of Melbourne, Parkville, Victoria, Australia. perucca@unipv.it
Hitchcock
Alison A
AA
Graham
Janet
J
O'Brien
Terence J
TJ
Lander
Cecilie M
CM
Eadie
Mervyn J
MJ
D000014:Abnormalities, Drug-Induced / Q000453:epidemiology / Q000209:etiology*; D000927:Anticonvulsants / Q000009:adverse effects* / Q000627:therapeutic use; D001315:Australia / Q000453:epidemiology; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D005315:Fetal Diseases; D005333:Fetus / Q000002:abnormalities*; D006801:Humans; D007231:Infant, Newborn; D000077213:Lamotrigine; D016015:Logistic Models; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy* / Q000453:epidemiology; D012042:Registries / Q000706:statistics & numerical data; D012306:Risk; D012307:Risk Factors; D013723:Teratogens; D014227:Triazines / Q000009:adverse effects; D014635:Valproic Acid / Q000009:adverse effects
D000927:Anticonvulsants; D013723:Teratogens; D014227:Triazines; D014635:Valproic Acid; D000077213:Lamotrigine