Lamotrigine and carbamazepine yield lower rates of major fetal malformation than does valproate when pregnant women take one of them as monotherapy for epilepsy during the first trimester, according to an updated analysis of data from the U.K. Epilepsy and Pregnancy Register.
This supports previous findings. In recent years, lamotrigine and carbamazepine have come to be regarded as generally safer than valproate for pregnant women, and there has been a significant shift away from prescribing valproate. But some experts have raised concerns that taking high doses of the "safer" agents may be just as teratogenic as taking lower doses of valproate, according to the authors of the new analysis.
In the current study, first author Dr. Ellen Campbell of the department of neurology at Royal Victoria Hospital, Belfast, Ireland, and her colleagues analyzed data from the 5,206 pregnancies in the register exposed to valproate, carbamazepine, or lamotrigine as monotherapy during the first trimester among women residing in Ireland and the United Kingdom between 1996 and 2012. The outcome of interest was major congenital malformation, defined as any abnormality of an essential embryonic structure requiring significant treatment and present at birth or discovered during the first 6 weeks of life (J. Neurol. Neurosurg. Psychiatry 2014 Feb. 3 [doi:10.1136/jnnp-2013-306318]).
A total of 1,290 fetuses were exposed to valproate, 1,718 to carbamazepine, and 2,198 to lamotrigine. There were 248 pregnancy losses, including 17 in which the fetus had a major congenital malformation.
The odds ratios for having a child with a major congenital malformation after exposure to valproate or carbamazepine monotherapy were 3.0 and 2.7, respectively. There was no significant difference in risk between lamotrigine and carbamazepine, the investigators said.
In addition, the mean daily dose of valproate was significantly higher for mothers of infants with malformations (1,031.2 mg), compared with mothers of infants without malformations (897.9 mg). In contrast, there was no significant dose-related difference in risk of malformations among infants of mothers who took lamotrigine or carbamazepine.
"In contrast to previous data, the major congenital malformation rate with high-dose lamotrigine was reassuring and even appeared to be lower than that for low-dose valproate," the researchers noted.
The rates of all subtypes of malformation were higher after exposure to valproate than after exposure to the other agents. For example, the likelihood of neural tube defects and facial clefts was much greater after exposure to valproate than after exposure to carbamazepine (OR, 4.45), as well as after exposure to lamotrigine (OR, 11.29). There also were greater odds of hypospadias and genitourinary defects after exposure to valproate than after carbamazepine (OR, 4.11) or lamotrigine (OR, 2.60).
Similarly, skeletal defects were more common after exposure to valproate than after carbamazepine (OR, 3.41) or lamotrigine (OR, 5.77). Cardiac defects followed the same pattern.
"This large observational study confirms low overall rates of major congenital malformations among women taking an antiepileptic drug during pregnancy, with over 96% of pregnancies resulting in a child without a major congenital malformation. In keeping with previously published data, the overall major congenital malformation rates seen with exposure to lamotrigine and carbamazepine were not that different from background, particularly when taken in doses of less than 400 mg/day and 1,000 mg/day, respectively. This is likely to be of reassurance to women with epilepsy and those treating them," Dr. Campbell and her associates wrote.
They added that it remains important to control seizures as well as to minimize teratogenicity, so for some pregnant women, valproate may be the appropriate antiepileptic drug to use if other agents aren’t an option.
The U.K. Epilepsy and Pregnancy Register is supported by the Epilepsy Research Foundation and several pharmaceutical companies. Dr. Campbell reported no relevant financial conflicts of interest. Some of her coauthors reported ties to numerous industry sources.