A clinician's approach to anticonvulsants.(DRUGS, PREGNANCY, AND LACTATION)

Historically, lithium has been a mainstay of treatment for bipolar disorder. However, over the last decade, anticonvulsant drugs such as sodium valproate and lamotrigine (Lamictal) have become more widely used to treat this disorder.

The use of lithium in the first trimester is associated with a 0.05%-0.1% risk for Ebstein's anomaly, a well-described and frequently serious cardiac malformation. But data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry and other international registries indicate that first-trimester exposure to sodium valproate is associated with an 8%-10% risk of major congenital malformations, notably neural tube defects and cardiac malformations.

As a result, many clinicians have been relieved to have the option of lamotrigine, which is an effective treatment for bipolar disorder and for which there had been extremely reassuring reproductive safety data over the last 5-7 years.

And until recently, several global teratovigilance programs had not found any indication that first-trimester use of this medication was associated with an increased risk for major congenital malformations.

In what is an important development, recent data from the NAAED registry note a prevalence rate of 2.7% for overall major malformations; however, five infants (8.9/1,000) had oral clefts. (See accompanying article.)

The baseline incidence of oral clefts in the general population has been calculated to be between 0.5 and 2.16 per 1,000 births; thus the data from the NAAED registry suggest at least a fourfold increase in the risk of cleft lip and palate or an absolute risk of approximately 0.9%. Interestingly, in five other registries surveyed, the frequency of oral clefts was 2.5 per 1,000 births, far less than reported by the NAAED Registry.

So how is the clinician to understand these new data, which suggest a signal of teratogenic risk, and how do the data inform the clinical care of patients who rely on the medication for control of chronic relapsing illnesses such as epilepsy or bipolar illness?