Early reports suggested that women with bipolar disorder may be at lower risk for onset or relapse of this disorder during pregnancy and that some women may be able to remain well during pregnancy despite medication discontinuation. However, more recent studies have suggested that recurrence of affective illness during pregnancy is relatively common among women with bipolar disorder. Dr. Adele Viguera and her colleagues at the Center for Women’s Mental Health reported that among pregnant bipolar women, relapse rates were very high (58%) in those women who discontinued maintenance treatment with lithium during pregnancy (Viguera et al 2000).

Maintenance treatment with a mood stabilizer during pregnancy can significantly reduce the risk of relapse; however, many of the medications commonly used in this setting, including lithium and valproic acid, carry some degree of teratogenic risk. First trimester exposure to lithium has been associated with an increased risk of cardiovascular malformation estimated to be between 1 in 2000 (0.05%) and 1 in 1000 (0.1%) (Cohen et al, 1994). The anticonvulsant valproic acid carries a much higher risk of teratogenesis, with rates of neural tube defect ranging from 1 to 8%. Prenatal exposure to valproic acid has also been associated with characteristic craniofacial abnormalities, cardiovascular malformation, limb defects and genital anomalies, as well as other central nervous system structural abnormalities.

While other anticonvulsants are being used with increasing regularity for the treatment of bipolar disorder (i.e., tiagabine, oxcarbazepine), there is limited information with respect to the reproductive safety of these agents. Recently information has been published that suggests that lamotrigine (Lamictal) may be another option for women with bipolar disorder who are planning pregnancies.

The International Lamotrigine Pregnancy Registry was created by GlaxoSmithKline (GSK) in 1992 to monitor pregnancies exposed to lamotrigine for the occurrence of major birth defects. Data from the Registry recently presented at the meeting of the American Academy of Neurology did not show an elevated risk of malformations associated with lamotrigine exposure (Messenheimer and Wiel, 2006). In a total of 680 first-trimester exposures to lamotrigine monotherapy, the frequency of major congenital malformations was 2.8% (n=19). These findings are consistent with previous reports which observed rates of malformation in lamotrigine-exposed infants similar to those observed in the general population (Tennis et al, 2002; Cunnington et al, 2005).

Other data presented at the Annual Meeting of the Teratology Society and included in a “Dear Health Care Professional” letter sent out by GlaxoSmithKline, the manufacturer of Lamictal, comes from the North-American Anti-Epileptic Drug Registry. In this study, the prevalence of major malformations in a total of 564 children exposed to lamotrigine monotherapy was observed to be 2.7%; however, five infants had oral clefts, indicating a prevalence rate of 8.9 per 1000 births (Holmes et al, 2006). In a comparison group of 221,746 unexposed births, the prevalence rate for oral clefts was 0.37/1000, indicating a 24-fold increase in risk of oral cleft in infants exposed to lamotrigine.

However, other registries have not demonstrated such a significant increase in risk for oral clefts. Among a total of 1,623 lamotrigine-exposed infants surveyed in five other anticonvulsant registries, four infants with oral clefts were identified, indicating a frequency of 1:405 or 2.5/1,000.

Although numerous studies have linked older anticonvulsants, including valproic acid and carbamazepine, to an increased risk of malformations, this study is the first to report an increase in the frequency of a specific major malformation among infants exposed to one of the newer anticonvulsant drugs. Clearly more data are essential to better evaluate the reproductive safety of lamotrigine; important questions regarding the safety of lamotrigine and other anticonvulsants might be best addressed by collaboration between multiple registries, including EURAP and the North-American Anti-Epileptic Drug Registry.

These data may signal an increase in risk of malformations in children exposed to lamotrigine; however, it is important to put this risk into perspective. If we assume that the findings from the North American registry are true, the absolute risk of having a child with cleft lip or palate is about 0.9%. While some women may elect to discontinue treatment with lamotrigine given the magnitude of this risk, many women with more brittle bipolar illness may require treatment with some type of mood stabilizer during pregnancy. However, the alternatives to lamotrigine also carry some risk. Exposure to valproic acid during the first trimester carries an unacceptably high risk of major malformations (over 10% in some samples), including neural tube defects. Lithium usage during the first trimester has been associated with a 0.1% risk of cardiovascular malformation. At this point, data regarding the reproductive safety of the newer anticonvulsants and atypical anti-psychotic agents is sparse. Thus, some women may elect to continue treatment with lamotrigine, acknowledging that, while there may be risks associated with this exposure, other treatment options are not risk-free. Ruta M. Nonacs, MD PhD

Cohen LS, Friedman JM, Jefferson JW, Johnson EM, Weiner ML. A reevaluation of risk of in utero exposure to lithium. JAMA. 1994 Jun 15;271(23):1828-9.

Cunnington M and Tennis P; International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Lamotrigine and the risk of malformations in pregnancy. Neurology 2005; 64; 955-960 [PDF]

Holmes LB, Wyszynski DF, Baldwin EJ, Habecker E, et al. Increased risk for non-syndromic cleft palate among infants exposed to lamotrigine during pregnancy. 46th Annual Meeting of the Teratology Society, June 24-29, 2006, Tucson, AZ.

Messenheimer JA, Wiel J. Thirteen year interim results from an International Observational Study of Pregnancy Outcomes Following Exposure to Lamotrigine. 58th Annual Meeting of the American Academy of Neurology, April 1-8, 2006, San Diego, CA.

Viguera AC, Nonacs R, Cohen LS, Tondo L, Murray A, Baldessarini RJ. Risk of recurrence of bipolar disorder in pregnant and nonpregnant women after discontinuing lithium maintenance. Am J Psychiatry. 2001 Oct;158(10):1741-2.

Tennis P, Eldridge RR; International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Preliminary results on pregnancy outcomes in women using lamotrigine. Epilepsia. 2002 Oct;43(10):1161-7.