Tricyclics. In case-control studies of more than 300,000 live births, researchers followed 414 incidences of first-trimester exposure to tricyclics. They discovered no significant association between fetal exposure to tricyclics and increased rates of congenital malformations.1
The few studies that have been performed suggest that no long-term effects stem from exposure in utero.26 Although these results suggest that prenatal exposure to tricyclics is relatively safe, more research is needed.
SSRIs. No significant teratogenic effects of SSRIs have been identified.
The manufacturer’s register for fluoxetine contains approximately 2,000 cases of treated patients, with no excess cases of congenital anomalies or malformations following prenatal exposure. Citalopram has the next largest database of in-utero exposure (n = 365), again with no increased risk for teratogenicity. Several smaller systematic reports are available on in-utero exposure to sertraline, paroxetine, or escitalopram.26
Most studies of pregnant women taking fluoxetine during the first trimester found no increased risk of obstetric complications—including spontaneous pregnancy loss, preterm labor, or low birth weight—compared with women not taking fluoxetine. Third-trimester use of fluoxetine may increase the risk for perinatal complications,27 but this effect has been reported inconsistently and requires further study.26 Effects of other SSRIs during the third trimester have not been systematically explored.
Case reports and 1 controlled study have addressed possible perinatal symptoms from in-utero exposure to SSRIs.28,29 Preliminary data show no adverse neurobehavioral function in exposed neonates.26
Electroconvulsive therapy (ECT) has been proven effective for acute mania and depression, demonstrating few deleterious effects on neonates. ECT has few side effects and may be safer than drug therapy in this population. Two reviews support the efficacy and relative safety of ECT during pregnancy, although more evidence is needed.30,31
Recommendations
Discuss pregnancy and medication risks with all women with bipolar disorder, regardless of plans for pregnancy (FIGURE). If psychotropic medication is used, prescribe carefully during the first trimester, using the minimum number of drugs and the lowest dosages needed to restore or maintain well-being.32
Pros and cons of switching. Some clinicians may encourage a patient to taper a medication during the first trimester because of its unknown or high teratogenicity. Depending on the patient’s illness severity, this might not be the optimal decision. A more conservative option would be to switch to a lower-risk drug during pregnancy.
Lithium has both antidepressant and antimanic properties and is less teratogenic than anticonvulsants in the first trimester. However, if lithium has not been successful for the woman’s mania prophylaxis in the past and she has experienced antimanic response to an anticonvulsant, switching to lithium or another anticonvulsant is not recommended.
Folate and neural tube defects. First-trimester exposure to carbamazepine or valproate increases the risk for neural tube defects; using the lowest available dosage may decrease the risk for spina bifida—at least with valproate.
Low maternal folate levels are often associated with neural tube defects from any cause.33 Valproate lowers folate levels by inhibiting 1 of the enzymes necessary for its formation, which may be a mechanism for the increased risk of spina bifida.34
• Precautionary folate supplementation. No study has demonstrated that folate supplementation reduces the risk of neural tube defects in women taking anticonvulsants during pregnancy.35 Nonetheless, we recommend that women who continue to take valproate or carbamazepine during pregnancy receive folate, 3 to 4 mg/d, as a precaution.
• Treating manic relapse. Patients who stop taking lithium, particularly those who halt therapy abruptly, incur a high rate of relapse.3 Counsel women taking lithium to plan their pregnancies to allow enough time to taper off the medication before conception, if they want to try this. Lithium should be decreased slowly—by approximately 50% every 2 weeks—to avoid relapse. Treat aggressively if relapse occurs during pregnancy. Consider:
- psychiatric hospitalization in case of psychosis or suicidal ideation
- reinstituting drug therapy with a less teratogenic agent
- ECT for a manic or depressive episode
As the pregnancy advances and the mother’s volume of distribution increases, dosage increases may be needed to maintain therapeutic drug levels.
Treating depressive relapse. Should depression occur during pregnancy, SSRIs or tricyclics added to mood stabilizer therapy have been shown to be effective, with few teratogenic effects.
Cognitive-behavioral and interpersonal psychotherapies also have shown efficacy in pregnant women with major depressive disorder36 and may be effective for gravidas with bipolar disorder. Cognitive psychotherapies, when used with medication, have been reported effective in preventing relapse in nongravid bipolar patients.36,37
Dr. Altshuler reports that she is a scientific adviser and consultant for Abbott, Lilly, Forest, and AstraZeneca. Dr. Yonkers and Ms. Richards report no financial relationship with any companies whose products are mentioned in this article.