Pregnancy All mood stabilizers are potentially teratogenic and the risks

Pregnancy All mood stabilizers are potentially teratogenic and the risks

and benefits of treatment must be carefully assessed in the context of use during pregnancy and breastfeeding.

LITHIUM Exposure of a fetus to lithium in the first trimester has been associated with an increased risk of Ebstein’s anomaly,

a cardiac defect characterized by a malformation of the tricuspid valve. Data from a voluntary, retrospective source, the Danish Registry of Lithium Babies, provided an estimated relative risk for Ebstein’s anomaly (compared to the general population) of 400. More recently, prospective cohort studies found risk ratios of up to 3 for all malformations and up to

7.7 for cardiac malformations. This corresponds to a risk of Ebstein’s anomaly of less than 1 in 2000. This could be seen as a tolerable level of risk, particularly for a patient who has failed other mood stabilizer treatments and becomes rapidly very ill when she is not on lithium.

ANTICONVULSANTS Anticonvulsants as a class are clearly the most dangerous of the mood stabilizers to use during pregnancy. Fetal exposure in the first trimester to monotherapy treatment with anti- convulsants increases the risk of major congenital malforma- tions 2–3 fold. When anticonvulsants are combined, the risk increases further. Valproate produces the greatest increase in risk of any individual anticonvulsant, being associated with major malformations at a rate several fold higher than other specific anticonvulsant, including carbamazepine. This excess risk associated with valproate is dose-related, becoming most evident at doses greater than 800–1000 mg/day. Among the newer anticonvulsants, lamotrigine has the largest prospec- tive dataset. Rates of major anomalies were 2.9, 12.5 and 2.7% following 1st trimester exposure to lamotrigine alone, lamotrigine with valproate, and lamotrigine with other anti- convulsants, respectively. These data have been interpreted to suggest that lamotrigine has a risk no greater than other anticonvulsants and less than that of valproate. Similar to

125 valproate, lamotrigine also produces greater rates of anoma-

MOOD STABILIZERS

lies at higher doses. There is insufficient data at present to evaluate the risk of congenital anomalies following first trimester exposure to oxcarbazepine. The specific congenital abnormalities most closely linked to anticonvulsant exposure are neural tube defects, especially spina bifida. Use of folate supplementation may reduce this risk, but certainly does not eliminate it. As with congenital anomalies in general, neural tube defects occur with greatest frequency following valproate exposure (1–5%) relative to carbamazepine exposure (0.5–1%).

ANTIPSYCHOTICS There are less data available to guide risk/benefit assessment when considering using an atypical antipsychotic in pregnancy, but there is no evidence at present of any clear increase in the rate of fetal anomalies overall or evidence for the pres- ence of any specific congenital syndrome associated with expo- sure. The typical antipsychotics have a much longer history of use in pregnancy and are also not associated with any specific syndrome. There is some evidence, however, that higher potency neuroleptics may be safer than lower potency agents.

GENERAL PRINCIPLES Because they are, of course, intimately interconnected, both the developing fetus and the mother must be considered in treating the pregnant women with bipolar disorder. Mood stabilizer discontinuation at any time is associated with an increased risk of relapse, which may lead to self-destructive or reckless behavior. In addition, we know from many preclin- ical studies that severe stress during pregnancy, in a range of species including primates, can produce long-standing abnor- malities in the hypothalamic-pituitary-adrenal axis and increase the vulnerability to behaviors suggestive of depression and anxiety. Therefore, the ideal of minimizing exposure to medica- tions during pregnancy may not always be the best option.

It is critical to carefully evaluate the potential risks and benefits of maintaining or discontinuing mood stabilizer treat- ment during pregnancy for each individual patient, in light