Psychiatric disorders are common in women of reproductive age. (1) Despite the morbidity associated with these disorders, there has been a tendency to avoid prescribing psychiatric medications during pregnancy. An expanding body of knowledge about the risks and benefits of these medications has made it possible to make more rational decisions about their use. (2,3) Growing evidence suggests that many of these agents are safe; however, there are some that clearly should be avoided.
This article reviews the risks and benefits of commonly used psychiatric medications. The use of these medications in lactation is the subject of a recent American Family Physician review. (4)
Risks of Psychiatric Medications
Psychiatric symptoms can affect pregnancy because of their effect on the mother's emotional state, functional status, ability to obtain proper prenatal care, and potential to engage in dangerous behavior. (2) After the birth of a child, untreated maternal mental illness may have an effect on the infant's development and well-being. (2,3,5)
All currently available psychopharmacologic agents and their metabolites cross the placenta, principally by simple diffusion. (6) The specific fetal serum levels are unknown, but they may be higher than maternal levels. (6) Medications can potentially affect the fetus in several ways: structural teratogenesis (birth defects), behavioral teratogenesis, and perinatal syndromes. (2,6)
STRUCTURAL TERATOGENESIS
The timing of exposure to chemical agents during development affects the risk for malformations. (7) The second through the eighth weeks postfertilization, during which time the development of major organ systems occurs, is the critical period of risk for structural teratogenesis. (7)
BEHAVIORAL TERATOGENESIS
Behavioral teratogenicity is the occurrence of behavior or neuropsychiatric symptoms in offspring after in utero exposure to a drug or toxin. (3) Subsequent prospective human studies have not shown convincing evidence for such an effect, perhaps because of the difficulty of separating the behavioral teratogenicity of maternal mental illness from drug effects. (3,5)
PERINATAL SYNDROMES
Administration of psychiatric medications proximate to delivery can cause what are termed perinatal syndromes (Table 1) (3,8-10) of drug intoxication or withdrawal. In some cases, these effects are reasonably well established and pharmacologically plausible, such as the somnolence and hypotonia of infants exposed to intrapartum benzodiazepines. (2) In most cases, the evidence is limited to case reports in which nonspecific neonatal effects (e.g., poor feeding and irritability) have been interpreted as possible evidence of exposure to, or withdrawal from, certain antidepressants. (8) The limited data are best viewed as potential class effects, and it is not possible to draw conclusions about specific agents within classes.
FDA Risk Categories
Table 2 (11) shows the five U.S. Food and Drug Administration (FDA) categories for drug use in pregnancy. These ratings have a number of limitations, including a lack of internal consistency within classes of medications; attempts to aggregate diverse information, such as risks, into a single rating; poor discrimination between different medications within a class; and lack of agreement with the findings of other credible sources. While physicians should be familiar with these ratings, they are likely to find a variety of online and print resources to be more useful. (7,12-16)
Risks of Specific Agents
ANTIDEPRESSANTS
The results of numerous studies that included thousands of pooled patients taking tricyclic antidepressants (TCAs) and the selective serotonin reuptake inhibitor (SSRI) fluoxetine (Prozac) support the relative safety of these medications for use throughout pregnancy. (8,17,18) Neither the TCAs nor fluoxetine has been associated with major teratogenic effects. (8,17,18) In addition, a well-designed follow-up study revealed no evidence of behavioral teratogenicity with these agents after up to seven years of follow-up. (19) There have been case reports of perinatal syndromes relating to all of these agents, but the effects appear to be mild, transient, and of questionable causation (Table 1). (3,8-10)
Fewer data are available about other widely used SSRIs. (18,20) Paroxetine (Paxil), sertraline (Zoloft), and citalopram (Celexa) have been studied prospectively in a few hundred women exposed at various times during pregnancy; these agents do not appear to increase the risk of teratogenesis. (18,20) Even fewer data are available about novel agents such as venlafaxine (Effexor), nefazodone (Serzone), or bupropion (Wellbutrin). (3) Limited data on the use of monoamine oxidase inhibitors are not reassuring, and use of these agents is not recommended during pregnancy. (3)
BENZODIAZEPINES
The potential teratogenicity of benzodiazepines remains controversial, but a recent meta-analysis suggested a twofold increase, at most, in the risk of orofacial clefts. (21) Although benzodiazepines are often used as primary pharmacotherapy in anxiety disorders, there are generally more effective and safer treatments, such as cognitive behavior therapy and SSRIs. (22) Perinatal use of benzodiazepines has been associated with hypotonia, apnea, hypothermia, and feeding difficulties, and it should be discouraged. (13) There is little data on behavioral teratogenesis, with a few reports suggesting developmental delay. (2) There are almost no data on the nonbenzodiazepine anxiolytic buspirone (BuSpar) during pregnancy. (13)
MOOD STABILIZING AGENTS
Lithium, valproic acid (Depakene), and carbamazepine (Tegretol) are commonly used in the treatment of bipolar disorder. Unfortunately, all of these agents are known teratogens. (23) Exposure to lithium in the first trimester is associated with a tenfold increase in Ebstein's anomaly, a condition of hypoplasia of the right ventricle and tricuspid valve abnormalities, from a baseline risk of one in 20,000 to, at most, one in 1,000. (23) There have been reports of a perinatal syndrome of cyanosis and hypotonicity (Table 1)3,8-10; one follow-up study did not find evidence of behavioral teratogenicity after lithium exposure. (9)
Valproic acid and carbamazepine have been associated with a marked (tenfold) increase in neural tube defects with first-trimester exposure, with incidences of 1 to 5 percent and 0.5 to 1.0 percent, respectively. (23) Oral clefts have also been associated with first-trimester exposure. (23) Data on neurobehavioral effects are conflicting, but no major effects have been identified. (2)
ANTIPSYCHOTIC AGENTS
Antipsychotic agents can generally be grouped into three classes: high-potency agents such as haloperidol (Haldol); low-potency agents such as chlorpromazine (Thorazine); and the newer agents such as risperidone (Risperdal), clozapine (Clozaril), and olanzapine (Zyprexa). A small but statistically significant increased risk for nonspecific teratogenic effects has been associated with first-trimester exposure to low-potency agents. (10) Among the high-potency agents, haloperidol has been the subject of the most study. It has been shown to be free of congenital malformations with first-trimester exposure and is a preferred agent during pregnancy. (10) There are insufficient data on the newer agents to allow any conclusions to be drawn about their safety profile. (10) Reports of transient perinatal effects have been described (Table 1). (3,8-10) There are limited data on behavioral teratogenesis. (10)
Individualizing Treatment Decisions
In individualizing treatment decisions, several general considerations must be addressed. The most important consideration is the patient's past level of function when not taking medication. An assessment of the level of function should include a history of previous psychiatric hospitalization (generally considered evidence of significant dysfunction); suicidality or similar self-destructive thoughts or behaviors; and an assessment of the patient's ability to meet home, educational, and occupational responsibilities. The natural history of symptoms and dysfunction during previous pregnancies and deliveries, if known, is also important, especially in patients with depressive and bipolar disorders.
If the patient has a psychotherapy-responsive condition, the possibility of substituting this form of therapy for medication should be considered within the context of patient preference, availability of quality psychotherapy and the patient's previous response to such therapy. Although patient preferences and values should be considered, mental illness can cause cognitive distortions that interfere with good decision-making. Ideally, preferences should be elicited when the patient is well.
DEPRESSIVE DISORDERS
