Ebstein's anomaly

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

In women, it is clear that the onset of major depression tends to occur in the child-bearing ages. (1) Studies have shown a similar incidence of major depressive episodes in matched gravid and nongravid women, so pregnancy appears to have neither a protective nor a detrimental effect. (24) In contrast, the postpartum period is one of high risk for the development of a depressive episode, particularly in women with a history of major depression (especially if it had a postpartum component), depressive symptoms during pregnancy, or bipolar disorder. (24,25)

The management of women with depression during pregnancy is based on balancing the potential risk of the symptoms against the potential risks of pharmacotherapy. (3) Antidepressant medications are among the best-studied medications in pregnancy, and the evidence of their safety is substantial. (2,8) Guidelines for the selection of treatments for depression in pregnant women are summarized in Table 3. (25,26)

BIPOLAR DISORDER

Little is known about the course of bipolar disorder during pregnancy, but the postpartum period is clearly one of high risk. (24,27) Postpartum relapse rates in women not treated with prophylactic mood stabilizers are 30 to 50 percent. (25) Initiation of treatment with a mood stabilizer before delivery or immediately postpartum markedly reduces this risk. (25) In addition, many patients who present with postpartum psychosis may be having an initial episode of bipolar disorder. (27) Again, treatment should be guided by the patient's history of previous and current mood symptoms balanced against the risks of pharmacotherapy, as detailed in Table 3. (25,26) Involvement of a psychiatrist will be helpful in characterizing the risk and predicted severity of relapse. Women taking mood stabilizing agents should be offered folate supplementation and prenatal screening for cardiac and neural tube defects, as indicated. (2,9,23)

PSYCHOTIC DISORDERS

There are few data on the impact of pregnancy on the course of schizophrenia. (2,3) The delusions, hallucinations, and disorganized thinking and behavior present in persons with untreated schizophrenia can have a particularly devastating effect on the person's overall function and ability to comply with prenatal care. (28) Chronic schizophrenia has an extremely high rate of relapse when medications are withdrawn. (2) Pharmacologic treatment is guided by the woman's psychiatric history, with continued maintenance treatment usually being the safest overall strategy. (2)

New-onset psychosis during pregnancy is a psychiatric and obstetric emergency. Careful diagnostic assessment to evaluate for psychiatric and organic disorders is necessary. Decisions regarding regular dosing or as-needed use of antipsychotics are guided by the patient's symptoms and the likely primary diagnosis. Ordinarily, these decisions are made in consultation with the patient's psychiatrist. (2)

ANXIETY DISORDERS

Pregnancy does not have a clear impact on the natural history of anxiety disorders, although there is an apparent risk of susceptibility in the postpartum period. (24) Patients on maintenance pharmacotherapy for these disorders show high rates of relapse with medication discontinuation. Cognitive behavior therapy has been shown to be an effective treatment modality in many of these disorders, and it may be a reasonable option for patients who wish to discontinue medications during pregnancy. (22)

If benzodiazepines are used during pregnancy, they should be avoided in the first trimester because of possible teratogenicity and before delivery because of an apparent perinatal syndrome. (2,19) In women receiving chronic daily benzodiazepine therapy who wish to conceive, medication should be weaned gradually (approximately 10 percent per week) and consideration given to cognitive behavior therapy or antidepressant therapy. (22) The best-studied agents for use during pregnancy are alprazolam (Xanax), clonazepam (Klonopin), and diazepam (Valium). (2)

Guidelines

Despite the many uncertainties about the effects of psychiatric disorders and various medications on the mother, fetus, and infant, there are guidelines for making decisions about using pharmacologic agents during pregnancy.

* The patient's psychiatric history is the best predictor of future functioning. The patient's diagnosis, severity of previous episodes, necessity for medication, and responsiveness to medication are strong predictors of the need for medication to maintain remission. Patients with schizophrenia, bipolar disorder, severe chronic depression, and panic disorder with agoraphobia are generally at risk for a high degree of dysfunction and morbidity with relapse. Patients with disorders such as dysthymia, generalized anxiety disorder, or panic disorder without agoraphobia may experience less of an impact on their functional status.

* Nonpharmacologic therapies may eliminate or reduce the need for medications in some disorders. Cognitive behavior therapy for anxiety disorders and interpersonal psychotherapy and cognitive behavior therapy for depressive disorders have proved efficacious.

* When medications are used, those that are most appropriate for the patient's condition should be chosen. The SSRIs are usually the agents of choice in the treatment of depressive and anxiety disorders.

* When there is a choice, medications should be selected on the basis of existing data.

* Collaboration and consultation with mental health professionals is an important aspect of treatment planning. Diagnosis, risk assessment, symptom monitoring, and optimal medication management can require special expertise and can be time intensive. Patients with chronic severe depressive and anxiety disorders, psychotic disorders, and bipolar disorders are particularly in need of specialty consultation and management.

* Psychotherapy, in addition to being an appropriate primary symptomatic treatment for some depressive and anxiety disorders, should be considered as a means of helping patients deal with issues related to their psychiatric disorder, pregnancy, and other life stresses.

* The patient should be educated about the known benefits, risks, and uncertainties of pharmacotherapy, and informed consent should be documented in the medical record.

* Contacting regional or university-based teratogenicity centers for up-to-date information on medications and as an additional source of risk counseling is another consideration.

REFERENCES

(1.) Frank JB, Weihs K, Minerva E, Lieberman DZ. Women's mental health in primary care. Depression, anxiety, somatization, eating disorders, and substance abuse. Med Clin North Am 1998;82:359-89.

(2.) Altshuler LL, Cohen L, Szuba MP, Burt VK, Gitlin M, Mintz J. Pharmacologic management of psychiatric illness during pregnancy: dilemmas and guidelines. Am J Psychiatry 1996;153:592-606.

(3.) Cohen LS, Rosenbaum JF. Psychotropic drug use during pregnancy: weighing the risks. J Clin Psychiatry 1998;59(suppl 2):18-28.

(4.) Spencer JP, Gonzales LS 3d, Barnhardt DJ. Medications in the breast-feeding mother. Am Fam Physician 2001;64:119-26.

(5.) Weinberg MK, Tronick EZ. The impact of maternal psychiatric illness on infant development. J Clin Psychiatry 1998;59(suppl 2):53-61.

(6.) Stowe ZN, Strader JR, Nemeroff CB. Psychopharmacology during pregnancy and lactation. In: Schatzberg AF, Nemeroff CB, eds. The American Psychiatric Press Textbook of psychopharmacology. 2d ed. Washington, D.C.: American Psychiatric Press, 1998:979-96.

(7.) Little BB, Gilstrap LC. Introduction to drugs in pregnancy. In: Gilstrap LC, Little BB, eds. Drugs and pregnancy. 2d ed. New York: Chapman & Hall, 1998:523.

(8.) Wisner KL, Gelenberg AJ, Leonard H, Zarin D, Frank E. Pharmacologic treatment of depression during pregnancy. JAMA 1999;282:1264-9.

(9.) Llewellyn A, Stowe ZN, Strader JR Jr. The use of lithium and management of women with bipolar disorder during pregnancy and lactation. J Clin Psychiatry 1998;59(suppl 6):57-64.

(10.) Trixler M, Tenyi T. Antipsychotic use in pregnancy. What are the best treatment options? Drug Saf 1997;16:403-10.

(11.) Physicians' desk reference. 54th ed. Montvale, N.J.: Medical Economics, 2000:345.

(12.) Hale TW. Medications and mothers' milk. 8th ed. Amarillo, Tex.: Pharmasoft Medical, 2000.

(13.) Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 5th ed. Baltimore: Williams & Wilkins, 1998.

(14.) Friedman JM, Polifka JE. The effects of neurologic and psychiatric drugs on the fetus and nursing infant: a handbook for health care professionals. Baltimore: Johns Hopkins University Press, 1998.

(15.) REPRORISK System. Reproductive risk information. Retrieved June 2002, from: www.micromedex.com/ products/reprorisk/.

(16.) Teratogen information system and the online version of Shepard's catalog of teratogenic agents. Retrieved June 2002, from: depts.washington.edu/ ~terisweb/teris/.

(17.) Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med 1996;335:1010-5.

(18.) Ericson A, Kallen B, Wiholm B. Delivery outcome after the use of antidepressants in early pregnancy. Eur J Clin Pharmacol 1999;55:503-8.

(19.) Nulman I, Rovet J, Stewart DE, Wolpin J, Gardner HA, Theis JG, et al. Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med 1997;336:258-62.

(20.) Kulin NA, Pastuszak A, Sage SR, Schick-Boschetto B, Spivey G, Feldkamp M, et al. Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study. JAMA 1998;279:609-10.

(21.) Dolovich LR, Addis A, Vaillancourt JM, Power JD, Koren G, Einarson TR. Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies. BMJ 1998;317:839-43.

(22.) Nesse RM, Zamorski MA. Anxiety disorders in primary care. In: Knesper DJ, Riba MB, Schwenk TL, eds. Primary care psychiatry. Philadelphia: Saunders, 1997:132-62.

(23.) Viguera AC, Cohen LS. The course and management of bipolar disorder during pregnancy. Psychopharmacol Bull 1998;34:339-46.

(24.) Altshuler LL, Hendrick V, Cohen LS. Course of mood and anxiety disorders during pregnancy and the postpartum period. J Clin Psychiatry 1998; 59(suppl 2):29-33.

(25.) Nonacs R, Cohen LS. Postpartum mood disorders: diagnosis and treatment guidelines. J Clin Psychiatry 1998;59(suppl 2):34-40.

(26.) Llewellyn A, Stowe ZN. Psychotropic medications in lactation. J Clin Psychiatry 1998;59(suppl 2):41-52.

(27.) Leibenluft E. Women and bipolar disorder: an update. Bull Menninger Clin 2000;64:5-17.

(28.) Bennedsen BE. Adverse pregnancy outcome in schizophrenic women: occurrence and risk factors. Schizophr Res 1998;33:1-26.

The authors indicate that they do not have any conflicts of interest. Sources of funding: none reported.

RANDY K. WARD, M.D., is assistant professor of family and community medicine, and of psychiatry and behavioral medicine, and director of the combined family medicine/ psychiatry residency program at the Medical College of Wisconsin in Milwaukee. He is a graduate of Northwestern University Medical School, Chicago, where he completed a residency and a fellowship in psychiatry. He subsequently completed a family practice residency at MacNeal Hospital in Berwyn, Ill., and a primary care faculty development fellowship at Michigan State University College of Human Medicine, East Lansing.

MARK A. ZAMORSKI, M.D., M.H.S.A., is clinical assistant professor of family medicine at the University of Michigan Medical School, Ann Arbor. He is a graduate of Michigan State University's College of Human Medicine, East Lansing, and completed a residency in family practice at the University of Michigan Medical School. He also earned a postgraduate degree in health services administration from the University of Michigan School of Public Health, Ann Arbor. Address correspondence to Randy Ward, M.D., Medical College of Wisconsin, St. Mary's Family Practice Center, 2320 N. Lake Dr., Milwaukee, WI 53211 (e-mail: rward@mcw.edu). Reprints are not available from the authors.

Members of various medical faculties develop articles for "Practical Therapeutics." This article is one in a series coordinated by the Department of Family Medicine at the University of Michigan Medical School, Ann Arbor. Guest editor of the series is Barbara S. Apgar, M.D., M.S., who is also an associate editor of AFP.

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