Treatment with psychopharmaceuticals may prove problematic for pregnant women. The decision to discontinue medications or to adjust dosages to minimize the risk to the fetus has to be addressed. The dynamic balance of treatment options, maternal concerns and practitioner responsibility depends upon staying abreast of the latest research in psychopharmacology and pregnancy.
Despite the widespread, long-standing notion that pregnancy is a time of happiness and emotional well-being, accumulating evidence suggests that pregnancy does not protect women from mental illness. Like their nonpregnant counterparts, pregnant women experience new onset and recurrent mood, anxiety and psychotic disorders. For example, like other women, as much as 20% of pregnant women experience minor or major depression (Gotlib et al., 1989; O'Hara, 1986). Moreover, premature discontinuation of antidepressants during pregnancy can precipitate a relapse of depressive symptoms (Nonacs and Cohen, 2002).
Like major depressive disorder, bipolar disorder (BD) affects pregnant women and poses substantial risk to the mother and fetus. Past history of BD tends to predict the course of illness during pregnancy. A study of recurrently ill women with BD who discontinued lithium (Eskalith, Lithobid) close to the time of conception suggested that the rate of relapse for pregnant women with BD is similar to the rate of relapse for nonpregnant, age-matched women with BD (Viguera et al., 2000). The study also indicated that the risk for postpartum decompensation is substantially increased even when lithium discontinuation is not associated with antepartum relapse.
The courses of schizophrenia, panic disorder and eating disorders vary--some women exhibit no change in symptoms, while some improve and others decompensate (Franko et al., 2001; McNeil et al., 1984; Wisner et al., 1996). Obsessive-compulsive disorder tends to worsen during pregnancy (Buttolph and Holland, 1990). Although there are no published studies on the course of generalized anxiety disorder in pregnancy, clinical experience suggests that pregnancy can exacerbate tension, worry and ruminations.
Symptomatic psychiatric illnesses have been associated with poor prenatal care, inadequate nutrition, impulsive behaviors, substance abuse and increased incidences of postpartum depression. Depression during pregnancy has been associated with preterm birth, smaller head circumferences, and lower birth weights and Apgar scores (Nonacs and Cohen, 2002).
Goals of treatment. The primary goal of treating psychiatric disorders during pregnancy is attaining mental health stability, while minimizing risks to the mother and fetus. Hence, sometimes the aim is reduction and management of symptoms rather than complete remission.
Factors relevant to treatment decision-making. It is important to consider the risks and benefits of all possible treatment options. Since more than half of all pregnancies in the United States are unplanned, knowing which medications have good track records in pregnancy is essential when prescribing psychotropic medications to women of childbearing age. Women with histories of psychiatric disorders should consult a perinatal psychiatrist (preferably with their partners) before attempting to become pregnant. Ideally, prior to conception, women should be stable and prepared to handle the stresses of both pregnancy and motherhood.
When advising a patient about treatment options, the severity of illness, history of symptoms off medications, current medications and plans for breast-feeding are important considerations. The presence of a stable support system (e.g., partner and family support) and the availability of child care assistance during the postpartum period are also important. All treatment decisions should be carefully documented and discussed with the patient and her partner, as well as other treating physicians.
Psychotherapy and psychosocial measures should be considered before prescribing medications and electroconvulsive therapy, particularly if the patient has mild symptoms or is in the early stages of pregnancy when major fetal organ systems are developing. Various forms of psychotherapy including cognitive-behavioral, interpersonal, insight-oriented, supportive, couple's and group therapy may be useful. Clinicians should encourage patients to decrease external stressors; ensure sufficient sleep; and minimize caffeine, nicotine and alcohol use.
Women who discover they are pregnant while taking psychotropic medications can be reassured that exposure during the first two weeks of gestation is relatively low risk because the uteroplacental circulation has not been established yet. If a woman has been stable over a prolonged period of time and the probability of relapsing is low, medications can be tapered and discontinued.
Psychotropic medications should be used when nonpharmacological treatments fail to maintain psychiatric well-being and when the risk of mental illness to the mother and fetus outweighs the risk of psychotropic medications. Medications should be considered in all women with severe disease, psychosis, suicidal ideation or poor weight gain. Whenever possible, they should be avoided during the first 12 weeks of pregnancy, the primary period of organogenesis.
The clinician should discuss the risks and benefits of medications during pregnancy with the patient so she can make educated and informed decisions about treatment. Including the patient's partner and obstetrician in the discussion is useful. Clinicians should be aware that the U.S. Food and Drug Administration's Use-In-Pregnancy ratings found in the PDR can be misleading. Treatment should reflect current published clinical data in addition to these ratings. Psychiatrists should help patients understand the limitations of the research, including the scarcity of prospective, double-blind, placebo-controlled studies and the dearth of data on the neurobehavioral sequelae of fetal exposure. Careful documentation of all discussions and treatment decisions is essential. Throughout the pregnancy, the clinician should re-evaluate the risks and benefits associated with medication exposure and continue or change the treatment based on changing clinical status.
When prescribing medications to pregnant women, doses should be as low as possible to maintain clinical efficacy. Of the antidepressant medications, tricyclic antidepressants and fluoxetine (Prozac) have been studied most extensively and do not seem to increase the risk of miscarriage or gross malformations. The literature for the newer selective serotonin reuptake inhibitors, sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox) and citalopram (Celexa), is more limited, but also supports reproductive safety. Monoamine oxidase inhibitors are contradicted in pregnancy because of the risk of hypertensive crisis. In a small study (n=150), the use of venlafaxine (Effexor) during pregnancy did not show an increase in the rates of major malformations (Einarson et al., 2001). Other antidepressant medications, including bupropion (Wellbutrin), nefazodone (Serzone) and mirtazapine (Remeron), have not been evaluated sufficiently during pregnancy.
Nulman et al. (1997) studied the long-term effects of in utero exposure to antidepressant medications. This study revealed that preschool-aged children exposed to fluoxetine (n=55) and tricyclic antidepressants (n=80) in utero were similar to age-matched, nonexposed children with respect to IQ, language and behavior.
The commonly used mood-stabilizing medications (lithium, valproic acid [divalproex sodium (Depakote)] and carbamazepine [Tegretol]) are associated with fetal abnormalities when used during the first trimester of pregnancy. Lithium exposure is associated with a 10 to 20 times increased risk of Ebstein's cardiac anomaly (Altshuler et al., 1996; Cohen et al., 1994). While this increase is substantial, the absolute risk is relatively low (0.1%) compared to the 1% to 5% risk of facial abnormalities and spina bifida associated with valproic acid and carbamazepine (Altshuler et al., 1996). Thus, lithium is the drug of choice when a mood-stabilizing medication must be used in pregnancy.
However, other cardiac malformations, hypotonia, poor suck reflex, hypoglycemia and cyanosis have been related to lithium exposure (Briggs et al., 1997; Cohen et al., 1994; Woody et al., 1971). In addition, there are isolated reports of neonatal goiter and diabetes insipidus, but no apparent neurobehavioral sequelae (Woody et al., 1971). Lithium should be given in multiple daily doses to avoid peaks of fetal exposure when administered during pregnancy. Maternal lithium levels should be monitored closely, as serum concentrations often drop in response to increased extracellular fluid volume and renal clearance. A high-resolution ultrasound at week 18 is advised to assess for congenital anomalies, especially cardiovascular malformations. During the last antepartum month, the maternal lithium level should be no higher than 0.9 mEq/L in order to avoid maternal lithium toxicity secondary to the sudden, large fluid shifts that tend to occur at delivery (Burt and Hendrick, 2001).
In addition to spina bifida and facial abnormalities, valproic acid and carbamazepine are associated with vitamin K-dependent clotting factor deficiency, possibly increasing the risk of bleeding in the fetus and neonate. It is not known whether folate supplementation beyond routine prenatal supplementation decreases these risks. Carbamazepine appears to increase the risk of cardiac malformations, oral clefts and urinary tract defects. Valproic acid may cause developmental delay. Because the newer anti-epileptic drugs lamotrigine (Lamictal), gabapentin (Neurontin) and topiramate (Topamax) are second-line agents for the treatment of BD and because there are very limited data for in utero exposure to these agents, these medications cannot be recommended for use in pregnancy (Morrell, 1996).
In a small (n=37) naturalistic report by Wisner et al. (2002), verapamil (Calan, Isoptin) effectively treated acute manic episodes and maintained mood stability in pregnant and nonpregnant women with BD. The authors noted that verapamil does not appear to be teratogenic but that further study is needed.
Until recently, high-potency neuroleptics were considered the safest antipsychotic medications in pregnancy (Altshuler et al., 1996). However, a study by Goldstein et al. (2000) found no evidence of increased risk in 23 cases of olanzapine (Zyprexa) exposure. This raises the question of whether olanzapine should be included as a possible treatment for pregnant women requiring an antipsychotic and/or a mood stabilizer. More data are needed.
The data on benzodiazepine use in pregnancy are mixed. Overall, the data suggest a very small (12 in 10,000) but increased risk of oral clefts associated with first trimester use (Altshuler et al., 1996; Dolovich et al., 1998). Late third-trimester use of benzodiazepines can be associated with perinatal syndromes such as hypotonia, withdrawal, poor feeding, apnea and low Apgar scores (Altshuler et al., 1996; McElhatton, 1994). Infrequent use, however, doesnot appear problematic.
When carried out with a multidisciplinary treatment team comprising a psychiatrist, anesthesiologist and obstetrician, ECT is safe in pregnancy and can rapidly treat severe psychiatric illness, including psychotic depression and uncontrollable mania (Miller, 1994). Special precautions must be taken during the procedure.
When treating women during pregnancy, a careful review of the most recent research is essential. A number of pharmaceutical manufacturers maintain registries of pregnancy outcomes in women using psychotropic medications. Referring to the Expert Consensus Guideline Series: Treatment of Depression in Women (Altshuler et al., 2001) and obtaining a consultation from a perinatal psychiatrist who specializes in treating women of childbearing age can be extremely helpful.
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