Treatment of Mood Disorders During Pregnancy

Weighing Treatment Options

With the advent of newer and better-tolerated antidepressants, as well as enhanced public awareness of available pharmacother-apy for depression, a growing number of women are prescribed antidepressant medications during the childbearing years. For women with recurrent major depression who are receiving maintenance antidepressant treatment and who plan to conceive, the clinician and patient must decide whether to maintain or to discontinue antidepressant treatment during pregnancy. Ideally, decisions regarding the use of psychotropic medications during pregnancy should be made prior to conception. Prior to pregnancy, the clinician must provide information regarding the patient's risk of relapse in the setting of medication discontinuation. The clinician must also take into account the risk of chronic, recurrent depression and its attendant morbidity in patients who experience depressive relapse after medication discontinuation (Keller et al. 1983; Mueller et al. 1999; Post 1992).

In patients with less severe depression, it may be appropriate to consider discontinuation of pharmacologic therapy during pregnancy. Nonpharmacologic interventions, including interpersonal psychotherapy (IPT) and cognitive-behavioral therapy (CBT), may be used prior to conception to facilitate the gradual tapering and discontinuation of an antidepressant medication in women planning to become pregnant. These modalities of treatment may reduce the risk of recurrent depressive symptoms during pregnancy, although this has not been studied systematically. Close monitoring during pregnancy is essential, even if all medications are discontinued and there is no apparent need for medication management. Women with histories of mood disorder who discontinue antidepressant treatment are at high risk for relapse, and early detection and treatment of recurrent illness during pregnancy may attenuate the morbidity associated with antenatal mood disorder.

Many women who discontinue antidepressant treatment during pregnancy do experience recurrent depressive symptoms. Thus, for women with more recurrent or refractory depressive illness, patient and clinician together may decide that the safest option that enhances the likelihood of sustaining euthymia is to continue pharmacologic treatment across pregnancy. In such a situation, the clinician should, when possible, select medications for use during pregnancy that have a well-characterized reproductive safety profile. Often this may involve switching from one psychotropic agent to another with a more complete reproductive safety profile. An example of this approach would be switching from mirtazapine, a medication for which there are almost no data regarding reproductive safety, to a better-characterized agent such as fluoxetine. In other situations, one may decide to use a medication for which information regarding reproductive safety is sparse. A example of such a scenario is when the clinician is treating refractory depressive illness in a patient who has been responsive to only one antidepressant and the data on reproductive safety are limited for that antidepressant (i.e., nefazodone). Such a patient may choose to continue this medication during pregnancy rather than risk relapse associated with discontinuation of the agent or a switch to another antidepressant.

Women may also experience new onset of depressive symptoms during pregnancy. For women who present with minor depressive symptoms, nonpharmacologic treatment strategies should be explored first. IPT or CBT may be beneficial for reducing the severity of depressive symptoms and may either limit or obviate the need for medications (Beck et al. 1979; Klerman et al. 1984; Spinelli 1997). In general, pharmacologic treatment is pursued when non-pharmacologic strategies have failed or when it is felt that the risks associated with psychiatric illness during pregnancy outweigh the risks of fetal exposure to a particular medication.

Nonpharmacologic Interventions

Until recently, there were few data on the role of nonpharmaco-logic treatments for depression during pregnancy. For women with mild to moderate depressive symptoms, nonpharmacologic interventions, including IPT (Klerman et al. 1984), cognitive therapy and CBT (Beck et al. 1979), and supportive psychotherapy, may be attractive alternatives to medication during pregnancy. in women who are receiving maintenance antidepressant treatment, non-pharmacologic interventions may potentially facilitate tapering of medication or may allow for use of lower dosages of medication.

IPT is a short-term, manual-driven psychotherapy that deals primarily with four major problem areas: grief, interpersonal disputes, role transitions, and interpersonal deficits (Keller et al. 1984). Given the importance of interpersonal relationships in couples expecting a child and the significant role transitions that take place during pregnancy and subsequent to delivery, IPT is ideally suited for the treatment of depressed pregnant women. Spinelli has adapted IPT for the treatment of women with antenatal depression, focusing on the role transitions and interpersonal disputes characteristic of pregnancy and motherhood. in a pilot study of 13 women (Spinelli 1997), IPT significantly reduced the severity of depressive symptoms and induced remission in all patients. Furthermore, none of the women followed after delivery (n = 10) developed postpartum depression. Although the findings from this study are limited by its small size and lack of a control group, the results are encouraging. Not only does this modality of treatment treat the acute symptoms of depression during pregnancy; it appears to decrease risk of depression after delivery. Larger prospective studies of IPT during pregnancy are currently under way and may identify subgroups of women who are particularly responsive to such treatment.

Pharmacologic Interventions

Many reviews have been published that describe available data (from anecdotal case reports and larger prospectively derived samples) regarding risks associated with fetal exposure to anti-depressants (Altshuler et al. 2001; Cohen and Rosenbaum 1997; Cohen et al. 1998; Cott and Wisner 2003). Although accumulated data over the past 30 years suggest that some antidepressants may be used safely during pregnancy (Altshuler et al. 1996; Cohen and Altshuler 1997; Wisner et al. 1999), information regarding the spectrum of attendant risks of prenatal exposure to psychotropic medications is still incomplete.

When considering the use of a psychiatric medication during pregnancy, the clinician must address four primary types of risk with respect to the developing fetus: 1) risk of pregnancy loss or miscarriage, 2) risk of organ malformation or teratogenesis, 3) risk of neonatal toxicity or withdrawal syndromes during the acute neonatal period, and 4) risk of long-term neurobehavioral sequelae (Cohen and Altshuler 1997). To provide guidance to physicians seeking information on the reproductive safety of various prescription medications, the FDA established a system that classifies medications into five risk categories (A, B, C, D, and X) based on data derived from human and animal studies. Category A medications are designated as safe for use during pregnancy, while category X drugs are contraindicated and are known to have risks to the fetus that outweigh any benefit to the patient. Most psychotropic medications are classified as category C, agents for which human studies are lacking and for which "risk cannot be ruled out." No psychotropic drugs are classified as safe for use during pregnancy (category A).

Unfortunately, this system of classification is frequently ambiguous and may sometimes be misleading. For example, certain tricyclic antidepressants (TCAs) have been labeled as category D, indicating "positive evidence of risk," although the pooled available data do not support this assertion and, in fact, suggest that these drugs are safe for use during pregnancy (Altshuler et al. 1996; Pastuszak et al. 1993). Therefore, the physician must rely on other sources of information when providing well-informed recommendations on the use of psychotropic medications during preg nancy. For obvious ethical reasons, it is not possible to conduct randomized, placebo-controlled studies on medication safety in pregnant populations. Therefore, much of the data on reproductive safety has been derived from retrospective studies and case reports, although more recent studies have used a prospective design (Chambers et al. 1996; Einarson et al. 2001a; Kulin et al. 1998; Nulman et al. 1997; Pastuszak et al. 1993).

Risk of Pregnancy Loss or Miscarriage

Recent attention has focused on whether certain antidepressants may increase the risk of early pregnancy loss. While most reports do not indicate that antidepressants increase the risk of miscarriage, several reports have suggested small increases in rates of spontaneous abortion among women treated with selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine re-uptake inhibitor (SNRI) antidepressants during the first trimester of pregnancy (Einarson et al. 2001a; Kulin et al. 1998; Pastuszak et al. 1993). In these reports, the observed differences did not reach statistical significance; rates of miscarriage in exposed women were in the range of what would be normally expected in women with no known exposure. An alternative explanation for the finding of slightly increased risk of miscarriage in antidepressant-exposed women is that depression itself is a factor that may contribute to increasing risk of spontaneous abortion (Sugiura-Oga-sawara et al. 2002). Some authors also suggest that the number of spontaneous abortions may have been overestimated, because some women taking medications at conception, when questioned during the follow-up interviews, may have chosen to report a miscarriage, when in fact they had decided to terminate their pregnancy (Einarson et al. 2001a). Further studies are needed to better define the risk of pregnancy loss.

Risk of Organ Malformation or Teratogenesis

The baseline incidence of major congenital malformations in newborns born in the United States is estimated to be 3%-4% (Fabro 1987). During the earliest stages of pregnancy, formation of major organ systems takes place and is complete within the first 12 weeks after conception. A teratogen is defined as an agent that interferes with this process and produces some type of organ malformation or dysfunction. Exposure to a toxic agent before 2 weeks of gestation is not associated with congenital malformations and is more likely to result in a nonviable blighted ovum (Langman 1985). For each organ or organ system, there exists a critical period during which development takes place and may be susceptible to the effects of a teratogen (Moore and Persaud 2003). For example, formation of the heart and great vessels takes place 4-9 weeks after conception. Formation of lip and palate is typically complete by week 10. Neural tube folding and closure, which form the brain and spinal cord, occur within the first 4 weeks of gestation.

To date, studies have not demonstrated a statistically increased risk of congenital malformations associated with prenatal exposure to antidepressants. Two meta-analyses combining studies with exposures to TCAs and SSRIs did not demonstrate an increase in risk of congenital malformation (Addis and Koren 2000; Altshuler et al. 1996). Data supporting the reproductive safety of fluoxetine (Chambers et al. 1996; Cohen et al. 2000; Goldstein 1995; Goldstein et al. 1991, 1997; Loebstein and Koren 1997; McElhat-ton et al. 1996; Nulman and Koren 1996) and citalopram (Ericson et al. 1999) are particularly robust. Four prospective studies have evaluated rates of congenital malformations in approximately 1,100 fluoxetine-exposed infants (Chambers et al. 1996; Goldstein 1995; Nulman and Koren 1996; Pastuszak et al. 1993). The postmarketing surveillance registry established by the manufacturer of fluoxetine and several other retrospective studies (McElhatton et al. 1996; Simon et al. 2002) complement these findings. These data, collected from more than 2,500 cases, indicate no increase in the risk of major congenital malformations in fluoxetine-exposed infants. Data regarding the use of citalopram come primarily from one prospective study of 969 infants with first-trimester exposure to SSRIs (including 375 exposures to citalopram) and other anti-depressants (Ericson et al. 1999).

Information regarding the reproductive safety of other SSRIs, including sertraline, paroxetine, fluvoxamine, and the SNRI venla-faxine, is gradually accumulating (Ericson et al. 1999; Inman et al. 1993; Kulin et al. 1998; McElhatton et al. 1996; Simon et al. 2002). In a retrospective study of 63 infants with first-trimester exposure to paroxetine, no increase in teratogenic risk was observed (Inman et al. 1993). In another report including 150 pregnant women, the use of venlafaxine during pregnancy did not increase the rate of major malformations above the expected baseline rate. While these initial reports are reassuring, larger samples are required to establish the reproductive safety of these newer antidepressants. It has been estimated that at least 500-600 exposures to a given drug must be collected to demonstrate a twofold increase in risk for a particular malformation over what is observed in the general population (Shepard 1989). Many studies, rather than assessing outcomes in infants exposed to a single antidepressant, observed outcomes in larger samples of infants exposed to any SSRI anti-depressant. In these pooled samples, no increase in the risk of malformation was observed in infants exposed to SSRIs (Ericson et al. 1999; Hendrick et al. 2003; Kulin et al. 1998; McElhatton et al. 1996; Simon et al. 2002). Although limited in terms of sample size, the data supporting the safety of SSRIs (as a class) and venlafaxine are increasingly reassuring.

Although early case reports suggested a possible association between first-trimester exposure to TCAs and limb malformation, 3 prospective and more than 10 retrospective studies have examined the risk of organ dysgenesis in over 400 cases of first-trimester exposure to TCAs (Altshuler et al. 1996; Cohen and Rosenbaum 1997; Loebstein and Koren 1997; McElhatton et al. 1996; Misri and Sivertz 1991). When evaluated on an individual basis and when pooled, these studies fail to indicate a significant association between fetal exposure to TCAs and risk of any major congenital anomaly. Among the TCAs, desipramine and nortriptyline are preferred since they are less anticholinergic and the least likely to exacerbate orthostatic hypotension that occurs during pregnancy.

While there is information to support the use of certain anti-depressants, including fluoxetine, citalopram, and the TCAs, during pregnancy, there are many fewer data on the reproductive safety of other antidepressants. A recent prospective study of women taking either nefazodone (n = 89) or trazodone (n = 58) during the first trimester of pregnancy suggested no increase in the risk of major malformation (Einarson et al. 2003). To date, prospective data on the use of mirtazapine and duloxetine are lacking. Scant information is available regarding the reproductive safety of monoamine oxidase inhibitors (MAOIs). One study in humans described an increase in congenital malformations after prenatal exposure to tranylcypromine and phenelzine, although the sample size was extremely small (Heinonen et al. 1977). Moreover, during labor and delivery, MAOIs may produce a hypertensive crisis should tocolytic medications, such as terbutaline, be used to forestall delivery. Given this lack of data, and the cumbersome restrictions associated with their use, MAOIs are typically avoided during pregnancy.

Data regarding the use of bupropion (Wellbutrin) are incomplete and somewhat difficult to interpret. Information collected by the manufacturer (GlaxoSmithKline) includes 426 pregnancy outcomes involving first-trimester exposure to bupropion. In this sample, there were 12 outcomes that involved major malformations. This represents a 2.8% risk of congenital malformation, which is consistent with the risk observed in women with no known teratogen exposure. While this information regarding the overall risk of malformation is reassuring, the most recent report revealed that 8 of the 12 cases involved malformations of the heart and great vessels. In addition, among the 16 retrospectively reported cases of malformations in bupropion-exposed infants, 7 involved cardiac defects. While these reports may signal a potential risk, the relatively small sample size and the high percentage of cases lost to follow-up (n=302) make it difficult to draw conclusions regarding the impact of bupropion on the developing cardiovascular system. Further studies regarding the reproductive safety of this medication are warranted, and its use during pregnancy, while not preferable, is not absolutely contraindicated.

While no study has observed an increase in risk of major congenital anomaly associated with antidepressant exposure, Chambers and colleagues (1996) noted increased risk of multiple "minor" malformations in fluoxetine-exposed infants. In this study, minor anomalies were defined as structural defects of no cosmetic or functional importance. In addition, this report suggested that late exposure to fluoxetine was associated with premature labor and poor neonatal adaptation. Interpretation of the findings of this study is limited by several methodological difficulties (Cohen and Rosenbaum 1997). For example, the fluoxe-tine-exposed women and control groups differed significantly in terms of important variables such as age, presence of psychiatric illness, and exposure to other medications. In addition, nonblinded raters were utilized, and only half of the fluoxetine-exposed infants were evaluated, which raises the question of selection bias. While further data are needed to ensure clinical confidence, the data collected thus far on fluoxetine suggest that it is unlikely to be a significant human teratogen.

Risk of Neonatal Toxicity or Withdrawal Syndromes

Neonatal toxicity or perinatal syndromes refers to a spectrum of physical and behavioral symptoms observed in the acute neonatal period that are attributed to drug exposure at or near the time of delivery. Over the past two decades, a wide range of transient neonatal distress syndromes associated with in utero exposure to (or potentially withdrawal from) antidepressants have been described; however, given the prevalence of antidepressant use during pregnancy and the anecdotal nature of these reports, the incidence of these adverse events is, in all probability, particularly low. Anecdotal reports that attribute these syndromes to drug exposure must be interpreted cautiously, and larger samples must be studied in order to establish a causal link between exposure to a particular medication and a frank perinatal syndrome.

Various case reports have described perinatal syndromes in infants exposed to TCAs in utero. A TCA withdrawal syndrome with characteristic symptoms of jitteriness, irritability, and, less commonly, seizure (Bromiker 1994; Cowe et al. 1982; Eggermont 1973; Schimmell et al. 1991; Webster 1973) has been observed. Withdrawal seizures have been reported only with clomipramine (Bromiker 1994; Cowe et al. 1982). In addition, neonatal toxicity attributed to the anticholinergic effect of TCAs, including symptoms of functional bowel obstruction and urinary retention, has been reported (Falterman and Richardson 1980; Shearer et al. 1972). In all cases, these symptoms were transient.

The extent to which prenatal exposure to fluoxetine or other SSRIs is associated with neonatal toxicity is still unclear and has been the subject of some debate. Concerns were first raised by Chambers and colleagues (1996), who suggested that third-trimester use of fluoxetine was associated with increased risk of neonatal complications and higher rates of admission to the special care nursery. since that time, several other studies have also described increased rates of admission to the special care nursery among SSRI-exposed infants (Casper et al. 2003; Cohen et al. 2000). More recently, several prospective studies have suggested that exposure to ssRis at the time of delivery may be associated with other types of perinatal complications, including poor neonatal adaptation, respiratory distress, jitteriness, and feeding problems (Casper et al. 2003; Laine et al. 2003; oberlander et al. 2004; Simon et al. 2002; Zeskind and Stephens 2004).

in addition, several reports have documented decreased gesta-tional age and lower birth-weight in SSRI-exposed children (Chambers et al. 1996; Ericson et al. 1999; Simon et al. 2002); however, Chambers and colleagues (1996) found that only third-trimester fluoxetine exposure was associated with shorter gestational age. in general, it appears that while this effect is statistically significant, it is relatively small. For example, in the study from Simon and colleagues (2002), the mean gestational age was 38.5 weeks in the SSRI-exposed infants, compared with 39.4 weeks in the nonex-posed group. other studies do not report differences in gestational age or birth-weight in SSRI-exposed versus nonexposed children (Cohen et al. 2000; Kulin et al. 1998; Laine et al. 2003; Pastuszak et al. 1993; Suri et al. 2004; Zeskind and Stephens 2004).

one of the largest of these studies, using a large database from a group-model HMO, compared neonatal outcomes following in utero exposure to TCAs (n =209) or SSRIs (n = 195) (Simon et al. 2002). There was an association between third-trimester exposure to SSRIs and lower Apgar scores; in contrast, TCA-exposed newborns did not differ from nonexposed control newborns with regard to these outcomes. Several other studies also observed lower Apgar scores in SSRI-exposed infants (Casper et al. 2003; Kallen 2004; Laine et al. 2003); however, not all studies have demonstrated differences in Apgar scores between exposed and non-exposed infants (Suri et al. 2004; Zeskind and Stephens 2004). It is reassuring to note that in the studies that demonstrated lower

Apgar scores, the difference in Apgar scores between exposed and nonexposed infants was small (less than 1 point), and the average Apgar scores in the exposed children remained high (above 7). Clinically, a score of 7 or greater at 5 minutes suggests that the baby's condition is good to excellent.

While the cumulative impression from some of these studies is that there is a small risk of neonatal distress syndrome in the setting of peripartum SSRI exposure, one of the difficulties in interpreting these data is that most of the studies do not take into consideration the impact of maternal mood on perinatal outcome. As there are reports which suggest that maternal depression may be associated with both preterm labor and poor neonatal outcomes (Orr and Miller 1995; Orr et al. 2002; Steer et al. 1992; Zuckerman et al. 1990), it is possible that depression itself (rather than the medications alone used to treat the depression) is responsible for the shorter gestation. Another significant shortcoming of the majority of these studies is that all but one (Laine et al. 2003) of the studies failed to use blind raters to assess neonatal outcomes. Most studies described observations of the child's behavior and symptoms made either by the physician or by the mother. This introduces the obvious risk of significant bias with overreporting of adverse events in children known by the rater to have had SSRI exposure.

Whether the reported symptoms of perinatal distress represent a direct effect of exposure to antidepressant or a discontinuation syndrome is not clear. In a prospective, controlled follow-up study, neonatal outcomes were assessed in 20 mothers taking 20-40 mg of either citalopram or fluoxetine and in 20 control mothers not receiving any psychotropic medication (Laine et al. 2003). The newborns were assessed by a blinded rater during the first 4 days of life and at the ages of 2 weeks and 2 months. In the exposed infants, symptoms of serotonergic overactivity were observed more frequently than in the control infants. The most frequently observed symptoms in the newborns included tremor, restlessness, and increased muscle tone. These symptoms resolved over the following 1-4 days, and no differences between the exposed and nonexposed infants at 2 weeks and 2 months were observed. Because the symptoms resolved quickly while SSRI con centrations were decreasing, the authors postulated that the symptoms were secondary to central nervous system serotonergic overstimulation rather than to SSRI withdrawal syndrome. Several other studies have also reported transient symptoms suggestive of serotonergic overactivity, with tremulousness being one of the most commonly reported symptoms (Casper et al. 2003; Zeskind and Stephens 2004).

Other studies attribute the symptoms to antidepressant withdrawal. Case reports of neonatal withdrawal in neonates exposed to paroxetine have been published and describe transient symptoms of irritability, excessive crying, increased muscle tone, feeding problems, sleep disruption, and respiratory distress (Costei et al. 2002; Dahl et al. 1997; Nordeng et al. 2001; Stiskal et al. 2001). In a prospectively ascertained sample of 55 neonates exposed to paroxetine proximate to delivery (dose range=10-60 mg; median = 20 mg), 22% (n = 12) had complications necessitating intensive treatment (Costei et al. 2002). The most common symptoms included respiratory distress (n = 9), hypoglycemia (n=2), and jaundice (n = 1), all of which resolved over 1-2 weeks without specific intervention. The extent to which other SSRIs (with longer half-lives) demonstrate similar risk for neonatal toxicity has yet to be explored. Furthermore, it is crucial to investigate other factors that modulate vulnerability to neonatal toxicity (e.g., prematurity, low birth-weight).

While there remains some controversy in this area, it is possible that the findings from these studies signal a potential problem. Reassuringly, the reported adverse events appear to be relatively short-lived and rarely require any type of medical intervention. Furthermore, there is no indication of longer-term problems, such as developmental delay, in children exposed to SSRIs in utero (Casper et al. 2003; Laine et al. 2003; Nulman et al. 1997, 2002; Simon et al. 2002). Clearly, further research is essential, but pending more controlled study, appropriate vigilance of exposed newborns after delivery is good clinical practice. However, it has been well documented that lowering the maintenance dosage in recurrently ill women with depression increases the risk of recurrence, which can occur on the cusp of an already high-risk period for women—namely, the postpartum period. Given the negative impact of maternal depression on the child's development, maintaining affective stability in the mother should be considered a highest and uncompromised priority. On the basis of a number of anecdotal reports of toxicity in infants born to mothers treated with antidepressants, some authors have recommended discontinuation of antidepressant medication several days or weeks prior to delivery to minimize the risk of neonatal toxicity. It is unclear at this point whether discontinuing or lowering the dosage of the mother's antidepressant shortly before delivery will reduce the risk of neonatal toxicity. Given the low incidence of neonatal tox-icity with most antidepressants, this practice carries significant risk, since it withdraws treatment from patients precisely as they are about to enter the postpartum period, a time of heightened risk for developing affective illness.

In October 2004, the FDA ordered drug manufacturers to include warnings in the packaging inserts regarding the use of certain antidepressants, including the SSRIs and venlafaxine (Effexor), during pregnancy. The labels now describe a spectrum of adverse events in newborns exposed to these drugs late in the third trimester, including jitteriness, irritability, hypoglycemia, feeding difficulties, respiratory distress, abnormal muscle tone, and constant crying. Complications requiring "prolonged hospitaliza-tion, respiratory support and tube feeding" are also mentioned. While transient and relatively benign adverse events have been reported, the more serious problems, such as prolonged hospitaliza-tion and the need for respiratory support, are not well supported by any objective data in the medical literature. Listing these in the label may do little but alarm patients and physicians and fail to inform the appropriate clinical path to pursue.

The labeling changes will likely create alarm about a potential clinical syndrome that has an extremely low incidence and modest clinical significance. While it is possible that some children may experience adverse events subsequent to delivery, it is important to put these concerns within a larger context. As noted earlier, reassuringly, the reported adverse events appear to be relatively short-lived and rarely require any type of medical intervention. Furthermore, as discussed below, there is no indication of longer-term neurobehavioral problems in children exposed to

SSRIs in utero (Casper et al. 2003; Laine et al. 2003; Nulman et al. 1997, 2002; Simon et al. 2002).

Risk of Long-Term Neurobehavioral Sequelae

Because neuronal migration and differentiation occur throughout pregnancy and into the early years of life, the central nervous system remains particularly vulnerable to toxic agents throughout pregnancy. However, insults that occur after neural-tube closure and folding produce changes in behavior and function, as opposed to gross structural abnormalities. Behavioral teratogenesis refers to the potential of a psychotropic drug administered prena-tally to cause long-term neurobehavioral sequelae. For example, are children who have been exposed to an antidepressant in utero at risk for cognitive or behavioral problems at a later point during development? Animal studies demonstrate changes in behavior and neurotransmitter function after prenatal exposure to a variety of psychotropic agents (Ali et al. 1986; Ansorge et al. 2004; Bonari et al. 2004; Vernadakis and Parker 1980; Vorhees et al. 1979). The extent to which these findings are of consequence to humans has yet to be demonstrated.

With regard to long-term neurobehavioral sequelae in children exposed to either fluoxetine or TCAs, the data are limited but reassuring. In a landmark study, Nulman and colleagues (1997) followed a cohort of children up to preschool age who had been exposed to either TCAs (n=80) or fluoxetine (n=55) in utero (most commonly during the first trimester), and compared these subjects to a cohort of nonexposed controls (n=84). Results indicated no significant differences in IQ, temperament, behavior, reactivity, mood, distractibility, or activity level between exposed and nonex-posed children. In a more recent report, the same group followed a cohort of children exposed to fluoxetine (n=40) or TCAs (n=47) for the entire duration of the pregnancy and demonstrated similar results (Nulman et al. 2002). The authors concluded that their findings support the hypothesis that fluoxetine and TCAs are not behavioral teratogens. However, these data are preliminary, and clearly further investigation into the long-term neurobehavioral effects of prenatal exposure to antidepressants, as well as other psychotropic medications, is warranted.

Electroconvulsive Therapy During Pregnancy

The use of electroconvulsive therapy (ECT) during pregnancy typically raises considerable anxiety on the part of clinicians and patients. Its safety record has been well documented over the last 50 years (Goldstein et al. 1941; Impasato et al. 1964; Remick and Maurice 1978). Requests for psychiatric consultation on pregnant patients requiring ECT tend to be emergent and dramatic. For example, expeditious treatment is imperative in instances of mania or psychotic depression with suicidal thoughts and disorganized thinking during pregnancy. Such clinical situations are associated with a danger from impulsivity or self-harm. The safety and efficacy of ECT in such settings are well described, particularly when the ECT is instituted in collaboration with a multidisciplinary treatment team, including an anesthesiologist, a psychiatrist, and an obstetrician (Miller 1994; Remick and Maurice 1978; Repke and Berger 1984; Wise et al. 1984). A limited course of treatment may be sufficient followed by institution of treatment with one agent or a combination of agents, such as antidepressants, neuro-leptics, benzodiazepines, or mood stabilizers.

ECT during pregnancy tends to be underused because of concerns that treatment will harm the fetus. Despite one report of pla-cental abruption associated with the use of ECT in pregnancy (Sherer et al. 1991), considerable experience supports its safe use in severely ill gravid women. Thus, it becomes the task of the psychiatric consultant to facilitate the most clinically appropriate intervention in the face of partially informed concerns or objections.

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