OVERVIEW

Psychiatric consultation to obstetric patients typically involves the evaluation and treatment of an array of psychopathology. Once thought to be a time of emotional well-being for women,¹ studies now suggest that pregnancy is not protective with respect to the emergence or persistence of psychiatric disorders.²^–⁷ Given the prevalence of mood and anxiety disorders in women during the childbearing years^8,⁹ and the number of women who receive treatment for these disorders, it is apparent that many women become pregnant either after the recent discontinuation of psychotropic medications or following a decision to maintain treatment during efforts to conceive. With increasing evidence of high rates of relapse following discontinuation of psychotropic medications (e.g., antidepressants,¹⁰ mood stabilizers,¹¹ antipsychotics,¹² and benzodiazepines¹³) and other data describing new-onset psychiatric illness during pregnancy,^2,^6,¹⁴ the value of psychiatric consultation during pregnancy and after delivery is evident.

Psychiatric evaluation of pregnant women requires careful assessment of symptoms such as anxiety or depression and decisions about the nature of those symptoms, such as (1) normative or pathological, (2) manifestations of a new-onset psychiatric disorder, or (3) an exacerbation of a previously diagnosed or undiagnosed psychiatric disorder. Unfortunately, screening for a psychiatric disorder during pregnancy or the puerperium is uncommon. Even when depressed pregnant women are identified, definitive treatment is frequently lacking.¹⁵ Screening for depression during pregnancy followed by thoughtful treatment can minimize maternal morbidity, as well as the potential impact of an untreated psychiatric disorder on infant development and family functioning. Pregnancy is an emotionally laden experience that evokes a spectrum of normal reactions, including heightened anxiety and increased reactivity of mood.

Normative experience needs to be distinguished from the manifestations of psychiatric disorders. Treatment of psychiatric disorders during pregnancy involves a thoughtful weighing of the risks and benefits of proposed interventions, such as pharmacological treatment and the documented ^16,¹⁷ and theoretical risks associated with untreated psychiatric disorders. In contrast to many other clinical conditions, treatment of psychiatric disorders during pregnancy is typically reserved for situations in which the disorder interferes significantly with maternal and fetal well-being; the threshold for the treatment of psychiatric disorders during pregnancy tends to be higher than with other conditions. Moreover, women with similar illness histories often make very different decisions about their care in collaboration with their physicians during pregnancy.

DIAGNOSIS AND TREATMENT OF MOOD DISORDERS DURING PREGNANCY

Although some reports describe pregnancy as a time of affective well-being ^1,¹⁸^–²⁰ that confers “protection” against psychiatric disorders, at least one prospective study describes equal rates of major and minor depression (approximating 10%) in gravid and nongravid women. Several other recent studies also note clinically significant depressive symptoms during pregnancy (antenatal depression).^2,^6,^21,²² Furthermore, women with histories of major depression appear to be at high risk for recurrent depression during pregnancy, particularly in the setting of antidepressant discontinuation.^5,²³

Diagnosis of depression during pregnancy can be difficult because disturbances in sleep and appetite, symptoms of fatigue, and changes in libido do not necessarily suggest an evolving affective disorder. Clinical features that may support the diagnosis of major depressive disorder (MDD) include anhedonia, feelings of guilt and hopelessness, and thoughts of suicide. Suicidal ideation is not uncommon ²⁴^–²⁶; however, risk of frank self-injurious or suicidal behaviors appears to be relatively low in women who develop depression during pregnancy.^25,²⁶

Treatment for depression during pregnancy is determined by the severity of the underlying disorder. Nonetheless, neurovegetative symptoms that interfere with maternal well-being require treatment. Women with mild to moderate depressive symptoms may benefit from nonpharmacological treatments that include supportive psychotherapy, cognitive therapy,²⁷ or interpersonal therapy (IPT),²⁸ all of which may ameliorate depressive symptoms. Given the importance of interpersonal relationships in couples who are expecting a child and the significant role transitions that take place during pregnancy and after delivery, IPT is ideally suited for the treatment of depressed pregnant women; preliminary but encouraging data support the efficacy of this intervention.²⁹

ANTIDEPRESSANT USE DURING PREGNANCY

Multiple reviews have been published over the last decade that describe available data (from anecdotal case reports and larger samples of patients) regarding risks associated with fetal exposure to antidepressants.^23,³⁰^–³⁴ Although accumulated data over the last 30 years suggest that some antidepressants may be used safely during pregnancy,³⁵^–³⁷ information regarding the full spectrum and relative severity of attendant risks of prenatal exposure to psychotropic medications is still incomplete.

As is the case with other medications, four types of risk are typically cited with respect to potential use of antidepressants during pregnancy: (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.³⁶ To provide guidance to physicians seeking information on the reproductive safety of various prescription medications, the Food and Drug Administration (FDA) has 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. Medications in category A are designated as safe for use during pregnancy, whereas 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 often ambiguous and may lead some to make conclusions that are not warranted. For example, certain tricyclic antidepressants (TCAs) have been labeled as category D agents, 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.^38,³⁹ Therefore, the physician must also rely on other sources of information when counseling patients about the potential use of psychotropic medications during pregnancy. Randomized, placebo-controlled studies examining the effects of medication use on pregnant populations are unethical for obvious reasons. Therefore, much of the data related to the profile of reproductive safety for a medication is derived from retrospective studies and case reports. More recently, studies that have evaluated the reproductive safety of antidepressants have used a more rigorous prospective design,³⁸^–⁴³ or have relied on large administrative databases or multicenter birth defect surveillance programs.^44,⁴⁵

To date, studies have not demonstrated a statistically increased risk of spontaneous miscarriage or congenital malformations associated with prenatal exposure to antidepressants.

Cumulative reports describing the reproductive safety of selective serotonin reuptake inhibitors (SSRIs) have been recently reviewed.^33,³⁴ These reports provide some relative reassurance that as a group of medicines, SSRIs do not constitute major teratogens. However, some recent reports have suggested that first-trimester exposure to paroxetine is associated with an increased risk of cardiac defects, including atrial and ventricular septal defects.⁴⁶^–⁴⁹ While these findings prompted the FDA to change the category label of paroxetine from C to D, more recently published studies have not demonstrated increased teratogenicity of paroxetine.^44,⁴⁵

Bupropion may be an attractive option for women who have not responded well to fluoxetine or TCAs. Data thus far have not indicated an increased risk of malformations associated with bupropion use during pregnancy.⁵⁰^–⁵²

There are limited data available on the use of the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine ⁴³ during pregnancy. Nonetheless, given the frequency of use of these medicines and the frequency of unplanned pregnancy,⁵³ the data supporting the safety of bupropion and venlafaxine are increasingly reassuring.

Despite the growing literature supporting the relative safety of fetal exposure to SSRIs, multiple reports have described adverse perinatal outcomes, including decreased gestational age, low birth weight, and poor neonatal adaptation.^40,^54,⁵⁵ However, other investigators have failed to note these same associations.^38,^56,⁵⁷ Particular concern has been raised regarding the potential effects of late pregnancy exposure to SSRIs, with one recent report noting symptoms including jitteriness, tachypnea, and tremulousness,⁵⁸ and another study reporting an increased risk of persistent pulmonary hypertension of the newborn (PPHN).⁵⁹ Further investigation is warranted to clarify the association between SSRI use and PPHN, as previous studies investigating neonatal outcomes in infants exposed to antidepressants in utero have not described serious complications with significant morbidity and instead described neonatal distress syndromes that were generally mild, transient, and did not require specific medical intervention. Unfortunately, the vast majority of reports that have attempted to delineate the potential effects of peripartum exposure to SSRIs have been limited by small sample size, nonsystematic assessment of infant outcome, and frequent use of nonblinded raters. Moreover, these studies typically have failed to assess the impact of maternal depression, which in and of itself may be associated with compromised perinatal outcome.¹⁷

While much research has addressed the effect of antidepressant drugs on risk for congenital malformation, less research has focused on the long-term effects of prenatal antidepressant exposure. Studies thus far have indicated that there were no differences between the children exposed to fluoxetine or TCAs during pregnancy and children who were not exposed during pregnancy in terms of IQ, language, temperament, behavior, reactivity, mood, distractibility, and activity level.^41,⁵⁶ In addition, there do not appear to be any differences in levels of internalizing behaviors in children exposed to SSRIs during pregnancy when compared to children of nondepressed mothers not on medication during pregnancy.⁶⁰ While the available data are reassuring, further investigation into the long-term neurobehavioral effects of prenantal exposure to antidepressants is warranted.

PHARMACOLOGICAL TREATMENT OF DEPRESSION DURING PREGNANCY: CLINICAL GUIDELINES

The last decade has brought increased attention to the question of how to best manage women who suffer from depression. Clinical lore previously suggested that women enjoyed positive mood during pregnancy, but more recent data suggest that subpopulations of patients may be at risk for recurrence or new onset of depression during pregnancy. There is also a greater appreciation that depression may exert an effect on fetal and neonatal well-being that needs to be taken into account in the risk-benefit decision-making process.^23,^30,^35,^37,⁶¹ The majority of women suffering from depression during pregnancy do not receive adequate treatment, even though this illness is relatively common.¹⁵ Despite the growing number of reviews on the subject, management of antenatal depression is still largely guided by practical experience, with few definitive data and no controlled treatment studies to inform treatment. The most appropriate treatment algorithm depends on the severity of the disorder and, ultimately, the patient’s wishes. Clinicians must work collaboratively with the patient to arrive at the safest decision based on available information. A patient’s psychiatric history, her current symptoms, and her attitude toward the use of psychiatric medications during pregnancy must be carefully assessed and factored into any decision.

In patients with less severe depression, it may be appropriate to consider discontinuation of pharmacological therapy during pregnancy. Though data on the use of IPT or cognitive-behavioral therapy (CBT) to facilitate antidepressant discontinuation before conception are not available, it makes clinical sense to pursue such treatment in women on maintenance antidepressant therapy who are planning to become pregnant. These modalities of treatment may reduce the risk of recurrent depressive symptoms during pregnancy, although as noted previously, this has not been studied systematically. Close monitoring of affective status during pregnancy is essential, even if all medications are discontinued and no need for reintroduction of antidepressant is apparent. Psychiatrically ill women are at high risk for relapse during pregnancy, and early detection and treatment of recurrent illness may significantly reduce the morbidity associated with having an antenatal affective disorder.

Many women who discontinue antidepressant treatment during pregnancy experience recurrent depressive symptoms.^62,⁶³ In one recent study, women who discontinued their medications were five times more likely to relapse as compared to women who maintained their antidepressant treatment across pregnancy.⁵ Thus, women with recurrent or refractory depressive illness may decide in collaboration with their clinician that the safest option is to continue pharmacological treatment during pregnancy in order to minimize the risk for recurrent illness. In this setting, the clinician should attempt to select medications during pregnancy that have a well-characterized reproductive safety profile, which may necessitate switching from one psychotropic to another with a better reproductive safety profile. An example would be switching from duloxetine, a medication for which there is sparse data on reproductive safety, or paroxetine, which may be associated with cardiac malformations, to an agent such as fluoxetine or citalopram. In other situations, one may decide to use a medication for which information regarding reproductive safety is sparse. A scenario that highlights this decision is a woman with refractory depressive illness who has responded only to one particular antidepressant for which specific data on reproductive safety are limited (e.g., venlafaxine). She may choose to continue this medication during pregnancy rather than risk (1) potential relapse associated with antidepressant discontinuation or (2) a switch to another antidepressant to which such a patient has no prior history of response.

Women may also experience the new onset of depressive symptoms during pregnancy. For women with minor depressive symptoms, nonpharmacological 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.²⁷^–²⁹ In general, pharmacological treatment is pursued when nonpharmacological strategies have failed or when it is thought that the risks associated with psychiatric illness during pregnancy outweigh the risks of fetal exposure to a particular medication.

In situations in which pharmacological treatment is more clearly indicated, the clinician should attempt to select the safest medication regimen, using, if possible, medications with the safest reproductive profile. Fluoxetine and citalopram, with rather extensive data supporting their reproductive safety, can be considered first-line choices. The TCAs and bupropion have also been relatively well characterized and can be considered reasonable treatment options during pregnancy. Among the TCAs, desipramine and nortriptyline are preferred because they are less anticholinergic and less likely to exacerbate orthostatic hypotension during pregnancy. The amount of literature on the reproductive safety of the newer SSRIs is growing, and these agents may be useful in certain settings.^33,^42,⁶⁴ Paroxetine, however, may be best avoided until the conflicting data regarding the association between fetal exposure to this antidepressant and atrial and ventricular septal defects⁴⁸ are more clearly delineated.⁴⁹ When prescribing medications during pregnancy, every attempt should be made to simplify the medication regimen. For instance, one may select a more sedating TCA for a woman with depression and a sleep disturbance instead of using an SSRI in combination with trazodone or a benzodiazepine.

In addition, the clinician must use an adequate dosage of medication. Frequently, the dosage of a medication is reduced during pregnancy in an attempt to limit risk to the fetus; however, this type of modification in treatment may instead place the woman at greater risk for recurrent illness. During pregnancy, changes in plasma volume and increases in hepatic metabolism and renal clearance may significantly affect drug levels.^65,⁶⁶ Several investigators have described a reduction (up to 65%) in serum levels of TCAs during pregnancy.^39,⁶⁷ Subtherapeutic levels may be associated with depressive relapse³⁹; therefore, an increase in daily TCA or SSRI dosage may be required to obtain remission.⁶⁸

With multiple studies supporting the finding of transient jitteriness, tremulousness, and tachypnea associated with peripartum use of SSRIs,^58,⁶⁹ some authors (as well as FDA-mandated labeling across the SSRIs) have suggested discontinuation of antidepressants just before delivery, presumably to minimize the risk of neonatal toxicity. Another potential rationale for antidepressant discontinuation proximate to delivery would derive from the assumption that this would attenuate the risk of PPHN, which has been associated with late-trimester exposure to SSRIs.⁵⁹ While the recommendation is intuitive, it is not data driven, and such a practice may actually carry significant risk as it withdraws treatment from patients precisely as they are about to enter the postpartum period, a time of heightened risk for affective illness.

Severely depressed patients who are acutely suicidal or psychotic require hospitalization, and electroconvulsive therapy (ECT) is frequently selected as the treatment of choice. Two reviews of ECT during pregnancy note the efficacy and safety of this procedure.^70,⁷¹ In a review of the 300 case reports of ECT during pregnancy published over the past 50 years, four premature labors have been reported and no premature ruptures of membranes have been reported. Given its relative safety, ECT may also be considered an alternative to conventional pharmacotherapy for women who wish to avoid extended exposure to psychotropic medications during pregnancy or for women who fail to respond to standard antidepressants.

BIPOLAR DISORDER DURING PREGNANCY

Women with bipolar disorder (BPD) have at times been counseled to defer pregnancy (given an apparent need for pharmacological therapy with mood stabilizers) or to terminate pregnancies following prenatal exposure to drugs such as lithium or valproic acid. Concerns regarding fetal exposure to lithium, for example, have typically been based on early reports of higher rates of cardiovascular malformations (e.g., Ebstein’s anomaly) following prenatal exposure to this drug.^72,⁷³ More recent data suggest that the risk of cardiovascular malformations following prenatal exposure to lithium is smaller than previous estimates (1 per 2,000 versus 1 per 1,000).⁷⁴ Prenatal screening with a high-resolution ultrasound and fetal echocardiography is recommended at or about 16 to 18 weeks of gestation to screen for cardiac anomalies. Nonetheless, for the bipolar woman faced with a decision regarding use of lithium during pregnancy, it is approp-riate to counsel such a patient about the very small risk of organ dysgenesis associated with prenatal exposure to this medicine.

Lamotrigine is another mood stabilizer that is an option for pregnant women with BPD who demonstrate a clear need for prophylaxis with a mood stabilizer. While previous reports did not show an elevated risk of malformations associated with lamotrigine exposure,⁷⁵^–⁷⁷ data from the North American Anti-Epileptic Drug Registry indicates increased risk of oral cleft in infants exposed to lamotrigine during the first trimester; the prevalence rate was approximately 9 per 1000 births.⁷⁸

Compared with lithium and lamotrigine, prenatal exposure to some anticonvulsants is associated with a far greater risk for organ malformation. An association between prenatal exposure to mood stabilizers, including valproic acid and carbamazepine, and neural tube defects (3% to 8%) and spina bifida (1%) also has been observed.⁷⁹^–⁸² Fetal exposure to anticonvulsants has been associated not only with relatively high rates of neural tube defects, such as spina bifida, but also with multiple anomalies (including midface hypoplasia [also known as the “anticonvulsant face”], congenital heart disease, cleft lip and/or palate, growth retardation, and microcephaly). Factors that may increase the risk for teratogenesis include high maternal serum anticonvulsant levels and exposure to more than one anticonvulsant. This finding of dose-dependent risk for teratogenesis is at variance with that for some other psychotropic medications (e.g., antidepressants). Thus, when using anticonvulsants during pregnancy, the lowest effective dose should be used, and anticonvulsant levels should be monitored closely and the dosage adjusted appropriately.

Information about the reproductive safety of newer anticonvulsants sometimes used to treat BPD, including gabapentin, oxcarbazepine, and topiramate, remains sparse.⁸³ Other efforts are underway to accumulate data from prospective registries regarding teratogenic risks across a broad range of anticonvulsants. The North American Antiepileptic Drug Pregnancy Registry recently was established as a way of collecting such information rapidly and efficiently (www.aedpregnancyregistry.org).

Prenatal screening following anticonvulsant exposure for congenital malformations (including cardiac anomalies) with fetal ultrasound at 18 to 22 weeks of gestation is recommended. The possibility of fetal neural tube defects should be evaluated with maternal serum alpha-fetoprotein (MSAFP) and ultrasonography. In addition, 4 mg a day of folic acid before conception and in the first trimester for women receiving anticonvulsants is frequently recommended. However, it should be noted that the supplemental use of folic acid to attenuate the risk of neural tube defects in the setting of anticonvulsant exposure has not been systematically evaluated.

Whereas use of mood stabilizers (including lithium and some anticonvulsants) has become the mainstay of treatment for the management of both acute mania and the maintenance phase of BPD, the majority of patients with BPD are not treated with monotherapy. Rather, use of adjunctive conventional and newer antipsychotics has become common clinical practice for many bipolar patients. Moreover, with growing data supporting the use of atypical antipsychotics as monotherapy in the treatment of BPD, patients and clinicians will seek information regarding the reproductive safety of these newer agents. To date, abundant data exist that supports the reproductive safety of typical antipsychotics; these data have been reviewed extensively elsewhere.³⁵ However, despite their growing use in psychiatry, available reproductive safety data regarding the atypical antipsychotics are limited, but increasing. Some patients who benefit from treatment with antipsychotics may decide with their clinician to discontinue the atypical antipsychotic or switch to a typical antipsychotic with a better-characterized safety profile. Atypical antipsychotics are best avoided if possible, although they are not absolutely contraindicated during pregnancy. Atypical antipsychotics should be reserved for use in more challenging clinical situations where treatment with more conventional agents has not been helpful. Given the limited data supporting the use of typical antipsychotics as monotherapy for BPD, that course of therapy should not be pursued.

The most appropriate treatment algorithm for managing reproductive-age women who wish to conceive or who are pregnant depends on the severity of the individual patient’s illness. Patients with histories of a single episode of mania and prompt, full recovery followed by sustained well-being may tolerate discontinuation of mood stabilizer before an attempt to conceive.^74,⁸⁴ Unfortunately, even among women with histories of prolonged well-being and sustained euthy-mia, discontinuation of prophylaxis for mania may be associated with subsequent relapse. For women with BPD and a history of multiple and frequent recurrences of mania or bipolar depression, several options can be considered. Some patients may choose to discontinue a mood stabilizer before conception as outlined previously. An alternative strategy for this high-risk group is to continue treatment until pregnancy is verified and then taper off of the mood stabilizer. Because the uteroplacental circulation is not established until approximately 2 weeks following conception, the risk of fetal exposure is minimal. Home pregnancy tests are reliable and can document pregnancy as early as 10 days following conception, and with a home ovulation predictor kit, a patient may be able to time her treatment discontinuation accurately. This strategy minimizes fetal exposure to drugs and extends the protective treatment up to the time of conception, which may be particularly prudent for older patients because the time required for them to conceive may be longer than for younger patients. However, a potential problem with this strategy is that it may lead to relatively abrupt discontinuation of treatment, thereby potentially placing the patient at increased risk for relapse. With close clinical follow-up, however, patients can be monitored for early signs of relapse, and medications may be reintroduced as needed. Another problem with the strategy of discontinuation of mood stabilizer when the patient is being treated with valproate is that the teratogenic effect of valproate occurs early in gestation, between weeks 4 and 5, often before patients even know they are pregnant. In such scenarios, any potential teratogenic insult from valproate may have already occurred by the time the patient actually documents the pregnancy.

For women who tolerate discontinuation of maintenance treatment, the decision of when to resume treatment is a matter for clinical judgment. Some patients and clinicians may prefer to await the initial appearance of symptoms before restarting medication; others may prefer to limit their risk of a major recurrence by restarting treatment after the first trimester of pregnancy. Preliminary data suggest that pregnant women with BPD who remain well throughout pregnancy may have a lower risk for postpartum relapse than those who become ill during pregnancy.⁸⁴

For women with particularly severe forms of BPD, such as with multiple severe episodes, and especially with psychosis and prominent thoughts of suicide, maintenance treatment with a mood stabilizer before and during pregnancy may be the safest option. If the patient decides to attempt conception, accepting the relatively small absolute increase in teratogenic risk with first-trimester exposure to lithium or lamotrigine with or without antipsychotic, for example, may be justified because such patients are at highest risk for clinical deterioration if pharmacological treatment is withdrawn. Many patients who are treated with sodium valproate or other newer anticonvulsants, such as gabapentin, for which there are particularly sparse reproductive safety data, may never have received a lithium trial before pregnancy. For such patients, a lithium trial before pregnancy may be a reasonable treatment option.

Even if all psychotropic medications have been safely discontinued, pregnancy in women with BPD should be considered as a high-risk pregnancy, because the risk of major psychiatric illness during pregnancy is increased in the absence of treatment with mood-stabilizing medication and is even higher postpartum. Extreme vigilance is required for early detection of an impending relapse of illness, and rapid intervention can significantly reduce morbidity and improve overall prognosis.

Although the impact of pregnancy on the natural course of BPD is not well described, studies suggest that any “protective” effects of pregnancy on risk for recurrence of mania or depression in women with BPD are limited,⁸⁴ and the risk for relapse and chronicity following discontinuation of mood stabilizers is high.⁸⁵^–⁸⁸ Given these data, clinicians and bipolar women who are either pregnant or who wish to conceive find themselves between a “teratologic rock and a clinical hard place.”⁸⁹