Psychiatric Illness During Pregnancy and the Postpartum Period

Antidepressants

Antidepressant use has grown increasingly common, with a study from the Centers for Disease Control and Prevention (CDC) reporting that more than 15% of reproductive-aged women filled a prescription for an antidepressant medication during the years 2008–2013. Although data accumulated over the last 30 years have suggested that some antidepressants have favorable risk–benefit profiles during pregnancy, information regarding the full spectrum and relative severity of risks of prenatal exposure to all psychotropic medications is still incomplete. Importantly, the risks of medication use must be balanced in each individual against the risks associated with untreated psychiatric disorders that might adversely affect the mother and the fetus.

As is the case with other medications, four types of risk are typically cited with respect to potential use of antidepressants during pregnancy: risk of pregnancy loss or miscarriage, risk of organ malformation or teratogenesis, risk of neonatal toxicity or withdrawal syndromes during the acute neonatal period, and risk of long-term neuro-behavioral sequelae. In the past, a system established by the U.S. Food and Drug Administration (FDA) that classified medications into five risk categories: A, B, C, D, and X, was used to inform physicians and patients about the reproductive safety of various prescription medications. In this system, medications in category A were designated safe for use during pregnancy, whereas category X drugs were contraindicated, because of known risks to the fetus that outweighed any benefit to the patient. This system of classification had noteworthy limitations. First, categorization was often ambiguous and could lead to unwarranted conclusions. Second, the categorization was often assigned on the basis of only a small amount of animal data when human data were sparse or absent. Third, when larger and more rigorous studies became available on the reproductive safety profile of a medication, the category was rarely altered. And finally, the categorization system failed to take into account the risks of the untreated maternal psychiatric disorder for the woman and her fetus. For these reasons, in June 2015 the FDA replaced this system with the Pregnancy and Lactation Labeling Rule (PLLR), which requires descriptive safety information regarding pregnancy and lactation in the drug label. This includes a risk summary, clinical considerations, and data subsections for use in pregnancy, lactation, and treatment of patients with reproductive potential. The letter classification system is now abolished and replaced by these more nuanced descriptions.

Randomized, placebo-controlled studies that examine the effects of medication use on pregnant populations are lacking and are largely considered unethical. Therefore, much of the data related to the profile of reproductive safety for a medication is derived from retrospective studies and case reports. Studies that have evaluated the reproductive safety of antidepressants have used a more rigorous prospective design, or they have relied on large administrative databases or multi-center birth-defect surveillance programs. The following paragraphs will provide an overview of currently available data on antidepressant use during pregnancy with regards to risk of pregnancy loss or miscarriage, risk of organ malformation or teratogenesis, risk of neonatal toxicity or withdrawal syndromes during the acute neonatal period, and risk of long-term neuro-behavioral sequelae.

Studies have not demonstrated a statistically increased risk of spontaneous miscarriage following prenatal exposure to antidepressants. When compared with women with depression, women on antidepressants do not experience a higher rate of miscarriage.

Regarding teratogenic risk, selective serotonin re-uptake inhibitors (SSRIs) have been studied extensively for safety during pregnancy. Large studies are reassuring; as a group of medicines, SSRIs are not major teratogens and do not increase risk of congenital malformation. Initially, some reports suggested that first-trimester exposure to paroxetine was an exception to this finding, and reported that paroxetine was associated with an increased risk of cardiac defects (including atrial and ventricular septal defects). More recent assessment of the data, including independent, peer-reviewed, comprehensive meta-analyses of studies assessing paroxetine exposure during the first trimester failed to demonstrate the increased teratogenicity of paroxetine. Therefore, like other SSRIs, paroxetine may still be considered a first-line agent for women who have responded well to it before pregnancy. Tricyclic antidepressants (TCAs) have also been shown in the pooled available data to be safe for use during pregnancy with regards to risk of congenital malformations.

Bupropion may be an attractive option for women who have not responded well to SSRIs or TCAs. Most data thus far have not indicated an increased risk of malformations associated with bupropion use during pregnancy. However, one recent study suggested the possibility of an increased risk of cardiovascular malformations. Bupropion deserves special consideration if a woman is attempting to abstain from smoking during pregnancy, as it helps with smoking cessation, and cigarettes are teratogenic. Bupropion may also be useful in treating attention deficit disorder, given that the reproductive safety profile of stimulants is more concerning than that of bupropion.

Serotonin–norepinephrine re-uptake inhibitors (SNRIs), including venlafaxine and duloxetine, have been less well studied than other classes of antidepressant medications during pregnancy, but emerging data are reassuring that first-trimester exposure to these medications is not associated with a clinically important increase in risk of major congenital malformations. Mirtazapine has not been thoroughly studied for safety during pregnancy. Case studies thus far have not identified any clear signal of increased risk of malformations, so preliminary data are reassuring, but large definitive trials are necessary to assess risks that might be rare and thus only observable with adequate sample sizes.

Despite the growing literature that supports the relative safety of fetal exposure to SSRIs, multiple reports have described adverse perinatal outcomes including decreased gestational age at delivery, low birth weight, and poor neonatal adaptation. However, others have not noted these associations. Particular concern has been raised regarding the potential effects of late-pregnancy exposure to SSRIs; some newborns who were exposed to SSRIs exhibit a transient period (limited to several days following delivery) of jitteriness, tachypnea, and tremulousness. In general, this neonatal adaption syndrome is a mild and benign syndrome not requiring any specific medical intervention.

Conflicting reports have also raised a question about whether SSRI use in later pregnancy is associated with a serious but rare developmental lung condition, persistent pulmonary hypertension of the newborn (PPHN). Chambers and colleagues raised this concern when they found an increased risk of PPHN with SSRI use in a nested case–controlled study. They reported the risk of PPHN with exposure to SSRIs after 20 weeks at about 1%. Other research has been reassuring, with multiple large studies showing that the risk is much lower than initially estimated, or even that there is no association between SSRI use and PPHN at all. Most recently, from a large Medicaid database of 3.8 million pregnancy outcomes, researchers demonstrated that the risk of PPHN was 0.3% for women who were treated with SSRIs, compared to 0.2% among those who were not. Readers must be mindful that PPHN is correlated with multiple risk factors, including cesarean section, race, body mass index, and other factors not associated with SSRI use.

Compared with the considerable data on risk of congenital malformations with prenatal antidepressant exposure, reproductive safety data regarding the long-term effects of prenatal antidepressant exposure on the developing fetal brain are more limited. In children exposed to fluoxetine, TCAs, venlafaxine, or no medication, no differences have been detected in behavioral or cognitive development (in terms of intelligence quotient, language, temperament, behavior, reactivity, mood, distractibility, and activity level) among groups when followed through early childhood. Some recent studies have reported that rates of anxiety, autism spectrum disorder, and attention deficit disorder are more common in antidepressant-exposed children; however, these studies do not account for the fact that maternal psychiatric illness itself is a known risk factor for these conditions. That the higher prevalence of these disorders is more likely due to genes and maternal illness rather than to the medication exposure is supported by studies that have controlled for confounding factors, such as maternal psychiatric diagnosis and exposure to other medications. While the data available are mostly reassuring, further investigation into the long-term neuro-behavioral effects of prenatal exposure to antidepressants is warranted.

Pharmacologic Treatment of Depression: Clinical Guidelines

Over the past several decades, as the pharmacologic treatment of depression has become more common, increased attention has been directed to the question of how to best manage women who suffer from depression throughout reproductive events. Clinical lore has suggested that women enjoyed positive mood during pregnancy, but more-recent data demonstrate that many women face substantial risk for recurrence or the new onset of depression during pregnancy. There is also a greater appreciation that depression poses risks for fetal and neonatal well-being that need to be taken into account during the risk–benefit decision-making process.

The majority of women who suffer from depression during pregnancy do not receive adequate treatment, despite the prevalence and consequences of untreated illness. Despite the growing number of reviews on the subject, management of prenatal depression is still largely guided by experience, with few definitive data and no controlled treatment studies to inform management. The best treatment algorithms depend on the severity of the disorder, the patient's psychiatric history, her current symptoms, her attitude toward the use of psychiatric medications during pregnancy, and, ultimately, the patient's wishes. Clinicians must work collaboratively with the patient to arrive at the safest treatment plan based on currently available information.

In patients with less-severe depression, discontinuation of pharmacologic therapy during pregnancy should be considered. Though data on the use of IPT or CBT to facilitate antidepressant discontinuation before conception are not available, it makes sense to pursue such treatment for women on maintenance antidepressant therapy who are planning to become pregnant. These treatment modalities have been shown to reduce depressive symptoms during pregnancy. Close monitoring of affective status is essential throughout pregnancy for women with a history of a mood disorder, regardless of whether medication is continued or discontinued. Psychiatrically ill women are at high risk for relapse during pregnancy, and early detection and treatment of recurrent illness can significantly reduce the morbidity associated with having prenatal affective illness.

Many women who discontinue antidepressants during pregnancy experience recurrent depressive symptoms. In one study, women who discontinued their medications were five times more likely to relapse (with a rate of relapse of 68%) as compared with women who maintained their antidepressants across pregnancy. Thus, women with recurrent or refractory depressive illness may decide (in collaboration with their clinician) that the safest option is to continue pharmacologic treatment during pregnancy to minimize the risk of recurrent illness. In this setting, the clinician should attempt to select medications during pregnancy that have a well-characterized reproductive safety profile that might obviate switching to one with a better reproductive safety profile.

In an ideal world, switching would occur before pregnancy and allow time for stabilization on a new medication. For example, one might switch from duloxetine, a medication for which there are sparse data on reproductive safety, 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, for example, a woman with refractory depression who has responded only to one particular antidepressant for which specific data on reproductive safety are limited (e.g., mirtazapine). She may choose to continue this medication during pregnancy rather than risk potential relapse associated with discontinuing the antidepressant or switching to another antidepressant for which the patient has no history of response.

Even if a woman continues taking an antidepressant during pregnancy, relapse can occur. Cohen and colleagues reported that 26% of women who continued antidepressants had a relapse of MDD during pregnancy. Therefore, careful monitoring is required even if maintenance medications are continued. Only a small amount of information is available on the pharmacokinetic profile of SSRIs and newer antidepressants across pregnancy, and some women experience lower serum medication levels in late pregnancy. Therefore, some women can require higher doses of medication as pregnancy progresses to maintain therapeutic benefits; this supports a need for frequent assessment. Older reports demonstrated that women might also have lower serum levels of TCAs in the third trimester.

Women might also experience the new onset of depressive symptoms during pregnancy. For women who present with minor depressive symptoms, non-pharmacologic treatment strategies should be explored first. IPT or CBT may be beneficial for reducing the severity of depressive symptoms and can limit or obviate the need for medications. 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.

In situations in which pharmacologic treatment is more clearly indicated, the clinician should select medications with the safest reproductive profile. SSRIs, with extensive data that support their reproductive safety, can be considered as first-line choices. Among the SSRIs, paroxetine is the most controversial (given reports regarding cardiovascular malformations with first-trimester exposure). However, as state previously, more comprehensive studies did not support this risk. Nevertheless, many women and their obstetric healthcare providers might remain apprehensive about use of paroxetine in pregnancy. 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.

When prescribing medications during pregnancy, an attempt should be made to simplify the medication regimen. For instance, one may select a more sedating antidepressant for a woman who presents with depression and a sleep disturbance instead of using a more activating antidepressant in combination with trazodone or a benzodiazepine.

In addition, the clinician must use an adequate dosage of medication to achieve or maintain remission. Often, 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 might instead place the woman at greater risk for recurrent illness. During pregnancy, changes in plasma volume and increases in hepatic metabolism and renal clearance can significantly affect drug levels. Several investigators have described a reduction (up to 65%) in serum levels of TCAs during pregnancy. Sub-therapeutic levels may be associated with depressive relapse; therefore, an increase in daily antidepressant dosage may be required to obtain remission.

With multiple studies supporting the finding of transient neonatal jitteriness, tremulousness, and tachypnea associated with peripartum use of SSRIs, some physicians have suggested discontinuing antidepressants just before delivery to minimize the risk of neonatal toxicity. Another potential rationale for discontinuing antidepressants before delivery is derived from the assumption this would attenuate the risk of PPHN that has been associated with third-trimester exposure to SSRIs. However, the recommendation is not data-driven and such a practice can actually carry significant risk because it withdraws treatment from a patient precisely as she is about to enter the postpartum period, a time of heightened risk for affective illness. In consideration of the well-characterized risks to the baby and to siblings in the family of a woman with maternal depression, treatment goals should include having a woman approach the postpartum period in remission from depression. The strategy of discontinuing medication before delivery, however, would increase the risk of a woman's entering the postpartum period with depression, and recovery could require substantial time.

Severely depressed patients who are acutely suicidal or psychotic require hospitalization and treatment; electroconvulsive therapy (ECT) is often selected as the treatment of choice. Reviews of ECT during pregnancy note the efficacy and safety of this procedure. In a review of the 339 cases of ECT during pregnancy published since 1941, only 11 of the 25 fetal or neonatal complications, including two deaths, were likely the result of ECT. Given its relative safety, ECT may also be considered an alternative to conventional pharmacotherapy for women who wish to avoid extended exposure to psychotropics during pregnancy or for women who fail to respond to standard antidepressants.