Curr Opin Psychiatry. 2009;22(1):13-18. ©2009 Lippincott Williams & Wilkins
Abstract and Introduction
Purpose of Review: The management of depression in pregnancy is complex, as it is based on balancing the risks with the benefits of treatment versus no treatment for both the mother and the fetus. The current literature in the field of reproductive psychiatry is difficult to navigate and at times contradictory. This article aims to review both nonpharmacological and pharmacological modalities in the treatment of perinatal depression. A literature review using PubMed and MEDLINE databases was used to collect literature from the past 2 years; however, given the relatively small amount of research in reproductive psychiatry, several salient articles from the past 5 years have also been included in this review.
Recent Findings: Recent US Food and Drug Administration and Health Canada warnings regarding poor neonatal adaptation and adverse perinatal outcomes associated with antidepressant use in pregnancy have changed patterns of practice for prescribing physicians. Many physicians are now left with a sense of indecisiveness regarding the safety of treating their depressed, pregnant patients. Similarly, these warnings have changed patients' attitudes and their willingness to consider pharmacological treatment for depression. Although these warnings demand attention and careful consideration, research has also shown that exposure to mental illness in pregnancy has deleterious short-term and long-term effects for the exposed mother and fetus.
Summary: The field of reproductive psychiatry is rapidly evolving. Clinicians need to keep abreast of changes in the management of depression during pregnancy. Ongoing research in this field is important so that the most up-to-date recommendations may be provided to pregnant women.
Pregnancy has typically been viewed as a time of emotional well being, one that the general public and many medical professionals feel confers emotional protection.[1••] Consequently, depression during pregnancy is often overlooked and underdiagnosed. Although there has long been a focus on depression in the postpartum period, with a wealth of existing research and numerous celebrity advocates contributing to public awareness, antenatal depression has been relegated to somewhat of an unnoticed disease, often lacking appropriate consideration and attention.
This is particularly a concern given that depression in pregnancy is common. One large meta-analysis has reported the range of antenatal depression to be between 6.5 and 12.9%. Similarly, a systematic review of the literature in 2004 estimated the prevalence of depression as 7.4% (2.2-12.6%), 12.8% (10.7-14.8%) and 12.0% (7.4-16.7%) for each trimester of pregnancy, respectively. Moreover, women with a history of major depression are at high risk for relapse during pregnancy, even more so if they discontinue antidepressant medications during this vulnerable period.
In addition, research from the past two decades has suggested a possible, though still controversial,[5•] link between perinatal maternal psychological distress and adverse neonatal outcomes. A review conducted by Alder et al.[6•] concluded that the presence of depression during pregnancy was an independent risk factor for subsequent adverse obstetric, fetal and neonatal outcomes. A growing body of research has demonstrated that some of the risks of untreated depression in pregnancy may include poor prenatal care, medical and obstetrical complications, self-medication, substance abuse, impaired bonding, suicide and an increased risk of relapse of depression in the postpartum period.[7•,8•,9]
It is of concern then, despite the identification of significant rates of depressive symptoms in pregnancy, that few pregnant women receive treatment. Women with serious mental illness during pregnancy continue to go undiagnosed and untreated.
Identification of Perinatal Depression
To date, there have been no definitive studies to explain the onset, chronicity, severity and relapse rates of depression in either the antenatal or postpartum periods. As such, we have come to distinguish perinatal depressive disorders by their timing rather than by their symptomatology.[1••] Additionally, although the criteria for major depression in pregnancy are the same as those for nonpuerperal depression, identification of a major depressive disorder in pregnancy can be difficult. Many depressive symptoms, including fatigue, sleep difficulties and changes in appetite and weight, can be evidenced in normal pregnancy and cannot necessarily be attributed to a depressive disorder.[12••]
Given the challenges in ascertaining a diagnosis, screening tools may assist in identifying women with a clinical depression. The Edinburgh Postnatal Depression Scale has been validated for use, screening not only postpartum depression but also depression during pregnancy.[13,14] Additionally, Altshuler et al.[12••] recently developed a well validated brief scale to screen for clinical depression in pregnant women with a past history of major depressive disorder.
Perinatal Depression Risk Factors
Factors that increase the risk of depression during pregnancy and in the postpartum period are a prior history of depression or premenstrual dysphoric disorder, younger age, limited social support, living alone, greater number of children, marital conflict[17•] and ambivalence about pregnancy. A history of depression during the antenatal phase remains one of the strongest predictors of depression during any subsequent pregnancy and during the postpartum period.
Nonpharmacological Treatments for Perinatal Depression
In women with mild depression, nonpharmacological treatment approaches may be useful.
Psychotherapy may be an effective nonpharmacological option for some women with perinatal depression. The two most commonly used forms of psychotherapy for depression are cognitive behavioral therapy (CBT), which aims to change patients' self-defeating thought patterns, and interpersonal therapy (IPT), which focuses on improving social interactions and coping with life transitions.
Several studies have reported that CBT is as effective as medication in treating mild-to-moderate depression; however, no published studies to date have examined its efficacy in treating depression in pregnancy. Currently, at our center, we are performing a study that will help investigate the use of CBT and its efficacy in the treatment of depression during pregnancy and in the postpartum period.
Alternately, there is some evidence to show that IPT may be an effective therapy in treating major depression in pregnancy. In one controlled clinical trial, 50 pregnant women meeting Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for major depression were randomized to receive either 16 weeks of IPT or a parenting education program. Using evidence-based mood rating scales, more than 50% of the women receiving IPT experienced a remission of their symptoms.
Unfortunately, there remains little current research on the effectiveness of other psychotherapeutic modalities for the treatment of perinatal depression. Though the effectiveness of group therapy for depression during pregnancy has not been reported, antenatal group therapy has been shown to be effective in preventing postpartum depression.
Other biological therapies may also hold value.
Studies examining the efficacy of light therapy in treating depression in pregnant women have shown some promising results. Oren et al. found that 14 out of 16 depressed, pregnant women treated over 3-5 weeks with bright light therapy experienced a significant improvement in their symptoms. Further case reports have also demonstrated that bright light therapy may be an effective and well tolerated mode of treatment for pregnant women with nonseasonal depression. However, the available evidence supporting the treatment of nonseasonal depression with light therapy remains limited and further research is warranted to better explore the use of this treatment modality.
Complementary and Alternative Therapies
Many other therapies have been investigated for use in the treatment of mood and anxiety disorders in the perinatal period, including exercise, acupuncture and herbal supplements.
Exercise has long been described as an important complementary therapy in the treatment of depression. In one study, women who exercised in the first and second trimesters of pregnancy reported less depression and anxiety than their counterparts who did not exercise.
Acupuncture may also hold promise for the treatment of depression in pregnancy. A small, randomized and controlled pilot study of acupuncture in pregnancy yielded a 69% response rate, an effect that was sustained at 10 weeks postpartum. Limitations in this study were its small size and homogeneous population.
Although good nutrition is important in pregnancy and for general well being, there is both little and conflicting evidence about the use of herbal supplements in the treatment of depression in pregnancy. St John's wort has been shown to be efficacious in the treatment of depression, but its efficacy has not, to date, been studied in the pregnant population. In contrast, a number of studies have been conducted to evaluate the value of ω-3 as a treatment alternative for depression in pregnancy. However, the results have been contradictory in nature, some studies indicating efficacy in the treatment of depression,[29•] whereas others have been equivocal.[30•] Further research is needed to clarify whether ω-3 fatty acids are an effective treatment for perinatal depression.
By virtue of the paucity of empirical evidence supporting the efficacy of nonpharmacological treatments, in conjunction with reports of the negative consequences of untreated mood and anxiety disorders, psychotropic medications remain the first-line treatment for pregnant women experiencing severe mood and anxiety disorders.[31••]
In recent years, an increasing number of studies have sought to better ascertain the reproductive safety of various antidepressants. Studies have investigated the use of tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs) and atypical antidepressants during pregnancy. Antidepressants are generally assumed to be efficacious for the treatment of depression in pregnant women; however, there are no available studies that quantify their efficacy in this population.
Instead, the research has primarily focused on analyzing the available data, in an effort to demonstrate a relationship between antidepressant exposure in pregnancy and resultant fetal and infant outcomes. Data regarding the potential teratogenicity of antidepressants have emerged from relatively small prospective observational studies, larger international birth registries, managed healthcare databases and case series. Here, the use of psychotropic medications in pregnancy is a cause of concern for physicians and their patients, given an identified potential risk for teratogenicity, perinatal syndromes and abnormal postnatal behavioral development.[33••] Although, generally, the absolute risk of malformation and side effects in the neonate remains low,[33••,34••] studies regarding poor neonatal adaptation and adverse perinatal outcomes associated with antidepressant use in pregnancy have led to US Food and Drug Administration and Health Canada warnings.[35-37]
Congenital Cardiac Malformations and Paroxetine
Although most of the data amassed to date suggest that SSRIs, as a class of drugs, are not major teratogens,[38••] between 2005 and 2006 several studies concluded that, when compared with other antidepressants in the same class, the maternal use of paroxetine during pregnancy did confer an increased risk of cardiovascular birth defects.[39,40•] In 2005, GlaxoSmithKline, the manufacturer of paroxetine, conducted an epidemiological database review of mothers administered antidepressants in the first trimester. The review found that, when compared with infants exposed to other antidepressants, those with first trimester exposure to paroxetine had a 1.5-2-fold increased risk of congenital cardiac malformations. As a result, the pharmaceutical company changed the product label warnings about the drug. More recently, the cardiovascular teratogenicity of paroxetine has been reviewed using data from prospective, unpublished cases comparing infants exposed to paroxetine early in the first trimester of pregnancy with unexposed cohorts. This review, in contrast, found no increased risk of cardiovascular defects following exposure to paroxetine; the incidence of congenital cardiovascular defects was well within the general population incidence of approximately 1%.[42••]
Persistent Pulmonary Hypertension and Antidepressant use in Pregnancy
Another recent concern regarding SSRI use in pregnancy has been that of a possible association between third trimester exposure to SSRIs and an increased risk of persistent pulmonary hypertension of the newborn (PPHN). One such study estimated the risk of PPHN to be approximately 1% in infants exposed to SSRIs after 20 weeks of gestation. However, a recent study in 2007 by Hernandez-Diaz et al.[44•] questioned the strength of this association. Their study was designed to identify possible predictors of PPHN, and although they were unable to completely rule out SSRI exposure as a potential risk factor for PPHN, they identified that many other maternal, delivery and infant factors were stronger predictors of risk.
Poor neonatal Adaptation and Antidepressant use in Pregnancy
Poor neonatal adaptation or neonatal behavioral syndrome, characterized by jitteriness, poor muscle tone, weak cry, respiratory distress, hypoglycemia, low Apgar scores and seizures has been associated with antidepressant use in pregnancy. Studies of third trimester exposure to SSRIs and SNRIs have demonstrated such effects.[46•,47] These symptoms start within hours of delivery, but generally require only supportive care and fully abate within 1-2 weeks. Poor neonatal adaptation may occur in upward of 30% of infants with exposure to SSRIs, with higher rates evidenced in premature infants.[45,48] In contrast, a controlled cohort study designed to look at the incidence of early adverse effects in neonates exposed to antidepressant drug use during pregnancy did not show a statistically significant difference in the incidence of poor neonatal adaptation in the exposed group compared with the nonexposed group.[49•]
Other Reported Concerns About Antidepressant use in Pregnancy
Debate continues regarding the other potential associations between antidepressant use and other fetal malformations. Using a retrospective case-control design to evaluate the risks of early exposure to SSRIs, Alwan et al.[34••] analyzed data from the National Birth Defects Prevention study. This study compared 9622 infants with selected major birth defects with 4092 controls without defects. Although some associations were found for an increased risk of omphalocele, craniosynostosis and anencephalapy with SSRI exposure, the absolute risk remained very small. However, other studies remain at odds with these data. From the available studies, the results and the diversity in the types of abnormalities reported make it difficult to definitively draw a causal link between SSRI exposure and any particular congenital abnormality.
Combining Pharmacological and Nonpharmacological Treatments
Evidence has indicated that the combination of CBT and antidepressants may be superior in the treatment of severe depression; however, the efficacy of concurrent therapy has not been examined in the pregnant population.[31••]
Antidepressant Treatment Selection
Treatment decisions should take into account the severity of symptoms, past history of depression and previous treatment response as well as patients' preferences.[50•] In our mental health clinic, we see pregnant women with a wide range of treatment issues.
If a woman currently in treatment with an antidepressant to which she has previously responded and is in a state of depression relapses during pregnancy, a dose increase of the same medication should be considered. A study examining the dosing requirements of SSRIs (including fluoxetine, paroxetine and sertraline) during pregnancy found that, in order to maintain euthymia, two-thirds of the women required a medication dose increase at 27.1 ± 7.1 weeks of gestation, suggesting a need for close monitoring of reemerging symptoms in the second half of pregnancy.
If an antidepressant is discontinued during pregnancy, there is a high risk for relapse of depressive symptoms. If this occurs, a history of a previous antidepressant response should be strongly considered and should guide the choice of a subsequent antidepressant trial; the increased likelihood of a response to a reintroduction of the same antidepressant may be preferable to the risk of exposure to multiple medications in the event of nonresponse.[50•] It is also important that women are treated with therapeutic doses of antidepressants, as suboptimal doses expose fetuses to both medication and undertreated illness.
Conversely, if a pregnant woman presents with significant depressive symptoms and has never used antidepressants, we recommend treatment with an antidepressant that genetically related family members have responded to. However, if no such information exists, and a new compound is to be started, our current choice of medication is sertraline. In mothers treated with SSRIs, umbilical cord serum concentrations were the lowest in neonates of mothers treated with sertraline as compared with other SSRIs, indicating low placental transfer. Sertraline also demonstrates a good safety record in pregnant and breastfeeding women.
In our clinical experience, when a pregnant woman with a mental illness attends the office of a reproductive psychiatrist, she carries with her a myriad of emotions such as guilt, stigma, embarrassment and apprehension. The treating clinician must be cognizant of and sensitive to these feelings, especially when a psychiatric diagnosis is confirmed and treatment is recommended. Most women, despite their mental illness, are reticent about medication use while pregnant. They need to be made aware of the risks associated with exposure to medication versus the exposure to the illness itself. No decision is risk free. Once the patient is ready to engage in therapy, our clinic recommends that women experiencing a moderate-to-severe depression in pregnancy be treated with antidepressants. We refer them to our clinical counselors for psychotherapy when warranted. Although there is a paucity of literature focusing on the role of psychoeducation alone for the treatment of depression in this specialized population, we feel psychoeducation is an important part of the treatment process and attempt to provide women with the most up-to-date evidence regarding treatment risks and benefits that will allow them to make informed decisions about their treatment. We promote communication among the medical professionals involved in the patient's prenatal care to avoid delivering conflicting messages to patients and causing further anxiety about treatment decisions.