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Major depressive disorder is common during childbearing. Depression that interferes with function develops in an estimated 14.5% of pregnant women. Some statistics are troubling in that only 13.8% of pregnant women who screen positive for depression actually receive treatment.
Major depressive disorder (MDD) is common during childbearing. Depression that interferes with function develops in an estimated 14.5% of pregnant women.1 In a recent population-based study, Munk-Olsen and colleagues2 determined the prevalence of psychiatric disorders relative to childbearing. The overall risk for any psychiatric episode after delivery was elevated for women during the first 3 postpartum months. However, the increased risk specifically for major depression remained elevated for 5 months after birth. These statistics are troubling in that only 13.8% of pregnant women who screen positive for depression actually receive treatment.3
MDD is associated with substantial perinatal risk directly related to the physiological sequelae of maternal psychiatric illness. Hypothalamic-pituitary-adrenal axis hyperactivity may directly affect fetal growth and increase corticotropin-releasing hormone release from the placenta, which affects the timing and onset of delivery.4 Furthermore, women with depression have a 2.5-fold increased risk for preeclampsia during pregnancy.5
Maternal health behaviors associated with MDD (such as cigarette and substance use, poor adherence to obstetrical care, deficient nutritional intake, and social isolation) increase the risk for poor pregnancy outcome.6,7 Although rare, maternal suicide attempts (which occur in 0.4 per 1000 pregnancies) are another potential complication of MDD.8 Fetal exposure to MDD has an adverse impact on later child development that is independent from the child’s exposure to maternal postpartum depression.9
These observations support consideration of maternal MDD as a potent risk factor to the mother, fetus, and family. Identification and treatment of depression during pregnancy deserves to be a public health priority to reduce the health burden for women, families, and communities.10
In this article, I discuss general principles of treatment of MDD during pregnancy, evidence-based treatments for outpatient care (psychotherapy, SSRI pharmacotherapy, electro-convulsive therapy [ECT], and morning bright light treatment), and the proposed FDA classification system for drug use during pregnancy.
Approach to intervention during pregnancy
According to principles of risk-to-benefit decision making during pregnancy, the patient is responsible for stating her preferences regarding the treatment options offered by the physician and for making a thoughtful choice.11 The major focus of treatment is typically maternal symptom reduction; however, a broader concept of optimizing pregnancy outcome is preferable.12 The physician must communicate information about risks, which is frequently challenging (Table).11,13,14
Ideally, women and their psychiatrists can select from a variety of treatment options for MDD; however, evidence-based mental health treatments are not universally accessible. Availability, acceptability, and cost (and, unfortunately, often limitations) must factor into the choice of treatment. The fragmentation of health care for young women also makes identification of a specific physician as a point of responsibility difficult.15,16 Moreover, depressed patients identified in primary care settings rarely complete referrals for mental health treatment. Newer models, such as collaborative care-an approach based on chronic disease management principles combined with experienced nonmedical specialists working with the primary care physician and mental health professional-have emerged and have been applied to care for childbearing women.17,18
When clinically feasible, nondrug treatments for depressed pregnant women are desirable to avoid fetal medication exposure. The standard evidence-based options are psycho-therapy and antidepressant medication or a combination of the two. ECT is also effective. A reasonably well-studied nondrug environmental intervention for MDD is morning bright light therapy.19
In the dynamic state of pregnancy, treatment efficacy can be affected by dramatic physiological and metabolic changes. Systematic monitoring with a repeated self-report or clinician-administered scale provides useful data throughout the pregnancy. Serial ratings can be used to assess response to an intervention and evaluate the need for additional therapies.
A practical and rapid clinician-administered measure is the Clinical Global Impressions Scale, a 7-point global severity and change scale.20 The Edinburgh Postnatal Depression Scale (EPDS), a 10-item self-report, has also been validated as a screening tool for depression during pregnancy. The EPDS has also been used successfully to assess response to a psychotherapeutic intervention21; a score of 15 or higher is associated with probable major depression during pregnancy.22
Although psychotherapy is not readily available in all practice settings, clinical experience shows that short-term therapies, such as cognitive-behavioral therapy, are effective during pregnancy. Spinelli and Endicott22 undertook a 16-week clinical trial to compare interpersonal psychotherapy for depression during pregnancy with a didactic parenting education (control) program. Thirty-eight pregnant women were included in the analysis. Outcome measures were based on the EPDS, the Beck Depression Inventory, and the Hamilton Rating Scale for Depression. Women who were randomized to either the interpersonal psychotherapy group or the control group showed some improvement, but women in the interpersonal psycho-therapy group showed greater improvement on all measures. The investigators concluded that interpersonal psychotherapy is effective and should be a first-line treatment in the hierarchy of therapies for antenatal MDD. This recommendation is consistent with expert recommendations and clinical wisdom.23
Freeman and colleagues24 also found benefits of supportive psycho-therapy. The investigators undertook a pilot investigation in antenatal women with MDD who were randomized to receive omega-3 fatty acids and provided manualized supportive psychotherapy. Their results showed no significant difference between omega-3 fatty acids and placebo; however, the manualized supportive psychotherapy was found to be effective.
If psychotherapy is not associated with a response, or if the depressive episode is severe, combination psychotherapy and antidepressant pharmacotherapy is warranted.23
SSRI pharmacotherapy is common among childbearing-aged women. An estimated 92,000 pregnant women are exposed to these agents each year.25 Many women who benefit from maintenance pharmacotherapy for recurrent MDD choose to continue treatment throughout pregnancy. Others elect a trial off medication around the time of conception. Pregnant women who discontinue antidepressant medication have a higher risk of relapse (68%) than those who maintain treatment (26%).26
With the first signs of depressive symptoms indicative of relapse, resumption of medication is advisable. From a clinical standpoint, tapering medication and instituting psycho-therapy is a reasonable strategy; however, no data are available to support the mitigation of recurrence risk.23
A woman’s treatment history is a primary criterion for drug selection. Previous response to a specific antidepressant with tolerable adverse effects is crucial information to support use of that agent for the individual patient. Switching from an effective agent to another drug risks nonresponse (with exposure to MDD and its sequelae for the mother and fetus) as well as potential new adverse effects. The use of alcohol and other drugs (including nonprescription drugs and smoking) during pregnancy must be documented by the physician before prescribing an antidepressant to avoid automatic implication of the antidepressant as causal if the outcome is negative.27
SSRIs have been the subject of substantial pregnancy exposure investigation compared with other drug classes. Two recent articles in the New England Journal of Medicine provided large-scale case-control data.28,29 The investigators from both studies concluded that the association of SSRI exposures with birth defects (if any) carries a small absolute risk, and in his editorial on the articles, Greene30 agreed.
Alwan and colleagues28 observed no association between overall exposure and defects previously related to SSRIs (particularly congenital heart defects). The investigators did find an association between maternal SSRI use and defects not previously reported, which suggests the possibility of association by chance. It is notable that only a small number of infants with defects had been exposed to an SSRI.
In the second article, Louik and colleagues29 reported that overall SSRI use was not associated with the defects reported by Alwan’s group nor with congenital heart defects. However, they found a doubling of the risk of septal defects associated specifically with sertraline (13 exposed patients) and a tripling of the risk of right ventricular outflow tract obstruction defects associated with paroxetine (6 exposed patients).
The baseline rate of right ventricular outflow tract obstruction defects is about 5.5 cases per 10,000 live births in the general population, so the absolute risk remains low. For example, even a 4-fold increase would raise the rate of malformation to just 2 per 1000 births (or less than 0.2%).29 The only association that overlapped with the findings of Alwan and colleagues was that between sertraline and omphalocele (odds ratio [OR], 5.7; 95% confidence interval [CI], 1.6 - 20.7, only 3 exposed patients). No significantly increased risks were associated with fluoxetine or non-SSRI antidepressants for any assessed birth defects.28
Einarson and colleagues31 evaluated the association of paroxetine with cardiovascular defects in infants who had been exposed during the first trimester. The investigators collected 1174 unpublished cases of exposed infants; an additional 2061 cases were identified from 5 previously published database studies. The rates of cardiovascular defects in the 1174 unpublished cases were 0.7% in the exposed group and 0.7% in the unexposed group. In the database group, the rate was 1.5%. The combined mean rate of cardiovascular defects was 1.2% (95% CI, 1.1 - 2.1). The authors concluded that paroxetine was not associated with an increased risk of cardiovascular defects.
Negative reproductive outcomes associated with SSRI exposure have been reported, however. Chambers and colleagues32 observed several adverse outcomes related to later gestational SSRI exposure. Their data showed a 3-fold increase in the rate of preterm birth (14.3%) in infants whose mothers were treated with fluoxetine after 25 weeks’ gestation compared with infants whose mothers stopped the drug earlier in pregnancy (4.1%) or those who had not been exposed (5.9%). Infants exposed to fluoxetine during late gestation had significantly lower birth weights than infants whose mothers discontinued the drug earlier or who served as controls.
In evaluating the association of reproductive outcomes related to drug exposure, a critical issue is the contribution of the underlying illness being treated. Suri and colleagues33 addressed this issue in their study of pregnant women in 3 exposure groups: those treated with an antidepressant for most of the pregnancy; those with MDD with no or brief drug exposure; and controls with neither exposure. The rates of preterm birth were 14.3%, 0%, 5.3%, respectively. The findings suggest that SSRI treatment rather than MDD is associated with an increased risk of preterm birth.
Oberlander and colleagues34 used population health data to link records of births with records of maternal health and prenatal maternal prescriptions for SSRI. A total of 119,547 neonates were identified and divided into 3 groups: those whose mothers had received a diagnosis of depression and had been treated with an antidepressant; those whose mothers had received a diagnosis of depression but had not been treated for the depression; and nonexposed controls-neonates whose mothers had neither received a diagnosis of depression nor been treated with antidepressant medication. To account for the expected differences between depressed wom-en who did and those who did not access drug therapy during pregnancy, propensity score matching was used to identify a comparison subgroup from the depressed mothers who had not been treated with antidepressants but otherwise had similar characteristics to those of the SSRI-treated mothers.
SSRI-exposed infants had lower birth weights, decreased mean gestational ages, and longer hospital stays. Findings also showed more neonatal respiratory distress, jaundice, and feeding problems in exposed infants than in infants of depressed unmedicated mothers. However, when compared with propensity score–matched neonates of depressed women, SSRI exposure was associated only with increased incidence of birth weight below the 10th percentile and respiratory distress.
These findings imply that MDD exposure and SSRI treatment yield similar reproductive outcomes (including preterm birth). Because the preterm birth rate in the United States is 12.5% and is the leading cause of perinatal morbidity and mortality, clarification of an association between SSRI and/or MDD and preterm birth is crucial.35
Late-gestational SSRI-exposed neonates have a 3-fold higher risk of neonatal behavioral syndrome-characterized by difficulty in feeding and sleeping, irritability, prolonged crying, tremors, and seizures-compared with infants with only early or no exposure.35 Most neonatal signs resolve within 2 weeks of birth, and follow-up results of affected infants have been normal.36,37
The risk of neonatal syndrome (transient CNS, motor, respiratory, and GI signs) in infants with prenatal serotonin reuptake inhibitor exposure may be moderated by infant genotype.38 The highest reported rates for neonatal syndrome after in utero SSRI exposure were 31% in a sample of infants who had been exposed only to fluoxetine, and 30% in a sample in which 62% had been exposed to paroxetine and 20% to fluoxetine.32,39
Chambers and colleagues40 found a relative risk of 6.1 for persistent pulmonary hypertension in neonates exposed after 20 weeks’ gestation. In line with the use of absolute risks, this translates into a rate of 6 to 12 per 1000 births in SSRI-exposed infants compared with 1 to 2 per 1000 births in the general population. The investigators hypothesized a continuum of respiratory problems in SSRI-exposed neo-nates in adapting to extrauterine oxygenation. Other reports of increased risk of neonatal respiratory distress after SSRI exposure have been published34,41,42; however, a recent study did not replicate this association.43
Use of the lowest effective dose to achieve remission during pregnancy reduces residual symptoms and exposure to the underlying disorder. The SSRI dosage may need to be increased to maintain clinical effectiveness because of the increased clearance during pregnancy. Sit and colleagues44 found that 4 of 5 patients who received citalopram/escitalopram and 5 of 6 patients who received sertraline had declining serum drug level/dose ratios between 20 weeks’ gestation and birth. By 12 weeks postpartum, the level/dose ratios were similar to those detected at 20 weeks’ gestation. Systematic clinical response monitoring is crucial during pregnancy.
ECT is a reasonable choice for the treatment of severely depressed pregnant women. Preparation for ECT during pregnancy should include obstetrical consultation and fetal monitoring, intravenous hydration, administration of a nonparticulate antacid, and elevation of the woman’s right hip to avoid compression of the great vessels.46
Although morning bright light therapy is widely appreciated as a treatment for seasonal affective disorder, it is also effective for nonseasonal MDD.47-49 Light therapy is perceived as physiologically natural, with mild and easily correctable adverse effects (eg, mild headache and eye irritation, slight nausea); therefore, it is appealing to pregnant women and their physicians. Oren and colleagues50 performed an open trial of bright light therapy in an A-B-A design in 16 pregnant women with MDD. After 3 weeks of treatment, the mean depression ratings improved by 49%.
This work was further explored in a double-blind, placebo-controlled pilot study by Epperson and colleagues.51 Ten pregnant women with MDD were randomly assigned to a 5-week clinical trial with a 7000 lux (active) or 500 lux (placebo) light box. Although there was a small mean group advantage of active treatment throughout the randomized controlled trial, it was not statistically significant. However, in a longer, 10-week trial, the active light produced a clear benefit (P = .001); the effect size (0.43) was similar to that seen in antidepressant drug trials. Successful treatment with bright morning light was associated with phase advances of the melatonin rhythm, which was assessed with serial saliva samples. These findings provide additional evidence for efficacy of bright light therapy for antepartum depression and underscore the need for an expanded randomized clinical trial.
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