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Treatment in Psychiatry   |    
Antenatal Depression: Navigating the Treatment Dilemmas
Marlene P. Freeman, M.D.
Am J Psychiatry 2007;164:1162-1165. doi:10.1176/appi.ajp.2007.07020341

“Ms. A” was a 35-year-old married Caucasian health care professional with a history of recurrent major depressive disorder that responded well to treatment with a selective serotonin reuptake inhibitor (SSRI). She discontinued her antidepressant prior to conception for a planned pregnancy because she did not want to expose her baby to medication. She soon relapsed, and by the first trimester of her pregnancy, she was in a major depressive episode. Her symptoms included anhedonia, tearfulness, irritability, insomnia, and diminished appetite. She presented for participation in an open-label pilot trial of omega-3 fatty acids for antenatal major depressive disorder (1). At intake, after hearing the risks and benefits of available treatment options, Ms. A declined antidepressant medication and a referral for psychotherapy and consented to participate in the study of omega-3 fatty acids, which she started at 16 weeks’ gestation. She was assessed every 2 weeks throughout pregnancy. At 8 weeks she had not responded to omega-3 fatty acids and was again presented with other treatment options, including medication and psychotherapy. She again declined these treatments and continued to do so throughout the remainder of her pregnancy. She was concerned about the safety of medications in pregnancy and believed that taking medication would make her a bad mother. She also declined referral for psychotherapy, stating that she was “too busy.” “Ms. B” was a 24-year-old married Hispanic woman with a 2-year-old son. She presented 20 weeks into a planned pregnancy. She had been looking forward to having a second child until the onset of a major depressive episode. While undergoing routine obstetrical screenings, she found herself hoping that testing would reveal fetal abnormalities so that she would have an excuse to end the pregnancy. However, screening and amniocentesis (after a false positive elevated maternal serum alpha-fetoprotein level) revealed no such abnormalities. She felt too depressed to imagine how the baby would be incorporated into her family and noted that she did not feel excitement about the baby. She was anhedonic and socially withdrawn. She had intermittent suicidal thoughts but stated that she would never harm herself because of her religious beliefs. Among her numerous psychosocial stressors was that her husband had recently started a new job that required him to move to another city, which meant that they were together only on weekends. Her functioning at work and as a mother was impaired by her depressive symptoms. Treatment options and the associated risks and benefits were explained to her. In the midst of the discussion about the risks and benefits of SSRIs, Ms. B stated, “I hear what you are saying, but I just want to feel better as soon as possible. I cannot think about the risks to the baby.”

Antenatal depression affects 10%–20% of pregnant women (2, 3). It is associated with a greater risk of negative pregnancy outcomes, such as prematurity, fetal distress, neonatal behavioral differences (4), and a greater risk of postpartum depression (5). Recent data emphasize that relapse rates for depression are high during pregnancy. Cohen and colleagues (6) found that 43% of a sample of pregnant women with a history of major depression experienced a major depressive episode during pregnancy; among women who discontinued antidepressant medication at the start of the pregnancy, the rate was 68%. Recent studies have raised concerns about teratogenicity and neonatal complications associated with commonly used antidepressants. However, there is substantial confusion and controversy about how to integrate new information regarding the possible risks of antidepressant medication into risk/benefit analyses for the treatment of antenatal depression. Moreover, in practice, risk/benefit assessments commonly overlook or minimize the risks associated with untreated maternal depression.

The selection of treatment for depression in a pregnant woman must take into account the well-being of both mother and baby in a context of limited risk-benefit data. The patient’s depressive symptoms themselves may also affect her decision making. In our women’s mental health program, we find that most mothers are exceedingly anxious about accepting antidepressant medication, and despite moderate to severe depressive symptoms and impaired functioning, they tend to focus on the risks of in utero exposure to medication rather than on the risks of untreated depression. Less frequently, we find that depressive symptoms have a negative impact on the mother’s ability to emotionally attach to her baby, which may interfere with her risk/benefit assessment in a different way.

Treatment decisions should be collaborative, involving the mother, the baby’s father when appropriate, and health care providers. The risks and benefits of treatment are complex, and the weight given to the factors involved varies among individuals.

Treatment decisions should take into account the severity of symptoms, past history of depression and treatment response, and patient preferences. In cases of mild depression, nonpharmacological treatments may be considered first. For pregnant women with moderate to severe depression, antidepressants are a reasonable part of a treatment plan. A history of previous postpartum depression or recurrent major depression is a risk factor for perinatal depression and may support the decision to use antidepressants during pregnancy.

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Antidepressants

Antidepressants are generally assumed to be efficacious for the treatment of depression in pregnant women, although a small amount of data suggest that higher doses might be necessary to maintain therapeutic benefit (7). Many women are concerned about possible in utero effects of antidepressants. Although most older data on tricyclic antidepressants and SSRIs do not suggest that antidepressants increase the risk of malformation or miscarriage (4), some more recent data have contributed to increased concerns. An association has been reported between first-trimester use of paroxetine and cardiovascular malformations (8). One recent study (9) suggested an association between maternal SSRI use after 20 weeks’ gestation and persistent pulmonary hypertension of the newborn, a rare but serious condition with significant morbidity and mortality. There is also growing concern about a neonatal withdrawal or adaptation syndrome and medical complications associated with use of antidepressants in late pregnancy (10, 11). Additionally, Suri and colleagues demonstrate in an article in this issue (12) that antidepressant use during pregnancy in women with a history of major depression is associated with a higher risk of premature delivery and lower gestational age at birth compared with women with a history of major depression who elected to discontinue medication during pregnancy as well as healthy comparison women. Suri et al. also found that the effect of antidepressants remained after the analyses controlled for severity and duration of depressive symptoms during pregnancy. Information about the long-term effects of in utero exposure to antidepressants is limited, although the available literature is generally reassuring about the lack of negative consequences, particularly with tricyclic antidepressants and fluoxetine (4).

Since antenatal depression is a risk factor for postpartum depression, the safety of treatment during breastfeeding should also be considered. Despite a few case reports of possible adverse effects in infants breastfed by mothers taking antidepressants, most data on antidepressant levels in breast milk and infant serum suggest a low level of infant exposure to antidepressants via breastfeeding (13). Relative to other antidepressants studied, use of fluoxetine during breastfeeding, perhaps particularly if it was also used during the pregnancy, may be more likely to result in higher infant blood levels and adverse neonatal effects (13).

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Nonpharmacological Treatments

Psychotherapy, including interpersonal psychotherapy, appears to be efficacious for antenatal depression and prevention of postpartum depression in women at risk (14–16). Unfortunately, many women have financial or time constraints that limit participation in psychotherapy. Bright light therapy also appears to be a promising treatment (17, 18). In cases of severe depression, ECT is considered a safe and effective treatment option during pregnancy, provided that appropriate precautions are taken (19). Exercise has been noted to have at least modest antidepressant effects, and the American College of Obstetricians and Gynecologists recommends 30 minutes of exercise daily during pregnancy (20, 21). In pilot studies (1, 22), our group has found omega-3 fatty acids for treatment of depression to be well accepted and well tolerated in pregnant and postpartum women.

In the selection of an antidepressant for a pregnant patient, previous response to a particular antidepressant rather than possible differences in risk among antidepressants should be strongly considered; the likelihood of a response with the same antidepressant may be preferable to the risk of exposure to multiple medications in the event of nonresponse. As suggested earlier, it is difficult to make definitive statements about the relative safety of the various antidepressants, although paroxetine should not be considered as a first-line medication during the first trimester because of its possible association with fetal cardiovascular malformations.

If a pregnant woman with major depression is unable to refrain from smoking, bupropion may be considered among the antidepressant options. Although safety information for bupropion in pregnancy is limited, cigarette smoking is known to have teratogenic effects, and bupropion is efficacious in smoking cessation as well as in treatment of depression.

Women who experience antenatal depression have a high risk of postpartum depression, and this risk should be considered during pregnancy. The possible effects on the fetus of maternal use of medication late in pregnancy must be balanced against the risk of postpartum depression and its effects on the mother and the baby. While some studies demonstrate low levels of medication exposure for breastfeeding infants during maternal antidepressant treatment, there have been some case reports of suspected adverse events (13). Fluoxetine has been observed at relatively high blood levels, which may have clinical adverse effects in breastfeeding infants. Since an antidepressant started during pregnancy will often be continued during the postpartum period, this should be a consideration for mothers who plan to breastfeed their infants (13).

After a woman and her health care provider have determined that an antidepressant will be part of her treatment plan, her other health care providers, such as her obstetrician and pediatrician, should be informed about the treatment and its rationale. This allows the patient to receive support for her treatment decisions, helping to minimize the potential for mixed messages to the patient and anxiety about her treatment decisions.

Sorting out the risks and benefits of treatment for depression, particularly those of antidepressant medications, is complicated in pregnancy. The selection of treatment should be based on the severity of symptoms, the patient’s depression history (including past response to medication), and the patient’s preferences. In women with mild depression, nonpharmacological approaches may be useful first-choice treatments. In women with moderate to severe depression or a history of previous postpartum depression or recurrent major depression, antidepressants should be strongly considered, alone or in combination with nonpharmacological treatment. The risks of antidepressant exposure to the baby are unclear, although some studies have suggested the potential for risks such as cardiac teratogenicity with paroxetine; persistent pulmonary hypertension of the newborn and other adverse outcomes with SSRIs; and preterm birth and lower gestational age at birth with antidepressants in general.

In the first case presented earlier, Ms. A was concerned about the safety of medication exposure for her baby and said she was “too busy” for psychotherapy. In fact, however, she felt that engaging in psychotherapy was too stigmatizing—it would mean that “something is really wrong with me.” Two months after delivery of a healthy baby, Ms. A decided to stop breastfeeding and to begin treatment with sertraline, which was selected because she had a good response to it in prior treatment. Her symptoms responded to sertraline within 6 weeks, at which time she accepted and followed through with a referral for psychotherapy. Within 3 months, she experienced a full remission of her major depressive episode. When asked if she wished she had accepted treatment with an antidepressant sooner, Ms. A stated emphatically that she did not regret her treatment decisions and under no circumstances would have accepted treatment with medication during pregnancy or while breastfeeding. Four years later, Ms. A has maintained remission from major depression while taking sertraline, except during a brief period when she tried a decreased dose of medication to reduce sexual side effects; she achieved remission again when the dose was increased, although the sexual side effects persist. Her child is healthy and is undergoing normal development.

On the other hand, Ms. B had difficulty integrating the risks pertaining to her baby into her decision-making process. She accepted an invitation to bring her husband into the decision-making process, and he participated in interviews by telephone and later in person. The patient and her husband were presented with treatment options and their risks and benefits. Ms. B and her husband came to the decision that the risks of treatment with an antidepressant were acceptable relative to the risks of untreated antenatal depression. Ms. B was started on a course of escitalopram in addition to psychotherapy. Escitalopram was selected because of a family history of a good response to this agent in the treatment of depression. Within 2 months, Ms. B noted improvement in her depressive symptoms and began to feel excitement about her baby.

+Received Feb. 21, 2007; revision received March 30, 2007; accepted April 2, 2007 (doi: 10.1176/appi.ajp.2007.07020341). From the Women’s Mental Health Program, University of Arizona College of Medicine, Tucson. Address correspondence and reprint requests to Dr. Freeman, Women’s Mental Health Center, University of Texas–Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390; marlene.freeman@utsouthwestern.edu (e-mail).

+CME Disclosure: Dr. Freeman has received research funding from NIMH, the U.S. Food and Drug Administration, the Institute for Mental Health Research (Arizona), Forest, Eli Lilly, and Reliant and has served as a consultant for Ther-Rx and Reliant. She has also received honoraria for peer-reviewed material published on the Internet and CME program content from AstraZeneca, Forest, and Ther-Rx and has received research materials from Pronova Biocare. APA policy requires disclosure by CME authors of unapproved or investigational use of products discussed in CME programs. Off-label use of medications by individual physicians is permitted and common. Decisions about off-label use can be guided by scientific literature and clinical experience.

1.Freeman MP, Hibbeln JR, Wisner KL, Watchman M, Gelenberg AJ: An open trial of omega-3 fatty acids for depression in pregnancy. Acta Neuropsychiatrica 2006; 18:21–24
 
2.Evans J, Heron J, Francomb H, Oke S, Golding J: Cohort study of depressed mood during pregnancy and after childbirth. BMJ 2001; 323:257–260
 
3.Marcus SM, Flynn HA, Blow FC, Barry KL: Depressive symptoms among pregnant women screened in obstetrics settings. J Womens Health (Larchmt) 2003; 12:373–380
 
4.Wisner KL, Zarin D, Holmboe E, Appelbaum P, Gelenberg AJ, Leonard HL, Frank E: Risk-benefit decision making for treatment of depression during pregnancy. Am J Psychiatry 2000; 157:1933–1940
 
5.Stowe ZN, Hostetter AL, Newport DJ: The onset of postpartum depression: implications for clinical screening in obstetrical and primary care. Am J Obstet Gynecol 2005; 192:522–526
 
6.Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, Suri R, Burt VK, Hendrick V, Remnick AM, Loughead A, Vitonis AF, Stowe ZN: Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA 2006; 295:499–507
 
7.Hostetter A, Stowe ZN, Strader JR Jr, McLaughlin E, Llewellyn A: Dose of selective serotonin uptake inhibitors across pregnancy: clinical implications. Depress Anxiety 2000; 11:51–57
 
8.GlaxoSmithKline: “Dear healthcare professional”: important prescribing information. Philadelphia, GlaxoSmithKline, Sept 2005 (www.fda.gov/medwatch/safety/2005/Paxil_dearhcp_letter.pdf)
 
9.Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, Mitchell AA: Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006; 354:579–587
 
10.Moses-Kolko EL, Bogen D, Perel J, Bregar A, Uhl K, Levin B, Wisner KL: Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA 2005; 293:2372–2383
 
11.Oberlander TF, Warburton W, Misri S, Aghajanian J, Hertzman C: Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data. Arch Gen Psychiatry 2006; 63:898–906
 
12.Suri R, Altshuler L, Hellemann G, Burt VK, Aquino A, Mintz J: Effects of antenatal depression and antidepressant treatment on gestational age at birth and risk of preterm birth. Am J Psychiatry 164:1206–1213
 
13.Weissman AM, Levy BT, Hartz AJ, Bentler S, Donohue M, Ellingrod VL, Wisner KL: Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants. Am J Psychiatry 2004; 161:1066–1078
 
14.Spinelli MG, Endicott J: Controlled clinical trial of interpersonal psychotherapy versus parenting education program for depressed pregnant women. Am J Psychiatry 2003; 160:555–562
 
15.Zlotnick C, Miller IW, Pearlstein T, Howard M, Sweeney P: A preventive intervention for pregnant women on public assistance at risk for postpartum depression. Am J Psychiatry 2006; 163:1443–1445
 
16.Dennis CL: Psychosocial and psychological interventions for prevention of postnatal depression: systematic review. BMJ 2005; 331:15–22
 
17.Oren DA, Wisner KL, Spinelli M, Epperson CN, Peindl KS, Terman JS, Terman M: An open trial of morning light therapy for treatment of antepartum depression. Am J Psychiatry 2002; 159:666–669
 
18.Epperson CN, Terman M, Terman JS, Hanusa BH, Oren DA, Peindl KS, Wisner KL: Randomized clinical trial of bright light therapy for antepartum depression: preliminary findings. J Clin Psychiatry 2004; 65:421–425
 
19.Miller LJ: Use of electroconvulsive therapy during pregnancy. Hosp Community Psychiatry 1994; 45:444–450
 
20.Trivedi MH, Greer TL, Grannemann BD, Chambliss HO, Jordan AN: Exercise as an augmentation strategy for treatment of major depression. J Psychiatr Pract 2006; 12:205–213
 
21.Artal R, O’Toole M: Guidelines of the American College of Obstetricians and Gynecologists for exercise during pregnancy and the postpartum period. Br J Sports Med 2003; 37:6–12
 
22.Freeman MP, Hibbeln JR, Wisner KL, Brumbach BH, Watchman M, Gelenberg AJ: Randomized dose-ranging pilot trial of omega-3 fatty acids for postpartum depression. Acta Psychiatr Scand 2006; 113:31–35
 
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References

1.Freeman MP, Hibbeln JR, Wisner KL, Watchman M, Gelenberg AJ: An open trial of omega-3 fatty acids for depression in pregnancy. Acta Neuropsychiatrica 2006; 18:21–24
 
2.Evans J, Heron J, Francomb H, Oke S, Golding J: Cohort study of depressed mood during pregnancy and after childbirth. BMJ 2001; 323:257–260
 
3.Marcus SM, Flynn HA, Blow FC, Barry KL: Depressive symptoms among pregnant women screened in obstetrics settings. J Womens Health (Larchmt) 2003; 12:373–380
 
4.Wisner KL, Zarin D, Holmboe E, Appelbaum P, Gelenberg AJ, Leonard HL, Frank E: Risk-benefit decision making for treatment of depression during pregnancy. Am J Psychiatry 2000; 157:1933–1940
 
5.Stowe ZN, Hostetter AL, Newport DJ: The onset of postpartum depression: implications for clinical screening in obstetrical and primary care. Am J Obstet Gynecol 2005; 192:522–526
 
6.Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, Suri R, Burt VK, Hendrick V, Remnick AM, Loughead A, Vitonis AF, Stowe ZN: Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA 2006; 295:499–507
 
7.Hostetter A, Stowe ZN, Strader JR Jr, McLaughlin E, Llewellyn A: Dose of selective serotonin uptake inhibitors across pregnancy: clinical implications. Depress Anxiety 2000; 11:51–57
 
8.GlaxoSmithKline: “Dear healthcare professional”: important prescribing information. Philadelphia, GlaxoSmithKline, Sept 2005 (www.fda.gov/medwatch/safety/2005/Paxil_dearhcp_letter.pdf)
 
9.Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, Mitchell AA: Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006; 354:579–587
 
10.Moses-Kolko EL, Bogen D, Perel J, Bregar A, Uhl K, Levin B, Wisner KL: Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA 2005; 293:2372–2383
 
11.Oberlander TF, Warburton W, Misri S, Aghajanian J, Hertzman C: Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data. Arch Gen Psychiatry 2006; 63:898–906
 
12.Suri R, Altshuler L, Hellemann G, Burt VK, Aquino A, Mintz J: Effects of antenatal depression and antidepressant treatment on gestational age at birth and risk of preterm birth. Am J Psychiatry 164:1206–1213
 
13.Weissman AM, Levy BT, Hartz AJ, Bentler S, Donohue M, Ellingrod VL, Wisner KL: Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants. Am J Psychiatry 2004; 161:1066–1078
 
14.Spinelli MG, Endicott J: Controlled clinical trial of interpersonal psychotherapy versus parenting education program for depressed pregnant women. Am J Psychiatry 2003; 160:555–562
 
15.Zlotnick C, Miller IW, Pearlstein T, Howard M, Sweeney P: A preventive intervention for pregnant women on public assistance at risk for postpartum depression. Am J Psychiatry 2006; 163:1443–1445
 
16.Dennis CL: Psychosocial and psychological interventions for prevention of postnatal depression: systematic review. BMJ 2005; 331:15–22
 
17.Oren DA, Wisner KL, Spinelli M, Epperson CN, Peindl KS, Terman JS, Terman M: An open trial of morning light therapy for treatment of antepartum depression. Am J Psychiatry 2002; 159:666–669
 
18.Epperson CN, Terman M, Terman JS, Hanusa BH, Oren DA, Peindl KS, Wisner KL: Randomized clinical trial of bright light therapy for antepartum depression: preliminary findings. J Clin Psychiatry 2004; 65:421–425
 
19.Miller LJ: Use of electroconvulsive therapy during pregnancy. Hosp Community Psychiatry 1994; 45:444–450
 
20.Trivedi MH, Greer TL, Grannemann BD, Chambliss HO, Jordan AN: Exercise as an augmentation strategy for treatment of major depression. J Psychiatr Pract 2006; 12:205–213
 
21.Artal R, O’Toole M: Guidelines of the American College of Obstetricians and Gynecologists for exercise during pregnancy and the postpartum period. Br J Sports Med 2003; 37:6–12
 
22.Freeman MP, Hibbeln JR, Wisner KL, Brumbach BH, Watchman M, Gelenberg AJ: Randomized dose-ranging pilot trial of omega-3 fatty acids for postpartum depression. Acta Psychiatr Scand 2006; 113:31–35
 
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1.
Major depressive disorder is estimated to affect what percent of pregnant women?
2.
First-trimester exposure to which of the following antidepressants has been associated with an increased risk of cardiovascular malformations?
3.
One study has suggested that maternal antidepressant use during pregnancy may be associated which of the following conditions?
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