Managing Depression During Pregnancy
Marlene P. Freeman, MD
Center for Women’s Mental Health, Massachusetts General Hospital, Boston
Conclusive data about the effects of depression in pregnancy and evidence for the efficacy and safety of antidepressant medications in pregnancy are meager. No published studies of antidepressant drug efficacy in pregnancy are available, and few well-controlled studies for antidepressant drug safety in pregnancy have been undertaken. Health and ethical considerations make it difficult to conduct randomized, controlled studies of depression in pregnant women. Although more evidence is needed, some data for the effects of both maternal depression and antidepressant treatment on fetal development and birth outcomes are available and provide clinicians with some guidance.
Likelihood of Depression During Pregnancy
Women are at greatest risk of major depressive episodes during the reproductive years,1 and therefore, it is reasonable to expect that a woman may become pregnant while receiving antidepressant treatment. Two thirds of American women will have at least 1 unplanned pregnancy,2 and family planning decisions may also change over the course of treatment; so regardless of what women report about family planning at the initiation of treatment, they may very likely become pregnant while being treated for depression. About 5% to 10% of women experience depression during pregnancy, thus depression is similarly common in pregnant women as in nonpregnant women.3
Risks of Untreated Maternal Depression
Untreated depression during pregnancy carries risks for both the mother and baby. Depression may negatively affect maternal weight gain and self care.3 Depression, anxiety, and stress may also contribute to preeclampsia.4 Risks to the baby associated with untreated maternal depression include preterm delivery,5 reduced birth weight,4 and reduced head size.4 Newborns cry more and are harder to soothe if mothers were anxious or depressed during pregnancy, and infants may have poorer psychomotor development and adaptation to new environments.4 In addition, untreated maternal depression can have psychosocial consequences that can affect the whole family, for example, hospitalization, relationship problems, inability to care for other children, and loss of employment.6 For more information on the effects of untreated postnatal depression, see “Postpartum Depression Treatment and Breastfeeding.”
Risks to Baby of Medications During Pregnancy
Some medications taken during pregnancy carry risks for the baby, and these teratogenic risks are currently rated by the FDA using letter grades (AV 1).7 Clinicians must weigh the evidence and balance the risk of medication use to the baby against the risks of the untreated maternal depression to the baby and mother. The system used by the FDA is extremely limited, in that the risks of the untreated maternal disorder are not taken into account, often there is a paucity of human data that informs category assignment, and new information is rarely used to update category assignment.
Although much of the older literature shows a lack of association between TCAs or SSRIs and major malformations or intrauterine death, in some but not all studies, neonates whose mothers took antidepressants in the third trimester had lower birth weight than controls and some had symptoms that are consistent with side effects or withdrawal.6
More recent studies8–13 have generated controversy about whether the teratogenic risks of antidepressant medications are greater than once thought. For example, non–peer-reviewed data8 associated paroxetine use during the first trimester of pregnancy with increased risk of cardiovascular malformations compared with first-trimester use of other antidepressants. Subsequent analyses,9,14,15 however, have not found an increased risk of major cardiac malformations with first-trimester use of paroxetine.
When taken in late pregnancy, SSRIs have been associated with PPHN, but the risk may be lower than initially reported by Chambers and colleagues in 2006.10 This serious pulmonary condition is rare in the general population (estimated at 1 or 2 infants per 1000 live births), but, in Chambers and colleagues’ epidemiologic case-controlled study,10 PPHN was found to be 6.1 times more likely in infants of women who used SSRIs after week 20 during pregnancy than in controls (95% CI=2.2 to 16.8). In a more recent Swedish study,11 the risk (3.6, 95% CI=1.2 to 8.3) was lower than that reported in the North American study.10 In absolute terms, the risk is rare and needs to be weighed against the untreated condition of the mother. Importantly, in these studies,10,11 the underlying maternal psychiatric symptoms were not considered in the analyses, and it is unknown whether maternal depression or anxiety could contribute to an increased risk. A recent study by Andrade et al16 did not show any increased risk of PPHN with SSRI use in late pregnancy.
Several other risks may be associated with prenatal SSRI exposure. Reduced birth weight for gestational age12 and increased risk of preterm birth13 have been reported among babies born to mothers taking SSRIs, although untreated maternal depression also seems to result in prematurity.17 Low birth weight and premature birth may be associated with MDD,4,5 but distinguishing which factor (depression or antidepressant use) influences the outcome more is challenging. In fact, women who continued to take SSRIs during pregnancy may have had more severe depression than women who discontinued treatment during pregnancy, further clouding the distinction between medication effects and depression effects.12
Withdrawal or toxicity syndromes have also been suspected in babies exposed to SSRIs late in gestation (AV 2).6,18 These effects are transient and are reported to resolve by 2 weeks of age, without lasting effects, with reported symptoms including jitteriness, trouble eating and sleeping, and fussiness.18
Risk of Relapse of Depression During Pregnancy
In a recent, prospective study19 of women who were followed during pregnancy and had histories of MDD, the rate of relapse of depression was 68% among pregnant women who discontinued medication compared with 26% of those who continued medication at the same dose (AV 3). Predictors of relapse include a longer duration of MDD (>5 years), more recurrent depression (>4 episodes), being unmarried, and being younger than 32 years.
While treatment guidelines are generally lacking and care must be individualized for each patient, in general, when antidepressants are used, the lowest effective dose should be prescribed. For many women, antidepressant use can be avoided or minimized by selecting nonmedication strategies.
Data are available for several nonpharmacologic treatments for depression during pregnancy. One of the most important treatment options includes psychotherapy.20 Bright light therapy has received some study in pilot trials and appears promising for the treatment of depression in pregnant women,21 and omega-3 fatty acids may be advantageous as add-on therapy and are well tolerated.22 For severe cases of depression in pregnancy, ECT is thought to be safe if appropriate precautions are taken.23
Clinicians should routinely counsel women with depression who are of childbearing age about risks and benefits of medications during pregnancy, because the likelihood of pregnancy is high whether or not it is planned. Clinicians and patients need to balance the risks of medication to the baby against the risks of depressive relapse to both baby and mother, remembering that pregnancy is not protective against depression. Treatment needs to be tailored to the individual patient, and nonpharmacologic options may be appropriate. More evidence-based treatment information is needed.
clozapine (FazaClo, Clozaril, and others), paroxetine (Paxil, Pexeva, and others)
ECT = electroconvulsive therapy, EEG = electroencephalographic, FDA = United States Food and Drug Administration, MDD = major depressive disorder, PPHN = persistent pulmonary hypertension of the newborn, SRI = serotonin reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor, TCA = tricyclic antidepressant
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- Kessler RC, McGonagle KA, Swartz M, et al. Sex and depression in the National Comorbidity Survey, I: lifetime prevalence, chronicity, and recurrence. J Affect Disord. 1993;29(2–3):85–96.
- Dell DL. Gynecology. In: Kornstein SG, Clayston AH, eds. Women's Mental Health: A Comprehensive Textbook. New York, NY: Guilford Press; 2002:359–368.
- Eberhard-Gran M, Eskild A, Opjordsmoen S. Treating mood disorders during pregnancy: safety considerations. Drug Saf. 2005;28(8):695–706.
- Mulder EJ, Robles de Medina PG, Huizink AC, et al. Prenatal maternal stress: effects on pregnancy and the (unborn) child. Early Hum Dev. 2002;70(1–2):3–14.
- Li D, Liu L, Odouli R. Presence of depressive symptoms during early pregnancy and the risk of preterm delivery: a prospective cohort study. Hum Reprod. 2009;24(1):146–153.
- Wisner KL, Gelenberg AJ, Leonard H, et al. Pharmacologic treatment of depression during pregnancy. JAMA. 1999;282(13):1264–1269.
- US Food and Drug Administration. Summary of proposed rule on pregnancy and lactation labeling. May 28, 2008. Available at: http://www.fda.gov/CDER/regulatory/pregnancy_labeling/summary.htm. Accessed Apr 7, 2009.
- Paroxetine [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2009. Available at: http://us.gsk.com/products/assets/us_paxil.pdf. Accessed Apr 7, 2009.
- Bérard A, Ramos E, Rey E, et al. First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage. Birth Defects Res B Dev Reprod Toxicol. 2007;80(1):18–27.
- Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med. 2006;354(6):579–587.
- Källén B, Olausson PO. Maternal use of selective serotonin re-uptake inhibitors and persistent pulmonary hypertension of the newborn. Pharmacoepidemiol Drug Saf. 2008;17(8):801–806.
- Oberlander TF, Warburton W, Misri S, et al. 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(8):898–906.
- Suri R, Altshuler L, Hellemann G, et al. Effects of antenatal depression and antidepressant treatment on gestational age at birth and risk of preterm birth. Am J Psychiatry. 2007;164(8):1206–1213.
- Einarson A, Pistelli A, DeSantis M, et al. Evaluation of the risk of congenital cardiovascular defects associated with use of paroxetine during pregnancy. Am J Psychiatry. 2008;165(6):749–752.
- Gentile S, Bellantuono C. Selective serotonin reuptake inhibitor exposure during early pregnancy and the risk of fetal major malformations: focus on paroxetine. J Clin Psychiatry. 2009;70(3):414–422.
- Andrade SE, McPhillips H, Loren D, et al. Antidepressant medication use and risk of persistent pulmonary hypertension of the newborn. Pharmacoepidemiol Drug Saf. 2009;18(3):246–252.
- Wisner KL, Sit DK, Hanusa BH, et al. Major depression and antidepressant treatment: impact on pregnancy and neonatal outcomes [published online ahead of print March 16, 2009]. Am J Psychiatry. doi: 10.1176/appi.ajp.2008.08081170.
- Moses-Kolko EL, Bogen D, Perel J, et al. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA. 2005;293(19):2372–2383.
- Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006;295(5):499–507.
- Spinelli MG. Interpersonal psychotherapy for depressed antepartum women: a pilot study. Am J Psychiatry. 1997;154(7):1028–1030.
- Oren DA, Wisner KL, Spinelli M, et al. An open trial of morning light therapy for treatment of antepartum depression. Am J Psychiatry. 2002;159(4):666–669.
- Freeman MP. Complementary and alternative medicine for perinatal depression. J Affect Disord. 2009;112(1–3):1–10.
- Miller LJ. Use of electroconvulsive therapy during pregnancy. Hosp Community Psychiatry. 1994;45(5):444–450.