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Anti-depressants, Pregnancy and Lactation

The following article was published in the newsletter Journal Watch in January 2007.

Antidepressants in Pregnancy: The Ongoing Story

The optimal approach for pregnant women with severe or longstanding depression may be to continue antidepressant treatment, but risks to fetuses are emerging.

Although pregnancy was once thought to protect against psychiatric disorders, gravid and nongravid women have similar risks for major depression, at 10% to 15%. Both depression and antidepressant treatment during pregnancy have been associated with risks. This year, several studies have provided new information regarding depression and antidepressant use during pregnancy.

Two studies add to concerns about undertreating depression during pregnancy beyond the risks for preterm birth and intrauterine growth retardation. In one study, researchers naturalistically followed 201 pregnant eurhymic women with histories of major depression; many women had highly recurrent illness. Of those who discontinued antidepressants during pregnancy, 68% relapsed, versus 26% of those remaining on antidepressants; half the relapses occurred during the first trimester. Relapse risk was significantly higher in women whose illness was highly recurrent (>4 episodes) or lengthy (>5 years). In the other study, concerning a smoking cessation program for pregnant smokers, women with dysthymia or minor depression tended to be less likely than nondepressed women to quit smoking. Dysthymic women increased their smoking, a worrisome finding because smoking is associated with preterm birth and Sudden Infant Death Syndrome.

Other studies in 2006 increased the concerns about the effects of antidepressants, especially SSRIs, on the fetus. In one study, amniotic-fluid concentrations of several SRIs, venlafaxine, and their metabolites were highly variable and in some cases vastly elevated above maternal serum levels. In another report, levels of nortiptyline and clomipramine in cord blood at delivery were close to maternal levels.

One year ago, the FDA warned of an increased rate of cardiac defects following in utero exposure to paroxetine and changed paroxetine’s fetal risk classification from Class C to Class D. This warning was based on two large, but unpublished and non-peer reviewed, studies showing a 1.5 to 2 times increased risk of cardiac (primarily ventricular and atrial septal) defects in newborns exposed to paroxetine in the first trimeseter. In December, the American College of Obstetrics and Gynecology advised against using paroxetine during pregnancy (Obstetrics & Gynecology 2006 Dec; 108:1601-3).

Other potential risks were also reported in 2006. A registry study of 119,547 live births showed higher rates of respiratory distress and birth weight below the 10th percentile in SSRI-exposed infants than in nonexposed infants. In another case-control study, SSRI exposure after week 20 was significantly associated with persistent pulmonary hypertension of the newborn (PPHN), a severe respiratory illness that ordinarily occurs in 1 to 2 of 100 births. The risk with SSRI exposure was significantly increased (adjusted odds ration, 6.1) although, given the low base rate, the number of SSRI-exposed babies with PPHN would remain very small (about 6-12 per 1000). Finally, in a study of 120 term infants, 30% of the 60 infants with prolonged in utero exposure to SSRIs, versus 0% of nonexposed infants, developed a neonatal abstinence syndrome, including a high-pitched cry, sleep disturbance, tremor, hypertonicity or myoclonus, tachypnea, and gastrointestinal symptoms. Symptoms peaked within 48 hours after birth and generally resolved within 4 days (Arch. Pediatr. Adolesc. Med. 2006 Feb; 160:173-6).

These findings complicate decisions about prescribing antidepressants in pregnancy. Women with longstanding, severe, or recurrent depression risk relapse during pregnancy with antidepressant discontinuation; the optimal approach may be to continue their antidepressants. However, increasing reports of fetal risks argue for caution in prescribing SSRIs during pregnancy, especially for less severely ill women. Until more data are available, it would be prudent to avoid paroxetine during pregnancy, if possible.

Alternative treatments for depression during pregnancy include psychotherapy (e.g., cognitive-behavioral or interpersonal therapy) and ECT. Therapeutic light and repetitive transcranial magnetic stimulation have occasionally been reported effective for treating depression in some pregnant women. Earlier concerns about risks for cardiac defects with bupropion have not been borne out (Pharmacoepidemiol Drug Saf, in press; AM J Obstet Gynecol 2550 Mar;192:932-6). Mirtazapine and venlafaxine have been examined in only one study each (J Clin Psychiartry 2006 Aug; 67:1280-4 and Am J Psychiatry 2001 Oct; 158:1728-30), but to date have not been associated with major malformations. Data are scant regarding duloxetine. All antidepressants have been associated with higher rates of spontaneous abortion. Overall, it remains crucial to individualize treatment and to discuss risks and benefits of antidepressants in pregnancy with depressed women how are, or may become, pregnant.

Deborah Cowley, MD