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Exposure to Mirtazapine During Pregnancy: A Prospective, Comparative Study of Birth Outcomes

Josephine Djulus, M.D.; Gideon Koren, M.D.; Thomas R. Einarson, Ph.D.; Lynda Wilton, Ph.D.; Saad Shakir, M.D.; Orna Diav-Citrin, M.D.; Deborah Kennedy, M.D.; Sharon Voyer Lavigne, M.Sc.; Marco De Santis, M.D.; and Adrienne Einarson, R.N.

Background: Mirtazapine is a novel piperazinoazepine antidepressant, unrelated to any known class of antidepressants. Currently, apart from a few case reports and case series in the literature, there are no studies evaluating the safety of this drug during pregnancy.

Objective: To determine whether mirtazapine increases the risk for major malformations in newborns when used by pregnant women.

Method: The study design was prospective, with 2 comparison groups: disease-matched pregnant women diagnosed with depression taking other antidepressants and pregnant women exposed to nonteratogens. The primary outcome was major malformations in neonates; secondary endpoints included spontaneous abortions, therapeutic abortions, gestational age at birth, and mean birth weight. Women were recruited from 5 teratogen information services in Toronto, Canada; Farmington, Conn., U.S.A.; Jerusalem, Israel; Rome, Italy; Sydney, Australia; and from the Drug Safety Research Unit in Southampton, United Kingdom. Women were recruited into the study from June 2002 to August 2005.

Results: We were able to follow 104 pregnancy outcomes in each drug group. There were 77 live births, 1 stillbirth, 20 spontaneous abortions, 6 therapeutic abortions, and 2 major malformations in the mirtazapine group. The mean SD birth weight was 3335 654g and the mean SD gestational age at delivery was 38.9 2.5 weeks. Most (95%) of the women took mirtazapine in the first trimester, but only 25% of the women took it throughout pregnancy. The differences among the 3 groups were in the rate of spontaneous abortions, which was higher in both antidepressant groups (19% in the mirtazapine group and 17% in the other antidepressant group) than in the nonteratogen group (11%), but none of the differences were statistically significant. The rate of preterm births (prior to 37 weeks' gestation) was also higher in the mirtazapine group (10%) and in the other antidepressant group (7%) than in the nonteratogen group (2%). The difference was statistically significant between the mirtazapine group and the nonteratogen group (p = .04).

Conclusion: Mirtazapine does not appear to increase the baseline rate of major malformations of 1% to 3%. However, the higher number of spontaneous abortions in the antidepressant groups confirms the higher rates of spontaneous abortions in pregnant women taking antidepressant medications found in previous studies.

(J Clin Psychiatry 2006;67:1280-1284)

Received Jan. 30, 2006; accepted March 22, 2006. From the Motherisk Program, Division of Clinical Pharmacology, the Hospital for Sick Children, Toronto, Ontario, Canada (Drs. Djulus, Koren, and Einarson and Ms. Einarson); the Drug Safety Research Unit, Southampton, United Kingdom (Drs. Wilton and Shakir); the Israel Teratogen Information Service, Israel Ministry of Health, Jerusalem, Israel (Dr. Diav-Citrin); the Mothersafe Program, Sydney, Australia (Dr. Kennedy); the Pregnancy Riskline, Farmington, Conn. (Ms. Voyer Lavigne); and the Telefono Rosso, Rome, Italy (Dr. De Santis). Dr. Koren is a Senior Scientist at the Canadian Institutes for Health Research.

This study was supported by an unrestricted educational grant from Organon International, Inc., Roseland, N.J., U.S.A.

The authors report no other significant commercial relationships relevant to the study.

This study is Fetox International Protocol No. 4.

Corresponding author and reprints: Adrienne Einarson, R.N., Motherisk Program, Division of Clinical Pharmacology, Hospital for Sick Children, 555 University Ave., Toronto, Ontario, Canada M5G 1X8 (e-mail: