ORIGINAL CONTRIBUTION

Pregnancy Outcome Following Maternal Exposure to Mirtazapine A Multicenter, Prospective Study Ursula Winterfeld, PhD,* Gil Klinger, MD,† Alice Panchaud, PhD,*‡ Sally Stephens, MD,§ Judy Arnon, PhD,‖ Heli Malm, MD, PhD,¶ Bernke te Winkel, PhD,# Maurizio Clementi, MD,** Alessandra Pistelli, MD,†† Eva Maňáková, MD,‡‡ Georgios Eleftheriou, MD,§§ Paul Merlob, MD,† Yusuf C. Kaplan, MD,‖‖ Thierry Buclin, MD,* and Laura E. Rothuizen, MD*

Abstract: This multicenter, observational prospective cohort study addresses the risk associated with exposure to mirtazapine during pregnancy. Pregnancy outcomes after exposure to mirtazapine were compared with 2 matched control groups: (1) exposure to any selective serotonin reuptake inhibitor (SSRI, control subjects with a psychiatric condition) and (2) no exposure to medication known to be teratogenic or any antidepressant (general control subjects). Data were collected by members of the European Network of Teratology Information Services between 1995 and 2011. Observations from 357 exposed pregnancies were compared with 357 pregnancies from each control group. The rate of major birth defects between the mirtazapine and the SSRI group did not differ significantly (4.5% vs 4.2%; odds ratio [OR], 1.1; 95% confidence interval [95% CI], 0.5–2.3; P = 0.9). A trend toward a higher rate of birth defects in the mirtazapine group compared with general control subjects (4.5% vs 1.9%; OR, 2.4; 95% CI, 0.9–6.3; P = 0.08) reached statistical significance after exclusion of chromosomal or genetic anomalies (4.1% vs 1.3%; OR, 3.3; 95% CI, 1.04–10.3; P = 0.03), but this difference became again nonsignificant if cases of exposure not comprising the first trimester were excluded from the analysis (3.4% vs 1.9%; OR, 1.8; 95% CI, 0.6–5.0; P = 0.26). The crude miscarriage rate did not differ significantly between the mirtazapine, the SSRI, and the general control groups (12.1% vs 12.0% vs 9.3%; P = 0.44). However, a higher rate of elective pregnancy termination was observed in the mirtazapine group compared with SSRI and general control subjects (7.8% vs 3.4% vs 5.6%; P = 0.03). This study did not observe a statistically significant difference in the rate of major birth defects after first-trimester exposure between mirtazapine, SSRI-exposed, and nonexposed pregnancies. A marginally higher rate of birth defects was, however, observed in the mirtazapine and SSRI groups compared

From the *STIS and Division of Clinical Pharmacology, University Hospital, Lausanne, Switzerland; †BELTIS Rabin Medical Center and Sackler School of Medicine, University of Tel-Aviv, Tel-Aviv, Israel; ‡School of Pharmaceutical Sciences, University of Geneva and Lausanne, Geneva, Switzerland; §UKTIS, Regional Drug and Therapeutics Centre, Newcastle-Upon-Tyne, United Kingdom; ‖The Israeli Teratology Information Service, Israel Ministry of Health, Jerusalem, Israel; ¶Teratology Information Service, Helsinki University Central Hospital and HUSLAB, Helsinki, Finland; #TIS, Netherlands Pharmacovigilance Centre Lareb, Den Bosch, The Netherlands; **Servizio di Informazione Teratologica, Padova; ††Centro di Riferimento Regionale di Tossicologia Perinatale, Azienda Ospedaliero Universitaria Careggi, Florence, Italy; ‡‡CZTIS, 3rd Faculty of Medicine, Charles University, Prague, Czech Republic; §§Poison Control, Bergamo, Italy; and ‖‖Terafar–Izmir Katip Celebi University Teratology Information, Training and Research Center, Izmir, Turkey. Received September 16, 2014; accepted after revision February 13, 2015. Reprints: Ursula Winterfeld, PhD, Division de Pharmacologie Clinique, Centre Hospitalier Universitaire Vaudois, Swiss Teratogen Information Service, Rue du Bugnon 17/01/104, 1011 Lausanne, Switzerland (e‐mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0271-0749 DOI: 10.1097/JCP.0000000000000309

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with the low rate of birth defects in our general control subjects. Overall pregnancy outcome after mirtazapine exposure was similar to that of the SSRI-exposed control group. Key Words: antidepressant, birth defect, mirtazapine, pregnancy (J Clin Psychopharmacol 2015;35: 250–259)

M

ajor depressive disorder is common in pregnant women with a prevalence rate ranging from 5% to 12%.1 The consequences of a major depressive episode during pregnancy include effects on the mother, child, and family. Despite limitations of many studies linked to maternal depression, this disorder has been consistently associated with a variety of negative neonatal (eg, increased preterm birth, low birth weight, decreased Apgar score, decreased breast-feeding initiation) and maternal outcomes (eg, suicide attempts, poor health behaviors, postpartum depression, bonding difficulties).2–5 Treatment of depression includes psychotherapy (cognitivebehavioral, interpersonal psychotherapy), antidepressant drugs,6 or a combination of both, with pharmacotherapy being the most effective in major depression.7 Maternal depression during pregnancy has been underrecognized because of a historic belief that pregnancy was “protective” against depression. Furthermore, severe depression often remains undertreated during pregnancy because of safety concerns regarding antidepressant use during pregnancy.8 On the other hand, antidepressant prescription is not uncommon in minor depression affecting women in childbearing age, resulting in unwanted exposures in unplanned pregnancies. Selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed antidepressants, and the incidence and prevalence of their use have consistently increased since their market release during the 1990s.9 Therefore, data on safety of antidepressants during pregnancy cover mainly SSRIs. Mirtazapine is a piperazinoazepine antidepressant chemically unrelated to SSRIs, tricyclic antidepressants, or monoamine oxidase inhibitors. It is presented as having a unique pharmacological profile and thus is supposed to differ in its efficacy and adverse effects profile in comparison with other antidepressants. A recent review, including findings from 29 randomized control trials, suggests that mirtazapine is likely to be more effective than either SSRIs or serotonin and noradrenaline reuptake inhibitors at 2 weeks of treatment, yet with no difference between groups at the end of the acute phase of treatment of approximately 6 weeks’ duration.10 The approved indication for mirtazapine is a major depressive episode, but several off-label uses have been explored, including posttraumatic stress disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, insomnia, undifferentiated somatoform disorder, and (as add-on therapy) in schizophrenia.11

Journal of Clinical Psychopharmacology • Volume 35, Number 3, June 2015

Journal of Clinical Psychopharmacology • Volume 35, Number 3, June 2015

There is a paucity of data on human exposure to mirtazapine in pregnancy. In animal reproduction studies, no evidence of teratogenicity occurred at doses up to 20 times the maximum recommended human dose. There are several case series12–18 and retrospective studies19–21 describing use of mirtazapine reported in the literature, none of them suggesting an embryo-fetal risk. Three small prospective cohort studies14,22,23 did not identify a significantly increased risk for major birth defects overall. Djulus et al22 observed a significantly higher rate of miscarriages and preterm births in the mirtazapine and the antidepressant control group, as compared with the control group exposed to no known teratogen. Despite reassuring data, additional prospective cohort studies are warranted to allow a better assessment of the overall safety of the use of this antidepressant in pregnancy. This study aimed at assessing the risk of mirtazapine exposure during pregnancy. The primary objective was the rate of major birth defects after first-trimester exposure to mirtazapine compared with an SSRI-exposed group and a general control group. Secondary objectives included determining effects on pregnancy outcome, birth weight, gestational age at delivery, and neonatal outcome of prospectively collected exposures to mirtazapine at any time during pregnancy.

MATERIALS AND METHODS This was a prospective, multicenter, controlled, observational study. Eligible subjects were pregnant women who themselves or whose physician contacted 1 of the 11 participating Teratology Information Services (TIS) during the period ranging from January 1995 to December 2011 seeking counsel about safety of exposure to therapeutic agents during pregnancy. Only prospectively gathered cases were considered (ie, pregnancy outcome or prenatal diagnostics were unknown at time of first TIS contact). All participating centers were members of the European Network of Teratology Information Services (ENTIS), an organization of services that

Mirtazapine Exposure During Pregnancy

offer expertise on possible teratogenic or fetotoxic risks related to exposure to medications and other agents during pregnancy and breast-feeding at an individual level. Standardized procedures for data collection were used by each center.24 The methodology of collaborative ENTIS study data collection has been detailed in previous studies.25 Maternal characteristics (age, tobacco use, alcohol consumption, and medical and obstetric history) as well as details of medication exposure (indication, timing in pregnancy, duration, dose, and concomitant medication) were also collected at initial TIS contact. After the expected date of delivery, follow-up was achieved through a structured telephone interview and/or mailed questionnaire to the patient and/or her health care professional. Answers to the following questions were requested: pregnancy outcome, gestational age at delivery, birth weight, birth defects, and neonatal complications. In most cases, follow-up data were recorded during the neonatal period. Pregnant women considered lost to follow-up were not included in the analysis. The rate of loss to follow-up differed between centers and ranged from 0% to 76% (median, 35%) in the mirtazapine and 5% to 77% (median, 37.5%) in the control groups. Pregnancy outcomes of patients from the mirtazapineexposed group were compared with the outcomes of 2 control groups. The first comparison group was defined as pregnant women who were exposed to any SSRI (control subjects with a psychiatric condition). The second comparison group consisted of pregnant women who were at no time during pregnancy exposed to any known major teratogens or fetotoxicants or to any antidepressant (general control subjects). Control subjects were selected randomly, and cases and control subjects were matched by TIS center, year of TIS contact (±2 years), maternal age (±2 years), and gestational age at time of call (±4 weeks). Data collections at first contact and follow-up were performed in the same way for the 3 groups. The primary outcome of interest was the rate of major birth defects after first-trimester exposure. Major birth defects were

TABLE 1. Maternal Characteristics and Obstetric History Characteristics Maternal age (y), median (IQR) (n = 336, 355, 357) Tobacco use, n (%) (n = 309, 309, 304) Alcohol consumption, n (%) (n = 256, 279, 309) GA at initial contact (wk), median (IQR) (n = 351, 357, 356) Previous pregnancies, n (%) (n = 327, 339, 332) 0 1 ≥2 Previous deliveries, n (%) (n = 327, 335, 332) 0 1 ≥2 Previous miscarriages, n (%) (n = 320, 326, 328) 0 1 ≥2 Previous ETOP, n (%) (n = 315, 320, 324) 0 ≥1

Mirtazapine (n = 357)

SSRI (n = 357)

Control Subjects (n = 357)

P

32 (28–35) 70 (22.7) 14 (5.5) 8 (6–12)

31 (27–35) 50 (16.2) 30 (10.8) 8 (6–11)

32 (28–36) 25 (8.2) 15 (4.9) 8 (6–12)

0.54

Pregnancy outcome following maternal exposure to mirtazapine: a multicenter, prospective study.

This multicenter, observational prospective cohort study addresses the risk associated with exposure to mirtazapine during pregnancy. Pregnancy outcom...
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