Risk of Vaginal Bleeding and Postpartum Hemorrhage After Use of Antidepressants in Pregnancy A Study From the Norwegian Mother and Child Cohort Study Angela Lupattelli, MscPharm,* Olav Spigset, MD, PhD,Þþ Gideon Koren, MD,§ and Hedvig Nordeng, PhD*|| Abstract: This study aimed to examine obstetric bleeding outcomes after exposure during pregnancy to selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic (TCAs), and other antidepressants (OADs). The Norwegian Mother and Child Cohort Study and the Medical Birth Registry of Norway constituted the data source for the present study. We included 57,279 pregnant women, of which 1.02% reported use of anti- depressants during pregnancy, mostly SSRIs/SNRIs (0.92%). We catego- rized exposure according to antidepressant use in pregnancy (SSRIs/SNRIs, n = 527; TCAs/OADs, n = 59; nonexposed, nondepressed, n = 55,411) with inclusion of a disease comparison group (nonexposed, depressed, n = 1282). We used logistic regression to estimate adjusted odds ratio (aOR) and 95% confidence interval (CI) for vaginal bleeding outcomes in pregnancy and postpartum hemorrhage. Compared with nonexposed subjects, first trimester exposure to SSRIs/ SNRIs or TCAs/OADs did not confer any increased risk of vaginal bleed- ing in early pregnancy (aOR, 0.91; 95% CI, 0.72Y1.16 and aOR, 0.83; 95% CI, 0.36Y1.92, respectively). No increased risk for vaginal bleeding in midpregnancy was observed among users of SSRIs/SNRIs (aOR, 0.81; 95% CI, 0.50Y1.31) or TCAs/OADs (aOR, 0.96; 95% CI, 0.26Y3.53) in second trimester. Exposure to SSRIs/SNRIs during gestational week 30 to childbirth did not confer any increased risk of postpartum hemorrhage after vaginal (aOR, 0.90; 95% CI, 0.47Y1.74) or cesarean (aOR, 1.47; 95% CI, 0.51Y4.22) delivery. Women in the disease compar- ison group presented a significant moderate increased risk of vaginal bleeding in early pregnancy (aOR, 1.22; 95% CI, 1.06Y1.39) and mid- pregnancy (aOR, 1.28; 95% CI, 1.07Y1.55) but not postpartum. Among this Norwegian cohort of pregnant women, use of antide- pressants in pregnancy was not associated with any obstetrical bleeding outcome. Key Words: pregnancy, antidepressants, vaginal bleeding, postpartum hemorrhage, the Norwegian Mother and Child Cohort Study (J Clin Psychopharmacol 2013;00: 00Y00) S ymptoms of depression are common in pregnancy 1 and up to 8% of women use antidepressants during this phase of life. 2,3 Although untreated depression may pose harm to both mother and fetus, 4 there have been concerns about the safety of antidepressant use during pregnancy, not least for the selective serotonin reuptake inhibitors (SSRIs). Recent research findings suggest SSRIs or antidepressants with high affinity to the sero- tonin transporter to be implicated in bleeding-related outcomes from the gastrointestinal tract among nonpregnant subjects. 5 The pharmacological plausibility behind the association SSRI- bleeding resides within the critical role played by serotonin in hemostasis. 6 However, little is known about bleeding outcomes from other sites than the gastrointestinal tract, such as the female genital tract. 7 Vaginal bleeding is common in pregnancy and its clinical significance depends on the gestational week and the bleeding characteristic. 8 Nonetheless, postpartum hemorrhage (PPH) is a leading cause of maternal morbidity and mortality. 9 To the best of our knowledge, no previous studies have investigated the relationship between use of SSRIs and other antidepressants, and vaginal bleeding throughout pregnancy. On the other hand, a single nested case-control study 10 examined the association SSRIs-PPH and detected no increased risk among women ex- posed to SSRIs (odds ratio [OR], 1.30; 95% confidence interval [CI], 0.98Y1.72) when compared with non-SSRIs. Because of the severity of PPH and because vaginal bleeding is a marker of an at-risk pregnancy, we aimed to investigate the putative as- sociation between obstetric bleeding outcomes and exposure to SSRIs and other antidepressants during pregnancy. MATERIALS AND METHODS Study Population and Data Collection Data from the Norwegian Mother and Child Cohort Study (MoBa) and records in the Medical Birth Registry of Norway (MBRN) provided the data used in this study. MoBa is a population-based prospective cohort study described in details elsewhere. 11 Pregnant women from Norway were recruited to the study through a postal invitation in connection with the routine ultrasound examination offered to all pregnant women at 17 to 18 weeks of gestation. At an assessment of the MoBa study in 2009, the participation rate was 43.5% of all women invited. 12 In the present study, information from MoBa was retrieved from 3 self-administered questionnaires. 13 The first (Q1) and third (Q3) questionnaires were completed in preg- nancy weeks 13 to 17 and 30, respectively, whereas the fourth BRIEF REPORT Journal of Clinical Psychopharmacology & Volume 00, Number 00, Month 2013 www.psychopharmacology.com 1 From the *Department of Pharmacy, School of Pharmacy, University of Oslo, Oslo; †Department of Clinical Pharmacology, St Olav’s University Hospital; ‡Department of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology, Trondheim, Norway; §The Motherisk Program, The Hospital for Sick Children, Toronto, Ontario, Canada; and ||Division of Mental Health, Norwegian Institute of Public Health, Oslo, Norway. Received October 22, 2012; accepted after revision May 13, 2013. Reprints: Angela Lupattelli, MscPharm, Department of Pharmacy, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, 0316 Oslo, Norway (e<mail: angela.lupattelli@farmasi.uio.no). The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/NIEHS (contract no. N01-ES-75558), NIH/NINDS (Grant 1 UO1 NS 047537-01 and Grant 2 UO1 NS 047537-06A1), and the Norwegian Research Council/FUGE (Grant 151918/S10). Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.psychopharmacology.com). Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 0271-0749 DOI: 10.1097/JCP.0000000000000036 Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.