title: Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants in Pregnancy and Congenital Anomalies: Analysis of Linked Databases in Wales, Norway and Funen, Denmark.
abstract: BACKGROUND
  Hypothesised associations between in utero exposure to selective serotonin reuptake inhibitors (SSRIs) and congenital anomalies, particularly congenital heart defects (CHD), remain controversial. We investigated the putative teratogenicity of SSRI prescription in the 91 days either side of first day of last menstrual period (LMP).
  
  
  RESULTS
  Three population-based EUROCAT congenital anomaly registries- Norway (2004-2010), Wales (2000-2010) and Funen, Denmark (2000-2010)-were linked to the electronic healthcare databases holding prospectively collected prescription information for all pregnancies in the timeframes available. We included 519,117 deliveries, including foetuses terminated for congenital anomalies, with data covering pregnancy and the preceding quarter, including 462,641 with data covering pregnancy and one year either side. For SSRI exposures 91 days either side of LMP, separately and together, odds ratios with 95% confidence intervals (ORs, 95%CI) for all major anomalies were estimated. We also explored: pausing or discontinuing SSRIs preconception, confounding, high dose regimens, and, in Wales, diagnosis of depression. Results were combined in meta-analyses. SSRI prescription 91 days either side of LMP was associated with increased prevalence of severe congenital heart defects (CHD) (as defined by EUROCAT guide 1.3, 2005) (34/12,962 [0.26%] vs. 865/506,155 [0.17%] OR 1.50, 1.06-2.11), and the composite adverse outcome of 'anomaly or stillbirth' (473/12962, 3.65% vs. 15829/506,155, 3.13%, OR 1.13, 1.03-1.24). The increased prevalence of all major anomalies combined did not reach statistical significance (3.09% [400/12,962] vs. 2.67% [13,536/506,155] OR 1.09, 0.99-1.21). Adjusting for socio-economic status left ORs largely unchanged. The prevalence of anomalies and severe CHD was reduced when SSRI prescriptions were stopped or paused preconception, and increased when >1 prescription was recorded, but differences were not statistically significant. The dose-response relationship between severe CHD and SSRI dose (meta-regression OR 1.49, 1.12-1.97) was consistent with SSRI-exposure related risk. Analyses in Wales suggested no associations between anomalies and diagnosed depression.
  
  
  CONCLUSIONS
  The additional absolute risk of teratogenesis associated with SSRIs, if causal, is small. However, the high prevalence of SSRI use augments its public health importance, justifying modifications to preconception care.
authors.affiliation: Department of Nursing, College of Human and Health Sciences, Swansea University, Swansea, United Kingdom.
authors.forename: Sue
authors.identifier: http://orcid.org/0000-0002-5691-2987
authors.initials: S
authors.lastname: Jordan
authors.affiliation: Queen Mary University of London, London, United Kingdom.
authors.forename: Joan K
authors.initials: JK
authors.lastname: Morris
authors.affiliation: Department of Nursing, College of Human and Health Sciences, Swansea University, Swansea, United Kingdom.
authors.forename: Gareth I
authors.initials: GI
authors.lastname: Davies
authors.affiliation: Public Health Wales, Swansea, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Tucker
authors.affiliation: Department of Nursing, College of Human and Health Sciences, Swansea University, Swansea, United Kingdom.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Thayer
authors.affiliation: Queen Mary University of London, London, United Kingdom.
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Luteijn
authors.affiliation: Public Health Wales, Swansea, United Kingdom.
authors.forename: Margery
authors.initials: M
authors.lastname: Morgan
authors.affiliation: Paediatric Department, Hospital Lillebaelt, Kolding, Denmark.
authors.forename: Ester
authors.initials: E
authors.lastname: Garne
authors.affiliation: Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anne V
authors.initials: AV
authors.lastname: Hansen
authors.affiliation: Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.|Department of Health Registries, Norwegian Institute of Public Health, Bergen, Norway.
authors.forename: Kari
authors.initials: K
authors.lastname: Klungsøyr
authors.affiliation: Department of Pharmacoepidemiology, Norwegian Institute of Public Health Bergen, Bergen, Norway.|Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
authors.forename: Anders
authors.initials: A
authors.lastname: Engeland
authors.affiliation: Centre for Maternal, Fetal and Infant Research, Ulster University, Newtownabbey, Co Antrim, Northern Ireland, United Kingdom.
authors.forename: Breidge
authors.initials: B
authors.lastname: Boyle
authors.affiliation: Centre for Maternal, Fetal and Infant Research, Ulster University, Newtownabbey, Co Antrim, Northern Ireland, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Dolk
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000453:epidemiology / Q000503:physiopathology*; D000328:Adult; D000928:Antidepressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D016208:Databases, Factual; D003718:Denmark; D003866:Depressive Disorder / Q000150:complications / Q000188:drug therapy / Q000453:epidemiology; D005260:Female; D006330:Heart Defects, Congenital / Q000139:chemically induced / Q000453:epidemiology / Q000503:physiopathology*; D006801:Humans; D009664:Norway; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy / Q000453:epidemiology* / Q000503:physiopathology; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D014852:Wales
chemical_list: D000928:Antidepressive Agents; D017367:Selective Serotonin Reuptake Inhibitors