title: EUROmediCAT signal detection: an evaluation of selected congenital anomaly-medication associations.
abstract: To evaluate congenital anomaly (CA)-medication exposure associations produced by the new EUROmediCAT signal detection system and determine which require further investigation.
  
  
  
  Data from 15 EUROCAT registries (1995-2011) with medication exposures at the chemical substance (5th level of Anatomic Therapeutic Chemical classification) and chemical subgroup (4th level) were analysed using a 50% false detection rate. After excluding antiepileptics, antidiabetics, antiasthmatics and SSRIs/psycholeptics already under investigation, 27 associations were evaluated. If evidence for a signal persisted after data validation, a literature review was conducted for prior evidence of human teratogenicity.
  
  
  
  Thirteen out of 27 CA-medication exposure signals, based on 389 exposed cases, passed data validation. There was some prior evidence in the literature to support six signals (gastroschisis and levonorgestrel/ethinylestradiol (OR 4.10, 95% CI 1.70-8.53; congenital heart disease/pulmonary valve stenosis and nucleoside/tide reverse transcriptase inhibitors (OR 5.01, 95% CI 1.99-14.20/OR 28.20, 95% CI 4.63-122.24); complete absence of a limb and pregnen (4) derivatives (OR 6.60, 95% CI 1.70-22.93); hypospadias and pregnadien derivatives (OR 1.40, 95% CI 1.10-1.76); hypospadias and synthetic ovulation stimulants (OR 1.89, 95% CI 1.28-2.70). Antipropulsives produced a signal for syndactyly while the literature revealed a signal for hypospadias. There was no prior evidence to support the remaining six signals involving the ordinary salt combinations, propulsives, bulk-forming laxatives, hydrazinophthalazine derivatives, gonadotropin releasing hormone analogues and selective serotonin agonists.
  
  
  
  Signals which strengthened prior evidence should be prioritized for further investigation, and independent evidence sought to confirm the remaining signals. Some chance associations are expected and confounding by indication is possible.
authors.affiliation: Centre for Maternal, Fetal and Infant Research, Institute of Nursing and Health Research, Ulster University, United Kingdom.
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Given
authors.affiliation: Centre for Maternal, Fetal and Infant Research, Institute of Nursing and Health Research, Ulster University, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Loane
authors.affiliation: Wolfson Institute of Preventive Medicine, Queen Mary University of London, United Kingdom.
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Luteijn
authors.affiliation: Wolfson Institute of Preventive Medicine, Queen Mary University of London, United Kingdom.
authors.forename: Joan K
authors.initials: JK
authors.lastname: Morris
authors.affiliation: Department of Pharmacy, University of Groningen, the Netherlands.
authors.forename: Lolkje T W
authors.initials: LT
authors.lastname: de Jong van den Berg
authors.affiliation: Paediatric Department, Hospital Lillebaelt, Kolding, Denmark.
authors.forename: Ester
authors.initials: E
authors.lastname: Garne
authors.affiliation: Division of Medical Genetics, CHUV, Lausanne, Switzerland.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Addor
authors.affiliation: Department of Medical Genetics and Reproductive Health, Children's University Hospital Zagreb, Croatia.
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Barisic
authors.affiliation: Eurocat Northern Netherlands, University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors.forename: Hermien
authors.initials: H
authors.lastname: de Walle
authors.affiliation: Department of Health Information and Research, Guardamangia, Malta.
authors.forename: Miriam
authors.initials: M
authors.lastname: Gatt
authors.affiliation: Medical Birth Registry of Norway, the Norwegian Institute of Public Health and Department of Global Public Health and Primary Care, University of Bergen, Norway.
authors.forename: Kari
authors.initials: K
authors.lastname: Klungsoyr
authors.affiliation: Paris Registry of Congenital Anomalies, Obstetrical, Perinatal and Pediatric Epidemiology Research Team, Center for Biostatistics and Epidemiology, INSERM U1153, Maternité de Port-Royal, PARIS, France.
authors.forename: Babak
authors.initials: B
authors.lastname: Khoshnood
authors.affiliation: Polish Registry of Congenital Malformations, Department of Medical Genetics, Poznan, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Latos-Bielenska
authors.affiliation: Provinciaal Instituut voor Hygiene (PIH), Antwerp, Belgium.
authors.forename: Vera
authors.initials: V
authors.lastname: Nelen
authors.affiliation: IMER Registry (Emilia Romagna Registry of Birth Defects), Centre for Clinical and Epidemiological Research, University of Ferrara and Azienda Ospedaliero Univerisitarion di Ferrara, Italy.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Neville
authors.affiliation: Health Service Executive, Cork, Ireland.
authors.forename: Mary
authors.initials: M
authors.lastname: O'Mahony
authors.affiliation: Epidemiology and Health Promotion Macro-Area Working Group, Unit of Environmental Epidemiology and Disease Registries, CNR Institute of Clinical Physiology, Pisa, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Pierini
authors.affiliation: CARIS - Congenital Anomaly Register and Information Service for Wales, Public Health Wales, Swansea, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Tucker
authors.affiliation: Mainz Model Birth Registry, University Children's Hospital Mainz, Germany.
authors.forename: Awi
authors.initials: A
authors.lastname: Wiesel
authors.affiliation: Centre for Maternal, Fetal and Infant Research, Institute of Nursing and Health Research, Ulster University, United Kingdom. h.dolk@ulster.ac.uk.
authors.forename: Helen
authors.initials: H
authors.lastname: Dolk
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000453:epidemiology*; D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data*; D000013:Congenital Abnormalities / Q000453:epidemiology*; D005060:Europe / Q000453:epidemiology; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D011247:Pregnancy; D012042:Registries
keywords: congenital anomalies; drug-induced anomalies; pharmacoepidemiology; pharmacovigilance; pregnancy; signal evaluation