title: EUROmediCAT signal detection: a systematic method for identifying potential teratogenic medication.
abstract: Information about medication safety in pregnancy is inadequate. We aimed to develop a signal detection methodology to routinely identify unusual associations between medications and congenital anomalies using data collected by 15 European congenital anomaly registries.
  
  
  
  EUROmediCAT database data for 14 950 malformed foetuses/babies with first trimester medication exposures in 1995-2011 were analyzed. The odds of a specific medication exposure (coded according to chemical substance or subgroup) for a specific anomaly were compared with the odds of that exposure for all other anomalies for 40 385 medication anomaly combinations in the data. Simes multiple testing procedure with a 50% false discovery rate (FDR) identified associations least likely to be due to chance and those associations with more than two cases with the exposure and the anomaly were selected for further investigation. The methodology was evaluated by considering the detection of well-known teratogens.
  
  
  
  The most common exposures were genitourinary system medications and sex hormones (35.2%), nervous system medications (28.0%) and anti-infectives for systemic use (25.7%). Fifty-two specific medication anomaly associations were identified. After discarding 10 overlapping and three protective associations, 39 associations were selected for further investigation. These associations included 16 which concerned well established teratogens, valproic acid (2) and maternal diabetes represented by use of insulin (14).
  
  
  
  Medication exposure data in the EUROmediCAT central database can be analyzed systematically to determine a manageable set of associations for validation and then testing in independent datasets. Detection of teratogens depends on frequency of exposure, level of risk and teratogenic specificity.
authors.affiliation: Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Luteijn
authors.affiliation: Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. j.k.morris@qmul.ac.uk.
authors.forename: Joan K
authors.initials: JK
authors.lastname: Morris
authors.affiliation: Paediatric Department, Hospital Lillebaelt, Kolding, Denmark.
authors.forename: Ester
authors.initials: E
authors.lastname: Garne
authors.affiliation: Centre for Maternal, Fetal and Infant Research, Institute of Nursing and Health Research, Ulster University, Newtownabbey, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Given
authors.affiliation: Department of Pharmacy, Unit of PharmacoEpidemiology and PharmacoEconomics, Groningen, The Netherlands.
authors.forename: Lolkje
authors.initials: L
authors.lastname: de Jong-van den Berg
authors.affiliation: Division of Medical Genetics, CHUV, Lausanne, Switzerland.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Addor
authors.affiliation: University Medical Centre of Groningen, Groningen, The Netherlands.
authors.forename: Marian
authors.initials: M
authors.lastname: Bakker
authors.affiliation: Department of Medical Genetics and Reproductive Health, Children's Hospital Zagreb, Medical School University of Zagreb, Zagreb, Croatia.
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Barisic
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, Bergen, Norway.
authors.forename: Kari
authors.initials: K
authors.lastname: Klungsoyr
authors.affiliation: Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Latos-Bielenska
authors.affiliation: Center for biostatistics and epidemiology, INSERM U1153, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lelong
authors.affiliation: Provinciaal Instituut voor Hygiene (PIH), Antwerp, Belgium.
authors.forename: Vera
authors.initials: V
authors.lastname: Nelen
authors.affiliation: IMER Registry (Emila Romagna Registry of Birth Defects), Center for Clinical and Epidemiological Research University of Ferrara and Azienda Ospedaliero- Universitaria di Ferrara, Ferrara, Italy.
authors.forename: Amanda
authors.initials: A
authors.lastname: Neville
authors.affiliation: Public Health Medicine, Health Service Executive, Cork, Ireland.
authors.forename: Mary
authors.initials: M
authors.lastname: O'Mahony
authors.affiliation: National Research Council (IFC-CNR), Institute of Clinical Pharmacology, Pisa, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Pierini
authors.affiliation: Congenital Anomaly Register and Information Service for Wales, Public Health Wales, Swansea, UK.
authors.forename: David
authors.initials: D
authors.lastname: Tucker
authors.affiliation: Department of Genetics, EUROCAT Northern Netherlands, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Hermien
authors.initials: H
authors.lastname: de Walle
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, Newtownabbey.
authors.forename: Maria
authors.initials: M
authors.lastname: Loane
authors.affiliation: Centre for Maternal, Fetal and Infant Research, Institute of Nursing and Health Research, Ulster University, Newtownabbey, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Dolk
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000453:epidemiology*; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data*; D016022:Case-Control Studies; D000013:Congenital Abnormalities / Q000453:epidemiology*; D016208:Databases, Factual / Q000706:statistics & numerical data*; D005060:Europe / Q000453:epidemiology; D005260:Female; D006801:Humans; D011247:Pregnancy; D012042:Registries; D013723:Teratogens; D055815:Young Adult
chemical_list: D013723:Teratogens
keywords: adverse drug reactions; congenital anomalies; drug safety; pharmacoepidemiology; pharmacovigilance; pregnancy