Johannes M Luteijn1, Joan K Morris2, Ester Garne3, Joanne Given4, Lolkje de Jong-van den Berg5, Marie-Claude Addor6, Marian Bakker7, Ingeborg Barisic8, Miriam Gatt9, Kari Klungsoyr10, Anna Latos-Bielenska11, Nathalie Lelong12, Vera Nelen13, Amanda Neville14, Mary O'Mahony15, Anna Pierini16, David Tucker17, Hermien de Walle18, Awi Wiesel19, Maria Loane20, Helen Dolk4. 1. Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. 2. 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. 3. Paediatric Department, Hospital Lillebaelt, Kolding, Denmark. 4. Centre for Maternal, Fetal and Infant Research, Institute of Nursing and Health Research, Ulster University, Newtownabbey, UK. 5. Department of Pharmacy, Unit of PharmacoEpidemiology and PharmacoEconomics, Groningen, The Netherlands. 6. Division of Medical Genetics, CHUV, Lausanne, Switzerland. 7. University Medical Centre of Groningen, Groningen, The Netherlands. 8. Department of Medical Genetics and Reproductive Health, Children's Hospital Zagreb, Medical School University of Zagreb, Zagreb, Croatia. 9. Department of Health Information and Research, Guardamangia, Malta. 10. 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. 11. Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland. 12. Center for biostatistics and epidemiology, INSERM U1153, Paris, France. 13. Provinciaal Instituut voor Hygiene (PIH), Antwerp, Belgium. 14. 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. 15. Public Health Medicine, Health Service Executive, Cork, Ireland. 16. National Research Council (IFC-CNR), Institute of Clinical Pharmacology, Pisa, Italy. 17. Congenital Anomaly Register and Information Service for Wales, Public Health Wales, Swansea, UK. 18. Department of Genetics, EUROCAT Northern Netherlands, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 19. Mainz Model Birth Registry, University Children's Hospital Mainz, Germany. 20. Centre for Maternal, Fetal and Infant Research, Institute of Nursing and Health Research, Ulster University, Newtownabbey.
Abstract
AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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: Johannes M Luteijn; Joan K Morris; Ester Garne; Joanne Given; Lolkje de Jong-van den Berg; Marie-Claude Addor; Marian Bakker; Ingeborg Barisic; Miriam Gatt; Kari Klungsoyr; Anna Latos-Bielenska; Nathalie Lelong; Vera Nelen; Amanda Neville; Mary O'Mahony; Anna Pierini; David Tucker; Hermien de Walle; Awi Wiesel; Maria Loane; Helen Dolk Journal: Br J Clin Pharmacol Date: 2016-08-04 Impact factor: 4.335
Authors: Patricia A Boyd; Martin Haeusler; Ingeborg Barisic; Maria Loane; Ester Garne; Helen Dolk Journal: Birth Defects Res A Clin Mol Teratol Date: 2011-03-07
Authors: Johannes M Luteijn; Joan K Morris; Ester Garne; Joanne Given; Lolkje de Jong-van den Berg; Marie-Claude Addor; Marian Bakker; Ingeborg Barisic; Miriam Gatt; Kari Klungsoyr; Anna Latos-Bielenska; Nathalie Lelong; Vera Nelen; Amanda Neville; Mary O'Mahony; Anna Pierini; David Tucker; Hermien de Walle; Awi Wiesel; Maria Loane; Helen Dolk Journal: Br J Clin Pharmacol Date: 2016-08-04 Impact factor: 4.335
Authors: Vinoj H Sewberath Misser; Arti Shankar; Ashna Hindori-Mohangoo; Jeffrey Wickliffe; Maureen Lichtveld; Dennis R A Mans Journal: Adv Pharmacoepidemiol Drug Saf Date: 2021-09-20
Authors: Joanne E Given; Maria Loane; Johannes M Luteijn; Joan K Morris; Lolkje T W de Jong van den Berg; Ester Garne; Marie-Claude Addor; Ingeborg Barisic; Hermien de Walle; Miriam Gatt; Kari Klungsoyr; Babak Khoshnood; Anna Latos-Bielenska; Vera Nelen; Amanda J Neville; Mary O'Mahony; Anna Pierini; David Tucker; Awi Wiesel; Helen Dolk Journal: Br J Clin Pharmacol Date: 2016-07-07 Impact factor: 4.335