Signal Detection in EUROmediCAT: Identification and Evaluation of Medication–Congenital Anomaly Associations and Use of VigiBase as a Complementary Source of Reference

Alana Cavadino, Lovisa Sandberg, Inger Öhman, Tomas Bergvall, Kristina Star, Helen Dolk, Maria Loane, Marie-Claude Addor, Ingeborg Barisic, Clara Cavero-Carbonell, Ester Garne, Miriam Gatt, Babak Khoshnood, Kari Klungsøyr, Anna Latos-Bielenska, Nathalie Lelong, Reneé Lutke, Anna Materna-Kiryluk, Vera Nelen, Amanda Nevill, Mary O’Mahony, Olatz Mokoroa, Anna Pierini, Hanitra Randrianaivo, Anke Rissmann, David Tucker, Awi Wiesel, Lyubov Yevtushok and Joan K Morris ()
Additional contact information
Alana Cavadino: the University of Auckland
Lovisa Sandberg: Uppsala Monitoring Centre
Inger Öhman: Uppsala Monitoring Centre
Tomas Bergvall: Uppsala Monitoring Centre
Kristina Star: Uppsala Monitoring Centre
Helen Dolk: Ulster University
Maria Loane: Ulster University
Marie-Claude Addor: University Hospital Center CHUV
Ingeborg Barisic: Medical School University of Zagreb
Clara Cavero-Carbonell: Foundation for the Promotion of Health and Biomedical Research in the Valencian Region
Ester Garne: Hospital Lillebaelt
Miriam Gatt: Malta Congenital Anomalies Registry, Directorate for Health Information and Research
Babak Khoshnood: Paris Registry of Congenital Malformations, Obstetrical, Perinatal and Paediatric Epidemiology Research Team, Centre for Biostatistics and Epidemiology, INSERM, UMR 1153
Kari Klungsøyr: University of Bergen
Anna Latos-Bielenska: Poznan University of Medical Sciences
Nathalie Lelong: Paris Registry of Congenital Malformations, Obstetrical, Perinatal and Paediatric Epidemiology Research Team, Centre for Biostatistics and Epidemiology, INSERM, UMR 1153
Reneé Lutke: University of Groningen, University Medical Centre Groningen
Anna Materna-Kiryluk: Poznan University of Medical Sciences
Vera Nelen: PIH
Amanda Nevill: University of Ferrara
Mary O’Mahony: Health Service Executive-South
Olatz Mokoroa: Public Health Division of Gipuzkoa
Anna Pierini: Institute of Clinical Physiology, National Research Council/Fondazione Toscana Gabriele Monasterio
Hanitra Randrianaivo: Unit of congenital malformations, REMACOR- Medical School University of La Réunion St Pierre
Anke Rissmann: Malformation Monitoring Centre Saxony-Anhalt, Medical Faculty Otto-von-Guericke-University
David Tucker: Public Health Wales Knowledge Directorate, Level 3, West Wing Block, Singleton Hospital
Awi Wiesel: Birth Registry Mainz Model, University Medical Center of Mainz
Lyubov Yevtushok: OMNI-Net Ukraine Birth Defects Program and Rivne Regional Medical Diagnostic Center
Joan K Morris: Population Health Research Institute, St George’s, University of London

Drug Safety, 2021, vol. 44, issue 7, No 5, 765-785

Abstract: Abstract Introduction Knowledge on the safety of medication use during pregnancy is often sparse. Pregnant women are generally excluded from clinical trials, and there is a dependence on post-marketing surveillance to identify teratogenic medications. Aims This study aimed to identify signals of potentially teratogenic medications using EUROmediCAT registry data on medication exposure in pregnancies with a congenital anomaly, and to investigate the use of VigiBase reports of adverse events of medications in the evaluation of these signals. Methods Signals of medication–congenital anomaly associations were identified in EUROmediCAT (21,636 congenital anomaly cases with 32,619 medication exposures), then investigated in a subset of VigiBase (45,749 cases and 165,121 exposures), by reviewing statistical reporting patterns and VigiBase case reports. Evidence from the literature and quantitative and qualitative aspects of both datasets were considered before recommending signals as warranting further independent investigation. Results EUROmediCAT analysis identified 49 signals of medication–congenital anomaly associations. Incorporating investigation in VigiBase and the literature, these were categorised as follows: four non-specific medications; 11 likely due to maternal disease; 11 well-established teratogens; two reviewed in previous EUROmediCAT studies with limited additional evidence; and 13 with insufficient basis for recommending follow-up. Independent investigations are recommended for eight signals: pregnen (4) derivatives with limb reduction; nitrofuran derivatives with cleft palate and patent ductus arteriosus; salicylic acid and derivatives with atresia or stenosis of other parts of the small intestine and tetralogy of Fallot; carbamazepine with atrioventricular septal defect and severe congenital heart defect; and selective beta-2-adrenoreceptor agonists with posterior urethral valve and/or prune belly. Conclusion EUROmediCAT data should continue to be used for signal detection, accompanied by information from VigiBase and review of the existing literature to prioritise signals for further independent evaluation.

Date: 2021
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DOI: 10.1007/s40264-021-01073-z

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