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

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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.

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Acknowledgements

The authors sincerely thank all the people throughout Europe who have been involved in providing and processing information for both EUROCAT and EUROmediCAT, including affected families, clinicians, health professionals, medical record clerks and registry staff. EUROCAT registries are funded as fully described in Paper 6 of Report 9 “EUROCAT Member Registries: Organization and Activities” available at http://onlinelibrary.wiley.com/doi/10.1002/bdra.20775/pdf. We would also like to thank Catherine Lynch and Carmel Mullaney for providing anonymised South East Ireland registry data for this study. Similarly, we are indebted to the national centres which make up the WHO Programme for International Drug Monitoring and provide reports to VigiBase. However, the opinions and conclusions of this study are not necessarily those of the various centres, nor of the WHO. We would also like to express our gratitude to Pia Caduff-Janosa for reviewing a previous version of the manuscript and providing valuable input.

Author information

Authors and Affiliations

  1. School of Population Health, the University of Auckland, Auckland, New Zealand

    Alana Cavadino

  2. Uppsala Monitoring Centre, Uppsala, Sweden

    Lovisa Sandberg, Inger Öhman, Tomas Bergvall & Kristina Star

  3. Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden

    Kristina Star

  4. Institute of Nursing and Health Research, Ulster University, Newtownabbey, Northern Ireland, UK

    Helen Dolk & Maria Loane

  5. Department of Woman-Mother-Child, University Hospital Center CHUV, CH 1011, Lausanne, Switzerland

    Marie-Claude Addor

  6. Children’s Hospital Zagreb, Centre of Excellence for Reproductive and Regenerative Medicine, Medical School University of Zagreb, Zagreb, Croatia

    Ingeborg Barisic

  7. Rare Diseases Research Unit, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region, Valencia, Spain

    Clara Cavero-Carbonell

  8. Paediatric Department, Hospital Lillebaelt, Kolding, Denmark

    Ester Garne

  9. Malta Congenital Anomalies Registry, Directorate for Health Information and Research, Tal-Pietà, Malta

    Miriam Gatt

  10. Paris Registry of Congenital Malformations, Obstetrical, Perinatal and Paediatric Epidemiology Research Team, Centre for Biostatistics and Epidemiology, INSERM, UMR 1153, Paris, France

    Babak Khoshnood & Nathalie Lelong

  11. Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway

    Kari Klungsøyr

  12. Department of Medical Genetics, Poznan University of Medical Sciences, Poznań, Poland

    Anna Latos-Bielenska & Anna Materna-Kiryluk

  13. Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands

    Reneé Lutke

  14. Department of Environment, PIH, Antwerp, Belgium

    Vera Nelen

  15. IMER Registry (Emila Romagna Registry of Birth Defects), Center for Clinical and Epidemiological Research, University of Ferrara, Azienda Ospedaliero, Italy

    Amanda Nevill

  16. Department of Public Health, Health Service Executive-South, Cork, Ireland

    Mary O’Mahony

  17. Basque Government, Department of Health, Public Health Division of Gipuzkoa, Donostia-San Sebastian, Spain

    Olatz Mokoroa

  18. Tuscany Registry of Congenital Defects (RTDC), Institute of Clinical Physiology, National Research Council/Fondazione Toscana Gabriele Monasterio, Pisa, Italy

    Anna Pierini

  19. Unit of congenital malformations, REMACOR- Medical School University of La Réunion St Pierre, Sainte-Clotilde, France

    Hanitra Randrianaivo

  20. Malformation Monitoring Centre Saxony-Anhalt, Medical Faculty Otto-von-Guericke-University, Magdeburg, Germany

    Anke Rissmann

  21. Congenital Anomaly Register and Information Service for Wales, Public Health Wales Knowledge Directorate, Level 3, West Wing Block, Singleton Hospital, Sketty Lane, Swansea, UK

    David Tucker

  22. Department of Pediatrics, Birth Registry Mainz Model, University Medical Center of Mainz, Mainz, Germany

    Awi Wiesel

  23. OMNI-Net Ukraine Birth Defects Program and Rivne Regional Medical Diagnostic Center, Rivne, Ukraine

    Lyubov Yevtushok

  24. Population Health Research Institute, St George’s, University of London, London, UK

    Joan K Morris

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  1. Alana Cavadino
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  29. Joan K Morris
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Corresponding author

Correspondence to Joan K Morris.

Ethics declarations

Funding

There was no specific funding for this study. EUROCAT registries are funded as described in “EUROCAT Member Registries: Organization and Processes” [56].

Conflict of interest

As of June 2020, Kristina Star is a full-time employee of AstraZeneca. However, all of her contributions to this work were made prior to the time of departure, as part of her employment at Uppsala Monitoring Centre. All other authors declare that they have no conflict of interest.

Ethics Approval

Not applicable.

Consent to participate

All data in EUROmediCAT and VigiBase are anonymised; therefore, patient informed consent for this particular study was not required.

Consent for publication

Not applicable.

Availability of data and material

EUROmediCAT encourages the use of its data and networks for pharmacovigilance and medication safety research. Individual data are only available to consortium members; however, EUROmediCAT can be commissioned to do a study, or engage in a collaborative study. Requests can be made at http://euromedicat.eu/currentresearchanddata/howtoproposeorcommissionspecificstudies. The VigiBase datasets generated and analysed during the current study are not publicly available due to agreements between contributors of data to the database used (VigiBase) and the custodian of this database. National centres (mainly national drug regulatory authorities) constituting the WHO Programme for International Drug Monitoring (PIDM) contribute data to VigiBase, and UMC is the custodian in its capacity as a WHO collaborating centre for international drug monitoring.

Code availability

Not applicable.

Author contributions

AC: Designed and conceptualised the manuscript; analysed the EUROmediCAT data; interpreted the data; drafted the manuscript; revised the manuscript. LS, IÖ, KS, TB: generated and analysed VigiBase data; interpreted the data: drafted the manuscript; revised the manuscript. HD, ML: Coordinated the dataflow and managed EUROmediCAT registry data; made substantial contributions to the acquisition of data; interpreted the data; revised the manuscript. MA, IB, CC, EG, MG, BK, KK, AL, NL, RL, AM, OM, VN, AN, MO, AP, HR, AR, DT, AW, LY: Managed EUROmediCAT registry data; made substantial contributions to the acquisition of data; revised the manuscript. JKM: Designed and conceptualised the manuscript; supervised the study; interpreted the data; drafted the manuscript; revised the manuscript. All authors read and approved the final version.

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Cavadino, A., Sandberg, L., Öhman, I. et al. Signal Detection in EUROmediCAT: Identification and Evaluation of Medication–Congenital Anomaly Associations and Use of VigiBase as a Complementary Source of Reference. Drug Saf 44, 765–785 (2021). https://doi.org/10.1007/s40264-021-01073-z

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