EUROmediCAT signal detection: A systematic method for identifying potential teratogenic medication

Johannes M Luteijn, Joan Morris, Ester Garne, Joanne Given, Lolkje de Jong-van den Berg, Marie-Claude Addor, Marian Bakker, Ingeborg Barisic, Mariam 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 LoaneHelen Dolk

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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 fetuses/babies with first trimester medication exposures in 1995-2011 were analysed. 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%). 52 specific medication-anomaly associations were identified. After discarding 10 overlapping and 3 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 analysed 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.
Original languageEnglish
Pages (from-to)1110-1122
JournalBritish Journal of Clinical Pharmacology
Issue number4
Early online date28 Jun 2016
Publication statusPublished online - 28 Jun 2016


  • Pharmacovigilance
  • Congenital Anomalies
  • Adverse Drug Reactions
  • Pharmacoepidemiology
  • Pregnancy
  • Drug Safety


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