EUROmediCAT signal detection: an evaluation of selected congenital anomaly-medication associations

Joanne 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

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To evaluate congenital anomaly (CA)-medication exposure associations produced by the new EUROmediCAT signal detection system and determine which require further investigation.

Data from 15 EUROCAT registries (1995-2011) with medication exposures at the chemical substance (5th level of Anatomic Therapeutic Chemical classification) and chemical subgroup (4th level) were analysed using a 50% false detection rate. After excluding antiepileptics, antidiabetics, antiasthmatics and SSRIs/psycholeptics already under investigation, 27 associations were evaluated. If evidence for a signal persisted after data validation, a literature review was conducted for prior evidence of human teratogenicity.

13/27 CA-medication exposure signals, based on 3-89 exposed cases, passed data validation. There was some prior evidence in the literature to support 6 signals (gastroschisis and levonorgestrel/ethinylestradiol (OR 4.10, 95% CI 1.70-8.53; congenital heart disease/pulmonary valve stenosis and nucleoside/tide reverse transcriptase inhibitors (OR 5.01, 95% CI 1.99-14.20/OR 28.20, 95% CI 4.63-122.24); complete absence of a limb and pregnen (4) derivatives (OR 6.60, 95% CI 1.70-22.93); hypospadias and pregnadien derivatives (OR 1.40, 95% CI 1.10-1.76); hypospadias and synthetic ovulation stimulants (OR 1.89, 95% CI 1.28-2.70). Antipropulsives produced a signal for syndactyly while the literature revealed a signal for hypospadias. There was no prior evidence to support the remaining 6 signals involving the ordinary salt combinations, propulsives, bulk-forming laxatives, hydrazinophthalazine derivatives, gonadotropin releasing hormone analogues and selective serotonin agonists.

Signals which strengthened prior evidence should be prioritised for further investigation, and independent evidence sought to confirm the remaining signals. Some chance associations are expected and confounding by indication is possible.
Original languageEnglish
Pages (from-to)1094-1109
Number of pages16
JournalBritish Journal of Clinical Pharmacology
Issue number4
Early online date29 Mar 2016
Publication statusPublished (in print/issue) - Oct 2016


  • congenital anomalies
  • drug-induced anomalies
  • pharmacoepidemiology
  • pharmacovigilance
  • pregnancy
  • signal evaluation


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