1. Dr. Johannes Michiel Luteijn Prof. Joan Morris BINOCAR Scientific Meeting Swansea, October 7 th, 2014 Thanks to: Lolkje de Jong-van den Berg Helen Dolk Ester Garne Joanne Given Maria Loane EUROCAT Post-marketing surveillance for congenital anomalies

2. Two studies estimated 57-79% of pregnant women in Northern Europe are exposed to prescription drugs during pregnancy. 1,2 Little is known about the safety of drugs in pregnancy, partly due to pregnant women not being involved in pre-marketing studies. 1 Bakker, M. K., Jentink, J., Vroom, F., Van Den Berg, P. B., De Walle, H. E., & De Jong-Van Den Berg, L. T. (2006). Drug prescription patterns before, during and after pregnancy for chronic, occasional and pregnancy-related drugs in the netherlands. BJOG : An International Journal of Obstetrics and Gynaecology, 113(5), 559-568 2 Engeland, A., Bramness, J. G., Daltveit, A. K., Ronning, M., Skurtveit, S., & Furu, K. (2008). Prescription drug use among fathers and mothers before and during pregnancy. A population-based cohort study of 106,000 pregnancies in norway 2004-2006. British Journal of Clinical Pharmacology, 65(5), 653-660 Drug use in pregnancy

3. Aim: To develop a method of signal detection to be used as a routine analysis tool. EUROmediCAT signal detection

4. Dataset 15 EUROCAT registries in EUROmediCAT Births from 1995-2011 14,950 registrations of congenital anomaly with at least a single exposure to a drug (ATC-code 5-digit+) Folic acid, minerals and vitamins not included as exposures Exclusions Anomalies with 1-4 digit ATC-code exposures only (n=1,288) Anomalies with no clear 1 st trimester exposure (n=13,377) Infants with a chromosomal anomaly

6. Dataset Drug exposure 5- and 7-digit ATC codes (n = 272, n = 505) Exposure collected mainly prospective to birth by healthcare professionals. Cases EUROCAT coding committee identified 59 subgroups of non- chromosomal congenital anomaly 3 Teratogenic mechanisms of medical drugs. Van Gelder MM, van Rooij IA, Miller RK, Zielhuis GA, de Jong-van den Berg LTW, Roeleveld N. Hum Reprod. Update. 2010 Jul-Aug;16(4):378-94 Potential drug-congenital anomaly signals must have at least 3 exposed cases

7. Analysis of drug-CA combinations Analysis by Fishers’ exact test A total of 59 congenital anomalies x 836 drug-codes. 49,324 analyses performed. 19,529 5-digit ATC-code analyses 29,795 7-digit ATC-code analyses Drug AAll other drugs excluding A Anomalyab All other anomaliescd

8. Fisher’s exact results for 7-digit ATC – anomaly combinations Observed Odds Ratio P-value 0.05

9. Multiple testing issues P Values Given there is no association - P = probability observed or more extreme result would occur P = 0.05 means that 5% of Fisher’s exact tests where there is no association will be “statistically significant” Ie 5% of 5,000 tests are likely to be false positives False Discovery Rate : Proportion of significant results that are expected to be false positives FDR of 5% means 5% of the “significant” results are likely to be false positives Ie 5% of significant results are likely to be false positives

10. False Discovery Rate Possible test results (Z-score) Density Distribution of test statistics if there are no associations B

11. False Discovery Rate Possible test results (Z-score) Density Distribution of test statistics if there are no associations Observed distribution of test statistics A B

12. False Discovery Rate 0.05 Observed Odds Ratio P-value 0.05 FDR = 5%

13. False Discovery Rate 0.05 Observed Odds Ratio P-value 0.05 FDR = 5% May exclude true associations

14. False Discovery Rate Observed Odds Ratio P-value 0.05 FDR = 50% FDR = 5% May exclude true associations

15. False Discovery Rate Observed Odds Ratio P-value 0.05 FDR = 5% May exclude true associations FDR = 50% May include too many false associations

16. 49,324 drug-CA combinations 19,529 5-digit drug combinations (including aggregate drug groups) 29,795 7-digit drug combinations 97 potential signals at (FDR= 0.5 ; p < 0.003) 31 potential signals at (FDR = 0.5 ; p < 0.0005) 128 potential signals Flowchart of analyses Multiple testing procedure (649 p-value < 0.05) Multiple testing procedure (886 p-value < 0.05)

17. Preliminary Results – Association tree Example – Spina bifida and N03AG01 (valproic acid) Congenital Anomaly ExposureExposed Cases Odds Ratio Neural Tube Defects N03AG304.1 (2.6 - 6.0) Spina BifidaN03AG297.4 (4.7 - 11.2) Neural Tube Defects N03AG01294.0 (2.6 - 6.0) Spina BifidaN03AG01287.3 (4.6 - 11.0) Cases not yet verified by registry

18. 49,324 drug-CA combinations 128 potential signals 115 potential signals 47,789 FDR > 0.5 13 Less than 3 exposed cases 77 Independent signals Subject to detailed follow-up 20 5-digit ATC code of 7-digit ATC associated with the same CA 6 Aggregate CA of a more specific CA associated with the same exposure 12 Protective associations Exclusions Flowchart of analyses

19. Validation of methodology Spina bifida and valproic acid † OR 7.25 (4.61-11.02) 28 Exposed cases Congenital heart defects and human insulin † OR 2.46 (1.81-3.35) 102 Exposed cases † Cases not yet verified by registry

20. The WHO-Uppsala Monitoring Centre receives reports of adverse drug reactions from all over the world. 66,000 reports of CA-related adverse drug reactions since 2000 70% American/Canadian Valuable independent dataset for testing signals Future work