1. Maternal first trimester lamotrigine exposure and risk of orofacial clefts: analysis using data from EUROCAT congenital anomaly registries Maria Loane, Hao Wang, Helen Dolk, Lolkje de Jon van den Berg, Joan Morris and the EUROCAT Antiepileptic Drug Working Group BINOCAR Scientific Meeting Swansea, October 7 th, 2014

2. Background Congenital Anomalies (CA) are rare occurring in approximately 2% of all births –Neural Tube Defects: 1 in 1,000 births –Gastroschisis (abdominal wall anomaly): 3 in 10,000 births –Orofacial clefts: 14 in 10,000 births Some medication exposures are rare –3-4 pregnancies in every 1,000 occur to women with epilepsy Rare outcomes + rare exposures require a large population coverage to achieve sufficient statistical power to detect specific associations EUROCAT CA registries can provide large population coverage

3. In 2006, the US Federal Drugs Agency issued an alert concerning an increased risk of orofacial clefts following 1 st trimester exposure to the new anti-epileptic drug (AED) lamotrigine Based on five cases of orofacial cleft following lamotrigine exposure in a US cohort when <1 expected [North American AED Pregnancy Registry. Holmes et al, 2008] RR for orofacial clefts = 10.4 (95% CI 4.3-24.9); RR for cleft palate = 21.0 (95% CI 6.8-65.1) Background to EUROCAT AED studies Holmes LB, et al. Increased frequency of isolated cleft palate exposed to lamotrigine during pregnancy. Neurology, 2008:70;2152-8.

4. EUROCAT AED Study Database Set up to evaluate the signal: Lamotrigine and orofacial clefts using data from 20 EUROCAT registries with drug exposure information for all congenital anomaly registrations. Aim of EUROCAT AED study: to investigate in an independent large dataset whether lamotrigine exposure is associated with a raised risk of orofacial clefts Study design: Case - malformed control study cases= orofacial clefts controls=all other malformations 3.9 million births in Europe 1995-2005 98,075 babies with congenital anomalies

5. Results of EUROCAT Lamotrigine study* 5.8% of CA registrations with any AED exposure Lamotrigine increased from 7.3% of all AEDs in 1995–1998 to 20.5% in 2002–2005 No increased risk of orofacial clefts relative to other malformations for Lamotrigine (LTG) monotherapy compared to no AED use –OR adjusted for maternal age= 0.67 (95% CI 0.10–2.34) –Based on 2 orofacial cleft cases with LTG exposure out of 40 CA registrations with LTG exposure * Dolk H, et al. Does lamotrigine use in pregnancy increase orofacial cleft risk relative to other malformations? Neurology 2008;71:714-722.

6. Conclusion of EUROCAT Lamotrigine study No evidence of a specific increased risk of isolated orofacial cleft relative other malformations due to lamotrigine monotherapy However, the confidence intervals still included a possible moderate risk

7. EUROCAT AED Follow-up studies Five annual update studies were conducted (2009- 2013) Objective To estimate first trimester exposure to LTG monotherapy in relation to the risk of orofacial clefts relative to other malformations more precisely To explore further whether lamotrigine exposure may be associated with other malformations

8. Updated literature review Review in 2012 identified 4 cohort studies with reported orofacial cleft rates among exposed pregnancies ( Hernández-Díaz) : –Only one or two orofacial cleft cases in each study –Rates of OC varied from 0.086% up to 0.16%, compared with the original signal in Holmes study of 0.44%. No independent confirmation of increased risk of OCs in relation to LTG from all studies in the literature combined [Dolk et al., 2012] Hernández-Díaz S, Smith CR, Shen A, Mittendorf R, Hauser WA, Yerby M, Holmes LB; North American AED Pregnancy Registry; North American AED Pregnancy Registry. Comparative safety of antiepileptic drugs during pregnancy. Neurology. 2012;78:1692-9. Dolk H, de Jong-van den Berg L, Loane M, Wang, H and Morris J (2012). Newer anticonvulsants: Lamotrigine. Birth Defects Research Part A Clinical and Molecular Teratology. 94: 959

9. Methods Criteria for EUROCAT registries to participate in the study : –maternal epilepsy or AED exposure recorded for at least 3 per 1,000 registrations –specific drug name or complete 7-digit ATC code available for at least 80% of AED exposed babies/fetus Study population –21 registries: 19 registries from the original study + Sweden + Finland –birth year covered 1995 - 2011 –total coverage of 10.1 million births –226,806 births (2.3%) with major congenital anomalies 27,291 (12%) chromosomal 199,515 (88%) non-chromosomal

10. Methods Cases: non-chromosomal OC registrations –ascertained by a panel of 3 medical geneticists, blind to exposure status –exclusion: OC secondary to another primary anomaly (n=1040)* OC associated with a chromosomal anomaly (n=954) Controls 1: non-chromosomal, non-OC registrations Controls 2: chromosomal, non-OC registrations *list of secondary clefts: anencephaly with cleft palate, holoprosencephaly sequence, ammiotic bands/ADAM sequence, Pierre Robin sequence, Cyclops, Marden Walker, Moebius, Poland syndrome.

11. Methods: Exposure definition Extracted registrations with coded maternal epilepsy or AED exposure (whether for epilepsy or not) Verified medication exposure and congenital anomalies with participating registries Exclusion: epileptic mothers without recorded AED exposure (n=574)

12. Methods: Analysis Exposures classified according to number of AEDs –monotherapy –polytherapy two (or more) sequential medications two (or more) medications used simultaneously Crude odds ratios (OR) compared to no AED exposure were calculated as well as ORs adjusted for maternal age, and adjusted for registry.

13. Results of EUROCAT studies combined Total AED exposed cases % of AED exposure among CA registrations Any AED1,3646.0 Any AED monotherapy1,0944.8 Any AED polytherapy2701.2 Lamotrigine monotherapy1570.7 Lamotrigine polytherapy1020.4 12% of all AED exposed registrations were exposed to lamotrigine monotherapy and 7% to lamotrigine polytherapy

14. Results: Cumulative number of registrations exposed to lamotrigine in each report Lamotrigine monotherapy Lamotrigine polytherapy TotalChromos omal TotalChromos omal original study401360 1 st update report501460 2 nd update report633501 3 rd update report896591 4 th update report1097722 5 th update report157101024

15. ORs for Lamotrigine monotherapy exposure compared to no AED exposure among non-chromosomal registrations Total Births (n)Isolated OC OR [95% CI] Isolated CP OR [95% CI] Original study3,881,5920.80 [0.11-2.85] 1.01 [0.03-5.57] First update (2009) 4,390,5940.27 [0.01-1.43] 0.80 [0.03-4.37] Second update (2010) 4,672,8250.66 [0.08-1.86] 0.99 [0.02-3.68] Third update (2011) 6,201,0361.07 [0.43-2.64] 1.29 [0.32-5.26] Fourth update (2012) 7,673,8451.01 [0.44-2.30] 1.49 [0.47-7.42] Fifth and final update (2013) 10,061,259 1.40 [0.77 - 2.53] 1.61 [0.66-3.94]

16. ORs for any AED exposure compared to no AED exposure for cleft palate cases Controls Isolated CP Isolated & multiple CP n=183921n=4240n=5398 No AED 18276341975328 Reference 11 Any AEDNumber9333452 monotherapyOR 1.58 (1.09 - 2.23)1.91 (1.41 - 2.53) OR adj age 1.58 (1.12 - 2.23)1.91 (1.44 - 2.53) OR adj region 1.53 (1.08 - 2.16)1.83 (1.38 - 2.43) Any AEDNumber225918 polytherapyOR 1.72 (0.77 - 3.32)2.71 (1.58 - 4.39) OR adj age 1.71 (0.88 - 3.33)2.69 (1.67 - 4.36) OR adj region 1.60 (0.82 - 3.12)2.51 (1.55 - 4.08) Significant increased risks for cleft palate for “any AED monotherapy”. There was a twofold risk of ‘Isolated and multiple’ cleft palate and any AED polytherapy.

17. Results - Exploratory analyses Distribution of malformation subgroups by lamotrigine exposure compared to non-AED exposed registrations Non-AED exposedLamotrigine exposed registrations non chromosomal anomaly subgroup 196670 registrations245 mono- or poly-147 monotherapy numberproportion %numberproportion %numberproportion % nervous system16,7528.53614.7 # 149.5 neural tube defects6,8223.5166.5 # 32.0 spina bifida4,0052.0166.5 # 32.0 respiratory4,4062.2145.8 # 96.1 # limb39,65220.26225.3 # 4127.9 # club foot without spina bifida9,0424.6156.1128.2 # # p<0.05

18. Club foot There is a significant excess of clubfoot with lamotrigine monotherapy. –12 cases compared to 6.8 expected, (p<0.05). Five of the 12 cases were observed in the original study, where the excess was first signaled. The first update reported an additional 2 cases, the second update 1, the third update 2, no cases were in the fourth update, and 2 additional cases were reported in the fifth update The 7 additional cases in the 5 update studies are in excess of the 4.9 additional cases expected, but this independent excess is no longer statistically significant (p=0.35).

19. The observed and expected cases of clubfoot exposed to lamotrigine monotherapy Number of clubfoot cases observedexpected original study51.9 1 st update only20.6 2 nd update only10.2 3 rd update only21.0 4 th update only00.9 5 th update only22.3 Total126.8

20. Conclusion This update does not change the conclusion of the original study For lamotrigine monotherapy exposure: –no evidence of an increased risk of isolated orofacial cleft –no evidence of an increased risk for isolated cleft palate relative to other non-chromosomal malformations No independent evidence of an association with clubfoot to confirm the signal we generated in the original study

21. Discussion Strengths –size of the population coverage (study covers 10 million births) –well validated, comparable, and specific information about CA diagnoses in exposed and unexposed pregnancies –validity of EUROCAT data supported by finding the well known association between valproic acid and spina bifida (NEJM, 2010) Limitation –no information on lamotrigine dose –not designed to assess a generalized increased risk of malformations with lamotrigine exposure –non-chromosomal control group may include malformations associated with lamotrigine exposure These studies have shown the unique worth of CA registries and their valuable contribution to the European database with regard to pharmacovigilance studies

22. Member of EUROCAT antiepileptic study group –Dr Vera Nelen, Belgium –Dr Christine Verellen–Dumoulin Belgium –Dr Ingeborg Barisic, Croatia –Dr Ester Garne, Denmark –Dr Annukka Ritvanen, Finland –Dr Babak Khoshnood, France –Dr Bérénice Doray, France –Dr Awi Wiesel, Germany –Dr Anke Rißmann, Germany –Dr Mary O’Mahony, Ireland –Dr Elisa Calzolari, Italy –Dr Anna Pierini, Italy –Dr Miriam Gatt, Malta –Dr Marian Bakker, Netherlands –Dr Kari Klungsoyr, Norway –Dr Anna Latos-Bielenska, Poland –Dr Jan P Mejnartowicz, Poland –Dr Larraitz Arriola, Spain –Dr Karin Kallen, Sweden –Dr Marie-Claude Addor, Switzerland –David Tucker, Un ited Kingdom –Dr Diana Wellesley, United Kingdom

23. Thank you!