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 7th, 2014
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
Background to EUROCAT AED
studies
• In 2006, the US Federal Drugs Agency issued an alert
concerning an increased risk of orofacial clefts following
1st 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)
Holmes LB, et al. Increased frequency of isolated cleft palate exposed to lamotrigine
during pregnancy. Neurology, 2008:70;2152-8.
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
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.
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
EUROCAT AED Follow-up studies
• Five annual update studies were conducted (20092013)
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
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
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
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.
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)
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.
Results of EUROCAT studies combined
Total AED
exposed cases
% of AED exposure
among CA
registrations
Any AED
1,364
6.0
Any AED monotherapy
1,094
4.8
Any AED polytherapy
270
1.2
Lamotrigine monotherapy
157
0.7
Lamotrigine polytherapy
102
0.4
12% of all AED exposed registrations were exposed to lamotrigine monotherapy
and 7% to lamotrigine polytherapy
Results: Cumulative number of registrations
exposed to lamotrigine in each report
Lamotrigine
monotherapy
Lamotrigine
polytherapy
Total
Chromos
omal
Total
Chromos
omal
original study
40
1
36
0
1st update report
50
1
46
0
2nd update report
63
3
50
1
3rd update report
89
6
59
1
4th update report
109
7
72
2
5th update report
157
10
102
4
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 study
3,881,592
0.80
[0.11-2.85]
1.01
[0.03-5.57]
First update
(2009)
4,390,594
0.27
[0.01-1.43]
0.80
[0.03-4.37]
Second update
(2010)
4,672,825
0.66
[0.08-1.86]
0.99
[0.02-3.68]
Third update
(2011)
6,201,036
1.07
[0.43-2.64]
1.29
[0.32-5.26]
Fourth update
(2012)
7,673,845
1.01
[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]
ORs for any AED exposure compared to no AED
exposure for cleft palate cases
Controls
n=183921
182763
Isolated
CP
n=4240
4197
1
34
Isolated & multiple
CP
n=5398
5328
1
52
No AED
Reference
Any AED
Number
monotherapy
OR
1.58 (1.09 - 2.23)
1.91 (1.41 - 2.53)
ORadj age
1.58 (1.12 - 2.23)
1.91 (1.44 - 2.53)
ORadj region
1.53 (1.08 - 2.16)
1.83 (1.38 - 2.43)
9
18
933
Any AED
Number
225
polytherapy
OR
1.72 (0.77 - 3.32)
2.71 (1.58 - 4.39)
ORadj age
1.71 (0.88 - 3.33)
2.69 (1.67 - 4.36)
ORadj 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.
Results - Exploratory analyses
Distribution of malformation subgroups by lamotrigine exposure compared
to non-AED exposed registrations
Non-AED exposed
non chromosomal anomaly
subgroup
Lamotrigine exposed registrations
196670 registrations
number
245 mono- or poly-
proportion %
number
proportion %
147 monotherapy
number
proportion %
16,752
8.5
36
14.7#
14
9.5
neural tube defects
6,822
3.5
16
6.5#
3
2.0
spina bifida
4,005
2.0
16
6.5#
3
2.0
respiratory
4,406
2.2
14
5.8#
9
6.1#
limb
39,652
20.2
62
25.3#
41
27.9#
club foot without
spina bifida
9,042
4.6
15
6.1
12
8.2#
nervous system
# p<0.05
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).
The observed and expected cases of clubfoot
exposed to lamotrigine monotherapy
Number of clubfoot cases
observed
expected
original study
5
1.9
1st update only
2
0.6
2nd update only
1
0.2
3rd update only
2
1.0
4th update only
0
0.9
5th update only
2
2.3
Total
12
6.8
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
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
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, United Kingdom
– Dr Diana Wellesley, United
Kingdom
Thank you!