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

• 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)

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.

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 (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

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 Chromosomal

Total Chromosomal

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 OCOR [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

ControlsIsolated

CPIsolated & multiple

CP n=183921 n=4240 n=5398No AED 182763 4197 5328Reference 1 1Any AED Number 933 34 52

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)

Any AED Number 225 9 18

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 Lamotrigine exposed registrations

non chromosomal anomaly subgroup

196670 registrations 245 mono- or poly- 147 monotherapy

number proportion % number proportion % number proportion %

nervous system 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#

# 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

TotalTotal 1212 6.86.8

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

Thank you!Thank you!