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Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies

Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies
Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies
Objective: To test previous signals of a risk of orofacial cleft (OC) and clubfoot with exposure to the antiepileptic lamotrigine, and to investigate risk of other congenital anomalies (CA).

Methods: This was a population-based case–malformed control study based on 21 EUROCAT CA registries covering 10.1 million births (1995–2011), including births to 2005 in which the clubfoot signal was generated and a subsequent independent study population of 6.3 million births. A total of 226,806 babies with CA included livebirths, stillbirths, and terminations of pregnancy following prenatal diagnosis. First-trimester lamotrigine monotherapy exposure in OC cases and clubfoot cases was compared to other nonchromosomal CA (controls). Odds ratios (OR) were adjusted for registry. An exploratory analysis compared the proportion of each standard EUROCAT CA subgroup among all babies with nonchromosomal CA exposed to lamotrigine monotherapy with non-AED exposed pregnancies.

Results: There were 147 lamotrigine monotherapy-exposed babies with nonchromosomal CA. For all OC, ORadj was 1.31 (95% confidence interval [CI] 0.73–2.33), isolated OC 1.45 (95% CI 0.80–2.63), isolated cleft palate 1.69 (95% CI 0.69–4.15). Overall ORadj for clubfoot was 1.83 (95% CI 1.01–3.31) and 1.43 (95% CI 0.66–3.08) in the independent study population. No other specific CA were significantly associated with lamotrigine monotherapy.

Conclusions: The risk of OC was not significantly raised and we estimate the excess risk of OC to be less than 1 in every 550 exposed babies. We have not found strong independent evidence of a risk of clubfoot subsequent to our original signal. Our study cannot assess the general malformation risk among lamotrigine-exposed pregnancies.
0028-3878
1716-1725
Dolk, Helen
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Wang, Hao
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Loane, Maria
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Morris, Joan
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Garne, Ester
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Addor, Marie-Claude
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Arriola, Larraitz
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Bakker, Marian
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Barisic, Ingeborg
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Doray, Berenice
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Gatt, Miriam
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Kallen, Karin
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Khoshnood, Babak
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Klungsoyr, Kari
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Lahesmaa-Korpinen, Anna-Maria
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Latos-Bielenska, Anna
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Mejnartowicz, Jan P.
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Nelen, Vera
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Neville, Amanda
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O'Mahony, Mary
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Pierini, Anna
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Rißmann, Anke
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Tucker, David
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Wellesley, Diana
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Wiesel, Awi
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de Jong-van den Berg, Lolkje T.W.
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Dolk, Helen
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Wang, Hao
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Loane, Maria
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Morris, Joan
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Garne, Ester
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Addor, Marie-Claude
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Arriola, Larraitz
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Bakker, Marian
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Barisic, Ingeborg
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Doray, Berenice
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Gatt, Miriam
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Kallen, Karin
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Khoshnood, Babak
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Klungsoyr, Kari
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Lahesmaa-Korpinen, Anna-Maria
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Latos-Bielenska, Anna
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Mejnartowicz, Jan P.
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Nelen, Vera
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Neville, Amanda
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O'Mahony, Mary
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Pierini, Anna
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Rißmann, Anke
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Tucker, David
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Wellesley, Diana
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Wiesel, Awi
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de Jong-van den Berg, Lolkje T.W.
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Dolk, Helen, Wang, Hao, Loane, Maria, Morris, Joan, Garne, Ester, Addor, Marie-Claude, Arriola, Larraitz, Bakker, Marian, Barisic, Ingeborg, Doray, Berenice, Gatt, Miriam, Kallen, Karin, Khoshnood, Babak, Klungsoyr, Kari, Lahesmaa-Korpinen, Anna-Maria, Latos-Bielenska, Anna, Mejnartowicz, Jan P., Nelen, Vera, Neville, Amanda, O'Mahony, Mary, Pierini, Anna, Rißmann, Anke, Tucker, David, Wellesley, Diana, Wiesel, Awi and de Jong-van den Berg, Lolkje T.W. (2016) Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies. Neurology, 86 (18), 1716-1725. (doi:10.1212/WNL.0000000000002540). (PMID:27053714)

Record type: Article

Abstract

Objective: To test previous signals of a risk of orofacial cleft (OC) and clubfoot with exposure to the antiepileptic lamotrigine, and to investigate risk of other congenital anomalies (CA).

Methods: This was a population-based case–malformed control study based on 21 EUROCAT CA registries covering 10.1 million births (1995–2011), including births to 2005 in which the clubfoot signal was generated and a subsequent independent study population of 6.3 million births. A total of 226,806 babies with CA included livebirths, stillbirths, and terminations of pregnancy following prenatal diagnosis. First-trimester lamotrigine monotherapy exposure in OC cases and clubfoot cases was compared to other nonchromosomal CA (controls). Odds ratios (OR) were adjusted for registry. An exploratory analysis compared the proportion of each standard EUROCAT CA subgroup among all babies with nonchromosomal CA exposed to lamotrigine monotherapy with non-AED exposed pregnancies.

Results: There were 147 lamotrigine monotherapy-exposed babies with nonchromosomal CA. For all OC, ORadj was 1.31 (95% confidence interval [CI] 0.73–2.33), isolated OC 1.45 (95% CI 0.80–2.63), isolated cleft palate 1.69 (95% CI 0.69–4.15). Overall ORadj for clubfoot was 1.83 (95% CI 1.01–3.31) and 1.43 (95% CI 0.66–3.08) in the independent study population. No other specific CA were significantly associated with lamotrigine monotherapy.

Conclusions: The risk of OC was not significantly raised and we estimate the excess risk of OC to be less than 1 in every 550 exposed babies. We have not found strong independent evidence of a risk of clubfoot subsequent to our original signal. Our study cannot assess the general malformation risk among lamotrigine-exposed pregnancies.

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Accepted/In Press date: 26 January 2016
e-pub ahead of print date: 6 April 2016
Published date: May 2016
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 392050
URI: http://eprints.soton.ac.uk/id/eprint/392050
ISSN: 0028-3878
PURE UUID: 04ed1852-ea66-4dda-bf3b-19316f34f962

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Date deposited: 14 Apr 2016 09:27
Last modified: 16 Dec 2019 19:10

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Contributors

Author: Helen Dolk
Author: Hao Wang
Author: Maria Loane
Author: Joan Morris
Author: Ester Garne
Author: Marie-Claude Addor
Author: Larraitz Arriola
Author: Marian Bakker
Author: Ingeborg Barisic
Author: Berenice Doray
Author: Miriam Gatt
Author: Karin Kallen
Author: Babak Khoshnood
Author: Kari Klungsoyr
Author: Anna-Maria Lahesmaa-Korpinen
Author: Anna Latos-Bielenska
Author: Jan P. Mejnartowicz
Author: Vera Nelen
Author: Amanda Neville
Author: Mary O'Mahony
Author: Anna Pierini
Author: Anke Rißmann
Author: David Tucker
Author: Diana Wellesley
Author: Awi Wiesel
Author: Lolkje T.W. de Jong-van den Berg

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