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

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

doi:10.1212/WNL.0000000000002540

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	1716-1725
Number of pages	10
Journal	Neurology
Volume	86
Issue number	18
DOIs	https://doi.org/10.1212/WNL.0000000000002540
Publication status	Published - 3-May-2016

Keywords

ANTIEPILEPTIC DRUGS
INCREASED FREQUENCY
MALFORMATIONS
CLUBFOOT
EPILEPSY
REGISTRY
PALATE

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Dolk, H., Wang, H., Loane, M., Morris, J., Garne, E., Addor, M-C., Arriola, L., Bakker, M., Barisic, I., Doray, B., Gatt, M., Kallen, K., Khoshnood, B., Klungsoyr, K., Lahesmaa-Korpinen, A-M., Latos-Bielenska, A., Mejnartowicz, J. P., Nelen, V., Neville, A., ... de Jong-van den Berg, L. T. W. (2016). Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies. Neurology, 86(18), 1716-1725. https://doi.org/10.1212/WNL.0000000000002540

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title = "Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies",

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.",

keywords = "ANTIEPILEPTIC DRUGS, INCREASED FREQUENCY, MALFORMATIONS, CLUBFOOT, EPILEPSY, REGISTRY, PALATE",

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

note = "{\textcopyright} 2016 American Academy of Neurology.",

year = "2016",

month = may,

day = "3",

doi = "10.1212/WNL.0000000000002540",

language = "English",

volume = "86",

pages = "1716--1725",

journal = "Neurology",

issn = "0028-3878",

publisher = "LIPPINCOTT WILLIAMS & WILKINS",

number = "18",

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Dolk, H, Wang, H, Loane, M, Morris, J, Garne, E, Addor, M-C, Arriola, L, Bakker, M, Barisic, I, Doray, B, Gatt, M, Kallen, K, Khoshnood, B, Klungsoyr, K, Lahesmaa-Korpinen, A-M, Latos-Bielenska, A, Mejnartowicz, JP, Nelen, V, Neville, A, O'Mahony, M, Pierini, A, Rissmann, A, Tucker, D, Wellesley, D, Wiesel, A & de Jong-van den Berg, LTW 2016, 'Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies', Neurology, vol. 86, no. 18, pp. 1716-1725. https://doi.org/10.1212/WNL.0000000000002540

TY - JOUR

T1 - Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies

AU - Dolk, Helen

AU - Wang, Hao

AU - Loane, Maria

AU - Morris, Joan

AU - Garne, Ester

AU - Addor, Marie-Claude

AU - Arriola, Larraitz

AU - Bakker, Marian

AU - Barisic, Ingeborg

AU - Doray, Berenice

AU - Gatt, Miriam

AU - Kallen, Karin

AU - Khoshnood, Babak

AU - Klungsoyr, Kari

AU - Lahesmaa-Korpinen, Anna-Maria

AU - Latos-Bielenska, Anna

AU - Mejnartowicz, Jan P.

AU - Nelen, Vera

AU - Neville, Amanda

AU - O'Mahony, Mary

AU - Pierini, Anna

AU - Rissmann, Anke

AU - Tucker, David

AU - Wellesley, Diana

AU - Wiesel, Awi

AU - de Jong-van den Berg, Lolkje T. W.

PY - 2016/5/3

Y1 - 2016/5/3

N2 - 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.

AB - 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.

KW - ANTIEPILEPTIC DRUGS

KW - INCREASED FREQUENCY

KW - MALFORMATIONS

KW - CLUBFOOT

KW - EPILEPSY

KW - REGISTRY

KW - PALATE

U2 - 10.1212/WNL.0000000000002540

DO - 10.1212/WNL.0000000000002540

M3 - Article

C2 - 27053714

SN - 0028-3878

VL - 86

SP - 1716

EP - 1725

JO - Neurology

JF - Neurology

IS - 18

ER -