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

Helen Dolk, Hao Wang, Maria Loane, Joan K 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 & 6 andre Anna Pierini, Anke Rissmann, David Tucker, Diana Wellesley, Awi Wiesel, Lolkje T.W. de Jong-van den Berg

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
TidsskriftNeurology
Vol/bind86
Udgave nummer18
Sider (fra-til)1716-25
ISSN0028-3878
DOI
StatusUdgivet - 2016

Fingeraftryk

Clubfoot
Confidence Intervals
Registries
Population
Stillbirth
Cleft Palate
First Pregnancy Trimester
Prenatal Diagnosis
Case-Control Studies
Odds Ratio

Citer dette

Dolk, H., Wang, H., Loane, M., Morris, J. K., Garne, E., Addor, M-C., ... 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), 1716-25. https://doi.org/10.1212/WNL.0000000000002540
Dolk, Helen ; Wang, Hao ; Loane, Maria ; Morris, Joan K ; 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 ; de Jong-van den Berg, Lolkje T.W. / Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies. I: Neurology. 2016 ; Bind 86, Nr. 18. s. 1716-25.
@article{c05aa4b047b140f1a95db80b18641bec,
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 = "Journal Article",
author = "Helen Dolk and Hao Wang and Maria Loane and Morris, {Joan K} 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 = "{\circledC} 2016 American Academy of Neurology.",
year = "2016",
doi = "10.1212/WNL.0000000000002540",
language = "English",
volume = "86",
pages = "1716--25",
journal = "Neurology",
issn = "0028-3878",
publisher = "Lippincott Williams & Wilkins",
number = "18",

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Dolk, H, Wang, H, Loane, M, Morris, JK, 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, bind 86, nr. 18, s. 1716-25. https://doi.org/10.1212/WNL.0000000000002540

Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies. / Dolk, Helen; Wang, Hao; Loane, Maria; Morris, Joan K; 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; de Jong-van den Berg, Lolkje T.W.

I: Neurology, Bind 86, Nr. 18, 2016, s. 1716-25.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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 K

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.

N1 - © 2016 American Academy of Neurology.

PY - 2016

Y1 - 2016

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 - Journal Article

U2 - 10.1212/WNL.0000000000002540

DO - 10.1212/WNL.0000000000002540

M3 - Journal article

VL - 86

SP - 1716

EP - 1725

JO - Neurology

JF - Neurology

SN - 0028-3878

IS - 18

ER -