Comparative Safety of Antiseizure Medication Monotherapy for Major Malformations

Jacqueline M. Cohen; Silje Alvestad; Carolyn E. Cesta; Marte Helene Bjørk; Maarit K. Leinonen; Mette Nørgaard; Kristjana Einarsdóttir; Anders Engeland; Mika Gissler; Øystein Karlstad; Kari Klungsøyr; Ingvild Odsbu; Johan Reutfors; Randi M. Selmer; Torbjörn Tomson; Sinna Pilgaard Ulrichsen; Helga Zoega; Kari Furu

doi:10.1002/ana.26561

Comparative Safety of Antiseizure Medication Monotherapy for Major Malformations

Jacqueline M. Cohen^*, Silje Alvestad, Carolyn E. Cesta, Marte Helene Bjørk, Maarit K. Leinonen, Mette Nørgaard, Kristjana Einarsdóttir, Anders Engeland, Mika Gissler, Øystein Karlstad, Kari Klungsøyr, Ingvild Odsbu, Johan Reutfors, Randi M. Selmer, Torbjörn Tomson, Sinna Pilgaard Ulrichsen, Helga Zoega, Kari Furu

^*Corresponding author for this work

Faculty of Medicine

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Abstract

Objective: This study was undertaken to examine the comparative safety of antiseizure medication (ASM) monotherapy in pregnancy with respect to risk of major congenital malformations (MCMs), overall and by MCM subtype. Methods: We conducted a population-based cohort study using national health register data from Denmark, Finland, Iceland, Norway, and Sweden (1996–2020). We compared pregnancies with first trimester exposure to lamotrigine monotherapy to ASM-unexposed, carbamazepine, valproate, oxcarbazepine, levetiracetam, and topiramate to lamotrigine monotherapy, and stratified monotherapy groups by dose. The outcome was nongenetic MCM and specific subtypes. We estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) with log-binomial regression and propensity score weights. Results: There was a higher crude risk of any MCM in pregnancies exposed to lamotrigine monotherapy (n = 8,339) compared to ASM-unexposed pregnancies (n = 4,866,362), but not after confounder adjustment (aRR = 0.97, 95% CI = 0.87–1.08). Compared to lamotrigine, there was an increased risk of malformations associated with valproate (n = 2,031, aRR = 2.05, 95% CI = 1.70–2.46) and topiramate (n = 509, aRR = 1.81, 95% CI = 1.26–2.60), which increased in a dose-dependent manner. We found no differences in malformation risk for carbamazepine (n = 2,674, aRR = 0.91, 95% CI = 0.72–1.15), oxcarbazepine (n = 1,313, aRR = 1.09, 95% CI = 0.83–1.44), or levetiracetam (n = 1,040, aRR = 0.78, 95% CI = 0.53–1.13). Valproate was associated with several malformation subtypes, including nervous system, cardiac, oral clefts, clubfoot, and hypospadias, whereas lamotrigine and carbamazepine were not. Interpretation: Topiramate is associated with an increased risk of MCM similar to that associated with valproate, but lower doses may mitigate the risks for both drugs. Conversely, we found no increased risks for lamotrigine, carbamazepine, oxcarbazepine, or levetiracetam, which is reassuring. ANN NEUROL 2022.

Original language	English
Journal	Annals of Neurology
DOIs	https://doi.org/10.1002/ana.26561
Publication status	Published - 12 Dec 2022

Bibliographical note

Funding Information:
The study was partly supported by the NordForsk Nordic Program on Health and Welfare (Nordic Pregnancy Drug Safety Studies, project No. 83539 and SCAN‐AED, project No. 83796), by the Research Council of Norway (International Pregnancy Drug Safety Studies, project No. 273366), and by the Research Council of Norway through its Centers of Excellence funding scheme (project No. 262700). H.Z. was supported by a UNSW Scientia Program Award during the conduct of the study.

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© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

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Annals of Neurology - 2022 - Cohen - Comparative Safety of Antiseizure Medication Monotherapy for Major MalformationsFinal published version, 755 KBLicence: CC BY-NC

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Cohen, J. M., Alvestad, S., Cesta, C. E., Bjørk, M. H., Leinonen, M. K., Nørgaard, M., Einarsdóttir, K., Engeland, A., Gissler, M., Karlstad, Ø., Klungsøyr, K., Odsbu, I., Reutfors, J., Selmer, R. M., Tomson, T., Ulrichsen, S. P., Zoega, H., & Furu, K. (2022). Comparative Safety of Antiseizure Medication Monotherapy for Major Malformations. Annals of Neurology. https://doi.org/10.1002/ana.26561

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title = "Comparative Safety of Antiseizure Medication Monotherapy for Major Malformations",

abstract = "Objective: This study was undertaken to examine the comparative safety of antiseizure medication (ASM) monotherapy in pregnancy with respect to risk of major congenital malformations (MCMs), overall and by MCM subtype. Methods: We conducted a population-based cohort study using national health register data from Denmark, Finland, Iceland, Norway, and Sweden (1996–2020). We compared pregnancies with first trimester exposure to lamotrigine monotherapy to ASM-unexposed, carbamazepine, valproate, oxcarbazepine, levetiracetam, and topiramate to lamotrigine monotherapy, and stratified monotherapy groups by dose. The outcome was nongenetic MCM and specific subtypes. We estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) with log-binomial regression and propensity score weights. Results: There was a higher crude risk of any MCM in pregnancies exposed to lamotrigine monotherapy (n = 8,339) compared to ASM-unexposed pregnancies (n = 4,866,362), but not after confounder adjustment (aRR = 0.97, 95% CI = 0.87–1.08). Compared to lamotrigine, there was an increased risk of malformations associated with valproate (n = 2,031, aRR = 2.05, 95% CI = 1.70–2.46) and topiramate (n = 509, aRR = 1.81, 95% CI = 1.26–2.60), which increased in a dose-dependent manner. We found no differences in malformation risk for carbamazepine (n = 2,674, aRR = 0.91, 95% CI = 0.72–1.15), oxcarbazepine (n = 1,313, aRR = 1.09, 95% CI = 0.83–1.44), or levetiracetam (n = 1,040, aRR = 0.78, 95% CI = 0.53–1.13). Valproate was associated with several malformation subtypes, including nervous system, cardiac, oral clefts, clubfoot, and hypospadias, whereas lamotrigine and carbamazepine were not. Interpretation: Topiramate is associated with an increased risk of MCM similar to that associated with valproate, but lower doses may mitigate the risks for both drugs. Conversely, we found no increased risks for lamotrigine, carbamazepine, oxcarbazepine, or levetiracetam, which is reassuring. ANN NEUROL 2022.",

author = "Cohen, {Jacqueline M.} and Silje Alvestad and Cesta, {Carolyn E.} and Bj{\o}rk, {Marte Helene} and Leinonen, {Maarit K.} and Mette N{\o}rgaard and Kristjana Einarsd{\'o}ttir and Anders Engeland and Mika Gissler and {\O}ystein Karlstad and Kari Klungs{\o}yr and Ingvild Odsbu and Johan Reutfors and Selmer, {Randi M.} and Torbj{\"o}rn Tomson and Ulrichsen, {Sinna Pilgaard} and Helga Zoega and Kari Furu",

note = "Funding Information: The study was partly supported by the NordForsk Nordic Program on Health and Welfare (Nordic Pregnancy Drug Safety Studies, project No. 83539 and SCAN‐AED, project No. 83796), by the Research Council of Norway (International Pregnancy Drug Safety Studies, project No. 273366), and by the Research Council of Norway through its Centers of Excellence funding scheme (project No. 262700). H.Z. was supported by a UNSW Scientia Program Award during the conduct of the study. Publisher Copyright: {\textcopyright} 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.",

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doi = "10.1002/ana.26561",

language = "English",

journal = "Annals of Neurology",

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Cohen, JM, Alvestad, S, Cesta, CE, Bjørk, MH, Leinonen, MK, Nørgaard, M, Einarsdóttir, K, Engeland, A, Gissler, M, Karlstad, Ø, Klungsøyr, K, Odsbu, I, Reutfors, J, Selmer, RM, Tomson, T, Ulrichsen, SP, Zoega, H & Furu, K 2022, 'Comparative Safety of Antiseizure Medication Monotherapy for Major Malformations', Annals of Neurology. https://doi.org/10.1002/ana.26561

TY - JOUR

T1 - Comparative Safety of Antiseizure Medication Monotherapy for Major Malformations

AU - Cohen, Jacqueline M.

AU - Alvestad, Silje

AU - Cesta, Carolyn E.

AU - Bjørk, Marte Helene

AU - Leinonen, Maarit K.

AU - Nørgaard, Mette

AU - Einarsdóttir, Kristjana

AU - Engeland, Anders

AU - Gissler, Mika

AU - Karlstad, Øystein

AU - Klungsøyr, Kari

AU - Odsbu, Ingvild

AU - Reutfors, Johan

AU - Selmer, Randi M.

AU - Tomson, Torbjörn

AU - Ulrichsen, Sinna Pilgaard

AU - Zoega, Helga

AU - Furu, Kari

N1 - Funding Information: The study was partly supported by the NordForsk Nordic Program on Health and Welfare (Nordic Pregnancy Drug Safety Studies, project No. 83539 and SCAN‐AED, project No. 83796), by the Research Council of Norway (International Pregnancy Drug Safety Studies, project No. 273366), and by the Research Council of Norway through its Centers of Excellence funding scheme (project No. 262700). H.Z. was supported by a UNSW Scientia Program Award during the conduct of the study. Publisher Copyright: © 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

PY - 2022/12/12

Y1 - 2022/12/12

N2 - Objective: This study was undertaken to examine the comparative safety of antiseizure medication (ASM) monotherapy in pregnancy with respect to risk of major congenital malformations (MCMs), overall and by MCM subtype. Methods: We conducted a population-based cohort study using national health register data from Denmark, Finland, Iceland, Norway, and Sweden (1996–2020). We compared pregnancies with first trimester exposure to lamotrigine monotherapy to ASM-unexposed, carbamazepine, valproate, oxcarbazepine, levetiracetam, and topiramate to lamotrigine monotherapy, and stratified monotherapy groups by dose. The outcome was nongenetic MCM and specific subtypes. We estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) with log-binomial regression and propensity score weights. Results: There was a higher crude risk of any MCM in pregnancies exposed to lamotrigine monotherapy (n = 8,339) compared to ASM-unexposed pregnancies (n = 4,866,362), but not after confounder adjustment (aRR = 0.97, 95% CI = 0.87–1.08). Compared to lamotrigine, there was an increased risk of malformations associated with valproate (n = 2,031, aRR = 2.05, 95% CI = 1.70–2.46) and topiramate (n = 509, aRR = 1.81, 95% CI = 1.26–2.60), which increased in a dose-dependent manner. We found no differences in malformation risk for carbamazepine (n = 2,674, aRR = 0.91, 95% CI = 0.72–1.15), oxcarbazepine (n = 1,313, aRR = 1.09, 95% CI = 0.83–1.44), or levetiracetam (n = 1,040, aRR = 0.78, 95% CI = 0.53–1.13). Valproate was associated with several malformation subtypes, including nervous system, cardiac, oral clefts, clubfoot, and hypospadias, whereas lamotrigine and carbamazepine were not. Interpretation: Topiramate is associated with an increased risk of MCM similar to that associated with valproate, but lower doses may mitigate the risks for both drugs. Conversely, we found no increased risks for lamotrigine, carbamazepine, oxcarbazepine, or levetiracetam, which is reassuring. ANN NEUROL 2022.

AB - Objective: This study was undertaken to examine the comparative safety of antiseizure medication (ASM) monotherapy in pregnancy with respect to risk of major congenital malformations (MCMs), overall and by MCM subtype. Methods: We conducted a population-based cohort study using national health register data from Denmark, Finland, Iceland, Norway, and Sweden (1996–2020). We compared pregnancies with first trimester exposure to lamotrigine monotherapy to ASM-unexposed, carbamazepine, valproate, oxcarbazepine, levetiracetam, and topiramate to lamotrigine monotherapy, and stratified monotherapy groups by dose. The outcome was nongenetic MCM and specific subtypes. We estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) with log-binomial regression and propensity score weights. Results: There was a higher crude risk of any MCM in pregnancies exposed to lamotrigine monotherapy (n = 8,339) compared to ASM-unexposed pregnancies (n = 4,866,362), but not after confounder adjustment (aRR = 0.97, 95% CI = 0.87–1.08). Compared to lamotrigine, there was an increased risk of malformations associated with valproate (n = 2,031, aRR = 2.05, 95% CI = 1.70–2.46) and topiramate (n = 509, aRR = 1.81, 95% CI = 1.26–2.60), which increased in a dose-dependent manner. We found no differences in malformation risk for carbamazepine (n = 2,674, aRR = 0.91, 95% CI = 0.72–1.15), oxcarbazepine (n = 1,313, aRR = 1.09, 95% CI = 0.83–1.44), or levetiracetam (n = 1,040, aRR = 0.78, 95% CI = 0.53–1.13). Valproate was associated with several malformation subtypes, including nervous system, cardiac, oral clefts, clubfoot, and hypospadias, whereas lamotrigine and carbamazepine were not. Interpretation: Topiramate is associated with an increased risk of MCM similar to that associated with valproate, but lower doses may mitigate the risks for both drugs. Conversely, we found no increased risks for lamotrigine, carbamazepine, oxcarbazepine, or levetiracetam, which is reassuring. ANN NEUROL 2022.

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U2 - 10.1002/ana.26561

DO - 10.1002/ana.26561

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SN - 0364-5134

JO - Annals of Neurology

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Comparative Safety of Antiseizure Medication Monotherapy for Major Malformations

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