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August 27, 2019; 93 (9) Article

Declining malformation rates with changed antiepileptic drug prescribing

An observational study

Torbjörn Tomson, Dina Battino, Erminio Bonizzoni, John Craig, Dick Lindhout, Emilio Perucca, Anne Sabers, Sanjeev V. Thomas, Frank Vajda, for The EURAP Study Group
First published August 7, 2019, DOI: https://doi.org/10.1212/WNL.0000000000008001
Torbjörn Tomson
From the Department of Clinical Neuroscience (T.T.), Karolinska Institutet; Department of Neurology (T.T.), Karolinska University Hospital, Stockholm, Sweden; Epilepsy Center, Department of Neurophysiology and Experimental Epileptology (D.B.), Fondazione IRCCS Istituto Neurologico Carlo Besta; Department of Clinical Science and Community (E.B.), Section of Medical Statistics, Biometry and Epidemiology “G.A. Maccacaro,” Faculty of Medicine and Surgery, University of Milan, Italy; Belfast Health and Social Care Trust (J.C.), Belfast, UK; Department of Genetics (D.L.), University Medical Center Utrecht; Stichting Epilepsie Instellingen Nederland (SEIN) (D.L.), Heemstede, the Netherlands; Department of Internal Medicine and Therapeutics (E.P.), University of Pavia; Clinical Trial Center (E.P.), IRCCS Mondino Foundation, Pavia, Italy; The Epilepsy Clinic, Department of Neurology (A.S.), Rigshospitalet-Blegdamsvej, University State Hospital, Copenhagen, Denmark; Department of Neurology (S.V.T.), Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala State, India; Departments of Medicine and Neurology (F.V.), University of Melbourne and Monash University; and Royal Melbourne Hospital (F.V.), Australia.
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Dina Battino
From the Department of Clinical Neuroscience (T.T.), Karolinska Institutet; Department of Neurology (T.T.), Karolinska University Hospital, Stockholm, Sweden; Epilepsy Center, Department of Neurophysiology and Experimental Epileptology (D.B.), Fondazione IRCCS Istituto Neurologico Carlo Besta; Department of Clinical Science and Community (E.B.), Section of Medical Statistics, Biometry and Epidemiology “G.A. Maccacaro,” Faculty of Medicine and Surgery, University of Milan, Italy; Belfast Health and Social Care Trust (J.C.), Belfast, UK; Department of Genetics (D.L.), University Medical Center Utrecht; Stichting Epilepsie Instellingen Nederland (SEIN) (D.L.), Heemstede, the Netherlands; Department of Internal Medicine and Therapeutics (E.P.), University of Pavia; Clinical Trial Center (E.P.), IRCCS Mondino Foundation, Pavia, Italy; The Epilepsy Clinic, Department of Neurology (A.S.), Rigshospitalet-Blegdamsvej, University State Hospital, Copenhagen, Denmark; Department of Neurology (S.V.T.), Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala State, India; Departments of Medicine and Neurology (F.V.), University of Melbourne and Monash University; and Royal Melbourne Hospital (F.V.), Australia.
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Erminio Bonizzoni
From the Department of Clinical Neuroscience (T.T.), Karolinska Institutet; Department of Neurology (T.T.), Karolinska University Hospital, Stockholm, Sweden; Epilepsy Center, Department of Neurophysiology and Experimental Epileptology (D.B.), Fondazione IRCCS Istituto Neurologico Carlo Besta; Department of Clinical Science and Community (E.B.), Section of Medical Statistics, Biometry and Epidemiology “G.A. Maccacaro,” Faculty of Medicine and Surgery, University of Milan, Italy; Belfast Health and Social Care Trust (J.C.), Belfast, UK; Department of Genetics (D.L.), University Medical Center Utrecht; Stichting Epilepsie Instellingen Nederland (SEIN) (D.L.), Heemstede, the Netherlands; Department of Internal Medicine and Therapeutics (E.P.), University of Pavia; Clinical Trial Center (E.P.), IRCCS Mondino Foundation, Pavia, Italy; The Epilepsy Clinic, Department of Neurology (A.S.), Rigshospitalet-Blegdamsvej, University State Hospital, Copenhagen, Denmark; Department of Neurology (S.V.T.), Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala State, India; Departments of Medicine and Neurology (F.V.), University of Melbourne and Monash University; and Royal Melbourne Hospital (F.V.), Australia.
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John Craig
From the Department of Clinical Neuroscience (T.T.), Karolinska Institutet; Department of Neurology (T.T.), Karolinska University Hospital, Stockholm, Sweden; Epilepsy Center, Department of Neurophysiology and Experimental Epileptology (D.B.), Fondazione IRCCS Istituto Neurologico Carlo Besta; Department of Clinical Science and Community (E.B.), Section of Medical Statistics, Biometry and Epidemiology “G.A. Maccacaro,” Faculty of Medicine and Surgery, University of Milan, Italy; Belfast Health and Social Care Trust (J.C.), Belfast, UK; Department of Genetics (D.L.), University Medical Center Utrecht; Stichting Epilepsie Instellingen Nederland (SEIN) (D.L.), Heemstede, the Netherlands; Department of Internal Medicine and Therapeutics (E.P.), University of Pavia; Clinical Trial Center (E.P.), IRCCS Mondino Foundation, Pavia, Italy; The Epilepsy Clinic, Department of Neurology (A.S.), Rigshospitalet-Blegdamsvej, University State Hospital, Copenhagen, Denmark; Department of Neurology (S.V.T.), Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala State, India; Departments of Medicine and Neurology (F.V.), University of Melbourne and Monash University; and Royal Melbourne Hospital (F.V.), Australia.
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Dick Lindhout
From the Department of Clinical Neuroscience (T.T.), Karolinska Institutet; Department of Neurology (T.T.), Karolinska University Hospital, Stockholm, Sweden; Epilepsy Center, Department of Neurophysiology and Experimental Epileptology (D.B.), Fondazione IRCCS Istituto Neurologico Carlo Besta; Department of Clinical Science and Community (E.B.), Section of Medical Statistics, Biometry and Epidemiology “G.A. Maccacaro,” Faculty of Medicine and Surgery, University of Milan, Italy; Belfast Health and Social Care Trust (J.C.), Belfast, UK; Department of Genetics (D.L.), University Medical Center Utrecht; Stichting Epilepsie Instellingen Nederland (SEIN) (D.L.), Heemstede, the Netherlands; Department of Internal Medicine and Therapeutics (E.P.), University of Pavia; Clinical Trial Center (E.P.), IRCCS Mondino Foundation, Pavia, Italy; The Epilepsy Clinic, Department of Neurology (A.S.), Rigshospitalet-Blegdamsvej, University State Hospital, Copenhagen, Denmark; Department of Neurology (S.V.T.), Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala State, India; Departments of Medicine and Neurology (F.V.), University of Melbourne and Monash University; and Royal Melbourne Hospital (F.V.), Australia.
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Emilio Perucca
From the Department of Clinical Neuroscience (T.T.), Karolinska Institutet; Department of Neurology (T.T.), Karolinska University Hospital, Stockholm, Sweden; Epilepsy Center, Department of Neurophysiology and Experimental Epileptology (D.B.), Fondazione IRCCS Istituto Neurologico Carlo Besta; Department of Clinical Science and Community (E.B.), Section of Medical Statistics, Biometry and Epidemiology “G.A. Maccacaro,” Faculty of Medicine and Surgery, University of Milan, Italy; Belfast Health and Social Care Trust (J.C.), Belfast, UK; Department of Genetics (D.L.), University Medical Center Utrecht; Stichting Epilepsie Instellingen Nederland (SEIN) (D.L.), Heemstede, the Netherlands; Department of Internal Medicine and Therapeutics (E.P.), University of Pavia; Clinical Trial Center (E.P.), IRCCS Mondino Foundation, Pavia, Italy; The Epilepsy Clinic, Department of Neurology (A.S.), Rigshospitalet-Blegdamsvej, University State Hospital, Copenhagen, Denmark; Department of Neurology (S.V.T.), Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala State, India; Departments of Medicine and Neurology (F.V.), University of Melbourne and Monash University; and Royal Melbourne Hospital (F.V.), Australia.
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Anne Sabers
From the Department of Clinical Neuroscience (T.T.), Karolinska Institutet; Department of Neurology (T.T.), Karolinska University Hospital, Stockholm, Sweden; Epilepsy Center, Department of Neurophysiology and Experimental Epileptology (D.B.), Fondazione IRCCS Istituto Neurologico Carlo Besta; Department of Clinical Science and Community (E.B.), Section of Medical Statistics, Biometry and Epidemiology “G.A. Maccacaro,” Faculty of Medicine and Surgery, University of Milan, Italy; Belfast Health and Social Care Trust (J.C.), Belfast, UK; Department of Genetics (D.L.), University Medical Center Utrecht; Stichting Epilepsie Instellingen Nederland (SEIN) (D.L.), Heemstede, the Netherlands; Department of Internal Medicine and Therapeutics (E.P.), University of Pavia; Clinical Trial Center (E.P.), IRCCS Mondino Foundation, Pavia, Italy; The Epilepsy Clinic, Department of Neurology (A.S.), Rigshospitalet-Blegdamsvej, University State Hospital, Copenhagen, Denmark; Department of Neurology (S.V.T.), Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala State, India; Departments of Medicine and Neurology (F.V.), University of Melbourne and Monash University; and Royal Melbourne Hospital (F.V.), Australia.
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Sanjeev V. Thomas
From the Department of Clinical Neuroscience (T.T.), Karolinska Institutet; Department of Neurology (T.T.), Karolinska University Hospital, Stockholm, Sweden; Epilepsy Center, Department of Neurophysiology and Experimental Epileptology (D.B.), Fondazione IRCCS Istituto Neurologico Carlo Besta; Department of Clinical Science and Community (E.B.), Section of Medical Statistics, Biometry and Epidemiology “G.A. Maccacaro,” Faculty of Medicine and Surgery, University of Milan, Italy; Belfast Health and Social Care Trust (J.C.), Belfast, UK; Department of Genetics (D.L.), University Medical Center Utrecht; Stichting Epilepsie Instellingen Nederland (SEIN) (D.L.), Heemstede, the Netherlands; Department of Internal Medicine and Therapeutics (E.P.), University of Pavia; Clinical Trial Center (E.P.), IRCCS Mondino Foundation, Pavia, Italy; The Epilepsy Clinic, Department of Neurology (A.S.), Rigshospitalet-Blegdamsvej, University State Hospital, Copenhagen, Denmark; Department of Neurology (S.V.T.), Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala State, India; Departments of Medicine and Neurology (F.V.), University of Melbourne and Monash University; and Royal Melbourne Hospital (F.V.), Australia.
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Frank Vajda
From the Department of Clinical Neuroscience (T.T.), Karolinska Institutet; Department of Neurology (T.T.), Karolinska University Hospital, Stockholm, Sweden; Epilepsy Center, Department of Neurophysiology and Experimental Epileptology (D.B.), Fondazione IRCCS Istituto Neurologico Carlo Besta; Department of Clinical Science and Community (E.B.), Section of Medical Statistics, Biometry and Epidemiology “G.A. Maccacaro,” Faculty of Medicine and Surgery, University of Milan, Italy; Belfast Health and Social Care Trust (J.C.), Belfast, UK; Department of Genetics (D.L.), University Medical Center Utrecht; Stichting Epilepsie Instellingen Nederland (SEIN) (D.L.), Heemstede, the Netherlands; Department of Internal Medicine and Therapeutics (E.P.), University of Pavia; Clinical Trial Center (E.P.), IRCCS Mondino Foundation, Pavia, Italy; The Epilepsy Clinic, Department of Neurology (A.S.), Rigshospitalet-Blegdamsvej, University State Hospital, Copenhagen, Denmark; Department of Neurology (S.V.T.), Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala State, India; Departments of Medicine and Neurology (F.V.), University of Melbourne and Monash University; and Royal Melbourne Hospital (F.V.), Australia.
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From the Department of Clinical Neuroscience (T.T.), Karolinska Institutet; Department of Neurology (T.T.), Karolinska University Hospital, Stockholm, Sweden; Epilepsy Center, Department of Neurophysiology and Experimental Epileptology (D.B.), Fondazione IRCCS Istituto Neurologico Carlo Besta; Department of Clinical Science and Community (E.B.), Section of Medical Statistics, Biometry and Epidemiology “G.A. Maccacaro,” Faculty of Medicine and Surgery, University of Milan, Italy; Belfast Health and Social Care Trust (J.C.), Belfast, UK; Department of Genetics (D.L.), University Medical Center Utrecht; Stichting Epilepsie Instellingen Nederland (SEIN) (D.L.), Heemstede, the Netherlands; Department of Internal Medicine and Therapeutics (E.P.), University of Pavia; Clinical Trial Center (E.P.), IRCCS Mondino Foundation, Pavia, Italy; The Epilepsy Clinic, Department of Neurology (A.S.), Rigshospitalet-Blegdamsvej, University State Hospital, Copenhagen, Denmark; Department of Neurology (S.V.T.), Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala State, India; Departments of Medicine and Neurology (F.V.), University of Melbourne and Monash University; and Royal Melbourne Hospital (F.V.), Australia.
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Declining malformation rates with changed antiepileptic drug prescribing
An observational study
Torbjörn Tomson, Dina Battino, Erminio Bonizzoni, John Craig, Dick Lindhout, Emilio Perucca, Anne Sabers, Sanjeev V. Thomas, Frank Vajda, for The EURAP Study Group
Neurology Aug 2019, 93 (9) e831-e840; DOI: 10.1212/WNL.0000000000008001

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Abstract

Objective Changes in prescribing patterns of antiepileptic drugs (AEDs) in pregnant women with epilepsy would be expected to affect the risk of major congenital malformations (MCMs). To test this hypothesis, we analyzed data from an international pregnancy registry (EURAP).

Methods EURAP is an observational prospective cohort study designed to determine the risk of MCMs after prenatal exposure to AEDs. The Cochrane-Armitage linear trend analysis was used to assess changes in AED treatment, prevalence of MCMs, and occurrence of generalized tonic-clonic seizures (GTCs) over 3 time periods: 2000–2005 (n = 4,760), 2006–2009 (n = 3,599), and 2010–2013 (n = 2,949).

Results There were pronounced changes in the use of specific AEDs over time, with a decrease in the use of valproic acid and carbamazepine and an increase in the use of lamotrigine and levetiracetam. The prevalence of MCMs with monotherapy exposure decreased from 6.0% in 2000–2005 to 4.4% in 2010–2013. The change over time in MCM frequency after monotherapy exposure showed a significant linear trend in the crude analysis (p = 0.0087), which was no longer present after adjustment for changes in AED treatment (p = 0.9923). There was no indication of an increase over time in occurrence of GTCs during pregnancy.

Conclusions There have been major changes in AED prescription patterns over the years covered by the study. In parallel, we observed a significant 27% decrease in the prevalence of MCMs. The results of adjusting the trend analysis for MCMs for changes in AED treatment suggest that changes in prescription patterns played a major role in the reduction of teratogenic events.

Glossary

AED=
antiepileptic drug;
EMA=
European Medicines Agency;
GTC=
generalized tonic-clonic;
MCM=
major congenital malformation

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • ↵* These authors contributed equally to this work.

  • Coinvestigators are listed at links.lww.com/WNL/A946.

  • Editorial, Page 375

  • Patient Page Page e935

  • Received December 20, 2018.
  • Accepted in final form April 1, 2019.
  • © 2019 American Academy of Neurology
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