SCAN-AED: Nordic register-based study of antiepileptic drugs in pregnancy
SCAN-AED is investigating the association between in utero exposure to antiepileptic drugs and folic acid supplements, and later disease in the mother and child.
SCAN-AED is a NordForsk funded Nordic multi-registry study aiming to find the optimal choice of antiepileptic drugs (AEDs) and folic acid treatment during pregnancy. We will examine the risk of physical and neuropsychiatric disease in the child after exposure to different antiepileptic drugs taken alone or in combination during pregnancy. We will also investigate how high dose folic acid modifies this risk. Maternal health during and after pregnancy will also be studied.
Uncontrolled epileptic seizures during pregnancy pose a risk both for the mother and child. Therefore, most women with epilepsy who are using antiepileptic drugs (AEDs) before conception need to do so during pregnancy as well. Unfortunately, many AEDs increase the risk of pregnancy complications and have teratogenic effects. Some AEDs cause major congenital malformations, autism spectrum disorders and impaired development in children exposed in utero. Women with epilepsy are advised to take a dose of folic acid up to 10 times higher than other women, based on the hypothesis that this might reduce the harmful effects of AEDs on the child. However, the efficacy and safety of this treatment strategy is not clear.
Several great joint international efforts have been made to shed light on the adverse effects of AEDs during pregnancy, but there are important unresolved questions due to the lack of statistical power in previous studies. SCAN-AED is a Nordic multi-register study aiming to find the optimal choice of AED and folic acid treatment during pregnancy. More specifically, we aim to examine the risk of physical and neuropsychiatric disease in the child after exposure to different antiepileptic drugs taken alone or in combination during pregnancy. We will also investigate how high dose folic acid modifies this risk. Maternal health during and after pregnancy will also be examined.
The project is a collaboration between epilepsy- and register-based research environments at Aarhus University (Denmark), University of Bergen (Norway), the National Institute for Health and Welfare (Finland) and Karolinska Institutet (Sweden). Data from Iceland will also be included. All five countries have similar population registries that can be linked by the personal identification number. The registers cover almost 20 million people, of whom about 120 000 will have active epilepsy. By linking the medical birth registries with information on maternal medication from the prescription registries, socioeconomic data from the National statistical institutions, and ICD codes for mothers and offspring from the patient registries, we will have an unselected material with very large statistical power that can be adjusted for important confounding factors. We will therefore be able to investigate the association between in utero exposure to various AED regimes and folic acid supplement doses, and later disease in the child and the mother. This study will thereby fill the knowledge gaps in international guidelines for pregnant women with epilepsy.
BIOS (core facility for biostatistics and data analysis, UiB)
The Norwegian Institute of Public Health (the NorPreSS study)
Nordic Microdata Access Network (NordMAN)
The project is financed by NordForsk
The group members are also funded by the University of Bergen, Helse Vest/Haukeland University Hospital, The Norwegian Epilepsy Association, Torbjørg Hauge’s legacy, Forsberg and Aulie’s legacy, Karolinska Insitutet, Aarhus Universitetssykehus, Universitetet i Aarhus, National Center for Epilepsy at Oslo University Hospital, and the National Institute for Health and Welfare in Finland.
Results and Publications
Publications in peer-reviewed journals:
Association of Prenatal Exposure to Antiseizure Medication With Risk of Autism and Intellectual Disability. Bjørk MH, Zoega H, Leinonen MK, Cohen JM, Dreier JW, Furu K, Gilhus NE, Gissler M, Hálfdánarson Ó, Igland J, Sun Y, Tomson T, Alvestad S, Christensen J. JAMA Neurol 2022 Jul 1;79(7):672-681. doi: 10.1001/jamaneurol.2022.1269.
Management of epilepsy in pregnancy: a report from the International League Against Epilepsy Task Force on Women and Pregnancy. Tomson T, Battino D, Bromley R, Kochen S, Meador K, Pennell P, Thomas SV. Epileptic Disord. 2019 Nov 29.
Prenatal exposure to valproate and risk of congenital malformations—Could we have known earlier?—A population-based cohort study. Christensen J, Trabjerg B, Sun Y, Gilhus NE, Bjørk MH, Tomson T, Dreier JW. Epilepsia. 2021 Sep 28. doi: 10.1111.
Abstracts and presentations:
Scandinavian multi-registry study of antiepileptic drug teratogenicity: the SCAN-AED study. Bjørk MH, Alvestad S, Gilhus NE, Dreier JW, Christensen J, Gissler M, Leinonen M, Tomson T. Oral presentation at the 11th NorPEN Meeting, Oslo 7-9 Nov 2018.
Scandinavian multi-registry study of antiepileptic drug teratogenicity: the SCAN-AED study. Bjørk MH, Alvestad S, Gilhus NE, Dreier JW, Christensen J, Gissler M, Leinonen M, Tomson T. Poster at the 5th Congress of European Academy of Neurology, Oslo June 30 – July 2, 2019.
SCAN-AED summary. Part of a joint position paper from the Danish Epidemiological Society, the Danish Society for Pharmacoepidemiology, and Statistics Denmark, 2019.
Autism and intellectual disability in children exposed to valproate, lamotrigine, carbamazepine and levetiracetam. Bjørk MH, Zoega H, Leinonen M, Alvestad S, Cohen JM, Dreier JW, Furu K, Gilhus NE, Gissler M, Hálfdánarson Ó, Igland J, Sun Y, Tomson T, Christensen J. Abstract for the 6th Congress of the European Academy of Neurology, 23-26 May 2020.
Prenatal antiseizure medication exposure and risk of autism and intellectual disability. SCAN-AED: a Nordic cohort study. Bjørk MH, Zoega H, Leinonen MK, Cohen JM, Dreier JW, Furu K, Gilhus NE, Gissler M, Hálfdánarson Ó, Igland J, Sun Y, Tomson T, Alvestad S, Christensen J. Oral presentation at the 7th Congress of the European Academy of Neurology, 19-22 June 2021.
Prenatal exposure to antiseizure medication and the full spectrum of diagnosed psychiatric disorders: A SCAN-AED study. Dreier JW, Bjørk MH, Alvestad S, Gissler M, Igland J, Leinonen MK, Sun Y, Cohen JM, Furu K, Zoega H, Tomson T, Christensen J. Oral presentation at the 7th Congress of the European Academy of Neurology, 19-22 June 2021.
International conference on antiepileptic drugs in pregnancy and risk for mother and child 2021
In May 2021, SCAN-AED and NorPreSS arranged the “International conference on antiepileptic drugs in pregnancy and risk for mother and child”. The conference was held in a digital format and gathered about 200 participants from 17 countries. Their professional backgrounds spanned from researchers, clinicians, pharmacologists, pharmacovigilance experts, and more. The program included presentations from the patient organization, young researchers, and leading scientists and clinicians in the field. The topics of the different sessions spanned from basic concepts of teratogenicity, methodological aspects, clinical aspects such as pharmacology, neurodevelopment, maternal morbidity and folate supplementation, as well as scientific presentations from SCAN-AED, NorPreSS and others. The conference received excellent feedback in the post-conference survey.
Administrative procedures and personal data protection measures
More than 30 Nordic registers have delivered data to SCAN-AED. The data are stored and managed safely at the research server of Statistics Denmark. Below is an account of the data administrative procedures in the project.
The source registers in SCAN-AED were the Birth Registers identifying the appropriate persons and passing personal identification numbers (PINs) to the other health registers and statistical agencies enabling extraction of data for them. The institutions responsible for the extraction and linkage were the national statistical agencies and in Norway: the Norwegian Prescription Database held by the Norwegian Institute of Public Health (NIPH), Sweden: the Swedish National Board of Health and Welfare, Finland: the Finnish Institute for Health and Welfare (THL) and the Social Insurance Institution of Finland (Kela), Denmark: The National Health Data Authority, and Iceland: the Icelandic Directorate of Health. In Finland, SCAN-AED is conducted under an ongoing project “Drugs and Pregnancy”. In Iceland, the files were provided by a similar study coordinated by the NIPH (NorPreSS).
Institutions responsible for the data extraction and linkage replaced PINs with case numbers before making data available for the researchers. Only investigators who were approved by all registry holders had access to the data. Datasets were delivered encrypted to the research server at Statistics Denmark.
The research environment of Statistics Denmark was used as this server is the only storage facility accepted by all the registry holders in the project. In particular, the medicinal legislation of Denmark limited the use of other research environments. The server is accessible by remote desktop. The Statistics Denmark server ensures that ID backtracking and other misuse is not possible by logging and monitoring the output export. Details concerning the rules for export of analysis results from the server can be found here, and are implemented to ensure that data security and confidentiality is guaranteed according to data protection legislation.
Transposing and merging of the files, variable harmonization and other procedures of critical importance were done by a specialized Stata programmer and epidemiologist employed by BIOS, UiB.
Harmonization of exposure and outcome variables and covariates from the different country registers were worked out by meetings/webinars in cooperation with the Nordic Pregnancy Drug Safety Studies (NorPreSS) study group.
For study participants (in Norwegian)
Dette er en nordisk registerstudie der formålet er å undersøke hvilke medikamentelle behandlingsstrategier i graviditeten som gir best fysisk og psykisk helse for mødre med epilepsi og deres barn. Vi vil koble Medisinsk fødselsregister med Reseptregisteret og Norsk Pasientregister i Norge, og tilsvarende i Sverige, Finland, Danmark og Island, samt innhente sosioøkonomisk informasjon fra de statistiske sentralbyråene. Data kobles av sentrale registermyndigheter og oppbevares trygt på en sikker forskningsserver. Det vil ikke være mulig å spore deltagernes identitet. Barn utsatt for epilepsimedikamenter i fosterlivet sammenlignes med barn uten slik eksponering med tanke på blant annet medfødte misdannelser og autisme. Vi deler barna inn i grupper etter type medikament og bruk av folsyretilskudd i statistiske modeller der også andre faktorer som kan påvirke utfallet tas høyde for. Mødrenes psykiske og fysiske helse under og etter graviditeten undersøkes også. Resultatene vil være fritt tilgjengelig gjennom publisering i åpne vitenskapelige kanaler.
Prosjektet er godkjent av regional etisk komité.
Telephone: (+47) 55 58 00 00
Visiting adress: Department of Neurology, Gamle hovedbygning, Jonas Liesvei 71, Haukeland Universitetssykehus
Marte Bjørk, MD PhD
Associate professor at the Department of Clinical Medicine, University of Bergen, and consultant neurologist at the Department of Neurology, Haukeland University Hospital. Principal investigator for SCAN-AED. Responsible for clinical guidelines for treatment of epilepsy in pregnancy in Norway. She...
Nils Erik Gilhus, MD PhD
Professor in neurology at University of Bergen and senior consultant at Department of Neurology, Haukeland University Hospital. Principle investigator (co) for SCAN-AED. He has been active in EAN, EFNS, UEMS-EBN, ISNI, Norwegian Brain Council, Norwegian Medical Association, NevroNor, Nansen...
Jakob Christensen, MD PhD
Jakob Christensen is an MD, with a PhD and Dr. Med. Sci. from Aarhus University. He is a certified specialist in Clinical Pharmacology and Neurology. He works as consultant neurologist at the Department of Neurology, Aarhus University Hospital. He is associate professor at Aarhus University Hospital...
Research Professor with faculty appointments at the National Institute for Health and Welfare, the University of Turku, Finland, the University of Oulu, Finland, and Karolinska Institute, Stockholm, Sweden. Main research focus has been in utilization of routinely collected health and welfare registers.
Maarit Leinonen, MD PhD
Project Manager in the “Drugs and Pregnancy” project, which is a joint project of the National Institute for Health and Welfare (THL), the Finnish Medicines Agency (FIMEA) and the Social Insurance Institution of Finland (Kela) launched in 2008. Project evaluates drug use during pregnancy and drug...
Torbjörn Tomson, MD PhD
Senior Professor of Neurology and Epileptology, Department of Clinical Neuroscience, Karolinska Institutet. Senior consultant Dept of Neurology, Karolinska University Hospital....
Silje Alvestad, MD PhD
Post-doctoral fellow in the SCAN-AED group at the University of Bergen, and consultant neurologist at the National Center for Epilepsy, Oslo, Norway. National coordinator of the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) in Norway.
Jannicke Igland, PhD
Statistician in the SCAN-AED project, associate professor and head of the Core facility for Biostatistics and Data analysis at Department of Global Public Health and Primary Care at the University of Bergen. Long experience with management and statistical analysis of registry data.
Julie Werenberg Dreier, MSPH PhD
Senior Researcher in the SCAN-AED group and epidemiologist with expertise in register-based studies within developmental epidemiology, including seizure disorders (epilepsy and febrile seizures), psychiatric disorders (e.g. autism and ADHD) and general cognitive development in children.
Yuelian Sun, MD PhD
Associate professor at Department of Neurology, Department of Clinical Medicine, Aarhus University.
Helga Zoega, PhD
The Icelandic team is headed by Helga Zoega, a pharmacoepidemiologist with expertise in utilisation and safety of medicines among vulnerable populations (e.g. pregnant women, children). She is a Professor of Public Health at the University of Iceland and Scientia Fellow at UNSWs Centre for Big Data...
Óskar Örn Hálfdánarson, PhD
Óskar Örn Hálfdánarson is a post-doctoral researcher who works at the Centre of Public Health at the University of Iceland and is a Visiting Fellow at the Centre for Big Data Research in Health (CBDRH) at the University of New South Wales (UNSW) in Sydney.
Researcher at the National Centre for Register-based Research, Aarhus University, Denmark. Working with management and statistical analysis of Danish registry data. Involved in different projects using register-based data to study the causes and consequences of psychiatric disorders including...