Levetiracetam (Epilepsy)

Exposed non-exposed, cohort studies

Study Country
Study period
Study design		 Data source Exposure definition Non-exposure definition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias
Alsaadi (Controls exposed to LTG)
2020 		United Arab Emirates
2008 - 2015
retrospective cohort 		The Obstetric Medicine Neurology Clinic at Corniche Hospital in Abu Dhabi, United Arab Emirates (UAE). Women with epilepsy who were taking Levetiracetam in monotherapy during the first trimester of pregnancy. exposed to other treatment, sick
Women with epilepsy who were taking Lamotrigine in monotherapy during the first trimester of pregnancy. 		1st trimester 46 / 13
Retrospective review: exposure pre-pregnancy and at conception until registered at the clinic was recorded.
Alsaadi (Controls unexposed sick)
2020 		United Arab Emirates
2008 - 2015
retrospective cohort 		The Obstetric Medicine Neurology Clinic at Corniche Hospital in Abu Dhabi, United Arab Emirates (UAE). Women with epilepsy who were taking Levetiracetam in monotherapy during the first trimester of pregnancy. unexposed, sick
Women with epilepsy who were not taking antiseizure drugs (ASDs) during the first trimester of pregnancy. 		1st trimester 46 / 40
Retrospective review: exposure pre-pregnancy and at conception until registered at the clinic was recorded.
Alsfouk (Levetiracetam)
2022 		Riyadh and Jeddah, Saudi Arabia.
2005 - 2020
retrospective cohort 		The King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh and Jeddah, Saudi Arabia. Epileptic mothers with levetiracetam monotherapy administered during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Epileptic mothers with lamotrigine monotherapy administered during pregnancy. 		during pregnancy (anytime or not specified) 24 / 15
Patients records.
Alsfouk (Levetiracetam) (Controls exposed to Lamotrigine, sick)
2021 		Riyadh and Jeddah, Saudi Arabia.
1993 - 2020
retrospective cohort 		The King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh and Jeddah, Saudi Arabia. Epileptic mothers with levetiracetam monotherapy administered during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Epileptic mothers with lamotrigine monotherapy administered during pregnancy. 		during pregnancy (anytime or not specified) 24 / 15
Patients’ electronic and paper-based medical records.
Alsfouk (Levetiracetam) (Controls unexposed, sick)
2021 		Riyadh and Jeddah, Saudi Arabia.
1993 - 2020
retrospective cohort 		The King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh and Jeddah, Saudi Arabia. Epileptic mothers with levetiracetam monotherapy administered during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Epileptic mothers who did not take antiseizure medications during pregnancies. 		during pregnancy (anytime or not specified) 24 / 30
Patients’ electronic and paper-based medical records.
AlSheikh (Levetiracetam) (Controls exposed to Lamotrigine, sick)
2020 		Saudi Arabia
2018 - 2019
prospective cohort 		King Fahd University Hospital Fetuses/neonates of patients with active epilepsy who received levetiracetam monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Fetuses/neonates of patients with active epilepsy who received lamotrigine monotherapy during pregnancy. 		during pregnancy (anytime or not specified) 9 / 20
Information was collected through a structured questionnaire ‘Questionnaire for Investigation of Epilepsy in Tropical Countries'.
AlSheikh (Levetiracetam) (Controls unexposed, sick)
2020 		Saudi Arabia
2018 - 2019
prospective cohort 		King Fahd University Hospital Fetuses/neonates of patients with active epilepsy who received levetiracetam monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Fetuses/neonates of patients with active epilepsy who did not take antiepileptic drugs during pregnancy. 		during pregnancy (anytime or not specified) 9 / 8
Information was collected through a structured questionnaire ‘Questionnaire for Investigation of Epilepsy in Tropical Countries'.
Arkilo (Levetiracetam)
2015 		USA
2006 - 2011
retrospective cohort 		Minnesota Epilepsy Group, P.A. of United Hospital and Children's Hospitals and Clinics of Minnesota Singleton whose epileptic mothers were exposed to levetiracetam monotherapy at any point during the pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Singleton whose epileptic mothers were exposed to lamotrigine monotherapy at any point during the pregnancy. 		during pregnancy (anytime or not specified) 11 / 24
Questionnaires were sent to women.
Artama (Levetiracetam) (Controls exposed to Lamotrigine, sick)
2013 		Finland
1996 - 2008
population based cohort retrospective 		The Medical Birth Register (MBR), the Finnish Malformation Register, the Special Refund Entitlement Register, the Register on Reimbursement Drugs and Cause-of-Death Register. Births in pregnant women with epilepsy exposed to levetiracetam in monotherapy 1 month prior to pregnancy and/or any time during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Births in pregnant women with epilepsy exposed to lamotrigine in monotherapy 1 month prior to pregnancy and/or any time during pregnancy. 		3rd trimester, during pregnancy (anytime or not specified) 13 / 173 Overlapping: For LBW and SGA: Artama 2013 included in a larger study published by Christensen 2024 ((longer study period, 5 countries and more pregnancies) => use of Christensen 2024 for these outcomes.
The Special Refund Entitlement Register and the Register on Reimbursement Drugs contained informations on maternal drug treatment under ATC category N03.
Artama (Levetiracetam) (Controls unexposed, disease free)
2013 		Finland
1996 - 2008
population based cohort retrospective 		The Medical Birth Register (MBR), the Finnish Malformation Register, the Special Refund Entitlement Register, the Register on Reimbursement Drugs and Cause-of-Death Register. Births in pregnant women with epilepsy exposed to levetiracetam in monotherapy 1 month prior to pregnancy and/or any time during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Births in pregnant women without epilepsy and unexposed to any antiepileptic drugs 1 month prior to pregnancy and/or any time during pregnancy. 		3rd trimester, during pregnancy (anytime or not specified) 13 / 721948 Overlapping: For LBW and SGA: Artama 2013 included in a larger study published by Christensen 2024 ((longer study period, 5 countries and more pregnancies) => use of Christensen 2024 for these outcomes.
The Special Refund Entitlement Register and the Register on Reimbursement Drugs contained informations on maternal drug treatment under ATC category N03.
Artama (Levetiracetam) (Controls unexposed, sick)
2013 		Finland
1996 - 2008
population based cohort retrospective 		The Medical Birth Register (MBR), the Finnish Malformation Register, the Special Refund Entitlement Register, the Register on Reimbursement Drugs and Cause-of-Death Register. Births in pregnant women with epilepsy exposed to levetiracetam in monotherapy 1 month prior to pregnancy and/or any time during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Births in pregnant women with epilepsy and unexposed to any antiepileptic drugs 1 month prior to pregnancy and/or any time during pregnancy. 		3rd trimester, during pregnancy (anytime or not specified) 13 / 1800 Overlapping: For LBW and SGA: Artama 2013 included in a larger study published by Christensen 2024 ((longer study period, 5 countries and more pregnancies) => use of Christensen 2024 for these outcomes.
The Special Refund Entitlement Register and the Register on Reimbursement Drugs contained informations on maternal drug treatment under ATC category N03.
Aydin (Levetiracetam) (Controls exposed to Lamotrigine, sick)
2020 		Turkey
2007 - 2017
retrospective cohort 		The Division of Perinatology, Department of Obstetrics and Gynecology, Hacettepe University Pregnant women with epilepsy who received levetiracetam in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Pregnant women with epilepsy who received lamotrigine in monotherapy during pregnancy. 		throughout pregnancy 10 / 7 There were no patients who had drug changes or discontinued during pregnancy.
Data were obtained from Perinatology Division’s computerized system. Antiepileptic drug use were reported.
Aydin (Levetiracetam) (Controls unexposed, sick)
2020 		Turkey
2007 - 2017
retrospective cohort 		The Division of Perinatology, Department of Obstetrics and Gynecology, Hacettepe University Pregnant women with epilepsy who received levetiracetam in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant women with epilepsy with no antiepileptic drugs during pregnancy. 		throughout pregnancy 10 / 22 There were no patients who had drug changes or discontinued during pregnancy.
Data were obtained from Perinatology Division’s computerized system. Antiepileptic drug use were reported.
Babic (Levetiracetam)
2014 		Serbia
1998 - 2008
prospective cohort 		Clinic of Neurology and Psychiatry for Children and Youth Children whose epileptic mothers were exposed to levetiracetam in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children whose epileptic mothers were exposed to lamotrigine in monotherapy during pregnancy. 		during pregnancy (anytime or not specified) 4 / 8
Not specified.
Battino
2024 		Worldwide (47 countries)
1999 - 2022
prospective cohort 		The International Registry of Antiepileptic Drugs and Pregnancy (EURAP). Pregnant women with epilepsy exposed to Levetiracetam monotherapy at the time of conception. exposed to other treatment, sick
Pregnant women with epilepsy exposed to lamotrigine monotherapy at the time of conception. 		early pregnancy 1325 / 3584 Overlapping/Update: (Major) malfo as a whole: Battino 2024 (1999-2022) updates and totally includes Tomson 2018 (1999-2016), Huber-Mollema 2019, Martinez 2018, Tomson 2011 => Use of Battino 2024 for these outcomes.
Reporting physicians collected information on drug therapy after each trimester.
Bhaskaran
2025 		India
Not specified.
prospective cohort 		The Kerala Registry of Epilepsy and Pregnancy (KREP). Children born to mothers with epilepsy with levetiracetam monotherapy during pregnancy. unexposed, disease free
Children born to mothers with no epilepsy during pregnancy and not exposed to antiseizure medications, chosen by convenience sampling from Child Development Centre which is a government aided tertiary care centre in South Kerala. 		during pregnancy (anytime or not specified) 10 / 50 Overlapping: LEV: data of Psychomotor and cognitive outcomes included in Thomas 2022a and b with more pregnancies and more relevant control groups => only langage outcomes of Bhaskaran 2025 reported here.
Not specified.
Bjørk (Levetiracetam) (Controls exposed to Lamotrigine, sick)
2018 		Norway
1999 - 2008
population based cohort propective 		The Norwegian Mother and Child Cohort Study (MoBa) and The Medical Birth Registry of Norway. Children of women with reported epilepsy and levetiracetam monotherapy use during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children of women with reported epilepsy and lamotrigine monotherapy use during pregnancy. 		during pregnancy (anytime or not specified) 16 / 104
Information on anti-epileptics use was obtained from the questionnaires completed by mothers during gestational weeks 17 to 19 (Q1) and 30 (Q2); and through the Medical Birth Registry of Norway.
Bjørk (Levetiracetam) (Controls exposed to Lamotrigine, sick)
2022 		Danemark, Finland, Iceland, Norway and Sweden.
1996 - 2017
population based cohort retrospective 		Social register data from Danemark, Finland, Iceland, Norway, Sweden for SCAN-AED: Nordic register-based study of antiepileptic drugs in pregnancy. Pregnacies in epileptic mothers (>90%) filling at least one levetiracetam monotherapy prescription from her last menstrual period until birth. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Pregnacies in epileptic mothers filling at least one lamotrigine monotherapy prescription from her last menstrual period until birth. 		during pregnancy (anytime or not specified) 1017 / 5073 Overlapping for ASD (2 outcomes): Dreier 2023 and Bjork 2022, with more pregnancies in Dreier 2023 => use of Dreier 2023 data. Intellectual disability not implemented owing to personal data protection restrictions on publishing cell counts less than 5.
Prescriptions through national prescription registers according to Anatomical Therapeutic Chemical classification codes N03, N05BA09, and S01EC01.
Bjørk (Levetiracetam) (Controls unexposed NOS)
2022 		Danemark, Finland, Iceland, Norway and Sweden.
1996 - 2017
population based cohort retrospective 		Social register data from Danemark, Finland, Iceland, Norway, Sweden for SCAN-AED: Nordic register-based study of antiepileptic drugs in pregnancy. Pregnacies in epileptic mothers (>90%) filling at least one levetiracetam monotherapy prescription from her last menstrual period until birth. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Pregnacies in mothers without antiseizure medication prescription from her last menstrual period until birth. 		during pregnancy (anytime or not specified) 1017 / 4463879 Overlapping for ASD (2 outcomes): Dreier 2023 and Bjork 2022, with more pregnancies in Dreier 2023 => use of Dreier 2023 data. Intellectual disability not implemented owing to personal data protection restrictions on publishing cell counts less than 5.
Prescriptions through national prescription registers according to Anatomical Therapeutic Chemical classification codes N03, N05BA09, and S01EC01.
Bjørk (Levetiracetam) (Controls unexposed, disease free)
2018 		Norway
1999 - 2008
population based cohort propective 		The Norwegian Mother and Child Cohort Study (MoBa) and The Medical Birth Registry of Norway. Children of women with reported epilepsy and levetiracetam monotherapy use during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
All children of mothers without reported epilepsy unexposed to antiepileptic drugs during pregnancy. 		during pregnancy (anytime or not specified) 16 / 104222
Information on anti-epileptics use was obtained from the questionnaires completed by mothers during gestational weeks 17 to 19 (Q1) and 30 (Q2); and through the Medical Birth Registry of Norway.
Bjørk (Levetiracetam) (Controls unexposed, sick)
2022 		Danemark, Finland, Iceland, Norway and Sweden.
1996 - 2017
population based cohort retrospective 		Social register data from Danemark, Finland, Iceland, Norway, Sweden for SCAN-AED: Nordic register-based study of antiepileptic drugs in pregnancy. Pregnacies in epileptic mothers filling at least one levetiracetam monotherapy prescription from her last menstrual period until birth. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnacies in epileptic mothers without antiseizure medication prescription from her last menstrual period until birth. 		during pregnancy (anytime or not specified) 1004 / 21634 Overlapping for ASD (2 outcomes): Dreier 2023 and Bjork 2022, with more pregnancies in Dreier 2023 => use of Dreier 2023 data. Intellectual disability not implemented owing to personal data protection restrictions on publishing cell counts less than 5.
Prescriptions through national prescription registers according to Anatomical Therapeutic Chemical classification codes N03, N05BA09, and S01EC01.
Bjørk (Levetiracetam) (Controls unexposed, sick)
2018 		Norway
1999 - 2008
population based cohort propective 		The Norwegian Mother and Child Cohort Study (MoBa) and The Medical Birth Registry of Norway. Children of women with reported epilepsy and levetiracetam monotherapy use during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Children of women with reported epilepsy but no antiepileptic drug intake during pregnancy. 		during pregnancy (anytime or not specified) 16 / 389 In this control group 127 (70.9%) reported inactive epilepsy defined as not using AEDs during the 2 years before conception or no seizures during the previous 5 years.
Information on anti-epileptics use was obtained from the questionnaires completed by mothers during gestational weeks 17 to 19 (Q1) and 30 (Q2); and through the Medical Birth Registry of Norway.
Bromley (Levetiracetam)
2016 		UK
2004 - 2007
retrospective cohort (registry) 		The UK Epilepsy and Pregnancy Register. Children whose epileptic mothers were exposed to levetiracetam monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Children whose epileptic mothers were untreated by antiepileptic drugs during their pregnancy. 		during pregnancy (anytime or not specified) 42 / 55 Design parts of this study were completed thanks to Morrow 2006. Families were not invited to participate if their child had a genetic condition associated with neurodevelopmental impairment.
Information was collected at registration and changes of antiepileptic drugs during pregnancy were detected during the follow-up duration by sending a standardised questionnaire to the patient's general practitioner. Other health care practitioners were contacted if identified.
Bromley (Levetiracetam) (Controls exposed to LTG)
2023 		United Kingdom
2014 - 2016
prospective cohort 		The NaME (Neurodevelopment of Babies Born to Mothers With Epilepsy) Study, recruiting across the North West and North East of England and from Northern Ireland, UK. Pregnant women with epilepsy exposed to Levetiracetam during pregnancy. exposed to other treatment, sick
Pregnant women with epilepsy exposed to Lamotrigine during pregnancy. 		during pregnancy (anytime or not specified) 70 / 106
The prescribed dose of the antiseizure medications was recorded prospectively from both medical records and maternal interviews at recruitment, and then again at ≥32 weeks gestation (by telephone interviews).
Bromley (Levetiracetam) (Controls unexposed, sick)
2023 		United Kingdom
2014 - 2016
prospective cohort 		The NaME (Neurodevelopment of Babies Born to Mothers With Epilepsy) Study, recruiting across the North West and North East of England and from Northern Ireland, UK. Pregnant women with epilepsy exposed to Levetiracetam during pregnancy. unexposed, sick
Pregnant women with epilepsy and with no antiseizure medication. 		during pregnancy (anytime or not specified) 70 / 80
The prescribed dose of the antiseizure medications was recorded prospectively from both medical records and maternal interviews at recruitment, and then again at ≥32 weeks gestation (by telephone interviews).
Christensen (Levetiracetam) (Epilepsy) (Controls exposed to LTG)
2024 		Denmark, Finland, Iceland, Norway, and Sweden
1996 - 2017
population based cohort retrospective 		Nordic population-based cohort study including register data from Denmark, Finland, Iceland, Norway, and Sweden–the SCAN-AED project. Children of mothers with epilepsy who had redeemed at least one prescription of Levetiracetam monotherapy from 30 days before the first day of the last menstrual period to the date of birth (i.e., the exposure period). exposed to other treatment, sick
Children of mothers who had redeemed at least one prescription of Lamotrigine monotherapy from 30 days before the first day of the last menstrual period to the date of birth (i.e., the exposure period). 		during pregnancy (anytime or not specified) 1063 / 5299 Overlapping: For LBW and SGA: Christensen 2024 totally included Artama 2013 => use of Christensen 2024 for these outcomes (longer study period, 5 countries and more pregnancies).
Prenatal exposure was identified via national prescription registers. These registers contain the Anatomical Therapeutic Chemical (ATC) classification code (www.whocc.no) and the date of dispensing.
Christensen (Levetiracetam) (Epilepsy) (Controls unexposed, general population)
2024 		Denmark, Finland, Iceland, Norway, and Sweden
1996 - 2017
population based cohort retrospective 		Nordic population-based cohort study including register data from Denmark, Finland, Iceland, Norway, and Sweden–the SCAN-AED project. Children of mothers with epilepsy who had redeemed at least one prescription of Levetiracetam monotherapy from 30 days before the first day of the last menstrual period to the date of birth (i.e., the exposure period). unexposed, sick
Children of mothers with epilepsy who had not redeemed prescription of anti-seizure medication. 		during pregnancy (anytime or not specified) 1063 / 22227 Overlapping: For LBW and SGA: Christensen 2024 totally included Artama 2013 => use of Christensen 2024 for these outcomes (longer study period, 5 countries and more pregnancies).
Prenatal exposure was identified via national prescription registers. These registers contain the Anatomical Therapeutic Chemical (ATC) classification code (www.whocc.no) and the date of dispensing.
Cohen (Levetiracetam) (Epilepsy) (Controls exposed to LTG)
2023 		Denmark, Finland, Iceland, Norway, and Sweden
1996 - 2020
population based cohort retrospective 		Health national registers from the 5 Nordic countries. Pregnancies in which the mother had filled one or more prescriptions of levetiracetam ([ATC] code N03AX14) monotherapy during the first trimester. exposed to other treatment, sick
Pregnancies in which the mother had filled one or more prescriptions of lamotrigine monotherapy during the first trimester. 		1st trimester 1040 / 8339 Main levetiracetam indication: 99% epilepsy. Overlapping: Cohen 2023 and Veiby 2014 => less of 50% of overlapping => the 2 studies were kept.
Data on filled prescriptions were obtained from the medical birth registers linked with registers for prescribed drugs.
Cohen (Levetiracetam) (Epilepsy) (Controls unexposed, NOS)
2023 		Denmark, Finland, Iceland, Norway, and Sweden
1996 - 2020
population based cohort retrospective 		Health national registers from the 5 Nordic countries. Pregnancies in which the mother had filled one or more prescriptions of levetiracetam ([ATC] code N03AX14) monotherapy during the first trimester. unexposed (general population or NOS)
Pregnancies in which the mother had not filled a prescription for any Antiseizure medication (ATC code N03A) from 90 days before LMP to the end of the first trimester. 		1st trimester 1040 / 4866362 Main levetiracetam indication: 99% epilepsy. Overlapping: Cohen 2023 and Veiby 2014 => less of 50% of overlapping => the 2 studies were kept.
Data on filled prescriptions were obtained from the medical birth registers linked with registers for prescribed drugs.
Coste (Levetiracetam) (Controls exposed to Lamotrigine, sick)
2020 		France
2011 - 2014
retrospective cohort (claims database) 		The French national health data system (SNDS) Children born from mothers exposed to levetiracetam monotherapy indicated for the treatment of epilepsy with at least one dispensing between the month preceding onset of pregnancy and its end. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children born from mothers exposed to lamotrigine monotherapy (i.e. with no other medication indicated for epilepsy) indicated for the treatment of epilepsy during pregnancy. 		during pregnancy (anytime or not specified) 621 / 2108 Children with a diagnosis of brain malformation (ICD-10 codes Q00 to Q04 and Q05.0 to Q05.4) during their stay in the maternity unit are excluded. Results are extracted from Blotière et al. 2020 because they reported aOR for vs LTG.
Defned by at least one dispensing of the drug to the mother between the beginning of the month preceding onset of pregnancy and the end of pregnancy. Mother had used this drug as monotherapy, defined by the use of a single drug during pregnancy.
Coste (Levetiracetam) (Controls unexposed, NOS)
2020 		France
2011 - 2014
retrospective cohort (claims database) 		The French national health data system (SNDS) Children born from mothers exposed to levetiracetam monotherapy indicated for the treatment of epilepsy with at least one dispensing between the month preceding onset of pregnancy and its end. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Children born from mothers not exposed to any antiepileptic drug during pregnancy. 		during pregnancy (anytime or not specified) 621 / 1710441 Children with a diagnosis of brain malformation (ICD-10 codes Q00 to Q04 and Q05.0 to Q05.4) during their stay in the maternity unit are excluded.
Defned by at least one dispensing of the drug to the mother between the beginning of the month preceding onset of pregnancy and the end of pregnancy. Mother had used this drug as monotherapy, defined by the use of a single drug during pregnancy.
Dreier (Levetiracetam) (Epilepsy) (Controls exposed to LTG)
2023 		Denmark, Finland, Iceland, Norway, and Sweden.
1996 - 2017
population based cohort propective 		A prospective, population-based register study within the SCAN-AED project, based on children born in Denmark, Finland, Iceland, Norway, and Sweden. Children prenatally exposed to Levetiracetam monotherapy, i.e whose mother had redeemed 1 or more prescriptions during the exposure window, which was defined as 30 days before the first day of the last menstrual period (estimated using gestational age in days at birth) until the date of birth. exposed to other treatment, sick
Children prenatally exposed to Lamotrigine monotherapy, i.e whose mother had redeemed 1 or more prescriptions during the exposure window, which was defined as 30 days before the first day of the last menstrual period (estimated using gestational age in days at birth) until the date of birth. 		during pregnancy (anytime or not specified) 1061 / 5288 Overlapping for ASD (2 outcomes): Dreier 2023 and Bjork 2022, with more pregnancies in Dreier 2023 => use of Dreier 2023 data.
Information on use of antiseizure medications was based on the national prescription registers, which contain information on all reimbursed prescription medications dispensed at pharmacies in each country, including date of dispensing and Anatomical Therapeutic Chemical (ATC) classification code.
Dreier (Levetiracetam) (Epilepsy) (Controls unexposed, sick)
2023 		Denmark, Finland, Iceland, Norway, and Sweden.
1996 - 2017
population based cohort propective 		A prospective, population-based register study within the SCAN-AED project, based on children born in Denmark, Finland, Iceland, Norway, and Sweden. Children prenatally exposed to Levetiracetam monotherapy, i.e whose mother had redeemed 1 or more prescriptions during the exposure window, which was defined as 30 days before the first day of the last menstrual period (estimated using gestational age in days at birth) until the date of birth. unexposed, sick
Children not prenatally exposed to antiseizure medication. 		during pregnancy (anytime or not specified) 1061 / 22203 Overlapping for ASD (2 outcomes): Dreier 2023 and Bjork 2022, with more pregnancies in Dreier 2023 => use of Dreier 2023 data.
Information on use of antiseizure medications was based on the national prescription registers, which contain information on all reimbursed prescription medications dispensed at pharmacies in each country, including date of dispensing and Anatomical Therapeutic Chemical (ATC) classification code.
Ertürk Çetin (Epilepsy) (Levetiracetam)
2024 		Turkey
Not specified.
prospective cohort 		Two university hospital epilepsy centers, Istanbul, Turkey. Pregnant women with a diagnosis of epilepsy who were continuously treated with Levetiracetam monotherapy from conception throughout pregnancy. exposed to other treatment, sick
Pregnant women with a diagnosis of epilepsy who were continuously treated with Lamotrigine monotherapy from conception throughout pregnancy. 		throughout pregnancy 18 / 9
Patients with a diagnosis of epilepsy and who become pregnant were selected and followed prospectively. All patients were compliant with the treatment. The compliance was assessed through clinical interviews (no details).
Hao (Controls exposed to LTG)
2025 		China
Not specified.
prospective cohort 		The West China Registry of Pregnancy in Epilepsy (WCRP_ Epi), an ongoing prospective multicenter cohort study based in Sichuan Province, Southwest China. Pregnant women with confirmed epilepsy that used levetiracetam monotherapy during the first trimester of pregnancy. exposed to other treatment, sick
Pregnant women with confirmed epilepsy that used lamotrigine monotherapy during the first trimester of pregnancy. 		1st trimester 268 / 84 Use of monotherapy data (table 2).
Treatment information was collected through case report forms mainly through face-to-face visits in the neurology clinic or remotely by video/telephone calls, at each trimester of pregnancy.
Hao (Controls unexposed, sick)
2025 		China
Not specified.
prospective cohort 		The West China Registry of Pregnancy in Epilepsy (WCRP_ Epi), an ongoing prospective multicenter cohort study based in Sichuan Province, Southwest China. Pregnant women with confirmed epilepsy that used levetiracetam monotherapy during the first trimester of pregnancy. unexposed, sick
Pregnant women with confirmed epilepsy and no anti-seizure medication use during the first trimester. 		1st trimester 268 / 261 Use of monotherapy data (table 2).
Treatment information was collected through case report forms mainly through face-to-face visits in the neurology clinic or remotely by video/telephone calls, at each trimester of pregnancy.
Hernández-Díaz (Levetiracetam) (Controls exposed to Lamotrigine, sick)
2012 		North America and Canada
1997 - 2011
prospective cohort 		The North American Antiepileptic Drug Pregnancy Register and the Active Malformations Surveillance Program. Infants of pregnant women who used levetiracetam for epileptic indication as monotherapy, during the first 4 lunar months after the last menstrual period (equal 16 weeks of gestation). (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Infants of pregnant women who used lamotrigine for mixed indications as monotherapy, during the first 4 lunar months after the last menstrual period (equal 16 weeks of gestation). 		1st trimester 450 / 1562 Less than 90% of women are taking Lamotrigine for epilepsy.
Women were questioned with a computer-assisted telephone interview 3 times.
Hernández-Díaz (Levetiracetam) (Controls unexposed, disease free)
2012 		North America and Canada
1997 - 2011
prospective cohort 		The North American Antiepileptic Drug Pregnancy Register and the Active Malformations Surveillance Program. Infants of pregnant women who used levetiracetam for epileptic indication as monotherapy, during the first 4 lunar months after the last menstrual period (equal 16 weeks of gestation). (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Infants of pregnant women, not taking an antiepileptic drug and without epilepsy, who were recruited from among the friends and family members of the enrolled women taking an antiepileptic drug. 		1st trimester 450 / 442
Women were questioned with a computer-assisted telephone interview 3 times.
Hoeltzenbein (Levetiracetam)
2024 		Germany
2000 - 2017
prospective cohort 		The Embryotox Center of Clinical Teratology and Drug Safety in Pregnancy (Embryotox), Berlin, Germany. Pregnancies with levetiracetam monotherapy for epilepsy during the first trimester. exposed to other treatment, sick
Pregnancies with monotherapy of lamotrigine in women with epilepsy. 		at least 1st trimester 221 / 469 The median daily levetiracetam dose at conception was 1500mg (interquartile range [IQR] =1000–2000mg, n=339). Data of overall levetiracetam cohort not reported because mono and polytherapies (60/40%).
Drug exposure is documented at the first consultation (when neither pregnancy outcome nor pathological results from prenatal diagnostics were known).
Hosny (Levetiracetam) (Controls exposed to Lamotrigine, sick)
2021 		Egypt
2018 - 2020
prospective cohort 		Kasr Al-Ainy Hospital, Cairo University, Egypt Pregnant women with epilepsy on levetiracetam monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Pregnant women with epilepsy on lamotrigine monotherapy during the first trimester. 		1st trimester 67 / 1 Each woman had one pregnancy during the study period. The correct figures were sent by the authors.
The following data were evaluated: seizure control 6 months before pregnancy, seizure control during each trimester, type and dose of ASMs at conception.
Hosny (Levetiracetam) (Controls unexposed, sick)
2021 		Egypt
2018 - 2020
prospective cohort 		Kasr Al-Ainy Hospital, Cairo University, Egypt Pregnant women with epilepsy on levetiracetam monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant women with epilepsy with no treatment during the first trimester. 		1st trimester 67 / 21 Each woman had one pregnancy during the study period. The correct figures were sent by the authors.
The following data were evaluated: seizure control 6 months before pregnancy, seizure control during each trimester, type and dose of ASMs at conception.
Huber-Mollema (Levetiracetam)
2019 		The Netherlands
2015 - 2018
prospective cohort 		The Dutch European Registry of Antiepileptic Drugs and Pregnancy (EURAP) Children age between 6 years and 7 years 11 months of mothers with epilepsy exposed to levetiracetam monotherapy starting before conception and continuing during the entire pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children age between 6 years and 7 years 11 months of mothers with epilepsy exposed to lamotrigine monotherapy starting before conception and continuing during the entire pregnancy. 		throughout pregnancy 30 / 88 The method for measuring exposure is not specified, although the EURAP registry method was thought to be used. Overlapping: For malformations: data totally included in Battino 2024 => not reported here.
The data concerning treatment at the time of conception are obtained by the physicians responsible for the women’s care and transferred online.
Husebye (Levetiracetam) (Controls exposed to Lamotrigine, sick)
2020 		Norway
1999 - 2008
population based cohort propective 		Norwegian Mother and Child Cohort Study (MoBa) and The Medical Birth Registry of Norway. Children of mothers with epilepsy exposed to levetiracetam monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children of mothers with epilepsy exposed to lamotrigine monotherapy during pregnancy. 		during pregnancy (anytime or not specified) 17 / 112
Information on the anti-epileptic (AED) use was obtained from the maternal questionnaires completed during gesta week 17–19 and week 30 and from Medical Birth Registry data. AEDs plasma concentrations were analysed in maternal and umbilical cord samples (73%) and were detected in 93% of children.
Husebye (Levetiracetam) (Controls unexposed, disease free)
2020 		Norway
1999 - 2008
population based cohort propective 		Norwegian Mother and Child Cohort Study (MoBa) and The Medical Birth Registry of Norway. Children of mothers with epilepsy exposed to levetiracetam monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Children of mothers without epilepsy. 		during pregnancy (anytime or not specified) 17 / 113674
Information on the anti-epileptic (AED) use was obtained from the maternal questionnaires completed during gesta week 17–19 and week 30 and from Medical Birth Registry data. AEDs plasma concentrations were analysed in maternal and umbilical cord samples (73%) and were detected in 93% of children.
Husebye (Levetiracetam) (Controls unexposed, sick)
2020 		Norway
1999 - 2008
population based cohort propective 		Norwegian Mother and Child Cohort Study (MoBa) and The Medical Birth Registry of Norway. Children of mothers with epilepsy exposed to levetiracetam monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Children of mothers with epilepsy unexposed to antiepileptic durgs during pregnancy. 		during pregnancy (anytime or not specified) 17 / 388 For this comparison group, results are only available according to folic acid intake.
Information on the anti-epileptic (AED) use was obtained from the maternal questionnaires completed during gesta week 17–19 and week 30 and from Medical Birth Registry data. AEDs plasma concentrations were analysed in maternal and umbilical cord samples (73%) and were detected in 93% of children.
Koc (Levetiracetam)
2018 		Turkey
2001 - 2017
retrospective cohort 		Ankara Training and Research Hospital files Pregnancies in women with epilepsy who were exposed to levetiracetam treatment during pregnancy in the form of monotherapy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnancies in women with epilepsy who did not receive any antiepileptic drug during pregnancy. 		during pregnancy (anytime or not specified) 30 / 35
The files were evaluated. The antiepileptic drug used by the patients were recorded.
Li (Levetiracetam) (Controls exposed to LTG)
2023 		China
2009 - 2022
prospective cohort 		A prospective cohort study entitled 'Construction and Application of the Women with Epilepsy of Child-bearing Age Ontology (WWECA)', with West China Hospital of Sichuan University as the main center. Women with epilepsy (WWE) using Levetiracetam monotherapy during pregnancy. exposed to other treatment, sick
Women with epilepsy (WWE) using Lamotrigine monotherapy during pregnancy. 		during pregnancy (anytime or not specified) 107 / 38 Authors did not provide analysis after monotherapy exposure but raw data of major congenital malformation provided in the e-Supp allowed to extract data for monotherapy => only this outcome reported here. Overlapping: He 2017 totally included in Li 2023.
The use of antiseizure medications on the included patients was registered by doctors and trained researchers.
Li (Levetiracetam) (Controls unexposed, sick)
2023 		China
2009 - 2022
prospective cohort 		A prospective cohort study entitled 'Construction and Application of the Women with Epilepsy of Child-bearing Age Ontology (WWECA)', with West China Hospital of Sichuan University as the main center. Women with epilepsy (WWE) using Levetiracetam monotherapy during pregnancy. unexposed, sick
Women with epilepsy (WWE) not using antiseizure medications during pregnancy. 		during pregnancy (anytime or not specified) 107 / 253 Authors did not provide analysis after monotherapy exposure but raw data of major congenital malformation provided in the e-Supp allowed to extract data for monotherapy => only this outcome reported here. Overlapping: He 2017 totally included in Li 2023.
The use of antiseizure medications on the included patients was registered by doctors and trained researchers.
Madley-Dowd_SE (Levetiracetam) (Controls exposed to LTG)
2024 		Sweden
1995 - 2020
population based cohort retrospective 		The Swedish Developmental Origins of Health and Disease (DOHaD) cohort, which is a registry study linking several national electronic data sources. Fetal exposure to Levetiracetam monotherapy for epilepsy indication at any time during the pregnancy period, i.e any pregnancy with self-reported consumption during pregnancy or a prescription 30 days before pregnancy or during pregnancy. exposed to other treatment, sick
Fetal exposure to Lamotrigine monotherapy for epilepsy indication at any time during the pregnancy period, i.e any pregnancy with self-reported consumption during pregnancy or a prescription 30 days before pregnancy or during pregnancy. 		during pregnancy (anytime or not specified) 556 / 2383 Data extracted from the e-Supp pdf (Table S10).
Self-reported maternal consumption of antiseizure medications were prospectively recorded at antenatal care visits (from a structured interview at the first visit at 8–10 weeks of gestation, supplemented from 2005 with drug all prescription dispensations in Sweden (tetrachoric correlation 0.98).
Madley-Dowd_SE (Levetiracetam) (Controls unexposed, sick)
2024 		Sweden
1995 - 2020
population based cohort retrospective 		The Swedish Developmental Origins of Health and Disease (DOHaD) cohort, which is a registry study linking several national electronic data sources. Fetal exposure to Levetiracetam monotherapy for epilepsy indication at any time during the pregnancy period, i.e any pregnancy with self-reported consumption during pregnancy or a prescription 30 days before pregnancy or during pregnancy. unexposed, sick
No fetal exposure to antiseizure medication at any time during the pregnancy period, restricted for epilepsy indication. 		during pregnancy (anytime or not specified) 556 / 10769 Data extracted from the excel file (Tab Fig S12) and the e-Supp pdf (Table S10).
Self-reported maternal consumption of antiseizure medications were prospectively recorded at antenatal care visits (from a structured interview at the first visit at 8–10 weeks of gestation, supplemented from 2005 with drug all prescription dispensations in Sweden (tetrachoric correlation 0.98).
Madley-Dowd_UK (Levetiracetam) (Epilepsy)
2024 		United Kingdom
1995 - 2018
retrospective cohort (claims database) 		The UK primary care-based Clinical Practice Research Datalink (CPRD) GOLD, with linkage to the CPRD Pregnancy Register, the CPRD Mother-Baby link, the Hospital Episode Statistics (HES) database, ... Fetal exposure to Levetiracetam monotherapy for epilepsy indication at any time during the pregnancy period, i.e any pregnancy with a prescription that started or ended during the pregnancy period. unexposed, sick
No fetal exposure to antiseizure medication at any time during the pregnancy period, restricted for epilepsy indication. 		during pregnancy (anytime or not specified) 174 / 4075 Partial overlapping of swedish data with Bjork 2022 and Dreier 2023 (IQ, ASD, ADHD) => these studies were kept and tagged. => Data extracted from the excel file (Tab Fig S12) and the e-Supp pdf (Table S10).
Prescriptions were identified from primary care records.
Margulis
2019 		Sweden
1996 - 2013
population based cohort retrospective 		Nationwide Swedish register data (the Swedish Medical Birth Register, The Prescribed Drug Register and the National Patient Register). Infants whose mothers reported use of levetiracetam monotherapy at any time during pregnancy. exposed to other treatment, sick
Infants whose mothers reported use of lamotrigine at any time during pregnancy. 		during pregnancy (anytime or not specified) 127 / 1812 Monotherapy results available in e-Supp tables (S3 File).
Information on exposure was obtained from prescriptions dispensed and from self-report in the first prenatal visit and from self-reports in subsequent prenatal visits.
Mari (Levetiracetam)
2022 		Rome, Italy
2009 - 2019
retrospective cohort 		The Epilepsy Center of Policlinico Tor Vergata and the Epilepsy Center of Policlinico Campus Bio-Medico Women with focal epilepsy (FE) or generalized epilepsy (GE) undergoing Anti-seizure medications monotherapy with levetiracetam. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Women with focal epilepsy (FE) or generalized epilepsy (GE) undergoing Anti-seizure medications monotherapy with lamotrigine. 		throughout pregnancy 17 / 11 In 46 out of 57 pregnancies, ASMs therapy remained unchanged during gestation (only one switch from CBZ to LEV, others are dosage-related).
Collected data at Epilepsy centers.
Meador (Controls exposed to LTG)
2023 		USA
2012 - 2016
prospective cohort 		The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a prospective, observational, multicentre cohort study at 20 specialty epilepsy centres in the USA. Children born to women with epilepsy treated with Levetiracetam monotherapy. exposed to other treatment, sick
Children born to women with epilepsy treated with lamotrigine monotherapy. 		during pregnancy (anytime or not specified) 74 / 90 Overlapping: Meador 2021 and 2023 used the same cohort in order to study the same outcome, at 2 different ages (=> use of the data on the older children, i.e Meador 2023).
Data for antiseizure medications were collected using a daily electronic diary and verified at study visits and with medical records.
Meador (Controls unexposed, disease free)
2023 		USA
2012 - 2016
prospective cohort 		The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a prospective, observational, multicentre cohort study at 20 specialty epilepsy centres in the USA. Children born to women with epilepsy treated with Levetiracetam monotherapy. unexposed, disease free
Children born to women without epilepsy. 		during pregnancy (anytime or not specified) 74 / 106 Overlapping: Meador 2021 and 2023 used the same cohort in order to study the same outcome, at 2 different ages (=> use of the data on the older children, i.e Meador 2023).
Data for antiseizure medications were collected using a daily electronic diary and verified at study visits and with medical records.
Meador (Levetiracetam) (Controls exposed to Lamotrigine, sick)
2020 		US
2012 - 2016
prospective cohort 		The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study (20 US tertiary epilepsy centers). Children born to pregnant women with epilepsy exposed to levetiracetam monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children born to pregnant women with epilepsy exposed to lamotrigine monotherapy during the first trimester. 		1st trimester 99 / 113
Data were obtained from participants and their medical records.
Meador (Levetiracetam) (Controls unexposed, disease free)
2020 		US
2012 - 2016
prospective cohort 		The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study (20 US tertiary epilepsy centers). Children born to pregnant women with epilepsy exposed to levetiracetam monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Children born to healthy pregnant women. 		1st trimester 99 / 106
Data were obtained from participants and their medical records.
Meador (Levetiracetam) (Controls unexposed, sick)
2020 		US
2012 - 2016
prospective cohort 		The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study (20 US tertiary epilepsy centers). Children born to pregnant women with epilepsy exposed to levetiracetam monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Children born to pregnant women with epilepsy with no antiepileptic drug use. 		1st trimester 99 / 15
Data were obtained from participants and their medical records.
Morrow (Levetiracetam) (Controls exposed to Lamotrigine, sick)
2006 		UK and Ireland
1996 - 2005
prospective cohort 		The UK Epilepsy and Pregnancy Register Infants of women with epilepsy exposed to levetiracetam in monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Infants of women with epilepsy exposed to lamotrigine in monotherapy during the first trimester. 		1st trimester 22 / 647 Exposure period is completed thanks to Campbell 2014 which is also a UKEPR based study.
Information was collected at registration and changes of antiepileptic drugs during pregnancy were detected during the follow-up duration by sending a standardised questionnaire to the patient's general practitioner. Other health care practitioners were contacted if identified.
Morrow (Levetiracetam) (Controls unexposed, sick)
2006 		UK and Ireland
1996 - 2005
prospective cohort 		The UK Epilepsy and Pregnancy Register Infants of women with epilepsy exposed to levetiracetam in monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Infants of women with epilepsy and who didn't take any antiepileptic drugs during pregnancy. 		1st trimester 22 / 227 Exposure period is completed thanks to Campbell 2014 which is also a UKEPR based study.
Information was collected at registration and changes of antiepileptic drugs during pregnancy were detected during the follow-up duration by sending a standardised questionnaire to the patient's general practitioner. Other health care practitioners were contacted if identified.
Pekoz (Levetiracetam) (Epilepsy) (Controls exposed to LTG)
2023 		Turkey
2014 - 2019
prospective cohort 		A Nationwide multicenter study, based on the neurology outpatient clinics of 21 centers in Turkey. Pregnant women with epilepsy (PWWE) receiving Levetiracetam as monotherapy. exposed to other treatment, sick
Pregnant women with epilepsy (PWWE) receiving Lamotrigine as monotherapy. 		during pregnancy (anytime or not specified) 152 / 141
The patients were examined by a neurologist every 2 months during pregnancy, and the use of Anti-seizure medications (ASMs) was assessed.
Pekoz (Levetiracetam) (Epilepsy) (Controls unexposed, sick)
2023 		Turkey
2014 - 2019
prospective cohort 		A Nationwide multicenter study, based on the neurology outpatient clinics of 21 centers in Turkey. Pregnant women with epilepsy (PWWE) receiving Levetiracetam as monotherapy. unexposed, sick
Pregnant women with epilepsy (PWWE), antiseizure medication free. 		during pregnancy (anytime or not specified) 152 / 43
The patients were examined by a neurologist every 2 months during pregnancy, and the use of Anti-seizure medications (ASMs) was assessed.
Razaz (Levetiracetam)
2024 		Denmark, Finland, Iceland, Norway and Sweden.
1996 - 2017
population based cohort retrospective 		The SCAN-AED project, using the Nordic register infrastructures. Mothers with epilepsy who filled a prescription for Levetiracetam monotherapy between the date of the last menstrual period (LMP) and the day of birth. unexposed, sick
Mothers with epilepsy who did not fill an antiseizure medication (ASM) prescription in the period between 90 days before the last menstrual period (LMP) and the day of birth. 		during pregnancy (anytime or not specified) 1009 / 19043
Prescription for antiseizure medication (ASM) was ascertained using nationwide prescription registers and identified ASMs based on Anatomical Therapeutic Chemical Classification.
Shallcross (Levetiracetam)
2011 		UK and Ireland
2003 - 2010
prospective cohort 		The UK Epilepsy and Pregnancy Register and the Liverpool and Manchester Neurodevelopment Group. Children born to women with epilepsy exposed to levetiracetam monotherapy throughout pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Children born to women without epilepsy, not taking medication during pregnancy. 		throughout pregnancy 51 / 97 Control children were recruited from the LMNDG program. Study design is partly completed with cited source [13].
Information was collected at registration and changes of antiepileptic drugs during pregnancy were detected during the follow-up duration by sending a standardised questionnaire to the patient's general practitioner. Other health care practitioners were contacted if identified.
Stjerna (Levetiracetam) (Epilepsy)
2024 		Czech Republic, Finland, Germany, Italy, Spain, Sweden and the Netherlands.
2008 - 2020
retrospective cohort 		The neurocognitive extension study (NCEP), an extension of the prospective EURAP study, a registry-based multicenter study. Children of mothers with epilepsy that used Levetiracetam monotherapy during the entire period from conception to birth. exposed to other treatment, sick
Children of mothers with epilepsy that used lamotrigine monotherapy during the entire period from conception to birth. 		throughout pregnancy 18 / 82 Use of adjusted continuous data (transformed in OR) rather than unadjusted dichotomised data. Indications: Epilepsy (Table 1). Overlapping: Huber-Mollema 2020 (n=99; NL only) totally included in Stjerna 2024 (n=162; 7 countries) => Use of Stjerna.
Prospectively collected data on antiseizure medications (ASMs) and seizures during pregnancy were retrieved from the core EURAP registry.
Thomas (Controls exposed to LTG)
2022 		India
1998 - 2019
prospective cohort 		The Kerala Registry of Epilepsy and Pregnancy (KREP), India. Infants of women with epilepsy who were exposed to Levetiracetam monotherapy at anytime during the antenatal period. exposed to other treatment, sick
Infants of women with epilepsy who were exposed to Lamotrigine monotherapy at anytime during the antenatal period. 		during pregnancy (anytime or not specified) 62 / 26 No use of delayed mental development, because discrepancy in LTG data '1/26 (11.5%)'.
Each pregnant woman in the Kerala Registry of Epilepsy and Pregnancy (KREP) maintained a pregnancy diary to record the daily use of antiseizure medications (ASMs). Data were then transferred to the clinical records of the registry during their clinic visits.
Thomas (Controls unexposed, sick)
2022 		India
1998 - 2019
prospective cohort 		The Kerala Registry of Epilepsy and Pregnancy (KREP), India. Infants of women with epilepsy who were exposed to Levetiracetam monotherapy at anytime during the antenatal period. unexposed, sick
Infants of women with epilepsy who were not exposed to any antiseizure medications (ASMs) during pregnancy. 		during pregnancy (anytime or not specified) 62 / 110 Trend of lower aMODQ and aMEDQ with medium and high doses, compared to low dose of the same drug.
Each pregnant woman in the Kerala Registry of Epilepsy and Pregnancy (KREP) maintained a pregnancy diary to record the daily use of antiseizure medications (ASMs). Data were then transferred to the clinical records of the registry during their clinic visits.
Thomas (Levetiracetam) (Controls exposed to Lamotrigine, sick)
2021 		India
1998 - 2019
prospective cohort 		The Kerala Registry of Epilepsy and Pregnancy (KREP) Children of women with epilepsy using levetiracetam monotherapy any time during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children of women with epilepsy using lamotrigine monotherapy any time during the first trimester of pregnancy. 		1st trimester 106 / 50 Study design completed with Thomas et al., 2017. Keni's 2018 malformations results are already reported in this publication.
Women were instructed to record the use of the antiepileptic drugs on a daily basis in the pregnancy diary that was given to them.
Thomas (Levetiracetam) (Controls unexposed, disease free)
2021 		India
1998 - 2015
prospective cohort 		The Kerala Registry of Epilepsy and Pregnancy (KREP) Children of women with epilepsy using levetiracetam monotherapy any time during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Children of women without epilepsy in the first trimester of pregnancy and not using antiepileptic drugs from the antenatal clinic of government hospital. 		1st trimester 30 / 319 This external control group is only available in the 2017 publication.
Women were instructed to record the use of the antiepileptic drugs on a daily basis in the pregnancy diary that was given to them.
Thomas (Levetiracetam) (Controls unexposed, sick)
2021 		India
1998 - 2019
prospective cohort 		The Kerala Registry of Epilepsy and Pregnancy (KREP) Children of women with epilepsy using levetiracetam monotherapy any time during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Children of women with epilepsy not using any antiepileptic drugs during the first trimester. 		1st trimester 106 / 340 Study design completed with Thomas et al., 2017.
Women were instructed to record the use of the antiepileptic drugs on a daily basis in the pregnancy diary that was given to them.
Tomson (Levetiracetam)
2015 		42 countries
1999 - 2013
prospective cohort 		The EURAP epilepsy and pregnancy registry Pregnancies in women with epilepsy treated with levetiracetam monotherapy at least during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Pregnancies in women with epilepsy treated with lamotrigine monotherapy at least during the first trimester. 		at least 1st trimester 324 / 1910 Pregnancies that occurred in women without epilepsy were excluded. EURAP registry: potential overlap.
The data concerning treatment at the time of conception are obtained by the physicians responsible for the women’s care and transferred online. (Intention-to-treat principle).
Tomson (Levetiracetam)
2018 		42 countries
1999 - 2016
prospective cohort 		The EURAP epilepsy and pregnancy registry Offspring exposed in utero to levetiracetam monotherapy during the first trimester and born from epileptic mothers. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Offspring exposed in utero to lamotrigine monotherapy during the first trimester and born from epileptic mothers. 		at least 1st trimester 599 / 2514 Overlapping/Update: (Major) malfo as a whole: Battino 2024 (1999-2022) updates and totally includes Tomson 2018 (1999-2016), Martinez 2018, Tomson 2011 => Not reported here (use of Battino 2024 for these outcomes).
Information obtained during early pregnancy and follow-up by the treating physician who transferred it online to a EURAP national coordinator. He then, reviewed the reports for completeness and accuracy before transmission to the EURAP central database.
Trivedi (Levetiracetam) (Controls exposed to Lamotrigine, sick)
2018 		India
1998 - 2015
prospective cohort 		The Kerala Registry of Epilepsy and Pregnancy (KREP) Pregnant women with epilepsy who used levetiracetam monotherapy any time during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Pregnant women with epilepsy who used lamotrigine monotherapy any time during the first trimester of pregnancy. 		1st trimester 63 / 48 Study design partly completed with cites source Thomas et al., 2017.
Women were instructed to record the use of the antiepileptic drugs on a daily basis in the pregnancy diary that was given to them.
Trivedi (Levetiracetam) (Controls unexposed, sick)
2018 		India
1998 - 2015
prospective cohort 		The Kerala Registry of Epilepsy and Pregnancy (KREP) Pregnant women with epilepsy who used levetiracetam monotherapy any time during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant women with epilepsy who were not on antiepileptic drug during their first trimester. 		1st trimester 63 / 178 Study design partly completed with cites source Thomas et al., 2017.
Women were instructed to record the use of the antiepileptic drugs on a daily basis in the pregnancy diary that was given to them.
Vajda (Levetiracetam) (Controls exposed to Lamotrigine, sick)
2013 		Australia
1999 - 2013
prospective cohort 		The Australian Register of Antiepileptic Drugs in Pregnancy. Offsprings from women with epilepsy exposed to levetiracetam in monotherapy in at least the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Offsprings from women with epilepsy exposed to lamotrigine in monotherapy in at least the first trimester of pregnancy. 		at least 1st trimester 63 / 315 Women taking AED for epilepsy are in majority (more than 90%). Vajda 2019 provides the most recent update for major malformations results for this register. Specific malformations results are extracted from the review by Weston et al. 2016.
Details are obtained by four in-depth telephone interviews with the women. Details provided by the participants are confirmed, as far as possible, by the treating medical practitioners.
Vajda (Levetiracetam) (Controls unexposed, sick)
2013 		Australia
1999 - 2013
prospective cohort 		The Australian Register of Antiepileptic Drugs in Pregnancy. Offsprings from women with epilepsy exposed to levetiracetam in monotherapy in at least the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Offsprings from women with epilepsy not exposed to antiepileptic drugs in at least the first trimester of pregnancy. 		at least 1st trimester 63 / 147 Women taking AED for epilepsy are in majority (more than 90%). Vajda 2019 provides the most recent update for malformations results for this register.
Details are obtained by four in-depth telephone interviews with the women. Details provided by the participants are confirmed, as far as possible, by the treating medical practitioners.
Vajda a (Levetiracetam) (Controls exposed to LTG)
2024 		Australia
1999 - 2023
prospective cohort 		The Australian Pregnancy Register of Antiepileptic Drugs (APR). Women with epilepsy exposed to Levetiracetam monotherapy during pregnancy. exposed to other treatment, sick
Women with epilepsy exposed to lamotrigine monotherapy during pregnancy. 		during pregnancy (anytime or not specified) 257 / 442 Overlapping between Vajda 2024a (1999 - 2023) and Vajda 2018 (1999 - 2016) based on the same register and for the almost same outcome (with or without elective termination) => Use of Vajda 2024a because accounting for more relevant confounders.
Not specified. All contact between the pregnant women and the Melbourne-based register has been by telephone.
Vajda a (Levetiracetam) (Controls unexposed sick)
2024 		Australia
1999 - 2023
prospective cohort 		The Australian Pregnancy Register of Antiepileptic Drugs (APR). Women with epilepsy exposed to levetiracetam monotherapy during pregnancy. unexposed, sick
Women with epilepsy unexposed to antiseizure medication during pregnancy. 		during pregnancy (anytime or not specified) 257 / 184 Overlapping between Vajda 2024a (1999 - 2023) and Vajda 2018 (1999 - 2016) based on the same register and for the almost same outcome (with or without elective termination) => Use of Vajda 2024a because accounting for more relevant confounders.
Not specified. All contact between the pregnant women and the Melbourne-based register has been by telephone.
Vajda b (Levetiracetam) (Epilepsy) (Controls exposed to Lamotrigine, sick)
2024 		Australia
1999 - 2022
prospective cohort 		The Raoul Wallenberg Australian Pregnancy Register of Antiepileptic Drugs (referred to as ‘Australian Pregnancy Register’ from this point forward). Women with epilepsy exposed to levetiracetam in monotherapy in early pregnancy. exposed to other treatment, sick
Women with epilepsy exposed to lamotrigine in monotherapy in early pregnancy. 		early pregnancy 187 / 473 Overlapping: Vajda 2024 totally included other APR data (Vajda 2019; Vajda 2007; 2010 (x2); 2012 (x2); 2013; 2014). Study design partly completed with Vajda 2013.
Details are obtained by four in-depth telephone interviews with the women (at time of enrolment; at approximately 28 weeks of pregnancy; after the 1st post-partum (pp) month, and at one year pp). The accuracy of the information provided by the pregnant women is checked with their treating doctors.
Vajda b (Levetiracetam) (Epilepsy) (Controls unexposed, sick)
2024 		Australia
1999 - 2022
prospective cohort 		The Raoul Wallenberg Australian Pregnancy Register of Antiepileptic Drugs (referred to as ‘Australian Pregnancy Register’ from this point forward). Women with epilepsy exposed to levetiracetam in monotherapy in early pregnancy. unexposed, sick
Women with epilepsy not treated with antiepileptic drugs in early pregnancy. 		at least 1st trimester 187 / 201 Overlapping: Vajda 2024 totally included other APR data (Vajda 2019; Vajda 2007; 2010 (x2); 2012 (x2); 2013; 2014). Study design partly completed with Vajda 2013.
Details are obtained by four in-depth telephone interviews with the women (at time of enrolment; at approximately 28 weeks of pregnancy; after the 1st post-partum (pp) month, and at one year pp). The accuracy of the information provided by the pregnant women is checked with their treating doctors.
Van Marter (Levetiracetam) (Controls unexposed, disease free)
2021 		US
2012 - 2016
prospective cohort 		The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study (20 US tertiary epilepsy centers). Children of pregnant women with epilepsy with exposure to levetiracetam monotherapy based on the mother’s prescribed antiepileptic drug at the time of enrollment. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Children of healthy pregnant women. 		at least 1st trimester 97 / 106 Exclusion criteria included history of psychogenic nonepileptic spells, expected IQ of less than 70, other major medical illness, and switching of ASMs in pregnancy before enrollment.
Prescribed antiepileptic drug at the time of enrollment. Data were collected from subjects and their medical records.
Van Marter (Levetiracetam) (Controls unexposed, sick)
2021 		US
2012 - 2016
prospective cohort 		The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study (20 US tertiary epilepsy centers). Children of pregnant women with epilepsy with exposure to levetiracetam monotherapy based on the mother’s prescribed antiepileptic drug at the time of enrollment. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Children of pregnant women with epilepsy without prescribed antiepileptic drug at the time of enrollment. 		at least 1st trimester 97 / 15 Exclusion criteria included history of psychogenic nonepileptic spells, expected IQ of less than 70, other major medical illness, and switching of ASMs in pregnancy before enrollment.
Prescribed antiepileptic drug at the time of enrollment. Data were collected from subjects and their medical records.
Veiby (Levetiracetam) (Controls exposed to Lamotrigine, sick)
2014 		Norway
1999 - 2011
population based cohort retrospective 		Medical Birth Registry of Norway Children exposed prenatally to levetiracetam as monotherapy indicated for their mothers' epilepsy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children exposed prenatally to lamotrigine as monotherapy indicated for their mothers' epilepsy. 		throughout pregnancy 114 / 593 We will only consider the subgroup of women exposed to antiepileptic drugs for the strict indication of epilepsy. Overlapping: Cohen 2023 and Veiby 2014 => less of 50% of overlapping => the 2 studies were kept.
A standardised notification form is filled in from the first prenatal visit with the general practitioner until discharge and transferred to the database by practitioners attending the delivery. (According to ATC Classification System).
Veiby (Levetiracetam) (Controls unexposed, disease free)
2014 		Norway
1999 - 2011
population based cohort retrospective 		Medical Birth Registry of Norway Children exposed prenatally to levetiracetam as monotherapy indicated for their mothers' epilepsy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
All unexposed children born to women without epilepsy. 		throughout pregnancy 114 / 771412 Overlapping: Cohen 2023 and Veiby 2014 => less of 50% of overlapping => the 2 studies were kept. We will only consider the subgroup of women exposed to antiepileptic drugs for the strict indication of epilepsy.
A standardised notification form is filled in from the first prenatal visit with the general practitioner until discharge and transferred to the database by practitioners attending the delivery. (According to ATC Classification System).
Veiby (Levetiracetam) (Controls unexposed, sick)
2014 		Norway
1999 - 2011
population based cohort retrospective 		Medical Birth Registry of Norway Children exposed prenatally to levetiracetam as monotherapy indicated for their mothers' epilepsy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Children born to women with a history of epilepsy but no antiepileptic drug treatment during pregnancy. 		throughout pregnancy 114 / 3773 Overlapping: Cohen 2023 and Veiby 2014 => less of 50% of overlapping => the 2 studies were kept. We will only consider the subgroup of women exposed to antiepileptic drugs for the strict indication of epilepsy.
A standardised notification form is filled in from the first prenatal visit with the general practitioner until discharge and transferred to the database by practitioners attending the delivery. (According to ATC Classification System).
Videman (Levetiracetam) (Controls exposed to Lamotrigine, sick)
2016 		Finland
2009 - 2013
prospective cohort 		The Helsinki University Hospital Newborns from epileptic women with fetal monotherapy levetiracetam exposure during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Newborns from epileptic women with fetal monotherapy lamotrigine exposure during pregnancy. 		during pregnancy (anytime or not specified) 7 / 8 Study design partly completed with a previous article of Videman 2016.
Exposure data (including daily doses and serum levels for oxcarbazepine, carbamazepine, valproic acid, lamotrigine, and levetiracetam) were obtained prospectively at outpatient visits taking place every trimester and postnatally.
Videman (Levetiracetam) (Controls unexposed, disease free)
2016 		Finland
2009 - 2013
prospective cohort 		The Helsinki University Hospital Newborns from epileptic women with fetal monotherapy levetiracetam exposure during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Newborns from women with no antiepileptic drug or other brain-acting medication. 		during pregnancy (anytime or not specified) 7 / 67 Study design partly completed with a previous article of Videman 2016.
Exposure data (including daily doses and serum levels for oxcarbazepine, carbamazepine, valproic acid, lamotrigine, and levetiracetam) were obtained prospectively at outpatient visits taking place every trimester and postnatally.
Wiggs
2024 		Sweden
1996 - 2016
population based cohort retrospective 		Cohort of individuals obtained from the Medical Birth Register (MBR), the National Patient Register (NPR). Children born to women with a recent epilepsy diagnosis who reported the use of Levetiracetam monotherapy at their first antenatal visit (8th-12th week of pregnancy). unexposed, sick
Children whose mothers had a recent diagnosis of epilepsy but who did not report the use of any antiseizure medications (ASMs) at their first antenatal visit. 		early pregnancy 185 / 9364 Overlapping: Razaz 2017 totally included in this study. Use of data in children born to women with a recent diagnosis of epilepsy prior to conception and with single antiseizure medication exposure. Total number of unexposed group based on eTable 3.
Information recorded at the first antenatal visit (8th-12th week of pregnancy) includes prescription drug use.

Case-control studies

Study Country
Study period
Study design		 Data source Case Control Exposition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias

Risk of bias: : NA;   : low;   : moderate;   : serious;   : critical;   : unclear;  

Empty. There are no case-control studies available for this drug.

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