Clonazepam (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
Al Bunyan (Epilepsy)
1999 		Saudi Arabia
1985 - 1994
retrospective cohort 		King Khalid University Hospital, Riyadh (KKUH) Children whose epileptic mothers were exposed to clonazepam monotherapy during the pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Children whose epileptic mothers did not take antiepileptic drugs during the pregnancy because their seizures were in remission and as a personal preference. 		during pregnancy (anytime or not specified) 1 / 10 The control group with the data of historical controls in Saudi Arabia isn't an adequate control group.
The antenatal and perinatal records of the pregnant epileptic patients were examined.
Artama (Epilepsy) (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 clonazepam 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) 14 / 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 (Epilepsy) (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 clonazepam 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) 14 / 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 (Epilepsy) (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 clonazepam 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) 14 / 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.
Battino (Epilepsy)
1992 		Italy
1977 - 1989
prospective cohort 		The Milan Collaborative Study on Epilepsy and Pregnancy, Italy. Offspring of epileptic mothers treated with clonazepam monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Offspring of epileptic mothers with no antiepileptic drugs administered. 		1st trimester 6 / 9 The results for the malformations are already available in Canger 1999 (a more recent publication with a larger exposed group) except for minor malformations.
At least every 4 weeks throughout the pregnancy blood samples were taken for measurement of antiepileptic drugs concentrations.
Battino (Epilepsy)
2024 		Worldwide (47 countries)
1999 - 2022
prospective cohort 		The International Registry of Antiepileptic Drugs and Pregnancy (EURAP). Pregnant women with epilepsy exposed to Clonazepam 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 52 / 3584 Overlapping: Battino 2024 (1999-2022) updates and totally includes Tomson 2018 (1999-2016), Tomson 2011 and Jimenez 2020 (1 center in Spain 2000-2018) => Use of Battino 2024 for the 8 (plus 16 in eSupp) ASM monotherapies studied here.
Reporting physicians collected information on drug therapy after each trimester.
Bjørk (Epilepsy) (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 filling at least one clonazepam 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) 318 / 5073 Overlapping for ASD (2 outcomes) and Intellectual disabilities (2 outcomes): Dreier 2023 and Bjork 2022, with more pregnancies in Dreier 2023 => use of Dreier 2023 data.
Prescriptions through national prescription registers according to Anatomical Therapeutic Chemical classification codes N03, N05BA09, and S01EC01.
Bjørk (Epilepsy) (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 filling at least one clonazepam 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) 318 / 4463879 Overlapping for ASD (2 outcomes) and Intellectual disabilities (2 outcomes): Dreier 2023 and Bjork 2022, with more pregnancies in Dreier 2023 => use of Dreier 2023 data.
Prescriptions through national prescription registers according to Anatomical Therapeutic Chemical classification codes N03, N05BA09, and S01EC01.
Bjørk (Epilepsy) (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 clonazepam 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) 318 / 21634 Overlapping for ASD (2 outcomes) and Intellectual disabilities (2 outcomes): Dreier 2023 and Bjork 2022, with more pregnancies in Dreier 2023 => use of Dreier 2023 data.
Prescriptions through national prescription registers according to Anatomical Therapeutic Chemical classification codes N03, N05BA09, and S01EC01.
Canger (Epilepsy)
1999 		Italy
1977 - 1996
prospective cohort 		The Epilepsy Center of the San Paolo Hospital in Milan or other in the Lombardy region. Infants of epileptic mothers exposed to clonazepam monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Infants of epileptic mothers unexposed to antiepileptic drugs during pregnancy. 		1st trimester 6 / 25 Most women gave birth at the San Paolo Hospital. Only the first pregnancies of each of the 517 women were included in the analysis.
The patients received monthly obstetric and neurologic examinations, and antiepileptic drug blood levels were tested monthly.
Christensen (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 Clonazepam 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) 339 / 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 (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 Clonazepam 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) 339 / 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.
D'Souza (Epilepsy) (Controls unexposed, disease free)
1991 		UK
1980 - 1982
prospective cohort 		Antenatal clinic of St Mary's Hospital. Infants born to epileptic mothers treated with clonazepam alone throughout pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Infants born to mothers without epilepsy not taking any drugs regularly. 		throughout pregnancy 1 / 62
Every two weeks, clinical assessment of seizure control, and adjustment of anticonvulsant dosage in accordance with serum drug concentration or clinical response.
D'Souza (Epilepsy) (Controls unexposed, sick)
1991 		UK
1980 - 1982
prospective cohort 		Antenatal clinic of St Mary's Hospital. Infants born to epileptic mothers treated with clonazepam alone throughout pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Infants whose mothers had a history of epilepsy but received no drugs during pregnancy. 		throughout pregnancy 1 / 8
Every two weeks, clinical assessment of seizure control, and adjustment of anticonvulsant dosage in accordance with serum drug concentration or clinical response.
Díaz-Romero (Epilepsy)
1999 		Mexico
1993 - 1996
cohort 		The Epilepsy Clinic of the National Institute of Perinatology. Full-term eutrophic newborns of epileptic mothers exposed to only clonazepam during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Offspring of epileptic women without seizures during pregnancy and without exposure to any drug. 		during pregnancy (anytime or not specified) 1 / 8 All newborns in the intensive care unit, and those with congenital malformations with a different specific recognizable etiology were excluded.
Not specified
Dreier (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 Clonazepam 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) 339 / 5288 Overlapping for ASD (2 outcomes) and Intellectual disabilities (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 (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 Clonazepam 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) 339 / 22203 Overlapping for ASD (2 outcomes) and Intellectual disabilities (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.
Endo (Epilepsy) (Controls unexposed, disease free)
2004 		Japan
1991 - 2000
retrospective cohort 		Yokohama City University Hospital. Newborns of epileptic mothers who take clonazepam monotherapy for epilepsy throughout pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Newborns of nonepileptic mothers. 		throughout pregnancy 1 / 656 30 (83.3%) cases of 36 pregnancies continued taking drugs throughout pregnancy. Three (8.3%) patients discontinued after week 13 of pregnancy. Some results do not coincide between table 1 and table 2 and are therefore not reported.
Medical records.
Endo (Epilepsy) (Controls unexposed, sick)
2004 		Japan
1991 - 2000
retrospective cohort 		Yokohama City University Hospital. Newborns of epileptic mothers who take clonazepam monotherapy for epilepsy throughout pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Newborns of epileptic mothers who had not taken any antiepileptic drugs. 		throughout pregnancy 1 / 1 30 (83.3%) cases of 36 pregnancies continued taking drugs throughout pregnancy. Three (8.3%) patients discontinued after week 13 of pregnancy. Some results do not coincide between table 1 and table 2 and are therefore not reported.
Medical records.
Gopinath (Epilepsy)
2015 		India
2010 - 2012
retrospective cohort (registry) 		The Kerala Registry of Epilepsy and Pregnancy (KREP) Children from epileptic mothers exposed to clonazepam in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Children attending to two nearby schools with no exposure. 		during pregnancy (anytime or not specified) 1 / 149 Study design partly completed with Thomas et al., 2007 from the same registry. OR not calculable (only 1 exposure, not SD available for the provided mean Full Scale IQ).
The details of antiepileptic drugs exposure per month were recorded on a monthly basis in the protocol from the month prior to pregnancy through the entire period of pregnancy and three-month post partum. The drug compliance and seizure frequency were ascertained with a detailed diary.
Guveli (Epilepsy)
2017 		Turkey
1990 - 2006
retrospective cohort 		Departments of Istanbul Faculty of Medicine, Istanbul University, Turkey. Children born from mothers with epilepsy on clonazepam monotherapy during pregnancy. unexposed, sick
Children born from mothers were not exposed to Antiepileptic drugs (AED) during pregnancy. 		during pregnancy (anytime or not specified) 2 / 26
The clinical data of patients (dosages of AEDs used during pregnancy) were recorded retrospectively from patient files.
Hvas (Epilepsy) (Controls unexposed, disease free)
2000 		Denmark
1989 - 1997
prospective cohort 		Department of Obstetrics and Gynaecology at Aarhus University Hospital. Children of women with epilepsy exposed to clonazepam monotherapy 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 chronic disease. 		1st trimester 15 / 24094
Women completed a questionnaire. They were categorised as users or nonusers of anticonvulsant drugs, by self-reported daily intake of any anticonvulsant drug during the first trimester.
Hvas (Epilepsy) (Controls unexposed, sick)
2000 		Denmark
1989 - 1997
prospective cohort 		Department of Obstetrics and Gynaecology at Aarhus University Hospital. Children of women with epilepsy exposed to clonazepam monotherapy 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 without treatment. 		1st trimester 15 / 106
Women completed a questionnaire. They were categorised as users or nonusers of anticonvulsant drugs, by self-reported daily intake of any anticonvulsant drug during the first trimester.
Kaaja (Epilepsy)
2003 		Finland
1980 - 1998
prospective cohort 		Department of Obstetrics and Gynecology from Helsinki University Central Hospital Infants whose epileptic mothers took clonazepam as monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Infants whose epileptic mothers didn't take any antiepileptic drugs during the first trimester. 		1st trimester 13 / 239
Follow-up of the pregnant women with epilepsy included assessment of serum concentration of antiepileptic drugs (AEDs) at the end of the first trimester. The serum concentrations of AED were known in 90.1% of the patients using these drugs.
Morrow (Epilepsy) (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 clonazepam 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 9 / 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 (Epilepsy) (Controls unexposed, sick)
2006 		UK and Ireland
1996 - 2005
prospective cohort 		The UK Epilepsy and Pregnancy Register Infants of women with epilepsy exposed to clonazepam 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 9 / 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.
Razaz (Epilepsy)
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 Clonazepam 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) 321 / 19043
Prescription for antiseizure medication (ASM) was ascertained using nationwide prescription registers and identified ASMs based on Anatomical Therapeutic Chemical Classification.
Robert (Epilepsy)
1986 		France
1976 - 1983
retrospective cohort 		Hospital of neurology and neurosurgery P. Wertheimer and three maternity wards in Lyon Infants born from epileptic mothers exposed during the first trimester to clonazepam in monotherapy. unexposed, sick
Infants born from epileptic mothers unexposed during the first trimester to any antiepileptic drugs. 		1st trimester 1 / 35
Questionnaires were sent to women identified in hospital records and the second collection of data was obtained from 3 maternity with computerized records.
Samrén (Epilepsy)
1999 		Netherlands
1972 - 1994
retrospective cohort 		28 hospitals in four provinces of the Netherlands and National Perinatal Data Base LVR. Children born to mothers with epilepsy and using clonazepam monotherapy at least during the first trimester of pregnancy unexposed, disease free
Children born to nonepileptic nonexposed women. 		at least 1st trimester 9 / 2000
Data were collected from medical records and include medication. The prescribed dose of the drugs was also retrieved from obstetric files.
Thomas (Epilepsy) (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 clonazepam 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 4 / 50
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 (Epilepsy) (Controls unexposed, sick)
2021 		India
1998 - 2019
prospective cohort 		The Kerala Registry of Epilepsy and Pregnancy (KREP) Children of women with epilepsy using clonazepam 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 4 / 340
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 (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 clonazepam in monotherapy in early pregnancy. exposed to other treatment, sick
Women with epilepsy exposed to lamotrigine in monotherapy in early pregnancy. 		early pregnancy 24 / 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 (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 clonazepam in monotherapy in early pregnancy. unexposed, sick
Women with epilepsy not treated with antiepileptic drugs in early pregnancy. 		at least 1st trimester 24 / 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.
Vajda a (Epilepsy) (Controls exposed to LTG)
2024 		Australia
1999 - 2023
prospective cohort 		The Australian Pregnancy Register of Antiepileptic Drugs (APR). Women with epilepsy exposed to Clonazepam monotherapy during pregnancy. exposed to other treatment, sick
Women with epilepsy exposed to lamotrigine monotherapy during pregnancy. 		during pregnancy (anytime or not specified) 17 / 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 (Epilepsy) (Controls unexposed sick)
2024 		Australia
1999 - 2023
prospective cohort 		The Australian Pregnancy Register of Antiepileptic Drugs (APR). Women with epilepsy exposed to Clonazepam monotherapy during pregnancy. unexposed, sick
Women with epilepsy unexposed to antiseizure medication during pregnancy. 		during pregnancy (anytime or not specified) 17 / 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.
Veiby (Epilepsy) (Controls exposed to Lamotrigine, sick)
2014 		Norway
1999 - 2011
population based cohort retrospective 		Medical Birth Registry of Norway Children exposed prenatally to clonazepam 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 40 / 593 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 (Epilepsy) (Controls unexposed, disease free)
2014 		Norway
1999 - 2011
population based cohort retrospective 		Medical Birth Registry of Norway Children exposed prenatally to clonazepam 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 40 / 771412 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 (Epilepsy) (Controls unexposed, sick)
2014 		Norway
1999 - 2011
population based cohort retrospective 		Medical Birth Registry of Norway Children exposed prenatally to clonazepam 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 40 / 3773 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).

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
Bànhidy (Epilepsy)
2011 		Hungary
1980 - 1996
case control 		Hungarian Congenital Abnormality Registry (HCAR), the National Birth Registry of the Central Statistical Office and the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA). Children affected with congenital abnormalities and who had mothers with medically recorded epilepsy. Newborn infants without congenital abnormality and who had mothers with medically recorded epilepsy. Mothers were mailed a questionnaire (after the selection of cases and controls) requested information on medicinal products taken during pregnancy and to send their prenatal maternity logbook and other medical records. Regional nurses were asked to visit and question the non-respondent. throughout pregnancy 95 / 90 Malformations caused by major mutant genes or chromosomal aberrations with preconceptional origin were excluded. Overlapping: Czeizel 1992 completely included in this publication (except for spina bifida, but no data for clonazepam).
Notification of cases with congenital abnormality is mandatory for physicians to the HCAR. Pathologists sent a copy of autopsy report for stillbirths and infant deaths cases and defect diagnosed in prenatal diagnostic centers with or without termination of pregnancy were also included.

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

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