Ethosuximide (All indications)

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
Battino (Ethosuximide) (Epilepsy)
2024 		Worldwide (47 countries)
1999 - 2022
prospective cohort 		The International Registry of Antiepileptic Drugs and Pregnancy (EURAP). Pregnant women with epilepsy exposed to Ethosuximide 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 18 / 3584 Overlapping/Update: 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) monotherapies studied.
Reporting physicians collected information on drug therapy after each trimester.
Christensen (Ethosuximide) (All indications) (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 who had redeemed at least one prescription of Ethosuximide 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) 11 / 8756 Denmark (1997–2017), Finland (1996–2016), Iceland (2004–2017), Norway (2005–2017), and Sweden (2006–2017).
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 (Ethosuximide) (All indications) (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 who had redeemed at least one prescription of Ethosuximide monotherapy from 30 days before the first day of the last menstrual period to the date of birth (i.e., the exposure period). unexposed (general population or NOS)
Children of mothers who had not redeemed prescription of anti-seizure medication. 		during pregnancy (anytime or not specified) 11 / 4467848 Denmark (1997–2017), Finland (1996–2016), Iceland (2004–2017), Norway (2005–2017), and Sweden (2006–2017).
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.
Dean (Ethosuximide)
2002 		Scotland
1976 - 2000
retrospective cohort 		Aberdeen Maternity Hospital, the antenatal clinic and postnatal wards. Children whose mothers took ethosuximide monotherapy in pregnancy and continued beyond the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Sibs of exposed cases not exposed to antiepileptic drugs in utero. Either the mothers had epilepsy or the child was born before epilepsy developed. 		at least 1st trimester 4 / 38 The data for major congenital malformations include all pregnancies surviving into the second trimester, whereas frequencies for other features were based on livebirths only. The vast majority of the mothers were treated for epilepsy.
A structured interview was carried out by a trained research nurse using questionnaires.
Kaaja (Ethosuximide)
2003 		Finland
1980 - 1998
prospective cohort 		Department of Obstetrics and Gynecology from Helsinki University Central Hospital Infants whose epileptic mothers took ethosuximide 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 2 / 239
Follow-up of the pregnant women with epilepsy included assessment of serum concentration of antiepileptic drugs at the end of the first trimester.
Källén (Ethosuximide) (Controls exposed to Lamotrigine, sick) (Indications NOS)
2013 		Swedish
1996 - 2011
population based cohort retrospective 		The Swedish Medical Birth Register, the Swedish Register of Prescribed Drugs the Register of Birth Defect and Hospital Discharge Register. Infants whose mothers used ethosuximide in monotherapy in early pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Infants whose mothers used lamotrigine in monotherapy in early pregnancy. 		early pregnancy 12 / 1084 Indications for antiepileptic drugs are not specified. Wide 2004 outcomes' are already included in Källèn et al 2013 or are not compared to an adequate control group. Follow-up period known thanks to author's email reply.
At the midwife interview at the first antenatal care visit, the woman was asked if she had used any drugs since she became pregnant. Or determined by the use of the Swedish Register of Prescribed Drugs (since 2006).
Källén (Ethsuximide) (Controls unexposed, NOS) (Indications NOS)
2013 		Swedish
1996 - 2011
population based cohort retrospective 		The Swedish Medical Birth Register, the Swedish Register of Prescribed Drugs, the Register of Birth Defect and Hospital Discharge Register. Infants whose mothers used ethosuximide in monotherapy in early pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Infants in population whose mothers used at least one of a central nervous system active drugs (less than 3%) or weren't exposed in early pregnancy. 		early pregnancy 12 / 1575847 Indications for antiepileptic drugs are not specified. Follow-up period known thanks to author's email reply.
At the midwife interview at the first antenatal care visit, the woman was asked if she had used any drugs since she became pregnant. Or determined by the use of the Swedish Register of Prescribed Drugs (since 2006).
Kilic (Ethosuximide) (Controls exposed to Lamotrigine, sick) (Mixed indications)
2014 		Denmark
1997 - 2008
population based cohort retrospective 		The Danish Medical Birth Registry, the Danish Civil Registration System, the Danish National Hospital Registry, and the Danish Register of Medicinal Product Statistics. Children whose mothers have been exposed to ethosuximide in monotherapy during the exposure window defined from 30 days before the estimated day of conception to the day prior to birth. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children whose mothers have been exposed to lamotrigine in monotherapy during the exposure window defined from 30 days before the estimated day of conception to the day prior to birth. 		during pregnancy (anytime or not specified) 1 / 880 Less than 90% of women are epileptic.
The Danish Register of Medicinal Product Statistics holds information on all redeemed prescriptions. Monotherapy exposure was defined as redemption of prescription for one type of AED with the Anatomical Therapeutic Codes.
Kilic (Ethosuximide) (Controls unexposed NOS) (Mixed indications)
2014 		Denmark
1997 - 2008
population based cohort retrospective 		The Danish Medical Birth Registry, the Danish Civil Registration System, the Danish National Hospital Registry, and the Danish Register of Medicinal Product Statistics. Children whose mothers have been exposed to ethosuximide in monotherapy during the exposure window defined from 30 days before the estimated day of conception to the day prior to birth. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Children whose mothers haven't been exposed to antiepileptic drugs 30 days before the estimated day of conception to the day of birth. 		during pregnancy (anytime or not specified) 1 / 676834 Less than 90% of women are epileptic.
The Danish Register of Medicinal Product Statistics holds information on all redeemed prescriptions. Monotherapy exposure was defined as redemption of prescription for one type of AED with the Anatomical Therapeutic Codes.
Kilic (Ethosuximide) (Controls unexposed, sick) (Mixed indications)
2014 		Denmark
1997 - 2008
population based cohort retrospective 		The Danish Medical Birth Registry, the Danish Civil Registration System, the Danish National Hospital Registry, and the Danish Register of Medicinal Product Statistics. Children whose mothers have been exposed to ethosuximide in monotherapy during the exposure window defined from 30 days before the estimated day of conception to the day prior to birth. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Children whose mothers have an epilepsy diagnosis and haven't been exposed to antiepileptic drugs 30 days before the estimated day of conception to the day of birth. 		during pregnancy (anytime or not specified) 1 / 5296 Less than 90% of women are epileptic.
The Danish Register of Medicinal Product Statistics holds information on all redeemed prescriptions. Monotherapy exposure was defined as redemption of prescription for one type of AED with the Anatomical Therapeutic Codes.
Kini (Ethosuximide) (Controls exposed to Lamotrigine, sick)
2006 		UK
1989 - 1999
retrospective cohort 		Epilepsy clinics in Manchester and Liverpool, and at a Central Manchester Maternity Hospital on behalf of the Liverpool and Manchester Neurodevelopmental Study Group (LMNDG). Children exposed to ethosuximide monotherapy during pregnancy and with epileptic mothers. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children exposed to lamotrigine monotherapy during pregnancy and with epileptic mothers. 		during pregnancy (anytime or not specified) 1 / 9 Because we don't know the exact number of children exposed to lamotrigine and analyzed for malformations, this outcome cannot be reported here.
Structured interviews were conducted with the mothers and medical records were available to confirm details in about 80% of participants.
Kini (Ethosuximide) (Controls unexposed, sick)
2006 		UK
1989 - 1999
retrospective cohort 		Epilepsy clinics in Manchester and Liverpool, and at a Central Manchester Maternity Hospital on behalf of the Liverpool and Manchester Neurodevelopmental Study Group (LMNDG). Children exposed to ethosuximide monotherapy during pregnancy and with epileptic mothers. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Children not exposed to antiepileptic drugs during pregnancy and with epileptic mothers. 		during pregnancy (anytime or not specified) 1 / 101 Because we don't know the exact number of children exposed to ethosuximide and analyzed for malformations, this outcome cannot be reported here.
Structured interviews were conducted with the mothers and medical records were available to confirm details in about 80% of participants.
Morrow (Ethosuximide) (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 ethosuximide 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 12 / 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 (Ethosuximide) (Controls unexposed, sick)
2006 		UK and Ireland
1996 - 2005
prospective cohort 		The UK Epilepsy and Pregnancy Register Infants of women with epilepsy exposed to ethosuximide 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 12 / 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.
Samrén (Ethosuximide)
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 ethosuximide 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 thedrugs was also retrieved from obstetric files.
Vajda (Ethosuximide) (Controls exposed to Lamotrigine, sick)
2019 		Australia
1999 - 2018
prospective cohort 		The Australian Register of Antiepileptic Drugs in Pregnancy. Offsprings born from women nearly always with epilepsy exposed to ethosuximide 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 born from women nearly always with epilepsy exposed to lamotrigine in monotherapy in at least the first trimester of pregnancy. 		at least 1st trimester 5 / 406 Women with epilepsy accounted for 98.3%. Completely overlap Vajda 2013 and 2014. Study design partly completed with Vajda 2013.
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 and through hospital records.
Vajda (Ethosuximide) (Controls unexposed, sick)
2019 		Australia
1999 - 2018
prospective cohort 		The Australian Register of Antiepileptic Drugs in Pregnancy. Offsprings born from women nearly always with epilepsy exposed to ethosuximide 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 born from women nearly always with epilepsy not treated with antiepileptic drugs in at least the first half of pregnancy. 		at least 1st trimester 5 / 176 Women with epilepsy accounted for 98.3%. Completely overlap Vajda 2013 and 2014. Study design partly completed with Vajda 2013.
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 and through hospital records.
Vajda a (Ethosuximide) (Controls exposed to LTG) (Epilepsy)
2024 		Australia
1999 - 2023
prospective cohort 		The Australian Pregnancy Register of Antiepileptic Drugs (APR). Women with epilepsy exposed to Ethosuximide monotherapy during pregnancy. exposed to other treatment, sick
Women with epilepsy exposed to lamotrigine monotherapy during pregnancy. 		during pregnancy (anytime or not specified) 4 / 442 Pregnancies terminated prematurely by known deliberate action were not included.
Not specified. All contact between the pregnant women and the Melbourne-based register has been by telephone.
Vajda a (Ethosuximide) (Controls unexposed sick) (Epilepsy)
2024 		Australia
1999 - 2023
prospective cohort 		The Australian Pregnancy Register of Antiepileptic Drugs (APR). Women with epilepsy exposed to Ethosuximide monotherapy during pregnancy. unexposed, sick
Women with epilepsy unexposed to antiseizure medication during pregnancy. 		during pregnancy (anytime or not specified) 4 / 184 Pregnancies terminated prematurely by known deliberate action were not included.
Not specified. All contact between the pregnant women and the Melbourne-based register has been by telephone.

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 (Ethosuximide)
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. Exposure period completed with Czeizel 1992.
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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