Primidone (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
Battino
2024 		Worldwide (47 countries)
1999 - 2022
prospective cohort 		The International Registry of Antiepileptic Drugs and Pregnancy (EURAP). Pregnant women with epilepsy exposed to Primidone 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 44 / 3584 Overlapping: Battino 2024 (1999-2022) updates and totally includes Tomson 2018 (1999-2016) and Tomson 2011 => Use of Battino 2024.
Reporting physicians collected information on drug therapy after each trimester.
Battino (Primidone)
1992 		Italy
1977 - 1989
prospective cohort 		The Milan Collaborative Study on Epilepsy and Pregnancy, Italy. Offspring of epileptic mothers treated with primidone 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 31 / 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 (Primidone)
1999 		Japan, Italy and Canada
1978 - 1991
prospective cohort 		Centers in Japan, Italy and Canada Infants whose epileptic mothers were exposed to primidone in monotherapy until term. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Infants whose epileptic mothers were not treated with antiepileptic drugs during pregnancy. 		throughout pregnancy 37 / 36 Each country has its own reference standards, then the data from the different countries are pooled. Exposition period deducted from Kaneko 1999.
Mothers were seen by an obstetrician and neurologist at least every 4 weeks throughout pregnancy, and blood samples were taken for the measurement of antiepileptic drugs concentrations.
Burja (Primidone) (Controls unexposed, disease free)
2006 		Slovenia
1998 - 2002
retrospective cohort (registry) 		Hospital neonatal and obstetric records at the Maribor Teaching Hospital Department of Perinatology, the Regional Hospital Discharge Registry and the the Perinatal Statistical Database of Slovenia. Newborn in women diagnosed as having epilepsy who had taken primidone in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Newborn in a randomized sample of pregnant women who had received no prescription at all (with the only diagnosis 'vaginal delivery') in the same period. 		during pregnancy (anytime or not specified) 1 / 211
Hospital neonatal and obstetric records at the MariborTeaching Hospital Department of Perinatology.
Burja (Primidone) (Controls unexposed, sick)
2006 		Slovenia
1998 - 2002
retrospective cohort (registry) 		Hospital neonatal and obstetric records at the Maribor Teaching Hospital Department of Perinatology, the Regional Hospital Discharge Registry and the the Perinatal Statistical Database of Slovenia. Newborn in women diagnosed as having epilepsy who had taken primidone in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Newborn in women diagnosed as having epilepsy who didn't take antiepileptic drugs during pregnancy. 		during pregnancy (anytime or not specified) 1 / 32
Hospital neonatal and obstetric records at the MariborTeaching Hospital Department of Perinatology.
Canger (Primidone)
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 primidone 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 35 / 25 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 (Primidone) (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 Primidone 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) 27 / 5299 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 (Primidone) (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 Primidone 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) 27 / 22227 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 (Primidone)
2002 		Scotland
1976 - 2000
retrospective cohort 		Aberdeen Maternity Hospital, the antenatal clinic and postnatal wards. Children whose mothers took primidone 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 2 / 38 The data for major congenital malformations include all pregnancies surviving into the second trimester. The vast majority of the mothers were treated for epilepsy.
A structured interview was carried out by a trained research nurse using questionnaires.
Kaaja (Primidone)
2003 		Finland
1980 - 1998
prospective cohort 		Department of Obstetrics and Gynecology from Helsinki University Central Hospital Infants whose epileptic mothers took primidone 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 6 / 239
Follow-up of the pregnant women with epilepsy included assessment of serum concentration of antiepileptic drugs at the end of the first trimester.
Kaneko (Primidone)
1999 		Japan, Italy and Canada.
1978 - 1991
prospective cohort 		Centers from Japan (Hirosaki, Fukushima, Nagoya, and Nagasaki), Italy (Milan), and Canada (Montreal). Offspring whose epileptic mothers were under primidone monotherapy until term. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Offspring from epileptic mothers without antiepileptic drug exposure until term. 		throughout pregnancy 35 / 98 Details about the design were completed thanks to Battino et al., 1999 publication. Kaneko 1999 overlapped with Kaneko 1988, Canger 1999 and Battino 1992.
Mothers were seen by an obstetrician and neurologist at least every 4 weeks throughout pregnancy, and blood samples were taken for the measurement of antiepileptic drugs concentrations.
Katz (Primidone)
2001 		USA
1990 - 2000
retrospective cohort 		Department of Neurology, New York University School of Medicine. Newborn of women with epilepsy exposed to primidone monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Newborn of women with epilepsy exposed to lamotrigine monotherapy during pregnancy. 		during pregnancy (anytime or not specified) 2 / 3 The analysis of developmental delay excluded the 20 pregnancies occurring within 1 year of chart review because of insufficient time to evaluate developmental milestones.
Telephone interviews were given to the patient as a supplement to the chart analysis. Spouses were interviewed only when additional information could not be provided by the patient.
Kini (Primidone) (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 primidone 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) 2 / 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 (Primidone) (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 primidone 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) 2 / 101 Because we don't know the exact number of children exposed to primidone 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.
Koch (Primidone)
1996 		Germany
1976 - 1983
prospective cohort 		Five obstetric departments and the Department of Neurology Free University of Berlin. Children born to epilepic mothers who had been exposed to primidone during fetal life. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Children born to mothers randomly recruited during their pregnancy from the same obstetric departments. 		during pregnancy (anytime or not specified) 14 / 65 Primidone and phenobarbitone are regarded as the same drug for the authors. Study design partly completed with cited source [13].
The pregnant women were asked to continuously monitor their seizures, treatment and additional illnesses.
Lowe (Primidone) (Controls unexposed, disease free)
1973 		UK (Wales)
1965 - 1971
population based cohort retrospective 		Total birth population of Cardiff Infants born to women who gave a history of having had an epileptic seizure at any time in their lives and exposed to primidone alone during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Infants born to women living in Cardiff who didn't gave a history of having had an epileptic seizure at any time in their lives. 		1st trimester 4 / 31632
Detailed information has been collected, coded, and computer stored. The hospital and general practitioner records of women with a history of epilepsy were traced and inspected.
Lowe (Primidone) (Controls unexposed, sick)
1973 		UK (Wales)
1965 - 1971
population based cohort retrospective 		Total birth population of Cardiff Infants born to women who gave a history of having had an epileptic seizure at any time in their lives and exposed to primidone alone during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Infants of mothers with a history of epilepsy but not on anticonvulsants. 		1st trimester 4 / 111
Detailed information has been collected, coded, and computer stored. The hospital and general practitioner records of women with a history of epilepsy were traced and inspected.
Samrén (Primidone)
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 primidone monotherapy at least during the first trimester of pregnancy unexposed, disease free
Children born to nonepileptic nonexposed women. 		at least 1st trimester 18 / 2000
Data were collected from medical records and include medication. The prescribed dose of thedrugs was also retrieved from obstetric files.
Steegers-Theunissen (Primidone)
1994 		Netherlands
Not specified
prospective cohort 		Five centres in the Netherlands: two university hospitals (of Amsterdam and of Nijmegen), and three general hospitals (Maria and Elisabeth hospital, Tilburg and Catharina hospital, Eindhoven). Singleton of epileptic women exposed to primidone monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Singleton of healthy women unexposed during pregnancy. 		during pregnancy (anytime or not specified) 1 / 106 Women could only participate if they or any first-degree relative had no genetic disorder known to cause major congenital malformations, and if they were not under treatment for infectious, metabolic, endocrine or malignant diseases.
The use of antiepileptic drugs was checked in each woman by measurement of the blood concentration. Data such as antiepileptic drug treatment were collected. The consulting doctors were finally contacted to obtain additional information on treatment regimen.
Titze (Primidone) (Controls unexposed, disease free)
2008 		Germany
1976 - 1984
prospective cohort 		Five antenatal clinics in the city of Berlin (West Germany). Adolescents whose epileptic mothers were exposed to primidone monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Adolescents from non-affected mothers. 		during pregnancy (anytime or not specified) 9 / 49
The pregnant women were asked to continuously monitor their treatment.
Titze (Primidone) (Controls unexposed, sick)
2008 		Germany
1976 - 1984
prospective cohort 		Five antenatal clinics in the city of Berlin (West Germany). Adolescents whose epileptic mothers were exposed to primidone monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Adolescents whose epileptic mothers weren't exposed to any antiepileptic drugs during pregnancy. 		during pregnancy (anytime or not specified) 9 / 13
The pregnant women were asked to continuously monitor their treatment.
Vajda (Primidone) (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 primidone 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 2 / 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 (Primidone) (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 primidone 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 2 / 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.

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 (Primidone)
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 Congenital abnormalities syndromes 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.
Czeizel (Primidone)
1992 		Hungary
1980 - 1987
case control 		The Hungarian Case-Control Surveillance of Congenital Anomalies. Children affected with congenital abnormalities born from treated or untreated mothers. Children without congenital abnormalities born from treated or untreated mothers. Mothers were mailed a questionnaire requested information on medicinal products taken during pregnancy and to send their prenatal maternity logbook which related drug prescriptions. Regional nurses were asked to visit and question the non-respondent. throughout pregnancy 100 / 54 Only one women was treated with primidone for eclampsia. The study design was partly completed thanks to the reference [6] cited in the publication. All congenital abnormalities except spina bifida are overlapped by the publication of Bànhidy 2011.
Notification of cases with congenital abnormality is mandatory for physicians to the HCAR. Pathologists sent autopsy report for stillbirths and infant deaths cases. Prenatally diagnosed and electively terminated malformed fetuses have also been registered.

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

master protocol

- About - Master protocol - Browse exposition - RSS - Made with in Lyon - Contact us - Privacy policy - Licence Creative Commons