Primidone AND Phenobarbital (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
Adams (Phenobarbital)
2022 		Boston, USA
1983-1993 1996-2000
retrospective cohort 		First at five maternity hospitals in the Boston area then during the second recruitment phase from a large health maintenance organization in the Boston area. Children following gestational exposure to phenobarbital monotherapy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Children born to antiseizure medication-unexposed women with seizure disorders. 		during pregnancy (anytime or not specified) 34 / 34 Pregnant women with any exposure to other agents known to be of teratogenic concern during pregnancy were excluded. Additionally, children who were born prematurely were excluded from the study.
Women were interviewed during the peri- and post- partum periods regarding multiple pregnancy characteristics and risks.
Al Bunyan (Phenobarbital)
1999 		Saudi Arabia
1985 - 1994
retrospective cohort 		King Khalid University Hospital, Riyadh (KKUH) Children whose epileptic mothers were exposed to phenobarbital 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) 2 / 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.
Barroso (Phenobarbital)
2015 		Brazil
2000 - 2010
retrospective cohort 		The register of the Sao Paulo Hospital’s obstetrics center. Newborns of epileptic parturients receiving phenobarbital monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Newborns of nonepileptic parturients who had deliveries immediately before and after the delivery of epileptic parturients. 		during pregnancy (anytime or not specified) 32 / 316
The complete medical records of both the mother and her newborn were later analyzed.
Battino (Phenobarbital or Primidone)
1999 		Japan, Italy and Canada
1978 - 1991
prospective cohort 		Centers in Japan, Italy and Canada Infants whose epileptic mothers were exposed to phenobarbital or 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 125 / 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.
Battino (Phenobarbital or Primidone)
1992 		Italy
1977 - 1989
prospective cohort 		The Milan Collaborative Study on Epilepsy and Pregnancy, Italy. Offspring of epileptic mothers treated with phenobarbital or 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 91 / 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.
Bech (Phenobarbital) (Controls exposed to Lamotrigine, sick) (Other indications)
2018 		Denmark
2005 - 2008
population based cohort propective 		The Danish Prescription Register, the Danish Medical Birth Register, the Danish Psychiatric Central Research Register and Danish National Patient Registry. Singleton offspring of mothers exposed to phenobarbital monotherapy within 90 days prior to conception to birth. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Singleton offspring of mothers exposed to lamotrigine monotherapy within 90 days prior to conception to birth. 		during pregnancy (anytime or not specified) 11 / 290
The Danish National Prescription Register was used to obtain data on redeemed prescriptions using Anatomical Therapeutic Chemical (ATC) codes.
Bech (Phenobarbital) (Controls unexposed, sick) (Other indications)
2018 		Denmark
2005 - 2008
population based cohort propective 		The Danish Prescription Register, the Danish Medical Birth Register, the Danish Psychiatric Central Research Register and Danish National Patient Registry. Singleton offspring of mothers exposed to phenobarbital monotherapy within 90 days prior to conception to birth. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Singleton offspring of mothers exposed to antiepileptic drugs at any time but not during pregnancy. 		during pregnancy (anytime or not specified) 11 / 434
The Danish National Prescription Register was used to obtain data on redeemed prescriptions using Anatomical Therapeutic Chemical (ATC) codes.
Bjørk (Phenobarbital) (Controls exposed to Lamotrigine, sick) (Mixed indications)
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 mothers filling at least one phenobarbital 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 mothers filling at least one lamotrigine monotherapy prescription from her last menstrual period until birth. 		during pregnancy (anytime or not specified) 175 / 7950 Excluded twins and triplets for statistical reasons and children with chromosomal disorders diagnosed before end of follow-up. 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 (Phenobarbital) (Controls unexposed NOS) (Mixed indications)
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 mothers filling at least one phenobarbital 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) 175 / 4463879 Excluded twins and triplets for statistical reasons and children with chromosomal disorders diagnosed before end of follow-up. 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 (Phenobarbital) (Controls unexposed, sick) (Mixed indications)
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 mothers filling at least one phenobarbital 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) 175 / 21634 Excluded twins and triplets for statistical reasons and children with chromosomal disorders diagnosed before end of follow-up. 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.
Blotière (Phenobarbital) (Controls exposed to Lamotrigine, sick) (Mixed indications)
2019 		France
2011 - 2015
retrospective cohort (claims database) 		The French national health insurance database (DCIR) and the French hospital discharge database (PMSI). Pregnancies exposed to phenobarbital monotherapy between 1 month before and 2 months after the beginning of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Pregnancies exposed to lamotrigine monotherapy between 1 month before and 2 months after the beginning of pregnancy. 		1st trimester 80 / 2997 Authors excluded twin pregnancies and pregnancies with a chromosomal abnormality identified. Less than 90% of exposed pregnancies have a proxy for epilepsy. Publication's OR were not kept when lower limit of the confidence interval or OR equal to 0.
The French national health insurance database contains all health care claims reimbursed by French National Health Insurance. Include dispensed drugs coded according to the ATC classification. Monotherapy was defined as the absence of any other antiepileptic drug dispensed during the same period.
Blotière (Phenobarbital) (Controls unexposed NOS) (Mixed indications)
2019 		France
2011 - 2015
retrospective cohort (claims database) 		The French national health insurance database (DCIR) and the French hospital discharge database (PMSI). Pregnancies exposed to phenobarbital monotherapy between 1 month before and 2 months after the beginning of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Pregnancies with no reimbursement for antiepileptic drugs. 		1st trimester 80 / 1875733 Authors excluded twin pregnancies and pregnancies with a chromosomal abnormality identified. Less than 90% of exposed pregnancies have a proxy for epilepsy. Publication's OR were not kept when lower limit of the confidence interval or OR equal to 0.
The French national health insurance database contains all health care claims reimbursed by French National Health Insurance. Include dispensed drugs coded according to the ATC classification. Monotherapy was defined as the absence of any other antiepileptic drug dispensed during the same period.
Burja (Phenobarbital or 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 phenobarbital or 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) 2 / 211
Hospital neonatal and obstetric records at the MariborTeaching Hospital Department of Perinatology.
Burja (Phenobarbital or 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 phenobarbital or 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) 2 / 32
Hospital neonatal and obstetric records at the MariborTeaching Hospital Department of Perinatology.
Canger (Phenobarbital or 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 phenobarbital or 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 118 / 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.
Cassina (Phenobarbital) (Controls exposed to Lamotrigine, sick) (Other indications)
2013 		Italy
2000 - 2008
prospective cohort 		Italian Teratology Information Services: Servizio di Informazione Teratologica, Telefono Rosso, Centro di Riferimento Regionale di Tossicologia Perinatale. Children whose mothers were treated with phenobarbital in monotherapy between the 5th and the 14th week after their last menstrual period in order to control non-epileptic disorders. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children whose mothers were exposed to lamotrigine in monotherapy between the 5th and the 14th week after their last menstrual period in order to control non-epileptic disorders. 		1st trimester 6 / 31 Chromosomal anomalies and genetic syndromes were excluded.
At the first contact with the service, pregnant women answered to a formulated questionnaire. In addition, details regarding the treatment with antiepileptic drugs taken after the first contact to the Teratology Information Service were ascertained by a follow-up telephone interview.
Cassina (Phenobarbital) (Controls unexposed, disease free) (Other indications)
2013 		Italy
2000 - 2008
prospective cohort 		Italian Teratology Information Services: Servizio di Informazione Teratologica, Telefono Rosso, Centro di Riferimento Regionale di Tossicologia Perinatale. Children whose mothers were treated with phenobarbital in monotherapy between the 5th and the 14th week after their last menstrual period in order to control non-epileptic disorders. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Healthy pregnant women randomly selected among patients who contacted the Teratology Information Services during their pregnancy with regard to exposure to agents known not to be teratogenic (i.e. paracetamol, hair dying, etc.) during a similar time frame. 		1st trimester 6 / 867 Chromosomal anomalies and genetic syndromes were excluded.
At the first contact with the service, pregnant women answered to a formulated questionnaire. In addition, details regarding the treatment with antiepileptic drugs taken after the first contact to the Teratology Information Service were ascertained by a follow-up telephone interview.
Christensen (Phenobarbital) (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 Phenobarbital 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) 183 / 8756 Overlapping: For LBW and SGA: Christensen 2024 totally included Kilic 2014 => 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 (Phenobarbital) (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 Phenobarbital 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) 183 / 4467848 Overlapping: For LBW and SGA: Christensen 2024 totally included Kilic 2014 => 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.
Coste (Phenobarbital) (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 phenobarbital 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 indicated for the treatment of epilepsy and bipolar disorder with at least one dispensing between the month preceding onset of pregnancy and its end. 		during pregnancy (anytime or not specified) 84 / 2813 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.
Coste (Phenobarbital) (Controls unexposed, NOS)
2020 		France
2011 - 2014
retrospective cohort (claims database) 		The French national health data system (SNDS) Children born from mothers exposed to phenobarbital 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) 84 / 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.
D'Souza (Phenobarbital) (Controls unexposed, disease free)
1991 		UK
1980 - 1982
prospective cohort 		Antenatal clinic of St Mary's Hospital. Infants born to epileptic mothers treated with phenobarbitone 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 4 / 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 (Phenobarbital) (Controls unexposed, sick)
1991 		UK
1980 - 1982
prospective cohort 		Antenatal clinic of St Mary's Hospital. Infants born to epileptic mothers treated with phenobarbital 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 4 / 8
Every two weeks, clinical assessment of seizure control, and adjustment of anticonvulsant dosage in accordance with serum drug concentration or clinical response.
Dean (Phenobarbital or Primidone)
2002 		Scotland
1976 - 2000
retrospective cohort 		Aberdeen Maternity Hospital, the antenatal clinic and postnatal wards. Children whose mothers took phenobarbital or 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 63 / 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. Developmental delay is already assessed in Dean et al. 2007.
A structured interview was carried out by a trained research nurse using questionnaires.
Dean (Phenobarbital) (Controls exposed to Lamotrigine, sick)
2007 		Scotland
1976 - 2002
retrospective cohort 		Aberdeen Maternity Hospital. Children whose epileptic mothers were exposed to phenobarbital 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 monotherapy during pregnancy. 		during pregnancy (anytime or not specified) 50 / 4 A previous publication (Dean 2002) gives a better review of the major malformations (includes dead malformed fetuses).
A trained research nurse undertook interviews recording antiepileptic drugs use in each pregnancy. Maternal antiepileptic drugs dose was verified from case records where possible.
Dean (Phenobarbital) (Controls unexposed, sick)
2007 		Scotland
1976 - 2002
retrospective cohort 		Aberdeen Maternity Hospital. Children whose epileptic mothers were exposed to phenobarbital 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 not exposed during pregnancy. 		during pregnancy (anytime or not specified) 50 / 46 A previous publication (Dean 2002) gives a better review of the major malformations.
A trained research nurse undertook interviews recording antiepileptic drugs use in each pregnancy. Maternal antiepileptic drugs dose was verified from case records where possible.
Díaz-Romero (Phenobarbital)
1999 		Mexico
1993 - 1996
cohort 		The Epilepsy Clinic of the National Institute of Perinatology. Full-term eutrophic newborns of epileptic mothers exposed to only phenobarbital 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) 2 / 8 All newborns in the intensive care unit, and those with congenital malformations with a different specific recognizable etiology were excluded.
Not specified
Dravet (Phenobarbital)
1992 		France
1984 - 1988
prospective cohort 		A geographically defined area of southeast France and The Bouche du Rhône Birth Defects Registry. Infants of mothers with epilepsy treated with phenobarbital alone during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Infants of women with epilepsy who did not receive any antiepileptic drugs during pregnancy. 		1st trimester 72 / 14 The number of unknown head circumference decrease the exposed sample size in the outcome result.
A physician of the team followed each pregnant women clinically until delivery. Most information was obtained by mail or telephone. All physicians were asked to measure plasma levels of antiepileptic drugs at each trimester of pregnancy and at the time of delivery.
Elkjaer (Phenobarbital)
2018 		Denmark
1997 - 2006
population based cohort propective 		The Danish Civil Registration System, the Danish Medical Birth Registry, the Danish Agency for Information Technology and Learning, the Danish Register of Medicinal Product Statistics. Children with phenobarbital monotherapy prescribed and redeemed within the exposure window defined from 30 days before the first day of the last menstrual period to 1 day before birth. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Children unexposed to any antiepileptic drugs in pregnancy. 		during pregnancy (anytime or not specified) 86 / 477162 There is no information about the exposure indication.
Information on medical exposure was retrieved from the Danish Register of Medicinal Product Statistics. Authors identified antiepileptic drugs with ATC codes N03A (AEDs) and N05BA09 (clobazam).
Endo (Phenobarbital) (Controls unexposed, disease free)
2004 		Japan
1991 - 2000
retrospective cohort 		Yokohama City University Hospital. Newborns of epileptic mothers who take phenobarbital 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 10 / 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 (Phenobarbital) (Controls unexposed, sick)
2004 		Japan
1991 - 2000
retrospective cohort 		Yokohama City University Hospital. Newborns of epileptic mothers who take phenobarbital 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 10 / 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.
Fedrick (Phenobarbital)
1973 		UK
1966 - 1970
retrospective cohort (registry) 		The Oxford Record Linkage Study Infants of epileptic mothers exposed to phenobarbital alone in the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Infants of epileptic mothers not taking drugs. 		1st trimester 41 / 19 The control series with three control pregnancies resulting in livebirths chosen for each pregnancy resulting in a livebirth to an epileptic mother cannot be used for defect control per antiepileptic drugs types.
In order to ascertain the drugs taken during the relevant pregnancies, the general practitioner of each epileptic mother was asked for details of all anticonvulsant drugs taken.
Hernández-Díaz (Phenobarbital)
2017 		United States and Canada
1997 - 2017
prospective cohort 		The North American Antiepileptic Drug Pregnancy Registry Infants born to women who used phenobarbital in monotherapy throughout pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Infants born to women who used lamotrigine in monotherapy throughout pregnancy. 		throughout pregnancy 178 / 1799 'Most women used their AED throughout pregnancy. The exception was topiramate'. The main indications for AED were epilepsy (91%).
Women were questioned with a computer-assisted telephone interview 3 times.
Hernández-Díaz (Phenobarbital) (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 phenobarbital 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 199 / 1562 Total congenital malformations results are completely overlapped by the update on the registry website. Less than 90% of women are taking Lamotrigine for epilepsy.
Women were questioned with a computer-assisted telephone interview 3 times.
Hernández-Díaz (Phenobarbital) (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 phenobarbital 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 199 / 442 Total congenital malformations results are completely overlapped by the update on the registry website.
Women were questioned with a computer-assisted telephone interview 3 times.
Holmes (Phenobarbital) (Controls unexposed, disease free)
2001 		United States
1986 - 1993
retrospective cohort 		Brigham and Women’s Hospital, Beth Israel Hospital, St. Margaret’s Hospital, St. Elizabeth’s Hospital, and Newton–Wellesley Hospital. Infants exposed in utero to phenobarbital in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Infants unexposed in utero to any antiepileptic drugs born to women with no history of seizure and closest in time from the corresponding exposed children. 		during pregnancy (anytime or not specified) 64 / 508 9% are exposed for other indications (no specified per type of AED).
Women are interviewed and completed questionnaires administered by a research assistant.
Holmes (Phenobarbital) (Controls unexposed, sick)
2001 		United States
1986 - 1993
retrospective cohort 		Brigham and Women’s Hospital, Beth Israel Hospital, St. Margaret’s Hospital, St. Elizabeth’s Hospital, and Newton–Wellesley Hospital. Infants exposed in utero to phenobarbital in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Infants unexposed in utero to any antiepileptic drugs born to women with a history of seizure. 		during pregnancy (anytime or not specified) 64 / 98 9% are exposed for other indications (no specified per type of AED).
Women are interviewed and completed questionnaires administered by a research assistant.
Kaaja (Phenobarbital or Primidone)
2003 		Finland
1980 - 1998
prospective cohort 		Department of Obstetrics and Gynecology from Helsinki University Central Hospital Infants whose epileptic mothers took phenobarbital or 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 11 / 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 (Phenobarbital or Primidone) (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 phenobarbital or primidone 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 26 / 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 (Phenobarbital or Primidone) (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 phenobarbital or primidone 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 26 / 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).
Kaneko (Phenobarbital or 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 phenobarbital or methylphenobarbital or 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 119 / 98 Methylphenobarbital and Phenobarbital were considered as the same drug. Details about the design were completed thanks to Battino et al. 1999. Kaneko 1999 overlapped with Kaneko 1988, Oguni 1992, Dansky 1982, 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.
Kasradze (Phenobarbital) (Controls exposed to Lamotrigine, sick)
2017 		Georgia
2001
prospective cohort 		The Georgian National Antiepileptic drugs-Pregnancy Registry (the Georgian registry of EURAP). Children born to epileptic mothers exposed to phenobarbital monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children born to epileptic mothers exposed to lamotrigine monotherapy during pregnancy. 		during pregnancy (anytime or not specified) 3 / 3 Children with major congenital malformations were excluded from the study.
Antiepileptic drugs and total daily dosage before pregnancy/at 1st trimester/at 2nd trimester/at 3rd trimester were assessed retrospectively during the mother's structured interview.
Kasradze (Phenobarbital) (Controls unexposed, disease free)
2017 		Georgia
2001
prospective cohort 		The Georgian National Antiepileptic drugs-Pregnancy Registry (the Georgian registry of EURAP). Children born to epileptic mothers exposed to phenobarbital monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Children born to mothers without epilepsy, with no antiepileptic drug or other drug treatment during pregnancy 		during pregnancy (anytime or not specified) 3 / 50 Children with major congenital malformations were excluded from the study.
Antiepileptic drugs and total daily dosage before pregnancy/at 1st trimester/at 2nd trimester/at 3rd trimester were assessed retrospectively during the mother's structured interview.
Katz (Phenobarbital or Primidone)
2001 		USA
1990 - 2000
retrospective cohort 		Department of Neurology, New York University School of Medicine. Newborn of women with epilepsy exposed to phenobarbital or 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) 7 / 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.
Kelly (Phenobarbital)
1984 		USA
1977 - 1982
prospective cohort 		The satellite epilepsy clinics and private clinics of the Department of Neurology at the University of Virginia Children and older sibs born to study epileptic mothers receiving phenobarbital alone at the time they were enrolled. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Children and older sibs born to study epileptic mothers not on anticonvulsant treatment at the time they were enrolled. 		during pregnancy (anytime or not specified) 13 / 21
Efforts were made to ensure that periodic determinations of blood levels of anticonvulsants were obtained, especially during pregnancy.
Kilic (Phenobarbital or Primidone) (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 phenobarbital or primidone 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) 116 / 880 Less than 90% of women are epileptic. Overlapping: For LBW and SGA: Kilic 2014 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 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 (Phenobarbital or Primidone) (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 phenobarbital or primidone 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) 116 / 676834 Less than 90% of women are epileptic. Overlapping: For LBW and SGA: Kilic 2014 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 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 (Phenobarbital or Primidone) (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 phenobarbital or primidone 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) 116 / 5296 Less than 90% of women are epileptic. Overlapping: For LBW and SGA: Kilic 2014 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 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 (Phenobarbital or 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 phenobarbital or 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) 4 / 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 (Phenobarbital or 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 phenobarbital or 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) 4 / 101 Because we don't know the exact number of children exposed to phenobarbital 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 (Phenobarbital or 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 phenobarbital or 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) 18 / 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.
Leite (Phenobarbital) (Epilepsy)
2024 		Brazil
2008 - 2021
retrospective cohort 		Prenatal and prepartum clinics in Maceio, Arapiraca and Santana do Ipanema, which are the reference institutions for the care of pregnant women with epilepsy in the state of Alagoas, Brazil. Pregnant women with epilepsy using phenobarbital in monotherapy. unexposed, disease free
Pregnant women without epilepsy (PWNE). 		during pregnancy (anytime or not specified) 70 / 492 Outcomes occurring during pregnancy (preeclampsia, oligohydramnios, abortions...) not reported here because it is not possible to know if exposure was before the outcome occurred (xls table in e-Supp showed that exposure only considered as Yes or No).
This was a retrospective cohort study with data collected from physical and electronic medical records.
Lowe (Phenobarbital or 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 phenobarbital or 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 57 / 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 (Phenobarbital or 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 phenobarbital or 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 57 / 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.
Miškov (Phenobarbital) (Controls exposed to Lamotrigine, sick)
2016 		Croatia
2003 - 2013
prospective cohort 		The Sestre milosrdnice University Hospital Center in Zagreb Pregnancies in women with epilepsy on phenobarbital monotherapy. (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 on lamotrigine monotherapy. 		during pregnancy (anytime or not specified) 3 / 37 Includes all Miskov's 2010 outcomes.
Data collected on pregnant women during outpatient visits to the neurologist, gynecologist and pediatrician neurologist.
Miškov (Phenobarbital) (Controls unexposed, disease free)
2016 		Croatia
2003 - 2013
prospective cohort 		The Sestre milosrdnice University Hospital Center in Zagreb Pregnancies in women with epilepsy on phenobarbital monotherapy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Pregnancies in healthy controls. 		during pregnancy (anytime or not specified) 3 / 147 Includes all Miskov's 2010 outcomes.
Data collected on pregnant women during outpatient visits to the neurologist, gynecologist and pediatrician neurologist.
Miškov (Phenobarbital) (Controls unexposed, sick)
2016 		Croatia
2003 - 2013
prospective cohort 		The Sestre milosrdnice University Hospital Center in Zagreb Pregnancies in women with epilepsy on phenobarbital monotherapy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnancies in women with epilepsy without antiepileptic drugs. 		during pregnancy (anytime or not specified) 3 / 4 Includes all Miskov's 2010 outcomes.
Data collected on pregnant women during outpatient visits to the neurologist, gynecologist and pediatrician neurologist.
Robert (Phenobarbital)
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 phenobarbital in monotherapy. unexposed, sick
Infants born from epileptic mothers unexposed during the first trimester to any antiepileptic drugs. 		1st trimester 40 / 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 (Phenobarbital or 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 phenobarbital, mephobarbital or methylphenobarbital or primidone monotherapy at least during the first trimester of pregnancy unexposed, disease free
Children born to nonepileptic nonexposed women. 		at least 1st trimester 196 / 2000 Mephobarbital or methylphenobarbital are synonyms and pro-drugs that are mainly metabolized into phenobarbital.
Data were collected from medical records and include medication. The prescribed dose of thedrugs was also retrieved from obstetric files.
Shankaran (Phenobarbital) (Other indications)
2002 		USA
Not specified.
randomized controlled trial 		10 centers that participate in the National Institute of Child Health and Human Development Neonatal Research Network Infants born to mothers who had received phenobarbital monotherapy before delivery in preterm labor (once intravenously, followed by 100 mg orally daily, until delivery). unexposed, sick
Infants born to mothers who had received intravenously an infusion of normal saline solution and daily maintenance doses of placebo orally until delivery in preterm labor. 		days before delivery 226 / 210 This study was performed as the follow-up component of a randomized controlled trial with infants <34 weeks of gestational age.
Pregnant women who were at 24 to 32 weeks of gestation were randomized to either 10 mg of phenobarbital per kilogram of body weight intravenously or an infusion of normal saline solution.
Shankaran (Phenobarbital) (Other indications)
1996 		USA
Not specified.
randomized controlled trial 		The newborn follow-up program at Children’s Hospital of Michigan. Infants born to mothers who had received phenobarbital monotherapy before delivery in preterm labor (once intravenously, followed by 100 mg orally daily, until delivery). unexposed, sick
Infants born to mothers who did not received treatment before delivery in preterm labor. 		days before delivery 41 / 55 This study was performed as the follow-up component of a randomized controlled trial. The psychomotor delay is already evaluated in Shankaran et al., 2002 as well as neonatal intracranial hemorrhage, cerebral palsy, hearing/visual impairment.
Women were assigned to control and treatment groups as part of a randomized controlled trial.
Steegers-Theunissen (Phenobarbital or 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 phenobarbital or 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) 13 / 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.
The NAAED (Phenobarbital) (Controls exposed to LTG) (Indications NOS)
2023 		North America and Canada
1997 - 2022
prospective cohort 		The North American Antiepileptic Drug Pregnancy Register Infants of pregnant women who used Phenobarbital as 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 pregnant women who used lamotrigine as monotherapy, during the first trimester. 		1st trimester 200 / 2461 Study design completed with Hernández-Díaz et al. 2012. Data extracted from the North American AED pregnancy registry website. Overlapping/update with Hernández-Díaz et al. 2012, previous website reports and Holmes 2004.
Women are interviewed at enrollment, at 7 months’ gestation and at 8 –12 weeks after the expected date of delivery. The computer-assisted interviews include questions on start and stop dates of each antiepileptic drugs taken, dose, frequency and changes in medication.
The NAAED (Phenobarbital) (Controls unexposed, disease free) (Indications NOS)
2023 		North America and Canada
1997 - 2022
prospective cohort 		The North American Antiepileptic Drug Pregnancy Register Infants of pregnant women who used Phenobarbital as monotherapy, during the first trimester. (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 200 / 1311 Study design completed with Hernández-Díaz et al. 2012. Data extracted from the North American AED pregnancy registry website. Overlapping/update with Hernández-Díaz et al. 2012, previous website reports and Holmes 2004. Use of internal control.
Women are interviewed at enrollment, at 7 months’ gestation and at 8 –12 weeks after the expected date of delivery. The computer-assisted interviews include questions on start and stop dates of each antiepileptic drugs taken, dose, frequency and changes in medication.
Thomas (Phenobarbital) (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 phenobarbitone 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 137 / 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 (Phenobarbital) (Controls unexposed, disease free)
2021 		India
1998 - 2015
prospective cohort 		The Kerala Registry of Epilepsy and Pregnancy (KREP) Children of women with epilepsy using phenobarbital 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 129 / 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 (Phenobarbital) (Controls unexposed, sick)
2021 		India
1998 - 2019
prospective cohort 		The Kerala Registry of Epilepsy and Pregnancy (KREP) Children of women with epilepsy using phenobarbitone 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 137 / 340 Study design completed with Thomas et al., 2017. Thomas et al., 2008 completely overlapped with 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 a (Phenobarbitone)
2022 		India
1998 - 2006
prospective cohort 		The Kerala Registry of Epilepsy and Pregnancy (KREPS), India. Children of women with epilepsy (CWWE) exposed to Phenobarbitone monotherapy during pregnancy. unexposed, sick
Children of women with epilepsy (CWWE) not exposed to antiseizure medications during pregnancy. 		during pregnancy (anytime or not specified) 12 / 11 Overlapping: Thomas 2022 included data on language and cognitive delay, also evaluated in Sreedharan et al., 2018; Thomas 2007 and Gopinath 2015, but with more exposed pregnancies, more relevant control group and older children => Use of Thomas 2022.
The details of Antiseizure medications exposure were extracted from the clinical records in the registry.
Thomas b (Phenobarbitone) (Epilepsy) (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 Phenobarbitone 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) 83 / 26 Overlapping/Update Thomas 2008b (1998 - 2004) totally included in Thomas 2022b (1998 - 2019): Use of Thomas 2022b (more exposed pregnancies). 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 b (Phenobarbitone) (Epilepsy) (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 Phenobarbitone 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) 83 / 110 Overlapping/Update Thomas 2008b (1998 - 2004) totally included in Thomas 2022b (1998 - 2019): Use of Thomas 2022b (more exposed pregnancies).
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.
Titze (Phenobarbital or 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 phenobarbital or 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) 12 / 49
The pregnant women were asked to continuously monitor their treatment.
Titze (Phenobarbital or 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 phenobarbital or 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) 12 / 13
The pregnant women were asked to continuously monitor their treatment.
Tomson (Phenobarbital or Primidone)
2018 		42 countries
1999 - 2016
prospective cohort 		The EURAP epilepsy and pregnancy registry Offspring exposed in utero to phenobarbital or primidone 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 334 / 2514 Martinez 2009 contains malformations results already included in this study. This study is an update of Tomson's 2011 publication. They excluded from the current analysis pregnancies occurring in women without epilepsy. EURAP registry: potential overlap.
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.
Tomson (Phenobarbital)
2015 		42 countries
1999 - 2013
prospective cohort 		The EURAP epilepsy and pregnancy registry Pregnancies in women with epilepsy treated with phenobarbital 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 260 / 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).
Trivedi (Phenobarbital) (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 phenobarbital 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 138 / 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.
Vajda (Phenobarbital or 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 phenobarbital or 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 4 / 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 (Phenobarbital or 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 phenobarbitone or 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 4 / 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.
Van der Pol (Phenobarbital) (Controls unexposed, disease free)
1991 		The Netherlands
1973 - 1981
prospective cohort 		The Groningen University Hospital Children born to epileptic mothers exposed to phenobarbital only throughout pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Children of nonepileptic mothers selected from singletons born in the same period. 		throughout pregnancy 13 / 61
The dosages of antiepileptic drugs were constant throughout pregnancy.
Van der Pol (Phenobarbital) (Controls unexposed, sick)
1991 		The Netherlands
1973 - 1981
prospective cohort 		The Groningen University Hospital Children born to epileptic mothers exposed to phenobarbital only throughout pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Children born to epileptic mothers not exposed to antiepileptic medication. 		throughout pregnancy 13 / 24
The dosages of antiepileptic drugs were constant throughout pregnancy.
Veiby (Phenobarbital) (Controls exposed to Lamotrigine, sick) (Mixed indications)
2014 		Norway
1999 - 2011
population based cohort retrospective 		Medical Birth Registry of Norway Children exposed prenatally to phenobarbital as monotherapy indicated for their mothers' epilepsy or other indications. (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 or other indications. 		throughout pregnancy 27 / 833 Exposure to antiepileptic drugs for the strict indication of epilepsy cannot be considered for the results of specific malformations. Thus, less than 90% of women are treated with Phenobarbital and Lamotrigine for epilepsy (Mixed indications).
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 (Phenobarbital) (Controls unexposed, disease free) (Mixed indications)
2014 		Norway
1999 - 2011
population based cohort retrospective 		Medical Birth Registry of Norway Children exposed prenatally to phenobarbital as monotherapy indicated for their mothers' epilepsy or other indications. (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 27 / 771412 Less than 90% of women are treated with Phenobarbital for epilepsy (Mixed indications).
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 (Phenobarbital) (Controls unexposed, sick) (Mixed indications)
2014 		Norway
1999 - 2011
population based cohort retrospective 		Medical Birth Registry of Norway Children exposed prenatally to phenobarbital as monotherapy indicated for their mothers' epilepsy or other indications. (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 27 / 3773 Exposure to antiepileptic drugs for the strict indication of epilepsy cannot be considered for the results of specific malformations. Thus, less than 90% of women are treated with Phenobarbital for epilepsy (Mixed indications).
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).
Waters (Phenobarbital) (Controls unexposed, disease free)
1994 		USA
1987 - 1990
prospective cohort 		The obstetrics service at Los Angeles County/University of Southern California Medical Center. Infants born to epileptic mothers exposed to phenobarbital 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 nonepileptic mothers selected from a computer-generated list of all women who gave birth in the same facility during this period. 		1st trimester 21 / 355 Mothers who abused alcohol and other drugs were excluded from both patient ad control groups.
An attending neurologist took a history, performed an examination, and monitored the administration of antiepileptic drugs throughout the pregnancy. Documented at each visit on a standard form.
Waters (Phenobarbital) (Controls unexposed, sick)
1994 		USA
1987 - 1990
prospective cohort 		The obstetrics service at Los Angeles County/University of Southern California Medical Center. Infants born to epileptic mothers exposed to phenobarbital during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnancies in women with epilepsy in which there was no exposure to antiepileptic drugs. 		1st trimester 21 / 15 Mothers who abused alcohol and other drugs were excluded from both patient ad control groups.
An attending neurologist took a history, performed an examination, and monitored the administration of antiepileptic drugs throughout the pregnancy. Documented at each visit on a standard form.
Yerby (Phenobarbital)
1992 		USA
Not specified.
prospective cohort 		The Child Development and Mental Retardation Center at the University of Washington. Infants of mothers with epilepsy treated by phenobarbital monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Infants of women without a chronic illness or a personal or family history of epilepsy. 		during pregnancy (anytime or not specified) 10 / 46 Women were excluded if they had another chronic illness and were not compliant.
Women with epilepsy had a determination of antiepileptic drug concentrations. They were scheduled for monthly visits and with their babies two times post partum

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 (Phenobarbital or 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.
Thomas a (Phenobarbital)
2008 		India
1998 - 2004
nested case control 		The Kerala Registry of Epilepsy and Pregnancy Infants with cardiac malformation defined as any major malformation of the heart or intrathoracic great vessels that is actually or potentially of functional significance. Infants without cardiac malformation. The maternal use of antiepileptic drugs is recorded in the protocol forms from the month prior to the last menstrual period through the entire pregnancy and postpartum period on a monthly basis. 1st trimester 36 / 426 Completely overlapped with Thomas et al., 2021.
A cardiologist blinded to antiepileptic drugs exposure of the infants carries out a clinical examination and echocardiogram on all infants. A second cardiologist confirmed malformation whenever required.

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

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