Phenytoin (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
Adab (Phenytoin)
2004 		UK
1989 - 1999
retrospective cohort 		The Mersey Regional Epilepsy Clinic, the Epilepsy Clinic at the Manchester Royal Infirmary and the antenatal clinic at St Mary’s Hospital. Children exposed to phenytoin monotherapy in utero and born to mothers with epilepsy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Children unexposed to antiepileptic drugs in utero and born to mothers with epilepsy. 		during pregnancy (anytime or not specified) 26 / 101 The language delay of this sample is better assessed in Vinten et al., 2009 (in discrete values).
A clinician conducted semi-structured interviews of mothers and clinical records were used to confirm information.
Adams (Phenytoin)
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 phenytoin 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) 40 / 40 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 (Phenytoin)
1999 		Saudi Arabia
1985 - 1994
retrospective cohort 		King Khalid University Hospital, Riyadh (KKUH) Children whose epileptic mothers were exposed to phenytoin 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) 9 / 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.
Alsfouk (Phenytoin) (Controls exposed to Lamotrigine, sick)
2021 		Riyadh and Jeddah, Saudi Arabia.
1993 - 2020
retrospective cohort 		The King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh and Jeddah, Saudi Arabia. Epileptic mothers with phenytoin monotherapy administered during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Epileptic mothers with lamotrigine monotherapy administered during pregnancy. 		during pregnancy (anytime or not specified) 1 / 15
Patients’ electronic and paper-based medical records.
Alsfouk (Phenytoin) (Controls unexposed, sick)
2021 		Riyadh and Jeddah, Saudi Arabia.
1993 - 2020
retrospective cohort 		The King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh and Jeddah, Saudi Arabia. Epileptic mothers with phenytoin monotherapy administered during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Epileptic mothers who did not take antiseizure medications during pregnancies. 		during pregnancy (anytime or not specified) 1 / 30
Patients’ electronic and paper-based medical records.
Arkilo (Phenytoin)
2015 		USA
2006 - 2011
retrospective cohort 		Minnesota Epilepsy Group, P.A. of United Hospital and Children's Hospitals and Clinics of Minnesota Singleton whose epileptic mothers were exposed to phenytoin monotherapy at any point during the pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Singleton whose epileptic mothers were exposed to lamotrigine monotherapy at any point during the pregnancy. 		during pregnancy (anytime or not specified) 5 / 24
Questionnaires were sent to women.
Artama (Phenytoin)
2005 		Finland
1991 - 2000
retrospective cohort (registry) 		The Medical Birth Register and the Social Insurance Institution (SII) of Finland. Children whose epileptic mothers were exposed to phenytoin as monotherapy during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Children whose epileptic mothers were untreated during the first trimester of pregnancy. 		1st trimester 38 / 939
Information on the antiepileptic drugs received during pregnancy was abstracted from medical records of the mothers with epilepsy.
Artama (Phenytoin) (Controls exposed to Lamotrigine, sick)
2013 		Finland
1996 - 2008
population based cohort retrospective 		The Medical Birth Register (MBR), the Finnish Malformation Register, the Special Refund Entitlement Register, the Register on Reimbursement Drugs and Cause-of-Death Register. Births in pregnant women with epilepsy exposed to phenytoin in monotherapy 1 month prior to pregnancy and/or any time during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Births in pregnant women with epilepsy exposed to lamotrigine in monotherapy 1 month prior to pregnancy and/or any time during pregnancy. 		3rd trimester, during pregnancy (anytime or not specified) 26 / 173
The Special Refund Entitlement Register and the Register on Reimbursement Drugs contained informations on maternal drug treatment under ATC category N03.
Artama (Phenytoin) (Controls unexposed, disease free)
2013 		Finland
1996 - 2008
population based cohort retrospective 		The Medical Birth Register (MBR), the Finnish Malformation Register, the Special Refund Entitlement Register, the Register on Reimbursement Drugs and Cause-of-Death Register. Births in pregnant women with epilepsy exposed to phenytoin in monotherapy 1 month prior to pregnancy and/or any time during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Births in pregnant women without epilepsy and unexposed to any antiepileptic drugs 1 month prior to pregnancy and/or any time during pregnancy. 		3rd trimester, during pregnancy (anytime or not specified) 26 / 721948
The Special Refund Entitlement Register and the Register on Reimbursement Drugs contained informations on maternal drug treatment under ATC category N03.
Artama (Phenytoin) (Controls unexposed, sick)
2013 		Finland
1996 - 2008
population based cohort retrospective 		The Medical Birth Register (MBR), the Finnish Malformation Register, the Special Refund Entitlement Register, the Register on Reimbursement Drugs and Cause-of-Death Register. Births in pregnant women with epilepsy exposed to phenytoin in monotherapy 1 month prior to pregnancy and/or any time during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Births in pregnant women with epilepsy and unexposed to any antiepileptic drugs 1 month prior to pregnancy and/or any time during pregnancy. 		3rd trimester, during pregnancy (anytime or not specified) 26 / 1800
The Special Refund Entitlement Register and the Register on Reimbursement Drugs contained informations on maternal drug treatment under ATC category N03.
Aydin (Phenytoin) (Controls exposed to Lamotrigine, sick)
2020 		Turkey
2007 - 2017
retrospective cohort 		The Division of Perinatology, Department of Obstetrics and Gynecology, Hacettepe University Pregnant women with epilepsy who received phenytoin in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Pregnant women with epilepsy who received lamotrigine in monotherapy during pregnancy. 		throughout pregnancy 1 / 7 There were no patients who had drug changes or discontinued during pregnancy.
Data were obtained from Perinatology Division’s computerized system. Antiepileptic drug use were reported.
Aydin (Phenytoin) (Controls unexposed, sick)
2020 		Turkey
2007 - 2017
retrospective cohort 		The Division of Perinatology, Department of Obstetrics and Gynecology, Hacettepe University Pregnant women with epilepsy who received phenytoin in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant women with epilepsy with no antiepileptic drugs during pregnancy. 		throughout pregnancy 1 / 22 There were no patients who had drug changes or discontinued during pregnancy.
Data were obtained from Perinatology Division’s computerized system. Antiepileptic drug use were reported.
Battino (Phenytoin)
1999 		Japan, Italy and Canada
1978 - 1991
prospective cohort 		Centers in Japan, Italy and Canada Infants whose epileptic mothers were exposed to phenytoin 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 118 / 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 (Phenytoin)
1992 		Milan
1977 - 1989
prospective cohort 		The Milan Collaborative Study on Epilepsy and Pregnancy Offspring of epileptic mothers treated with phenytoin 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 27 / 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.
Bromley (Phenytoin) (Controls exposed to Lamotrigine, sick)
2008 		UK
2000 - 2006
prospective cohort 		The Liverpool and Manchester Neurodevelopment Group (LMNDG). Live births were to women with epilepsy exposed to phenytoin monotherapy at the beginning of gestation. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Live births were to women with epilepsy exposed to lamotrigine monotherapy at the beginning of gestation. 		early pregnancy 9 / 44
Information is collected during the pregnancy regarding the mother's epilepsy and medical history. Maternal epilepsy information and pregnancy were verified using medical case notes.
Bromley (Phenytoin) (Controls unexposed, disease free)
2008 		UK
2000 - 2006
prospective cohort 		The Liverpool and Manchester Neurodevelopment Group (LMNDG). Live births were to women with epilepsy exposed to phenytoin monotherapy at the beginning of gestation. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Live births born to women without epilepsy who were not taking medication. 		early pregnancy 9 / 336
Information is collected during the pregnancy regarding the mother's epilepsy and medical history. Maternal epilepsy information and pregnancy were verified using medical case notes.
Bromley (Phenytoin) (Controls unexposed, sick)
2008 		UK
2000 - 2006
prospective cohort 		The Liverpool and Manchester Neurodevelopment Group (LMNDG). Live births were to women with epilepsy exposed to phenytoin monotherapy at the beginning of gestation. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Children born to women with epilepsy who were not medicated during the time of the pregnancy. 		early pregnancy 9 / 47
Information is collected during the pregnancy regarding the mother's epilepsy and medical history. Maternal epilepsy information and pregnancy were verified using medical case notes.
Canger (Phenytoin)
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 phenytoin 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 31 / 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.
Cohen (Phenytoin)
2011 		UK and USA
1999 - 2004
prospective cohort 		25 epilepsy centers in the USA and UK. Infants of women exposed to phenytoin in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Infants of women exposed to lamotrigine in monotherapy during pregnancy. 		during pregnancy (anytime or not specified) 40 / 76 A nonexposed control group was not included. Total number of children exposed to each antiepileptic drugs is not specified, so the number of mothers is reported instead.
They obtained information from the patients, their seizure or medication diary, or review of their medical records.
Cohen (Phenytoin)
2013 		USA and UK
1999 - 2004
prospective cohort 		25 epilepsy centers in the USA and UK. Infants of women exposed to phenytoin in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Infants of women exposed to lamotrigine in monotherapy during pregnancy. 		during pregnancy (anytime or not specified) 31 / 63 A nonexposed control group was not included.
They obtained information from the patients, their seizure or medication diary, or review of their medical records.
D'Souza (Phenytoin) (Controls unexposed, disease free)
1991 		UK
1980 - 1982
prospective cohort 		Antenatal clinic of St Mary's Hospital. Infants born to epileptic mothers treated with phenytoin 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 22 / 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 (Phenytoin) (Controls unexposed, sick)
1991 		UK
1980 - 1982
prospective cohort 		Antenatal clinic of St Mary's Hospital. Infants born to epileptic mothers treated with phenytoin 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 22 / 8
Every two weeks, clinical assessment of seizure control, and adjustment of anticonvulsant dosage in accordance with serum drug concentration or clinical response.
Dean (Phenytoin)
2002 		Scotland
1976 - 2000
retrospective cohort 		Aberdeen Maternity Hospital, the antenatal clinic and postnatal wards. Children whose mothers took phenytoin 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 25 / 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 (Phenytoin) (Controls exposed to Lamotrigine, sick)
2007 		Scotland
1976 - 2002
retrospective cohort 		Aberdeen Maternity Hospital. Children whose epileptic mothers were exposed to phenytoin 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) 24 / 4 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.
Dean (Phenytoin) (Controls unexposed, sick)
2007 		Scotland
1976 - 2002
retrospective cohort 		Aberdeen Maternity Hospital. Children whose epileptic mothers were exposed to phenytoin 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) 24 / 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 (Phenytoin)
1999 		Mexico
1993 - 1996
cohort 		The Epilepsy Clinic of the National Institute of Perinatology. Full-term eutrophic newborns of epileptic mothers exposed to only phenytoin 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) 21 / 8 All newborns in the intensive care unit, and those with congenital malformations with a different specific recognizable etiology were excluded.
Not specified
Fedrick (Phenytoin)
1973 		UK
1966 - 1970
retrospective cohort (registry) 		The Oxford Record Linkage Study Infants of epileptic mothers exposed to phenytoin 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 33 / 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.
Forsberg (Phenytoin) (Controls unexposed NOS)
2011 		Sweden
1973 - 1986
retrospective cohort (registry) 		Swedish Medical Birth Register, the Patient Register (formerly Hospital Discharge Register), a local study at South Hospital, Stockholm and The Swedish School Mark Registry. Children identified with maternal epilepsy who had been exposed to phenytoin monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
All other children born in Sweden between the study period. 		during pregnancy (anytime or not specified) 316 / 1307083 These analyses were made after exclusion of children with a diagnosis of a congenital malformation.
The Medical Birth Register is built from data in standardized medical records. To identify the use of anticonvulsants, the original medical documents were retrieved and scrutinized and the information was added to the records of deliveries from women with epilepsy.
Forsberg (Phenytoin) (Controls unexposed, sick)
2011 		Sweden
1973 - 1986
retrospective cohort (registry) 		Swedish Medical Birth Register, the Patient Register (formerly Hospital Discharge Register), a local study at South Hospital, Stockholm and The Swedish School Mark Registry. Children identified with maternal epilepsy who had been exposed to phenytoin monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Children identified with maternal epilepsy but no use of antiepileptic drug. 		during pregnancy (anytime or not specified) 316 / -9 These analyses were made after exclusion of children with a diagnosis of a congenital malformation. Number of children identified with maternal epilepsy but no use of antiepileptic drug not specified.
The Medical Birth Register is built from data in standardized medical records. To identify the use of anticonvulsants, the original medical documents were retrieved and scrutinized and the information was added to the records of deliveries from women with epilepsy.
He (Phenytoin) (Controls exposed to Lamotrigine, sick)
2017 		China
2009 - 2015
prospective cohort 		The epilepsy center of West China Second University Hospital of Sichuan University Pregnancies in which phenytoin monotherapy was used during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Pregnancies in which lamotrigine monotherapy was used during pregnancy. 		during pregnancy (anytime or not specified) 4 / 8 Patients who developed epilepsy during pregnancy or after delivery were not included.
Data collected included antiepileptic drug use.
He (Phenytoin) (Controls unexposed, sick)
2017 		China
2009 - 2015
prospective cohort 		The epilepsy center of West China Second University Hospital of Sichuan University Pregnancies in which phenytoin monotherapy was used during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnancies in which antiepileptic drugs were never used before and during pregnancy. 		during pregnancy (anytime or not specified) 4 / 31 Patients who developed epilepsy during pregnancy or after delivery were not included.
Data collected included antiepileptic drug use.
Hernández-Díaz (Phenytoin) (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 phenytoin 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 416 / 1562 Less than 90% of women are taking Lamotrigine for epilepsy.
Women were questioned with a computer-assisted telephone interview 3 times.
Hernández-Díaz (Phenytoin) (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 phenytoin 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 416 / 442
Women were questioned with a computer-assisted telephone interview 3 times.
Holmes (Phenytoin) (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 phenytoin 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) 87 / 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 (Phenytoin) (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 phenytoin 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) 87 / 98 9% are exposed for other indications (no specified per type of AED).
Women are interviewed and completed questionnaires administered by a research assistant.
Hvas (Phenytoin) (Controls unexposed, disease free)
2000 		Denmark
1989 - 1997
retrospective cohort 		Department of Obstetrics and Gynaecology at Aarhus University Hospital. Children of women with epilepsy exposed to phenytoin monotherapy during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Children of women without chronic disease. 		1st trimester 1 / 24094
Women completed a questionnaire. They were categorised as users or nonusers of anticonvulsant drugs, by self-reported daily intake of any anticonvulsant drug during the first trimester.
Hvas (Phenytoin) (Controls unexposed, sick)
2000 		Denmark
1989 - 1997
retrospective cohort 		Department of Obstetrics and Gynaecology at Aarhus University Hospital. Children of women with epilepsy exposed to phenytoin monotherapy during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Children of women with epilepsy without treatment. 		1st trimester 1 / 106
Women completed a questionnaire. They were categorised as users or nonusers of anticonvulsant drugs, by self-reported daily intake of any anticonvulsant drug during the first trimester.
Kaaja (Phenytoin)
2003 		Finland
1980 - 1998
prospective cohort 		Department of Obstetrics and Gynecology from Helsinki University Central Hospital Infants whose epileptic mothers took phenytoin 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 124 / 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 (Phenytoin)
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 phenytoin 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 132 / 98 Details about the design were completed thanks to Battino et al., 1999 publication. 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.
Katz (Phenytoin)
2001 		USA
1990 - 2000
retrospective cohort 		Department of Neurology, New York University School of Medicine. Newborn of women with epilepsy exposed to phenytoin 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) 6 / 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 (Phenytoin)
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 diphenylhydantoin 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) 41 / 21
Efforts were made to ensure that periodic determinations of blood levels of anticonvulsants were obtained, especially during pregnancy.
Kini (Phenytoin) (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 phenytoin 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) 26 / 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 (Phenytoin) (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 phenytoin 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) 26 / 101 A better review of the WISC score for children aged 6 and above are provided by Adab 2004 publication.
Structured interviews were conducted with the mothers and medical records were available to confirm details in about 80% of participants.
Koch (Phenytoin)
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 phenytoin 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) 13 / 65 Study design partly completed with cited source [13].
The pregnant women were asked to continuously monitor their seizures, treatment and additional illnesses.
Lowe (Phenytoin) (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 phenytoin 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 9 / 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 (Phenytoin) (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 phenytoin 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 9 / 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.
Mawer (Phenytoin) (Controls exposed to Lamotrigine, sick)
2010 		UK
2000 - 2006
prospective cohort 		11 National Health Service (NHS) hospitals within Merseyside and Greater Manchester. Children born to mothers with epilepsy exposed to phenytoin monotherapy in utero. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children born to mothers with epilepsy exposed to lamotrigine monotherapy in utero. 		1st trimester 7 / 40 Kini's 2007 malformation results are overlapped. Specific major malformations' numerators are extracted from the review by Weston et al. 2016 because not classified per types in the original publication. Period of exposure confirm by author's email.
The research nurse recorded personal and medical history with forms. An epilepsy specialist confirmed antiepileptic medication. Information from the patient was supplemented from clinical records.
Mawer (Phenytoin) (Controls unexposed, disease free)
2010 		UK
2000 - 2006
prospective cohort 		11 National Health Service (NHS) hospitals within Merseyside and Greater Manchester. Children born to mothers with epilepsy exposed to phenytoin monotherapy in utero. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Children born to mothers without epilepsy who attended the same clinic on the same day or a few days later. 		1st trimester 7 / 315 Kini's 2007 malformation results are overlapped. Specific major malformations' numerators are extracted from the review by Weston et al. 2016 because not classified per types in the original publication. Period of exposure confirm by author's email.
The research nurse recorded personal and medical history with forms. An epilepsy specialist confirmed antiepileptic medication. Information from the patient was supplemented from clinical records.
Mawer (Phenytoin) (Controls unexposed, sick)
2010 		UK
2000 - 2006
prospective cohort 		11 National Health Service (NHS) hospitals within Merseyside and Greater Manchester. Children born to mothers with epilepsy exposed to phenytoin monotherapy in utero. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Children born to women with untreated epilepsy, who took no antiepileptic drugs before or during pregnancy. 		1st trimester 7 / 46 Kini's 2007 malformation results are overlapped. Specific major malformations' numerators are extracted from the review by Weston et al. 2016 because not classified per types in the original publication. Period of exposure confirm by author's email.
The research nurse recorded personal and medical history with forms. An epilepsy specialist confirmed antiepileptic medication. Information from the patient was supplemented from clinical records.
Meador (Phenytoin)
2013 		UK and USA.
1999 - 2004
prospective cohort 		25 centers in the USA and UK. Infants of epileptic mothers exposed to phenytoin in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Infants of epileptic mothers exposed to lamotrigine in monotherapy during pregnancy. 		during pregnancy (anytime or not specified) 55 / 100 A nonexposed control group was not included. Meador 2020 and Cohen 2019 are re-examination or an assessment of subscales of data already assessed in this publication. Cognitif assessment in Meador 2009 and 2011 (x2) is better assessed in this publication.
They obtained information from the patients, their seizure or medication diary, or review of their medical records and assessed antiepileptic drug levels for 229 (75%) mothers.
Meador (Phenytoin)
2011 		UK and USA
1999 - 2004
prospective cohort 		25 epilepsy centers in the USA and UK. Infants of women exposed to phenytoin in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Infants of women exposed to lamotrigine in monotherapy during pregnancy. 		during pregnancy (anytime or not specified) 39 / 70 A non-exposed control group was not included.
They obtained information from the patients, their seizure or medication diary, or review of their medical records.
Meador (Phenytoin)
2006 		USA and UK
1999 - 2004
prospective cohort 		25 centers across UK and USA. Infants of women exposed to phenytoin in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Infants of women exposed to lamotrigine in monotherapy during pregnancy. 		during pregnancy (anytime or not specified) 56 / 98 Malformations secondary to known genetic disorders and chromosomal abnormalities are not considered within the major malformation group. 108 women with epilepsy are also used in Mawer 2010 so there is a 33% overlap for malformations.
They obtained information from the patients, their seizure or medication diary, or review of their medical records.
Meador (Phenytoin)
2009 		UK and USA
1999 - 2004
prospective cohort 		25 centers across UK and USA. Infants of women exposed to phenytoin in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Infants of women exposed to lamotrigine in monotherapy during pregnancy. 		during pregnancy (anytime or not specified) 52 / 99 Meador 2011 is completely overlapped with this study which gives a better review of the IQ at age 3 years old (more exposed pregnancies). The cognitive delay at 3 years old is already evaluated in Meador et al., 2013.
They obtained information from the patients, their seizure or medication diary, or review of their medical records.
Miškov (Phenytoin) (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 phenytoin 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) 1 / 37 Includes all Miskov's 2010 outcomes.
Data collected on pregnant women during outpatient visits to the neurologist, gynecologist and pediatrician neurologist.
Miškov (Phenytoin) (Controls unexposed, disease free)
2016 		Croatia
2003 - 2013
prospective cohort 		The Sestre milosrdnice University Hospital Center in Zagreb Pregnancies in women with epilepsy on phenytoin 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) 1 / 147 Includes all Miskov's 2010 outcomes.
Data collected on pregnant women during outpatient visits to the neurologist, gynecologist and pediatrician neurologist.
Miškov (Phenytoin) (Controls unexposed, sick)
2016 		Croatia
2003 - 2013
prospective cohort 		The Sestre milosrdnice University Hospital Center in Zagreb Pregnancies in women with epilepsy on phenytoin 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) 1 / 4 Includes all Miskov's 2010 outcomes.
Data collected on pregnant women during outpatient visits to the neurologist, gynecologist and pediatrician neurologist.
Morrow (Phenytoin) (Controls exposed to Lamotrigine, sick)
2006 		UK and Ireland
1996 - 2005
prospective cohort 		The UK Epilepsy and Pregnancy Register Infants of women with epilepsy exposed to phenytoin in monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Infants of women with epilepsy exposed to lamotrigine in monotherapy during the first trimester. 		1st trimester 82 / 647 Exposure period is completed thanks to Campbell 2014 which is also a UKEPR based study.
Information was collected at registration and changes of antiepileptic drugs during pregnancy were detected during the follow-up duration by sending a standardised questionnaire to the patient's general practitioner. Other health care practitioners were contacted if identified.
Morrow (Phenytoin) (Controls unexposed, sick)
2006 		UK and Ireland
1996 - 2005
prospective cohort 		The UK Epilepsy and Pregnancy Register Infants of women with epilepsy exposed to phenytoin in monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Infants of women with epilepsy and who didn't take any antiepileptic drugs during pregnancy. 		1st trimester 82 / 227 Exposure period is completed thanks to Campbell 2014 which is also a UKEPR based study.
Information was collected at registration and changes of antiepileptic drugs during pregnancy were detected during the follow-up duration by sending a standardised questionnaire to the patient's general practitioner. Other health care practitioners were contacted if identified.
Pennell (Phenytoin)
2012 		USA and UK
1999 - 2004
prospective cohort 		25 centers in the United States and United Kingdom Infants of women exposed to phenytoin in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Infants of women exposed to lamotrigine in monotherapy during pregnancy. 		during pregnancy (anytime or not specified) 55 / 98
They obtained information from the patients, their seizure or medication diary, or review of their medical records.
Samrén (Phenytoin)
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 phenytoin monotherapy at least during the first trimester of pregnancy unexposed, disease free
Children born to nonepileptic nonexposed women. 		at least 1st trimester 151 / 2000
Data were collected from medical records and include medication. The prescribed dose of thedrugs was also retrieved from obstetric files.
Sonneveld (Phenytoin) (Controls unexposed NOS)
1990 		Tasmania
1981- 1988
prospective cohort 		The Tasmanian Obstetric and Perinatal audit Epileptic pregnancies exposed to phenytoin monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Total number of deliveries during the study period. 		during pregnancy (anytime or not specified) 79 / 56557 The total population of this study serves as a control group, thus it includes the exposed group but accounting only for 0.6% of the sample. In the result authors used 55953 for the total number of deliveries when all perinatal deaths are excluded.
Since 1981, drugs ingested during pregnancy have been included in the information collected.
Sonneveld (Phenytoin) (Controls unexposed, sick)
1990 		Tasmania
1981- 1988
prospective cohort 		The Tasmanian Obstetric and Perinatal audit Epileptic pregnancies exposed to phenytoin monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Epileptic pregnancies who used no anticonvulsant drug therapy. 		during pregnancy (anytime or not specified) 79 / 87
Since 1981, drugs ingested during pregnancy have been included in the information collected.
Steegers-Theunissen (Phenytoin)
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 phenytoin 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) 8 / 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.
Thomas (Phenytoin)
2022 		India
1998 - 2006
prospective cohort 		The Kerala Registry of Epilepsy and Pregnancy (KREPS), India. Children of women with epilepsy (CWWE) exposed to Phenytoin monotherapy during pregnancy. unexposed, sick
Children of women with epilepsy (CWWE) not exposed to antiseizure medications during pregnancy. 		during pregnancy (anytime or not specified) 10 / 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 (Phenytoin) (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 phenytoin 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 119 / 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 (Phenytoin) (Controls unexposed, disease free)
2021 		India
1998 - 2015
prospective cohort 		The Kerala Registry of Epilepsy and Pregnancy (KREP) Children of women with epilepsy using phenytoin 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 106 / 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 (Phenytoin) (Controls unexposed, sick)
2021 		India
1998 - 2019
prospective cohort 		The Kerala Registry of Epilepsy and Pregnancy (KREP) Children of women with epilepsy using phenytoin 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 119 / 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 b (Phenytoin)
2008 		India
1998 - 2004
prospective cohort 		The Kerala Registry of Epilepsy and Pregnancy Infants whose epileptic mothers were on phenytoin monotherapy anytime during the pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Infants not prenatally exposed to antiepileptic drugs anytime during the pregnancy. 		during pregnancy (anytime or not specified) 29 / 32 The Developmental Assessment Scale for Indian Infants (DASII) is an adaptation of the Bayley Scale of Infant Development standardized for Indian infants.
The daily dosage of antiepileptic drugs for each month of pregnancy was recorded.
Titze (Phenytoin) (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 hydantoin 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 most common antiepileptic drugs were diphenylhydantoin' so the hydantoin group is assessed as predominantly phenytoin exposure.
The pregnant women were asked to continuously monitor their treatment.
Titze (Phenytoin) (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 hydantoin 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 most common antiepileptic drugs were diphenylhydantoin' so the hydantoin group is assessed as predominantly phenytoin exposure.
The pregnant women were asked to continuously monitor their treatment.
Tomson (Phenytoin)
2018 		42 countries
1999 - 2016
prospective cohort 		The EURAP epilepsy and pregnancy registry Offspring exposed in utero to phenytoin 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 125 / 2514 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.
Trivedi (Phenytoin) (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 phenytoin 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 129 / 48 Study design partly completed with cites source Thomas et al., 2017.
Women were instructed to record the use of the antiepileptic drugs on a daily basis in the pregnancy diary that was given to them.
Trivedi (Phenytoin) (Controls unexposed, sick)
2018 		India
1998 - 2015
prospective cohort 		The Kerala Registry of Epilepsy and Pregnancy (KREP) Pregnant women with epilepsy who used phenytoin monotherapy any time during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant women with epilepsy who were not on antiepileptic drug during their first trimester. 		1st trimester 129 / 178 Study design partly completed with cites source Thomas et al., 2017.
Women were instructed to record the use of the antiepileptic drugs on a daily basis in the pregnancy diary that was given to them.
Vajda (Phenytoin) (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 phenytoin 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 44 / 406 Women with epilepsy accounted for 98.3%. Completely overlap Vajda 2007; 2010 (x2); 2012 (x2); 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 (Phenytoin) (Controls exposed to Lamotrigine, sick)
2013 		Australia
1999 - 2013
prospective cohort 		The Australian Register of Antiepileptic Drugs in Pregnancy. Offsprings from women with epilepsy exposed to phenytoin in monotherapy in at least the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Offsprings from women with epilepsy exposed to lamotrigine in monotherapy in at least the first trimester of pregnancy. 		at least 1st trimester 44 / 315 Women taking AED for epilepsy are in majority (more than 90%). Vajda 2019 provides the most recent update for major malformations results for this register. Specific malformations' results are extracted from the review by Weston et al. 2016.
Details are obtained by four in-depth telephone interviews with the women. Details provided by the participants are confirmed, as far as possible, by the treating medical practitioners.
Vajda (Phenytoin) (Controls exposed to Lamotrigine, sick)
2018 		Australia
1999 - 2016
prospective cohort 		The Australian Register of Antiepileptic Drugs in Pregnancy. Offsprings of pregnant women with epilepsy exposed to phenytoin in monotherapy throughout. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Offsprings of pregnant women with epilepsy exposed to lamotrigine in monotherapy throughout. 		throughout pregnancy 42 / 382
Details are obtained by four in-depth telephone interviews with the women. Details provided by the participants are confirmed, as far as possible, by the treating medical practitioners.
Vajda (Phenytoin) (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 phenytoin 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 44 / 176 Women with epilepsy accounted for 98.3%. Completely overlap Vajda 2007; 2010 (x2); 2012 (x2); 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 (Phenytoin) (Controls unexposed, sick)
2013 		Australia
1999 - 2013
prospective cohort 		The Australian Register of Antiepileptic Drugs in Pregnancy. Offsprings from women with epilepsy exposed to phenytoin in monotherapy in at least the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Offsprings from women with epilepsy not exposed to antiepileptic drugs in at least the first trimester of pregnancy. 		at least 1st trimester 44 / 147 Women taking AED for epilepsy are in majority (more than 90%). Vajda 2019 provides the most recent update for major malformations results for this register. Specific malformations' results are extracted from the review by Weston et al. 2016.
Details are obtained by four in-depth telephone interviews with the women. Details provided by the participants are confirmed, as far as possible, by the treating medical practitioners.
Vajda (Phenytoin) (Controls unexposed, sick)
2018 		Australia
1999 - 2016
prospective cohort 		The Australian Register of Antiepileptic Drugs in Pregnancy. Offsprings of pregnant women with epilepsy exposed to phenytoin in monotherapy throughout. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Offsprings of pregnant women with epilepsy that have been untreated in at least the first half of pregnancy. 		throughout pregnancy 42 / 170
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.
Viinikainen (Phenytoin) (Controls unexposed, disease free) a
2006 		Finland
1989 - 2000
prospective cohort 		Community-based pregnancy registry at the Kuopio University Hospital. Pregnancies of mothers who had active epilepsy and were using phenytoin in monotherapy before conception and through the whole pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Pregnancies of mothers without epilepsy and unexposed to antiepileptic drugs. 		throughout pregnancy 2 / 24778 Multiple pregnancies and pregnancies with evident neonatal chromosomal abnormalities were excluded.
Obstetric data derived from the pregnancy registry and supplemented with medical records. And plasma levels of the antiepileptic drugs were monitoring during pregnancy at each control visit.
Viinikainen (Phenytoin) (Controls unexposed, sick) a
2006 		Finland
1989 - 2000
prospective cohort 		Community-based pregnancy registry at the Kuopio University Hospital. Pregnancies of mothers who had active epilepsy and were using phenytoin in monotherapy before conception and through the whole pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnancies of mothers who reported having previous history of epilepsy but no need for antiepileptic drugs at the time of the pregnancy. 		throughout pregnancy 2 / 52 Multiple pregnancies and pregnancies with evident neonatal chromosomal abnormalities were excluded.
Obstetric data derived from the pregnancy registry and supplemented with medical records. And plasma levels of the antiepileptic drugs were monitoring during pregnancy at each control visit.
Vinten (Phenytoin)
2005 		UK
Not specified.
retrospective cohort 		Specialist epilepsy clinics and obstetric clinics from the Liverpool and Manchester region (belong to the Liverpool and Manchester Neurodevelopment Study Group). Children born to epileptic mothers on phenytoin monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Children born to epileptic mothers not on antiepileptic medication during their pregnancy. 		during pregnancy (anytime or not specified) 21 / 83 Repeat population groups and the same data are already obtained in Adab 2004 for all the neurodevelopmental outcomes (with more exposed pregnancies and better scale) except the verbal IQ score <69. Vinten 2009 langage assessment is overlapped.
The women recruited were initially interviewed to ascertain information including the antiepileptic drug dose throughout the pregnancy. Clinical records were used to confirm the medical information.
Waters (Phenytoin) (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 phenytoin 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 28 / 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 (Phenytoin) (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 phenytoin 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 28 / 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.
Wide (Phenytoin)
2000 		Sweden
1985 - 1995
prospective cohort 		The Sodersjukhuset Hospital in the south-east region of Stockholm. First-born infants whose epileptic mothers were continuously treated with phenytoin monotherapy from conception throughout pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Children born in the same hospital within 2 days of the study subjects of mothers not treated with antiepileptic drugs. 		throughout pregnancy 22 / 87 Sex-matched control infants were found for 69 of 87 (87 of 100) subjects, but the other matching criteria were fulfilled for the total study group.
Mothers attended the outpatient clinic for pregnant women with epilepsy at the department of neurology where drug plasma levels were determined at monthly intervals.
Yerby (Phenytoin)
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 phenytoin 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) 12 / 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
Arteaga-Vázquez (Phenytoin)
2012 		Mexico
1978 - 2010
case control 		Registro y Vigilancia Epidemiológica de Malformaciones Congénitas (RYVEMCE): 36 hospitals participated from different states of the Mexican Republic. Newborn with one or more congenital malformations. Newborn control without congenital malformations which is the birth following the newborn with congenital malformations of the same sex born at the same hospital. The intake of anticonvulsants was obtained by direct interview of the mother during the first 24 hours after delivery or by consulting the obstetric record. 1st trimester 71 / 95
Clinical examination systematized of all consecutive births that occur in the hospitals that participate in the program. Uniform information is obtained through the filling of a specifically designed clinical form for the registry.
Bànhidy (Phenytoin)
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 (Phenytoin)
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 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.
Thomas a (Phenytoin)
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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