Phenobarbital (All indications)

Study	Type of data	Exposure measurement	Outcome assessment	Adjustment
Adams (Phenobarbital), 2022	retrospective cohort	Women were interviewed during the peri- and post- partum periods regarding multiple pregnancy characteristics and risks.	A blinded psychometrist who performed The Wechsler Intelligence Scale for Children, 3rd Edition (WISC-III) to measure general mental abilities in the context of a comprehensive neuropsychological testing battery.	Each ASM-exposed group was matched to an unexposed group of mothers according to educational and socioeconomic characteristics, and their children were then selected to match according to gender and age at testing.
Al Bunyan (Phenobarbital), 1999	retrospective cohort	The antenatal and perinatal records of the pregnant epileptic patients were examined.	Records and the post-partum examinations were carried out by a paediatrician who documented any congenital anomalies present.	Not specified.
Bànhidy (Phenobarbital), 2011	case control	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.	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.	Matched according to sex, birth week in the year when cases were born, and district of parents’ residence.
Barroso (Phenobarbital), 2015	retrospective cohort	The complete medical records of both the mother and her newborn were later analyzed.	The complete medical records of both the mother and her newborn were later analyzed. To classify the congenital anomalies, they selected all cases independently if these alterations were malformations, disruptions or deformations.	None.
Battino (Phenobarbital), 1992	prospective cohort	At least every 4 weeks throughout the pregnancy blood samples were taken for measurement of antiepileptic drugs concentrations.	Vital data of newborns at birth were recorded according to a standardized protocol; a more detailed clinical examination was performed on Day 5.	None.
Battino (Phenobarbital), 1999	prospective cohort	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.	The vital data of newborns at birth were recorded according to a standardized protocol; a more detailed clinical examination was performed on the fifth day. The infants were weighed within 1 hour of life, and their head circumference measured.	No adjustment for this group of exposure.
Battino (Phenobarbital) (Epilepsy), 2024	prospective cohort	Reporting physicians collected information on drug therapy after each trimester.	Abnormalities in the offspring were recorded descriptively by reporting physicians. A committee blinded to type of exposure assessed and categorized these abnormalities. When necessary, the committee solicited additional information from the reporting physicians.	Exclusion of pregnancies exposed to known teratogenic drugs, and those with comorbidities associated with teratogenic risks. No adjustment for this group of comparison.
Bech (Phenobarbital) (Controls exposed to Lamotrigine, sick) (Other indications), 2018	population based cohort propective	The Danish National Prescription Register was used to obtain data on redeemed prescriptions using Anatomical Therapeutic Chemical (ATC) codes.	The Danish Psychiatric Central Register and Danish National Patient Registry were used to identify children's learning disabilities diagnosis using ICD-10 codes for: mental retardation, specific development disorders, ASD, emotional/behavioural disorders or having special educational needs.	No adjustment for this group of exposure and comparison.
Bech (Phenobarbital) (Controls unexposed, sick) (Other indications), 2018	population based cohort propective	The Danish National Prescription Register was used to obtain data on redeemed prescriptions using Anatomical Therapeutic Chemical (ATC) codes.	The Danish Psychiatric Central Register and Danish National Patient Registry were used to identify children's learning disabilities diagnosis using ICD-10 codes for: mental retardation, specific development disorders, ASD, emotional/behavioural disorders or having special educational needs.	Adjustments were made for maternal age at birth, educational level, smoking status, epilepsy, affective disorders, other psychiatric disorders, birth year, preterm birth, Apgar score and birth weight relative to GA.
Bjørk (Phenobarbital) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2022	population based cohort retrospective	Prescriptions through national prescription registers according to Anatomical Therapeutic Chemical classification codes N03, N05BA09, and S01EC01.	Severe neurodevelopmental disorders are diagnosed by child psychiatrists and psychologists in specialist health care in the Nordic countries and recorded with International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes.	No adjustment for this control group.
Bjørk (Phenobarbital) (Controls unexposed NOS) (Mixed indications), 2022	population based cohort retrospective	Prescriptions through national prescription registers according to Anatomical Therapeutic Chemical classification codes N03, N05BA09, and S01EC01.	Severe neurodevelopmental disorders are diagnosed by child psychiatrists and psychologists in specialist health care in the Nordic countries and recorded with International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes.	Adjusted for maternal age, education and marital status, parity, child’s birth year, sex, and country of birth. All the models were run with separate strata for country and year. Plus maternal use of antidepressants or opioids, depression, anxiety, personality disorders, number of chronic somatic diseases, and number of hospitalizations the year before last menstrual period.
Bjørk (Phenobarbital) (Controls unexposed, sick) (Mixed indications), 2022	population based cohort retrospective	Prescriptions through national prescription registers according to Anatomical Therapeutic Chemical classification codes N03, N05BA09, and S01EC01.	Severe neurodevelopmental disorders are diagnosed by child psychiatrists and psychologists in specialist health care in the Nordic countries and recorded with International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes.	No adjustment for this control group.
Blotière (Phenobarbital) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2019	retrospective cohort (claims database)	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.	The French hospital discharge database (PMSI) provides detailes medical information including discharge diagnosis ICD-10 codes and medical procedures. Major congenital malformations (MCMs) were selected from the list of MCMs of the European Surveillance of Congenital Anomalies (EUROCAT) network.	No adjustment for this group of comparison.
Blotière (Phenobarbital) (Controls unexposed NOS) (Mixed indications), 2019	retrospective cohort (claims database)	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.	The French hospital discharge database (PMSI) provides detailes medical information including discharge diagnosis ICD-10 codes and medical procedures. Major congenital malformations (MCMs) were selected from the list of MCMs of the European Surveillance of Congenital Anomalies (EUROCAT) network.	For major congenital malformations with <5 cases per treatment group, authors calculated crude odds ratios with exact confidence intervals. For major congenital malformations with at least 5 cases per treatment group, ORs were adjusted for maternal age, mother’s eligibility for CMU-C, year of start of pregnancy, preconception folic acid supplementation, and pregestational diabetes.
Burja (Phenobarbital) (Controls unexposed, disease free), 2006	retrospective cohort (registry)	Hospital neonatal and obstetric records at the MariborTeaching Hospital Department of Perinatology.	Data on the main outcome measures were recorded by health practitioners and extracted from the Regional Hospital Discharge Registry. The data are transferred from the registry to the Perinatal Statistical Database of Slovenia. Diagnoses were classified according to ICD10.	None.
Burja (Phenobarbital) (Controls unexposed, sick), 2006	retrospective cohort (registry)	Hospital neonatal and obstetric records at the MariborTeaching Hospital Department of Perinatology.	Data on the main outcome measures were recorded by health practitioners and extracted from the Regional Hospital Discharge Registry. The data are transferred from the registry to the Perinatal Statistical Database of Slovenia. Diagnoses were classified according to ICD10.	None.
Canger (Phenobarbital), 1999	prospective cohort	The patients received monthly obstetric and neurologic examinations, and antiepileptic drug blood levels were tested monthly.	At the time of delivery the infants underwent a standardized examination by a pediatrician, and a more detailed clinical examination on day 5 in San Paolo Hospital only and during the first months in other hospitals (if so medical records were also acquired).	None.
Cassina (Phenobarbital) (Controls exposed to Lamotrigine, sick) (Other indications), 2013	prospective cohort	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.	Women or their physicians were contacted for a follow-up telephone interview to collect information about major birth defects. The data collected by interview are reliable, since all the Italian children have to undergo periodic pediatric evaluations.	No adjustment for this group of comparison.
Cassina (Phenobarbital) (Controls unexposed, disease free) (Other indications), 2013	prospective cohort	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.	Women or their physicians were contacted for a follow-up telephone interview to collect information about major birth defects. The data collected by interview are reliable, since all the Italian children have to undergo periodic pediatric evaluations.	No adjustment for this group of exposure.
Christensen (Phenobarbital) (All indications) (Controls exposed to LTG), 2024	population based cohort retrospective	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.	Information on birth weight, gestational age and head circumference at birth was obtained from the medical birth registers for all births occurring at 22 weeks’ gestation or later.	Singleton only. No adjustment for this group of comparison.
Christensen (Phenobarbital) (All indications) (Controls unexposed, general population), 2024	population based cohort retrospective	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.	Information on birth weight, gestational age and head circumference at birth was obtained from the medical birth registers for all births occurring at 22 weeks’ gestation or later.	Singleton only. All models were adjusted for country of birth, year of birth, sex of child, maternal age, maternal parity, maternal marital or cohabitation status, pre-pregnancy hospital admittances, maternal education, smoking in early pregnancy, maternal psychiatric history (F00-F99), and use of psychotropic drugs in pregnancy (ATC N06A, N05A, N05B, excl. N05BA09) and maternal epilepsy.
Coste (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2020	retrospective cohort (claims database)	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.	Diagnoses of mental and behavioural disorders by the attribution of long-term disease status and/or hospital admission (ICD-10 codes). Health care utilization by reimbursement of at least one speech therapy session; one orthoptist consultation; one psychiatrist or child psychiatrist consultation.	No adjustment for this group of comparison.
Coste (Phenobarbital) (Controls unexposed, NOS), 2020	retrospective cohort (claims database)	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.	Diagnoses of mental and behavioural disorders by the attribution of long-term disease status and/or hospital admission (ICD-10 codes). Health care utilization by reimbursement of at least one speech therapy session; one orthoptist consultation; one psychiatrist or child psychiatrist consultation.	Adjusted for: mother’s age, Complementary Universal Health Insurance scheme, diagnosis of mental illness other than tobacco and alcohol use disorders, antipsychotic drug use during the year preceding pregnancy, indicator of severity of psychiatric morbidity, indicator of tobacco use, indicator of alcohol use, folic acid, SSRI during pregnancy, child’s sex, gestational age and birth weight.
D'Souza (Phenobarbital) (Controls unexposed, disease free), 1991	prospective cohort	Every two weeks, clinical assessment of seizure control, and adjustment of anticonvulsant dosage in accordance with serum drug concentration or clinical response.	Each infant was examined by a paediatrician and a geneticist, neither of whom was aware of whether the mother was in the study group or the control group.	Matched for maternal age, parity, and social class.
D'Souza (Phenobarbital) (Controls unexposed, sick), 1991	prospective cohort	Every two weeks, clinical assessment of seizure control, and adjustment of anticonvulsant dosage in accordance with serum drug concentration or clinical response.	Each infant was examined by a paediatrician and a geneticist, neither of whom was aware of whether the mother was in the study group or the control group.	No matching for this group of exposure.
Dean (Phenobarbital), 2002	retrospective cohort	A structured interview was carried out by a trained research nurse using questionnaires.	Standardised assessment was carried out by a trained research nurse using examination schedules. Clinical photographs were assessed for facial features. Behavior disorders, developmental delay and later childhood medical problems were recorded and/or diagnosed by specialists.	None.
Dean (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2007	retrospective cohort	A trained research nurse undertook interviews recording antiepileptic drugs use in each pregnancy. Maternal antiepileptic drugs dose was verified from case records where possible.	A trained research nurse undertook interviews recording children’s medical and developmental histories. Malformations and medical histories for the children were confirmed by hospital record review and clinical examination. Facial photographs were reviewed for features of FACS by blinded physicians	None.
Dean (Phenobarbital) (Controls unexposed, sick), 2007	retrospective cohort	A trained research nurse undertook interviews recording antiepileptic drugs use in each pregnancy. Maternal antiepileptic drugs dose was verified from case records where possible.	A trained research nurse undertook interviews recording children’s medical and developmental histories. Malformations and medical histories for the children were confirmed by hospital record review and clinical examination. Facial photographs were reviewed for features of FACS by blinded physicians	None.
Díaz-Romero (Phenobarbital), 1999	cohort	Not specified	The neonates were evaluated by the principal author who used a metallic calliper calibrated in millimeters and a glazed fiberglass tape for the head circumference. The measurements were performed twice and collected by a second observer; the final value was the average of both measurements.	None.
Dravet (Phenobarbital), 1992	prospective cohort	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.	A physician of the team followed each pregnant women clinically until delivery. Most information was obtained by mail or telephone. A sheet for the examination of each neonate with the checklist of malfomations registered by Eurocat was added.	No adjustment for this group of exposure.
Elkjaer (Phenobarbital), 2018	population based cohort propective	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).	Information on school performance was provided by the Danish Agency for Information Technology and Learning. The cognitive abilities are assessed using academic tests conducted from 2010 to 2014. Congenital malformations were defined as diagnoses based on ICD-10 Q0 to Q99.	Adjusted for test year, child sex, and maternal education and household income at birth.
Endo (Phenobarbital) (Controls unexposed, disease free), 2004	retrospective cohort	Medical records.	Medical records.	Not specified.
Endo (Phenobarbital) (Controls unexposed, sick), 2004	retrospective cohort	Medical records.	Medical records.	Not specified.
Fedrick (Phenobarbital), 1973	retrospective cohort (registry)	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.	For hospital births, informations are abstracted by clerks from hospital notes and in domiciliary deliveries the midwife who delivered the infant sends her notes and clerks then abstract and code the information. General files were also searched for any subsequent hospital admissions or deaths.	None.
Guveli (Phenobarbital) (Epilepsy), 2017	retrospective cohort	The clinical data of patients (dosages of AEDs used during pregnancy) were recorded retrospectively from patient files.	Echocardiography was checked by a pediatric cardiologist. Parents and children were examined and photographed by a medical geneticist. Children older than six months were examined by a pediatric dentist for developmental dental anomalies (blinded to exposure).	None.
Hernández-Díaz (Phenobarbital), 2017	prospective cohort	Women were questioned with a computer-assisted telephone interview 3 times.	Women were questioned with a computer-assisted telephone interview 3 times and medical records were obtained.	Confunders included calendar year, maternal age, race, diabetes, cigarette smoking, alcohol use, periconceptional folic acid supplementation, illicit drug use, and education.
Hernández-Díaz (Phenobarbital) (Epilepsy), 2012	prospective cohort	Women were questioned with a computer-assisted telephone interview 3 times.	Women were questioned with a computer-assisted telephone interview 3 times and medical records were obtained. The written descriptions in the pediatricians’ examinations were reviewed separately by the clinical teratologist.	No adjustment for this group of comparison.
Holmes (Phenobarbital) (Controls unexposed, disease free), 2001	retrospective cohort	Women are interviewed and completed questionnaires administered by a research assistant.	The infants were examined by a study physician or the results of the pediatrician’s examination were reviewed if a mother chose not to enroll. For major malformations: features found on prenatal ultrasonography but not on physical examination were excluded.	For cigarette and alcohol use, substance abuse, severity of seizures, and head circumference and height of the mother.
Holmes (Phenobarbital) (Controls unexposed, sick), 2001	retrospective cohort	Women are interviewed and completed questionnaires administered by a research assistant.	The infants were examined by a study physician or the results of the pediatrician’s examination were reviewed if a mother chose not to enroll. For major malformations: features found on prenatal ultrasonography but not on physical examination were excluded.	No adjustment for this group of comparison.
Kaaja (Phenobarbital), 2003	prospective cohort	Follow-up of the pregnant women with epilepsy included assessment of serum concentration of antiepileptic drugs at the end of the first trimester.	Infants were examined by a neonatologist at birth and at discharge from the hospital and charts for the infants admitted to the pediatric clinic or in case of termination of pregnancy were reviewed. Autopsy was performed on stillbirth.	No adjustment for this group of exposure.
Källén (Phenobarbital) (Controls exposed to Lamotrigine, sick) (Indications NOS), 2013	population based cohort retrospective	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).	The Swedish Medical Birth Registry contain information based on standardized medical records from the first and further antenatal visit, the delivery and the paediatric examination. Supplemented with data from the Register of Birth Defects and Hospital Discharge Register.	No adjustment for this group of comparison.
Källén (Phenobarbital) (Controls unexposed, NOS) (Indications NOS), 2013	population based cohort retrospective	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).	The Swedish Medical Birth Registry contain information based on standardized medical records from the first and further antenatal visit, the delivery and the paediatric examination. Supplemented with data from the Register of Birth Defects and Hospital Discharge Register.	Adjustment was made for year of birth, maternal age (5-year class), parity, smoking in early pregnancy and BMI.
Kaneko (Phenobarbital), 1999	prospective cohort	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.	Congenital malformations were examined at each center at birth, at 5 days, and at the 1-month visit by a team of obstetricians and neurologists, according to a standardized check-list based on the report of the Japanese Association of Obstetricians for Maternal Welfare.	None.
Kasradze (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2017	prospective cohort	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.	Two forms of Wechsler Preschool and Primary Scale of Intelligence (WPPSI-4) were used to assess intellectual functioning for children aged 2.6–3.1 years and for children aged 4.0–7.7 years. All tests were performed in the Epilepsy Centre by two qualified blinded neuropsychologists.	No matching for this group of comparison.
Kasradze (Phenobarbital) (Controls unexposed, disease free), 2017	prospective cohort	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.	Two forms of Wechsler Preschool and Primary Scale of Intelligence (WPPSI-4) were used to assess intellectual functioning for children aged 2.6–3.1 years and for children aged 4.0–7.7 years. All tests were performed in the Epilepsy Centre by two qualified blinded neuropsychologists.	Age and gender-matched.
Katz (Phenobarbital), 2001	retrospective cohort	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.	Data collected in chart review about the newborn included the presence of developmental delay. Including pervasive developmental delay (based on the DSM-IV-TR criteria), combined or isolated speech and gross motor delay and attention deficit disorder with speech and auditory processing delay.	None.
Kelly (Phenobarbital), 1984	prospective cohort	Efforts were made to ensure that periodic determinations of blood levels of anticonvulsants were obtained, especially during pregnancy.	Each child born at the University Hospital was examined neonatally by one of the investigators. When birth occurred elsewhere, newborn records were requested. Then further evaluation was conducted later on at clinic visits or home visits. Data were augmented by local health records.	None.
Kilic (Phenobarbital) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014	population based cohort retrospective	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.	The Danish Medical Birth Registry contains data on newborn babies including information on gestational age at birth, birth weight, and head circumference.	No adjustment for this group of comparison.
Kilic (Phenobarbital) (Controls unexposed NOS) (Mixed indications), 2014	population based cohort retrospective	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.	The Danish Medical Birth Registry contains data on newborn babies including information on gestational age at birth, birth weight, and head circumference.	No adjustment for this group of comparison.
Kilic (Phenobarbital) (Controls unexposed, sick) (Mixed indications), 2014	population based cohort retrospective	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.	The Danish Medical Birth Registry contains data on newborn babies including information on gestational age at birth, birth weight, and head circumference.	No adjustment for this group of comparison.
Kini (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2006	retrospective cohort	Structured interviews were conducted with the mothers and medical records were available to confirm details in about 80% of participants.	A clinical examination was carried out to check the growth parameters and detect dysmorphic features and malformations. Clinical photographs were reviewed based on whether the gestalt was suggestive of fetal anticonvulsant syndrome by a panel of blind dysmorphologists.	None.
Kini (Phenobarbital) (Controls unexposed, sick), 2006	retrospective cohort	Structured interviews were conducted with the mothers and medical records were available to confirm details in about 80% of participants.	A clinical examination was carried out to check the growth parameters and detect dysmorphic features and malformations. Clinical photographs were reviewed based on whether the gestalt was suggestive of fetal anticonvulsant syndrome by a panel of blind dysmorphologists.	None.
Koch (Phenobarbital), 1996	prospective cohort	The pregnant women were asked to continuously monitor their seizures, treatment and additional illnesses.	Authors developed their own neonatal score consisted of symptoms of apathy and hyperexcitability. Then six-year-old children were examined for major and minor neurological dysfunction with the examination of Touwen. The examiners were not blinded for this part of the study.	Matched for five variables, namely socioeconomic status (lower and middle class), age of the mother at delivery, parity, amount of smoking during pregnancy and number of abortions previous to the subject’s birth.
Leite (Phenobarbital) (Epilepsy), 2024	retrospective cohort	This was a retrospective cohort study with data collected from physical and electronic medical records.	This was a retrospective cohort study with data collected from physical and electronic medical records.	For analysis in monotherapy: no adjustment.
Lowe (Phenobarbital) (Controls unexposed, disease free), 1973	population based cohort retrospective	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.	Detailed information has been collected, coded, and computer stored whether the infant is observed to be congenitally malformed.	None.
Lowe (Phenobarbital) (Controls unexposed, sick), 1973	population based cohort retrospective	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.	Detailed information has been collected, coded, and computer stored whether the infant is observed to be congenitally malformed.	None.
Miškov (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2016	prospective cohort	Data collected on pregnant women during outpatient visits to the neurologist, gynecologist and pediatrician neurologist.	Newborns were examined by pediatrician neurologist/geneticist at Clinical Department of Pediatrics and followed up yearly. Data on the control group were obtained from Clinical Department of Gynecology and Obstetrics and Clinical Department of Pediatrics .	Not specified.
Miškov (Phenobarbital) (Controls unexposed, disease free), 2016	prospective cohort	Data collected on pregnant women during outpatient visits to the neurologist, gynecologist and pediatrician neurologist.	Newborns were examined by pediatrician neurologist/geneticist at Clinical Department of Pediatrics and followed up yearly. Data on the control group were obtained from Clinical Department of Gynecology and Obstetrics and Clinical Department of Pediatrics .	Not specified.
Miškov (Phenobarbital) (Controls unexposed, sick), 2016	prospective cohort	Data collected on pregnant women during outpatient visits to the neurologist, gynecologist and pediatrician neurologist.	Newborns were examined by pediatrician neurologist/geneticist at Clinical Department of Pediatrics and followed up yearly. Data on the control group were obtained from Clinical Department of Gynecology and Obstetrics and Clinical Department of Pediatrics .	Not specified.
Robert (Phenobarbital), 1986	retrospective cohort	Questionnaires were sent to women identified in hospital records and the second collection of data was obtained from 3 maternity with computerized records.	Questionnaires were sent to women identified in hospital records and the second collection of data was obtained from 3 maternity with computerized records.	None.
Samrén (Phenobarbital), 1999	retrospective cohort	Data were collected from medical records and include medication. The prescribed dose of thedrugs was also retrieved from obstetric files.	Data were collected from medical records and include information on pregnancy and child. Information on major congenital abnormalities was completed with information from the pediatrician whenever necessary.	Matched for age (±2 years) and parity of the mother, and sex, birth year, and hospital of delivery of the child.
Shankaran (Phenobarbital) (Other indications), 1996	randomized controlled trial	Women were assigned to control and treatment groups as part of a randomized controlled trial.	Growth parameters were assessed. Receptive and expressive language were assessed with different tests based on the competence of the child. The Bayley Scales of Infant Development and the McCarthy Scales of Children’s Abilities were administered. Audiologic and ophtalmologic examination were done.	No adjustment. Randomisation.
Shankaran (Phenobarbital) (Other indications), 2002	randomized controlled trial	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.	Certified testers who were trained to reliability and who were unaware of the treatment assignment status administered the Bayley scales of infant development, performed the neurologic examinations, a standard eye examination and hearing status. Cranial sonograms were interpreted by 3 radiologist.	No adjustment. Randomisation.
Steegers-Theunissen (Phenobarbital), 1994	prospective cohort	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 infants were examined systematically for major malformations according to the ICD9 British Paediatric Association System and for minor malformations according to Mehes and Stalder by a trained research fellow.	None.
The NAAED (Phenobarbital) (Controls exposed to LTG) (Indications NOS), 2023	prospective cohort	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.	Women were questioned with a computer-assisted telephone interview 3 times and medical records were obtained. The written descriptions in the pediatricians’ examinations were reviewed separately by the clinical teratologist.	No adjustment for this group of comparison.
The NAAED (Phenobarbital) (Controls unexposed, disease free) (Indications NOS), 2023	prospective cohort	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.	Women were questioned with a computer-assisted telephone interview 3 times and medical records were obtained. The written descriptions in the pediatricians’ examinations were reviewed separately by the clinical teratologist.	Not specified.
Thomas (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2021	prospective cohort	Women were instructed to record the use of the antiepileptic drugs on a daily basis in the pregnancy diary that was given to them.	Screening for major congenital malformation with antenatal screening by serum alpha fetoprotein estimation and detailed anomaly scan between 12 and 18 weeks of pregnancy; physical examination at birth, at 3 months of age (at least) and at 1 year of age if possible.	No adjustment for this group of comparison.
Thomas (Phenobarbital) (Controls unexposed, disease free), 2021	prospective cohort	Women were instructed to record the use of the antiepileptic drugs on a daily basis in the pregnancy diary that was given to them.	Screening for major congenital malformation with antenatal screening by serum alpha fetoprotein estimation and detailed anomaly scan between 12 and 18 weeks of pregnancy; physical examination at birth, at 3 months of age (at least) and at 1 year of age if possible.	None.
Thomas (Phenobarbital) (Controls unexposed, sick), 2021	prospective cohort	Women were instructed to record the use of the antiepileptic drugs on a daily basis in the pregnancy diary that was given to them.	Screening for major congenital malformation with antenatal screening by serum alpha fetoprotein estimation and detailed anomaly scan between 12 and 18 weeks of pregnancy; physical examination at birth, at 3 months of age (at least) and at 1 year of age if possible.	Adjusted for age and educational status of mother, and epilepsy class.
Thomas a (Phenobarbital), 2008	nested case control	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.	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.	None.
Thomas a (Phenobarbitone), 2022	prospective cohort	The details of Antiseizure medications exposure were extracted from the clinical records in the registry.	Assessment of intelligence and language was performed with the Wechsler Intelligence Scale for Children (WISC 4) or Adult (if > 18 years) and clinical examination of language fundamentals (CELF 4). The assessors were blinded to the details of the antenatal antiseizure medications exposure.	None.
Thomas b (Phenobarbitone) (Epilepsy) (Controls exposed to LTG), 2022	prospective cohort	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.	Developmental paediatricians and developmental therapists, who were blinded to antenatal ASM exposure evaluated motor and mental development of infants (>12 months) using the Developmental Assessment Scale for Indian Infants (an Indian adaptation of the Bayley Scale of Infant Development).	None (the adjusted motor and mental development quotients (aMODQ and aMEDQ) not provided, only their difference from the reference group (unexposed infants)).
Thomas b (Phenobarbitone) (Epilepsy) (Controls unexposed, sick), 2022	prospective cohort	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.	Developmental paediatricians and developmental therapists, who were blinded to antenatal ASM exposure evaluated motor and mental development of infants (>12 months) using the Developmental Assessment Scale for Indian Infants (an Indian adaptation of the Bayley Scale of Infant Development).	None (the adjusted motor and mental development quotients (aMODQ and aMEDQ) not provided, only their difference from the reference group (unexposed infants)).
Titze (Phenobarbital) (Controls unexposed, disease free), 2008	prospective cohort	The pregnant women were asked to continuously monitor their treatment.	In adolescents, the German versions of the revised Wechsler Intelligence Scales for children and for adults were applied.	Matched for socioeconomic status (SES), nicotine consumption in the last trimester, maternal age at birth, parity, and number of previous abortions. No adjustment for this group of exposure.
Titze (Phenobarbital) (Controls unexposed, sick), 2008	prospective cohort	The pregnant women were asked to continuously monitor their treatment.	In adolescents, the German versions of the revised Wechsler Intelligence Scales for children and for adults were applied.	No matching for this group of comparison. No adjustment for this group of exposure.
Tomson (Phenobarbital), 2018	prospective cohort	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.	Abnormalities in the offspring were reported descriptively by enrolling physicians These reports were reviewed and classified (2005 EUROCAT criteria) by an outcome committee unaware of the type of exposure. Supplementary information from the reporting physician can be request.	None.
Tomson (Phenobarbital), 2015	prospective cohort	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).	Information is collected by the reporting physician, before being forwarded to a national coordinator who then sends it to the central database.	No adjustment for this group of exposure.
Trivedi (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2018	prospective cohort	Women were instructed to record the use of the antiepileptic drugs on a daily basis in the pregnancy diary that was given to them.	Women were under regular antenatal follow up by the obstetricians.	No adjustment for this group of comparison.
Vajda (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2019	prospective cohort	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.	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.	None.
Vajda (Phenobarbital) (Controls unexposed, sick), 2019	prospective cohort	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.	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.	None.
Van der Pol (Phenobarbital) (Controls unexposed, disease free), 1991	prospective cohort	The dosages of antiepileptic drugs were constant throughout pregnancy.	An age-specific neurologic examination conducted by an examiner. Three Dutch tests for reading, spelling and arithmetic were applied. Assessment of child's behavior with parents and teachers questionnaires, the child behavior check list and the children's behavior questionnaire (teachers only).	Matched for their mother's parity and for birth weight, gestational age, sex, age at follow-up, and social class.
Van der Pol (Phenobarbital) (Controls unexposed, sick), 1991	prospective cohort	The dosages of antiepileptic drugs were constant throughout pregnancy.	An age-specific neurologic examination conducted by an examiner. Three Dutch tests for reading, spelling and arithmetic were applied. Assessment of child's behavior with parents and teachers questionnaires, the child behavior check list and the children's behavior questionnaire (teachers only).	No matching for this group of exposure.
Veiby (Phenobarbital) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014	population based cohort retrospective	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).	A standardised notification form is filled in from the first prenatal visit until discharge and transferred to the database by practitioners attending the delivery. (Coded according to ICD-10). Additional information on congenital malformations came from Norwegian pediatric wards.	No adjustment for this group of comparison.
Veiby (Phenobarbital) (Controls unexposed, disease free) (Mixed indications), 2014	population based cohort retrospective	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).	A standardised notification form is filled in from the first prenatal visit until discharge and transferred to the database by practitioners attending the delivery. (Coded according to ICD-10). Additional information on congenital malformations came from Norwegian pediatric wards.	Adjusted for maternal age, parity, smoking, folate supplementation, and maternal chronic disease other than epilepsy.
Veiby (Phenobarbital) (Controls unexposed, sick) (Mixed indications), 2014	population based cohort retrospective	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).	A standardised notification form is filled in from the first prenatal visit until discharge and transferred to the database by practitioners attending the delivery. (Coded according to ICD-10). Additional information on congenital malformations came from Norwegian pediatric wards.	No adjustment for this group of comparison.
Waters (Phenobarbital) (Controls unexposed, disease free), 1994	prospective cohort	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.	Infants underwent a standardized examination by a physician and/or nurse trained to recognize major and minor anomalies. Data from the obstetric clinic and the infants' delivery charts.	None.
Waters (Phenobarbital) (Controls unexposed, sick), 1994	prospective cohort	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.	Infants underwent a standardized examination by a physician and/or nurse trained to recognize major and minor anomalies. Data from the obstetric clinic and the infants' delivery charts.	None.
Yerby (Phenobarbital), 1992	prospective cohort	Women with epilepsy had a determination of antiepileptic drug concentrations. They were scheduled for monthly visits and with their babies two times post partum	The infants of both case and control mothers were examined by a blinded developmental pediatrician. A checklist for major and minor malformations was used, and facial measurements were taken.	None.

master protocol