Topiramate (All indications)

Study	Type of data	Exposure measurement	Outcome assessment	Adjustment
Alsfouk (Topiramate) (Controls exposed to Lamotrigine, sick), 2021	retrospective cohort	Patients’ electronic and paper-based medical records.	Patients’ electronic and paper-based medical records.	None.
Alsfouk (Topiramate) (Controls unexposed, sick), 2021	retrospective cohort	Patients’ electronic and paper-based medical records.	Patients’ electronic and paper-based medical records.	None.
AlSheikh (Topiramate) (Controls exposed to Lamotrigine, sick), 2020	prospective cohort	Information was collected through a structured questionnaire ‘Questionnaire for Investigation of Epilepsy in Tropical Countries'.	Information was collected through a structured questionnaire ‘Questionnaire for Investigation of Epilepsy in Tropical Countries'. From the history, and through QuadraMed® hospital database (ICD-9 coding system).	None.
AlSheikh (Topiramate) (Controls unexposed, sick), 2020	prospective cohort	Information was collected through a structured questionnaire ‘Questionnaire for Investigation of Epilepsy in Tropical Countries'.	Information was collected through a structured questionnaire ‘Questionnaire for Investigation of Epilepsy in Tropical Countries'. From the history, and through QuadraMed® hospital database (ICD-9 coding system).	None.
Arkilo (Topiramate), 2015	retrospective cohort	Questionnaires were sent to women.	Questionnaires were sent to women. The developmental outcomes were assessed at 2 years of age by developmental specialists assigned by the school districts.	None.
Babic (Topiramate), 2014	prospective cohort	Not specified.	The authors evaluated the pregnancy complications and perinatal outcomes in their patients.	None.
Bank (Topiramate) (Mixed indications) , 2017	prospective cohort	Medical records were obtained for review from the treating obstetrician, the delivery hospital, and the treating pediatrician. Umbilical cord and maternal venous blood were collected to measure total anti-epileptic levels by liquid chromatography/mass spectrometry.	Medical records were obtained for review from the treating obstetrician, the delivery hospital, and the treating pediatrician.	None.
Battino (Topiramate) (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 (Topiramate) (Mixed 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 (Topiramate) (Controls exposed to Lamotrigine, sick), 2018	population based cohort propective	Information on anti-epileptics use was obtained from the questionnaires completed by mothers during gestational weeks 17 to 19 (Q1) and 30 (Q2); and through the Medical Birth Registry of Norway.	The instruments are based on parent-reported measures. Autistic traits were evaluated using the Modified Checklist for Autism (M-CHAT) at 18 months (missed any 3 of 23 items or 2 of 6 critical items) and Social Communication Questionnaire (SCQ) at 36 months (score of 13 or more).	No adjustment for this group of exposure.
Bjørk (Topiramate) (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 (Topiramate) (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 and education, marital status, parity, child’s birth year, sex, country of birth. Plus maternal use of antidepressants, opioids, depression, anxiety, personality disorders, chronic somatic diseases, hospitalizations the year before. Repeating analyses after adjusting for maternal neurodevelopmental disorders, body mass index and smoking did not change estimates.
Bjørk (Topiramate) (Controls unexposed, disease free), 2018	population based cohort propective	Information on anti-epileptics use was obtained from the questionnaires completed by mothers during gestational weeks 17 to 19 (Q1) and 30 (Q2); and through the Medical Birth Registry of Norway.	The instruments are based on parent-reported measures. Autistic traits were evaluated using the Modified Checklist for Autism (M-CHAT) at 18 months (missed any 3 of 23 items or 2 of 6 critical items) and Social Communication Questionnaire (SCQ) at 36 months (score of 13 or more).	No adjustment for this group of exposure.
Bjørk (Topiramate) (Controls unexposed, sick), 2018	population based cohort propective	Information on anti-epileptics use was obtained from the questionnaires completed by mothers during gestational weeks 17 to 19 (Q1) and 30 (Q2); and through the Medical Birth Registry of Norway.	The instruments are based on parent-reported measures. Autistic traits were evaluated using the Modified Checklist for Autism (M-CHAT) at 18 months (missed any 3 of 23 items or 2 of 6 critical items) and Social Communication Questionnaire (SCQ) at 36 months (score of 13 or more).	No adjustment for this group of exposure.
Bjørk (Topiramate) (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 (Topiramate) (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 (Topiramate) (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.
Bromley (Topiramate), 2016	retrospective cohort (registry)	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.	Assessments were conducted blinded by authors with the WISC–Fourth Edition or the WPPSI–Third Edition. Specific cognitive domains were assessed utilizing subtests from the NEPSY and the Clinical Evaluation of Language Fundamentals–Fourth Edition and parental rating using the BASC.	None.
Christensen (Topiramate) (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 (Topiramate) (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.
Cohen (Topiramate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2019	retrospective cohort (claims database)	The Medicaid Analytic Extract data include prescriptions filled on an outpatient basis.	Claims in maternal or infant records after 20 weeks of gestation and were validated based on medical record review. The outcomes are assessed with ICD-9 diagnosis.	Adjustment for demographic factors and risk factors for ischemic placental disease and preterm birth, potential indication for mood stabilizer use, other psychiatric and pain diagnoses, other psychiatric and pain medications (LMP-90 to LMP 140), and severity/health service utilization proxies.
Cohen (Topiramate) (Controls unexposed NOS) (Mixed indications), 2019	retrospective cohort (claims database)	The Medicaid Analytic Extract data include prescriptions filled on an outpatient basis.	Claims in maternal or infant records after 20 weeks of gestation and were validated based on medical record review. The outcomes are assessed with ICD-9 diagnosis.	Adjustment for demographic factors and risk factors for ischemic placental disease and preterm birth, potential indication for mood stabilizer use, other psychiatric and pain diagnoses, other psychiatric and pain medications (LMP-90 to LMP 140), and severity/health service utilization proxies.
Cohen (Topiramate) (Mixed indications) (Controls exposed to LTG), 2023	population based cohort retrospective	Data on filled prescriptions were obtained from the medical birth registers linked with registers for prescribed drugs.	The primary outcome was major congenital malformation diagnosed within 1 year of birth and recorded in the medical birth, patient, malformation, or death register.	Adjusted for maternal age, delivery year, country, parity, multiple pregnancy, cohabitation, maternal country of birth, indications for antiseizure medication, diabetes, hypertension, psychiatric conditions, other medication used in 1st trimester and indicators of health care utilization in the 90 days before pregnancy. Exclusion of first trimester exposure to known teratogenic drugs or infection.
Cohen (Topiramate) (Mixed indications) (Controls unexposed, NOS), 2023	population based cohort retrospective	Data on filled prescriptions were obtained from the medical birth registers linked with registers for prescribed drugs.	The primary outcome was major congenital malformation diagnosed within 1 year of birth and recorded in the medical birth, patient, malformation, or death register.	Adjusted for maternal age, delivery year, country, parity, multiple pregnancy, cohabitation, maternal country of birth, indications for antiseizure medication, diabetes, hypertension, psychiatric conditions, other medication used in 1st trimester and indicators of health care utilization in the 90 days before pregnancy. Exclusion of first trimester exposure to known teratogenic drugs or infection.
Coste (Topiramate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 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.	Sociodemographic, folic acid, SSRI during pregnancy, antipsychotic drug use during the year preceding pregnancy, a proxy for severity of mental disorders, history of mental and behavioural disorders not related to alcohol or smoking, indicator of tobacco use and alcohol use, child’s sex, gestational age and birth weight.
Coste (Topiramate) (Controls unexposed, NOS) (Mixed indications), 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.
Dreier (Topiramate) (Epilepsy) (Controls exposed to LTG), 2023	population based cohort propective	Information on use of antiseizure medications was based on the national prescription registers, which contain information on all reimbursed prescription medications dispensed at pharmacies in each country, including date of dispensing and Anatomical Therapeutic Chemical (ATC) classification code.	Information on psychiatric disorders was retrieved from the patient registers, which contain diagnostic information from inpatient admissions and outpatient visits in specialist care.	Singletons only. No adjustment for this group of comparison.
Dreier (Topiramate) (Epilepsy) (Controls unexposed, sick), 2023	population based cohort propective	Information on use of antiseizure medications was based on the national prescription registers, which contain information on all reimbursed prescription medications dispensed at pharmacies in each country, including date of dispensing and Anatomical Therapeutic Chemical (ATC) classification code.	Information on psychiatric disorders was retrieved from the patient registers, which contain diagnostic information from inpatient admissions and outpatient visits in specialist care.	Singletons only. Adjusted for year of birth, country of birth, sex of the child, smoking in pregnancy, use of antidepressants (ATC code N06A) in pregnancy, and maternal characteristics assessed at the time of birth (age, parity, highest level of completed education, and psychiatric co-morbidity).
Hao (Topiramate) (Epilepsy) (Controls exposed to LTG), 2025	prospective cohort	Treatment information was collected through case report forms mainly through face-to-face visits in the neurology clinic or remotely by video/telephone calls, at each trimester of pregnancy.	The study data came primarily from the neurology clinics, and additional data were abstracted from the electronic medical record system at the four centers. Potential malformations are reviewed by obstetric, neonatology, and pediatric specialists for confirmation.	None.
Hao (Topiramate) (Epilepsy) (Controls unexposed, sick), 2025	prospective cohort	Treatment information was collected through case report forms mainly through face-to-face visits in the neurology clinic or remotely by video/telephone calls, at each trimester of pregnancy.	The study data came primarily from the neurology clinics, and additional data were abstracted from the electronic medical record system at the four centers. Potential malformations are reviewed by obstetric, neonatology, and pediatric specialists for confirmation.	None.
Hernández-Díaz (Topiramate), 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.
Hernandez-Diaz (Topiramate) (Epilepsy), 2024	retrospective cohort (claims database)	Medicaid beneficiaries nationwide, and the Merative MarketScan Commercial Claims and Encounters Database, two data sources that contain information on dispensed outpatient prescription medications.	Clinical diagnoses of autism spectrum disorder were ascertained with the use of a validated claims-based algorithm that requires at least two visits with codes for autism spectrum disorder at or after the age of 1 year.	Exclusion of children with chromosomal anomalies. Propensity score–adjusted for cohort source, maternal age, US region, year of delivery, mental health or developmental conditions, health care use, alcohol, tobacco or substance use disorder, other medications (antidepressants, antipsychotics, ...), comorbidities (diabetes, hypertension, ...), multiple gestation, prenatal vitamin dispensing...
Hernandez-Diaz (Topiramate) (Mixed indications), 2018	prospective cohort	In the Medicaid Analytic eXtract, use of medications is identified by drug-dispensing claims that include National Drug Codes. Exposure was defined as filling ≥1 prescriptions during the first trimester of pregnancy.	From inpatient or outpatient ICD-9 diagnoses code of 749.xx recorded on >1 date or 1 date and also a related procedure codes in the infant records. Maternal records were also considered because claims are sometimes recorded under the mother while the infant’s Medicaid enrollment is being processed.	Adjustment on maternal age, race, topiramate indications, obesity, smoking, comorbidities, concomitant medications, and proxies for overall health status (e.g., Obstetric Comorbidity Index, number of hospitalizations).
Hernández-Díaz (Topiramate) (Mixed indications), 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.	Potential confounders for adjustment not specified.
Hernández-Díaz (Topiramate) (Mixed indications) (Controls exposed to Lamotrigine, sick), 2014	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 neonates’ doctors were asked to return copies of their examination findings.	No adjustment for those outcomes.
Hernández-Díaz (Topiramate) (Mixed indications) (Controls unexposed, disease free), 2014	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 neonates’ doctors were asked to return copies of their examination findings.	No adjustment for those outcomes.
Husebye (Topiramate) (Controls exposed to Lamotrigine, sick), 2020	population based cohort propective	Information on the anti-epileptic (AED) use was obtained from the maternal questionnaires completed during gesta week 17–19 and week 30 and from Medical Birth Registry data. AEDs were detected in 93% of maternal blood and umbilical samples collected.	Parent-reported screening instruments: the Ages and Stages Questionnaires (at 5 years) the Speech and Language Assessment Scale (at 5 years) and the Norwegian instrument Twenty Statements about Language-related Difficulties (at 5 and 8 years).	No adjustment for this group of comparison.
Husebye (Topiramate) (Controls unexposed, disease free), 2020	population based cohort propective	Information on the anti-epileptic (AED) use was obtained from the maternal questionnaires completed during gesta week 17–19 and week 30 and from Medical Birth Registry data. AEDs plasma concentrations were analysed in maternal and umbilical cord samples (73%) and were detected in 93% of children.	Parent-reported screening instruments: the Ages and Stages Questionnaires (at 5 years) the Speech and Language Assessment Scale (at 5 years) and the Norwegian instrument Twenty Statements about Language-related Difficulties (at 5 and 8 years).	Maternal age, parental SES, low household income, parity, maternal prepregnancy BMI, maternal report of familial language delay (5y model), smoking and alcohol (8y model), maternal anxiety/depression, Apgar score at 5 min, gestational age, report of seldom/never helping child read letters and sounds during a typical week (5y model) or report of never reading to their child (8y model).
Husebye (Topiramate) (Controls unexposed, sick), 2020	population based cohort propective	Information on the anti-epileptic (AED) use was obtained from the maternal questionnaires completed during gesta week 17–19 and week 30 and from Medical Birth Registry data. AEDs plasma concentrations were analysed in maternal and umbilical cord samples (73%) and were detected in 93% of children.	Parent-reported screening instruments: the Ages and Stages Questionnaires (at 5 years) the Speech and Language Assessment Scale (at 5 years) and the Norwegian instrument Twenty Statements about Language-related Difficulties (at 5 and 8 years).	No adjustment for this group of comparison.
Källén (Topiramate) (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 (Topiramate) (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.
Kilic (Topiramate) (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 (Topiramate) (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 (Topiramate) (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.
Li (Topiramate) (Controls exposed to LTG), 2023	prospective cohort	The use of antiseizure medications on the included patients was registered by doctors and trained researchers.	After delivery, the offspring of the Women with epilepsy (WWE) were followed up by pediatricians. Offspring health was assessed by a multidisciplinary team, composed mainly of pediatricians and pediatric neurologists.	No adjustment. The exclusion criteria were as follows: (1) intelligence quotient (IQ) <70, ... (4) a voluntary termination of pregnancy of the mother’s personal choice and unrelated to fetal health.
Li (Topiramate) (Controls unexposed, sick), 2023	prospective cohort	The use of antiseizure medications on the included patients was registered by doctors and trained researchers.	After delivery, the offspring of the Women with epilepsy (WWE) were followed up by pediatricians. Offspring health was assessed by a multidisciplinary team, composed mainly of pediatricians and pediatric neurologists.	No adjustment. The exclusion criteria were as follows: (1) intelligence quotient (IQ) <70, ... (4) a voluntary termination of pregnancy of the mother’s personal choice and unrelated to fetal health.
Lyons (Topiramate) (Indications NOS), 2023	retrospective cohort (claims database)	Exposure determined using outpatient dispensing data and National Drug Codes.	Oral clefts were defined based on a validated algorithm by requiring the presence of either (1) at least two diagnosis codes (using ICD-9-CM) on different dates, or (2) one diagnosis code for oral cleft and one procedure or related surgery code in the mother's or the infant's record.	Propensity score models: maternal age, indications for topiramate, obesity, smoking, other maternal health conditions (i.e., depression, hypertension, ...), medication use (i.e., other anticonvulsants, antidepressants, ...), Combined comorbidity score, and indicators of healthcare utilization. Singletons only. Exclusion of mother-infant pairs with known teratogen use in the first trimester.
Madley-Dowd_SE (Topiramate) (Controls exposed to LTG) (Mixed indications), 2024	population based cohort retrospective	Self-reported maternal consumption of antiseizure medications were prospectively recorded at antenatal care visits (from a structured interview at the first visit at 8–10 weeks of gestation, supplemented from 2005 with drug all prescription dispensations in Sweden (tetrachoric correlation 0.98).	Inpatient and specialized outpatient diagnoses were obtained using ICD-8/9/10 codes from the National Patient Registry, and to further identify cases of ADHD, prescription information on licensed ADHD medications was also incorporated.	Adjusted for ASM presumed indication, any maternal neurodevelopmental diagnoses, maternal age, residential region, hazardous drinking or illicit drug use during pregnancy, gravidity, maternal health care use and seizure events (year before pregnancy), use of antipsychotics/ antidepressants (year before pregnancy), hyperemesis or antiemetic prescriptions, year of birth and socioeconomic position.
Madley-Dowd_SE (Topiramate) (Controls unexposed, general pop) (Mixed indications), 2024	population based cohort retrospective	Self-reported maternal consumption of antiseizure medications were prospectively recorded at antenatal care visits (from a structured interview at the first visit at 8–10 weeks of gestation, supplemented from 2005 with drug all prescription dispensations in Sweden (tetrachoric correlation 0.98).	Inpatient and specialized outpatient diagnoses were obtained using ICD-8/9/10 codes from the National Patient Registry, and to further identify cases of ADHD, prescription information on licensed ADHD medications was also incorporated.	Adjusted for ASM presumed indication, any maternal neurodevelopmental diagnoses, maternal age, residential region, hazardous drinking or illicit drug use during pregnancy, gravidity, maternal health care use and seizure events (year before pregnancy), use of antipsychotics/ antidepressants (year before pregnancy), hyperemesis or antiemetic prescriptions, year of birth and socioeconomic position.
Madley-Dowd_SE (Topiramate) (Controls unexposed, sibling) (Mixed indications), 2024	population based cohort retrospective	Self-reported maternal consumption of antiseizure medications were prospectively recorded at antenatal care visits (from a structured interview at the first visit at 8–10 weeks of gestation, supplemented from 2005 with drug all prescription dispensations in Sweden (tetrachoric correlation 0.98).	Inpatient and specialized outpatient diagnoses were obtained using ICD-8/9/10 codes from the National Patient Registry, and to further identify cases of ADHD, prescription information on licensed ADHD medications was also incorporated.	Adjusted for ASM presumed indication, any maternal neurodevelopmental diagnoses, maternal age, residential region, hazardous drinking or illicit drug use during pregnancy, gravidity, maternal health care use and seizure events (year before pregnancy), use of antipsychotics/ antidepressants (year before pregnancy), hyperemesis or antiemetic prescriptions, year of birth and socioeconomic position.
Madley-Dowd_UK (Topiramate) (Controls exposed to LTG) (Mixed indications), 2024	retrospective cohort (claims database)	Prescriptions were identified from primary care records.	Diagnoses were obtained from primary care records using Read codes for all patients and from inpatient and outpatient Hospital Episode Statistics (HES) using ICD-10 codes. For ADHD, prescription on ADHD medications (methylphenidate, dexamfetamine, lisdexamfetamine and atomoxetine) was incorporated.	Adjusted for ASM presumed indication, any maternal neurodevelopmental diagnoses, maternal age, residential region, hazardous drinking or illicit drug use during pregnancy, gravidity, maternal health care use and seizure events (year before pregnancy), use of antipsychotics/ antidepressants (year before pregnancy), hyperemesis or antiemetics, year of birth and socioeconomic position.
Madley-Dowd_UK (Topiramate) (Controls unexposed, general pop) (Mixed indications), 2024	retrospective cohort (claims database)	Prescriptions were identified from primary care records.	Diagnoses were obtained from primary care records using Read codes for all patients and from inpatient and outpatient Hospital Episode Statistics (HES) using ICD-10 codes. For ADHD, prescription on ADHD medications (methylphenidate, dexamfetamine, lisdexamfetamine and atomoxetine) was incorporated.	Adjusted for ASM presumed indication, any maternal neurodevelopmental diagnoses, maternal age, residential region, hazardous drinking or illicit drug use during pregnancy, gravidity, maternal health care use and seizure events (year before pregnancy), use of antipsychotics/ antidepressants (year before pregnancy), hyperemesis or antiemetic prescriptions, year of birth and socioeconomic position.
Madley-Dowd_UK (Topiramate) (Controls unexposed, sibling) (Mixed indications), 2024	retrospective cohort (claims database)	Prescriptions were identified from primary care records.	Diagnoses were obtained from primary care records using Read codes for all patients and from inpatient and outpatient Hospital Episode Statistics (HES) using ICD-10 codes. For ADHD, prescription on ADHD medications (methylphenidate, dexamfetamine, lisdexamfetamine and atomoxetine) was incorporated.	Sibling. Adjusted for ASM presumed indication, any maternal neurodevelopmental diagnoses, maternal age, residential region, hazardous drinking or illicit drug use during pregnancy, gravidity, maternal health care use and seizure events (year before pregnancy), use of antipsychotics/ antidepressants (year before pregnancy), hyperemesis or antiemetics, year of birth and socioeconomic position.
Margulis (Topiramate) (Mixed indication), 2012	case control	Exposure information is collected after delivery by means of a detailed computer-assisted telephone interview.	Information on the presence of congenital malformations is obtained from hospital discharges and medical records and experts review.	Matched sets were formed on the basis of year (2-year categories), region of birth and study.
Mawer (Topiramate) (Controls exposed to Lamotrigine, sick), 2010	prospective cohort	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.	Congenital abnormalities were identified from reports of fetal scans and paediatric medical examination of the baby before discharge. Major malformations were distinguished from minor anomalies using Eurocat instructions and those with chromosome abnormalities were not included.	No matching for this group of comparison. No adjustement.
Mawer (Topiramate) (Controls unexposed, disease free), 2010	prospective cohort	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.	Congenital abnormalities were identified from reports of fetal scans and paediatric medical examination of the baby before discharge. Major malformations were distinguished from minor anomalies using Eurocat instructions and those with chromosome abnormalities were not included.	Matched for age (within a five-year band), for parity, for residential district (postal code) and employment. No adjustement.
Mawer (Topiramate) (Controls unexposed, sick), 2010	prospective cohort	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.	Congenital abnormalities were identified from reports of fetal scans and paediatric medical examination of the baby before discharge. Major malformations were distinguished from minor anomalies using Eurocat instructions and those with chromosome abnormalities were not included.	No matching for this group of comparison. No adjustement.
Meador (Topiramate) (Controls exposed to Lamotrigine, sick), 2021	prospective cohort	Data were collected from participants using a daily electronic diary that was verified at study visits and with medical records.	Data were collected from participants using a daily electronic diary that was verified at study visits and with medical records.	Adjusted for mother's IQ, education level, and post-birth average Beck Anxiety Inventory (BAI) score, and child's sex, ethnicity, and birthweight.
Meador (Topiramate) (Controls exposed to Lamotrigine, sick), 2020	prospective cohort	Data were obtained from participants and their medical records.	Data were obtained from participants and their medical records.	No adjustment for this group of exposure.
Meador (Topiramate) (Controls unexposed, disease free), 2021	prospective cohort	Data were collected from participants using a daily electronic diary that was verified at study visits and with medical records.	Data were collected from participants using a daily electronic diary that was verified at study visits and with medical records.	Adjusted for mother's IQ, education level, and post-birth average Beck Anxiety Inventory (BAI) score, and child's sex, ethnicity, and birthweight.
Meador (Topiramate) (Controls unexposed, disease free), 2020	prospective cohort	Data were obtained from participants and their medical records.	Data were obtained from participants and their medical records.	No adjustment for this group of exposure.
Meador (Topiramate) (Controls unexposed, sick), 2020	prospective cohort	Data were obtained from participants and their medical records.	Data were obtained from participants and their medical records.	No adjustment for this group of exposure.
Mines (Topiramate) (Other indications), 2014	retrospective cohort (claims database)	Exposure was ascertained from prescription claims data or pharmacy data of KPNC. Claims for drug dispensings include National Drug Codes. They considered a mother exposed if a drug was dispensed during first trimester or earlier, if calculated day’s supply extended into the first trimester.	From databases diagnoses and procedures are identified by the International Classification of Disease, 9th Revision, Clinical Modification and Current Procedural Terminology codes. Each clinician independently reviewed the clinical data to confirm case status and to classify the type of oral cleft.	The following variables were included in both propensity score models: maternal age, infant sex, multiple gestation, prematurity, calendar year, geographic region, tobacco smoking, seizures or epilepsy, migraine, psychiatric or chronic pain conditions, diabetes, hypertension, obesity, dispensings of folic acid antagonists, and dispensings of suspected pharmaceutical teratogens.
Morrow (Topiramate) (Controls exposed to Lamotrigine, sick), 2006	prospective cohort	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.	Outcome data were collected by sending the patient’s general practitioner a standardised questionnaire for completion during the follow-up duration. Other health care practitioners were contacted if identified. Pregnancy losses with no major malformation are excluded.	No adjustment for this group of comparison.
Morrow (Topiramate) (Controls unexposed, sick), 2006	prospective cohort	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.	Outcome data were collected by sending the patient’s general practitioner a standardised questionnaire for completion during the follow-up duration. Other health care practitioners were contacted if identified. Pregnancy losses with no major malformation are excluded.	No adjustment for this group of exposure.
Nadebaum (Topiramate), 2011	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.	Children participated in neuropsychological examination and all assessors were blinded to drug exposure: the Clinical Evaluation of Language Fundamentals, fourth edition and the Wechsler Intelligence Scale for Children, fourth edition were administered.	None.
Ornoy (Topiramate), 2008	prospective cohort	Details of exposure were collected during pregnancy at the initial contact before pregnancy outcome was known, using a structured questionnaire.	After the expected date of delivery, follow-up was conducted with the woman, her physician or midwife via a telephone interview and/or mailed questionnaire. When anomaly is reported, medical records were requested and a paediatrician contacted the mother for details and verification.	No adjustment for this group of exposure.
Razaz (Topiramate) (Epilepsy), 2024	population based cohort retrospective	Prescription for antiseizure medication (ASM) was ascertained using nationwide prescription registers and identified ASMs based on Anatomical Therapeutic Chemical Classification.	All maternal and neonatal conditions were ascertained from each country’s Medical Birth Register, Patient Register, and Cause of Death Register records, according to the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10).	Singleton only. Adjusted for maternal age, parity, birth year, child’s sex, mother’s education, marital status, country, maternal prepregnancy psychiatric comorbidity, number of somatic diagnoses, and hospitalizations in the year preceding pregnancy.
Richards (Topiramate) (Controls exposed to Lamotrigine, sick) (Indications NOS), 2019	population based cohort retrospective	Obtained from the Pharmaceutical Collection database. Any redeemed prescription of an antiepileptic drug belonging to the Anatomical Therapeutic Chemical class N03A. Monotherapy is defined as if only one type of AED was prescribed during the exposure window.	Children are screened for their emotional and physical development with two questionnaires, the Parental Evaluation of Development Status (PEDS) tool and the Strengths and Difficulties Questionnaire (SDQ), which is completed by parents and teachers.	No adjustment for this group of comparison. (Adjusted risk ratios were not calculated because of the small numbers of children prenatally exposed).
Richards (Topiramate) (Controls unexposed, NOS) (Indications NOS), 2019	population based cohort retrospective	Obtained from the Pharmaceutical Collection database. Any redeemed prescription of an antiepileptic drug belonging to the Anatomical Therapeutic Chemical class N03A. Monotherapy is defined as if only one type of AED was prescribed during the exposure window.	Children are screened for their emotional and physical development with two questionnaires, the Parental Evaluation of Development Status (PEDS) tool and the Strengths and Difficulties Questionnaire (SDQ), which is completed by parents and teachers.	No adjustment for this group of comparison. (Adjusted risk ratios were not calculated because of the small numbers of children prenatally exposed).
Rihtman (Topiramate) (Mixed indications), 2012	prospective cohort	Details of exposure were collected during pregnancy at the initial contact.	Stanford-Binet 5th, Beery developmental test of visual-motor integration, Developmental coordination disorder questionnaire (Little DCDQ), Miller Function Participation Scales (M-FUN), Conner's rating scale. Tests results were obtained through questionnaires (parents, teachers) or a testing session.	Matched to two control children by gender and as closely matched by age as possible.
The NAAED (Topiramate) (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 (Topiramate) (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 (Topiramate) (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 (Topiramate) (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 (Topiramate) (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 (Topiramate) (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 (Topiramate) (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)).
Tomson (Topiramate), 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.
Trivedi (Topiramate) (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.
Trivedi (Topiramate) (Controls unexposed, 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.	Adjusted for enrollment status, age at conception, type of epilepsy, folic acid use in pregnancy, seizures in pregnancy, Generalised Tonic Clonic Seizures in pregnancy, prior spontaneous fetal loss, parental major congenital malformation.
Vajda (Topiramate) (Controls exposed to Lamotrigine, sick), 2013	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.	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.	None.
Vajda (Topiramate) (Controls unexposed, sick), 2013	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.	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.	None.
Vajda a (Topiramate) (Controls exposed to LTG) (Epilepsy), 2024	prospective cohort	Not specified. All contact between the pregnant women and the Melbourne-based register has been by telephone.	The register has collected data concerning each woman’s medical details at enrolment, at about 28 WG and around the end of the first post-partum month. The accuracy of the information provided by the pregnant women was checked with their treating medical practitioners, as far as feasible.	Exclusion of previous ‘lost’ pregnancies and pregnancies where either parent had a foetal malformation.
Vajda a (Topiramate) (Controls unexposed sick) (Epilepsy), 2024	prospective cohort	Not specified. All contact between the pregnant women and the Melbourne-based register has been by telephone.	The register has collected data concerning each woman’s medical details at enrolment, at about 28 WG and around the end of the first post-partum month. The accuracy of the information provided by the pregnant women was checked with their treating medical practitioners, as far as feasible.	Exclusion of previous ‘lost’ pregnancies and pregnancies where either parent had a foetal malformation.
Vajda b (Topiramate) (Epilepsy) (Controls exposed to Lamotrigine, sick), 2024	prospective cohort	Details are obtained by four in-depth telephone interviews with the women (at time of enrolment; at approximately 28 weeks of pregnancy; after the 1st post-partum (pp) month, and at one year pp). The accuracy of the information provided by the pregnant women is checked with their treating doctors.	Details are obtained by four in-depth telephone interviews with the women (at time of enrolment; at approximately 28 weeks of pregnancy; after the 1st post-partum (pp) month, and at one year pp). The accuracy of the information provided by the pregnant women is checked with their treating doctors.	None.
Vajda b (Topiramate) (Epilepsy) (Controls unexposed, sick), 2024	prospective cohort	Details are obtained by four in-depth telephone interviews with the women (at time of enrolment; at approximately 28 weeks of pregnancy; after the 1st post-partum (pp) month, and at one year pp). The accuracy of the information provided by the pregnant women is checked with their treating doctors.	Details are obtained by four in-depth telephone interviews with the women (at time of enrolment; at approximately 28 weeks of pregnancy; after the 1st post-partum (pp) month, and at one year pp). The accuracy of the information provided by the pregnant women is checked with their treating doctors.	None.
Veiby (Topiramate) (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 (Topiramate) (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 (Topiramate) (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.
Wood (Topiramate), 2015	prospective cohort	Details are obtained by four in-depth telephone interviews with the women. And treating doctors are contacted to confirm medical details.	Assessments with the Childhood Autism Rating Scale (CARS) were conducted by two authors blinded to drug exposure status of the child and clinical diagnosis of the mother and a consensus meetings conducted to confirm scoring.	None.

master protocol