Levetiracetam (Epilepsy)

Study	Type of data	Exposure measurement	Outcome assessment	Adjustment
Alsaadi (Controls exposed to LTG), 2020	retrospective cohort	Retrospective review: exposure pre-pregnancy and at conception until registered at the clinic was recorded.	Retrospective review of pregnancy outcomes recorded during clinic visits: foetal anomaly scans were requested from all patients; pregnancy outcomes in the form of miscarriage, live birth and still birth were documented and all neonates were examined by a neonatologist at birth for malformations.	None.
Alsaadi (Controls unexposed sick), 2020	retrospective cohort	Retrospective review: exposure pre-pregnancy and at conception until registered at the clinic was recorded.	Retrospective review of pregnancy outcomes recorded during clinic visits: foetal anomaly scans were requested from all patients; pregnancy outcomes in the form of miscarriage, live birth and still birth were documented and all neonates were examined by a neonatologist at birth for malformations.	None.
Alsfouk (Levetiracetam), 2022	retrospective cohort	Patients records.	Patients records.	None.
Alsfouk (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2021	retrospective cohort	Patients’ electronic and paper-based medical records.	Patients’ electronic and paper-based medical records.	None.
Alsfouk (Levetiracetam) (Controls unexposed, sick), 2021	retrospective cohort	Patients’ electronic and paper-based medical records.	Patients’ electronic and paper-based medical records.	None.
AlSheikh (Levetiracetam) (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 (Levetiracetam) (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 (Levetiracetam), 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.
Artama (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2013	population based cohort retrospective	The Special Refund Entitlement Register and the Register on Reimbursement Drugs contained informations on maternal drug treatment under ATC category N03.	The Medical Birth Register data are collected from all maternity hospitals. Information on all deaths is revised and supplemented from the Cause-of-Death Register. Information on malformations are obtained from the Finnish Malformation Register.	No adjustment for this group of comparison.
Artama (Levetiracetam) (Controls unexposed, disease free), 2013	population based cohort retrospective	The Special Refund Entitlement Register and the Register on Reimbursement Drugs contained informations on maternal drug treatment under ATC category N03.	The Medical Birth Register data are collected from all maternity hospitals. Information on all deaths is revised and supplemented from the Cause-of-Death Register. Information on malformations are obtained from the Finnish Malformation Register.	Adjusted for maternal age at delivery, parity, university hospital district, socioeconomic status and major congenital anomalies.
Artama (Levetiracetam) (Controls unexposed, sick), 2013	population based cohort retrospective	The Special Refund Entitlement Register and the Register on Reimbursement Drugs contained informations on maternal drug treatment under ATC category N03.	The Medical Birth Register data are collected from all maternity hospitals. Information on all deaths is revised and supplemented from the Cause-of-Death Register. Information on malformations are obtained from the Finnish Malformation Register.	Adjusted for maternal age at delivery, parity, university hospital district, socioeconomic status and major congenital anomalies.
Aydin (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2020	retrospective cohort	Data were obtained from Perinatology Division’s computerized system. Antiepileptic drug use were reported.	Data were obtained from Perinatology Division’s computerized system.	None.
Aydin (Levetiracetam) (Controls unexposed, sick), 2020	retrospective cohort	Data were obtained from Perinatology Division’s computerized system. Antiepileptic drug use were reported.	Data were obtained from Perinatology Division’s computerized system.	None.
Babic (Levetiracetam), 2014	prospective cohort	Not specified.	The authors evaluated the pregnancy complications and perinatal outcomes in their patients.	None.
Battino, 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. Covariates: Parental history of major congenital malformations, types of epilepsy, folic acid, parity, offspring sex, time period, geographical region, and tonic-clonic seizures during first trimester of pregnancy.
Bhaskaran, 2025	prospective cohort	Not specified.	Speech and language skills were assessed using Receptive–Expressive Emergent Language Scale (REELS) (birth- 36 mo). The behavioral, speech and developmental assessments were blinded, and the examiners did not know the status of children as cases or comparative group.	Children with any history of meningitis, encephalitis or head trauma were excluded from the study. No adjustment.
Bjørk (Levetiracetam) (Controls exposed to Lamotrigine, sick), 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 (Levetiracetam) (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 (Levetiracetam) (Controls unexposed NOS), 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 (Levetiracetam) (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 (Levetiracetam) (Controls unexposed, sick), 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 (Levetiracetam) (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.
Bromley (Levetiracetam), 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.
Bromley (Levetiracetam) (Controls exposed to LTG), 2023	prospective cohort	The prescribed dose of the antiseizure medications was recorded prospectively from both medical records and maternal interviews at recruitment, and then again at ≥32 weeks gestation (by telephone interviews).	Birth or fetal outcome, including information on congenital anomalies, was taken from hospital records. At 24 months (=/ 6 months) the Bayley Scales of Infant and Toddler Development was completed at home, with the child by 2 senior blinded assessors.	Multiple regression model results not extractable. Women were excluded if they had a significant level of learning disability (e.g., unable to live independently), had another acute or chronic health condition for which they were taking a concomitant medication (non- ASM) with a known teratogenic profile (e.g., isotretinoin, warfarin, mycophenolate).
Bromley (Levetiracetam) (Controls unexposed, sick), 2023	prospective cohort	The prescribed dose of the antiseizure medications was recorded prospectively from both medical records and maternal interviews at recruitment, and then again at ≥32 weeks gestation (by telephone interviews).	Birth or fetal outcome, including information on congenital anomalies, was taken from hospital records. At 24 months (=/ 6 months) the Bayley Scales of Infant and Toddler Development was completed at home, with the child by 2 senior blinded assessors.	Multiple regression model results not extractable. Women were excluded if they had a significant level of learning disability (e.g., unable to live independently), had another acute or chronic health condition for which they were taking a concomitant medication (non- ASM) with a known teratogenic profile (e.g., isotretinoin, warfarin, mycophenolate).
Christensen (Levetiracetam) (Epilepsy) (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 (Levetiracetam) (Epilepsy) (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).
Cohen (Levetiracetam) (Epilepsy) (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 (Levetiracetam) (Epilepsy) (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 (Levetiracetam) (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.	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. Further adjusted for hospitalisation for epilepsy during pregnancy.
Coste (Levetiracetam) (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.
Dreier (Levetiracetam) (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 (Levetiracetam) (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).
Ertürk Çetin (Epilepsy) (Levetiracetam), 2024	prospective cohort	Patients with a diagnosis of epilepsy and who become pregnant were selected and followed prospectively. All patients were compliant with the treatment. The compliance was assessed through clinical interviews (no details).	Children were evaluated for major and minor congenital malformations until 1 year of age, by a detailed examination by the same neonatologist. Denver Developmental Screening Test can be administered by trained individuals.	None.
Hao (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 (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 (Levetiracetam) (Controls exposed to Lamotrigine, sick), 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.
Hernández-Díaz (Levetiracetam) (Controls unexposed, disease free), 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.	Neither restriction to pure prospective enrollees, nor adjustment for potential confounders, nor restriction to women with epilepsy, nor use of AED information from medical records (data not shown) changed the results significantly.
Hoeltzenbein (Levetiracetam), 2024	prospective cohort	Drug exposure is documented at the first consultation (when neither pregnancy outcome nor pathological results from prenatal diagnostics were known).	Follow-up of pregnancy and infant outcome, including the regular German pediatric examination at the age of 4–5 weeks, is recorded approximately 8 weeks after the estimated date of delivery via mailed questionnaires or structured telephone interview.	Adjusted for maternal age, body mass index, smoking, alcohol consumption, previous spontaneous abortions, previous live births, previous children with major birth defects or genetic disorders, folic acid at conception, and preexisting diabetes. Exclusion of women with anxiolytics for seizures (unless during delivery), with treatment of malignancies, with teratogenic comedications or fetotoxicants.
Hosny (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2021	prospective cohort	The following data were evaluated: seizure control 6 months before pregnancy, seizure control during each trimester, type and dose of ASMs at conception.	Result of high-resolution ultra-sonography in the 14th to 16th gestational weeks was recorded.	No adjustment.
Hosny (Levetiracetam) (Controls unexposed, sick), 2021	prospective cohort	The following data were evaluated: seizure control 6 months before pregnancy, seizure control during each trimester, type and dose of ASMs at conception.	Result of high-resolution ultra-sonography in the 14th to 16th gestational weeks was recorded.	No adjustment.
Huber-Mollema (Levetiracetam), 2019	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.	Mother and father completed the Child Behavior Checklist and the Social Emotional Questionnaire online. Parents completed an online questionnaire on demographic information, development, and child needs.	No adjustment for this comparison group.
Husebye (Levetiracetam) (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 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.
Husebye (Levetiracetam) (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 (Levetiracetam) (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.
Koc (Levetiracetam), 2018	retrospective cohort	The files were evaluated. The antiepileptic drug used by the patients were recorded.	Controls were performed in the first month and in the first year after birth as far as possible for the presence of major congenital malformations determined according to definitions and lists in the EUROCAT.	None.
Li (Levetiracetam) (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 (Levetiracetam) (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.
Madley-Dowd_SE (Levetiracetam) (Controls exposed to LTG), 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.	No adjustment for this group of comparison.
Madley-Dowd_SE (Levetiracetam) (Controls unexposed, sick), 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 (Levetiracetam) (Epilepsy), 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.
Margulis, 2019	population based cohort retrospective	Information on exposure was obtained from prescriptions dispensed and from self-report in the first prenatal visit and from self-reports in subsequent prenatal visits.	Study endpoints were ascertained from the Medical Birth Register, that collects information from standardized delivery charts.	Adjusted for maternal age at delivery, education, country of origin, marital status, early pregnancy body mass index, smoking in current pregnancy, alcohol dependence, diabetes (preexisting and gestational), hypertension (preexisting and gestational), epilepsy, depression, bipolar disorder, migraine, chronic pain, other psychiatric disorders, and year of delivery.
Mari (Levetiracetam), 2022	retrospective cohort	Collected data at Epilepsy centers.	During each trimester of pregnancy and in the post-partum period, defned as 3 months after childbirth, women underwent periodic clinical follow-up visits through specialist medical examination and foetal screening tests.	None.
Meador (Controls exposed to LTG), 2023	prospective cohort	Data for antiseizure medications were collected using a daily electronic diary and verified at study visits and with medical records.	All neuropsychological assessments were administered and scored by assessors blinded to antiseizure medication exposures. A Verbal Index score was calculated by averaging scores on relevant subsets of 3 different scales.	Linear regression model adjusted for mother's 3rd trimester max observed ratio ABL, IQ, education level, Week Gestational Age at enrollment, post-birth average anxiety score (BAI), household income, and child's sex and ethnicity. Least Square means were derived using used proportionally weighted coefficients.
Meador (Controls unexposed, disease free), 2023	prospective cohort	Data for antiseizure medications were collected using a daily electronic diary and verified at study visits and with medical records.	All neuropsychological assessments were administered and scored by assessors blinded to antiseizure medication exposures. A Verbal Index score was calculated by averaging scores on relevant subsets of 3 different scales.	Linear regression model adjusted for mother's 3rd trimester max observed ratio ABL, IQ, education level, Week Gestational Age at enrollment, post-birth average anxiety score (BAI), household income, and child's sex and ethnicity. Least Square means were derived using used proportionally weighted coefficients.
Meador (Levetiracetam) (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 (Levetiracetam) (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 (Levetiracetam) (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.
Morrow (Levetiracetam) (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 (Levetiracetam) (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.
Pekoz (Levetiracetam) (Epilepsy) (Controls exposed to LTG), 2023	prospective cohort	The patients were examined by a neurologist every 2 months during pregnancy, and the use of Anti-seizure medications (ASMs) was assessed.	After deliver, and at 1 and 3 months the newborns were examined by a neonatologist. Sex, weight, height and head circumference of the newborn, whether the congenital malformation was major or minor, and perinatal or maternel death were also recorded in the database.	No adjustment. Patients without a definitive diagnosis of epilepsy, who did not attend regular follow-up visits, or who were exposed to other medications that might be teratogenic in the first trimester were excluded from this study.
Pekoz (Levetiracetam) (Epilepsy) (Controls unexposed, sick), 2023	prospective cohort	The patients were examined by a neurologist every 2 months during pregnancy, and the use of Anti-seizure medications (ASMs) was assessed.	After deliver, and at 1 and 3 months the newborns were examined by a neonatologist. Sex, weight, height and head circumference of the newborn, whether the congenital malformation was major or minor, and perinatal or maternel death were also recorded in the database.	No adjustment. Patients without a definitive diagnosis of epilepsy, who did not attend regular follow-up visits, or who were exposed to other medications that might be teratogenic in the first trimester were excluded from this study.
Razaz (Levetiracetam), 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.
Shallcross (Levetiracetam), 2011	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.	Children were assessed by an assistant psychologist or by authors and all children within the study completed the Griffiths Mental Development Scale. All examiners were trained in use of the Griffiths to ensure uniform objectivity in testing.	Data not shown: 'linear regression analysis was performed controlling for the following variables: seizures in pregnancy, gestational age, maternal full-scale IQ, maternal age, child age at assessment, SES, exposure to nicotine, exposure to alcohol, and drug used in pregnancy.'
Stjerna (Levetiracetam) (Epilepsy), 2024	retrospective cohort	Prospectively collected data on antiseizure medications (ASMs) and seizures during pregnancy were retrieved from the core EURAP registry.	Neurocognitive evaluations of the children were carried out at the age of 6–7 years at each site by a neuropsychologist or psychologist blinded to the exposure data. The majority of the children were assessed with the Wechsler Intelligence Scale for Children (WISC-III) and NEPSY-II scales.	Exclusion of significant pre-, peri- and postnatal neurological co-morbidity of the child, such as known chromosomal/ genetic syndromes or gestational age less than 37 weeks. Continuous data adjusted for maternal IQ (VIQ, PIQ or FSIQ), sex assigned at birth, type of maternal epilepsy and paternal education (university or other). Dichotomised data not adjusted.
Thomas (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 (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)).
Thomas (Levetiracetam) (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 (Levetiracetam) (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 (Levetiracetam) (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.
Tomson (Levetiracetam), 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.
Tomson (Levetiracetam), 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 (Levetiracetam) (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 (Levetiracetam) (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 (Levetiracetam) (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 (Levetiracetam) (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 (Levetiracetam) (Controls exposed to LTG), 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 (Levetiracetam) (Controls unexposed sick), 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 (Levetiracetam) (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 (Levetiracetam) (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.
Van Marter (Levetiracetam) (Controls unexposed, disease free), 2021	prospective cohort	Prescribed antiepileptic drug at the time of enrollment. Data were collected from subjects and their medical records.	Data were collected from subjects and their medical records.	Only p-value adjustment.
Van Marter (Levetiracetam) (Controls unexposed, sick), 2021	prospective cohort	Prescribed antiepileptic drug at the time of enrollment. Data were collected from subjects and their medical records.	Data were collected from subjects and their medical records.	Only p-value adjustment.
Veiby (Levetiracetam) (Controls exposed to Lamotrigine, sick), 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 (Levetiracetam) (Controls unexposed, disease free), 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 (Levetiracetam) (Controls unexposed, sick), 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.
Videman (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2016	prospective cohort	Exposure data (including daily doses and serum levels for oxcarbazepine, carbamazepine, valproic acid, lamotrigine, and levetiracetam) were obtained prospectively at outpatient visits taking place every trimester and postnatally.	The first author performed the tests. The Griffiths Mental Developmental Scale was used to evaluate the developmental status of the infant. To assess the clinical neurological status, we used the Hammersmith Infant Neurological Examination (HINE). All examiners were blinded	No adjustment for this group of exposure.
Videman (Levetiracetam) (Controls unexposed, disease free), 2016	prospective cohort	Exposure data (including daily doses and serum levels for oxcarbazepine, carbamazepine, valproic acid, lamotrigine, and levetiracetam) were obtained prospectively at outpatient visits taking place every trimester and postnatally.	The first author performed the tests. The Griffiths Mental Developmental Scale was used to evaluate the developmental status of the infant. To assess the clinical neurological status, we used the Hammersmith Infant Neurological Examination (HINE). All examiners were blinded	No adjustment for this group of exposure.
Wiggs, 2024	population based cohort retrospective	Information recorded at the first antenatal visit (8th-12th week of pregnancy) includes prescription drug use.	Birth defects were identified birth defects using ICD-9 and ICD-10 diagnoses recorded in the the Medical Birth Register (MBR) at discharge from the hospital after birth and inpatient and outpatient diagnoses recorded in the National Patient Register.	Singleton. Adjusted for maternal report of tobacco and psychotropic medication (lithium, antidepressants, anxiolytics, sedatives, antipsychotics, ADHD medications, analgesics) use at enrollment to antenatal care, parity, year of birth, parental psychiatric diagnoses before conception, parents’ age, country of origin, cohabitation status and maternal hospitalizations for epilepsy the year before.

master protocol