Lamotrigine (Epilepsy)

Study	Type of data	Exposure measurement	Outcome assessment	Adjustment
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, 2021	retrospective cohort	Patients’ electronic and paper-based medical records.	Patients’ electronic and paper-based medical records.	None.
AlSheikh, 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.
Artama (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 (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, 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.
Baker (Controls unexposed, disease free), 2015	prospective cohort	An epilepsy specialist confirmed antiepileptic drugs.	The children IQ's were assessed by research assistants blinded to the exposure or maternal epilepsy status with the Differential Ability Scales. All neuropsychological assessments were double scored. Information was collected on educational intervention, defined as an educational need.	Significant confounders are socioeconomic status, maternal IQ, maternal age and gestational age of child at birth.
Baker (Controls unexposed, sick), 2015	prospective cohort	An epilepsy specialist confirmed antiepileptic drugs.	The children IQ's were assessed by research assistants blinded to the exposure or maternal epilepsy status with the Differential Ability Scales. All neuropsychological assessments were double scored. Information was collected on educational intervention, defined as an educational need.	No adjustment for this group of comparison.
Bjørk (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 (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.	No adjustment for this control group.
Bjørk (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 (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.
Borthen (Controls unexposed, disease free), 2011	retrospective cohort	Informations were extracted from a standardised antenatal form filled in by doctors and transferred to the database by practitioners attending the delivery and also from the neurological case records (according to ATC Classification System).	A standardised antenatal form is filled in by doctors and transferred to the database by practitioners attending the delivery. The hospital case records from all consultations, from labour and delivery and for the newborn were asked.	Matched for age and parity.
Borthen (Controls unexposed, disease free), 2010	population based cohort retrospective	A standardised antenatal form is filled in by doctors and transferred to the database by practitioners attending the delivery. Pregnancies registered with an anticonvulsant drug (according to ATC Classification System) were categorised as exposed.	A standardised antenatal form is filled in by doctors and transferred to the database by practitioners attending the delivery. It requests dichotomous data (yes/no) on both procedures and complications during labour and delivery with detailed information in free text.	Adjusted for maternal age (years), < 20, 20–34, ≥ 35; maternal education (years), < 11, 11–14, ≥ 15; parity, 0, 1 ; smoking, no/yes; diabetes, no/yes (except for postpartum atony and haemorrhage, where diabetes is excluded).
Borthen (Controls unexposed, sick), 2010	population based cohort retrospective	A standardised antenatal form is filled in by doctors and transferred to the database by practitioners attending the delivery. Pregnancies registered with an anticonvulsant drug (according to ATC Classification System) were categorised as exposed.	A standardised antenatal form is filled in by doctors and transferred to the database by practitioners attending the delivery. It requests dichotomous data (yes/no) on both procedures and complications during labour and delivery with detailed information in free text.	No adjustment for this group of comparison.
Borthen (Controls unexposed, sick), 2011	retrospective cohort	Informations were extracted from a standardised antenatal form filled in by doctors and transferred to the database by practitioners attending the delivery and also from the neurological case records (according to ATC Classification System).	A standardised antenatal form is filled in by doctors and transferred to the database by practitioners attending the delivery. The hospital case records from all consultations, from labour and delivery and for the newborn were asked.	No adjustment and matching for this group of exposure.
Bromley (Controls unexposed, disease free), 2010	prospective cohort	The research nurse took a personal and medical history in accordance with the prospectively designed Patient Basic and Control Basic Record Forms. An epilepsy specialist confirmed antiepileptic medication. Information from the patient was supplemented from clinical records.	Each child was assessed by an assistant psychologist blinded using the Griffiths Mental Development Scales in either their local hospital or their home. Feedback on the child’s development was provided to the families, and, where necessary, referrals to specialist services were made.	Matched for age, within a 5-year band, and for parity. No adjustment.
Bromley (Controls unexposed, disease free), 2013	prospective cohort	Information was recorded from maternal interview and checked against medical records. An epilepsy specialist confirmed antiepileptic durg type and dose.	Information was collected on confirmed diagnosis of ASD, ADHD and dyspraxia. Indication that a child had seen a specialist was documented and followed up with the diagnosing health professional, family doctor or school nurse. The researchers played no clinical role in the diagnosis of the child.	Candidate variables were seizures during pregnancy, maternal IQ, maternal age, socio-economic status, alcohol or nicotine exposure, gender and gestational age at birth. But the variables kept in the final regression model are not specified (data not shown).
Bromley (Controls unexposed, sick), 2010	prospective cohort	The research nurse took a personal and medical history in accordance with the prospectively designed Patient Basic and Control Basic Record Forms. An epilepsy specialist confirmed antiepileptic medication. Information from the patient was supplemented from clinical records.	Each child was assessed by an assistant psychologist blinded using the Griffiths Mental Development Scales in either their local hospital or their home. Feedback on the child’s development was provided to the families, and, where necessary, referrals to specialist services were made.	No matching for this group of exposure. No adjustment.
Bromley (Controls unexposed, sick), 2013	prospective cohort	Information was recorded from maternal interview and checked against medical records. An epilepsy specialist confirmed antiepileptic durg type and dose.	Information was collected on confirmed diagnosis of ASD, ADHD and dyspraxia. Indication that a child had seen a specialist was documented and followed up with the diagnosing health professional, family doctor or school nurse. The researchers played no clinical role in the diagnosis of the child.	No adjustment for this group of comparison.
Bromley (Lamotrigine) (Epilepsy), 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).
Campbell, 2014	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.	None.
Cassina, 2013	prospective cohort	At the first contact with the service, pregnant women answered to a formulated questionnaire. In addition, details regarding the treatment with antiepileptic drugs taken after the first contact to the Teratology Information Service were ascertained by a follow-up telephone interview.	Women or their physicians were contacted for a follow-up telephone interview to collect information about major birth defects. The data collected by interview are reliable, since all the Italian children have to undergo periodic pediatric evaluations.	No adjustment for this group of exposure.
Charlton, 2011	retrospective cohort (claims database)	Data generated during routine clinical practice in the UK General Practice Research Database (GPRD). All prescriptions issued by general practitioners are recorded in the database.	Children who had ≥ 1 medical codes relating to any type of congenital malformation using a list based on ICD-9 codes were identified in the UK General Practice Research Database. All codes identified were verified by supporting evidence in the form of free text or photocopied records.	None.
Charlton (Controls unexposed, disease free), 2017	retrospective cohort (claims database)	Determined from issued prescription records. The UK Clinical Practice Research Datalink contains anonymised, patient medical and prescribing records routinely collected within general practice.	All children in the study population with a diagnosis recorded were identified based on Read codes in their electronic record. The neurodevelopmental disorders identified were verified by the authors by supporting evidence in the form of free text or photocopied records.	Matching on maternal age at pregnancy start, year of delivery, sex of the child and GP practice/socioeconomic status of general practitioner practice and adjusts for alcohol drinking status.
Charlton (Controls unexposed, sick), 2017	retrospective cohort (claims database)	Determined from issued prescription records. The UK Clinical Practice Research Datalink contains anonymised, patient medical and prescribing records routinely collected within general practice.	All children in the study population with a diagnosis recorded were identified based on Read codes in their electronic record. The neurodevelopmental disorders identified were verified by the authors by supporting evidence in the form of free text or photocopied records.	No matching and adjustment for this group of comparison.
Christensen (Lamotrigine) (Epilepsy), 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, 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 all potential confounding factors including demographic factors, 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 by inclusion of propensity score stratification weights.
Cohen-Israel, 2018	retrospective cohort	The women were identified by a search of the Beilinson Teratology Information Service which contains complete records.	Obtained from the medical charts of the mothers and the neonates and departmental records. Long-term data obtained from the medical files and by a telephone interview using an ad-hoc questionnaire.	Matched for gestational age and date of birth
Cummings, 2011	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.	Children were evaluated by a single researcher blinded to exposure, assessment consisted of a physical and neurodevelopmental examination using The Bayley Scales of Infant Development (42 months and younger) and the Griffiths Scale of Infant Development (older than 42 months).	The only confounding variables which persisted as significant adverse factors, were age, gender and socioeconomic status.
Dean, 2007	retrospective cohort	A trained research nurse undertook interviews recording antiepileptic drugs use in each pregnancy. Maternal antiepileptic drugs dose was verified from case records where possible.	A trained research nurse undertook interviews recording children’s medical and developmental histories. Malformations and medical histories for the children were confirmed by hospital record review and clinical examination. Facial photographs were reviewed for features of FACS by blinded physicians	None.
Diav-Citrin, 2017	prospective cohort	Details of exposure were collected during pregnancy at the initial contact before pregnancy outcome was known, using a structured questionnaire.	Follow-up via a telephone interview and a questionnaire. If anomalies an attempt was made to obtain medical records. Classification was done by a blind pediatrician using EUROCAT Guide 1.4. Abnormalities detected by prenatal ultrasonography (if verified postnatally or by autopsy) were included.	None.
Dreier, 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).
Gopinath, 2015	retrospective cohort (registry)	The details of antiepileptic drugs exposure per month were recorded on a monthly basis in the protocol from the month prior to pregnancy through the entire period of pregnancy and three-month post partum. The drug compliance and seizure frequency were ascertained with a detailed diary.	Test battery was administered to participants in both the groups. The IQ of children was measured on Wechsler Intelligence Scale for Children, fourth edition (WISC-IV). The Wechsler Memory Scale-Visual Reproduction (WMS-VR) and Rey Auditory Verbal Learning Test (RAVLT) and the Trail Making Test.	No matching for this group of comparison.
Hao, 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.
He, 2017	prospective cohort	Data collected included antiepileptic drug use.	Clinical records were scanned to verify pregnancy complication and delivery complication. Neonatologist ascertained the health of offspring (neonatal asphyxia, congenital malformation or Apgar score less than or equal to 7).	None.
Hernandez-Diaz, 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...
Holmes, 2008	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 blinded to exposure status.	None.
Hosny, 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.
Husebye (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 (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.
Kasradze, 2017	prospective cohort	Antiepileptic drugs and total daily dosage before pregnancy/at 1st trimester/at 2nd trimester/at 3rd trimester were assessed retrospectively during the mother's structured interview.	Two forms of Wechsler Preschool and Primary Scale of Intelligence (WPPSI-4) were used to assess intellectual functioning for children aged 2.6–3.1 years and for children aged 4.0–7.7 years. All tests were performed in the Epilepsy Centre by two qualified blinded neuropsychologists.	Age and gender-matched.
Kini, 2006	retrospective cohort	Structured interviews were conducted with the mothers and medical records were available to confirm details in about 80% of participants.	A clinical examination was carried out to check the growth parameters and detect dysmorphic features and malformations. Clinical photographs were reviewed based on whether the gestalt was suggestive of fetal anticonvulsant syndrome by a panel of blind dysmorphologists.	None.
Leite, 2024	retrospective cohort	This was a retrospective cohort study with data collected from physical and electronic medical records.	This was a retrospective cohort study with data collected from physical and electronic medical records.	For analysis in monotherapy: no adjustment.
Li, 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 (Lamotrigine) (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 (Lamotrigine) (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.
Mawer (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 (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 exposure. No adjustement.
Meador, 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), 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 (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.
Miškov (Controls unexposed, disease free), 2016	prospective cohort	Data collected on pregnant women during outpatient visits to the neurologist, gynecologist and pediatrician neurologist.	Newborns were examined by pediatrician neurologist/geneticist at Clinical Department of Pediatrics and followed up yearly. Data on the control group were obtained from Clinical Department of Gynecology and Obstetrics and Clinical Department of Pediatrics .	None.
Miškov (Controls unexposed, sick), 2016	prospective cohort	Data collected on pregnant women during outpatient visits to the neurologist, gynecologist and pediatrician neurologist.	Newborns were examined by pediatrician neurologist/geneticist at Clinical Department of Pediatrics and followed up yearly. Data on the control group were obtained from Clinical Department of Gynecology and Obstetrics and Clinical Department of Pediatrics .	None.
Pekoz (Lamotrigine) (Epilepsy), 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.
Petersen (Controls unexposed NOS), 2017	retrospective cohort (claims database)	The Health Improvement Network (THIN) provides data on patients’ clinical and prescribing records. Prescriptions are issued electronically via the general practice computer systems.	Diagnostic codes for congenital malformations in the records of children were identified using codes from the Read code chapter starting with P (congenital anomalies). Those diagnostic codes were then identified in consultation with a GP (one of the authors) and in accordance with the EUROCAT guide.	Adjustments for maternal age, sex of child, quintiles of Townsend deprivation score and indication for treatment.
Petersen (Controls unexposed, sick), 2017	retrospective cohort (claims database)	The Health Improvement Network (THIN) provides data on patients’ clinical and prescribing records. Prescriptions are issued electronically via the general practice computer systems.	Diagnostic codes for congenital malformations in the records of children were identified using codes from the Read code chapter starting with P (congenital anomalies). Those diagnostic codes were then identified in consultation with a GP (one of the authors) and in accordance with the EUROCAT guide.	Adjustments for maternal age, sex of child, quintiles of Townsend deprivation score and indication for treatment.
Razaz (Lamotrigine), 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.
Ren (Lamotrigine) (Epilepsy), 2023	population based cohort propective	Information on medical exposure was retrieved from the Danish Register of Medicinal Product Statistics.	Information on school performance was provided by the Danish Agency for Information Technology and Learning. The cognitive abilities are assessed using academic tests conducted from 2010 to 2014.	Adjusted for year of examination, child sex, and maternal level of education, family income, maternal age at childbirth, parity, Danish origin, maternal history of epilepsy, maternal history of any psychiatric disorder, in utero exposure to antidepressant, antipsychotics or anxiolytics. Singletons only.
Rihtman, 2013	prospective cohort	Details of exposure were collected during pregnancy at the initial contact before pregnancy outcome was known.	Stanford-Binet 5th, Developmental Coordination Disorder Questionnaire, Beery Developmental Test, Miller Function Participation Scales, Sensory Profile, BRIEF, Connor's scale. Tests results were obtained through questionnaires (parents, teachers) or examinations by blind assessors.	None.
Thomas (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 (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 (Lamotrigine) (Epilepsy), 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)).
Trivedi, 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, 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, 2025	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, 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.
Van Marter (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 (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.
Vanya (Controls unexposed, sick), 2015	retrospective cohort	The epilepsy-related data evaluated included antiepileptic drugs therapy (NOS).	The evaluated parameters were minor or major congenital malformation (NOS).	None.
Veiby (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 (Controls unexposed, disease free) a, 2013	prospective cohort	Reported by the mother in the first MoBa questionnaire (weeks 13-17) as well as recorded in the compulsory Medical Birth Registry by the attending physician and midwife at delivery.	Parent-reported screening tools: Ages and stages questionnaire, Bailey Scales of Infant Development, and the Infant Characteristics Questionnaire.	Adjusted for maternal age, parity, education, folate supplementation, smoking, depression/anxiety, breastfeeding (number of months), and child malformation.
Veiby (Controls unexposed, disease free) b, 2013	prospective cohort	Questionnaires were filled out by the mothers (at gestational week 13–17) and medical hospital-records were examined to validate the self-reported use of antiepileptic drugs during pregnancy.	Parent-reported screening tools: The Ages and Stages Questionnaire, The 40-item Social Communication Questionnaire, the Modified Checklist for Autism in Toddlers, the 14-item Early Screening of Autistic Traits, items from the Child Behaviour Checklist and DSM-IV and the Child Behaviour Checklist.	Adjusted for maternal age, parity, education, smoking, periconceptional folate use, (and child low birth weight anxiety/depression, and malformation for neurodevelopmental) and maternal body weight in weight outcomes.
Veiby (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.
Veiby (Controls unexposed, sick) a, 2013	prospective cohort	Reported by the mother in the first MoBa questionnaire (weeks 13-17) as well as recorded in the compulsory Medical Birth Registry by the attending physician and midwife at delivery.	Parent-reported screening tools: Ages and stages questionnaire, Bailey Scales of Infant Development, and the Infant Characteristics Questionnaire.	No adjustment for this group of comparison.
Veiby (Controls unexposed, sick) b, 2013	prospective cohort	Questionnaires were filled out by the mothers (at gestational week 13–17) and medical hospital-records were examined to validate the self-reported use of antiepileptic drugs during pregnancy.	Parent-reported screening tools: The Ages and Stages Questionnaire, The 40-item Social Communication Questionnaire, the Modified Checklist for Autism in Toddlers, the 14-item Early Screening of Autistic Traits, items from the Child Behaviour Checklist and DSM-IV and the Child Behaviour Checklist.	No adjustment for this group of comparison.
Videman, 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