Pregabalin (All indications)

Study	Type of data	Exposure measurement	Outcome assessment	Adjustment
Battino (Epilepsy), 2024	prospective cohort	Reporting physicians collected information on drug therapy after each trimester.	Abnormalities in the offspring were recorded descriptively by reporting physicians. A committee blinded to type of exposure assessed and categorized these abnormalities. When necessary, the committee solicited additional information from the reporting physicians.	Exclusion of pregnancies exposed to known teratogenic drugs, and those with comorbidities associated with teratogenic risks. No adjustment for this group of comparison.
Bjørk (Controls exposed to Lamotrigine, sick) (Mixed indications), 2022	population based cohort retrospective	Prescriptions through national prescription registers according to Anatomical Therapeutic Chemical classification codes N03, N05BA09, and S01EC01.	Severe neurodevelopmental disorders are diagnosed by child psychiatrists and psychologists in specialist health care in the Nordic countries and recorded with International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes.	No adjustment for this control group.
Bjørk (Controls unexposed NOS) (Mixed indications), 2022	population based cohort retrospective	Prescriptions through national prescription registers according to Anatomical Therapeutic Chemical classification codes N03, N05BA09, and S01EC01.	Severe neurodevelopmental disorders are diagnosed by child psychiatrists and psychologists in specialist health care in the Nordic countries and recorded with International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes.	Adjusted for maternal age, education and marital status, parity, child’s birth year, sex, and country of birth. All the models were run with separate strata for country and year. Plus maternal use of antidepressants or opioids, depression, anxiety, personality disorders, number of chronic somatic diseases, and number of hospitalizations the year before last menstrual period.
Bjørk (Controls unexposed, sick) (Mixed indications), 2022	population based cohort retrospective	Prescriptions through national prescription registers according to Anatomical Therapeutic Chemical classification codes N03, N05BA09, and S01EC01.	Severe neurodevelopmental disorders are diagnosed by child psychiatrists and psychologists in specialist health care in the Nordic countries and recorded with International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes.	No adjustment for this control group.
Blotière (Controls exposed to Lamotrigine, sick) (Other indications), 2019	retrospective cohort (claims database)	The French national health insurance database contains all health care claims reimbursed by French National Health Insurance. Include dispensed drugs coded according to the ATC classification. Monotherapy was defined as the absence of any other antiepileptic drug dispensed during the same period.	The French hospital discharge database (PMSI) provides detailes medical information including discharge diagnosis ICD-10 codes and medical procedures. Major congenital malformations (MCMs) were selected from the list of MCMs of the European Surveillance of Congenital Anomalies (EUROCAT) network.	No adjustment for this group of comparison.
Blotière (Controls unexposed NOS) (Other indications), 2019	retrospective cohort (claims database)	The French national health insurance database contains all health care claims reimbursed by French National Health Insurance. Include dispensed drugs coded according to the ATC classification. Monotherapy was defined as the absence of any other antiepileptic drug dispensed during the same period.	The French hospital discharge database (PMSI) provides detailes medical information including discharge diagnosis ICD-10 codes and medical procedures. Major congenital malformations (MCMs) were selected from the list of MCMs of the European Surveillance of Congenital Anomalies (EUROCAT) network.	For major congenital malformations with <5 cases per treatment group, authors calculated crude odds ratios with exact confidence intervals. For major congenital malformations with at least 5 cases per treatment group, ORs were adjusted for maternal age, mother’s eligibility for CMU-C, year of start of pregnancy, preconception folic acid supplementation, and pregestational diabetes.
Christensen (All indications) (Controls exposed to LTG), 2024	population based cohort retrospective	Prenatal exposure was identified via national prescription registers. These registers contain the Anatomical Therapeutic Chemical (ATC) classification code (www.whocc.no) and the date of dispensing.	Information on birth weight, gestational age and head circumference at birth was obtained from the medical birth registers for all births occurring at 22 weeks’ gestation or later.	Singleton only. No adjustment for this group of comparison.
Christensen (All indications) (Controls unexposed, general population), 2024	population based cohort retrospective	Prenatal exposure was identified via national prescription registers. These registers contain the Anatomical Therapeutic Chemical (ATC) classification code (www.whocc.no) and the date of dispensing.	Information on birth weight, gestational age and head circumference at birth was obtained from the medical birth registers for all births occurring at 22 weeks’ gestation or later.	Singleton only. All models were adjusted for country of birth, year of birth, sex of child, maternal age, maternal parity, maternal marital or cohabitation status, pre-pregnancy hospital admittances, maternal education, smoking in early pregnancy, maternal psychiatric history (F00-F99), and use of psychotropic drugs in pregnancy (ATC N06A, N05A, N05B, excl. N05BA09) and maternal epilepsy.
Coste (Controls exposed to Lamotrigine, sick) (Mixed indications), 2020	retrospective cohort (claims database)	Defned by at least one dispensing of the drug to the mother between the beginning of the month preceding onset of pregnancy and the end of pregnancy. Mother had used this drug as monotherapy, defined by the use of a single drug during pregnancy.	Diagnoses of mental and behavioural disorders by the attribution of long-term disease status and/or hospital admission (ICD-10 codes). Health care utilization by reimbursement of at least one speech therapy session; one orthoptist consultation; one psychiatrist or child psychiatrist consultation.	Sociodemographic, folic acid, SSRI during pregnancy, antipsychotic drug use during the year preceding pregnancy, a proxy for severity of mental disorders, history of mental and behavioural disorders not related to alcohol or smoking, indicator of tobacco use and alcohol use, child’s sex, gestational age and birth weight.
Coste (Controls unexposed, NOS) (Mixed indications), 2020	retrospective cohort (claims database)	Defned by at least one dispensing of the drug to the mother between the beginning of the month preceding onset of pregnancy and the end of pregnancy. Mother had used this drug as monotherapy, defined by the use of a single drug during pregnancy.	Diagnoses of mental and behavioural disorders by the attribution of long-term disease status and/or hospital admission (ICD-10 codes). Health care utilization by reimbursement of at least one speech therapy session; one orthoptist consultation; one psychiatrist or child psychiatrist consultation.	Adjusted for: mother’s age, Complementary Universal Health Insurance scheme, diagnosis of mental illness other than tobacco and alcohol use disorders, antipsychotic drug use during the year preceding pregnancy, indicator of severity of psychiatric morbidity, indicator of tobacco use, indicator of alcohol use, folic acid, SSRI during pregnancy, child’s sex, gestational age and birth weight.
Dreier (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 (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).
Dudukina (Controls exposed to LTG) (Mixed indications), 2023	population based cohort retrospective	Data were obtained from the national health databases, including prescription registries, and linked at secure servers of the participating countries. Population-based healthcare registries routinely captured dispensing of prescription medications to pregnant women.	Data were obtained from the national health databases, including birth registries, patient registries and psychiatric registries (diagnoses are registered based on the International Classification of Diseases, 9th revision (ICD-9) or 10th revision (ICD-10)).	Calendar year of delivery; maternal age; marital/cohabiting status; smoking during pregnancy; obesity; single or multiple gestation; hospital-recorded morbidity; indicators of maternal healthcare utilization in the 12 previous months; for congenital malformations outcome: maternal medication use. Exclusion of births with exposure to medications known as potentially teratogenic.
Dudukina (Controls unexposed, NOS) (Mixed indications), 2023	population based cohort retrospective	Data were obtained from the national health databases, including prescription registries, and linked at secure servers of the participating countries. Population-based healthcare registries routinely captured dispensing of prescription medications to pregnant women.	Data were obtained from the national health databases, including birth registries, patient registries and psychiatric registries (diagnoses are registered based on the International Classification of Diseases, 9th revision (ICD-9) or 10th revision (ICD-10)).	Calendar year of delivery; maternal age; marital/cohabiting status; smoking during pregnancy; obesity; single or multiple gestation; hospital-recorded morbidity; indicators of maternal healthcare utilization in the 12 previous months; for congenital malformations outcome: maternal medication use. Exclusion of births with exposure to medications known as potentially teratogenic.
Källén (Controls exposed to Lamotrigine, sick) (Indications NOS), 2013	population based cohort retrospective	At the midwife interview at the first antenatal care visit, the woman was asked if she had used any drugs since she became pregnant. Or determined by the use of the Swedish Register of Prescribed Drugs (since 2006).	The Swedish Medical Birth Registry contain information based on standardized medical records from the first and further antenatal visit, the delivery and the paediatric examination. Supplemented with data from the Register of Birth Defects and Hospital Discharge Register.	No adjustment.
Källén (Controls unexposed, NOS) (Indications NOS), 2013	population based cohort retrospective	At the midwife interview at the first antenatal care visit, the woman was asked if she had used any drugs since she became pregnant. Or determined by the use of the Swedish Register of Prescribed Drugs (since 2006).	The Swedish Medical Birth Registry contain information based on standardized medical records from the first and further antenatal visit, the delivery and the paediatric examination. Supplemented with data from the Register of Birth Defects and Hospital Discharge Register.	No adjustment.
Kaskal (Indications NOS), 2024	cohort	Health information of the patients was acquired from the health recordings and through telephone from the infants’ mothers (no other details).	Health information of the patients was acquired from the health recordings and through telephone from the infants’ mothers (no other details).	No adjustment. The exclusion criteria for both groups were to use a known major teratogenic drug during pregnancy.
Kilic (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014	population based cohort retrospective	The Danish Register of Medicinal Product Statistics holds information on all redeemed prescriptions. Monotherapy exposure was defined as redemption of prescription for one type of AED with the Anatomical Therapeutic Codes.	The Danish Medical Birth Registry contains data on newborn babies including information on gestational age at birth, birth weight, and head circumference.	No adjustment for this group of comparison.
Kilic (Controls unexposed NOS) (Mixed indications), 2014	population based cohort retrospective	The Danish Register of Medicinal Product Statistics holds information on all redeemed prescriptions. Monotherapy exposure was defined as redemption of prescription for one type of AED with the Anatomical Therapeutic Codes.	The Danish Medical Birth Registry contains data on newborn babies including information on gestational age at birth, birth weight, and head circumference.	No adjustment for this group of comparison.
Kilic (Controls unexposed, sick) (Mixed indications), 2014	population based cohort retrospective	The Danish Register of Medicinal Product Statistics holds information on all redeemed prescriptions. Monotherapy exposure was defined as redemption of prescription for one type of AED with the Anatomical Therapeutic Codes.	The Danish Medical Birth Registry contains data on newborn babies including information on gestational age at birth, birth weight, and head circumference.	No adjustment for this group of comparison.
Madley-Dowd_SE (Pregabalin) (Controls exposed to LTG) (Mixed indications), 2024	population based cohort retrospective	Self-reported maternal consumption of antiseizure medications were prospectively recorded at antenatal care visits (from a structured interview at the first visit at 8–10 weeks of gestation, supplemented from 2005 with drug all prescription dispensations in Sweden (tetrachoric correlation 0.98).	Inpatient and specialized outpatient diagnoses were obtained using ICD-8/9/10 codes from the National Patient Registry, and to further identify cases of ADHD, prescription information on licensed ADHD medications was also incorporated.	Adjusted for ASM presumed indication, any maternal neurodevelopmental diagnoses, maternal age, residential region, hazardous drinking or illicit drug use during pregnancy, gravidity, maternal health care use and seizure events (year before pregnancy), use of antipsychotics/ antidepressants (year before pregnancy), hyperemesis or antiemetic prescriptions, year of birth and socioeconomic position.
Madley-Dowd_SE (Pregabalin) (Controls unexposed, general pop) (Mixed indications), 2024	population based cohort retrospective	Self-reported maternal consumption of antiseizure medications were prospectively recorded at antenatal care visits (from a structured interview at the first visit at 8–10 weeks of gestation, supplemented from 2005 with drug all prescription dispensations in Sweden (tetrachoric correlation 0.98).	Inpatient and specialized outpatient diagnoses were obtained using ICD-8/9/10 codes from the National Patient Registry, and to further identify cases of ADHD, prescription information on licensed ADHD medications was also incorporated.	Adjusted for ASM presumed indication, any maternal neurodevelopmental diagnoses, maternal age, residential region, hazardous drinking or illicit drug use during pregnancy, gravidity, maternal health care use and seizure events (year before pregnancy), use of antipsychotics/ antidepressants (year before pregnancy), hyperemesis or antiemetic prescriptions, year of birth and socioeconomic position.
Madley-Dowd_SE (Pregabalin) (Controls unexposed, sibling) (Mixed indications), 2024	population based cohort retrospective	Self-reported maternal consumption of antiseizure medications were prospectively recorded at antenatal care visits (from a structured interview at the first visit at 8–10 weeks of gestation, supplemented from 2005 with drug all prescription dispensations in Sweden (tetrachoric correlation 0.98).	Inpatient and specialized outpatient diagnoses were obtained using ICD-8/9/10 codes from the National Patient Registry, and to further identify cases of ADHD, prescription information on licensed ADHD medications was also incorporated.	Adjusted for ASM presumed indication, any maternal neurodevelopmental diagnoses, maternal age, residential region, hazardous drinking or illicit drug use during pregnancy, gravidity, maternal health care use and seizure events (year before pregnancy), use of antipsychotics/ antidepressants (year before pregnancy), hyperemesis or antiemetic prescriptions, year of birth and socioeconomic position.
Madley-Dowd_UK (Pregabalin) (Controls exposed to LTG) (Mixed indications), 2024	retrospective cohort (claims database)	Prescriptions were identified from primary care records.	Diagnoses were obtained from primary care records using Read codes for all patients and from inpatient and outpatient Hospital Episode Statistics (HES) using ICD-10 codes. For ADHD, prescription on ADHD medications (methylphenidate, dexamfetamine, lisdexamfetamine and atomoxetine) was incorporated.	Adjusted for ASM presumed indication, any maternal neurodevelopmental diagnoses, maternal age, residential region, hazardous drinking or illicit drug use during pregnancy, gravidity, maternal health care use and seizure events (year before pregnancy), use of antipsychotics/ antidepressants (year before pregnancy), hyperemesis or antiemetics, year of birth and socioeconomic position.
Madley-Dowd_UK (Pregabalin) (Controls unexposed, general pop) (Mixed indications), 2024	retrospective cohort (claims database)	Prescriptions were identified from primary care records.	Diagnoses were obtained from primary care records using Read codes for all patients and from inpatient and outpatient Hospital Episode Statistics (HES) using ICD-10 codes. For ADHD, prescription on ADHD medications (methylphenidate, dexamfetamine, lisdexamfetamine and atomoxetine) was incorporated.	Adjusted for ASM presumed indication, any maternal neurodevelopmental diagnoses, maternal age, residential region, hazardous drinking or illicit drug use during pregnancy, gravidity, maternal health care use and seizure events (year before pregnancy), use of antipsychotics/ antidepressants (year before pregnancy), hyperemesis or antiemetic prescriptions, year of birth and socioeconomic position.
Madley-Dowd_UK (Pregabalin) (Controls unexposed, sibling) (Mixed indications), 2024	retrospective cohort (claims database)	Prescriptions were identified from primary care records.	Diagnoses were obtained from primary care records using Read codes for all patients and from inpatient and outpatient Hospital Episode Statistics (HES) using ICD-10 codes. For ADHD, prescription on ADHD medications (methylphenidate, dexamfetamine, lisdexamfetamine and atomoxetine) was incorporated.	Sibling. Adjusted for ASM presumed indication, any maternal neurodevelopmental diagnoses, maternal age, residential region, hazardous drinking or illicit drug use during pregnancy, gravidity, maternal health care use and seizure events (year before pregnancy), use of antipsychotics/ antidepressants (year before pregnancy), hyperemesis or antiemetics, year of birth and socioeconomic position.
Margulis (Pregabalin) (Indications other than epilepsy), 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.
Patorno_MAX and MaketScan (Other indications), 2017	retrospective cohort (claims database)	The Medicaid Analytic Extract data include prescriptions filled on an outpatient basis.	The Medicaid Analytic Extract data include inpatient and outpatient diagnoses and procedure with codes from the ICD-9 in the maternal (first month after delivery) or infant (first 3 months afterdate of birth) record.	Adjusted for maternal age at delivery, race/ethnicity, year of delivery, smoking, multiple gestation, maternal conditions (n = 20 covariates), concomitant medication use (n = 19), and general markers of burden of disease (n = 8).
Razaz (Epilepsy), 2024	population based cohort retrospective	Prescription for antiseizure medication (ASM) was ascertained using nationwide prescription registers and identified ASMs based on Anatomical Therapeutic Chemical Classification.	All maternal and neonatal conditions were ascertained from each country’s Medical Birth Register, Patient Register, and Cause of Death Register records, according to the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10).	Singleton only. Adjusted for maternal age, parity, birth year, child’s sex, mother’s education, marital status, country, maternal prepregnancy psychiatric comorbidity, number of somatic diagnoses, and hospitalizations in the year preceding pregnancy.
The NAAED (Controls exposed to LTG) (Indications NOS), 2023	prospective cohort	Women are interviewed at enrollment, at 7 months’ gestation and at 8 –12 weeks after the expected date of delivery. The computer-assisted interviews include questions on start and stop dates of each antiepileptic drugs taken, dose, frequency and changes in medication.	Women were questioned with a computer-assisted telephone interview 3 times and medical records were obtained. The written descriptions in the pediatricians’ examinations were reviewed separately by the clinical teratologist.	No adjustment for this group of comparison.
The NAAED (Controls unexposed, disease free) (Indications NOS), 2023	prospective cohort	Women are interviewed at enrollment, at 7 months’ gestation and at 8 –12 weeks after the expected date of delivery. The computer-assisted interviews include questions on start and stop dates of each antiepileptic drugs taken, dose, frequency and changes in medication.	Women were questioned with a computer-assisted telephone interview 3 times and medical records were obtained. The written descriptions in the pediatricians’ examinations were reviewed separately by the clinical teratologist.	Not specified.
Vajda (Controls exposed to Lamotrigine, sick), 2019	prospective cohort	Details are obtained by four in-depth telephone interviews with the women. Details provided by the participants are confirmed, as far as possible, by the treating medical practitioners and through hospital records.	Details are obtained by four in-depth telephone interviews with the women. Details provided by the participants are confirmed, as far as possible, by the treating medical practitioners and through hospital records.	None.
Vajda (Controls unexposed, sick), 2019	prospective cohort	Details are obtained by four in-depth telephone interviews with the women. Details provided by the participants are confirmed, as far as possible, by the treating medical practitioners and through hospital records.	Details are obtained by four in-depth telephone interviews with the women. Details provided by the participants are confirmed, as far as possible, by the treating medical practitioners and through hospital records.	None.
Veiby (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014	population based cohort retrospective	A standardised notification form is filled in from the first prenatal visit with the general practitioner until discharge and transferred to the database by practitioners attending the delivery. (According to ATC Classification System).	A standardised notification form is filled in from the first prenatal visit until discharge and transferred to the database by practitioners attending the delivery. (Coded according to ICD-10). Additional information on congenital malformations came from Norwegian pediatric wards.	No adjustment for this group of comparison.
Veiby (Controls unexposed, disease free) (Mixed indications), 2014	population based cohort retrospective	A standardised notification form is filled in from the first prenatal visit with the general practitioner until discharge and transferred to the database by practitioners attending the delivery. (According to ATC Classification System).	A standardised notification form is filled in from the first prenatal visit until discharge and transferred to the database by practitioners attending the delivery. (Coded according to ICD-10). Additional information on congenital malformations came from Norwegian pediatric wards.	No adjustment for this group of exposure.
Veiby (Controls unexposed, sick) (Mixed indications), 2014	population based cohort retrospective	A standardised notification form is filled in from the first prenatal visit with the general practitioner until discharge and transferred to the database by practitioners attending the delivery. (According to ATC Classification System).	A standardised notification form is filled in from the first prenatal visit until discharge and transferred to the database by practitioners attending the delivery. (Coded according to ICD-10). Additional information on congenital malformations came from Norwegian pediatric wards.	No adjustment for this group of comparison.
Winterfeld (Other indications), 2016	prospective cohort	Information on medication exposure were collected at initial contact during pregnancy, and so before the outcome was known.	Follow-up was achieved through a structured telephone interview or mailed questionnaire to the patient or her health care professional. Two blinded independent specialists classified birth defects as major or minor using 2 standard classifications.	Matched according to center, year of contact, maternal age, and stage of pregnancy at time of call. No adjustment for this group of exposure.

master protocol