Clonazepam (Epilepsy)

Study	Type of data	Exposure measurement	Outcome assessment	Adjustment
Al Bunyan (Epilepsy), 1999	retrospective cohort	The antenatal and perinatal records of the pregnant epileptic patients were examined.	Records and the post-partum examinations were carried out by a paediatrician who documented any congenital anomalies present.	Not specified.
Artama (Epilepsy) (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 (Epilepsy) (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 (Epilepsy) (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.	Singletons. Adjustment for maternal age at delivery, parity, university hospital district, socioeconomic status and major congenital anomalies.
Bànhidy (Epilepsy), 2011	case control	Mothers were mailed a questionnaire (after the selection of cases and controls) requested information on medicinal products taken during pregnancy and to send their prenatal maternity logbook and other medical records. Regional nurses were asked to visit and question the non-respondent.	Notification of cases with congenital abnormality is mandatory for physicians to the HCAR. Pathologists sent a copy of autopsy report for stillbirths and infant deaths cases and defect diagnosed in prenatal diagnostic centers with or without termination of pregnancy were also included.	Matched according to sex, birth week in the year when cases were born, and district of parents’ residence.
Battino (Epilepsy), 1992	prospective cohort	At least every 4 weeks throughout the pregnancy blood samples were taken for measurement of antiepileptic drugs concentrations.	Vital data of newborns at birth were recorded according to a standardized protocol; a more detailed clinical examination was performed on Day 5.	None.
Battino (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 (Epilepsy) (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 (Epilepsy) (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 (Epilepsy) (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.
Canger (Epilepsy), 1999	prospective cohort	The patients received monthly obstetric and neurologic examinations, and antiepileptic drug blood levels were tested monthly.	At the time of delivery the infants underwent a standardized examination by a pediatrician, and a more detailed clinical examination on day 5 in San Paolo Hospital only and during the first months in other hospitals (if so medical records were also acquired).	None.
Christensen (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 (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).
D'Souza (Epilepsy) (Controls unexposed, disease free), 1991	prospective cohort	Every two weeks, clinical assessment of seizure control, and adjustment of anticonvulsant dosage in accordance with serum drug concentration or clinical response.	Each infant was examined by a paediatrician and a geneticist, neither of whom was aware of whether the mother was in the study group or the control group.	Matched for maternal age, parity, and social class.
D'Souza (Epilepsy) (Controls unexposed, sick), 1991	prospective cohort	Every two weeks, clinical assessment of seizure control, and adjustment of anticonvulsant dosage in accordance with serum drug concentration or clinical response.	Each infant was examined by a paediatrician and a geneticist, neither of whom was aware of whether the mother was in the study group or the control group.	No matching for this group of exposure.
Díaz-Romero (Epilepsy), 1999	cohort	Not specified	The neonates were evaluated by the principal author who used a metallic calliper calibrated in millimeters and a glazed fiberglass tape for the head circumference. The measurements were performed twice and collected by a second observer; the final value was the average of both measurements.	None.
Dreier (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 (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).
Endo (Epilepsy) (Controls unexposed, disease free), 2004	retrospective cohort	Medical records.	Medical records.	None.
Endo (Epilepsy) (Controls unexposed, sick), 2004	retrospective cohort	Medical records.	Medical records.	Not specified.
Gopinath (Epilepsy), 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.
Guveli (Epilepsy), 2017	retrospective cohort	The clinical data of patients (dosages of AEDs used during pregnancy) were recorded retrospectively from patient files.	Echocardiography was checked by a pediatric cardiologist. Parents and children were examined and photographed by a medical geneticist. Children older than six months were examined by a pediatric dentist for developmental dental anomalies (blinded to exposure).	None.
Hvas (Epilepsy) (Controls unexposed, disease free), 2000	prospective cohort	Women completed a questionnaire. They were categorised as users or nonusers of anticonvulsant drugs, by self-reported daily intake of any anticonvulsant drug during the first trimester.	Women completed a questionnaire. Information about major congenital malformations was also collected.	Singleton only. All women who reported chronic disease other than epilepsy were excluded. No adjustment for this group of exposure.
Hvas (Epilepsy) (Controls unexposed, sick), 2000	prospective cohort	Women completed a questionnaire. They were categorised as users or nonusers of anticonvulsant drugs, by self-reported daily intake of any anticonvulsant drug during the first trimester.	Women completed a questionnaire. Information about major congenital malformations was also collected.	Singleton only. All women who reported chronic disease other than epilepsy were excluded. No adjustment for this group of exposure.
Kaaja (Epilepsy), 2003	prospective cohort	Follow-up of the pregnant women with epilepsy included assessment of serum concentration of antiepileptic drugs (AEDs) at the end of the first trimester. The serum concentrations of AED were known in 90.1% of the patients using these drugs.	Infants were examined by a neonatologist at birth and at discharge from the hospital and charts for the infants admitted to the pediatric clinic or in case of termination of pregnancy were reviewed. Autopsy was performed on stillbirth.	No adjustment for this group of exposure.
Morrow (Epilepsy) (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 (Epilepsy) (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.
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.
Robert (Epilepsy), 1986	retrospective cohort	Questionnaires were sent to women identified in hospital records and the second collection of data was obtained from 3 maternity with computerized records.	Questionnaires were sent to women identified in hospital records and the second collection of data was obtained from 3 maternity with computerized records.	None.
Samrén (Epilepsy), 1999	retrospective cohort	Data were collected from medical records and include medication. The prescribed dose of the drugs was also retrieved from obstetric files.	Data were collected from medical records and include information on pregnancy and child. Information on major congenital abnormalities was completed with information from the pediatrician whenever necessary.	Matched for age (±2 years) and parity of the mother, and sex, birth year, and hospital of delivery of the child.
Thomas (Epilepsy) (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 (Epilepsy) (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.
Vajda (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 (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.
Vajda a (Epilepsy) (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 (Epilepsy) (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.
Veiby (Epilepsy) (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 (Epilepsy) (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 (Epilepsy) (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.

master protocol