Clonazepam (Psy and Mixed indications)

Study	Type of data	Exposure measurement	Outcome assessment	Adjustment
Bech (Indications other than epilepsy), 2014	population based cohort retrospective	Use of antiepileptic drugs are identified in the Danish Register of Medicinal Product Statistics which comprises records of all prescriptions redeemed.	The Danish medical birth registry includes information on all live births and stillbirths in Denmark. Spontaneous abortions were identified in the Danish national hospital discharge register. Diagnoses are classified based on the International classification of diseases.	Adjusted for maternal age (thirds), cohabitation (yes/no), income (dichotomised at the median), education (<10, 10-12, >12 years), history of severe mental disorder (yes/no), and history of drug misuse (yes/no).
Bech (Mixed indications), 2018	population based cohort propective	The Danish National Prescription Register was used to obtain data on redeemed prescriptions using Anatomical Therapeutic Chemical (ATC) codes.	The Danish Psychiatric Central Register and Danish National Patient Registry were used to identify children's learning disabilities diagnosis using ICD-10 codes for: mental retardation, specific development disorders, ASD, emotional/behavioural disorders or having special educational needs.	Adjustments were made for maternal age at birth, educational level, smoking status, epilepsy, affective disorders, other psychiatric disorders, birth year, preterm birth, Apgar score and birth weight relative to gestational age.
Bjørk (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.
Blotière (Indications other than epilepsy), 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.	Exclusion of twin pregnancies. For major congenital malformations (MCMs) with <5 cases per treatment group, authors calculated crude odds ratios with exact confidence intervals. For MCMs 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 (Indications NOS), 2013	population based cohort propective	The Danish Prescription Register holds information on prescriptions. Monotherapy exposure was defined as redemption of prescription for one type of AED with the Anatomical Therapeutic Codes.	The Danish Psychiatric Central Register was used to identify children's diagnosis : ICD-10 codes F84.0, F84.1, F84.5, F84.8, and F84.9 for autism spectrum disorder and F84.0 for childhood autism. And also the National Hospital Register to identify children diagnosed with congenital malformations.	Adjusted for risk factors for autism (parental age at conception, parental psychiatric history, gestational age, birth weight, sex of the child, congenital malformations, and parity).
Christensen (Indications NOS), 2019	population based cohort propective	The Danish Prescription Register holds information on prescriptions. Monotherapy exposure was defined as redemption of prescription for one type of AED with the Anatomical Therapeutic Codes.	The Danish Psychiatric Central Register was used to identify children's diagnosis : ICD-10 codes F90 and F98.8 for ADHD. And also the Danish National Prescription Registry to identify offspring who used medication that is used for ADHD treatment.	Adjusted for maternal age at conception, maternal psychiatric history, maternal diabetes, sex of the child, year of birth, and parity.
Christensen (Indications other than 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.
Christensen (Mixed indications), 2015	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 antiepileptic drugs with the Anatomical Therapeutic Codes (ATC code) N03A (AEDs) and N05BA09 (clobazam).	The Danish Medical Birth Registry contains data on newborn children including information on gestational age and Apgar score (0–10) at birth (5 min).	Singletons only. No adjustment (results adjusted for maternal age and smoking, but when analysing individual drugs, there were too few exposed cases to allow for adjusted estimates).
Coste (Indications other than epilepsy), 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.	Neurodev: adjusted for: mother’s age, Complementary Universal Health Insurance, 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.
Elkjaer (Indications, NOS), 2018	population based cohort propective	Information on medical exposure was retrieved from the Danish Register of Medicinal Product Statistics. Authors identified antiepileptic drugs with ATC codes N03A (AEDs) and N05BA09 (clobazam).	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. Congenital malformations were defined as diagnoses based on ICD-10 Q0 to Q99.	Adjusted for test year, child sex, and maternal education and household income at birth.
Eros (Indications NOS), 2002	case control	Exposure data collected from 3 sources: a post-paid structured questionnaire sent to the parents immediately after the selection of cases/controls; maternal prenatal care logbook (in which obstetricians must record all prescribed drugs); nurses visited non-responding families.	The Hungarian Congenital Abnormality Registry (HCAR), in which notification by physicians of cases with Congenital anomalies is mandatory (including infant deaths and usual stillborn fetuses). Controls were selected from the National Birth Registry of the Central Statistical Office.	Controls matched to every case according to sex, birth week in the year when the case was born, and district of parents’ residence. No adjustment for this group of exposure.
Källén (Indications NOS), 2013	population based cohort retrospective	At the midwife interview at the first antenatal care visit, the woman was asked if she had used any drugs since she became pregnant. Or determined by the use of the Swedish Register of Prescribed Drugs (since 2006).	The Swedish Medical Birth Registry contain information based on standardized medical records from the first and further antenatal visit, the delivery and the paediatric examination. Supplemented with data from the Register of Birth Defects and Hospital Discharge Register.	Adjustment was made for year of birth, maternal age (5-year class), parity, smoking in early pregnancy and body mass index.
Kilic (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.	Singletons only. Adjusted for potential confounding factors, including maternal age, smoking, substance abuse, cohabitation, income, education, and parity.
Noh (Mixed indications), 2022	population based cohort retrospective	The Health Insurance Review and Assessment Service (HIRA) database that comprises notably healthcare utilization (e.g., drug prescription and medical procedure).	Major congenital malformations were identified by diagnostic records, according to the ICD-10 codes defined by the European Surveillance of Congenital Anomalies classification.	Exclusion of exposures to known teratogens during 1st trimester. Adjusted for maternal age, type of insurance, maternal psychiatric conditions (e.g., bipolar disorder, depression/mood disorder, anxiety, and sleep disorder), maternal conditions (e.g., epilepsy, headache, diabetes, hypertension), parity, plurality, concomitant medications (e.g., antidepressants, ...), and healthcare utilization.
Oberlander (Controls unexposed, disease free) (Indications other than epilepsy), 2004	prospective cohort	Measure of plasma level of maternal SSRI medications.	Concern about respiratory or other symptoms on the part of the family physician, midwife or obstetrician led to assessment by the pediatrician. Physicians who had been asked to assess distressed newborns were partially blinded to the infants' prenatal exposure status. Physician reviewed chart.	None. Maternal age and gravidity did not vary significantly between subject groups.
Oberlander (Controls unexposed, sick) (Indications other than epilepsy), 2004	prospective cohort	Measure of plasma level of maternal SSRI medications.	Concern about respiratory or other symptoms on the part of the family physician, midwife or obstetrician led to assessment by the pediatrician. Physicians who had been asked to assess distressed newborns were partially blinded to the infants' prenatal exposure status. Physician reviewed chart.	None. Maternal age and gravidity did not vary significantly between subject groups.
Sheehy (Indications NOS), 2019	nested case control	The Quebec Public Prescription Drug Insurance Plan database (drug name, start date, dose, and duration).	The data sources included the medical service database the Régie de l’assurance maladie du Québec (diagnoses, medical procedures, ...) and the MedEcho database (in-hospital diagnoses and procedures, including gestational age for planned abortions, spontaneous abortions, and deliveries).	Adjusted for (1) maternal sociodemographic variables (2) maternal chronic conditions (hypertension, diabetes, depression/anxiety, alcohol ...), (3) health care resources utilization, (4) pregnancy-associated variables, (5) concomitant exposure to antidepressants and/or antipsychotics. Matched by gestational age and calendar year. Exclusion of women with epilepsy and exposed to known teratogens.
The NAAED (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.	None.
Tinker (Mixed indications), 2019	case control	Detailed information notably about medication use during pregnancy (including over-the-counter (OTC) and prescription medication) was collected from the mothers via computer-assisted telephone interviews conducted between 6 weeks and 24 months after the estimated date of delivery (EDD).	Cases were identified in the The National Birth Defects Prevention Study. The NBDPS clinical data for birth defect cases were abstracted from medical records and classified by clinical experts. Controls were selected from birth certificates or hospital records in the same area.	For associations with at least 5 exposed cases: adjusted for maternal age, race/ethnicity, maternal education, any maternal cigarette smoking or antidepressant medication use in the first trimester (no adjustment if < 5 cases). Exclusion of mothers who reported use of an antiepileptic other than a benzodiazepine in the first trimester.
Veiby (Mixed indications), 2014	population based cohort retrospective	A standardised notification form is filled in from the first prenatal visit with the general practitioner until discharge and transferred to the database by practitioners attending the delivery. (According to ATC Classification System).	A standardised notification form is filled in from the first prenatal visit until discharge and transferred to the database by practitioners attending the delivery. (Coded according to ICD-10). Additional information on congenital malformations came from Norwegian pediatric wards.	Adjusted for maternal age, parity, smoking, folate supplementation, and maternal chronic disease other than epilepsy.

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