Clonazepam (Psy and Mixed indications)

Exposed non-exposed, cohort studies

Study Country
Study period
Study design		 Data source Exposure definition Non-exposure definition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias
Bech (Indications other than epilepsy)
2014 		Denmark
1997 - 2008
population based cohort retrospective 		The Danish medical birth register, the Danish national hospital discharge register and the Danish Register of Medicinal Product Statistics. Pregnancies that never having a diagnosis of epilepsy and with a prescription of clonazepam redeemed during pregnancy. unexposed (general population or NOS)
Pregnancies that did not redeem any antiepileptic drug prescription in the exposure window. 		1st and 2nd trimester 219 / 812862 Data for women without epilepsy. High daily dose for different drugs was defined as: clonazepam >4 mg/day.
Use of antiepileptic drugs are identified in the Danish Register of Medicinal Product Statistics which comprises records of all prescriptions redeemed.
Bech (Mixed indications)
2018 		Denmark
2005 - 2008
population based cohort propective 		The Danish Prescription Register, the Danish Medical Birth Register, the Danish Psychiatric Central Research Register and Danish National Patient Registry. Singleton offspring of mothers exposed to clonazepam monotherapy within 90 days prior to conception to birth. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Singleton offspring of mothers exposed to antiepileptic drugs at any time but not during pregnancy. 		during pregnancy (anytime or not specified) 43 / 434
The Danish National Prescription Register was used to obtain data on redeemed prescriptions using Anatomical Therapeutic Chemical (ATC) codes.
Bjørk (Mixed indications)
2022 		Danemark, Finland, Iceland, Norway and Sweden.
1996 - 2017
population based cohort retrospective 		Social register data from Danemark, Finland, Iceland, Norway, Sweden for SCAN-AED: Nordic register-based study of antiepileptic drugs in pregnancy. Pregnacies in mothers filling at least one clonazepam (antiepileptic) monotherapy prescription from her last menstrual period until birth. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Pregnacies in mothers without antiseizure medication prescription from her last menstrual period until birth. 		during pregnancy (anytime or not specified) 1182 / 4463879 Overlapping between Daugaard 2020 and Bjork 2022 for Intellectual disabilities (2 outcomes), and Christensen 2013 and Bjork for ASD (2 outcomes) with more pregnancies in Bjork 2022 => use of Bjork 2022 data.
Prescriptions through national prescription registers according to Anatomical Therapeutic Chemical classification codes N03, N05BA09, and S01EC01.
Blotière (Indications other than epilepsy)
2019 		France
2011 - 2015
retrospective cohort (claims database) 		The French national health insurance database (DCIR) and the French hospital discharge database (PMSI). Pregnancies exposed to clonazepam (antiepileptic) monotherapy between 1 month before and 2 months after the beginning of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Pregnancies with no reimbursement for antiepileptic drugs. 		1st trimester 980 / 1875733 Authors excluded twin pregnancies and pregnancies with a chromosomal abnormality identified. Less than 10% of exposed pregnancies have a proxy for epilepsy. Publication's OR were not kept when lower limit of the confidence interval or OR equal to 0.
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.
Christensen (Indications NOS)
2013 		Denmark
1996 - 2006
population based cohort propective 		The Danish Civil Registration System, the Medical Birth Register and the Danish Register of Medicinal Product Statistics. Children whose mothers have been exposed to clonazepam in (antiepileptic) monotherapy during the exposure window defined from 30 days before the estimated day of conception to the day of birth. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Children whose mothers haven't been exposed to clonazepam during the exposure window defined from 30 days before the estimated day of conception to the day of birth. 		during pregnancy (anytime or not specified) 269 / 655233 Overlapping: For ASD diagnosis/risk : data of Christensen 2013 included in Bjork 2022 because longer study period and 5 countries => use of Bjork 2022 data. Indications not specified.
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.
Christensen (Indications NOS)
2019 		Denmark
1997 - 2011
population based cohort propective 		The Danish Psychiatric Central Research Register, the Danish National Prescription Registry, the Danish Civil Registration System and the Danish Medical Birth Registry. Children whose mothers have been exposed to clonazepam in (antiepileptic) monotherapy during the exposure window defined from 30 days before the estimated day of conception to the day of birth. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Children whose mothers haven't been exposed to antiepileptic drugs during the exposure window defined from 30 days before the estimated day of conception to the day of birth. 		during pregnancy (anytime or not specified) 314 / 899941 Indications not specified.
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.
Christensen (Indications other than epilepsy)
2024 		Denmark, Finland, Iceland, Norway, and Sweden
1996 - 2017
population based cohort retrospective 		Nordic population-based cohort study including register data from Denmark, Finland, Iceland, Norway, and Sweden–the SCAN-AED project. Children of mothers without epilepsy who had redeemed at least one prescription of Clonazepam monotherapy from 30 days before the first day of the last menstrual period to the date of birth (i.e., the exposure period). unexposed (general population or NOS)
Children of mothers without epilepsy who had not redeemed prescription of anti-seizure medication. 		during pregnancy (anytime or not specified) 1019 / 4445621 Denmark (1997–2017), Finland (1996–2016), Iceland (2004–2017), Norway (2005–2017), and Sweden (2006–2017).
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.
Christensen (Mixed indications)
2015 		Denmark
1997 - 2008
population based cohort retrospective 		The Danish Civil Registration System, the Danish Medical Birth Registry and the Danish Register of Medicinal Product Statistics. Children whose mothers have been exposed to clonazepam (in antiepileptic monotherapy) during the exposure window defined from 30 days before the estimated day of conception to the day prior to birth. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Children whose mothers have not been exposed to antiepileptic drugs (N03A (AEDs) and N05BA09 (clobazam)). 		during pregnancy (anytime or not specified) 260 / 674115 76% of all exposed mothers have epilepsy (no specific information for clonazepam). Authors reported data for mono and/or polytherapy => Use of monotherapy data.
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).
Coste (Indications other than epilepsy)
2020 		France
2011 - 2014
retrospective cohort (claims database) 		The French national health data system (SNDS) Children born from mothers exposed to clonazepam monotherapy (antiepileptic) with at least one dispensing between the month preceding onset of pregnancy and its end. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Children born from mothers not exposed to any antiepileptic drug during pregnancy. 		during pregnancy (anytime or not specified) 1246 / 1710441 Overlapping: Blotiere 2020 and Coste 2020 => same data, with more outcomes in Coste 2020. The number of women considered to be treated for epilepsy and exposed to monotherapy for clonazepam <100 => Mainly (>90%) indications other than epilepsy.
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.
Elkjaer (Indications, NOS)
2018 		Denmark
1997 - 2006
population based cohort propective 		The Danish Civil Registration System, the Danish Medical Birth Registry, the Danish Agency for Information Technology and Learning, the Danish Register of Medicinal Product Statistics. Children with clonazepam monotherapy (among antiepileptics) prescribed and redeemed within the exposure window defined from 30 days before the first day of the last menstrual period to 1 day before birth. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Children unexposed to any antiepileptic drugs in pregnancy. 		during pregnancy (anytime or not specified) 188 / 477162 There is no information about the exposure indication.
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).
Källén (Indications NOS)
2013 		Swedish
1996 - 2011
population based cohort retrospective 		The Swedish Medical Birth Register, the Swedish Register of Prescribed Drugs, the Register of Birth Defect and Hospital Discharge Register. Infants whose mothers used clonazepam in (antiepileptic) monotherapy in early pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Infants in population whose mothers used at least one of a central nervous system active drugs (less than 3%) or weren't exposed in early pregnancy. 		early pregnancy 106 / 1575847 Indications for antiepileptic drugs are not specified. Follow-up period known thanks to author's email reply.
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).
Kilic (Mixed indications)
2014 		Denmark
1997 - 2008
population based cohort retrospective 		The Danish Medical Birth Registry, the Danish Civil Registration System, the Danish National Hospital Registry, and the Danish Register of Medicinal Product Statistics. Children whose mothers have been exposed to clonazepam (in antiepileptic monotherapy) during the exposure window defined from 30 days before the estimated day of conception to the day prior to birth. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Children whose mothers have not been exposed to antiepileptic drugs ((ATC) N03A (AEDs) and N05BA09 (clobazam)) 30 days before the estimated day of conception to the day of birth. 		during pregnancy (anytime or not specified) 262 / 676834 Less than 90% of women are epileptic. For LBW and SGA: overlapping between Kilic (1997 - 2008) and Christensen (1997–2017), with more pregnancies in Christensen => LBW and SGA not reported here.
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.
Noh (Mixed indications)
2022 		South Korea
2011 - 2018
population based cohort retrospective 		A nationwide retrospective cohort study using healthcare data retrieved from the Health Insurance Review and Assessment Service (HIRA) database. Pregnant women who filled at least Clonazepam prescription during the first trimester (first 90 days of pregnancy). unexposed, sick
Pregnant women who were not prescribed any benzodiazepine from 3 months before the last menstrual period to the end of the first trimester (with similar psychiatric conditions after propensity score). 		1st trimester 1454 / 3053381 Propensity scored adjusted for indications and led to an unexposed cohort with similar psychiatric conditions => considered as unexposed, sick control groups.
The Health Insurance Review and Assessment Service (HIRA) database that comprises notably healthcare utilization (e.g., drug prescription and medical procedure).
Oberlander (Controls unexposed, disease free) (Indications other than epilepsy)
2004 		Canada
1996 - 2000
prospective cohort 		The British Columbia Women's Hospital (Vancouver, British Columbia). Infants prenatally exposed to Selective serotonin reuptake inhibitors (SSRIs) combined with the benzodiazepine clonazepam. unexposed, disease free
Term-born infants whose mother did not use psychotropic or antidepressant medications during pregnancy, without history of maternal mental illness and with no other serious comorbid pathology). 		during pregnancy (anytime or not specified) 18 / 23 Overlapping: psychomotor and cognitive outcomes in Reebye 2002; 2012 and special neonatal care in Misri 2004 totally included in Oberlander 2004 thus these outcomes extracted from Oberlander 2004 (more details and little more exposures).
Measure of plasma level of maternal SSRI medications.
Oberlander (Controls unexposed, sick) (Indications other than epilepsy)
2004 		Canada
1996 - 2000
prospective cohort 		The British Columbia Women's Hospital (Vancouver, British Columbia). Infants prenatally exposed to Selective serotonin reuptake inhibitors (SSRIs) combined with the benzodiazepine clonazepam. unexposed, sick
Infants prenatally exposed to Selective serotonin reuptake inhibitors (SSRIs) alone. 		during pregnancy (anytime or not specified) 18 / 28 Overlapping: psychomotor and cognitive outcomes in Reebye 2002; 2012 and special neonatal care in Misri 2004 totally included in Oberlander 2004 thus these outcomes extracted from Oberlander 2004 (more details and little more exposures).
Measure of plasma level of maternal SSRI medications.
The NAAED (Indications NOS)
2023 		North America and Canada
1997 - 2023
prospective cohort 		The North American Antiepileptic Drug Pregnancy Register (NAAED). Infants of pregnant women who used Clonazepam as monotherapy, during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Infants of pregnant women, not taking an antiepileptic drug and without epilepsy, who were recruited from among the friends and family members of the enrolled women taking an antiepileptic drug. 		1st trimester 120 / 1330 Study design completed with the publication of Hernández-Díaz et al. 2012. Data extracted from the North American AED pregnancy registry website. Overlapping/update with Hernández-Díaz et al. 2012 and previous website reports. Use of internal control.
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.
Veiby (Mixed indications)
2014 		Norway
1999 - 2011
population based cohort retrospective 		The Medical Birth Registry of Norway and the Register of Pregnancy Terminations. Children exposed prenatally to clonazepam as (antiepileptic) monotherapy indicated for their mothers' epilepsy or other indications. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
All unexposed children born to women without epilepsy. 		throughout pregnancy 113 / 771412 Among the 113 pregnancies exposed to clonazepam, 40 were epileptic and 73 not => less than 90% of women are treated with Clonazepam for epilepsy (considered as a mixed of indications)
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).

Case-control studies

Study Country
Study period
Study design		 Data source Case Control Exposition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias
Eros (Indications NOS)
2002 		Hungary
1980 - 1996
case control 		The Hungarian Case–Control Surveillance of Congenital Abnormalities (HCCSCA). Newborn infants with isolated congenital abnormality (CA) and multiple CA. Exclusions of some mild congenital abnormalities and minor congenital abnormality (methods in Czeizel 1999). Two or three newborn infants without congenital anomalies matched to every case according to sex, birth week in the year when the case was born, and district of parents’ residence from the National Birth Registry of the Central Statistical Office. 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. during pregnancy (anytime or not specified) 22865 / 38151
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.
Sheehy (Indications NOS)
2019 		Canada
1998 - 2015
nested case control 		A nested case-control study within the Quebec Pregnancy Cohort, Montreal, Quebec, Canada. Pregnancies ending with spontaneous abortion (pregnancy loss between between the beginning of the sixth week of gestation and the 19th completed week of gestation, excluding planned or induced abortions). Pregnancies ending with live births (5 for each case) randomly selected at the index date and matched with the case pregnancy by gestational age and calendar year. The Quebec Public Prescription Drug Insurance Plan database (drug name, start date, dose, and duration). early pregnancy 27149 / 134305
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).
Tinker (Mixed indications)
2019 		USA
1997 - 2011
case control 		The National Birth Defects Prevention Study (NBDPS), a large population-based multicenter case–control study of major birth defects. Live bom, stillborn, or induced terminations with at least one of the 30 different birth defects (excluding chromosomal or monogenic disorders) diagnosed prenatally, at birth, or during the first year of life. Liveborn infants without major birth defects identified on the same catchment area and month of birth as the cases. 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). 1st trimester -9 / 11614 Total number of cases not provided by authors (number of cases provided for each kind of malformations or group of malformations).
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.

Risk of bias: : NA;   : low;   : moderate;   : serious;   : critical;   : unclear;  

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