Clonazepam (Psy and Mixed indications) - Medication and Pregnancy KB

Clonazepam (Psy and Mixed indications)

Exposed non-exposed studies (cohort)

Study	Country Study period	Population source	Exposure definition	Non-exposure definition	Sample size	Rmk
Bech (Indications other than epilepsy), 2014	Denmark 1997 - 2008	All clinically recognised pregnancies with an estimated date of conception and a known pregnancy outcome during the study period.	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.	219 / 812862	Data for women without epilepsy. High daily dose for different drugs was defined as: clonazepam >4 mg/day.
Bech (Mixed indications), 2018	Denmark 2005 - 2008	All births in Denmark were identified during the study period in the Danish Medical Birth Register and only offspring of mothers exposed to antiepileptic drugs were included.	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.	43 / 434
Bjørk (Mixed indications), 2022	Danemark, Finland, Iceland, Norway and Sweden. 1996 - 2017	Singleton births born from mothers from five Nordic countries.	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.	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.
Blotière (Indications other than epilepsy), 2019	France 2011 - 2015	All pregnancies ending between the study period with at least 20 weeks of gestation.	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.	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.
Christensen (Indications NOS), 2013	Denmark 1996 - 2006	All children born alive in Denmark during the study period.	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.	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.
Christensen (Indications NOS), 2019	Denmark 1997 - 2011	All singleton children born alive in Denmark during the study period.	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.	314 / 899941	Indications not specified.
Christensen (Indications other than epilepsy), 2024	Denmark, Finland, Iceland, Norway, and Sweden 1996 - 2017	All live-born singletons born of women without epilepsy in the included countries during the study periods.	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.	1019 / 4445621	Denmark (1997–2017), Finland (1996–2016), Iceland (2004–2017), Norway (2005–2017), and Sweden (2006–2017).
Christensen (Mixed indications), 2015	Denmark 1997 - 2008	All singleton live born children in Denmark during the study period.	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)).	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.
Coste (Indications other than epilepsy), 2020	France 2011 - 2014	All liveborn singleton children born during the study period. The mother had to be covered by the national health insurance general scheme for salaried workers and to have had at least one health expenditure reimbursement over the 2 years preceding the onset of pregnancy.	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.	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.
Elkjaer (Indications, NOS), 2018	Denmark 1997 - 2006	All children born alive in Denmark between the study period.	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.	188 / 477162	There is no information about the exposure indication.
Källén (Indications NOS), 2013	Swedish 1996 - 2011	Nearly all births in Sweden during the study period (1,575,847) are registered in The Swedish Medical Birth 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.	106 / 1575847	Indications for antiepileptic drugs are not specified. Follow-up period known thanks to author's email reply.
Kilic (Mixed indications), 2014	Denmark 1997 - 2008	All singleton live-born children in Denmark during the study period.	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.	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.
Noh (Mixed indications), 2022	South Korea 2011 - 2018	All pregnancies in women aged 20 to 45 years at delivery resulting in live births from 1 January 2011 to 31 December 2018, in South Korea.	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).	1454 / 3053381	Propensity scored adjusted for indications and led to an unexposed cohort with similar psychiatric conditions => considered as unexposed, sick control groups.
Oberlander (Controls unexposed, disease free) (Indications other than epilepsy), 2004	Canada 1996 - 2000	Mothers and their infants studied during pregnancy as a part of a larger study of the effects of psychotropic medication use during and following pregnancy.	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).	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).
Oberlander (Controls unexposed, sick) (Indications other than epilepsy), 2004	Canada 1996 - 2000	Mothers and their infants studied during pregnancy as a part of a larger study of the effects of psychotropic medication use during and following pregnancy.	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.	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).
The NAAED (Indications NOS), 2023	North America and Canada 1997 - 2023	Pregnant women who are taking an antiepileptic drug for any reason and had a liveborn infant, a stillborn infant, or a pregnancy terminated because of a fetal abnormality and enrolled as 'pure' or 'traditional' enrollees.	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.	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.
Veiby (Mixed indications), 2014	Norway 1999 - 2011	All deliveries in Norway at 12 or more weeks of gestation, recorded in the database during the study period.	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.	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)

Case-control studies (cohort)

Study	Country Study period	Case	Control	Sample size	Rmk
Eros (Indications NOS), 2002	Hungary 1980 - 1996	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.	22865 / 38151
Sheehy (Indications NOS), 2019	Canada 1998 - 2015	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.	27149 / 134305
Tinker (Mixed indications), 2019	USA 1997 - 2011	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.	-9 / 11614	Total number of cases not provided by authors (number of cases provided for each kind of malformations or group of malformations).

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