| Study | Country Study period |
Population source | Exposure definition | Non-exposure definition | Sample size | Rmk |
|---|---|---|---|---|---|---|
| Al Bunyan (Epilepsy), 1999 |
Saudi Arabia 1985 - 1994 |
Pregnant epileptic patients followed up in the neurology clinics during the study period. | Children whose epileptic mothers were exposed to clonazepam monotherapy during the pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Children whose epileptic mothers did not take antiepileptic drugs during the pregnancy because their seizures were in remission and as a personal preference. |
1 / 10 | The control group with the data of historical controls in Saudi Arabia isn't an adequate control group. |
| Artama (Epilepsy) (Controls exposed to Lamotrigine, sick), 2013 |
Finland 1996 - 2008 |
All singleton births (n = 751,139) in Finland during the study period. | Births in pregnant women with epilepsy exposed to clonazepam in monotherapy 1 month prior to pregnancy and/or any time during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Births in pregnant women with epilepsy exposed to lamotrigine in monotherapy 1 month prior to pregnancy and/or any time during pregnancy. |
14 / 173 | Overlapping: For LBW and SGA: Artama 2013 included in a larger study published by Christensen 2024 ((longer study period, 5 countries and more pregnancies) => use of Christensen 2024 for these outcomes. |
| Artama (Epilepsy) (Controls unexposed, disease free), 2013 |
Finland 1996 - 2008 |
All singleton births (n = 751,139) in Finland during the study period. | Births in pregnant women with epilepsy exposed to clonazepam in monotherapy 1 month prior to pregnancy and/or any time during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Births in pregnant women without epilepsy and unexposed to any antiepileptic drugs 1 month prior to pregnancy and/or any time during pregnancy. |
14 / 721948 | Overlapping: For LBW and SGA: Artama 2013 included in a larger study published by Christensen 2024 (longer study period, 5 countries and more pregnancies) => use of Christensen 2024 for these outcomes. |
| Artama (Epilepsy) (Controls unexposed, sick), 2013 |
Finland 1996 - 2008 |
All singleton births (n = 751,139) in Finland during the study period. | Births in pregnant women with epilepsy exposed to clonazepam in monotherapy 1 month prior to pregnancy and/or any time during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Births in pregnant women with epilepsy and unexposed to any antiepileptic drugs 1 month prior to pregnancy and/or any time during pregnancy. |
14 / 1800 | Overlapping: For LBW and SGA: Artama 2013 included in a larger study published by Christensen 2024 ((longer study period, 5 countries and more pregnancies) => use of Christensen 2024 for these outcomes. |
| Battino (Epilepsy), 1992 |
Italy 1977 - 1989 |
Epileptic patients were followed prospectively from the beginning of the pregnancy during the study period in the context of the Milan Collaborative Study on Epilepsy and Pregnancy. | Offspring of epileptic mothers treated with clonazepam monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Offspring of epileptic mothers with no antiepileptic drugs administered. |
6 / 9 | The results for the malformations are already available in Canger 1999 (a more recent publication with a larger exposed group) except for minor malformations. |
| Battino (Epilepsy), 2024 |
Worldwide (47 countries) 1999 - 2022 |
Pregnant women with epilepsy exposed to antiseizure medications at the time of conception and enrolled within the 16th week of gestation, where fetal outcome had not yet been determined. | Pregnant women with epilepsy exposed to Clonazepam monotherapy at the time of conception. |
exposed to other treatment, sick
Pregnant women with epilepsy exposed to lamotrigine monotherapy at the time of conception. |
52 / 3584 | Overlapping: Battino 2024 (1999-2022) updates and totally includes Tomson 2018 (1999-2016), Tomson 2011 and Jimenez 2020 (1 center in Spain 2000-2018) => Use of Battino 2024 for the 8 (plus 16 in eSupp) ASM monotherapies studied here. |
| Bjørk (Epilepsy) (Controls exposed to Lamotrigine, sick), 2022 |
Danemark, Finland, Iceland, Norway and Sweden. 1996 - 2017 |
Singleton births born from mothers from five Nordic countries. | Pregnacies in epileptic mothers filling at least one clonazepam monotherapy prescription from her last menstrual period until birth. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Pregnacies in epileptic mothers filling at least one lamotrigine monotherapy prescription from her last menstrual period until birth. |
318 / 5073 | Overlapping for ASD (2 outcomes) and Intellectual disabilities (2 outcomes): Dreier 2023 and Bjork 2022, with more pregnancies in Dreier 2023 => use of Dreier 2023 data. |
| Bjørk (Epilepsy) (Controls unexposed NOS), 2022 |
Danemark, Finland, Iceland, Norway and Sweden. 1996 - 2017 |
Singleton births born from mothers from five Nordic countries. | Pregnacies in epileptic mothers filling at least one clonazepam 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. |
318 / 4463879 | Overlapping for ASD (2 outcomes) and Intellectual disabilities (2 outcomes): Dreier 2023 and Bjork 2022, with more pregnancies in Dreier 2023 => use of Dreier 2023 data. |
| Bjørk (Epilepsy) (Controls unexposed, sick), 2022 |
Danemark, Finland, Iceland, Norway and Sweden. 1996 - 2017 |
Singleton births born from mothers from five Nordic countries. | Pregnacies in epileptic mothers filling at least one clonazepam 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, sick
Pregnacies in epileptic mothers without antiseizure medication prescription from her last menstrual period until birth. |
318 / 21634 | Overlapping for ASD (2 outcomes) and Intellectual disabilities (2 outcomes): Dreier 2023 and Bjork 2022, with more pregnancies in Dreier 2023 => use of Dreier 2023 data. |
| Canger (Epilepsy), 1999 |
Italy 1977 - 1996 |
517 women with epilepsy reffered to the study mainly from the Milan metropolitan and suburban areas or other Italian regions. They were followed up during the preconceptional period and/or from the beginning of pregnancy. | Infants of epileptic mothers exposed to clonazepam monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Infants of epileptic mothers unexposed to antiepileptic drugs during pregnancy. |
6 / 25 | Most women gave birth at the San Paolo Hospital. Only the first pregnancies of each of the 517 women were included in the analysis. |
| Christensen (Epilepsy) (Controls exposed to LTG), 2024 |
Denmark, Finland, Iceland, Norway, and Sweden 1996 - 2017 |
All live-born singletons born of women with epilepsy in the included countries during the study periods. | Children of mothers with 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). |
exposed to other treatment, sick
Children of mothers who had redeemed at least one prescription of Lamotrigine monotherapy from 30 days before the first day of the last menstrual period to the date of birth (i.e., the exposure period). |
339 / 5299 | Overlapping: For LBW and SGA: Christensen 2024 totally included Artama 2013 => use of Christensen 2024 for these outcomes (longer study period, 5 countries and more pregnancies). |
| Christensen (Epilepsy) (Controls unexposed, general population), 2024 |
Denmark, Finland, Iceland, Norway, and Sweden 1996 - 2017 |
All live-born singletons born of women with epilepsy in the included countries during the study periods. | Children of mothers with 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, sick
Children of mothers with epilepsy who had not redeemed prescription of anti-seizure medication. |
339 / 22227 | Overlapping: For LBW and SGA: Christensen 2024 totally included Artama 2013 => use of Christensen 2024 for these outcomes (longer study period, 5 countries and more pregnancies). |
| D'Souza (Epilepsy) (Controls unexposed, disease free), 1991 |
UK 1980 - 1982 |
A group of pregnant mothers each of whom gave a history of grand mal epilepsy and who were referred to the antenatal clinic during the study period. | Infants born to epileptic mothers treated with clonazepam alone throughout pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Infants born to mothers without epilepsy not taking any drugs regularly. |
1 / 62 | |
| D'Souza (Epilepsy) (Controls unexposed, sick), 1991 |
UK 1980 - 1982 |
A group of pregnant mothers each of whom gave a history of grand mal epilepsy and who were referred to the antenatal clinic during the study period. | Infants born to epileptic mothers treated with clonazepam alone throughout pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Infants whose mothers had a history of epilepsy but received no drugs during pregnancy. |
1 / 8 | |
| Díaz-Romero (Epilepsy), 1999 |
Mexico 1993 - 1996 |
Full-term eutrophic newborns of epileptic mothers who attended the Epilepsy Clinic of the National Institute of Perinatology, a third-level gyneco-obstetric center in Mexico City during the study period. | Full-term eutrophic newborns of epileptic mothers exposed to only clonazepam during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Offspring of epileptic women without seizures during pregnancy and without exposure to any drug. |
1 / 8 | All newborns in the intensive care unit, and those with congenital malformations with a different specific recognizable etiology were excluded. |
| Dreier (Epilepsy) (Controls exposed to LTG), 2023 |
Denmark, Finland, Iceland, Norway, and Sweden. 1996 - 2017 |
Live-born singleton children of mothers with epilepsy in Denmark (1997-2017), Finland (1996- 2016), Iceland (2004-2017), Norway (2005-2017), and Sweden (2006-2017). | Children prenatally exposed to Clonazepam monotherapy, i.e whose mother had redeemed 1 or more prescriptions during the exposure window, which was defined as 30 days before the first day of the last menstrual period (estimated using gestational age in days at birth) until the date of birth. |
exposed to other treatment, sick
Children prenatally exposed to Lamotrigine monotherapy, i.e whose mother had redeemed 1 or more prescriptions during the exposure window, which was defined as 30 days before the first day of the last menstrual period (estimated using gestational age in days at birth) until the date of birth. |
339 / 5288 | Overlapping for ASD (2 outcomes) and Intellectual disabilities (2 outcomes): Dreier 2023 and Bjork 2022, with more pregnancies in Dreier 2023 => use of Dreier 2023 data. |
| Dreier (Epilepsy) (Controls unexposed, sick), 2023 |
Denmark, Finland, Iceland, Norway, and Sweden. 1996 - 2017 |
Live-born singleton children of mothers with epilepsy in Denmark (1997-2017), Finland (1996- 2016), Iceland (2004-2017), Norway (2005-2017), and Sweden (2006-2017). | Children prenatally exposed to Clonazepam monotherapy, i.e whose mother had redeemed 1 or more prescriptions during the exposure window, which was defined as 30 days before the first day of the last menstrual period (estimated using gestational age in days at birth) until the date of birth. |
unexposed, sick
Children not prenatally exposed to antiseizure medication. |
339 / 22203 | Overlapping for ASD (2 outcomes) and Intellectual disabilities (2 outcomes): Dreier 2023 and Bjork 2022, with more pregnancies in Dreier 2023 => use of Dreier 2023 data. |
| Endo (Epilepsy) (Controls unexposed, disease free), 2004 |
Japan 1991 - 2000 |
Newborn of mothers with epilepsy at Yokohama City University Hospital during the study period and total deliveries excluding epilepsy cases of 1991 and 1992 at the same hospital. | Newborns of epileptic mothers who take clonazepam monotherapy for epilepsy throughout pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Newborns of nonepileptic mothers. |
1 / 656 | 30 (83.3%) cases of 36 pregnancies continued taking drugs throughout pregnancy. Three (8.3%) patients discontinued after week 13 of pregnancy. Some results do not coincide between table 1 and table 2 and are therefore not reported. |
| Endo (Epilepsy) (Controls unexposed, sick), 2004 |
Japan 1991 - 2000 |
Newborn of mothers with epilepsy at Yokohama City University Hospital during the study period and total deliveries excluding epilepsy cases of 1991 and 1992 at the same hospital. | Newborns of epileptic mothers who take clonazepam monotherapy for epilepsy throughout pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Newborns of epileptic mothers who had not taken any antiepileptic drugs. |
1 / 1 | 30 (83.3%) cases of 36 pregnancies continued taking drugs throughout pregnancy. Three (8.3%) patients discontinued after week 13 of pregnancy. Some results do not coincide between table 1 and table 2 and are therefore not reported. |
| Gopinath (Epilepsy), 2015 |
India 2010 - 2012 |
All children of women with epilepsy born in the registry between April 1998 and December 2001. | Children from epileptic mothers exposed to clonazepam in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed (general population or NOS)
Children attending to two nearby schools with no exposure. |
1 / 149 | Study design partly completed with Thomas et al., 2007 from the same registry. OR not calculable (only 1 exposure, not SD available for the provided mean Full Scale IQ). |
| Guveli (Epilepsy), 2017 |
Turkey 1990 - 2006 |
Children born from mothers with epilepsy, who got pregnant between 1990-2006, while they were either followed up by the epilepsy outpatient clinics or applied to the clinic after birth. | Children born from mothers with epilepsy on clonazepam monotherapy during pregnancy. |
unexposed, sick
Children born from mothers were not exposed to Antiepileptic drugs (AED) during pregnancy. |
2 / 26 | |
| Hvas (Epilepsy) (Controls unexposed, disease free), 2000 |
Denmark 1989 - 1997 |
Singleton pregnancies in Danish-speaking women who attended for antenatal care and delivered at Aarhus University Hospital during the study period. All women who reported chronic disease other than epilepsy were excluded. | Children of women with epilepsy exposed to clonazepam monotherapy during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Children of women without chronic disease. |
15 / 24094 | |
| Hvas (Epilepsy) (Controls unexposed, sick), 2000 |
Denmark 1989 - 1997 |
Singleton pregnancies in Danish-speaking women who attended for antenatal care and delivered at Aarhus University Hospital during the study period. All women who reported chronic disease other than epilepsy were excluded. | Children of women with epilepsy exposed to clonazepam monotherapy during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Children of women with epilepsy without treatment. |
15 / 106 | |
| Kaaja (Epilepsy), 2003 |
Finland 1980 - 1998 |
All women with epilepsy regardless of whether they used antiepileptic drugs during the index pregnancy. | Infants whose epileptic mothers took clonazepam as monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Infants whose epileptic mothers didn't take any antiepileptic drugs during the first trimester. |
13 / 239 | |
| Morrow (Epilepsy) (Controls exposed to Lamotrigine, sick), 2006 |
UK and Ireland 1996 - 2005 |
Pregnant women with epilepsy, whether or not they were taking an AED, either in monotherapy or polytherapy, and who were referred to the register before the outcome of the pregnancy was known. | Infants of women with epilepsy exposed to clonazepam in monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Infants of women with epilepsy exposed to lamotrigine in monotherapy during the first trimester. |
9 / 647 | Exposure period is completed thanks to Campbell 2014 which is also a UKEPR based study. |
| Morrow (Epilepsy) (Controls unexposed, sick), 2006 |
UK and Ireland 1996 - 2005 |
Pregnant women with epilepsy, whether or not they were taking an antiepileptic drug, either in monotherapy or polytherapy, and who were referred to the register before the outcome of the pregnancy was known. | Infants of women with epilepsy exposed to clonazepam in monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Infants of women with epilepsy and who didn't take any antiepileptic drugs during pregnancy. |
9 / 227 | Exposure period is completed thanks to Campbell 2014 which is also a UKEPR based study. |
| Razaz (Epilepsy), 2024 |
Denmark, Finland, Iceland, Norway and Sweden. 1996 - 2017 |
All singleton births at 22 or more completed gestational weeks in the 5 Nordic countries during the different study periods. | Mothers with epilepsy who filled a prescription for Clonazepam monotherapy between the date of the last menstrual period (LMP) and the day of birth. |
unexposed, sick
Mothers with epilepsy who did not fill an antiseizure medication (ASM) prescription in the period between 90 days before the last menstrual period (LMP) and the day of birth. |
321 / 19043 | |
| Robert (Epilepsy), 1986 |
France 1976 - 1983 |
148 infants born of epileptic women were identified from two sources: hospital records of women having had an EEG between 1976 and 1983 and 3 maternity with computerized records from 1979 - 1983. | Infants born from epileptic mothers exposed during the first trimester to clonazepam in monotherapy. |
unexposed, sick
Infants born from epileptic mothers unexposed during the first trimester to any antiepileptic drugs. |
1 / 35 | |
| Samrén (Epilepsy), 1999 |
Netherlands 1972 - 1994 |
Offspring of women with epilepsy, with or without antiepileptic drug use during pregnancy, born during the study period. | Children born to mothers with epilepsy and using clonazepam monotherapy at least during the first trimester of pregnancy |
unexposed, disease free
Children born to nonepileptic nonexposed women. |
9 / 2000 | |
| Thomas (Epilepsy) (Controls exposed to Lamotrigine, sick), 2021 |
India 1998 - 2019 |
All pregnancies with known outcomes in women with epilepsy enrolled in the registry during 1998 - 2013 and the diagnosis of epilepsy was confirmed before registration. | Children of women with epilepsy using clonazepam monotherapy any time during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Children of women with epilepsy using lamotrigine monotherapy any time during the first trimester of pregnancy. |
4 / 50 | |
| Thomas (Epilepsy) (Controls unexposed, sick), 2021 |
India 1998 - 2019 |
All pregnancies with known outcomes in women with epilepsy enrolled in the registry during 1998 - 2013 and the diagnosis of epilepsy was confirmed before registration. | Children of women with epilepsy using clonazepam monotherapy any time during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Children of women with epilepsy not using any antiepileptic drugs during the first trimester. |
4 / 340 | |
| Vajda (Epilepsy) (Controls exposed to Lamotrigine, sick), 2024 |
Australia 1999 - 2022 |
Pregnant women with epilepsy collected in the Raoul Wallenberg Australian Pregnancy Register of Antiepileptic Drugs between 1999 and mid- 2022. | Women with epilepsy exposed to clonazepam in monotherapy in early pregnancy. |
exposed to other treatment, sick
Women with epilepsy exposed to lamotrigine in monotherapy in early pregnancy. |
24 / 473 | Overlapping: Vajda 2024 totally included other APR data (Vajda 2019; Vajda 2007; 2010 (x2); 2012 (x2); 2013; 2014). Study design partly completed with Vajda 2013. |
| Vajda (Epilepsy) (Controls unexposed, sick), 2024 |
Australia 1999 - 2022 |
Pregnant women with epilepsy collected in the Raoul Wallenberg Australian Pregnancy Register of Antiepileptic Drugs between 1999 and mid- 2022. | Women with epilepsy exposed to clonazepam in monotherapy in early pregnancy. |
unexposed, sick
Women with epilepsy not treated with antiepileptic drugs in early pregnancy. |
24 / 201 | Overlapping: Vajda 2024 totally included other APR data (Vajda 2019; Vajda 2007; 2010 (x2); 2012 (x2); 2013; 2014). Study design partly completed with Vajda 2013. |
| Vajda a (Epilepsy) (Controls exposed to LTG), 2024 |
Australia 1999 - 2023 |
Women with epilepsy (WWE), with voluntary inclusion, with known outcomes but in which that outcome was unknown at the time of the pregnancy’s enrolment. | Women with epilepsy exposed to Clonazepam monotherapy during pregnancy. |
exposed to other treatment, sick
Women with epilepsy exposed to lamotrigine monotherapy during pregnancy. |
17 / 442 | Overlapping between Vajda 2024a (1999 - 2023) and Vajda 2018 (1999 - 2016) based on the same register and for the almost same outcome (with or without elective termination) => Use of Vajda 2024a because accounting for more relevant confounders. |
| Vajda a (Epilepsy) (Controls unexposed sick), 2024 |
Australia 1999 - 2023 |
Women with epilepsy (WWE), with voluntary inclusion, with known outcomes but in which that outcome was unknown at the time of the pregnancy’s enrolment. | Women with epilepsy exposed to Clonazepam monotherapy during pregnancy. |
unexposed, sick
Women with epilepsy unexposed to antiseizure medication during pregnancy. |
17 / 184 | Overlapping between Vajda 2024a (1999 - 2023) and Vajda 2018 (1999 - 2016) based on the same register and for the almost same outcome (with or without elective termination) => Use of Vajda 2024a because accounting for more relevant confounders. |
| Veiby (Epilepsy) (Controls exposed to Lamotrigine, sick), 2014 |
Norway 1999 - 2011 |
777,785 deliveries recorded in the database during the study period. | Children exposed prenatally to clonazepam as monotherapy indicated for their mothers' epilepsy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Children exposed prenatally to lamotrigine as monotherapy indicated for their mothers' epilepsy. |
40 / 593 | We will only consider the subgroup of women exposed to antiepileptic drugs for the strict indication of epilepsy. |
| Veiby (Epilepsy) (Controls unexposed, disease free), 2014 |
Norway 1999 - 2011 |
777,785 deliveries recorded in the database during the study period. | Children exposed prenatally to clonazepam as monotherapy indicated for their mothers' epilepsy. (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. |
40 / 771412 | We will only consider the subgroup of women exposed to antiepileptic drugs for the strict indication of epilepsy. |
| Veiby (Epilepsy) (Controls unexposed, sick), 2014 |
Norway 1999 - 2011 |
777,785 deliveries recorded in the database during the study period. | Children exposed prenatally to clonazepam as monotherapy indicated for their mothers' epilepsy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Children born to women with a history of epilepsy but no antiepileptic drug treatment during pregnancy. |
40 / 3773 | We will only consider the subgroup of women exposed to antiepileptic drugs for the strict indication of epilepsy. |
| Study | Country Study period |
Case | Control | Sample size | Rmk |
|---|---|---|---|---|---|
| Bànhidy (Epilepsy), 2011 |
Hungary 1980 - 1996 |
Children affected with congenital abnormalities and who had mothers with medically recorded epilepsy. | Newborn infants without congenital abnormality and who had mothers with medically recorded epilepsy. | 95 / 90 | Malformations caused by major mutant genes or chromosomal aberrations with preconceptional origin were excluded. Overlapping: Czeizel 1992 completely included in this publication (except for spina bifida, but no data for clonazepam). |
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