| Study | Country Study period |
Population source | Exposure definition | Non-exposure definition | Sample size | Rmk |
|---|---|---|---|---|---|---|
| Adab (Valproate), 2004 |
UK 1989 - 1999 |
Women (n=219) with epilepsy with children (n= 375) aged between 6 months to 16 years were identified and agreed to participate. | Children exposed to valproate monotherapy in utero and born to mothers with epilepsy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Children unexposed to antiepileptic drugs in utero and born to mothers with epilepsy. |
63 / 101 | Major and minor malformations results are overlapped by Kini 2006. Vinten et al., 2009 is completely overlapped for the language and cognitive delay assessment (with more exposed pregnancies and better scale in this publication). |
| Al Bunyan (Valproate), 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 valproate 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. |
5 / 10 | The control group with the data of historical controls in Saudi Arabia isn't an adequate control group. |
| Alsfouk (Valproate), 2022 |
Riyadh and Jeddah, Saudi Arabia. 2005 - 2020 |
Pregnant women with epilepsy followed up prospectively between the study period. | Epileptic mothers with valproate monotherapy administered during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Epileptic mothers with lamotrigine monotherapy administered during pregnancy. |
12 / 15 | |
| Alsfouk (Valproate) (Controls exposed to Lamotrigine, sick), 2021 |
Riyadh and Jeddah, Saudi Arabia. 1993 - 2020 |
Pregnant women with epilepsy followed up prospectively between the study period. | Epileptic mothers with valproate monotherapy administered during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Epileptic mothers with lamotrigine monotherapy administered during pregnancy. |
12 / 15 | |
| Alsfouk (Valproate) (Controls unexposed, sick), 2021 |
Riyadh and Jeddah, Saudi Arabia. 1993 - 2020 |
Pregnant women with epilepsy followed up prospectively between the study period. | Epileptic mothers with valproate monotherapy administered during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Epileptic mothers who did not take antiseizure medications during pregnancies. |
12 / 30 | |
| AlSheikh (Valproate) (Controls exposed to Lamotrigine, sick), 2020 |
Saudi Arabia 2018 - 2019 |
Pregnant patients with active epilepsy admitted to the Obstetrics and Gynecology outpatient clinic and those seeking follow-up from our outpatient clinic. Patients on treatment and who had at least one seizure in the past one year. | Fetuses/neonates of patients with active epilepsy who received valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Fetuses/neonates of patients with active epilepsy who received lamotrigine monotherapy during pregnancy. |
1 / 20 | |
| AlSheikh (Valproate) (Controls unexposed, sick), 2020 |
Saudi Arabia 2018 - 2019 |
Pregnant patients with active epilepsy admitted to the Obstetrics and Gynecology outpatient clinic and those seeking follow-up from our outpatient clinic. Patients on treatment and who had at least one seizure in the past one year. | Fetuses/neonates of patients with active epilepsy who received valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Fetuses/neonates of patients with active epilepsy who did not take antiepileptic drugs during pregnancy. |
1 / 8 | |
| Arkilo (Valproate), 2015 |
USA 2006 - 2011 |
Women with epilepsy who were pregnant between the study period and exposed to monotherapy antiepileptic medication at any point during the pregnancy. | Singleton whose epileptic mothers were exposed to valproate monotherapy at any point during the pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Singleton whose epileptic mothers were exposed to lamotrigine monotherapy at any point during the pregnancy. |
2 / 24 | |
| Artama (Valproate), 2005 |
Finland 1991 - 2000 |
Children born during the study period (n= 2350) to women who became eligible for full reimbursement for antiepileptic drugs with epilepsy as indication diagnosed before the birth. | Children whose epileptic mothers were exposed to valproate as 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 whose epileptic mothers were untreated during the first trimester of pregnancy. |
263 / 939 | |
| Artama (Valproate) (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 valproate 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. |
706 / 173 | |
| Artama (Valproate) (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 valproate 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. |
706 / 721948 | |
| Artama (Valproate) (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 valproate 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. |
706 / 1800 | |
| Aydin (Valproate) (Controls exposed to Lamotrigine, sick), 2020 |
Turkey 2007 - 2017 |
Pregnant women with epilepsy who delivered and had follow ups at the division of perinatalogy between the study period. | Pregnant women with epilepsy who received valproate in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Pregnant women with epilepsy who received lamotrigine in monotherapy during pregnancy. |
11 / 7 | There were no patients who had drug changes or discontinued during pregnancy. |
| Aydin (Valproate) (Controls unexposed, sick), 2020 |
Turkey 2007 - 2017 |
Pregnant women with epilepsy who delivered and had follow ups at the division of perinatalogy between the study period. | Pregnant women with epilepsy who received valproate in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Pregnant women with epilepsy with no antiepileptic drugs during pregnancy. |
11 / 22 | There were no patients who had drug changes or discontinued during pregnancy. |
| Babic (Valproate), 2014 |
Serbia 1998 - 2008 |
During the study period 21 women (25 pregnancies) with juvenile myoclonic epilepsy were enrolled. | Children whose epileptic mothers were exposed to valproate in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Children whose epileptic mothers were exposed to lamotrigine in monotherapy during pregnancy. |
6 / 8 | |
| Baker (Valproate) (Controls exposed to Lamotrigine, sick), 2015 |
UK 2000 - 2004 |
Women with and without epilepsy were recruited from antenatal clinics between the study period. | Children born to women with epilepsy and exposed to valproate monotherapy in utero. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Children born to women with epilepsy and exposed to lamotrigine monotherapy in utero. |
59 / 36 | Women were excluded from recruitment if they had a severe learning disability or other chronic health condition requiring medication. Neuro-developmental disorders (as a whole) better assess in Bromley et al. 2013. |
| Baker (Valproate) (Controls unexposed, disease free), 2015 |
UK 2000 - 2004 |
Women with and without epilepsy were recruited from antenatal clinics between the study period. | Children born to women with epilepsy and exposed to valproate monotherapy in utero. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Children born to women without epilepsy recruited from the same antenatal clinics of similar age, parity, and employment and residing within the same postal area. |
59 / 287 | Women were excluded from recruitment if they had a severe learning disability or other chronic health condition requiring medication. Neuro-developmental disorders (as a whole) better assess in Bromley et al. 2013. |
| Baker (Valproate) (Controls unexposed, sick), 2015 |
UK 2000 - 2004 |
Women with and without epilepsy were recruited from antenatal clinics between the study period. | Children born to women with epilepsy and exposed to valproate monotherapy in utero. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Children born to women with epilepsy and unexposed to antiepileptic drugs in utero. |
59 / 34 | Women were excluded from recruitment if they had a severe learning disability or other chronic health condition requiring medication. Neuro-developmental disorders (as a whole) better assess in Bromley et al. 2013. |
| Ban (Valproate) (Mixed indications) (Controls exposed to Lamotrigine, sick), 2015 |
UK 1990 - 2013 |
All singleton live births of mothers aged 15–44 years between the study period from a nationally representative database of UK computerised primary care records. | Singleton live births of mothers exposed to valproate monotherapy in first trimester of pregnancy (from four weeks before conception up to the end of 1st trimester). (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Singleton live births of mothers exposed to lamotrigine monotherapy in first trimester of pregnancy (from four weeks before conception up to the end of 1st trimester). |
214 / 273 | 'Among mothers prescribed AEDs in pregnancy, the majority (81%) had epilepsy'. Total major congenital malformations results are already assessed in Petersen et al. 2017. |
| Ban (Valproate) (Mixed indications) (Controls unexposed NOS), 2015 |
UK 1990 - 2013 |
All singleton live births of mothers aged 15–44 years between the study period from a nationally representative database of UK computerised primary care records. | Singleton live births of mothers exposed to valproate monotherapy in first trimester of pregnancy (from four weeks before conception up to the end of 1st trimester). (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed (general population or NOS)
Singleton live births of mothers without antiepileptic drugs in pregnancy. |
214 / 257153 | 'Among mothers prescribed AEDs in pregnancy, the majority (81%) had epilepsy'. Total major congenital malformations results are already assessed in Petersen et al. 2017. |
| Bank (Valproate) (Mixed indications), 2017 |
USA 2002 - 2006 |
Only pregnant women who were treated with antiepileptic drugs for epilepsy or bipolar disorder who chose to continue antiepileptic drugs during pregnancy and whose infants had umbilical cord antiepileptic drugs levels drawn at the time of delivery were included. | Singleton pregnancies in mothers taking valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Singleton pregnancies in mothers taking lamotrigine monotherapy during pregnancy. |
6 / 36 | |
| Battino (Valproate), 1992 |
Milan 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 valproate 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. |
22 / 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 (Valproate), 1999 |
Japan, Italy and Canada 1978 - 1991 |
Female patient of childbearing age with epilepsy who visited clinics and who consented to be followed throughout their pregnancy. The data from three studies carried out in Canada, Japan and Italy were pooled. | Infants whose epileptic mothers were exposed to valproate in monotherapy until term. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Infants whose epileptic mothers were not treated with antiepileptic drugs during pregnancy. |
70 / 36 | Each country has its own reference standards, then the data from the different countries are pooled. Exposition period deducted from Kaneko 1999. |
| Bech (Valproate) (Controls exposed to Lamotrigine, sick) (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 valproate monotherapy within 90 days prior to conception to birth. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Singleton offspring of mothers exposed to lamotrigine monotherapy within 90 days prior to conception to birth. |
55 / 290 | |
| Bech (Valproate) (Controls unexposed, sick) (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 valproate 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. |
55 / 434 | |
| Bjørk (Valproate) (Controls exposed to Lamotrigine, sick), 2018 |
Norway 1999 - 2008 |
Pregnancies registered in the MoBa cohort when information concerning use of folic acid supplements and/or plasma folate concentration during pregnancy was available. | Children of women with reported epilepsy and valproate monotherapy use during 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 reported epilepsy and lamotrigine monotherapy use during pregnancy. |
40 / 104 | |
| Bjørk (Valproate) (Controls exposed to Lamotrigine, sick) (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 valproate 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 mothers filling at least one lamotrigine monotherapy prescription from her last menstrual period until birth. |
2421 / 7950 | Overlapping between Daugaard 2020, Dreier 2023 and Bjork 2022 for Intellectual disabilities (2 outcomes), and Christensen 2013, Dreier and Bjork for ASD (2 outcomes) with more pregnancies in Bjork 2022 => use of Bjork 2022 data. |
| Bjørk (Valproate) (Controls unexposed NOS) (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 valproate 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. |
2421 / 4463879 | Overlapping between Daugaard 2020, Dreier 2023 and Bjork 2022 for Intellectual disabilities (2 outcomes), and Christensen 2013, Dreier and Bjork for ASD (2 outcomes) with more pregnancies in Bjork 2022 => use of Bjork 2022 data. |
| Bjørk (Valproate) (Controls unexposed, disease free), 2018 |
Norway 1999 - 2008 |
Pregnancies registered in the MoBa cohort when information concerning use of folic acid supplements and/or plasma folate concentration during pregnancy was available. | Children of women with reported epilepsy and valproate monotherapy use during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
All children of mothers without reported epilepsy unexposed to antiepileptic drugs during pregnancy. |
40 / 104222 | |
| Bjørk (Valproate) (Controls unexposed, sick), 2018 |
Norway 1999 - 2008 |
Pregnancies registered in the MoBa cohort when information concerning use of folic acid supplements and/or plasma folate concentration during pregnancy was available. | Children of women with reported epilepsy and valproate monotherapy use during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Children of women with reported epilepsy but no antiepileptic drug intake during pregnancy. |
40 / 389 | In this control group 127 (70.9%) reported inactive epilepsy defined as not using AEDs during the 2 years before conception or no seizures during the previous 5 years. |
| Bjørk (Valproate) (Controls unexposed, sick) (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 valproate 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. |
2421 / 21634 | Overlapping between Daugaard 2020, Dreier 2023 and Bjork 2022 for Intellectual disabilities (2 outcomes), and Christensen 2013, Dreier and Bjork for ASD (2 outcomes) with more pregnancies in Bjork 2022 => use of Bjork 2022 data. |
| Blotière (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2019 |
France 2011 - 2015 |
All pregnancies ending between the study period with at least 20 weeks of gestation | Pregnancies exposed to valproate 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). |
exposed to other treatment, sick
Pregnancies exposed to lamotrigine monotherapy between 1 month before and 2 months after the beginning of pregnancy. |
913 / 2997 | Authors excluded twin pregnancies and pregnancies with a chromosomal abnormality identified. Less than 90% 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. |
| Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 |
France 2011 - 2015 |
All pregnancies ending between the study period with at least 20 weeks of gestation | Pregnancies exposed to valproate 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. |
913 / 1875733 | Authors excluded twin pregnancies and pregnancies with a chromosomal abnormality identified. Less than 90% 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. |
| Borthen (Valproate) (Controls exposed to Lamotrigine, sick), 2010 |
Norway 1999 - 2005 |
All singleton births and the first child in multiple pregnancies were included (n= 365107). Miscarriages and stillbirths below week 21 were also included. | Births in women who gave a past or present history of epilepsy and exposed to valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Births in women who gave a past or present history of epilepsy and exposed to lamotrigine monotherapy during pregnancy. |
215 / 233 | |
| Borthen (Valproate) (Controls exposed to Lamotrigine, sick), 2011 |
Norway 1999 - 2006 |
During the study period, 38 483 deliveries took place at Haukeland University Hospital. | Women with epilepsy using valproate as monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Women with epilepsy using lamotrigine as monotherapy during pregnancy. |
19 / 30 | A previous publication (Borthen 2010) gives a better review of the outcomes 'caesarean', 'postpartum haemorrhage' and 'induction of labour' (adjusted OR and largest exposed population). As Veiby 2014 for the outcome 'major malformations'. |
| Borthen (Valproate) (Controls unexposed, disease free), 2010 |
Norway 1999 - 2005 |
All singleton births and the first child in multiple pregnancies were included (n= 365107). Miscarriages and stillbirths below week 21 were also included. | Births in women who gave a past or present history of epilepsy and exposed to valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Births in women without a past or present history of epilepsy and unexposed to any antiepileptic drugs during pregnancy. |
215 / 362302 | |
| Borthen (Valproate) (Controls unexposed, disease free), 2011 |
Norway 1999 - 2006 |
During the study period, 38 483 deliveries took place at Haukeland University Hospital. | Women with epilepsy using valproate as monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Women without epilepsy recruited and identified from the database randomly selected among the deliveries in the same week at the same hospital as the case with epilepsy. |
19 / 205 | A previous publication (Borthen 2010) gives a better review of the outcomes 'caesarean', 'postpartum haemorrhage' and 'induction of labour' (adjusted OR and largest exposed population). As Veiby 2014 for the outcome 'major malformations'. |
| Borthen (Valproate) (Controls unexposed, sick), 2010 |
Norway 1999 - 2005 |
All singleton births and the first child in multiple pregnancies were included (n= 365107). Miscarriages and stillbirths below week 21 were also included. | Births in women who gave a past or present history of epilepsy and exposed to valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Births in women who gave a past or present history of epilepsy and unexposed to any antiepileptic drugs during pregnancy. |
215 / 1863 | |
| Borthen (Valproate) (Controls unexposed, sick), 2011 |
Norway 1999 - 2006 |
During the study period, 38 483 deliveries took place at Haukeland University Hospital. | Women with epilepsy using valproate as monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Women with epilepsy not using any antiepileptic drugs during pregnancy. |
19 / 89 | A previous publication (Borthen 2010) gives a better review of the outcomes 'caesarean', 'postpartum haemorrhage' and 'induction of labour' (adjusted OR and largest exposed population). As Veiby 2014 for the outcome 'major malformations'. |
| Bromley (Valproate), 2016 |
UK 2004 - 2007 |
Pregnant women with epilepsy, whether or not they were taking an antiepileptic drug in monotherapy and whose infant had been a live birth between the study period. | Children whose epileptic mothers were exposed to valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Children whose epileptic mothers were untreated by antiepileptic drugs during their pregnancy. |
47 / 55 | Design parts of this study were completed thanks to Morrow 2006. Families were not invited to participate if their child had a genetic condition associated with neurodevelopmental impairment. |
| Bromley (Valproate) (Controls exposed to Lamotrigine, sick), 2010 |
UK 2000 - 2006 |
Midwives in the antenatal clinics approached each woman, who gave a history of epilepsy, whatever her stage of gestation. | Children born to mothers with epilepsy exposed to valproate monotherapy in utero. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Children born to mothers with epilepsy exposed to lamotrigine monotherapy in utero. |
42 / 34 | Study design partly completed with Mawer et al., 2010. The locomotor dimension is already evaluated in Bromley et al., 2013 and language disorders/delay in Baker et al., 2015 (older children and better scales). |
| Bromley (Valproate) (Controls exposed to Lamotrigine, sick), 2013 |
UK 2000 - 2004 |
Children born to pregnant women epileptic or not, recruited from antenatal clinics. | Children born to epileptic mothers exposed to valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Children born to epileptic mothers exposed to lamotrigine monotherapy during pregnancy. |
59 / 36 | The children or mothers who had conditions likely to influence neurodevelopmental outcome were excluded. The result for autism spectrum disorders is an update compares to the preliminary findings presented in Bromley 2008. |
| Bromley (Valproate) (Controls unexposed, disease free), 2010 |
UK 2000 - 2006 |
Midwives in the antenatal clinics approached each woman, who gave a history of epilepsy, whatever her stage of gestation. | Children born to mothers with epilepsy exposed to valproate monotherapy in utero. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Children born to mothers without epilepsy were recruited from the same antenatal clinics. |
42 / 230 | Study design partly completed with Mawer et al., 2010. 52% of the exposed group and 43% of the control group is overlapped with Shallcross 2011. Locomotor dimension evaluated in Bromley et al., 2013 and language disorders/delay in Baker et al., 2015. |
| Bromley (Valproate) (Controls unexposed, disease free), 2013 |
UK 2000 - 2004 |
Children born to pregnant women epileptic or not, recruited from antenatal clinics. | Children born to epileptic mothers exposed to valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Children born to women without epilepsy. |
59 / 285 | The children or mothers who had conditions likely to influence neurodevelopmental outcome were excluded. The result for autism spectrum disorders is an update compares to the preliminary findings presented in Bromley 2008. |
| Bromley (Valproate) (Controls unexposed, sick), 2010 |
UK 2000 - 2006 |
Midwives in the antenatal clinics approached each woman, who gave a history of epilepsy, whatever her stage of gestation. | Children born to mothers with epilepsy exposed to valproate monotherapy in utero. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Children born to mothers with epilepsy not exposed to antiepileptic drugs in utero. |
42 / 27 | Study design partly completed with Mawer et al., 2010. The locomotor dimension is already evaluated in Bromley et al., 2013 and language disorders/delay in Baker et al., 2015 (older children and better scales). |
| Bromley (Valproate) (Controls unexposed, sick), 2013 |
UK 2000 - 2004 |
Children born to pregnant women epileptic or not, recruited from antenatal clinics. | Children born to epileptic mothers exposed to valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Children were born to women with epilepsy who were not taking medication during their pregnancy. |
59 / 34 | The children or mothers who had conditions likely to influence neurodevelopmental outcome were excluded. The result for autism spectrum disorders is an update compares to the preliminary findings presented in Bromley 2008. |
| Burja (Valproate) (Controls unexposed, disease free), 2006 |
Slovenia 1998 - 2002 |
Newborns and their mothers who gave birth at the Maribor Department of Obstetric and Perinatology during the study period. | Newborn in women diagnosed as having epilepsy who had taken valproate in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Newborn in a randomized sample of pregnant women who had received no prescription at all (with the only diagnosis 'vaginal delivery') in the same period. |
2 / 211 | |
| Burja (Valproate) (Controls unexposed, sick), 2006 |
Slovenia 1998 - 2002 |
Newborns and their mothers who gave birth at the Maribor Department of Obstetric and Perinatology during the study period. | Newborn in women diagnosed as having epilepsy who had taken valproate in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Newborn in women diagnosed as having epilepsy who didn't take antiepileptic drugs during pregnancy. |
2 / 32 | |
| Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 |
UK and Ireland 1996 - 2012 |
Women with epilepsy who became pregnant while taking valproate, carbamazepine or lamotrigine in monotherapy, and who were referred before the outcome of the pregnancy was known. | Infants of women with epilepsy exposed to valproate 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. |
1290 / 2198 | Morrow et al., 2009 specific malformations results and major malformations results from Morrow et al., 2006 and Campbell et al., 2013 are completely overlapped by this publication. Study design was partly completed with Morrow 2006. |
| Campbell (Valproate) (Controls unexposed, sick), 2014 |
UK and Ireland 1996 - 2012 |
Women with epilepsy who became pregnant while taking valproate, carbamazepine or lamotrigine in monotherapy, and who were referred before the outcome of the pregnancy was known. | Infants of women with epilepsy exposed to valproate 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 on no antiepileptic drugs during pregnancy. |
1290 / 541 | Study design was partly completed with Morrow 2006. Morrow et al., 2006 major malformations results are completely overlapped by this publication with a larger exposed group. |
| Canger (Valproate), 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 valproate 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. |
44 / 25 | Only the first pregnancies of each of the 517 women were included in the analysis. |
| Cassina (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2013 |
Italy 2000 - 2008 |
695 pregnant epileptic or non-epileptic women exposed to antiepileptic drugs therapy had been registered during the study period. | Children whose epileptic or non-epileptic mothers were treated with valproate in monotherapy between the 5th and the 14th week after their last menstrual period. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Children whose epileptic or non-epileptic mothers were treated with lamotrigine in monotherapy between the 5th and the 14th week after their last menstrual period. |
159 / 57 | Chromosomal anomalies and genetic syndromes were excluded. Less than 90% of women are treated with Valproate or Lamotrigine for epilepsy. |
| Cassina (Valproate) (Controls unexposed, disease free) (Mixed indications), 2013 |
Italy 2000 - 2008 |
695 pregnant epileptic or non-epileptic women exposed to antiepileptic drugs therapy had been registered during the study period. | Children whose epileptic or non-epileptic mothers were treated with valproate in monotherapy between the 5th and the 14th week after their last menstrual period. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Healthy pregnant women randomly selected among patients who contacted the Teratology Information Services during their pregnancy with regard to exposure to agents known not to be teratogenic (i.e. paracetamol, hair dying, etc.) during a similar time frame. |
159 / 867 | Chromosomal anomalies and genetic syndromes were excluded. Less than 90% of women are treated with Valproate for epilepsy. |
| Charlton (Valproate), 2017 |
UK 2000 - 2006 |
All pregnancies to women with epilepsy were identified in the database, where the pregnancy ended in a live delivery between the study period. And subsequently matched mother–child pairs without epilepsy from the same database. | Mother–child pairs where the mother had epilepsy and received valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Mother–child pairs where the mother did not meet the epilepsy criteria and had not been prescribed an antiepileptic drug at any time prior to her child turning age 6 years. |
118 / 6048 | The results obtained by the Liverpool and Manchester Neurodevelopment Group are already obtained by the publication of Bromley 2013, thus, only those extracted from the UK Clinical Practice Research Datalink are implemented here. |
| Charlton (Valproate) (Controls exposed to Lamotrigine, sick), 2011 |
UK 1990 - 2006 |
Mother-baby pairs whose mothers are identified as having epilepsy and who were, or had been, permanently registered at a general practirioner practice considered by the database. | Infants of mother-baby pairs who had valproate monotherapy exposure 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 mother-baby pairs who had lamotrigine monotherapy exposure during the first trimester. |
225 / 98 | The results obtained by the UK Epilepsy and Pregnancy Register are already obtained in the publication of Morrow 2006, thus, only those extracted from the UK General Practice Research Database are implemented here. |
| Charlton (Valproate) (Controls unexposed, sick), 2011 |
UK 1990 - 2006 |
Mother-baby pairs whose mothers are identified as having epilepsy and who were, or had been, permanently registered at a general practirioner practice considered by the database. | Infants of mother-baby pairs who had valproate monotherapy exposure during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Infants of mother-baby pairs who had no antiepleptic drug exposure during the first trimester. |
225 / 902 | The results obtained by the UK Epilepsy and Pregnancy Register are already obtained in the publication of Morrow 2006, thus, only those extracted from the UK General Practice Research Database are implemented here. |
| Christensen (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2013 |
Denmark 1996 - 2006 |
All children born alive in Denmark during the study period. | Children whose mothers have been exposed to valproate in 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). |
exposed to other treatment, sick
Children whose mothers have been exposed to lamotrigine in monotherapy during the exposure window defined from 30 days before the estimated day of conception to the day of birth. |
388 / 647 | Less than 90% of exposed (monotherapy and polytherapy) mothers have epilepsy. Overlapping: For ASD diagnosis/risk : data of Christensen 2019 included in Bjork 2022 because longer study period and 5 countries => use of Bjork 2022 data. |
| Christensen (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2015 |
Denmark 1997 - 2008 |
All singleton live born children in Denmark during the study period. | Children whose mothers have been exposed to valproate in 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). |
exposed to other treatment, sick
Children whose mothers have been exposed to lamotrigine in monotherapy during the exposure window defined from 30 days before the estimated day of conception to the day prior to birth. |
337 / 875 | 76% of all exposed mothers have epilepsy. |
| Christensen (Valproate) (Controls unexposed NOS) (Mixed indications), 2013 |
Denmark 1996 - 2006 |
All children born alive in Denmark during the study period. | Children whose mothers have been exposed to valproate in 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 valproate during the exposure window defined from 30 days before the estimated day of conception to the day of birth. |
388 / 655107 | Overlapping: For ASD diagnosis/risk : data of Christensen 2019 included in Bjork 2022 because longer study period and 5 countries => use of Bjork 2022 data. Less than 90% of exposed (monotherapy and polytherapy) mothers have epilepsy. |
| Christensen (Valproate) (Controls unexposed NOS) (Mixed indications), 2015 |
Denmark 1997 - 2008 |
All singleton live born children in Denmark during the study period. | Children whose mothers have been exposed to valproate in monotherapy during the exposure window defined from 30 days before the estimated day of conception to the day prior to birth. |
unexposed (general population or NOS)
Children whose mothers haven't been exposed to antiepileptic drugs. |
337 / 674115 | 76% of all exposed mothers have epilepsy. |
| Christensen (Valproate) (Controls unexposed, sick) (Mixed indications), 2015 |
Denmark 1997 - 2008 |
All singleton live born children in Denmark during the study period. | Children whose mothers have been exposed to valproate in 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, sick
Children whose epileptic mothers haven't been exposed to antiepileptic drugs. |
337 / 5261 | 76% of all exposed mothers have epilepsy. |
| Cohen (Valproate), 2011 |
UK and USA 1999 - 2004 |
Pregnant women with epilepsy who were taking a single antiepileptic drug in one of the 25 centers across UK and USA. | Infants of women exposed to valproate in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Infants of women exposed to lamotrigine in monotherapy during pregnancy. |
46 / 76 | A nonexposed control group was not included. Total number of children exposed to each antiepileptic drugs is not specified, so the number of mothers is reported instead. |
| Cohen (Valproate), 2013 |
USA and UK 1999 - 2004 |
Pregnant women (n=192) with epilepsy who were taking a single antiepileptic drug in one of the 25 epilepsy centers across UK and USA. | Infants of women exposed to valproate in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Infants of women exposed to lamotrigine in monotherapy during pregnancy. |
45 / 63 | A nonexposed control group was not included. |
| Cohen (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2019 |
USA 2000 - 2010 |
Deliveries during the study period in mothers 12-55 years of age with continuous enrollment from 3 months before pregnancy until 1 month after delivery. They are linked to live born infants in the database. | Pregnancies in women with at least one dispensed prescription for valproate monotherapy (no other mood stabilizers or other anticonvulsants) in the first 20 weeks of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Pregnancies in women with at least one dispensed prescription for lamotrigine monotherapy (no other mood stabilizers or other anticonvulsants) in the first 20 weeks of pregnancy. |
2398 / 2682 | Authors excluded deliveries with a major congenital malformation (identified by ICD-9). |
| Cohen (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 |
USA 2000 - 2010 |
Deliveries during the study period in mothers 12-55 years of age with continuous enrollment from 3 months before pregnancy until 1 month after delivery. They are linked to live born infants in the database. | Pregnancies in women with at least one dispensed prescription for valproate monotherapy (no other mood stabilizers or other anticonvulsants) in the first 20 weeks of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed (general population or NOS)
Pregnancies in patients with no dispensing of lithium or any anticonvulsant (including those not used as mood stabilizers) from 3 months before pregnancy until 20 weeks of gestation. |
2398 / 1440631 | Authors excluded deliveries with a major congenital malformation (identified by ICD-9). |
| Cohen (Valproate) (Mixed indications) (Controls exposed to LTG), 2023 |
Denmark, Finland, Iceland, Norway, and Sweden 1996 - 2020 |
All pregnancies in the general population, including singleton and multiple births, live births and stillbirths, with a gestational age of at least 22 weeks occurring during the study period (terminations of pregnancy for fetal anomaly (TOPFAs) recorded in Norway, Finland and Denmark but not in Sweden or Iceland). | Pregnancies in which the mother had filled one or more prescriptions of valproate ([ATC] code N03AG01) monotherapy during the first trimester. |
exposed to other treatment, sick
Pregnancies in which the mother had filled one or more prescriptions of lamotrigine monotherapy during the first trimester. |
2031 / 8339 | Main valproate indications: 80% epilepsy; 11% unknown; 9% bipolar disorder. Overlapping: Cohen 2023 included totally Christensen 2021 (excluded); and for Kallen 2013 and Veiby 2014 => less of 50% of overlapping => the 2 studies were kept. |
| Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 |
Denmark, Finland, Iceland, Norway, and Sweden 1996 - 2020 |
All pregnancies in the general population, including singleton and multiple births, live births and stillbirths, with a gestational age of at least 22 weeks occurring during the study period (terminations of pregnancy for fetal anomaly (TOPFAs) recorded in Norway, Finland and Denmark but not in Sweden or Iceland). | Pregnancies in which the mother had filled one or more prescriptions of valproate ([ATC] code N03AG01) monotherapy during the first trimester. |
unexposed (general population or NOS)
Pregnancies in which the mother had not filled a prescription for any Antiseizure medication (ATC code N03A) from 90 days before LMP to the end of the first trimester. |
2031 / 4866362 | Main valproate indications: 80% epilepsy; 11% unknown; 9% bipolar disorder. Overlapping: Cohen 2023 included totally Christensen 2021 (excluded); and for Kallen 2013 and Veiby 2014 => less of 50% of overlapping => the 2 studies were kept. |
| Coste (Valproate) (Controls exposed to Lamotrigine, sick), 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 valproate monotherapy indicated for the treatment of epilepsy 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). |
exposed to other treatment, sick
Children born from mothers exposed to lamotrigine monotherapy (i.e. with no other medication indicated for epilepsy) indicated for the treatment of epilepsy during pregnancy. |
991 / 2108 | Children with a diagnosis of brain malformation (ICD-10 codes Q00 to Q04 and Q05.0 to Q05.4) during their stay in the maternity unit are excluded. Results are extracted from Blotière et al. 2020 because they reported aOR for vs LTG. |
| Coste (Valproate) (Controls unexposed, NOS), 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 valproate monotherapy indicated for the treatment of epilepsy with at least one dispensing between the beginning of 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. |
991 / 1710441 | Children with a diagnosis of brain malformation (ICD-10 codes Q00 to Q04 and Q05.0 to Q05.4) during their stay in the maternity unit are excluded. |
| Cummings (Valproate) (Controls exposed to Lamotrigine, sick), 2011 |
Northern Ireland 2002 - 2005 |
Infants and children born to mothers with epilepsy taking one of three antiepileptic drugs (lamotrigine, sodium valproate or carbamazepine) as monotherapy throughout pregnancy and enrolled on the UK Epilepsy and Pregnancy Register. And control children are identified from the Child Health System database. | Children born to epileptic mothers taking valproate as monotherapy throughout pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Children born to epileptic mothers taking lamotrigine as monotherapy throughout pregnancy. |
58 / 35 | Women who were taking any other prescribed medication other than folic acid or iron supplements are excluded. The method for exposition measure isn't recalled here but it's always the same for this register. |
| Cummings (Valproate) (Controls unexposed, disease free), 2011 |
Northern Ireland 2002 - 2005 |
Infants and children born to mothers with epilepsy taking one of three antiepileptic drugs (lamotrigine, sodium valproate or carbamazepine) as monotherapy throughout pregnancy and enrolled on the UK Epilepsy and Pregnancy Register. And control children are identified from the Child Health System database. | Children born to epileptic mothers taking valproate as monotherapy throughout pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Children born to healthy women not taking prescribed medication other than folic acid or iron supplements during pregnancy. |
58 / 44 | Women who were taking any other prescribed medication other than folic acid or iron supplements are excluded. The method for exposition measure isn't recalled here but it's always the same for this register. |
| D'Souza (Valproate) (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 valproate 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 (Valproate) (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 valproate 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 | |
| Dean (Valproate), 2002 |
Scotland 1976 - 2000 |
Children of mothers taking antiepileptic drugs in pregnancy during the study period were ascertained from hospital obstetric records. | Children whose mothers took valproate monotherapy in pregnancy and continued beyond the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Sibs of exposed cases not exposed to antiepileptic drugs in utero. Either the mothers had epilepsy or the child was born before epilepsy developed. |
47 / 38 | The data for major congenital malformations include all pregnancies surviving into the second trimester. The vast majority of the mothers were treated for epilepsy. Developmental delay is already assessed in Dean et al. 2007. |
| Dean (Valproate) (Controls exposed to Lamotrigine, sick), 2007 |
Scotland 1976 - 2002 |
Children of mothers who were prescribed antiepileptic drugs during a pregnancy between the study period were identified from hospital records. | Children whose epileptic mothers were exposed to valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Children whose epileptic mothers were exposed to lamotrigine monotherapy during pregnancy. |
61 / 4 | A previous publication (Dean 2002) gives a better review of the major malformations. |
| Dean (Valproate) (Controls unexposed, sick), 2007 |
Scotland 1976 - 2002 |
Children of mothers who were prescribed antiepileptic drugs during a pregnancy between the study period were identified from hospital records. | Children whose epileptic mothers were exposed to valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Children whose epileptic mothers were not exposed during pregnancy. |
61 / 46 | A previous publication (Dean 2002) gives a better review of the major malformations. |
| Deshmukh (Valproate), 2016 |
North America and Canada 1997 - 2010 |
Pregnant women with epilepsy who had prospectively enrolled in the registry while taking LTG, VPA, or CBZ as monotherapy to suppress seizures throughout pregnancy, and whose exposed children were 3- to 6-years-old.. | Children of women who used valproate as monotherapy throughout pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Children of women who used lamotrigine as monotherapy throughout pregnancy. |
51 / 104 | Study design completed with cited source [28]. Major malformation rate of this sample is already assessed in Hernández-Díaz 2012. |
| Diav-Citrin (Valproate) (Mixed indications), 2008 |
Israel 1994 - 2004 |
Pregnant women who contacted (directly or through their healthcare provider) the Teratology Information Service regarding gestational valproate exposure during the study period. | Pregnant women with at least first trimester exposure to valproate for mixed indications in monotherapy. |
unexposed (general population or NOS)
Callers women who had been counselled (over a similar timeframe) during pregnancy in regard to exposures known to be nonteratogenic or foetotoxic. |
89 / 1315 | Less than 90% of women are taking Valproate for epilepsy. |
| Díaz-Romero (Valproate), 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 valproate 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. |
10 / 8 | All newborns in the intensive care unit, and those with congenital malformations with a different specific recognizable etiology were excluded. |
| Dravet (Valproate), 1992 |
France 1984 - 1988 |
Letters and notification forms were mailed to health care practitioners in the region to identify before any information was available about the fetus all pregnant women with epilepsy, treated or untreated with antiepileptic drugs. | Infants of mothers with epilepsy treated with valproate alone during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Infants of women with epilepsy who did not receive any antiepileptic drugs during pregnancy. |
39 / 14 | The number of unknown head circumference decrease the exposed sample size in the outcome result. |
| Dreier (Valproate), 2021 |
Danemark, Finland, Iceland, Norway, Sweden 1996 (depends)-2017 |
Live-born singleton children from women with epilepsy in five Nordic countries. | Offspring of women with prescription for valproate monotherapy from 90 days before pregnancy to birth. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Offspring of women with epilepsy not using antiseizure medication in pregnancy. |
1943 / -9 | Unknown number in the exposed and unexposed group (abstract). |
| Dreier (Valproate) (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 Valproate 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. |
1952 / 5288 | Overlapping for ASD (2 outcomes) and Intellectual disabilities (2 outcomes): Dreier 2023 and Bjork 2022, with more pregnancies in Bjork 2022 because all indications included => use of Bjork 2022. For ADHD: Christensen 2019 totally included in Dreier 2023. |
| Dreier (Valproate) (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 valproate 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. |
1952 / 22203 | Overlapping for ASD (2 outcomes) and Intellectual disabilities (2 outcomes): Dreier 2023 and Bjork 2022, with more pregnancies in Bjork 2022 because all indications included => use of Bjork 2022. For ADHD: Christensen 2019 totally included in Dreier 2023. |
| Elkjaer (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2018 |
Denmark 1997 - 2006 |
All children born alive in Denmark between the study period. | Children with valproate monotherapy 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). |
exposed to other treatment, sick
Children with lamotrigine monotherapy 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. |
253 / 396 | For learning disorders: Overlapping: this publication totally included the data of Elkjaer, 2018, for an higher academic grade => use of Ren 2023. Mixed indication (172/232 epilepsy (74%)). |
| Elkjaer (Valproate) (Controls unexposed NOS) (Mixed indications), 2018 |
Denmark 1997 - 2006 |
All children born alive in Denmark between the study period. | Children with valproate monotherapy 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. |
253 / 477162 | For learning disorders: Overlapping: this publication totally included the data of Elkjaer, 2018, for an higher academic grade => use of Ren 2023. Mixed indication (172/232 epilepsy (74%)). |
| Endo (Valproate) (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 valproate monotherapy for epilepsy at least until week 13 of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Newborns of nonepileptic mothers. |
6 / 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 (Valproate) (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 valproate 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. |
6 / 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. |
| Eriksson (Valproate), 2005 |
Finland 1989 - 2000 |
Women with epilepsy who had given birth between the study period in the area of the Kuopio University Hospital. | Pregnancies in which the mother had used valproate during conception and throughout pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Pregnancies in which the mother reported having previous history of epilepsy but had not needed antiepileptic drugs during pregnancy. |
21 / 13 | The period of exposure is specified in Viinikainen 2006. The cognitive delay of this sample at the same age is already assessed in Viinikainen 2006, thus, not reported here. |
| Gaily (Valproate) (Controls unexposed, disease free), 2004 |
Helsinki 1989 - 1994 |
All 306 liveborn children (including siblings) born at Helsinki University Hospital during the study period to mothers with a history of seizures or epilepsy. | Children of mothers with epilepsy exposed to valproate monotherapy during the second half of the pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
The next child born at the same hospital to a nonepileptic mother and unexposed to antiepileptic drugs. |
13 / 141 | |
| Gaily (Valproate) (Controls unexposed, sick), 2004 |
Helsinki 1989 - 1994 |
All 306 liveborn children (including siblings) born at Helsinki University Hospital during the study period to mothers with a history of seizures or epilepsy. | Children of mothers with epilepsy exposed to valproate monotherapy during the second half of the pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Children of mothers with epilepsy with no drug exposure. |
13 / 45 | |
| Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 |
North America and Canada 1997 - 2011 |
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 valproate for epileptic indication as monotherapy, during the first 4 lunar months after the last menstrual period (equal 16 weeks of gestation). (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Infants of pregnant women who used lamotrigine for mixed indications as monotherapy, during the first 4 lunar months after the last menstrual period (equal 16 weeks of gestation). |
323 / 1562 | Total congenital malformations results are completely overlapped by the update on the registry website. Less than 90% of women are taking Lamotrigine for epilepsy. |
| Hernández-Díaz (Valproate) (Controls unexposed, disease free), 2012 |
North America and Canada 1997 - 2011 |
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 valproate for epileptic indication as monotherapy, during the first 4 lunar months after the last menstrual period (equal 16 weeks of gestation). (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. |
323 / 442 | Total congenital malformations results are completely overlapped by the update on the registry website. |
| Hosny (Valproate) (Controls exposed to Lamotrigine, sick), 2021 |
Egypt 2018 - 2020 |
Pregnant women with epilepsy enrolled within the first trimester recruited from the epilepsy outpatient clinic and several private epilepsy centers during the study period. | Pregnant women with epilepsy on valproate 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
Pregnant women with epilepsy on lamotrigine monotherapy during the first trimester. |
8 / 1 | Each woman had one pregnancy during the study period. The correct figures were sent by the authors. |
| Hosny (Valproate) (Controls unexposed, sick), 2021 |
Egypt 2018 - 2020 |
Pregnant women with epilepsy enrolled within the first trimester recruited from the epilepsy outpatient clinic and several private epilepsy centers during the study period. | Pregnant women with epilepsy on valproate monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Pregnant women with epilepsy with no treatment during the first trimester. |
8 / 21 | Each woman had one pregnancy during the study period. |
| Huber-Mollema (Valproate), 2019 |
The Netherlands 2015 - 2018 |
Children of mothers with epilepsy identified from the EURAP‐NL database. Recruitment of women ideally occurs within the first 16 weeks of pregnancy. | Children age between 6 years and 7 years 11 months of mothers with epilepsy exposed to valproate monotherapy starting before conception and continuing during the entire pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Children age between 6 years and 7 years 11 months of mothers with epilepsy exposed to lamotrigine monotherapy starting before conception and continuing during the entire pregnancy. |
26 / 88 | The method for measuring exposure is not specified, although the EURAP registry method was thought to be used. |
| Husebye (Valproate) (Controls exposed to Lamotrigine, sick), 2020 |
Norway 1999 - 2008 |
Children of mothers with and without epilepsy included in the MoBa cohort. | Children of mothers with epilepsy exposed to valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Children of mothers with epilepsy exposed to lamotrigine monotherapy during pregnancy. |
40 / 112 | |
| Husebye (Valproate) (Controls unexposed, disease free), 2020 |
Norway 1999 - 2008 |
Children of mothers with and without epilepsy included in the MoBa cohort. | Children of mothers with epilepsy exposed to valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Children of mothers without epilepsy. |
40 / 113674 | |
| Husebye (Valproate) (Controls unexposed, sick), 2020 |
Norway 1999 - 2008 |
Children of mothers with and without epilepsy included in the MoBa cohort. | Children of mothers with epilepsy exposed to valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Children of mothers with epilepsy unexposed to antiepileptic durgs during pregnancy. |
40 / 388 | For this comparison group, results are only available according to folic acid intake. |
| Hvas (Valproate) (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 valproate 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. |
12 / 24094 | |
| Hvas (Valproate) (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 valproate 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. |
12 / 106 | |
| Jäger-Roman (Valproate), 1986 |
Germany 1976 - 1983 |
All mother-child pairs were participants in a prospective longitudinal study in Berlin where the mothers were randomly recruited during their pregnancy. | Infants exposed to valproate monotherapy and born from an epileptic mother. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed (general population or NOS)
Infants prenatally unexposed to antiepileptic drugs. |
14 / 116 | |
| Kaaja (Valproate), 2003 |
Finland 1980 - 1998 |
All women with epilepsy regardless of whether they used antiepileptic drugs during the index pregnancy. | Infants whose epileptic mothers took valproate 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. |
61 / 239 | |
| Källén (Valproate) (Controls exposed to Lamotrigine, sick) (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 valproate in monotherapy in early pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Infants whose mothers used lamotrigine in monotherapy in early pregnancy. |
697 / 1084 | Overlapping: Cohen 2023 and Kallen 2013 => less of 50% of overlapping => the 2 studies were kept. Razaz 2017; Wide 2004; Bodén 2012 outcomes' included in Källèn 2013 or not compared to an adequate control group. Follow-up period: author's email reply. |
| Källén (Valproate) (Controls unexposed, NOS) (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 valproate in 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. |
697 / 1575847 | Overlapping: Cohen 2023 and Kallen 2013 => less of 50% of overlapping => the 2 studies were kept. Follow-up period known thanks to author's email reply. Bodén 2012 malformation results' already included in this publication with more exposed pregnancies. |
| Kaneko (Valproate), 1999 |
Japan, Italy and Canada. 1978 - 1991 |
Female patient of childbearing age with epilepsy who visited clinics and who consented to be followed throughout their pregnancy. The data from three studies carried out in Canada, Japan and Italy were pooled. | Offspring whose epileptic mothers were under valproate monotherapy until term. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Offspring from epileptic mothers without antiepileptic drug exposure until term. |
81 / 98 | Details about the design were completed thanks to Battino et al., 1999 publication. Kaneko 1999 overlapped with Kaneko 1986, 1988, 1992, Oguni 1992, Dansky 1982, Canger 1999 and Battino 1992. |
| Kasradze (Valproate) (Controls exposed to Lamotrigine, sick), 2017 |
Georgia 2001 |
Women with epilepsy whose children had reached ages from 36 to 72 months at the time of the study and registered in the registry. | Children born to epileptic mothers exposed to valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Children born to epileptic mothers exposed to lamotrigine monotherapy during pregnancy. |
18 / 3 | Children with major congenital malformations were excluded from the study. |
| Kasradze (Valproate) (Controls unexposed, disease free), 2017 |
Georgia 2001 |
Women with epilepsy whose children had reached ages from 36 to 72 months at the time of the study and registered in the registry. | Children born to epileptic mothers exposed to valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Children born to mothers without epilepsy, with no antiepileptic drug or other drug treatment during pregnancy. |
18 / 50 | Children with major congenital malformations were excluded from the study. |
| Katz (Valproate), 2001 |
USA 1990 - 2000 |
The clinical histories of women with epilepsy cared for at the center, contributing 103 newborns during the study period. | Newborn of women with epilepsy exposed to valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Newborn of women with epilepsy exposed to lamotrigine monotherapy during pregnancy. |
4 / 3 | The analysis of developmental delay excluded the 20 pregnancies occurring within 1 year of chart review because of insufficient time to evaluate developmental milestones. |
| Kilic (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 |
Denmark 1997 - 2008 |
All singleton live-born children in Denmark during the study period. | Children whose mothers have been exposed to valproate in 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). |
exposed to other treatment, sick
Children whose mothers have been exposed to lamotrigine in monotherapy during the exposure window defined from 30 days before the estimated day of conception to the day prior to birth. |
343 / 880 | Less than 90% of women are epileptic. |
| Kilic (Valproate) (Controls unexposed NOS) (Mixed indications), 2014 |
Denmark 1997 - 2008 |
All singleton live-born children in Denmark during the study period. | Children whose mothers have been exposed to valproate in 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 haven't been exposed to antiepileptic drugs 30 days before the estimated day of conception to the day of birth. |
343 / 676834 | Less than 90% of women are epileptic. |
| Kilic (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 |
Denmark 1997 - 2008 |
All singleton live-born children in Denmark during the study period. | Children whose mothers have been exposed to valproate in 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, sick
Children whose mothers have an epilepsy diagnosis and haven't been exposed to antiepileptic drugs 30 days before the estimated day of conception to the day of birth. |
343 / 5296 | Less than 90% of women are epileptic. |
| Kini (Valproate) (Controls exposed to Lamotrigine, sick), 2006 |
UK 1989 - 1999 |
375 children aged between 6 months and 16 years from 219 mothers with epilepsy exposed and not exposed to antiepileptic drugs during pregnancy attending epilepsy clinics or antenatal care between the study period. | Children exposed to valproate monotherapy during pregnancy and with epileptic mothers. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Children exposed to lamotrigine monotherapy during pregnancy and with epileptic mothers. |
63 / 9 | Because we don't know the exact number of children exposed to lamotrigine and analyzed for malformations, this outcome cannot be reported here. |
| Kini (Valproate) (Controls unexposed, sick), 2006 |
UK 1989 - 1999 |
375 children aged between 6 months and 16 years from 219 mothers with epilepsy exposed and not exposed to antiepileptic drugs during pregnancy attending epilepsy clinics or antenatal care between the study period. | Children exposed to valproate monotherapy during pregnancy and with epileptic mothers. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Children not exposed to antiepileptic drugs during pregnancy and with epileptic mothers. |
63 / 101 | A better review of the WISC score for children aged 6 and above are provided by Adab 2004 publication. |
| Koch (Valproate), 1996 |
Germany 1976 - 1983 |
Children born to epileptic women who had been treated during pregnancy with antiepileptic drug monotherapy of either primidone/phenobarbitone, phenytoin or valproic acid were studied in detail. The mothers were randomly recruited during their pregnancy from five obstetric departments within the city of Berlin. | Children born to epilepic mothers who had been exposed to valproate during fetal life. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed (general population or NOS)
Children born to mothers randomly recruited during their pregnancy from the same obstetric departments. |
8 / 65 | Study design partly completed with cited source [13]. Prematurity outcome is already documented by Jäger-Roman 1986 with more exposed pregnancies. |
| Li (Valproate) (Controls exposed to LTG), 2023 |
China 2009 - 2022 |
All pregnant participants occurring between 2009 and 2022 in the cohort of women with epilepsy (WWE) of childbearing age (20–45 years old) enrolled from 31 medical institutions. | Women with epilepsy (WWE) using Valproate monotherapy during pregnancy. |
exposed to other treatment, sick
Women with epilepsy (WWE) using Lamotrigine monotherapy during pregnancy. |
31 / 38 | Overlapping: He 2017 totally included in Li 2023. Authors did not provide analysis after monotherapy exposure but raw data of major congenital malformation provided in the e-Supp allowed to extract data for monotherapy => only this outcome reported here. |
| Li (Valproate) (Controls unexposed, sick), 2023 |
China 2009 - 2022 |
All pregnant participants occurring between 2009 and 2022 in the cohort of women with epilepsy (WWE) of childbearing age (20–45 years old) enrolled from 31 medical institutions. | Women with epilepsy (WWE) using Valproate monotherapy during pregnancy. |
unexposed, sick
Women with epilepsy (WWE) not using antiseizure medications during pregnancy. |
31 / 253 | Overlapping: He 2017 totally included in Li 2023. Authors did not provide analysis after monotherapy exposure but raw data of major congenital malformation provided in the e-Supp allowed to extract data for monotherapy => only this outcome reported here. |
| Mawer (Valproate) (Controls exposed to Lamotrigine, sick), 2010 |
UK 2000 - 2006 |
Midwives in the antenatal clinics approached each woman, who gave a history of epilepsy (n=231), whatever her stage of gestation. | Children born to mothers with epilepsy exposed to valproate monotherapy in utero. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Children born to mothers with epilepsy exposed to lamotrigine monotherapy in utero. |
57 / 40 | Kini's 2007 malformation results are overlapped. 39% WWE also actively participated in a NEAD study Meador 2006. Specific major malformations' numerators are extracted from the review by Weston et al. 2016. Period of exposure confirm by author's email. |
| Mawer (Valproate) (Controls unexposed, disease free), 2010 |
UK 2000 - 2006 |
Women with epilepsy (WWE) and the healthy woman controls attending the same clinic. | Children born to mothers with epilepsy exposed to valproate monotherapy in utero. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Children born to mothers without epilepsy who attended the same clinic on the same day or a few days later. |
57 / 315 | Kini's 2007 malformation results are overlapped. Specific major malformations' numerators are extracted from the review by Weston et al. 2016 because not classified per types in the original publication. Period of exposure confirm by author's email. |
| Mawer (Valproate) (Controls unexposed, sick), 2010 |
UK 2000 - 2006 |
Midwives in the antenatal clinics approached each woman, who gave a history of epilepsy (n=231), whatever her stage of gestation. | Children born to mothers with epilepsy exposed to valproate monotherapy in utero. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Children born to women with untreated epilepsy, who took no antiepileptic drugs before or during pregnancy. |
57 / 46 | Kini's 2007 malformation results are overlapped. Specific major malformations' numerators are extracted from the review by Weston et al. 2016 because not classified per types in the original publication. Period of exposure confirm by author's email. |
| McVearry (Valproate), 2009 |
UK and USA 1999 - 2004 |
Pregnant women age 18–35 at time of pregnancy with epilepsy who were taking a single antiepileptic drug for a minimum period of 6 months and enrolled during the first trimester. | Preschool children whose mothers were exposed to valproate in monotherapy during pregnancy for a minimum period of 6 months. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Preschool children whose mothers were exposed to lamotrigine in monotherapy during pregnancy. |
9 / 17 | In utero AED monotherapy exposure for a minimum period of six months. |
| Meador (Valproate), 2006 |
USA and UK 1999 - 2004 |
Pregnant women with epilepsy treated with antiepileptic drugs in monotherapy. | Infants of women exposed to valproate in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Infants of women exposed to lamotrigine in monotherapy during pregnancy. |
69 / 98 | Malformations secondary to known genetic disorders and chromosomal abnormalities are not considered within the major malformation group. 108 women with epilepsy are also used in Mawer 2010 so there is a 33% overlap for malformations. |
| Meador (Valproate), 2009 |
UK and USA 1999 - 2004 |
Livebirths (n=309) of pregnant women with epilepsy who were receiving antiepileptic drugs in monotherapy. | Infants of women exposed to valproate in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Infants of women exposed to lamotrigine in monotherapy during pregnancy. |
60 / 99 | Meador 2011 is completely overlapped with this study which gives a better review of the IQ at age 3 years old (more exposed pregnancies). The cognitive delay at 3 years old is already evaluated in Meador et al., 2013. |
| Meador (Valproate), 2011 |
UK and USA 1999 - 2004 |
Pregnant women (n=211) with epilepsy who were taking a single antiepileptic drug in one of the 25 centers across UK and USA. | Infants of women exposed to valproate in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Infants of women exposed to lamotrigine in monotherapy during pregnancy. |
43 / 70 | A non-exposed control group was not included. |
| Meador (Valproate), 2013 |
UK and USA. 1999 - 2004 |
Livebirths (n=311) of pregnant women with epilepsy who were receiving a single antiepileptic drug in one of the 25 centers across UK and USA between the study period. | Infants of epileptic mothers exposed to valproate in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Infants of epileptic mothers exposed to lamotrigine in monotherapy during pregnancy. |
62 / 100 | A nonexposed control group was not included. Meador 2020 and Cohen 2019 are re-examination or an assessment of subscales of data already assessed in this publication. Cognitif assessment in Meador 2009 and 2011 (x2) is better assessed in this publication. |
| Miškov (Valproate) (Controls exposed to Lamotrigine, sick), 2016 |
Croatia 2003 - 2013 |
Pregnant women with epilepsy during the study period at the the Sestre milosrdnice University Hospital Center. | Pregnancies in women with epilepsy on valproate monotherapy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Pregnancies in women with epilepsy on lamotrigine monotherapy. |
6 / 37 | Includes all Miskov's 2010 outcomes. |
| Miškov (Valproate) (Controls unexposed, disease free), 2016 |
Croatia 2003 - 2013 |
Pregnant women with epilepsy during the study period at the the Sestre milosrdnice University Hospital Center. | Pregnancies in women with epilepsy on valproate monotherapy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Pregnancies in healthy controls. |
6 / 147 | Includes all Miskov's 2010 outcomes. |
| Miškov (Valproate) (Controls unexposed, sick), 2016 |
Croatia 2003 - 2013 |
Pregnant women with epilepsy during the study period at the the Sestre milosrdnice University Hospital Center. | Pregnancies in women with epilepsy on valproate monotherapy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Pregnancies in women with epilepsy without antiepileptic drugs. |
6 / 4 | Includes all Miskov's 2010 outcomes. |
| Nadebaum (Valproate), 2011 |
Australia 2007 - 2009 |
160 women with epilepsy and their 173 children aged 6 to 8 years recruited through the register. | Children exposed to valproate monotherapy in utero from epileptic mother. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Children exposed to lamotrigine monotherapy in utero from epileptic mother. |
23 / 9 | Children with major birth defects or a diagnosis of epilepsy were ineligible for the study to avoid possible confounding effects of these known risk factors for intellectual impairment. |
| Pekoz (Valproate) (Epilepsy) (Controls exposed to LTG), 2023 |
Turkey 2014 - 2019 |
Pregnant women with epilepsy (PWWE) followed up at the participating centers during the study period, with a live birth. | Pregnant women with epilepsy (PWWE) receiving Valproate as monotherapy. |
exposed to other treatment, sick
Pregnant women with epilepsy (PWWE) receiving Lamotrigine as monotherapy. |
82 / 141 | |
| Pekoz (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 |
Turkey 2014 - 2019 |
Pregnant women with epilepsy (PWWE) followed up at the participating centers during the study period, with a live birth. | Pregnant women with epilepsy (PWWE) receiving Valproate as monotherapy. |
unexposed, sick
Pregnant women with epilepsy (PWWE), antiseizure medication free. |
82 / 43 | |
| Pennell (Valproate), 2012 |
USA and UK 1999 - 2004 |
Pregnant women with epilepsy (n=329) producing 311 live births, who were taking a single antiepileptic drug at time of conception to enrollment in one of the 25 centers across UK and USA. | Infants of women exposed to valproate in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Infants of women exposed to lamotrigine in monotherapy during pregnancy. |
62 / 98 | |
| Petersen (Valproate) (Controls exposed to Lamotrigine, sick), 2017 |
UK 1995 - 2014 |
Pregnant women who gave live birth within the database. They were subsequently linked their clinical records to those of the children with the same household identifier if they were registered with the same general practice within 6 months after the children were born. | Women with a record of epilepsy prescribed valproate monotherapy 31–105 days after the start of the pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Women with a record of epilepsy prescribed lamotrigine 31–105 days after the start of the pregnancy without valproate or carbamazepine polytherapy. |
157 / 344 | 'It is possible that individuals who were prescribed lamotrigine could also be prescribed other antiepileptics, however less than 0.01% were prescribed other AEDs (i.e. other than valproate and carbamazepine) during pregnancy.' (author's email) |
| Petersen (Valproate) (Controls unexposed NOS), 2017 |
UK 1995 - 2014 |
Pregnant women who gave live birth within the database. They were subsequently linked their clinical records to those of the children with the same household identifier if they were registered with the same general practice within 6 months after the children were born. | Women prescribed valproate monotherapy 31–105 days after the start of the pregnancy. 90% of the women prescribed valproate had a record of epilepsy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed (general population or NOS)
Women with no records of antiepileptic drug treatment in the pregnancy or 28 days prior to the first day of last menstrual period (LMP). |
176 / 239151 | The sample was then restricted to one randomly chosen pregnancy per woman as pregnancies in the same woman may not be independent. |
| Petersen (Valproate) (Controls unexposed, sick), 2017 |
UK 1995 - 2014 |
Pregnant women who gave live birth within the database. They were subsequently linked their clinical records to those of the children with the same household identifier if they were registered with the same general practice within 6 months after the children were born. | Women with a record of epilepsy prescribed valproate monotherapy 31–105 days after the start of the pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Women with a record of epilepsy but with no records of antiepileptic drug treatment in the pregnancy or 28 days prior to the first day of last menstrual period (LMP). |
157 / 2844 | The sample was then restricted to one randomly chosen pregnancy per woman as pregnancies in the same woman may not be independent. |
| Putignano (Valproate), 2019 |
Italy 2005 - 2011 |
Pregnant women living in 7 of 15 local health units in the Lombardy Region, who delivered between the study period, were identified through the hospital discharge form database. | Newborns from mothers receiving >1 prescription of valproate monotherapy during the whole pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed (general population or NOS)
Newborns from mothers receiving other pharmacological treatment (receiving ≥1 drug prescription excluding antiepileptic drugs and teratogens). |
131 / 917 | |
| Ren (Valproate) (Mixed indications), 2023 |
Denmark 1997 - 2002 |
All live-born singletons in Denmark between the study period. | Children exposed in utero to valproate monotherapy, 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 in utero to any antiepileptic drugs within the exposure time window during pregnancy. |
232 / 370569 | Overlapping: this publication totally included the data of Elkjaer, 2018, for an higher academic grade => use of Ren 2023. Mixed indication (172/232 epilepsy (74%)). |
| Richards (Valproate) (Controls exposed to Lamotrigine, sick) (Indications NOS), 2019 |
New Zealand 2008 - 2012 |
Between 2012 and 2016, 89% of all eligible four-year-olds participated in the program. | Children exposed to valproate monotherapy during pregnancy (the exposure window was defined as nine months before the day of birth). (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Children exposed to lamotrigine monotherapy during pregnancy (the exposure window was defined as nine months before the day of birth). |
161 / 149 | The National Minimum Dataset does not provide reliable diagnosis information. Indications not specified. |
| Richards (Valproate) (Controls unexposed, NOS) (Indications NOS), 2019 |
New Zealand 2008 - 2012 |
Between 2012 and 2016, 89% of all eligible four-year-olds participated in the program. | Children exposed to valproate monotherapy during pregnancy (the exposure window was defined as nine months before the day of birth). (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed (general population or NOS)
All other children unexposed to antiepileptic drug in utero who had a Before School Check (B4SC) in the study period. |
161 / 286966 | The National Minimum Dataset does not provide reliable diagnosis information. Indications not specified. |
| Rihtman (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2013 |
Israel 2001 - 2006 |
Pregnant or pre-pregnant women who contacted the Teratogen Information Service during the study period with queries concerning valproate or lamotrigine. | Children exposed to valproate monotherapy for a minimum of the first trimester of pregnancy born from mothers with or without epilepsy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Children exposed to lamotrigine monotherapy for a minimum of the first trimester of pregnancy born from mothers with or without epilepsy. |
30 / 42 | Exclusion criteria (all groups) were genetic abnormalities and full scale IQ of less than 70. |
| Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 |
Israel 2001 - 2006 |
Pregnant or pre-pregnant women who contacted the Teratogen Information Service during the study period with queries concerning valproate or lamotrigine. | Children exposed to valproate monotherapy for a minimum of the first trimester of pregnancy born from mothers with or without epilepsy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed (general population or NOS)
Children within the specified age-range and identified via word-of-mouth. |
30 / 52 | Exclusion criteria (all groups) were genetic abnormalities and full scale IQ of less than 70. |
| Robert (Valproate), 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 valproate in monotherapy. |
unexposed, sick
Infants born from epileptic mothers unexposed during the first trimester to any antiepileptic drugs. |
15 / 35 | |
| Samrén (Valproate), 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 valproate monotherapy at least during the first trimester of pregnancy |
unexposed, disease free
Children born to nonepileptic nonexposed women. |
158 / 2000 | |
| Shallcross (Valproate), 2011 |
UK and Ireland 2003 - 2010 |
Women taking levetiracetam or valproate monotherapy during their pregnancy and with an IQ above 70 and whose children were below the age of 2 years at the time of assessment were recruited. | Children born to women with epilepsy exposed to valproate monotherapy throughout pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Children born to women without epilepsy, not taking medication during pregnancy. |
44 / 97 | Children exposed to VPA already assessed in the LMNDG program were included in the exposed group (50%) as for the control children (100%). So overlapped with Bromley 2010. Study design is partly completed with cited source [13]. |
| Steegers-Theunissen (Valproate), 1994 |
Netherlands Not specified |
Epileptic and healthy control women visiting the outpatient departments were recruited before conception and just one singleton pregnancy per woman is studied. | Singleton of epileptic women exposed to valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Singleton of healthy women unexposed during pregnancy. |
19 / 106 | Women could only participate if they or any first-degree relative had no genetic disorder known to cause major congenital malformations, and if they were not under treatment for infectious, metabolic, endocrine or malignant diseases. |
| The NAAED (Controls exposed to Lamotrigine, sick) (Indications NOS), 2022 |
North America and Canada 1997 - 2020 |
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 valproate as 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 pregnant women who used lamotrigine as monotherapy, during the first trimester. |
336 / 2333 | Study design completed with the publication of Hernández-Díaz et al. 2012. Data extracted from the North American AED pregnancy registry website. Indications not specified. |
| The NAAED (Controls unexposed, disease free) (Indications NOS), 2022 |
North America and Canada 1997 - 2020 |
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 valproate 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. |
336 / 1201 | Study design completed with Hernández-Díaz et al., 2012. Data extracted from the NAAED registry website. Internal control group reported rather than the external (for relevance purpose). Indications not specified. Wyszynski et al., 2005 overlapped. |
| Thomas (Valproate), 2022 |
India 1998 - 2006 |
Children (13–21 years) of women with epilepsy (CWWE) who were 13 years old or older on 31 December 2019 and had undergone developmental assessment at one year. | Children of women with epilepsy (CWWE) exposed to Valproate monotherapy during pregnancy. |
unexposed, sick
Children of women with epilepsy (CWWE) not exposed to antiseizure medications during pregnancy. |
33 / 11 | Overlapping: Thomas 2022 included data on language and cognitive delay, also evaluated in Sreedharan et al., 2018; Thomas 2007 and Gopinath 2015, but with more exposed pregnancies, more relevant control group and older children => Use of Thomas 2022. |
| Thomas (Valproate) (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 valproate 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. |
341 / 50 | Study design completed with Thomas et al., 2017. Keni's 2018 malformations results are already reported in this publication. |
| Thomas (Valproate) (Controls unexposed, disease free), 2021 |
India 1998 - 2015 |
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 valproate 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, disease free
Children of women without epilepsy in the first trimester of pregnancy and not using antiepileptic drugs from the antenatal clinic of government hospital. |
268 / 319 | This external control group is only available in the 2017 publication. |
| Thomas (Valproate) (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 valproate 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. |
341 / 340 | Study design completed with Thomas et al., 2017. Thomas et al., 2008 completely overlapped with this publication. |
| Thomas b (Valproate), 2008 |
India 1998 - 2004 |
395 infants born to mothers with epilepsy enrolled in the preconception period or during early pregnancy before the fetal outcome is known. | Infants whose epileptic mothers were on valproate monotherapy anytime during the pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Infants not prenatally exposed to antiepileptic drugs anytime during the pregnancy. |
71 / 32 | The Developmental Assessment Scale for Indian Infants (DASII) is an adaptation of the Bayley Scale of Infant Development standardized for Indian infants. |
| Titze (Valproate) (Controls unexposed, disease free), 2008 |
Germany 1976 - 1984 |
Adolescents born during the study period from mothers randomly recruited during their pregnancy, were asked to participate if they had been followed up to 6 years of age. | Adolescents whose epileptic mothers were exposed to valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Adolescents from non-affected mothers. |
3 / 49 | |
| Titze (Valproate) (Controls unexposed, sick), 2008 |
Germany 1976 - 1984 |
Adolescents born during the study period from mothers randomly recruited during their pregnancy, were asked to participate if they had been followed up to 6 years of age. | Adolescents whose epileptic mothers were exposed to valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Adolescents whose epileptic mothers weren't exposed to any antiepileptic drugs during pregnancy. |
3 / 13 | |
| Tomson (Valproate), 2018 |
42 countries 1999 - 2016 |
Pregnancies registered in the database during the study period who had been exposed to antiepileptic drug monotherapy and had complete follow-up data up to 1 year. They were enrolled within gestation week 16 and before fetal outcome is known. | Offspring exposed in utero to valproate monotherapy during the first trimester and born from epileptic mothers. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Offspring exposed in utero to lamotrigine monotherapy during the first trimester and born from epileptic mothers. |
1381 / 2514 | Martinez' 2009 and 2018 malformations results already included in this study. This study is an update of Tomson's 2011 publication. They excluded from the current analysis pregnancies occurring in women without epilepsy. EURAP registry: potential overlap. |
| Tomson (Valproate), 2015 |
42 countries 1999 - 2013 |
Pregnant women (n=6,146) treated with antiepileptic drugs for any indication at the time of conception, enrolment within gestation week 16 and before fetal outcome is known. | Pregnancies in women with epilepsy treated with valproate monotherapy at least during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Pregnancies in women with epilepsy treated with lamotrigine monotherapy at least during the first trimester. |
1171 / 1910 | Pregnancies that occurred in women without epilepsy were excluded. EURAP registry: potential overlap. |
| Trivedi (Valproate) (Controls exposed to Lamotrigine, sick), 2018 |
India 1998 - 2015 |
All women with epilepsy who had completed their pregnancies and enrolled in the registry between the study period. The diagnosis of epilepsy was confirmed before registration. | Pregnant women with epilepsy who used valproate 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
Pregnant women with epilepsy who used lamotrigine monotherapy any time during the first trimester of pregnancy. |
322 / 48 | Study design partly completed with cites source Thomas et al., 2017. |
| Trivedi (Valproate) (Controls unexposed, sick), 2018 |
India 1998 - 2015 |
All women with epilepsy who had completed their pregnancies and enrolled in the registry between the study period. The diagnosis of epilepsy was confirmed before registration. | Pregnant women with epilepsy who used valproate 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
Pregnant women with epilepsy who were not on antiepileptic drug during their first trimester. |
322 / 178 | Study design partly completed with cites source Thomas et al., 2017. |
| Vajda (Valproate) (Controls exposed to Lamotrigine, sick), 2019 |
Australia 1999 - 2018 |
Pregnant women taking antiepileptic drugs for any indications or not treated with antiepileptic drugs in at least the first half of pregnancy. | Offsprings born from women nearly always with epilepsy exposed to valproate in monotherapy in at least 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
Offsprings born from women nearly always with epilepsy exposed to lamotrigine in monotherapy in at least the first trimester of pregnancy. |
290 / 406 | Women with epilepsy accounted for 98.3%. Completely overlap Vajda 2004 (x2); 2005; 2007 (x2); 2010 (x2); 2012 (x2); 2013; 2014 and Jazayeri 2018. Study design partly completed with Vajda 2013. |
| Vajda (Valproate) (Controls exposed to Lamotrigine, sick), 2018 |
Australia 1999 - 2016 |
Pregnant women whether treated with antiepileptic drugs or left untreated in at least the first half of pregnancy. | Offsprings of pregnant women with epilepsy exposed to valproate in monotherapy throughout. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Offsprings of pregnant women with epilepsy exposed to lamotrigine in monotherapy throughout. |
284 / 382 | |
| Vajda (Valproate) (Controls exposed to Lamotrigine, sick), 2013 |
Australia 1999 - 2013 |
Pregnant women with epilepsy whether treated with antiepileptic drugs or left untreated or pregnant women taking antiepileptic drugs for other purposes. | Offsprings from women with epilepsy exposed to valproate in monotherapy in at least 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
Offsprings from women with epilepsy exposed to lamotrigine in monotherapy in at least the first trimester of pregnancy. |
271 / 315 | Women taking AED for epilepsy are in majority (more than 90%). Vajda 2019 provides the most recent update for major malformations results for this register. Specific malformations' results are extracted from the review by Weston et al. 2016. |
| Vajda (Valproate) (Controls unexposed, sick), 2019 |
Australia 1999 - 2018 |
Pregnant women taking antiepileptic drugs for any indications or not treated with antiepileptic drugs in at least the first half of pregnancy. | Offsprings born from women nearly always with epilepsy exposed to valproate in monotherapy in at least the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Offsprings born from women nearly always with epilepsy not treated with antiepileptic drugs in at least the first half of pregnancy. |
290 / 176 | Women with epilepsy accounted for 98.3%. Completely overlap Vajda 2004 (x2); 2005; 2007 (x2); 2010 (x2); 2012 (x2); 2013 (x2); 2014; 2016; Eadie 2005 and Jazayeri 2018. Study design partly completed with Vajda 2013. |
| Vajda (Valproate) (Controls unexposed, sick), 2018 |
Australia 1999 - 2016 |
Pregnant women whether treated with antiepileptic drugs or left untreated in at least the first half of pregnancy. | Offsprings of pregnant women with epilepsy exposed to valproate in monotherapy throughout. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Offsprings of pregnant women with epilepsy that have been untreated in at least the first half of pregnancy. |
284 / 170 | |
| Vajda (Valproate) (Controls unexposed, sick), 2013 |
Australia 1999 - 2013 |
Pregnant women with epilepsy whether treated with antiepileptic drugs or left untreated or pregnant women taking antiepileptic drugs for other purposes. | Offsprings from women with epilepsy exposed to valproate in monotherapy in at least the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Offsprings from women with epilepsy not exposed to antiepileptic drugs in at least the first trimester of pregnancy. |
271 / 147 | Women taking AED for epilepsy are in majority (more than 90%). Vajda 2019 provides the most recent update for major malformations results for this register. Specific malformations' results are extracted from the review by Weston et al. 2016. |
| Vanya (Valproate) (Controls exposed to Lamotrigine, sick), 2015 |
Hungary 2000 - 2014 |
All pregnant women with epilepsy who contacted the department between the study period. | Neonates of epileptic women treated with valproate monotherapy throughout the nine months of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Neonates of epileptic women treated with lamotrigine monotherapy throughout the nine months of pregnancy. |
14 / 6 | Chromosomal anomalies and genetic syndromes were excluded from the study. The only exploitable outcome with a control group concern major congenital malformation. |
| Vanya (Valproate) (Controls unexposed, sick), 2015 |
Hungary 2000 - 2014 |
All pregnant women with epilepsy who contacted the department between the study period. | Neonates of epileptic women treated with valproate monotherapy throughout the nine months of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Neonates of epileptic women treatment-naive for antiepileptic drugs during pregnancy (not exposed to antiepileptic drugs). |
14 / 20 | Chromosomal anomalies and genetic syndromes were excluded from the study. The only exploitable outcome with a control group concern major congenital malformation. |
| Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 |
Norway 1999 - 2011 |
777,785 deliveries recorded in the database during the study period. | Children exposed prenatally to valproate as monotherapy indicated for their mothers' epilepsy or other indications. (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 or other indications. |
333 / 833 | Overlapping: Cohen 2023 and Veiby 2014 => less of 50% of overlapping => the 2 studies were kept. Less than 90% of women are treated with Valproate and Lamotrigine for epilepsy (Mixed indications). |
| Veiby (Valproate) (Controls exposed to Lamotrigine, sick) a, 2013 |
Norway 1999 - 2008 |
108,976 children were registered in the Norwegian Mother and Child Cohort Study cohort from pregnant women attending routine ultrasonographic scanning recruited from hospitals and maternity units. | Children exposed to valproate monotherapy during pregnancy born from epileptic mothers. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Children exposed to lamotrigine monotherapy during pregnancy born from epileptic mothers. |
27 / 71 | Overlap for the neuro-developmental outcomes at 18 and 36 months old and the 'weight less than 10th percentile' outcomes with Bjørk 2018. |
| Veiby (Valproate) (Controls exposed to Lamotrigine, sick) b, 2013 |
Western Norway, Hordaland County. 1999 - 2008 |
107,072 pregnancies were registered in the MoBa cohort with a total of 108,976 children, constituting approximately 18 % of all births in Norway during this period. | Children exposed to valproate monotherapy during pregnancy born from epileptic mothers. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Children exposed to lamotrigine monotherapy during pregnancy born from epileptic mothers. |
40 / 104 | Veiby 2013 major malformations results are already included in Veiby 2014 and risk of ASD better studied in Bjørk 2018 (with more exposed pregnancies). Small for gestationnal age results of Farmen 2015 are completely overlapped by this study. |
| Veiby (Valproate) (Controls unexposed, disease free) (Mixed indications), 2014 |
Norway 1999 - 2011 |
777,785 deliveries recorded in the database during the study period. | Children exposed prenatally to valproate as 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. |
333 / 771412 | Overlapping: Cohen 2023 and Veiby 2014 => less of 50% of overlapping => the 2 studies were kept. Less than 90% of women are treated with Valproate for epilepsy (Mixed indications). |
| Veiby (Valproate) (Controls unexposed, disease free) a, 2013 |
Norway 1999 - 2008 |
108,976 children were registered in the Norwegian Mother and Child Cohort Study cohort from pregnant women attending routine ultrasonographic scanning recruited from hospitals and maternity units. | Children exposed to valproate monotherapy during pregnancy born from epileptic mothers. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Children of parents without epilepsy unexposed to antiepileptic drugs during pregnancy. |
27 / 77770 | Overlap for the neuro-developmental outcomes at 18 and 36 months old and the 'weight less than 10th percentile' outcomes with Bjørk 2018. |
| Veiby (Valproate) (Controls unexposed, disease free) b, 2013 |
Western Norway, Hordaland County. 1999 - 2008 |
107,072 pregnancies were registered in the MoBa cohort with a total of 108,976 children, constituting approximately 18 % of all births in Norway during this period. | Children exposed to valproate monotherapy during pregnancy born from epileptic mothers. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Children of parents without epilepsy unexposed to antiepileptic drugs during pregnancy. |
40 / 107597 | Veiby 2013 major malformations results are already included in Veiby 2014 and risk of ASD better studied in Bjørk 2018 (with more exposed pregnancies). Small for gestationnal age results of Farmen 2015 are completely overlapped by this study. |
| Veiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 |
Norway 1999 - 2011 |
777,785 deliveries recorded in the database during the study period. | Children exposed prenatally to valproate as 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, sick
Children born to women with a history of epilepsy but no antiepileptic drug treatment during pregnancy. |
333 / 3773 | Overlapping: Cohen 2023 and Veiby 2014 => less of 50% of overlapping => the 2 studies were kept. Less than 90% of women are treated with Valproate for epilepsy (Mixed indications). |
| Veiby (Valproate) (Controls unexposed, sick) a, 2013 |
Norway 1999 - 2008 |
108,976 children were registered in the Norwegian Mother and Child Cohort Study cohort from pregnant women attending routine ultrasonographic scanning recruited from hospitals and maternity units. | Children exposed to valproate monotherapy during pregnancy born from epileptic mothers. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Children of mothers with epilepsy unexposed to antiepileptic drugs during pregnancy. |
27 / 276 | Overlap for the neuro-developmental outcomes at 18 and 36 months old and the 'weight less than 10th percentile' outcomes with Bjørk 2018. |
| Veiby (Valproate) (Controls unexposed, sick) b, 2013 |
Western Norway, Hordaland County. 1999 - 2008 |
107,072 pregnancies were registered in the MoBa cohort with a total of 108,976 children, constituting approximately 18 % of all births in Norway during this period. | Children exposed to valproate monotherapy during pregnancy born from epileptic mothers. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Children of mothers with epilepsy not treated with antiepileptic drugs during pregnancy. |
40 / 393 | Veiby 2013 major malformations results are already included in Veiby 2014 and risk of ASD better studied in Bjørk 2018 (with more exposed pregnancies). Small for gestationnal age results of Farmen 2015 are completely overlapped by this study. |
| Videman (Valproate) (Controls exposed to Lamotrigine, sick), 2016 |
Finland 2009 - 2013 |
All pregnant women with epilepsy (PWE) treated with antiepileptic drugs living in Helsinki between the study period. Pregnant women with no antiepileptic drug or other brain-acting medication was recruited by a nurse during regular pregnancy monitoring in an outpatient clinic or by a newspaper announcement. | Newborns from epileptic women with fetal monotherapy valproate exposure during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Newborns from epileptic women with fetal monotherapy lamotrigine exposure during pregnancy. |
5 / 8 | Study design partly completed with a previous article of Videman 2016. |
| Videman (Valproate) (Controls unexposed, disease free), 2016 |
Finland 2009 - 2013 |
All pregnant women with epilepsy (PWE) treated with antiepileptic drugs living in Helsinki between the study period. Pregnant women with no antiepileptic drug or other brain-acting medication was recruited by a nurse during regular pregnancy monitoring in an outpatient clinic or by a newspaper announcement. | Newborns from epileptic women with fetal monotherapy valproate exposure during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Newborns from women with no antiepileptic drug or other brain-acting medication. |
5 / 67 | Study design partly completed with a previous article of Videman 2016. |
| Viinikainen (Valproate) (Controls unexposed, disease free) a, 2006 |
Finland 1989 - 2000 |
24,778 singleton pregnancies in 16,598 women and 179 of these were pregnancies of women with epilepsy followed up during the pregnancy by the Department of Neurology and gave birth in the hospital. | Pregnancies of mothers who had active epilepsy and were using valproate in monotherapy before conception and through the whole pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Pregnancies of mothers without epilepsy and unexposed to antiepileptic drugs. |
28 / 24778 | Multiple pregnancies and pregnancies with evident neonatal chromosomal abnormalities were excluded. |
| Viinikainen (Valproate) (Controls unexposed, sick) a, 2006 |
Finland 1989 - 2000 |
24,778 singleton pregnancies in 16,598 women and 179 of these were pregnancies of women with epilepsy followed up during the pregnancy by the Department of Neurology and gave birth in the hospital. | Pregnancies of mothers who had active epilepsy and were using valproate in monotherapy before conception and through the whole pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Pregnancies of mothers who reported having previous history of epilepsy but no need for antiepileptic drugs at the time of the pregnancy. |
28 / 52 | Multiple pregnancies and pregnancies with evident neonatal chromosomal abnormalities were excluded. |
| Viinikainen (Valproate) b, 2006 |
Finland 1989 - 2000 |
Women with epilepsy who had given birth between the study period in the area of the Kuopio University Hospital. | Pregnancies in which the mother had used valproate during conception and throughout pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Pregnancies in which the mother reported having previous history of epilepsy but had not needed antiepileptic drugs during pregnancy. |
13 / 13 | None evident malformations and any other causes for possible neurological dysfunctions, e.g. signs suggestive for chromosomal or metabolic diseases were found. The evaluators were blinded. Partly completed with Eriksson 2005. |
| Vinten (Valproate), 2005 |
UK Not specified. |
Women with a diagnosis of epilepsy who had children aged between 6 and 16 years recruited from specialist epilepsy clinics and obstetric clinics from the Liverpool and Manchester region. | Children born to epileptic mothers on valproate monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Children born to epileptic mothers not on antiepileptic medication during their pregnancy. |
42 / 83 | Repeat population groups and the same data are already obtained in Adab 2004 for all the neurodevelopmental outcomes except the IQ score within the extremely low range (IQ<69). |
| Wen (Valproate) (Mixed indications), 2017 |
USA 1999 - 2009 |
All female Florida Medicaid enrollees who delivered a live singleton infant between 2000 and 2009. | Infants with maternal exposure to dose of valproate dispensed during 14 days before the first day of the mother’s last menstrual period to the infant’s birth date. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed (general population or NOS)
Infants with no maternal exposure to any antiepileptic drugs during pregnancy. |
226 / 43956 | In the Demographic and Clinical Characteristics of Study Participants women in the exposed group are diagnosed with epilepsy and other diseases therefore 'mixed indications' group. |
| Wiggs (Valproate), 2020 |
Sweden 1996 - 2011 |
Children born in Sweden during the study period and to women with epilepsy any time before childbirth. | Children whose epileptic mothers reported use of valproate monotherapy in the first trimester (77% were found to have filled prescriptions later in pregnancy: second or third trimester). (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Children whose epileptic mothers reported no use of antiseizure medications. |
-9 / 11298 | Children who were multiples were dropped. Crude data are not specified for monotherapy exposure. |
| Wood (Valproate), 2015 |
Australia 2007 - 2010 |
Women with epilepsy and their children (aged 6–8 years) exposed in utero with antiepileptic drugs were identified through the Australian Pregnancy Register for Women on Antiepileptic Medication (APR). | Children of women with epilepsy exposed to valproate in monotherapy during 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 exposed to lamotrigine in monotherapy during pregnancy. |
26 / 9 | Children with major birth defects or a diagnosis of epilepsy were excluded, as these conditions are known risk factors for autism spectrum disorders. Child's IQ results are already reported by the publication of Nadebaum 2011. |
| Study | Country Study period |
Case | Control | Sample size | Rmk |
|---|---|---|---|---|---|
| Arteaga-Vázquez (Valproate), 2012 |
Mexico 1978 - 2010 |
Newborn with one or more congenital malformations. | Newborn control without congenital malformations which is the birth following the newborn with congenital malformations of the same sex born at the same hospital. | 71 / 95 | |
| Bànhidy (Valproate), 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 | Congenital abnormalities syndromes caused by major mutant genes or chromosomal aberrations with preconceptional origin were excluded. Exposure period completed with Czeizel 1992. |
| Czeizel (Valproate), 1992 |
Hungary 1980 - 1987 |
Children affected with congenital abnormalities born from treated or untreated mothers. | Children without congenital abnormalities born from treated or untreated mothers. | 100 / 54 | The study design was partly completed thanks to the reference [6] cited in the publication. All congenital abnormalities except spina bifida are overlapped by the publication of Bànhidy 2011. |
| Källén (Valproate), 1994 |
Sweden 1973 - 1991 |
Infants with spina bifida. | Infants whose mothers had epilepsy and were matched. | 9 / 18 | |
| Thomas a (Valproate), 2008 |
India 1998 - 2004 |
Infants with cardiac malformation defined as any major malformation of the heart or intrathoracic great vessels that is actually or potentially of functional significance. | Infants without cardiac malformation. | 36 / 426 | Completely overlapped with Thomas et al., 2021. |
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