| Study | Country Study period Study design |
Data source | Exposure definition | Non-exposure definition | Exposition period | Sample size (exposed/unexposed) Or (case / control) |
Remarks | Risk of bias |
|---|---|---|---|---|---|---|---|---|
|
Alsaadi (Lamotrigine) (Epilepsy) (Controls unexposed sick) 2020 |
United Arab Emirates 2008 - 2015 retrospective cohort |
The Obstetric Medicine Neurology Clinic at Corniche Hospital in Abu Dhabi, United Arab Emirates (UAE). | Women with epilepsy who were taking Lamotrigine in monotherapy during the first trimester of pregnancy. |
unexposed, sick
Women with epilepsy who were not taking antiseizure drugs (ASDs) during the first trimester of pregnancy. |
1st trimester | 13 / 40 | ||
| Retrospective review: exposure pre-pregnancy and at conception until registered at the clinic was recorded. | ||||||||
|
Alsfouk (Lamotrigine) 2021 |
Riyadh and Jeddah, Saudi Arabia. 1993 - 2020 retrospective cohort |
The King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh and Jeddah, Saudi Arabia. | Epileptic mothers with lamotrigine 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. |
during pregnancy (anytime or not specified) | 15 / 30 | ||
| Patients’ electronic and paper-based medical records. | ||||||||
|
AlSheikh (Lamotrigine) 2020 |
Saudi Arabia 2018 - 2019 prospective cohort |
King Fahd University Hospital | Fetuses/neonates of patients with active epilepsy who received lamotrigine 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. |
during pregnancy (anytime or not specified) | 20 / 8 | ||
| Information was collected through a structured questionnaire ‘Questionnaire for Investigation of Epilepsy in Tropical Countries'. | ||||||||
|
Artama (Lamotrigine) (Controls unexposed, disease free) 2013 |
Finland 1996 - 2008 population based cohort retrospective |
The Medical Birth Register (MBR), the Finnish Malformation Register, the Special Refund Entitlement Register, the Register on Reimbursement Drugs and Cause-of-Death Register. | Births in pregnant women with epilepsy exposed to lamotrigine 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. |
3rd trimester, during pregnancy (anytime or not specified) | 173 / 721948 | Overlapping: For LBW and SGA: Artama 2013 included in a larger study published by Christensen 2024 ((longer study period, 5 countries and more pregnancies) => use of Christensen 2024 for these outcomes. | |
| The Special Refund Entitlement Register and the Register on Reimbursement Drugs contained informations on maternal drug treatment under ATC category N03. | ||||||||
|
Artama (Lamotrigine) (Controls unexposed, sick) 2013 |
Finland 1996 - 2008 population based cohort retrospective |
The Medical Birth Register (MBR), the Finnish Malformation Register, the Special Refund Entitlement Register, the Register on Reimbursement Drugs and Cause-of-Death Register. | Births in pregnant women with epilepsy exposed to lamotrigine 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. |
3rd trimester, during pregnancy (anytime or not specified) | 173 / 1800 | Overlapping: For LBW and SGA: Artama 2013 included in a larger study published by Christensen 2024 ((longer study period, 5 countries and more pregnancies) => use of Christensen 2024 for these outcomes. | |
| The Special Refund Entitlement Register and the Register on Reimbursement Drugs contained informations on maternal drug treatment under ATC category N03. | ||||||||
|
Aydin (Lamotrigine) 2020 |
Turkey 2007 - 2017 retrospective cohort |
The Division of Perinatology, Department of Obstetrics and Gynecology, Hacettepe University | Pregnant women with epilepsy who received lamotrigine 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. |
throughout pregnancy | 7 / 22 | There were no patients who had drug changes or discontinued during pregnancy. | |
| Data were obtained from Perinatology Division’s computerized system. Antiepileptic drug use were reported. | ||||||||
|
Baker (Lamotrigine) (Controls unexposed, disease free) 2015 |
UK 2000 - 2004 prospective cohort |
11 National Health Service hospitals. | Children born to women with epilepsy and exposed to lamotrigine 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. |
during pregnancy (anytime or not specified) | 36 / 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. | |
| An epilepsy specialist confirmed antiepileptic drugs. | ||||||||
|
Baker (Lamotrigine) (Controls unexposed, sick) 2015 |
UK 2000 - 2004 prospective cohort |
11 National Health Service hospitals. | Children born to women with epilepsy and exposed to lamotrigine 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. |
during pregnancy (anytime or not specified) | 36 / 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. | |
| An epilepsy specialist confirmed antiepileptic drugs. | ||||||||
|
Ban (Lamotrigine) (Mixed indications) 2015 |
UK 1990 - 2013 prospective cohort |
The Health Improvement Network (THIN). | 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). (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. |
1st trimester | 273 / 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 with more exposed pregnancies. | |
| Relevant drug prescription in mothers’ primary care electronic health records from four weeks before conception to childbirth. | ||||||||
|
Bech (Lamotrigine) (Mixed indications) 2018 |
Denmark 2005 - 2008 population based cohort propective |
The Danish Prescription Register, the Danish Medical Birth Register, the Danish Psychiatric Central Research Register and Danish National Patient Registry. | Singleton offspring of mothers exposed to lamotrigine monotherapy within 90 days prior to conception to birth. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Singleton offspring of mothers exposed to antiepileptic drugs at any time but not during pregnancy. |
during pregnancy (anytime or not specified) | 290 / 434 | ||
| The Danish National Prescription Register was used to obtain data on redeemed prescriptions using Anatomical Therapeutic Chemical (ATC) codes. | ||||||||
|
Bjørk (Lamotrigine) (Controls unexposed NOS) (Mixed indications) 2022 |
Danemark, Finland, Iceland, Norway and Sweden. 1996 - 2017 population based cohort retrospective |
Social register data from Danemark, Finland, Iceland, Norway, Sweden for SCAN-AED: Nordic register-based study of antiepileptic drugs in pregnancy. | Pregnacies in mothers filling at least one lamotrigine monotherapy prescription from her last menstrual period until birth. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed (general population or NOS)
Pregnacies in mothers without antiseizure medication prescription from her last menstrual period until birth. |
during pregnancy (anytime or not specified) | 7950 / 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. | |
| Prescriptions through national prescription registers according to Anatomical Therapeutic Chemical classification codes N03, N05BA09, and S01EC01. | ||||||||
|
Bjørk (Lamotrigine) (Controls unexposed, disease free) 2018 |
Norway 1999 - 2008 population based cohort propective |
The Norwegian Mother and Child Cohort Study (MoBa) and the Medical Birth Registry of Norway. | Children of women with reported epilepsy and lamotrigine 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. |
during pregnancy (anytime or not specified) | 104 / 104222 | ||
| Information on anti-epileptics use was obtained from the questionnaires completed by mothers during gestational weeks 17 to 19 (Q1) and 30 (Q2); and through the Medical Birth Registry of Norway. | ||||||||
|
Bjørk (Lamotrigine) (Controls unexposed, sick) 2018 |
Norway 1999 - 2008 population based cohort propective |
The Norwegian Mother and Child Cohort Study (MoBa) and The Medical Birth Registry of Norway. | Children of women with reported epilepsy and lamotrigine 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. |
during pregnancy (anytime or not specified) | 104 / 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. | |
| Information on anti-epileptics use was obtained from the questionnaires completed by mothers during gestational weeks 17 to 19 (Q1) and 30 (Q2); and through the Medical Birth Registry of Norway. | ||||||||
|
Bjørk (Lamotrigine) (Controls unexposed, sick) (Mixed indications) 2022 |
Danemark, Finland, Iceland, Norway and Sweden. 1996 - 2017 population based cohort retrospective |
Social register data from Danemark, Finland, Iceland, Norway, Sweden for SCAN-AED: Nordic register-based study of antiepileptic drugs in pregnancy. | Pregnacies in mothers filling at least one lamotrigine 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. |
during pregnancy (anytime or not specified) | 7950 / 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. | |
| Prescriptions through national prescription registers according to Anatomical Therapeutic Chemical classification codes N03, N05BA09, and S01EC01. | ||||||||
|
Blotière (Lamotrigine) (Mixed indications) 2019 |
France 2011 - 2015 retrospective cohort (claims database) |
The French national health insurance database (DCIR) and the French hospital discharge database (PMSI). | Pregnancies exposed to lamotrigine monotherapy between 1 month before and 2 months after the beginning of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed (general population or NOS)
Pregnancies with no reimbursement for antiepileptic drugs. |
1st trimester | 2997 / 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. | |
| The French national health insurance database contains all health care claims reimbursed by French National Health Insurance. Include dispensed drugs coded according to the ATC classification. Monotherapy was defined as the absence of any other antiepileptic drug dispensed during the same period. | ||||||||
|
Borthen (Lamotrigine) (Controls unexposed, disease free) 2010 |
Norway 1999 - 2005 population based cohort retrospective |
The Medical Birth Registry of Norway, the National Population Registry | Births in women who gave a past or present history of epilepsy and exposed to lamotrigine 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. |
during pregnancy (anytime or not specified) | 233 / 362302 | ||
| A standardised antenatal form is filled in by doctors and transferred to the database by practitioners attending the delivery. Pregnancies registered with an anticonvulsant drug (according to ATC Classification System) were categorised as exposed. | ||||||||
|
Borthen (Lamotrigine) (Controls unexposed, disease free) 2011 |
Norway 1999 - 2006 retrospective cohort |
The Medical Birth Registry of Norway and the National Population Registry | Women with epilepsy using lamorigine 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. |
during pregnancy (anytime or not specified) | 30 / 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'. | |
| Informations were extracted from a standardised antenatal form filled in by doctors and transferred to the database by practitioners attending the delivery and also from the neurological case records (according to ATC Classification System). | ||||||||
|
Borthen (Lamotrigine) (Controls unexposed, sick) 2010 |
Norway 1999 - 2005 population based cohort retrospective |
The Medical Birth Registry of Norway, the National Population Registry | Births in women who gave a past or present history of epilepsy and exposed to lamotrigine 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. |
during pregnancy (anytime or not specified) | 233 / 1863 | ||
| A standardised antenatal form is filled in by doctors and transferred to the database by practitioners attending the delivery. Pregnancies registered with an anticonvulsant drug (according to ATC Classification System) were categorised as exposed. | ||||||||
|
Borthen (Lamotrigine) (Controls unexposed, sick) 2011 |
Norway 1999 - 2006 retrospective cohort |
The Medical Birth Registry of Norway and the National Population Registry | Women with epilepsy using lamorigine 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. |
during pregnancy (anytime or not specified) | 30 / 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'. | |
| Informations were extracted from a standardised antenatal form filled in by doctors and transferred to the database by practitioners attending the delivery and also from the neurological case records (according to ATC Classification System). | ||||||||
|
Bromley (Lamotrigine) (Controls unexposed, disease free) 2010 |
UK 2000 - 2006 prospective cohort |
11 different National Health Service hospitals within Merseyside and Greater Manchester (LMNDG: the Liverpool and Manchester Neurodevelopment Group) | Children born to mothers with epilepsy exposed to lamotrigine 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. |
during pregnancy (anytime or not specified) | 34 / 230 | 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). | |
| The research nurse took a personal and medical history in accordance with the prospectively designed Patient Basic and Control Basic Record Forms. An epilepsy specialist confirmed antiepileptic medication. Information from the patient was supplemented from clinical records. | ||||||||
|
Bromley (Lamotrigine) (Controls unexposed, disease free) 2013 |
UK 2000 - 2004 prospective cohort |
The Liverpool and Manchester Neurodevelopment Group (LMNDG) | Children born to epileptic mothers exposed to lamotrigine 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. |
during pregnancy (anytime or not specified) | 36 / 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. | |
| Information was recorded from maternal interview and checked against medical records. An epilepsy specialist confirmed antiepileptic durg type and dose. | ||||||||
|
Bromley (Lamotrigine) (Controls unexposed, sick) 2010 |
UK 2000 - 2006 prospective cohort |
11 different National Health Service hospitals within Merseyside and Greater Manchester (LMNDG: the Liverpool and Manchester Neurodevelopment Group) | Children born to mothers with epilepsy exposed to lamotrigine 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. |
during pregnancy (anytime or not specified) | 34 / 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). | |
| The research nurse took a personal and medical history in accordance with the prospectively designed Patient Basic and Control Basic Record Forms. An epilepsy specialist confirmed antiepileptic medication. Information from the patient was supplemented from clinical records. | ||||||||
|
Bromley (Lamotrigine) (Controls unexposed, sick) 2013 |
UK 2000 - 2004 prospective cohort |
The Liverpool and Manchester Neurodevelopment Group (LMNDG) | Children born to epileptic mothers exposed to lamotrigine 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. |
during pregnancy (anytime or not specified) | 36 / 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. | |
| Information was recorded from maternal interview and checked against medical records. An epilepsy specialist confirmed antiepileptic durg type and dose. | ||||||||
|
Bromley (Lamotrigine) (Epilepsy) 2023 |
United Kingdom 2014 - 2016 prospective cohort |
The NaME (Neurodevelopment of Babies Born to Mothers With Epilepsy) Study, recruiting across the North West and North East of England and from Northern Ireland, UK. | Pregnant women with epilepsy exposed to lamotrigine during pregnancy. |
unexposed, sick
Pregnant women with epilepsy and with no antiseizure medication. |
during pregnancy (anytime or not specified) | 106 / 80 | ||
| The prescribed dose of the antiseizure medications was recorded prospectively from both medical records and maternal interviews at recruitment, and then again at ≥32 weeks gestation (by telephone interviews). | ||||||||
|
Campbell (Lamotrigine) 2014 |
UK and Ireland 1996 - 2012 prospective cohort |
The United Kingdom Epilepsy and Pregnancy Register | Infants of women with epilepsy exposed to lamotrigine 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. |
1st trimester | 2198 / 541 | Study design was partly completed with Morrow 2006. Major malformation results in Morrow et al., 2006 are completely overlapped by this publication (with more exposed pregnancies). | |
| Information was collected at registration and changes of antiepileptic drugs during pregnancy were detected during the follow-up duration by sending a standardised questionnaire to the patient's general practitioner. Other health care practitioners were contacted if identified. | ||||||||
|
Cassina (Lamotrigine) (Mixed indications) 2013 |
Italy 2000 - 2008 prospective cohort |
Italian Teratology Information Services: Servizio di Informazione Teratologica, Telefono Rosso, Centro di Riferimento Regionale di Tossicologia Perinatale. | 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. (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. |
1st trimester | 57 / 867 | Chromosomal anomalies and genetic syndromes were excluded. Less than 90% of women are treated with Lamotrigine for epilepsy. | |
| At the first contact with the service, pregnant women answered to a formulated questionnaire. In addition, details regarding the treatment with antiepileptic drugs taken after the first contact to the Teratology Information Service were ascertained by a follow-up telephone interview. | ||||||||
|
Charlton (Lamotrigine) 2011 |
UK 1990 - 2006 retrospective cohort (claims database) |
The UK General Practice Research Database (GPRD) and the UK Epilepsy and Pregnancy Register. | Infants of mother-baby pairs who had lamotigine 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. |
1st trimester | 98 / 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. | |
| Data generated during routine clinical practice in the UK General Practice Research Database (GPRD). All prescriptions issued by general practitioners are recorded in the database. | ||||||||
|
Charlton (Lamotrigine) (Controls unexposed, disease free) 2017 |
UK 2000 - 2006 retrospective cohort (claims database) |
The UK Clinical Practice Research Datalink (CPRD) | Mother–child pairs where the mother had epilepsy and received lamotrigine 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. |
during pregnancy (anytime or not specified) | 122 / 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. | |
| Determined from issued prescription records. The UK Clinical Practice Research Datalink contains anonymised, patient medical and prescribing records routinely collected within general practice. | ||||||||
|
Charlton (Lamotrigine) (Controls unexposed, sick) 2017 |
UK 2000 - 2006 retrospective cohort (claims database) |
The UK Clinical Practice Research Datalink (CPRD) | Mother–child pairs where the mother had epilepsy and received lamotrigine monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Mother–child pairs where the mother had epilepsy and no antiepileptic drug exposure during pregnancy. |
during pregnancy (anytime or not specified) | 122 / 472 | 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. | |
| Determined from issued prescription records. The UK Clinical Practice Research Datalink contains anonymised, patient medical and prescribing records routinely collected within general practice. | ||||||||
|
Christensen (Lamotrigine) (All indications) 2024 |
Denmark, Finland, Iceland, Norway, and Sweden 1996 - 2017 population based cohort retrospective |
Nordic population-based cohort study including register data from Denmark, Finland, Iceland, Norway, and Sweden–the SCAN-AED project. | Children of mothers who had redeemed at least one prescription of Lamotrigine monotherapy from 30 days before the first day of the last menstrual period to the date of birth (i.e., the exposure period). |
unexposed (general population or NOS)
Children of mothers who had not redeemed prescription of anti-seizure medication. |
during pregnancy (anytime or not specified) | 8756 / 4467848 | Overlapping: For LBW and SGA: Christensen 2024 totally included Kilic 2014 and Artama 2013 => use of Christensen 2024 for these outcomes (longer study period, 5 countries and more pregnancies). | |
| Prenatal exposure was identified via national prescription registers. These registers contain the Anatomical Therapeutic Chemical (ATC) classification code (www.whocc.no) and the date of dispensing. | ||||||||
|
Christensen (Lamotrigine) (Controls unexposed NOS) (Mixed indications) 2015 |
Denmark 1997 - 2008 population based cohort propective |
The Danish Civil Registration System, the Danish Medical Birth Registry and the Danish Register of Medicinal Product Statistics. | Children whose mothers have been exposed to lamotrigine 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. |
during pregnancy (anytime or not specified) | 875 / 674115 | 76% of all exposed mothers have epilepsy. | |
| The Danish Register of Medicinal Product Statistics holds information on all redeemed prescriptions. Monotherapy exposure was defined as redemption of prescription for one type of AED with the Anatomical Therapeutic Codes. | ||||||||
|
Christensen (Lamotrigine) (Controls unexposed, sick) (Mixed indications) 2015 |
Denmark 1997 - 2008 population based cohort propective |
The Danish Civil Registration System, the Danish Medical Birth Registry and the Danish Register of Medicinal Product Statistics. | Children whose mothers have been exposed to lamotrigine 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. |
during pregnancy (anytime or not specified) | 875 / 5261 | 76% of all exposed mothers have epilepsy. | |
| The Danish Register of Medicinal Product Statistics holds information on all redeemed prescriptions. Monotherapy exposure was defined as redemption of prescription for one type of AED with the Anatomical Therapeutic Codes. | ||||||||
|
Christensen (Lamotrigine) (Indications NOS) 2013 |
Denmark 1996 - 2006 population based cohort propective |
The Danish Civil Registration System, the Medical Birth Register and the Danish Register of Medicinal Product Statistics. | Children whose mothers have been exposed to lamotrigine 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 lamotrigine during the exposure window defined from 30 days before the estimated day of conception to the day of birth. |
during pregnancy (anytime or not specified) | 647 / 654747 | Overlapping: For ASD diagnosis/risk : data of Christensen 2013 included in Bjork 2022 because longer study period and 5 countries => use of Bjork 2022 data. Indications not specified. | |
| The Danish Prescription Register holds information on prescriptions. Monotherapy exposure was defined as redemption of prescription for one type of AED with the Anatomical Therapeutic Codes. | ||||||||
|
Cohen (Lamotrigine) (Mixed indications) 2019 |
USA 2000 - 2010 retrospective cohort (claims database) |
Medicaid Analytic eXtract (MAX) | 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. (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. |
early pregnancy | 2682 / 1440631 | Authors excluded deliveries with a major congenital malformation (identified by ICD-9). | |
| The Medicaid Analytic Extract data include prescriptions filled on an outpatient basis. | ||||||||
|
Cohen (Lamotrigine) (Mixed indications) 2023 |
Denmark, Finland, Iceland, Norway, and Sweden 1996 - 2020 population based cohort retrospective |
Health national registers from the 5 Nordic countries. | Pregnancies in which the mother had filled one or more prescriptions of lamotrigine ([ATC] code N03AX09) 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. |
1st trimester | 8339 / 4866362 | Main lamotrigine indications: 56% epilepsy; 30% 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. | |
| Data on filled prescriptions were obtained from the medical birth registers linked with registers for prescribed drugs. | ||||||||
|
Cohen-Israel (Lamotrigine) 2018 |
Israel 2004 – 2014 retrospective cohort |
The Beilinson Teratology Information Service | Children of epileptic women treated with lamotrigine (in monotherapy for 91.6%) during the first trimester of pregnancy. |
unexposed, disease free
Children born at the same hospital to healthy women. |
1st trimester | 83 / 83 | Statistical analysis performed separately for the monotherapy and combined therapy subgroups yielded no significant differences for any of the variables; therefore, all lamotrigine-treated patients were considered as a single group. | |
| The women were identified by a search of the Beilinson Teratology Information Service which contains complete records. | ||||||||
|
Coste (Lamotrigine) (Controls unexposed NOS) (Mixed indications) 2020 |
France 2011 - 2014 retrospective cohort (claims database) |
The French national health data system (SNDS) | Children born from mothers exposed to lamotrigine monotherapy indicated for the treatment of epilepsy and bipolar disorder with at least one dispensing between the beginning of the month preceding onset of pregnancy and its end. (Subgroup of exposure among the whole exposed group in the study). |
unexposed (general population or NOS)
Children born from mothers not exposed to either antiepileptic drug or any drugs for bipolar disorder during pregnancy. |
during pregnancy (anytime or not specified) | 2813 / 1707707 | 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. | |
| Defned by at least one dispensing of the drug to the mother between the beginning of the month preceding onset of pregnancy and the end of pregnancy. Mother had used this drug as monotherapy, defined by the use of a single drug during pregnancy. | ||||||||
|
Cummings (Lamotrigine) 2011 |
Northern Ireland 2002 - 2005 retrospective cohort (registry) |
The UK Epilepsy and Pregnancy Register and the Child Health System database. | Children born to epileptic mothers taking lamotrigine 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. |
throughout pregnancy | 35 / 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. | |
| Information was collected at registration and changes of antiepileptic drugs during pregnancy were detected during the follow-up duration by sending a standardised questionnaire to the patient's general practitioner. | ||||||||
|
Dean (Lamotrigine) 2007 |
Scotland 1976 - 2002 retrospective cohort |
Aberdeen Maternity Hospital. | Children whose epileptic mothers were exposed to lamotrigine 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. |
during pregnancy (anytime or not specified) | 4 / 46 | ||
| A trained research nurse undertook interviews recording antiepileptic drugs use in each pregnancy. Maternal antiepileptic drugs dose was verified from case records where possible. | ||||||||
|
Diav-Citrin (Lamotrigine) 2017 |
Israel 1997 - 2008 prospective cohort |
The Israeli Teratology Information Service | Pregnancies with at least first trimester exposure to lamotrigine for epilepsy in monotherapy. |
unexposed, disease free
Pregnancies from a randomly selected group of women counseled (over a similar timeframe) during pregnancy in regard to exposures known to be nonteratogenic and without chronic diseases. |
at least 1st trimester | 114 / 865 | After one of the authors double-checked the raw data, the result on congenital malformations is 6/114 and not 7/114 'there were indeed 6 malformations in the epilepsy group'. All congenital malformations results is overlapped by Rihtman et al. 2013. | |
| Details of exposure were collected during pregnancy at the initial contact before pregnancy outcome was known, using a structured questionnaire. | ||||||||
|
Dreier (Lamotrigine) (Epilepsy) 2023 |
Denmark, Finland, Iceland, Norway, and Sweden. 1996 - 2017 population based cohort propective |
A prospective, population-based register study within the SCAN-AED project, based on children born in Denmark, Finland, Iceland, Norway, and Sweden. | 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. |
unexposed, sick
Children not prenatally exposed to antiseizure medication. |
during pregnancy (anytime or not specified) | 5288 / 22203 | Overlapping for ASD (2 outcomes): Dreier 2023 and Bjork 2022, with more pregnancies in Dreier 2023 => use of Dreier 2023 data. Not the same category of age for Intellectual disabilities. | |
| Information on use of antiseizure medications was based on the national prescription registers, which contain information on all reimbursed prescription medications dispensed at pharmacies in each country, including date of dispensing and Anatomical Therapeutic Chemical (ATC) classification code. | ||||||||
|
Galbally 2020 |
Australia Not specified. retrospective cohort |
Two Australian tertiary obstetric hospitals: Mercy Hospital for Women in Melbourne, Victoria and King Edward Memorial Hospital in Perth. | Pregnant women exposed to lamotrigine during any trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Pregnant women not exposed to atypical antipsychotics. |
during pregnancy (anytime or not specified) | 19 / 181 | Five women were excluded from the analyses due to having comorbid diagnoses associated with GDM; these were pre-existing diabetes (n = 2) and bulimia nervosa (n = 3). | |
| Specific medications and dose were extracted from hospital records. | ||||||||
|
Gopinath (Lamotrigine) 2015 |
India 2010 - 2012 retrospective cohort (registry) |
The Kerala Registry of Epilepsy and Pregnancy (KREP) | Children from epileptic mothers exposed to lamotrigine in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Children from epileptic mothers without any antiepileptic drugs exposure during pregnancy. |
during pregnancy (anytime or not specified) | 1 / 16 | Study design partly completed with Thomas et al., 2007 from the same registry. | |
| The details of antiepileptic drugs exposure per month were recorded on a monthly basis in the protocol from the month prior to pregnancy through the entire period of pregnancy and three-month post partum. The drug compliance and seizure frequency were ascertained with a detailed diary. | ||||||||
|
Hao (Lamotrigine) (Epilepsy) 2025 |
China Not specified. prospective cohort |
The West China Registry of Pregnancy in Epilepsy (WCRP_ Epi), an ongoing prospective multicenter cohort study based in Sichuan Province, Southwest China. | Pregnant women with confirmed epilepsy that used lamotrigine monotherapy during the first trimester of pregnancy. |
unexposed, sick
Pregnant women with confirmed epilepsy and no anti-seizure medication use during the first trimester. |
1st trimester | 84 / 261 | Use of monotherapy data (table 2). | |
| Treatment information was collected through case report forms mainly through face-to-face visits in the neurology clinic or remotely by video/telephone calls, at each trimester of pregnancy. | ||||||||
|
Hernandez-Diaz (Lamotrigine) (Epilepsy) 2024 |
USA 2000 - 2020 retrospective cohort (claims database) |
Medicaid beneficiaries nationwide, and the Merative MarketScan Commercial Claims and Encounters Database (referred as MarketScan). | Women with epilepsy with at least one dispensing for Lamotrigine monotherapy during the second half of pregnancy (defined as week 19 of gestation to delivery), which is a period of substantial synaptogenesis. |
unexposed, sick
Women with epilepsy without any dispensing of antiseizure medication between 90 days before the last menstrual period and delivery. |
2nd and/or 3rd trimester | 3134 / 8815 | In antiseizure medication meta-analysis : use of monotherapy data only => for this study, use of the secondary analyses, where exposure is defined as monotherapy (only provided for the Epilepsy-Restricted Cohort). => No use of the full-cohort data. | |
| Medicaid beneficiaries nationwide, and the Merative MarketScan Commercial Claims and Encounters Database, two data sources that contain information on dispensed outpatient prescription medications. | ||||||||
|
Hernández-Díaz (Lamotrigine) (Mixed indications) 2014 |
United States and Canada 1997 - 2012 prospective cohort |
The North American Antiepileptic Drug Pregnancy Register | Infants of women exposed to lamotrigine for mixed indications as monotherapy throughout pregnancy. (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 drugs and without epilepsy who had been recruited among the friends and relatives of antiepileptic drugs-exposed participants. |
throughout pregnancy | 1581 / 457 | Less than 90% of women are taking Lamotrigine for epilepsy. Most women used their antiepileptic drug throughout pregnancy. | |
| Women were questioned with a computer-assisted telephone interview 3 times. | ||||||||
|
Holmes (Lamotrigine) 2008 |
North America and Canada 1997 - 2006 prospective cohort |
The North American Antiepileptic Drug Pregnancy Register and the Active Malformations Surveillance Program. | Infants of women who had taken lamotrigine as monotherapy during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed (general population or NOS)
Unexposed newborn infants in the Active Malformations Surveillance Program at Brigham and Women’s Hospital surveyed between 1972 and 1974 and between 1979 and 2000. |
1st trimester | 684 / 206224 | Major malformations results are already assessed in Hernández-Díaz 2012 with more exposed pregnancies. | |
| Women were questioned with a computer-assisted telephone interview 3 times. | ||||||||
|
Holmes (Lamotrigine) (Mixed indications) 2011 |
North America and Canada 1997 - 2011 prospective cohort |
The North American Antiepileptic Drug Pregnancy Register and the Active Malformations Surveillance Program. | 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). (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Infant of pregnant women not taking an antiepileptic drugs and without epilepsy who had been recruited among the friends and relatives of antiepileptic drugs-exposed participants. |
1st trimester | 1118 / 209 | Less than 90% of women are taking Lamotrigine for epilepsy. Major malformations results are already assessed in Hernández-Díaz 2012 with more exposed pregnancies. | |
| Women were questioned with a computer-assisted telephone interview 3 times. | ||||||||
|
Hosny 2021 |
Egypt 2018 - 2020 prospective cohort |
Kasr Al-Ainy Hospital, Cairo University, Egypt | Pregnant women with epilepsy on lamotrigine monotherapy during the first trimester. |
unexposed, sick
Pregnant women with epilepsy with no treatment during the first trimester. |
1st trimester | 3 / 21 | Each woman had one pregnancy during the study period. | |
| The following data were evaluated: seizure control 6 months before pregnancy, seizure control during each trimester, type and dose of ASMs at conception. | ||||||||
|
Husebye (Lamotrigine) (Controls unexposed, disease free) 2020 |
Norway 1999 - 2008 population based cohort propective |
Norwegian Mother and Child Cohort Study (MoBa) and The Medical Birth Registry of Norway. | Children of mothers with epilepsy exposed to lamotrigine 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. |
during pregnancy (anytime or not specified) | 112 / 113674 | ||
| Information on the anti-epileptic (AED) use was obtained from the maternal questionnaires completed during gesta week 17–19 and week 30 and from Medical Birth Registry data. AEDs plasma concentrations were analysed in maternal and umbilical cord samples (73%) and were detected in 93% of children. | ||||||||
|
Husebye (Lamotrigine) (Controls unexposed, sick) 2020 |
Norway 1999 - 2008 population based cohort propective |
Norwegian Mother and Child Cohort Study (MoBa) and The Medical Birth Registry of Norway. | Children of mothers with epilepsy exposed to lamotrigine 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. |
during pregnancy (anytime or not specified) | 112 / 388 | For this comparison group, results are only available according to folic acid intake. | |
| Information on the anti-epileptic (AED) use was obtained from the maternal questionnaires completed during gesta week 17–19 and week 30 and from Medical Birth Registry data. AEDs plasma concentrations were analysed in maternal and umbilical cord samples (73%) and were detected in 93% of children. | ||||||||
|
Källén (Lamotrigine) (Indications NOS) 2013 |
Swedish 1996 - 2011 population based cohort retrospective |
The Swedish Medical Birth Register, the Swedish Register of Prescribed Drugs, the Register of Birth Defect and Hospital Discharge Register. | Infants whose mothers used lamotigine 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. |
early pregnancy | 1084 / 1575847 | Overlapping: Cohen 2023 and Kallen 2013: less of 50% of overlapping => the 2 studies were kept. Overlapping: oral cleft, major and cardiac malfo => included in Wiggs 2024 => Not reported here. Follow-up period: author's email reply. | |
| At the midwife interview at the first antenatal care visit, the woman was asked if she had used any drugs since she became pregnant. Or determined by the use of the Swedish Register of Prescribed Drugs (since 2006). | ||||||||
|
Kasradze (Lamotrigine) 2017 |
Georgia 2001 prospective cohort |
The Georgian National Antiepileptic drugs-Pregnancy Registry (the Georgian registry of EURAP). | Children born to epileptic mothers exposed to lamotrigine 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 |
during pregnancy (anytime or not specified) | 3 / 50 | Children with major congenital malformations were excluded from the study. | |
| Antiepileptic drugs and total daily dosage before pregnancy/at 1st trimester/at 2nd trimester/at 3rd trimester were assessed retrospectively during the mother's structured interview. | ||||||||
|
Kernizan 2019 |
USA 2014 - 2017 retrospective cohort |
Retrospective cohort of patients referred to Maternal Fetal Care Center, St Louis, Missouri. | Pregnant women with bipolar disorder exposed to lamotrigine during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Pregnant women with bipolar disorder not exposed to mood stabilizer during pregnancy. |
during pregnancy (anytime or not specified) | 13 / 140 | The majority of patients (88%, n = 69) were on a single mood stabilizer. | |
| Not reported. | ||||||||
|
Kernizan (Lamotrigine) (Bipolar disorder) 2024 |
USA 2014 - 2017 retrospective cohort |
The Maternal and Fetal Care Center at SSM Health St. Mary's Hospital Center, St Louis, Missouri, USA. | Neonates of mothers with a diagnosis of bipolar disorder treated with lamotrigine monotherapy during pregnancy. |
unexposed, sick
Neonates of mothers with untreated bipolar disorder. |
during pregnancy (anytime or not specified) | 13 / 139 | Women using a combination of multiple mood stabilizers or switching mood stabilizer medications during pregnancy were excluded (n = 22 pregnancies). | |
| Data was collected from a review of electronic medical records. Maternal information collected included bipolar treatment regimens at the first visit, throughout pregnancy, and at delivery. | ||||||||
|
Kilic (Lamotrigine) (Controls unexposed NOS) (Mixed indications) 2014 |
Denmark 1997 - 2008 population based cohort retrospective |
The Danish Medical Birth Registry, the Danish Civil Registration System, the Danish National Hospital Registry, and the Danish Register of Medicinal Product Statistics. | Children whose mothers have been exposed to lamotrigine 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. |
during pregnancy (anytime or not specified) | 880 / 676834 | Less than 90% of women are epileptic. Overlapping: For LBW and SGA: Kilic 2014 included in a larger study published by Christensen 2024 ((longer study period, 5 countries and more pregnancies) => use of Christensen 2024 for these outcomes. | |
| The Danish Register of Medicinal Product Statistics holds information on all redeemed prescriptions. Monotherapy exposure was defined as redemption of prescription for one type of AED with the Anatomical Therapeutic Codes. | ||||||||
|
Kilic (Lamotrigine) (Controls unexposed, sick) (Mixed indications) 2014 |
Denmark 1997 - 2008 population based cohort retrospective |
The Danish Medical Birth Registry, the Danish Civil Registration System, the Danish National Hospital Registry, and the Danish Register of Medicinal Product Statistics. | Children whose mothers have been exposed to lamotrigine 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. |
during pregnancy (anytime or not specified) | 880 / 5296 | Less than 90% of women are epileptic. Overlapping: For LBW and SGA: Kilic 2014 included in a larger study published by Christensen 2024 ((longer study period, 5 countries and more pregnancies) => use of Christensen 2024 for these outcomes. | |
| The Danish Register of Medicinal Product Statistics holds information on all redeemed prescriptions. Monotherapy exposure was defined as redemption of prescription for one type of AED with the Anatomical Therapeutic Codes. | ||||||||
|
Kini (Lamotrigine) 2006 |
UK 1989 - 1999 retrospective cohort |
Epilepsy clinics in Manchester and Liverpool, and at a Central Manchester Maternity Hospital on behalf of the Liverpool and Manchester Neurodevelopmental Study Group (LMNDG). | Children exposed to lamotrigine 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. |
during pregnancy (anytime or not specified) | 9 / 101 | Because we don't know the exact number of children exposed to lamotrigine and analyzed for malformations, this outcome cannot be reported here. | |
| Structured interviews were conducted with the mothers and medical records were available to confirm details in about 80% of participants. | ||||||||
|
Leite (Lamotrigine) (Epilepsy) 2024 |
Brazil 2008 - 2021 retrospective cohort |
Prenatal and prepartum clinics in Maceio, Arapiraca and Santana do Ipanema, which are the reference institutions for the care of pregnant women with epilepsy in the state of Alagoas, Brazil. | Pregnant women with epilepsy using lamotrigine in monotherapy. |
unexposed, disease free
Pregnant women without epilepsy (PWNE). |
during pregnancy (anytime or not specified) | 5 / 492 | Outcomes occurring during pregnancy (preeclampsia, oligohydramnios, abortions...) not reported here because it is not possible to know if exposure was before the outcome occurred (xls table in e-Supp showed that exposure only considered as Yes or No). | |
| This was a retrospective cohort study with data collected from physical and electronic medical records. | ||||||||
|
Li (Lamotrigine) (Epilepsy) 2023 |
China 2009 - 2022 prospective cohort |
A prospective cohort study entitled 'Construction and Application of the Women with Epilepsy of Child-bearing Age Ontology (WWECA)', with West China Hospital of Sichuan University as the main center. | Women with epilepsy (WWE) using Lamotrigine monotherapy during pregnancy. |
unexposed, sick
Women with epilepsy (WWE) not using antiseizure medications during pregnancy. |
during pregnancy (anytime or not specified) | 38 / 253 | 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. Overlapping: He 2017 totally included in Li 2023. | |
| The use of antiseizure medications on the included patients was registered by doctors and trained researchers. | ||||||||
|
Madley-Dowd_SE (Lamotrigine) (Controls unexposed, general pop) (Mixed indications) 2024 |
Sweden 1995 - 2020 population based cohort retrospective |
The Swedish Developmental Origins of Health and Disease (DOHaD) cohort, which is a registry study linking several national electronic data sources. | Fetal exposure to Lamotrigine monotherapy for any indications at any time during the pregnancy period, i.e any pregnancy with self-reported consumption during pregnancy or a prescription 30 days before pregnancy or during pregnancy. |
unexposed (general population or NOS)
No fetal exposure to antiseizure medication at any time during the pregnancy period. |
during pregnancy (anytime or not specified) | 5035 / 2651210 | Partial overlapping of swedish data with Bjork 2022 and Dreier 2023 (IQ, ASD, ADHD) => these studies were kept and tagged. => Data extracted from the e-Supp pdf (Table S1; S2 and S6). | |
| Self-reported maternal consumption of antiseizure medications were prospectively recorded at antenatal care visits (from a structured interview at the first visit at 8–10 weeks of gestation, supplemented from 2005 with drug all prescription dispensations in Sweden (tetrachoric correlation 0.98). | ||||||||
|
Madley-Dowd_SE (Lamotrigine) (Controls unexposed, sibling) (Mixed indications) 2024 |
Sweden 1995 - 2020 population based cohort retrospective |
The Swedish Developmental Origins of Health and Disease (DOHaD) cohort, which is a registry study linking several national electronic data sources. | Siblings with fetal exposure to Lamotrigine monotherapy for any indications at any time during the pregnancy period, i.e any pregnancy with self-reported consumption during pregnancy or a prescription 30 days before pregnancy or during pregnancy. |
sibling
Discordant siblings without fetal exposure to antiseizure medication at any time during the pregnancy period. |
during pregnancy (anytime or not specified) | -9 / -9 | Large overlapping of swedish data with Bjork 2022 (for IQ and ASD) => only use of UK data for these outcomes. Only ADHD reported here => Data extracted from the e-Supp pdf (Table S8) and excel (Figure S8 – Discordant Sibling Analysis). | |
| Self-reported maternal consumption of antiseizure medications were prospectively recorded at antenatal care visits (from a structured interview at the first visit at 8–10 weeks of gestation, supplemented from 2005 with drug all prescription dispensations in Sweden (tetrachoric correlation 0.98). | ||||||||
|
Madley-Dowd_UK (Lamotrigine) (Controls unexposed, general pop) (Mixed indications) 2024 |
United Kingdom 1995 - 2018 retrospective cohort (claims database) |
The UK primary care-based Clinical Practice Research Datalink (CPRD) GOLD, with linkage to the CPRD Pregnancy Register, the CPRD Mother-Baby link, the Hospital Episode Statistics (HES) database, ... | Fetal exposure to Lamotrigine monotherapy for any indications at any time during the pregnancy period, i.e any pregnancy with a prescription that started or ended during the pregnancy period. |
unexposed (general population or NOS)
No fetal exposure to antiseizure medication at any time during the pregnancy period. |
during pregnancy (anytime or not specified) | 939 / 514066 | Partial overlapping of swedish data with Bjork 2022 and Dreier 2023 (IQ, ASD, ADHD) => these studies were kept and tagged. => Data extracted from the e-Supp pdf (Table S1, S2 and S6). | |
| Prescriptions were identified from primary care records. | ||||||||
|
Madley-Dowd_UK (Lamotrigine) (Controls unexposed, sibling) (Mixed indications) 2024 |
United Kingdom 1995 - 2018 retrospective cohort (claims database) |
The UK primary care-based Clinical Practice Research Datalink (CPRD) GOLD, with linkage to the CPRD Pregnancy Register, the CPRD Mother-Baby link, the Hospital Episode Statistics (HES) database, ... | Siblings with fetal exposure to Lamotrigine monotherapy for any indications at any time during the pregnancy period, i.e any pregnancy with a prescription that started or ended during the pregnancy period. |
sibling
Discordant siblings without fetal exposure to antiseizure medication at any time during the pregnancy period. |
during pregnancy (anytime or not specified) | -9 / -9 | Partial overlapping of swedish data with Bjork 2022 and Dreier 2023 (IQ, ASD, ADHD) => these studies were kept and tagged. => Data extracted from the e-Supp pdf (Table S8) and excel (Figure S8 – Discordant Sibling Analysis). | |
| Prescriptions were identified from primary care records. | ||||||||
|
Mawer (Lamotrigine) (Controls unexposed, disease free) 2010 |
UK 2000 - 2006 prospective cohort |
11 National Health Service (NHS) hospitals within Merseyside and Greater Manchester. | Children born to mothers with epilepsy exposed to lamotrigine 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. |
1st trimester | 40 / 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. | |
| The research nurse recorded personal and medical history with forms. An epilepsy specialist confirmed antiepileptic medication. Information from the patient was supplemented from clinical records. | ||||||||
|
Mawer (Lamotrigine) (Controls unexposed, sick) 2010 |
UK 2000 - 2006 prospective cohort |
11 National Health Service (NHS) hospitals within Merseyside and Greater Manchester. | Children born to mothers with epilepsy exposed to lamotrigine 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. |
1st trimester | 40 / 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. | |
| The research nurse recorded personal and medical history with forms. An epilepsy specialist confirmed antiepileptic medication. Information from the patient was supplemented from clinical records. | ||||||||
|
Meador (Lamotrigine) 2023 |
USA 2012 - 2016 prospective cohort |
The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a prospective, observational, multicentre cohort study at 20 specialty epilepsy centres in the USA. | Children born to women with epilepsy treated with Lamotrigine monotherapy. |
unexposed, disease free
Children born to women without epilepsy. |
during pregnancy (anytime or not specified) | 90 / 106 | Imputations analysis reported here. Overlapping: Meador 2021 and 2023 used the same cohort in order to study the same outcome, at 2 different ages (=> use of the data on the older children, i.e Meador 2023). | |
| Data for antiseizure medications were collected using a daily electronic diary and verified at study visits and with medical records. | ||||||||
|
Meador (Lamotrigine) (Controls unexposed, disease free) 2020 |
US 2012 - 2016 prospective cohort |
The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study (20 US tertiary epilepsy centers). | Children born to pregnant women with epilepsy exposed to lamotrigine monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Children born to healthy pregnant women. |
1st trimester | 113 / 106 | ||
| Data were obtained from participants and their medical records. | ||||||||
|
Meador (Lamotrigine) (Controls unexposed, sick) 2020 |
US 2012 - 2016 prospective cohort |
The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study (20 US tertiary epilepsy centers). | Children born to pregnant women with epilepsy exposed to lamotrigine monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Children born to pregnant women with epilepsy with no antiepileptic drug use. |
1st trimester | 113 / 15 | ||
| Data were obtained from participants and their medical records. | ||||||||
|
Miškov (Lamotrigine) (Controls unexposed, disease free) 2016 |
Croatia 2003 - 2013 prospective cohort |
The Sestre milosrdnice University Hospital Center in Zagreb | Pregnancies in women with epilepsy on lamotrigine monotherapy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Pregnancies in healthy controls. |
during pregnancy (anytime or not specified) | 37 / 147 | Includes all Miskov's 2010 outcomes. | |
| Data collected on pregnant women during outpatient visits to the neurologist, gynecologist and pediatrician neurologist. | ||||||||
|
Miškov (Lamotrigine) (Controls unexposed, sick) 2016 |
Croatia 2003 - 2013 prospective cohort |
The Sestre milosrdnice University Hospital Center in Zagreb | Pregnancies in women with epilepsy on lamotrigine 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. |
during pregnancy (anytime or not specified) | 37 / 4 | Includes all Miskov's 2010 outcomes. | |
| Data collected on pregnant women during outpatient visits to the neurologist, gynecologist and pediatrician neurologist. | ||||||||
|
Pekoz (Lamotrigine) (Epilepsy) 2023 |
Turkey 2014 - 2019 prospective cohort |
A Nationwide multicenter study, based on the neurology outpatient clinics of 21 centers in Turkey. | Pregnant women with epilepsy (PWWE) receiving Lamotrigine as monotherapy. |
unexposed, sick
Pregnant women with epilepsy (PWWE), antiseizure medication free. |
during pregnancy (anytime or not specified) | 141 / 43 | ||
| The patients were examined by a neurologist every 2 months during pregnancy, and the use of Anti-seizure medications (ASMs) was assessed. | ||||||||
|
Petersen (Lamotrigine) (Controls unexposed NOS) 2017 |
UK 1995 - 2014 retrospective cohort (claims database) |
The Health Improvement Network (THIN) | Women prescribed lamotrigine 31–105 days after the start of the pregnancy without valproate or carbamazepine polytherapy. 96% of the women prescribed lamotrigine 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). |
1st trimester | 357 / 239151 | '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) | |
| The Health Improvement Network (THIN) provides data on patients’ clinical and prescribing records. Prescriptions are issued electronically via the general practice computer systems. | ||||||||
|
Petersen (Lamotrigine) (Controls unexposed, sick) 2017 |
UK 1995 - 2014 retrospective cohort (claims database) |
The Health Improvement Network (THIN) | Women with a record of epilepsy prescribed lamotrigine 31–105 days after the start of the pregnancy without valproate or carbamazepine polytherapy. (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). |
1st trimester | 344 / 2844 | '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) | |
| The Health Improvement Network (THIN) provides data on patients’ clinical and prescribing records. Prescriptions are issued electronically via the general practice computer systems. | ||||||||
|
Razaz (Epilepsy) 2024 |
Denmark, Finland, Iceland, Norway and Sweden. 1996 - 2017 population based cohort retrospective |
The SCAN-AED project, using the Nordic register infrastructures. | Mothers with epilepsy who filled a prescription for Lamotrigine monotherapy between the date of the last menstrual period (LMP) and the day of birth. |
unexposed, sick
Mothers with epilepsy who did not fill an antiseizure medication (ASM) prescription in the period between 90 days before the last menstrual period (LMP) and the day of birth. |
during pregnancy (anytime or not specified) | 5080 / 19043 | ||
| Prescription for antiseizure medication (ASM) was ascertained using nationwide prescription registers and identified ASMs based on Anatomical Therapeutic Chemical Classification. | ||||||||
|
Ren (Lamotrigine) (Mixed indications) 2023 |
Denmark 1997 - 2002 population based cohort propective |
The Danish Civil Registration System, the Danish Medical Birth Registry, the Danish Agency for Information Technology and Learning, the Danish Register of Medicinal Product Statistics. | Children exposed in utero to 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. (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. |
during pregnancy (anytime or not specified) | 192 / 370569 | Mixed indication (166/192 epilepsy (86%)). Overlapping: this publication totally included the data of Elkjaer, 2018, for an higher academic grade => use of Ren 2023. | |
| Information on medical exposure was retrieved from the Danish Register of Medicinal Product Statistics. | ||||||||
|
Richards (Lamotrigine) (Indications NOS) 2019 |
New Zealand 2008 - 2012 population based cohort retrospective |
The Pharmaceutical Collection, the National Minimum Dataset (NMDS; hospital events), and the Before School Check (B4SC) database. | Children exposed to lamotrigine 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. |
during pregnancy (anytime or not specified) | 149 / 286966 | The National Minimum Dataset does not provide reliable diagnosis information. Indications not specified. | |
| Obtained from the Pharmaceutical Collection database. Any redeemed prescription of an antiepileptic drug belonging to the Anatomical Therapeutic Chemical class N03A. Monotherapy is defined as if only one type of AED was prescribed during the exposure window. | ||||||||
|
Rihtman (Lamotrigine) 2013 |
Israel 2001 - 2006 prospective cohort |
The Israeli Teratogen Information Service | Children exposed to lamotrigine 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. |
at least 1st trimester | 42 / 52 | Exclusion criteria (all groups) were genetic abnormalities and full scale IQ of less than 70. Gestational diabetes not reported because it is not possible to know if exposure was before the outcome occurred. | |
| Details of exposure were collected during pregnancy at the initial contact before pregnancy outcome was known. | ||||||||
|
The NAAED (Indications NOS) 2023 |
North America and Canada 1997 - 2022 prospective cohort |
The North American Antiepileptic Drug Pregnancy Register | Infants of pregnant women who used Lamotrigine as monotherapy, during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Infants of pregnant women, not taking an antiepileptic drug and without epilepsy, who were recruited from among the friends and family members of the enrolled women taking an antiepileptic drug. |
1st trimester | 2461 / 1311 | Study design completed with the publication of Hernández-Díaz et al. 2012. Data extracted from the North American AED pregnancy registry website. Overlapping/update with Hernández-Díaz et al. 2012 and previous website reports. Use of internal control. | |
| Women are interviewed at enrollment, at 7 months’ gestation and at 8 –12 weeks after the expected date of delivery. The computer-assisted interviews include questions on start and stop dates of each antiepileptic drugs taken, dose, frequency and changes in medication. | ||||||||
|
Thomas (Lamotrigine) (Controls unexposed, disease free) 2021 |
India 1998 - 2015 prospective cohort |
The Kerala Registry of Epilepsy and Pregnancy (KREP) | Children of women with epilepsy using lamotrigine 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. |
1st trimester | 38 / 319 | This external control group is only available in the 2017 publication. | |
| Women were instructed to record the use of the antiepileptic drugs on a daily basis in the pregnancy diary that was given to them. | ||||||||
|
Thomas (Lamotrigine) (Controls unexposed, sick) 2021 |
India 1998 - 2019 prospective cohort |
The Kerala Registry of Epilepsy and Pregnancy (KREP) | Children of women with epilepsy using lamotrigine 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. |
1st trimester | 50 / 340 | Study design completed with Thomas et al., 2017. | |
| Women were instructed to record the use of the antiepileptic drugs on a daily basis in the pregnancy diary that was given to them. | ||||||||
|
Thomas (Lamotrigine) (Epilepsy) 2022 |
India 1998 - 2019 prospective cohort |
The Kerala Registry of Epilepsy and Pregnancy (KREP), India. | Infants of women with epilepsy who were exposed to Lamotrigine monotherapy at anytime during the antenatal period. |
unexposed, sick
Infants of women with epilepsy who were not exposed to any antiseizure medications (ASMs) during pregnancy. |
during pregnancy (anytime or not specified) | 26 / 110 | No use of delayed mental development, because discrepancy in LTG data '1/26 (11.5%)'. | |
| Each pregnant woman in the Kerala Registry of Epilepsy and Pregnancy (KREP) maintained a pregnancy diary to record the daily use of antiseizure medications (ASMs). Data were then transferred to the clinical records of the registry during their clinic visits. | ||||||||
|
Trivedi (Lamotrigine) 2018 |
India 1998 - 2015 prospective cohort |
The Kerala Registry of Epilepsy and Pregnancy (KREP) | Pregnant women with epilepsy who used lamotrigine 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. |
1st trimester | 48 / 178 | Study design partly completed with cites source Thomas et al., 2017. | |
| Women were instructed to record the use of the antiepileptic drugs on a daily basis in the pregnancy diary that was given to them. | ||||||||
|
Vajda (Epilepsy) 2025 |
Australia 1999 - 2023 prospective cohort |
The Raoul Wallenberg Australian Pregnancy Register of Antiepileptic Drugs (referred to as ‘Australian Pregnancy Register’ from this point forward). | Women with epilepsy exposed to lamotrigine in monotherapy in early pregnancy. |
unexposed, sick
Women with epilepsy not treated with antiepileptic drugs in early pregnancy. |
at least 1st trimester | 490 / 214 | Overlapping: Vajda 2025 totally included other APR data (Vajda 2024; Vajda 2019; Vajda 2007; 2010 (x2); 2012 (x2); 2013; 2014). Study design partly completed with Vajda 2024. | |
| Details are obtained by four in-depth telephone interviews with the women (at time of enrolment; at approximately 28 weeks of pregnancy; after the 1st post-partum (pp) month, and at one year pp). The accuracy of the information provided by the pregnant women is checked with their treating doctors. | ||||||||
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Vajda (Lamotrigine) 2013 |
Australia 1999 - 2013 prospective cohort |
The Australian Register of Antiepileptic Drugs in Pregnancy. | Offsprings from women with epilepsy exposed to lamotrigine 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. |
at least 1st trimester | 315 / 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. | |
| Details are obtained by four in-depth telephone interviews with the women. Details provided by the participants are confirmed, as far as possible, by the treating medical practitioners. | ||||||||
|
Vajda (Lamotrigine) (Epilepsy) 2024 |
Australia 1999 - 2023 prospective cohort |
The Australian Pregnancy Register of Antiepileptic Drugs (APR). | Women with epilepsy exposed to Lamotrigine monotherapy during pregnancy. |
unexposed, sick
Women with epilepsy unexposed to antiseizure medication during pregnancy. |
during pregnancy (anytime or not specified) | 442 / 184 | Overlapping between Vajda 2024a (1999 - 2023) and Vajda 2018 (1999 - 2016) based on the same register and for the almost same outcome (with or without elective termination) => Use of Vajda 2024a because accounting for more relevant confounders. | |
| Not specified. All contact between the pregnant women and the Melbourne-based register has been by telephone. | ||||||||
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Van Marter (Lamotrigine) (Controls unexposed, disease free) 2021 |
US 2012 - 2016 prospective cohort |
The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study (20 US tertiary epilepsy centers). | Children of pregnant women with epilepsy with exposure to lamotrigine monotherapy based on the mother’s prescribed antiepileptic drug at the time of enrollment. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Children of healthy pregnant women. |
at least 1st trimester | 110 / 106 | Exclusion criteria included history of psychogenic nonepileptic spells, expected IQ of less than 70, other major medical illness, and switching of ASMs in pregnancy before enrollment. | |
| Prescribed antiepileptic drug at the time of enrollment. Data were collected from subjects and their medical records. | ||||||||
|
Van Marter (Lamotrigine) (Controls unexposed, sick) 2021 |
US 2012 - 2016 prospective cohort |
The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study (20 US tertiary epilepsy centers). | Children of pregnant women with epilepsy with exposure to lamotrigine monotherapy based on the mother’s prescribed antiepileptic drug at the time of enrollment. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Children of pregnant women with epilepsy without prescribed antiepileptic drug at the time of enrollment. |
at least 1st trimester | 110 / 15 | Exclusion criteria included history of psychogenic nonepileptic spells, expected IQ of less than 70, other major medical illness, and switching of ASMs in pregnancy before enrollment. | |
| Prescribed antiepileptic drug at the time of enrollment. Data were collected from subjects and their medical records. | ||||||||
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Vanya (Lamotrigine) (Controls unexposed, sick) 2015 |
Hungary 2000 - 2014 retrospective cohort |
Department of Obstetrics and Gynaecology Albert Szent-Györgyi Medical Health Center University of Szeged | Neonates of epileptic women treated with lamotrigine 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). |
throughout pregnancy | 6 / 20 | Chromosomal anomalies and genetic syndromes were excluded from the study. The only exploitable outcome with a control group concern major congenital malformation. | |
| The epilepsy-related data evaluated included antiepileptic drugs therapy (NOS). | ||||||||
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Veiby (Lamotrigine) (Controls unexposed, disease free) (Mixed indications) 2014 |
Norway 1999 - 2011 population based cohort retrospective |
Medical Birth Registry of Norway | Children exposed prenatally to lamotrigine 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. |
throughout pregnancy | 833 / 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 Lamotrigine for epilepsy (Mixed indications). | |
| A standardised notification form is filled in from the first prenatal visit with the general practitioner until discharge and transferred to the database by practitioners attending the delivery. (According to ATC Classification System). | ||||||||
|
Veiby (Lamotrigine) (Controls unexposed, disease free) a 2013 |
Norway 1999 - 2008 prospective cohort |
Norwegian Mother and Child Cohort Study (MoBa) and The Medical Birth Registry of Norway. | Children exposed to lamotrigine 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. |
during pregnancy (anytime or not specified) | 71 / 77770 | Overlap for the neuro-developmental outcomes at 18 and 36 months old and the 'weight less than 10th percentile' outcomes with Bjørk 2018 and Veiby 2013b. | |
| Reported by the mother in the first MoBa questionnaire (weeks 13-17) as well as recorded in the compulsory Medical Birth Registry by the attending physician and midwife at delivery. | ||||||||
|
Veiby (Lamotrigine) (Controls unexposed, disease free) b 2013 |
Western Norway, Hordaland County. 1999 - 2008 prospective cohort |
Norwegian Mother and Child Cohort Study (MoBa) and The Medical Birth Registry of Norway. | Children exposed to lamotrigine 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. |
during pregnancy (anytime or not specified) | 104 / 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. | |
| Questionnaires were filled out by the mothers (at gestational week 13–17) and medical hospital-records were examined to validate the self-reported use of antiepileptic drugs during pregnancy. | ||||||||
|
Veiby (Lamotrigine) (Controls unexposed, sick) (Mixed indications) 2014 |
Norway 1999 - 2011 population based cohort retrospective |
Medical Birth Registry of Norway | Children exposed prenatally to lamotrigine 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. |
throughout pregnancy | 833 / 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 Lamotrigine for epilepsy (Mixed indications). | |
| A standardised notification form is filled in from the first prenatal visit with the general practitioner until discharge and transferred to the database by practitioners attending the delivery. (According to ATC Classification System). | ||||||||
|
Veiby (Lamotrigine) (Controls unexposed, sick) a 2013 |
Norway 1999 - 2008 prospective cohort |
Norwegian Mother and Child Cohort Study (MoBa) and The Medical Birth Registry of Norway. | Children exposed to lamotrigine 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. |
during pregnancy (anytime or not specified) | 71 / 276 | Overlap for the neuro-developmental outcomes at 18 and 36 months old and the 'weight less than 10th percentile' outcomes with Bjørk 2018 and Veiby 2013 b. | |
| Reported by the mother in the first MoBa questionnaire (weeks 13-17) as well as recorded in the compulsory Medical Birth Registry by the attending physician and midwife at delivery. | ||||||||
|
Veiby (Lamotrigine) (Controls unexposed, sick) b 2013 |
Western Norway, Hordaland County. 1999 - 2008 prospective cohort |
Norwegian Mother and Child Cohort Study (MoBa) and The Medical Birth Registry of Norway. | Children exposed to lamotrigine 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. |
during pregnancy (anytime or not specified) | 104 / 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. | |
| Questionnaires were filled out by the mothers (at gestational week 13–17) and medical hospital-records were examined to validate the self-reported use of antiepileptic drugs during pregnancy. | ||||||||
|
Videman (Lamotrigine) 2016 |
Finland 2009 - 2013 prospective cohort |
The Helsinki University Hospital | Newborns from epileptic women with fetal monotherapy lamotrigine 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. |
during pregnancy (anytime or not specified) | 8 / 67 | Study design partly completed with a previous article of Videman 2016. | |
| Exposure data (including daily doses and serum levels for oxcarbazepine, carbamazepine, valproic acid, lamotrigine, and levetiracetam) were obtained prospectively at outpatient visits taking place every trimester and postnatally. | ||||||||
|
Wiggs (Epilepsy) (Lamotrigine) 2024 |
Sweden 1996 - 2016 population based cohort retrospective |
Cohort of individuals obtained from the Medical Birth Register (MBR), the National Patient Register (NPR). | Children born to women with recent epilepsy diagnosis who reported the use of Lamotrigine monotherapy at their first antenatal visit (8th-12th week of pregnancy). |
unexposed, sick
Children whose mothers had a recent diagnosis of epilepsy but who did not report the use of any antiseizure medications (ASMs) at their first antenatal visit. |
early pregnancy | 1412 / 9364 | Use of data in children born to women with a recent diagnosis of epilepsy prior to conception and with single antiseizure medication exposure. Total number of unexposed group based on eTable 3. Adjusted (according to figure titles). | |
| Information recorded at the first antenatal visit (8th-12th week of pregnancy) includes prescription drug use. | ||||||||
| Study | Country Study period Study design |
Data source | Case | Control | Exposition | Exposition period | Sample size (exposed/unexposed) Or (case / control) |
Remarks | Risk of bias |
|---|---|---|---|---|---|---|---|---|---|
|
Dolk (Lamotrigine) (Mixed indications) 2016 |
Europe 1995 – 2011 case control |
21 EUROCAT Congenital Anomaly registries | Babies with nonsyndromic orofacial clefts or with nonchromosomal clubfoot excluding spina bifida sequence. | Babies with nonchromosomal major congenital anomaly excluding orofacial clefts or with nonchromosomal nonclubfoot major congenital anomaly. | The EUROCAT central database contains medications taken in the first trimester of pregnancy (Anatomical Therapeutic Chemical coded). Information is mainly obtained from medical records of pregnancy, and some registries also use maternal interviews after birth or prescription databases. | 1st trimester | -9 / 182897 | Among lamotrigine monotherapy exposures, 77.1% were recorded with maternal epilepsy. Crude data for lamotrigine restricted to first trimester exposure are unknown. | |
| Anomalies are coded by ICD-9/10 codes. | |||||||||
Risk of bias: : NA; : low; : moderate; : serious; : critical; : unclear;
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