Valproate (Paternal exposure)

Exposed non-exposed, cohort studies

Study Country
Study period
Study design		 Data source Exposure definition Non-exposure definition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias
Botton
2025 		France
2010 - 2015
retrospective cohort (claims database) 		The EPI-MERES registry, created by EPI-PHARE using data from the French National Health Data System (SNDS), France. Children whose father had at least one reimbursed dispensing of a valproic acid–based (or valproate) medication indicated for epilepsy in the four months preceding the conception date. exposed to other treatment, sick
Children whose father had at least one reimbursed dispensing of lamotrigine ot levetiracetam in the four months preceding the conception date. 		Paternal exposure: epigenetic window only (3–xxx months preconception), Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception) 4773 / 3115 Results from monotherapy were preferred over those from mono/polytherapy, so that the findings could be more attributable to the substances of interest. Inversion of ICD-10 codes for learning and communication disorders in table S1 but not in results.
Exposure data were extracted from the French National Health Data System (SNDS), that contains reimbursement data for healthcare expenses and hospitalizations for more than 99% of residents in France.
Christensen (Controls exposed to LTG/LEV)
2024 		Denmark
1997 - 2017
population based cohort retrospective 		Danish nationwide healthcare registers: the Danish Medical Birth Registry, the Danish National Prescription Registry, the Danish National Patient Register, the Danish Register of Causes of Death and the Danish Psychiatric Central Research Register. Children of fathers who filled 1or more prescriptions for valproate (in monotherapy for neurodevelopmental disorders (NDDs)) immediately before or during the time of spermatogenesis (ie, 3 months prior to conception plus 30 days to account for prescriptions filled just prior to spermatogenesis). exposed to other treatment, sick
Children of fathers who filled 1or more prescriptions for lamotrigine (or levetiracetam, both in monotherapy for NDDs) immediately before or during the time of spermatogenesis (ie, 3 months prior to conception plus 30 days to account for prescriptions filled just prior to spermatogenesis). 		Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception) 1336 / 1663 Methods and results available in Christensen 2024 were completed with Christensen 2025 (for neurodevelopmental disorders as a whole, Intellectual disability, ASD and ADHD), because monotherapy and additional confounders take into account.
Redeemed prescriptions, including information on all prescriptions for ASM filled by patients that are prescribed by hospital physicians, private specialists, or general practitioners, were extracted from the Danish National Prescription Registery.
Christensen (Controls unexposed, general pop)
2024 		Denmark
1997 - 2017
population based cohort retrospective 		Danish nationwide healthcare registers: the Danish Medical Birth Registry, the Danish National Prescription Registry, the Danish National Patient Register, the Danish Register of Causes of Death and the Danish Psychiatric Central Research Register. Children of fathers who filled 1or more prescriptions for valproate immediately before or during the time of spermatogenesis (ie, from 120 days prior to the beginning of pregnancy: 3 months prior to conception plus 30 days to account for prescriptions filled just prior to spermatogenesis). unexposed (general population or NOS)
Children of fathers who did not fill prescriptions for valproate immediately before or during the time of spermatogenesis (ie, from 120 days prior to the beginning of pregnancy: 3 months prior to conception plus 30 days to account for prescriptions filled just prior to spermatogenesis). 		Paternal exposure: epigenetic window only (3–xxx months preconception), Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception) 1336 / 1234017 When available, the results from monotherapy were preferred over those from mono/polytherapy, so that the findings could be more attributable to the substances of interest.
Redeemed prescriptions, including information on all prescriptions for ASM filled by patients that are prescribed by hospital physicians, private specialists, or general practitioners, were extracted from the Danish National Prescription Registery.
Christensen (Controls unexposed, sibling)
2024 		Denmark
1997 - 2017
population based cohort retrospective 		Danish nationwide healthcare registers: the Danish Medical Birth Registry, the Danish National Prescription Registry, the Danish National Patient Register, the Danish Register of Causes of Death and the Danish Psychiatric Central Research Register. Children of fathers who filled 1 or more prescriptions for valproate immediately before or during the time of spermatogenesis (ie, 120 days prior to the beginning of pregnancy: 3 months prior to conception plus 30 days to account for prescriptions filled just prior to spermatogenesis). sibling
Sibling children with discordant paternal exposure regarding valproate. 		Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception) 303 / 381
Redeemed prescriptions, including information on all prescriptions for ASM filled by patients that are prescribed by hospital physicians, private specialists, or general practitioners, were extracted from the Danish National Prescription Registery.
Christensen (Controls unexposed, sick)
2024 		Denmark
1997 - 2017
population based cohort retrospective 		Danish nationwide healthcare registers: the Danish Medical Birth Registry, the Danish National Prescription Registry, the Danish National Patient Register, the Danish Register of Causes of Death and the Danish Psychiatric Central Research Register. Children of fathers with epilepsy who filled 1or more prescriptions for valproate immediately before or during the time of spermatogenesis (ie, 120 days prior to the beginning of pregnancy: 3 months prior to conception plus 30 days to account for prescriptions filled just prior to spermatogenesis). unexposed, sick
Children of fathers with epilepsy who did not filled prescription for valproate immediately before or during the time of spermatogenesis (ie, 120 days prior to the beginning of pregnancy: 3 months prior to conception plus 30 days to account for prescriptions filled just prior to spermatogenesis). 		Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception) 1052 / 11308
Redeemed prescriptions, including information on all prescriptions for ASM filled by patients that are prescribed by hospital physicians, private specialists, or general practitioners, were extracted from the Danish National Prescription Registery.
Colas_Norway
2025 		Norway
2010 - 2019
population based cohort retrospective 		Population-based, nationwide, cohort study conducted using registries from Norway: the Norwegian Patient Registry, the Medical Birth Registry, the Cause of Death Register, the Norwegian Prescription Database, ... Offspring paternally exposed to valproate in monotherapy within 3 months prior to conception (during the spermatogenic risk window). exposed to other treatment, sick
Offspring paternally exposed to lamotrigine or levetiracetam in monotherapy within 3 months prior to conception (during the spermatogenic risk window). 		Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception) 413 / 1058 Overlapping between Colas 2025 (2010 - 2019), Razaz 2026 (2010 - 2018) and Meng 2026 (2010-2015) => use of the data with a higher number of exposures and/or better ROB confusion, or older children i.e Meng 2026 for ASD and ADHD and Razaz for NDDs.
Exposure information was derived from prescription data, as recorded in the National Prescription Registry.
Meng_Norway (Controls exposed to LTG/LEV)
2026 		Norway
2010 - 2015
population based cohort retrospective 		Population-based health-registry linkage in Norway: the Medical Birth Registry of Norway, the Norwegian Patient Registry, the Norwegian Prescription Database, and the Norwegian Control and Payment of Health Reimbursements Database. Children born to fathers with prescription of valproate monotherapy (ATC code: N03AG01; no other antiseizure medications) during spermatozoa development period (during the 90 days preceding the estimated date of conception). exposed to other treatment, sick
Children born to fathers with prescription of lamotrigine or levetiracetam monotherapy during spermatozoa development period (during the 90 days preceding the estimated date of conception). 		Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception) 319 / 730 Overlapping for ASD and ADHD between Meng 2026 and Razaz 2026: use of Meng 2026 because best ROB confusion and longer follow up (8.7 years versus 5.2 years).
Paternal use of valproate (ATC code: N03AG01) was based on the Norwegian prescription registry. Data available: the dispensing date, quantity dispensed, and number of days supplied.
Meng_Norway (Controls unexposed, general pop)
2026 		Norway
2010 - 2015
population based cohort retrospective 		Population-based health-registry linkage in Norway: the Medical Birth Registry of Norway, the Norwegian Patient Registry, the Norwegian Prescription Database, and the Norwegian Control and Payment of Health Reimbursements Database. Children born to fathers with prescription of valproate monotherapy (ATC code: N03AG01; no other antiseizure medications) during spermatozoa development period (during the 90 days preceding the estimated date of conception). unexposed (general population or NOS)
Children born to fathers with no exposure to any antiseizure medications during the 90 days prior to conception. 		Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception) 319 / 337109
Paternal use of valproate (ATC code: N03AG01) was based on the Norwegian prescription registry. Data available: the dispensing date, quantity dispensed, and number of days supplied.
Meng_Norway (Controls unexposed, sick)
2026 		Norway
2010 - 2015
population based cohort retrospective 		Population-based health-registry linkage in Norway: the Medical Birth Registry of Norway, the Norwegian Patient Registry, the Norwegian Prescription Database, and the Norwegian Control and Payment of Health Reimbursements Database. Children born to fathers with prescription of valproate monotherapy (ATC code: N03AG01; no other antiseizure medications) during spermatozoa development period (during the 90 days preceding the estimated date of conception). unexposed, sick
Children born to fathers with an indication for antiseizure medication and no exposure to any antiseizure medications during the 90 days prior to conception. 		Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception) 304 / 121306 Overlapping for ASD and ADHD between Meng 2026 and Razaz 2026: use of Meng 2026 because best ROB confusion and longer follow up (8.7 years versus 5.2 years).
Paternal use of valproate (ATC code: N03AG01) was based on the Norwegian prescription registry. Data available: the dispensing date, quantity dispensed, and number of days supplied.
Meng_Taiwan (Controls exposed to LTG/LEV)
2026 		Taiwan
2010 - 2015
population based cohort retrospective 		Population-based health-registry linkage in Taiwan: the National Birth Certificate Application database, National Health Insurance Research Database, and the Maternal and Child Health Database. Children born to fathers with prescription of valproate monotherapy (ATC code: N03AG01; no other antiseizure medications) during spermatozoa development period (during the 90 days preceding the estimated date of conception). exposed to other treatment, sick
Children born to fathers with prescription of lamotrigine or levetiracetam monotherapy during spermatozoa development period (during the 90 days preceding the estimated date of conception). 		Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception) 564 / 96
Paternal use of valproate (ATC code: N03AG01) was based on the National Health Insurance Database (NHI). Data available: the dispensing date, quantity dispensed, and number of days supplied.
Meng_Taiwan (Controls unexposed, general pop)
2026 		Taiwan
2010 - 2015
population based cohort retrospective 		Population-based health-registry linkage in Taiwan: the National Birth Certificate Application database, National Health Insurance Research Database, and the Maternal and Child Health Database. Children born to fathers with prescription of valproate monotherapy (ATC code: N03AG01; no other antiseizure medications) during spermatozoa development period (during the 90 days preceding the estimated date of conception). unexposed (general population or NOS)
Children born to fathers with no exposure to any antiseizure medications during the 90 days prior to conception. 		Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception) 564 / 1045300
Paternal use of valproate (ATC code: N03AG01) was based on the National Health Insurance Database (NHI). Data available: the dispensing date, quantity dispensed, and number of days supplied.
Meng_Taiwan (Controls unexposed, sick)
2026 		Taiwan
2010 - 2015
population based cohort retrospective 		Population-based health-registry linkage in Taiwan: the National Birth Certificate Application database, National Health Insurance Research Database, and the Maternal and Child Health Database. Children born to fathers with prescription of valproate monotherapy (ATC code: N03AG01; no other antiseizure medications) during spermatozoa development period (during the 90 days preceding the estimated date of conception). unexposed, sick
Children born to fathers with an indication for antiseizure medication and no exposure to any antiseizure medications during the 90 days prior to conception. 		Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception) 543 / 500498
Paternal use of valproate (ATC code: N03AG01) was based on the National Health Insurance Database (NHI). Data available: the dispensing date, quantity dispensed, and number of days supplied.
Razaz_Norway
2026 		Norway
2010 - 2018
population based cohort retrospective 		Population-based cohort study of Norway that linked the Norwegian Medical Birth Registry, the Norwegian Patient Registry and the Norwegian Prescribed Drug Registry. Children whose fathers were exposed to valproate only (among antiseizure medications) during spermatogenesis (defined as filling ≥1 prescription from 120 days before the first day of the LMP to LMP 14 days). exposed to other treatment, sick
Children whose fathers were exposed to lamotrigine only or levetiracetam only (among antiseizure medications) during spermatogenesis (defined as filling ≥1 prescription from 120 days before the first day of the LMP to LMP 14 days). 		Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception) 463 / 1109 Overlapping for ASD and ADHD between Meng 2026 and Razaz 2026: use of Meng 2026 because best ROB confusion and longer follow up (8.7 years versus 5.2 years). High-dose valproate was associated with higher non-significant point estimates for NDD.
The Norwegian Prescribed Drug Registry contains information on all dispensed prescriptions in Norwegian pharmacies from 2004 and onwards.
Razaz_Sweden
2026 		Sweden
2007 - 2020
population based cohort retrospective 		Population-based cohort study of Sweden that linked the Swedish Medical Birth Register, the National Patient Register and the Prescribed Drug Registry. Children whose fathers were exposed to valproate only (among antiseizure medications) during spermatogenesis (defined as filling ≥1 prescription from 120 days before the first day of the LMP to LMP 14 days). exposed to other treatment, sick
Children whose fathers were exposed to lamotrigine only or levetiracetam only (among antiseizure medications) during spermatogenesis (defined as filling ≥1 prescription from 120 days before the first day of the LMP to LMP 14 days). 		Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception) 1595 / 3097 Overlapping: SE databases used in Colas 2025 (1997-2019), Tomson 2020 (1997-2016) and Razaz 2026 (2007-2020)=> use of the data with a higher number of exposures and better ROB confusion, i.e Razaz 2026 for ASD, ADHD, IQ and Tomson 2020 for Malformations.
The Prescribed Drug Registry contains data on all dispensed medications nationwide, classified by the Anatomical Therapeutic Chemical (ATC) system, since 1 July 2005.
Tomson
2020 		Sweden
2006 - 2016
population based cohort retrospective 		Swedish national registries: the Swedish Medical Birth Register, the National Patient Register, the Prescribed Drug Registry. Singleton offsprings born to fathers with epilepsy exposed to valproate in monotherapy within 74 days (ie, the duration of spermatogenesis) prior to or at the time of conception. unexposed, sick
Singleton offsprings born to fathers with epilepsy unexposed to antiepileptic drugs within 74 days (ie, the duration of spermatogenesis) prior to or at the time of conception. 		Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception) 458 / 2457 Overlapping: SE databases used in Colas 2025 (1997-2019), Tomson 2020 (1997-2016) and Razaz 2026 (2007-2020)=> use of the data with a higher number of exposures and better ROB confusion, i.e Razaz 2026 for ASD, ADHD, IQ and Tomson 2020 for Malformations.
Dispensation of all antiepileptic drugs were identified through the Prescribed Drug Registry belonging to ATC class N03A given to both parents.

Case-control studies

Study Country
Study period
Study design		 Data source Case Control Exposition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias

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

Empty. There are no case-control studies available for this drug.

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