Valproate (Paternal exposure) - Medication and Pregnancy KB

Valproate (Paternal exposure)

Exposed non-exposed studies (cohort)

Study	Country Study period	Population source	Exposure definition	Non-exposure definition	Sample size	Rmk
Botton, 2025	France 2010 - 2015	Children from the EPI-MERES registry who were born alive between 2010 and 2015, with an identified father (aged at least 12 years) and mother (aged 15 to 49 years).	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.	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.
Christensen (Controls exposed to LTG/LEV), 2024	Denmark 1997 - 2017	All singletons born alive in Denmark between January 1, 1997, and December 31, 2017, identified in the Medical Birth 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).	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.
Christensen (Controls unexposed, general pop), 2024	Denmark 1997 - 2017	All singletons born alive in Denmark between January 1, 1997, and December 31, 2017, identified in the Medical Birth 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).	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.
Christensen (Controls unexposed, sibling), 2024	Denmark 1997 - 2017	All singletons born alive in Denmark between January 1, 1997, and December 31, 2017, identified in the Medical Birth 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.	303 / 381
Christensen (Controls unexposed, sick), 2024	Denmark 1997 - 2017	All singletons born alive in Denmark between January 1, 1997, and December 31, 2017, identified in the Medical Birth 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).	1052 / 11308
Colas_Norway, 2025	Norway 2010 - 2019	All singleton live births (and stillbirths, and spontaneous abortions for malformation outcomes), linked to both parents, and from fathers who received 1 or more antiseizure medications , regardless of the indication, and with records in the database for 12 or more months prior to the linked maternal LMP2 date.	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).	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.
Meng_Norway (Controls exposed to LTG/LEV), 2026	Norway 2010 - 2015	All live-born singleton children with birth dates between January 1, 2010, and December 31, 2015, and followed up until 2021.	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).	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).
Meng_Norway (Controls unexposed, general pop), 2026	Norway 2010 - 2015	All live-born singleton children with birth dates between January 1, 2010, and December 31, 2015, and followed up until 2021.	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.	319 / 337109
Meng_Norway (Controls unexposed, sick), 2026	Norway 2010 - 2015	All live-born singleton children with birth dates between January 1, 2010, and December 31, 2015, and followed up until 2021.	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.	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).
Meng_Taiwan (Controls exposed to LTG/LEV), 2026	Taiwan 2010 - 2015	All live-born singleton children with birth dates between January 1, 2010, and December 31, 2015, and followed up until 2021.	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).	564 / 96
Meng_Taiwan (Controls unexposed, general pop), 2026	Taiwan 2010 - 2015	All live-born singleton children with birth dates between January 1, 2010, and December 31, 2015, and followed up until 2021.	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.	564 / 1045300
Meng_Taiwan (Controls unexposed, sick), 2026	Taiwan 2010 - 2015	All live-born singleton children with birth dates between January 1, 2010, and December 31, 2015, and followed up until 2021.	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.	543 / 500498
Razaz_Norway, 2026	Norway 2010 - 2018	All singleton live births at ≥22 completed gestational weeks identified in the Medical Birth Registers, between 1 January 2010 and 31 December 2018.	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).	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.
Razaz_Sweden, 2026	Sweden 2007 - 2020	All singleton live births at ≥22 completed gestational weeks identified in the Medical Birth Registers, between 1 January 2007 and 31 December 2020.	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).	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.
Tomson, 2020	Sweden 2006 - 2016	All singleton live births at ≥22 completed gestational weeks in Sweden from 2006 through 2016 as identified in the Swedish Medical Birth Register.	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.	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.

Case-control studies (cohort)

Study	Country Study period	Case	Control	Sample size	Rmk

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

12 studies, not fulfilled eligibility criteria, were excluded. See excluded tab for the list of these studies and reason of exclusion.

master protocol