Valproate (Paternal exposure)

Study	Type of data	Exposure measurement	Outcome assessment	Adjustment
Botton, 2025	retrospective cohort (claims database)	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.	Neurodevelopmental disorders were identified based on hospitalization and long-term condition diagnoses, reimbursements for methylphenidate (a medication indicated for ADHD), and speech-therapy procedures related to communication or learning disorders.	Exclusion of children with a brain malformation, medically assisted reproduction conceived, whose mother use VPA, CBZ, or TOP in pregnancy. PS for children sex, year of birth, preterm, SGA, LBW, hypoxia; Maternal/paternal age, mental health disorders, TSA, ADHD, TDI, epilepsy; Maternal social deprivation index, income level, psychotropics during pregnancy, proxy for obesity, smoking and alcohol.
Christensen (Controls exposed to LTG/LEV), 2024	population based cohort retrospective	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.	Major congenital malformations during the child’s first year of life using the primary and secondary diagnoses from the Danish National Patient Register. Neurodevelopmental disorders were identified from the Danish Psychiatric Central Research Register.	Singletons. Exclusion of children whose mothers had valproate during pregnancy. Adjusted for child's sex, year of birth, paternal and maternal age at child’s birth, paternal and maternal psychiatric diagnosis, psychotropic medication use, epilepsy diagnosis, and highest completed educational level. NDDs: exclusion of children with epilepsy; of parents with malfo or NDDs; with epileptic mothers.
Christensen (Controls unexposed, general pop), 2024	population based cohort retrospective	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.	Major congenital malformations during the child’s first year of life using the primary and secondary diagnoses from the Danish National Patient Register. Neurodevelopmental disorders were identified from the Danish Psychiatric Central Research Register.	Singletons. Exclusion of children whose mothers had valproate during pregnancy. Adjusted for sex of the child, year of birth, paternal and maternal age at the time of the child’s birth, and paternal and maternal psychiatric diagnosis, psychotropic medication use, epilepsy diagnosis, and highest completed educational level. Sensitivity analysis: excluding mothers and fathers with teratogenic drugs.
Christensen (Controls unexposed, sibling), 2024	population based cohort retrospective	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.	Major congenital malformations during the child’s first year of life using the primary and secondary diagnoses from the Danish National Patient Register. Neurodevelopmental disorders were identified from the Danish Psychiatric Central Research Register.	Singletons. Exclusion of children whose mothers had valproate during pregnancy. Sibling analysis (genetic and environmental factors) adjusted for sex of the child, year of birth, and paternal and maternal age at the time of the child’s birth).
Christensen (Controls unexposed, sick), 2024	population based cohort retrospective	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.	Major congenital malformations during the child’s first year of life using the primary and secondary diagnoses from the Danish National Patient Register. Neurodevelopmental disorders were identified from the Danish Psychiatric Central Research Register.	Singletons. Exclusion of children whose mothers had valproate during pregnancy. Adjusted for sex of the child, year of birth, paternal and maternal age at the time of the child’s birth, and paternal and maternal psychiatric diagnosis, psychotropic medication use, epilepsy diagnosis, and highest completed educational level.
Colas_Norway, 2025	population based cohort retrospective	Exposure information was derived from prescription data, as recorded in the National Prescription Registry.	All diagnosis outcomes of interest in live births based on the National Patient Registries (ICD-10 codes) and Cause of Death Registers and Medical Birth Registries.	Singletons. Exclusion of parents with neurodev disorders (NDD) or congenital malformations history; offspring maternally exposed to ASMs in utero or diagnosed with epilepsy and/or exposed to ASM after birth (for NDD). NDD: Adjusted for offspring gender; maternal affective/neurotic disorders, ges diabetes, obesity, smoking, psychiatric medications; Paternal psychiatric disorders, substance abuse, …
Meng_Norway (Controls exposed to LTG/LEV), 2026	population based cohort retrospective	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.	For the Norwegian cohort, only the Norwegian Patient Registry data (capturing inpatient/outpatient specialist diagnoses) were included for outcome assessment. Outcomes were defined using algorithms developed in the US, which have high positive predictive value.	Singletons only. Adjusted for year of the offspring’s birth, maternal and paternal age, maternal comorbidities or paternal indications for ASM use (epilepsy, psychiatric disorders, somatic conditions), maternal and paternal chronic comorbidities (sleep disorders, substance abuse, NDDs), other maternal and paternal medication use and maternal smoking and obesity.
Meng_Norway (Controls unexposed, general pop), 2026	population based cohort retrospective	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.	For the Norwegian cohort, only the Norwegian Patient Registry data (capturing inpatient/outpatient specialist diagnoses) were included for outcome assessment. Outcomes were defined using algorithms developed in the US, which have high positive predictive value.	Singletons only. No adjustment.
Meng_Norway (Controls unexposed, sick), 2026	population based cohort retrospective	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.	For the Norwegian cohort, only the Norwegian Patient Registry data (capturing inpatient/outpatient specialist diagnoses) were included for outcome assessment. Outcomes were defined using algorithms developed in the US, which have high positive predictive value.	Singletons only. Adjusted for year of the offspring’s birth, maternal and paternal age, maternal comorbidities or paternal indications for ASM use (epilepsy, psychiatric disorders, somatic conditions), maternal and paternal chronic comorbidities (sleep disorders, substance abuse, NDDs), other maternal and paternal medication use and maternal smoking and obesity.
Meng_Taiwan (Controls exposed to LTG/LEV), 2026	population based cohort retrospective	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.	For the Norwegian cohort, the National Health Insurance Database (NHI) data (covering inpatient/outpatient diagnoses) were considered. Outcomes were defined using algorithms developed in the US, which have high positive predictive value.	Singletons only. Adjusted for year of the offspring’s birth, maternal and paternal age, maternal comorbidities or paternal indications for ASM use (epilepsy, psychiatric disorders, somatic conditions), maternal and paternal chronic comorbidities (sleep disorders, substance abuse, NDDs), other maternal and paternal medication use and maternal smoking and obesity.
Meng_Taiwan (Controls unexposed, general pop), 2026	population based cohort retrospective	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.	For the Norwegian cohort, the National Health Insurance Database (NHI) data (covering inpatient/outpatient diagnoses) were considered. Outcomes were defined using algorithms developed in the US, which have high positive predictive value.	Singletons only. No adjustment.
Meng_Taiwan (Controls unexposed, sick), 2026	population based cohort retrospective	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.	For the Norwegian cohort, the National Health Insurance Database (NHI) data (covering inpatient/outpatient diagnoses) were considered. Outcomes were defined using algorithms developed in the US, which have high positive predictive value.	Singletons only. Adjusted for year of the offspring’s birth, maternal and paternal age, maternal comorbidities or paternal indications for ASM use (epilepsy, psychiatric disorders, somatic conditions), maternal and paternal chronic comorbidities (sleep disorders, substance abuse, NDDs), other maternal and paternal medication use and maternal smoking and obesity.
Razaz_Norway, 2026	population based cohort retrospective	The Norwegian Prescribed Drug Registry contains information on all dispensed prescriptions in Norwegian pharmacies from 2004 and onwards.	Offspring diagnoses were extracted from the National Patient Register in both Sweden and Norway. The Norwegian Patient Registry includes data on all inpatient and outpatient contactsin specialist healthcare, and from 2008 onwards, with diagnostic codes coded according to ICD-10.	Singletons only. Exclusion of children whose mothers used valproate during pregnancy. Adjusted for sex of the child, year of birth, maternal cohabitation status, paternal and maternal age at the time of the child’s birth, paternal and maternal psychiatric diagnosis, paternal and maternal psychotropic medication use, maternal and paternal epilepsy diagnosis.
Razaz_Sweden, 2026	population based cohort retrospective	The Prescribed Drug Registry contains data on all dispensed medications nationwide, classified by the Anatomical Therapeutic Chemical (ATC) system, since 1 July 2005.	Offspring diagnoses were extracted from the National Patient Register that includes inpatient care from 1987 and outpatient specialist care from 2001, with diagnoses coded using International Classification of Diseases, Ninth Revision (1987–1996) and ICD-10 (from 1997).	Singletons only. Exclusion of children whose mothers used valproate during pregnancy. Adjusted for sex of the child, year of birth, maternal cohabitation status, paternal and maternal age at the time of the child’s birth, parental education level, paternal and maternal psychiatric diagnosis, paternal and maternal psychotropic medication use, maternal and paternal epilepsy diagnosis.
Tomson, 2020	population based cohort retrospective	Dispensation of all antiepileptic drugs were identified through the Prescribed Drug Registry belonging to ATC class N03A given to both parents.	Diagnoses of malformations during the first year of life and clinically ascertained diagnoses of autism spectrum disorder, attention deficit hyperactivity disorder and intellectual disability were identified in the Medical Birth Register and the National Patient Register.	Children who had both parents with epilepsy were excluded. Singleton only. Adjusted for maternal age, paternal age, parity, maternal education, maternal smoking, maternal any psychiatric disorder, paternal any psychiatric disorder, child’s sex, birth weight for gestational age and year of birth.

master protocol