Valproate (Paternal exposure)

Severe cognitive developmental delay (Mental retardation) (> 6 years old)

id	Study   Auto Meng_Taiwan (Controls unexposed, sick), 2026Razaz_Sweden, 2026Botton, 2025Christensen (Controls exposed to LTG/LEV), 2024	Lib. in paper	Exposition period  Auto during pregnancy (anytime or not specified)1st trimester2nd trimester3rd trimester2nd and/or 3rd trimesterthroughout pregnancyearly pregnancydays before deliverylate pregnancypreconception-onlypericonceptionalpreconceptional for kinetic reasonat least 1st trimester3 months (or more) before pregnancy or during pregnancy1st and 2nd trimester3 months or more before pregnancy or1st trimesterPaternal exp. genotoxic window only (0–3 months preconception)Paternal exposure: epigenetic window only (3–xxx months preconception)Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception)Paternal exposure: other window	Study type  All studies Case control excluded Only case control	Control type    Auto unexposed (general population or NOS)unexposed, sickunexposed, disease freeexposed to other treatment, sicknot specifiedsiblingwhatever (meta-analysis)	Tags	OR 95%CI	x1/n1 x0/n0	no cases	no exposed	ROB	Ref.
S18944 R80557	Meng_Taiwan (Controls unexposed, sick), 2026	Developmental Coordination Disorder - At least 2 diagnoses on different dates ICD-9 and ICD-10: F70.xx-F79.xx - Follow up: between 6 and 12 years	Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception)	population based cohort retrospective	unexposed, sick	Adjustment: Yes Paternal ASMs: monotherapy	1.09 [0.57;2.09]	10/543   4,864/500,498	4,874	543		ref
S18948 R80587	Razaz_Sweden, 2026	Intellectual disability (ID) - One diagnosis ICD-10 code for ID: F70– F79 - Median age at the end of follow-up: 6.6 years	Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception)	population based cohort retrospective	exposed to other treatment, sick	Adjustment: Yes Paternal ASMs: monotherapy	1.20 [0.65;2.21]	22/1,500   33/2,906	55	1,500		ref
S18654 R79278	Botton, 2025	Intellectual Developmental Disorder - ICD10: F70-F79 - Median follow up (years): 11.9 (IQR [10.3 - 13.3]) for valproate; 11.2 (IQR [9.9 - 12.8]) for control	Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception)	retrospective cohort (claims database)	exposed to other treatment, sick	Adjustment: Yes Paternal ASMs: monotherapy	2.07 [0.78;5.53]	25/3,484   5/2,041	30	3,484		ref
S18646 R79289	Christensen (Controls exposed to LTG/LEV), 2024	Intellectual disability - ICD-10 codes F70-79 - Median age [IQR] age at the end of follow-up: 10.6 [5.4-15.0] years for valproate; 5.5 [2.7-9.3] years for controls	Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception)	population based cohort retrospective	exposed to other treatment, sick	Adjustment: Yes Paternal ASMs: monotherapy	1.85 [0.72;4.76]	21/961   7/1,401	28	961		ref
					Total	4 studies	1.35 [0.93;1.95]		4,987	6,488
x1: number of endpoints among exposed, n1: number of exposed; x0: number of endpoints among non exposed, n0: number of non exposed; C: calculated odds ratio from numbers of events and effectives

Forest plot

Sensitivity analysis

Publication bias and p-hacking diagnosis

Sub-groups analysis using all included studies

excluded