Valproate (Paternal exposure)

ASD (Autism spectrum disorder): Diagnosis/Risk

id	Study   Auto Meng_Norway (Controls exposed to LTG/LEV), 2026Meng_Norway (Controls unexposed, sick), 2026Meng_Taiwan (Controls unexposed, sick), 2026Razaz_Sweden, 2026Botton, 2025Christensen (Controls exposed to LTG/LEV), 2024Christensen (Controls unexposed, general pop), 2024Christensen (Controls unexposed, sibling), 2024Christensen (Controls unexposed, sick), 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.
S18660 R80571	Meng_Norway (Controls exposed to LTG/LEV), 2026	Autism spectrum disorder (ASD) - At least 2 diagnoses on different dates ICD-9 and ICD-10: F84.xx (except F84.2x, F84.3x) - Follow up: between 6 and 12 years	Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception)	population based cohort retrospective	exposed to other treatment, sick excluded	Adjustment: Yes Paternal ASMs: monotherapy	1.66 [0.55;4.98] excluded (control group)	7/319   10/730	17	319		ref
S18942 R80572	Meng_Norway (Controls unexposed, sick), 2026	Autism spectrum disorder (ASD) - At least 2 diagnoses on different dates ICD-9 and ICD-10: F84.xx (except F84.2x, F84.3x) - 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	1.48 [0.82;2.68]	7/304   1,199/121,306	1,206	304		ref
S18944 R80573	Meng_Taiwan (Controls unexposed, sick), 2026	Autism spectrum disorder (ASD) - At least 2 diagnoses on different dates ICD-9 and ICD-10: F84.xx (except F84.2x, F84.3x) - 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	1.14 [0.67;1.93]	15/543   10,373/500,498	10,388	543		ref
S18948 R80590	Razaz_Sweden, 2026	Autism spectrum disorder (ASD) - One diagnosis ICD-10 code for ASD: F84, excluding F84.2–F84.4 - 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	1.24 [0.84;1.83]	59/1,500   81/2,906	140	1,500		ref
S18654 R79304	Botton, 2025	Autism spectrum disorders - ICD10: F84 (excl F84.2-F84.3) - 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	1.04 [0.64;1.71]	53/3,484   28/2,041	81	3,484		ref
S18646 R79305	Christensen (Controls exposed to LTG/LEV), 2024	Autism spectrum disorder - ICD-10 code F84 (excluding F84.2-F84.4) - 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 excluded	Adjustment: Yes Paternal ASMs: monotherapy	0.69 [0.37;1.28] excluded (control group)	24/961   31/1,401	55	961		ref
S18644 R79306	Christensen (Controls unexposed, general pop), 2024	Autism spectrum disorders - ICD10: F84 (excl F84.2-F84.4) - Median follow-up about 10 years (IQR 5-15)	Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception)	population based cohort retrospective	unexposed (general population or NOS) excluded	Adjustment: No Paternal ASMs: monotherapy	0.82 [0.54;1.24] excluded (control group)	-/1,017   24,479/1,234,017	-	1,017		ref
S18647 R79307	Christensen (Controls unexposed, sibling), 2024	Autism spectrum disorders - ICD10: F84 (excl F84.2-F84.4) - Median follow-up about 10 years (IQR 5-15)	Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception)	population based cohort retrospective	sibling excluded	Adjustment: Yes Paternal ASMs: mono/polytherapy or not specified	0.54 [0.14;2.12] excluded (control group)	7/303   17/381	24	303		ref
S18645 R79308	Christensen (Controls unexposed, sick), 2024	Autism spectrum disorders - ICD10: F84 (excl F84.2-F84.4) - Median follow-up about 10 years (IQR 5-15)	Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception)	population based cohort retrospective	unexposed, sick	Adjustment: Yes Paternal ASMs: mono/polytherapy or not specified	0.85 [0.57;1.26]	27/1,052   298/11,308	325	1,052		ref
					Total	5 studies	1.10 [0.89;1.35]		12,140	6,883
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 18646, 18644, 18647, 18660

Umbrella review (other published meta-analyses)