Valproate (Paternal exposure)

Neuro-developmental disorders (as a whole)

R analysis
id Study   Lib. in paper Exposition period    Study type  Control type 
 
Tags OR 95%CI x1/n1 x0/n0 no cases no exposed ROB Ref.
S18947
R80579
Razaz_Norway, 2026 Neurodevelopmental disorders - One diagnosis for Intellectual disability (ICD-10: F70– F79), psychological development disorders (F80–F83), autism spectrum disorder (F84, excluding F84.2–F84.4), and ADHD (F90.0, F98.8) - Median age at the end of follow-up: 5.2 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 [0.70;2.04] 21/460   39/1,101 60 460
ref
S18948
R80584
Razaz_Sweden, 2026 Neurodevelopmental disorders - One diagnosis for Intellectual disability (ICD-10: F70– F79), psychological development disorders (F80–F83), autism spectrum disorder (F84, excluding F84.2–F84.4), and ADHD (F90.0, F98.8) - 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 1.03 [0.82;1.30] 159/1,500   247/2,906 406 1,500
ref
S18654
R79276
Botton, 2025 Neurodevelopmental disorders - ICD10: F90.x and/or methylphenidate prescription; 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 1.17 [0.98;1.40] 414/3,484   199/2,041 613 3,484
ref
S18646
R79288
Christensen (Controls exposed to LTG/LEV), 2024 Neurodevelopmental disorders - Intellectual disability, Disorders of psychological development, Autism spectrum disorders, ADHD - 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 1.02 [0.67;1.54]
excluded (control group)
67/961   50/1,401 117 961
ref
S18644
R79233
Christensen (Controls unexposed, general pop), 2024 Neurodevelopmental disorders - Intellectual disability, Disorders of psychological development, Autism spectrum disorders, ADHD - 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: Yes Paternal ASMs: monotherapy 1.13 [0.88;1.44]
excluded (control group)
-/1,017   51,437/1,234,017 - 1,017
ref
S18647
R79253
Christensen (Controls unexposed, sibling), 2024 Neurodevelopmental disorders - Intellectual disability, Disorders of psychological development, Autism spectrum disorders, ADHD - 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 1.30 [0.51;3.31]
excluded (control group)
16/303   23/381 39 303
ref
S18645
R79242
Christensen (Controls unexposed, sick), 2024 Neurodevelopmental disorders - Intellectual disability, Disorders of psychological development, Autism spectrum disorders, ADHD - 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 1.09 [0.85;1.39] 70/1,052   622/11,308 692 1,052
ref
Total 4 studies 1.11 [0.99;1.25] 1,771 6,496
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

StudyTE95% CIn casesn exposedweightROBABCDEF Razaz_Norway, 2026Razaz_Norway, 2026 1.20[0.70; 2.04]604605%ROB confusion: seriousROB selection: unclearROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: moderate Razaz_Sweden, 2026Razaz_Sweden, 2026 1.03[0.82; 1.30]4061,50027%ROB confusion: seriousROB selection: unclearROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: moderate Botton, 2025Botton, 2025 1.17[0.98; 1.40]6133,48445%ROB confusion: moderateROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Christensen (Controls unexposed, sick), 2024Christensen, 2024 1 1.09[0.85; 1.39]6921,05224%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Total (4 studies) I2 = 0% 1.11[0.99; 1.25]1,7716,4960.55.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, sick;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.11[0.99; 1.25]1,7716,4960%NARazaz_Norway, 2026 Razaz_Sweden, 2026 Botton, 2025 Christensen (Controls unexposed, sick), 2024 4 case control studiescase control studies 0 Type of controls unexposed, sickunexposed, sick 1.09[0.85; 1.39]6921,052 -NAChristensen (Controls unexposed, sick), 2024 1 exposed to other treatment, sickexposed to other treatment, sick 1.12[0.98; 1.28]1,0795,4440%NARazaz_Norway, 2026 Razaz_Sweden, 2026 Botton, 2025 3 Tags Adjustment   - Yes  - Yes 1.11[0.99; 1.25]1,7716,4960%NARazaz_Norway, 2026 Razaz_Sweden, 2026 Botton, 2025 Christensen (Controls unexposed, sick), 2024 4 Paternal ASMs   - mono/polytherapy or not specified  - mono/polytherapy or not specified 1.09[0.85; 1.39]6921,052 -NAChristensen (Controls unexposed, sick), 2024 1   - monotherapy  - monotherapy 1.12[0.98; 1.28]1,0795,4440%NARazaz_Norway, 2026 Razaz_Sweden, 2026 Botton, 2025 3 All studiesAll studies 1.11[0.99; 1.25]1,7716,4960%NARazaz_Norway, 2026 Razaz_Sweden, 2026 Botton, 2025 Christensen (Controls unexposed, sick), 2024 40.55.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-0.60.70.3270.000Razaz_Norway, 2026Razaz_Sweden, 2026Botton, 2025Christensen (Controls unexposed, sick), 2024

Asymetry test p-value = NaN (by Egger's regression)

not enought points

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 18646, 18644, 18647

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.13[0.88; 1.45]51,4281,017 -NAChristensen (Controls unexposed, general pop), 2024 1 unexposed, sick controlsunexposed, sick controls 1.09[0.85; 1.39]6921,052 -NAChristensen (Controls unexposed, sick), 2024 1 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.11[0.98; 1.26]1,1966,4050%NARazaz_Norway, 2026 Razaz_Sweden, 2026 Botton, 2025 Christensen (Controls exposed to LTG/LEV), 2024 4 siblingssiblings 1.30[0.51; 3.31]39303 -NAChristensen (Controls unexposed, sibling), 2024 10.510.01.0