Valproate (Paternal exposure)

Language disorders/delay

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.
S18660
R80539		 Meng_Norway (Controls exposed to LTG/LEV), 2026 Developmental Speech/Language Disorder - At least 2 diagnoses on different dates ICD-9 and ICD-10: F80.xx (except F80.4x), H93.25 - 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 1.12 [0.37;3.35]
excluded (control group) 		5/319   10/730 15 319
ref
S18942
R80544		 Meng_Norway (Controls unexposed, sick), 2026 Developmental Speech/Language Disorder - At least 2 diagnoses on different dates ICD-9 and ICD-10: F80.xx (except F80.4x), H93.25 - 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 2.87 [0.99;8.34] 5/304   778/121,306 783 304
ref
S18945
R80563		 Meng_Taiwan (Controls exposed to LTG/LEV), 2026 Developmental Speech/Language Disorder - At least 2 diagnoses on different dates ICD-9 and ICD-10: F80.xx (except F80.4x), H93.25 - 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 2.28 [0.88;5.90]
excluded (control group) 		69/564   6/96 75 564
ref
S18944
R80555		 Meng_Taiwan (Controls unexposed, sick), 2026 Developmental Speech/Language Disorder - At least 2 diagnoses on different dates ICD-9 and ICD-10: F80.xx (except F80.4x), H93.25 - 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 1.27 [0.98;1.63] 68/543   42,119/500,498 42,187 543
ref
S18654
R79280		 Botton, 2025 Communication disorders - ICD10: F80.x (except F80.4) and/or speech therapy - 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 1.22 [0.94;1.57] 213/3,484   97/2,041 310 3,484
ref
Total 3 studies 1.28 [1.05;1.57] 43,280 4,331
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 Meng_Norway (Controls unexposed, sick), 2026Meng_Norway, 2026 1 2.87[0.99; 8.34]7833044%ROB confusion: moderateROB selection: lowROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: low Meng_Taiwan (Controls unexposed, sick), 2026Meng_Taiwan, 2026 2 1.27[0.98; 1.63]42,18754349%ROB confusion: moderateROB selection: lowROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: low Botton, 2025Botton, 2025 1.22[0.94; 1.57]3103,48448%ROB confusion: moderateROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Total (3 studies) I2 = 15% 1.28[1.05; 1.57]43,2804,3310.510.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, sick; 2: Controls unexposed, sick;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.28[1.05; 1.57]43,2804,33115%NAMeng_Norway (Controls unexposed, sick), 2026 Meng_Taiwan (Controls unexposed, sick), 2026 Botton, 2025 3 case control studiescase control studies 0 Type of controls unexposed, sickunexposed, sick 1.61[0.78; 3.32]42,97084753%NAMeng_Norway (Controls unexposed, sick), 2026 Meng_Taiwan (Controls unexposed, sick), 2026 2 exposed to other treatment, sickexposed to other treatment, sick 1.22[0.94; 1.58]3103,484 -NABotton, 2025 1 Tags Adjustment   - Yes  - Yes 1.28[1.05; 1.57]43,2804,33115%NAMeng_Norway (Controls unexposed, sick), 2026 Meng_Taiwan (Controls unexposed, sick), 2026 Botton, 2025 3 Paternal ASMs   - monotherapy  - monotherapy 1.28[1.05; 1.57]43,2804,33115%NAMeng_Norway (Controls unexposed, sick), 2026 Meng_Taiwan (Controls unexposed, sick), 2026 Botton, 2025 3 All studiesAll studies 1.28[1.05; 1.57]43,2804,33115%NAMeng_Norway (Controls unexposed, sick), 2026 Meng_Taiwan (Controls unexposed, sick), 2026 Botton, 2025 30.510.01.0

Publication bias and p-hacking diagnosis

funnel plot

Funnel plot not drawn. Less than 3 points.

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

not enought points

p values plot

Funnel plot not drawn. Less than 3 points.

Sub-groups analysis using all included studies

excluded 18660, 18945

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed, sick controlsunexposed, sick controls 1.61[0.78; 3.32]42,97084753%NAMeng_Norway (Controls unexposed, sick), 2026 Meng_Taiwan (Controls unexposed, sick), 2026 2 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.26[0.99; 1.61]4004,3670%NAMeng_Norway (Controls exposed to LTG/LEV), 2026 Meng_Taiwan (Controls exposed to LTG/LEV), 2026 Botton, 2025 30.510.01.0