Valproate (All indications) updated on 04-22-2025

Learning disorders

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.
S19391
R82381		 Honybun (Controls exposed to LTG) (Valproate) (Epilepsy), 2026 Academic Outcomes: Sentence comprehension - Wide Range Achievement Test–Fifth Edition - Children aged 3–18 years (mean age about 10 years) during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick excluded Adjustment: No extrapolated (cont. endpoint) 3.80 [1.09;13.29]
excluded (control group) 		-/16   -/19 - 16
ref
S19387
R82341		 Honybun (Controls unexposed, sick) (Valproate) (Epilepsy), 2026 Academic Outcomes: Sentence comprehension - Wide Range Achievement Test–Fifth Edition - Children aged 3–18 years (mean age about 10 years) during pregnancy (anytime or not specified) prospective cohort unexposed, sick Adjustment: No extrapolated (cont. endpoint) 25.49 [5.14;126.49] -/16   -/13 - 16
ref
S19382
R82295		 Straub (Controls exposed to LTG) (Valproate) (Epilepsy), 2026 Learning difficulty - ICD-10 codes: F81.0, F81.2, F81.8x, R48.0 - Mean follow up (full cohort): 3.4 years during pregnancy (anytime or not specified) retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No 3.81 [1.67;8.66] C
excluded (control group) 		11/796   12/3,273 23 796
ref
S19374
R82207		 Straub (Controls unexposed, sick) (Valproate) (Epilepsy), 2026 Learning difficulty - ICD-10 codes: F81.0, F81.2, F81.8x, R48.0 - Mean follow up (full cohort): 3.4 years during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed, sick Adjustment: Yes 1.13 [0.54;2.38] 11/796   43/8,887 54 796
ref
S15246
R62690		 Ren (Valproate) (Mixed indications), 2023 Danish at 9th grade - Mean age 16.1 (SD 0.4) years during pregnancy (anytime or not specified) population based cohort propective unexposed (general population or NOS) Adjustment: Yes extrapolated (cont. endpoint) 1.27 [1.00;1.60] -/232   -/370,569 - 232
ref
Total 3 studies 2.39 [0.79;7.18] 54 1,044
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 Honybun (Controls unexposed, sick) (Valproate) (Epilepsy), 2026Honybun, 2026 1 25.49[5.14; 126.49]-1622%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: criticalROB mesure: lowROB reporting: moderate Straub (Controls unexposed, sick) (Valproate) (Epilepsy), 2026Straub, 2026 2 1.13[0.54; 2.38]5479636%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: unclearROB mesure: criticalROB reporting: moderate Ren (Valproate) (Mixed indications), 2023Ren, 2023 3 1.27[1.00; 1.60]-23242%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Total (3 studies) I2 = 85% 2.39[0.79; 7.18]541,0440.5100.01.0ROB: A: confounding, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, sick) (Valproate) (Epilepsy; 2: Controls unexposed, sick) (Valproate) (Epilepsy; 3: Valproate) (Mixed indications;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 2.39[0.79; 7.18]541,04485%NAHonybun (Controls unexposed, sick) (Valproate) (Epilepsy), 2026 Straub (Controls unexposed, sick) (Valproate) (Epilepsy), 2026 Ren (Valproate) (Mixed indications), 2023 3 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.27[1.00; 1.61]-232 -NARen (Valproate) (Mixed indications), 2023 1 unexposed, sickunexposed, sick 4.93[0.23; 104.10]5481292%NAHonybun (Controls unexposed, sick) (Valproate) (Epilepsy), 2026 Straub (Controls unexposed, sick) (Valproate) (Epilepsy), 2026 2 Tags Adjustment   - No  - No 25.49[5.14; 126.45]-16 -NAHonybun (Controls unexposed, sick) (Valproate) (Epilepsy), 2026 1   - Yes  - Yes 1.26[1.00; 1.57]541,0280%NAStraub (Controls unexposed, sick) (Valproate) (Epilepsy), 2026 Ren (Valproate) (Mixed indications), 2023 2 extrapolated (cont. endpoint)extrapolated (cont. endpoint) 5.10[0.27; 95.70]-24892%NAHonybun (Controls unexposed, sick) (Valproate) (Epilepsy), 2026 Ren (Valproate) (Mixed indications), 2023 2 All studiesAll studies 2.39[0.79; 7.18]541,04485%NAHonybun (Controls unexposed, sick) (Valproate) (Epilepsy), 2026 Straub (Controls unexposed, sick) (Valproate) (Epilepsy), 2026 Ren (Valproate) (Mixed indications), 2023 30.5100.01.0

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 19391, 19382

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.27[1.00; 1.61]-232 -NARen (Valproate) (Mixed indications), 2023 1 unexposed, sick controlsunexposed, sick controls 4.93[0.23; 104.10]5481292%NAHonybun (Controls unexposed, sick) (Valproate) (Epilepsy), 2026 Straub (Controls unexposed, sick) (Valproate) (Epilepsy), 2026 2 exposed to other treatment, sick controlsexposed to other treatment, sick controls 3.81[1.91; 7.56]238120%NAHonybun (Controls exposed to LTG) (Valproate) (Epilepsy), 2026 Straub (Controls exposed to LTG) (Valproate) (Epilepsy), 2026 20.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Karain (Epilepsy) (Educational outcomes (Spec ...Karain (Epilepsy) (Educational outcomes (Special educational needs, Learning difficulties/classroom support, School-related behaviour, Academic performance)) 2.38[1.25; 4.53]81%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT4 metaPregmetaPreg 2.39[0.79; 7.18]85%1,044----Honybun (Controls unexposed, sick) (Valproate) (Epilepsy), 2026 Straub (Controls unexposed, sick) (Valproate) (Epilepsy), 2026 Ren (Valproate) (Mixed indications), 2023 30.510.01.0