Valproate (Epilepsy) updated on 04-22-2025

Limb defects

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.
S19433
R82807		 Seo (Valproate) (Epilepsy), 2026 Limb defects 1st trimester population based cohort retrospective unexposed, sick Adjustment: Yes 1.50 [0.26;8.71] -/-   -/- - -
ref
S17504
R73563		 Wiggs, 2024 Musculoskeletal system malformations early pregnancy population based cohort retrospective unexposed, sick Adjustment: Yes 2.12 [1.38;3.26] -/624   -/12,666 - 624
ref
S12860
R48522		 Thomas (Valproate) (Controls exposed to Lamotrigine, sick), 2021 Skeletal malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 1.32 [0.07;24.97] C
excluded (control group) 		4/341   0/50 4 341
ref
S12861
R48532		 Thomas (Valproate) (Controls unexposed, sick), 2021 Skeletal malformations 1st trimester prospective cohort unexposed, sick Adjustment: No 2.01 [0.36;11.03] C 4/341   2/340 6 341
ref
S318
R14443		 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Skeletal defects 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No 5.77 [1.59;21.02] 10/1,220   3/2,098 13 1,220
ref
S10732
R39688		 De Jonge (Valproate), 2013 Limb malformations 1st trimester case control unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 2.24 [0.14;36.66] C 0/35   184/29,372 184 35
ref
S10293
R37695		 Vajda (Valproate) (Controls exposed to Lamotrigine, sick), 2013 Skeletal / Limb Malformations at least 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 15.46 [0.87;275.68] C
excluded (control group) 		6/271   0/315 6 271
ref
S10294
R37701		 Vajda (Valproate) (Controls unexposed, sick), 2013 Skeletal / Limb Malformations at least 1st trimester prospective cohort unexposed, sick Adjustment: No 3.31 [0.39;27.72] C 6/271   1/147 7 271
ref
S9848
R35353		 Mawer (Valproate) (Controls exposed to Lamotrigine, sick), 2010 Skeletal / Limb Malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 0.69 [0.04;11.43] C
excluded (control group) 		1/53   1/37 2 53
ref
S9849
R35359		 Mawer (Valproate) (Controls unexposed, disease free), 2010 Skeletal / Limb Malformations 1st trimester prospective cohort unexposed, disease free excluded Adjustment: No Matched 16.57 [0.67;412.47] C
excluded (control group) 		1/53   0/285 1 53
ref
S9850
R35365		 Mawer (Valproate) (Controls unexposed, sick), 2010 Skeletal / Limb Malformations 1st trimester prospective cohort unexposed, sick Adjustment: No 2.36 [0.09;59.46] C 1/53   0/41 1 53
ref
S6099
R35923		 Artama (Valproate), 2005 Certain musculoskeletal deformities and Other anomalies of limbs 1st trimester retrospective cohort (registry) unexposed, sick Adjustment: No 4.18 [1.50;11.63] C 8/263   7/939 15 263
ref
Total 8 studies 2.47 [1.74;3.51] 226 2,807
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 Seo (Valproate) (Epilepsy), 2026Seo, 2026 1 1.50[0.26; 8.71]--4%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Wiggs, 2024Wiggs, 2024 2.12[1.38; 3.26]-62467%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Thomas (Valproate) (Controls unexposed, sick), 2021Thomas, 2021 2 2.01[0.36; 11.03]63414%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014Campbell, 2014 3 5.77[1.59; 21.02]131,2207%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA De Jonge (Valproate), 2013De Jonge, 2013 4 2.24[0.14; 36.66]184352%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Vajda (Valproate) (Controls unexposed, sick), 2013Vajda, 2013 5 3.31[0.39; 27.72]72713%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Mawer (Valproate) (Controls unexposed, sick), 2010Mawer, 2010 6 2.36[0.09; 59.46]1531%ROB confusion: criticalROB selection: moderateROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Artama (Valproate), 2005Artama, 2005 7 4.18[1.50; 11.63]1526312%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Total (8 studies) I2 = 0% 2.47[1.74; 3.51]2262,8070.520.01.0ROB: A: confounding, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Valproate) (Epilepsy; 2: Valproate) (Controls unexposed, sick; 3: Valproate) (Controls exposed to Lamotrigine, sick; 4: Valproate; 5: Valproate) (Controls unexposed, sick; 6: Valproate) (Controls unexposed, sick; 7: Valproate;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 2.47[1.73; 3.53]422,7720%NASeo (Valproate) (Epilepsy), 2026 Wiggs, 2024 Thomas (Valproate) (Controls unexposed, sick), 2021 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Vajda (Valproate) (Controls unexposed, sick), 2013 Mawer (Valproate) (Controls unexposed, sick), 2010 Artama (Valproate), 2005 7 case control studiescase control studies 2.24[0.14; 36.66]18435 -NADe Jonge (Valproate), 2013 1 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 2.24[0.14; 36.66]18435 -NADe Jonge (Valproate), 2013 1 unexposed, sickunexposed, sick 2.31[1.60; 3.34]291,5520%NASeo (Valproate) (Epilepsy), 2026 Wiggs, 2024 Thomas (Valproate) (Controls unexposed, sick), 2021 Vajda (Valproate) (Controls unexposed, sick), 2013 Mawer (Valproate) (Controls unexposed, sick), 2010 Artama (Valproate), 2005 6 exposed to other treatment, sickexposed to other treatment, sick 5.77[1.59; 20.98]131,220 -NACampbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 1 Tags Adjustment   - No  - No 3.76[1.96; 7.23]2262,1830%NAThomas (Valproate) (Controls unexposed, sick), 2021 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 De Jonge (Valproate), 2013 Vajda (Valproate) (Controls unexposed, sick), 2013 Mawer (Valproate) (Controls unexposed, sick), 2010 Artama (Valproate), 2005 6   - Yes  - Yes 2.08[1.37; 3.16]-6240%NASeo (Valproate) (Epilepsy), 2026 Wiggs, 2024 2 Monotherapy   - no or not specified  - no or not specified 2.24[0.14; 36.66]18435 -NADe Jonge (Valproate), 2013 1 All studiesAll studies 2.47[1.74; 3.51]2262,8070%NASeo (Valproate) (Epilepsy), 2026 Wiggs, 2024 Thomas (Valproate) (Controls unexposed, sick), 2021 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 De Jonge (Valproate), 2013 Vajda (Valproate) (Controls unexposed, sick), 2013 Mawer (Valproate) (Controls unexposed, sick), 2010 Artama (Valproate), 2005 80.520.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.94.81.9760.000Seo (Valproate) (Epilepsy), 2026Wiggs, 2024Thomas (Valproate) (Controls unexposed, sick), 2021Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014De Jonge (Valproate), 2013Vajda (Valproate) (Controls unexposed, sick), 2013Mawer (Valproate) (Controls unexposed, sick), 2010Artama (Valproate), 2005

Asymetry test p-value = 0.4725 (by Egger's regression)

slope=0.7717 (0.2176); intercept=0.3285 (0.4287); t=0.7664; p=0.4725

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 9848, 9849, 10293, 12860

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 5.30[0.64; 43.70]185880%NADe Jonge (Valproate), 2013 Mawer (Valproate) (Controls unexposed, disease free), 2010 2 unexposed, sick controlsunexposed, sick controls 2.31[1.60; 3.34]291,5520%NASeo (Valproate) (Epilepsy), 2026 Wiggs, 2024 Thomas (Valproate) (Controls unexposed, sick), 2021 Vajda (Valproate) (Controls unexposed, sick), 2013 Mawer (Valproate) (Controls unexposed, sick), 2010 Artama (Valproate), 2005 6 exposed to other treatment, sick controlsexposed to other treatment, sick controls 4.00[1.34; 11.91]251,8856%NAThomas (Valproate) (Controls exposed to Lamotrigine, sick), 2021 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Vajda (Valproate) (Controls exposed to Lamotrigine, sick), 2013 Mawer (Valproate) (Controls exposed to Lamotrigine, sick), 2010 40.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Tanoshima (Musculoskeletal anomalies)Tanoshima (Musculoskeletal anomalies) 3.32[2.26; 4.88]0%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT18 Yang (Epilepsy) (Musculoskeletal Anomalies)Yang (Epilepsy) (Musculoskeletal Anomalies) 2.88[1.98; 4.19]0%-Eexposed to other treatment, sickAnyduring pregnancy (anytime or not specified)studies TTT15 metaPregmetaPreg 2.47[1.74; 3.51]0%2,807----Seo (Valproate) (Epilepsy), 2026 Wiggs, 2024 Thomas (Valproate) (Controls unexposed, sick), 2021 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 De Jonge (Valproate), 2013 Vajda (Valproate) (Controls unexposed, sick), 2013 Mawer (Valproate) (Controls unexposed, sick), 2010 Artama (Valproate), 2005 80.510.01.0