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

Oro-facial clefts

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.
S17499
R73522		 Wiggs (Epilepsy) (Valproate), 2024 Cleft lip and cleft palate early pregnancy population based cohort retrospective unexposed, sick Adjustment: Yes 2.65 [0.92;7.66] -/624   -/12,666 - 624
ref
S15201
R62352		 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Orofacial clefts 1st trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes 3.21 [1.73;5.96] -/2,031   -/4,866,362 - 2,031
ref
S10174
R46500		 Blotière (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2019 Oro-facial clefts 1st trimester retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No 4.95 [1.39;17.58] C
excluded (control group) 		6/913   4/2,997 10 913
ref
S10051
R46495		 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Oro-facial clefts 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No 4.40 [1.97;9.83] C 6/913   2,815/1,875,733 2,821 913
ref
S9359
R32737		 Tomson (Valproate), 2018 Cleft lip or palate at least 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No 3.65 [0.91;14.63] C 6/1,381   3/2,514 9 1,381
ref
S9333
R32559		 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Facial cleft 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No 11.29 [2.54;50.12] 13/1,220   2/2,098 15 1,220
ref
S9325
R32517		 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Orofacial clefts throughout pregnancy population based cohort retrospective exposed to other treatment, sick Adjustment: No 0.83 [0.03;20.52] C 0/333   1/833 1 333
ref
S10231
R37484		 Hernández-Díaz (Valproate), 2012 Oral clefts 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No Controls: mixed indications 2.79 [0.81;9.57] C 4/323   7/1,562 11 323
ref
Total 7 studies 3.57 [2.43;5.25] 2,857 6,825
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 Wiggs (Epilepsy) (Valproate), 2024Wiggs, 2024 1 2.65[0.92; 7.66]-62413%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023Cohen, 2023 2 3.21[1.73; 5.96]-2,03139%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019Blotière, 2019 3 4.40[1.97; 9.83]2,82191323%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Tomson (Valproate), 2018Tomson, 2018 4 3.65[0.91; 14.63]91,3818%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014Campbell, 2014 5 11.29[2.54; 50.12]151,2207%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014Veiby, 2014 6 0.83[0.03; 20.52]13331%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Hernández-Díaz (Valproate), 2012Hernández-Díaz, 2012 7 2.79[0.81; 9.57]1132310%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Total (7 studies) I2 = 0% 3.57[2.43; 5.25]2,8576,8250.250.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

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

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 3.57[2.43; 5.25]2,8576,8250%NAWiggs (Epilepsy) (Valproate), 2024 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Tomson (Valproate), 2018 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Hernández-Díaz (Valproate), 2012 7 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 3.61[2.21; 5.89]2,8212,9440%NACohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 2 unexposed, sickunexposed, sick 2.65[0.92; 7.65]-624 -NAWiggs (Epilepsy) (Valproate), 2024 1 exposed to other treatment, sickexposed to other treatment, sick 4.07[1.86; 8.90]363,2574%NATomson (Valproate), 2018 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Hernández-Díaz (Valproate), 2012 4 Tags Adjustment   - No  - No 4.22[2.43; 7.34]2,8574,1700%NABlotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Tomson (Valproate), 2018 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Hernández-Díaz (Valproate), 2012 5   - Yes  - Yes 3.06[1.79; 5.22]-2,6550%NAWiggs (Epilepsy) (Valproate), 2024 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 2 Controls   - mixed indications  - mixed indications 2.79[0.81; 9.57]11323 -NAHernández-Díaz (Valproate), 2012 1 All studiesAll studies 3.57[2.43; 5.25]2,8576,8250%NAWiggs (Epilepsy) (Valproate), 2024 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Tomson (Valproate), 2018 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Hernández-Díaz (Valproate), 2012 70.250.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.85.11.9610.000Wiggs (Epilepsy) (Valproate), 2024Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019Tomson (Valproate), 2018Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014Hernández-Díaz (Valproate), 2012

Asymetry test p-value = 0.8969 (by Egger's regression)

slope=1.3279 (0.4352); intercept=-0.1144 (0.8392); t=0.1363; p=0.8969

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 10174

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 3.61[2.21; 5.89]2,8212,9440%NACohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 2 unexposed, sick controlsunexposed, sick controls 2.65[0.92; 7.65]-624 -NAWiggs (Epilepsy) (Valproate), 2024 1 exposed to other treatment, sick controlsexposed to other treatment, sick controls 4.29[2.23; 8.23]464,1700%NABlotière (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2019 Tomson (Valproate), 2018 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Hernández-Díaz (Valproate), 2012 50.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Tanoshima (Epilepsy) (Cleft lip and/or palate)Tanoshima (Epilepsy) (Cleft lip and/or palate) 3.37[2.09; 5.42]9%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT11 metaPregmetaPreg 3.57[2.43; 5.25]0%6,825----Wiggs (Epilepsy) (Valproate), 2024 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Tomson (Valproate), 2018 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Hernández-Díaz (Valproate), 2012 70.510.01.0