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

Spina bifida

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.
S19424
R82737		 Kim (Controls exposed to LTG) (Valproate) (Indications NOS), 2026 Spina bifida 1st trimester population based cohort retrospective exposed to other treatment, sick excluded Adjustment: No 3.24 [0.34;31.22] C
excluded (control group) 		3/667   1/718 4 667
ref
S19425
R82748		 Kim (Controls unexposed, NOS) (Valproate) (Indications NOS), 2026 Spina bifida 1st trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes 2.25 [0.70;7.20] 3/667   5,503/2,489,078 5,506 667
ref
S10174
R37202		 Blotière (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2019 Spina bifida 1st trimester retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No 19.82 [2.38;164.84] C
excluded (control group) 		6/913   1/2,997 7 913
ref
S10051
R36476		 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Spina bifida 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: Yes 19.40 [8.60;43.50] 6/913   616/1,875,733 622 913
ref
S9325
R32515		 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Spina bifida throughout pregnancy population based cohort retrospective exposed to other treatment, sick excluded Adjustment: No 7.53 [0.31;185.42] C
excluded (control group) 		1/333   0/833 1 333
ref
S9327
R32524		 Veiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 Spina bifida throughout pregnancy population based cohort retrospective unexposed, sick Adjustment: No Controls: epilepsy indication 3.79 [0.39;36.49] C 1/333   3/3,773 4 333
ref
S9293
R32278		 Charlton (Valproate) (Controls exposed to Lamotrigine, sick), 2011 Spina bifida 1st trimester retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No 3.98 [0.21;74.64] C
excluded (control group) 		4/225   0/98 4 225
ref
S9294
R32281		 Charlton (Valproate) (Controls unexposed, sick), 2011 Spina bifida 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: No 8.02 [1.50;43.50] 4/225   2/902 6 225
ref
S9329
R32529		 Viinikainen (Valproate) (Controls unexposed, sick) a, 2006 Spina bifida throughout pregnancy prospective cohort unexposed, sick Adjustment: No 5.83 [0.23;148.09] C 1/28   0/52 1 28
ref
S9330
R32537		 Artama (Valproate), 2005 Spina bifida 1st trimester retrospective cohort (registry) unexposed, sick Adjustment: No 40.09 [2.21;727.45] C 5/263   0/939 5 263
ref
S17494
R73492		 Cornel (Valproate) (Indications NOS), 1996 Spina bifida 1st trimester case control unexposed (general population or NOS) Adjustment: No 10.25 [1.76;41.66] 3/12   126/4,002 129 12
ref
S9343
R32592		 Källén (Valproate), 1994 Spina bifida during pregnancy (anytime or not specified) excluded nested case control unexposed, sick Adjustment: No Matched no data
excluded (exposition period) 		1/1   0/6 1 1
ref
S9338
R32584		 Czeizel (Valproate), 1992 Spina bifida throughout pregnancy case control unexposed, sick Adjustment: No 3.00 [0.08;107.45] C 1/2   1/4 2 2
ref
Total 8 studies 7.92 [3.67;17.11] 6,275 2,443
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 Kim (Controls unexposed, NOS) (Valproate) (Indications NOS), 2026Kim, 2026 1 2.25[0.70; 7.20]5,50666721%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019Blotière, 2019 2 19.40[8.60; 43.50]62291327%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Veiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014Veiby, 2014 3 3.79[0.39; 36.49]43339%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Charlton (Valproate) (Controls unexposed, sick), 2011Charlton, 2011 4 8.02[1.50; 43.50]622514%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Viinikainen (Valproate) (Controls unexposed, sick) a, 2006Viinikainen, 2006 5 5.83[0.23; 148.09]1285%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Artama (Valproate), 2005Artama, 2005 6 40.09[2.21; 727.45]52636%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Cornel (Valproate) (Indications NOS), 1996Cornel, 1996 7 10.25[1.76; 41.66]1291215%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: unclearROB mesure: unclearROB reporting: moderate Czeizel (Valproate), 1992Czeizel, 1992 8 3.00[0.08; 107.45]224%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Total (8 studies) I2 = 36% 7.92[3.67; 17.11]6,2752,4430.9100.01.0ROB: A: confounding, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, NOS) (Valproate) (Indications NOS; 2: Valproate) (Controls unexposed NOS) (Mixed indications; 3: Valproate) (Controls unexposed, sick) (Mixed indications; 4: Valproate) (Controls unexposed, sick; 5: Valproate) (Controls unexposed, sick) ; 6: Valproate; 7: Valproate) (Indications NOS; 8: Valproate;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 7.82[2.89; 21.19]6,1442,42953%NAKim (Controls unexposed, NOS) (Valproate) (Indications NOS), 2026 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Veiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 Charlton (Valproate) (Controls unexposed, sick), 2011 Viinikainen (Valproate) (Controls unexposed, sick) a, 2006 Artama (Valproate), 2005 6 case control studiescase control studies 8.38[1.97; 35.64]131140%NACornel (Valproate) (Indications NOS), 1996 Czeizel (Valproate), 1992 2 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 7.85[1.93; 31.98]6,2571,59277%NAKim (Controls unexposed, NOS) (Valproate) (Indications NOS), 2026 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Cornel (Valproate) (Indications NOS), 1996 3 unexposed, sickunexposed, sick 7.45[2.50; 22.18]188510%NAVeiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 Charlton (Valproate) (Controls unexposed, sick), 2011 Viinikainen (Valproate) (Controls unexposed, sick) a, 2006 Artama (Valproate), 2005 Czeizel (Valproate), 1992 5 Tags Adjustment   - No  - No 8.26[3.36; 20.27]1478630%NAVeiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 Charlton (Valproate) (Controls unexposed, sick), 2011 Viinikainen (Valproate) (Controls unexposed, sick) a, 2006 Artama (Valproate), 2005 Cornel (Valproate) (Indications NOS), 1996 Czeizel (Valproate), 1992 6   - Yes  - Yes 6.89[0.84; 56.83]6,1281,58089%NAKim (Controls unexposed, NOS) (Valproate) (Indications NOS), 2026 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 2 Controls   - epilepsy indication  - epilepsy indication 3.79[0.39; 36.49]4333 -NAVeiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 1 All studiesAll studies 7.92[3.67; 17.11]6,2752,44336%NAKim (Controls unexposed, NOS) (Valproate) (Indications NOS), 2026 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Veiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 Charlton (Valproate) (Controls unexposed, sick), 2011 Viinikainen (Valproate) (Controls unexposed, sick) a, 2006 Artama (Valproate), 2005 Cornel (Valproate) (Indications NOS), 1996 Czeizel (Valproate), 1992 80.5100.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.46.42.1910.000Kim (Controls unexposed, NOS) (Valproate) (Indications NOS), 2026Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019Veiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014Charlton (Valproate) (Controls unexposed, sick), 2011Viinikainen (Valproate) (Controls unexposed, sick) a, 2006Artama (Valproate), 2005Cornel (Valproate) (Indications NOS), 1996Czeizel (Valproate), 1992

Asymetry test p-value = 0.5200 (by Egger's regression)

slope=2.6749 (0.7686); intercept=-0.6806 (0.9962); t=0.6832; p=0.5200

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 9293, 9325, 10174, 19424

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 7.85[1.93; 31.98]6,2571,59277%NAKim (Controls unexposed, NOS) (Valproate) (Indications NOS), 2026 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Cornel (Valproate) (Indications NOS), 1996 3 unexposed, sick controlsunexposed, sick controls 7.45[2.50; 22.18]188510%NAVeiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 Charlton (Valproate) (Controls unexposed, sick), 2011 Viinikainen (Valproate) (Controls unexposed, sick) a, 2006 Artama (Valproate), 2005 Czeizel (Valproate), 1992 5 exposed to other treatment, sick controlsexposed to other treatment, sick controls 7.26[2.06; 25.56]162,1380%NAKim (Controls exposed to LTG) (Valproate) (Indications NOS), 2026 Blotière (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2019 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Charlton (Valproate) (Controls exposed to Lamotrigine, sick), 2011 40.510.01.0