Valproate (All indications)

Behavioral 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.
S15237
R62631		 Dreier (Valproate) (Epilepsy) (Controls exposed to LTG), 2023 Oppositional defiant disorder and conduct disorder - Corresponding ICD-10 F-chapter - Up to 22 years of age during pregnancy (anytime or not specified) population based cohort propective exposed to other treatment, sick excluded Adjustment: No 2.92 [1.41;6.05] C
excluded (control group) 		15/1,952   14/5,288 29 1,952
ref
S15228
R62514		 Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Oppositional defiant disorder and conduct disorder - Corresponding ICD-10 F-chapter - Up to 22 years of age during pregnancy (anytime or not specified) population based cohort propective unexposed, sick Adjustment: Yes 0.79 [0.43;1.46] 15/1,952   110/22,203 125 1,952
ref
S9404
R32969		 Huber-Mollema (Valproate), 2019 Externalizing problems (The Child Behavior Checklist) (Completed by mothers) Clinical cutoff throughout pregnancy prospective cohort exposed to other treatment, sick Adjustment: No 1.67 [0.57;4.92] C 6/25   14/88 20 25
ref
S9374
R32793		 Bromley (Valproate), 2016 Maladaptive behavior: Aggression (BASC) (5-9 years old) during pregnancy (anytime or not specified) retrospective cohort (registry) unexposed, sick Adjustment: No extrapolated (cont. endpoint) 0.80 [0.39;1.61] -/47   -/55 - 47
ref
S9390
R32867		 Cohen (Valproate), 2013 Agression in mean (BASC scale) (Parent ratings) during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick Adjustment: Yes extrapolated (cont. endpoint) 1.00 [0.50;2.01] -/45   -/61 - 45
ref
S9424
R33067		 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) b, 2013 Aggressive symptoms ≥ 2SD (at 36 months) (the Child Behaviour Checklist) during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick excluded Adjustment: No 0.76 [0.07;7.80] C
excluded (control group) 		1/19   3/44 4 19
ref
S9426
R33085		 Veiby (Valproate) (Controls unexposed, disease free) b, 2013 Aggressive symptoms ≥ 2SD (at 36 months) (the Child Behaviour Checklist) during pregnancy (anytime or not specified) prospective cohort unexposed, disease free excluded Adjustment: No 1.20 [0.20;9.40]
excluded (control group) 		1/19   1,786/43,571 1,787 19
ref
S9427
R33099		 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Aggressive symptoms ≥ 2SD (at 36 months) (the Child Behaviour Checklist) during pregnancy (anytime or not specified) prospective cohort unexposed, sick Adjustment: No 1.66 [0.18;14.97] C 1/19   5/154 6 19
ref
Total 5 studies 0.93 [0.65;1.34] 151 2,088
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 Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023Dreier, 2023 1 0.79[0.43; 1.46]1251,95234%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: moderate Huber-Mollema (Valproate), 2019Huber-Mollema, 2019 2 1.67[0.57; 4.92]202511%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: criticalROB mesure: moderateROB reporting: moderate Bromley (Valproate), 2016Bromley, 2016 3 0.80[0.39; 1.61]-4726%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Cohen (Valproate), 2013Cohen, 2013 4 1.00[0.50; 2.01]-4527%ROB confusion: moderateROB selection: lowROB classification: lowROB missing: criticalROB mesure: lowROB reporting: low Veiby (Valproate) (Controls unexposed, sick) b, 2013Veiby, 2013 5 1.66[0.18; 14.97]6193%ROB confusion: criticalROB selection: lowROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Total (5 studies) I2 = 0% 0.93[0.65; 1.34]1512,0880.25.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Valproate) (Epilepsy) (Controls unexposed, sick; 2: Valproate; 3: Valproate; 4: Valproate; 5: Valproate) (Controls unexposed, sick) ;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 0.93[0.65; 1.34]1512,0880%NADreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Huber-Mollema (Valproate), 2019 Bromley (Valproate), 2016 Cohen (Valproate), 2013 Veiby (Valproate) (Controls unexposed, sick) b, 2013 5 case control studiescase control studies 0 Type of controls unexposed, sickunexposed, sick 0.82[0.52; 1.29]1312,0180%NADreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Bromley (Valproate), 2016 Veiby (Valproate) (Controls unexposed, sick) b, 2013 3 exposed to other treatment, sickexposed to other treatment, sick 1.16[0.65; 2.09]20700%NAHuber-Mollema (Valproate), 2019 Cohen (Valproate), 2013 2 Tags Adjustment   - No  - No 1.03[0.58; 1.83]26910%NAHuber-Mollema (Valproate), 2019 Bromley (Valproate), 2016 Veiby (Valproate) (Controls unexposed, sick) b, 2013 3   - Yes  - Yes 0.88[0.55; 1.39]1251,9970%NADreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Cohen (Valproate), 2013 2 extrapolated (cont. endpoint)extrapolated (cont. endpoint) 0.90[0.55; 1.47]-920%NABromley (Valproate), 2016 Cohen (Valproate), 2013 2 All studiesAll studies 0.93[0.65; 1.34]1512,0880%NADreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Huber-Mollema (Valproate), 2019 Bromley (Valproate), 2016 Cohen (Valproate), 2013 Veiby (Valproate) (Controls unexposed, sick) b, 2013 50.25.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-2.62.61.3480.000Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023Huber-Mollema (Valproate), 2019Bromley (Valproate), 2016Cohen (Valproate), 2013Veiby (Valproate) (Controls unexposed, sick) b, 2013

Asymetry test p-value = 0.1433 (by Egger's regression)

slope=-0.5826 (0.2778); intercept=1.3400 (0.6799); t=1.9709; p=0.1433

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 9424, 9426, 15237

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.20[0.18; 8.23]1,78719 -NAVeiby (Valproate) (Controls unexposed, disease free) b, 2013 1 unexposed, sick controlsunexposed, sick controls 0.82[0.52; 1.29]1312,0180%NADreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Bromley (Valproate), 2016 Veiby (Valproate) (Controls unexposed, sick) b, 2013 3 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.60[0.87; 2.95]532,04137%NADreier (Valproate) (Epilepsy) (Controls exposed to LTG), 2023 Huber-Mollema (Valproate), 2019 Cohen (Valproate), 2013 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) b, 2013 40.510.01.0