Valproate (Epilepsy) updated on 04-22-2025

ADHD (Attention deficit hyperactivity disorder): Diagnosis/Risk

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.
S17439
R73290
Madley-Dowd_SE (Valproate) (Controls exposed to LTG), 2024 Attention Deficit Hyperactivity Disorder - ICD-8/9/10 codes and/or ADHD medication prescription - Mean 5-20 years old (according groups) during pregnancy (anytime or not specified) population based cohort retrospective exposed to other treatment, sick excluded Adjustment: No Partial overlapping 3.47 [2.63;4.58] C
excluded (control group)
113/792   109/2,383 222 792
ref
S17440
R73291
Madley-Dowd_SE (Valproate) (Controls unexposed, sick), 2024 Attention Deficit Hyperactivity Disorder - ICD-8/9/10 codes and/or ADHD medication prescription - Mean 5-20 years old (according groups) during pregnancy (anytime or not specified) population based cohort retrospective unexposed, sick Adjustment: Yes Partial overlapping 1.21 [0.99;1.47] 113/792   929/10,769 1,042 792
ref
S17261
R72266
Madley-Dowd_UK (Valproate) (Controls exposed to LTG) (Epilepsy), 2024 Attention Deficit Hyperactivity Disorder - ICD10 codes and/or ADHD medication prescription - Median follow up 9.32 (5.54-12.83) years old during pregnancy (anytime or not specified) retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No 1.28 [0.53;3.09] C
excluded (control group)
8/354   14/791 22 354
ref
S17256
R72267
Madley-Dowd_UK (Valproate) (Controls unexposed, sick) (Epilepsy), 2024 Attention Deficit Hyperactivity Disorder - ICD10 codes and/or ADHD medication prescription - Median follow up 9.32 (5.54-12.83) years old during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed, sick Adjustment: Yes 1.50 [0.62;3.63] 8/354   38/4,075 46 354
ref
S15877
R65469
Dreier (Valproate) (Epilepsy) (Controls exposed to LTG), 2023 Attention-deficit/hyperactivity disorder (ADHD) - 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 3.14 [2.37;4.16] C
excluded (control group)
106/1,952   95/5,288 201 1,952
ref
S15878
R65483
Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Attention-deficit/hyperactivity disorder (ADHD) - 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 1.41 [1.10;1.81] 106/1,952   528/22,203 634 1,952
ref
S7508
R46565
Huber-Mollema (Valproate), 2019 Diagnosis of ADHD throughout pregnancy prospective cohort exposed to other treatment, sick Adjustment: No 1.38 [0.25;7.58] C 2/26   5/88 7 26
ref
S7309
R46567
Bromley (Valproate), 2016 Maladaptive behavior: Attention (BASC) (5-9 years old) during pregnancy (anytime or not specified) retrospective cohort (registry) unexposed, sick Adjustment: No extrapolated (cont. endpoint) 0.89 [0.44;1.79] -/47   -/55 - 47
ref
S6662
R46561
Bromley (Valproate) (Controls exposed to Lamotrigine, sick), 2013 Attention deficit hyperactivity disorder (at 6 years old) during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick excluded Adjustment: No 0.60 [0.01;30.84] C
excluded (control group)
0/50   0/30 0 50
ref
S6659
R46562
Bromley (Valproate) (Controls unexposed, disease free), 2013 Attention deficit hyperactivity disorder (at 6 years old) during pregnancy (anytime or not specified) prospective cohort unexposed, disease free excluded Adjustment: No 4.31 [0.08;220.05] C
excluded (control group)
0/50   0/214 0 50
ref
S6602
R46563
Bromley (Valproate) (Controls unexposed, sick), 2013 Attention deficit hyperactivity disorder (at 6 years old) during pregnancy (anytime or not specified) prospective cohort unexposed, sick Adjustment: No 0.52 [0.01;26.73] C 0/50   0/26 0 50
ref
S7295
R46564
Cohen (Valproate), 2013 Children with either ADHD inattentive OR combined types > 1 SD (from the Attention Problems and Hyperactivity scales of the BASC) (Both Parent and Teacher) during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick Adjustment: No 1.84 [0.46;7.35] C 6/28   4/31 10 28
ref
S6353
R46568
Veiby (Valproate) (Controls exposed to Lamotrigine, sick) b, 2013 ADHD symptoms ≥ 2SD (at 36 months) (Specific checklist) (Parent-reported) 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
S5506
R46569
Veiby (Valproate) (Controls unexposed, disease free) b, 2013 ADHD symptoms ≥ 2SD (at 36 months) (Specific checklist) (Parent-reported) during pregnancy (anytime or not specified) prospective cohort unexposed, disease free excluded Adjustment: No 1.30 [0.20;9.90]
excluded (control group)
1/19   1,743/43,571 1,744 19
ref
S6350
R46570
Veiby (Valproate) (Controls unexposed, sick) b, 2013 ADHD symptoms ≥ 2SD (at 36 months) (Specific checklist) (Parent-reported) during pregnancy (anytime or not specified) prospective cohort unexposed, sick Adjustment: No 2.08 [0.22;19.67] C 1/19   4/154 5 19
ref
S5543
R46571
Viinikainen (Valproate) b, 2006 Conners' Teacher Rating Scale Global Index scores >1 SD throughout pregnancy prospective cohort unexposed, sick Adjustment: No Matched 0.90 [0.10;7.78] C 2/12   2/11 4 12
ref
S7175
R46560
Adab (Valproate), 2004 Attention deficit hyperactivity disorder during pregnancy (anytime or not specified) retrospective cohort unexposed, sick Adjustment: No 8.31 [0.39;175.93] C 2/63   0/101 2 63
ref
Total 10 studies 1.28 [1.10;1.48] 1,750 3,343
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 Madley-Dowd_SE (Valproate) (Controls unexposed, sick), 2024Madley-Dowd_SE, 2024 1 1.21[0.99; 1.47]1,04279255%ROB confusion: moderateROB selection: lowROB classification: lowROB missing: lowROB mesure: moderateROB reporting: moderate Madley-Dowd_UK (Valproate) (Controls unexposed, sick) (Epilepsy), 2024Madley-Dowd_UK, 2024 2 1.50[0.62; 3.63]463543%ROB confusion: moderateROB selection: lowROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023Dreier, 2023 3 1.41[1.10; 1.81]6341,95235%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Huber-Mollema (Valproate), 2019Huber-Mollema, 2019 4 1.38[0.25; 7.58]7261%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: criticalROB mesure: moderateROB reporting: moderate Bromley (Valproate), 2016Bromley, 2016 5 0.89[0.44; 1.79]-474%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Bromley (Valproate) (Controls unexposed, sick), 2013Bromley, 2013 6 0.52[0.01; 26.73]0500%ROB confusion: criticalROB selection: lowROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Cohen (Valproate), 2013Cohen, 2013 7 1.84[0.46; 7.35]10281%ROB confusion: criticalROB selection: lowROB classification: lowROB missing: criticalROB mesure: lowROB reporting: low Veiby (Valproate) (Controls unexposed, sick) b, 2013Veiby, 2013 8 2.08[0.22; 19.67]5190%ROB confusion: criticalROB selection: lowROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Viinikainen (Valproate) b, 2006Viinikainen, 2006 9 0.90[0.10; 7.78]4120%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: moderateROB mesure: lowROB reporting: moderate Adab (Valproate), 2004Adab, 2004 10 8.31[0.39; 175.93]2630%ROB confusion: criticalROB selection: criticalROB classification: lowROB missing: criticalROB mesure: lowROB reporting: moderate Total (10 studies) I2 = 0% 1.28[1.10; 1.48]1,7503,3430.220.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Valproate) (Controls unexposed, sick; 2: Valproate) (Controls unexposed, sick) (Epilepsy; 3: Valproate) (Epilepsy) (Controls unexposed, sick; 4: Valproate; 5: Valproate; 6: Valproate) (Controls unexposed, sick; 7: Valproate; 8: Valproate) (Controls unexposed, sick) ; 9: Valproate) ; 10: Valproate;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.28[1.10; 1.48]1,7503,3430%NAMadley-Dowd_SE (Valproate) (Controls unexposed, sick), 2024 Madley-Dowd_UK (Valproate) (Controls unexposed, sick) (Epilepsy), 2024 Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Huber-Mollema (Valproate), 2019 Bromley (Valproate), 2016 Bromley (Valproate) (Controls unexposed, sick), 2013 Cohen (Valproate), 2013 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Viinikainen (Valproate) b, 2006 Adab (Valproate), 2004 10 case control studiescase control studies 0 Type of controls unexposed, sickunexposed, sick 1.27[1.10; 1.48]1,7333,2890%NAMadley-Dowd_SE (Valproate) (Controls unexposed, sick), 2024 Madley-Dowd_UK (Valproate) (Controls unexposed, sick) (Epilepsy), 2024 Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Bromley (Valproate), 2016 Bromley (Valproate) (Controls unexposed, sick), 2013 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Viinikainen (Valproate) b, 2006 Adab (Valproate), 2004 8 exposed to other treatment, sickexposed to other treatment, sick 1.64[0.56; 4.81]17540%NAHuber-Mollema (Valproate), 2019 Cohen (Valproate), 2013 2 Tags Adjustment   - No  - No 1.15[0.68; 1.97]282450%NAHuber-Mollema (Valproate), 2019 Bromley (Valproate), 2016 Bromley (Valproate) (Controls unexposed, sick), 2013 Cohen (Valproate), 2013 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Viinikainen (Valproate) b, 2006 Adab (Valproate), 2004 7   - Yes  - Yes 1.29[1.11; 1.50]1,7223,0980%NAMadley-Dowd_SE (Valproate) (Controls unexposed, sick), 2024 Madley-Dowd_UK (Valproate) (Controls unexposed, sick) (Epilepsy), 2024 Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 3 extrapolated (cont. endpoint)extrapolated (cont. endpoint) 0.89[0.44; 1.80]-47 -NABromley (Valproate), 2016 1 MatchedMatched 0.90[0.10; 7.78]412 -NAViinikainen (Valproate) b, 2006 1 Partial overlappingPartial overlapping 1.21[0.99; 1.47]1,042792 -NAMadley-Dowd_SE (Valproate) (Controls unexposed, sick), 2024 1 All studiesAll studies 1.28[1.10; 1.48]1,7503,3430%NAMadley-Dowd_SE (Valproate) (Controls unexposed, sick), 2024 Madley-Dowd_UK (Valproate) (Controls unexposed, sick) (Epilepsy), 2024 Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Huber-Mollema (Valproate), 2019 Bromley (Valproate), 2016 Bromley (Valproate) (Controls unexposed, sick), 2013 Cohen (Valproate), 2013 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Viinikainen (Valproate) b, 2006 Adab (Valproate), 2004 100.220.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.75.02.4180.000Madley-Dowd_SE (Valproate) (Controls unexposed, sick), 2024Madley-Dowd_UK (Valproate) (Controls unexposed, sick) (Epilepsy), 2024Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023Huber-Mollema (Valproate), 2019Bromley (Valproate), 2016Bromley (Valproate) (Controls unexposed, sick), 2013Cohen (Valproate), 2013Veiby (Valproate) (Controls unexposed, sick) b, 2013Viinikainen (Valproate) b, 2006Adab (Valproate), 2004

Asymetry test p-value = 0.5593 (by Egger's regression)

slope=0.2169 (0.0717); intercept=0.1847 (0.3031); t=0.6093; p=0.5593

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 6662, 6659, 6353, 5506, 15877, 17439, 17261

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.65[0.29; 9.46]1,744690%NABromley (Valproate) (Controls unexposed, disease free), 2013 Veiby (Valproate) (Controls unexposed, disease free) b, 2013 2 unexposed, sick controlsunexposed, sick controls 1.27[1.10; 1.48]1,7333,2890%NAMadley-Dowd_SE (Valproate) (Controls unexposed, sick), 2024 Madley-Dowd_UK (Valproate) (Controls unexposed, sick) (Epilepsy), 2024 Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Bromley (Valproate), 2016 Bromley (Valproate) (Controls unexposed, sick), 2013 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Viinikainen (Valproate) b, 2006 Adab (Valproate), 2004 8 exposed to other treatment, sick controlsexposed to other treatment, sick controls 2.80[2.10; 3.73]4663,22125%NAMadley-Dowd_SE (Valproate) (Controls exposed to LTG), 2024 Madley-Dowd_UK (Valproate) (Controls exposed to LTG) (Epilepsy), 2024 Dreier (Valproate) (Epilepsy) (Controls exposed to LTG), 2023 Huber-Mollema (Valproate), 2019 Bromley (Valproate) (Controls exposed to Lamotrigine, sick), 2013 Cohen (Valproate), 2013 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) b, 2013 70.510.01.0