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

ADHD (Attention deficit hyperactivity disorder): Diagnosis

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.
S17423
R73165		 Madley-Dowd_SE (Valproate) (Controls exposed to LTG) (Mixed indications), 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: Yes Partial overlapping 1.38 [1.13;1.68]
excluded (control group) 		164/1,178   243/5,035 407 1,178
ref
S17424
R73171		 Madley-Dowd_SE (Valproate) (Controls unexposed, general pop) (Mixed indications), 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 (general population or NOS) Adjustment: Yes Partial overlapping 1.18 [1.01;1.39] 164/1,178   147,608/2,651,210 147,772 1,178
ref
S17425
R73177		 Madley-Dowd_SE (Valproate) (Controls unexposed, sibling) (Mixed indications), 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 sibling excluded Adjustment: Yes Partial overlapping 1.26 [0.81;1.96]
excluded (control group) 		-/-   -/- - -
ref
S17286
R72342		 Madley-Dowd_UK (Valproate) (Controls exposed to LTG) (Mixed indications), 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: Yes 0.90 [0.38;2.15]
excluded (control group) 		10/423   14/939 24 423
ref
S17271
R72299		 Madley-Dowd_UK (Valproate) (Controls unexposed, general pop) (Mixed indications), 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 (general population or NOS) Adjustment: Yes 1.48 [0.71;3.07] 10/423   4,794/514,066 4,804 423
ref
S17279
R72324		 Madley-Dowd_UK (Valproate) (Controls unexposed, sibling) (Mixed indications), 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) sibling excluded Adjustment: Yes 4.00 [1.39;11.47]
excluded (control group) 		-/-   -/- - -
ref
S15237
R62630		 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
S15228
R62513		 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
S9404
R32953		 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
S9377
R32811		 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
S9380
R32827		 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
S9383
R32843		 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
S9390
R32860		 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
S9278
R32186		 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 7 studies 1.26 [1.10;1.43] 153,229 3,720
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, general pop) (Mixed indications), 2024Madley-Dowd_SE, 2024 1 1.18[1.01; 1.39]147,7721,17867%ROB confusion: seriousROB selection: lowROB classification: lowROB missing: lowROB mesure: moderateROB reporting: moderate Madley-Dowd_UK (Valproate) (Controls unexposed, general pop) (Mixed indications), 2024Madley-Dowd_UK, 2024 2 1.48[0.71; 3.07]4,8044233%ROB confusion: seriousROB 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]6341,95228%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) (Controls unexposed, sick), 2013Bromley, 2013 5 0.52[0.01; 26.73]0500%ROB confusion: criticalROB selection: lowROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Cohen (Valproate), 2013Cohen, 2013 6 1.84[0.46; 7.35]10281%ROB confusion: criticalROB selection: lowROB classification: lowROB missing: criticalROB mesure: lowROB reporting: low Adab (Valproate), 2004Adab, 2004 7 8.31[0.39; 175.93]2630%ROB confusion: criticalROB selection: criticalROB classification: lowROB missing: criticalROB mesure: lowROB reporting: moderate Total (7 studies) I2 = 0% 1.26[1.10; 1.43]153,2293,7200.220.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Valproate) (Controls unexposed, general pop) (Mixed indications; 2: Valproate) (Controls unexposed, general pop) (Mixed indications; 3: Valproate) (Epilepsy) (Controls unexposed, sick; 4: Valproate; 5: Valproate) (Controls unexposed, sick; 6: Valproate; 7: Valproate;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.26[1.10; 1.43]153,2293,7200%NAMadley-Dowd_SE (Valproate) (Controls unexposed, general pop) (Mixed indications), 2024 Madley-Dowd_UK (Valproate) (Controls unexposed, general pop) (Mixed indications), 2024 Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Huber-Mollema (Valproate), 2019 Bromley (Valproate) (Controls unexposed, sick), 2013 Cohen (Valproate), 2013 Adab (Valproate), 2004 7 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.19[1.02; 1.39]152,5761,6010%NAMadley-Dowd_SE (Valproate) (Controls unexposed, general pop) (Mixed indications), 2024 Madley-Dowd_UK (Valproate) (Controls unexposed, general pop) (Mixed indications), 2024 2 unexposed, sickunexposed, sick 1.42[1.11; 1.82]6362,0650%NADreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Bromley (Valproate) (Controls unexposed, sick), 2013 Adab (Valproate), 2004 3 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 1.81[0.68; 4.82]191670%NAHuber-Mollema (Valproate), 2019 Bromley (Valproate) (Controls unexposed, sick), 2013 Cohen (Valproate), 2013 Adab (Valproate), 2004 4   - Yes  - Yes 1.25[1.10; 1.43]153,2103,5530%NAMadley-Dowd_SE (Valproate) (Controls unexposed, general pop) (Mixed indications), 2024 Madley-Dowd_UK (Valproate) (Controls unexposed, general pop) (Mixed indications), 2024 Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 3 Partial overlappingPartial overlapping 1.18[1.01; 1.38]147,7721,178 -NAMadley-Dowd_SE (Valproate) (Controls unexposed, general pop) (Mixed indications), 2024 1 All studiesAll studies 1.26[1.10; 1.43]153,2293,7200%NAMadley-Dowd_SE (Valproate) (Controls unexposed, general pop) (Mixed indications), 2024 Madley-Dowd_UK (Valproate) (Controls unexposed, general pop) (Mixed indications), 2024 Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Huber-Mollema (Valproate), 2019 Bromley (Valproate) (Controls unexposed, sick), 2013 Cohen (Valproate), 2013 Adab (Valproate), 2004 70.220.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.75.02.4180.000Madley-Dowd_SE (Valproate) (Controls unexposed, general pop) (Mixed indications), 2024Madley-Dowd_UK (Valproate) (Controls unexposed, general pop) (Mixed indications), 2024Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023Huber-Mollema (Valproate), 2019Bromley (Valproate) (Controls unexposed, sick), 2013Cohen (Valproate), 2013Adab (Valproate), 2004

Asymetry test p-value = 0.2236 (by Egger's regression)

slope=0.1694 (0.0647); intercept=0.5084 (0.3661); t=1.3888; p=0.2236

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 9377, 9380, 15237, 17423, 17425, 17286, 17279

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.19[1.02; 1.40]152,5761,6510%NAMadley-Dowd_SE (Valproate) (Controls unexposed, general pop) (Mixed indications), 2024 Madley-Dowd_UK (Valproate) (Controls unexposed, general pop) (Mixed indications), 2024 Bromley (Valproate) (Controls unexposed, disease free), 2013 3 unexposed, sick controlsunexposed, sick controls 1.42[1.11; 1.82]6362,0650%NADreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Bromley (Valproate) (Controls unexposed, sick), 2013 Adab (Valproate), 2004 3 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.66[0.95; 2.90]6493,65780%NAMadley-Dowd_SE (Valproate) (Controls exposed to LTG) (Mixed indications), 2024 Madley-Dowd_UK (Valproate) (Controls exposed to LTG) (Mixed indications), 2024 Dreier (Valproate) (Epilepsy) (Controls exposed to LTG), 2023 Huber-Mollema (Valproate), 2019 Bromley (Valproate) (Controls exposed to Lamotrigine, sick), 2013 Cohen (Valproate), 2013 6 siblingssiblings 2.02[0.66; 6.17]--74%NAMadley-Dowd_SE (Valproate) (Controls unexposed, sibling) (Mixed indications), 2024 Madley-Dowd_UK (Valproate) (Controls unexposed, sibling) (Mixed indications), 2024 20.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Andrade (Valproate) (Attention-deficit/hypera ...Andrade (Valproate) (Attention-deficit/hyperactivity disorder (ADHD) (Adjusted hazard ratio) (Mono- and/or polytherapy)) 1.62[1.30; 2.01]59%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT2 Andrade (Valproate) (Attention-deficit/hypera ...Andrade (Valproate) (Attention-deficit/hyperactivity disorder (ADHD) (Adjusted hazard ratio) (Monotherapy)) 1.62[1.30; 2.01]59%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT2 Andrade (Valproate) (Attention-deficit/hypera ...Andrade (Valproate) (Attention-deficit/hyperactivity disorder (ADHD) (Unadjusted risk ratio) (Control LTG)) 1.51[0.45; 5.08]NA-Eexposed to other treatment, sickAnyduring pregnancy (anytime or not specified)studies TTT1 Andrade (Valproate) (Attention-deficit/hypera ...Andrade (Valproate) (Attention-deficit/hyperactivity disorder (ADHD) (Unadjusted risk ratio) (Mono- and/or polytherapy)) 2.29[1.89; 2.79]0%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT3 metaPregmetaPreg 1.26[1.10; 1.43]0%3,720----Madley-Dowd_SE (Valproate) (Controls unexposed, general pop) (Mixed indications), 2024 Madley-Dowd_UK (Valproate) (Controls unexposed, general pop) (Mixed indications), 2024 Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Huber-Mollema (Valproate), 2019 Bromley (Valproate) (Controls unexposed, sick), 2013 Cohen (Valproate), 2013 Adab (Valproate), 2004 70.510.01.0