Valproate (All indications)

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.
S15237
R63068
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
R63069
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
S9430
R46516
Wiggs (Valproate), 2020 Attention-deficit/hyperactivity disorder (after 2 years of age) at least 1st trimester population based cohort retrospective unexposed, sick Adjustment: Yes 1.74 [1.28;2.38] -/-   -/11,298 - -
ref
S9404
R46515
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
S9416
R46518
Richards (Valproate) (Controls exposed to Lamotrigine, sick) (Indications NOS), 2019 The Strengths and Difficulties Questionnaire - parent-completed (SDQP) Hyperactivity ≥7 (at 4 years old) during pregnancy (anytime or not specified) population based cohort retrospective exposed to other treatment, sick excluded Adjustment: Yes 0.67 [0.31;1.42]
excluded (control group)
10/161   13/149 23 161
ref
S9417
R46519
Richards (Valproate) (Controls unexposed, NOS) (Indications NOS), 2019 The Strengths and Difficulties Questionnaire - parent-completed (SDQP) Hyperactivity ≥7 (at 4 years old) during pregnancy (anytime or not specified) population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes 1.35 [0.71;2.58] 10/161   11,841/286,966 11,851 161
ref
S9374
R46517
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
S9377
R46509
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
R46510
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
R46511
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
R46514
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
S9450
R46520
Rihtman (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2013 Conners’ Parent - ADHD Index (mean age 4-5 years old) at least 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No Controls: epilepsy indication extrapolated (cont. endpoint) 2.74 [1.13;6.67]
excluded (control group)
-/29   -/39 - 29
ref
S9451
R46521
Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Conners’ Parent - ADHD Index (mean age 4-5 years old) at least 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No extrapolated (cont. endpoint) 3.38 [1.45;7.88] -/29   -/52 - 29
ref
S9424
R46522
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
S9426
R46523
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
S9427
R46524
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
S9428
R46525
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
S9278
R46508
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 11 studies 1.52 [1.28;1.81] 12,513 2,387
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 1.41[1.10; 1.81]6341,95248%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Wiggs (Valproate), 2020Wiggs, 2020 2 1.74[1.28; 2.38]--31%ROB confusion: seriousROB selection: lowROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Huber-Mollema (Valproate), 2019Huber-Mollema, 2019 3 1.38[0.25; 7.58]7261%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: criticalROB mesure: moderateROB reporting: moderate Richards (Valproate) (Controls unexposed, NOS) (Indications NOS), 2019Richards, 2019 4 1.35[0.71; 2.58]11,8511617%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: criticalROB mesure: moderateROB reporting: moderate Bromley (Valproate), 2016Bromley, 2016 5 0.89[0.44; 1.79]-476%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]10282%ROB confusion: criticalROB selection: lowROB classification: lowROB missing: criticalROB mesure: lowROB reporting: low Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013Rihtman, 2013 8 3.38[1.45; 7.88]-294%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Veiby (Valproate) (Controls unexposed, sick) b, 2013Veiby, 2013 9 2.08[0.22; 19.67]5191%ROB confusion: criticalROB selection: lowROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Viinikainen (Valproate) b, 2006Viinikainen, 2006 10 0.90[0.10; 7.78]4121%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: moderateROB mesure: lowROB reporting: moderate Adab (Valproate), 2004Adab, 2004 11 8.31[0.39; 175.93]2630%ROB confusion: criticalROB selection: criticalROB classification: lowROB missing: criticalROB mesure: lowROB reporting: moderate Total (11 studies) I2 = 0% 1.52[1.28; 1.81]12,5132,3870.220.01.0ROB: 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) (Controls unexposed, NOS) (Indications NOS; 5: Valproate; 6: Valproate) (Controls unexposed, sick; 7: Valproate; 8: Valproate) (Controls unexposed, NOS) (Mixed indications; 9: Valproate) (Controls unexposed, sick) ; 10: Valproate) ; 11: Valproate;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.52[1.28; 1.81]12,5132,3870%NADreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Wiggs (Valproate), 2020 Huber-Mollema (Valproate), 2019 Richards (Valproate) (Controls unexposed, NOS) (Indications NOS), 2019 Bromley (Valproate), 2016 Bromley (Valproate) (Controls unexposed, sick), 2013 Cohen (Valproate), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Viinikainen (Valproate) b, 2006 Adab (Valproate), 2004 11 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 2.05[0.84; 5.01]11,85119065%NARichards (Valproate) (Controls unexposed, NOS) (Indications NOS), 2019 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 2 unexposed, sickunexposed, sick 1.48[1.23; 1.78]6452,1430%NADreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Wiggs (Valproate), 2020 Bromley (Valproate), 2016 Bromley (Valproate) (Controls unexposed, sick), 2013 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Viinikainen (Valproate) b, 2006 Adab (Valproate), 2004 7 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 1.60[0.98; 2.62]282747%NAHuber-Mollema (Valproate), 2019 Bromley (Valproate), 2016 Bromley (Valproate) (Controls unexposed, sick), 2013 Cohen (Valproate), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Viinikainen (Valproate) b, 2006 Adab (Valproate), 2004 8   - Yes  - Yes 1.52[1.26; 1.82]12,4852,1130%NADreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Wiggs (Valproate), 2020 Richards (Valproate) (Controls unexposed, NOS) (Indications NOS), 2019 3 extrapolated (cont. endpoint)extrapolated (cont. endpoint) 1.70[0.46; 6.27]-7682%NABromley (Valproate), 2016 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 2 MatchedMatched 0.90[0.10; 7.78]412 -NAViinikainen (Valproate) b, 2006 1 All studiesAll studies 1.52[1.28; 1.81]12,5132,3870%NADreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Wiggs (Valproate), 2020 Huber-Mollema (Valproate), 2019 Richards (Valproate) (Controls unexposed, NOS) (Indications NOS), 2019 Bromley (Valproate), 2016 Bromley (Valproate) (Controls unexposed, sick), 2013 Cohen (Valproate), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Viinikainen (Valproate) b, 2006 Adab (Valproate), 2004 110.220.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.75.22.4180.000Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023Wiggs (Valproate), 2020Huber-Mollema (Valproate), 2019Richards (Valproate) (Controls unexposed, NOS) (Indications NOS), 2019Bromley (Valproate), 2016Bromley (Valproate) (Controls unexposed, sick), 2013Cohen (Valproate), 2013Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013Veiby (Valproate) (Controls unexposed, sick) b, 2013Viinikainen (Valproate) b, 2006Adab (Valproate), 2004

Asymetry test p-value = 0.7516 (by Egger's regression)

slope=0.3902 (0.1270); intercept=0.1424 (0.4363); t=0.3264; p=0.7516

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 9377, 9380, 9450, 9424, 9426, 9416, 15237

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.89[1.12; 3.20]13,5952595%NARichards (Valproate) (Controls unexposed, NOS) (Indications NOS), 2019 Bromley (Valproate) (Controls unexposed, disease free), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Veiby (Valproate) (Controls unexposed, disease free) b, 2013 4 unexposed, sick controlsunexposed, sick controls 1.48[1.23; 1.78]6452,1430%NADreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Wiggs (Valproate), 2020 Bromley (Valproate), 2016 Bromley (Valproate) (Controls unexposed, sick), 2013 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Viinikainen (Valproate) b, 2006 Adab (Valproate), 2004 7 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.66[0.86; 3.22]2452,26563%NADreier (Valproate) (Epilepsy) (Controls exposed to LTG), 2023 Huber-Mollema (Valproate), 2019 Richards (Valproate) (Controls exposed to Lamotrigine, sick) (Indications NOS), 2019 Bromley (Valproate) (Controls exposed to Lamotrigine, sick), 2013 Cohen (Valproate), 2013 Rihtman (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2013 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) b, 2013 70.510.01.0