Valproate (Epilepsy)

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.
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
S8008
R46566		 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
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 9 studies 1.48 [1.23;1.78] 662 2,197
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]6341,95254%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Wiggs (Valproate), 2020Wiggs, 2020 2 1.74[1.28; 2.38]--35%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 Bromley (Valproate), 2016Bromley, 2016 4 0.89[0.44; 1.79]-477%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA 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]10282%ROB confusion: criticalROB selection: lowROB classification: lowROB missing: criticalROB mesure: lowROB reporting: low Veiby (Valproate) (Controls unexposed, sick) b, 2013Veiby, 2013 7 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 8 0.90[0.10; 7.78]4121%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: moderateROB mesure: lowROB reporting: moderate Adab (Valproate), 2004Adab, 2004 9 8.31[0.39; 175.93]2630%ROB confusion: criticalROB selection: criticalROB classification: lowROB missing: criticalROB mesure: lowROB reporting: moderate Total (9 studies) I2 = 0% 1.48[1.23; 1.78]6622,1970.220.01.0ROB: 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; 5: Valproate) (Controls unexposed, sick; 6: Valproate; 7: Valproate) (Controls unexposed, sick) ; 8: Valproate) ; 9: Valproate;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.48[1.23; 1.78]6622,1970%NADreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Wiggs (Valproate), 2020 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 9 case control studiescase control studies 0 Type of controls 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 1.15[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 1.53[1.25; 1.88]6341,9527%NADreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Wiggs (Valproate), 2020 2 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 All studiesAll studies 1.48[1.23; 1.78]6622,1970%NADreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Wiggs (Valproate), 2020 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 90.220.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.75.12.4180.000Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023Wiggs (Valproate), 2020Huber-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 = 0.9389 (by Egger's regression)

slope=0.3994 (0.1110); intercept=-0.0316 (0.3972); t=0.0795; p=0.9389

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 6662, 6659, 6353, 5506, 15877

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 1.48[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 2.93[2.24; 3.84]2222,0750%NADreier (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 50.510.01.0