Valproate (Epilepsy)

ADHD (Attention deficit hyperactivity disorder): 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.
S7508
R25085		 Huber-Mollema (Valproate), 2019 ADHD total (Social Emotional Questionnaire) (Completed by mothers) Clinical cutoff throughout pregnancy prospective cohort exposed to other treatment, sick Adjustment: No 0.66 [0.07;5.88] C 1/26   5/87 6 26
ref
S7309
R28374		 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
S7295
R21121		 Cohen (Valproate), 2013 Children with either ADHD inattentive OR combined types > 1 SD (from the Attention Problems and Hyperactivity scales of the BASC) (Parent) during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick Adjustment: No 2.20 [0.77;6.33] C 10/45   7/61 17 45
ref
S6353
R17269		 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
R17241		 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
R17253		 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
R20627		 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
Total 5 studies 1.15 [0.68;1.96] 32 149
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 Huber-Mollema (Valproate), 2019Huber-Mollema, 2019 1 0.66[0.07; 5.88]6266%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: criticalROB mesure: moderateROB reporting: moderate Bromley (Valproate), 2016Bromley, 2016 2 0.89[0.44; 1.79]-4757%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Cohen (Valproate), 2013Cohen, 2013 3 2.20[0.77; 6.33]174525%ROB confusion: criticalROB selection: lowROB classification: lowROB missing: criticalROB mesure: lowROB reporting: low Veiby (Valproate) (Controls unexposed, sick) b, 2013Veiby, 2013 4 2.08[0.22; 19.67]5196%ROB confusion: criticalROB selection: lowROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Viinikainen (Valproate) b, 2006Viinikainen, 2006 5 0.90[0.10; 7.78]4126%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: moderateROB mesure: lowROB reporting: moderate Total (5 studies) I2 = 0% 1.15[0.68; 1.96]321490.25.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

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

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.15[0.68; 1.96]321490%NAHuber-Mollema (Valproate), 2019 Bromley (Valproate), 2016 Cohen (Valproate), 2013 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Viinikainen (Valproate) b, 2006 5 case control studiescase control studies 0 Type of controls unexposed, sickunexposed, sick 0.95[0.50; 1.81]9780%NABromley (Valproate), 2016 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Viinikainen (Valproate) b, 2006 3 exposed to other treatment, sickexposed to other treatment, sick 1.75[0.68; 4.54]23710%NAHuber-Mollema (Valproate), 2019 Cohen (Valproate), 2013 2 Tags Adjustment   - No  - No 1.15[0.68; 1.96]321490%NAHuber-Mollema (Valproate), 2019 Bromley (Valproate), 2016 Cohen (Valproate), 2013 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Viinikainen (Valproate) b, 2006 5 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 1.15[0.68; 1.96]321490%NAHuber-Mollema (Valproate), 2019 Bromley (Valproate), 2016 Cohen (Valproate), 2013 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Viinikainen (Valproate) b, 2006 50.25.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-2.72.81.3750.000Huber-Mollema (Valproate), 2019Bromley (Valproate), 2016Cohen (Valproate), 2013Veiby (Valproate) (Controls unexposed, sick) b, 2013Viinikainen (Valproate) b, 2006

Asymetry test p-value = 0.7981 (by Egger's regression)

slope=0.0110 (0.5332); intercept=0.2460 (0.8806); t=0.2793; p=0.7981

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 6353, 5506

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.30[0.18; 9.15]1,74419 -NAVeiby (Valproate) (Controls unexposed, disease free) b, 2013 1 unexposed, sick controlsunexposed, sick controls 0.95[0.50; 1.81]9780%NABromley (Valproate), 2016 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Viinikainen (Valproate) b, 2006 3 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.56[0.65; 3.76]27900%NAHuber-Mollema (Valproate), 2019 Cohen (Valproate), 2013 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) b, 2013 30.510.01.0