Valproate (All indications)

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.
S9404
R32970		 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
S9416
R33031		 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
R33041		 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
R32796		 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
S9390
R32865		 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
S9450
R33212		 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
R33247		 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
R33066		 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
R33084		 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
R33098		 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
R33115		 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 7 studies 1.51 [0.99;2.32] 11,883 339
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]6264%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: criticalROB mesure: moderateROB reporting: moderate Richards (Valproate) (Controls unexposed, NOS) (Indications NOS), 2019Richards, 2019 2 1.35[0.71; 2.58]11,85116129%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: criticalROB mesure: moderateROB reporting: moderate Bromley (Valproate), 2016Bromley, 2016 3 0.89[0.44; 1.79]-4726%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Cohen (Valproate), 2013Cohen, 2013 4 2.20[0.77; 6.33]174514%ROB confusion: criticalROB selection: lowROB classification: lowROB missing: criticalROB mesure: lowROB reporting: low Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013Rihtman, 2013 5 3.38[1.45; 7.88]-2920%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Veiby (Valproate) (Controls unexposed, sick) b, 2013Veiby, 2013 6 2.08[0.22; 19.67]5193%ROB confusion: criticalROB selection: lowROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Viinikainen (Valproate) b, 2006Viinikainen, 2006 7 0.90[0.10; 7.78]4124%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: moderateROB mesure: lowROB reporting: moderate Total (7 studies) I2 = 16% 1.51[0.99; 2.32]11,8833390.210.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Valproate; 2: Valproate) (Controls unexposed, NOS) (Indications NOS; 3: Valproate; 4: Valproate; 5: Valproate) (Controls unexposed, NOS) (Mixed indications; 6: Valproate) (Controls unexposed, sick) ; 7: Valproate) ;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.51[0.99; 2.32]11,88333916%NAHuber-Mollema (Valproate), 2019 Richards (Valproate) (Controls unexposed, NOS) (Indications NOS), 2019 Bromley (Valproate), 2016 Cohen (Valproate), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Viinikainen (Valproate) b, 2006 7 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 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 1.59[0.88; 2.87]3217828%NAHuber-Mollema (Valproate), 2019 Bromley (Valproate), 2016 Cohen (Valproate), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Viinikainen (Valproate) b, 2006 6   - Yes  - Yes 1.35[0.71; 2.57]11,851161 -NARichards (Valproate) (Controls unexposed, NOS) (Indications NOS), 2019 1 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 1.51[0.99; 2.32]11,88333916%NAHuber-Mollema (Valproate), 2019 Richards (Valproate) (Controls unexposed, NOS) (Indications NOS), 2019 Bromley (Valproate), 2016 Cohen (Valproate), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Viinikainen (Valproate) b, 2006 70.210.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-2.73.11.3750.000Huber-Mollema (Valproate), 2019Richards (Valproate) (Controls unexposed, NOS) (Indications NOS), 2019Bromley (Valproate), 2016Cohen (Valproate), 2013Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013Veiby (Valproate) (Controls unexposed, sick) b, 2013Viinikainen (Valproate) b, 2006

Asymetry test p-value = 0.9936 (by Egger's regression)

slope=0.4026 (0.5202); intercept=-0.0089 (1.0447); t=0.0085; p=0.9936

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 9450, 9424, 9426, 9416

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.91[0.98; 3.73]13,59520933%NARichards (Valproate) (Controls unexposed, NOS) (Indications NOS), 2019 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Veiby (Valproate) (Controls unexposed, disease free) b, 2013 3 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 1.33[0.65; 2.72]5028044%NAHuber-Mollema (Valproate), 2019 Richards (Valproate) (Controls exposed to Lamotrigine, sick) (Indications NOS), 2019 Cohen (Valproate), 2013 Rihtman (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2013 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) b, 2013 50.510.01.0