Valproate (All indications)

Cognitive developmental disorders/delay (3-6 years old)

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.
S9391
R46549		 Coste (Valproate) (Controls exposed to Lamotrigine, sick), 2020 Diagnosis Mental retardation (F70–F79) (mean age of 3.7 years old) during pregnancy (anytime or not specified) retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: Yes 4.00 [1.90;8.60]
excluded (control group) 		15/991   10/2,108 25 991
ref
S9392
R46550		 Coste (Valproate) (Controls unexposed, NOS), 2020 Diagnosis Mental retardation (F70–F79) (mean age of 3.6 years old) during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: Yes 5.10 [3.10;8.50] 15/991   3,398/1,710,441 3,413 991
ref
S9408
R46544		 Kasradze (Valproate) (Controls exposed to Lamotrigine, sick), 2017 Full scale IQ (WPPSI-4) (mean age 4-4.5 years old) during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick excluded Adjustment: No extrapolated (cont. endpoint) 0.40 [0.04;3.75]
excluded (control group) 		-/18   -/3 - 18
ref
S9409
R46545		 Kasradze (Valproate) (Controls unexposed, disease free), 2017 Full scale IQ (WPPSI-4) (mean age 4-4.5 years old) during pregnancy (anytime or not specified) prospective cohort unexposed, disease free Adjustment: No extrapolated (cont. endpoint) Matched 11.27 [3.89;32.66] -/18   -/50 - 18
ref
S9398
R46543		 Deshmukh (Valproate), 2016 Vineland-II Adaptative Behavior Scales - Low and moderately low in the overall ABC (Adaptative Behavior Composite) throughout pregnancy prospective cohort exposed to other treatment, sick Adjustment: Yes 9.09 [1.35;50.00] 10/51   3/104 13 51
ref
S9414
R46546		 Meador (Valproate), 2013 IQ <85 (DAS) (at 4.5 years old) during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick Adjustment: Yes 2.03 [0.61;6.78] C 6/39   6/73 12 39
ref
S9450
R46547		 Rihtman (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2013 Stanford Binet Intelligence Scales, Fifth Edition (SB5) - GIQ (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) 1.29 [0.54;3.06]
excluded (control group) 		-/29   -/41 - 29
ref
S9451
R46548		 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Stanford Binet Intelligence Scales, Fifth Edition (SB5) - GIQ (mean age 4-5 years old) at least 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No extrapolated (cont. endpoint) 2.33 [1.01;5.38] -/29   -/52 - 29
ref
S9394
R46541		 Cummings (Valproate) (Controls exposed to Lamotrigine, sick), 2011 Mild or significant delay (score ≥1, <2 SD or ≥2 SD below the mean) (Bayley Scales of Infant Development or the Griffiths Scale) (mean age in years: m1=2.9 and m0=2.7) throughout pregnancy retrospective cohort (registry) exposed to other treatment, sick excluded Adjustment: No 22.34 [2.86;174.78] C
excluded (control group) 		23/58   1/35 24 58
ref
S9395
R46542		 Cummings (Valproate) (Controls unexposed, disease free), 2011 Mild or significant delay (score ≥1, <2 SD or ≥2 SD below the mean) (Bayley Scales of Infant Development or the Griffiths Scale) (mean age in years: m1=2.9 and m0=4.3) throughout pregnancy retrospective cohort (registry) unexposed, disease free Adjustment: Yes 26.10 [4.90;139.00] 23/58   2/44 25 58
ref
S9402
R46552		 Gaily (Valproate) (Controls unexposed, sick), 2004 Mental retardation (Verbal and nonverbal IQ <70) 2nd and/or 3rd trimester prospective cohort unexposed, sick Adjustment: No 1.79 [0.15;21.49] C 1/13   2/45 3 13
ref
Total 7 studies 5.06 [2.73;9.37] 3,466 1,199
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 Coste (Valproate) (Controls unexposed, NOS), 2020Coste, 2020 1 5.10[3.10; 8.50]3,41399126%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Kasradze (Valproate) (Controls unexposed, disease free), 2017Kasradze, 2017 2 11.27[3.89; 32.66]-1816%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: criticalROB mesure: lowROB reporting: moderate Deshmukh (Valproate), 2016Deshmukh, 2016 3 9.09[1.35; 50.00]13519%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: criticalROB mesure: moderateROB reporting: moderate Meador (Valproate), 2013Meador, 2013 4 2.03[0.61; 6.78]123914%ROB confusion: moderateROB selection: lowROB classification: lowROB missing: moderateROB mesure: lowROB reporting: low Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013Rihtman, 2013 5 2.33[1.01; 5.38]-2920%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Cummings (Valproate) (Controls unexposed, disease free), 2011Cummings, 2011 6 26.10[4.90; 139.00]255810%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: unclearROB mesure: lowROB reporting: moderate Gaily (Valproate) (Controls unexposed, sick), 2004Gaily, 2004 7 1.79[0.15; 21.49]3135%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: criticalROB mesure: lowROB reporting: moderate Total (7 studies) I2 = 52% 5.06[2.73; 9.37]3,4661,1990.5100.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

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

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 5.06[2.73; 9.37]3,4661,19952%NACoste (Valproate) (Controls unexposed, NOS), 2020 Kasradze (Valproate) (Controls unexposed, disease free), 2017 Deshmukh (Valproate), 2016 Meador (Valproate), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Cummings (Valproate) (Controls unexposed, disease free), 2011 Gaily (Valproate) (Controls unexposed, sick), 2004 7 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 6.26[2.81; 13.95]3,4381,09667%NACoste (Valproate) (Controls unexposed, NOS), 2020 Kasradze (Valproate) (Controls unexposed, disease free), 2017 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Cummings (Valproate) (Controls unexposed, disease free), 2011 4 unexposed, sickunexposed, sick 1.79[0.15; 21.49]313 -NAGaily (Valproate) (Controls unexposed, sick), 2004 1 exposed to other treatment, sickexposed to other treatment, sick 3.67[0.87; 15.44]259045%NADeshmukh (Valproate), 2016 Meador (Valproate), 2013 2 Tags Adjustment   - No  - No 4.12[1.20; 14.14]36065%NAKasradze (Valproate) (Controls unexposed, disease free), 2017 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Gaily (Valproate) (Controls unexposed, sick), 2004 3   - Yes  - Yes 5.86[2.49; 13.79]3,4631,13952%NACoste (Valproate) (Controls unexposed, NOS), 2020 Deshmukh (Valproate), 2016 Meador (Valproate), 2013 Cummings (Valproate) (Controls unexposed, disease free), 2011 4 extrapolated (cont. endpoint)extrapolated (cont. endpoint) 4.94[1.06; 23.14]-4781%NAKasradze (Valproate) (Controls unexposed, disease free), 2017 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 2 MatchedMatched 11.27[3.89; 32.66]-18 -NAKasradze (Valproate) (Controls unexposed, disease free), 2017 1 All studiesAll studies 5.06[2.73; 9.37]3,4661,19952%NACoste (Valproate) (Controls unexposed, NOS), 2020 Kasradze (Valproate) (Controls unexposed, disease free), 2017 Deshmukh (Valproate), 2016 Meador (Valproate), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Cummings (Valproate) (Controls unexposed, disease free), 2011 Gaily (Valproate) (Controls unexposed, sick), 2004 70.5100.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.94.61.5210.000Coste (Valproate) (Controls unexposed, NOS), 2020Kasradze (Valproate) (Controls unexposed, disease free), 2017Deshmukh (Valproate), 2016Meador (Valproate), 2013Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013Cummings (Valproate) (Controls unexposed, disease free), 2011Gaily (Valproate) (Controls unexposed, sick), 2004

Asymetry test p-value = 0.7693 (by Egger's regression)

slope=1.4041 (0.6063); intercept=0.3874 (1.2511); t=0.3096; p=0.7693

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 9394, 9450, 9408, 9391

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 6.26[2.81; 13.95]3,4381,09667%NACoste (Valproate) (Controls unexposed, NOS), 2020 Kasradze (Valproate) (Controls unexposed, disease free), 2017 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Cummings (Valproate) (Controls unexposed, disease free), 2011 4 unexposed, sick controlsunexposed, sick controls 1.79[0.15; 21.49]313 -NAGaily (Valproate) (Controls unexposed, sick), 2004 1 exposed to other treatment, sick controlsexposed to other treatment, sick controls 2.91[1.25; 6.75]741,18660%NACoste (Valproate) (Controls exposed to Lamotrigine, sick), 2020 Kasradze (Valproate) (Controls exposed to Lamotrigine, sick), 2017 Deshmukh (Valproate), 2016 Meador (Valproate), 2013 Rihtman (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2013 Cummings (Valproate) (Controls exposed to Lamotrigine, sick), 2011 60.510.01.0