Valproate (Epilepsy)

Psychomotor developmental disorders/delay

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.
S8117
R24932		 Deshmukh (Valproate), 2016 Vineland-II Adaptative Behavior Scales - Low and moderately low in the motor skills domain throughout pregnancy prospective cohort exposed to other treatment, sick Adjustment: Yes 11.11 [2.04;50.00] 16/51   8/104 24 51
ref
S9943
R35749		 Videman (Valproate) (Controls exposed to Lamotrigine, sick), 2016 Griffiths Mental Developmental Scale - Locomotor (at the age of 7 months) during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick excluded Adjustment: No extrapolated (cont. endpoint) 3.94 [0.47;32.94]
excluded (control group) 		-/5   -/8 - 5
ref
S9945
R35761		 Videman (Valproate) (Controls unexposed, disease free), 2016 Griffiths Mental Developmental Scale - Locomotor (at the age of 7 months) during pregnancy (anytime or not specified) prospective cohort unexposed, disease free Adjustment: No extrapolated (cont. endpoint) 6.88 [1.27;37.31] -/5   -/59 - 5
ref
S6662
R18420		 Bromley (Valproate) (Controls exposed to Lamotrigine, sick), 2013 Dyspraxia (at 6 years old) during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick excluded Adjustment: No 1.21 [0.10;13.92] C
excluded (control group) 		2/50   1/30 3 50
ref
S6659
R18408		 Bromley (Valproate) (Controls unexposed, disease free), 2013 Dyspraxia (at 6 years old) during pregnancy (anytime or not specified) prospective cohort unexposed, disease free excluded Adjustment: No 22.47 [1.06;475.80] C
excluded (control group) 		2/50   0/214 2 50
ref
S6602
R18105		 Bromley (Valproate) (Controls unexposed, sick), 2013 Dyspraxia (at 6 years old) during pregnancy (anytime or not specified) prospective cohort unexposed, sick Adjustment: No 2.68 [0.12;58.07] C 2/50   0/26 2 50
ref
S7232
R20846		 Cohen (Valproate), 2011 Motor Index score (the Bayley Scales of Infant Development (BSID-II)) during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick Adjustment: Yes extrapolated (cont. endpoint) 1.67 [0.80;3.48] -/38   -/62 - 38
ref
S5567
R19099		 Shallcross (Valproate), 2011 Locomotor (Griffiths scale) throughout pregnancy prospective cohort unexposed, disease free Adjustment: No extrapolated (cont. endpoint) 3.08 [1.59;5.96] -/44   -/97 - 44
ref
S6585
R18061		 Thomas b (Valproate), 2008 Impaired Motor Development Quotient < 84 (The Developmental Assessment Scale (DAS II)) during pregnancy (anytime or not specified) prospective cohort unexposed, sick Adjustment: No 1.57 [0.63;3.89] C 27/71   9/32 36 71
ref
S5543
R14424		 Viinikainen (Valproate) b, 2006 Touwen's test Neurological dysfunction/impairment throughout pregnancy prospective cohort unexposed, sick Adjustment: No Matched 3.44 [0.53;22.43] C 5/13   2/13 7 13
ref
S7175
R27088		 Adab (Valproate), 2004 Dyspraxia during pregnancy (anytime or not specified) retrospective cohort unexposed, sick Adjustment: No 1.07 [0.17;6.59] C 2/63   3/101 5 63
ref
S7276
R21051		 Koch (Valproate), 1996 Minor neurological dysfunction (at age 6) (Touwen) during pregnancy (anytime or not specified) prospective cohort unexposed (general population or NOS) Adjustment: No Matched 7.50 [1.32;42.51] C 4/8   4/34 8 8
ref
Total 9 studies 2.72 [1.74;4.24] 82 343
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 Deshmukh (Valproate), 2016Deshmukh, 2016 1 11.11[2.04; 50.00]24517%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: criticalROB mesure: moderateROB reporting: moderate Videman (Valproate) (Controls unexposed, disease free), 2016Videman, 2016 2 6.88[1.27; 37.31]-56%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: criticalROB mesure: lowROB reporting: moderate Bromley (Valproate) (Controls unexposed, sick), 2013Bromley, 2013 3 2.68[0.12; 58.07]2502%ROB confusion: criticalROB selection: lowROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Cohen (Valproate), 2011Cohen, 2011 4 1.67[0.80; 3.48]-3824%ROB confusion: moderateROB selection: lowROB classification: lowROB missing: criticalROB mesure: lowROB reporting: moderate Shallcross (Valproate), 2011Shallcross, 2011 5 3.08[1.59; 5.96]-4427%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Thomas b (Valproate), 2008Thomas b, 2008 6 1.57[0.63; 3.89]367118%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: criticalROB mesure: lowROB reporting: moderate Viinikainen (Valproate) b, 2006Viinikainen, 2006 7 3.44[0.53; 22.43]7135%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: moderateROB mesure: lowROB reporting: moderate Adab (Valproate), 2004Adab, 2004 8 1.07[0.17; 6.59]5636%ROB confusion: criticalROB selection: criticalROB classification: lowROB missing: criticalROB mesure: lowROB reporting: moderate Koch (Valproate), 1996Koch, 1996 9 7.50[1.32; 42.51]886%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Total (9 studies) I2 = 18% 2.72[1.74; 4.24]823430.550.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Valproate; 2: Valproate) (Controls unexposed, disease free; 3: Valproate) (Controls unexposed, sick; 4: Valproate; 5: Valproate; 6: Valproate; 7: Valproate) ; 8: Valproate; 9: Valproate;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 2.72[1.74; 4.24]8234318%NADeshmukh (Valproate), 2016 Videman (Valproate) (Controls unexposed, disease free), 2016 Bromley (Valproate) (Controls unexposed, sick), 2013 Cohen (Valproate), 2011 Shallcross (Valproate), 2011 Thomas b (Valproate), 2008 Viinikainen (Valproate) b, 2006 Adab (Valproate), 2004 Koch (Valproate), 1996 9 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 3.74[2.09; 6.68]8570%NAVideman (Valproate) (Controls unexposed, disease free), 2016 Shallcross (Valproate), 2011 Koch (Valproate), 1996 3 unexposed, sickunexposed, sick 1.71[0.83; 3.53]501970%NABromley (Valproate) (Controls unexposed, sick), 2013 Thomas b (Valproate), 2008 Viinikainen (Valproate) b, 2006 Adab (Valproate), 2004 4 exposed to other treatment, sickexposed to other treatment, sick 3.75[0.60; 23.54]248978%NADeshmukh (Valproate), 2016 Cohen (Valproate), 2011 2 Tags Adjustment   - No  - No 2.75[1.75; 4.33]582540%NAVideman (Valproate) (Controls unexposed, disease free), 2016 Bromley (Valproate) (Controls unexposed, sick), 2013 Shallcross (Valproate), 2011 Thomas b (Valproate), 2008 Viinikainen (Valproate) b, 2006 Adab (Valproate), 2004 Koch (Valproate), 1996 7   - Yes  - Yes 3.75[0.60; 23.54]248978%NADeshmukh (Valproate), 2016 Cohen (Valproate), 2011 2 extrapolated (cont. endpoint)extrapolated (cont. endpoint) 2.62[1.42; 4.83]-8731%NAVideman (Valproate) (Controls unexposed, disease free), 2016 Cohen (Valproate), 2011 Shallcross (Valproate), 2011 3 MatchedMatched 5.23[1.46; 18.71]15210%NAViinikainen (Valproate) b, 2006 Koch (Valproate), 1996 2 All studiesAll studies 2.72[1.74; 4.24]8234318%NADeshmukh (Valproate), 2016 Videman (Valproate) (Controls unexposed, disease free), 2016 Bromley (Valproate) (Controls unexposed, sick), 2013 Cohen (Valproate), 2011 Shallcross (Valproate), 2011 Thomas b (Valproate), 2008 Viinikainen (Valproate) b, 2006 Adab (Valproate), 2004 Koch (Valproate), 1996 90.550.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.74.71.8820.000Deshmukh (Valproate), 2016Videman (Valproate) (Controls unexposed, disease free), 2016Bromley (Valproate) (Controls unexposed, sick), 2013Cohen (Valproate), 2011Shallcross (Valproate), 2011Thomas b (Valproate), 2008Viinikainen (Valproate) b, 2006Adab (Valproate), 2004Koch (Valproate), 1996

Asymetry test p-value = 0.2937 (by Egger's regression)

slope=0.4842 (0.4672); intercept=0.9246 (0.8146); t=1.1351; p=0.2937

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 6662, 6659, 9943

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 3.98[2.25; 7.04]101070%NAVideman (Valproate) (Controls unexposed, disease free), 2016 Bromley (Valproate) (Controls unexposed, disease free), 2013 Shallcross (Valproate), 2011 Koch (Valproate), 1996 4 unexposed, sick controlsunexposed, sick controls 1.71[0.83; 3.53]501970%NABromley (Valproate) (Controls unexposed, sick), 2013 Thomas b (Valproate), 2008 Viinikainen (Valproate) b, 2006 Adab (Valproate), 2004 4 exposed to other treatment, sick controlsexposed to other treatment, sick controls 2.90[1.07; 7.84]2714440%NADeshmukh (Valproate), 2016 Videman (Valproate) (Controls exposed to Lamotrigine, sick), 2016 Bromley (Valproate) (Controls exposed to Lamotrigine, sick), 2013 Cohen (Valproate), 2011 40.510.01.0