Valproate (All indications) updated on 04-22-2025

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.
S16621
R69705		 Thomas b (Valproate) (Epilepsy) (Controls exposed to LTG), 2022 Delayed motor development quotient (< 84, i.e one SD of the mean) - The developmental assessment scale for Indian infants (DASII) - Between 12-24 months of age (mean (SD): 15.3 (3.9) months)) during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick excluded Adjustment: No 12.15 [1.61;91.52] C
excluded (control group) 		69/211   1/26 70 211
ref
S16622
R69706		 Thomas b (Valproate) (Epilepsy) (Controls unexposed, sick), 2022 The motor development quotient (MODQ) - The developmental assessment scale for Indian infants (DASII) - Between 12-24 months of age (mean (SD): 15.3 (3.9) months)) during pregnancy (anytime or not specified) prospective cohort unexposed, sick Adjustment: No extrapolated (cont. endpoint) 2.04 [1.34;3.12] -/211   -/110 - 211
ref
S9398
R32935		 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
S9942
R35743		 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
S9944
R35755		 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
S9377
R32812		 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
S9380
R32828		 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
S9383
R32844		 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
S9450
R33203		 Rihtman (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2013 Miller Function and Participation Scales (MFUN) - Fine Motor (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) 1.66 [0.71;3.90]
excluded (control group) 		-/30   -/42 - 30
ref
S9451
R33238		 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Miller Function and Participation Scales (MFUN) - Fine Motor (mean age 4-5 years old) at least 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No extrapolated (cont. endpoint) 5.14 [2.19;12.07] -/30   -/52 - 30
ref
S9389
R32854		 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
S9418
R33044		 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
S9428
R33104		 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
S9278
R32187		 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
S9410
R32988		 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 10 studies 2.94 [2.01;4.29] 46 513
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 Thomas b (Valproate) (Epilepsy) (Controls unexposed, sick), 2022Thomas b, 2022 1 2.04[1.34; 3.12]-21128%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: unclearROB mesure: lowROB reporting: moderate Deshmukh (Valproate), 2016Deshmukh, 2016 2 11.11[2.04; 50.00]24515%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: criticalROB mesure: moderateROB reporting: moderate Videman (Valproate) (Controls unexposed, disease free), 2016Videman, 2016 3 6.88[1.27; 37.31]-55%ROB confusion: unclearROB selection: lowROB classification: moderateROB missing: criticalROB mesure: lowROB reporting: moderate Bromley (Valproate) (Controls unexposed, sick), 2013Bromley, 2013 4 2.68[0.12; 58.07]2501%ROB confusion: criticalROB selection: lowROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013Rihtman, 2013 5 5.14[2.19; 12.07]-3014%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Cohen (Valproate), 2011Cohen, 2011 6 1.67[0.80; 3.48]-3817%ROB confusion: moderateROB selection: lowROB classification: lowROB missing: criticalROB mesure: lowROB reporting: moderate Shallcross (Valproate), 2011Shallcross, 2011 7 3.08[1.59; 5.96]-4419%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Viinikainen (Valproate) b, 2006Viinikainen, 2006 8 3.44[0.53; 22.43]7134%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: moderateROB mesure: lowROB reporting: moderate Adab (Valproate), 2004Adab, 2004 9 1.07[0.17; 6.59]5634%ROB confusion: criticalROB selection: criticalROB classification: lowROB missing: criticalROB mesure: lowROB reporting: moderate Koch (Valproate), 1996Koch, 1996 10 7.50[1.32; 42.51]884%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Total (10 studies) I2 = 26% 2.94[2.01; 4.29]465130.550.01.0ROB: 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) (Controls unexposed, disease free; 4: Valproate) (Controls unexposed, sick; 5: Valproate) (Controls unexposed, NOS) (Mixed indications; 6: Valproate; 7: Valproate; 8: Valproate) ; 9: Valproate; 10: Valproate;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 2.94[2.01; 4.29]4651326%NAThomas b (Valproate) (Epilepsy) (Controls unexposed, sick), 2022 Deshmukh (Valproate), 2016 Videman (Valproate) (Controls unexposed, disease free), 2016 Bromley (Valproate) (Controls unexposed, sick), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Cohen (Valproate), 2011 Shallcross (Valproate), 2011 Viinikainen (Valproate) b, 2006 Adab (Valproate), 2004 Koch (Valproate), 1996 10 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 4.13[2.56; 6.68]8870%NAVideman (Valproate) (Controls unexposed, disease free), 2016 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Shallcross (Valproate), 2011 Koch (Valproate), 1996 4 unexposed, sickunexposed, sick 2.03[1.37; 3.03]143370%NAThomas b (Valproate) (Epilepsy) (Controls unexposed, sick), 2022 Bromley (Valproate) (Controls unexposed, sick), 2013 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 2.84[2.01; 4.02]224248%NAThomas b (Valproate) (Epilepsy) (Controls unexposed, sick), 2022 Videman (Valproate) (Controls unexposed, disease free), 2016 Bromley (Valproate) (Controls unexposed, sick), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Shallcross (Valproate), 2011 Viinikainen (Valproate) b, 2006 Adab (Valproate), 2004 Koch (Valproate), 1996 8   - Yes  - Yes 3.75[0.60; 23.54]248978%NADeshmukh (Valproate), 2016 Cohen (Valproate), 2011 2 extrapolated (cont. endpoint)extrapolated (cont. endpoint) 2.68[1.77; 4.08]-32839%NAThomas b (Valproate) (Epilepsy) (Controls unexposed, sick), 2022 Videman (Valproate) (Controls unexposed, disease free), 2016 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Cohen (Valproate), 2011 Shallcross (Valproate), 2011 5 MatchedMatched 5.23[1.46; 18.71]15210%NAViinikainen (Valproate) b, 2006 Koch (Valproate), 1996 2 All studiesAll studies 2.94[2.01; 4.29]4651326%NAThomas b (Valproate) (Epilepsy) (Controls unexposed, sick), 2022 Deshmukh (Valproate), 2016 Videman (Valproate) (Controls unexposed, disease free), 2016 Bromley (Valproate) (Controls unexposed, sick), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Cohen (Valproate), 2011 Shallcross (Valproate), 2011 Viinikainen (Valproate) b, 2006 Adab (Valproate), 2004 Koch (Valproate), 1996 100.550.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.74.81.8820.000Thomas b (Valproate) (Epilepsy) (Controls unexposed, sick), 2022Deshmukh (Valproate), 2016Videman (Valproate) (Controls unexposed, disease free), 2016Bromley (Valproate) (Controls unexposed, sick), 2013Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013Cohen (Valproate), 2011Shallcross (Valproate), 2011Viinikainen (Valproate) b, 2006Adab (Valproate), 2004Koch (Valproate), 1996

Asymetry test p-value = 0.1471 (by Egger's regression)

slope=0.5816 (0.2875); intercept=1.0269 (0.6396); t=1.6055; p=0.1471

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 9377, 9380, 9450, 9942, 16621

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 4.31[2.68; 6.92]101370%NAVideman (Valproate) (Controls unexposed, disease free), 2016 Bromley (Valproate) (Controls unexposed, disease free), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Shallcross (Valproate), 2011 Koch (Valproate), 1996 5 unexposed, sick controlsunexposed, sick controls 2.03[1.37; 3.03]143370%NAThomas b (Valproate) (Epilepsy) (Controls unexposed, sick), 2022 Bromley (Valproate) (Controls unexposed, sick), 2013 Viinikainen (Valproate) b, 2006 Adab (Valproate), 2004 4 exposed to other treatment, sick controlsexposed to other treatment, sick controls 2.79[1.37; 5.69]9738539%NAThomas b (Valproate) (Epilepsy) (Controls exposed to LTG), 2022 Deshmukh (Valproate), 2016 Videman (Valproate) (Controls exposed to Lamotrigine, sick), 2016 Bromley (Valproate) (Controls exposed to Lamotrigine, sick), 2013 Rihtman (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2013 Cohen (Valproate), 2011 60.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Veroniki b (NMA) (Psychomotor developmental delay)Veroniki b (NMA) (Psychomotor developmental delay) 4.16[2.04; 8.75]NA-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT-9 metaPregmetaPreg 2.94[2.01; 4.29]26%513----Thomas b (Valproate) (Epilepsy) (Controls unexposed, sick), 2022 Deshmukh (Valproate), 2016 Videman (Valproate) (Controls unexposed, disease free), 2016 Bromley (Valproate) (Controls unexposed, sick), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Cohen (Valproate), 2011 Shallcross (Valproate), 2011 Viinikainen (Valproate) b, 2006 Adab (Valproate), 2004 Koch (Valproate), 1996 100.510.01.0