Valproate (Epilepsy) updated on 04-22-2025

Cognitive developmental disorders/delay (< 3 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.
S16797
R70490		 Thomas b (Controls exposed to LTG), 2022 The mental development quotient (MEDQ) - 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 extrapolated (cont. endpoint) 2.39 [1.14;5.03]
excluded (control group) 		-/211   -/26 - 211
ref
S16798
R70493		 Thomas b (Controls unexposed, sick), 2022 The mental development quotient (MEDQ) - 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) 2.43 [1.59;3.71] -/211   -/110 - 211
ref
S9943
R53623		 Videman (Valproate) (Controls exposed to Lamotrigine, sick), 2016 Griffiths Mental Developmental Scale - General quotient (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) 5.78 [0.65;51.17]
excluded (control group) 		-/5   -/8 - 5
ref
S9945
R53624		 Videman (Valproate) (Controls unexposed, disease free), 2016 Griffiths Mental Developmental Scale - General quotient (at the age of 7 months) during pregnancy (anytime or not specified) prospective cohort unexposed, disease free Adjustment: No extrapolated (cont. endpoint) 31.41 [5.37;183.85] -/5   -/59 - 5
ref
S7304
R53620		 Meador (Valproate), 2013 the Bayley Scales of Infant Development (BSID) <85 (at 2 years old) during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick Adjustment: Yes 3.66 [1.37;9.76] C 12/29   11/68 23 29
ref
S5567
R53621		 Shallcross (Valproate), 2011 Overall development quotient (Griffiths scale) <84 throughout pregnancy prospective cohort unexposed, disease free Adjustment: No 3.79 [1.59;9.07] C 15/43   12/97 27 43
ref
S7186
R53617		 Bromley (Valproate) (Controls exposed to Lamotrigine, sick), 2010 Overall ability below average performance (≤ 84) (Griffiths) (mean age 10 months old) during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick excluded Adjustment: No 2.32 [0.73;7.41] C
excluded (control group) 		12/42   5/34 17 42
ref
S7184
R53618		 Bromley (Valproate) (Controls unexposed, disease free), 2010 Overall ability below average performance (≤ 84) (Griffiths) (mean age 10 months old) during pregnancy (anytime or not specified) prospective cohort unexposed, disease free excluded Adjustment: No Matched 3.60 [1.76;7.57]
excluded (control group) 		12/42   18/230 30 42
ref
S7185
R53619		 Bromley (Valproate) (Controls unexposed, sick), 2010 Overall ability below average performance (≤ 84) (Griffiths) (mean age 10 months old) during pregnancy (anytime or not specified) prospective cohort unexposed, sick Adjustment: No 5.00 [1.02;24.48] C 12/42   2/27 14 42
ref
Total 5 studies 4.09 [2.17;7.69] 64 330
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 (Controls unexposed, sick), 2022Thomas b, 2022 1 2.43[1.59; 3.71]-21135%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: unclearROB mesure: lowROB reporting: moderate Videman (Valproate) (Controls unexposed, disease free), 2016Videman, 2016 2 31.41[5.37; 183.85]-510%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: criticalROB mesure: lowROB reporting: moderate Meador (Valproate), 2013Meador, 2013 3 3.66[1.37; 9.76]232921%ROB confusion: moderateROB selection: lowROB classification: lowROB missing: moderateROB mesure: lowROB reporting: low Shallcross (Valproate), 2011Shallcross, 2011 4 3.79[1.59; 9.07]274323%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Bromley (Valproate) (Controls unexposed, sick), 2010Bromley, 2010 5 5.00[1.02; 24.48]144211%ROB confusion: unclearROB selection: lowROB classification: lowROB missing: moderateROB mesure: lowROB reporting: moderate Total (5 studies) I2 = 53% 4.09[2.17; 7.69]643300.9100.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

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

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 4.09[2.17; 7.69]6433053%NAThomas b (Controls unexposed, sick), 2022 Videman (Valproate) (Controls unexposed, disease free), 2016 Meador (Valproate), 2013 Shallcross (Valproate), 2011 Bromley (Valproate) (Controls unexposed, sick), 2010 5 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 9.44[1.21; 73.44]274877%NAVideman (Valproate) (Controls unexposed, disease free), 2016 Shallcross (Valproate), 2011 2 unexposed, sickunexposed, sick 2.55[1.69; 3.84]142530%NAThomas b (Controls unexposed, sick), 2022 Bromley (Valproate) (Controls unexposed, sick), 2010 2 exposed to other treatment, sickexposed to other treatment, sick 3.66[1.37; 9.76]2329 -NAMeador (Valproate), 2013 1 Tags Adjustment   - No  - No 4.58[1.97; 10.65]4130164%NAThomas b (Controls unexposed, sick), 2022 Videman (Valproate) (Controls unexposed, disease free), 2016 Shallcross (Valproate), 2011 Bromley (Valproate) (Controls unexposed, sick), 2010 4   - Yes  - Yes 3.66[1.37; 9.76]2329 -NAMeador (Valproate), 2013 1 extrapolated (cont. endpoint)extrapolated (cont. endpoint) 7.52[0.62; 90.81]-21687%NAThomas b (Controls unexposed, sick), 2022 Videman (Valproate) (Controls unexposed, disease free), 2016 2 All studiesAll studies 4.09[2.17; 7.69]6433053%NAThomas b (Controls unexposed, sick), 2022 Videman (Valproate) (Controls unexposed, disease free), 2016 Meador (Valproate), 2013 Shallcross (Valproate), 2011 Bromley (Valproate) (Controls unexposed, sick), 2010 50.5100.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.14.11.0820.000Thomas b (Controls unexposed, sick), 2022Videman (Valproate) (Controls unexposed, disease free), 2016Meador (Valproate), 2013Shallcross (Valproate), 2011Bromley (Valproate) (Controls unexposed, sick), 2010

Asymetry test p-value = 0.0544 (by Egger's regression)

slope=0.3517 (0.2919); intercept=2.3129 (0.7522); t=3.0749; p=0.0544

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 7186, 7184, 9943, 16797

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 5.56[2.15; 14.35]579061%NAVideman (Valproate) (Controls unexposed, disease free), 2016 Shallcross (Valproate), 2011 Bromley (Valproate) (Controls unexposed, disease free), 2010 3 unexposed, sick controlsunexposed, sick controls 2.55[1.69; 3.84]142530%NAThomas b (Controls unexposed, sick), 2022 Bromley (Valproate) (Controls unexposed, sick), 2010 2 exposed to other treatment, sick controlsexposed to other treatment, sick controls 2.80[1.68; 4.68]402870%NAThomas b (Controls exposed to LTG), 2022 Videman (Valproate) (Controls exposed to Lamotrigine, sick), 2016 Meador (Valproate), 2013 Bromley (Valproate) (Controls exposed to Lamotrigine, sick), 2010 40.510.01.0