Valproate (All indications)

Cognitive developmental disorders/delay (> 6 years old)

R analysis

id	Study	Lib. in paper	Exposition period	Study type All studies Case control excluded Only case control	Control type	Tags	OR 95%CI	x1/n1 x0/n0	no cases	no exposed	ROB	Ref.
S12708 R53673	Bjørk (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2022	Diagnosis of intellectual disability (ID): mild ID (F70), moderate ID (F71), severe ID (F72), and profound ID (F73) (between 6.1 and 7.9 years old)	during pregnancy (anytime or not specified)	population based cohort retrospective	exposed to other treatment, sick excluded	Adjustment: No	7.97 [5.07;12.52] ^C excluded (control group)	64/2,421 27/7,950	91	2,421		ref
S12519 R53674	Bjørk (Valproate) (Controls unexposed NOS) (Mixed indications), 2022	Diagnosis of intellectual disability (ID): mild ID (F70), moderate ID (F71), severe ID (F72), and profound ID (F73) (between 6.1 and 7.9 years old)	during pregnancy (anytime or not specified)	population based cohort retrospective	unexposed (general population or NOS) excluded	Adjustment: Yes	4.77 [3.73;6.10] excluded (control group)	64/2,421 16,384/4,463,879	16,448	2,421		ref
S12707 R53675	Bjørk (Valproate) (Controls unexposed, sick) (Mixed indications), 2022	Diagnosis of intellectual disability (ID): mild ID (F70), moderate ID (F71), severe ID (F72), and profound ID (F73) (between 6.1 and 7.9 years old)	during pregnancy (anytime or not specified)	population based cohort retrospective	unexposed, sick	Adjustment: No Controls: epilepsy indication	4.20 [3.11;5.66] ^C	64/2,421 139/21,634	203	2,421		ref
S15275 R62802	Thomas (Valproate), 2022	Full-scale IQ - Wechsler Intelligence Scale for Children or Adult - Ages 13 to 21 years (mean of 16.5 ± 2.2 years)	during pregnancy (anytime or not specified)	prospective cohort	unexposed, sick	Adjustment: No extrapolated (cont. endpoint)	1.31 [0.38;4.52]	-/33 -/11	-	33		ref
S9374 R53666	Bromley (Valproate), 2016	Full-scale IQ <85 (Wechsler Preschool and Primary Scale of Intelligence (WPPSI) / Wechsler Intelligence Scale for Children (WISC)) (5-9 years old)	during pregnancy (anytime or not specified)	retrospective cohort (registry)	unexposed, sick	Adjustment: No	4.11 [1.04;16.19] ^C	9/47 3/55	12	47		ref
S9371 R53663	Baker (Valproate) (Controls exposed to Lamotrigine, sick), 2015	Mean child Full scale IQ - Differential ability scales (DAS) (age mean >6 years old)	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No extrapolated (cont. endpoint)	3.48 [1.49;8.14] excluded (control group)	-/51 -/29	-	51		ref
S9372 R53664	Baker (Valproate) (Controls unexposed, disease free), 2015	IQ <85 - Differential ability scales (DAS) (age mean >6 years old)	during pregnancy (anytime or not specified)	prospective cohort	unexposed, disease free excluded	Adjustment: Yes	6.83 [3.02;15.45] excluded (control group)	-/51 -/210	-	51		ref
S9373 R53665	Baker (Valproate) (Controls unexposed, sick), 2015	Mean child Full scale IQ - Differential ability scales (DAS) (age mean >6 years old)	during pregnancy (anytime or not specified)	prospective cohort	unexposed, sick	Adjustment: No extrapolated (cont. endpoint)	3.76 [1.54;9.19]	-/51 -/25	-	51		ref
S9414 R53670	Meador (Valproate), 2013	IQ <85 (DAS) (at 6 years old)	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick	Adjustment: Yes	7.02 [1.42;34.66] ^C	8/49 2/74	10	49		ref
S9415 R53671	Nadebaum (Valproate), 2011	Full-scale child's IQ (WISC)	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick	Adjustment: No extrapolated (cont. endpoint)	5.19 [1.20;22.40]	-/23 -/9	-	23		ref
S9421 R53678	Titze (Valproate) (Controls unexposed, disease free), 2008	Learning disability (IQ<70) (German versions of the revised Wechsler Intelligence Scales for children and for adults)	during pregnancy (anytime or not specified)	prospective cohort	unexposed, disease free excluded	Adjustment: No Matched	19.40 [0.31;1195.39] ^C excluded (control group)	0/3 0/49	0	3		ref
S9422 R53679	Titze (Valproate) (Controls unexposed, sick), 2008	Learning disability (IQ<70) (German versions of the revised Wechsler Intelligence Scales for children and for adults)	during pregnancy (anytime or not specified)	prospective cohort	unexposed, sick	Adjustment: No	1.53 [0.05;49.80] ^C	0/3 1/13	1	3		ref
S9428 R53672	Viinikainen (Valproate) b, 2006	Full Scale IQ (FIQ) < 1SD (Wechsler Intelligence Scale for Children (WISC III))	throughout pregnancy	prospective cohort	unexposed, sick	Adjustment: No Matched	18.33 [0.88;380.72] ^C	5/13 0/13	5	13		ref
S9429 R53680	Vinten (Valproate), 2005	IQ score <69 (Wechsler Intelligence Scale for Children (WISC III)) (Aged between 6 and 16 years)	during pregnancy (anytime or not specified)	retrospective cohort	unexposed, sick	Adjustment: No	3.47 [1.14;10.56] ^C	9/41 6/80	15	41		ref
S9278 R53662	Adab (Valproate), 2004	Mean Full Scale IQ (Wechsler Intelligence Scale for Children (WISC)) (Aged between 6 and 16 years)	during pregnancy (anytime or not specified)	retrospective cohort	unexposed, sick	Adjustment: No extrapolated (cont. endpoint)	1.26 [0.64;2.50]	-/41 -/80	-	41		ref
S9401 R53667	Gaily (Valproate) (Controls unexposed, disease free), 2004	Full scale IQ (Wechsler Preschool and Primary Scale of Intelligence Revised (WPPSI-R) or Wechsler Intelligence Scale for Children Revised (WISC-R))	2nd and/or 3rd trimester	prospective cohort	unexposed, disease free excluded	Adjustment: No extrapolated (cont. endpoint)	2.40 [0.85;6.75] excluded (control group)	-/13 -/140	-	13		ref
S9402 R53668	Gaily (Valproate) (Controls unexposed, sick), 2004	Full scale IQ (Wechsler Preschool and Primary Scale of Intelligence Revised (WPPSI-R) or Wechsler Intelligence Scale for Children Revised (WISC-R))	2nd and/or 3rd trimester	prospective cohort	unexposed, sick	Adjustment: No extrapolated (cont. endpoint)	1.82 [0.59;5.59]	-/13 -/45	-	13		ref
					Total	11 studies	2.99 [2.00;4.48]		246	2,735
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

1: Valproate) (Controls unexposed, sick) (Mixed indications; 2: Valproate; 3: Valproate; 4: Valproate) (Controls unexposed, sick; 5: Valproate; 6: Valproate; 7: Valproate) (Controls unexposed, sick; 8: Valproate) ; 9: Valproate; 10: Valproate; 11: Valproate) (Controls unexposed, sick;

Sensitivity analysis

Publication bias and p-hacking diagnosis

funnel plot

Asymetry test p-value = 0.6218 (by Egger's regression)

slope=1.3227 (0.2538); intercept=-0.3288 (0.6437); t=0.5108; p=0.6218

p values plot

Sub-groups analysis using all included studies

excluded 9401, 9421, 9371, 9372, 12708, 12519

S12708 R53673	Bjørk (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2022	Diagnosis of intellectual disability (ID): mild ID (F70), moderate ID (F71), severe ID (F72), and profound ID (F73) (between 6.1 and 7.9 years old) (318)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	7.97 [5.07;12.52]	64/2421 27/7950
S12519 R53674	Bjørk (Valproate) (Controls unexposed NOS) (Mixed indications), 2022	Diagnosis of intellectual disability (ID): mild ID (F70), moderate ID (F71), severe ID (F72), and profound ID (F73) (between 6.1 and 7.9 years old) (318)	during pregnancy (anytime or not specified)	unexposed (general population or NOS)	4.77 [3.73;6.10]	64/2421 16384/4463879
S12707 R53675	Bjørk (Valproate) (Controls unexposed, sick) (Mixed indications), 2022	Diagnosis of intellectual disability (ID): mild ID (F70), moderate ID (F71), severe ID (F72), and profound ID (F73) (between 6.1 and 7.9 years old) (318)	during pregnancy (anytime or not specified)	unexposed, sick	4.20 [3.11;5.66]	64/2421 139/21634
S15275 R62802	Thomas (Valproate), 2022	Full-scale IQ - Wechsler Intelligence Scale for Children or Adult - Ages 13 to 21 years (mean of 16.5 ± 2.2 years) (318)	during pregnancy (anytime or not specified)	unexposed, sick	1.31 [0.38;4.52]	-9/33 -9/11
S9374 R53666	Bromley (Valproate), 2016	Full-scale IQ <85 (Wechsler Preschool and Primary Scale of Intelligence (WPPSI) / Wechsler Intelligence Scale for Children (WISC)) (5-9 years old) (318)	during pregnancy (anytime or not specified)	unexposed, sick	4.11 [1.04;16.19]	9/47 3/55
S9371 R53663	Baker (Valproate) (Controls exposed to Lamotrigine, sick), 2015	Mean child Full scale IQ - Differential ability scales (DAS) (age mean >6 years old) (318)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	3.48 [1.49;8.14]	-9/51 -9/29
S9372 R53664	Baker (Valproate) (Controls unexposed, disease free), 2015	IQ <85 - Differential ability scales (DAS) (age mean >6 years old) (318)	during pregnancy (anytime or not specified)	unexposed, disease free	6.83 [3.02;15.45]	-9/51 -9/210
S9373 R53665	Baker (Valproate) (Controls unexposed, sick), 2015	Mean child Full scale IQ - Differential ability scales (DAS) (age mean >6 years old) (318)	during pregnancy (anytime or not specified)	unexposed, sick	3.76 [1.54;9.19]	-9/51 -9/25
S9414 R53670	Meador (Valproate), 2013	IQ <85 (DAS) (at 6 years old) (318)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	7.02 [1.42;34.66]	8/49 2/74
S9415 R53671	Nadebaum (Valproate), 2011	Full-scale child's IQ (WISC) (318)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	5.19 [1.20;22.40]	-9/23 -9/9
S9421 R53678	Titze (Valproate) (Controls unexposed, disease free), 2008	Learning disability (IQ<70) (German versions of the revised Wechsler Intelligence Scales for children and for adults) (318)	during pregnancy (anytime or not specified)	unexposed, disease free	19.40 [0.31;1195.39]	0/3 0/49
S9422 R53679	Titze (Valproate) (Controls unexposed, sick), 2008	Learning disability (IQ<70) (German versions of the revised Wechsler Intelligence Scales for children and for adults) (318)	during pregnancy (anytime or not specified)	unexposed, sick	1.53 [0.05;49.80]	0/3 1/13
S9428 R53672	Viinikainen (Valproate) b, 2006	Full Scale IQ (FIQ) < 1SD (Wechsler Intelligence Scale for Children (WISC III)) (318)	throughout pregnancy	unexposed, sick	18.33 [0.88;380.72]	5/13 0/13
S9429 R53680	Vinten (Valproate), 2005	IQ score <69 (Wechsler Intelligence Scale for Children (WISC III)) (Aged between 6 and 16 years) (318)	during pregnancy (anytime or not specified)	unexposed, sick	3.47 [1.14;10.56]	9/41 6/80
S9278 R53662	Adab (Valproate), 2004	Mean Full Scale IQ (Wechsler Intelligence Scale for Children (WISC)) (Aged between 6 and 16 years) (318)	during pregnancy (anytime or not specified)	unexposed, sick	1.26 [0.64;2.50]	-9/41 -9/80
S9401 R53667	Gaily (Valproate) (Controls unexposed, disease free), 2004	Full scale IQ (Wechsler Preschool and Primary Scale of Intelligence Revised (WPPSI-R) or Wechsler Intelligence Scale for Children Revised (WISC-R)) (318)	2nd and/or 3rd trimester	unexposed, disease free	2.40 [0.85;6.75]	-9/13 -9/140
S9402 R53668	Gaily (Valproate) (Controls unexposed, sick), 2004	Full scale IQ (Wechsler Preschool and Primary Scale of Intelligence Revised (WPPSI-R) or Wechsler Intelligence Scale for Children Revised (WISC-R)) (318)	2nd and/or 3rd trimester	unexposed, sick	1.82 [0.59;5.59]	-9/13 -9/45