Valproate (All indications)

Severe cognitive developmental delay (Mental retardation) (> 6 years old)

id	Study   Auto Bjørk (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2022Bjørk (Valproate) (Controls unexposed NOS) (Mixed indications), 2022Bjørk (Valproate) (Controls unexposed, sick) (Mixed indications), 2022Meador (Valproate), 2013Titze (Valproate) (Controls unexposed, disease free), 2008Titze (Valproate) (Controls unexposed, sick), 2008Viinikainen (Valproate) b, 2006Vinten (Valproate), 2005Gaily (Valproate) (Controls unexposed, disease free), 2004	Lib. in paper	Exposition period  Auto during pregnancy (anytime or not specified)1st trimester2nd trimester3rd trimester2nd and/or 3rd trimesterthroughout pregnancyearly pregnancydays before deliverylate pregnancypreconception-onlypericonceptionalpreconceptional for kinetic reasonat least 1st trimester3 months (or more) before pregnancy or during pregnancy1st and 2nd trimester3 months or more before pregnancy or1st trimester	Study type  All studies Case control excluded Only case control	Control type    Auto unexposed (general population or NOS)unexposed, sickunexposed, disease freeexposed to other treatment, sicknot specifiedwhatever (meta-analysis)	Tags	OR 95%CI	x1/n1 x0/n0	no cases	no exposed	ROB	Ref.
S12708 R47948	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 R47161	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 R47945	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
S9414 R33006	Meador (Valproate), 2013	IQ <70 (DAS) (at 6 years old)	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick	Adjustment: Yes	7.90 [0.37;168.31] C	2/49   0/74	2	49		ref
S9421 R33053	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 R33054	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 R33107	Viinikainen (Valproate) b, 2006	Full Scale IQ (FIQ) < 2SD (Wechsler Intelligence Scale for Children (WISC III))	throughout pregnancy	prospective cohort	unexposed, sick	Adjustment: No Matched	5.95 [0.26;138.26] C	2/13   0/13	2	13		ref
S9429 R33117	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
S9401 R32945	Gaily (Valproate) (Controls unexposed, disease free), 2004	Mental retardation (Verbal and nonverbal IQ <70)	2nd and/or 3rd trimester	prospective cohort	unexposed, disease free	Adjustment: No	3.83 [0.37;39.75] C	1/13   3/141	4	13		ref
					Total	6 studies	4.15 [3.12;5.51]		227	2,540
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

Sensitivity analysis

Publication bias and p-hacking diagnosis

Sub-groups analysis using all included studies

excluded 9421, 12708, 12519