Valproate (Epilepsy)

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

id	Study   Auto Dreier (Valproate) (Epilepsy) (Controls exposed to LTG), 2023Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023Meador (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.
S15877 R65486	Dreier (Valproate) (Epilepsy) (Controls exposed to LTG), 2023	Intellectual disability - Corresponding ICD-10 F-chapter - Up to 22 years of age	during pregnancy (anytime or not specified)	population based cohort propective	exposed to other treatment, sick excluded	Adjustment: No	6.69 [4.47;10.02] C excluded (control group)	81/1,952   34/5,288	115	1,952		ref
S15878 R65476	Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023	Intellectual disability - Corresponding ICD-10 F-chapter - Up to 22 years of age	during pregnancy (anytime or not specified)	population based cohort propective	unexposed, sick	Adjustment: Yes	2.70 [1.94;3.74]	81/1,952   184/22,203	265	1,952		ref
S7304 R21154	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
S6123 R15992	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
S6124 R15993	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
S5543 R14427	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
S6782 R19153	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
S7235 R20860	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	2.81 [2.06;3.82]		289	2,071
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 6123, 15877