Valproate (All indications)

Cognitive developmental disorders/delay (< 3 years old)

id	Study   Auto Videman (Valproate) (Controls exposed to Lamotrigine, sick), 2016Videman (Valproate) (Controls unexposed, disease free), 2016Meador (Valproate), 2013Shallcross (Valproate), 2011Bromley (Valproate) (Controls exposed to Lamotrigine, sick), 2010Bromley (Valproate) (Controls unexposed, disease free), 2010Bromley (Valproate) (Controls unexposed, sick), 2010Thomas b (Valproate), 2008	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.
S9942 R53631	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
S9944 R53632	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
S9414 R53628	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
S9418 R53629	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
S9376 R53625	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
S9379 R53626	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
S9382 R53627	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
S9420 R53630	Thomas b (Valproate), 2008	Impaired Mental Development Quotient < 84 (The Developmental Assessment Scale (DAS II))	during pregnancy (anytime or not specified)	prospective cohort	unexposed, sick	Adjustment: No	1.52 [0.63;3.68] C	29/71   10/32	39	71		ref
					Total	5 studies	4.09 [1.87;8.96]		103	190
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 9376, 9379, 9942