Valproate (All indications)

Severe cognitive developmental delay (Mental retardation) (3-6 years old)

id	Study   Auto Coste (Valproate) (Controls exposed to Lamotrigine, sick), 2020Coste (Valproate) (Controls unexposed, NOS), 2020Meador (Valproate), 2013Cummings (Valproate) (Controls exposed to Lamotrigine, sick), 2011Cummings (Valproate) (Controls unexposed, disease free), 2011Gaily (Valproate) (Controls unexposed, sick), 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.
S9391 R32880	Coste (Valproate) (Controls exposed to Lamotrigine, sick), 2020	Diagnosis Mental retardation (F70–F79) (mean age of 3.7 years old)	during pregnancy (anytime or not specified)	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: Yes	4.00 [1.90;8.60] excluded (control group)	15/991   10/2,108	25	991		ref
S9392 R32898	Coste (Valproate) (Controls unexposed, NOS), 2020	Diagnosis Mental retardation (F70–F79) (mean age of 3.6 years old)	during pregnancy (anytime or not specified)	retrospective cohort (claims database)	unexposed (general population or NOS)	Adjustment: Yes	5.10 [3.10;8.50]	15/991   3,398/1,710,441	3,413	991		ref
S9414 R33004	Meador (Valproate), 2013	IQ <70 (DAS) (at 4.5 years old)	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick	Adjustment: Yes	18.91 [0.99;361.27] C	4/39   0/73	4	39		ref
S9394 R32924	Cummings (Valproate) (Controls exposed to Lamotrigine, sick), 2011	Significant delay (score ≥2 SD below the mean) (Bayley Scales of Infant Development or the Griffiths Scale) (mean age in years: m1=2.9 and m0=2.7)	throughout pregnancy	retrospective cohort (registry)	exposed to other treatment, sick excluded	Adjustment: No	7.23 [0.39;134.94] C excluded (control group)	5/58   0/35	5	58		ref
S9395 R32927	Cummings (Valproate) (Controls unexposed, disease free), 2011	Significant delay (score ≥2 SD below the mean) (Bayley Scales of Infant Development or the Griffiths Scale) (mean age in years: m1=2.9 and m0=4.3)	throughout pregnancy	retrospective cohort (registry)	unexposed, disease free	Adjustment: No	4.06 [0.46;36.05] C	5/58   1/44	6	58		ref
S9402 R32949	Gaily (Valproate) (Controls unexposed, sick), 2004	Mental retardation (Verbal and nonverbal IQ <70)	2nd and/or 3rd trimester	prospective cohort	unexposed, sick	Adjustment: No	1.79 [0.15;21.49] C	1/13   2/45	3	13		ref
					Total	4 studies	5.02 [3.12;8.08]		3,426	1,101
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 9394, 9391