Valproate (All indications)

Nervous system anomalies

id	Study   Auto Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023Thomas (Valproate) (Controls exposed to Lamotrigine, sick), 2021Thomas (Valproate) (Controls unexposed, sick), 2021Ban (Valproate) (Mixed indications) (Controls exposed to Lamotrigine, sick), 2015Ban (Valproate) (Mixed indications) (Controls unexposed NOS), 2015Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014	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.
S15201 R62350	Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023	Nervous system malformation	1st trimester	population based cohort retrospective	unexposed (general population or NOS)	Adjustment: Yes	2.69 [1.56;4.62]	-/2,031   -/4,866,362	-	2,031		ref
S12862 R48538	Thomas (Valproate) (Controls exposed to Lamotrigine, sick), 2021	Neural malformations	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	1.03 [0.05;20.18] C excluded (control group)	3/341   0/50	3	341		ref
S12864 R48550	Thomas (Valproate) (Controls unexposed, sick), 2021	Neural malformations	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	7.04 [0.36;136.85] C	3/341   0/340	3	341		ref
S9442 R33160	Ban (Valproate) (Mixed indications) (Controls exposed to Lamotrigine, sick), 2015	Nervous system anomaly	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	6.44 [0.31;134.91] C excluded (control group)	2/214   0/273	2	214		ref
S9443 R33165	Ban (Valproate) (Mixed indications) (Controls unexposed NOS), 2015	Nervous system anomaly	1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No	6.60 [1.63;26.67] C	2/214   367/257,153	369	214		ref
S9325 R32506	Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014	Nervous system	throughout pregnancy	population based cohort retrospective	exposed to other treatment, sick	Adjustment: No	2.51 [0.16;40.18] C	1/333   1/833	2	333		ref
					Total	4 studies	3.08 [1.88;5.03]		374	2,919
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 9442, 12862