Valproate (All indications)

Spina bifida

id	Study   Auto Blotière (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2019Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014Veiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014Charlton (Valproate) (Controls exposed to Lamotrigine, sick), 2011Charlton (Valproate) (Controls unexposed, sick), 2011Viinikainen (Valproate) (Controls unexposed, sick) a, 2006Artama (Valproate), 2005Källén (Valproate), 1994Czeizel (Valproate), 1992	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.
S10174 R37202	Blotière (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2019	Spina bifida	1st trimester	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: No	19.82 [2.38;164.84] C excluded (control group)	6/913   1/2,997	7	913		ref
S10051 R36476	Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019	Spina bifida	1st trimester	retrospective cohort (claims database)	unexposed (general population or NOS)	Adjustment: Yes	19.40 [8.60;43.50]	6/913   616/1,875,733	622	913		ref
S9325 R32515	Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014	Spina bifida	throughout pregnancy	population based cohort retrospective	exposed to other treatment, sick excluded	Adjustment: No	7.53 [0.31;185.42] C excluded (control group)	1/333   0/833	1	333		ref
S9327 R32524	Veiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014	Spina bifida	throughout pregnancy	population based cohort retrospective	unexposed, sick	Adjustment: No Controls: epilepsy indication	3.79 [0.39;36.49] C	1/333   3/3,773	4	333		ref
S9293 R32278	Charlton (Valproate) (Controls exposed to Lamotrigine, sick), 2011	Spina bifida	1st trimester	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: No	3.98 [0.21;74.64] C excluded (control group)	4/225   0/98	4	225		ref
S9294 R32281	Charlton (Valproate) (Controls unexposed, sick), 2011	Spina bifida	1st trimester	retrospective cohort (claims database)	unexposed, sick	Adjustment: No	8.02 [1.50;43.50]	4/225   2/902	6	225		ref
S9329 R32529	Viinikainen (Valproate) (Controls unexposed, sick) a, 2006	Spina bifida	throughout pregnancy	prospective cohort	unexposed, sick	Adjustment: No	5.83 [0.23;148.09] C	1/28   0/52	1	28		ref
S9330 R32537	Artama (Valproate), 2005	Spina bifida	1st trimester	retrospective cohort (registry)	unexposed, sick	Adjustment: No	40.09 [2.21;727.45] C	5/263   0/939	5	263		ref
S9343 R32592	Källén (Valproate), 1994	Spina bifida	during pregnancy (anytime or not specified) excluded	nested case control	unexposed, sick	Adjustment: No Matched	no data excluded (exposition period)	1/1   0/6	1	1		ref
S9338 R32584	Czeizel (Valproate), 1992	Spina bifida	throughout pregnancy	case control	unexposed, sick	Adjustment: No	3.00 [0.08;107.45] C	1/2   1/4	2	2		ref
					Total	6 studies	13.80 [7.20;26.46]		640	1,764
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 9293, 9325, 10174