Valproate (All indications)

Neural Tube Defects

id	Study   Auto Tomson (Valproate), 2018Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014Vajda (Valproate) (Controls exposed to Lamotrigine, sick), 2013Vajda (Valproate) (Controls unexposed, sick), 2013Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012Bànhidy (Valproate), 2011Mawer (Valproate) (Controls exposed to Lamotrigine, sick), 2010Mawer (Valproate) (Controls unexposed, disease free), 2010Mawer (Valproate) (Controls unexposed, sick), 2010Canger (Valproate), 1999	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.
S9359 R32738	Tomson (Valproate), 2018	Neural tube defects	at least 1st trimester	prospective cohort	exposed to other treatment, sick	Adjustment: No	29.46 [3.90;222.36] C	16/1,381   1/2,514	17	1,381		ref
S9333 R32558	Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014	Neural tube defect	1st trimester	prospective cohort	exposed to other treatment, sick	Adjustment: No	11.29 [2.54;50.12]	13/1,220   2/2,098	15	1,220		ref
S10295 R37702	Vajda (Valproate) (Controls exposed to Lamotrigine, sick), 2013	Neural Tube Malformations	at least 1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	17.90 [1.02;314.95] C excluded (control group)	7/271   0/315	7	271		ref
S10296 R37706	Vajda (Valproate) (Controls unexposed, sick), 2013	Neural Tube Malformations	at least 1st trimester	prospective cohort	unexposed, sick	Adjustment: No	8.34 [0.47;147.07] C	7/271   0/147	7	271		ref
S10231 R37482	Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012	Neural tube defects	1st trimester	prospective cohort	exposed to other treatment, sick	Adjustment: No Controls: mixed indications	9.78 [1.78;53.63] C	4/323   2/1,562	6	323		ref
S9331 R32550	Bànhidy (Valproate), 2011	Neural tube defects	throughout pregnancy	case control	unexposed, sick	Adjustment: No Matched	2.00 [0.10;39.08] C	1/6   1/11	2	6		ref
S9312 R35336	Mawer (Valproate) (Controls exposed to Lamotrigine, sick), 2010	Neural Tube Malformations	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	0.70 [0.01;35.84] C excluded (control group)	0/53   0/37	0	53		ref
S9317 R35340	Mawer (Valproate) (Controls unexposed, disease free), 2010	Neural Tube Malformations	1st trimester	prospective cohort	unexposed, disease free excluded	Adjustment: No Matched	1.80 [0.07;44.79] C excluded (control group)	0/53   1/285	1	53		ref
S9318 R35344	Mawer (Valproate) (Controls unexposed, sick), 2010	Neural Tube Malformations	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	0.77 [0.01;39.72] C	0/53   0/41	0	53		ref
S9335 R32576	Canger (Valproate), 1999	Neural tube defects	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	7.00 [0.37;132.29] C	5/44   0/25	5	44		ref
					Total	7 studies	9.34 [4.08;21.40]		52	3,298
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 9312, 9317, 10295