Valproate (Epilepsy)

Limb defects

id	Study   Auto Thomas (Valproate) (Controls exposed to Lamotrigine, sick), 2021Thomas (Valproate) (Controls unexposed, sick), 2021Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014De Jonge (Valproate), 2013Vajda (Valproate) (Controls exposed to Lamotrigine, sick), 2013Vajda (Valproate) (Controls unexposed, sick), 2013Mawer (Valproate) (Controls exposed to Lamotrigine, sick), 2010Mawer (Valproate) (Controls unexposed, disease free), 2010Mawer (Valproate) (Controls unexposed, sick), 2010Artama (Valproate), 2005	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.
S12860 R48522	Thomas (Valproate) (Controls exposed to Lamotrigine, sick), 2021	Skeletal malformations	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	1.32 [0.07;24.97] C excluded (control group)	4/341   0/50	4	341		ref
S12861 R48532	Thomas (Valproate) (Controls unexposed, sick), 2021	Skeletal malformations	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	2.01 [0.36;11.03] C	4/341   2/340	6	341		ref
S318 R14443	Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014	Skeletal defects	1st trimester	prospective cohort	exposed to other treatment, sick	Adjustment: No	5.77 [1.59;21.02]	10/1,220   3/2,098	13	1,220		ref
S10732 R39688	De Jonge (Valproate), 2013	Limb malformations	1st trimester	case control	unexposed (general population or NOS)	Adjustment: No Monotherapy: no or not specified	2.24 [0.14;36.66] C	0/35   184/29,372	184	35		ref
S10293 R37695	Vajda (Valproate) (Controls exposed to Lamotrigine, sick), 2013	Skeletal / Limb Malformations	at least 1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	15.46 [0.87;275.68] C excluded (control group)	6/271   0/315	6	271		ref
S10294 R37701	Vajda (Valproate) (Controls unexposed, sick), 2013	Skeletal / Limb Malformations	at least 1st trimester	prospective cohort	unexposed, sick	Adjustment: No	3.31 [0.39;27.72] C	6/271   1/147	7	271		ref
S9848 R35353	Mawer (Valproate) (Controls exposed to Lamotrigine, sick), 2010	Skeletal / Limb Malformations	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	0.69 [0.04;11.43] C excluded (control group)	1/53   1/37	2	53		ref
S9849 R35359	Mawer (Valproate) (Controls unexposed, disease free), 2010	Skeletal / Limb Malformations	1st trimester	prospective cohort	unexposed, disease free excluded	Adjustment: No Matched	16.57 [0.67;412.47] C excluded (control group)	1/53   0/285	1	53		ref
S9850 R35365	Mawer (Valproate) (Controls unexposed, sick), 2010	Skeletal / Limb Malformations	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	2.36 [0.09;59.46] C	1/53   0/41	1	53		ref
S6099 R35923	Artama (Valproate), 2005	Certain musculoskeletal deformities and Other anomalies of limbs	1st trimester	retrospective cohort (registry)	unexposed, sick	Adjustment: No	4.18 [1.50;11.63] C	8/263   7/939	15	263		ref
					Total	6 studies	3.76 [1.96;7.23]		226	2,183
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 9848, 9849, 10293, 12860