Valproate (All indications)

Microcephaly / Small head circumference for gestational age

id	Study   Auto Blotière (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2019Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019Pennell (Valproate), 2012Kini (Valproate) (Controls unexposed, sick), 2006Battino (Valproate), 1999Díaz-Romero (Valproate), 1999Dravet (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 R37203	Blotière (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2019	Microcephaly (until 24 months of age, identifiable by: Q02; brain MRI; according to the EUROCAT definition)	1st trimester	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: No	1.09 [0.04;26.89] C excluded (control group)	0/913   1/2,997	1	913		ref
S10051 R36477	Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019	Microcephaly (until 24 months of age, identifiable by: Q02; brain MRI; according to the EUROCAT definition)	1st trimester	retrospective cohort (claims database)	unexposed (general population or NOS)	Adjustment: No	2.34 [0.15;37.55] C	0/913   438/1,875,733	438	913		ref
S9323 R32490	Pennell (Valproate), 2012	Microcephaly at birth (head circumference < 3 percentile)	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick	Adjustment: No	1.27 [0.34;4.83] C	4/38   6/71	10	38		ref
S9346 R32602	Kini (Valproate) (Controls unexposed, sick), 2006	Head circumference in children aged between 6 months and 16 years <3rd centile	during pregnancy (anytime or not specified)	retrospective cohort	unexposed, sick	Adjustment: No	1.66 [0.46;5.96] C	5/63   5/101	10	63		ref
S9369 R32758	Battino (Valproate), 1999	Small head circumferences (at birth < 10th percentile)	throughout pregnancy	prospective cohort	unexposed, sick	Adjustment: No	0.68 [0.14;3.26] C	4/57   3/30	7	57		ref
S9370 R32759	Díaz-Romero (Valproate), 1999	Head circumference <2 SD at birth (measured by a physician and correlated with sex and with gestational age)	during pregnancy (anytime or not specified)	cohort	unexposed, sick	Adjustment: No	0.79 [0.01;44.65] C	0/10   0/8	0	10		ref
S9341 R32589	Dravet (Valproate), 1992	Isolated microcephaly at birth (head circumference >2 SD lower than those given in the reference tables adjusted for gestational age at birth)	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	3.12 [0.34;28.74] C	6/31   1/14	7	31		ref
					Total	6 studies	1.36 [0.67;2.78]		472	1,112
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 10174