Phenytoin (All indications)

Microcephaly / Small head circumference for gestational age

id	Study   Auto Pennell (Phenytoin), 2012Holmes (Phenytoin) (Controls unexposed, disease free), 2001Holmes (Phenytoin) (Controls unexposed, sick), 2001Battino (Phenytoin), 1999Díaz-Romero (Phenytoin), 1999Nulman (Phenytoin) (Controls unexposed, sick) (Mixed indications), 1997Kelly (Phenytoin), 1984	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.
S9216 R31979	Pennell (Phenytoin), 2012	Microcephaly at birth (head circumference < 3 percentile)	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick	Adjustment: No	0.98 [0.26;3.69] C	4/48   6/71	10	48		ref
S9202 R31927	Holmes (Phenytoin) (Controls unexposed, disease free), 2001	Microcephaly at birth (Head circumference more than 2 SD below the mean value for the same race, sex and gestational age)	during pregnancy (anytime or not specified)	retrospective cohort	unexposed, disease free excluded	Adjustment: No	0.73 [0.09;5.88] C excluded (control group)	1/87   8/508	9	87		ref
S9203 R31936	Holmes (Phenytoin) (Controls unexposed, sick), 2001	Microcephaly at birth (Head circumference more than 2 SD below the mean value for the same race, sex and gestational age)	during pregnancy (anytime or not specified)	retrospective cohort	unexposed, sick	Adjustment: No	0.55 [0.05;6.14] C	1/87   2/96	3	87		ref
S9254 R32094	Battino (Phenytoin), 1999	Small head circumferences (at birth < 10th percentile)	throughout pregnancy	prospective cohort	unexposed, sick	Adjustment: No	0.57 [0.13;2.45] C	6/100   3/30	9	100		ref
S9255 R32095	Díaz-Romero (Phenytoin), 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	0.37 [0.01;20.14] C	0/21   0/8	0	21		ref
S9274 R32159	Nulman (Phenytoin) (Controls unexposed, sick) (Mixed indications), 1997	Microcephaly at unknown age (head circumference ≤ 2 SD from the mean of children of the same age and sex)	at least 1st trimester	prospective cohort	unexposed, sick	Adjustment: No Controls: epilepsy indication	1.39 [0.06;31.88] C	2/33   0/9	2	33		ref
S9233 R32039	Kelly (Phenytoin), 1984	Microcephaly at unknown age (head circumference < 5th centile)	during pregnancy (anytime or not specified)	prospective cohort	unexposed, sick	Adjustment: No	0.50 [0.03;8.42] C	1/41   1/21	2	41		ref
					Total	6 studies	0.72 [0.32;1.63]		26	330
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 9202