Phenytoin (All indications)

Limb defects

id	Study   Auto Thomas (Phenytoin) (Controls exposed to Lamotrigine, sick), 2021Thomas (Phenytoin) (Controls unexposed, sick), 2021Vajda (Phenytoin) (Controls exposed to Lamotrigine, sick), 2013Vajda (Phenytoin) (Controls unexposed, sick), 2013Mawer (Phenytoin) (Controls exposed to Lamotrigine, sick), 2010Mawer (Phenytoin) (Controls unexposed, disease free), 2010Mawer (Phenytoin) (Controls unexposed, sick), 2010Morrow (Phenytoin) (Controls exposed to Lamotrigine, sick), 2006Artama (Phenytoin), 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.
S12850 R48456	Thomas (Phenytoin) (Controls exposed to Lamotrigine, sick), 2021	Skeletal malformations	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	1.26 [0.05;31.56] C excluded (control group)	1/119   0/50	1	119		ref
S12852 R48468	Thomas (Phenytoin) (Controls unexposed, sick), 2021	Skeletal malformations	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	1.43 [0.13;15.94] C	1/119   2/340	3	119		ref
S10300 R37747	Vajda (Phenytoin) (Controls exposed to Lamotrigine, sick), 2013	Skeletal / Limb Malformations	at least 1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	7.23 [0.14;369.08] C excluded (control group)	0/44   0/315	0	44		ref
S10301 R37760	Vajda (Phenytoin) (Controls unexposed, sick), 2013	Skeletal / Limb Malformations	at least 1st trimester	prospective cohort	unexposed, sick	Adjustment: No	1.11 [0.04;27.86] C	0/44   1/147	1	44		ref
S9209 R35369	Mawer (Phenytoin) (Controls exposed to Lamotrigine, sick), 2010	Skeletal / Limb Malformations	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	1.82 [0.07;49.76] C excluded (control group)	0/7   1/37	1	7		ref
S9210 R35373	Mawer (Phenytoin) (Controls unexposed, disease free), 2010	Skeletal / Limb Malformations	1st trimester	prospective cohort	unexposed, disease free excluded	Adjustment: No Matched	43.77 [0.80;2381.04] C excluded (control group)	0/7   0/285	0	7		ref
S9211 R35377	Mawer (Phenytoin) (Controls unexposed, sick), 2010	Skeletal / Limb Malformations	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	6.23 [0.11;342.42] C	0/7   0/41	0	7		ref
S9238 R32062	Morrow (Phenytoin) (Controls exposed to Lamotrigine, sick), 2006	Skeletal abnormalities	1st trimester	prospective cohort	exposed to other treatment, sick	Adjustment: No	1.58 [0.08;33.23] C	0/82   2/647	2	82		ref
S9224 R35925	Artama (Phenytoin), 2005	Certain musculoskeletal deformities and Other anomalies of limbs	1st trimester	retrospective cohort (registry)	unexposed, sick	Adjustment: No	3.60 [0.43;30.01] C	1/38   7/939	8	38		ref
					Total	5 studies	2.20 [0.64;7.52]		14	290
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 9209, 9210, 10300, 12850