Methotrexate (Pre-conception only)

Major congenital malformations

id	Study   Auto Svirsky, 2017Dawson, 2014Weber-Schoendorfer (Controls exposed to other treatment, sick), 2014Weber-Schoendorfer (Controls unexposed, disease free), 2014	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 specifiedsiblingwhatever (meta-analysis)	Tags	OR 95%CI	x1/n1 x0/n0	no cases	no exposed	ROB	Ref.
S6697 R18867	Svirsky, 2017	Serious birth malformation	preconceptional for kinetic reason	retrospective cohort	unexposed, sick	Adjustment: No Exposed group: MTX (monotherapy) MTX more than 3 months before pregnancy MTX treatment for ectopic pregnancy	1.19 [0.07;19.35] C	1/89   1/106	2	89		ref
S10346 R37888	Dawson, 2014	Major birth defects	preconceptional for kinetic reason	case control	unexposed (general population or NOS)	Adjustment: No Exposed group: MTX (polytherapy or not specified) Indications: Any or not specified MTX less than 3 months before pregnancy	0.92 [0.18;4.72] C	5/7   27,618/37,729	27,623	7		ref
S10348 R37940	Weber-Schoendorfer (Controls exposed to other treatment, sick), 2014	Major birth defects	preconceptional for kinetic reason	prospective cohort	exposed to other treatment, sick excluded	Adjustment: Yes Exposed group: MTX (polytherapy or not specified) Indications: Inflammatory diseases Matched MTX less than 3 months before pregnancy	1.10 [0.30;4.20] excluded (control group)	4/114   14/393	18	114		ref
S10349 R37959	Weber-Schoendorfer (Controls unexposed, disease free), 2014	Major birth defects	preconceptional for kinetic reason	prospective cohort	unexposed, disease free	Adjustment: Yes Exposed group: MTX (polytherapy or not specified) Indications: Inflammatory diseases Matched MTX less than 3 months before pregnancy	1.60 [0.40;7.30]	4/114   29/1,001	33	114		ref
					Total	3 studies	1.24 [0.45;3.42]		27,658	210
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 10348