TNF-alpha inhibitors

Limb defects

id	Study   Auto Carman - Etanercept (Controls unexposed, disease free), 2017Carman - Etanercept (Controls unexposed, sick), 2017Bröms a (Controls unexposed, disease free), 2016Bröms a (Controls unexposed, sick), 2016Cooper, 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 specifiedwhatever (meta-analysis)	Tags	OR 95%CI	x1/n1 x0/n0	no cases	no exposed	ROB	Ref.
S4098 R8753	Carman - Etanercept (Controls unexposed, disease free), 2017	Musculoskeletal malformations	during pregnancy (anytime or not specified)	retrospective cohort (claims database)	unexposed, disease free excluded	Adjustment: No	0.60 [0.14;2.62] C excluded (control group)	2/210   17/1,078	19	210		ref
S4099 R8768	Carman - Etanercept (Controls unexposed, sick), 2017	Musculoskeletal malformations	during pregnancy (anytime or not specified) excluded	retrospective cohort (claims database)	unexposed, sick	Adjustment: No	0.57 [0.14;2.40] C excluded (exposition period)	2/210   32/1,932	34	210		ref
S3194 R5165	Bröms a (Controls unexposed, disease free), 2016	Limbs	3 months or more before pregnancy or1st trimester	population based cohort retrospective	unexposed, disease free excluded	Adjustment: No	0.76 [0.31;1.83] C excluded (control group)	5/683   12,039/1,250,192	12,044	683		ref
S3193 R5143	Bröms a (Controls unexposed, sick), 2016	Limbs	3 months or more before pregnancy or1st trimester excluded	population based cohort retrospective	unexposed, sick	Adjustment: Yes	0.77 [0.27;1.69] excluded (exposition period)	5/683   206/21,549	211	683		ref
S4074 R8639	Cooper, 2014	Musculoskeletal defects	1st trimester	retrospective cohort (claims database)	unexposed, sick	Adjustment: No	3.07 [0.06;156.65] C	0/56   0/171	0	56		ref
					Total	1 studies	3.07 [0.06;156.65]		0	56
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 3194, 4098