Etanercept

All congenital malformations (majors, minors, majors and minors, or unspecified)

id	Study   Auto De Lorenzo (Controls unexposed, disease free), 2020De Lorenzo (Controls unexposed, sick), 2020Drechsel, 2020Fu, 2019Carman (Control unexposed, disease free), 2017Carman (Control unexposed, sick), 2017Hoxha, 2017Bröms (controls unexposed, disease free), 2016Bröms (controls unexposed, sick), 2016Chambers, 2015Weber-Schoendorfer, 2015Viktil (Controls exposed to other treatments), 2012Viktil (Controls unexposed, NOS), 2012Hyrich, 2006	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.
S4961 R13017	De Lorenzo (Controls unexposed, disease free), 2020	Malformations	at least 1st trimester	retrospective cohort	unexposed, disease free excluded	Adjustment: No	17.50 [1.28;238.92] C excluded (control group)	2/6   1/36	3	6		ref
S4960 R13011	De Lorenzo (Controls unexposed, sick), 2020	Malformations	at least 1st trimester	retrospective cohort	unexposed, sick	Adjustment: No	45.00 [1.78;1138.73] C	2/6   0/32	2	6		ref
S4994 R13078	Drechsel, 2020	Major congenital malformations	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	2.53 [0.10;67.19] C	0/9   1/66	1	9		ref
S4996 R13097	Fu, 2019	Congenital malformation (major or minor)	1st trimester	randomized controlled trial	unexposed, sick	Adjustment: Randomisation	1.59 [0.14;17.92] C	2/85   1/67	3	85		ref
S3011 R11374	Carman (Control unexposed, disease free), 2017	Major malformations	during pregnancy (anytime or not specified)	retrospective cohort (claims database)	unexposed, disease free excluded	Adjustment: No	0.95 [0.49;1.85] C excluded (control group)	11/210   59/1,078	70	210		ref
S3010 R11375	Carman (Control unexposed, sick), 2017	Major malformations	during pregnancy (anytime or not specified) excluded	retrospective cohort (claims database)	unexposed, sick	Adjustment: No	1.08 [0.57;2.05] C excluded (exposition period)	11/210   94/1,932	105	210		ref
S3004 R11377	Hoxha, 2017	Congenital malformation	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	0.19 [0.01;5.20] C	0/17   1/11	1	17		ref
S4081 R11372	Bröms (controls unexposed, disease free), 2016	Any major birth defect	3 months or more before pregnancy or1st trimester	population based cohort retrospective	unexposed, disease free excluded	Adjustment: No	1.71 [1.13;2.59] C excluded (control group)	24/344   52,592/1,250,192	52,616	344		ref
S3195 R11373	Bröms (controls unexposed, sick), 2016	Any major birth defect	3 months or more before pregnancy or1st trimester excluded	population based cohort retrospective	unexposed, sick	Adjustment: Yes	1.49 [0.92;2.28] excluded (exposition period)	24/344   1,019/21,549	1,043	344		ref
S3137 R11376	Chambers, 2015	Major birth defects in live born infants	at least 1st trimester	prospective cohort	unexposed, sick	Adjustment: Yes	2.77 [1.04;7.35]	-/-   -/-	-	-		ref
S2913 R11379	Weber-Schoendorfer, 2015	Major birth defects	1st trimester	prospective cohort	unexposed, disease free	Adjustment: No	3.71 [1.47;9.40] C	6/111   21/1,385	27	111		ref
S13722 R53454	Viktil (Controls exposed to other treatments), 2012	Major malformations	3 months or more before pregnancy or1st trimester	population based cohort propective	exposed to other treatment, sick excluded	Adjustment: No	0.37 [0.02;6.16] C excluded (control group)	0/37   50/1,424	50	37		ref
S13723 R53456	Viktil (Controls unexposed, NOS), 2012	Major malformations	3 months or more before pregnancy or1st trimester excluded	population based cohort propective	unexposed (general population or NOS)	Adjustment: No	0.41 [0.03;6.70] C excluded (exposition period)	0/37   5,000/154,976	5,000	37		ref
S4998 R15978	Hyrich, 2006	Major fetal abnormalities	1st trimester	retrospective cohort	unexposed, sick	Adjustment: No	0.79 [0.01;44.65] C	0/10   0/8	0	10		ref
					Total	7 studies	2.93 [1.53;5.60]		34	238
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 13722, 4081, 3011, 4961