Adalimumab

Major congenital malformations

id	Study   Auto Chambers (Controls unexposed, disease free), 2019Chambers (Controls, sick), 2019Hoxha, 2017Bröms (controls unexposed, disease free), 2016Bröms (controls unexposed, sick), 2016Weber-Schoendorfer, 2015Casanova, 2013Viktil (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 specifiedwhatever (meta-analysis)	Tags	OR 95%CI	x1/n1 x0/n0	no cases	no exposed	ROB	Ref.
S5069 R13216	Chambers (Controls unexposed, disease free), 2019	Major Birth Defects	at least 1st trimester	prospective cohort	unexposed, disease free excluded	Adjustment: Yes	1.43 [0.33;6.27] excluded (control group)	22/221   12/198	34	221		ref
S5068 R13201	Chambers (Controls, sick), 2019	Major Birth Defects	at least 1st trimester	prospective cohort	unexposed, sick	Adjustment: Yes	1.10 [0.45;2.73]	22/221   8/106	30	221		ref
S3006 R4293	Hoxha, 2017	Congenital malformation	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	2.50 [0.12;50.45] C	1/5   1/11	2	5		ref
S4061 R8592	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	1.35 [0.69;2.64] C excluded (control group)	9/161   52,592/1,250,192	52,601	161		ref
S3197 R5199	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	1.22 [0.58;2.27] excluded (exposition period)	9/161   1,019/21,549	1,028	161		ref
S2911 R4109	Weber-Schoendorfer, 2015	Major birth defects	1st trimester	prospective cohort	unexposed, disease free	Adjustment: No	4.15 [1.86;9.23] C	9/150   21/1,385	30	150		ref
S3090 R4745	Casanova, 2013	Congenital malformations (NOS)	3 months (or more) before pregnancy or during pregnancy excluded	retrospective cohort	exposed to other treatment, sick	Adjustment: No	21.13 [1.26;354.49] C excluded (exposition period)	1/16   1/318	2	16		ref
S13724 R53457	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	5.57 [0.26;117.63] C excluded (control group)	0/3   50/1,458	50	3		ref
S13725 R53459	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	6.00 [0.29;124.97] C excluded (exposition period)	0/3   5,000/154,976	5,000	3		ref
S5001 R13117	Hyrich, 2006	Major fetal abnormalities	1st trimester	retrospective cohort	unexposed, sick	Adjustment: No	5.00 [0.07;366.35] C	0/2   0/8	0	2		ref
					Total	4 studies	2.30 [0.94;5.64]		62	378
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 13724, 4061, 5069