Adalimumab

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

id	Study   Auto De Lorenzo (Controls unexposed, disease free), 2020De Lorenzo (Controls unexposed, sick), 2020Chambers (Controls unexposed, disease free), 2019Chambers (Controls, sick), 2019Hoxha, 2017Bröms (controls unexposed, disease free), 2016Bröms (controls unexposed, sick), 2016Weber-Schoendorfer, 2015Seirafi, 2014Casanova, 2013Viktil (Controls exposed to other treatments), 2012Viktil (Controls unexposed, NOS), 2012Schnitzler (Unexposed control, disease free), 2011Schnitzler (Unexposed control, sick), 2011Hyrich, 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.
S5066 R13191	De Lorenzo (Controls unexposed, disease free), 2020	Malformations	at least 1st trimester	retrospective cohort	unexposed, disease free excluded	Adjustment: No	7.67 [0.21;278.90] C excluded (control group)	0/2   1/36	1	2		ref
S5067 R13197	De Lorenzo (Controls unexposed, sick), 2020	Malformations	at least 1st trimester	retrospective cohort	unexposed, sick	Adjustment: No	21.00 [0.30;1469.95] C	0/2   0/32	0	2		ref
S5069 R15979	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 R15980	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 R11357	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 R11349	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 R11350	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 R11361	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 R11353	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 R53458	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 R53460	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
S3121 R4855	Schnitzler (Unexposed control, disease free), 2011	Malformations (NOS)	3 months (or more) before pregnancy or during pregnancy	prospective cohort	unexposed, disease free excluded	Adjustment: No	30.27 [1.10;836.04] C excluded (control group)	1/7   0/56	1	7		ref
S3122 R4856	Schnitzler (Unexposed control, sick), 2011	Malformations (NOS)	3 months (or more) before pregnancy or during pregnancy excluded	prospective cohort	unexposed, sick	Adjustment: No	12.83 [0.71;231.76] C excluded (exposition period)	1/7   1/78	2	7		ref
S5001 R15981	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	5 studies	2.51 [1.06;5.97]		62	380
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 3121, 13724, 4061, 5069, 5066