TNF-alpha inhibitors

Major congenital malformations

id	Study   Auto Drechsel, 2020Fu - Etanercept, 2019De Lima, 2018Carman - Etanercept (Controls unexposed, disease free), 2017Carman - Etanercept (Controls unexposed, sick), 2017Chambers - Adalimumab (Controls unexposed, sick, ADA only), 2017Hoxha, 2017Bröms a (Controls unexposed, disease free), 2016Bröms a (Controls unexposed, sick), 2016Agosti, 2015Chambers - Etanercept, 2015Weber-Schoendorfer, 2015Cooper, 2014Diav-Citrin (Controls exposed to other treatments), 2014Diav-Citrin (Controls unexposed, disease free), 2014Casanova, 2013Viktil (Controls exposed to other treatments), 2012Viktil (Controls unexposed, NOS), 2012	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.
S4995 R13092	Drechsel, 2020	Major congenital malformations	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	1.59 [0.06;41.24] C	0/14   1/66	1	14		ref
S4997 R13103	Fu - Etanercept, 2019	Congenital malformations (majors)	1st trimester	randomized controlled trial	unexposed, sick	Adjustment: Randomisation	0.79 [0.05;12.80] C	1/85   1/67	2	85		ref
S3123 R4860	De Lima, 2018	Major congenital abnormalities	at least 1st trimester	prospective cohort	exposed to other treatment, sick	Adjustment: No	0.79 [0.01;43.11] C	0/15   0/12	0	15		ref
S4098 R8746	Carman - Etanercept (Controls 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
S4099 R8761	Carman - Etanercept (Controls 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
S4106 R8796	Chambers - Adalimumab (Controls unexposed, sick, ADA only), 2017	Major birth defects among all pregnancies	at least 1st trimester	prospective cohort	unexposed, sick	Adjustment: Yes	0.91 [0.37;2.23]	-/-   -/-	-	-		ref
S3009 R4305	Hoxha, 2017	Congenital malformation	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	0.43 [0.02;7.66] C	1/24   1/11	2	24		ref
S3194 R5156	Bröms a (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	1.53 [1.12;2.08] C excluded (control group)	43/683   52,592/1,250,192	52,635	683		ref
S3193 R5134	Bröms a (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	1.32 [0.93;1.82] excluded (exposition period)	43/683   1,019/21,549	1,062	683		ref
S3069 R4684	Agosti, 2015	Major malformations	during pregnancy (anytime or not specified) excluded	retrospective cohort	unexposed, sick	Adjustment: No	3.13 [0.12;81.01] C excluded (exposition period)	1/24   0/24	1	24		ref
S4104 R8792	Chambers - Etanercept, 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
S2888 R4105	Weber-Schoendorfer, 2015	Major birth defects	1st trimester	prospective cohort	unexposed, disease free	Adjustment: Yes	2.20 [1.01;4.80]	21/421   21/1,385	42	421		ref
S4074 R8624	Cooper, 2014	Major congenital malformations	1st trimester	retrospective cohort (claims database)	unexposed, sick	Adjustment: Yes	1.59 [0.30;8.47]	2/56   4/171	6	56		ref
S2897 R4080	Diav-Citrin (Controls exposed to other treatments), 2014	Major malformations	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	0.72 [0.16;3.12] C excluded (control group)	3/65   5/79	8	65		ref
S2893 R4066	Diav-Citrin (Controls unexposed, disease free), 2014	Major malformations	1st trimester	prospective cohort	unexposed, disease free	Adjustment: No	1.98 [0.51;7.69] C	3/65   8/336	11	65		ref
S3014 R4502	Casanova, 2013	Congenital malformations (NOS)	3 months (or more) before pregnancy or during pregnancy excluded	retrospective cohort	exposed to other treatment, sick	Adjustment: No	4.58 [0.28;74.22] C excluded (exposition period)	1/60   1/271	2	60		ref
S13730 R53469	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	0.34 [0.02;5.67] C excluded (control group)	0/40   50/1,421	50	40		ref
S13731 R53471	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	0.38 [0.02;6.18] C excluded (exposition period)	0/40   5,000/154,976	5,000	40		ref
					Total	9 studies	1.67 [1.08;2.58]		64	680
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 13730, 2897, 3194, 4098