TNF-alpha inhibitors

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, 2020Moens (Controls exposed to Vedolizumab), 2020Moens (Controls unexposed, sick), 2020Duricova, 2019Fu - Etanercept, 2019Chaparro, 2018De Lima, 2018Luu, 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), 2016De Lima (Controls unexposed, disease free), 2016Agosti, 2015Chambers - Etanercept, 2015Weber-Schoendorfer, 2015Cooper, 2014Diav-Citrin (Controls exposed to other treatments), 2014Diav-Citrin (Controls unexposed, disease free), 2014Seirafi, 2014Casanova, 2013Viktil (Controls exposed to other treatments), 2012Viktil (Controls unexposed, NOS), 2012Schnitzler (Controls unexposed, disease free), 2011Schnitzler (Unexposed control, sick), 2011Verstappen, 2011	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.
S4958 R12999	De Lorenzo (Controls unexposed, disease free), 2020	Malformations	at least 1st trimester	retrospective cohort	unexposed, disease free excluded	Adjustment: No	7.00 [0.57;85.39] C excluded (control group)	2/12   1/36	3	12		ref
S4959 R13005	De Lorenzo (Controls unexposed, sick), 2020	Malformations	at least 1st trimester	retrospective cohort	unexposed, sick	Adjustment: No	16.58 [0.73;376.16] C	2/12   0/32	2	12		ref
S4995 R13095	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
S4952 R12991	Moens (Controls exposed to Vedolizumab), 2020	Congenital anomalies (NOS)	at least 1st trimester	retrospective cohort	exposed to other treatment, sick excluded	Adjustment: No	0.51 [0.11;2.37] C excluded (control group)	4/162   3/64	7	162		ref
S4951 R12986	Moens (Controls unexposed, sick), 2020	Congenital anomalies (NOS)	at least 1st trimester	retrospective cohort	unexposed, sick	Adjustment: No	1.35 [0.30;6.13] C	4/162   3/163	7	162		ref
S3072 R4708	Duricova, 2019	Congenital malformations	during pregnancy (anytime or not specified) excluded	retrospective cohort	unexposed, disease free	Adjustment: No	0.82 [0.28;2.40] C excluded (exposition period)	7/72   8/69	15	72		ref
S4997 R13101	Fu - Etanercept, 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
S3066 R4667	Chaparro, 2018	Congenital malformations (NOS)	3 months (or more) before pregnancy or during pregnancy excluded	retrospective cohort	unexposed, sick	Adjustment: No before conception and/or during pregnancy	2.10 [1.02;4.33] C excluded (exposition period)	21/388   12/453	33	388		ref
S3123 R11336	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
S3093 R4771	Luu, 2018	Malformations	during pregnancy (anytime or not specified) excluded	retrospective cohort (claims database)	exposed to other treatment, sick	Adjustment: No	0.98 [0.72;1.33] C excluded (exposition period)	49/799   303/4,836	352	799		ref
S4098 R11330	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 R11331	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 R11333	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 R11339	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 R11328	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 R11329	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
S3070 R4688	De Lima (Controls unexposed, disease free), 2016	Congenital Abnormalities	1st and 2nd trimester	prospective cohort	unexposed, disease free	Adjustment: No	1.04 [0.31;3.49] C	3/83   28/804	31	83		ref
S3069 R4679	Agosti, 2015	Congenital malformations (severe or not)	during pregnancy (anytime or not specified) excluded	retrospective cohort	unexposed, sick	Adjustment: No	1.00 [0.18;5.53] C excluded (exposition period)	3/24   3/24	6	24		ref
S4104 R11334	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 R4104	Weber-Schoendorfer, 2015	All birth defects	1st trimester	prospective cohort	unexposed, disease free	Adjustment: Yes	1.64 [1.10;2.60]	52/423   87/1,393	139	423		ref
S4074 R11335	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 R11337	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 R11338	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
S3037 R4576	Seirafi, 2014	Congenital malformations	3 months (or more) before pregnancy or during pregnancy excluded	retrospective cohort	unexposed, sick	Adjustment: No before conception and/or during pregnancy	0.25 [0.03;2.42] C excluded (exposition period)	1/118   3/90	4	118		ref
S3014 R11332	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 R53470	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 R53472	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
S3017 R4524	Schnitzler (Controls unexposed, disease free), 2011	Malformations (NOS)	3 months (or more) before pregnancy or during pregnancy	prospective cohort	unexposed, disease free excluded	Adjustment: No before conception and/or during pregnancy	4.11 [0.16;103.53] C excluded (control group)	1/42   0/56	1	42		ref
S3018 R4523	Schnitzler (Unexposed control, sick), 2011	Malformations (NOS)	3 months (or more) before pregnancy or during pregnancy excluded	prospective cohort	unexposed, sick	Adjustment: No before conception and/or during pregnancy	1.88 [0.11;30.81] C excluded (exposition period)	1/42   1/78	2	42		ref
S2916 R13111	Verstappen, 2011	Congenital malformations	early pregnancy	prospective cohort	unexposed, sick	Adjustment: No	1.80 [0.24;13.44] C	2/32   2/56	4	32		ref
					Total	13 studies	1.57 [1.16;2.14]		206	971
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 3017, 13730, 2897, 3194, 4098, 4958, 4952