TNF-alpha inhibitors

Early intrauterine death (< 22 weeks)

R analysis
id Study   Lib. in paper Exposition period    Study type 
 Control type 
 
Tags OR 95%CI x1/n1 x0/n0 no cases no exposed ROB Ref.
S4995
R13079		 Drechsel, 2020 Miscarriage 1st trimester prospective cohort unexposed, sick Adjustment: No 0.92 [0.24;3.59] C 3/21   13/85 16 21
ref
S4997
R13100		 Fu - Etanercept, 2019 Miscarriages 1st trimester randomized controlled trial unexposed, sick Adjustment: Randomisation 0.30 [0.14;0.67] C 10/95   26/93 36 95
ref
S4098
R8758		 Carman - Etanercept (Controls unexposed, disease free), 2017 Spontaneous abortion (miscarriages, ectopic pregnancies, and trophoblastic pregnancies) during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed, disease free excluded Adjustment: No 1.06 [0.79;1.42] C
excluded (control group) 		69/337   329/1,685 398 337
ref
S4099
R8771		 Carman - Etanercept (Controls unexposed, sick), 2017 Spontaneous abortion (miscarriages, ectopic pregnancies, and trophoblastic pregnancies) during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed, sick Adjustment: No 1.22 [0.92;1.62] C 69/337   498/2,861 567 337
ref
S4106
R8797		 Chambers - Adalimumab (Controls unexposed, sick, ADA only), 2017 Spontaneous abortion (NOS) at least 1st trimester prospective cohort unexposed, sick Adjustment: Yes 2.22 [0.67;7.29] -/-   -/- - -
ref
S4104
R8793		 Chambers - Etanercept, 2015 Spontaneous abortion (NOS) at least 1st trimester prospective cohort unexposed, sick Adjustment: Yes 0.47 [0.20;1.12] -/370   -/164 - 370
ref
S2888
R4115		 Weber-Schoendorfer, 2015 Spontaneous pregnancy loss of a fetus <500 g or if weight not known <23 completed weeks after LMP. 1st trimester prospective cohort unexposed, disease free Adjustment: Yes 1.06 [0.70;1.70] 43/461   116/1,475 159 461
ref
S2897
R4076		 Diav-Citrin (Controls exposed to other treatments), 2014 Miscarriage (before or at 20 completed weeks) 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 1.97 [0.63;6.15] C
excluded (control group) 		9/83   5/86 14 83
ref
S2893
R4057		 Diav-Citrin (Controls unexposed, disease free), 2014 Miscarriage (before or at 20 completed weeks) 1st trimester prospective cohort unexposed, disease free Adjustment: Yes 1.96 [0.64;5.96] 9/83   10/341 19 83
ref
S3037
R4567		 Seirafi, 2014 Miscarriages (foetal loss prior to 20 weeks post-conception) 3 months (or more) before pregnancy or during pregnancy excluded retrospective cohort unexposed, sick Adjustment: No before conception and/or during pregnancy 1.86 [0.63;5.48] C
excluded (exposition period) 		12/133   5/99 17 133
ref
S2916
R4127		 Verstappen, 2011 Spontaneous abortion (NOS) early pregnancy prospective cohort unexposed, sick Adjustment: No 1.67 [0.67;4.16] C 12/50   11/69 23 50
ref
Total 8 studies 0.99 [0.66;1.48] 820 1,417
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

StudyTE95% CIn casesn exposedweightROBABCDEF Drechsel, 2020Drechsel, 2020 0.92[0.24; 3.59]16217%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Fu - Etanercept, 2019Fu - Etanercept, 2019 0.30[0.14; 0.67]369513%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Carman - Etanercept (Controls unexposed, sick), 2017Carman - Etanercept, 2017 1 1.22[0.92; 1.62]56733722%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Chambers - Adalimumab (Controls unexposed, sick, ADA only), 2017Chambers - Adalimumab, 2017 2 2.22[0.67; 7.29]--8%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Chambers - Etanercept, 2015Chambers - Etanercept, 2015 0.47[0.20; 1.12]-37012%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Weber-Schoendorfer, 2015Weber-Schoendorfer, 2015 1.06[0.70; 1.70]15946119%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Diav-Citrin (Controls unexposed, disease free), 2014Diav-Citrin, 2014 3 1.96[0.64; 5.96]19839%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Verstappen, 2011Verstappen, 2011 1.67[0.67; 4.16]235011%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Total (8 studies) I2 = 60% 0.99[0.66; 1.48]8201,4170.25.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, sick; 2: Controls unexposed, sick, ADA only; 3: Controls unexposed, disease free;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.16[0.89; 1.52]7841,32217%NADrechsel, 2020 Carman - Etanercept (Controls unexposed, sick), 2017 Chambers - Adalimumab (Controls unexposed, sick, ADA only), 2017 Chambers - Etanercept, 2015 Weber-Schoendorfer, 2015 Diav-Citrin (Controls unexposed, disease free), 2014 Verstappen, 2011 7 case control studiescase control studies 0 RCTRCT 0.30[0.14; 0.67]3695 -NAFu - Etanercept, 2019 1 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.15[0.76; 1.75]1785441%NAWeber-Schoendorfer, 2015 Diav-Citrin (Controls unexposed, disease free), 2014 2 unexposed, sickunexposed, sick 0.89[0.49; 1.60]64287369%NADrechsel, 2020 Fu - Etanercept, 2019 Carman - Etanercept (Controls unexposed, sick), 2017 Chambers - Adalimumab (Controls unexposed, sick, ADA only), 2017 Chambers - Etanercept, 2015 Verstappen, 2011 6 Tags Adjustment   - No  - No 1.24[0.95; 1.62]6064080%NADrechsel, 2020 Carman - Etanercept (Controls unexposed, sick), 2017 Verstappen, 2011 3   - Randomisation  - Randomisation 0.30[0.14; 0.67]3695 -NAFu - Etanercept, 2019 1   - Yes  - Yes 1.10[0.60; 2.00]17891451%NAChambers - Adalimumab (Controls unexposed, sick, ADA only), 2017 Chambers - Etanercept, 2015 Weber-Schoendorfer, 2015 Diav-Citrin (Controls unexposed, disease free), 2014 4 All studiesAll studies 0.99[0.66; 1.48]8201,41760%NADrechsel, 2020 Fu - Etanercept, 2019 Carman - Etanercept (Controls unexposed, sick), 2017 Chambers - Adalimumab (Controls unexposed, sick, ADA only), 2017 Chambers - Etanercept, 2015 Weber-Schoendorfer, 2015 Diav-Citrin (Controls unexposed, disease free), 2014 Verstappen, 2011 80.15.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-1.61.60.8310.000Drechsel, 2020Fu - Etanercept, 2019Carman - Etanercept (Controls unexposed, sick), 2017Chambers - Adalimumab (Controls unexposed, sick, ADA only), 2017Chambers - Etanercept, 2015Weber-Schoendorfer, 2015Diav-Citrin (Controls unexposed, disease free), 2014Verstappen, 2011

Asymetry test p-value = 0.6808 (by Egger's regression)

slope=0.1907 (0.3368); intercept=-0.4925 (1.1397); t=0.4321; p=0.6808

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 2897, 4098

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.09[0.86; 1.38]5768810%NACarman - Etanercept (Controls unexposed, disease free), 2017 Weber-Schoendorfer, 2015 Diav-Citrin (Controls unexposed, disease free), 2014 3 unexposed, sick controlsunexposed, sick controls 0.89[0.49; 1.60]64287369%NADrechsel, 2020 Fu - Etanercept, 2019 Carman - Etanercept (Controls unexposed, sick), 2017 Chambers - Adalimumab (Controls unexposed, sick, ADA only), 2017 Chambers - Etanercept, 2015 Verstappen, 2011 6 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.97[0.63; 6.15]1483 -NADiav-Citrin (Controls exposed to other treatments), 2014 10.510.01.0