Methotrexate (Post-conception)

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

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.
S7205
R20461		 Howren, 2020 Congenital anomalies 1st trimester retrospective cohort unexposed, sick Adjustment: Yes Exposed group: MTX (polytherapy or not specified) Indications: Inflammatory diseases 6.58 [1.15;37.75] -/-   -/6,064 - -
ref
S10694
R39526		 Cooper (Controls exposed to other treatment, sick), 2014 Major congenital malformations 1st trimester retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No Exposed group: MTX (polytherapy or not specified) Indications: Inflammatory diseases 0.86 [0.11;6.73] C
excluded (control group) 		1/23   19/379 20 23
ref
S8721
R29503		 Cooper (Controls unexposed, sick), 2014 Major congenital malformations 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes Exposed group: MTX (polytherapy or not specified) Indications: Inflammatory diseases 1.96 [0.23;17.00] 1/23   4/171 5 23
ref
S6761
R41693		 Dawson, 2014 Major birth defects 1st trimester case control unexposed (general population or NOS) Adjustment: No Exposed group: MTX (polytherapy or not specified) Indications: Any or not specified 1.83 [0.40;8.36] C 10/12   27,613/37,724 27,623 12
ref
S6775
R41697		 Weber-Schoendorfer (Controls exposed to other treatment, sick), 2014 Major birth defects at least 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: Yes Exposed group: MTX (polytherapy or not specified) Indications: Inflammatory diseases Matched 1.80 [0.60;5.70]
excluded (control group) 		7/106   14/393 21 106
ref
S10347
R41698		 Weber-Schoendorfer (Controls unexposed, disease free), 2014 Major birth defects at least 1st trimester prospective cohort unexposed, disease free Adjustment: Yes Exposed group: MTX (polytherapy or not specified) Indications: Inflammatory diseases Matched 3.10 [1.03;9.50] 7/106   29/1,001 36 106
ref
S8745
R41736		 Viktil (Controls exposed to other treatment, sick), 2012 Major malformations 3 months (or more) before pregnancy or during pregnancy population based cohort retrospective exposed to other treatment, sick excluded Adjustment: No Exposed group: MTX (polytherapy or not specified) Indications: Inflammatory diseases 1.85 [0.10;32.87] C
excluded (control group) 		0/8   50/1,453 50 8
ref
S10362
R41696		 Viktil (Controls unexposed NOS), 2012 Major malformations at least 1st trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: No Exposed group: MTX (polytherapy or not specified) Indications: Inflammatory diseases 10.00 [0.41;245.45] C 0/2   5,000/154,976 5,000 2
ref
Total 5 studies 3.16 [1.52;6.54] 32,664 143
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 Howren, 2020Howren, 2020 6.58[1.15; 37.75]--17%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Cooper (Controls unexposed, sick), 2014Cooper, 2014 1 1.96[0.23; 17.00]52311%ROB confusion: seriousROB selection: criticalROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Dawson, 2014Dawson, 2014 1.83[0.40; 8.36]27,6231223%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Weber-Schoendorfer (Controls unexposed, disease free), 2014Weber-Schoendorfer, 2014 2 3.10[1.03; 9.50]3610643%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: moderate Viktil (Controls unexposed NOS), 2012Viktil, 2012 3 10.00[0.41; 245.45]5,00025%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Total (5 studies) I2 = 0% 3.16[1.52; 6.54]32,6641430.520.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, sick; 2: Controls unexposed, disease free; 3: Controls unexposed NOS;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 3.71[1.62; 8.51]5,0411310%NAHowren, 2020 Cooper (Controls unexposed, sick), 2014 Weber-Schoendorfer (Controls unexposed, disease free), 2014 Viktil (Controls unexposed NOS), 2012 4 case control studiescase control studies 1.83[0.40; 8.36]27,62312 -NADawson, 2014 1 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 2.85[1.20; 6.75]32,6591200%NADawson, 2014 Weber-Schoendorfer (Controls unexposed, disease free), 2014 Viktil (Controls unexposed NOS), 2012 3 unexposed, sickunexposed, sick 4.07[1.05; 15.78]5230%NAHowren, 2020 Cooper (Controls unexposed, sick), 2014 2 Tags Adjustment   - No  - No 2.50[0.63; 9.86]32,623140%NADawson, 2014 Viktil (Controls unexposed NOS), 2012 2   - Yes  - Yes 3.46[1.46; 8.16]411290%NAHowren, 2020 Cooper (Controls unexposed, sick), 2014 Weber-Schoendorfer (Controls unexposed, disease free), 2014 3 Exposed group   - MTX (polytherapy or not specified)  - MTX (polytherapy or not specified) 3.16[1.52; 6.54]32,6641430%NAHowren, 2020 Cooper (Controls unexposed, sick), 2014 Dawson, 2014 Weber-Schoendorfer (Controls unexposed, disease free), 2014 Viktil (Controls unexposed NOS), 2012 5 Indications   - Any or not specified  - Any or not specified 1.83[0.40; 8.36]27,62312 -NADawson, 2014 1   - Inflammatory diseases  - Inflammatory diseases 3.71[1.62; 8.51]5,0411310%NAHowren, 2020 Cooper (Controls unexposed, sick), 2014 Weber-Schoendorfer (Controls unexposed, disease free), 2014 Viktil (Controls unexposed NOS), 2012 4 MatchedMatched 3.10[1.02; 9.41]36106 -NAWeber-Schoendorfer (Controls unexposed, disease free), 2014 1 All studiesAll studies 3.16[1.52; 6.54]32,6641430%NAHowren, 2020 Cooper (Controls unexposed, sick), 2014 Dawson, 2014 Weber-Schoendorfer (Controls unexposed, disease free), 2014 Viktil (Controls unexposed NOS), 2012 50.520.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.85.01.9600.000Howren, 2020Cooper (Controls unexposed, sick), 2014Dawson, 2014Weber-Schoendorfer (Controls unexposed, disease free), 2014Viktil (Controls unexposed NOS), 2012

Asymetry test p-value = 0.5391 (by Egger's regression)

slope=0.5937 (0.8486); intercept=0.7060 (1.0214); t=0.6912; p=0.5391

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 8745, 10694, 6775

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 2.85[1.20; 6.75]32,6591200%NADawson, 2014 Weber-Schoendorfer (Controls unexposed, disease free), 2014 Viktil (Controls unexposed NOS), 2012 3 unexposed, sick controlsunexposed, sick controls 4.07[1.05; 15.78]5230%NAHowren, 2020 Cooper (Controls unexposed, sick), 2014 2 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.52[0.57; 4.08]411290%NACooper (Controls exposed to other treatment, sick), 2014 Weber-Schoendorfer (Controls exposed to other treatment, sick), 2014 20.510.01.0