Methotrexate (Pre-conception only)

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.
S10377
R38128		 Howren, 2020 Congenital anomalies preconceptional for kinetic reason retrospective cohort unexposed, sick Adjustment: Yes Exposed group: MTX (polytherapy or not specified) Indications: Inflammatory diseases MTX less than 3 months before pregnancy 1.12 [0.15;8.59] -/-   -/6,064 - -
ref
S6697
R41699		 Svirsky, 2017 Serious birth malformation preconceptional for kinetic reason retrospective cohort unexposed, sick Adjustment: No Exposed group: MTX (monotherapy) MTX more than 3 months before pregnancy MTX treatment for ectopic pregnancy 1.19 [0.07;19.35] C 1/89   1/106 2 89
ref
S10346
R41702		 Dawson, 2014 Major birth defects preconceptional for kinetic reason case control unexposed (general population or NOS) Adjustment: No Exposed group: MTX (polytherapy or not specified) Indications: Any or not specified MTX less than 3 months before pregnancy 0.92 [0.18;4.72] C 5/7   27,618/37,729 27,623 7
ref
S10348
R41700		 Weber-Schoendorfer (Controls exposed to other treatment, sick), 2014 Major birth defects preconceptional for kinetic reason prospective cohort exposed to other treatment, sick excluded Adjustment: Yes Exposed group: MTX (polytherapy or not specified) Indications: Inflammatory diseases Matched MTX less than 3 months before pregnancy 1.10 [0.30;4.20]
excluded (control group) 		4/114   14/393 18 114
ref
S10349
R41701		 Weber-Schoendorfer (Controls unexposed, disease free), 2014 Major birth defects preconceptional for kinetic reason prospective cohort unexposed, disease free Adjustment: Yes Exposed group: MTX (polytherapy or not specified) Indications: Inflammatory diseases Matched MTX less than 3 months before pregnancy 1.60 [0.40;7.30] 4/114   29/1,001 33 114
ref
S7264
R27104		 Matsui, 2003 Major and minor congenital anomalies preconceptional for kinetic reason retrospective cohort unexposed, sick Adjustment: No Exposed group: MTX (polytherapy or not specified) Indication: Gestational Trophoblastic Tumor (GTT) MTX more than 3 months before pregnancy 10.81 [0.37;315.20] C 0/4   1/115 1 4
ref
Total 5 studies 1.41 [0.59;3.38] 27,659 214
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 1.12[0.15; 8.59]--19%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Svirsky, 2017Svirsky, 2017 1.19[0.07; 19.35]28910%ROB confusion: criticalROB selection: criticalROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Dawson, 2014Dawson, 2014 0.92[0.18; 4.72]27,623728%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Weber-Schoendorfer (Controls unexposed, disease free), 2014Weber-Schoendorfer, 2014 1 1.60[0.40; 7.30]3311436%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: moderate Matsui, 2003Matsui, 2003 10.81[0.37; 315.20]147%ROB confusion: criticalROB selection: criticalROB classification: moderateROB missing: lowROB mesure: unclearROB reporting: moderate Total (5 studies) I2 = 0% 1.41[0.59; 3.38]27,6592140.250.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, disease free;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.68[0.60; 4.71]362070%NAHowren, 2020 Svirsky, 2017 Weber-Schoendorfer (Controls unexposed, disease free), 2014 Matsui, 2003 4 case control studiescase control studies 0.92[0.18; 4.72]27,6237 -NADawson, 2014 1 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.25[0.42; 3.71]27,6561210%NADawson, 2014 Weber-Schoendorfer (Controls unexposed, disease free), 2014 2 unexposed, sickunexposed, sick 1.76[0.40; 7.66]3930%NAHowren, 2020 Svirsky, 2017 Matsui, 2003 3 Tags Adjustment   - No  - No 1.40[0.38; 5.16]27,6261000%NASvirsky, 2017 Dawson, 2014 Matsui, 2003 3   - Yes  - Yes 1.42[0.44; 4.61]331140%NAHowren, 2020 Weber-Schoendorfer (Controls unexposed, disease free), 2014 2 Exposed group   - MTX (monotherapy)  - MTX (monotherapy) 1.19[0.07; 19.35]289 -NASvirsky, 2017 1   - MTX (polytherapy or not specified)  - MTX (polytherapy or not specified) 1.44[0.57; 3.61]27,6571250%NAHowren, 2020 Dawson, 2014 Weber-Schoendorfer (Controls unexposed, disease free), 2014 Matsui, 2003 4 Indication   - Gestational Trophoblastic Tumor (GTT)  - Gestational Trophoblastic Tumor (GTT) 10.81[0.37; 315.20]14 -NAMatsui, 2003 1 Indications   - Any or not specified  - Any or not specified 0.92[0.18; 4.72]27,6237 -NADawson, 2014 1   - Inflammatory diseases  - Inflammatory diseases 1.42[0.44; 4.61]331140%NAHowren, 2020 Weber-Schoendorfer (Controls unexposed, disease free), 2014 2 MatchedMatched 1.60[0.37; 6.84]33114 -NAWeber-Schoendorfer (Controls unexposed, disease free), 2014 1 MTX less than 3 months before pregnancyMTX less than 3 months before pregnancy 1.22[0.47; 3.18]27,6561210%NAHowren, 2020 Dawson, 2014 Weber-Schoendorfer (Controls unexposed, disease free), 2014 3 MTX more than 3 months before pregnancyMTX more than 3 months before pregnancy 2.92[0.34; 24.99]3930%NASvirsky, 2017 Matsui, 2003 2 MTX treatment for ectopic pregnancyMTX treatment for ectopic pregnancy 1.19[0.07; 19.35]289 -NASvirsky, 2017 1 All studiesAll studies 1.41[0.59; 3.38]27,6592140%NAHowren, 2020 Svirsky, 2017 Dawson, 2014 Weber-Schoendorfer (Controls unexposed, disease free), 2014 Matsui, 2003 50.250.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.04.42.0650.000Howren, 2020Svirsky, 2017Dawson, 2014Weber-Schoendorfer (Controls unexposed, disease free), 2014Matsui, 2003

Asymetry test p-value = 0.3060 (by Egger's regression)

slope=-0.7963 (0.9673); intercept=1.1933 (0.9693); t=1.2310; p=0.3060

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 10348

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.25[0.42; 3.71]27,6561210%NADawson, 2014 Weber-Schoendorfer (Controls unexposed, disease free), 2014 2 unexposed, sick controlsunexposed, sick controls 1.76[0.40; 7.66]3930%NAHowren, 2020 Svirsky, 2017 Matsui, 2003 3 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.10[0.29; 4.12]18114 -NAWeber-Schoendorfer (Controls exposed to other treatment, sick), 2014 10.510.01.0