Thiopurines (Azathioprine, Mercaptopurin) updated on 07-28-2025

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.
S18482
R78423		 Vestergaard, 2024 Congenital Malformations during pregnancy (anytime or not specified) excluded retrospective cohort unexposed, sick Adjustment: No Indications: Inflammatory Bowel disease (IBD) 0.70 [0.32;1.56] C
excluded (exposition period) 		8/111   37/372 45 111
ref
S13740
R53550		 Reynolds, 2022 Congenital abnormality (using the EUROCAT definition) throughout pregnancy retrospective cohort unexposed, sick Adjustment: No Indications: Systemic lupus erythematosus (SLE) 1.14 [0.20;6.32] C 2/87   4/197 6 87
ref
S12244
R46719		 Kanis, 2021 Major congenital abnormalities at least 1st trimester retrospective cohort unexposed, sick Adjustment: No Indications: Inflammatory Bowel disease (IBD) 1.34 [0.58;3.11] 8/240   10/564 18 240
ref
S12218
R45546		 Mahadevan, 2021 Congenital malformations 3 months (or more) before pregnancy or during pregnancy excluded prospective cohort unexposed, sick Adjustment: Yes Indications: Inflammatory Bowel disease (IBD) 1.40 [0.80;2.70]
excluded (exposition period) 		-/242   -/379 - 242
ref
S6698
R52669		 Alami, 2017 All birth defects (major and minor, exclusion of chromosomal abnormalities) at least 1st trimester prospective cohort unexposed, sick Adjustment: No Indications: Any or not specified 1.36 [0.44;4.20] 7/96   6/110 13 96
ref
S13582
R52654		 Ban (Controls unexposed, disease free), 2014 Major congenital anomalies (any) 1st trimester retrospective cohort (claims database) unexposed, disease free excluded Adjustment: No Indications: Inflammatory Bowel disease (IBD) 1.22 [0.50;2.98] C
excluded (control group) 		5/149   10,645/384,811 10,650 149
ref
S11392
R46715		 Ban (Controls unexposed, sick), 2014 Major congenital anomalies (any) 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes Indications: Inflammatory Bowel disease (IBD) 1.27 [0.48;3.39] 5/149   41/1,554 46 149
ref
S10792
R52302		 Casanova, 2013 Congenital malformations 3 months (or more) before pregnancy or during pregnancy excluded retrospective cohort exposed to other treatment, sick Adjustment: No Indications: Inflammatory Bowel disease (IBD) 1.70 [0.11;27.41] C
excluded (exposition period) 		1/187   1/318 2 187
ref
S6692
R46720		 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 Indications: Any or not specified 1.18 [0.42;3.34] C
excluded (control group) 		4/101   46/1,360 50 101
ref
S13579
R52645		 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 Indications: Any or not specified 1.24 [0.45;3.36] C
excluded (exposition period) 		4/101   5,000/154,976 5,004 101
ref
S11905
R44826		 Colvin, 2010 Birth defects (> 90% majors) 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No Indications: Any or not specified 1.50 [0.40;6.30] 2/29   4,993/106,045 4,995 29
ref
S6258
R18033		 Cleary (Controls unexposed, NOS), 2009 All malformations early pregnancy population based cohort retrospective unexposed (general population or NOS) excluded Adjustment: Yes Indications: Any or not specified 1.41 [0.98;2.04]
excluded (control group) 		30/481   55,548/1,181,450 55,578 481
ref
S12174
R45195		 Cleary (Controls unexposed, sick), 2009 All malformations early pregnancy population based cohort retrospective unexposed, sick Adjustment: Yes Indications: Any or not specified 1.34 [0.92;1.95] 30/481   90/1,739 120 481
ref
S8427
R46718		 Goldstein, 2007 Major congenital malformations at least 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No Indications: Any or not specified 1.70 [0.37;3.69] 6/172   6/200 12 172
ref
S6628
R18385		 Langagergaard (Controls unexposed, NOS), 2007 Congenital abnormalities (ICD-10: Q0.00 to Q99.9) 1st trimester population based cohort retrospective unexposed (general population or NOS) excluded Adjustment: Yes Indications: Any or not specified Matched 2.30 [1.00;5.20]
excluded (control group) 		6/64   49/1,243 55 64
ref
S6656
R18390		 Langagergaard (Controls unexposed, sick), 2007 Congenital abnormalities (ICD-10: Q0.00 to Q99.9) 1st trimester population based cohort retrospective unexposed, sick Adjustment: Yes Indications: Any or not specified 1.10 [0.50;2.90] 6/64   15/174 21 64
ref
S13766
R53607		 Dejaco, 2005 Malformations (NOS) during pregnancy (anytime or not specified) excluded prospective cohort unexposed, sick Adjustment: No Indications: Inflammatory Bowel disease (IBD) 0.33 [0.01;8.57] C
excluded (exposition period) 		0/26   1/27 1 26
ref
S11066
R46717		 Francella, 2003 Major congenital abnormalities (fetal defect aborted and major defect) throughout pregnancy retrospective cohort unexposed, sick Adjustment: No Indications: Inflammatory Bowel disease (IBD) 1.73 [0.18;16.71] C 1/14   4/94 5 14
ref
Total 9 studies 1.33 [1.02;1.75] 5,236 1,332
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 Reynolds, 2022Reynolds, 2022 1.14[0.20; 6.32]6873%ROB confusion: criticalROB selection: unclearROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Kanis, 2021Kanis, 2021 1.34[0.58; 3.11]1824011%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Alami, 2017Alami, 2017 1.36[0.44; 4.20]13966%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: lowROB mesure: unclearROB reporting: moderate Ban (Controls unexposed, sick), 2014Ban, 2014 1 1.27[0.48; 3.39]461498%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: unclearROB reporting: moderate Colvin, 2010Colvin, 2010 1.50[0.40; 6.30]4,995294%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: lowROB mesure: unclearROB reporting: moderate Cleary (Controls unexposed, sick), 2009Cleary, 2009 2 1.34[0.92; 1.95]12048153%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Goldstein, 2007Goldstein, 2007 1.70[0.37; 3.69]121726%ROB confusion: criticalROB selection: criticalROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Langagergaard (Controls unexposed, sick), 2007Langagergaard, 2007 3 1.10[0.50; 2.90]216410%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Francella, 2003Francella, 2003 1.73[0.18; 16.71]5141%ROB confusion: criticalROB selection: unclearROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Total (9 studies) I2 = 0% 1.33[1.02; 1.75]5,2361,3320.55.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, sick; 2: Controls unexposed, sick; 3: Controls unexposed, sick;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.33[1.02; 1.75]5,2361,3320%NAReynolds, 2022 Kanis, 2021 Alami, 2017 Ban (Controls unexposed, sick), 2014 Colvin, 2010 Cleary (Controls unexposed, sick), 2009 Goldstein, 2007 Langagergaard (Controls unexposed, sick), 2007 Francella, 2003 9 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.61[0.67; 3.91]5,0072010%NAColvin, 2010 Goldstein, 2007 2 unexposed, sickunexposed, sick 1.31[0.98; 1.74]2291,1310%NAReynolds, 2022 Kanis, 2021 Alami, 2017 Ban (Controls unexposed, sick), 2014 Cleary (Controls unexposed, sick), 2009 Langagergaard (Controls unexposed, sick), 2007 Francella, 2003 7 Tags Adjustment   - No  - No 1.42[0.86; 2.34]5,0496380%NAReynolds, 2022 Kanis, 2021 Alami, 2017 Colvin, 2010 Goldstein, 2007 Francella, 2003 6   - Yes  - Yes 1.30[0.94; 1.80]1876940%NABan (Controls unexposed, sick), 2014 Cleary (Controls unexposed, sick), 2009 Langagergaard (Controls unexposed, sick), 2007 3 Indications   - Any or not specified  - Any or not specified 1.34[0.98; 1.82]5,1618420%NAAlami, 2017 Colvin, 2010 Cleary (Controls unexposed, sick), 2009 Goldstein, 2007 Langagergaard (Controls unexposed, sick), 2007 5   - Inflammatory Bowel disease (IBD)  - Inflammatory Bowel disease (IBD) 1.34[0.72; 2.47]694030%NAKanis, 2021 Ban (Controls unexposed, sick), 2014 Francella, 2003 3   - Systemic lupus erythematosus (SLE)  - Systemic lupus erythematosus (SLE) 1.14[0.20; 6.32]687 -NAReynolds, 2022 1 All studiesAll studies 1.33[1.02; 1.75]5,2361,3320%NAReynolds, 2022 Kanis, 2021 Alami, 2017 Ban (Controls unexposed, sick), 2014 Colvin, 2010 Cleary (Controls unexposed, sick), 2009 Goldstein, 2007 Langagergaard (Controls unexposed, sick), 2007 Francella, 2003 90.55.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-2.73.01.3880.000Reynolds, 2022Kanis, 2021Alami, 2017Ban (Controls unexposed, sick), 2014Colvin, 2010Cleary (Controls unexposed, sick), 2009Goldstein, 2007Langagergaard (Controls unexposed, sick), 2007Francella, 2003

Asymetry test p-value = 0.6765 (by Egger's regression)

slope=0.2607 (0.0717); intercept=0.0747 (0.1717); t=0.4353; p=0.6765

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 6628, 6258, 6692, 13582

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.50[1.12; 2.02]71,2908950%NABan (Controls unexposed, disease free), 2014 Colvin, 2010 Cleary (Controls unexposed, NOS), 2009 Goldstein, 2007 Langagergaard (Controls unexposed, NOS), 2007 5 unexposed, sick controlsunexposed, sick controls 1.31[0.98; 1.74]2291,1310%NAReynolds, 2022 Kanis, 2021 Alami, 2017 Ban (Controls unexposed, sick), 2014 Cleary (Controls unexposed, sick), 2009 Langagergaard (Controls unexposed, sick), 2007 Francella, 2003 70.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Akbari (Congenital abnormalities)Akbari (Congenital abnormalities) 1.45[0.99; 2.13]0%-Wwhatever (meta-analysis)Before-Any3 months (or more) before pregnancy or during pregnancystudies TTT5 Mozaffari (Congenital abnormality)Mozaffari (Congenital abnormality) 0.99[0.27; 3.61]0%-Eexposed to other treatment, sickAnyduring pregnancy (anytime or not specified)studies TTT3 Mozaffari (Congenital abnormality)Mozaffari (Congenital abnormality) 2.95[1.03; 8.43]NA-U,Sunexposed, sickAnyduring pregnancy (anytime or not specified)studies TTT2 Zhang (Congenital malformations)Zhang (Congenital malformations) 1.25[0.84; 1.87]0%-Eexposed to other treatment, sickAnyduring pregnancy (anytime or not specified)studies TTT7 Hutson (Congenital malformations (vs disease- ...Hutson (Congenital malformations (vs disease-matched controls (with or without on other medications))) 1.37[0.92; 2.05]0%-U,Sunexposed, sickAnyduring pregnancy (anytime or not specified)studies TTT6 Hutson (Congenital malformations (vs disease- ...Hutson (Congenital malformations (vs disease-matched controls not on other medications)) 2.67[1.07; 6.63]0%-U,Sunexposed, sickAnyduring pregnancy (anytime or not specified)studies TTT2 Hutson (Congenital malformations (vs disease- ...Hutson (Congenital malformations (vs disease-matched controls on other medications)) 1.15[0.73; 1.81]0%-Eexposed to other treatment, sickAnyduring pregnancy (anytime or not specified)studies TTT2 Hutson (Congenital malformations (vs healthy ...Hutson (Congenital malformations (vs healthy or general population control)) 1.45[1.07; 1.96]0%-U,GPunexposed (general population or NOS)Anyduring pregnancy (anytime or not specified)studies TTT4 metaPregmetaPreg 1.33[1.02; 1.75]0%1,332----Reynolds, 2022 Kanis, 2021 Alami, 2017 Ban (Controls unexposed, sick), 2014 Colvin, 2010 Cleary (Controls unexposed, sick), 2009 Goldstein, 2007 Langagergaard (Controls unexposed, sick), 2007 Francella, 2003 90.510.01.0