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

Major congenital malformations

id	Study   Auto Meyer, 2025Reynolds, 2022Kanis, 2021Alami, 2017Ban (Controls unexposed, disease free), 2014Ban (Controls unexposed, sick), 2014Casanova, 2013Viktil (Controls exposed to other treatments), 2012Viktil (Controls unexposed, NOS), 2012Colvin, 2010Cleary (Controls unexposed, NOS), 2009Goldstein, 2007Francella, 2003	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 trimesterPaternal exp. genotoxic window only (0–3 months preconception)Paternal exposure: epigenetic window only (3–xxx months preconception)Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception)Paternal exposure: other window	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 specifiedsiblingwhatever (meta-analysis)	Tags	OR 95%CI	x1/n1 x0/n0	no cases	no exposed	ROB	Ref.
S17723 R74777	Meyer, 2025	All major congenital malformations (75 individual major congenital malformations)	1st trimester	population based cohort retrospective	unexposed, sick	Adjustment: Yes Indications: Inflammatory Bowel disease (IBD)	1.15 [0.93;1.43]	103/5,223   505/28,827	608	5,223		ref
S13740 R53542	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 R46197	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
S6698 R44367	Alami, 2017	All major congenital malformations	at least 1st trimester	prospective cohort	unexposed, sick	Adjustment: No Indications: Any or not specified	2.96 [0.56;15.64]	5/96   2/110	7	96		ref
S13582 R52650	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 R44248	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 R52301	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 R45930	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 R52644	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 R44827	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 R16691	Cleary (Controls unexposed, NOS), 2009	Relatively severe malformations	early pregnancy	population based cohort retrospective	unexposed (general population or NOS)	Adjustment: Yes Indications: Any or not specified	1.50 [0.97;2.30]	21/481   38,228/1,181,450	38,249	481		ref
S8427 R27092	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
S11066 R44831	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	1.25 [1.05;1.49]		43,946	6,491
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 6692, 13582