Thiouracil, propylthiouracil, benzylthiouracil

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

id	Study   Auto Yoshihara (Controls exposed to MMI), 2021Yoshihara (Controls unexposed, sick), 2021Andersen 2019 (control exposed to MMI/CMZ), 2019Andersen 2019 (control unexposed, disease free), 2019Seo (control exposed to MMI), 2018Seo (control unexposed, NOS), 2018Andersen 2017 (control exposed to MMI/CMZ), 2017Andersen 2017 (control unexposed, disease free), 2017Andersen 2017 (control unexposed, sick), 2017Hawken (control exposed to MMI), 2016Gianetti (control exposed to MMI), 2015Gianetti (control unexposed, sick), 2015Lo (control exposed to MMI), 2015Lo (control unexposed, sick), 2015Korelitz (control exposed to MMI), 2013Korelitz (control exposed to MMI), 2013Korelitz (control unexposed, disease free), 2013Korelitz (control unexposed, sick), 2013Yoshihara (control exposed to MMI), 2012Yoshihara (control unexposed, sick), 2012Banhidy, 2011Chen (Control exposed to MMI), 2011Chen (control unexposed, disease free), 2011Chen (control unexposed, sick), 2011Rosenfeld, 2009Wing (control exposed to MMI), 1994Wing (control unexposed, sick), 1994	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 trimester	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.
S8484 R27829	Yoshihara (Controls exposed to MMI), 2021	Birth defects	1st trimester	retrospective cohort	exposed to other treatment, sick excluded	Adjustment: No	2.69 [0.16;45.39] C excluded (control group)	30/541   0/23	30	541		ref
S8481 R27763	Yoshihara (Controls unexposed, sick), 2021	Birth defects	1st trimester	retrospective cohort	unexposed, sick	Adjustment: No	0.97 [0.57;1.66] C	30/541   27/475	57	541		ref
S3448 R6451	Andersen 2019 (control exposed to MMI/CMZ), 2019	All birth defects (ICD-10: Q00-99)	early pregnancy	population based cohort retrospective	exposed to other treatment, sick excluded	Adjustment: No	0.86 [0.64;1.14] C excluded (control group)	74/889   151/1,574	225	889		ref
S3449 R6466	Andersen 2019 (control unexposed, disease free), 2019	All birth defects (ICD-10: Q00-99)	early pregnancy	population based cohort retrospective	unexposed, disease free	Adjustment: Yes	1.17 [0.91;1.49]	74/889   77,791/1,159,181	77,865	889		ref
S3366 R6151	Seo (control exposed to MMI), 2018	Overall congenital malformations (Q00 to Q99)	1st trimester	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: No	0.86 [0.68;1.08] C excluded (control group)	699/9,930   91/1,120	790	9,930		ref
S3367 R6163	Seo (control unexposed, NOS), 2018	Overall congenital malformations (Q00 to Q99)	1st trimester	retrospective cohort (claims database)	unexposed (general population or NOS)	Adjustment: Yes	1.16 [1.07;1.25]	699/9,930   170,716/2,872,109	171,415	9,930		ref
S3340 R5751	Andersen 2017 (control exposed to MMI/CMZ), 2017	Birth defects (ICD­10: Q00-­Q99)	early pregnancy	population based cohort retrospective	exposed to other treatment, sick excluded	Adjustment: No	0.94 [0.42;2.13] C excluded (control group)	14/218   11/162	25	218		ref
S3339 R5734	Andersen 2017 (control unexposed, disease free), 2017	Birth defects (ICD­10: Q00-Q99)	early pregnancy	population based cohort retrospective	unexposed, disease free excluded	Adjustment: Yes	0.89 [0.52;1.54] excluded (control group)	14/218   54,827/682,343	54,841	218		ref
S3338 R5717	Andersen 2017 (control unexposed, sick), 2017	Birth defects (ICD­10: Q00-Q99)	early pregnancy	population based cohort retrospective	unexposed, sick	Adjustment: No	0.71 [0.40;1.26] C	14/218   136/1,551	150	218		ref
S3422 R6370	Hawken (control exposed to MMI), 2016	Malformations	1st trimester	retrospective cohort	exposed to other treatment, sick	Adjustment: No	0.11 [0.01;2.29] C	0/13   4/17	4	13		ref
S3564 R11278	Gianetti (control exposed to MMI), 2015	Major malformations	at least 1st trimester	retrospective cohort	exposed to other treatment, sick excluded	Adjustment: No	12.47 [0.59;264.54] C excluded (control group)	2/52   0/124	2	52		ref
S3565 R11279	Gianetti (control unexposed, sick), 2015	Major malformations	throughout pregnancy	retrospective cohort	unexposed, sick	Adjustment: No	1.99 [0.35;11.17] C	2/52   4/203	6	52		ref
S3377 R6251	Lo (control exposed to MMI), 2015	Congenital anomalies (ICD-9)	during pregnancy (anytime or not specified)	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: No	0.88 [0.11;6.93] C excluded (control group)	15/507   1/30	16	507		ref
S3371 R6193	Lo (control unexposed, sick), 2015	Congenital anomalies (ICD-9)	during pregnancy (anytime or not specified) excluded	retrospective cohort (claims database)	unexposed, sick	Adjustment: No	0.66 [0.37;1.18] C excluded (exposition period)	15/507   52/1,171	67	507		ref
S8718 R29465	Korelitz (control exposed to MMI), 2013	Any congenital defect	3 months (or more) before pregnancy or during pregnancy	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: No	1.32 [0.56;3.12] C excluded (control group)	66/915   6/108	72	915		ref
S3387 R6314	Korelitz (control exposed to MMI), 2013	Any congenital defect	3 months (or more) before pregnancy or during pregnancy	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: No	1.32 [0.56;3.12] C excluded (control group)	66/915   6/108	72	915		ref
S3388 R6322	Korelitz (control unexposed, disease free), 2013	Any congenital defect	3 months (or more) before pregnancy or during pregnancy	retrospective cohort (claims database)	unexposed, disease free excluded	Adjustment: Yes	1.22 [0.95;1.57] excluded (control group)	66/915   37,351/634,858	37,417	915		ref
S3389 R6330	Korelitz (control unexposed, sick), 2013	Any congenital defect	3 months (or more) before pregnancy or during pregnancy excluded	retrospective cohort (claims database)	unexposed, sick	Adjustment: No	1.15 [0.86;1.53] C excluded (exposition period)	66/915   205/3,236	271	915		ref
S3355 R11283	Yoshihara (control exposed to MMI), 2012	Major malformations	1st trimester	retrospective cohort	exposed to other treatment, sick excluded	Adjustment: No	0.45 [0.28;0.72] C excluded (control group)	26/1,399   50/1,231	76	1,399		ref
S3354 R11284	Yoshihara (control unexposed, sick), 2012	Major malformations	1st trimester	retrospective cohort	unexposed, sick	Adjustment: Yes	0.66 [0.41;1.03]	26/1,399   40/1,906	66	1,399		ref
S3415 R35108	Banhidy, 2011	Congenital abnormalities	throughout pregnancy	case control	unexposed, sick	Adjustment: No	1.64 [0.10;26.69] C	1/2   70/185	71	2		ref
S3346 R11274	Chen (Control exposed to MMI), 2011	Major congenital anomalies	during pregnancy (anytime or not specified)	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: No	1.28 [0.07;23.33] C excluded (control group)	5/630   0/73	5	630		ref
S3347 R11275	Chen (control unexposed, disease free), 2011	Major congenital anomalies	during pregnancy (anytime or not specified)	retrospective cohort (claims database)	unexposed, disease free excluded	Adjustment: No	1.22 [0.50;3.02] C excluded (control group)	5/630   92/14,150	97	630		ref
S3348 R11276	Chen (control unexposed, sick), 2011	Major congenital anomalies	during pregnancy (anytime or not specified) excluded	population based cohort retrospective	unexposed, sick	Adjustment: Yes	1.10 [0.40;3.06] excluded (exposition period)	5/630   15/2,127	20	630		ref
S3374 R11280	Rosenfeld, 2009	Major birth defects	1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No	0.38 [0.05;2.84] C	1/80   34/1,066	35	80		ref
S3393 R11281	Wing (control exposed to MMI), 1994	Major congenital anomalies, first trimester exposure	1st trimester	cohort	exposed to other treatment, sick excluded	Adjustment: No	0.12 [0.00;2.93] C excluded (control group)	0/99   1/36	1	99		ref
S3394 R11282	Wing (control unexposed, sick), 1994	Congenital anomalies, first trimester exposure	1st trimester	cohort	unexposed, sick	Adjustment: No	0.14 [0.01;3.52] C	0/99   1/43	1	99		ref
					Total	10 studies	0.99 [0.81;1.21]		249,670	13,223
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 3393, 3346, 3347, 3355, 3387, 8718, 3388, 3564, 3377, 3340, 3339, 3366, 3448, 8484