Hydroxychloroquine (All indications except Antiphospholipid Syndrom)

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.
S13648
R52934		 Chambers (Controls unexposed, disease free), 2022 Major birth defects in all pregnancies excluding lost to follow-up at least 1st trimester prospective cohort unexposed, disease free excluded Adjustment: Yes Indication HCQ: Rheumatic diseases as a whole (Systemic lupus erythematosus, Rheumatoid arthritis, Sjogren's syndrome...) Matched 0.78 [0.31;1.99]
excluded (control group) 		21/241   14/248 35 241
ref
S13649
R52950		 Chambers (Controls unexposed, sick), 2022 Major birth defects in all pregnancies excluding lost to follow-up at least 1st trimester prospective cohort unexposed, sick Adjustment: Yes Indication HCQ: Rheumatic diseases as a whole (Systemic lupus erythematosus, Rheumatoid arthritis, Sjogren's syndrome...) Matched 1.36 [0.70;2.64] 21/241   19/265 40 241
ref
S13666
R53374		 Reynolds, 2022 Congenital abnormality (using the EUROCAT definition) throughout pregnancy retrospective cohort unexposed, sick Adjustment: No Indication HCQ: Systemic lupus erythematosus (SLE) 1.83 [0.33;10.18] C 4/149   2/135 6 149
ref
S13676
R53141		 Andersson (Controls exposed to corticosteroides), 2021 Major birth defects 1st trimester population based cohort retrospective exposed to other treatment, sick excluded Adjustment: No Indication HCQ: Any or not specified Matched 1.00 [0.41;2.45]
excluded (control group) 		10/214   10/214 20 214
ref
S13677
R53145		 Andersson (Controls unexposed, NOS), 2021 Major birth defects 1st trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: No Indication HCQ: Any or not specified Matched 0.91 [0.38;2.18] -/228   -/- - 228
ref
S13645
R52902		 Bérard, 2021 Major congenital malformations 1st trimester nested case control unexposed (general population or NOS) Adjustment: Yes Indication HCQ: Any or not specified 1.15 [0.65;2.04] 16/103   23,975/230,972 23,991 103
ref
S13680
R53164		 Howley - BDS study, 2021 Major birth defects early pregnancy case control unexposed (general population or NOS) Adjustment: No Indication HCQ: Rheumatic diseases as a whole (Systemic lupus erythematosus, Rheumatoid arthritis, Sjogren's syndrome...) 0.62 [0.23;1.62] C 10/17   29,828/42,689 29,838 17
ref
S13681
R53172		 Howley - NBDPS study, 2021 Major birth defects early pregnancy case control unexposed (general population or NOS) Adjustment: No Indication HCQ: Rheumatic diseases as a whole (Systemic lupus erythematosus, Rheumatoid arthritis, Sjogren's syndrome...) 1.29 [0.43;3.93] C 14/18   31,454/43,064 31,468 18
ref
S13682
R53174		 Huybrechts (Controls unexposed, NOS), 2021 Major malformations 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) excluded Adjustment: No Indication HCQ: Any or not specified 1.51 [1.27;1.81]
excluded (control group) 		112/2,045   112,908/3,198,589 113,020 2,045
ref
S13683
R53184		 Huybrechts (Controls unexposed, sick), 2021 Major malformations 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes Indication HCQ: Rheumatic diseases as a whole (Systemic lupus erythematosus, Rheumatoid arthritis, Sjogren's syndrome...) 1.26 [1.04;1.54] 112/2,045   937/21,679 1,049 2,045
ref
S13657
R53046		 Howren, 2020 Congenital anomalies 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes Indication HCQ: Rheumatic diseases as a whole (Systemic lupus erythematosus, Rheumatoid arthritis, Sjogren's syndrome...) 2.74 [0.92;8.13] -/-   -/- - -
ref
S13687
R53206		 Leroux, 2015 Congenital malformation throughout pregnancy retrospective cohort unexposed, sick Adjustment: No Indication HCQ: Systemic lupus erythematosus (SLE) 0.21 [0.01;4.10] C 0/38   4/77 4 38
ref
S13651
R52988		 Cooper (controls exposed to TNF-I), 2014 Major congenital malformations 1st trimester retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No Indication HCQ: Rheumatic diseases as a whole (Systemic lupus erythematosus, Rheumatoid arthritis, Sjogren's syndrome...) 1.94 [0.42;8.86] C
excluded (control group) 		13/194   2/56 15 194
ref
S13652
R53018		 Cooper (controls unexposed, sick), 2014 Major congenital malformations 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes Indication HCQ: Rheumatic diseases as a whole (Systemic lupus erythematosus, Rheumatoid arthritis, Sjogren's syndrome...) 3.11 [0.99;9.77] 13/194   4/171 17 194
ref
S13709
R53383		 Langen, 2014 Fetal anomalies at least 1st trimester retrospective cohort exposed to other treatment, sick Adjustment: No Indication HCQ: Rheumatoid arthritis (RA) 3.78 [0.14;101.83] C 1/13   0/15 1 13
ref
S13679
R53155		 Diav-Citrin, 2013 Major anomalies at least 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No Indication HCQ: Rheumatic diseases as a whole (Systemic lupus erythematosus, Rheumatoid arthritis, Sjogren's syndrome...) 2.20 [0.87;5.56] C 7/97   15/440 22 97
ref
S13734
R53478		 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 Indication HCQ: Any or not specified 2.12 [0.74;6.09] C
excluded (control group) 		4/58   46/1,360 50 58
ref
S13684
R53186		 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 Indication HCQ: Any or not specified 2.22 [0.80;6.14] C
excluded (exposition period) 		4/58   5,000/154,976 5,004 58
ref
S13678
R53147		 Colvin, 2010 Birth defects (> 90% majors) 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No Indication HCQ: Any or not specified 2.60 [0.80;8.80] 3/26   4,992/106,048 4,995 26
ref
S13672
R53122		 Vroom (controls exposed to sulfasalazine), 2009 Any malformations (n=12 : heart, skull, eye, foot and genitourinary defects, central nervous system and hernias) 1st trimester retrospective cohort (claims database) exposed to other treatment, sick Adjustment: No Indication HCQ: Any or not specified 0.78 [0.24;2.47] 4/26   25/132 29 26
ref
S13650
R53373		 Clowse, 2006 Major malformations at least 1st trimester prospective cohort unexposed, sick Adjustment: No Indication HCQ: Systemic lupus erythematosus (SLE) 0.51 [0.06;4.64] C 1/79   4/163 5 79
ref
S13656
R53044		 Frassi, 2004 Malformations during pregnancy (anytime or not specified) excluded prospective cohort unexposed, sick Adjustment: No Indication HCQ: Connective tissue diseases (CTD) 0.71 [0.12;4.41] C
excluded (exposition period) 		2/71   3/77 5 71
ref
S13653
R53028		 Costedoat-Chalumeau, 2003 Malformations throughout pregnancy prospective cohort unexposed, sick Adjustment: No Indication HCQ: Any or not specified 0.38 [0.08;1.73] C 3/117   4/61 7 117
ref
S13701
R53348		 Buchanan, 1996 Malformations during pregnancy (anytime or not specified) excluded retrospective cohort unexposed, sick Adjustment: No Indication HCQ: Systemic lupus erythematosus (SLE) 1.43 [0.09;23.83] C
excluded (exposition period) 		1/31   1/44 2 31
ref
Total 16 studies 1.27 [1.05;1.53] 91,472 3,391
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 Chambers (Controls unexposed, sick), 2022Chambers, 2022 1 1.36[0.70; 2.64]402418%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Reynolds, 2022Reynolds, 2022 1.83[0.33; 10.18]61491%ROB confusion: criticalROB selection: unclearROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Andersson (Controls unexposed, NOS), 2021Andersson, 2021 2 0.91[0.38; 2.18]-2284%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Bérard, 2021Bérard, 2021 1.15[0.65; 2.04]23,99110310%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Howley - BDS study, 2021Howley - BDS study, 2021 0.62[0.23; 1.62]29,838174%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: moderate Howley - NBDPS study, 2021Howley - NBDPS study, 2021 1.29[0.43; 3.93]31,468183%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Huybrechts (Controls unexposed, sick), 2021Huybrechts, 2021 3 1.26[1.04; 1.54]1,0492,04553%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: unclearROB reporting: moderate Howren, 2020Howren, 2020 2.74[0.92; 8.13]--3%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Leroux, 2015Leroux, 2015 0.21[0.01; 4.10]4380%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Cooper (controls unexposed, sick), 2014Cooper, 2014 4 3.11[0.99; 9.77]171943%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Langen, 2014Langen, 2014 3.78[0.14; 101.83]1130%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: moderate Diav-Citrin, 2013Diav-Citrin, 2013 2.20[0.87; 5.56]22974%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Colvin, 2010Colvin, 2010 2.60[0.80; 8.80]4,995262%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Vroom (controls exposed to sulfasalazine), 2009Vroom, 2009 5 0.78[0.24; 2.47]29263%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: unclearROB reporting: moderate Clowse, 2006Clowse, 2006 0.51[0.06; 4.64]5791%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: moderate Costedoat-Chalumeau, 2003Costedoat-Chalumeau, 2003 0.38[0.08; 1.73]71171%ROB confusion: criticalROB selection: unclearROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Total (16 studies) I2 = 4% 1.27[1.05; 1.53]91,4723,3910.210.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, sick; 2: Controls unexposed, NOS; 3: Controls unexposed, sick; 4: controls unexposed, sick; 5: controls exposed to sulfasalazine;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.35[1.05; 1.73]6,1753,25310%NAChambers (Controls unexposed, sick), 2022 Reynolds, 2022 Andersson (Controls unexposed, NOS), 2021 Huybrechts (Controls unexposed, sick), 2021 Howren, 2020 Leroux, 2015 Cooper (controls unexposed, sick), 2014 Langen, 2014 Diav-Citrin, 2013 Colvin, 2010 Vroom (controls exposed to sulfasalazine), 2009 Clowse, 2006 Costedoat-Chalumeau, 2003 13 case control studiescase control studies 1.02[0.65; 1.61]85,2971380%NABérard, 2021 Howley - BDS study, 2021 Howley - NBDPS study, 2021 3 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.22[0.84; 1.78]90,3144899%NAAndersson (Controls unexposed, NOS), 2021 Bérard, 2021 Howley - BDS study, 2021 Howley - NBDPS study, 2021 Diav-Citrin, 2013 Colvin, 2010 6 unexposed, sickunexposed, sick 1.35[0.94; 1.93]1,1282,86322%NAChambers (Controls unexposed, sick), 2022 Reynolds, 2022 Huybrechts (Controls unexposed, sick), 2021 Howren, 2020 Leroux, 2015 Cooper (controls unexposed, sick), 2014 Clowse, 2006 Costedoat-Chalumeau, 2003 8 exposed to other treatment, sickexposed to other treatment, sick 0.93[0.31; 2.79]30390%NALangen, 2014 Vroom (controls exposed to sulfasalazine), 2009 2 Tags Adjustment   - No  - No 1.08[0.73; 1.60]66,3758085%NAReynolds, 2022 Andersson (Controls unexposed, NOS), 2021 Howley - BDS study, 2021 Howley - NBDPS study, 2021 Leroux, 2015 Langen, 2014 Diav-Citrin, 2013 Colvin, 2010 Vroom (controls exposed to sulfasalazine), 2009 Clowse, 2006 Costedoat-Chalumeau, 2003 11   - Yes  - Yes 1.33[1.08; 1.65]25,0972,5837%NAChambers (Controls unexposed, sick), 2022 Bérard, 2021 Huybrechts (Controls unexposed, sick), 2021 Howren, 2020 Cooper (controls unexposed, sick), 2014 5 Indication HCQ   - Any or not specified  - Any or not specified 1.05[0.68; 1.62]29,0225009%NAAndersson (Controls unexposed, NOS), 2021 Bérard, 2021 Colvin, 2010 Vroom (controls exposed to sulfasalazine), 2009 Costedoat-Chalumeau, 2003 5   - Rheumatic diseases as a whole (Syst ...  - Rheumatic diseases as a whole (Systemic lupus erythematosus, Rheumatoid arthritis, Sjogren's syndrome...) 1.41[1.05; 1.89]62,4342,61222%NAChambers (Controls unexposed, sick), 2022 Howley - BDS study, 2021 Howley - NBDPS study, 2021 Huybrechts (Controls unexposed, sick), 2021 Howren, 2020 Cooper (controls unexposed, sick), 2014 Diav-Citrin, 2013 7   - Rheumatoid arthritis (RA)  - Rheumatoid arthritis (RA) 3.78[0.14; 101.83]113 -NALangen, 2014 1   - Systemic lupus erythematosus (SLE)  - Systemic lupus erythematosus (SLE) 0.85[0.25; 2.90]152660%NAReynolds, 2022 Leroux, 2015 Clowse, 2006 3 MatchedMatched 1.17[0.69; 1.99]404690%NAChambers (Controls unexposed, sick), 2022 Andersson (Controls unexposed, NOS), 2021 2 All studiesAll studies 1.27[1.05; 1.53]91,4723,3914%NAChambers (Controls unexposed, sick), 2022 Reynolds, 2022 Andersson (Controls unexposed, NOS), 2021 Bérard, 2021 Howley - BDS study, 2021 Howley - NBDPS study, 2021 Huybrechts (Controls unexposed, sick), 2021 Howren, 2020 Leroux, 2015 Cooper (controls unexposed, sick), 2014 Langen, 2014 Diav-Citrin, 2013 Colvin, 2010 Vroom (controls exposed to sulfasalazine), 2009 Clowse, 2006 Costedoat-Chalumeau, 2003 160.110.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.04.22.0160.000Chambers (Controls unexposed, sick), 2022Reynolds, 2022Andersson (Controls unexposed, NOS), 2021Bérard, 2021Howley - BDS study, 2021Howley - NBDPS study, 2021Huybrechts (Controls unexposed, sick), 2021Howren, 2020Leroux, 2015Cooper (controls unexposed, sick), 2014Langen, 2014Diav-Citrin, 2013Colvin, 2010Vroom (controls exposed to sulfasalazine), 2009Clowse, 2006Costedoat-Chalumeau, 2003

Asymetry test p-value = 0.9087 (by Egger's regression)

slope=0.2464 (0.1241); intercept=-0.0448 (0.3839); t=0.1168; p=0.9087

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 13734, 13651, 13676, 13682, 13648

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.33[1.04; 1.69]203,3692,77516%NAChambers (Controls unexposed, disease free), 2022 Andersson (Controls unexposed, NOS), 2021 Bérard, 2021 Howley - BDS study, 2021 Howley - NBDPS study, 2021 Huybrechts (Controls unexposed, NOS), 2021 Diav-Citrin, 2013 Colvin, 2010 8 unexposed, sick controlsunexposed, sick controls 1.35[0.94; 1.93]1,1282,86322%NAChambers (Controls unexposed, sick), 2022 Reynolds, 2022 Huybrechts (Controls unexposed, sick), 2021 Howren, 2020 Leroux, 2015 Cooper (controls unexposed, sick), 2014 Clowse, 2006 Costedoat-Chalumeau, 2003 8 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.09[0.58; 2.06]654470%NAAndersson (Controls exposed to corticosteroides), 2021 Cooper (controls exposed to TNF-I), 2014 Langen, 2014 Vroom (controls exposed to sulfasalazine), 2009 40.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Sperber (Autoimmune diseases) (Congenital defects)Sperber (Autoimmune diseases) (Congenital defects) 0.66[0.25; 1.75]0%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT4 Duan (SLE indication) (Congenital malformations)Duan (SLE indication) (Congenital malformations) 0.53[0.14; 2.04]0%-U,Sunexposed, sickAllthroughout pregnancystudies TTT4 metaPregmetaPreg 1.27[1.05; 1.53]4%3,391----Chambers (Controls unexposed, sick), 2022 Reynolds, 2022 Andersson (Controls unexposed, NOS), 2021 Bérard, 2021 Howley - BDS study, 2021 Howley - NBDPS study, 2021 Huybrechts (Controls unexposed, sick), 2021 Howren, 2020 Leroux, 2015 Cooper (controls unexposed, sick), 2014 Langen, 2014 Diav-Citrin, 2013 Colvin, 2010 Vroom (controls exposed to sulfasalazine), 2009 Clowse, 2006 Costedoat-Chalumeau, 2003 160.510.01.0