Hydroxychloroquine (All indications except Antiphospholipid Syndrom) updated on 10-07-2022

Major congenital malformations

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
R52920		 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
R52936		 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
R53073		 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
R53138		 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
R53142		 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
R52901		 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
R53158		 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
R53166		 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
R53173		 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
R53175		 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
S13651
R52959		 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
R52989		 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
S13679
R53150		 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
R53477		 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
R53185		 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
R53146		 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
S13650
R52958		 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
S13653
R53024		 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
Total 12 studies 1.26 [1.06;1.50] 91,438 3,314
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]402417%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]23,9911039%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]29,838173%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]1,0492,04563%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: unclearROB reporting: moderate Cooper (controls unexposed, sick), 2014Cooper, 2014 4 3.11[0.99; 9.77]171942%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: unclearROB 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 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 (12 studies) I2 = 2% 1.26[1.06; 1.50]91,4383,3140.210.01.0ROB: 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;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.34[1.04; 1.72]6,1413,17610%NAChambers (Controls unexposed, sick), 2022 Reynolds, 2022 Andersson (Controls unexposed, NOS), 2021 Huybrechts (Controls unexposed, sick), 2021 Cooper (controls unexposed, sick), 2014 Diav-Citrin, 2013 Colvin, 2010 Clowse, 2006 Costedoat-Chalumeau, 2003 9 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 1.29[0.95; 1.74]1,1242,82512%NAChambers (Controls unexposed, sick), 2022 Reynolds, 2022 Huybrechts (Controls unexposed, sick), 2021 Cooper (controls unexposed, sick), 2014 Clowse, 2006 Costedoat-Chalumeau, 2003 6 Tags Adjustment   - No  - No 1.14[0.72; 1.80]66,34173117%NAReynolds, 2022 Andersson (Controls unexposed, NOS), 2021 Howley - BDS study, 2021 Howley - NBDPS study, 2021 Diav-Citrin, 2013 Colvin, 2010 Clowse, 2006 Costedoat-Chalumeau, 2003 8   - Yes  - Yes 1.28[1.08; 1.53]25,0972,5830%NAChambers (Controls unexposed, sick), 2022 Bérard, 2021 Huybrechts (Controls unexposed, sick), 2021 Cooper (controls unexposed, sick), 2014 4 Indication HCQ   - Any or not specified  - Any or not specified 1.09[0.64; 1.88]28,99347426%NAAndersson (Controls unexposed, NOS), 2021 Bérard, 2021 Colvin, 2010 Costedoat-Chalumeau, 2003 4   - Rheumatic diseases as a whole (Syst ...  - Rheumatic diseases as a whole (Systemic lupus erythematosus, Rheumatoid arthritis, Sjogren's syndrome...) 1.33[1.01; 1.74]62,4342,61215%NAChambers (Controls unexposed, sick), 2022 Howley - BDS study, 2021 Howley - NBDPS study, 2021 Huybrechts (Controls unexposed, sick), 2021 Cooper (controls unexposed, sick), 2014 Diav-Citrin, 2013 6   - Systemic lupus erythematosus (SLE)  - Systemic lupus erythematosus (SLE) 1.13[0.29; 4.39]112280%NAReynolds, 2022 Clowse, 2006 2 MatchedMatched 1.17[0.69; 1.99]404690%NAChambers (Controls unexposed, sick), 2022 Andersson (Controls unexposed, NOS), 2021 2 All studiesAll studies 1.26[1.06; 1.50]91,4383,3142%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 Cooper (controls unexposed, sick), 2014 Diav-Citrin, 2013 Colvin, 2010 Clowse, 2006 Costedoat-Chalumeau, 2003 120.110.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-2.62.91.3520.000Chambers (Controls unexposed, sick), 2022Reynolds, 2022Andersson (Controls unexposed, NOS), 2021Bérard, 2021Howley - BDS study, 2021Howley - NBDPS study, 2021Huybrechts (Controls unexposed, sick), 2021Cooper (controls unexposed, sick), 2014Diav-Citrin, 2013Colvin, 2010Clowse, 2006Costedoat-Chalumeau, 2003

Asymetry test p-value = 0.9271 (by Egger's regression)

slope=0.2400 (0.1311); intercept=-0.0429 (0.4578); t=0.0938; p=0.9271

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 1.29[0.95; 1.74]1,1242,82512%NAChambers (Controls unexposed, sick), 2022 Reynolds, 2022 Huybrechts (Controls unexposed, sick), 2021 Cooper (controls unexposed, sick), 2014 Clowse, 2006 Costedoat-Chalumeau, 2003 6 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.19[0.55; 2.56]354080%NAAndersson (Controls exposed to corticosteroides), 2021 Cooper (controls exposed to TNF-I), 2014 20.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Kaplan (All indications) (Major congenital ma ...Kaplan (All indications) (Major congenital malformations) 1.13[0.59; 2.17]16%-Wwhatever (meta-analysis)T1+at least 1st trimesterstudies TTT6 metaPregmetaPreg 1.26[1.06; 1.50]2%3,314----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 Cooper (controls unexposed, sick), 2014 Diav-Citrin, 2013 Colvin, 2010 Clowse, 2006 Costedoat-Chalumeau, 2003 120.510.01.0