Hydroxychloroquine (All indications except Antiphospholipid Syndrom)

Late intrauterine deaths (> 22 weeks)

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
R52925
Chambers (Controls unexposed, disease free), 2022 Stillbirth (> 20 weeks of gestation) at least 1st trimester prospective cohort unexposed, disease free excluded Adjustment: No Indication HCQ: Rheumatic diseases as a whole (Systemic lupus erythematosus, Rheumatoid arthritis, Sjogren's syndrome...) Matched 0.33 [0.01;8.19] C
excluded (control group)
0/279   1/279 1 279
ref
S13649
R52941
Chambers (Controls unexposed, sick), 2022 Stillbirth (> 20 weeks of gestation) at least 1st trimester prospective cohort unexposed, sick Adjustment: No Indication HCQ: Rheumatic diseases as a whole (Systemic lupus erythematosus, Rheumatoid arthritis, Sjogren's syndrome...) Matched 1.00 [0.02;50.58] C 0/279   0/279 0 279
ref
S13769
R53862
Canti, 2021 Intrauterine death (> 24 GW) throughout pregnancy prospective cohort unexposed, sick Adjustment: No Indication HCQ: Systemic lupus erythematosus (SLE) 0.20 [0.01;5.20] C 0/39   1/25 1 39
ref
S13707
R53365
Abd Rahman, 2020 Fetal loss >= 24 weeks during pregnancy (anytime or not specified) retrospective cohort unexposed, sick Adjustment: No Indication HCQ: Systemic lupus erythematosus (SLE) 0.72 [0.09;5.47] 2/47   2/35 4 47
ref
S13713
R53408
Mollerach, 2019 Fetal death (NOS) throughout pregnancy retrospective cohort unexposed, sick Adjustment: No Indication HCQ: Rheumatic diseases as a whole (Systemic lupus erythematosus, Rheumatoid arthritis, Sjogren's syndrome...) 1.15 [0.04;29.83] C 0/14   1/48 1 14
ref
S13715
R53419
Seo, 2019 Stillbirth (after 20 weeks’ gestation) throughout pregnancy retrospective cohort unexposed, sick Adjustment: No Indication HCQ: Systemic lupus erythematosus (SLE) 1.19 [0.26;5.52] C 4/80   3/71 7 80
ref
S13651
R52960
Cooper (controls exposed to TNF-I), 2014 Fetal death (mean 34.5 weeks) 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...) 1.45 [0.07;30.63] C
excluded (control group)
2/194   0/56 2 194
ref
S13652
R52990
Cooper (controls unexposed, sick), 2014 Fetal death (mean 34.5 weeks) 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...) 0.35 [0.05;2.44] 2/194   4/171 6 194
ref
S13679
R53156
Diav-Citrin, 2013 Stillbirth 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...) 0.99 [0.11;8.93] C 1/115   4/455 5 115
ref
S13700
R53338
Al Arfaj, 2010 Stillbirth (> 24 weeks of gestation) during pregnancy (anytime or not specified) retrospective cohort unexposed, sick Adjustment: No Indication HCQ: Systemic lupus erythematosus (SLE) 0.28 [0.04;2.23] C 1/69   11/222 12 69
ref
S13650
R52952
Clowse, 2006 Stillbirth (pregnancy loss after 20 weeks) throughout pregnancy prospective cohort unexposed, sick Adjustment: No Indication HCQ: Systemic lupus erythematosus (SLE) 0.72 [0.20;2.65] C 3/49   13/157 16 49
ref
S13702
R53357
Chakravarty, 2005 Second or third trimester pregnancy losses during pregnancy (anytime or not specified) retrospective cohort unexposed, sick Adjustment: No Indication HCQ: Systemic lupus erythematosus (SLE) 3.96 [0.07;209.57] C 0/13   0/50 0 13
ref
S13671
R53115
Tincani, 2005 Fetal deaths during pregnancy (anytime or not specified) prospective cohort unexposed, sick Adjustment: No Indication HCQ: Connective tissue diseases (CTD) 5.41 [0.26;114.53] C 2/76   0/80 2 76
ref
S13653
R53020
Costedoat-Chalumeau, 2003 Fetal death (after 20 weeks’ gestation) throughout pregnancy prospective cohort unexposed, sick Adjustment: No Indication HCQ: Any or not specified 0.26 [0.02;2.89] C 1/133   2/70 3 133
ref
S13701
R53346
Buchanan, 1996 Fetal death (>= 12 weeks gestation) during pregnancy (anytime or not specified) retrospective cohort unexposed, sick Adjustment: No Indication HCQ: Systemic lupus erythematosus (SLE) 0.87 [0.20;3.91] C 3/36   5/53 8 36
ref
Total 13 studies 0.73 [0.41;1.30] 65 1,144
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 1.00[0.02; 50.58]02792%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Canti, 2021Canti, 2021 0.20[0.01; 5.20]1393%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Abd Rahman, 2020Abd Rahman, 2020 0.72[0.09; 5.47]4478%ROB confusion: criticalROB selection: criticalROB classification: unclearROB missing: unclearROB mesure: unclearROB reporting: moderate Mollerach, 2019Mollerach, 2019 1.15[0.04; 29.83]1143%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Seo, 2019Seo, 2019 1.19[0.26; 5.52]78014%ROB confusion: seriousROB selection: lowROB classification: unclearROB missing: unclearROB mesure: moderateROB reporting: moderate Cooper (controls unexposed, sick), 2014Cooper, 2014 2 0.35[0.05; 2.44]61949%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Diav-Citrin, 2013Diav-Citrin, 2013 0.99[0.11; 8.93]51157%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Al Arfaj, 2010Al Arfaj, 2010 0.28[0.04; 2.23]12698%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Clowse, 2006Clowse, 2006 0.72[0.20; 2.65]164920%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Chakravarty, 2005Chakravarty, 2005 3.96[0.07; 209.57]0132%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Tincani, 2005Tincani, 2005 5.41[0.26; 114.53]2764%ROB confusion: criticalROB selection: unclearROB classification: unclearROB missing: unclearROB mesure: moderateROB reporting: unclear Costedoat-Chalumeau, 2003Costedoat-Chalumeau, 2003 0.26[0.02; 2.89]31336%ROB confusion: criticalROB selection: unclearROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Buchanan, 1996Buchanan, 1996 0.87[0.20; 3.91]83615%ROB confusion: criticalROB selection: unclearROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Total (13 studies) I2 = 0% 0.73[0.41; 1.30]651,1440.220.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

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

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 0.73[0.41; 1.30]651,1440%NAChambers (Controls unexposed, sick), 2022 Canti, 2021 Abd Rahman, 2020 Mollerach, 2019 Seo, 2019 Cooper (controls unexposed, sick), 2014 Diav-Citrin, 2013 Al Arfaj, 2010 Clowse, 2006 Chakravarty, 2005 Tincani, 2005 Costedoat-Chalumeau, 2003 Buchanan, 1996 13 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 0.99[0.11; 8.93]5115 -NADiav-Citrin, 2013 1 unexposed, sickunexposed, sick 0.72[0.39; 1.30]601,0290%NAChambers (Controls unexposed, sick), 2022 Canti, 2021 Abd Rahman, 2020 Mollerach, 2019 Seo, 2019 Cooper (controls unexposed, sick), 2014 Al Arfaj, 2010 Clowse, 2006 Chakravarty, 2005 Tincani, 2005 Costedoat-Chalumeau, 2003 Buchanan, 1996 12 Tags Adjustment   - No  - No 0.79[0.43; 1.44]599500%NAChambers (Controls unexposed, sick), 2022 Canti, 2021 Abd Rahman, 2020 Mollerach, 2019 Seo, 2019 Diav-Citrin, 2013 Al Arfaj, 2010 Clowse, 2006 Chakravarty, 2005 Tincani, 2005 Costedoat-Chalumeau, 2003 Buchanan, 1996 12   - Yes  - Yes 0.35[0.05; 2.44]6194 -NACooper (controls unexposed, sick), 2014 1 Indication HCQ   - Any or not specified  - Any or not specified 0.26[0.02; 2.89]3133 -NACostedoat-Chalumeau, 2003 1   - Connective tissue diseases (CTD)  - Connective tissue diseases (CTD) 5.41[0.26; 114.53]276 -NATincani, 2005 1   - Rheumatic diseases as a whole (Syst ...  - Rheumatic diseases as a whole (Systemic lupus erythematosus, Rheumatoid arthritis, Sjogren's syndrome...) 0.65[0.19; 2.31]126020%NAChambers (Controls unexposed, sick), 2022 Mollerach, 2019 Cooper (controls unexposed, sick), 2014 Diav-Citrin, 2013 4   - Systemic lupus erythematosus (SLE)  - Systemic lupus erythematosus (SLE) 0.74[0.37; 1.49]483330%NACanti, 2021 Abd Rahman, 2020 Seo, 2019 Al Arfaj, 2010 Clowse, 2006 Chakravarty, 2005 Buchanan, 1996 7 MatchedMatched 1.00[0.02; 50.58]-279 -NAChambers (Controls unexposed, sick), 2022 1 All studiesAll studies 0.73[0.41; 1.30]651,1440%NAChambers (Controls unexposed, sick), 2022 Canti, 2021 Abd Rahman, 2020 Mollerach, 2019 Seo, 2019 Cooper (controls unexposed, sick), 2014 Diav-Citrin, 2013 Al Arfaj, 2010 Clowse, 2006 Chakravarty, 2005 Tincani, 2005 Costedoat-Chalumeau, 2003 Buchanan, 1996 130.120.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.84.52.4300.000Chambers (Controls unexposed, sick), 2022Canti, 2021Abd Rahman, 2020Mollerach, 2019Seo, 2019Cooper (controls unexposed, sick), 2014Diav-Citrin, 2013Al Arfaj, 2010Clowse, 2006Chakravarty, 2005Tincani, 2005Costedoat-Chalumeau, 2003Buchanan, 1996

Asymetry test p-value = 0.6851 (by Egger's regression)

slope=-0.5588 (0.6300); intercept=0.2472 (0.5934); t=0.4165; p=0.6851

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 13651, 13648

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 0.70[0.11; 4.28]63940%NAChambers (Controls unexposed, disease free), 2022 Diav-Citrin, 2013 2 unexposed, sick controlsunexposed, sick controls 0.72[0.39; 1.30]601,0290%NAChambers (Controls unexposed, sick), 2022 Canti, 2021 Abd Rahman, 2020 Mollerach, 2019 Seo, 2019 Cooper (controls unexposed, sick), 2014 Al Arfaj, 2010 Clowse, 2006 Chakravarty, 2005 Tincani, 2005 Costedoat-Chalumeau, 2003 Buchanan, 1996 12 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.45[0.07; 30.63]2194 -NACooper (controls exposed to TNF-I), 2014 10.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Sperber (Autoimmune diseases) (Fetal deaths ( ...Sperber (Autoimmune diseases) (Fetal deaths (> 20 weeks of gestation)) 0.94[0.14; 6.54]72%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT4 Duan (SLE indication) (Stillbirth)Duan (SLE indication) (Stillbirth) 1.00[0.50; 2.00]0%-U,Sunexposed, sickAllthroughout pregnancystudies TTT6 Kaplan (All indications) (Stillbirth)Kaplan (All indications) (Stillbirth) 0.69[0.35; 1.34]0%-Wwhatever (meta-analysis)T1+at least 1st trimesterstudies TTT6 metaPregmetaPreg 0.73[0.41; 1.30]0%1,144----Chambers (Controls unexposed, sick), 2022 Canti, 2021 Abd Rahman, 2020 Mollerach, 2019 Seo, 2019 Cooper (controls unexposed, sick), 2014 Diav-Citrin, 2013 Al Arfaj, 2010 Clowse, 2006 Chakravarty, 2005 Tincani, 2005 Costedoat-Chalumeau, 2003 Buchanan, 1996 130.510.01.0