Hydroxychloroquine (All indications except Antiphospholipid Syndrom)

Intrauterine deaths (as a whole 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.
S13697
R53282		 Louthrenoo, 2021 Pregnancy loss during pregnancy (anytime or not specified) retrospective cohort unexposed, sick Adjustment: No Indication HCQ: Systemic lupus erythematosus (SLE) 0.75 [0.23;2.33] 8/43   11/47 19 43
ref
S13699
R53336		 Kroese, 2017 Intrauterine death (sum of < and > 10 weeks of gestation) during pregnancy (anytime or not specified) retrospective cohort unexposed, sick Adjustment: No Indication HCQ: Systemic lupus erythematosus (SLE) 2.83 [1.07;7.52] C 10/30   12/80 22 30
ref
S13687
R53197		 Leroux, 2015 Fetal death throughout pregnancy retrospective cohort unexposed, sick Adjustment: No Indication HCQ: Systemic lupus erythematosus (SLE) 1.95 [0.37;10.11] C 3/41   3/77 6 41
ref
S13672
R53123		 Vroom (controls exposed to sulfasalazine), 2009 Termination of pregnancy (1st or 2nd trimester) 1st trimester retrospective cohort (claims database) exposed to other treatment, sick Adjustment: Yes Indication HCQ: Any or not specified 0.77 [0.36;1.61] 26/39   132/178 158 39
ref
S13656
R53043		 Frassi, 2004 Intrauterine deaths during pregnancy (anytime or not specified) prospective cohort unexposed, sick Adjustment: No Indication HCQ: Connective tissue diseases (CTD) 1.81 [0.42;7.84] C 5/76   3/80 8 76
ref
S13653
R53022		 Costedoat-Chalumeau, 2003 Abortions (spontaneous, fetal and therapeutic) throughout pregnancy prospective cohort unexposed, sick Adjustment: No Indication HCQ: Any or not specified 0.73 [0.32;1.68] C 16/133   11/70 27 133
ref
Total 6 studies 1.13 [0.69;1.85] 240 362
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 Louthrenoo, 2021Louthrenoo, 2021 0.75[0.23; 2.33]194314%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Kroese, 2017Kroese, 2017 2.83[1.07; 7.52]223019%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Leroux, 2015Leroux, 2015 1.95[0.37; 10.11]6418%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Vroom (controls exposed to sulfasalazine), 2009Vroom, 2009 1 0.77[0.36; 1.61]1583926%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Frassi, 2004Frassi, 2004 1.81[0.42; 7.84]87610%ROB confusion: criticalROB selection: unclearROB classification: unclearROB missing: unclearROB mesure: criticalROB reporting: unclear Costedoat-Chalumeau, 2003Costedoat-Chalumeau, 2003 0.73[0.32; 1.68]2713323%ROB confusion: criticalROB selection: unclearROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Total (6 studies) I2 = 26% 1.13[0.69; 1.85]2403620.210.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: controls exposed to sulfasalazine;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.13[0.69; 1.85]24036226%NALouthrenoo, 2021 Kroese, 2017 Leroux, 2015 Vroom (controls exposed to sulfasalazine), 2009 Frassi, 2004 Costedoat-Chalumeau, 2003 6 case control studiescase control studies 0 Type of controls unexposed, sickunexposed, sick 1.30[0.71; 2.38]8232328%NALouthrenoo, 2021 Kroese, 2017 Leroux, 2015 Frassi, 2004 Costedoat-Chalumeau, 2003 5 exposed to other treatment, sickexposed to other treatment, sick 0.77[0.36; 1.63]15839 -NAVroom (controls exposed to sulfasalazine), 2009 1 Tags Adjustment   - No  - No 1.30[0.71; 2.38]8232328%NALouthrenoo, 2021 Kroese, 2017 Leroux, 2015 Frassi, 2004 Costedoat-Chalumeau, 2003 5   - Yes  - Yes 0.77[0.36; 1.63]15839 -NAVroom (controls exposed to sulfasalazine), 2009 1 Indication HCQ   - Any or not specified  - Any or not specified 0.75[0.43; 1.31]1851720%NAVroom (controls exposed to sulfasalazine), 2009 Costedoat-Chalumeau, 2003 2   - Connective tissue diseases (CTD)  - Connective tissue diseases (CTD) 1.81[0.42; 7.84]876 -NAFrassi, 2004 1   - Systemic lupus erythematosus (SLE)  - Systemic lupus erythematosus (SLE) 1.64[0.69; 3.86]4711433%NALouthrenoo, 2021 Kroese, 2017 Leroux, 2015 3 All studiesAll studies 1.13[0.69; 1.85]24036226%NALouthrenoo, 2021 Kroese, 2017 Leroux, 2015 Vroom (controls exposed to sulfasalazine), 2009 Frassi, 2004 Costedoat-Chalumeau, 2003 60.210.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-2.02.11.0090.000Louthrenoo, 2021Kroese, 2017Leroux, 2015Vroom (controls exposed to sulfasalazine), 2009Frassi, 2004Costedoat-Chalumeau, 2003

Asymetry test p-value = 0.3097 (by Egger's regression)

slope=-0.9100 (0.8855); intercept=1.9949 (1.7161); t=1.1625; p=0.3097

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed, sick controlsunexposed, sick controls 1.30[0.71; 2.38]8232328%NALouthrenoo, 2021 Kroese, 2017 Leroux, 2015 Frassi, 2004 Costedoat-Chalumeau, 2003 5 exposed to other treatment, sick controlsexposed to other treatment, sick controls 0.77[0.36; 1.63]15839 -NAVroom (controls exposed to sulfasalazine), 2009 10.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Clowse (All SLE (lupus) pregnancies) (Fetal l ...Clowse (All SLE (lupus) pregnancies) (Fetal loss after 10 weeks) 0.83[0.63; 1.09]NA-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT7 metaPregmetaPreg 1.13[0.69; 1.85]26%362----Louthrenoo, 2021 Kroese, 2017 Leroux, 2015 Vroom (controls exposed to sulfasalazine), 2009 Frassi, 2004 Costedoat-Chalumeau, 2003 60.510.01.0