Antimycotic Azoles (all routes except local only) updated on 01-29-2025

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.
S17833
R75259		 Berard - Fluconazole, 2019 Major congenital malformation (according ICD-9 and 10) 1st trimester nested case control unexposed (general population or NOS) Adjustment: Yes Fluconazole not specified or mixed dose 1.18 [0.95;1.48] 142/1,313   19,346/225,286 19,488 1,313
ref
S17734
R74913		 Howley - Fluconazole, 2016 At least one or more of 30 different categories of major structural birth defects 1st trimester case control unexposed (general population or NOS) Adjustment: No Fluconazole not specified or mixed dose 2.69 [1.15;6.32] C 44/50   31,601/43,207 31,645 50
ref
S17735
R74916		 Molgaard-Nielsen - Fluconazole, 2013 Major birth defects 1st trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Fluconazole not specified or mixed dose 1.06 [0.92;1.21] 210/7,352   25,159/968,236 25,369 7,352
ref
S17748
R75067		 De Santis - Itraconazole, 2009 Major congenital anomalies 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No Matched 0.87 [0.19;3.95] C 3/163   4/190 7 163
ref
S17728
R74810		 Kazy - Ketoconazole, 2005 Congenital abnormality 1st trimester case control unexposed (general population or NOS) Adjustment: Yes 1.40 [0.40;4.80] 5/11   22,838/60,983 22,843 11
ref
S17747
R75054		 Bar-Oz - Itraconazole, 2000 Major birth defects 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No Matched 0.67 [0.23;1.95] 5/156   9/187 14 156
ref
S17745
R75029		 Jick - Fluconazole and Itraconazole (Oral), 1999 Congenital anomaly 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No 1.37 [0.59;3.18] C 7/322   26/1,629 33 322
ref
S17733
R74843		 Mastroiacovo - Fluconazole, 1996 Congenital anomalies that warranted medical or surgical treatment 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: Yes Fluconazole not specified or mixed dose Matched 1.07 [0.41;2.77] 7/177   17/409 24 177
ref
Total 8 studies 1.11 [0.99;1.24] 99,423 9,544
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 Berard - Fluconazole, 2019Berard - Fluconazole, 2019 1.18[0.95; 1.48]19,4881,31326%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Howley - Fluconazole, 2016Howley - Fluconazole, 2016 2.69[1.15; 6.32]31,645502%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: moderate Molgaard-Nielsen - Fluconazole, 2013Molgaard-Nielsen - Fluconazole, 2013 1.06[0.92; 1.21]25,3697,35267%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate De Santis - Itraconazole, 2009De Santis - Itraconazole, 2009 0.87[0.19; 3.95]71631%ROB confusion: criticalROB selection: criticalROB classification: moderateROB missing: unclearROB mesure: criticalROB reporting: moderate Kazy - Ketoconazole, 2005Kazy - Ketoconazole, 2005 1.40[0.40; 4.80]22,843111%ROB confusion: unclearROB selection: criticalROB classification: moderateROB missing: lowROB mesure: unclearROB reporting: moderate Bar-Oz - Itraconazole, 2000Bar-Oz - Itraconazole, 2000 0.67[0.23; 1.95]141561%ROB confusion: criticalROB selection: criticalROB classification: moderateROB missing: criticalROB mesure: criticalROB reporting: moderate Jick - Fluconazole and Itraconazole (Oral), 1999Jick - Fluconazole and Itraco..., 1999 1 1.37[0.59; 3.18]333222%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Mastroiacovo - Fluconazole, 1996Mastroiacovo - Fluconazole, 1996 1.07[0.41; 2.77]241771%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: criticalROB reporting: moderate Total (8 studies) I2 = 0% 1.11[0.99; 1.24]99,4239,5440.210.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Oral;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.06[0.93; 1.21]25,4478,1700%NAMolgaard-Nielsen - Fluconazole, 2013 De Santis - Itraconazole, 2009 Bar-Oz - Itraconazole, 2000 Jick - Fluconazole and Itraconazole (Oral), 1999 Mastroiacovo - Fluconazole, 1996 5 case control studiescase control studies 1.47[0.88; 2.46]73,9761,37441%NABerard - Fluconazole, 2019 Howley - Fluconazole, 2016 Kazy - Ketoconazole, 2005 3 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.11[0.99; 1.24]99,4239,5440%NABerard - Fluconazole, 2019 Howley - Fluconazole, 2016 Molgaard-Nielsen - Fluconazole, 2013 De Santis - Itraconazole, 2009 Kazy - Ketoconazole, 2005 Bar-Oz - Itraconazole, 2000 Jick - Fluconazole and Itraconazole (Oral), 1999 Mastroiacovo - Fluconazole, 1996 8 Tags Adjustment   - No  - No 1.35[0.72; 2.50]31,69969133%NAHowley - Fluconazole, 2016 De Santis - Itraconazole, 2009 Bar-Oz - Itraconazole, 2000 Jick - Fluconazole and Itraconazole (Oral), 1999 4   - Yes  - Yes 1.09[0.97; 1.23]67,7248,8530%NABerard - Fluconazole, 2019 Molgaard-Nielsen - Fluconazole, 2013 Kazy - Ketoconazole, 2005 Mastroiacovo - Fluconazole, 1996 4 Fluconazole not specified or mixed doseFluconazole not specified or mixed dose 1.16[0.95; 1.41]76,5268,89239%NABerard - Fluconazole, 2019 Howley - Fluconazole, 2016 Molgaard-Nielsen - Fluconazole, 2013 Mastroiacovo - Fluconazole, 1996 4 MatchedMatched 0.87[0.46; 1.66]454960%NADe Santis - Itraconazole, 2009 Bar-Oz - Itraconazole, 2000 Mastroiacovo - Fluconazole, 1996 3 All studiesAll studies 1.11[0.99; 1.24]99,4239,5440%NABerard - Fluconazole, 2019 Howley - Fluconazole, 2016 Molgaard-Nielsen - Fluconazole, 2013 De Santis - Itraconazole, 2009 Kazy - Ketoconazole, 2005 Bar-Oz - Itraconazole, 2000 Jick - Fluconazole and Itraconazole (Oral), 1999 Mastroiacovo - Fluconazole, 1996 80.210.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-1.81.90.9260.000Berard - Fluconazole, 2019Howley - Fluconazole, 2016Molgaard-Nielsen - Fluconazole, 2013De Santis - Itraconazole, 2009Kazy - Ketoconazole, 2005Bar-Oz - Itraconazole, 2000Jick - Fluconazole and Itraconazole (Oral), 1999Mastroiacovo - Fluconazole, 1996

Asymetry test p-value = 0.4688 (by Egger's regression)

slope=0.0607 (0.0776); intercept=0.3706 (0.4793); t=0.7732; p=0.4688

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 controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.11[0.99; 1.24]99,4239,5440%NABerard - Fluconazole, 2019 Howley - Fluconazole, 2016 Molgaard-Nielsen - Fluconazole, 2013 De Santis - Itraconazole, 2009 Kazy - Ketoconazole, 2005 Bar-Oz - Itraconazole, 2000 Jick - Fluconazole and Itraconazole (Oral), 1999 Mastroiacovo - Fluconazole, 1996 80.510.01.0