Benzodiazepines (Psy and mixed indications) updated on 02-10-2025

Congenital heart defects

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.
S17044
R75075		 Chuang - BZDs, 2024 Heart defects 1st trimester population based cohort retrospective unexposed, sick Adjustment: Yes BZD Coexposure: Not specified 1.03 [0.96;1.11] 1,032/50,272   45,397/2,632,733 46,429 50,272
ref
S15381
R63386		 Noh - BZDs, 2022 Congenital heart defects 1st trimester population based cohort retrospective unexposed, sick Adjustment: Yes BZD Coexposure: No (among psychiatric (ATD and/or psychotropics) medications) 1.16 [1.10;1.23] 1,358/35,385   83,584/3,053,381 84,942 35,385
ref
S15593
R64173		 Tinker - BZDs, 2019 Heart defect (any) 1st trimester case control unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Yes (with psychiatric (ATD and/or psychotropics) medications) 0.90 [0.60;1.20] 90/171   12,108/23,560 12,198 171
ref
S15330
R63125		 Ban - Diazepam (Other indications) (Controls unexposed, disease free), 2014 Heart malformations 1st trimester retrospective cohort (claims database) unexposed, disease free excluded Adjustment: Yes BZD Coexposure: No (among psychiatric (ATD and/or psychotropics) medications) Indication BZD: Psychiatric diseases (depression, anxiety, ...) 1.34 [0.63;2.86]
excluded (control group) 		12/1,159   2,642/351,785 2,654 1,159
ref
S15327
R63095		 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Heart malformations 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes BZD Coexposure: No (among psychiatric (ATD and/or psychotropics) medications) Indication BZD: Psychiatric diseases (depression, anxiety, ...) 1.29 [0.60;2.80] 12/1,159   149/19,193 161 1,159
ref
S15587
R64144		 Källén - BZDs, 2013 Any cardiac defects early pregnancy population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Not specified 1.25 [0.92;1.71] 40/2,537   -/1,575,847 - 2,537
ref
S15335
R63155		 Oberlander - BZDs, 2008 Cardiovascular congenital defects 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No BZD Coexposure: No (among psychiatric (ATD and/or psychotropics) medications) 1.08 [0.45;2.62] C 5/968   512/107,320 517 968
ref
S15500
R63700		 Bonnot - Temazepam, 2003 Cardiovascular malformations 1st trimester case control unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Not specified 2.24 [1.05;4.79] 11/-   2,523/- 2,534 -
ref
S15535
R63828		 Czeizel - Diazepam, 2003 Cardiovascular congenital anomalies 1st trimester case control unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Yes (with psychiatric (ATD and/or psychotropics) medications) Matched 1.30 [1.00;1.80] -/-   4,476/- - -
ref
S15322
R63051		 Ornoy - BZDs, 1998 Congenital heart defects (CHD) at least 1st trimester prospective cohort unexposed, disease free Adjustment: No BZD Coexposure: Yes (with psychiatric (ATD and/or psychotropics) medications) 4.34 [0.48;39.03] C 4/355   1/382 5 355
ref
S15338
R63166		 Tikkanen - Diazepam, 1992 Cardiovascular malformations 1st trimester nested case control unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Not specified 0.50 [0.02;10.00] 2/10   404/1,152 406 10
ref
S15493
R63672		 Rothman - Diazepam, 1979 Congenital heart disease (defects) early pregnancy case control unexposed (general population or NOS) Adjustment: No BZD Coexposure: Not specified 2.24 [1.15;4.36] C 15/37   375/1,607 390 37
ref
Total 11 studies 1.15 [1.03;1.28] 147,582 90,894
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 Chuang - BZDs, 2024Chuang - BZDs, 2024 1.03[0.96; 1.11]46,42950,27232%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Noh - BZDs, 2022Noh - BZDs, 2022 1.16[1.10; 1.23]84,94235,38534%ROB confusion: moderateROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: low Tinker - BZDs, 2019Tinker - BZDs, 2019 0.90[0.60; 1.20]12,1981718%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: unclearROB reporting: moderate Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014Ban - Diazepam, 2014 1 1.29[0.60; 2.80]1611,1592%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: moderateROB mesure: unclearROB reporting: moderate Källén - BZDs, 2013Källén - BZDs, 2013 1.25[0.92; 1.71]-2,5379%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: criticalROB reporting: moderate Oberlander - BZDs, 2008Oberlander - BZDs, 2008 1.08[0.45; 2.62]5179681%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: unclearROB reporting: moderate Bonnot - Temazepam, 2003Bonnot - Temazepam, 2003 2.24[1.05; 4.79]2,534-2%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: criticalROB mesure: unclearROB reporting: critical Czeizel - Diazepam, 2003Czeizel - Diazepam, 2003 1.30[1.00; 1.80]--10%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Ornoy - BZDs, 1998Ornoy - BZDs, 1998 4.34[0.48; 39.03]53550%ROB confusion: criticalROB selection: criticalROB classification: moderateROB missing: criticalROB mesure: criticalROB reporting: moderate Tikkanen - Diazepam, 1992Tikkanen - Diazepam, 1992 0.50[0.02; 10.00]406100%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: critical Rothman - Diazepam, 1979Rothman - Diazepam, 1979 2.24[1.15; 4.36]390372%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: unclearROB reporting: moderate Total (11 studies) I2 = 47% 1.15[1.03; 1.28]147,58290,8940.210.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Other indications) (Controls unexposed, sick;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.11[1.02; 1.22]132,05490,67642%NAChuang - BZDs, 2024 Noh - BZDs, 2022 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Källén - BZDs, 2013 Oberlander - BZDs, 2008 Ornoy - BZDs, 1998 6 case control studiescase control studies 1.37[0.94; 2.00]15,52821856%NATinker - BZDs, 2019 Bonnot - Temazepam, 2003 Czeizel - Diazepam, 2003 Tikkanen - Diazepam, 1992 Rothman - Diazepam, 1979 5 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.30[1.03; 1.65]16,0504,07833%NATinker - BZDs, 2019 Källén - BZDs, 2013 Oberlander - BZDs, 2008 Bonnot - Temazepam, 2003 Czeizel - Diazepam, 2003 Ornoy - BZDs, 1998 Tikkanen - Diazepam, 1992 Rothman - Diazepam, 1979 8 unexposed, sickunexposed, sick 1.10[0.99; 1.22]131,53286,81670%NAChuang - BZDs, 2024 Noh - BZDs, 2022 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 3 Tags Adjustment   - No  - No 1.80[1.00; 3.22]9121,36013%NAOberlander - BZDs, 2008 Ornoy - BZDs, 1998 Rothman - Diazepam, 1979 3   - Yes  - Yes 1.12[1.02; 1.24]146,67089,53447%NAChuang - BZDs, 2024 Noh - BZDs, 2022 Tinker - BZDs, 2019 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Källén - BZDs, 2013 Bonnot - Temazepam, 2003 Czeizel - Diazepam, 2003 Tikkanen - Diazepam, 1992 8 BZD Coexposure   - No (among psychiatric (ATD and/or p ...  - No (among psychiatric (ATD and/or psychotropics) medications) 1.16[1.10; 1.23]85,62037,5120%NANoh - BZDs, 2022 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Oberlander - BZDs, 2008 3   - Not specified  - Not specified 1.34[0.97; 1.84]49,75952,85662%NAChuang - BZDs, 2024 Källén - BZDs, 2013 Bonnot - Temazepam, 2003 Tikkanen - Diazepam, 1992 Rothman - Diazepam, 1979 5   - Yes (with psychiatric (ATD and/or p ...  - Yes (with psychiatric (ATD and/or psychotropics) medications) 1.14[0.78; 1.67]12,20352650%NATinker - BZDs, 2019 Czeizel - Diazepam, 2003 Ornoy - BZDs, 1998 3 Indication BZD   - Psychiatric diseases (depression, a ...  - Psychiatric diseases (depression, anxiety, ...) 1.29[0.60; 2.79]1611,159 -NABan - Diazepam (Other indications) (Controls unexposed, sick), 2014 1 MatchedMatched 1.30[0.97; 1.74]-- -NACzeizel - Diazepam, 2003 1 All studiesAll studies 1.15[1.03; 1.28]147,58290,89447%NAChuang - BZDs, 2024 Noh - BZDs, 2022 Tinker - BZDs, 2019 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Källén - BZDs, 2013 Oberlander - BZDs, 2008 Bonnot - Temazepam, 2003 Czeizel - Diazepam, 2003 Ornoy - BZDs, 1998 Tikkanen - Diazepam, 1992 Rothman - Diazepam, 1979 110.210.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.73.91.9020.000Chuang - BZDs, 2024Noh - BZDs, 2022Tinker - BZDs, 2019Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014Källén - BZDs, 2013Oberlander - BZDs, 2008Bonnot - Temazepam, 2003Czeizel - Diazepam, 2003Ornoy - BZDs, 1998Tikkanen - Diazepam, 1992Rothman - Diazepam, 1979

Asymetry test p-value = 0.2528 (by Egger's regression)

slope=0.0852 (0.0368); intercept=0.6220 (0.5091); t=1.2218; p=0.2528

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 15330

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.29[1.05; 1.59]23,2025,23923%NATinker - BZDs, 2019 Ban - Diazepam (Other indications) (Controls unexposed, disease free), 2014 Källén - BZDs, 2013 Oberlander - BZDs, 2008 Bonnot - Temazepam, 2003 Czeizel - Diazepam, 2003 Ornoy - BZDs, 1998 Tikkanen - Diazepam, 1992 Rothman - Diazepam, 1979 9 unexposed, sick controlsunexposed, sick controls 1.10[0.99; 1.22]131,53286,81670%NAChuang - BZDs, 2024 Noh - BZDs, 2022 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 30.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Grigoriadis - BZDs (Cardiac malformations)Grigoriadis - BZDs (Cardiac malformations) 1.27[0.98; 1.65]NA-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT4 Veroniki a (NMA) (Clobazam) (All indications) ...Veroniki a (NMA) (Clobazam) (All indications) (Cardiac malformations) 5.56[0.48; 35.18]NA-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT-9 Veroniki a (NMA) (Clonazepam) (All indication ...Veroniki a (NMA) (Clonazepam) (All indications) (Cardiac malformations) 3.04[0.60; 10.14]NA-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT-9 Enato - BZDs (Cardiovascular malformations (C ...Enato - BZDs (Cardiovascular malformations (Case–control studies)) 1.27[0.69; 2.32]38%-Wwhatever (meta-analysis)T11st trimesterstudies TTT3 metaPregmetaPreg 1.15[1.03; 1.28]47%90,894----Chuang - BZDs, 2024 Noh - BZDs, 2022 Tinker - BZDs, 2019 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Källén - BZDs, 2013 Oberlander - BZDs, 2008 Bonnot - Temazepam, 2003 Czeizel - Diazepam, 2003 Ornoy - BZDs, 1998 Tikkanen - Diazepam, 1992 Rothman - Diazepam, 1979 110.510.01.0