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

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.
S17713
R74722		 Bjorkstedt - BZDs, 2025 Major congenital anomalies (excluding minor anomalies according to the EUROCAT guidelines) during pregnancy (anytime or not specified) excluded retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Not specified 2.11 [1.17;3.81]
excluded (exposition period) 		16/199   -/5,594 - 199
ref
S17044
R71302		 Chuang - BZDs, 2024 Major congenital malformations 1st trimester population based cohort retrospective unexposed, sick Adjustment: Yes BZD Coexposure: Not specified 1.03 [0.98;1.09] 1,704/50,272   75,526/2,632,733 77,230 50,272
ref
S17870
R75495		 Delteil - BZDs (Controls unexposed, NOS), 2023 Major congenital malformations during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed (general population or NOS) excluded Adjustment: No BZD Coexposure: Yes (with psychiatric (ATD and/or psychotropics) medications) 0.98 [0.73;1.32] C
excluded (control group) 		47/2,517   1,558/82,163 1,605 2,517
ref
S15610
R75487		 Delteil - BZDs (Controls unexposed, sick), 2023 Major congenital malformations during pregnancy (anytime or not specified) excluded retrospective cohort (claims database) unexposed, sick Adjustment: No BZD Coexposure: Yes (with psychiatric (ATD and/or psychotropics) medications) 0.92 [0.56;1.51] C
excluded (exposition period) 		47/2,517   24/1,180 71 2,517
ref
S16749
R70375		 The NAAED - Clonazepam, 2023 Major congenital malformations 1st trimester prospective cohort unexposed, disease free Adjustment: No BZD Coexposure: No (among antiseizure medications) 2.25 [0.64;7.88] C 3/120   15/1,330 18 120
ref
S15381
R63385		 Noh - BZDs, 2022 Overall major congenital malformations 1st trimester population based cohort retrospective unexposed, sick Adjustment: Yes BZD Coexposure: No (among psychiatric (ATD and/or psychotropics) medications) 1.11 [1.06;1.15] 2,322/35,385   156,896/3,053,381 159,218 35,385
ref
S15447
R63536		 Szpunar - BZDs, 2022 Major malformations 1st trimester prospective cohort unexposed, sick Adjustment: Yes BZD Coexposure: Yes (with psychiatric (ATD and/or psychotropics) medications) Indication BZD: Psychiatric diseases (depression, anxiety, ...) 0.92 [0.35;2.41] 5/156   32/925 37 156
ref
S15330
R63124		 Ban - Diazepam (Other indications) (Controls unexposed, disease free), 2014 Any major congenital anomalies (excluding genetic anomalies and anomalies attributed to known teratogens, e.g. anomalies due to maternal infections and fetal alcohol syndrome) 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, ...) 1.02 [0.63;1.64]
excluded (control group) 		31/1,159   9,368/351,785 9,399 1,159
ref
S15327
R63094		 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Any major congenital anomalies (excluding genetic anomalies and anomalies attributed to known teratogens, e.g. anomalies due to maternal infections and fetal alcohol syndrome) 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, ...) 0.99 [0.61;1.61] 31/1,159   518/19,193 549 1,159
ref
S15621
R64490		 Veiby - Clonazepam (Mixed indications), 2014 Major malformations throughout pregnancy population based cohort retrospective unexposed, disease free Adjustment: Yes BZD Coexposure: No (among antiseizure medications) 0.65 [0.16;2.62] 2/113   22,371/771,412 22,373 113
ref
S15587
R64142		 Källén - BZDs, 2013 Relatively severe malformations early pregnancy population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Not specified 1.11 [0.92;1.35] 108/2,537   49,499/1,575,847 49,607 2,537
ref
S15335
R63154		 Oberlander - BZDs, 2008 Major congenital anomalies 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No BZD Coexposure: No (among psychiatric (ATD and/or psychotropics) medications) 1.02 [0.71;1.46] C 31/968   3,369/107,320 3,400 968
ref
S15535
R63818		 Czeizel - Diazepam, 2003 Major congenital anomalies 1st trimester case control unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Yes (with psychiatric (ATD and/or psychotropics) medications) Matched 1.20 [1.10;1.40] -/-   22,874/- - -
ref
S15322
R63050		 Ornoy - BZDs, 1998 Infants with major anomalies at least 1st trimester prospective cohort unexposed, disease free Adjustment: No BZD Coexposure: Yes (with psychiatric (ATD and/or psychotropics) medications) 1.20 [0.50;2.80] 11/355   10/382 21 355
ref
S15310
R62974		 Laegreid a - BZDs, 1992 Major malformations throughout pregnancy prospective cohort unexposed, disease free Adjustment: No BZD Coexposure: No (among psychiatric (ATD and/or psychotropics) medications) Indication BZD: Psychiatric diseases (depression, anxiety, ...) 1.75 [0.10;29.93] C 1/17   1/29 2 17
ref
S15424
R63495		 Bracken - Diazepam, 1981 Major congenital malformations 1st trimester case control unexposed (general population or NOS) Adjustment: No BZD Coexposure: Not specified Indication BZD: Psychiatric diseases (depression, anxiety, ...) 2.77 [1.67;4.61] C 34/61   1,336/4,277 1,370 61
ref
S15380
R63370		 Greenberg - BZDs, 1977 Congenital abnormalities (minor abnormalities excluded) 1st trimester case control unexposed (general population or NOS) Adjustment: No BZD Coexposure: Not specified 1.22 [0.70;2.11] C 29/53   800/1,605 829 53
ref
S15440
R63513		 Kullander - Chlordiazepoxide, 1976 Major malformations (gross and insignificant major malfo) 1st trimester nested case control unexposed (general population or NOS) Adjustment: No BZD Coexposure: Not specified 0.61 [0.15;2.48] C 2/84   198/5,118 200 84
ref
Total 14 studies 1.12 [1.04;1.21] 314,854 91,280
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[0.98; 1.09]77,23050,27229%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate The NAAED - Clonazepam, 2023The NAAED - Clonazepam, 2023 2.25[0.64; 7.88]181200%ROB confusion: criticalROB selection: unclearROB classification: moderateROB missing: unclearROB mesure: criticalROB reporting: low Noh - BZDs, 2022Noh - BZDs, 2022 1.11[1.06; 1.15]159,21835,38530%ROB confusion: moderateROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: low Szpunar - BZDs, 2022Szpunar - BZDs, 2022 0.92[0.35; 2.41]371561%ROB confusion: seriousROB selection: unclearROB classification: moderateROB missing: unclearROB mesure: unclearROB reporting: low Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014Ban - Diazepam, 2014 1 0.99[0.61; 1.61]5491,1592%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: moderateROB mesure: unclearROB reporting: moderate Veiby - Clonazepam (Mixed indications), 2014Veiby - Clonazepam, 2014 2 0.65[0.16; 2.62]22,3731130%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Källén - BZDs, 2013Källén - BZDs, 2013 1.11[0.92; 1.35]49,6072,53711%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: criticalROB reporting: moderate Oberlander - BZDs, 2008Oberlander - BZDs, 2008 1.02[0.71; 1.46]3,4009684%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: unclearROB reporting: moderate Czeizel - Diazepam, 2003Czeizel - Diazepam, 2003 1.20[1.10; 1.40]--18%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Ornoy - BZDs, 1998Ornoy - BZDs, 1998 1.20[0.50; 2.80]213551%ROB confusion: criticalROB selection: criticalROB classification: moderateROB missing: criticalROB mesure: criticalROB reporting: moderate Laegreid a - BZDs, 1992Laegreid a - BZDs, 1992 1.75[0.10; 29.93]2170%ROB confusion: criticalROB selection: unclearROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Bracken - Diazepam, 1981Bracken - Diazepam, 1981 2.77[1.67; 4.61]1,370612%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: moderate Greenberg - BZDs, 1977Greenberg - BZDs, 1977 1.22[0.70; 2.11]829532%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: criticalROB mesure: unclearROB reporting: moderate Kullander - Chlordiazepoxide, 1976Kullander - Chlordiazepoxide, 1976 0.61[0.15; 2.48]200840%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Total (14 studies) I2 = 45% 1.12[1.04; 1.21]314,85491,2800.210.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Other indications) (Controls unexposed, sick; 2: Mixed indications;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.08[1.05; 1.11]312,45591,0820%NAChuang - BZDs, 2024 The NAAED - Clonazepam, 2023 Noh - BZDs, 2022 Szpunar - BZDs, 2022 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Veiby - Clonazepam (Mixed indications), 2014 Källén - BZDs, 2013 Oberlander - BZDs, 2008 Ornoy - BZDs, 1998 Laegreid a - BZDs, 1992 10 case control studiescase control studies 1.42[0.89; 2.27]2,39919872%NACzeizel - Diazepam, 2003 Bracken - Diazepam, 1981 Greenberg - BZDs, 1977 Kullander - Chlordiazepoxide, 1976 4 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.23[1.03; 1.47]77,8204,30838%NAThe NAAED - Clonazepam, 2023 Veiby - Clonazepam (Mixed indications), 2014 Källén - BZDs, 2013 Oberlander - BZDs, 2008 Czeizel - Diazepam, 2003 Ornoy - BZDs, 1998 Laegreid a - BZDs, 1992 Bracken - Diazepam, 1981 Greenberg - BZDs, 1977 Kullander - Chlordiazepoxide, 1976 10 unexposed, sickunexposed, sick 1.07[1.01; 1.13]237,03486,97240%NAChuang - BZDs, 2024 Noh - BZDs, 2022 Szpunar - BZDs, 2022 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 4 Tags Adjustment   - No  - No 1.40[0.93; 2.11]5,8401,65850%NAThe NAAED - Clonazepam, 2023 Oberlander - BZDs, 2008 Ornoy - BZDs, 1998 Laegreid a - BZDs, 1992 Bracken - Diazepam, 1981 Greenberg - BZDs, 1977 Kullander - Chlordiazepoxide, 1976 7   - Yes  - Yes 1.09[1.04; 1.14]309,01489,62228%NAChuang - BZDs, 2024 Noh - BZDs, 2022 Szpunar - BZDs, 2022 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Veiby - Clonazepam (Mixed indications), 2014 Källén - BZDs, 2013 Czeizel - Diazepam, 2003 7 BZD Coexposure   - No (among antiseizure medications)  - No (among antiseizure medications) 1.26[0.37; 4.23]22,39123340%NAThe NAAED - Clonazepam, 2023 Veiby - Clonazepam (Mixed indications), 2014 2   - No (among psychiatric (ATD and/or p ...  - No (among psychiatric (ATD and/or psychotropics) medications) 1.11[1.06; 1.15]163,16937,5290%NANoh - BZDs, 2022 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Oberlander - BZDs, 2008 Laegreid a - BZDs, 1992 4   - Not specified  - Not specified 1.23[0.95; 1.60]129,23653,00774%NAChuang - BZDs, 2024 Källén - BZDs, 2013 Bracken - Diazepam, 1981 Greenberg - BZDs, 1977 Kullander - Chlordiazepoxide, 1976 5   - Yes (with psychiatric (ATD and/or p ...  - Yes (with psychiatric (ATD and/or psychotropics) medications) 1.20[1.06; 1.35]585110%NASzpunar - BZDs, 2022 Czeizel - Diazepam, 2003 Ornoy - BZDs, 1998 3 Indication BZD   - Psychiatric diseases (depression, a ...  - Psychiatric diseases (depression, anxiety, ...) 1.44[0.72; 2.90]1,9581,39368%NASzpunar - BZDs, 2022 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Laegreid a - BZDs, 1992 Bracken - Diazepam, 1981 4 MatchedMatched 1.20[1.06; 1.35]-- -NACzeizel - Diazepam, 2003 1 All studiesAll studies 1.12[1.04; 1.21]314,85491,28045%NAChuang - BZDs, 2024 The NAAED - Clonazepam, 2023 Noh - BZDs, 2022 Szpunar - BZDs, 2022 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Veiby - Clonazepam (Mixed indications), 2014 Källén - BZDs, 2013 Oberlander - BZDs, 2008 Czeizel - Diazepam, 2003 Ornoy - BZDs, 1998 Laegreid a - BZDs, 1992 Bracken - Diazepam, 1981 Greenberg - BZDs, 1977 Kullander - Chlordiazepoxide, 1976 140.210.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.43.51.7380.000Chuang - BZDs, 2024The NAAED - Clonazepam, 2023Noh - BZDs, 2022Szpunar - BZDs, 2022Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014Veiby - Clonazepam (Mixed indications), 2014Källén - BZDs, 2013Oberlander - BZDs, 2008Czeizel - Diazepam, 2003Ornoy - BZDs, 1998Laegreid a - BZDs, 1992Bracken - Diazepam, 1981Greenberg - BZDs, 1977Kullander - Chlordiazepoxide, 1976

Asymetry test p-value = 0.4284 (by Egger's regression)

slope=0.0749 (0.0259); intercept=0.3652 (0.4455); t=0.8197; p=0.4284

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 15330, 17870

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.21[1.03; 1.42]110,0845,46733%NAThe NAAED - Clonazepam, 2023 Ban - Diazepam (Other indications) (Controls unexposed, disease free), 2014 Veiby - Clonazepam (Mixed indications), 2014 Källén - BZDs, 2013 Oberlander - BZDs, 2008 Czeizel - Diazepam, 2003 Ornoy - BZDs, 1998 Laegreid a - BZDs, 1992 Bracken - Diazepam, 1981 Greenberg - BZDs, 1977 Kullander - Chlordiazepoxide, 1976 11 unexposed, sick controlsunexposed, sick controls 1.07[1.01; 1.13]237,03486,97240%NAChuang - BZDs, 2024 Noh - BZDs, 2022 Szpunar - BZDs, 2022 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 40.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Dolovich - BZDs (Major malformations (Case-co ...Dolovich - BZDs (Major malformations (Case-control studies)) 3.01[1.32; 6.84]-Wwhatever (meta-analysis)T11st trimesterstudies TTT4 Dolovich - BZDs (Major malformations (Cohort ...Dolovich - BZDs (Major malformations (Cohort studies)) 0.90[0.61; 1.35]-Wwhatever (meta-analysis)T11st trimesterstudies TTT7 Enato - BZDs (Major malformations (Cohort stu ...Enato - BZDs (Major malformations (Cohort studies)) 1.06[0.91; 1.25]0%-Wwhatever (meta-analysis)T11st trimesterstudies TTT9 Veroniki a (NMA) (Clobazam) (All indications) ...Veroniki a (NMA) (Clobazam) (All indications) (Overall major congenital malformations) 3.48[0.52; 13.84]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) (Overall major congenital malformations) 1.13[0.59; 2.02]NA-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT-9 metaPregmetaPreg 1.12[1.04; 1.21]45%91,280----Chuang - BZDs, 2024 The NAAED - Clonazepam, 2023 Noh - BZDs, 2022 Szpunar - BZDs, 2022 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Veiby - Clonazepam (Mixed indications), 2014 Källén - BZDs, 2013 Oberlander - BZDs, 2008 Czeizel - Diazepam, 2003 Ornoy - BZDs, 1998 Laegreid a - BZDs, 1992 Bracken - Diazepam, 1981 Greenberg - BZDs, 1977 Kullander - Chlordiazepoxide, 1976 140.510.01.0