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

Nervous system anomalies

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
R71303		 Chuang - BZDs, 2024 Nervous system malformations 1st trimester population based cohort retrospective unexposed, sick Adjustment: Yes BZD Coexposure: Not specified 0.88 [0.74;1.04] 154/50,272   7,154/2,632,733 7,308 50,272
ref
S15381
R63373		 Noh - BZDs, 2022 Nervous system malformations 1st trimester population based cohort retrospective unexposed, sick Adjustment: Yes BZD Coexposure: Not specified 1.05 [0.89;1.24] 155/40,846   10,032/3,053,381 10,187 40,846
ref
S15330
R63130		 Ban - Diazepam (Other indications) (Controls unexposed, disease free), 2014 Nervous system malformations 1st trimester retrospective cohort (claims database) unexposed, disease free excluded Adjustment: No BZD Coexposure: No (among psychiatric (ATD and/or psychotropics) medications) Indication BZD: Psychiatric diseases (depression, anxiety, ...) 0.59 [0.08;4.18] C
excluded (control group) 		1/1,159   517/351,785 518 1,159
ref
S15327
R63100		 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Nervous system malformations 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: No BZD Coexposure: No (among psychiatric (ATD and/or psychotropics) medications) Indication BZD: Psychiatric diseases (depression, anxiety, ...) 0.53 [0.07;3.91] C 1/1,159   31/19,193 32 1,159
ref
S15499
R63698		 Bonnot - Prazepam, 2003 Nervous system malformation 1st trimester case control unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Not specified 6.79 [1.80;25.73] 3/-   725/- 728 -
ref
S15451
R64098		 Laegreid - BZDs, 1990 Congenital malformations of the nervous system during pregnancy (anytime or not specified) excluded case control unexposed (general population or NOS) Adjustment: No BZD Coexposure: Not specified 21.75 [2.78;170.00] C
excluded (exposition period) 		3/5   4/62 7 5
ref
S15336
R63164		 Winship - BZDs, 1984 Central nervous system (CNS) defects 1st trimester case control unexposed (general population or NOS) Adjustment: No BZD Coexposure: Not specified 1.00 [0.44;2.26] 14/28   750/1,500 764 28
ref
Total 5 studies 1.04 [0.78;1.39] 19,019 92,305
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 0.88[0.74; 1.04]7,30850,27242%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Noh - BZDs, 2022Noh - BZDs, 2022 1.05[0.89; 1.24]10,18740,84642%ROB confusion: moderateROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: low Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014Ban - Diazepam, 2014 1 0.53[0.07; 3.91]321,1592%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: moderateROB mesure: unclearROB reporting: moderate Bonnot - Prazepam, 2003Bonnot - Prazepam, 2003 6.79[1.80; 25.73]728-4%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: criticalROB mesure: unclearROB reporting: critical Winship - BZDs, 1984Winship - BZDs, 1984 1.00[0.44; 2.26]7642810%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: unclearROB reporting: moderate Total (5 studies) I2 = 63% 1.04[0.78; 1.39]19,01992,3050.220.01.0ROB: 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 0.96[0.83; 1.11]17,52792,27719%NAChuang - BZDs, 2024 Noh - BZDs, 2022 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 3 case control studiescase control studies 2.42[0.37; 15.71]1,4922883%NABonnot - Prazepam, 2003 Winship - BZDs, 1984 2 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 2.42[0.37; 15.71]1,4922883%NABonnot - Prazepam, 2003 Winship - BZDs, 1984 2 unexposed, sickunexposed, sick 0.96[0.83; 1.11]17,52792,27719%NAChuang - BZDs, 2024 Noh - BZDs, 2022 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 3 Tags Adjustment   - No  - No 0.91[0.43; 1.95]7961,1870%NABan - Diazepam (Other indications) (Controls unexposed, sick), 2014 Winship - BZDs, 1984 2   - Yes  - Yes 1.08[0.76; 1.53]18,22391,11881%NAChuang - BZDs, 2024 Noh - BZDs, 2022 Bonnot - Prazepam, 2003 3 BZD Coexposure   - No (among psychiatric (ATD and/or p ...  - No (among psychiatric (ATD and/or psychotropics) medications) 0.53[0.07; 3.91]321,159 -NABan - Diazepam (Other indications) (Controls unexposed, sick), 2014 1   - Not specified  - Not specified 1.06[0.78; 1.44]18,98791,14671%NAChuang - BZDs, 2024 Noh - BZDs, 2022 Bonnot - Prazepam, 2003 Winship - BZDs, 1984 4 Indication BZD   - Psychiatric diseases (depression, a ...  - Psychiatric diseases (depression, anxiety, ...) 0.53[0.07; 3.91]321,159 -NABan - Diazepam (Other indications) (Controls unexposed, sick), 2014 1 All studiesAll studies 1.04[0.78; 1.39]19,01992,30563%NAChuang - BZDs, 2024 Noh - BZDs, 2022 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Bonnot - Prazepam, 2003 Winship - BZDs, 1984 50.220.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-2.42.41.2200.000Chuang - BZDs, 2024Noh - BZDs, 2022Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014Bonnot - Prazepam, 2003Winship - BZDs, 1984

Asymetry test p-value = 0.4947 (by Egger's regression)

slope=-0.1143 (0.1558); intercept=0.9061 (1.1688); t=0.7753; p=0.4947

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) 1.67[0.41; 6.74]2,0101,18770%NABan - Diazepam (Other indications) (Controls unexposed, disease free), 2014 Bonnot - Prazepam, 2003 Winship - BZDs, 1984 3 unexposed, sick controlsunexposed, sick controls 0.96[0.83; 1.11]17,52792,27719%NAChuang - BZDs, 2024 Noh - BZDs, 2022 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 30.510.01.0