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

Early intrauterine deaths (< 22 weeks) / Spontaneous abortions

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.
S17707
R74697		 Ishikawa - BZDs, 2024 Miscarriage (4 - 22 weeks of gestation) during pregnancy (anytime or not specified) nested case control unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Not specified 1.43 [1.30;1.57] 848/2,639   43,270/173,796 44,118 2,639
ref
S15611
R64440		 Meng b - BZDs, 2023 Miscarriage (between 8th-19th weeks of gestation; ICD-9 codes 631, 632, 634, 637, 640; ICD-10 codes 631, 632, 634, 637, 640) during pregnancy (anytime or not specified) other unexposed, sick Adjustment: Yes BZD Coexposure: Not specified Matched 1.69 [1.52;1.87] -/-   0/- - -
ref
S15405
R63471		 Lee - Alprazolam, 2022 Spontaneous Abortion 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Not specified 2.38 [1.20;4.69] 14/96   38/629 52 96
ref
S15446
R63534		 Zanisi - BZDs, 2022 Spontaneous abortion during pregnancy (anytime or not specified) cohort unexposed (general population or NOS) Adjustment: No BZD Coexposure: No (among psychiatric (ATD and/or psychotropics) medications) 5.78 [1.17;28.42] -/99   -/158 - 99
ref
S15423
R63494		 Sheehy - BZDs (Controls unexposed, NOS), 2019 Spontaneous abortion (6th to 19th completed week of gestation) - ICD-9 diagnosis code 634 or ICD-10 diagnosis code O03 early pregnancy nested case control unexposed (general population or NOS) excluded Adjustment: Yes BZD Coexposure: Not specified Matched 1.85 [1.61;2.12]
excluded (control group) 		375/1,163   26,774/160,291 27,149 1,163
ref
S15411
R63482		 Sheehy - BZDs (Controls unexposed, sick), 2019 Spontaneous abortion (6th to 19th completed week of gestation) - ICD-9 diagnosis code 634 or ICD-10 diagnosis code O03 early pregnancy nested case control unexposed, sick Adjustment: Yes BZD Coexposure: Not specified Indication BZD: Psychiatric diseases (depression, anxiety, ...) Matched 2.85 [1.72;4.72] 198/570   3,221/15,382 3,419 570
ref
S15326
R63092		 Bech - Clonazepam, 2014 Spontaneous abortions (ICD codes O02.0-O03.9) 1st and 2nd trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Not specified 1.91 [1.54;2.37] 60/219   108,273/812,862 108,333 219
ref
S18301
R77073		 Ban (Controls unexposed, disease free), 2012 Miscarriage (NOS) during pregnancy (anytime or not specified) population based cohort retrospective unexposed, disease free excluded Adjustment: Yes BZD Coexposure: No (among psychiatric (ATD and/or psychotropics) medications) 1.60 [1.40;1.90]
excluded (control group) 		520/3,392   -/- - 3,392
ref
S18302
R77076		 Ban (Controls unexposed, sick), 2012 Miscarriage (NOS) during pregnancy (anytime or not specified) population based cohort retrospective unexposed, sick Adjustment: Yes BZD Coexposure: No (among psychiatric (ATD and/or psychotropics) medications) 1.60 [1.30;1.90] 520/3,392   -/- - 3,392
ref
S15322
R63049		 Ornoy - BZDs, 1998 Spontaneous abortions at least 1st trimester prospective cohort unexposed, disease free Adjustment: No BZD Coexposure: Yes (with psychiatric (ATD and/or psychotropics) medications) 2.00 [1.10;3.40] 40/460   22/424 62 460
ref
S15449
R63539		 Milkovich - Chlordiazepoxide, 1974 Fetal deaths before 20 weeks of gestation during pregnancy (anytime or not specified) retrospective cohort unexposed, sick Adjustment: No BZD Coexposure: Not specified Indication BZD: Psychiatric diseases (depression, anxiety, ...) 1.95 [1.08;3.51] C 20/186   31/532 51 186
ref
Total 9 studies 1.74 [1.53;1.98] 156,035 7,661
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 Ishikawa - BZDs, 2024Ishikawa - BZDs, 2024 1.43[1.30; 1.57]44,1182,63925%ROB confusion: moderateROB selection: moderateROB classification: moderateROB missing: criticalROB mesure: moderateROB reporting: moderate Meng b - BZDs, 2023Meng b - BZDs, 2023 1.69[1.52; 1.87]--24%ROB confusion: lowROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Lee - Alprazolam, 2022Lee - Alprazolam, 2022 2.38[1.20; 4.69]52963%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: criticalROB mesure: unclearROB reporting: moderate Zanisi - BZDs, 2022Zanisi - BZDs, 2022 5.78[1.17; 28.42]-991%ROB confusion: criticalROB selection: unclearROB classification: unclearROB missing: unclearROB mesure: unclearROB reporting: unclear Sheehy - BZDs (Controls unexposed, sick), 2019Sheehy - BZDs, 2019 1 2.85[1.72; 4.72]3,4195705%ROB confusion: lowROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: critical Bech - Clonazepam, 2014Bech - Clonazepam, 2014 1.91[1.54; 2.37]108,33321916%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Ban (Controls unexposed, sick), 2012Ban, 2012 2 1.60[1.30; 1.90]-3,39218%ROB confusion: seriousROB selection: criticalROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Ornoy - BZDs, 1998Ornoy - BZDs, 1998 2.00[1.10; 3.40]624604%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: criticalROB mesure: criticalROB reporting: moderate Milkovich - Chlordiazepoxide, 1974Milkovich - Chlordiazepoxide, 1974 1.95[1.08; 3.51]511864%ROB confusion: criticalROB selection: unclearROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: critical Total (9 studies) I2 = 58% 1.74[1.53; 1.98]156,0357,6610.520.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, sick; 2: Controls unexposed, sick;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.73[1.59; 1.87]108,4984,4520%NAMeng b - BZDs, 2023 Lee - Alprazolam, 2022 Zanisi - BZDs, 2022 Bech - Clonazepam, 2014 Ban (Controls unexposed, sick), 2012 Ornoy - BZDs, 1998 Milkovich - Chlordiazepoxide, 1974 7 case control studiescase control studies 1.93[0.99; 3.76]47,5373,20986%NAIshikawa - BZDs, 2024 Sheehy - BZDs (Controls unexposed, sick), 2019 2 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.80[1.39; 2.33]152,5653,51364%NAIshikawa - BZDs, 2024 Lee - Alprazolam, 2022 Zanisi - BZDs, 2022 Bech - Clonazepam, 2014 Ornoy - BZDs, 1998 5 unexposed, sickunexposed, sick 1.74[1.50; 2.02]3,4704,14835%NAMeng b - BZDs, 2023 Sheehy - BZDs (Controls unexposed, sick), 2019 Ban (Controls unexposed, sick), 2012 Milkovich - Chlordiazepoxide, 1974 4 Tags Adjustment   - No  - No 2.11[1.42; 3.13]1137450%NAZanisi - BZDs, 2022 Ornoy - BZDs, 1998 Milkovich - Chlordiazepoxide, 1974 3   - Yes  - Yes 1.70[1.49; 1.95]155,9226,91668%NAIshikawa - BZDs, 2024 Meng b - BZDs, 2023 Lee - Alprazolam, 2022 Sheehy - BZDs (Controls unexposed, sick), 2019 Bech - Clonazepam, 2014 Ban (Controls unexposed, sick), 2012 6 BZD Coexposure   - No (among psychiatric (ATD and/or p ...  - No (among psychiatric (ATD and/or psychotropics) medications) 2.36[0.74; 7.49]-3,49159%NAZanisi - BZDs, 2022 Ban (Controls unexposed, sick), 2012 2   - Not specified  - Not specified 1.76[1.50; 2.07]155,9733,71068%NAIshikawa - BZDs, 2024 Meng b - BZDs, 2023 Lee - Alprazolam, 2022 Sheehy - BZDs (Controls unexposed, sick), 2019 Bech - Clonazepam, 2014 Milkovich - Chlordiazepoxide, 1974 6   - Yes (with psychiatric (ATD and/or p ...  - Yes (with psychiatric (ATD and/or psychotropics) medications) 2.00[1.14; 3.52]62460 -NAOrnoy - BZDs, 1998 1 Indication BZD   - Psychiatric diseases (depression, a ...  - Psychiatric diseases (depression, anxiety, ...) 2.43[1.65; 3.56]3,4707560%NASheehy - BZDs (Controls unexposed, sick), 2019 Milkovich - Chlordiazepoxide, 1974 2 MatchedMatched 2.07[1.26; 3.40]3,41957075%NAMeng b - BZDs, 2023 Sheehy - BZDs (Controls unexposed, sick), 2019 2 All studiesAll studies 1.74[1.53; 1.98]156,0357,66158%NAIshikawa - BZDs, 2024 Meng b - BZDs, 2023 Lee - Alprazolam, 2022 Zanisi - BZDs, 2022 Sheehy - BZDs (Controls unexposed, sick), 2019 Bech - Clonazepam, 2014 Ban (Controls unexposed, sick), 2012 Ornoy - BZDs, 1998 Milkovich - Chlordiazepoxide, 1974 90.520.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-2.12.50.9770.000Ishikawa - BZDs, 2024Meng b - BZDs, 2023Lee - Alprazolam, 2022Zanisi - BZDs, 2022Sheehy - BZDs (Controls unexposed, sick), 2019Bech - Clonazepam, 2014Ban (Controls unexposed, sick), 2012Ornoy - BZDs, 1998Milkovich - Chlordiazepoxide, 1974

Asymetry test p-value = 0.0164 (by Egger's regression)

slope=0.3500 (0.0516); intercept=1.7314 (0.5517); t=3.1383; p=0.0164

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 18301, 15423

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.72[1.49; 1.98]180,2258,06864%NAIshikawa - BZDs, 2024 Lee - Alprazolam, 2022 Zanisi - BZDs, 2022 Sheehy - BZDs (Controls unexposed, NOS), 2019 Bech - Clonazepam, 2014 Ban (Controls unexposed, disease free), 2012 Ornoy - BZDs, 1998 7 unexposed, sick controlsunexposed, sick controls 1.74[1.50; 2.02]3,9814,14835%NAMeng b - BZDs, 2023 Sheehy - BZDs (Controls unexposed, sick), 2019 Ban (Controls unexposed, sick), 2012 Milkovich - Chlordiazepoxide, 1974 40.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Grigoriadis - BZDs (Spontaneous abortion (NOS))Grigoriadis - BZDs (Spontaneous abortion (NOS)) 1.86[1.43; 2.42]76%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT5 metaPregmetaPreg 1.74[1.53; 1.98]58%7,661----Ishikawa - BZDs, 2024 Meng b - BZDs, 2023 Lee - Alprazolam, 2022 Zanisi - BZDs, 2022 Sheehy - BZDs (Controls unexposed, sick), 2019 Bech - Clonazepam, 2014 Ban (Controls unexposed, sick), 2012 Ornoy - BZDs, 1998 Milkovich - Chlordiazepoxide, 1974 90.510.01.0