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.
S19571
R83559		 Huybrechts _ Marketscan, 2026 Spontaneous abortions early pregnancy retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Not specified 1.08 [1.04;1.12] -/29,712   -/- - 29,712
ref
S19570
R83558		 Huybrechts _ Medicaid, 2026 Spontaneous abortions early pregnancy retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Not specified 1.09 [1.06;1.12] -/39,825   -/- - 39,825
ref
S19610
R83651		 Ishikawa (Controls unexposed, general pop), 2026 Miscarriage between the beginning of the 4th week and 22nd week of gestation early pregnancy nested case control unexposed (general population or NOS) excluded Adjustment: Yes BZD Coexposure: Not specified 1.24 [1.14;1.36]
excluded (control group) 		1,076/3,357   62,406/250,508 63,482 3,357
ref
S19612
R83652		 Ishikawa (Controls unexposed, sick), 2026 Miscarriage between the beginning of the 4th week and 22nd week of gestation early pregnancy nested case control unexposed, sick Adjustment: Yes BZD Coexposure: Not specified 1.12 [1.00;1.25] -/-   2,573/- - -
ref
S19615
R83657		 Li, 2026 Spontaneous abortions early pregnancy population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Not specified 1.65 [1.55;1.74] 2,387/59,521   5,182/396,823 7,569 59,521
ref
S19617
R83660		 Meng _ Case-Case-Time-Control, 2026 Miscarriage before gestational week 20 early pregnancy case-(case)-time-control inapropriate design unexposed, sick BZD Coexposure: Not specified Matched 1.62 [0.84;3.10] -/-   0/- - -
ref
S19618
R83661		 Meng _ Case-Control, 2026 Miscarriage before gestational week 20 early pregnancy case control unexposed (general population or NOS) BZD Coexposure: Not specified Matched 1.41 [1.24;1.61] -/-   0/- - -
ref
S19611
R83659		 Meng _ Case-Time-Control, 2026 Miscarriage before gestational week 20 early pregnancy case-time-control inapropriate design unexposed, sick BZD Coexposure: Not specified Matched 1.86 [1.29;2.68] -/-   0/- - -
ref
S19619
R83662		 Meng _ Sequential Target Trial Emulation, 2026 Miscarriage (GW 3–20) early pregnancy retrospective cohort unexposed (general population or NOS) BZD Coexposure: Not specified Matched 1.29 [1.14;1.44] -/780   -/711,136 - 780
ref
S15611
R64440		 Meng - BZDs, 2024 Miscarriage (between 8th-19th weeks of gestation; ICD-9 codes 631, 632, 634, 637, 640; ICD-10 codes O02, O03, O20) during pregnancy (anytime or not specified) case-time-control inapropriate design unexposed, sick Adjustment: Yes BZD Coexposure: Not specified Matched 1.69 [1.52;1.87] -/-   0/- - -
ref
S18554
R78881		 Kitchin - Long acting BZDs, 2022 Miscarriage (ICD-9634–639 Pregnancy losses between 4-22 weeks) 1st trimester case control unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Not specified Matched 1.30 [1.04;1.61] 122/374   17,948/71,905 18,070 374
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 14 studies 1.45 [1.28;1.63] 137,556 135,234
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 Huybrechts _ Marketscan, 2026Huybrechts _ Marketscan, 2026 1.08[1.04; 1.12]-29,71211%ROB confusion: unclearROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Huybrechts _ Medicaid, 2026Huybrechts _ Medicaid, 2026 1.09[1.06; 1.12]-39,82511%ROB confusion: unclearROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Ishikawa (Controls unexposed, sick), 2026Ishikawa, 2026 1 1.12[1.00; 1.25]--10%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: criticalROB mesure: moderateROB reporting: moderate Li, 2026Li, 2026 1.65[1.55; 1.74]7,56959,52111%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Meng _ Case-Control, 2026Meng _ Case-Control, 2026 1.41[1.24; 1.61]--10%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Meng _ Sequential Target Trial Emulation, 2026Meng _ Sequential Target Trial Emulation, 2026 1.29[1.14; 1.44]-78010%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Kitchin - Long acting BZDs, 2022Kitchin - Long acting BZDs, 2022 1.30[1.04; 1.61]18,0703748%ROB confusion: seriousROB selection: criticalROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Lee - Alprazolam, 2022Lee - Alprazolam, 2022 2.38[1.20; 4.69]52962%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 2 2.85[1.72; 4.72]3,4195704%ROB confusion: lowROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: critical Bech - Clonazepam, 2014Bech - Clonazepam, 2014 1.91[1.54; 2.37]108,3332198%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Ban (Controls unexposed, sick), 2012Ban, 2012 3 1.60[1.30; 1.90]-3,3929%ROB confusion: seriousROB selection: criticalROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Ornoy - BZDs, 1998Ornoy - BZDs, 1998 2.00[1.10; 3.40]624603%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: criticalROB mesure: criticalROB reporting: moderate Milkovich - Chlordiazepoxide, 1974Milkovich - Chlordiazepoxide, 1974 1.95[1.08; 3.51]511863%ROB confusion: criticalROB selection: unclearROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: critical Total (14 studies) I2 = 95% 1.45[1.28; 1.63]137,556135,2340.520.01.0ROB: A: confounding, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, sick; 2: Controls unexposed, sick; 3: Controls unexposed, sick;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.47[1.27; 1.71]116,067134,29096%NAHuybrechts _ Marketscan, 2026 Huybrechts _ Medicaid, 2026 Li, 2026 Meng _ Sequential Target Trial Emulation, 2026 Lee - Alprazolam, 2022 Zanisi - BZDs, 2022 Bech - Clonazepam, 2014 Ban (Controls unexposed, sick), 2012 Ornoy - BZDs, 1998 Milkovich - Chlordiazepoxide, 1974 10 case control studiescase control studies 1.40[1.12; 1.75]21,48994483%NAIshikawa (Controls unexposed, sick), 2026 Meng _ Case-Control, 2026 Kitchin - Long acting BZDs, 2022 Sheehy - BZDs (Controls unexposed, sick), 2019 4 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.41[1.23; 1.62]134,086131,08696%NAHuybrechts _ Marketscan, 2026 Huybrechts _ Medicaid, 2026 Li, 2026 Meng _ Case-Control, 2026 Meng _ Sequential Target Trial Emulation, 2026 Kitchin - Long acting BZDs, 2022 Lee - Alprazolam, 2022 Zanisi - BZDs, 2022 Bech - Clonazepam, 2014 Ornoy - BZDs, 1998 10 unexposed, sickunexposed, sick 1.65[1.16; 2.36]3,4704,14887%NAIshikawa (Controls unexposed, sick), 2026 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 1.42[1.23; 1.64]137,443133,70996%NAHuybrechts _ Marketscan, 2026 Huybrechts _ Medicaid, 2026 Ishikawa (Controls unexposed, sick), 2026 Li, 2026 Kitchin - Long acting BZDs, 2022 Lee - Alprazolam, 2022 Sheehy - BZDs (Controls unexposed, sick), 2019 Bech - Clonazepam, 2014 Ban (Controls unexposed, sick), 2012 9 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 1.40[1.23; 1.59]137,494131,28396%NAHuybrechts _ Marketscan, 2026 Huybrechts _ Medicaid, 2026 Ishikawa (Controls unexposed, sick), 2026 Li, 2026 Meng _ Case-Control, 2026 Meng _ Sequential Target Trial Emulation, 2026 Kitchin - Long acting BZDs, 2022 Lee - Alprazolam, 2022 Sheehy - BZDs (Controls unexposed, sick), 2019 Bech - Clonazepam, 2014 Milkovich - Chlordiazepoxide, 1974 11   - 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 1.42[1.21; 1.68]21,4891,72468%NAMeng _ Case-Control, 2026 Meng _ Sequential Target Trial Emulation, 2026 Kitchin - Long acting BZDs, 2022 Sheehy - BZDs (Controls unexposed, sick), 2019 4 All studiesAll studies 1.45[1.28; 1.63]137,556135,23495%NAHuybrechts _ Marketscan, 2026 Huybrechts _ Medicaid, 2026 Ishikawa (Controls unexposed, sick), 2026 Li, 2026 Meng _ Case-Control, 2026 Meng _ Sequential Target Trial Emulation, 2026 Kitchin - Long acting BZDs, 2022 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 140.520.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-2.12.30.9770.000Huybrechts _ Marketscan, 2026Huybrechts _ Medicaid, 2026Ishikawa (Controls unexposed, sick), 2026Li, 2026Meng _ Case-Control, 2026Meng _ Sequential Target Trial Emulation, 2026Kitchin - Long acting BZDs, 2022Lee - Alprazolam, 2022Zanisi - BZDs, 2022Sheehy - BZDs (Controls unexposed, sick), 2019Bech - Clonazepam, 2014Ban (Controls unexposed, sick), 2012Ornoy - BZDs, 1998Milkovich - Chlordiazepoxide, 1974

Asymetry test p-value = 0.0256 (by Egger's regression)

slope=0.0730 (0.0486); intercept=3.3381 (1.3100); t=2.5482; p=0.0256

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 18301, 15423, 19610

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.45[1.28; 1.64]225,228138,99896%NAHuybrechts _ Marketscan, 2026 Huybrechts _ Medicaid, 2026 Ishikawa (Controls unexposed, general pop), 2026 Li, 2026 Meng _ Case-Control, 2026 Meng _ Sequential Target Trial Emulation, 2026 Kitchin - Long acting BZDs, 2022 Lee - Alprazolam, 2022 Zanisi - BZDs, 2022 Sheehy - BZDs (Controls unexposed, NOS), 2019 Bech - Clonazepam, 2014 Ban (Controls unexposed, disease free), 2012 Ornoy - BZDs, 1998 13 unexposed, sick controlsunexposed, sick controls 1.66[1.32; 2.08]6,5454,14885%NAIshikawa (Controls unexposed, sick), 2026 Meng _ Case-Case-Time-Control, 2026 Meng _ Case-Time-Control, 2026 Meng - BZDs, 2024 Sheehy - BZDs (Controls unexposed, sick), 2019 Ban (Controls unexposed, sick), 2012 Milkovich - Chlordiazepoxide, 1974 7 design cohort studycohort study 1.47[1.27; 1.71]116,067134,29096%NAHuybrechts _ Marketscan, 2026 Huybrechts _ Medicaid, 2026 Li, 2026 Meng _ Sequential Target Trial Emulation, 2026 Lee - Alprazolam, 2022 Zanisi - BZDs, 2022 Bech - Clonazepam, 2014 Ban (Controls unexposed, sick), 2012 Ornoy - BZDs, 1998 Milkovich - Chlordiazepoxide, 1974 10 case controlcase control 1.40[1.12; 1.75]21,48994483%NAIshikawa (Controls unexposed, sick), 2026 Meng _ Case-Control, 2026 Kitchin - Long acting BZDs, 2022 Sheehy - BZDs (Controls unexposed, sick), 2019 4 case-time-controlcase-time-control 1.29[1.17; 1.43]18,0701,1540%NAMeng _ Sequential Target Trial Emulation, 2026 Kitchin - Long acting BZDs, 2022 2 case-case-time-controlcase-case-time-control 1.41[1.24; 1.61]-- -NAMeng _ Case-Control, 2026 1 otherother 00.510.01.0

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 1.45[1.28; 1.63]95%135,234----Huybrechts _ Marketscan, 2026 Huybrechts _ Medicaid, 2026 Ishikawa (Controls unexposed, sick), 2026 Li, 2026 Meng _ Case-Control, 2026 Meng _ Sequential Target Trial Emulation, 2026 Kitchin - Long acting BZDs, 2022 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 140.510.01.0