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

Low birth weight (< 2500g)

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.
S16811
R70535		 Christensen - Clonazepam (Indications other than epilepsy), 2024 Low birth weight (<2500 g) during pregnancy (anytime or not specified) population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: No (among antiseizure medications) Indication BZD: Psychiatric diseases (depression, anxiety, ...) 0.96 [0.73;1.28] 59/1,019   140,436/4,445,621 140,495 1,019
ref
S15488
R63667		 Kelty - Alprazolam (Controls unexposed, disease free), 2023 Birth weight < 2,500 g during pregnancy (anytime or not specified) retrospective cohort unexposed, disease free excluded Adjustment: No BZD Coexposure: Not specified 1.10 [0.38;3.19] C
excluded (control group) 		6/48   11/96 17 48
ref
S15487
R63663		 Kelty - Alprazolam (Controls unexposed, sick), 2023 Birth weight < 2,500 g during pregnancy (anytime or not specified) retrospective cohort unexposed, sick Adjustment: No BZD Coexposure: Not specified 1.23 [0.42;3.61] C 6/48   10/96 16 48
ref
S15405
R63473		 Lee - Alprazolam, 2022 Low birth weight (< 2,500 g) 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Not specified 3.65 [1.22;11.00] 6/80   10/476 16 80
ref
S15446
R63533		 Zanisi - BZDs, 2022 Low birth weight during pregnancy (anytime or not specified) cohort unexposed (general population or NOS) Adjustment: No BZD Coexposure: No (among psychiatric (ATD and/or psychotropics) medications) 3.11 [0.88;10.93] -/-   -/- - -
ref
S15584
R64106		 Coste - Clonazepam (Mixed indications), 2020 Weight at birth <2500 g during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No BZD Coexposure: No (among antiseizure medications) 1.63 [1.33;1.99] C 105/1,246   91,455/1,710,441 91,560 1,246
ref
S15319
R63020		 Freeman - BZDs, 2018 Low birth weight (< 2500 grams) during pregnancy (anytime or not specified) prospective cohort unexposed, sick Adjustment: Yes BZD Coexposure: Yes (with psychiatric (ATD and/or psychotropics) medications) Indication BZD: Psychiatric diseases (depression, anxiety, ...) 2.33 [0.63;8.59] 7/112   16/398 23 112
ref
S15533
R63800		 Ogawa - BZDs, 2018 Low birth weight 2nd and/or 3rd trimester nested case control unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Yes (with psychiatric (ATD and/or psychotropics) medications) 1.55 [0.96;2.50] -/-   1,624/- - -
ref
S15314
R63008		 Yonkers - BZDs, 2017 Low birth weight (< 2500 grams) during pregnancy (anytime or not specified) prospective cohort unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Not specified Indication BZD: Psychiatric diseases (depression, anxiety, ...) 3.41 [1.61;7.26] 11/67   -/- - 67
ref
S15587
R64164		 Källén - BZDs, 2013 Low birth weigh (< 2500 grams) 2nd and/or 3rd trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Not specified 1.40 [1.14;1.72] 97/-   -/- - -
ref
S17712
R74714		 Hironaka - BZDs (Control exposed to Atypical antipsy), 2011 Low birth weight (< 2500 g) during pregnancy (anytime or not specified) retrospective cohort exposed to other treatment, sick excluded Adjustment: No BZD Coexposure: Not specified Indication BZD: Psychiatric diseases (depression, anxiety, ...) 1.89 [0.03;112.07] C
excluded (control group) 		0/5   0/9 0 5
ref
S17710
R74702		 Hironaka - BZDs (Control unexposed, disease free), 2011 Low birth weight (< 2500 g) during pregnancy (anytime or not specified) retrospective cohort unexposed, disease free excluded Adjustment: No BZD Coexposure: Not specified Indication BZD: Psychiatric diseases (depression, anxiety, ...) 2.18 [0.11;42.54] C
excluded (control group) 		0/5   13/278 13 5
ref
S17711
R74708		 Hironaka - BZDs (Control unexposed, sick), 2011 Low birth weight (< 2500 g) during pregnancy (anytime or not specified) retrospective cohort unexposed, sick Adjustment: No BZD Coexposure: Not specified Indication BZD: Psychiatric diseases (depression, anxiety, ...) 0.56 [0.01;37.57] C 0/5   0/3 0 5
ref
S15320
R63033		 Calderon-Margalit - BZDs, 2009 Low Birth-Weight (< 2500gr) during pregnancy (anytime or not specified) prospective cohort unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Yes (with psychiatric (ATD and/or psychotropics) medications) 7.43 [4.15;13.30] 33/85   137/2,493 170 85
ref
Total 11 studies 1.99 [1.42;2.79] 232,280 2,662
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 Christensen - Clonazepam (Indications other than epilepsy), 2024Christensen - Clonazepam, 2024 1 0.96[0.73; 1.28]140,4951,01915%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Kelty - Alprazolam (Controls unexposed, sick), 2023Kelty - Alprazolam, 2023 2 1.23[0.42; 3.61]16486%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Lee - Alprazolam, 2022Lee - Alprazolam, 2022 3.65[1.22; 11.00]16806%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: criticalROB mesure: unclearROB reporting: moderate Zanisi - BZDs, 2022Zanisi - BZDs, 2022 3.11[0.88; 10.93]--5%ROB confusion: criticalROB selection: unclearROB classification: unclearROB missing: unclearROB mesure: unclearROB reporting: unclear Coste - Clonazepam (Mixed indications), 2020Coste - Clonazepam, 2020 3 1.63[1.33; 1.99]91,5601,24615%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Freeman - BZDs, 2018Freeman - BZDs, 2018 2.33[0.63; 8.59]231125%ROB confusion: seriousROB selection: unclearROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Ogawa - BZDs, 2018Ogawa - BZDs, 2018 1.55[0.96; 2.50]--12%ROB confusion: moderateROB selection: lowROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Yonkers - BZDs, 2017Yonkers - BZDs, 2017 3.41[1.61; 7.26]-679%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Källén - BZDs, 2013Källén - BZDs, 2013 1.40[1.14; 1.72]--15%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Hironaka - BZDs (Control unexposed, sick), 2011Hironaka - BZDs, 2011 4 0.56[0.01; 37.57]051%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Calderon-Margalit - BZDs, 2009Calderon-Margalit - BZDs, 2009 7.43[4.15; 13.30]1708511%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Total (11 studies) I2 = 79% 1.99[1.42; 2.79]232,2802,6620.220.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Indications other than epilepsy; 2: Controls unexposed, sick; 3: Mixed indications; 4: Control unexposed, sick;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 2.08[1.42; 3.04]232,2802,66282%NAChristensen - Clonazepam (Indications other than epilepsy), 2024 Kelty - Alprazolam (Controls unexposed, sick), 2023 Lee - Alprazolam, 2022 Zanisi - BZDs, 2022 Coste - Clonazepam (Mixed indications), 2020 Freeman - BZDs, 2018 Yonkers - BZDs, 2017 Källén - BZDs, 2013 Hironaka - BZDs (Control unexposed, sick), 2011 Calderon-Margalit - BZDs, 2009 10 case control studiescase control studies 1.55[0.96; 2.50]-- -NAOgawa - BZDs, 2018 1 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 2.08[1.43; 3.01]232,2412,49785%NAChristensen - Clonazepam (Indications other than epilepsy), 2024 Lee - Alprazolam, 2022 Zanisi - BZDs, 2022 Coste - Clonazepam (Mixed indications), 2020 Ogawa - BZDs, 2018 Yonkers - BZDs, 2017 Källén - BZDs, 2013 Calderon-Margalit - BZDs, 2009 8 unexposed, sickunexposed, sick 1.53[0.68; 3.46]391650%NAKelty - Alprazolam (Controls unexposed, sick), 2023 Freeman - BZDs, 2018 Hironaka - BZDs (Control unexposed, sick), 2011 3 Tags Adjustment   - No  - No 1.64[1.35; 1.99]91,5761,2990%NAKelty - Alprazolam (Controls unexposed, sick), 2023 Zanisi - BZDs, 2022 Coste - Clonazepam (Mixed indications), 2020 Hironaka - BZDs (Control unexposed, sick), 2011 4   - Yes  - Yes 2.22[1.34; 3.67]140,7041,36387%NAChristensen - Clonazepam (Indications other than epilepsy), 2024 Lee - Alprazolam, 2022 Freeman - BZDs, 2018 Ogawa - BZDs, 2018 Yonkers - BZDs, 2017 Källén - BZDs, 2013 Calderon-Margalit - BZDs, 2009 7 BZD Coexposure   - No (among antiseizure medications)  - No (among antiseizure medications) 1.26[0.75; 2.12]232,0552,26589%NAChristensen - Clonazepam (Indications other than epilepsy), 2024 Coste - Clonazepam (Mixed indications), 2020 2   - No (among psychiatric (ATD and/or p ...  - No (among psychiatric (ATD and/or psychotropics) medications) 3.11[0.88; 10.96]-- -NAZanisi - BZDs, 2022 1   - Not specified  - Not specified 1.94[1.14; 3.29]3220049%NAKelty - Alprazolam (Controls unexposed, sick), 2023 Lee - Alprazolam, 2022 Yonkers - BZDs, 2017 Källén - BZDs, 2013 Hironaka - BZDs (Control unexposed, sick), 2011 5   - Yes (with psychiatric (ATD and/or p ...  - Yes (with psychiatric (ATD and/or psychotropics) medications) 3.05[0.95; 9.73]19319788%NAFreeman - BZDs, 2018 Ogawa - BZDs, 2018 Calderon-Margalit - BZDs, 2009 3 Indication BZD   - Psychiatric diseases (depression, a ...  - Psychiatric diseases (depression, anxiety, ...) 1.73[0.71; 4.23]140,5181,20372%NAChristensen - Clonazepam (Indications other than epilepsy), 2024 Freeman - BZDs, 2018 Yonkers - BZDs, 2017 Hironaka - BZDs (Control unexposed, sick), 2011 4 All studiesAll studies 1.99[1.42; 2.79]232,2802,66279%NAChristensen - Clonazepam (Indications other than epilepsy), 2024 Kelty - Alprazolam (Controls unexposed, sick), 2023 Lee - Alprazolam, 2022 Zanisi - BZDs, 2022 Coste - Clonazepam (Mixed indications), 2020 Freeman - BZDs, 2018 Ogawa - BZDs, 2018 Yonkers - BZDs, 2017 Källén - BZDs, 2013 Hironaka - BZDs (Control unexposed, sick), 2011 Calderon-Margalit - BZDs, 2009 110.220.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-5.15.72.5800.000Christensen - Clonazepam (Indications other than epilepsy), 2024Kelty - Alprazolam (Controls unexposed, sick), 2023Lee - Alprazolam, 2022Zanisi - BZDs, 2022Coste - Clonazepam (Mixed indications), 2020Freeman - BZDs, 2018Ogawa - BZDs, 2018Yonkers - BZDs, 2017Källén - BZDs, 2013Hironaka - BZDs (Control unexposed, sick), 2011Calderon-Margalit - BZDs, 2009

Asymetry test p-value = 0.2140 (by Egger's regression)

slope=0.2252 (0.2027); intercept=1.3719 (1.0260); t=1.3371; p=0.2140

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 17712, 17710, 15488

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.98[1.40; 2.81]233,9762,55081%NAChristensen - Clonazepam (Indications other than epilepsy), 2024 Kelty - Alprazolam (Controls unexposed, disease free), 2023 Lee - Alprazolam, 2022 Zanisi - BZDs, 2022 Coste - Clonazepam (Mixed indications), 2020 Ogawa - BZDs, 2018 Yonkers - BZDs, 2017 Källén - BZDs, 2013 Hironaka - BZDs (Control unexposed, disease free), 2011 Calderon-Margalit - BZDs, 2009 10 unexposed, sick controlsunexposed, sick controls 1.53[0.68; 3.46]391650%NAKelty - Alprazolam (Controls unexposed, sick), 2023 Freeman - BZDs, 2018 Hironaka - BZDs (Control unexposed, sick), 2011 3 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.89[0.03; 112.07]-5 -NAHironaka - BZDs (Control exposed to Atypical antipsy), 2011 10.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Grigoriadis - BZDs (Low birth weight)Grigoriadis - BZDs (Low birth weight) 2.34[1.41; 3.88]85%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT6 metaPregmetaPreg 1.99[1.42; 2.79]79%2,662----Christensen - Clonazepam (Indications other than epilepsy), 2024 Kelty - Alprazolam (Controls unexposed, sick), 2023 Lee - Alprazolam, 2022 Zanisi - BZDs, 2022 Coste - Clonazepam (Mixed indications), 2020 Freeman - BZDs, 2018 Ogawa - BZDs, 2018 Yonkers - BZDs, 2017 Källén - BZDs, 2013 Hironaka - BZDs (Control unexposed, sick), 2011 Calderon-Margalit - BZDs, 2009 110.510.01.0