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

Small for gestational age (weight)

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
R70536		 Christensen - Clonazepam (Indications other than epilepsy), 2024 Small for gestational age (a z-score for birth weight ≤10th percentile for gestational week, sex, and country (including newborns with congenital malformations)) 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, ...) 1.22 [1.02;1.45] 164/1,019   443,851/4,445,621 444,015 1,019
ref
S15397
R63467		 Chan - BZDs, 2023 Small for gestational age (birth weight <2 standard deviations [SD] below the mean for gestational age) during pregnancy (anytime or not specified) population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Yes (with psychiatric (ATD and/or psychotropics) medications) 0.61 [0.34;1.07] 12/1,060   9,028/531,164 9,040 1,060
ref
S15488
R63666		 Kelty - Alprazolam (Controls unexposed, disease free), 2023 Low birth weight for gestational age during pregnancy (anytime or not specified) retrospective cohort unexposed, disease free excluded Adjustment: No BZD Coexposure: Not specified 3.27 [1.22;8.79] C
excluded (control group) 		11/48   8/96 19 48
ref
S15487
R63662		 Kelty - Alprazolam (Controls unexposed, sick), 2023 Low birth weight for gestational age during pregnancy (anytime or not specified) retrospective cohort unexposed, sick Adjustment: No BZD Coexposure: Not specified 4.46 [1.54;12.95] C 11/48   6/96 17 48
ref
S17848
R75325		 Meng a - BZDs (Controls unexposed, sibling), 2023 Small for gestational age (birthweight below the 10th percentile for gestational age by sex) early pregnancy population based cohort retrospective sibling excluded Adjustment: Yes BZD Coexposure: Yes (with psychiatric (ATD and/or psychotropics) medications) 1.15 [1.07;1.23]
excluded (control group) 		-/-   -/- - -
ref
S15409
R63481		 Meng a - BZDs (Controls unexposed, sick), 2023 Small for gestational age (birthweight below the 10th percentile for gestational age by sex) early pregnancy population based cohort retrospective unexposed, sick Adjustment: Yes BZD Coexposure: Yes (with psychiatric (ATD and/or psychotropics) medications) 1.15 [1.12;1.18] 6,859/61,220   271,318/2,747,697 278,177 61,220
ref
S15584
R64108		 Coste - Clonazepam (Mixed indications), 2020 Small for gestational age (weight) during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No BZD Coexposure: No (among antiseizure medications) 1.35 [1.14;1.59] C 159/1,246   167,376/1,710,441 167,535 1,246
ref
S15587
R64165		 Källén - BZDs, 2013 Small for gestational age (NOS) 2nd and/or 3rd trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Not specified 1.23 [0.96;1.58] 58/-   -/- - -
ref
S15320
R63034		 Calderon-Margalit - BZDs, 2009 Small for Gestational Age infant (birth weight 2 standard deviations below the mean for the newborn’s gestational age at birth) 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) 0.83 [0.24;2.88] 3/85   70/2,493 73 85
ref
Total 7 studies 1.20 [1.05;1.38] 898,857 64,678
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 1.22[1.02; 1.45]444,0151,01921%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Chan - BZDs, 2023Chan - BZDs, 2023 0.61[0.34; 1.07]9,0401,0605%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Kelty - Alprazolam (Controls unexposed, sick), 2023Kelty - Alprazolam, 2023 2 4.46[1.54; 12.95]17482%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Meng a - BZDs (Controls unexposed, sick), 2023Meng a - BZDs, 2023 3 1.15[1.12; 1.18]278,17761,22033%ROB confusion: lowROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Coste - Clonazepam (Mixed indications), 2020Coste - Clonazepam, 2020 4 1.35[1.14; 1.59]167,5351,24622%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Källén - BZDs, 2013Källén - BZDs, 2013 1.23[0.96; 1.58]--16%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Calderon-Margalit - BZDs, 2009Calderon-Margalit - BZDs, 2009 0.83[0.24; 2.88]73851%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Total (7 studies) I2 = 61% 1.20[1.05; 1.38]898,85764,6780.210.01.0ROB: 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: Controls unexposed, sick; 4: Mixed indications;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.20[1.05; 1.38]898,85764,67861%NAChristensen - Clonazepam (Indications other than epilepsy), 2024 Chan - BZDs, 2023 Kelty - Alprazolam (Controls unexposed, sick), 2023 Meng a - BZDs (Controls unexposed, sick), 2023 Coste - Clonazepam (Mixed indications), 2020 Källén - BZDs, 2013 Calderon-Margalit - BZDs, 2009 7 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.19[1.01; 1.41]620,6633,41045%NAChristensen - Clonazepam (Indications other than epilepsy), 2024 Chan - BZDs, 2023 Coste - Clonazepam (Mixed indications), 2020 Källén - BZDs, 2013 Calderon-Margalit - BZDs, 2009 5 unexposed, sickunexposed, sick 2.03[0.55; 7.53]278,19461,26884%NAKelty - Alprazolam (Controls unexposed, sick), 2023 Meng a - BZDs (Controls unexposed, sick), 2023 2 Tags Adjustment   - No  - No 2.17[0.69; 6.85]167,5521,29479%NAKelty - Alprazolam (Controls unexposed, sick), 2023 Coste - Clonazepam (Mixed indications), 2020 2   - Yes  - Yes 1.15[1.04; 1.27]731,30563,38430%NAChristensen - Clonazepam (Indications other than epilepsy), 2024 Chan - BZDs, 2023 Meng a - BZDs (Controls unexposed, sick), 2023 Källén - BZDs, 2013 Calderon-Margalit - BZDs, 2009 5 BZD Coexposure   - No (among antiseizure medications)  - No (among antiseizure medications) 1.29[1.14; 1.45]611,5502,2650%NAChristensen - Clonazepam (Indications other than epilepsy), 2024 Coste - Clonazepam (Mixed indications), 2020 2   - Not specified  - Not specified 2.10[0.61; 7.29]174881%NAKelty - Alprazolam (Controls unexposed, sick), 2023 Källén - BZDs, 2013 2   - Yes (with psychiatric (ATD and/or p ...  - Yes (with psychiatric (ATD and/or psychotropics) medications) 0.91[0.56; 1.46]287,29062,36560%NAChan - BZDs, 2023 Meng a - BZDs (Controls unexposed, sick), 2023 Calderon-Margalit - BZDs, 2009 3 Indication BZD   - Psychiatric diseases (depression, a ...  - Psychiatric diseases (depression, anxiety, ...) 1.22[1.02; 1.45]444,0151,019 -NAChristensen - Clonazepam (Indications other than epilepsy), 2024 1 All studiesAll studies 1.20[1.05; 1.38]898,85764,67861%NAChristensen - Clonazepam (Indications other than epilepsy), 2024 Chan - BZDs, 2023 Kelty - Alprazolam (Controls unexposed, sick), 2023 Meng a - BZDs (Controls unexposed, sick), 2023 Coste - Clonazepam (Mixed indications), 2020 Källén - BZDs, 2013 Calderon-Margalit - BZDs, 2009 70.210.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-1.81.80.7610.000Christensen - Clonazepam (Indications other than epilepsy), 2024Chan - BZDs, 2023Kelty - Alprazolam (Controls unexposed, sick), 2023Meng a - BZDs (Controls unexposed, sick), 2023Coste - Clonazepam (Mixed indications), 2020Källén - BZDs, 2013Calderon-Margalit - BZDs, 2009

Asymetry test p-value = 0.5617 (by Egger's regression)

slope=0.1358 (0.0261); intercept=0.4734 (0.7621); t=0.6211; p=0.5617

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 15488, 17848

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.22[1.00; 1.48]620,7313,45854%NAChristensen - Clonazepam (Indications other than epilepsy), 2024 Chan - BZDs, 2023 Kelty - Alprazolam (Controls unexposed, disease free), 2023 Coste - Clonazepam (Mixed indications), 2020 Källén - BZDs, 2013 Calderon-Margalit - BZDs, 2009 6 unexposed, sick controlsunexposed, sick controls 2.03[0.55; 7.53]278,19461,26884%NAKelty - Alprazolam (Controls unexposed, sick), 2023 Meng a - BZDs (Controls unexposed, sick), 2023 2 siblingssiblings 1.15[1.07; 1.23]-- -NAMeng a - BZDs (Controls unexposed, sibling), 2023 10.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Veroniki a (NMA) (Clobazam) (All indications) ...Veroniki a (NMA) (Clobazam) (All indications) (Prenatal growth restriction) 4.47[1.60; 11.18]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) (Prenatal growth restriction) 1.15[0.59; 2.06]NA-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT-9 Grigoriadis - BZDs (Small for gestational age)Grigoriadis - BZDs (Small for gestational age) 1.34[0.97; 1.86]46%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT-9 metaPregmetaPreg 1.20[1.05; 1.38]61%64,678----Christensen - Clonazepam (Indications other than epilepsy), 2024 Chan - BZDs, 2023 Kelty - Alprazolam (Controls unexposed, sick), 2023 Meng a - BZDs (Controls unexposed, sick), 2023 Coste - Clonazepam (Mixed indications), 2020 Källén - BZDs, 2013 Calderon-Margalit - BZDs, 2009 70.510.01.0