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

Neonatal medical care

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.
S15488
R63668		 Kelty - Alprazolam (Controls unexposed, disease free), 2023 Admission to the special care unit during pregnancy (anytime or not specified) retrospective cohort unexposed, disease free excluded Adjustment: No BZD Coexposure: Not specified 0.94 [0.39;2.26] C
excluded (control group) 		9/48   19/96 28 48
ref
S15487
R63664		 Kelty - Alprazolam (Controls unexposed, sick), 2023 Admission to the special care unit during pregnancy (anytime or not specified) retrospective cohort unexposed, sick Adjustment: No BZD Coexposure: Not specified 0.94 [0.39;2.26] C 9/48   19/96 28 48
ref
S15319
R63026		 Freeman - BZDs, 2018 Neonatal Intensive Care Unit (NICU) admission 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, ...) 2.02 [1.11;3.66] 32/144   125/649 157 144
ref
S15314
R63009		 Yonkers - BZDs, 2017 Neonatal Ventilatory Support (use of a ventilator or continuous positive airway pressure) 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, ...) 2.85 [1.17;6.94] 7/67   -/- - 67
ref
S15518
R63752		 Salisbury - BZDs (Controls unexposed, disease free), 2016 Neonatal intensive care unit admission during pregnancy (anytime or not specified) prospective cohort unexposed, disease free excluded Adjustment: No BZD Coexposure: Yes (with psychiatric (ATD and/or psychotropics) medications) Co-administration Indication BZD: Psychiatric diseases (depression, anxiety, ...) 3.88 [0.61;24.65] C
excluded (control group) 		2/10   4/66 6 10
ref
S15519
R63770		 Salisbury - BZDs (Controls unexposed, sick), 2016 Neonatal intensive care unit admission during pregnancy (anytime or not specified) prospective cohort unexposed, sick Adjustment: No BZD Coexposure: Yes (with psychiatric (ATD and/or psychotropics) medications) Co-administration Indication BZD: Psychiatric diseases (depression, anxiety, ...) 13.75 [1.11;169.61] C 2/10   1/56 3 10
ref
S15320
R63036		 Calderon-Margalit - BZDs, 2009 Neonatal Intensive Care Unit (NICU) admission 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) 4.33 [2.45;7.63] 28/85   157/2,493 185 85
ref
S15524
R63790		 Oberlander - Clonazepam (Controls unexposed, disease free), 2004 Poor neonatal adaptation (high level of medical care and observation) during pregnancy (anytime or not specified) prospective cohort unexposed, disease free excluded Adjustment: No BZD Coexposure: Yes (with psychiatric (ATD and/or psychotropics) medications) Co-administration Indication BZD: Psychiatric diseases (depression, anxiety, ...) 6.68 [1.18;37.79] C
excluded (control group) 		7/18   2/23 9 18
ref
S15525
R63796		 Oberlander - Clonazepam (Controls unexposed, sick), 2004 Poor neonatal adaptation (high level of medical care and observation) during pregnancy (anytime or not specified) prospective cohort unexposed, sick Adjustment: No BZD Coexposure: Yes (with psychiatric (ATD and/or psychotropics) medications) Co-administration Indication BZD: Psychiatric diseases (depression, anxiety, ...) 1.91 [0.53;6.84] C 7/18   7/28 14 18
ref
S15310
R62973		 Laegreid a - BZDs, 1992 Care on neonatal ward throughout pregnancy prospective cohort unexposed, disease free Adjustment: No BZD Coexposure: No (among psychiatric (ATD and/or psychotropics) medications) Indication BZD: Psychiatric diseases (depression, anxiety, ...) 4.38 [1.05;18.30] C 7/17   4/29 11 17
ref
Total 7 studies 2.55 [1.56;4.17] 398 389
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 Kelty - Alprazolam (Controls unexposed, sick), 2023Kelty - Alprazolam, 2023 1 0.94[0.39; 2.26]284816%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Freeman - BZDs, 2018Freeman - BZDs, 2018 2.02[1.11; 3.66]15714422%ROB confusion: seriousROB selection: unclearROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Yonkers - BZDs, 2017Yonkers - BZDs, 2017 2.85[1.17; 6.94]-6716%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Salisbury - BZDs (Controls unexposed, sick), 2016Salisbury - BZDs, 2016 2 13.75[1.11; 169.61]3103%ROB confusion: seriousROB selection: unclearROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Calderon-Margalit - BZDs, 2009Calderon-Margalit - BZDs, 2009 4.33[2.45; 7.63]1858523%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Oberlander - Clonazepam (Controls unexposed, sick), 2004Oberlander - Clonazepam, 2004 3 1.91[0.53; 6.84]141810%ROB confusion: criticalROB selection: lowROB classification: unclearROB missing: lowROB mesure: moderateROB reporting: moderate Laegreid a - BZDs, 1992Laegreid a - BZDs, 1992 4.38[1.05; 18.30]11179%ROB confusion: criticalROB selection: unclearROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Total (7 studies) I2 = 47% 2.55[1.56; 4.17]3983890.250.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

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

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 2.55[1.56; 4.17]39838947%NAKelty - Alprazolam (Controls unexposed, sick), 2023 Freeman - BZDs, 2018 Yonkers - BZDs, 2017 Salisbury - BZDs (Controls unexposed, sick), 2016 Calderon-Margalit - BZDs, 2009 Oberlander - Clonazepam (Controls unexposed, sick), 2004 Laegreid a - BZDs, 1992 7 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 3.89[2.47; 6.12]1961690%NAYonkers - BZDs, 2017 Calderon-Margalit - BZDs, 2009 Laegreid a - BZDs, 1992 3 unexposed, sickunexposed, sick 1.78[0.92; 3.43]20222037%NAKelty - Alprazolam (Controls unexposed, sick), 2023 Freeman - BZDs, 2018 Salisbury - BZDs (Controls unexposed, sick), 2016 Oberlander - Clonazepam (Controls unexposed, sick), 2004 4 Tags Adjustment   - No  - No 2.28[0.85; 6.10]569351%NAKelty - Alprazolam (Controls unexposed, sick), 2023 Salisbury - BZDs (Controls unexposed, sick), 2016 Oberlander - Clonazepam (Controls unexposed, sick), 2004 Laegreid a - BZDs, 1992 4   - Yes  - Yes 2.96[1.80; 4.84]34229639%NAFreeman - BZDs, 2018 Yonkers - BZDs, 2017 Calderon-Margalit - BZDs, 2009 3 BZD Coexposure   - No (among psychiatric (ATD and/or p ...  - No (among psychiatric (ATD and/or psychotropics) medications) 4.38[1.05; 18.30]1117 -NALaegreid a - BZDs, 1992 1   - Not specified  - Not specified 1.63[0.55; 4.86]2811567%NAKelty - Alprazolam (Controls unexposed, sick), 2023 Yonkers - BZDs, 2017 2   - Yes (with psychiatric (ATD and/or p ...  - Yes (with psychiatric (ATD and/or psychotropics) medications) 3.00[1.66; 5.41]35925742%NAFreeman - BZDs, 2018 Salisbury - BZDs (Controls unexposed, sick), 2016 Calderon-Margalit - BZDs, 2009 Oberlander - Clonazepam (Controls unexposed, sick), 2004 4 Co-administrationCo-administration 3.76[0.60; 23.64]172847%NASalisbury - BZDs (Controls unexposed, sick), 2016 Oberlander - Clonazepam (Controls unexposed, sick), 2004 2 Indication BZD   - Psychiatric diseases (depression, a ...  - Psychiatric diseases (depression, anxiety, ...) 2.47[1.60; 3.81]1852560%NAFreeman - BZDs, 2018 Yonkers - BZDs, 2017 Salisbury - BZDs (Controls unexposed, sick), 2016 Oberlander - Clonazepam (Controls unexposed, sick), 2004 Laegreid a - BZDs, 1992 5 All studiesAll studies 2.55[1.56; 4.17]39838947%NAKelty - Alprazolam (Controls unexposed, sick), 2023 Freeman - BZDs, 2018 Yonkers - BZDs, 2017 Salisbury - BZDs (Controls unexposed, sick), 2016 Calderon-Margalit - BZDs, 2009 Oberlander - Clonazepam (Controls unexposed, sick), 2004 Laegreid a - BZDs, 1992 70.250.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.14.01.5380.000Kelty - Alprazolam (Controls unexposed, sick), 2023Freeman - BZDs, 2018Yonkers - BZDs, 2017Salisbury - BZDs (Controls unexposed, sick), 2016Calderon-Margalit - BZDs, 2009Oberlander - Clonazepam (Controls unexposed, sick), 2004Laegreid a - BZDs, 1992

Asymetry test p-value = 0.8108 (by Egger's regression)

slope=0.8117 (0.6209); intercept=0.3618 (1.4340); t=0.2523; p=0.8108

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 15524, 15518, 15488

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 2.97[1.63; 5.41]23924547%NAKelty - Alprazolam (Controls unexposed, disease free), 2023 Yonkers - BZDs, 2017 Salisbury - BZDs (Controls unexposed, disease free), 2016 Calderon-Margalit - BZDs, 2009 Oberlander - Clonazepam (Controls unexposed, disease free), 2004 Laegreid a - BZDs, 1992 6 unexposed, sick controlsunexposed, sick controls 1.78[0.92; 3.43]20222037%NAKelty - Alprazolam (Controls unexposed, sick), 2023 Freeman - BZDs, 2018 Salisbury - BZDs (Controls unexposed, sick), 2016 Oberlander - Clonazepam (Controls unexposed, sick), 2004 40.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Grigoriadis - BZDs (Neonatal Intensive Care U ...Grigoriadis - BZDs (Neonatal Intensive Care Unit admission) 2.61[1.64; 4.14]55%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT4 metaPregmetaPreg 2.55[1.56; 4.17]47%389----Kelty - Alprazolam (Controls unexposed, sick), 2023 Freeman - BZDs, 2018 Yonkers - BZDs, 2017 Salisbury - BZDs (Controls unexposed, sick), 2016 Calderon-Margalit - BZDs, 2009 Oberlander - Clonazepam (Controls unexposed, sick), 2004 Laegreid a - BZDs, 1992 70.510.01.0