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

Cleft lip with or without cleft palate

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.
S16123
R66888		 Laspro - BZDs, 2024 Any cleft lip (ICD 10 codes Q36 or Q37) during pregnancy (anytime or not specified) excluded nested case control unexposed (general population or NOS) Adjustment: No BZD Coexposure: Not specified 1.19 [1.09;1.29]
excluded (exposition period) 		563/-   5,676/- 6,239 -
ref
S15464
R63595		 Blotière - Clonazepam (Other indications), 2019 Cleft lip with or without cleft palate 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No BZD Coexposure: No (among antiseizure medications) 0.58 [0.04;9.35] C 0/980   1,637/1,875,733 1,637 980
ref
S15593
R64210		 Tinker - BZDs, 2019 Cleft lip with or without cleft palate 1st trimester case control unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Yes (with psychiatric (ATD and/or psychotropics) medications) 1.20 [0.70;1.80] 27/108   3,059/14,511 3,086 108
ref
S15535
R63820		 Czeizel - Diazepam, 2003 Cleft lip /- palate 1st trimester case control unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Yes (with psychiatric (ATD and/or psychotropics) medications) Matched 1.60 [0.90;2.70] -/-   1,378/- - -
ref
S15490
R63671		 Cornel - BZDs - MACDP, 1996 Cleft lip with or without palate 1st trimester case control unexposed (general population or NOS) Adjustment: No BZD Coexposure: Not specified 3.07 [1.46;5.96] -/-   0/- - -
ref
S15489
R63670		 Cornel - Oxazepam - The NNL registry, 1996 Cleft lip with or without palate 1st trimester case control unexposed (general population or NOS) Adjustment: No BZD Coexposure: Not specified 8.17 [1.26;42.20] 3/8   274/4,006 277 8
ref
S17769
R75086		 Robert - BZDs, 1994 Cleft lip with/without cleft palate 1st trimester case control unexposed (general population or NOS) Adjustment: No BZD Coexposure: Not specified 3.55 [1.34;8.13] 8/-   84/- 92 -
ref
S15357
R63171		 Czeizel - Diazepam, 1987 Isolated cleft lip and/or cleft palate 1st trimester case control unexposed (general population or NOS) Adjustment: No BZD Coexposure: Not specified Matched 0.94 [0.47;1.88] C 16/33   614/1,227 630 33
ref
S15361
R63193		 Rosenberg - Diazepam, 1983 Cleft lip with or without cleft palate 1st trimester case control unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Not specified 0.80 [0.40;1.70] 10/64   435/2,879 445 64
ref
S15497
R63694		 Aarskog - Diazepam, 1975 Cleft lip with or without cleft palate 1st trimester case control unexposed (general population or NOS) Adjustment: No BZD Coexposure: Not specified 5.77 [1.60;20.88] C 6/10   93/451 99 10
ref
S15362
R63197		 Saxen - BZDs, 1975 Isolated cleft lip with or without cleft palate 1st trimester nested case control unexposed (general population or NOS) Adjustment: No BZD Coexposure: Not specified Matched 2.81 [0.88;8.96] C 11/15   221/447 232 15
ref
Total 10 studies 1.86 [1.22;2.85] 6,498 1,218
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 Blotière - Clonazepam (Other indications), 2019Blotière - Clonazepam, 2019 1 0.58[0.04; 9.35]1,6379802%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Tinker - BZDs, 2019Tinker - BZDs, 2019 1.20[0.70; 1.80]3,08610816%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: unclearROB reporting: moderate Czeizel - Diazepam, 2003Czeizel - Diazepam, 2003 1.60[0.90; 2.70]--15%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Cornel - BZDs - MACDP, 1996Cornel - BZDs - MACDP, 1996 3.07[1.46; 5.96]--13%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: unclearROB mesure: unclearROB reporting: moderate Cornel - Oxazepam - The NNL registry, 1996Cornel - Oxazepam - The NNL registry, 1996 8.17[1.26; 42.20]27784%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: unclearROB mesure: unclearROB reporting: moderate Robert - BZDs, 1994Robert - BZDs, 1994 3.55[1.34; 8.13]92-10%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: unclearROB reporting: moderate Czeizel - Diazepam, 1987Czeizel - Diazepam, 1987 0.94[0.47; 1.88]6303313%ROB confusion: criticalROB selection: criticalROB classification: moderateROB missing: moderateROB mesure: unclearROB reporting: moderate Rosenberg - Diazepam, 1983Rosenberg - Diazepam, 1983 0.80[0.40; 1.70]4456412%ROB confusion: seriousROB selection: criticalROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Aarskog - Diazepam, 1975Aarskog - Diazepam, 1975 5.77[1.60; 20.88]99107%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: unclearROB mesure: unclearROB reporting: moderate Saxen - BZDs, 1975Saxen - BZDs, 1975 2.81[0.88; 8.96]232158%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Total (10 studies) I2 = 59% 1.86[1.22; 2.85]6,4981,2180.220.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Other indications;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 0.58[0.04; 9.35]1,637980 -NABlotière - Clonazepam (Other indications), 2019 1 case control studiescase control studies 1.92[1.24; 2.96]4,86123863%NATinker - BZDs, 2019 Czeizel - Diazepam, 2003 Cornel - BZDs - MACDP, 1996 Cornel - Oxazepam - The NNL registry, 1996 Robert - BZDs, 1994 Czeizel - Diazepam, 1987 Rosenberg - Diazepam, 1983 Aarskog - Diazepam, 1975 Saxen - BZDs, 1975 9 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.86[1.22; 2.85]6,4981,21859%NABlotière - Clonazepam (Other indications), 2019 Tinker - BZDs, 2019 Czeizel - Diazepam, 2003 Cornel - BZDs - MACDP, 1996 Cornel - Oxazepam - The NNL registry, 1996 Robert - BZDs, 1994 Czeizel - Diazepam, 1987 Rosenberg - Diazepam, 1983 Aarskog - Diazepam, 1975 Saxen - BZDs, 1975 10 Tags Adjustment   - No  - No 2.66[1.45; 4.88]2,9671,04654%NABlotière - Clonazepam (Other indications), 2019 Cornel - BZDs - MACDP, 1996 Cornel - Oxazepam - The NNL registry, 1996 Robert - BZDs, 1994 Czeizel - Diazepam, 1987 Aarskog - Diazepam, 1975 Saxen - BZDs, 1975 7   - Yes  - Yes 1.22[0.86; 1.72]3,53117211%NATinker - BZDs, 2019 Czeizel - Diazepam, 2003 Rosenberg - Diazepam, 1983 3 BZD Coexposure   - No (among antiseizure medications)  - No (among antiseizure medications) 0.58[0.04; 9.35]1,637980 -NABlotière - Clonazepam (Other indications), 2019 1   - Not specified  - Not specified 2.33[1.24; 4.39]1,77513069%NACornel - BZDs - MACDP, 1996 Cornel - Oxazepam - The NNL registry, 1996 Robert - BZDs, 1994 Czeizel - Diazepam, 1987 Rosenberg - Diazepam, 1983 Aarskog - Diazepam, 1975 Saxen - BZDs, 1975 7   - Yes (with psychiatric (ATD and/or p ...  - Yes (with psychiatric (ATD and/or psychotropics) medications) 1.36[0.95; 1.94]3,0861080%NATinker - BZDs, 2019 Czeizel - Diazepam, 2003 2 MatchedMatched 1.45[0.87; 2.42]8624831%NACzeizel - Diazepam, 2003 Czeizel - Diazepam, 1987 Saxen - BZDs, 1975 3 All studiesAll studies 1.86[1.22; 2.85]6,4981,21859%NABlotière - Clonazepam (Other indications), 2019 Tinker - BZDs, 2019 Czeizel - Diazepam, 2003 Cornel - BZDs - MACDP, 1996 Cornel - Oxazepam - The NNL registry, 1996 Robert - BZDs, 1994 Czeizel - Diazepam, 1987 Rosenberg - Diazepam, 1983 Aarskog - Diazepam, 1975 Saxen - BZDs, 1975 100.220.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.33.91.6980.000Blotière - Clonazepam (Other indications), 2019Tinker - BZDs, 2019Czeizel - Diazepam, 2003Cornel - BZDs - MACDP, 1996Cornel - Oxazepam - The NNL registry, 1996Robert - BZDs, 1994Czeizel - Diazepam, 1987Rosenberg - Diazepam, 1983Aarskog - Diazepam, 1975Saxen - BZDs, 1975

Asymetry test p-value = 0.1832 (by Egger's regression)

slope=-0.1231 (0.4527); intercept=1.6783 (1.1520); t=1.4569; p=0.1832

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.86[1.22; 2.85]7,8671,21859%NABlotière - Clonazepam (Other indications), 2019 Tinker - BZDs, 2019 Czeizel - Diazepam, 2003 Cornel - BZDs - MACDP, 1996 Cornel - Oxazepam - The NNL registry, 1996 Robert - BZDs, 1994 Czeizel - Diazepam, 1987 Rosenberg - Diazepam, 1983 Aarskog - Diazepam, 1975 Saxen - BZDs, 1975 100.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Veroniki a (NMA) (Clobazam) (All indications) ...Veroniki a (NMA) (Clobazam) (All indications) (Cleft lip/palate) Out of scale23.20[0.71; 209.10]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) (Cleft lip/palate) Out of scale13.63[0.28; 103.10]NA-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT-9 metaPregmetaPreg 1.86[1.22; 2.85]59%1,218----Blotière - Clonazepam (Other indications), 2019 Tinker - BZDs, 2019 Czeizel - Diazepam, 2003 Cornel - BZDs - MACDP, 1996 Cornel - Oxazepam - The NNL registry, 1996 Robert - BZDs, 1994 Czeizel - Diazepam, 1987 Rosenberg - Diazepam, 1983 Aarskog - Diazepam, 1975 Saxen - BZDs, 1975 100.510.01.0