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

Oro-facial clefts

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.
S17044
R75077		 Chuang - BZDs, 2024 Oral clefts 1st trimester population based cohort retrospective unexposed, sick Adjustment: Yes BZD Coexposure: Not specified 1.17 [0.91;1.49] 77/50,272   3,242/2,632,733 3,319 50,272
ref
S16123
R66886		 Laspro - BZDs, 2024 Oral clefts (ICD 10 codes Q35 or Q36 or Q37) during pregnancy (anytime or not specified) excluded nested case control unexposed (general population or NOS) Adjustment: No BZD Coexposure: Not specified 1.29 [1.22;1.37]
excluded (exposition period) 		1,179/-   10,919/- 12,098 -
ref
S15381
R63378		 Noh - BZDs, 2022 Oral clefts 1st trimester population based cohort retrospective unexposed, sick Adjustment: Yes BZD Coexposure: Not specified 0.89 [0.68;1.16] 60/40,846   4,252/3,053,381 4,312 40,846
ref
S15464
R63607		 Blotière - Clonazepam (Other indications), 2019 Oro-facial clefts 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No BZD Coexposure: No (among antiseizure medications) 0.68 [0.10;4.83] C 1/980   2,815/1,875,733 2,816 980
ref
S15330
R63131		 Ban - Diazepam (Other indications) (Controls unexposed, disease free), 2014 Oro-facial cleft 1st trimester retrospective cohort (claims database) unexposed, disease free excluded Adjustment: No BZD Coexposure: No (among psychiatric (ATD and/or psychotropics) medications) Indication BZD: Psychiatric diseases (depression, anxiety, ...) 0.33 [0.02;5.23] C
excluded (control group) 		0/1,159   464/351,785 464 1,159
ref
S15327
R63101		 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Oro-facial cleft 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: No BZD Coexposure: No (among psychiatric (ATD and/or psychotropics) medications) Indication BZD: Psychiatric diseases (depression, anxiety, ...) 0.23 [0.01;3.80] C 0/1,159   35/19,193 35 1,159
ref
S15587
R64145		 Källén - BZDs, 2013 Orofacial clefts early pregnancy population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Not specified 0.54 [0.11;1.59] 3/2,537   -/1,575,847 - 2,537
ref
S15578
R64095		 Bonnot - BZDs, 2001 Oral clefts (cleft lip/palate) 1st trimester case control unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Not specified 1.17 [0.78;1.77] 26/-   1,157/- 1,183 -
ref
S17769
R75087		 Robert - BZDs, 1994 Cleft palate and/or cleft lip (ICD-9: 749) 1st trimester case control unexposed (general population or NOS) Adjustment: No BZD Coexposure: Not specified 2.81 [1.12;6.22] 9/-   123/- 132 -
ref
S15451
R64099		 Laegreid - BZDs, 1990 Cleft palate and cleft lip during pregnancy (anytime or not specified) excluded case control unexposed (general population or NOS) Adjustment: No BZD Coexposure: Not specified 14.50 [1.60;131.70] C
excluded (exposition period) 		2/4   4/62 6 4
ref
S15448
R63537		 Shiono - Diazepam, 1984 Oral clefts 1st trimester cohort unexposed (general population or NOS) Adjustment: No BZD Coexposure: Not specified 1.22 [0.17;8.95] 1/854   31/32,395 32 854
ref
S15497
R63692		 Aarskog - Diazepam, 1975 Oral clefts 1st trimester case control unexposed (general population or NOS) Adjustment: No BZD Coexposure: Not specified 6.02 [1.73;20.98] C 7/11   104/462 111 11
ref
S15362
R63195		 Saxen - BZDs, 1975 Oral clefts 1st trimester nested case control unexposed (general population or NOS) Adjustment: No BZD Coexposure: Not specified Matched 2.10 [1.07;4.10] C 27/40   572/1,149 599 40
ref
Total 10 studies 1.30 [0.95;1.79] 12,539 96,699
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 Chuang - BZDs, 2024Chuang - BZDs, 2024 1.17[0.91; 1.49]3,31950,27223%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Noh - BZDs, 2022Noh - BZDs, 2022 0.89[0.68; 1.16]4,31240,84622%ROB confusion: moderateROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: low Blotière - Clonazepam (Other indications), 2019Blotière - Clonazepam, 2019 1 0.68[0.10; 4.83]2,8169802%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014Ban - Diazepam, 2014 2 0.23[0.01; 3.80]351,1591%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: moderateROB mesure: unclearROB reporting: moderate Källén - BZDs, 2013Källén - BZDs, 2013 0.54[0.11; 1.59]-2,5375%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: criticalROB reporting: moderate Bonnot - BZDs, 2001Bonnot - BZDs, 2001 1.17[0.78; 1.77]1,183-18%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: criticalROB mesure: unclearROB reporting: critical Robert - BZDs, 1994Robert - BZDs, 1994 2.81[1.12; 6.22]132-9%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: unclearROB reporting: moderate Shiono - Diazepam, 1984Shiono - Diazepam, 1984 1.22[0.17; 8.95]328542%ROB confusion: criticalROB selection: unclearROB classification: moderateROB missing: unclearROB mesure: unclearROB reporting: moderate Aarskog - Diazepam, 1975Aarskog - Diazepam, 1975 6.02[1.73; 20.98]111115%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: unclearROB mesure: unclearROB reporting: moderate Saxen - BZDs, 1975Saxen - BZDs, 1975 2.10[1.07; 4.10]5994012%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Total (10 studies) I2 = 56% 1.30[0.95; 1.79]12,53996,6990.220.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Other indications; 2: Other indications) (Controls unexposed, sick;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.01[0.85; 1.21]10,51496,6480%NAChuang - BZDs, 2024 Noh - BZDs, 2022 Blotière - Clonazepam (Other indications), 2019 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Källén - BZDs, 2013 Shiono - Diazepam, 1984 6 case control studiescase control studies 2.16[1.16; 4.03]2,0255166%NABonnot - BZDs, 2001 Robert - BZDs, 1994 Aarskog - Diazepam, 1975 Saxen - BZDs, 1975 4 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.67[0.99; 2.82]4,8734,42250%NABlotière - Clonazepam (Other indications), 2019 Källén - BZDs, 2013 Bonnot - BZDs, 2001 Robert - BZDs, 1994 Shiono - Diazepam, 1984 Aarskog - Diazepam, 1975 Saxen - BZDs, 1975 7 unexposed, sickunexposed, sick 1.01[0.77; 1.33]7,66692,27739%NAChuang - BZDs, 2024 Noh - BZDs, 2022 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 3 Tags Adjustment   - No  - No 2.15[1.17; 3.95]3,7253,04429%NABlotière - Clonazepam (Other indications), 2019 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Robert - BZDs, 1994 Shiono - Diazepam, 1984 Aarskog - Diazepam, 1975 Saxen - BZDs, 1975 6   - Yes  - Yes 1.04[0.87; 1.25]8,81493,65512%NAChuang - BZDs, 2024 Noh - BZDs, 2022 Källén - BZDs, 2013 Bonnot - BZDs, 2001 4 BZD Coexposure   - No (among antiseizure medications)  - No (among antiseizure medications) 0.68[0.10; 4.83]2,816980 -NABlotière - Clonazepam (Other indications), 2019 1   - No (among psychiatric (ATD and/or p ...  - No (among psychiatric (ATD and/or psychotropics) medications) 0.23[0.01; 3.80]351,159 -NABan - Diazepam (Other indications) (Controls unexposed, sick), 2014 1   - Not specified  - Not specified 1.36[0.98; 1.89]9,68894,56063%NAChuang - BZDs, 2024 Noh - BZDs, 2022 Källén - BZDs, 2013 Bonnot - BZDs, 2001 Robert - BZDs, 1994 Shiono - Diazepam, 1984 Aarskog - Diazepam, 1975 Saxen - BZDs, 1975 8 Indication BZD   - Psychiatric diseases (depression, a ...  - Psychiatric diseases (depression, anxiety, ...) 0.23[0.01; 3.80]351,159 -NABan - Diazepam (Other indications) (Controls unexposed, sick), 2014 1 MatchedMatched 2.10[1.07; 4.10]59940 -NASaxen - BZDs, 1975 1 All studiesAll studies 1.30[0.95; 1.79]12,53996,69956%NAChuang - BZDs, 2024 Noh - BZDs, 2022 Blotière - Clonazepam (Other indications), 2019 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Källén - BZDs, 2013 Bonnot - BZDs, 2001 Robert - BZDs, 1994 Shiono - Diazepam, 1984 Aarskog - Diazepam, 1975 Saxen - BZDs, 1975 100.120.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.43.61.7090.000Chuang - BZDs, 2024Noh - BZDs, 2022Blotière - Clonazepam (Other indications), 2019Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014Källén - BZDs, 2013Bonnot - BZDs, 2001Robert - BZDs, 1994Shiono - Diazepam, 1984Aarskog - Diazepam, 1975Saxen - BZDs, 1975

Asymetry test p-value = 0.4793 (by Egger's regression)

slope=0.0214 (0.1917); intercept=0.5705 (0.7689); t=0.7420; p=0.4793

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 15330

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.59[0.95; 2.66]5,3375,59847%NABlotière - Clonazepam (Other indications), 2019 Ban - Diazepam (Other indications) (Controls unexposed, disease free), 2014 Källén - BZDs, 2013 Bonnot - BZDs, 2001 Robert - BZDs, 1994 Shiono - Diazepam, 1984 Aarskog - Diazepam, 1975 Saxen - BZDs, 1975 8 unexposed, sick controlsunexposed, sick controls 1.01[0.77; 1.33]7,66692,27739%NAChuang - BZDs, 2024 Noh - BZDs, 2022 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 30.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Dolovich - BZDs (Oral cleft (Case-control stu ...Dolovich - BZDs (Oral cleft (Case-control studies)) 1.79[1.13; 2.82]-Wwhatever (meta-analysis)T11st trimesterstudies TTT6 Dolovich - BZDs (Oral cleft (Cohort studies))Dolovich - BZDs (Oral cleft (Cohort studies)) 1.19[0.34; 4.15]-Wwhatever (meta-analysis)T11st trimesterstudies TTT3 metaPregmetaPreg 1.30[0.95; 1.79]56%96,699----Chuang - BZDs, 2024 Noh - BZDs, 2022 Blotière - Clonazepam (Other indications), 2019 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Källén - BZDs, 2013 Bonnot - BZDs, 2001 Robert - BZDs, 1994 Shiono - Diazepam, 1984 Aarskog - Diazepam, 1975 Saxen - BZDs, 1975 100.510.01.0