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

Microcephaly / Small head circumference for gestational age

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
R70537		 Christensen - Clonazepam (Indications other than epilepsy), 2024 Microcephaly (z-score for head circumference ≤3rd 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, ...) 1.26 [0.94;1.69] 52/1,019   133,324/4,445,621 133,376 1,019
ref
S15464
R63585		 Blotière - Clonazepam (Other indications), 2019 Microcephaly (until 24 months of age, identifiable by: Q02; brain MRI; according to the EUROCAT definition) 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No BZD Coexposure: No (among antiseizure medications) 10.20 [2.10;30.00] 3/980   438/1,875,733 441 980
ref
S15319
R63028		 Freeman - BZDs, 2018 Small head circumference 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, ...) 3.89 [1.25;12.03] 8/144   20/650 28 144
ref
S15535
R63834		 Czeizel - Diazepam, 2003 Microcephaly 1st trimester case control unexposed (general population or NOS) Adjustment: Yes BZD Coexposure: Yes (with psychiatric (ATD and/or psychotropics) medications) Matched no data -/-   118/- - -
ref
Total 4 studies 3.22 [0.94;11.08] 133,845 2,143
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 1.26[0.94; 1.69]133,3761,01941%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: lowROB mesure: unclearROB reporting: moderate Blotière - Clonazepam (Other indications), 2019Blotière - Clonazepam, 2019 2 10.20[2.10; 30.00]44198028%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Freeman - BZDs, 2018Freeman - BZDs, 2018 3.89[1.25; 12.03]2814431%ROB confusion: seriousROB selection: unclearROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Czeizel - Diazepam, 2003Czeizel - Diazepam, 2003 0.50[0.00; 6.90]--0%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Total (4 studies) I2 = 75% 3.22[0.94; 11.08]133,8452,1430.250.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Indications other than epilepsy; 2: Other indications;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 3.26[0.90; 11.83]133,8452,14383%NAChristensen - Clonazepam (Indications other than epilepsy), 2024 Blotière - Clonazepam (Other indications), 2019 Freeman - BZDs, 2018 3 case control studiescase control studies Czeizel - Diazepam, 2003 1 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 3.19[0.47; 21.76]133,8171,99978%NAChristensen - Clonazepam (Indications other than epilepsy), 2024 Blotière - Clonazepam (Other indications), 2019 Czeizel - Diazepam, 2003 3 unexposed, sickunexposed, sick 3.89[1.25; 12.07]28144 -NAFreeman - BZDs, 2018 1 Tags Adjustment   - No  - No 10.20[2.70; 38.55]441980 -NABlotière - Clonazepam (Other indications), 2019 1   - Yes  - Yes 1.83[0.76; 4.41]133,4041,16344%NAChristensen - Clonazepam (Indications other than epilepsy), 2024 Freeman - BZDs, 2018 Czeizel - Diazepam, 2003 3 BZD Coexposure   - No (among antiseizure medications)  - No (among antiseizure medications) 3.23[0.42; 24.81]133,8171,99989%NAChristensen - Clonazepam (Indications other than epilepsy), 2024 Blotière - Clonazepam (Other indications), 2019 2   - Yes (with psychiatric (ATD and/or p ...  - Yes (with psychiatric (ATD and/or psychotropics) medications) 3.89[1.25; 12.07]281440%NAFreeman - BZDs, 2018 Czeizel - Diazepam, 2003 2 Indication BZD   - Psychiatric diseases (depression, a ...  - Psychiatric diseases (depression, anxiety, ...) 1.93[0.66; 5.63]133,4041,16372%NAChristensen - Clonazepam (Indications other than epilepsy), 2024 Freeman - BZDs, 2018 2 MatchedMatched Czeizel - Diazepam, 2003 1 All studiesAll studies 3.22[0.94; 11.08]133,8452,14375%NAChristensen - Clonazepam (Indications other than epilepsy), 2024 Blotière - Clonazepam (Other indications), 2019 Freeman - BZDs, 2018 Czeizel - Diazepam, 2003 40.250.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.96.12.5000.000Christensen - Clonazepam (Indications other than epilepsy), 2024Blotière - Clonazepam (Other indications), 2019Freeman - BZDs, 2018Czeizel - Diazepam, 2003

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

not enought points

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) 3.23[0.42; 24.81]133,8171,99989%NAChristensen - Clonazepam (Indications other than epilepsy), 2024 Blotière - Clonazepam (Other indications), 2019 2 unexposed, sick controlsunexposed, sick controls 3.89[1.25; 12.07]28144 -NAFreeman - BZDs, 2018 10.510.01.0