Benzodiazepines (Psy and mixed indications)

Table   Graphic  
individual studies
OutcomeTE95% CIn casesn exposedkPub. bias Congenital malformations All congenital malformations (majors, minors, majors and minors, or unspecified) Hartz - Chlordiazepoxide, 1975 Kullander - Chlordiazepoxide, 1976 Greenberg - BZDs, 1977 Bracken - Diazepam, 1981 Laegreid a - BZDs, 1992 Ornoy - BZDs, 1998 Czeizel - Diazepam, 2003 Oberlander - BZDs, 2008 Yamane - Etizolam, 2011 Källén - BZDs, 2013 Veiby - Clonazepam (Mixed indications), 2014 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Szpunar - BZDs, 2022 Noh - BZDs, 2022 Lee - Alprazolam, 2022 The NAAED - Clonazepam, 2023 Chuang - BZDs, 2024 171.11[1.03; 1.19]340,48091,826low Major congenital malformations Kullander - Chlordiazepoxide, 1976 Greenberg - BZDs, 1977 Bracken - Diazepam, 1981 Laegreid a - BZDs, 1992 Ornoy - BZDs, 1998 Czeizel - Diazepam, 2003 Oberlander - BZDs, 2008 Källén - BZDs, 2013 Veiby - Clonazepam (Mixed indications), 2014 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Noh - BZDs, 2022 Szpunar - BZDs, 2022 The NAAED - Clonazepam, 2023 Chuang - BZDs, 2024 141.12[1.04; 1.21]337,71991,280low Congenital heart defects Rothman - Diazepam, 1979 Tikkanen - Diazepam, 1992 Ornoy - BZDs, 1998 Bonnot - Temazepam, 2003 Czeizel - Diazepam, 2003 Oberlander - BZDs, 2008 Källén - BZDs, 2013 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Tinker - BZDs, 2019 Noh - BZDs, 2022 Chuang - BZDs, 2024 111.15[1.03; 1.28]152,08090,896low Oro-facial clefts Aarskog - Diazepam, 1975 Saxen - BZDs, 1975 Shiono - Diazepam, 1984 Robert - BZDs, 1994 Bonnot - BZDs, 2001 Källén - BZDs, 2013 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Blotière - Clonazepam (Other indications), 2019 Noh - BZDs, 2022 Chuang - BZDs, 2024 101.30[0.95; 1.79]12,53996,716low Cleft lip with or without cleft palate Aarskog - Diazepam, 1975 Saxen - BZDs, 1975 Rosenberg - Diazepam, 1983 Czeizel - Diazepam, 1987 Robert - BZDs, 1994 Cornel - Oxazepam - The NNL registry, 1996 Cornel - BZDs - MACDP, 1996 Czeizel - Diazepam, 2003 Blotière - Clonazepam (Other indications), 2019 Tinker - BZDs, 2019 101.86[1.22; 2.85]7,8671,218low Cleft palate Safra - Diazepam, 1975 Aarskog - Diazepam, 1975 Saxen - BZDs, 1975 Rosenberg - Diazepam, 1983 Czeizel - Diazepam, 1987 Robert - BZDs, 1994 Czeizel - Diazepam, 2003 Blotière - Clonazepam (Other indications), 2019 Tinker - BZDs, 2019 91.30[0.89; 1.90]4,0031,180not evaluable Nervous system anomalies Winship - BZDs, 1984 Bonnot - Prazepam, 2003 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Noh - BZDs, 2022 Chuang - BZDs, 2024 51.04[0.78; 1.39]19,01992,305not evaluable Ano-rectal atresia and stenosis Safra - Diazepam, 1975 Czeizel - Diazepam, 2003 Bonnot - Lorazepam, 2003 Tinker - BZDs, 2019 Blotière - Clonazepam (Other indications), 2019 52.14[0.65; 7.05]2,0871,083not evaluable Eye defects Czeizel - Diazepam, 2003 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Noh - BZDs, 2022 Cifuentes - Alprazolam, 2025 41.11[0.72; 1.70]8,40242,114not evaluable Genital anomalies Robert - BZDs, 1994 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Noh - BZDs, 2022 Chuang - BZDs, 2024 41.10[0.98; 1.25]16,43092,277not evaluable Microcephaly / Small head circumference for gestational age Czeizel - Diazepam, 2003 Freeman - BZDs, 2018 Blotière - Clonazepam (Other indications), 2019 Christensen - Clonazepam (Indications other than epilepsy), 2024 43.22[0.94; 11.08]133,9542,143not evaluable Urinary malformations Robert - BZDs, 1994 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Noh - BZDs, 2022 Chuang - BZDs, 2024 41.04[0.94; 1.15]24,49192,277not evaluable Ventricular septal defect Tikkanen - Diazepam, 1991 Robert - BZDs, 1994 Oberlander - BZDs, 2008 Tinker - BZDs, 2019 Blotière - Clonazepam (Other indications), 2019 51.10[0.70; 1.71]6,6672,050not evaluable Club foot / Talipes equinovarus Czeizel - Diazepam, 2003 Källén - BZDs, 2013 Blotière - Clonazepam (Other indications), 2019 31.00[0.69; 1.45]4,0983,517not evaluable Diaphragmatic hernia Safra - Diazepam, 1975 Tinker - BZDs, 2019 Blotière - Clonazepam (Other indications), 2019 Noh - BZDs, 2022 41.16[0.68; 1.99]1,76941,927not evaluable Digestive system anomalies Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Noh - BZDs, 2022 Chuang - BZDs, 2024 31.16[1.03; 1.30]16,40192,277not evaluable Ear, face and neck anomalies Robert - BZDs, 1994 Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Noh - BZDs, 2022 31.05[0.74; 1.51]2,01742,005not evaluable Hypospadias Czeizel - Diazepam, 2003 Blotière - Clonazepam (Other indications), 2019 Tinker - BZDs, 2019 30.67[0.36; 1.23]8,946983not evaluable Limb defects Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Noh - BZDs, 2022 Chuang - BZDs, 2024 30.94[0.82; 1.08]16,58792,277not evaluable Limb reduction defects (LRD) Safra - Diazepam, 1975 Bonnot - Clorazepate, 2003 Czeizel - Diazepam, 2003 32.61[1.46; 4.68]1,13516not evaluable Neural Tube Defects Safra - Diazepam, 1975 Czeizel - Diazepam, 2003 Tinker - BZDs, 2019 31.08[0.69; 1.68]3,354111not evaluable Oesophageal atresia with or without tracheo-oesophageal fistula Safra - Diazepam, 1975 Czeizel - Diazepam, 2003 Tinker - BZDs, 2019 Blotière - Clonazepam (Other indications), 2019 41.86[1.06; 3.25]1,3691,088not evaluable Polydactyly Robert - BZDs, 1994 Czeizel - Diazepam, 2003 Källén - BZDs, 2013 31.06[0.67; 1.68]1,7302,537not evaluable Respiratory system anomalies Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Noh - BZDs, 2022 Chuang - BZDs, 2024 31.01[0.83; 1.22]6,65992,277not evaluable Abdominal wall defects Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 Noh - BZDs, 2022 21.09[0.73; 1.64]1,31542,005not evaluable Atrial septal defect Oberlander - BZDs, 2008 Blotière - Clonazepam (Other indications), 2019 Tinker - BZDs, 2019 31.21[0.78; 1.89]6,3712,055not evaluable Gastroschisis Czeizel - Diazepam, 2003 Blotière - Clonazepam (Other indications), 2019 Tinker - BZDs, 2019 31.24[0.70; 2.18]1,8721,071not evaluable Omphalocele Safra - Diazepam, 1975 Blotière - Clonazepam (Other indications), 2019 Tinker - BZDs, 2019 31.07[0.39; 2.93]7171,080not evaluable Atresia or stenosis of other parts of small intestine Safra - Diazepam, 1975 Czeizel - Diazepam, 2003 21.08[0.41; 2.88]15916not evaluable Atrioventricular septal defect Blotière - Clonazepam (Other indications), 2019 Tinker - BZDs, 2019 21.89[0.83; 4.31]8981,067not evaluable Cardiac septal defects Tinker - BZDs, 2019 Noh - BZDs, 2022 21.13[1.07; 1.19]72,88440,961not evaluable Chromosomal abnormalities Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014 10.52[0.07; 3.79]331,159not evaluable Coarctation of aorta Blotière - Clonazepam (Other indications), 2019 Tinker - BZDs, 2019 20.63[0.29; 1.37]1,9321,067not evaluable Craniosynostosis Blotière - Clonazepam (Other indications), 2019 Tinker - BZDs, 2019 20.62[0.33; 1.17]2,3451,070not evaluable Ebstein's anomaly Blotière - Clonazepam (Other indications), 2019 118.96[1.17; 307.53]50980not evaluable Hydrocephaly Czeizel - Diazepam, 2003 Tinker - BZDs, 2019 21.08[0.51; 2.26]82484not evaluable Spina bifida Blotière - Clonazepam (Other indications), 2019 Tinker - BZDs, 2019 20.84[0.41; 1.73]1,8571,068not evaluable Tetralogy of Fallot Blotière - Clonazepam (Other indications), 2019 Tinker - BZDs, 2019 21.37[0.75; 2.49]1,7811,075not evaluable Anophthalmos/micropthalmos Tinker - BZDs, 2019 12.50[0.90; 6.92]23085not evaluable Anotia Tinker - BZDs, 2019 11.60[0.69; 3.73]68587not evaluable Aortic valve atresia/stenosis Tinker - BZDs, 2019 11.10[0.40; 3.06]51085not evaluable Bilateral renal agenesis including Potter syndrome Blotière - Clonazepam (Other indications), 2019 112.68[0.79; 204.77]75980not evaluable Bladder exstrophy and/or epispadia Blotière - Clonazepam (Other indications), 2019 111.61[0.72; 187.25]82980not evaluable Congenital cataract Cifuentes - Alprazolam, 2025 11.76[0.25; 12.63]1,36194not evaluable Congenital glaucoma Cifuentes - Alprazolam, 2025 13.42[0.21; 55.24]35193not evaluable Down syndrom / Trisomy 21 Safra - Diazepam, 1975 10.61[0.13; 2.75]5216not evaluable Ear malformations Czeizel - Diazepam, 2003 10.60[0.19; 1.85]351-not evaluable Genetic syndromes and microdeletions Bonnot - Oxazepam, 2001 10.43[0.23; 0.81]2,28028not evaluable Hypoplastic left heart (HLH/HLHS) Blotière - Clonazepam (Other indications), 2019 14.42[0.28; 70.98]216980not evaluable Hypoplastic right heart (HRH/HRHS) Blotière - Clonazepam (Other indications), 2019 114.40[0.89; 232.77]66980not evaluable Minor congenital malformations Kullander - Chlordiazepoxide, 1976 10.55[0.22; 1.36]55187not evaluable Pulmonary valve atresia Blotière - Clonazepam (Other indications), 2019 16.28[0.39; 100.91]152980not evaluable Pulmonary valve stenosis Tinker - BZDs, 2019 11.10[0.67; 1.81]1,53298not evaluable Syndactyly Robert - BZDs, 1994 13.08[0.70; 13.57]--not evaluable Transposition of the great vessels Tinker - BZDs, 2019 10.90[0.38; 2.11]76587not evaluable Growth parameters and prematurity Preterm (< 37 weeks) Calderon-Margalit - BZDs, 2009 Hironaka - BZDs (Control unexposed, sick), 2011 Källén - BZDs, 2013 Kilic - Clonazepam (Mixed indications), 2014 Yonkers - BZDs, 2017 Ogawa - BZDs, 2018 Freeman - BZDs, 2018 Coste - Clonazepam (Mixed indications), 2020 Lee - Alprazolam, 2022 Zanisi - BZDs, 2022 Delteil - BZDs (Controls unexposed, sick), 2023 Chan - BZDs, 2023 Meng a - BZDs (Controls unexposed, sick), 2023 131.51[1.29; 1.77]412,36666,644critical Low birth weight (< 2500g) Calderon-Margalit - BZDs, 2009 Hironaka - BZDs (Control unexposed, sick), 2011 Källén - BZDs, 2013 Yonkers - BZDs, 2017 Ogawa - BZDs, 2018 Freeman - BZDs, 2018 Coste - Clonazepam (Mixed indications), 2020 Lee - Alprazolam, 2022 Zanisi - BZDs, 2022 Kelty - Alprazolam (Controls unexposed, sick), 2023 Christensen - Clonazepam (Indications other than epilepsy), 2024 111.99[1.42; 2.79]233,9852,662low Small for gestational age (weight) Calderon-Margalit - BZDs, 2009 Källén - BZDs, 2013 Coste - Clonazepam (Mixed indications), 2020 Kelty - Alprazolam (Controls unexposed, sick), 2023 Chan - BZDs, 2023 Meng a - BZDs (Controls unexposed, sick), 2023 Christensen - Clonazepam (Indications other than epilepsy), 2024 71.20[1.05; 1.38]898,90664,678not evaluable Extremely preterm (< 28 weeks) Coste - Clonazepam (Mixed indications), 2020 Delteil - BZDs (Controls unexposed, sick), 2023 21.56[0.19; 12.75]2,0483,763not evaluable Very preterm (28 to 32 weeks) Coste - Clonazepam (Mixed indications), 2020 Delteil - BZDs (Controls unexposed, sick), 2023 21.32[0.80; 2.15]10,6663,763not evaluable Macrosomia (> 4000g) Freeman - BZDs, 2018 Coste - Clonazepam (Mixed indications), 2020 20.86[0.76; 0.97]577,5331,358not evaluable Large for gestational age (weight) Källén - BZDs, 2013 11.17[0.92; 1.48]63-not evaluable Maternal consequences Caesarean Oberlander - Clonazepam (Controls unexposed, sick), 2004 Hironaka - BZDs (Control unexposed, sick), 2011 Salisbury - BZDs (Controls unexposed, sick), 2016 Yonkers - BZDs, 2017 Kelty - Alprazolam (Controls unexposed, sick), 2023 51.78[1.15; 2.77]111148not evaluable Preeclampsia Hironaka - BZDs (Control unexposed, sick), 2011 Yonkers - BZDs, 2017 Freeman - BZDs, 2018 30.95[0.56; 1.62]148216not evaluable Gestational diabetes Hironaka - BZDs (Control unexposed, sick), 2011 10.56[0.01; 37.57]-5not evaluable Assisted deliveries (forceps, vacuum, ...) Laegreid a - BZDs, 1992 13.75[1.06; 13.26]1817not evaluable Postpartum hemorrhage Jackson - BZDs, 2024 13.51[2.61; 4.73]3,131542not evaluable Neonatal disorders Neonatal medical care Laegreid a - BZDs, 1992 Oberlander - Clonazepam (Controls unexposed, sick), 2004 Calderon-Margalit - BZDs, 2009 Salisbury - BZDs (Controls unexposed, sick), 2016 Yonkers - BZDs, 2017 Freeman - BZDs, 2018 Kelty - Alprazolam (Controls unexposed, sick), 2023 72.55[1.56; 4.17]398389not evaluable Low Apgar score (< 7) (at 5 min) Calderon-Margalit - BZDs, 2009 Källén - BZDs, 2013 Christensen - Clonazepam (Mixed indications), 2015 Freeman - BZDs, 2018 42.19[1.94; 2.48]9,112453not evaluable Low Apgar score (< 7) (NOS) Laegreid a - BZDs, 1992 Hironaka - BZDs (Control unexposed, sick), 2011 21.44[0.23; 9.13]422not evaluable Jaundice / Icterus Laegreid a - BZDs, 1992 Källén - BZDs, 2013 21.21[0.98; 1.48]9117not evaluable Neonatal disorders (as a whole) Källén - BZDs, 2013 Coste - Clonazepam (Mixed indications), 2020 21.48[1.08; 2.04]222,7311,246not evaluable Neonatal hypoglycemia Laegreid a - BZDs, 1992 Källén - BZDs, 2013 21.38[1.19; 1.60]18517not evaluable Withdrawal syndrome / Neonatal abstinence syndrome / Poor neonatal adaptation Huybrechts - BZDs, 2017 Zanisi - BZDs, 2022 23.24[0.40; 26.39]2,4025,361not evaluable Feeding difficulty Freeman - BZDs, 2018 11.40[0.65; 3.03]9496not evaluable Fetal distress Laegreid a - BZDs, 1992 12.62[0.66; 10.46]1117not evaluable Low Apgar score (< 7) (at 1 min) 0----- Neonatal hypertonia Laegreid b - BZDs, 1992 114.28[0.68; 298.39]316not evaluable Neonatal hypotonia Laegreid b - BZDs, 1992 15.77[0.54; 61.12]416not evaluable Long term consequences Child/Infant death (> 28 days of life) Coste - Clonazepam (Mixed indications), 2020 10.58[0.15; 2.34]4,6971,246not evaluable Intrauterine deaths Early intrauterine deaths (< 22 weeks) / Spontaneous abortions Milkovich - Chlordiazepoxide, 1974 Ornoy - BZDs, 1998 Ban (Controls unexposed, sick), 2012 Bech - Clonazepam, 2014 Sheehy - BZDs (Controls unexposed, sick), 2019 Zanisi - BZDs, 2022 Lee - Alprazolam, 2022 Meng b - BZDs, 2023 Ishikawa - BZDs, 2024 91.74[1.53; 1.98]156,5467,661serious Late intrauterine deaths (> 22 weeks) / Stillbirths Milkovich - Chlordiazepoxide, 1974 Lee - Alprazolam, 2022 Meng a - BZDs (Controls unexposed, sick), 2023 31.16[1.07; 1.26]29,83562,257not evaluable Perinatal death Laegreid c - BZDs, 1992 Ban (Controls unexposed, sick), 2012 Kelty - Alprazolam (Controls unexposed, disease free), 2023 32.47[1.07; 5.68]893,452not evaluable Elective/induced termination of pregnancy Ornoy - BZDs, 1998 Ban (Controls unexposed, sick), 2012 22.45[1.36; 4.43]7303,852not evaluable Intrauterine deaths (as a whole or unspecified) Ornoy - BZDs, 1998 12.72[1.85; 4.00]148460not evaluable Neuro-developmental disorders ADHD (Attention deficit hyperactivity disorder): Diagnosis/Risk Viggedal - BZDs, 1993 Figueroa - BZDs, 2010 Christensen - Clonazepam (Indications NOS), 2019 Lupattelli - BZDs, 2019 Chen - BZDs (Controls unexposed, sick), 2022 Chan - BZDs, 2023 61.20[0.99; 1.46]27,9609,156serious ASD (Autism spectrum disorder): Diagnosis Coste - Clonazepam (Mixed indications), 2020 Chen - BZDs (Controls unexposed, sick), 2022 Bjørk - Clonazepam (Mixed indications), 2022 Delteil - BZDs (Controls unexposed, sick), 2023 Chan - BZDs, 2023 51.10[0.75; 1.61]42,78413,103not evaluable ADHD (Attention deficit hyperactivity disorder): Diagnosis Figueroa - BZDs, 2010 Christensen - Clonazepam (Indications NOS), 2019 Chen - BZDs (Controls unexposed, sick), 2022 Chan - BZDs, 2023 41.11[0.93; 1.32]28,8739,117not evaluable ASD (Autism spectrum disorder): Diagnosis/Risk Coste - Clonazepam (Mixed indications), 2020 Chen - BZDs (Controls unexposed, sick), 2022 Bjørk - Clonazepam (Mixed indications), 2022 Chan - BZDs, 2023 41.11[0.72; 1.72]42,75010,920not evaluable Psychomotor developmental disorders/delay Laegreid b - BZDs, 1992 Mortensen - BZDs, 2003 Oberlander - Clonazepam (Controls unexposed, sick), 2004 33.17[0.73; 13.75]43116not evaluable Childhood autism (F84.0) Christensen - Clonazepam (Indications NOS), 2013 Delteil - BZDs (Controls unexposed, sick), 2023 20.93[0.42; 2.05]2,0892,786not evaluable Cognitive developmental disorders/delay (< 3 years old) Viggedal - BZDs, 1993 Oberlander - Clonazepam (Controls unexposed, sick), 2004 23.26[1.46; 7.26]-34not evaluable ADHD (Attention deficit hyperactivity disorder): Risk Viggedal - BZDs, 1993 Lupattelli - BZDs, 2019 21.96[0.59; 6.50]739not evaluable Cognitive developmental disorders/delay (> 6 years old) Bjørk - Clonazepam (Mixed indications), 2022 11.76[1.06; 2.92]16,3991,182not evaluable Neuro-developmental disorders (as a whole) Coste - Clonazepam (Mixed indications), 2020 Bjørk - Clonazepam (Mixed indications), 2022 21.31[1.03; 1.66]78,3712,428not evaluable Severe cognitive developmental delay (Mental retardation) (> 6 years old) Bjørk - Clonazepam (Mixed indications), 2022 11.76[1.06; 2.92]16,3991,182not evaluable Cognitive developmental disorders/delay (3-6 years old) Coste - Clonazepam (Mixed indications), 2020 10.60[0.19; 1.85]3,4011,246not evaluable Language disorders/delay Coste - Clonazepam (Mixed indications), 2020 10.90[0.72; 1.13]72,1091,246not evaluable Learning disorders Elkjaer - Clonazepam (Indications, NOS), 2018 11.14[1.00; 1.29]-101not evaluable Severe cognitive developmental delay (Mental retardation) (3-6 years old) Coste - Clonazepam (Mixed indications), 2020 10.60[0.19; 1.85]3,4011,246not evaluable0.0100.01.0

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