Benzodiazepines (Psy and mixed indications)

Exposed non-exposed studies (cohort)

Study	Country Study period	Population source	Exposure definition	Non-exposure definition	Sample size	Rmk
Ban (Controls unexposed, disease free), 2012	The United Kingdom (UK). 1990 - 2009	All clinically recognised singleton pregnancies among women aged 15– 45 years that ended in live birth, stillbirth, termination or miscarriage.	Pregnant women with prescriptions for any benzodiazepines (alone - i.e. no other psychotropic medication of interest) during the first trimester.	unexposed, disease free Pregnant women without any indication of current or prior depression or anxiety.	3392 / -9	Mothers were grouped into eight mutually exclusive categories according to their diagnostic and treatment status. Number of unexposed women not provided.
Ban (Controls unexposed, sick), 2012	The United Kingdom (UK). 1990 - 2009	All clinically recognised singleton pregnancies among women aged 15– 45 years that ended in live birth, stillbirth, termination or miscarriage.	Pregnant women with prescriptions for any benzodiazepines (alone - i.e. no other psychotropic medication of interest) during the first trimester.	unexposed, sick Pregnant women with un-medicated depression or anxiety, i.e with current depression or anxiety but no prescriptions during the first trimester.	3392 / -9	Mothers were grouped into eight mutually exclusive categories according to their diagnostic and treatment status. Number of unexposed women not provided.
Ban - Diazepam (Other indications) (Controls unexposed, disease free), 2014	The United Kingdom (UK) 1990 - 2010	All singleton live births for women aged 15–45 years included in the Health Improvement Network (THIN) (covering 5% of the total UK population).	Children born to women with prescription of diazepam (without concurrent prescriptions of antidepressants) in women’s primary care electronic health records from four weeks before the estimated onset of the last menstrual period up to 12 weeks.	unexposed, disease free Children born to women without depression or anxiety.	1159 / 351785	This study assessed 2 different benzodiazepines. In order to avoid redundancy of controls, only 1 was reported in the meta-analysis of class, i.e the substance with the most exposures (i.e Diazepam).
Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014	The United Kingdom (UK) 1990 - 2010	All singleton live births for women aged 15–45 years included in the Health Improvement Network (THIN) (covering 5% of the total UK population).	Children born to women with prescription of diazepam (without concurrent prescriptions of antidepressants) in women’s primary care electronic health records from four weeks before the estimated onset of the last menstrual period up to 12 weeks.	unexposed, sick Children born to women with depression or anxiety but with no first trimester psychotropic medication.	1159 / 19193	Unexposed sick: Depression or anxiety (including generalised anxiety disorder, panic attacks, insomnia and other anxiety related disorder) in the year before pregnancy or during pregnancy. Only Diazepam was reported in the class MA (control redundancy).
Bech - Clonazepam, 2018	Denmark 2005 - 2008	All births in Denmark were identified during the study period in the Danish Medical Birth Register and only offspring of mothers exposed to antiepileptic drugs were included.	Singleton offspring of mothers exposed to clonazepam monotherapy within 90 days prior to conception to birth. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed, sick Singleton offspring of mothers exposed to antiepileptic drugs at any time but not during pregnancy.	43 / 434
Bech - Clonazepam, 2014	Denmark 1997 - 2008	All clinically recognised pregnancies with an estimated date of conception and a known pregnancy outcome during the study period.	Pregnancies that never having a diagnosis of epilepsy and with a prescription of clonazepam redeemed during pregnancy.	unexposed (general population or NOS) Pregnancies that did not redeem any antiepileptic drug prescription in the exposure window.	219 / 812862	Data for women without epilepsy. High daily dose for different drugs was defined as: clonazepam >4 mg/day.
Bjorkstedt - BZDs, 2025	Finland 2009 - 2015	All Finnish primiparous women with no previous diagnosis of diabetes mellitus who delivered a singleton between 1 January 2009 and 31 December 2015.	Women who purchased benzodiazepine derivatives, anxiolytics (prescription of ATC code N05BA) during pregnancy.	unexposed (general population or NOS) Women who did not purchase benzodiazepine derivatives, anxiolytics (ATC code N05BA) during pregnancy.	199 / 5594
Bjørk - Clonazepam (Mixed indications), 2022	Danemark, Finland, Iceland, Norway and Sweden. 1996 - 2017	Singleton births born from mothers from five Nordic countries.	Pregnacies in mothers filling at least one clonazepam (antiepileptic) monotherapy prescription from her last menstrual period until birth. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed (general population or NOS) Pregnacies in mothers without antiseizure medication prescription from her last menstrual period until birth.	1182 / 4463879	Excluded twins and triplets for statistical reasons and children with chromosomal disorders diagnosed before end of follow-up. About 27% of pregnancies in epileptic women => considered as a mixed of indications.
Blotière - Clonazepam (Other indications), 2019	France 2011 - 2015	All pregnancies ending between the study period with at least 20 weeks of gestation.	Pregnancies exposed to clonazepam (antiepileptic) monotherapy between 1 month before and 2 months after the beginning of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed (general population or NOS) Pregnancies with no reimbursement for antiepileptic drugs.	980 / 1875733	Authors excluded twin pregnancies and pregnancies with a chromosomal abnormality identified. Less than 10% of exposed pregnancies have a proxy for epilepsy. Publication's OR were not kept when lower limit of the confidence interval or OR equal to 0.
Calderon-Margalit - BZDs, 2009	USA 1996 - nr	Pregnant mothers who initiated prenatal care before 20 weeks’ gestation and planned to deliver at either one of the two study hospitals.	Pregnant women who used Benzodiazepine during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed (general population or NOS) Pregnant women who did not use psychotropic medications during pregnancy.	85 / 2493	Of the women who were taking psychotropic medications, 235 (78%) took only one medication, 51 (17%) used two medications, and 14 (5%) used three or more medications.
Chan - BZDs, 2023	Hong Kong 2001 - 2018	All pregnancy episodes of women who delivered a live birth between January 1, 2001, and December 31, 2018.	Children exposed gestationally to benzodiazepines, i.e whose mothers were prescribed benzodiazepines during the pregnancy period.	unexposed (general population or NOS) Children whose mothers did not use sedatives during pregnancy.	1060 / 531164	'As some sedatives may be used for the management of epilepsies, the pregnancy episodes where mothers had a history of epilepsy were removed'.
Chen - BZDs (Controls unexposed, NOS), 2022	Taiwan 2004 - 2017	All live-born children with full-term births (>37 weeks).	Benzodiazepine exposure during pregnancy (first trimester to third trimester), defined as having at least one benzodiazepine prescription dispensed.	unexposed (general population or NOS) No benzodiazepine exposure during pregnancy.	76411 / 1440435	Authors provided 3 risk estimates per outcomes, according to trimester of exposure => Use of risk estimate with more exposed pregnancies (i.e, 1st trimester).
Chen - BZDs (Controls unexposed, sibling), 2022	Taiwan 2004 - 2017	All discordant pairs of differentially exposed siblings live-born children with full-term births (>37 weeks).	Sibling exposed to benzodiazepine in utero (first trimester to third trimester), defined as having at least one benzodiazepine prescription dispensed.	sibling Sibling unexposed to benzodiazepine in utero, in the same time frame.	26652 / 29233	Authors provided 3 risk estimates per outcomes, according to trimester of exposure => Use of risk estimate with more exposed pregnancies (i.e, 1st trimester).
Chen - BZDs (Controls unexposed, sick), 2022	Taiwan 2004 - 2017	Live-born children with full-term births (>37 weeks) of mothers with anxiety disorders or depression.	Children of mothers with anxiety disorders or depression with maternal benzodiazepine exposures during the first, second, and third trimester of pregnancy, defined as having at least one benzodiazepine prescription dispensed.	unexposed, sick Children of mothers with anxiety disorders or depression without maternal benzodiazepine exposures during pregnancy.	8963 / 30832	Authors provided 3 risk estimates per outcomes, according to trimester of exposure => Use of risk estimate with more exposed pregnancies (i.e, 1st trimester).
Christensen - Clonazepam (Indications NOS), 2013	Denmark 1996 - 2006	All children born alive in Denmark during the study period.	Children whose mothers have been exposed to clonazepam in (antiepileptic) monotherapy during the exposure window defined from 30 days before the estimated day of conception to the day of birth. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed (general population or NOS) Children whose mothers haven't been exposed to clonazepam during the exposure window defined from 30 days before the estimated day of conception to the day of birth.	269 / 655233	Indications not specified. Overlapping: For ASD diagnosis/risk : data of Christensen 2013 included in Bjork 2022 because longer study period and 5 countries => use of Bjork 2022 data for these 2 outcomes.
Christensen - Clonazepam (Indications NOS), 2019	Denmark 1997 - 2011	All singleton children born alive in Denmark during the study period.	Children whose mothers have been exposed to clonazepam in (antiepileptic) monotherapy during the exposure window defined from 30 days before the estimated day of conception to the day of birth. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed (general population or NOS) Children whose mothers haven't been exposed to antiepileptic drugs during the exposure window defined from 30 days before the estimated day of conception to the day of birth.	314 / 899941	Indications not specified.
Christensen - Clonazepam (Indications other than epilepsy), 2024	Denmark, Finland, Iceland, Norway, and Sweden 1996 - 2017	All live-born singletons born of women without epilepsy in the included countries during the study periods.	Children of mothers without epilepsy who had redeemed at least one prescription of Clonazepam monotherapy from 30 days before the first day of the last menstrual period to the date of birth (i.e., the exposure period).	unexposed (general population or NOS) Children of mothers without epilepsy who had not redeemed prescription of anti-seizure medication.	1019 / 4445621	This study assessed 2 benzodiazepines (BZDs), thus to avoid redundancy of controls, only 1 cannot be used in the BZDs meta-analysis, this one hith most exposed pregnancies (i.e Clonazepam).
Christensen - Clonazepam (Mixed indications), 2015	Denmark 1997 - 2008	All singleton live born children in Denmark during the study period.	Children whose mothers have been exposed to clonazepam (in antiepileptic monotherapy) during the exposure window defined from 30 days before the estimated day of conception to the day prior to birth. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed (general population or NOS) Children whose mothers have not been exposed to antiepileptic drugs (N03A (AEDs) and N05BA09 (clobazam)).	260 / 674115	76% of all exposed mothers have epilepsy (no specific information for clonazepam). Authors reported data for mono and/or polytherapy => Use of monotherapy data.
Chuang - BZDs, 2024	Taiwan 2004 - 2018	Pregnant people aged 15–50 years with singleton births between Jan 1, 2004, and Dec 31, 2018.	Pregnant people with use of benzodiazepines during the first trimester of pregnancy defined as at least one prescription of benzodiazepines.	unexposed, sick Pregnant people with no prescription for benzodiazepines from 30 days before the date of the estimated last menstrual period to the end of the first trimester.	50272 / 2632733	Use of confirmatory analyses for BZDs only (not concomitant use). After PS-FSW, same maternal conditions => control group considered as unexposed, sick.
Coste - Clonazepam (Mixed indications), 2020	France 2011 - 2014	All liveborn singleton children born during the study period. The mother had to be covered by the national health insurance general scheme for salaried workers and to have had at least one health expenditure reimbursement over the 2 years preceding the onset of pregnancy.	Children born from mothers exposed to clonazepam (antiepileptic) monotherapy with at least one dispensing between the month preceding onset of pregnancy and its end. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed (general population or NOS) Children born from mothers not exposed to any antiepileptic drug during pregnancy.	1246 / 1710441	Overlapping: Blotiere 2020 and Coste 2020 => same data, with more outcomes in Coste 2020 => Use of Coste 2020. Children with a diagnosis of brain malformation (ICD-10 codes Q00 to Q04 and Q05.0 to Q05.4) are excluded.
Delteil - BZDs (Controls unexposed, NOS), 2023	France 2004 - 2013	Children born alive during the study period in Haute-Garonne, included in the EFEMERIS database.	Children born of women with at least one prescription of benzodiazepines (ATC code N05BA and N05CD) during pregnancy.	unexposed (general population or NOS) Children born of women without prescription of benzodiazepines during the 3 months before pregnancy and during pregnancy.	2517 / 82163	Mainly monotherapy of BZD (90% with 1 different BZD) but co-exposure with antidepressants (27%), antipsychotics (7%°, antiseizure medications (3.8%).
Delteil - BZDs (Controls unexposed, sick), 2023	France 2004 - 2013	Children born alive during the study period in Haute-Garonne, included in the EFEMERIS database.	Children born of women with at least one prescription of benzodiazepines (ATC code N05BA and N05CD) during pregnancy.	unexposed, sick Children born of women with at least one prescription of benzodiazepines during the 3 months before pregnancy but not during pregnancy.	2517 / 1180	Mainly monotherapy of BZD (90% with 1 different BZD) but co-exposure with antidepressants (27%), antipsychotics (7%°, antiseizure medications (3.8%).
Elkjaer - Clonazepam (Indications, NOS), 2018	Denmark 1997 - 2006	All children born alive in Denmark between the study period.	Children with clonazepam monotherapy (among antiepileptics) prescribed and redeemed within the exposure window defined from 30 days before the first day of the last menstrual period to 1 day before birth. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed (general population or NOS) Children unexposed to any antiepileptic drugs in pregnancy.	188 / 477162	There is no information about the exposure indication.
Figueroa - BZDs, 2010	USA 1997 - 2006	Children and their families for which there was information on service utilization by the mother during pregnancy and by the children until they were 4 years old;	Children born to mothers with a prescription filled of Benzodiazepines during pregnancy.	unexposed, sick Children born to depressed mothers who were not exposed to antidepressants during pregnancy	311 / 3532
Freeman - BZDs, 2018	USA 2008 - 2018	Pregnant women with histories of psychiatric morbidity who are exposed and unexposed to psychiatric medications during pregnancy.	Pregnant women who reported any use of a benzodiazepine (alprazolam, clonazepam, diazepam, lorazepam, and temazepam) anytime during pregnancy.	unexposed, sick Pregnant women who remained unexposed to benzodiazepines during the full pregnancy.	144 / 650	Women who used a benzodiazepine during pregnancy: 21.5% of exposed women having anxiety as their primary diagnosis and 74.1% having anxiety as a primary or secondary diagnosis.
Hartz - Chlordiazepoxide, 1975	USA 1958 - 1966	Pregnancies and their outcomes seen in one of the 12 university-affiliated hospitals.	Children exposed in utero to Chlordiazepoxide.	unexposed (general population or NOS) Children not exposed in utero to Chlordiazepoxide or Meprobamate.	740 / 48412	Overall mortality cannot be reported because the total number of exposed pregnancies considered for this outcome was not clearly provided; and Neurodevelopmental data cannot reported because only means were provided.
Hironaka - BZDs (Control exposed to Atypical antipsy), 2011	Japan 2005 - 2009	Female patients who delivered at Nagoya University Hospital.	Women with mental disorders (but without any other complications) taking benzodiazepines. (This is a subgroup of exposure among the whole exposed group considered in the study).	exposed to other treatment, sick Women with mental disorders (but without any other complications) taking atypical antipsychotics. (This is a subgroup of exposure among the whole exposed group considered in the study).	5 / 9
Hironaka - BZDs (Control unexposed, disease free), 2011	Japan 2005 - 2009	Female patients who delivered at Nagoya University Hospital.	Women with schizophrenia (but without any other complications) taking benzodiazepines. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed, disease free Women without mental disorders.	5 / 278
Hironaka - BZDs (Control unexposed, sick), 2011	Japan 2005 - 2009	Female patients who delivered at Nagoya University Hospital.	Women with schizophrenia (but without any other complications) taking benzodiazepines. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed, sick Women with schizophrenia without medication during pregnancy.	5 / 3
Huybrechts - BZDs, 2017	USA 2000 - 2010	All pregnancies in women aged 12- 55 who were linked to a liveborn infant and who required to have filled at least one outpatient prescription for an opioid analgesic during the 45 days before delivery.	Pregnant women who required for an opioid analgesic prescription and also filled a prescription for benzodiazepines during the 45 days before delivery.	unexposed, sick Pregnant women who received opioids but who did not fill an outpatient prescription for the psychotropic medication of interest during the 180 days before delivery.	5361 / 191863	They also tended to have a higher cumulative dose of opioids during the last 45 days of their pregnancy, which was most prominent for users of benzodiazepines (mean dose 1352 mg v 291 mg oral morphine equivalents)
Jackson - BZDs, 2024	U.S.A 2019 - 2022	All pregnant patients who delivered at 23 weeks of gestational age or greater at seven hospitals within a large academic health system in New York.	Prenatal exposure to a monotherapy of benzodiazepines (alprazolam, diazepam, lorazepam).	unexposed, disease free No prenatal exposure to benzodiazepines (alprazolam, diazepam, lorazepam).	542 / 106564
Källén - BZDs, 2013	Sweden 1996 - 2011	Nearly all births in Sweden during the study period (1,575,847) are registered in The Swedish Medical Birth Register.	Infants whose mothers used benzodiazepines during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed (general population or NOS) Infants in population whose mothers used at least one of a central nervous system active drugs (less than 3%) or weren't exposed in early pregnancy.	2537 / 1575847	Overlapping: Kallen 2012 (2006-2008) and Reis 2013 (1995-2008) almost included in Kallen 2013 (1995-2011), with more pregnancies and outcomes in Kallen 2013 => Kallen 2013 used. Follow-up period known thanks to author's email reply.
Kelty - Alprazolam (Controls unexposed, disease free), 2023	Australia 2014 - 2018	All women who had given birth during the study period.	All women who had been dispensed two or more scripts of alprazolam during pregnancy, with a combined minimum of 40 tablets.	unexposed, disease free Women who had no record of alprazolam dispensing at any time.	48 / 96	Women in this group were dispensed a median of four prescriptions during pregnancy (IQR: 2–6), with a median of 200 tablets (IQR: 100–357) dispensed during pregnancy.
Kelty - Alprazolam (Controls unexposed, sick), 2023	Australia 2014 - 2018	All women who had given birth during the study period.	All women who had been dispensed two or more scripts of alprazolam during pregnancy, with a combined minimum of 40 tablets.	unexposed, sick All women who had been dispensed alprazolam prior to conception or following birth (but not during pregnancy)	48 / 96	Women in this group were dispensed a median of four prescriptions during pregnancy (IQR: 2–6), with a median of 200 tablets (IQR: 100–357) dispensed during pregnancy.
Kilic - Clonazepam (Mixed indications), 2014	Denmark 1997 - 2008	All singleton live-born children in Denmark during the study period.	Children whose mothers have been exposed to clonazepam (in antiepileptic monotherapy) during the exposure window defined from 30 days before the estimated day of conception to the day prior to birth. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed (general population or NOS) Children whose mothers have not been exposed to antiepileptic drugs ((ATC) N03A (AEDs) and N05BA09 (clobazam)) 30 days before the estimated day of conception to the day of birth.	262 / 676834	Less than 90% of women are epileptic. Less than 90% of women are epileptic. For LBW and SGA: overlapping between Kilic (1997 - 2008) and Christensen (1997–2017), with more pregnancies in Christensen => LBW and SGA not reported here.
Laegreid a - BZDs, 1992	Sweden 1984 - 1986	Children of mothers identified by the doctors at the general maternity outpatient unit and the obstetricians at the 2 delivery departments and by psychiatrists in the city of Gothenburg.	Children with maternal use of benzodiazepines (BZD) only during pregnancy.	unexposed, disease free Children born of mothers who had no recorded psychiatric disease and without use of psychotropic drugs during pregnancy, randomly selected from 3 maternal welfare centers in Gothenburg.	17 / 29	Fifteen of these mothers used oxazepam (15-60 mg daily) or diazepam (5-30 mg daily) alone or in combination and 1 mother lorazepam (5-15 mg daily). All BZD group diagnosed as having a psychiatric disease; 2 depression and 14 anxiety.
Laegreid b - BZDs, 1992	Sweden 1984 - 1986	Children of mothers identified by the doctors at the general maternity outpatient unit and the obstetricians at the 2 delivery departments and by psychiatrists in the city of Gothenburg.	Children with maternal use of benzodiazepines (BZD) only during pregnancy.	unexposed, disease free Children born of mothers who had no recorded psychiatric disease and without use of psychotropic drugs during pregnancy, randomly selected from 3 maternal welfare centers in Gothenburg.	17 / 29	Fifteen of these mothers used oxazepam (15-60 mg daily) or diazepam (5-30 mg daily) alone or in combination and 1 mother lorazepam (5-15 mg daily). All BZD group diagnosed as having a psychiatric disease; 2 depression and 14 anxiety.
Lee - Alprazolam, 2022	South Korea 2000 - 2019	Pregnant women who participated in in the Mother-Safe Program, a teratogen information service that provides evidence-based information on the safety and risk of exposure during pregnancy.	Pregnant women exposed to alprazolam during pregnancy.	unexposed (general population or NOS) Pregnant women exposed to non-teratogenic drugs including acetaminophen and chlorpheniramine during pregnancy.	96 / 629	The main reasons for taking alprazolam were irritable: bowel syndrome (IBS) (20.8%), depression (16.7%), and common cold (12.5%). Cumulative doses during pregnancy ranged from 1.00 mg/kg to 61.00 mg/kg (median 16.00 mg/kg).
Lupattelli - BZDs, 2019	Norway 1999 - 2008	Live-birth, singleton pregnancy-child dyads within women self-reporting depressive/anxiety disorders, or sleeping problems, or pain-related disorders.	Pregnant women who reported the use of any Benzodiazepines during pregnancy on at least one of the three questionnaires.	unexposed, sick Pregnant women who did not report the use of Benzodiazepines or z-hypnotics during pregnancy.	68 / -9	For BZD: data available for Depressive/Anxiety Disorder Stratuma. Indications in the total cohort (BZD and/or z-hypnotic): depressive/anxiety, sleeping, and pain disorders. Ages and Stages Questionnaire not indexed because scale not enough informative.
Meng a - BZDs (Controls unexposed, sibling), 2023	Taiwan 2004 - 2018	All singleton pregnancies of females aged 15–50 years who gave birth during the study period.	Sibling with at least one benzodiazepine prescription received by the mother during early pregnancy (the first 20 weeks of pregnancy).	sibling Discordant matched sibling without benzodiazepine or Z-hypnotic prescriptions from 30 days before the date of the estimated last menstrual period to the end of the 20th week of pregnancy.	-9 / -9	Number of exposures not provided (authors provided number of Exposure discordant pairs and number of Case discordant pairs).
Meng a - BZDs (Controls unexposed, sick), 2023	Taiwan 2004 - 2018	All singleton pregnancies of females aged 15–50 years who gave birth during the study period.	At least one benzodiazepine prescription received by a mother during early pregnancy (the first 20 weeks of pregnancy).	unexposed, sick Pregnant women with no benzodiazepine or Z-hypnotic prescriptions from 30 days before the date of the estimated last menstrual period to the end of the 20th week of pregnancy.	61975 / 2772076	Use of results obtained with PS-FSW because more exposures, with a sick control group and sensitivity analyses (sibling control study, and paternal negative control design) that obtained similar results.
Meng b - BZDs, 2023	Taiwan 2004 - 2018	Women with pregnancies from both the two national health databases.	Women receiving at least 1 prescription of benzodiazepine during the risk period only (1-28 days before miscarriage).	unexposed, sick Women receiving at least 1 prescription of benzodiazepine during the reference period only (181-208 days before the last menstrual period).	136134 / 134864	Use of Case-Time-Control (CTC) Design OR => nb of exposures/cases/controls not applicable; and the main Reference period, i.e 181 to 208 days before the last menstrual period.
Milkovich - Chlordiazepoxide, 1974	USA 1959 - 1966	Pregnant women with minor psychoneurotic compliants who reported for prenatal care at the East San Francisco Bay Area facilites of the Kaiser program.	Pregnant women who received prescriptions of Chlordiazepoxide, for anxiety, during pregnancy.	unexposed, sick Pregnant women with no prescription of Chlordiazepoxide, for anxiety, during the first 42 days of pregnancy (and very few were given between the 43rd and the 84th days).	175 / 509
Mortensen - BZDs, 2003	Denmark 1991 - 1996	Pregnant women gave birth to a child	Pregnant women who had redeemed prescriptions for benzodiazepines during pregnancy.	unexposed (general population or NOS) Randomly selected pregnant women who had not redeemed any prescriptions on psychotropic or anti-epileptic drugs during their pregnancy.	82 / 1304	Estimates did not significantly changed when authors analysed the data after excluding the part of the Boel test related to hearing.
Noh - BZDs, 2022	South Korea 2011 - 2018	All pregnancies in women aged 20 to 45 years at delivery resulting in live births from 1 January 2011 to 31 December 2018, in South Korea.	Pregnant women who filled at least one benzodiazepine prescription during the first trimester (first 90 days of pregnancy).	unexposed, sick Pregnant women who were not prescribed any benzodiazepine from 3 months before the last menstrual period to the end of the first trimester (with similar psychiatric conditions after propensity score).	40846 / 3053381	For major and heart malformations: use of monotherapy results. Propensity scored adjusted for indications and led to an unexposed cohort with similar psychiatric conditions => considered as unexposed, sick control groups.
Oberlander - BZDs, 2008	Canada 1997 - 2002	About (92.7%) all live births (hospital and home births) in British Columbia during the study period.	Infants exposed to Benzodiazepines only in the first trimester of pregnancy.	unexposed (general population or NOS) Infants with no exposure to either of these drugs (serotonin reuptake inhibitor SRI or benzodiazepine) in the first trimester of pregnancy.	968 / 107320	Data on Benzodiazepines only (n=968) used rather than SRI’s and benzodiazepines (n=359). Lorazepam and clonazepam the most frequent benzodiazepines prescribed during the first trimester.
Oberlander - Clonazepam (Controls unexposed, disease free), 2004	Canada 1996 - 2000	Mothers and their infants studied during pregnancy as a part of a larger study of the effects of psychotropic medication use during and following pregnancy.	Infants prenatally exposed to Selective serotonin reuptake inhibitors (SSRIs) combined with the benzodiazepine clonazepam.	unexposed, disease free Term-born infants whose mother did not use psychotropic or antidepressant medications during pregnancy, without history of maternal mental illness and with no other serious comorbid pathology).	18 / 23	Overlapping: psychomotor and cognitive outcomes in Reebye 2002; 2012 and special neonatal care in Misri 2004 totally included in Oberlander 2004 thus these outcomes extracted from Oberlander 2004 (more details and little more exposures).
Oberlander - Clonazepam (Controls unexposed, sick), 2004	Canada 1996 - 2000	Mothers and their infants studied during pregnancy as a part of a larger study of the effects of psychotropic medication use during and following pregnancy.	Infants prenatally exposed to Selective serotonin reuptake inhibitors (SSRIs) combined with the benzodiazepine clonazepam.	unexposed, sick Infants prenatally exposed to Selective serotonin reuptake inhibitors (SSRIs) alone.	18 / 28	Overlapping: psychomotor and cognitive outcomes in Reebye 2002; 2012 and special neonatal care in Misri 2004 totally included in Oberlander 2004 thus these outcomes extracted from Oberlander 2004 (more details and little more exposures).
Ornoy - BZDs, 1998	Israel 1988 - 1996	All women contacted the Israeli Teratogen Information Service (ITIS) regarding information on the possible risk to the developing embryo and fetus.	Pregnant women exposed to benzodiazepines.	unexposed, disease free Healthy pregnant women with nonteratogenic exposures.	460 / 424	The vast majority of women (98%) took the drugs in the first trimester of pregnancy => considered as at least 1st trimester exposure (30% entire pregnancy).
Radojcic - BZDs, 2017	The Netherlands. 2002 - 2006	All pregnant women resident in Rotterdam and whose delivery date was from April 2002 to January 2006.	Pregnant women with any use of benzodiazepines during pregnancy, assessed by self-reports and prescription records.	unexposed, disease free Pregnant women with no exposure to Benzodiazepines and benzodiazepine-related medications (BBRMs) and exposed to a low score of maternal anxiety or phobic anxiety symptoms.	104 / 5609	According to prescription records: benzodiazepine-related medication were largely in minority (< 10%) compared to benzodiazepines => Considered as benzodiazepines.
Salisbury - BZDs (Controls unexposed, disease free), 2016	USA Not specified.	Singleton pregnant women between 18 and 40 years old, 23–34 weeks gestation with a healthy singleton pregnancy (without illicit drugs, drugs for hypertension or diabetes, ...).	Infants of women who use Selective serotonin reuptake inhibitors (SSRI) with concomitant benzodiazepine for at least 4 weeks at any time during pregnancy among women with a current or lifetime diagnosis of a unipolar mood disorder.	unexposed, disease free Infants of women who did not meet criteria for any psychiatric disorder or report use of psychotropic medications during their entire pregnancy.	10 / 66	Stress-abstinence signs; hypertonia and hypotonia => not reported because continuous data. Exposed group: fetal exposure status in utero was SSRI use with concomitant benzodiazepine use (6 Lorazepam; 2 Clonazepam and 2 Alprazolam).
Salisbury - BZDs (Controls unexposed, sick), 2016	USA Not specified.	Singleton pregnant women between 18 and 40 years old, 23–34 weeks gestation with a healthy singleton pregnancy (without illicit drugs, drugs for hypertension or diabetes, ...).	Infants of women who use Selective serotonin reuptake inhibitors (SSRI) with concomitant benzodiazepine for at least 4 weeks at any time during pregnancy among women with a current or lifetime diagnosis of a unipolar mood disorder.	unexposed, sick Infants of women pharmacologically untreated maternal depression.	10 / 56	Stress-abstinence signs; hypertonia and hypotonia => not reported because continuous data. Exposed group: fetal exposure status in utero was SSRI use with concomitant benzodiazepine use (6 Lorazepam; 2 Clonazepam and 2 Alprazolam).
Shiono - Diazepam, 1984	USA Not specified.	Not specified.	Pregnant women that had used diazepam during the first trimester of pregnancy.	unexposed (general population or NOS) Pregnant women that had not used diazepam during the first trimester of pregnancy.	854 / 32395
Szpunar - BZDs, 2022	USA 2008 - 2021	Pregnant women recruited through provider referral, self‐referral, and the Massachusetts General Hospital (MGH) Center for Women's Mental Health website.	Pregnant women who took a benzodiazepine during the first trimester of pregnancy, which included the benzodiazepines alprazolam, clonazepam, diazepam, lorazepam, and temazepam.	unexposed, sick Pregnant women with psychiatric disorder(s) who did not take any benzodiazepines during pregnancy (but who were treated with other psychotropic medications, such as antipsychotics, antidepressants, and/or stimulants, in similar proportion than exposed group => considered unexposed, sick).	151 / 902	Chromosomal and single‐gene abnormalities and minor anomalies are excluded from the analysis. Participants who did not complete the study due to elective termination of pregnancy after determination of a fetal malformation were included in the analysis.
The NAAED - Clonazepam, 2023	North America and Canada 1997 - 2023	Pregnant women who are taking an antiepileptic drug for any reason and had a liveborn infant, a stillborn infant, or a pregnancy terminated because of a fetal abnormality and enrolled as 'pure' or 'traditional' enrollees.	Infants of pregnant women who used Clonazepam as monotherapy, during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed, disease free Infants of pregnant women, not taking an antiepileptic drug and without epilepsy, who were recruited from among the friends and family members of the enrolled women taking an antiepileptic drug.	120 / 1330	Study design completed with the publication of Hernández-Díaz et al. 2012. Data extracted from the North American AED pregnancy registry website. Overlapping/update with Hernández-Díaz et al. 2012 and previous website reports. Use of internal control.
Veiby - Clonazepam (Mixed indications), 2014	Norway 1999 - 2011	All deliveries in Norway at 12 or more weeks of gestation, recorded in the database during the study period.	Children exposed prenatally to clonazepam as (antiepileptic) monotherapy indicated for their mothers' epilepsy or other indications. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed, disease free All unexposed children born to women without epilepsy.	113 / 771412	Among the 113 pregnancies exposed to clonazepam, 40 were epileptic and 73 not => less than 90% of women are treated with Clonazepam for epilepsy (considered as a mixed of indications)
Viggedal - BZDs, 1993	Sweden 1984 - 1986	Children of mothers identified by the doctors at the general maternity outpatient unit and the obstetricians at the 2 delivery departments and by psychiatrists in the city of Gothenburg.	Children with maternal use of benzodiazepines (BZD) only during pregnancy.	unexposed, disease free Children born of mothers who had no recorded psychiatric disease and without use of psychotropic drugs during pregnancy, randomly selected from 3 maternal welfare centers in Gothenburg.	17 / 29	Exposed mothers had a psychiatric diagnosis including anxiety disorder, predominantly panic disorder (DSM-III-R 300.01) in 14, and depressive disorder (DSM-III-R 311.00) in 2.
Yamane - Etizolam, 2011	Japan Not specified.	Pregnant women who visited the Counseling Clinic for Pregnancy and Medicine of Toranomon Hospital.	Pregnant women who used Etizolam in the early stage of pregnancy.	unexposed (general population or NOS) Pregnant women who used acetaminophen without teratogenic effects.	224 / -9	Number of pregnant women in the control group not provided in the Abstract.
Yonkers - BZDs, 2017	USA 2005 - 2009	Pregnant women of at least 18 years of age and that had not yet reached 17 weeks of pregnancy.	Pregnant women positive for depressive episode in past 5 years or antidepressant treatment, using benzodiazepine during pregnancy.	unexposed (general population or NOS) Pregnant women not using benzodiazepine.	67 / -9	Overlapping: Yonkers 2014 (that studied only one outcome (preterm)) totally included in Yonkers 2017. At any point in pregnancy, 67 women underwent benzodiazepine (56 in the first trimester, 15 in the second trimester, and 11 in the third trimester).
Zanisi - BZDs, 2022	Italy 2018 - 2020	Pregnant women who contacted the Bergamo Teratology Information Service (TIS) between 1 January 2018 and 31 December 2020.	Pregnant women exposed to benzodiazepines alone.	unexposed (general population or NOS) Pregnant women exposed to acetaminophen/amoxicillin.	99 / 158

Case-control studies (cohort)

Study	Country Study period	Case	Control	Sample size	Rmk
Aarskog - Diazepam, 1975	Norway 1967 - 1975	Infants with oral clefts only (without additional major birth defects).	Infants without malformations.	-9 / 362
Bonnot - Bromazepam, 2003	France 1976 - 1997	Infants with the studied congenital malformation.	Infants with a malformations other than this one studied.	-9 / -9	Total number of infants with a congenital malformation is 13703, but the number of cases changes according to the studied malformations. Raw data not sufficient to calculate OR (data for 'control' groups not available).
Bonnot - BZDs, 2001	France 1976 - 1998	Infants with the studied congenital malformation.	Infants with a malformations other than this one studied.	-9 / -9	Data completed with Bonnot 2003. Total number of infants with a congenital malformation is 13703, but the number of cases changes according to the studied malformations. Raw data not sufficient to calculate OR (data for 'control' groups not available).
Bonnot - Clorazepate, 2003	France 1976 - 1997	Infants with the studied congenital malformation.	Infants with a malformations other than this one studied.	-9 / -9	Total number of infants with a congenital malformation is 13703, but the number of cases changes according to the studied malformations. Raw data not sufficient to calculate OR (data for 'control' groups not available).
Bonnot - Lorazepam, 2003	France 1976 - 1997	Infants with the studied congenital malformation.	Infants with a malformations other than this one studied.	-9 / -9	Total number of infants with a congenital malformation is 13703, but the number of cases changes according to the studied malformations. Raw data not sufficient to calculate OR (data for 'control' groups not available).
Bonnot - Oxazepam, 2001	France 1976 - 1998	Infants with the studied congenital malformation.	Infants with a malformations other than this one studied.	-9 / -9	Data completed with Bonnot 2003. Total number of infants with a congenital malformation is 13703, but the number of cases changes according to the studied malformations. Raw data not sufficient to calculate OR (data for 'control' groups not available).
Bonnot - Prazepam, 2003	France 1976 - 1997	Infants with the studied congenital malformation.	Infants with a malformations other than this one studied.	-9 / -9	Total number of infants with a congenital malformation is 13703, but the number of cases changes according to the studied malformations. Raw data not sufficient to calculate OR (data for 'control' groups not available).
Bonnot - Temazepam, 2003	France 1976 - 1997	Infants with the studied congenital malformation.	Infants with a malformations other than this one studied.	-9 / -9	Total number of infants with a congenital malformation is 13703, but the number of cases changes according to the studied malformations. Raw data not sufficient to calculate OR (data for 'control' groups not available).
Bracken - Diazepam, 1981	USA 1974 - 1976	All newborns and stillborns with major congenital malformations, delivered at 5 major Connecticut hospitals and at 2 pediatric clinics or delivered elsewhere and referred to the 5 hospitals before 1 year of age.	Sampling of all apparently healthy live births in the 5 major Connecticut hospitals, randomly selected (subsequent ones from the delivery room log book).	1370 / 2968	This study assessed 2 different benzodiazepines. In order to avoid redundancy of controls, only 1 was reported in the meta-analysis of class, i.e the substance with the most exposed cases (i.e Diazepam).
Cifuentes - Alprazolam, 2025	Europe (13 countries) 1995 - 2019	Registrants (liveborn, stillborn, or induced terminations) with congenital ocular anomalies (COA).	Registrants with major congenital anomalies (excluding genetic syndromes) other than congenital ocular anomalies (COA) and nervous system anomalies (except spina bifida) as central nervous system development is closely linked to eye development.	4185 / 232718	Use of nongenetic controls (cases of CA other than COA excluding genetic syndromes),
Cornel - BZDs - MACDP, 1996	USA 1968 - 1980	Babies born with a cleft lip with or without cleft palate.	Healthy control babies.	-9 / 3029
Cornel - Oxazepam - The NNL registry, 1996	The Netherlands 1981 - 1994	Infants with a cleft lip with or without cleft palate.	All infants notified with other anomalies.	277 / 3737
Correa-Villasenor - BZDs, 1994	USA 1981 - 1989	Liveborn infants with Ebstein's anomaly of the tricuspid valve.	infants without cardiovascular malformations (CVM) selected from area hospitals by a computer algorithm to achieve a representative sample of the regional livebirth cohort.	44 / 3572
Czeizel - Diazepam, 2003	Hungary 1980 - 1996	Newborn infants with isolated congenital abnormality (CA) and multiple CA. Exclusions of some mild congenital abnormalities and minor congenital abnormality (methods in Czeizel 1999).	Two newborn infants without congenital anomalies matched to every case according to sex, birth week in the year when the case was born, and district of parents’ residence from the National Birth Registry of the Central Statistical Office.	22865 / 38151	Overlapping: same data used by Kjaer 2007. The main analysis (both maternal self-reported and medically recorded) was reported here (even if the only medically recorded (logbooks and discharge summaries) was also evaluated separately).
Czeizel - Diazepam, 1987	Hungary 1970 - 1976	Infants born with facial clefting born during the study period.	Infants born witout facial clefting born during the study period.	1201 / 1201	Use of Retrospective case control study. This study assessed 3 different benzodiazepines. In order to avoid redundancy of controls, only 1 was reported in the meta-analysis of class, i.e the substance with the most exposed cases (i.e Diazepam).
Greenberg - BZDs, 1977	United Kingdom (England and Wales). 1969 - 1974	Children with congenital abnormalities (all minor malformations were eliminated).	Children without congenital abnormalities born in the same practice within 3 months of the date of birth of an abnormal baby.	836 / 836
Ishikawa - BZDs, 2024	Japan 2005 - 2022	Women whose pregnancies ended in a miscarriage that occurred between the beginning of the fourth and 22nd weeks of gestation.	Women randomly selected from the entire cohort of pregnancies by risk-set sampling with replacement and were individually matched to the cases (3:1).	44118 / 132317	Exposure to benzodiazepines was used as a positive control.
Kullander - Chlordiazepoxide, 1976	Sweden 1963 - 1965	Infants with different kinds of malformations.	Infants without malformations.	751 / 5002
Laegreid - BZDs, 1990	Sweden 1985 - 1986	Infants born alive in the study period with one or more of the selected diagnoses (embryopathy and fetopathy, unspecified; unspecified congenital malformations of the nervous system; cleft palate and cleft lip; and congenital malformations of the urinary tract).	The next child to be born after a study child, and who survived the neonatal period.	25 / 109	The following BZD were included in the screening: DZP, desmethyl-diazepam (d-m-DzP), fluni- trazepam, oxazepam (OZP), clonazepam, nitrazepam and lorazepam.
Laegreid c - BZDs, 1992	Sweden 1985 - 1986	Pregnancies resulting in perinatally dead infants (stillborn and neonatal death.	Pregnancies resulting in surviving infants born immediately after each perinatally dead infant.	73 / 73	73 perinatal deaths (39 stillborn and 34 neonatally dead).
Laspro - BZDs, 2024	USA 2013 - 2023	Newborns with oral clefts (ICD 10 codes Q35 or Q36 or Q37).	Newborns without oral clefts.	12098 / -9	P-values were calculated, while to account for multiple testing (693 hypotheses) Benjamini-Hochberg (BH) corrections were performed with a false discovery rate (Q) of 0.05 => use of Table 4. Bejamini Hochberg Correction when available.
Ogawa - BZDs, 2018	Japan 2005 - 2014	Mothers who had experienced preterm birth or had given birth to a low birth weight infant.	Mothers who had neither experienced preterm birth nor had given birth to a low birth weight infant, as recorded in the claims data.	1615 / 40224
Robert - BZDs, 1994	Australia, France, Israel, Italy Japan, and South America. 1990 - 1991	Infants with malformations of the a specific type.	Infants with malformations of another type than that under study.	-9 / -9	The number of cases and controls depends on the malformation studied.
Rosenberg - Diazepam, 1983	USA 1976 - 1982	Children with oral clefts (cleft lip with or without cleft palate; cleft palate alone).	Children with all other malformations.	611 / 2498	Cases of cleft lip with or without cleft palate: n= 445; and cases of cleft palate alone: n=166.
Rothman - Diazepam, 1979	USA 1973 - 1975	All infants with congenital heart disease born to Massachusetts women.	Births selected randomly from the roster of all Massachusetts births.	390 / 1254	This study assessed 2 different benzodiazepines. In order to avoid redundancy of controls, only 1 was reported in the meta-analysis of class, i.e the substance with the most exposed cases (i.e Diazepam). Use of 90% confidence interval provided.
Safra - Diazepam, 1975	USA 1970 - ?	All interviewed mothers who had infants with the birth-defect rubric being examined (in particular cleft lip with or without cleft palate).	All interviewed mothers except those who had infants with the birth-defect rubric being examined.	49 / 229	Overlapping for Cleft lip with or without cleft palate: Safra 1975 (1970- ? but before 1975) probably included in Cornel 1996 (1968 - 1980) => Outcome not reported here.
Saxen - BZDs, 1975	Finland 1967 - 1971	Children with oral clefts.	Children without oral clefts chosen for each study child by matching according to season of birth and domicile of the mother.	599 / 590
Sheehy - BZDs (Controls unexposed, NOS), 2019	Canada 1998 - 2015	Pregnancies ending with spontaneous abortion (pregnancy loss between between the beginning of the sixth week of gestation and the 19th completed week of gestation, excluding planned or induced abortions).	Pregnancies ending with live births (5 for each case) randomly selected at the index date and matched with the case pregnancy by gestational age and calendar year.	27149 / 134305	Among the 1163 pregnancies exposed to benzodiazepines in early pregnancy, 1128 (97.0%) women received only 1 specific benzodiazepine agent and 897 (77.1%) had only 1 prescription filled.
Sheehy - BZDs (Controls unexposed, sick), 2019	Canada 1998 - 2015	Pregnancies with mood and anxiety disorders ending with spontaneous abortion (pregnancy loss between between the beginning of the sixth week of gestation and the 19th completed week of gestation, excluding planned or induced abortions).	Pregnancies with mood and anxiety disorders ending with live births (5 for each case) randomly selected at the index date and matched with the case pregnancy by gestational age and calendar year.	3419 / 12533	Extraction of data of eTable 9. Association Between Benzodiazepine Exposure During Early Pregnancy and the Risk of Spontaneous Abortion Among Pregnancies of Women With Mood and Anxiety Disorders Diagnosis in the 12 Months Before LMP Until Index Date.
Tikkanen - Diazepam, 1991	Finland 1982 - 1983	All infants born in Finland with a ventricular septal defect (VSD),diagnosed between the 20th week of gestation and one year of age, and verified by paediatric cardiologists.	Non-malformed infants randomly selected from all deliveries.	150 / 756
Tikkanen - Diazepam, 1992	Finland 1982 - 1983	All infants born in Finland with a conus arteriosus syndrome (CAS), diagnosed between the 20th week of gestation and one year of age, and verified by paediatric cardiologists.	Non-malformed infants randomly selected from all deliveries.	90 / 756
Tikkanen - Diazepam, 1992	Finland 1982 - 1983	Infants (live and stillbirths) with cardiovascular malformations, diagnosed by echocardiography, cardiac catheterization, surgery, or autopsy.	Non-malformed infants randomly selected from all deliveries.	406 / 756
Tinker - BZDs, 2019	USA 1997 - 2011	Live bom, stillborn, or induced terminations with at least one of the 30 different birth defects (excluding chromosomal or monogenic disorders) diagnosed prenatally, at birth, or during the first year of life.	Liveborn infants without major birth defects identified on the same catchment area and month of birth as the cases.	-9 / 11614	Total number of cases not provided by authors (number of cases provided for each kind of malformations or group of malformations).
Winship - BZDs, 1984	United Kingdom Jan 1981 - Dec 1981	Child (liveborn and stillborn) with actual or suspected defects, notified at the Committee on Safety of Medicines (CSM).	Liveborn child without a congenital abnormality from the same medical practice.	764 / 764

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