| Study | Country Study period Study design |
Data source | Exposure definition | Non-exposure definition | Exposition period | Sample size (exposed/unexposed) Or (case / control) |
Remarks | Risk of bias |
|---|---|---|---|---|---|---|---|---|
|
Ban (Controls unexposed, disease free) 2012 |
The United Kingdom (UK). 1990 - 2009 population based cohort retrospective |
The Health Improvement Network (THIN), a nationally representative database of computerised primary care medical records collected at 446 general practices (primary health care units). | 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. |
during pregnancy (anytime or not specified) | 3392 / -9 | Mothers were grouped into eight mutually exclusive categories according to their diagnostic and treatment status. Number of unexposed women not provided. | |
| Prescriptions of all antidepressants, hypnotics, and anxiolytics extracted of The Health Improvement Network (THIN) that contains electronic medical records. | ||||||||
|
Ban (Controls unexposed, sick) 2012 |
The United Kingdom (UK). 1990 - 2009 population based cohort retrospective |
The Health Improvement Network (THIN), a nationally representative database of computerised primary care medical records collected at 446 general practices (primary health care units). | 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. |
during pregnancy (anytime or not specified) | 3392 / -9 | Mothers were grouped into eight mutually exclusive categories according to their diagnostic and treatment status. Number of unexposed women not provided. | |
| Prescriptions of all antidepressants, hypnotics, and anxiolytics extracted of The Health Improvement Network (THIN) that contains electronic medical records. | ||||||||
|
Ban - Diazepam (Other indications) (Controls unexposed, disease free) 2014 |
The United Kingdom (UK) 1990 - 2010 retrospective cohort (claims database) |
The Health Improvement Network (THIN), UK. | 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. |
1st trimester | 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). | |
| Exposure was obtained from The Health Improvement Network (THIN), where anonymised children’s and mothers’ medical records from 495 general practices throughout the UK were linked. Prescriptions are automatically entered. | ||||||||
|
Ban - Diazepam (Other indications) (Controls unexposed, sick) 2014 |
The United Kingdom (UK) 1990 - 2010 retrospective cohort (claims database) |
The Health Improvement Network (THIN), UK. | 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. |
1st trimester | 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). | |
| Exposure was obtained from The Health Improvement Network (THIN), where anonymised children’s and mothers’ medical records from 495 general practices throughout the UK were linked. Prescriptions are automatically entered. | ||||||||
|
Bech - Clonazepam 2014 |
Denmark 1997 - 2008 population based cohort retrospective |
The Danish medical birth register, the Danish national hospital discharge register and the Danish Register of Medicinal Product Statistics. | 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. |
1st and 2nd trimester | 219 / 812862 | Data for women without epilepsy. High daily dose for different drugs was defined as: clonazepam >4 mg/day. | |
| Use of antiepileptic drugs are identified in the Danish Register of Medicinal Product Statistics which comprises records of all prescriptions redeemed. | ||||||||
|
Bech - Clonazepam 2018 |
Denmark 2005 - 2008 population based cohort propective |
The Danish Prescription Register, the Danish Medical Birth Register, the Danish Psychiatric Central Research Register and Danish National Patient Registry. | 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. |
during pregnancy (anytime or not specified) | 43 / 434 | ||
| The Danish National Prescription Register was used to obtain data on redeemed prescriptions using Anatomical Therapeutic Chemical (ATC) codes. | ||||||||
|
Bjorkstedt - BZDs 2025 |
Finland 2009 - 2015 retrospective cohort (claims database) |
A register-based cohort study conducted in the city of Vantaa, Finland (Helsinki metropolitan area), by linking the Finnish Medical Birth Register, the Finnish Social Insurance Institution and the Register on Congenital Malformations. | 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. |
during pregnancy (anytime or not specified) | 199 / 5594 | ||
| Purchase dates and ATC codes were obtained through Finnish Social Insurance Institution. | ||||||||
|
Bjørk - Clonazepam (Mixed indications) 2022 |
Danemark, Finland, Iceland, Norway and Sweden. 1996 - 2017 population based cohort retrospective |
Social register data from Danemark, Finland, Iceland, Norway, Sweden for SCAN-AED: Nordic register-based study of antiepileptic drugs in pregnancy. | 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. |
during pregnancy (anytime or not specified) | 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. | |
| Prescriptions through national prescription registers according to Anatomical Therapeutic Chemical classification codes N03, N05BA09, and S01EC01. | ||||||||
|
Blotière - Clonazepam (Other indications) 2019 |
France 2011 - 2015 retrospective cohort (claims database) |
The French national health insurance database (DCIR) and the French hospital discharge database (PMSI). | 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. |
1st trimester | 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. | |
| The French national health insurance database contains all health care claims reimbursed by French National Health Insurance. Include dispensed drugs coded according to the ATC classification. Monotherapy was defined as the absence of any other antiepileptic drug dispensed during the same period. | ||||||||
|
Calderon-Margalit - BZDs 2009 |
USA 1996 - nr prospective cohort |
The ongoing Omega Study, a prospective cohort study of pregnant mothers who attended prenatal care clinics affiliated with Swedish Medical Center (Seattle, Washington) and Tacoma General Hospital (Tacoma, Washington). | 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. |
during pregnancy (anytime or not specified) | 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. | |
| Participants were interviewed during a prenatal visit prior to 20 weeks of gestation by trained research personnel using a structured questionnaire. Data on medications used during pregnancy were retrieved from both questionnaires and medical records. | ||||||||
|
Chan - BZDs 2023 |
Hong Kong 2001 - 2018 population based cohort retrospective |
The Clinical Data Analysis and Reporting System (CDARS), that contains anonymised electronic health records of all residents (over 7.4 million) from public hospitals and health institutes of the Hospital Authority in Hong Kong. | 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. |
during pregnancy (anytime or not specified) | 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'. | |
| Prescriptions of any sedatives listed in Chapter 4.1 of the British National Formulary (BNF) were extracted from the Clinical Data Analysis and Reporting System (CDARS). | ||||||||
|
Chen - BZDs (Controls unexposed, NOS) 2022 |
Taiwan 2004 - 2017 retrospective cohort (claims database) |
The birth certificate registration and the Taiwan National Health Insurance Research Database, Taiwan. | 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. |
1st trimester, 2nd trimester, 3rd trimester | 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). | |
| Prescriptions were identified in dispensation records from the ambulatory care orders and expenditures for prescriptions dispensed at contracted pharmacies, including all prescribed and filled medication dispensations of general practitioners and specialists. | ||||||||
|
Chen - BZDs (Controls unexposed, sibling) 2022 |
Taiwan 2004 - 2017 retrospective cohort (claims database) |
The birth certificate registration and the Taiwan National Health Insurance Research Database, Taiwan. | 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. |
1st trimester, 2nd trimester, 3rd trimester | 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). | |
| Prescriptions were identified in dispensation records from the ambulatory care orders and expenditures for prescriptions dispensed at contracted pharmacies, including all prescribed and filled medication dispensations of general practitioners and specialists. | ||||||||
|
Chen - BZDs (Controls unexposed, sick) 2022 |
Taiwan 2004 - 2017 retrospective cohort (claims database) |
The birth certificate registration and the Taiwan National Health Insurance Research Database, Taiwan. | 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. |
1st trimester, 2nd trimester, 3rd trimester | 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). | |
| Prescriptions were identified in dispensation records from the ambulatory care orders and expenditures for prescriptions dispensed at contracted pharmacies, including all prescribed and filled medication dispensations of general practitioners and specialists. | ||||||||
|
Christensen - Clonazepam (Indications NOS) 2013 |
Denmark 1996 - 2006 population based cohort propective |
The Danish Civil Registration System, the Medical Birth Register and the Danish Register of Medicinal Product Statistics. | 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. |
during pregnancy (anytime or not specified) | 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. | |
| The Danish Prescription Register holds information on prescriptions. Monotherapy exposure was defined as redemption of prescription for one type of AED with the Anatomical Therapeutic Codes. | ||||||||
|
Christensen - Clonazepam (Indications NOS) 2019 |
Denmark 1997 - 2011 population based cohort propective |
The Danish Psychiatric Central Research Register, the Danish National Prescription Registry, the Danish Civil Registration System and the Danish Medical Birth Registry. | 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. |
during pregnancy (anytime or not specified) | 314 / 899941 | Indications not specified. | |
| The Danish Prescription Register holds information on prescriptions. Monotherapy exposure was defined as redemption of prescription for one type of AED with the Anatomical Therapeutic Codes. | ||||||||
|
Christensen - Clonazepam (Indications other than epilepsy) 2024 |
Denmark, Finland, Iceland, Norway, and Sweden 1996 - 2017 population based cohort retrospective |
Nordic population-based cohort study including register data from Denmark, Finland, Iceland, Norway, and Sweden–the SCAN-AED project. | 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. |
during pregnancy (anytime or not specified) | 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). | |
| Prenatal exposure was identified via national prescription registers. These registers contain the Anatomical Therapeutic Chemical (ATC) classification code (www.whocc.no) and the date of dispensing. | ||||||||
|
Christensen - Clonazepam (Mixed indications) 2015 |
Denmark 1997 - 2008 population based cohort retrospective |
The Danish Civil Registration System, the Danish Medical Birth Registry and the Danish Register of Medicinal Product Statistics. | 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)). |
during pregnancy (anytime or not specified) | 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. | |
| The Danish Register of Medicinal Product Statistics holds information on all redeemed prescriptions. Monotherapy exposure was defined as redemption of prescription for one type of antiepileptic drugs with the Anatomical Therapeutic Codes (ATC code) N03A (AEDs) and N05BA09 (clobazam). | ||||||||
|
Chuang - BZDs 2024 |
Taiwan 2004 - 2018 population based cohort retrospective |
The Taiwan’s National Birth Certificate Application database, the Maternal and Child Health database, and Taiwan’s National Health Insurance database. | 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. |
1st 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. | |
| The National Health Insurance (NHI) database in Taiwan that provides detailed information on prescriptions. | ||||||||
|
Coste - Clonazepam (Mixed indications) 2020 |
France 2011 - 2014 retrospective cohort (claims database) |
The French national health data system (SNDS) | 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. |
during pregnancy (anytime or not specified) | 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. | |
| Defned by at least one dispensing of the drug to the mother between the beginning of the month preceding onset of pregnancy and the end of pregnancy. Mother had used this drug as monotherapy, defined by the use of a single drug during pregnancy. | ||||||||
|
Delteil - BZDs (Controls unexposed, NOS) 2023 |
France 2004 - 2013 retrospective cohort (claims database) |
EFEMERIS (Évaluation chez la Femme Enceinte des MÉdicaments et de leurs RISques) database, and the Registre des Handicaps de l'Enfant en Haute-Garonne (RHE31), Haute-Garonne, France. | 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. |
during pregnancy (anytime or not specified) | 2517 / 82163 | Mainly monotherapy of BZD (90% with 1 different BZD) but co-exposure with antidepressants (27%), antipsychotics (7%°, antiseizure medications (3.8%). | |
| Prescriptions obtained from the French Health Insurance database (Haute Garonne). | ||||||||
|
Delteil - BZDs (Controls unexposed, sick) 2023 |
France 2004 - 2013 retrospective cohort (claims database) |
EFEMERIS (Évaluation chez la Femme Enceinte des MÉdicaments et de leurs RISques) database, and the Registre des Handicaps de l'Enfant en Haute-Garonne (RHE31), Haute-Garonne, France. | 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. |
during pregnancy (anytime or not specified) | 2517 / 1180 | Mainly monotherapy of BZD (90% with 1 different BZD) but co-exposure with antidepressants (27%), antipsychotics (7%°, antiseizure medications (3.8%). | |
| Prescriptions obtained from the French Health Insurance database (Haute Garonne). | ||||||||
|
Elkjaer - Clonazepam (Indications, NOS) 2018 |
Denmark 1997 - 2006 population based cohort propective |
The Danish Civil Registration System, the Danish Medical Birth Registry, the Danish Agency for Information Technology and Learning, the Danish Register of Medicinal Product Statistics. | 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. |
during pregnancy (anytime or not specified) | 188 / 477162 | There is no information about the exposure indication. | |
| Information on medical exposure was retrieved from the Danish Register of Medicinal Product Statistics. Authors identified antiepileptic drugs with ATC codes N03A (AEDs) and N05BA09 (clobazam). | ||||||||
|
Figueroa - BZDs 2010 |
USA 1997 - 2006 retrospective cohort (claims database) |
The MarketScan data used in this study, collected by Thompson Reuters (previously Medstat), obtained from large self-insured employers from all states, except Alaska and Hawaii. | 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 |
during pregnancy (anytime or not specified) | 311 / 3532 | ||
| The MarketScan data contain information including prescription claims and the date of the service. | ||||||||
|
Freeman - BZDs 2018 |
USA 2008 - 2018 prospective cohort |
The National Pregnancy Registry for Atypical Antipsychotics (or the Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics). | 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. |
during pregnancy (anytime or not specified) | 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. | |
| Medication exposure was obtained through maternal report by interviews at 3 points during the study (2 times during pregnancy). Women were asked to report detailed medication usage information at each interview, including all medications taken, dose, and the timing of use across pregnancy. | ||||||||
|
Hartz - Chlordiazepoxide 1975 |
USA 1958 - 1966 prospective cohort |
The Collaborative Perinatal Project, based on 12 university)affiliated hospitals in the United States of America. | Children exposed in utero to Chlordiazepoxide. |
unexposed (general population or NOS)
Children not exposed in utero to Chlordiazepoxide or Meprobamate. |
early pregnancy, late pregnancy | 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. | |
| A history of drug use covering the period of the pregnancy (and 1 month before) was obtained by interview of each woman, on entry into the study. Then it was also obtained at 4-week intervals during the pregnancy and confirmed by the attending physician or by review of the hospital or clinic record. | ||||||||
|
Hironaka - BZDs (Control exposed to Atypical antipsy) 2011 |
Japan 2005 - 2009 retrospective cohort |
Nagoya University Hospital, Japan | 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). |
during pregnancy (anytime or not specified) | 5 / 9 | ||
| The subjects’ medical records were investigated concerning medication history. | ||||||||
|
Hironaka - BZDs (Control unexposed, disease free) 2011 |
Japan 2005 - 2009 retrospective cohort |
Nagoya University Hospital, Japan | 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. |
during pregnancy (anytime or not specified) | 5 / 278 | ||
| The subjects’ medical records were investigated concerning medication history. | ||||||||
|
Hironaka - BZDs (Control unexposed, sick) 2011 |
Japan 2005 - 2009 retrospective cohort |
Nagoya University Hospital, Japan | 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. |
during pregnancy (anytime or not specified) | 5 / 3 | ||
| The subjects’ medical records were investigated concerning medication history. | ||||||||
|
Huybrechts - BZDs 2017 |
USA 2000 - 2010 retrospective cohort (claims database) |
The nationwide Medicaid Analytic eXtract (MAX) | 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. |
late pregnancy | 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) | |
| The Medicaid Analytic eXtract (MAX) that includes prescriptions filled on an outpatient basis. | ||||||||
|
Jackson - BZDs 2024 |
U.S.A 2019 - 2022 retrospective cohort (claims database) |
Inpatient electronic medical record system (Sunrise Clinical Manager, Allscripts Corp., Chicago, IL) of 7 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). |
during pregnancy (anytime or not specified) | 542 / 106564 | ||
| Benzodiazepine exposure was determined by its presence or absence in the medication reconciliation document completed during hospital admission. | ||||||||
|
Källén - BZDs 2013 |
Sweden 1996 - 2011 population based cohort retrospective |
The Swedish Medical Birth Register, the Swedish Register of Prescribed Drugs, the Register of Birth Defect and Hospital Discharge 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. |
2nd and/or 3rd trimester, 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. | |
| At the midwife interview at the first antenatal care visit, the woman was asked if she had used any drugs since she became pregnant. Or determined by the use of the Swedish Register of Prescribed Drugs (since 2006 and for exposure during 2nd or 3rd trimester). | ||||||||
|
Kelty - Alprazolam (Controls unexposed, disease free) 2023 |
Australia 2014 - 2018 retrospective cohort |
Administrative linked data from the Western Australia (WA) Department of Health, Australia. | 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. |
during pregnancy (anytime or not specified) | 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. | |
| Prescription database. | ||||||||
|
Kelty - Alprazolam (Controls unexposed, sick) 2023 |
Australia 2014 - 2018 retrospective cohort |
Administrative linked data from the Western Australia (WA) Department of Health, Australia. | 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) |
during pregnancy (anytime or not specified) | 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. | |
| Prescription database. | ||||||||
|
Kilic - Clonazepam (Mixed indications) 2014 |
Denmark 1997 - 2008 population based cohort retrospective |
The Danish Medical Birth Registry, the Danish Civil Registration System, the Danish National Hospital Registry, and the Danish Register of Medicinal Product Statistics. | 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. |
during pregnancy (anytime or not specified) | 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. | |
| The Danish Register of Medicinal Product Statistics holds information on all redeemed prescriptions. Monotherapy exposure was defined as redemption of prescription for one type of AED with the Anatomical Therapeutic Codes. | ||||||||
|
Laegreid a - BZDs 1992 |
Sweden 1984 - 1986 prospective cohort |
The general maternity outpatient unit and 2 delivery departments in Gothenburg and all the psychiatrists in the city of Gothenburg, Sweden. | 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. |
throughout pregnancy | 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. | |
| Mothers were interviewed prior to delivery about their use of prescribed and non-prescribed drugs during pregnancy, including psychotropic drugs during pregnancy. | ||||||||
|
Laegreid b - BZDs 1992 |
Sweden 1984 - 1986 prospective cohort |
The general maternity outpatient unit and 2 delivery departments in Gothenburg and all the psychiatrists in the city of Gothenburg, Sweden. | 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. |
throughout pregnancy | 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. | |
| Mothers were interviewed prior to delivery about their use of prescribed and non-prescribed drugs during pregnancy, including psychotropic drugs during pregnancy. | ||||||||
|
Lee - Alprazolam 2022 |
South Korea 2000 - 2019 prospective cohort |
A pregnancy exposure registry established from the Korean Mother-Safe Program, South Korea. | 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. |
1st trimester | 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). | |
| Medications taken during pregnancy were asked at the time of counselling. In addition, the daily dose, duration of alprazolam administration, and the reason for taking it were asked in the exposed group. | ||||||||
|
Lupattelli - BZDs 2019 |
Norway 1999 - 2008 prospective cohort |
The Norwegian Mother and Child cohort study (MoBa). | 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. |
2nd trimester, late 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. | |
| Data were gathered prospectively via 2 prenatal self-administered questionnaires at week 17 (questionnaire 1) and week 30 (questionnaire 3). | ||||||||
|
Meng a - BZDs (Controls unexposed, sibling) 2023 |
Taiwan 2004 - 2018 population based cohort retrospective |
A nationwide, population-based cohort study in Taiwan using three data sources: Taiwan’s National Birth Certificate Application database, the National Health Insurance database, and the Maternal and Child Health Database. | 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. |
early pregnancy | -9 / -9 | Number of exposures not provided (authors provided number of Exposure discordant pairs and number of Case discordant pairs). | |
| The National Health Insurance (NHI) database that comprises anonymised health insurance claims for visits, procedures, and prescriptions for more than 99% of the population in Taiwan (about 23 million). | ||||||||
|
Meng a - BZDs (Controls unexposed, sick) 2023 |
Taiwan 2004 - 2018 population based cohort retrospective |
A nationwide, population-based cohort study in Taiwan using three data sources: Taiwan’s National Birth Certificate Application database, the National Health Insurance database, and the Maternal and Child Health Database. | 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. |
early 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. | |
| The National Health Insurance (NHI) database that comprises anonymised health insurance claims for visits, procedures, and prescriptions for more than 99% of the population in Taiwan (about 23 million). | ||||||||
|
Meng b - BZDs 2023 |
Taiwan 2004 - 2018 other |
The Taiwan’s National Birth Certificate Application database and the National Health Insurance database. | 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). |
during pregnancy (anytime or not specified) | 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. | |
| The National Health Insurance (NHI) database that comprises anonymized prescriptions for more than 99% of the population in Taiwan. | ||||||||
|
Milkovich - Chlordiazepoxide 1974 |
USA 1959 - 1966 retrospective cohort |
The Child Health and Development Studies based on pregnant women included in the East San Francisco Bay Area facilities of the Kaiser-Permanent Medical Care 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). |
during pregnancy (anytime or not specified) | 175 / 509 | ||
| For each gravida, the Studies have available data on all drugs prescribed not only in the prenatal clinical but in any Permanente or Kaiser medical-care facility, from the combined clinia and hospital medical record. | ||||||||
|
Mortensen - BZDs 2003 |
Denmark 1991 - 1996 population based cohort retrospective |
The National Health Service in North Jutland County and the County Birth Registry, Denmark. | 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. |
during pregnancy (anytime or not specified) | 82 / 1304 | Estimates did not significantly changed when authors analysed the data after excluding the part of the Boel test related to hearing. | |
| The National Health Service in North Jutland County which partly refunds the costs of selected, prescribed drugs. | ||||||||
|
Noh - BZDs 2022 |
South Korea 2011 - 2018 population based cohort retrospective |
A nationwide retrospective cohort study using healthcare data retrieved from the Health Insurance Review and Assessment Service (HIRA) database. | 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). |
1st trimester | 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. | |
| The Health Insurance Review and Assessment Service (HIRA) database that comprises notably healthcare utilization (e.g., drug prescription and medical procedure). | ||||||||
|
Oberlander - BZDs 2008 |
Canada 1997 - 2002 retrospective cohort (claims database) |
Population-based health-care utilization databases from the province of British Columbia. | 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. |
1st trimester | 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. | |
| PharmaNet, a province-wide network recording all prescriptions dispensed by British Columbian pharmacists outside hospitals. | ||||||||
|
Oberlander - Clonazepam (Controls unexposed, disease free) 2004 |
Canada 1996 - 2000 prospective cohort |
The British Columbia Women's Hospital (Vancouver, British Columbia). | 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). |
during pregnancy (anytime or not specified) | 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). | |
| Measure of plasma level of maternal SSRI medications. | ||||||||
|
Oberlander - Clonazepam (Controls unexposed, sick) 2004 |
Canada 1996 - 2000 prospective cohort |
The British Columbia Women's Hospital (Vancouver, British Columbia). | 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. |
during pregnancy (anytime or not specified) | 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). | |
| Measure of plasma level of maternal SSRI medications. | ||||||||
|
Ornoy - BZDs 1998 |
Israel 1988 - 1996 prospective cohort |
The Israeli Teratogen Information Service (ITIS). | Pregnant women exposed to benzodiazepines. |
unexposed, disease free
Healthy pregnant women with nonteratogenic exposures. |
at least 1st trimester | 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). | |
| Exposure identified at the initial call to the Teratogen Information Service. | ||||||||
|
Radojcic - BZDs 2017 |
The Netherlands. 2002 - 2006 prospective cohort |
The Generation R Study, a population-based prospective birth cohort, Rotterdam, the Netherlands. | 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. |
during pregnancy (anytime or not specified) | 104 / 5609 | According to prescription records: benzodiazepine-related medication were largely in minority (< 10%) compared to benzodiazepines => Considered as benzodiazepines. | |
| In order to optimize ascertainment of medication use, two sources of information were used and combined into one exposure variable: (1) self-reports assessed with questionnaires in each trimester of pregnancy and (2) prescription records from pharmacies. | ||||||||
|
Salisbury - BZDs (Controls unexposed, disease free) 2016 |
USA Not specified. prospective cohort |
A prospective, naturalistic cohort study from Women and Infants’ Hospital, Providence; Alpert Medical School of Brown University, Providence; the Butler Hospital, Providence; University of Maryland, College Park; ... | 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. |
during pregnancy (anytime or not specified) | 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). | |
| Maternal self-report assessments during pregnancy. | ||||||||
|
Salisbury - BZDs (Controls unexposed, sick) 2016 |
USA Not specified. prospective cohort |
A prospective, naturalistic cohort study from Women and Infants’ Hospital, Providence; Alpert Medical School of Brown University, Providence; the Butler Hospital, Providence; University of Maryland, College Park; ... | 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. |
during pregnancy (anytime or not specified) | 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). | |
| Maternal self-report assessments during pregnancy. | ||||||||
|
Shiono - Diazepam 1984 |
USA Not specified. cohort |
The Birth Defects Study of the National Institute of Child Health and Human Development and Kaiser Permanente. | 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. |
1st trimester | 854 / 32395 | ||
| At their first prenatal visit, women were asked if they had used diazepam during the first trimester of pregnancy. | ||||||||
|
Szpunar - BZDs 2022 |
USA 2008 - 2021 prospective cohort |
The Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications (NPRPM). | 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). |
1st trimester | 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. | |
| Participants are interviewed three times: (1) at enrollment during pregnancy; (2) 7 months gestation; and (3) 12 weeks postpartum. Data collection includes medication and supplement use including dosages. | ||||||||
|
The NAAED - Clonazepam 2023 |
North America and Canada 1997 - 2023 prospective cohort |
The North American Antiepileptic Drug Pregnancy Register (NAAED). | 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. |
1st trimester | 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. | |
| Women are interviewed at enrollment, at 7 months’ gestation and at 8 –12 weeks after the expected date of delivery. The computer-assisted interviews include questions on start and stop dates of each antiepileptic drugs taken, dose, frequency and changes in medication. | ||||||||
|
Veiby - Clonazepam (Mixed indications) 2014 |
Norway 1999 - 2011 population based cohort retrospective |
The Medical Birth Registry of Norway and the Register of Pregnancy Terminations. | 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. |
throughout pregnancy | 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) | |
| A standardised notification form is filled in from the first prenatal visit with the general practitioner until discharge and transferred to the database by practitioners attending the delivery. (According to ATC Classification System). | ||||||||
|
Viggedal - BZDs 1993 |
Sweden 1984 - 1986 prospective cohort |
The general maternity outpatient unit and 2 delivery departments in Gothenburg and all the psychiatrists in the city of Gothenburg, Sweden. | 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. |
throughout pregnancy | 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. | |
| Referred women were interviewed prior to delivery about their use of alcohol, cigarettes and prescribed and non-prescribed drugs during pregnancy; this information was also confirmed by their psychiatrists. | ||||||||
|
Yamane - Etizolam 2011 |
Japan Not specified. cohort |
The Counseling Clinic for Pregnancy and Medicine of Toranomon Hospital, Tokyo, Japan. | Pregnant women who used Etizolam in the early stage of pregnancy. |
unexposed (general population or NOS)
Pregnant women who used acetaminophen without teratogenic effects. |
early pregnancy | 224 / -9 | Number of pregnant women in the control group not provided in the Abstract. | |
| Not specified. | ||||||||
|
Yonkers - BZDs 2017 |
USA 2005 - 2009 prospective cohort |
The Yale University School of Medicine and 137 collaborating hospitals and private practices throughout Connecticut and southern Massachusetts, USA. | 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. |
during pregnancy (anytime or not specified) | 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). | |
| After screening, participants were interviewed at home prior to 17 weeks of pregnancy and reinterviewed by telephone at 28 (±2) weeks’ gestation to obtain information about use of any substances or prescribed medications. | ||||||||
|
Zanisi - BZDs 2022 |
Italy 2018 - 2020 cohort |
The Bergamo Teratology Information Service, Bergamo, Italy. | Pregnant women exposed to benzodiazepines alone. |
unexposed (general population or NOS)
Pregnant women exposed to acetaminophen/amoxicillin. |
during pregnancy (anytime or not specified) | 99 / 158 | ||
| Not specified. | ||||||||
| Study | Country Study period Study design |
Data source | Case | Control | Exposition | Exposition period | Sample size (exposed/unexposed) Or (case / control) |
Remarks | Risk of bias |
|---|---|---|---|---|---|---|---|---|---|
|
Aarskog - Diazepam 1975 |
Norway 1967 - 1975 case control |
The Children's Hospital in Bergen and the Medical Birth Registry of Norway. | Infants with oral clefts only (without additional major birth defects). | Infants without malformations. | A questionary on drug consumption during the first trimester was sent to mothers of cases (no information for controls). | 1st trimester | -9 / 362 | ||
| Not specified. | |||||||||
|
Bonnot - Bromazepam 2003 |
France 1976 - 1997 case control |
European Institut of Genomutations (IEG), Lyon, France. | Infants with the studied congenital malformation. | Infants with a malformations other than this one studied. | The medical records are checked to obtain data on treatment intake and other exposures or risks. | 1st trimester | -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). | |
| After having defined a population, often on geographical criteria, these networks set up birth observatories in order to exhaustively identify neonatal malformations in their reference population. | |||||||||
|
Bonnot - BZDs 2001 |
France 1976 - 1998 case control |
European Institut of Genomutations (IEG), Lyon, France. | Infants with the studied congenital malformation. | Infants with a malformations other than this one studied. | The medical records are checked to obtain data on treatment intake and other exposures or risks. | 1st trimester | -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). | |
| After having defined a population, often on geographical criteria, these networks set up birth observatories in order to exhaustively identify neonatal malformations in their reference population. | |||||||||
|
Bonnot - Clorazepate 2003 |
France 1976 - 1997 case control |
European Institut of Genomutations (IEG), Lyon, France. | Infants with the studied congenital malformation. | Infants with a malformations other than this one studied. | The medical records are checked to obtain data on treatment intake and other exposures or risks. | 1st trimester | -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). | |
| After having defined a population, often on geographical criteria, these networks set up birth observatories in order to exhaustively identify neonatal malformations in their reference population. | |||||||||
|
Bonnot - Lorazepam 2003 |
France 1976 - 1997 case control |
European Institut of Genomutations (IEG), Lyon, France. | Infants with the studied congenital malformation. | Infants with a malformations other than this one studied. | The medical records are checked to obtain data on treatment intake and other exposures or risks. | 1st trimester | -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). | |
| After having defined a population, often on geographical criteria, these networks set up birth observatories in order to exhaustively identify neonatal malformations in their reference population. | |||||||||
|
Bonnot - Oxazepam 2001 |
France 1976 - 1998 case control |
European Institut of Genomutations (IEG), Lyon, France. | Infants with the studied congenital malformation. | Infants with a malformations other than this one studied. | The medical records are checked to obtain data on treatment intake and other exposures or risks. | 1st trimester | -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). | |
| After having defined a population, often on geographical criteria, these networks set up birth observatories in order to exhaustively identify neonatal malformations in their reference population. | |||||||||
|
Bonnot - Prazepam 2003 |
France 1976 - 1997 case control |
European Institut of Genomutations (IEG), Lyon, France. | Infants with the studied congenital malformation. | Infants with a malformations other than this one studied. | The medical records are checked to obtain data on treatment intake and other exposures or risks. | 1st trimester | -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). | |
| After having defined a population, often on geographical criteria, these networks set up birth observatories in order to exhaustively identify neonatal malformations in their reference population. | |||||||||
|
Bonnot - Temazepam 2003 |
France 1976 - 1997 case control |
European Institut of Genomutations (IEG), Lyon, France. | Infants with the studied congenital malformation. | Infants with a malformations other than this one studied. | The medical records are checked to obtain data on treatment intake and other exposures or risks. | 1st trimester | -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). | |
| After having defined a population, often on geographical criteria, these networks set up birth observatories in order to exhaustively identify neonatal malformations in their reference population. | |||||||||
|
Bracken - Diazepam 1981 |
USA 1974 - 1976 case control |
Five major Connecticut hospitals and at 2 pediatric clinics, Connecticut, USA. | 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). | Information concerning exposure to drugs were obtained using a standardized questionnaire given by trained interviewers (after delivery). All drugs used in each month of pregnancy were recorded and classified (physician also contacted for less than 10% of reported drugs). | 1st trimester | 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). | |
| The medical records of all potential cases as judged by initial hospital diagnosis were examined by an internist or pediatrician associated with the study. Attending physician were contacted when necessary to obtain more information. | |||||||||
|
Cifuentes - Alprazolam 2025 |
Europe (13 countries) 1995 - 2019 case control |
A case-malformed-control study using the EUROmediCAT database, including data from data from 19 registries from EUROCAT the European network for surveillance of congenital anomalies and from EFEMERIS. | 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. | Information on maternal medication exposure was primarily obtained from maternity records. Additional data sources for some registries included: infant medical records, general practitioner records, pregnancy passports, and maternal interviews conducted before or after birth. EFEMERIS: dispensing. | 1st trimester | 4185 / 232718 | Use of nongenetic controls (cases of CA other than COA excluding genetic syndromes), | |
| Cases and controls were obtained in registries from EUROCAT, the European network for surveillance of congenital anomalies. | |||||||||
|
Cornel - BZDs - MACDP 1996 |
USA 1968 - 1980 case control |
The Metropolitan Atlanta Congenital Defects Program (MACDP), USA. | Babies born with a cleft lip with or without cleft palate. | Healthy control babies. | The data were collected by telephone interviews with parents in 1982 and 1983 and concerned the experiences of families of babies born in the Atlanta area from 1968 through 1980 (no other details). | 1st trimester | -9 / 3029 | ||
| The data were collected by telephone interviews with parents in 1982 and 1983 and concerned the experiences of families of babies born in the Atlanta area from 1968 through 1980 (no other details). | |||||||||
|
Cornel - Oxazepam - The NNL registry 1996 |
The Netherlands 1981 - 1994 case control |
The Northern Netherlands (NNL) registry, member of the EUropean Registration Of Congenital Anomalies (EUROCAT). | Infants with a cleft lip with or without cleft palate. | All infants notified with other anomalies. | The registry personnel actively collect information by going through hospital records. Data were supplied by pediatricians, obstetricians, midwives, general practitioners (GP's), clinical geneticists, and several other medical specialists. The data include on maternal drug use during pregnancy. | 1st trimester | 277 / 3737 | ||
| The registry personnel actively collect information by going through hospital records. Data were supplied by pediatricians, obstetricians, midwives, general practitioners (GP's), clinical geneticists, and several other medical specialists. The data include diagnostic information. | |||||||||
|
Correa-Villasenor - BZDs 1994 |
USA 1981 - 1989 case control |
The Baltimore-Washington Infant Study (BWIS), a regional case-control investigation of congenital heart disease, USA. | 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. | Home interviews with case and control parents were conducted within 18 months of birth of study subjects. A structured, standardized questionnaire, administered by trained interviewers, obtained information, notably on therapeutic drugs. | 3 months or more before pregnancy or1st trimester | 44 / 3572 | ||
| A diagnostic update was obtained from a clinical follow-up report or from the autopsy findings. | |||||||||
|
Czeizel - Diazepam 2003 |
Hungary 1980 - 1996 case control |
The Hungarian Case–Control Surveillance of Congenital Abnormalities (HCCSCA). | 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. | Exposure data collected from 3 sources: a post-paid structured questionnaire sent to the parents requesting drugs taken during pregnancy, according to gestational months; maternal prenatal care logbook (in which obstetricians must record all prescribed drugs); nurses visited non-responding families. | 1st trimester, during pregnancy (anytime or not specified) | 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). | |
| The Hungarian Congenital Abnormality Registry (HCAR), in which notification by physicians of cases with Congenital anomalies is mandatory (including infant deaths and usual stillborn fetuses). Controls were selected from the National Birth Registry of the Central Statistical Office. | |||||||||
|
Czeizel - Diazepam 1987 |
Hungary 1970 - 1976 case control |
The Hungarian Congenital Malformation Registry (HCMR). | Infants born with facial clefting born during the study period. | Infants born witout facial clefting born during the study period. | A reply-paid postal questionnaire was sent to all parents notably concerning the drugs taken (with a printed list of drugs to be red before filling in the questionnaire). The prenatal care booklet of the pregnancies and all medical documents were also studied. | 1st trimester, during pregnancy (anytime or not specified) | 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). | |
| Cases were identified in the Hungarian Congenital Malformation Registry (HCMR) and controls were identified using the records of the obstetrical institutions. | |||||||||
|
Greenberg - BZDs 1977 |
United Kingdom (England and Wales). 1969 - 1974 case control |
The information passed in the Office of population censuses and surveys (OPCS), United Kingdom. | 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. | Medical officers or community physicians were asked to identify the baby and the general practitioner, who was then interviewed by one of the Committee's medical field workers notably about drugs prescribed during the first trimester (only information obtained from written notes was used). | 1st trimester | 836 / 836 | ||
| The doctor, midwife, or health visitor attending the birth of an abnormal baby may report the abnormality to the area health authority. This information is then passed to the OPCS. Though voluntary, it is believed that notification of visible and severe malformations is reasonably complete. | |||||||||
|
Ishikawa - BZDs 2024 |
Japan 2005 - 2022 nested case control |
The administrative claims database from JMDC Inc. (Tokyo, Japan), which contains all inpatient (including those during hospitalization), outpatient, and pharmacy claims received from the insurers. | 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). | Exposure were identified according to the WHO-ATC or alternate entries in the administrative claims database from JMDC Inc. (Tokyo, Japan), which contains pharmacy claims received from the insurers. | during pregnancy (anytime or not specified) | 44118 / 132317 | Exposure to benzodiazepines was used as a positive control. | |
| Birth outcomes was unavailable in the Japanese claims database. Pregnancies and birth outcomes were estimated using two methods: the first one was for those whose pregnancy-and birth outcome-related entries were available, and their pregnancies and birth outcomes were estimated using these entries. | |||||||||
|
Kullander - Chlordiazepoxide 1976 |
Sweden 1963 - 1965 nested case control |
The Department of Gynecology and Obstetrics and the Department of Embryology, University of Lund, Sweden. | Infants with different kinds of malformations. | Infants without malformations. | Information on drug use was obtained mainly from the questionnaires administered to pregnant women, sometimes supplemented from hospital records etc. Information was usually collected before the outcome of the pregnancy was known. The (approximate) time of intake of each drug used was recorded. | 1st trimester | 751 / 5002 | ||
| All living children were carefully investigated by a pediatrician after birth and were followed to about 1 year old at the child health centres. Autopsy was performed and the age at death was recorded. The presence of major and minor malformations was recorded for all infants. | |||||||||
|
Laegreid - BZDs 1990 |
Sweden 1985 - 1986 case control |
The East Hospital (the only children's hospltal in Gothenburg), Gothenburg, Sweden. | 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. | Serum benzodiazepine (BZD) concentrations from the maternal blood samples were analysed 1.2 to 1.5 years after the birth of the probands. All analyses of maternal serum were blind. | during pregnancy (anytime or not specified) | 25 / 109 | The following BZD were included in the screening: DZP, desmethyl-diazepam (d-m-DzP), fluni- trazepam, oxazepam (OZP), clonazepam, nitrazepam and lorazepam. | |
| The diagnostic register at the East Hospital and the files of dead neonates were reviewed. All the diagnoses had been made independently before the study started by the paediatrician in charge of the neonatal unit or by the clinical pathologist. | |||||||||
|
Laegreid c - BZDs 1992 |
Sweden 1985 - 1986 case control |
Obstetric units and pediatric department in hospitals of the city of Gothenburg, Sweden. | Pregnancies resulting in perinatally dead infants (stillborn and neonatal death. | Pregnancies resulting in surviving infants born immediately after each perinatally dead infant. | The use of benzodiazepines was assessed by biochemical screening (blood sample in early pregnancy at around gestational week 12) combined with review of maternity health clinic records, while the use of other drugs was assessed by maternity health clinic review only. | during pregnancy (anytime or not specified) | 73 / 73 | 73 perinatal deaths (39 stillborn and 34 neonatally dead). | |
| All the histories from the municipal antenatal clinics and the obstetric and neonatal departments were reviewed retrospectively. In the case of autopsy, which was performed in 67 of the 73 cases (92%), the records were reviewed. | |||||||||
|
Laspro - BZDs 2024 |
USA 2013 - 2023 nested case control |
EPIC Cosmos, a database incorporating health information of 180 million patients, throughout the United States from approximately 180 US institutions utilizing EPIC medical records. | Newborns with oral clefts (ICD 10 codes Q35 or Q36 or Q37). | Newborns without oral clefts. | Gestational medication use was identified by medications, prescribed, provider-administered, or reported use by mothers at any point during pregnancy. | during pregnancy (anytime or not specified) | 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. | |
| Oral cleft cohorts were isolated using a combination of ICD codes, from the EPIC medical records. | |||||||||
|
Ogawa - BZDs 2018 |
Japan 2005 - 2014 nested case control |
Claims data supplied by the Japan Medical Data Center (JMDC) Ltd, Tokyo Japan. | 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. | For each person, the Japan Medical Data Center (JMDC) database includes prescriptions. The classification of drugs is based on the Anatomical Therapeutic Chemical classification system of the European Pharmaceutical Market Research Association. | 2nd and/or 3rd trimester | 1615 / 40224 | ||
| For each person, the Japan Medical Data Center (JMDC) database includes an encrypted personal identifier, age, gender and diagnoses. | |||||||||
|
Robert - BZDs 1994 |
Australia, France, Israel, Italy Japan, and South America. 1990 - 1991 case control |
Eight malformation registries participating in the MADRE (MAlformation DRug Exposure surveillance) project. | Infants with malformations of the a specific type. | Infants with malformations of another type than that under study. | All exposure data were collected retrospectively and reporting monthly, quarterly or once in every 6-month period (based on hospital records or by direct inquiry to the mother in the postpartum period). | 1st trimester | -9 / -9 | The number of cases and controls depends on the malformation studied. | |
| Data on malformations come from the malformation registers which participate in the study (mainly hospital-based data). | |||||||||
|
Rosenberg - Diazepam 1983 |
USA 1976 - 1982 case control |
A continuing program of birth defects surveillance in three metropolitan areas: Boston, Philadelphia and Toronto, USA. | Children with oral clefts (cleft lip with or without cleft palate; cleft palate alone). | Children with all other malformations. | Six months after birth, the mother was interviewed in her home. Nurse interviewers administered a standard questionnaire to obtain notably information of prenatal exposures. The mother is then asked about the use of 17 specifically named drugs, including Diazepam. | 1st trimester | 611 / 2498 | Cases of cleft lip with or without cleft palate: n= 445; and cases of cleft palate alone: n=166. | |
| The children were identified through systematic contact with collaborating physicians, clinics and institutions (no further details). | |||||||||
|
Rothman - Diazepam 1979 |
USA 1973 - 1975 case control |
Massachusetts births, and in particular the New England Regional Infant Cardiac Program (NERICP), USA. | All infants with congenital heart disease born to Massachusetts women. | Births selected randomly from the roster of all Massachusetts births. | After each year of the study period, questionnaires were mailed to mothers of all control subjects and cases identified during that year. The questionnaire inquired notably about drugs prior to and during early pregnancy. | early pregnancy | 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. | |
| Cases were mainly from the roster of the New England Regional Infant Cardiac Program (NERICP), a service program designed to provide specialized care to all infants born in New England with serious congenital heart disease. Controls were selected randomly from the roster of all Massachusetts births. | |||||||||
|
Safra - Diazepam 1975 |
USA 1970 - ? case control |
The Metropolitan Atlanta Congenital Defects Program in Atlanta, Georgia, USA. | 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. | Women whose infants had certain selected defects have been interviewed, using a standard questionary, with questions notably on drug use in pregnancy (collected mostly through open-ended questions, in general interviews completed about 4 months post-partum). | 1st trimester | 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. | |
| The infants were identified from the Metropolitan Atlanta Congenital Defects Program in Atlanta. A computer program screens the birth-defect rubrics for first-trimester exposure to each drug code. | |||||||||
|
Saxen - BZDs 1975 |
Finland 1967 - 1971 nested case control |
The Finnish Register of Congenital Malformations. | 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. | Details about notably prenatal drug consumption are collected from the records of antenatal wards (covering 99% of the pregnant women) and by a questionary filled in during an interview after delivery. The information was usually obtained from the prospectively filled antenatal records. | 1st trimester | 599 / 590 | ||
| The Finnish Register of Congenital Malformations, based on compulsory notification of all malformations detected in children under one year of age. | |||||||||
|
Sheehy - BZDs (Controls unexposed, NOS) 2019 |
Canada 1998 - 2015 nested case control |
A nested case-control study within the Quebec Pregnancy Cohort, Montreal, Quebec, Canada. | 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. | The Quebec Public Prescription Drug Insurance Plan database (drug name, start date, dose, and duration). | early pregnancy | 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. | |
| The data sources included the medical service database the Régie de l’assurance maladie du Québec (diagnoses, medical procedures, ...) and the MedEcho database (in-hospital diagnoses and procedures, including gestational age for planned abortions, spontaneous abortions, and deliveries). | |||||||||
|
Sheehy - BZDs (Controls unexposed, sick) 2019 |
Canada 1998 - 2015 nested case control |
A nested case-control study within the Quebec Pregnancy Cohort, Montreal, Quebec, Canada. | 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. | The Quebec Public Prescription Drug Insurance Plan database (drug name, start date, dose, and duration). | early pregnancy | 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. | |
| The data sources included the medical service database the Régie de l’assurance maladie du Québec (diagnoses, medical procedures, ...) and the MedEcho database (in-hospital diagnoses and procedures, including gestational age for planned abortions, spontaneous abortions, and deliveries). | |||||||||
|
Tikkanen - Diazepam 1992 |
Finland 1982 - 1983 nested case control |
The Children's Cardiac Register and the Finnish Register of Congenital Malformation, Finland. | 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. | All the mothers were interviewed at maternity welfare centers by a midwife using a structured questionnaire, after delivery (approximately 94-96 days days (range 14-154)) and including questions about medications use during pregnancy. | 1st trimester | 90 / 756 | ||
| Cardiovascular malformations were identified independently from the Finnish Register of Congenital Malformations or the Children's Cardiac Register. Pediatricians, especially pediatric cardiologists, send their notifications of cardiovascular malformations to these registers. | |||||||||
|
Tikkanen - Diazepam 1992 |
Finland 1982 - 1983 nested case control |
The Finnish Register of Congenital Malformations or the Children's Cardiac Register. | Infants (live and stillbirths) with cardiovascular malformations, diagnosed by echocardiography, cardiac catheterization, surgery, or autopsy. | Non-malformed infants randomly selected from all deliveries. | All the mothers were interviewed at maternity welfare centers by a midwife using a structured questionnaire, after delivery (approximately 90-100 days days (range 14-54)) and including questions about medications use during pregnancy. | 1st trimester | 406 / 756 | ||
| Cardiovascular malformations were identified independently from the Finnish Register of Congenital Malformations or the Children's Cardiac Register. Pediatricians, especially pediatric cardiologists, send their notifications of cardiovascular malformations to these registers. | |||||||||
|
Tikkanen - Diazepam 1991 |
Finland 1982 - 1983 nested case control |
The Children's Cardiac Register and the Finnish Register of Congenital Malformation, Finland. | 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. | All the mothers were interviewed at maternity welfare centers by a midwife using a structured questionnaire, after delivery (approximately 84-96 days days (range 14-180)) and including questions about medications use during pregnancy. | 1st trimester | 150 / 756 | ||
| Cardiovascular malformations were identified independently from the Finnish Register of Congenital Malformations or the Children's Cardiac Register. Pediatricians, especially pediatric cardiologists, send their notifications of cardiovascular malformations to these registers. | |||||||||
|
Tinker - BZDs 2019 |
USA 1997 - 2011 case control |
The National Birth Defects Prevention Study (NBDPS), a large population-based multicenter case–control study of major birth defects. | 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. | Detailed information notably about medication use during pregnancy (including over-the-counter (OTC) and prescription medication) was collected from the mothers via computer-assisted telephone interviews conducted between 6 weeks and 24 months after the estimated date of delivery (EDD). | 1st trimester | -9 / 11614 | Total number of cases not provided by authors (number of cases provided for each kind of malformations or group of malformations). | |
| Cases were identified in the The National Birth Defects Prevention Study. The NBDPS clinical data for birth defect cases were abstracted from medical records and classified by clinical experts. Controls were selected from birth certificates or hospital records in the same area. | |||||||||
|
Winship - BZDs 1984 |
United Kingdom Jan 1981 - Dec 1981 case control |
The Committee on Safety of Medicines (CSM) by the Office of Population Censuses and Surveys (OPCS), United Kingdom. | 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. | Information of the drugs prescribed was obtained from the family doctors' records only and is therefore, not necessarily a complete record of drugs taken (it excluded hospital prescriptions and over the counter medicines). | 1st trimester | 764 / 764 | ||
| Information on each study and control child and their mothers was obtained from the records of the family doctors, who were interviewed by part time medical officers of the Committee on Safety of Medicines (CSM). Data were notably collected on outcome of pregnancy and congenital abnormality. | |||||||||
Risk of bias: : NA; : low; : moderate; : serious; : critical; : unclear;
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