Benzodiazepines (Psy and mixed indications)

Study	Type of data	Exposure measurement	Outcome assessment	Adjustment
Aarskog - Diazepam, 1975	case control	A questionary on drug consumption during the first trimester was sent to mothers of cases (no information for controls).	Not specified.	None.
Ban (Controls unexposed, disease free), 2012	population based cohort retrospective	Prescriptions of all antidepressants, hypnotics, and anxiolytics extracted of The Health Improvement Network (THIN) that contains electronic medical records.	The Health Improvement Network (THIN), a database of computerised primary care medical records	Relative risk ratio adjusted for maternal age at the end of pregnancy, household socioeconomic status, maternal smoking status before delivery and body mass index before pregnancy.
Ban (Controls unexposed, sick), 2012	population based cohort retrospective	Prescriptions of all antidepressants, hypnotics, and anxiolytics extracted of The Health Improvement Network (THIN) that contains electronic medical records.	The Health Improvement Network (THIN), a database of computerised primary care medical records	Relative risk ratio adjusted for maternal age at the end of pregnancy, household socioeconomic status, maternal smoking status before delivery and body mass index before pregnancy.
Ban - Diazepam (Other indications) (Controls unexposed, disease free), 2014	retrospective cohort (claims database)	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.	All diagnostic recordings of major congenital anomalies (excluding genetic anomalies and anomalies attributed to known teratogens, e.g. anomalies due to maternal infections and fetal alcohol syndrome) are extracted from the children’s general practice records.	Singletons only. Exclusion of women with serious mental illness (i.e. bipolar disorder, schizophrenia and other related psychotic disorders) or with epilepsy diagnoses or with prescriptions of antiepileptic drugs in pregnancy. Adjusted for the year of the child’s birth, maternal age at childbirth, socioeconomic status, smoking and body mass index.
Ban - Diazepam (Other indications) (Controls unexposed, sick), 2014	retrospective cohort (claims database)	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.	All diagnostic recordings of major congenital anomalies (excluding genetic anomalies and anomalies attributed to known teratogens, e.g. anomalies due to maternal infections and fetal alcohol syndrome) are extracted from the children’s general practice records.	Singletons only. Exclusion of women with serious mental illness (i.e. bipolar disorder, schizophrenia and other related psychotic disorders) or with epilepsy diagnoses or with prescriptions of antiepileptic drugs in pregnancy. Adjusted for the year of the child’s birth, maternal age at childbirth, socioeconomic status, smoking and body mass index.
Bech - Clonazepam, 2018	population based cohort propective	The Danish National Prescription Register was used to obtain data on redeemed prescriptions using Anatomical Therapeutic Chemical (ATC) codes.	The Danish Psychiatric Central Register and Danish National Patient Registry were used to identify children's learning disabilities diagnosis using ICD-10 codes for: mental retardation, specific development disorders, ASD, emotional/behavioural disorders or having special educational needs.	Adjustments were made for maternal age at birth, educational level, smoking status, epilepsy, affective disorders, other psychiatric disorders, birth year, preterm birth, Apgar score and birth weight relative to gestational age.
Bech - Clonazepam, 2014	population based cohort retrospective	Use of antiepileptic drugs are identified in the Danish Register of Medicinal Product Statistics which comprises records of all prescriptions redeemed.	The Danish medical birth registry includes information on all live births and stillbirths in Denmark. Spontaneous abortions were identified in the Danish national hospital discharge register. Diagnoses are classified based on the International classification of diseases.	Adjusted for maternal age (thirds), cohabitation (yes/no), income (dichotomised at the median), education (<10, 10-12, >12 years), history of severe mental disorder (yes/no), and history of drug misuse (yes/no).
Bjorkstedt - BZDs, 2025	retrospective cohort (claims database)	Purchase dates and ATC codes were obtained through Finnish Social Insurance Institution.	Outcomes extracted from the Finnish Medical Birth Register and the Register on Congenital Malformations. Each anomaly was assessed by a medical doctor and coded using ICD-10 codes for Congenital malformations, deformations, and chromosomal abnormalities (ICD-10 codes Q00–Q99).	Only primiparous. Women with pregestational diagnosis of diabetes mellitus were excluded. Adjusted for age, educational attainment, body mass index, smoking, gestational diabetes mellitus, and pregnancy duration.
Bjørk - Clonazepam (Mixed indications), 2022	population based cohort retrospective	Prescriptions through national prescription registers according to Anatomical Therapeutic Chemical classification codes N03, N05BA09, and S01EC01.	Severe neurodevelopmental disorders are diagnosed by child psychiatrists and psychologists in specialist health care in the Nordic countries and recorded with International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes.	Adjusted for maternal age, education and marital status, parity, child’s birth year, sex, and country of birth. All the models were run with separate strata for country and year. Plus maternal use of antidepressants or opioids, depression, anxiety, personality disorders, number of chronic somatic diseases, and number of hospitalizations the year before last menstrual period.
Blotière - Clonazepam (Other indications), 2019	retrospective cohort (claims database)	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.	The French hospital discharge database (PMSI) provides detailes medical information including discharge diagnosis ICD-10 codes and medical procedures. Major congenital malformations (MCMs) were selected from the list of MCMs of the European Surveillance of Congenital Anomalies (EUROCAT) network.	Exclusion of twin pregnancies. For major congenital malformations (MCMs) with <5 cases per treatment group, authors calculated crude odds ratios with exact confidence intervals. For MCMs with at least 5 cases per treatment group, ORs were adjusted for maternal age, mother’s eligibility for CMU-C, year of start of pregnancy, preconception folic acid supplementation, and pregestational diabetes.
Bonnot - Bromazepam, 2003	case control	The medical records are checked to obtain data on treatment intake and other exposures or risks.	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.	Adjusted for age and parity.
Bonnot - BZDs, 2001	case control	The medical records are checked to obtain data on treatment intake and other exposures or risks.	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.	Adjusted for age and parity.
Bonnot - Clorazepate, 2003	case control	The medical records are checked to obtain data on treatment intake and other exposures or risks.	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.	Adjusted for age and parity.
Bonnot - Lorazepam, 2003	case control	The medical records are checked to obtain data on treatment intake and other exposures or risks.	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.	Adjusted for age and parity.
Bonnot - Oxazepam, 2001	case control	The medical records are checked to obtain data on treatment intake and other exposures or risks.	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.	Adjusted for age and parity.
Bonnot - Prazepam, 2003	case control	The medical records are checked to obtain data on treatment intake and other exposures or risks.	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.	Adjusted for age and parity.
Bonnot - Temazepam, 2003	case control	The medical records are checked to obtain data on treatment intake and other exposures or risks.	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.	Adjusted for age and parity.
Bracken - Diazepam, 1981	case control	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).	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.	None.
Calderon-Margalit - BZDs, 2009	prospective cohort	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.	Information on pregnancy outcome was ascertained by reviewing hospital labor and delivery medical records and clinic records after delivery.	Adjustments for maternal age, race, years of education, marital status, smoking during pregnancy, preeclampsia, parity, and singleton/multiple pregnancy.
Chan - BZDs, 2023	population based cohort retrospective	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).	Clinical information is recorded by healthcare professionals and routinely transferred the Clinical Data Analysis and Reporting System that contains electronic health records of all residents from public hospitals and Hospital Authority (43 hospitals, 122 outpatient clinics including specialist).	Propensity score including maternal age at delivery, calendar year at delivery, parity, birth hospital, multiple pregnancy, infant’s sex, maternal psychiatric and neurological conditions, maternal physical conditions, maternal medication history, maternal behaviours including smoking, alcohol consumption, illicit drug use, and maternal socioeconomic status.
Chen - BZDs (Controls unexposed, NOS), 2022	retrospective cohort (claims database)	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.	The diagnoses were ascertained on the basis of at least 1 inpatient record or at least 3 outpatient diagnoses based on the International Classification of Diseases, 9th Revision (ICD-9) for ADHD (ICD-9 code 314) and ASD (ICD-9 code 299) and ICD-10 criteria for ADHD (F90) and ASD (F84).	Full-terms only. For adjusted associations, it was controlled for year of birth, maternal and paternal nationality, gestational age, parity, maternal smoking during pregnancy, maternal opioid use, parental age at childbirth, and parental history of mental disorders. Negative control (paternal exposure).
Chen - BZDs (Controls unexposed, sibling), 2022	retrospective cohort (claims database)	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.	The diagnoses were ascertained on the basis of at least 1 inpatient record or at least 3 outpatient diagnoses based on the International Classification of Diseases, 9th Revision (ICD-9) for ADHD (ICD-9 code 314) and ASD (ICD-9 code 299) and ICD-10 criteria for ADHD (F90) and ASD (F84).	Full-terms only. For adjusted associations, it was controlled for year of birth, maternal and paternal nationality, gestational age, parity, maternal smoking during pregnancy, maternal opioid use, parental age at childbirth, and parental history of mental disorders. Negative control (paternal exposure).
Chen - BZDs (Controls unexposed, sick), 2022	retrospective cohort (claims database)	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.	The diagnoses were ascertained on the basis of at least 1 inpatient record or at least 3 outpatient diagnoses based on the International Classification of Diseases, 9th Revision (ICD-9) for ADHD (ICD-9 code 314) and ASD (ICD-9 code 299) and ICD-10 criteria for ADHD (F90) and ASD (F84).	Full-terms only. For adjusted associations, it was controlled for year of birth, parity, gestational age, low-income family status, maternal and paternal nationality, paternal and maternal age at child birth, paternal and maternal history of mental disorders, smoking during pregnancy, and maternal opioid drug use.
Christensen - Clonazepam (Indications NOS), 2013	population based cohort propective	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.	The Danish Psychiatric Central Register was used to identify children's diagnosis : ICD-10 codes F84.0, F84.1, F84.5, F84.8, and F84.9 for autism spectrum disorder and F84.0 for childhood autism. And also the National Hospital Register to identify children diagnosed with congenital malformations.	Adjusted for risk factors for autism (parental age at conception, parental psychiatric history, gestational age, birth weight, sex of the child, congenital malformations, and parity).
Christensen - Clonazepam (Indications NOS), 2019	population based cohort propective	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.	The Danish Psychiatric Central Register was used to identify children's diagnosis : ICD-10 codes F90 and F98.8 for ADHD. And also the Danish National Prescription Registry to identify offspring who used medication that is used for ADHD treatment.	Adjusted for maternal age at conception, maternal psychiatric history, maternal diabetes, sex of the child, year of birth, and parity.
Christensen - Clonazepam (Indications other than epilepsy), 2024	population based cohort retrospective	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.	Information on birth weight, gestational age and head circumference at birth was obtained from the medical birth registers for all births occurring at 22 weeks’ gestation or later.	Singleton only. All models were adjusted for country of birth, year of birth, sex of child, maternal age, maternal parity, maternal marital or cohabitation status, pre-pregnancy hospital admittances, maternal education, smoking in early pregnancy, maternal psychiatric history (F00-F99), and use of psychotropic drugs in pregnancy (ATC N06A, N05A, N05B, excl. N05BA09) and maternal epilepsy.
Christensen - Clonazepam (Mixed indications), 2015	population based cohort retrospective	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).	The Danish Medical Birth Registry contains data on newborn children including information on gestational age and Apgar score (0–10) at birth (5 min).	Singletons only. No adjustment (results adjusted for maternal age and smoking, but when analysing individual drugs, there were too few exposed cases to allow for adjusted estimates).
Chuang - BZDs, 2024	population based cohort retrospective	The National Health Insurance (NHI) database in Taiwan that provides detailed information on prescriptions.	Congenital malformations, defined by the ICD-9 and ICD-10, were documented in either the maternal or infant medical records using data from the National Birth Certificate Application (BCA) database.	Same illness. Singletons only. Exposure to known teratogens excluded. Adjusted for maternal age, nationality, sex of the infant, year of birth, psychiatric conditions (ie, depression, anxiety, bipolar disorder, insomnia, and schizophrenia), comorbidities (ie, epilepsy, hypertension, diabetes, ...), lifestyle factors (alcohol, obesity, tobacco, drug), co-medications, obstetric comorbidity index.
Cifuentes - Alprazolam, 2025	case control	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.	Cases and controls were obtained in registries from EUROCAT, the European network for surveillance of congenital anomalies.	Exclusions of mothers who reported with the use of known major teratogens and infectious diseases during pregnancy that could had have an impact on eye development. Adjusted by 5-years periods, maternal age at delivery and EUROCAT registry.
Cornel - BZDs - MACDP, 1996	case control	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).	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).	None.
Cornel - Oxazepam - The NNL registry, 1996	case control	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.	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.	None.
Correa-Villasenor - BZDs, 1994	case control	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.	A diagnostic update was obtained from a clinical follow-up report or from the autopsy findings.	Adjusted for family history of cardiovascular malformations, maternal age, varnishing and number of previous miscarriages.
Coste - Clonazepam (Mixed indications), 2020	retrospective cohort (claims database)	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.	Diagnoses of mental and behavioural disorders by the attribution of long-term disease status and/or hospital admission (ICD-10 codes). Health care utilization by reimbursement of at least one speech therapy session; one orthoptist consultation; one psychiatrist or child psychiatrist consultation.	Neurodev: adjusted for: mother’s age, Complementary Universal Health Insurance, diagnosis of mental illness other than tobacco and alcohol use disorders, antipsychotic drug use during the year preceding pregnancy, indicator of severity of psychiatric morbidity, indicator of tobacco use, indicator of alcohol use, folic acid, SSRI during pregnancy, child’s sex, gestational age and birth weight.
Czeizel - Diazepam, 2003	case control	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.	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.	Controls matched to every case according to sex, birth week in the year when the case was born, and district of parents’ residence. Adjusted for maternal disorders (psychiatric disease and others) and other drug uses. No difference in the mean maternal age and birth order.
Czeizel - Diazepam, 1987	case control	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.	Cases were identified in the Hungarian Congenital Malformation Registry (HCMR) and controls were identified using the records of the obstetrical institutions.	Three controls were matched to each index case by birth place, week of birth, sex, and outcome (stillbirth, infant death, or survivor).
Delteil - BZDs (Controls unexposed, NOS), 2023	retrospective cohort (claims database)	Prescriptions obtained from the French Health Insurance database (Haute Garonne).	Children with neurodevelopmental disorders obtained from the Registry of Children's Disabilities in Haute-Garonne (RHE31), France.	Neurodev: Adjusted for maternal age, child sex, receives long-term care benefits, number of drugs prescribed in pregnancy, valproate exposure during pregnancy, history of hospitalisation for anxiety. Other confounders considered: maternal hypertension, maternal history or gestational diabetes, parity, gestational age, parental educational level. Sub-analysis excluding women exposed to valproate.
Delteil - BZDs (Controls unexposed, sick), 2023	retrospective cohort (claims database)	Prescriptions obtained from the French Health Insurance database (Haute Garonne).	Children with neurodevelopmental disorders obtained from the Registry of Children's Disabilities in Haute-Garonne (RHE31), France.	Neurodev: Adjusted for maternal age, child sex, receives long-term care benefits, number of drugs prescribed in pregnancy, valproate exposure during pregnancy, history of hospitalisation for anxiety. Other confounders considered: maternal hypertension, maternal history or gestational diabetes, parity, gestational age, parental educational level. Sub-analysis excluding women exposed to valproate.
Elkjaer - Clonazepam (Indications, NOS), 2018	population based cohort propective	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).	Information on school performance was provided by the Danish Agency for Information Technology and Learning. The cognitive abilities are assessed using academic tests conducted from 2010 to 2014. Congenital malformations were defined as diagnoses based on ICD-10 Q0 to Q99.	Adjusted for test year, child sex, and maternal education and household income at birth.
Figueroa - BZDs, 2010	retrospective cohort (claims database)	The MarketScan data contain information including prescription claims and the date of the service.	Outpatient and inpatient claims with a primary or secondary diagnosis of ADHD and prescription claims for stimulants, determined by national drug coding, were identified.	Controlled for demographic and perinatal factors (including maternal age group, gender of the child, urban or rural metropolitan statistical area, year of birth, and age at last claim and at end of eligibility), parental mental health diagnoses, the use of other psychotropics during pregnancy, and maternal mental health visits by year of the child’s life.
Freeman - BZDs, 2018	prospective cohort	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.	Obstetric and neonatal outcome data were obtained through maternal report and medical record review (primary source). Trained research coordinators used a standard neonatal/maternal outcome report form to abstract information, a process which was then repeated by a senior study investigator.	A propensity score was created using hypothesized confounders selected a priori: maternal age, diagnosis of anxiety, psychiatric illness chronicity, as well as use of antidepressants, anticonvulsants, typical antipsychotics, atypical antipsychotics, and lithium anytime during pregnancy, and use of alcohol, cigarettes, or multivitamins during the first trimester.
Greenberg - BZDs, 1977	case control	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).	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.	It was accepted as controls only babies born within three months of the case baby. Maternal age and parity similar in cases and controls. Use of results excluding any family with a history of congenital malformation.
Hartz - Chlordiazepoxide, 1975	prospective cohort	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.	Children were examined at birth, four further examinations were performed before the fourth birthday and were then followed with further medical and psychologic examinations until the 8th birthday.	Factors incorporated with the multivariate analysis: maternal age, sex of child, birth weight, duration of pregnancy, single umbilical artery, hypertension during pregnancy, hemorrhagic and placental factors, hydramnios, maternal diabetes mellitus, hyperthyroidism, convulsive disorders (...) and history of congenital defects in 1st order relatives. Exclusion of multiple pregnancies and rubella.
Hironaka - BZDs (Control exposed to Atypical antipsy), 2011	retrospective cohort	The subjects’ medical records were investigated concerning medication history.	Medical records.	None
Hironaka - BZDs (Control unexposed, disease free), 2011	retrospective cohort	The subjects’ medical records were investigated concerning medication history.	Medical records.	None.
Hironaka - BZDs (Control unexposed, sick), 2011	retrospective cohort	The subjects’ medical records were investigated concerning medication history.	Medical records.	None.
Huybrechts - BZDs, 2017	retrospective cohort (claims database)	The Medicaid Analytic eXtract (MAX) that includes prescriptions filled on an outpatient basis.	The Medicaid Analytic eXtract (MAX) that includes medical visits, admissions to hospital, inpatient or outpatient diagnoses and procedures. Neonatal drug withdrawal was defined based on the presence of ICD-9 code 779.5x in maternal or infant claims from delivery to one month after delivery.	Adjusted for the specific opioid compound and dose expressed in morphine equivalents, calendar year, demographics (age, race/ethnicity), obstetric characteristics (multiple gestation, preterm delivery, pre-eclampsia), pain and psychiatric diagnoses, indicators of substance abuse or dependence, concomitant medications, and general markers of disease burden (intensity of healthcare use).
Ishikawa - BZDs, 2024	nested case control	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.	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.	Exclusion of women with recurrent pregnancy loss, antiphospholipid syndrome, medications at risk of miscarriage. Adjusted for indications (schizophrenia, manic episodes, bipolar, depressive or anxiety disorder), uterine diseases (endometriosis, uterus and cervix malformations, ...), maternal comorbidities (polycystic ovarian, diabetes, obesity, or thyroid disorders), alcohol/tobacco dependence,...
Jackson - BZDs, 2024	retrospective cohort (claims database)	Benzodiazepine exposure was determined by its presence or absence in the medication reconciliation document completed during hospital admission.	Clinical data were obtained from the inpatient electronic medical record system. Outcome was determined by the presence of an ICD-10 diagnosis code for postpartum hemorrhage (PPH) and a procedure code for blood transfusion.	Adjustment for induction of labor, multiple gestation, >4 previous vaginal births, prior cesarean or uterine incision, large uterine fibroids, fetal demise, polyhydramnios, placental abruption, placenta accreta, placenta previa, known coagulopathy, anemia (hematocrit <30%), and thrombocytopenia, advanced maternal age, obesity, public health insurance, and race and ethnicity group.
Källén - BZDs, 2013	population based cohort retrospective	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).	The Swedish Medical Birth Registry contain information based on standardized medical records from the first and further antenatal visit, the delivery and the paediatric examination. Supplemented with data from the Register of Birth Defects and Hospital Discharge Register.	Adjustment was made for year of birth, maternal age (5-year class), parity, smoking in early pregnancy and body mass index.
Kelty - Alprazolam (Controls unexposed, disease free), 2023	retrospective cohort	Prescription database.	For the neonate, the Midwives Notification System, Hospital Morbidity Data Collection, and the Western Australia Death Register were used to ascertain information on neonatal health outcomes. Characteristics of labor and delivery were taken from the Midwives Notification System.	Comparison groups were matched 2:1 to the alprazolam during pregnancy group on smoking status during pregnancy, maternal age and having previously been pregnant (yes/no). Singleton pregnancies only. No difference of maternal age, smoking, maternal diabetes, socio-economic indexes for area.
Kelty - Alprazolam (Controls unexposed, sick), 2023	retrospective cohort	Prescription database.	For the neonate, the Midwives Notification System, Hospital Morbidity Data Collection, and the Western Australia Death Register were used to ascertain information on neonatal health outcomes. Characteristics of labor and delivery were taken from the Midwives Notification System.	Comparison groups were matched 2:1 to the alprazolam during pregnancy group on smoking status during pregnancy and having previously been pregnant (yes/no). Singleton pregnancies only. No difference of maternal age, smoking, maternal diabetes, socio-economic indexes for area.
Kilic - Clonazepam (Mixed indications), 2014	population based cohort retrospective	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.	The Danish Medical Birth Registry contains data on newborn babies including information on gestational age at birth, birth weight, and head circumference.	Singletons only. Adjusted for potential confounding factors, including maternal age, smoking, substance abuse, cohabitation, income, education, and parity.
Kullander - Chlordiazepoxide, 1976	nested case control	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.	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.	None.
Laegreid - BZDs, 1990	case control	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.	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.	None.
Laegreid a - BZDs, 1992	prospective cohort	Mothers were interviewed prior to delivery about their use of prescribed and non-prescribed drugs during pregnancy, including psychotropic drugs during pregnancy.	All the obstetric and neonatal records from the 3 infant groups were carefully reviewed to characterize the pregnancy and the perinatal period. The neurologic examination was in all the infants performed by one of the study team. It was not possible to perform the evaluation blind in all infants.	None. No significant differences in educational level between case- and control-mothers.
Laegreid b - BZDs, 1992	prospective cohort	Mothers were interviewed prior to delivery about their use of prescribed and non-prescribed drugs during pregnancy, including psychotropic drugs during pregnancy.	Somatic growth was taken from child health records at the regular checks at 6, 10 and 18 months of age. The children were examined for neurodevelopment in their homes by one of the study team. It was not possible to perform the evaluation blind in all infants.	None.
Laegreid c - BZDs, 1992	case control	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.	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.	None.
Laspro - BZDs, 2024	nested case control	Gestational medication use was identified by medications, prescribed, provider-administered, or reported use by mothers at any point during pregnancy.	Oral cleft cohorts were isolated using a combination of ICD codes, from the EPIC medical records.	None.
Lee - Alprazolam, 2022	prospective cohort	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.	Not specified.	Adjusted for age, parity, body mass index, alcohol intake, smoking, education, and occupation.
Lupattelli - BZDs, 2019	prospective cohort	Data were gathered prospectively via 2 prenatal self-administered questionnaires at week 17 (questionnaire 1) and week 30 (questionnaire 3).	Child outcomes were parent reported via completion of widely used, validated diagnostic measures of child development and behavior, including the Ages and Stages Questionnaires (ASQ - 6 items per domain) and the Conners’ Parent Rating Scale–Revised (CPRS-R: 12 items for ADHD).	Singletons only. Weighted for maternal folate intake, parity, marital status, body mass index, income, smoking and alcohol use in pregnancy, maternal and paternal education, self-reported comedication (antiepileptics, antidepressants, ...) severity of maternal depression/anxiety; history of major depression; painfulness of maternal adverse life events close to the pregnancy; obstetric comorbidity.
Meng a - BZDs (Controls unexposed, sibling), 2023	population based cohort retrospective	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).	The National Birth Certificate Application (BCA) database that includes notably gestational age at birth, birth date of newborns, singleton or multiple pregnancy, birthweight, and birth outcomes.	Siblings. Singletons only. Adjusted for maternal age, sex of the infant, birth year, psychiatric medical conditions, tobacco use, alcohol use, drug abuse, and obstetric comorbidity index scores.
Meng a - BZDs (Controls unexposed, sick), 2023	population based cohort retrospective	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).	The National Birth Certificate Application (BCA) database that includes notably gestational age at birth, birth date of newborns, singleton or multiple pregnancy, birthweight, and birth outcomes.	Singletons only. Propensity score (PS-FSW) to control for maternal age and nationality, sex of the infant and year of birth, indications for use (eg, anxiety, insomnia, depression, schizophrenia, epilepsy, and bipolar disorder), lifestyle factors (obesity, tobacco, alcohol, ...), chronic maternal comorbidities (hypertension, diabetes, ...), medication use, obstetric comorbidity, health-care use.
Meng b - BZDs, 2023	other	The National Health Insurance (NHI) database that comprises anonymized prescriptions for more than 99% of the population in Taiwan.	The National Health Insurance (NHI) database that comprises anonymized health insurance claims for visits and procedures for more than 99% of the population and the Birth Certificate Application (BCA) database (all live births and stillbirths > 20 gestational weeks or birth weight > 500g).	Controls matched for the birth year and a disease risk score (based on age, psychiatric medical conditions, lifestyle factors (obesity, tobacco, alcohol, drug misuse), chronic comorbidities (diabetes, hypertension, hyperlipidemia, …), medication use, and health care use). Adjusted for the comedication use (antidepressants, opioid analgesics, anticonvulsant, Z-hypnotics, and other anxiolytics).
Milkovich - Chlordiazepoxide, 1974	retrospective cohort	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.	All the data analysez here are derived from physicians' notations in the mothers' medical records.	None.
Mortensen - BZDs, 2003	population based cohort retrospective	The National Health Service in North Jutland County which partly refunds the costs of selected, prescribed drugs.	All Danish children are offered health consultations at home, provided by a specially trained health nurse, notably the Boel test, performed when the child is 7– 10 months old. It is a psychomotor development test based on 14 items including screening tests for hearing, sight, and motor attention.	Adjusted for gestational age, birth weight, breastfeeding, residence, and the child’s age for conception when the Boel test was done. Restricting the analysis to only full-term children (gestational age 37 weeks or more) did not change the estimates.
Noh - BZDs, 2022	population based cohort retrospective	The Health Insurance Review and Assessment Service (HIRA) database that comprises notably healthcare utilization (e.g., drug prescription and medical procedure).	Major congenital malformations were identified by diagnostic records, according to the ICD-10 codes defined by the European Surveillance of Congenital Anomalies classification.	Exclusion of exposures to known teratogens during 1st trimester. Adjusted for maternal age, type of insurance, maternal psychiatric conditions (e.g., bipolar disorder, depression/mood disorder, anxiety, and sleep disorder), maternal conditions (e.g., epilepsy, headache, diabetes, hypertension), parity, plurality, concomitant medications (e.g., antidepressants, ...), and healthcare utilization.
Oberlander - BZDs, 2008	retrospective cohort (claims database)	PharmaNet, a province-wide network recording all prescriptions dispensed by British Columbian pharmacists outside hospitals.	Five administrative sources housed in the BC Linked Health Database: British Columbia registry of births, hospital separation records, the PharmaCare registry of subsidized prescriptions; the Medical Services Plan physician billing records; and the registry of Medical Services Plan subscribers.	None (adjustment provided for risk difference but not for relative risk or odd ratio). Exclusion of co-exposure to anticonvulsivants.
Oberlander - Clonazepam (Controls unexposed, disease free), 2004	prospective cohort	Measure of plasma level of maternal SSRI medications.	Concern about respiratory or other symptoms on the part of the family physician, midwife or obstetrician led to assessment by the pediatrician. Physicians who had been asked to assess distressed newborns were partially blinded to the infants' prenatal exposure status. Physician reviewed chart.	None. Maternal age and gravidity did not vary significantly between subject groups.
Oberlander - Clonazepam (Controls unexposed, sick), 2004	prospective cohort	Measure of plasma level of maternal SSRI medications.	Concern about respiratory or other symptoms on the part of the family physician, midwife or obstetrician led to assessment by the pediatrician. Physicians who had been asked to assess distressed newborns were partially blinded to the infants' prenatal exposure status. Physician reviewed chart.	None. Maternal age and gravidity did not vary significantly between subject groups.
Ogawa - BZDs, 2018	nested case control	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.	For each person, the Japan Medical Data Center (JMDC) database includes an encrypted personal identifier, age, gender and diagnoses.	Inclusion of first singleton pregnancy. Women with alcohol or nicotine dependence were excluded. Adjusted for maternal age, preeclampsia, chorioamnionitis, diabetes, hypertension, systemic lupus erythematosus, asthma, hyperthyroidism and hypothyroidism.
Ornoy - BZDs, 1998	prospective cohort	Exposure identified at the initial call to the Teratogen Information Service.	Outcomes are based on the information provided by the women or their physicians, by telephone or follow up form sent to participants. The majority of our follow-ups were from the mothers.	None.
Radojcic - BZDs, 2017	prospective cohort	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.	Use of 2 standardized instruments: 1) child emotional and behavioral problems were reported by the mother using Child Behavior Checklist for ages 1 1/2 to 5 (CBCL 1 1/2 - 5); 2) additionally, the Teacher Report Form (TRF) was assessed at age 6 1/ 2 years.	Adjusted for child age and gender, maternal age, socioeconomic status, smoking, drinking habits during pregnancy, SSRI use in pregnancy and maternal prenatal anxiety symptom. Very low use of other psychoactive medications.
Robert - BZDs, 1994	case control	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).	Data on malformations come from the malformation registers which participate in the study (mainly hospital-based data).	None.
Rosenberg - Diazepam, 1983	case control	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.	The children were identified through systematic contact with collaborating physicians, clinics and institutions (no further details).	Adjusted for year, time between birth and interview, area, maternal characteristics (age smoking, history infection during 1st trimester, history of convulsive disorder/anticonvulsivants, history of diabetes, use of benzodiazepines (other than diazepam)), sex of the child, history of cleft lip or palate in the mother, father, sibling and suspicion by the mother that diazepam is teratogen.
Rothman - Diazepam, 1979	case control	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.	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.	The results presented by authors in the publication are from the unstratified data because the data were free of confounding by any of the factors examined (parity, maternal age, educational background and insulin use).
Safra - Diazepam, 1975	case control	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).	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.	None.
Salisbury - BZDs (Controls unexposed, disease free), 2016	prospective cohort	Maternal self-report assessments during pregnancy.	Infant medical records were reviewed for Neonatal Intensive Care Unit admission and medical conditions. Infants were assessed with the Neonatal Intensive Care Unit Network Neurobehavioral Scale. Certified examiners, blind to group status, conducted assessments on day 2, 4, 7, 14 and 30.	Model adjusted for covariates of gestational age at birth, infant sex, socioeconomic status and Inventory of Depressive Symptomatology. Only mothers not using illicit drugs, without medication for hypertension or diabetes, drinking less than one-half of a drink equivalent of alcohol per day and smoking less than 5 cigarettes per day in the first trimester with no smoking in the others. No preterm.
Salisbury - BZDs (Controls unexposed, sick), 2016	prospective cohort	Maternal self-report assessments during pregnancy.	Infant medical records were reviewed for Neonatal Intensive Care Unit admission and medical conditions. Infants were assessed with the Neonatal Intensive Care Unit Network Neurobehavioral Scale. Certified examiners, blind to group status, conducted assessments on day 2, 4, 7, 14 and 30.	Model adjusted for covariates of gestational age at birth, infant sex, socioeconomic status and Inventory of Depressive Symptomatology. Only mothers not using illicit drugs, without medication for hypertension or diabetes, drinking less than one-half of a drink equivalent of alcohol per day and smoking less than 5 cigarettes per day in the first trimester with no smoking in the others. No preterm.
Saxen - BZDs, 1975	nested case control	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.	The Finnish Register of Congenital Malformations, based on compulsory notification of all malformations detected in children under one year of age.	Controls matched for season of birth and domicile of the mother.
Sheehy - BZDs (Controls unexposed, NOS), 2019	nested case control	The Quebec Public Prescription Drug Insurance Plan database (drug name, start date, dose, and duration).	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).	Adjusted for (1) maternal sociodemographic variables (2) maternal chronic conditions (hypertension, diabetes, depression/anxiety, alcohol ...), (3) health care resources utilization, (4) pregnancy-associated variables, (5) concomitant exposure to antidepressants and/or antipsychotics. Matched by gestational age and calendar year. Exclusion of women with epilepsy and exposed to known teratogens.
Sheehy - BZDs (Controls unexposed, sick), 2019	nested case control	The Quebec Public Prescription Drug Insurance Plan database (drug name, start date, dose, and duration).	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).	Adjusted for (1) maternal sociodemographic variables (2) maternal chronic conditions (hypertension, diabetes, depression/anxiety, alcohol ...), (3) health care resources utilization, (4) pregnancy-associated variables, (5) concomitant exposure to antidepressants and/or antipsychotics. Matched by gestational age and calendar year. Exclusion of women with epilepsy and exposed to known teratogens.
Shiono - Diazepam, 1984	cohort	At their first prenatal visit, women were asked if they had used diazepam during the first trimester of pregnancy.	Not specified.	None.
Szpunar - BZDs, 2022	prospective cohort	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.	At the postpartum, participants provide neonatal information and they provide pediatric records (including from specialists). Malformations are identified by thorough review of medical records by trained research staff and confirmed by one of the principal investigators.	Potential confounding factor (body mass index, alcohol use, antipsychotic use, antidepressant use, anticonvulsivant use, cigarette use, education, maternal age, primary diagnosis), was added individually to the crude logistic regression model to examine the change in OR for major malformations compared with the unadjusted model.
The NAAED - Clonazepam, 2023	prospective cohort	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.	Women were questioned with a computer-assisted telephone interview 3 times and medical records were obtained. The written descriptions in the pediatricians’ examinations were reviewed separately by the clinical teratologist.	None.
Tikkanen - Diazepam, 1991	nested case control	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.	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.	No adjustment for this group pf exposure.
Tikkanen - Diazepam, 1992	nested case control	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.	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.	No adjustment for this group of exposure.
Tikkanen - Diazepam, 1992	nested case control	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.	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.	Adjusted for confounding factors such as the threat of miscarriage (no further details).
Tinker - BZDs, 2019	case control	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).	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.	For associations with at least 5 exposed cases: adjusted for maternal age, race/ethnicity, maternal education, any maternal cigarette smoking or antidepressant medication use in the first trimester (no adjustment if < 5 cases). Exclusion of mothers who reported use of an antiepileptic other than a benzodiazepine in the first trimester.
Veiby - Clonazepam (Mixed indications), 2014	population based cohort retrospective	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).	A standardised notification form is filled in from the first prenatal visit until discharge and transferred to the database by practitioners attending the delivery. (Coded according to ICD-10). Additional information on congenital malformations came from Norwegian pediatric wards.	Adjusted for maternal age, parity, smoking, folate supplementation, and maternal chronic disease other than epilepsy.
Viggedal - BZDs, 1993	prospective cohort	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.	The neurodevelopment was assessed at birth and at 6, 10 and 18 months of age by a paediatrician and their mental development at 5, 10 and 18 months of age by one of three trained psychologists. The psychologists were unaware of the group of children to which the particular infant belonged.	None. No significant differences in educational level between case- and control-mothers.
Winship - BZDs, 1984	case control	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).	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.	The control child was the nearest normal birth in the practice within three months after the birth of the study child.
Yamane - Etizolam, 2011	cohort	Not specified.	Not specified.	None.
Yonkers - BZDs, 2017	prospective cohort	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.	Maternal and birth outcomes were abstracted from the medical records.	Multifetal pregnancies or receiving insulin treatment for diabetes were excluded. Adjusted for panic disorder, generalized anxiety disorder (GAD), benzodiazepine use, SRI use, maternal age, race/ethnicity, educational level, smoking, heavy drinking, illicit drug, major depressive episode (MDE), and posttraumatic stress disorder (PTSD) during pregnancy (and previous preterm for LBW and preterm).
Zanisi - BZDs, 2022	cohort	Not specified.	Not specified.	None.

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