Diazepam

Study	Type of data	Exposure measurement	Outcome assessment	Adjustment
Aarskog, 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 (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 (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.
Bracken, 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.
Czeizel, 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).
Czeizel, 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.
Källén, 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).	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.
Laspro, 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.
Meng a (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 (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, 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).
Noh, 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.
Rosenberg, 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, 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, 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.
Sheehy, 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, 1984	cohort	At their first prenatal visit, women were asked if they had used diazepam during the first trimester of pregnancy.	Not specified.	None.
Tikkanen, 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, 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).
Tikkanen, 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.
Tinker, 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.

master protocol