Diazepam

Exposed non-exposed, cohort studies

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 (Other indications) (Controls unexposed, disease free)
2014 		United Kingdom
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 (Other indications) (Controls unexposed, sick)
2014 		United Kingdom
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.
Källén
2013 		Swedish
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 Diazepam in early 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. 		early pregnancy 865 / 1575847 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).
Meng a (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 Diazepam 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 (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 Diazepam 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 13726 / 2771077 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
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 Diazepam during the risk period only (1-28 days before miscarriage). unexposed, sick
Women receiving at least 1 prescription of Diazepam 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.
Noh
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 Diazepam 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 17923 / 3053381 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).
Shiono
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.

Case-control studies

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
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.
Bracken
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.
Czeizel
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.
Czeizel
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.
Laspro
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.
Rosenberg
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
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
1975 		USA
Not specified.
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
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.
Sheehy
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
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
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.
Tikkanen
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
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.
Tinker
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. For analyses of hypospadias, only male control infants were included => OR not provided and insufficient data to be calculated.
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.

Risk of bias: : NA;   : low;   : moderate;   : serious;   : critical;   : unclear;  

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