Chlordiazepoxide

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
Hartz
1975 		USA
1958 - 1966
prospective cohort 		The Collaborative Perinatal Project, based on 12 university)affiliated hospitals in the United States of America. Children exposed in utero to Chlordiazepoxide. unexposed (general population or NOS)
Children not exposed in utero to Chlordiazepoxide or Meprobamate. 		early pregnancy, late pregnancy 740 / 48412 Overall mortality cannot be reported because the total number of exposed pregnancies considered for this outcome was not clearly provided; and Neurodevelopmental data cannot reported because only means were provided.
A history of drug use covering the period of the pregnancy (and 1 month before) was obtained by interview of each woman, on entry into the study. Then it was also obtained at 4-week intervals during the pregnancy and confirmed by the attending physician or by review of the hospital or clinic record.
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 Chlordiazepoxide 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 Chlordiazepoxide 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 943 / 2753670 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).
Milkovich
1974 		USA
1959 - 1966
retrospective cohort 		The Child Health and Development Studies based on pregnant women included in the East San Francisco Bay Area facilities of the Kaiser-Permanent Medical Care Program. Liveborn infants of women who received prescriptions of Chlordiazepoxide, for anxiety, during pregnancy. unexposed, sick
Liveborn infants of women with no prescription of Chlordiazepoxide, for anxiety, during the first 42 days of pregnancy (and very few were given between the 43rd and the 84th days). 		during pregnancy (anytime or not specified) 175 / 509
For each gravida, the Studies have available data on all drugs prescribed not only in the prenatal clinical but in any Permanente or Kaiser medical-care facility, from the combined clinia and hospital medical record.
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 Chlordiazepoxide 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 381 / 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).

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
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
2004 		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 Czeizel 2004, Czeizel 2003 and Eros 2002 used the same dataset to assess several benzodiazepines. To avoid redundancy of cases and controls, only the study with the most exposed cases was reported in the meta-analysis of class.
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.
Kullander
1976 		Sweden
1963 - 1965
nested case control 		The Department of Gynecology and Obstetrics and the Department of Embryology, University of Lund, Sweden. Infants with different kinds of malformations. Infants without malformations. Information on drug use was obtained mainly from the questionnaires administered to pregnant women, sometimes supplemented from hospital records etc. Information was usually collected before the outcome of the pregnancy was known. The (approximate) time of intake of each drug used was recorded. 1st trimester 751 / 5002
All living children were carefully investigated by a pediatrician after birth and were followed to about 1 year old at the child health centres. Autopsy was performed and the age at death was recorded. The presence of major and minor malformations was recorded for all infants.
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 The authors provided a 90% confidence interval, without adjustment => here a 95% confidence interval was calculated to be homogeneous with other studies.
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.
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).

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

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