Alprazolam

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
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 alprazolam 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 444 / 1575847 Follow-up period known thanks to author's email reply. For major malformations: upper CI value may be incorrect (1.97 [1.38;2.02]).
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).
Kelty (Controls unexposed, disease free)
2023 		Australia
2014 - 2018
retrospective cohort 		Administrative linked data from the Western Australia (WA) Department of Health, Australia. All women who had been dispensed two or more scripts of alprazolam during pregnancy, with a combined minimum of 40 tablets. unexposed, disease free
Women who had no record of alprazolam dispensing at any time. 		during pregnancy (anytime or not specified) 48 / 96 Women in this group were dispensed a median of four prescriptions during pregnancy (IQR: 2–6), with a median of 200 tablets (IQR: 100–357) dispensed during pregnancy.
Prescription database.
Kelty (Controls unexposed, sick)
2023 		Australia
2014 - 2018
retrospective cohort 		Administrative linked data from the Western Australia (WA) Department of Health, Australia. All women who had been dispensed two or more scripts of alprazolam during pregnancy, with a combined minimum of 40 tablets. unexposed, sick
All women who had been dispensed alprazolam prior to conception or following birth (but not during pregnancy) 		during pregnancy (anytime or not specified) 48 / 96 Women in this group were dispensed a median of four prescriptions during pregnancy (IQR: 2–6), with a median of 200 tablets (IQR: 100–357) dispensed during pregnancy.
Prescription database.
Lee
2022 		South Korea
2000 - 2019
prospective cohort 		A pregnancy exposure registry established from the Korean Mother-Safe Program, South Korea. Pregnant women exposed to alprazolam during pregnancy. unexposed (general population or NOS)
Pregnant women exposed to non-teratogenic drugs including acetaminophen and chlorpheniramine during pregnancy. 		1st trimester 96 / 629 The main reasons for taking alprazolam were irritable: bowel syndrome (IBS) (20.8%), depression (16.7%), and common cold (12.5%). Cumulative doses during pregnancy ranged from 1.00 mg/kg to 61.00 mg/kg (median 16.00 mg/kg).
Medications taken during pregnancy were asked at the time of counselling. In addition, the daily dose, duration of alprazolam administration, and the reason for taking it were asked in the exposed group.
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 Alprazolam 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 Alprazolam 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 14299 / 2771325 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 Alprazolam during the risk period only (1-28 days before miscarriage). unexposed, sick
Women receiving at least 1 prescription of Alprazolam 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 Alprazolam 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 1473 / 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
Cifuentes
2025 		Europe (13 countries)
1995 - 2019
case control 		A case-malformed-control study using the EUROmediCAT database, including data from data from 19 registries from EUROCAT the European network for surveillance of congenital anomalies and from EFEMERIS. Registrants (liveborn, stillborn, or induced terminations) with congenital ocular anomalies (COA). Registrants with major congenital anomalies (excluding genetic syndromes) other than congenital ocular anomalies (COA) and nervous system anomalies (except spina bifida) as central nervous system development is closely linked to eye development. Information on maternal medication exposure was primarily obtained from maternity records. Additional data sources for some registries included: infant medical records, general practitioner records, pregnancy passports, and maternal interviews conducted before or after birth. EFEMERIS: dispensing. 1st trimester 4185 / 232718 Use of nongenetic controls (cases of CA other than COA excluding genetic syndromes),
Cases and controls were obtained in registries from EUROCAT, the European network for surveillance of congenital anomalies.
Eros
2002 		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 or three 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 immediately after the selection of cases/controls; maternal prenatal care logbook (in which obstetricians must record all prescribed drugs); nurses visited non-responding families. during pregnancy (anytime or not specified) 22865 / 38151
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.
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).
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 (number of cases provided for each kind of malformations or group of malformations).
Cases were identified in the The National Birth Defects Prevention Study. The NBDPS clinical data for birth defect cases were abstracted from medical records and classified by clinical experts. Controls were selected from birth certificates or hospital records in the same area.

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

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