Azoles (local routes only)

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
Araujo - Sertaconazole (Topical)
2022 		France
2004 - 2018
retrospective cohort (claims database) 		The EFEMERIS database, the Haute-Garonne region, France. Pregnant women exposed to sertaconazole at least once during pregnancy. unexposed (general population or NOS)
Pregnant women not exposed to sertaconazole at least once during pregnancy. 		1st trimester, during pregnancy (anytime or not specified) 16222 / 91976
The EFEMERIS database was used, which contained medications prescribed and dispensed to pregnant women in the Haute-Garonne region.
Daniel - Clotrimazole and/or miconazole (Vaginal)
2018 		Israel
2003 - 2009
retrospective cohort (claims database) 		Soroka Medical Center, Clalit Health Services, Israel. Dispensation of vaginal clotrimazole and/or miconazole from the first day of the last menstrual period until the date of admission to the hospital for pregnancies that resulted in spontaneous abortion or until 20 weeks of pregnancy for pregnancies that ended with birth. unexposed (general population or NOS)
No dispensation of anti-mycotic medication (vaginal or oral). 		1st trimester 3246 / 62137 Vaginal exposure.
Medication dispensions during pregnancy were retrieved from the CHS medication database which contains all drug dispensions (prescription or OTC) to all patients insured by CHS in both community and hospital pharmacies.
Jick - Azole (Topical route)
1999 		United Kingdom
Not specified
retrospective cohort (claims database) 		The United Kingdom General Practice Research Database (GPRD). Pregnant women who received a prescription for topical azole in the first trimester of pregnancy. unexposed (general population or NOS)
Pregnant women not exposed to fluconazole or other azole. 		1st trimester 492 / 1629
General Practice Research Database of prescription.
Molgaard-Nielsen - Clotrimazole/miconazole (Vaginal) (Controls exposed to pivmecillinam)
2016 		Denmark
1997 - 2013
population based cohort retrospective 		Nationwide register-based cohort study in Denmark Exposure to vaginal azole antifungals (intravaginal clotrimazole or miconazole) during the specific time windows: gestational week 7 to 22 and week 7 to birth for spontaneous abortion and stillbirth, respectively. exposed to other treatment, sick
Exposure to pivmecillinam during the specific time windows: gestational week 7 to 22 and week 7 to birth for spontaneous abortion and stillbirth, respectively. 		during pregnancy (anytime or not specified) 4301 / 4357
Information on prescriptions for oral fluconazole (a prescription-only drug) was obtained from the National Prescription Register.
Molgaard-Nielsen - Clotrimazole/miconazole (Vaginal) (Controls unexposed, NOS)
2016 		Denmark
1997 - 2013
population based cohort retrospective 		Nationwide register-based cohort study in Denmark Exposure to vaginal azole antifungals (intravaginal clotrimazole or miconazole) during the specific time windows: gestational week 7 to 22 and week 7 to birth for spontaneous abortion and stillbirth, respectively. unexposed (general population or NOS)
No exposure to fluconazole during the specific time windows: gestational week 7 to 22 and week 7 to birth for spontaneous abortion and stillbirth, respectively. 		during pregnancy (anytime or not specified) 4301 / 1400113
Information on prescriptions for oral fluconazole (a prescription-only drug) was obtained from the National Prescription Register.
Rotem - Clotrimazole (Vaginal)
2018 		Israel
1999 - 2009
retrospective cohort (claims database) 		Four computerised databases in the Soroka Medical Center, Beer-Sheva, Israel. Women who were dispensed with clotrimazole vaginal tables during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Pregnancies that were not exposed to either drug from the azoles family (e.g. vaginal, systemic or topical formulation). 		1st trimester 1993 / 95781 Vaginal exposure
Data for drugs dispensed during pregnancy were provided by the Clalit HMO medication database.
Zhu - Azoles (Local routes)
2020 		USA
2000 - 2014
retrospective cohort (claims database) 		A cohort study with data from the nationwide Medicaid Analytic eXtract (MAX). Pregnant women who filled one or more prescriptions for topical/vaginal azoles during the first trimester and had no dispensing for other oral antifungal agents between 90 days before the LMP and the end of the 1st trimester. (This is a subgroup of exposure among the whole exposed group). unexposed (general population or NOS)
Pregnant women with no prescriptions for oral antifungal agents during the baseline and first trimester periods. 		1st trimester 82090 / 1875257 'Exclusions were pregnancies with a chromosomal abnormality or exposure to a known teratogenic drug during the first trimester...'.
The Medicaid Analytic eXtract (MAX) including dispensing records for outpatient prescription drugs for reimbursement.

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
Abdel-Salam - Clotrimazole
2000 		Hungary
1980 - 1996
case control 		The Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA). Newborn infants (including infant deaths and usual stillborn fetuses) with isolated microcephaly. Newborn infants (including infant deaths and usual stillborn fetuses) without congenital abnormalities. 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. during pregnancy (anytime or not specified) 109 / 218 Study design completed with other studies published on the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA).
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.
Carter - Clotrimazole
2008 		USA
1997 - 2003
case control 		National Birth Defects Prevention Study (NBDPS), USA Cases with selected birth defects (included live births, stillbirths 20 weeks or longer or greater than 500 g, or elective terminations). Live births without birth defects that were randomly selected from birth certificates or birth hospitals in the geographic regions monitored by the state surveillance systems. Structured maternal interviews were conducted mainly by telephone in English or Spanish no later than 24 months after the expected date of delivery (EDD) to obtain data on maternal exposures during pregnancy. 1st trimester 12274 / 4774 Study analyzing several local azoles => to avoid redundancy of cases and controls, only 1 substance was reported here, this one with the most exposed cases.
Cases and controls were identified by the birth defects surveillance systems in 10 states of USA. Medical records were obtained for all cases and reviewed by clinical geneticists.
Czeizel - Clotrimazole
1999 		Hungary
1980 - 1992
case control 		The Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA). Infants (liveborn infants, stillborn infants, and electively aborted fetuses) with congenital abnormalities (CAs) were selected from the Hungarian Congenital Abnormality Registry. Infants without congenital abnormalities, matched according to sex, birth week, and district of parents' residence selected from the national birth registry of the Central Statistical Office. The exposure data were obtained: (i) prospectively through antenatal care logbooks and other medical records; (ii) retrospectively by questionnaires completed by mothers; and (iii) by the help of regional nurses who visited and questioned all nonrespondent case and 200 control mothers. 1st trimester, during pregnancy (anytime or not specified) 18515 / 32804 Overlapping: Abdel-Salam 2000, Vermes 2015 and Medveczky 2004 studied specifically 3 outcomes (Microcephaly; oesophagial atresia; neural tube defects) on the same database and a longer period (1980 - 1996) => these outcomes are not reported here.
The Hungarian Congenital Abnormality Registry (HCAR), in which notification by physicians of cases with Congenital anomalies is mandatory. Autopsy was obligatory for all infant deaths during the study period (1980-1992),and pathologists sent a copy of a detailed autopsy report to the Registry.
Kazy b - Metronidazole (Vaginal)
2005 		Hungary
1980 - 1996
case control 		The Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA). Cases with congenital abnormalities (CAs) were selected from the Hungarian Congenital Abnormality Registry. Controls were extracted from from the National Birth Registry of the Central Statistical Office. The exposure data were obtained: (i) prospectively through antenatal care logbooks and other medical records; (ii) retrospectively by questionnaires completed by mothers; and (iii) by the help of regional nurses who visited and questioned all nonrespondent case and 200 control mothers. 1st trimester, during pregnancy (anytime or not specified) 22843 / 38151 Database analyzing several local azoles => to avoid redundancy of cases and controls, only 1 substance reported here, this one with the most exposed cases: Czeizel 1999, except for 2 outcomes: Esophageal atresia/stenosis and Rectal/anal atresia/stenosis.
Not specified.
Medveczky - Clotrimazole
2004 		Hungary
1980 - 1996
case control 		The Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA). Newborn infants (including infant deaths and usual stillborn fetuses) with Neural tube defects with non-syndromic (i.e. isolated anencephaly, spina bifida aperta/cystica, encephalocele). Newborn infants (including infant deaths and usual stillborn fetuses) without congenital abnormalities. 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 1202 / 38151 Study design completed with other studies published on the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA). For metronidazole, data not reported because already included (Kazy 2005b; Czeizel 1998).
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.
Rosa - Clotrimazole
1987 		USA
1980 - 1983
case control 		COMPASS, a database generated by Health Information Designs from routinely computerized Medicaid invoices for prescriptions and diagnoses Patients aged zero to four years with suspected birth defect diagnoses, pregnancies ending in spontaneous abortions (ICD9 634-634.9). Deliveries not linked to birth defects. Medicaid invoices for prescriptions. 1st trimester, 3 months (or more) before pregnancy or during pregnancy 6564 / 97775 Study on the efficacy of azole in an obstetrical indication, including the intrauterine deaths and/or late pregnancy and/or neonatal outcomes that are studied as efficacy criteria rather than safety one. => Not reported here.
Medicaid invoices for diagnoses.
Ross - Clotrimazole
2003 		USA and Canada
1983 - 1988
case control 		The registration files of the former Children’s Cancer Group (CCG) and general population. Children diagnosed with acute leukemia (i.e., acute myeloid leukemia, AML and acute lymphoblastic leukemia, ALL) in the first 18 months of life. Children without leukemia identified through random digit dialing. Exposure information was collected from mothers using a structured telephone questionnaire. All prescription drugs recorded in the medical record were abstracted, including data for the trimester of pregnancy the drug was prescribed based upon gestational ages recorded in medical records. during pregnancy (anytime or not specified) 243 / 393
Signed medical record release forms were obtained and complete copies of medical records were requested. Data were abstracted from medical records by two registered nurses using a structured protocol.
Zarante - Clotrimazole (Vaginal)
2009 		Colombia
2001- 2006
case control 		The Institute of Human Genetics of the Pontificia Universidad Javeriana, an active member of the Latin-American Collaborative Study of Congenital Malformations (ECLAMC) which is an international registry of congenital malformations . All newborns and stillborns of weight >500 g that presented only one craniofacial malformation, not associated with any other congenital condition. The next non-malformed same sex child born in the same hospital. Information collected in 10 Colombian hospitals (NOS). during pregnancy (anytime or not specified) 374 / 728
Information collected in 10 Colombian hospitals (NOS).
Zarante - Metronidazole (Vaginal)
2009 		Colombia
2001- 2006
case control 		The Institute of Human Genetics of the Pontificia Universidad Javeriana, an active member of the Latin-American Collaborative Study of Congenital Malformations (ECLAMC) which is an international registry of congenital malformations . All newborns and stillborns of weight >500 g that presented only one craniofacial malformation, not associated with any other congenital condition. The next non-malformed same sex child born in the same hospital. Information collected in 10 Colombian hospitals (NOS). during pregnancy (anytime or not specified) 374 / 728
Information collected in 10 Colombian hospitals (NOS).

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

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