Antimycotic Azoles (all routes except local 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
Bar-Oz - Itraconazole
2000 		International
1989 - 1998
prospective cohort 		The international pharmacovigilance department of the manufacturer of itraconazole. Pregnant patients who were known to have first-trimester exposure to itraconazole. unexposed (general population or NOS)
Pregnant women not exposed to any known teratogens and who contacted the Motherisk Program, a Canadian teratogen information service. 		1st trimester 199 / 198 Oral exposure. In cases in which data were available, however, the daily itraconazole doses ranged between 50 and 800 mg (median, 200 mg). Mean exposure duration 8.5±12.4j (range, 1-90 days; median, 3 days).
Details (timing and dose) of maternal drug therapy were reported by the treating physician.
De Santis - Itraconazole
2009 		Italy
2002 - 2006
prospective cohort 		Two teratology information services (TIS; Telefono Rosso-TIS in Rome and CEPIG [CEntro per l’Informazione Genetica]-TIS in Padua). Pregnant women exposed during their first trimester to oral itraconazole therapy. unexposed (general population or NOS)
Pregnant women exposed only to non-teratogenic (e.g. paracetamol [acetaminophen], hair dying) substances during their first trimester. 		1st trimester 206 / 207 Oral exposure. The mean daily dose of drug was 182.23±62.58 mg and the mean duration of therapy was 6.9±6.4 days.
A structured questionnaire used to collect information about maternal medical features and details of itraconazole therapy (dosage and timing).
Inman - Fluconazole
1994 		United Kingdom
1988 - 1989
retrospective cohort 		A prescription-event monitoring (PEM) carried out at the Drug Safety Research Unit (DSRU). Pregnancies in which Fluconazole was prescribed after the last monthly period (LMP). unexposed, sick
Pregnancies in which Fluconazole was prescribed before the last monthly period (LMP). 		during pregnancy (anytime or not specified) 60 / 192 Study on azole in an obstetrical indication, including only the intrauterine deaths and/or late pregnancy and/or neonatal outcomes that are studied as efficacy criteria rather than safety one. => Not reported here.
The patients were identified by means of copies of prescriptions supplied to the Drug Safety Research Unit (DSRU) in confidence by the Prescription Pricing Authority.
Jick - Fluconazole and Itraconazole (Oral)
1999 		United Kingdom
Not specified
retrospective cohort (claims database) 		The United Kingdom General Practice Research Database (GPRD). Pregnant women who received a prescription for oral azole in the first trimester of pregnancy. (Addition of oral fluconazole and oral azole, i.e itraconazole). unexposed (general population or NOS)
Pregnant women not exposed to fluconazole or other azole. 		1st trimester 322 / 1629 (Oral fluconazole: 92% received the single 150-mg dose preparation)
General Practice Research Database of prescription.
Mastroiacovo - Fluconazole
1996 		Italy
1992 - 1994
prospective cohort 		Three Teratology Information Service (TIS) centers. Pregnant women who were treated with fluconazole during the first 12 completed weeks of gestation. unexposed (general population or NOS)
Pregnant women who had not been exposed to fluconazole and who had contacted the three centers during the same period for exposure to agents that are known not to be teratogenic or embryotoxic, such as dental X-ray studies, acetaminophen, penicillin, and hair dye. 		1st trimester 226 / 452 The total dose exposure was in the range of 100 to 2100 mg, with a median of 200 mg. The most frequent dosage was 150 mg, as a single dose (105 women, 46.5%), or multiple doses of 150 mg (81 women, 35.8%). Other were exposed to 50 mg or 100 mg.
Staff physicians conduct a consultation that includes administering a structured interview with a detailed history of prescription and nonprescription drug use that included information on the commercial preparation, dosage, indication, and time during pregnancy when the drug was taken.
Molgaard-Nielsen - Fluconazole
2013 		Denmark
1996 - 2011
population based cohort retrospective 		Registry-based cohort of liveborn infants in Denmark Women who fill prescriptions for oral fluconazole agents during the first trimester. unexposed (general population or NOS)
Women who did not fill prescriptions for oral azole antifungal agents during the first trimester. 		1st trimester 7352 / 968236 Oral exposure. Dose response studied.
Prescriptions for oral fluconazole that were filled by the women during pregnancy was obtained from the National Prescription Registry.
Molgaard-Nielsen - Fluconazole (Oral) (Controls exposed to pivmecillinam)
2016 		Denmark
1997 - 2013
population based cohort retrospective 		Nationwide register-based cohort study in Denmark. Exposure to oral fluconazole 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) 5387 / 4357
Information on prescriptions for oral fluconazole (a prescription-only drug) was obtained from the National Prescription Register.
Molgaard-Nielsen - Fluconazole (Oral) (Controls unexposed, NOS)
2016 		Denmark
1997 - 2013
population based cohort retrospective 		Nationwide register-based cohort study in Denmark Exposure to oral fluconazole 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)
Non 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) 5387 / 1400113 Use of Oral Fluconazole. Analysis of dose response: low dose (150-300 mg) vs high dose (350-5600 mg).
Information on prescriptions for oral fluconazole (a prescription-only drug) was obtained from the National Prescription Register.
Norgaard - Fluconazole
2008 		Denmark
1991 - 2005
retrospective cohort (claims database) 		Four Danish counties, which, with their 1.6 million inhabitants, account for 31% of the Danish population. Fluconazole prescriptions in pregnant women who redeemed a fluconazole prescription during the first trimester. unexposed (general population or NOS)
No prescriptions for fluconazole during the entire study period. 		1st trimester 1079 / 170453 Overlapping: data on 'All malformations', 'Hypospadias', 'Heart defect', 'Stillbirth' not reported here because same database was used by Molgaard-Nielsen 2013 and 2016 for a longer period (1996-2011; 1997-2003) and all the country.
Prescription databases.
Pasternak - Fluconazole
2018 		Sweden and Norway
2005 - 2015
population based cohort retrospective 		Nationwide registers of Sweden and Norway. Oral fluconazole exposure at any time during pregnancy, as defined by filled prescriptions. unexposed (general population or NOS)
No fluconazole exposure at any time during pregnancy, as defined by filled prescriptions. 		during pregnancy (anytime or not specified) 10669 / 106690 Oral exposure. Dose effect analysis.
Prescription database.
Sorensen - Fluconazole
1999 		Denmark
1991 - 1996
retrospective cohort (claims database) 		The Danish North Jutland Pharmaco-Epidemiological Prescription Database and the Danish Medical Birth Registry. Women with prescriptions filled of fluconazole just before or during pregnancy (classified in three time windows). unexposed (general population or NOS)
Women who did not receive any reimbursed prescriptions 30 days before or during their pregnancies. 		1st trimester, during pregnancy (anytime or not specified) 165 / 13327 Overlapping: For malformations: No overlapping between Sørensen 1999 (1991-1996) and Molgaard-Nielsen 2013 (1996-2011) => use of these 2 studies. For stillbirth, preterm and LBW: Norgaard 2008 (1991-2005) included Sørensen => use of Norgaard (adjusted).
The population-based Pharmaco-Epidemiological Prescription Database of the County of North Jutland, Denmark was used to identify prescriptions. It includes the personal identification number, the drug prescribed according to ATC classification, and the date of the prescription.
Zhu - Fluconazole
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 oral fluconazole 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 37650 / 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
Berard - Fluconazole
2019 		Canada
1998 - 2015
nested case control 		The Quebec Pregnancy Cohort, Canada. Case of spontaneous abortion or stillbirth or major malformations. Pregnancies not ending in spontaneous abortion or stillbirth (random sampling control) or major malformations (all live-births used as controls). The Quebec Prescription Drug Insurance database. The filled prescription data were validated comparing them with maternal reports (the positive predictive value of prescription drug data to be ≥ 87% and the negative predictive value to be ≥ 92%). 1st trimester, during pregnancy (anytime or not specified) 29458 / 291410 Results (low dose versus unexposed; high dose versus unexposed) were meta-analysed to obtained data whatever dose. 'Analyses of major congenital malformation ... excluded chromosomal abnormalities or pregnancies exposed to known teratogens'.
Identification from the medical claims databases: Régie de l’assurance maladie du Québec (RAMQ) (outpatient diagnoses, procedures, women’s and physicians’ socioeconomic status), hospitalization archive database (MED-ÉCHO: diagnoses and procedures) and the Institut de la statistique du Québec (ISQ).
Carter - Miconazole
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 This database was used to assess several azoles => To avoid redundancy of cases and controls, only 1 was used => this one with more exposed cases (ie Miconazole) => thus results of concerned outcomes not reported for the class MA.
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.
Howley - Fluconazole
2016 		USA
1997 - 2011
case control 		The National Birth Defects Prevention Study NBDPS Infants with one or more of 30 different categories of major structural birth defects (cases), excluding those attributed to a known chromosomal or single- gene abnormality. Live births without birth defects randomly selected from hospital records or birth certificates in the same time period and geographic area as the cases. Exposures before and during pregnancy were collected by trained interviewers conducted computer-assisted telephone interviews with the mothers of case and control infants between 6 weeks and 24 months after the estimated date of delivery. 1st trimester 31645 / 11612 Partial overlapping between Carter 2008 (1997-2003) and Howley 2016 (1997-2011) for some outcomes and for Fluconazole. Because there is a very little part of Fluconazole exposure in 'Azoles exposure' in the Carter's study, the 2 studies were kept.
Clinical information was abstracted from case medical records. The clinical record of each case was reviewed by a clinical geneticists.
Kazy - Ketoconazole
2005 		Hungary
1980 - 1996
case control 		Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA) Cases with isolated and multiple congenital anomalies selected from the Hungarian Congenital Abnormality Registry. Newborn infants without congenital abnormality. The exposure data were obtained prospectively through antenatal care logbooks and other medical records, and retrospectively through questionnaires completed by the infants’ mothers. 1st trimester 22843 / 38151 Oral ketoconazole exposure.
The Hungarian Congenital Abnormality Registry (HCAR), in which notification by physicians of cases with Congenital anomalies is mandatory. Controls were selected from the National Birth Registry of the Central Statistical Office.
Kerr - Miconazole
2018 		USA and Canada
1993 - 2015
case control 		Slone Epidemiology Center Birth Defects Study (BDS). Infants with microcephaly alone (“isolated”) and microcephaly that included other major birth defects (“non-isolated”). Nonmalformed live-born infants. Within 6 months of delivery, trained BDS nurse- interviewers contacted mothers to complete a roughly 1-hr computer-assisted telephone interview, including medications during pregnancy. 1st trimester, 2nd trimester, 3rd trimester 166 / 12059 Authors analyzed separately 'isolated' microcephaly and 'non-isolated' microcephaly. Only isolated microcephaly are indexed in MetaPreg. Cases with chromosomal or syndrome diagnosis and potential congenital infections were excluded.
Cases and controls were ascertained at participating hospitals or birth defect registries in the same areas.
Rosa - Miconazole
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 - Miconazole
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.
Santos - Fluconazole
2011 		Canada
1998 - 2003
nested case control 		The Québec Pregnancy Registry, built from the linkage of three administrative databases. A pregnancy resulting in small-for-gestational-age (SGA) newborn, that weighed less than the tenth percentile according to the Canadian gender specific reference curves. A pregnancy resulting in a newborn that weighed greater or equal to the tenth percentile. The Régie de l’assurance maladie du Québec (RAMQ) database, that provides information on prescriptions filled for residents insured by Québec’s Public Drug Insurance Plan. Data are available for physician-based diagnoses, therapeutic procedures, characteristics of patient, and healthcare providers. 2nd and/or 3rd trimester 8192 / 55146
The Med-Echo database that records hospitalisation data such as gestational age for deliveries for all Quebec residents. It also records the gestational age for planned abortions, miscarriages, and deliveries.

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

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