Antimycotic Azoles (all routes except local only) - Medication and Pregnancy KB

Antimycotic Azoles (all routes except local only)

Exposed non-exposed studies (cohort)

Study	Country Study period	Population source	Exposure definition	Non-exposure definition	Sample size	Rmk
Bar-Oz - Itraconazole, 2000	International 1989 - 1998	Exposed pregnancies reported to manufacturer by the treating physician at the time of exposure and non exposed pregnancies who contacted the Motherisk Program.	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.	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).
De Santis - Itraconazole, 2009	Italy 2002 - 2006	Women who contacted on of the two teratology information services.	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.	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.
Inman - Fluconazole, 1994	United Kingdom 1988 - 1989	Pregnancies identified by means of copies of prescriptions supplied to the Drug Safety Research Unit (DSRU) in confidence by the Prescription Pricing Authority.	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).	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.
Jick - Fluconazole and Itraconazole (Oral), 1999	United Kingdom Not specified	Not specified	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.	322 / 1629	(Oral fluconazole: 92% received the single 150-mg dose preparation)
Mastroiacovo - Fluconazole, 1996	Italy 1992 - 1994	Pregnant women who contacted one of the three Teratology Information Service 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.	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.
Molgaard-Nielsen - Fluconazole, 2013	Denmark 1996 - 2011	All liveborn infants who were born in Denmark during the study period.	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.	7352 / 968236	Oral exposure. Dose response studied.
Molgaard-Nielsen - Fluconazole (Oral) (Controls exposed to pivmecillinam), 2016	Denmark 1997 - 2013	All pregnancies ending with a singleton live birth, stillbirth, spontaneous abortion, and other abortive outcomes (including ectopic pregnancy, hydatidiform mole, other abnormal products of gestation, or induced abortion) 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.	5387 / 4357
Molgaard-Nielsen - Fluconazole (Oral) (Controls unexposed, NOS), 2016	Denmark 1997 - 2013	All pregnancies ending with a singleton live birth, stillbirth, spontaneous abortion, and other abortive outcomes (including ectopic pregnancy, hydatidiform mole, other abnormal products of gestation, or induced abortion) 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.	5387 / 1400113	Use of Oral Fluconazole. Analysis of dose response: low dose (150-300 mg) vs high dose (350-5600 mg).
Norgaard - Fluconazole, 2008	Denmark 1991 - 2005	All female residents of 4 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.	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.
Pasternak - Fluconazole, 2018	Sweden and Norway 2005 - 2015	All pregnancies with singleton live births and stillbirths.	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.	10669 / 106690	Oral exposure. Dose effect analysis.
Sorensen - Fluconazole, 1999	Denmark 1991 - 1996	All singleton pregnant women in the county who gave birth in the period from 1991 to 96.	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.	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).
Zhu - Fluconazole, 2020	USA 2000 - 2014	Pregnant women aged 12-55 who were continuously enrolled in Medicaid from three or more months before the last menstrual period to one or more months after delivery, and liveborn infants.	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.	37650 / 1875257	'Exclusions were pregnancies with a chromosomal abnormality or exposure to a known teratogenic drug during the first trimester...'.

Case-control studies (cohort)

Study	Country Study period	Case	Control	Sample size	Rmk
Berard - Fluconazole, 2019	Canada 1998 - 2015	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).	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'.
Carter - Miconazole, 2008	USA 1997 - 2003	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.	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.
Howley - Fluconazole, 2016	USA 1997 - 2011	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.	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.
Kazy - Ketoconazole, 2005	Hungary 1980 - 1996	Cases with isolated and multiple congenital anomalies selected from the Hungarian Congenital Abnormality Registry.	Newborn infants without congenital abnormality.	22843 / 38151	Oral ketoconazole exposure.
Kerr - Miconazole, 2018	USA and Canada 1993 - 2015	Infants with microcephaly alone (“isolated”) and microcephaly that included other major birth defects (“non-isolated”).	Nonmalformed live-born infants.	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.
Rosa - Miconazole, 1987	USA 1980 - 1983	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.	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.
Ross - Miconazole, 2003	USA and Canada 1983 - 1988	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.	243 / 393
Santos - Fluconazole, 2011	Canada 1998 - 2003	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.	8192 / 55146

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