High-dose animal studies have revealed evidence of embryolethality, fetotoxicity, and teratogenicity. There are no controlled data in human pregnancy.

Several epidemiologic studies do not indicate an increased risk of congenital anomalies associated with low-dose exposure during pregnancy (most patients received a single 150 mg oral dose). Data from several hundred pregnant women treated with standard doses (less than 200 mg/day), as a single or repeated dose in the first trimester, show no adverse fetal effects.

A few cases of a distinctive and rare pattern of birth defects have been reported in infants exposed in utero to high-dose maternal fluconazole (400 to 800 mg/day) during most or all of the first trimester. Brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease have been observed in these infants. These effects are similar to those observed in animal studies.

A malformed infant girl was born prematurely to a woman who received 400 mg/day throughout pregnancy for disseminated coccidioidomycosis. The infant displayed cranioschisis of the frontal bones, craniostenosis of the sagittal suture, hypoplasia of the nasal bones, cleft palate, humoral-radial fusion, bowed tibia and femur, bilateral femoral fractures, contractures of both upper and lower extremities, and defects of the fingers and toes. The infant died shortly after birth.

Two additional cases of congenital malformations were reported in infants born to women receiving this drug during or beyond the first trimester of pregnancy. Craniofacial, skeletal and cardiac malformations were evident. Only 1 infant survived.

A 24-year-old pregnant woman at week 16 of gestation was treated with this drug for Candida albicans sepsis. She received 10 mg/kg for 50 days total. Following treatment for sepsis, the remainder of her pregnancy took a normal course. At week 39 gestation she delivered a healthy female with no signs of congenital abnormalities. At 2 years of age, the baby showed normal growth and mental development.

In a retrospective population-based study in Northern Denmark, 1079 women who had a live birth or a stillbirth after the 20th week of gestation and who redeemed at least 1 prescription for this drug during the first trimester were compared to a cohort comprised of 170,453 pregnant women who redeemed no fluconazole prescription during pregnancy. The women were selected through the Danish Medical Birth Registry. Data on medication use, birth outcome, and covariates were extracted from population-based healthcare databases. Among 1079 women who used this drug during the first trimester, 797 (74%) received a total of 150 mg, 235 (22%) received 300 mg, 24 (2%) received 350 mg, and 23 (2%) received 600 mg. These women gave birth to 44 (4.1%) children with congenital malformations. The 170,453 women without fluconazole prescriptions gave birth to 6152 (3.6%) children with congenital malformations. The study found no overall increased risk of congenital malformations after exposure to short-course treatment with this drug in early pregnancy.

AU TGA pregnancy category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.

US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

US FDA pregnancy category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

AU: Use should be avoided, except in severe or potentially life-threatening fungal infections when the benefit outweighs the risk to the fetus.
UK: Standard doses and short-term therapies are not recommended unless clearly needed; high-dose and/or prolonged regimens should not be used during pregnancy, except for potentially life-threatening infections.
US: If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.

AU TGA pregnancy category: D
US FDA pregnancy category: D (all indications except vaginal candidiasis)
US FDA pregnancy category: C (single 150 mg tablet for vaginal candidiasis)

See references

LactMed/WHO: Use is considered acceptable.
-AU: Use is not recommended.
-UK: Breastfeeding may continue after a single dose up to 200 mg; breastfeeding is not recommended after repeated dosing or after a high dose.
-US: Caution is recommended.

Excreted into human milk: Yes

Comments: The effects in the nursing infant are unknown.

This drug is excreted in human milk at levels lower than or similar to maternal plasma levels. Amounts excreted into breast milk are less than the neonatal dose.

According to the Academy of Breastfeeding Medicine, this drug is often used to treat breast candidiasis in nursing mothers, especially if recurrent or persistent infections; no adequate clinical trials on fluconazole in Candida mastitis available. This drug is often used simultaneously in the mother and infant when other therapies fail. Most often the maternal regimen is 400 mg once followed by 200 mg daily for at least 2 week or until pain resolved; 1 Australian study used 150 mg every other day until breast pain resolved. The amount of fluconazole in breast milk with these maternal doses is not sufficient to treat oral thrush in the infant.

A peak milk level of 4.1 mg/L was observed 2 hours after the dose on day 20 postpartum in a woman taking 200 mg orally once a day for 18 days; half-life of elimination from breast milk was 26.9 hours. Another woman received a single 150 mg oral dose at 12 weeks postpartum; highest milk levels were 2.9 and 2.7 mg/L at 2 and 5 hours after the dose, respectively, and milk drug levels were 1.8 and 1 mg/L at 24 and 48 hours after the dose, respectively; half-life in milk was about 30 hours. Using peak milk level data from these 2 patients, an exclusively breastfed infant whose mother was taking 200 mg daily would receive 0.6 mg/kg/day (maximum), which is 60% of the recommended dose for neonates younger than 2 weeks and 20% of the dose used in older infants for oral thrush.

A nursing woman who received a single 150 mg oral dose to treat vaginal candidiasis had breast milk:plasma ratios of 0.46, 0.85, 0.85, and 0.83 at 2, 5, 24, and 48 hours, respectively, indicating relatively high levels of drug in the breast milk.

In a study of this drug for treatment of lactation-associated thrush of the breasts, mothers took an average of 7.3 capsules (range: 1 to 29 capsules) of 150 mg every other day until pain resolved. Seven of the 96 women reported side effects possibly due to fluconazole in their breastfed infants, including flushed cheeks, gastrointestinal upset, and runny or mucous stools.

At least 2 neonates received a dose of 6 mg/kg. One infant developed a small, transient elevation in liver function tests which resolved with dose reduction. These cases suggest this drug may be safely used during breastfeeding, as infants would receive significantly less drug; more experience needed to establish safety.

See references