Fetal Risk Summary
Fluconazole is a synthetic triazole antifungal agent. In studies with pregnant rabbits, abortions were noted at a dose 2060 times the recommended human dose (RHD) but no fetal anomalies (1). In pregnant rats, doses below 2060 times the RHD produced increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation, and delays in ossification). At doses of 2060 times the RHD and higher, embryo deaths were observed as well as structural abnormalities consisting of wavy ribs, cleft palate, and abnormal craniofacial ossification (1). These effects were thought to be consistent with inhibition of estrogen synthesis (1).
One hypothesis for the teratogenic effects of phenytoin involves the production of toxic intermediates, such as an epoxide (arene oxide) (2). Because fluconazole inhibits the cytochrome P450 pathway responsible for phenytoin metabolism, authors of a 1999 study reasoned that the drug combination could provide a test of the hypothesis. The theory was not supported, however, when pretreatment with a nonembryotoxic fluconazole dose doubled (from 6.2% to 13.3%; p
It is not known if fluconazole crosses the human placenta. The molecular weight (about 306) is low enough, however, that passage to the fetus should be expected.
A case published in 1992 described the pregnancy outcome in a 22-year-old black woman who was treated before and throughout gestation with fluconazole, 400 mg/day orally, for disseminated coccidioidomycosis (3). Premature rupture of the membranes occurred at 27 weeks’ gestation; 1 week later, a cesarean section was performed because of chorioamnionitis. A 1145-g female infant with grossly dysmorphic features and with Apgar scores of 0 and 6 at 1 and 5 minutes, respectively, was delivered. The infant died shortly after birth. Anatomic abnormalities included cranioschisis of the frontal bones, craniostenosis of the sagittal suture, hypoplasia of the nasal bones, cleft palate, humeral-radial fusion, bowed tibia and femur, bilateral femoral fractures, contractures of both upper and lower extremities, an incompletely formed right thumb, medial deviation of both feet with a short left first toe, and short right first, fourth, and fifth toes (3). No evidence of coccidioidomycosis was found on microscopic examination.
A 1996 publication described three infants (one of whom is described above) with congenital malformations who had been exposed to fluconazole in utero during the 1st trimester or beyond (4). One woman with Coccidioides immitis meningitis took 800 mg/day of fluconazole through the first 7 weeks of pregnancy, then resumed therapy during the 9th week of gestation and continued until delivery by cesarean section at 38 weeks’ gestation. The male infant was small for gestational age (1878 g), was cyanotic, and had poor tone. He suffered a femur fracture when his limbs were straightened for measurement shortly after birth. Multiple malformations were observed involving the head and face: brachycephaly, maxillary hypoplasia, small ear helices, exotropia, craniofacial disproportion, large anterior fontanelle, trigonocephaly, supraorbital ridge hypoplasia, and micrognathia; the skeleton: femoral bowing, femoral fracture, thin clavicles, ribs, and long bones, and diffuse osteopenia; and the heart: tetralogy of Fallot, pulmonary artery hypoplasia, patent foramen ovale, and patent ductus arteriosus.
The pregnancy outcome of a woman (her second pregnancy), first described by Lee et al. in 1992 (3), was also reviewed in the above 1996 Reference. In her next pregnancy (her third), she delivered a healthy male infant (4). Although she had been told to take fluconazole 400 mg/day, nontherapeutic serum levels documented that the patient was not compliant with these instructions. After this, the woman conceived a fourth time, and therapeutic serum fluconazole concentrations were documented while she was taking 400 mg/day. Therapy was discontinued when her pregnancy was diagnosed at 4 months’ gestation. The full-term female infant (weight not specified) had multiple malformations involving the head and face: cleft palate, low ears, tracheomalacia, rudimentary epiglottis, and proptosis; the skeleton: femoral bowing, clavicular fracture, thin wavy ribs, absent distal phalanx (toe), and arachnodactyly; and the heart: ventricular septal defect and pulmonary artery hypoplasia. The infant died at age 3 months from complications related to her tracheomalacia.
The anomalies noted in the 1992 case report were at first thought to be consistent with an autosomal recessive genetic disorder known as the Antley-Bixler syndrome (3). But because of the second case in the same mother and the third infant, the defects were now thought to represent the teratogenic effect of fluconazole (4). Moreover, several of the defects observed were similar to those described in fetal rats exposed to fluconazole.
The FDA in January 1996 received a report of congenital defects in an infant exposed to 800 mg/day of fluconazole during the 1st trimester (F. Rosa, personal communication, FDA, 1996). Similar to the case described by Lee et al. (3), the infant had craniostenosis of the sagittal suture and a rare bilateral humeral-radial fusion anomaly. Other malformations were rocker-bottom feet and orbital hypoplasia. Additional individual adverse reports involving fluconazole that were received by the FDA included three cases of cleft palate, one case each of miscarriage with severe shortening of all limbs and of syndactyly, both after a single 150-mg dose in the 1st trimester, and single cases of hydrocephalus, omphalocele, and deafness.
A 1997 case report described a 27-year-old woman with chronic C. immitis meningitis who was treated with fluconazole (400 mg/day through the fourth or fifth week, then 800 mg/day) during the first 9 weeks of an unknown pregnancy (5). Fluconazole was stopped when the pregnancy was diagnosed and amphotericin B therapy was initiated. At 22 weeks’ gestation, amphotericin B was discontinued and fluconazole was restarted at 1200 mg/day. Spontaneous rupture of the membranes occurred at 31 weeks’ and a 1300-g male infant was delivered by cesarean section. Craniofacial anomalies noted in the newborn included a soft calvarium, widely separated sutures, prominent forehead, mild exorbitism, a large pear-shaped nose, and small ears with overfolded helices (5). Other malformations included immobile elbows, hypoplastic nails, subluxed hips, rocker-bottom feet, and bilateral radio-humeral synostosis. Because of the similarity to the other reported cases, the authors concluded that fluconazole produces a Antley-Bixler-like syndrome (5). [Note: The malformations observed in this infant are very similar to those described by Rosa above, and may be the same case.] In contrast to the above adverse outcomes, a retrospective review of 289 pregnancies was reported in which the mothers received either a single 150-mg dose (N = 275), multiple 50-mg doses (N = 3), or multiple 150-mg doses (N=11) of fluconazole (6). All of the women were treated during (gestational age of exposure not specified) or shortly before pregnancy for vaginal candidiasis, even though the authors noted that fluconazole was contraindicated for the treatment of this condition in pregnancy. The outcomes of the 289 pregnancies included 178 infants (5 sets of twins), 39 (13.5%) spontaneous abortions, 38 elective abortions, 2 ectopic pregnancies, and 37 unknown outcomes. Four infants with anomalies were observed, but in each case the mother had taken fluconazole before conception (1 week to >26 weeks before the last monthly menstrual period).
A prospective study published in 1996 compared the pregnancy outcomes of 226 women exposed to fluconazole during the 1st trimester with 452 women exposed to nonteratogenic agents (7). The dosage taken by the exposed group consisted of a single, 150 mg dose (N=105, 47%), multiple doses of 150 mg (N=81, 36%), 50 mg single dose (N=3, 1%), 50 mg multiple doses (N=23, 10%), 100 mg single dose (N=5, 2%), or 100 mg multiple doses (N=9, 4%). Most women (90.7%) were treated for vaginal candidiasis. There were no differences between the two groups in the number of miscarriages, stillbirths, congenital malformations, prematurity, low birth weight, cesarean section, or prolonged hospital stay. Seven (4.0% of live births) of the exposed women delivered infants with anomalies compared to 17 (4.2% of live births) of controls. There was no pattern among the congenital anomalies in the exposed group except for two cases of trisomy 21.
A brief 1996 case report described a normal pregnancy outcome in a 24-year-old woman treated with 21 days of fluconazole (600 mg/day) (because of intolerance to amphotericin B) for Torulopsis glabrata fungemia beginning at 14 weeks’ gestation (8). Although the patient’s course was complicated by shock and intracerebral hemorrhage, she eventually delivered at term a healthy 2.95-kg infant (sex not specified) who was doing well at 18 months of age.
In another 1996 case report, a 24-year-old woman at about 19 weeks’ gestation had chorioretinitis, candidiasis, fever, pneumonia, and low body weight attributed to Candida albicans sepsis (9). Because of massive nausea and vomiting after a test dose of amphotericin B, she was treated with IV fluconazole (10 mg/kg/day or about 400 mg/day) for 16 days and then the same dosage orally for another 34 days. She responded well to the antifungal therapy and gave birth at 39 weeks’ to a healthy 2.834-kg female infant with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. The infant had normal growth and mental development at 2 years of age (9).
A regional drug information center reported the pregnancy outcomes of 16 women (17 outcomes, 1 set of twins) who had called to inquire about the effect of fluconazole on their pregnancies (10). The median fluconazole dose was 300 mg (range 1501000 mg) starting at 4 6 weeks’ gestation (range 126 weeks). The twins were stillborn (no malformations) but the other 15 newborns were normal.
A 1998 non-interventional observational cohort study described the outcomes of pregnancies in women who had been prescribed one or more of 34 newly marketed drugs by general practitioners in England (11). Data were obtained by questionnaires sent to the prescribing physicians one month after the expected or possible date of delivery. In 831 (78%) of the pregnancies, a newly marketed drug was thought to have been taken during the 1st trimester with birth defects noted in 14 (2.5%) singleton births of the 557 newborns (10 sets of twins). In addition, two birth defects were observed in aborted fetuses. However, few of the aborted fetuses were examined. Fluconazole was taken during the 1st trimester in 48 pregnancies, but the dose and duration of therapy were not specified. The outcomes of these pregnancies included 4 spontaneous abortions, 5 elective abortions, 4 pregnancies lost to follow-up, and 37 normal newborns (3 premature; 2 sets of full-term twins) (11). Although no congenital malformations were observed, the study lacked the sensitivity to identify minor anomalies because of the absence of standardized examinations. Late appearing major defects may also have been missed due to the timing of the questionnaires.
A short 1998 report described the pregnancy outcome of a 38-year-old woman who had been treated with a single 150-mg oral dose of fluconazole about the date of conception (12). Chorionic villus sampling was conducted at 12 weeks’ gestation finding a normal karyotype (46,XY). The male infant, delivered by cesarean section at 39 weeks’, had an encephalocele. Echocardiography revealed dextrocardia and that both the pulmonary artery and the aorta emerged from the right ventricle (12). He died at 7 days of age. The cause of the anomalies was unknown, but it could not have been secondary to fluconazole because of the timing of the exposure.
A 42-year-old woman with achalasia at 31 weeks’ gestation was diagnosed with Candida esophagitis (13). IV fluconazole, 150 mg/day, was given for 14 days with resolution of the vomiting and lessening of her nausea. She was treated before and after fluconazole with parenteral hyperalimentation. An apparently healthy 2.438-kg female infant, Apgar scores of 9 and 9 at 1 and 5 minutes, respectively, was delivered at 38 weeks’ gestation.
In a 1999 report, fluconazole exposures and pregnancy outcomes were examined using the Danish Jutland Pharmaco-Epidemiological Prescription Database (14). A total of 165 women who had received a single, oral 150-mg dose of fluconazole for vaginal candidiasis just before or during pregnancy from 1991 to 1996 were identified. Of these, 121 had been exposed during the 1st trimester. The outcomes of exposed women were compared to the outcomes of 13,327 women who had not received any prescription medication during their pregnancies (controls). In the comparison of exposed newborns to controls, no elevated risk for preterm delivery (odds ratio [OR] 1.17, 95% confidence interval [CI] 0.632.17) or low birth weight (OR 1.19, 95% CI 0.373.79) was discovered. Similarly, the prevalence of congenital malformations was 3.3% (4 of 121) in exposed compared to 5.2% (697 of 13,327) in controls (OR 0.65, 95% CI 0.241.77) (14).
In summary, although the data are very limited, the use of fluconazole during the 1st trimester appears to be teratogenic with continuous daily doses of 400 mg/day or more. The malformations may resemble those observed in the Antley-Bixler syndrome. The published experience with the use of smaller doses, such as those prescribed for vaginal fungal infections, suggests that the risk for adverse outcomes is low, if it exists at all. A 1998 review concurred with this assessment (15). In those instances in which continuous, high-dose fluconazole is the only therapeutic choice during the 1st trimester, the patient should be informed of the potential risk to her fetus.
Breast Feeding Summary
Fluconazole is excreted into human milk (16,17). A 42-year-old lactating 54.5-kg woman was taking fluconazole 200 mg once daily (16). On her 18th day of therapy (8 days postpartum), milk samples were obtained at 0.5 hour before a dose and at 2, 4, and 10 hours after a dose. Serum samples were drawn 0.5 hour before the dose and 4 hours after the dose. On her last day of therapy (20 days postpartum), milk samples were again collected at 12, 24, 36, and 48 hours after the dose. Peak milk concentrations of fluconazole, up to 4.1 g/mL, were measured 2 hours after the mother’s dose. The milk:plasma ratios at 0.5 hour before dose and 4 hours after dose were both 0.90. The elimination half-lives in the milk and serum were 26.9 hours and 18.6 hours, respectively. No mention was made of the nursing infant.
A 29-year-old woman who was nursing her 12-week-old infant developed a vaginal fungal infection (17). Breast feeding was halted at the patient’s request and she was given 150 mg of fluconazole orally. Fluconazole concentrations were determined in milk (pooled from both breasts) and plasma samples obtained at 2, 5, 24, and 48 hours after the dose. Milk concentrations were 2.93, 2.66, 1.76, and 0.98 g/mL, respectively, while plasma concentrations were 6.42, 2.79, 2.52, and 1.19 g/mL, respectively. The milk:plasma ratios were 0.46, 0.85, 0.85, and 0.83, respectively, with half-lives of 30 and 35 hours, respectively, in the milk and plasma. The author estimated that after three plasma half-lives, 87.5% of the dose would have been eliminated from a woman with normal renal function, thereby greatly reducing the amount of drug a nursing infant would ingest (17).
Although the risk to a nursing infant from exposure to fluconazole in breast milk is unknown, the safe use of this antifungal agent in neonates has been reported (18,19 and 20). A brief 1989 report described a 48-day-old infant, born at 36 weeks’ gestation, who was treated with IV fluconazole, 6 mg/kg/day, for disseminated Candida albicans (18). The dosage was reduced to 3 mg/kg/day when a slight, transient increase in serum transaminase values was measured. The infant was discharged home at 80 days of age in good condition. In the second case, IV fluconazole 6 mg/kg/day was administered for 20 days to an approximately 6-week-old, premature infant (born at 28 weeks’ gestation) with a disseminated Candida albicans infection (19). Results of follow-up studies of the infant during the next 4 months were apparently normal. In a similar case, a 1-month-old premature infant was treated with IV fluconazole (5 mg/kg for 1 hour daily) for 21 days and orally for 8 days for meningitis caused by a Candida species (20). He was doing well at 9 months of age.
The safety of fluconazole during breast feeding cannot be completely extrapolated from these cases, but the dose administered to these infants far exceeds the amount they would have received via breast milk. Since no drug-induced toxicity was encountered in the infants, fluconazole is probably safe to use during breast feeding.
- Product information. Diflucan. Pfizer, 2001.
- Tiboni GM, Iammarrone E, Giampietro F, Lamonaca D, Bellati U, Di Ilio C. Teratological interaction between the bis-triazole antifungal agent fluconazole and the anticonvulsant drug phenytoin. Teratology 1999;59:817.
- Lee BE, Feinberg M, Abraham JJ, Murthy AR. Congenital malformations in an infant born to a woman treated with fluconazole. Pediatr Infect Dis J 1992;11:10624.
- Pursley TJ, Blomquist IK, Abraham J, Andersen HF, Bartley JA. Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis 1996;22:33640.
- Aleck KA, Bartley DL. Multiple malformation syndrome following fluconazole use in pregnancy: report of an additional patient. Am J Med Genet 1997;72:2536.
- Inman W, Pearce G, Wilton L. Safety of fluconazole in the treatment of vaginal candidiasis. A prescription-event monitoring study, with special Reference to the outcome of pregnancy. Eur J Clin Pharmacol 1994;46:1158.
- Mastroiacovo P, Mazzone T, Botto LD, Serafini MA, Finardi A, Caramelli L, Fusco D. Prospective assessment of pregnancy outcomes after first-trimester exposure to fluconazole. Am J Obstet Gynecol 1996;175:164550.
- Kremery V Jr, Huttova M, Masar O. Teratogenicity of fluconazole. Pediatr Infect Dis 1996;15:841.
- Wiesinger EC, Mayerhofer S, Wenisch C, Breyer S, Graninger W. Fluconazole in Candida albicans sepsis during pregnancy: case report and review of the literature. Infection 1996;24:2636.
- Campomori A, Bonati M. Fluconazole treatment for vulvovaginal candidiasis during pregnancy. Ann Pharmacother 1997;1189.
- Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol 1998;105:8829.
- Sanchez JM, Moya G. Fluconazole teratogenicity. Prenat Diagn 1998;18:8623.
- Kalish RB, Garry D, Figueroa R. Achalasia with Candida esophagitis during pregnancy. Obstet Gynecol 1999;94:850.
- Sorensen HT, Nielsen GL, Olesen C, Larsen H, Steffensen FH, Schonheyder HC, Olsen J, Czeizel AE. Risk of malformations and other outcomes in children exposed to fluconazole in utero. Br J Clin Pharmacol 1999;48:2348.
- King CT, Rogers PD, Cleary JD, Chapman SW. Antifungal therapy during pregnancy. Clin Infect Dis 1998;27:115160.
- Schilling CG, Seay RE, Larson TA, Meier KR. Excretion of fluconazole in human breast milk (abstract no. 130). Pharmacotherapy 1993;13:287.
- Force RW. Fluconazole concentrations in breast milk. Pediatr Infect Dis J 1995;14:2356.
- Viscoli C, Castagnola E, Corsini M, Gastaldi R, Soliani M, Terragna A. Fluconazole therapy in an underweight infant. Eur J Clin Microbiol Infect Dis 1989;8:9256.
- Wiest DB, Fowler SL, Garner SS, Simons DR. Fluconazole in neonatal disseminated candidiasis. Arch Dis Child 1991;66:1002.
- Gurses N, Kalayci AG. Fluconazole monotherapy for Candidal meningitis in a premature infant. Clin Infect Dis 1996;23:6456.