|TERIS Agent Number:||1181||Bibliographic Search Date:||07/2018|
|Fluconazole is a triazole antifungal agent used to treat mycotic infections. A single oral dose of 150 mg, repeated once if necessary, is administered in the treatment of vaginal candidiasis. Higher doses (200-800 mg/day orally or intravenously) are used chronically in severe systemic illnesses.|
Magnitude of Teratogenic Risk to Child Born After Exposure During Gestation:
HIGH DOSE, CHRONIC USE: MODERATE TO HIGH
LOW SINGLE ORAL DOSE: MINIMAL
Quality and Quantity of Data on Which Risk Estimate is Based:
HIGH DOSE, CHRONIC USE: FAIR
LOW SINGLE ORAL DOSE: FAIR
1) THE OCCURRENCE OF A SIMILAR, DISTINCTIVE, AND RARE PATTERN OF CONGENITAL ANOMALIES IN FIVE CHILDREN WHOSE MOTHERS HAD ALL BEEN TREATED CHRONICALLY WITH HIGH-DOSE FLUCONAZOLE DURING PREGNANCY, A RARE EXPOSURE, MAKES IT LIKELY THAT THIS TREATMENT WAS CAUSAL (SEE BELOW).
2) THE MODERATE TO HIGH RISK ASSOCIATED WITH HIGH DOSES OF FLUCONAZOLE REFLECTS THE SEVERITY OF THE TERATOGENIC EFFECT, IF IT OCCURS. THE FREQUENCY WITH WHICH THIS EMBRYOPATHY OCCURS WHEN A WOMAN IS TREATED WITH HIGH-DOSE FLUCONAZOLE EARLY IN PREGNANCY IS UNKNOWN.
3) SOME OF THE MALFORMATIONS THAT OCCUR IN FLUCONAZOLE EMBRYOPATHY CAN BE PRENATALLY DIAGNOSED BY ULTRASOUND EXAMINATION IN THE SECOND TRIMESTER OF PREGNANCY (OLDANI ET AL., 2015; TZETIS ET AL., 2016), BUT THE RELIABILITY OF SUCH TESTING IS UNKNOWN.
4) AVAILABLE EPIDEMIOLOGICAL STUDIES OF CONGENITAL ANOMALIES AND MATERNAL TREATMENT WITH A SINGLE LOW DOSE OF FLUCONAZOLE DURING PREGNANCY ARE INCONSISTENT AND DIFFICULT TO INTERPRET.
Summary of Teratology Studies:
Five children have been described with a similar and very unusual pattern of congenital anomalies whose mothers were treated during most or all of the first trimester of pregnancy with high-dose (400-800 mg/day) fluconazole for systemic mycotic infections (Lee et al., 1992; Pursley et al., 1996; Aleck & Bartley, 1997; Lopez-Rangel & Van Allen, 2005). The features seen in these infants include brachycephaly, craniosynostosis, proptosis, cleft palate, femoral bowing, thin ribs and long bones, multiple symphalangism, arthrogryposis, and congenital heart defects. Two of the children died in infancy. The published descriptions of some of these cases are incomplete, two of the affected children were sibs, and the pattern of anomalies resembles the Antley-Bixler syndrome. The occurrence of a similar rare pattern of congenital anomalies in five children whose mothers received daily high-dose fluconazole, a very unusual treatment during pregnancy, suggests a causal relationship.
Antley-Bixler syndrome is an autosomal recessive condition caused by mutations of POR, the gene for cytochrome P450 oxidoreductase (Scott & Miller, 2008; Idkowiak et al., 2017). Affected individuals have skeletal abnormalities that are very similar to those reported in the five children described above who are thought to have fluconazole embryopathy, as well as frequent genital and other anomalies that have not been observed in children with putative fluconazole embryopathy (Idkowiak et al., 2017). A pathogenic link between these two phenotypes is suggested by the fact that fluconazole inhibits hepatic cytochrome P450 (Cassina et al., 2017). A similar skeletal phenotype without associated genital abnormalities has also been reported in some children with dominant mutations of the FGFR2 gene (Reardon et al., 2000; McGlaughlin et al., 2010).
The frequency of this embryopathy among the infants of women who were treated early in pregnancy with daily high-dose fluconazole for systemic mycotic infections is unknown. Although single-dose oral treatment is much more frequently used, fluconazole embryopathy has not been reported after such therapy early in pregnancy.
The prevalence of congenital anomalies overall was no greater than expected among 7352 infants whose mothers had filled prescriptions for fluconazole during the first trimester of pregnancy in a population-based Danish record linkage study (Molgaard-Nielsen et al., 2013). An association was seen with tetralogy of Fallot (odds ratio=3.16, 95% confidence interval 1.49-6.71) in this study. No association was found with maternal fluconazole use during the first trimester of pregnancy and any of 14 other congenital anomalies or categories of anomalies for which associations with the use of azole antifungal agents had previously been suspected. The frequency of congenital anomalies was not increased among the infants of 1079 women who received first trimester prescriptions for oral fluconazole (usually 150 mg as a single dose) in an earlier, partially overlapping Danish record linkage study (Norgaard et al., 2008).
In a cohort study performed through the UK General Practice Research Database, the frequency of congenital anomalies was not increased among the infants of 234 women who received prescriptions for a single oral dose (usually 150 mg) of fluconazole in the first trimester of pregnancy (Jick, 1999). The frequency of congenital anomalies was not increased among 175 infants of women who were treated with fluconazole during the first trimester of pregnancy in a prospective study performed through Italian teratogen information services (Mastroiacovo et al., 1996). The indication for treatment in most of these women was vaginal candidiasis, the median total dose was 200 mg, and the treatment was usually provided as a single dose. No consistent pattern of anomalies was seen among the affected infants in any of these studies.
Maternal use of fluconazole during the first trimester of pregnancy, usually briefly for treatment of vaginal candidiasis, was more frequent than expected among 2016 infants with cleft lip with or without cleft palate (odds ratio=5.53, 95% confidence interval 1.68-18.24) and among 768 infants with d-transposition of the great arteries (odds ratio=7.56, 95% confidence interval 1.22-35.45) in the National Birth Defects Prevention Study (Howley et al., 2016). Given the prevalence of cleft lip with or without cleft palate and d-transposition of the great arteries in the general population, the absolute risk of these defects would be 0.4% and 0.2%, respectively, among the infants of women treated with fluconazole during the first trimester, if these associations were real and causal. No association of maternal fluconazole treatment was found among 1207 infants with tetralogy of Fallot, 1602 infants with cleft palate, 1597 infants with craniosynostosis, or 24,455 infants with various other congenital anomalies in this study.
An increased frequency of spontaneous abortion was observed in the pregnancies of 3315 women who redeemed prescriptions for oral fluconazole between seven and 22 weeks of gestation in a Danish record linkage study (hazard ratio=1.48, 95% confidence interval 1.23-1.77) (Molgaard-Nielsen et al., 2016). Almost 90% of these women received low-dose treatment, and there was no significant difference in the hazard ratio between women who received low doses and women who received high doses. The frequency of spontaneous abortion or stillbirth was not found to be significantly increased in two smaller epidemiological studies of women who had taken oral fluconazole during the first trimester of pregnancy (Mastroiacovo et al., 1996; Norgaard et al., 2008).
No association with maternal oral fluconazole treatment was found among 5382 pregnancies that ended in stillbirth in the Danish study, although an association was seen in women whose most recent prescription was for more than 350 mg of fluconazole (hazard ratio=4.10, 95% confidence interval 1.89-8.90) (Molgaard-Nielsen et al., 2016). In a larger Swedish and Norwegian cohort study that included twice the number of fluconazole-exposed-pregnancies as the Danish study, maternal receipt of a prescription for fluconazole during pregnancy was not associated with an increased risk of stillbirth or neonatal death, but the number of women exposed to doses above 300 mg/day was small (Pasternak et al., 2018).
Anogenital distance was reduced in four 3-month-old male infants whose mothers received a single low dose of fluconazole during the critical period of genital development (Mogensen et al., 2017). Even if this reduction is real, it is not clear whether reduced anogenital distance has any clinical consequences in humans.
Increased frequencies of embryonic death and rib anomalies occurred in the offspring of pregnant mice treated with 3 times the maximum human dose of fluconazole (Tiboni et al., 1999). Increased frequencies of fetal death and anomalies were observed when pregnant mice were treated orally with single doses of fluconazole 44 times the maximum used therapeutically in humans (Tiboni & Giampietro, 2005). Cleft palate and skeletal and renal anomalies were seen most often, and typical dependence on gestational time of administration was demonstrated. No teratogenic effect was found when pregnant mice were treated with parenteral fluconazole in a dose within the human therapeutic range (Tiboni et al., 2003). Skeletal, craniofacial, and palatal anomalies were seen among the offspring of rats treated during pregnancy with 5-20 times the maximum human dose of fluconazole (Tachibana et al., 1987; Lee et al., 1992), but these studies are not published in sufficient detail to permit independent evaluation. No teratogenic effect was found among the offspring of pregnant rabbits treated with <1-1.25 times the maximum human dose of fluconazole (Tachibana et al., 1987).
Aleck KA, Bartley DL: Multiple malformation syndrome following fluconazole use in pregnancy: report of an additional patient. Am J Med Genet 72(3):253-256, 1997. [C]
Cassina M, Cagnoli GA, Zuccarello D, Di Gianantonio E, Clementi M: Human teratogens and genetic phenocopies. Understanding pathogenesis through human genes mutation. Eur J Med Genet 60(1):22-31, 2017. [R]
Howley MM, Carter TC, Browne ML, Romitti PA, Cunniff CM, Druschel CM: Fluconazole use and birth defects in the National Birth Defects Prevention Study. Am J Obstet Gynecol 214(5):657.e1-657.e9, 2016. [E]
Idkowiak J, Cragun D, Hopkin RJ, Arlt W: Cytochrome P450 Oxidoreductase Deficiency [updated 2017 August 3]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A (eds). GeneReviews® [Internet]. Seattle, Wash.: University of Washington, 1993-2019 (accessed January 2019). [R]
Jick SS: Pregnancy outcomes after maternal exposure to fluconazole. Pharmacotherapy 19(2):221-222, 1999. [E]
Lee BE, Feinberg M, Abraham JJ, Murthy ARK: Congenital malformations in an infant born to a woman treated with fluconazole. Pediatr Infect Dis J 11(12):1062-1064, 1992. [C] & [A]
Lopez-Rangel E, Van Allen MI: Prenatal exposure to fluconazole: an identifiable dysmorphic phenotype. Birth Defects Res A Clin Mol Teratol 73(11):919-923, 2005. [C]
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 175(6):1645-1650, 1996. [E]
McGlaughlin KL, Witherow H, Dunaway DJ, David DJ, Anderson PJ: Spectrum of Antley-Bixler syndrome. J Craniofac Surg 21(5):1560-1564, 2010. [C]
Mogensen DM, Pihl MB, Skakkebaek NE, Andersen HR, Juul A, Kyhl HB, Swan S, Kristensen DM, Andersen MS, Lind DV, Jensen TK: Prenatal exposure to antifungal medication may change anogenital distance in male offspring: a preliminary study. Environ Health 16(1):68, 2017. [E]
Molgaard-Nielsen D, Pasternak B, Hviid A: Use of oral fluconazole during pregnancy and the risk of birth defects. N Engl J Med 369(9):830-839, 2013. [E]
Molgaard-Nielsen D, Svanstrom H, Melbye M, Hviid A, Pasternak B: Association between use of oral fluconazole during pregnancy and risk of spontaneous abortion and stillbirth. JAMA 315(1):58-67, 2016. [E]
Norgaard M, Pedersen L, Gislum M, Erichsen R, Sogaard KK, Schonheyder HC, Sorensen HT: Maternal use of fluconazole and risk of congenital malformations: a Danish population-based cohort study. J Antimicrob Chemother 62(1):172-176, 2008. [E]
Oldani E, Garel C, Bucourt M, Carbillon L: Prenatal diagnosis of Antley-Bixler syndrome and POR deficiency. Am J Case Rep 16:882-885, 2015. [C]
Pasternak B, Wintzell V, Furu K, Engeland A, Neovius M, Stephansson O: Oral fluconazole in pregnancy and risk of stillbirth and neonatal death. JAMA 319(22):2333-2335, 2018. [E]
Pursley TJ, Blomquist IK, Abraham J, Andersen HF, Bartley JA: Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis 22(2):336-340, 1996. [C]
Reardon W, Smith A, Honour JW, Hindmarsh P, Das D, Rumsby G, Nelson I, Malcolm S, Ades L, Sillence D, Kumar D, DeLozier-Blanchet C, McKee S, Kelly T, McKeehan WL, Baraitser M, Winter RM: Evidence for digenic inheritance in some cases of Antley-Bixler syndrome? J Med Genet 37(1):26-32, 2000. [S]
Scott RR, Miller WL: Genetic and clinical features of P450 oxidoreductase deficiency. Horm Res 69(5):266-275, 2008. [R]
Tachibana M, Noguchi Y, Monro AM: Toxicology of fluconazole in experimental animals. In: Fromtling RA (ed). Recent Trends in the Discovery, Development and Evaluation of Antifungal Agents. Barcelona, Spain: JR Prous Science Publishers, 1987, pp 93-102. [A]
Tiboni GM, Giampietro F: Murine teratology of fluconazole: evaluation of developmental phase specificity and dose dependence. Pediatr Res 58(1):94-99, 2005. [A]
Tiboni GM, Giampietro F, Angelucci S, Moio P, Bellati U, Di Ilio C: Additional investigation on the potentiation of phenytoin teratogenicity by fluconazole. Toxicol Lett 145(3):219-229, 2003. [A]
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 59(2):81-87, 1999. [A]
Tzetis M, Konstantinidou A, Sofocleous C, Kosma K, Mitrakos A, Tzannatos C, Kitsiou-Tzeli S: Compound heterozygosity of a paternal submicroscopic deletion and a maternal missense mutation in POR gene: Antley-Bixler syndrome phenotype in three sibling fetuses. Birth Defects Res A Clin Mol Teratol 106(7):536-541, 2016. [C]