Antifungals

1.      Czeizel AE, Toth M, Rockenbauer M. No teratogenic effect after clotrimazole therapy during pregnancy.    Epidemiology 1999 Jul;10(4):437-40 We evaluated the potential teratogenic effects of vaginal and/or topical administration of clotrimazole in the large population-based dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities (1980-1992). The dataset included 18,515 case pregnancies and 32,804 control pregnancies; 7.1% of case and 7.7% of control women used clotrimazole during pregnancy. Clotrimazole use was not clearly associated with an increase in the total (fetal + birth) prevalence of any congenital abnormality group. There was, however, a suggestion that clotrimazole use was associated with a decrease in the prevalence of undescended testis (prevalence odds ratio = 0.72; 95% confidence interval = 0.54-0.95).

2.      Sobel JD. Use of antifungal drugs in pregnancy: a focus on safety. Drug Saf 2000 Jul;23(1):77-85 The use of antifungals in pregnancy requires special consideration for the safety of the developing fetus. Clinicians now have an increased repertoire of both topical and systemic antimycotics available to treat superficial or mucotaneous fungal infections including Candida vaginitis. The ability of many nontopical antifungals to penetrate the placenta and achieve measurable, often therapeutic, concentrations in cord blood, fetal tissue and amniotic fluid means that evidence exists of successful treatment of all varieties of systemic fungal disease in pregnant women, even with placental involvement. However, for the same reasons, safety considerations remain a concern. Although the use of azoles as topical agents for superficial infections is both efficacious and well tolerated, especially when used for short periods, systemic azole therapy is not recommended in pregnancy. Accordingly, amphotericin B remains the drug of choice for systemic, invasive mycotic infections, whether life-threatening or less severe. Unfortunately little if any information is available regarding the safety of the newer lipid formulations of amphotericin B. There is a general reluctance to perform randomised, comparative studies involving antifungal agents in pregnancy, hence cumulative anecdotal reports form much of the available data; animal studies, although useful, have several drawbacks. There is a need for additional safe and effective new antifungal agents for widespread use in pregnant women.

3.      Dean JL, Wolf JE, Ranzini AC, Laughlin MA. Use of amphotericin B during pregnancy: case report and review. Clin Infect Dis 1994 Mar;18(3):364-8. Unlike the situation with many antimicrobial agents, there is limited experience with the use of amphotericin B during pregnancy. Although reports of fungal infections during pregnancy have been published, few describe fungemia with either Candida or Torulopsis species. We present a case of fungemia due to Torulopsis glabrata that occurred during pregnancy and that was treated with amphotericin B. Drug concentrations were measured in placental tissue, cord serum, and infant serum at delivery. Although the last dose of amphotericin B was administered 4 weeks before delivery, the concentrations in all three specimens were still within the MIC ranges for most strains of Candida albicans and T. glabrata as measured by broth dilution. We speculate that persistent tissue concentrations of amphotericin B most likely contributed to the sustained hypokalemia in the mother and the increased creatinine level in the infant. In the latter case, placental tissue may have served as the reservoir from which amphotericin B was slowly released into fetal circulation.

4.      Young GL, Jewell D. Topical treatment for vaginal candidiasis (thrush) in pregnancy. Cochrane Database Syst Rev 2001;(4):CD000225. BACKGROUND: Vaginal candidiasis (moniliasis or thrush) is a common and frequently distressing infection for many women. It is even more common in pregnancy. There is no evidence that thrush in pregnancy is harmful to the baby. OBJECTIVES: The objective of this review was to assess the effects of different methods of treating vaginal candidiasis in pregnancy. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group Trials Register. In addition, the Cochrane Controlled Trials Register (CENTRAL/CCTR) was searched. Date of last search: March 2001. SELECTION CRITERIA: Randomised trials of any treatment for vaginal candidiasis in pregnancy. DATA COLLECTION AND ANALYSIS: Two reviewers assessed trial quality and extracted data. MAIN RESULTS: Ten trials were included. Based on five trials, imidazole drugs were more effective than nystatin when treating vaginal candidiasis in pregnancy (odds ratio 0.21, 95% confidence interval 0.16 to 0.29). In turn, Nystatin was as effective as hydrargaphen in one trial (odds ratio 0.29, 95% confidence interval 0.05-1.84). A trial of clotrimazole was more effective than placebo (odds ratio 0.14, 95% confidence interval 0.06 to 0.31). Single dose treatment was no more or less effective than three or four days treatment. However, two trials involving 81 women, showed that treatment lasting for four days was less effective than treatment for seven days (odds ratio 11.7, 95% confidence interval 4.21 to 29.15). Based on two trials, treatment for seven days was no more or less effective than treatment for 14 days (odds ratio 0.41, 95% confidence interval 0.16 to 1.05). Terconazole was as effective as clotrimazole (odds ratio 1.41, 95% confidence interval 0.28- 7.10). REVIEWER'S CONCLUSIONS: Topical imidazole appears to be more effective than nystatin for treating symptomatic vaginal candidiasis in pregnancy. Treatments for seven days may be necessary in pregnancy rather than the shorter courses more commonly used in non-pregnant women.

5.      Rosa FW, Baum C, Shaw M. Pregnancy outcomes after first-trimester vaginitis drug therapy. Obstet Gynecol 1987 May;69(5):751-5. Prescription frequencies in the first trimester were compared for miconazole, clotrimazole, nystatin, candicidin, aminacrine compounds, and metronidazole before deliveries involving congenital anomalies versus those not linked to congenital anomalies. Prescriptions before spontaneous abortions were compared with those in the first trimester of deliveries and with those before legal abortions. No statistically significant association was observed with any of these agents for the overall frequency of birth defects or for specific birth defects analyzed (cardiovascular defects, oral clefts, and spina bifida). Two hundred fifty miconazole exposures among 4264 spontaneous abortions, compared with 2236 in the first trimester of 55,736 deliveries, provided an estimated relative risk of 1.4 (95% confidence limits 1.2-1.5). One hundred twelve treatments with clotrimazole among the spontaneous abortions, compared with 1086 among the deliveries, provided a relative risk of 1.4 (95% confidence limits 1.1-1.6). In contrast, large numbers of exposures to nystatin and aminacrine compounds did not show this association, suggesting that spontaneous abortions are caused by the imidazole agents miconazole and clotrimazole rather than the condition being treated. Because many associations were examined without previous hypotheses, and because the data were inadequate to show an elevated risk for clotrimazole when comparing spontaneous with legal abortion exposures, these findings are considered to be a signal for further studies rather than definitive in themselves

6.      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 Aug;48(2):234-8. AIM: Fluconazole is an active drug systematically used in the oral treatment of vaginal candidiasis and other fungal diseases. We examined the risk of malformations and other birth outcomes following pregnancy related exposures. METHOD: From 1 January 1991 to 31 December 1996 we identified 165 women who had taken fluconazole just before or during pregnancy in the Pregnancy Outcome Section of the North Jutland Pharmacoepidemiological Prescription Database, Denmark, which is linked to the Danish Medical Birth Registry. We compared their birth outcomes (malformation, low birth weight and preterm delivery) with the outcomes among 13 327 women who did not receive any prescriptions during their pregnancies. RESULTS: The prevalence of malformation was 3.3% (four cases) among the 121 women, who had used fluconazole in the first trimester, and 5.2% (697 cases) in offspring to controls (odds ratio: 0.65, 95% confidence limits: 0.24-1.77). Furthermore, we did not find any significantly elevated risk of preterm delivery (odds ratio: 1.17, 95% confidence limits: 0.63-2.17) and low birth weight (odds ratio: 1.19, 95% confidence limits: 0.37-3.79). CONCLUSION: The study showed no increased risk of congenital malformations, low birth weight or preterm birth in offspring to women who had used single dose fluconazole before conception or during pregnancy.

7.      Jick SS. Pregnancy outcomes after maternal exposure to fluconazole. Pharmacotherapy 1999 Feb;19(2):221-2. We evaluated pregnancy outcomes in 234 women exposed to fluconazole, 492 exposed to a topically administered azole preparation, 88 exposed to an oral azole preparation other than fluconazole, and 1629 not exposed to any of these agents during the first trimester of pregnancy Relative risks of having a baby with a congenital disorder for women exposed to fluconazole, oral azoles, and topical azoles in the first trimester of pregnancy compared with those who were unexposed were 1.1 (95% CI 0.4-3.3), 2.1 (95% CI 0.7-6.8), and 0.6 (95% CI 0.2-1.6), respectively These results provide reassurance that fluconazole exposure in the first trimester of pregnancy does not materially increase the risk of congenital disorders in infants.

8.      King CT, Rogers PD, Cleary JD, Chapman SW. Antifungal therapy during pregnancy. Clin Infect Dis 1998 Nov;27(5):1151-60. Careful consideration of the benefit to the mother and the risk to the fetus is required when prescribing antifungal therapy in pregnancy. Imidazoles are considered safe as topical therapy for fungal skin infections during pregnancy. Nystatin is minimally absorbed and is effective for vaginal therapy. Although vaginal use of the imidazoles is probably safe during the later stages of pregnancy, their systemic absorption is higher than when applied to the skin. The systemic antifungal drug with which there has been the most experience in pregnancy is amphotericin B. There have been no reports of teratogenesis attributed to this agent. There is evidence to suggest that fluconazole exhibits dose-dependent teratogenic effects; however, it appears to be safe at lower doses (150 mg/day). Ketoconazole, flucytosine, and griseofulvin have been shown to be teratogenic and/or embryotoxic in animals. Iodides have been associated with congenital goiter and should not be used during pregnancy.

9.      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 Dec;175(6):1645-50.  OBJECTIVE: Our purpose was to study prospectively the pregnancy outcome after first-trimester exposure to fluconazole, an effective antifungal agent teratogenic in animals. STUDY DESIGN: We conducted a prospective cohort study of women who contacted three Italian teratogen information services. We compared the pregnancy outcomes of 226 women exposed to fluconazole with that of 452 women exposed to nonteratogenic agents, with use of logistic regression to control for potential confounders. RESULTS: Among the 226 pregnancies exposed to fluconazole there were 22 miscarriages, 1 stillbirth, and 7 infants with congenital anomalies. The prevalence of these outcomes and of neonatal growth parameters and the rate of neonatal complications were similar to those in the reference group. Women in the fluconazole group had a fivefold increased occurrence of induced abortions. CONCLUSIONS: First-trimester exposure to fluconazole does not appear to increase the prevalence of miscarriages, congenital anomalies, and low birth weight.

10.  Pursley TJ, Blomquist IK, Abraham J, Andersen HF, Bartley JA. Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis 1996 Feb;22(2):336-40. Fluconazole has been associated with various teratisms in animals, including craniofacial ossification defects, thin, wavy ribs, and renal pelvis defects. We describe three infants born to women who were receiving fluconazole through or beyond the first trimester of pregnancy. All of the infants had congenital anomalies; no other drug was implicated. Only one of the three infants survived. Their anomalies, similar to those observed in animal studies, were largely craniofacial, skeletal (i.e., thin, wavy ribs and ossification defects), and cardiac. One of these infants was previously reported as having Antley-Bixler syndrome; however, given the chronology described herein and the similarity of this infant to the others, we conclude that her deformities also represent the potent teratogenic effect of fluconazole.

11.  Bar-Oz B, Moretti ME, Bishai R, Mareels G, Van Tittelboom T, Verspeelt J, Koren G. Pregnancy outcome after in utero exposure to itraconazole: a prospective cohort study. Am J Obstet Gynecol 2000 Sep;183(3):617-20. OBJECTIVE: This study was undertaken to determine whether itraconazole use during the first trimester of pregnancy was associated with increased risks of major malformations, spontaneous abortions, premature deliveries, and neonatal complications. STUDY DESIGN: In a prospective cohort study pregnant women exposed to oral itraconazole were matched with control subjects not exposed to any known teratogens. Primary outcome was the rate of major malformations. Secondary outcomes were live birth rate, rates of spontaneous abortion and therapeutic abortion, gestational age at delivery, birth weight, and neonatal complications. RESULTS: A total of 229 women exposed to itraconazole were reported to the manufacturer, 198 of whom used the drug during the first trimester of pregnancy. The rate of major malformations in the study group (156 live births) was 3.2%, compared with 4.8% in the control group (187 live births; relative risk, 0.67; 95% confidence interval, 0. 23-1.95). The rate of any pregnancy loss was higher in the exposed group (relative risk, 1.75; 95% confidence interval, 1.47-2.09). Birth weight was lower in the itraconazole group, although that difference may not be clinically significant. Gestational age at birth, rate of preterm delivery, Apgar scores at 1 and 5 minutes, and neonatal complications were comparable between the groups. CONCLUSION: Our study supports the hypothesis that the use of itraconazole during pregnancy is safe. Further surveillance and reporting of pregnancy outcomes will help to support this conclusion.

12.  Cummings AM, Hedge JL, Laskey J. Ketoconazole impairs early pregnancy and the decidual cell response via alterations in ovarian function. Fundam Appl Toxicol 1997 Dec;40(2):238-46. Ketoconazole (KCZ) is an imidazole antifungal agent that also affects P450 enzymes of the mammalian steroidogenic system. Several steps in the ovarian steroidogenesis pathway are known to be inhibited by KCZ, but previous work has failed to address the ramifications of such inhibition with respect to early pregnancy. In initial studies, Holtzman rats (8-10/group) were administered 10-100 mg/kg KCZ during days 1-8 of pregnancy. On day 9, evaluations revealed a reduction at both 75 and 100 mg KCZ/kg in the number of implantation sites and serum progesterone levels as well as an increase in ovarian weight. The decidual cell response (DCR) was blocked by KCZ in parallel with decreased serum progesterone and increased ovarian weight, indicating direct interference with uterine function. KCZ had no effect when given to long-term-ovariectomized rats that were hormone supplemented to permit the DCR, indicating that the ovary was at least one site of KCZ action on early pregnancy. Measurement of ovarian progesterone production in vitro from ovaries removed from rats treated in vivo with KCZ indicated a decline in progesterone production, suggesting a direct effect of KCZ on ovarian steroidogenesis. These data demonstrate that KCZ can compromise early pregnancy and appears to do so by inhibiting progesterone synthesis in the ovary.