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Antifungal Drugs During Pregnancy An Updated Review
Antifungal Drugs During Pregnancy An Updated Review
Introduction fetus) provide a general framework that do not take into account
the stage of pregnancy (Table 1). They globally reflect the paucity
Pregnancy should be considered as a condition with increased vul- of available information (Table 2).
nerability to infections, including some life-threatening fungal The last focus on antifungal drugs in pregnancy was published in
infections, but paradoxically little is known regarding optimal anti- 2003 by Moudgal and Sobel.6 Within the last 10 years the FDA has
fungal regimens and dosages in this setting.1 Drug prescription provided approval for three new antifungal drugs: posaconazole,
during pregnancy requires a delicate assessment of the balance micafungin and anidulafungin. Additional data regarding triazole
between maternal benefit and fetal risks, including fetal loss, con- use and antifungal recommendations have emerged, raising the
genital malformations, organ toxicity and prematurity. In addition need for an update on antifungal drug use in pregnancy.
to the pharmacodynamics, pharmacokinetics and intrinsic anti-
fungal activity of a given drug, specific parameters should be
Methods
added to the challenging equation of antifungal prescription in
pregnant women: term of pregnancy, level of fetal drug exposure We reviewed the computerized literature available in the PubMed database.
and maternal physiological pharmacokinetic changes.2 Indeed The literature from January 1949 through December 2013 was queried
vomiting-increased gastric pH, cardiac output, intestinal blood using the terms, ‘pregnant’, ‘pregnancy’, ‘prenatal’, ‘fetal’, ‘fetus’, ‘terato-
flow and time of intestinal process can modify oral absorption. genicity’, ‘toxicity’, ‘placenta’, ‘birth defect’, ‘azoles’, ‘fluconazole’, ‘itracon-
azole’, ‘voriconazole’, ‘posaconazole’, ‘miconazole’, ‘echinocandins’,
Increased intra- and extravascular blood flow and reduced serum
‘caspofungin’, ‘micafungin’, ‘anidulafungin’, ‘flucytosine’, ‘5FC’, ‘polyene’,
albumin concentration enhance the distribution of unbound drugs.
‘amphotericin B’, ‘liposomal amphotericin B’, ‘nystatin’, ‘terbinafine’, ‘griseo-
Finally, increased renal filtration/elimination and increased (3A4, fulvin’, ‘aspergillosis’, ‘cryptococcosis’, ‘coccidioidomycosis’, ‘histoplasmo-
2D6, 2C9, 2A6) or decreased (1A2, 2C19) cytochrome activities sis’, ‘candidiasis’, ‘sporotrichosis’, ‘scedosporiosis’ and ‘fusariosis’. Animal
can modify drug clearance. Fetal exposure relies on the drug’s data and human case reports and studies were analysed. English, French,
ability to cross the placenta, depending on the stage of pregnancy German and Spanish publications were screened. Data published before
(placental maturation with enhanced fetal exposure in later term) the last update in 2003 are presented in the ‘What was known?’ sections,
and on intrinsic drug parameters (liposolubility, molecular weight, whereas more recent data are presented in the ‘What is new?’ sections.
protein binding).3 – 5 ‘Key points’, summarizing the main data, are provided for each drug.
Because pregnancy is a duly established contraindication for
controlled studies involving antifungal drugs, data in this setting Immunity during pregnancy and fungal
are extremely limited and based on in vitro or animal studies,
pharmacological investigations, limited case reports and expert
infections
opinions. In this setting, the FDA definitions for pregnancy risk cat- Pregnancy is a unique and complex situation during which the
egories (A to X, in accordance with product’s estimated toxicity for maternal immune system faces two issues: defending both the
# The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail: journals.permissions@oup.com
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Table 1. Classification of prescription drugs by the US FDA according to the Table 2. Antifungal drugs and risk category in pregnancy (adapted from
risk in pregnancy39 the Federal Register)39
Pregnancy Designation
risk category Description
Polyenes
A controlled studies of women failed to demonstrate a risk to amphotericin B B
the fetus in the first trimester, and the possibility of fetal nystatina A
harm appears remote
Azoles
B either animal studies do not indicate a risk to the fetus and
ketoconazole C
there have been no controlled studies in pregnant
fluconazole
women, or animal studies have indicated fetal risk but
low-dose regimen (150 mg/day) C
controlled studies of pregnant women failed to
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during the first trimester (5/5) and beyond [4/5, until 4 months most Aspergillus species. It was shown to be embryotoxic and
and 31 weeks of gestation (n¼ 1, each) or throughout pregnancy teratogenic in rodents, inducing craniofacial and rib abnormal-
(n¼ 2)]. Lesions included trapezoidocephaly, mid-facial hypopla- ities.21 However, a prospective study involving 229 women
sia, cartilage abnormalities with multiple synostoses and skeletal exposed to itraconazole, including 198 during the first trimester
fractures. Abnormalities were similar to those reported in the [daily doses ranged from 50 to 800 mg (median ¼200 mg) for a
Antley–Bixler syndrome.26 In contrast, in mothers exposed during median of 3 days (range 1 – 90)], failed to identify any increased
the first trimester to single doses of 50–150 mg of fluconazole, no risk of fetal malformation.36 A significantly higher rate of early
adverse fetal outcome was observed.28 fetal loss was reported (12% versus 4% in the control group),
but questions were raised regarding a recall bias in the control
What is new? The FDA reclassified fluconazole from category C group that had a very low rate of early fetal loss.
to category D (except for single 150 mg doses for vaginal candid-
iasis).29 In addition, animal studies have helped further confirm What is new? Animal studies have further analysed the terato-
the teratogenicity of high-dose fluconazole in rodents, with iden- genicity of high-dose itraconazole in mice and have shown that
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Key points Voriconazole is labelled category D (FDA) because of September 2010, respectively. Micafungin crosses the placenta
its embryotoxic/teratogenic effects in rodents and rabbits. Data and was shown to be embryotoxic and teratogenic in rabbits (vis-
on pregnancy exposure are limited to a single observation with ceral abnormalities and abortions at the equivalent of 4 times the
good materno-fetal outcome. It should not be considered in recommended human dose).44
pregnancy, except in life-threatening maternal disease without Anidulafungin crosses the placenta of pregnant rats and was
a therapeutic alternative. shown to be possibly teratogenic in rodents (skeletal abnormal-
ities reported at the equivalent of 2 times the recommended
Posaconazole human dose, but in the range of a historical control database).
It was associated with reduced fetal weight in pregnant rabbits
Posaconazole is the most recently available triazole. It received
at the equivalent of 4 times the recommended human dose.45
EMA and FDA approval in October 2005 and September 2006,
Whether either drug transfers across the human placenta
respectively. It has expanded antifungal spectrum including
remains unknown. High molecular weight (around 1100) and
Mucorales and has otherwise broad spectrum against most of
extensive plasma binding could limit the amount of crossing,
the common yeasts and moulds.41
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to study further its fetal toxicity and it should not be considered in What was known?
pregnancy, except after the first trimester in life-threatening
Oral reproduction studies did not evidence any embryo–fetotoxi-
maternal infections where the benefits of adding flucytosine
city in rabbits and rats administered up to 23 times the maximum
may justify the risk.
recommended human dose.21 Whether or not terbinafine crosses
the human placenta is unknown and human oral exposure during
Systemic polyenes pregnancy has never been reported. Although it is classified as
Polyenes are among the oldest antifungal drugs. They bind to pregnancy category B, oral prescription should be postponed until
ergosterol, forming transmembrane pores leading to ionic leak- after delivery. Breastfeeding should also be avoided, given terbina-
age and fungal death. fine’s active excretion in milk.59 In contrast, topical terbinafine dis-
Amphotericin B displays the broadest antifungal spectrum, plays minimal absorption and can be prescribed in pregnancy.
including most yeasts, moulds including Mucorales and dimorphic
fungi. Lipid formulations were later developed to limit amphoter- What is new?
icin B nephrotoxicity: liposomal, colloidal dispersion and lipid com-
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Malassezia furfur, dermatophytes), and oral and vulvo-vaginal used as a nail lacquer in onychomycosis. This drug presents with
candidiasis. poor systemic absorption and it was not shown to be deleterious
in animal pregnancies.21 Systemic absorption is considered very
What was known? Topical azoles are not or are minimally low, if it occurs at all. Amorolfine may hence be used in pregnancy.
absorbed and hence are allowed at any stage of pregnancy.
Potassium iodide
What is new? A miconazole muco-adhesive tablet received EMA
and FDA approval in June 2008 and April 2010, respectively. The Potassium iodide is still used in some geographical areas for the
FDA has assigned miconazole, irrespective of its galenic formula- treatment of cutaneous sporotrichosis or basidiobolosis because
tion, to pregnancy category C. Like other topical azoles, animal of its efficacy, safety and low cost. Iodides readily cross the pla-
studies did not evidence embryo – fetotoxicity or teratogenicity centa and their use has been associated with fetal goitre develop-
with topical miconazole. No specific study has been performed ment with some cases of tracheal compression and death;
in pregnancy, and miconazole should only be used in this setting alternatively, other authors have reported fetal exposure during
19
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Table 3. Main practice guidelines regarding the treatment of invasive fungal infections in pregnancy
Term of pregnancy
Pathogen Practice guidelines Year first trimester second– third trimester Alternative proposition
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34 Mølgaard-Nielsen D, Pasternak B, Hviid A. Use of oral fluconazole 58 Figueiró-Filho EA, El Beitune P, Queiroz GT et al. Visceral leishmaniasis
during pregnancy and the risk of birth defects. New Engl J Med 2013; and pregnancy: analysis of cases reported in a central-western region of
369: 830– 9. Brazil. Arch Gynecol Obstet 2008; 278: 13 –6.
35 Bean LM, Jackson JR, Dobak WJ et al. Intra-amniotic fluconazole ther- 59 Lamisil Package Insert. 1992.
apy for Candida albicans intra-amniotic infection. Obstet Gynecol 2013; 60 Aly R. Ecology and epidemiology of dermatophyte infections. J Am
121: 452– 4. Acad Dermatol 1994; 31: S21– 25.
36 Bar-Oz B, Moretti ME, Bishai R et al. Pregnancy outcome after in utero 61 Rubin A, Dvornik D. Placental transfer of griseofulvin. Am J Obstet
exposure to itraconazole: a prospective cohort study. Am J Obstet Gynecol Gynecol 1965; 92: 882– 3.
2000; 183: 617–20.
62 Rosa FW, Hernandez C, Carlo WA. Griseofulvin teratology, including two
37 Tiboni GM, Marotta F, Del Corso A et al. Defining critical periods for thoracopagus conjoined twins. Lancet 1987; 1: 171.
itraconazole-induced cleft palate, limb defects and axial skeletal malfor-
63 Czeizel AE, Métneki J, Kazy Z et al. A population-based case – control
mations in the mouse. Toxicol Lett 2006; 167: 8– 18.
study of oral griseofulvin treatment during pregnancy. Acta Obstet
38 De Santis M, Di Gianantonio E, Cesari E et al. First-trimester itraconazole Gynecol Scand 2004; 83: 827– 31.
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