J Antimicrob Chemother 2015; 70: 14 22

doi:10.1093/jac/dku355 Advance Access publication 8 September 2014

Antifungal drugs during pregnancy: an updated review

Benot Pilmis1, Vincent Jullien2, Jack Sobel3, Marc Lecuit1, Olivier Lortholary1 and Caroline Charlier1*
1
Infectious Diseases Department, Universite Paris Descartes, Sorbonne Paris Cite, Centre dInfectiologie Necker-Pasteur, Hopital
Necker-Enfants Malades, Paris, France; 2Pharmacology Department, Universite Paris Descartes, Sorbonne Paris Cite, Inserm U1129,
Hopital Europeen Georges-Pompidou, Paris, France; 3Wayne State University, Detroit, MI, USA

*Corresponding author. Tel: +33-1-44-49-52-62; Fax: +33-1-44-49-54-40; E-mail: caroline.charlier@nck.aphp.fr

Antifungal prescription remains a challenge in pregnant women because of uncertainties regarding fetal toxicity
and altered maternal pharmacokinetic parameters that may affect efficacy or increase maternal and fetal
toxicity. We present updated data reviewing the available knowledge and current recommendations regarding
antifungal prescription in pregnancy. Amphotericin B remains the first-choice parenteral drug in spite of its well-
established toxicity. Topical drugs are used throughout pregnancy because of limited absorption. Recent data
have clarified the teratogenic effect of high-dose fluconazole during the first trimester and provided reassuring
cumulative data regarding its use at a single low dose in this key period. Recent data have also provided additional
safety data on itraconazole and lipidic derivatives of amphotericin B. Regarding newer antifungal drugs, including
posaconazole and echinocandins, clinical data are critically needed before considering prescription in pregnancy.

Keywords: fetus, placenta, antifungal therapy, fungal infections

Introduction
Pregnancy should be considered as a condition with increased vul-
nerability to infections, including some life-threatening fungal
infections, but paradoxically little is known regarding optimal anti-
fungal regimens and dosages in this setting.1 Drug prescription
during pregnancy requires a delicate assessment of the balance
between maternal benefit and fetal risks, including fetal loss, con-
genital malformations, organ toxicity and prematurity. In addition
to the pharmacodynamics, pharmacokinetics and intrinsic anti-
fungal activity of a given drug, specific parameters should be
added to the challenging equation of antifungal prescription in
pregnant women: term of pregnancy, level of fetal drug exposure
and maternal physiological pharmacokinetic changes.2 Indeed
vomiting-increased gastric pH, cardiac output, intestinal blood
flow and time of intestinal process can modify oral absorption.
Increased intra- and extravascular blood flow and reduced serum
albumin concentration enhance the distribution of unbound drugs.
Finally, increased renal filtration/elimination and increased (3A4,
2D6, 2C9, 2A6) or decreased (1A2, 2C19) cytochrome activities
can modify drug clearance. Fetal exposure relies on the drugs
ability to cross the placenta, depending on the stage of pregnancy
(placental maturation with enhanced fetal exposure in later term)
and on intrinsic drug parameters (liposolubility, molecular weight,
protein binding).3 5
Because pregnancy is a duly established contraindication for
controlled studies involving antifungal drugs, data in this setting
are extremely limited and based on in vitro or animal studies,
pharmacological investigations, limited case reports and expert
opinions. In this setting, the FDA definitions for pregnancy risk cat-
egories (A to X, in accordance with products estimated toxicity for
fetus) provide a general framework that do not take into account
the stage of pregnancy (Table 1). They globally reflect the paucity
of available information (Table 2).
The last focus on antifungal drugs in pregnancy was published in
2003 by Moudgal and Sobel.6 Within the last 10 years the FDA has
provided approval for three new antifungal drugs: posaconazole,
micafungin and anidulafungin. Additional data regarding triazole
use and antifungal recommendations have emerged, raising the
need for an update on antifungal drug use in pregnancy.
Methods
We reviewed the computerized literature available in the PubMed database.
The literature from January 1949 through December 2013 was queried
using the terms, pregnant, pregnancy, prenatal, fetal, fetus, terato-
genicity, toxicity, placenta, birth defect, azoles, fluconazole, itracon-
azole, voriconazole, posaconazole, miconazole, echinocandins,
caspofungin, micafungin, anidulafungin, flucytosine, 5FC, polyene,
amphotericin B, liposomal amphotericin B, nystatin, terbinafine, griseo-
fulvin, aspergillosis, cryptococcosis, coccidioidomycosis, histoplasmo-
sis, candidiasis, sporotrichosis, scedosporiosis and fusariosis. Animal
data and human case reports and studies were analysed. English, French,
German and Spanish publications were screened. Data published before
the last update in 2003 are presented in the What was known? sections,
whereas more recent data are presented in the What is new? sections.
Key points, summarizing the main data, are provided for each drug.
Immunity during pregnancy and fungal
infections
Pregnancy is a unique and complex situation during which the
maternal immune system faces two issues: defending both the

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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
high-dose regimen (400 600 mg/day) D
demonstrate a risk
itraconazole C
C either animal studies indicate a fetal risk and there have
voriconazole D
been no controlled studies of women, or there are no
posaconazole Cb
available reports of studies of women or animals
topical azoles C
D there is positive evidence of fetal risk, but there may be
certain situations where the benefit may outweigh the Echinocandins
risk (e.g. life-threatening or serious diseases for which caspofungin Cb
other drugs are ineffective or carry a greater risk) micafungin Cb
X there is definite fetal risk, according to studies of animals or anidulafungin Cb
humans or on the basis of human experience, and the
Antimetabolites
risk clearly outweighs any benefit in pregnant women.
flucytosine C

Squalene epoxidase inhibitors

mother and fetus from pathogens, while at the same time toler-
ating the fathers fetal antigens. Immune functions are known to
vary according to the phases of pregnancy, being more
pro-inflammatory during implantation and delivery, and anti-
inflammatory in-between.7 Post-implantation is characterized
by both an up-regulation of monocytes displaying enhanced
phagocytosis and IL1b and IL12 secretion ability, and a down-
regulation of T cells displaying diminished proliferation and IL2/6
secretion ability.8 Humoral response is not altered.9 Recent work
has emphasized the highly antigen-specific nature of regulatory
T cell-driven maternal tolerance,10 which would not hamper
adequate maternal immune responses against most pathogens.
Yet pregnant women are considered at higher risk for some infec-
tions, like listeriosis, and for severe manifestations during dengue,
measles or influenza.11 13
With regard to fungal infections, two main types can occur:
(i) Vulvo-vaginal candidiasis. This affects 75% of women at least
once during their lifetime but occurs in up to 20% of pregnant
women.14 Treatment failures and recurrences are frequently
reported in this setting. Higher vaginal glycogen content is
thought to play a major part in their development, favouring
Candida sp. growth. In addition, oestrogen enhances the
adherence of yeasts to vaginal epithelial cells, facilitating
blastospore proliferation and germination.14
(ii) Systemic fungal infections. Some systemic fungal infections
appear more severe in pregnant women. Indeed the last tri-
mester and immediate post-partum time are associated
with higher risk of disseminated coccidioidomycosis.1,15 17
Histoplasmosis and blastomycosis might also be more fre-
quently disseminated during pregnancy.18,19 Pulmonary
cryptococcosis has seldom been described in young immuno-
competent women.20 Other systemic mycoses do not appear
to be significantly influenced by pregnancy.
terbinafine B
Miscellaneous
griseofulvine C
a
Topical antifungal.
b
No human data.
Antifungal agents and pregnancy
Systemic azoles
Azoles include imidazoles (see the Topical drugs section) and
more recent triazoles (ketoconazole, itraconazole, fluconazole,
voriconazole and posaconazole). They act by targeting the C14a
demethylase and thereby inhibiting the biosynthesis of ergosterol,
an essential component of fungal cell membranes. Animal and
human data provide evidence that azoles could be teratogenic.
Ketoconazole
Ketoconazole has been shown to be teratogenic and embryotoxic
at high doses (80 mg/kg/day) in animals.21 Although ketocon-
azole has been shown to cross the placental barrier poorly in ani-
mal studies, it could theoretically affect sex organ differentiation
in the fetus.22,23
Fluconazole
What was known? Fluconazole is a systemic triazole with fungi-
static effect only on yeasts like Candida sp. and Cryptococcus sp.
It crosses the placenta and was shown to be embryotoxic in
rabbits and embryo fetotoxic and teratogenic in rats, inducing
craniofacial and rib abnormalities.24 Five observations of congenital
abnormalities in children exposed in utero have been reported.25 27
Their mothers had received fluconazole (400 mg/day or above)

15
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during the first trimester (5/5) and beyond [4/5, until 4 months
and 31 weeks of gestation (n 1, each) or throughout pregnancy
(n 2)]. Lesions included trapezoidocephaly, mid-facial hypopla-
sia, cartilage abnormalities with multiple synostoses and skeletal
fractures. Abnormalities were similar to those reported in the
AntleyBixler syndrome.26 In contrast, in mothers exposed during
the first trimester to single doses of 50150 mg of fluconazole, no
adverse fetal outcome was observed.28
What is new? The FDA reclassified fluconazole from category C
to category D (except for single 150 mg doses for vaginal candid-
iasis).29 In addition, animal studies have helped further confirm
the teratogenicity of high-dose fluconazole in rodents, with iden-
tification of the phase of maximal sensitivity (day 10 of gestation),
and of the dose dependence of lesions that mostly involve bra-
chial arches.30,31
Most importantly, large epidemiological studies have helped
clarify the risk of fluconazole at low doses. Nrgaard et al.,32 in
a Danish population-based study performed from 1991 2005,
identified 1079 pregnant women prescribed fluconazole during
the first trimester, of whom 797 received 150 mg, 235 received
300 mg and only 47 (4%) 350 or 600 mg. No increase in malfor-
mation, fetal loss, preterm birth or low birth weight was found
(OR 1.0, range 0.7 1.3).32 Carter et al.33 analysed patients
from the US National Birth Defects Prevention prospective case
control study. Among 7047 women, 84 and 59 exposures to anti-
fungals were reported in cases and controls, respectively.
Exposures mostly involved miconazole, terconazole and clotrima-
zole, but included fluconazole in 12 cases. Dosages and duration
were not specified. A slight increase in hypoplastic left heart
syndrome was noted (OR 2.3, range 1.04 5.06), along with a non-
significant increase in diaphragmatic hernia. Craniofacial malfor-
mations that were previously reported with fluconazole were not
significantly increased. Recently, Mlgaard-Nielsen et al.34 pro-
vided the largest and strongest information on the safety of low
doses of fluconazole in first-trimester pregnancies. They analysed
fluconazole, itraconazole and ketoconazole first-trimester pre-
scriptions for all Danish pregnant women from 1996 to 2011. A
total of 976 000 children with antenatal exposure were identified;
7352 were exposed to fluconazole. Cumulative doses were
150 mg (n 4082, 56%), 300 mg (n 2252, 31%) or 350
600 mg (n 1018, 14%). Risk of birth defect was not significantly
increased in this cohort (OR 1.06, 0.92 1.21) and no increase in
the previously described malformation pattern was found.
Finally, Bean et al.35 reported the safety and efficacy of
intra-amniotic fluconazole 50 100 mg/week for 6 8 weeks in
two patients with chorioamniotitis caused by Candida albicans.
Key points Fluconazole is embryofetotoxic and teratogenic in
rodents and rabbits. Total fluconazole dose .300 mg should be
considered teratogenic and remains contraindicated throughout
pregnancy, with FDA designation D. A single low dose (300 mg
total dose) of fluconazole does not increase the risk of congenital
disorders and may be considered in the absence of a topical alter-
native after the first trimester.
Itraconazole
What was known? Itraconazole is a triazole with a broader spec-
trum of activity than fluconazole, including endemic fungi and
16
most Aspergillus species. It was shown to be embryotoxic and
teratogenic in rodents, inducing craniofacial and rib abnormal-
ities.21 However, a prospective study involving 229 women
exposed to itraconazole, including 198 during the first trimester
[daily doses ranged from 50 to 800 mg (median 200 mg) for a
median of 3 days (range 1 90)], failed to identify any increased
risk of fetal malformation.36 A significantly higher rate of early
fetal loss was reported (12% versus 4% in the control group),
but questions were raised regarding a recall bias in the control
group that had a very low rate of early fetal loss.
What is new? Animal studies have further analysed the terato-
genicity of high-dose itraconazole in mice and have shown that
the phase of maximal sensitivity and pattern of malformation
are similar to those related to fluconazole.37 A large epidemio-
logical study has helped clarify the risk of itraconazole during
early pregnancy. De Santis et al.38 compared 206 Italian women
exposed during the first trimester and 207 controls. First-trimester
exposure to itraconazole was again not associated with increased
risk of malformation (mean daily dose of 182+63 mg for a mean
of 6.9+6.4 days). It was, however, associated with an increase in
early fetal loss (11% versus 4.8%) that was not reported in former
studies.38
Key points Itraconazole is embryotoxic and teratogenic in
rodents. Clinical studies have not detected any increased risk
during pregnancy, especially during the first trimester, and the
FDA labels itraconazole category C. Given the risk conveyed by
the azole family in humans, the drug should still be avoided dur-
ing pregnancy, especially during the first trimester. The manu-
facturer therefore recommends that effective contraception
should be continued throughout treatment and for 2 months
thereafter.
Voriconazole
What was known? Voriconazole is an azole displaying fungi-
static activity against Candida spp. and Candida neoformans and
fungicidal activity against Aspergillus fumigatus. Like other azoles,
voriconazole has been shown to be teratogenic in rodents at high
but also low doses (equivalent of 0.3 times the recommended
human maintenance dose) with skeletal and visceral abnormal-
ities.21 Plasma oestradiol concentration was reduced in pregnant
rats at all studied doses. It was also shown to be embryo
fetotoxic in rabbits, and classified as category D by the FDA due
to the lack of human data. The drug is therefore contraindicated
during pregnancy.39
What is new? Since its approval by the FDA and the EMA in 2002,
only one report of voriconazole exposure during pregnancy has
been reported. Indeed, our group recently reported the observa-
tion of a neutropenic pregnant woman with life-threatening
refractory invasive aspergillosis who received voriconazole during
the second and third trimesters of pregnancy. No adverse fetal/
neonatal outcome was evidenced at birth or at a 6 month
follow-up visit.40 Until further information is available, voriconazole
remains contraindicated in pregnancy, and should be considered
only in life-threatening cases in the absence of safer treatment
alternatives after the completion of the first trimester.
Review
Key points Voriconazole is labelled category D (FDA) because of
its embryotoxic/teratogenic effects in rodents and rabbits. Data
on pregnancy exposure are limited to a single observation with
good materno-fetal outcome. It should not be considered in
pregnancy, except in life-threatening maternal disease without
a therapeutic alternative.
Posaconazole
Posaconazole is the most recently available triazole. It received
EMA and FDA approval in October 2005 and September 2006,
respectively. It has expanded antifungal spectrum including
Mucorales and has otherwise broad spectrum against most of
the common yeasts and moulds.41
What is new? The manufacturer has reported teratogenic
effects in rats at 1.4 times the recommended human dose (skel-
etal malformations and rib abnormalities). It was also shown to
be embryotoxic and teratogenic in rabbits, at 2.9 5.2 times the
recommended human dose (reduction in body weight gain of
females, reduction in litter size).42 No published human data are
available but the FDA labels posaconazole category C.
Key points The FDA labels posaconazole category C. It is embry-
otoxic and teratogenic in rodents and rabbits. No human data are
available so far and it should not be considered in pregnancy,
except in life-threatening maternal disease without a therapeutic
alternative.
Isavuconazole
Isavuconazole is a new investigational azole with broad-spectrum
and large coverage of both yeasts and moulds, including
Mucorales. It is currently in Phase III of clinical development. To
our knowledge, no data regarding isavuconazole and pregnancy
have been reported.
Echinocandins
Echinocandins inhibit the 1,3-b-D-glucan synthase involved in fun-
gal wall synthesis. They display an excellent tolerance profile, and
a broad fungal spectrum, including yeasts such as Candida spp.
and Aspergillus spp., but not Cryptococcus spp. or moulds like
Mucorales and Fusarium spp.
What was known?
Caspofungin was approved in January 2001 by the FDA and in
October 2001 by the EMA. It crosses the placenta of rats and rab-
bits and was shown to be embryotoxic and teratogenic in both at
the recommended human dose (reduction of litter size, ossification
and rib malformations).43 It is not known if it crosses the human
placenta. Its molecular weight and extensive plasma binding
could limit the amount of crossing, but this could be counterba-
lanced by the long half-life of the molecule (911 h).21 No case of
caspofungin exposure during pregnancy has been reported.
What is new?
Two new echinocandins have been commercialized within the last
10 years.
The FDA and the EMA approved micafungin in March 2005 and
April 2008, respectively, and anidulafungin in February 2006 and
JAC
September 2010, respectively. Micafungin crosses the placenta
and was shown to be embryotoxic and teratogenic in rabbits (vis-
ceral abnormalities and abortions at the equivalent of 4 times the
recommended human dose).44
Anidulafungin crosses the placenta of pregnant rats and was
shown to be possibly teratogenic in rodents (skeletal abnormal-
ities reported at the equivalent of 2 times the recommended
human dose, but in the range of a historical control database).
It was associated with reduced fetal weight in pregnant rabbits
at the equivalent of 4 times the recommended human dose.45
Whether either drug transfers across the human placenta
remains unknown. High molecular weight (around 1100) and
extensive plasma binding could limit the amount of crossing,
but this could be counterbalanced by the long half-life (16
50 h).21 There are no available data on the use of these drugs in
pregnancy.
Key points
All echinocandins are classified as pregnancy category C agents;
embryotoxic and teratogenic effects have been reported in
rodents and rabbits. Human data are still non-existent in 2014,
and these drugs are not considered safe during pregnancy.
Flucytosine
Flucytosine was originally developed as an antimetabolite. It is
also converted in fungal cells into fluorouracil, which interferes
with both DNA and protein synthesis. Its antifungal spectrum is
limited to yeasts (Candida spp., Cryptococcus spp.). Side effects
include bone marrow, liver and gastrointestinal tract toxicities;
they are mostly related to the small amount (,5%) of flucytosine
converted into fluorouracil during intravenous infusion or in the
gastrointestinal tract upon ingestion.46
What was known?
Flucytosine has been shown to be teratogenic in rats at the
equivalent of 0.27 4.7 times the recommended human dose
(bone and craniofacial malformations).47 Fluorouracil crosses
the human placenta and achieves high concentrations in amniotic
fluid and cord blood. It has been shown to be teratogenic and
embryotoxic in rodents given the equivalent of human doses,
but not in monkeys.21 Structural abnormalities have been
reported in aborted fetuses exposed in the first trimester, contra-
indicating its use during this period.21 No increased adverse effect
was noted thereafter. Flucytosine is classified as category C by the
FDA. Seven case reports have been published describing good
maternal fetal outcome following administration during the
first (n 1), second (n2) and third (n 4) trimesters.6,48,49
What is new?
To our knowledge, no new report of pregnancy exposure has been
published over the last 10 years. International recommendations,
however, have been published suggesting the use of flucytosine in
selected situations, detailed below.50
Key points
Flucytosine is classified as category C by the FDA. Limited case
reports did not evidence adverse outcome after flucytosine
exposure during the second and third trimesters. Data are lacking
17
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to study further its fetal toxicity and it should not be considered in
pregnancy, except after the first trimester in life-threatening
maternal infections where the benefits of adding flucytosine
may justify the risk.
Systemic polyenes
Polyenes are among the oldest antifungal drugs. They bind to
ergosterol, forming transmembrane pores leading to ionic leak-
age and fungal death.
Amphotericin B displays the broadest antifungal spectrum,
including most yeasts, moulds including Mucorales and dimorphic
fungi. Lipid formulations were later developed to limit amphoter-
icin B nephrotoxicity: liposomal, colloidal dispersion and lipid com-
plex forms. A lipid complex form of amphotericin B was approved
by the FDA in 1997 and by the EMA 1 year later. A liposomal col-
loidal dispersion form was approved by the FDA in 1996.
What was known?
Amphotericin B is the safest systemic antifungal drug in preg-
nancy. Maternal nephrotoxicity is reported to be similar to that
of non-pregnant patients.6 Amphotericin B crosses the placenta
and achieves therapeutic concentrations in the fetal circulation,
with cord blood:maternal serum ratios ranging from 0.38 to
1.51,52 No teratogenicity has been shown in rodents or rabbits at
10 times the recommended human dose, even during the first tri-
mester.21,53 55 The safety of lipid formulations was, however,
poorly evaluated.6
What is new?
Case reports and series have provided further insight into the
safety and efficacy of liposomal amphotericin B in pregnancy.
Mueller et al.56 retrospectively compared liposomal amphotericin
B and sodium stibogluconate in 39 Sudanese pregnant women
with visceral leishmaniasis. First- or second-trimester abortion
was reported in 13/23 (57%) women receiving sodium stibogluco-
nate versus 0/16 in the liposomal amphotericin B group. No fetal
malformations were reported. Pagliano et al.57 and Figueiro-Filho
et al.58 additionally reported five and four cases of visceral leish-
maniasis treated with liposomal amphotericin B during pregnancy
(median term of 11+2 and 28+7 weeks of gestation, respect-
ively). All had good maternal and fetal/neonatal outcome.
Key points
Amphotericin B is classified as category B by the FDA. It is consid-
ered as the safest antifungal drug in pregnancy and is a major tool
in the fungal armamentarium in this setting. Liposomal ampho-
tericin B should also be considered safe in pregnancy. Data regard-
ing other lipidic derivatives remain scarce and they should be used
only in case of unavailability of other polyenes.
Terbinafine
Terbinafine is an allyamine available as topical and oral prepara-
tions. It acts by selectively inhibiting the fungal squalene epoxi-
dase, which increases squalene to toxic levels, thus killing fungal
cells. It is indicated for the treatment of dermatophytic skin infec-
tions, onychomycosis and other cutaneous dermatophytoses,
including chromomycosis and mycetoma, which are usually not
therapeutic emergencies during pregnancy.
18
What was known?
Oral reproduction studies did not evidence any embryofetotoxi-
city in rabbits and rats administered up to 23 times the maximum
recommended human dose.21 Whether or not terbinafine crosses
the human placenta is unknown and human oral exposure during
pregnancy has never been reported. Although it is classified as
pregnancy category B, oral prescription should be postponed until
after delivery. Breastfeeding should also be avoided, given terbina-
fines active excretion in milk.59 In contrast, topical terbinafine dis-
plays minimal absorption and can be prescribed in pregnancy.
What is new?
No new data have arisen regarding the use of terbinafine during
pregnancy.
Key points
Terbinafine is classified as category B by the FDA. It was not shown
to be toxic in animal pregnancies, but human data are not avail-
able, hence hampering its systemic use in pregnancy. In contrast,
topical terbinafine, which has limited absorption ability, can be
prescribed.
Griseofulvin
Griseofulvin is an orally administered fungistatic drug that acts by
altering DNA replication thereby blocking fungal mitosis. It is indi-
cated in dermatophytoses and classified as category C by the
FDA.39,60
What was known?
Griseofulvin crosses the placenta61 and was shown to be tumori-
genic, embryotoxic and teratogenic in rodents at 3 45 times the
recommended human dose.21 Data on human exposure during
pregnancy are scarce. An FDA report suggested a possible associ-
ation between griseofulvin prescription and conjoined twins that
was not confirmed later.62
What is new?
A Hungarian retrospective study based on the Hungarian case
control cohort compared 38151 normal pregnancies and 22843
pregnancies with birth defects in relation to their exposure to
griseofulvin (reported in 7 and 21 cases, respectively).63 It did
not appear to be associated with any birth defect or with any
excess of conjoined twins.62
Key points
Griseofulvin is classified as category C by the FDA. It is carcino-
genic, embryotoxic and teratogenic in rodents. Human data are
too limited to allow its use in pregnancy, especially in the first
trimester.
Topical drugs
Topical azoles
Topical azoles include bifonazole, clotrimazole, fenticonazole, iso-
conazole, ketoconazole, omoconazole, oxiconazole, sertacona-
zole, tioconazole, miconazole and econazole. They are indicated
for superficial fungal infections involving the skin (Candida sp.
Review
Malassezia furfur, dermatophytes), and oral and vulvo-vaginal
candidiasis.
What was known? Topical azoles are not or are minimally
absorbed and hence are allowed at any stage of pregnancy.
What is new? A miconazole muco-adhesive tablet received EMA
and FDA approval in June 2008 and April 2010, respectively. The
FDA has assigned miconazole, irrespective of its galenic formula-
tion, to pregnancy category C. Like other topical azoles, animal
studies did not evidence embryo fetotoxicity or teratogenicity
with topical miconazole. No specific study has been performed
in pregnancy, and miconazole should only be used in this setting
in the absence of an alternative and if benefits outweigh risk.6,21
Miconazole cream was also evaluated in two studies from the
Hungarian CaseControl Surveillance of Congenital Abnormalities,
which compiled 22843 newborns/fetuses with congenital abnormal-
ities and 38151 control newborns from 1980 to 1996. Treatment
with topical miconazole during the first trimester did not increase
the risk of congenital abnormalities (OR 0.9, range 0.61.6),64 but
combined vaginal metronidazole and miconazole therapy may be
associated with a slight increase in polydactily or syndactily (OR
1.2, range 1.01.3).2
Nystatin
What was known? Nystatin is poorly absorbed orally, if at all. No
animal data are available for this drug. Nystatin is classified as
category A by the FDA in pregnancy.39
What is new? Czeizel et al.65 investigated the teratogenicity of
oral nystatin during pregnancy. In this population-based case
control study, treatment with oral nystatin during pregnancy
was identified in 249 of .50 000 pregnant women. It was asso-
ciated with a slightly increased risk of congenital abnormalities
compared with unexposed women (OR 1.2, range 1.0 1.6). The
authors identified a possible association between exposure to
oral nystatin and hypospadias (OR 1.94, range 1.22 3.09) that
requires further confirmation.66
Key points Nystatin is classified as category A by the FDA. It is
poorly absorbed and for many years was considered safe during
pregnancy. However, recent Hungarian data raise the possibility of
a slightly increased risk of hypospadias in exposed fetuses.
Accordingly it may be prudent to avoid use during the critical per-
iod for this malformation (8 14 weeks of gestation).
Terbinafine
Terbinafine is detailed above.
Ciclopiroxolamine
Ciclopiroxolamine is only used topically and displays poor sys-
temic absorption. It is classified as category B by the FDA and
may be used in pregnancy if the benefit justifies the potential
risk to the fetus.67,68
Amorolfine
Amorolfine is a morpholine derivative that acts by inhibition of the
fungal ergosterol biosynthesis, leading to membrane permeability
and disruption of key fungal metabolic processes. Amorolfine is
JAC
used as a nail lacquer in onychomycosis. This drug presents with
poor systemic absorption and it was not shown to be deleterious
in animal pregnancies.21 Systemic absorption is considered very
low, if it occurs at all. Amorolfine may hence be used in pregnancy.
Potassium iodide
Potassium iodide is still used in some geographical areas for the
treatment of cutaneous sporotrichosis or basidiobolosis because
of its efficacy, safety and low cost. Iodides readily cross the pla-
centa and their use has been associated with fetal goitre develop-
ment with some cases of tracheal compression and death;
alternatively, other authors have reported fetal exposure during
the third trimester without deleterious materno-fetal conse-
quence.69 71
Key points for topical antifungal drugs Topical antifungals all
display limited if any systemic absorption, and they may be
used in pregnancy, except for potassium iodide, which was
shown to be associated with fetal goitre.
Updated therapeutic recommendations in
pregnant women
Updated available recommendations regarding the main
systemic fungal infections are summarized in Table 3.
Amphotericin B and its lipid derivatives are considered the corner-
stone of treatment in any invasive fungal infection during preg-
nancy. Some experts like Bercovitch et al.16 additionally suggest
that fluconazole could be considered after the first trimester in
the absence of an alternative agent.
Superficial infections during pregnancy require topical treat-
ment, which can be prescribed throughout pregnancy, including
topical azoles. Superficial fungal infections requiring systemic
treatment, like dermatophytic onychomycosis, chromomycosis
and mycetoma, should be treated after delivery.
Gaps of knowledge and future prospects
The need for precise knowledge regarding antifungals in preg-
nant women is greater than ever before. A rising number of
immunocompromised patients experience pregnancy. Their vul-
nerability towards fungal infections is higher than that of the
general population or other pregnant women, and exacerbates
the need for precise and accurate data regarding the use of anti-
fungal drugs in pregnancy. More than 4000 pregnancies have
already been reported worldwide in solid-organ-transplanted
women. 72 Tailored immunosuppressive protocols have also
helped young women with auto-immune disorders both protect
their fertility and better control their underlying disease, and
hence undergo a pregnancy. In addition, emerging fungal infec-
tions, as exemplified by the Cryptococcus gattii North American
outbreak, have recently been reported outside their classical
geographical areas; they have the potential to affect immuno-
competent pregnant women from previously unaffected
areas.73
Yet this update illustrates the slow progress made in the field of
antifungal use in pregnancy. Where do we stand 10 years after
the latest review? Studies have further established the teratogenic
effect of high-dose fluconazole during the first trimester, and yet
19
20

Review
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

Coccidioidomycosis IDSA 2005 amphotericin B lipid formulation amphotericin B lipid formulation

Galgiani et al.74 2 5 mg/kg/day 2 5 mg/kg/day
amphotericin B deoxycholate
0.51.5 mg/kg/day
Bercovitch et al.16 2011 non-meningeal infection non-meningeal infection if possible avoid azoles during the
amphotericin-based regimen fluconazole/itraconazole first trimester in non-meningeal
(400 mg/day) infections; azoles are an
meningeal infection meningeal infection alternative to intrathecal
intrathecal amphotericin fluconazole/itraconazole amphotericin during the first
(400 mg/day) trimester
intrathecal amphotericin is an
alternative to azoles in
meningeal infection in the first
trimester
Aspergillosis IDSA 2008 no specific recommendation no specific recommendation
Walsh et al.75
Disseminated IDSA 2010 amphotericin B deoxycholate amphotericin B deoxycholate fluconazole should ideally be
cryptococcosis Perfect et al.50 0.51.5 mg/kg/day 0.5 1.5 mg/kg/day started after delivery, and, if not
amphotericin B lipid formulation amphotericin B lipid formulation possible, after the first trimester
2 5 mg/kg/day 2 5 mg/kg/day
+flucytosine +flucytosine
Blastomycosis IDSA 2008 amphotericin B lipid formulation amphotericin B lipid formulation
Chapman et al.76 2 5 mg/kg/day 2 5 mg/kg/day
Histoplasmosis IDSA 2007 amphotericin B lipid formulation amphotericin B lipid formulation amphotericin B deoxycholate
Wheat et al.77 2 5 mg/kg/day 2 5 mg/kg/day 0.51.5 mg/kg/day
Invasive candidiasis IDSA 2009 amphotericin B lipid formulation amphotericin B lipid formulation
Pappas et al.78 2 5 mg/kg/day 2 5 mg/kg/day
amphotericin B deoxycholate amphotericin B deoxycholate
0.51.5 mg/kg/day 0.5 1.5 mg/kg/day
Sporotrichosis IDSA 2007
cutaneous lesion Kauffman et al.79 local hyperthermia local hyperthermia
invasive disease amphotericin B lipid formulation amphotericin B lipid formulation
2 5 mg/kg/day 2 5 mg/kg/day
amphotericin B deoxycholate amphotericin B deoxycholate
0.71 mg/kg/day 0.7 1 mg/kg/day
Review
have provided considerable reassuring data regarding its use at
single and low dose in this key period. Studies have also provided
additional safety data on lipid derivatives of amphotericin B.
However, major continuing gaps remain to be filled. We have
experienced in the last 10 years a large expansion of the antifun-
gal armamentarium, with the rise of new drugs exhibiting an
excellent tolerance profile and efficacy and a new activity spec-
trum. Despite these advances, amphotericin B deoxycholate,
one of the oldest antifugals and for sure the one displaying the
worst tolerance profile, remains in 2014 the pivotal antifungal
drug in pregnant women. Fetal toxicity indeed remains the
major therapeutic concern, above potential maternal toxicity.
Alternatives are almost non-existent. Whereas some experts con-
sider the use of fluconazole in very selected situations after the
first trimester, the safety of long-term exposure to fluconazole
beyond this period has still not been assessed. Posaconazole
and echinocandins have never been evaluated in pregnant
women, and should therefore not be used. Because only scant
pharmacokinetics and tolerance data are available, careful phar-
macovigilance and reporting of any antifungal prescription during
pregnancy is mandatory to improve our knowledge on drug safety
and efficacy during pregnancy. Meanwhile, cautious multidiscip-
linary evaluation of the maternal fetal risks and benefits should
guide a personalized and expert antifungal prescription.
Funding
This study was supported by internal funding.
Transparency declarations
O. L. has received payments for lectures from Astellas, Merck Sharp &
Dohme, Pfizer and Gilead, is a member of Gileads board and has received
grants from Merck Sharp & Dohme. All other authors: none to declare.
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