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Am J Clin Dermatol (2013) 14:351358

DOI 10.1007/s40257-013-0041-9

THERAPY IN PRACTICE

The Management of Acne Vulgaris in Pregnancy


Fiona M. Meredith Anthony D. Ormerod

Published online: 31 August 2013


 Springer International Publishing Switzerland 2013

Abstract Acne vulgaris is a common condition in adolescence and also for many women of childbearing age.
The management of acne in pregnancy is complicated by
the lack of clinical studies and pharmacokinetic data in
this patient population and safety concerns regarding
retinoid use in pregnancy. Of primary concern to both
patients and clinicians is the safety profile of medications
used during pregnancy. This review seeks to clarify what
management options are available to treat acne during
pregnancy and what data are available to guide decision
making. Topical treatments are considered the safest
option during pregnancy. They have the best safety profile
and minimize the levels of systemic absorption, and
therefore the least risk of fetal exposure. If these are
applied properly with a strong emphasis on adherence,
excellent results can be achieved.

1 Introduction
1.1 Background
Acne vulgaris is an extremely common condition in the
adolescent population, with 1520 % of young people
having moderate to severe disease [1, 2]. This tends to
settle in adulthood but there is a group of women who
continue to have ongoing acne or develop acne for the first
F. M. Meredith
Department of Dermatology, Aberdeen Royal Infirmary,
Foresterhill, Aberdeen AB25 2ZN, UK
A. D. Ormerod (&)
Division of Applied Medicine, University of Aberdeen,
Polwarth Building, Foresterhill, Aberdeen AB25 2ZD, UK
e-mail: a.d.ormerod@abdn.ac.uk

time when older [3]. One German study found that acne
persisted into the 20s and 30s in around 64 % and 43 % of
individuals, respectively [4]. A British study found 12 % of
women had facial acne that appeared to persist into middle
age [5].
In women with both new and pre-existing acne, the
management of the condition during pregnancy can be
particularly challenging as there are limited therapeutic
options available to them. Owing to the hazards associated
with clinical research in a pregnant population, no trials of
acne treatment have been published in this patient group.
This means that relevant safety data have been extrapolated
from the use of medications for other reasons. The available evidence is mainly restricted to observational studies
and often with small samples sizes. There are pregnancyexposure registries that collect data on the use of certain
medications in pregnancy. However, there are no relevant
registries for acne treatments [6].
Acne severity can vary significantly, from mild
comedonal disease to severe, scarring, inflammatory
lesions that can be accompanied by systemic symptoms.
Treatment decisions during pregnancy will inevitably be
influenced by the severity of the acne balanced against the
safety profile of proposed treatments. In addition, as
approximately half of the six million pregnancies in the
USA each year are unplanned, many women will be
exposed to drugs before they know they are pregnant [7]. It
is also important to note the stage of pregnancy at which
the exposure occurs as this will alter the risk substantially
depending on the medication.
Many guidelines have been created for the management
of acne [8, 9]. The aim of this review is to review the
published evidence to identify effective treatments for acne
and to then assess the safety of using these therapies in
pregnancy.

352

F. M. Meredith, A. D. Ormerod

Table 1 Summary of US FDA categories for medication use in pregnancy [15]


Category

Description

Controlled studies show no risk: Adequate, well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in
any trimester of pregnancy

No evidence of risk in humans: Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal
abnormalities despite adverse findings in animals,
or
In the absence of adequate human studies, animal studies show no fetal risk. The chance of fetal harm is remote, but remains a
possibility

Risk cannot be ruled out: Adequate, well-controlled human studies are lacking, and animal studies have shown a risk to the fetus or
are lacking as well

Positive evidence of risk: Studies in humans, or investigational or post-marketing data, have demonstrated fetal risk. Nevertheless,
potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a
life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective

Contraindicated in pregnancy: Studies in animals or humans, or investigational or post-marketing reports, have demonstrated positive
evidence of fetal abnormalities or a risk that clearly outweighs any possible benefit to the patient

There is a chance of fetal harm if the drug is administered during pregnancy, but the potential benefits may outweigh the potential risk

1.2 Literature Review


The following sources were searched: Ovid, MEDLINE,
EMBASE, and Pubmed. No date restrictions were applied
but studies were limited to English language only. The
keywords used were pregnancy; acne; teratogenicity;
safety; guidelines; retinoids; isotretinoin; topical;
steroids; antibiotics; laser; light; benzoyl peroxide;
salicyclic acid; congenital; tetracycline; clindamycin; erythromycin; azithromycin; and azelaic acid.
Hand searches of the references of retrieved papers were
also performed, as were online searches of the UKTIS,
ORTIS, MIMS, and the British National Formulary (see
Useful Resources section).
1.3 Physiologic Skin Changes in Pregnancy
There are many physiologic changes in the skin associated
with pregnancy. Sebaceous and eccrine gland secretion
increases, whereas apocrine gland activity decreases [10,
11]. In a small, prospective cohort study of 140 pregnant
women, of the 19 patients with acne 11 noted regression of
their disease and 8 observed an aggravation of their skin
during pregnancy [12].

leading to decreased total plasma concentrations. However,


as a result of decreased protein binding, there is more
available free drug that compensates for these factors,
limiting their impact [14].
1.5 Current Guidance
In 1979, the US Food and Drug Administration (FDA)
introduced a pregnancy category system to guide safe
prescription of medications during pregnancy [15]. The
criteria are summarized in Table 1. Whilst helpful, some
think that the categorization is overly simplistic and lacks
information about the severity, nature, and available
treatments of any possible effect on the fetus [16]. The
American Society of Teratology proposed that the classification system was changed to give more evidence-based
narrative statements [17].
In 2008, the FDA proposed major revisions to drug
labeling that will eliminate the current pregnancy categories and provide more detailed information to guide prescribing. As of February 2011, the Final Rule is in the
writing and clearance process [18].
Taking into account these limitations, the FDA categories for some commonly used acne preparations are summarized in Table 2.

1.4 Pharmacokinetics in Pregnancy


Physiologic changes in pregnancy alter the absorption,
distribution, and clearance of medications [13]. This is due
to a variety of factors including delayed gastric emptying,
increased plasma volume, increased renal blood flow, and
the induction of the hepatic cytochrome P450 system by
estrogens and progesterones [13]. In general, these changes
cause decreased absorption and increased elimination

2 Topical Preparations
Topical agents are the mainstay of treatment for mild to
moderate acne [9]. Some topical medications do not have a
pregnancy category as systemic absorption is generally
considered to be minimal, unless use is extensive, intensive, or prolonged [19]. More recently, many combination

Management of Acne Vulgaris in Pregnancy


Table 2 US FDA categories of
medication used in acne
management [18, 19]

In pregnancy class C, if dose


exceeds recommended daily
allowance

353

Category

Oral medications

Topical medications

Erythromycin, clindamycin

Clindamycin, erythromycin, azelaic acid

Spironolactone, trimethoprim,
corticosteroids

Adapalene, tretinoin, benzoyl peroxide, nicotinamidea,


salicylic acid

Tetracycline, doxycycline,
minocycline

Isotretinoin

Tazarotene

Table 3 Summary of case reports of birth defects associated with topical retinoid use
Case report

Topical agent used

Duration of use

Quantity
used

Gestation at
delivery

Congenital defect reported

Camera and
Pregliasco [23]

Tretinoin 0.05 % cream

Before conception and


up to 11 weeks
gestation

Not stated

41 weeks

Hypoplastic ear, atresia of the


external auditory meatus

Lipson et al. [24]

Tretinoin 0.05 % alcoholbased topical application

Before conception and


up to 5 weeks gestation

Not stated

Not stated

Supraumbilical hernia,
diaphragmatic hemia, pericardial
defect, dextroposition of the
heart, right upper limb defect

Selcen et al. [25]

Tretinoin 0.025 % topical


preparation

Before conception and


up to 2 to 3 months
gestation

Not stated

41 weeks

Absence of ear and external


auditory canal

NavarreBelhassen et al.
[26]

Tretinoin 0.05 % alcoholbased topical application

Before conception and


up to 2 months
gestation

Not stated

40 weeks

Coarctation of the aorta,


hypoplastic left hand,
hypertelorism, small ear canals

Autret et al. [27]

Adapalene 0.1 % gel

Before conception and


up to 13 weeks

0.3 mg
daily

Termination
at 22 weeks

Anophthalmia agenesis of the


optic chiasma

topical therapies have been developed for use in acne.


These have not been included in this review as we have
focused on the individual active ingredients and their safety
profile.
The absorption of topical therapies is influenced by
many factors including the following:

Amount of agent applied


Surface area of application
Length of application time
Frequency of application
Application to broken skin/erosions
Choice of vehicle used
Thickness of stratum corneum

2.1 Benzoyl Peroxide


Benzoyl peroxide is a commonly used acne treatment that
comes in a variety of strengths (2.510 %) and formulations (cream, gel, wash, aqueous gel). Benzoyl peroxide
works as a keratolytic, comedolytic, and anti-inflammatory
agent. Its antimicrobial activity is based on generating
highly reactive oxygen radicals, an effect to which Propionibacterium acnes has not developed resistance [20].

There is some evidence that benzoyl peroxide is


absorbed systemically and, in an animal model, the
absorbed benzoyl peroxide was excreted rapidly in urine as
benzoic acid [21], which was unaffected by the concentration of benzoyl peroxide used. This rapid renal clearance
prevents hepatic conjugation to hippuric acid [22].
There are no studies looking at the use of topical benzoyl peroxide in pregnancy and so it has been assigned
FDA pregnancy category C. As only about 5 % of the
benzoyl peroxide applied topically was found to be
absorbed in one study, the potential risk during pregnancy
is low [22].
2.2 Topical Retinoids
There are four topical retinoids used in the treatment of
acne: tretinoin, isotretinoin, tazarotene, and adapalene.
These are often used as the first-line treatment for mild to
moderate acne, especially when mainly comedonal.
There have been some case reports of birth defects in
babies who had prenatal exposure to topical retinoids.
There have been four case reports of congenital birth
defects after the use of topical tretinoin in early pregnancy
(see Table 3) [2326]. There has also been one case report

354

of anophthalmia that was thought to be associated with


topical adapalene use [27].
These reports were particularly concerning as the birth
defects were similar to those whose mothers had taken oral
isotretinoin [28]. However, a subsequent case control study
did not show an increased risk for major congenital defects
[29]. Most recently, a prospective observational study of
235 women exposed to a topical retinoid during their first
trimester were compared with 444 women in the control
group (matched for maternal and gestational age). No
significant differences in major or minor birth defects were
detected between the two groups. However, this sample
size could not exclude infrequent outcomes or a smaller
effect than a two to three times increase in risk [30].
A formal consensus on the safety of topical retinoids in
pregnancy is lacking [31] and because the manufacturers
advise that they should not be used during pregnancy, this
treatment cannot be recommended at present.

F. M. Meredith, A. D. Ormerod

However, salicylates do occur naturally in the diet and


subsequent cohort studies showed no increase in risk [36].
Salicylism has occurred using methyl salicylate ointments
and high concentrations of salicylic acid on widespread
areas of hyperkeratotic skin, but there are no known cases
resulting from salicylic acid acne products [32].
2.6 Nicotinamide
Nicotinamide is the amide of nicotinic acid (vitamin B3).
Again, it is a normal dietary constituent present in the
diet. Regarding systemic absorption, just over 10 % of
the total applied dose of nicotinamide was absorbed over
5 days in a human study [37]. Topical nicotinamide use
is not restricted during pregnancy (although the manufacturers advise caution in the first trimester), but oral
nicotinamide changes from class A to pregnancy class C
if the dose exceeds the recommended daily allowance
[19].

2.3 Topical Antibiotics


2.7 Abrasive Agents
Because of the increasing problem of antibiotic resistance,
monotherapy with topical antibiotics is generally not recommended [9]. The main topical antibiotics used are
clindamycin and erythromycin.
Clindamycin is a semi-synthetic derivative of lincomycin that inhibits bacterial protein synthesis by attaching to
the bacterial ribosome [32]. It is available in a gel, lotion,
or topical solution [33]. It has been assigned FDA pregnancy category B, as animal studies have failed to reveal
evidence of teratogenicity when high doses of clindamycin
are given systemically.
Erythromycin is a macrolide antibiotic available as a
gel, solution, or ointment. Percutaneous absorption of
erythromycin is very low [32]. Oral and topical erythromycin formulations are both FDA category B, as animal
studies have shown no evidence of teratogenicity [32].
2.4 Azelaic Acid
Azelaic acid has antimicrobial and anticomedonal properties [8]. This is a naturally occurring dicarboxylic acid
found in wholegrain cereals such as wheat, rye, and barley
[34]. One study found that after application of the 20 %
cream formulation, 3.6 % of the dermal applied dose was
percutaneously absorbed [35]. It is categorized as FDA
pregnancy class B, as animal studies have shown no teratogenicity but human data are not available.
2.5 Salicylic Acid
Salicylates were thought to be teratogenic because of animal data showing an increase in cardiac malformations.

Although many cosmetic face washes and scrubs contain


abrasive agents, these are not considered beneficial in acne
[33].

3 Oral Preparations
3.1 Oral Antibiotics
Outside of pregnancy, oral antibiotics are commonly prescribed as a second-line therapy for acne. The most commonly prescribed are tetracyclines: doxycycline,
oxytetracycline, lymecycline (not available in the USA),
minocycline, and tetracycline.
There has been increasing concern about the risk of
antibiotic resistance [38] and the use of oral and topical
antibiotics concurrently (unless chemically similar agents).
Antibiotic resistance can develop within 12 weeks [39] and
is thought to impede therapeutic response.
Penicillins, erythromycin, and cephalosporins are
thought to have the best safety profile in pregnancy [40],
with erythromycin the oral antibiotic most commonly used
for acne in pregnancy.
3.1.1 Tetracyclines
Tetracyclines should not be used during pregnancy, as use
in the second and third trimester can cause discoloration of
teeth and bones. Fatty liver of pregnancy in the third trimester has also been attributed to tetracycline ingestion
[41]. There is no firm evidence that first-trimester use is

Management of Acne Vulgaris in Pregnancy

associated with major birth defects but their use is not


recommended at any stage of pregnancy.
3.1.2 Trimethoprim
Trimethoprim is a dihydrofolate reductase inhibitor that
reduces the conversion of folate to its more active metabolites. A retrospective case-control study found that in
early pregnancy, trimethoprim may increase the risk of
cardiovascular defects, oral clefts, and urinary tract defects,
particularly among the infants of women who do not use a
multivitamin containing folic acid [40].
3.1.3 Clindamycin
Oral clindamycin has been shown to be effective in the
management of acne [42] but is known to be a cause of
antibiotic-associated diarrhea [43] and colitis [33]. Clindamycin use also increases the risk of Clostridium difficile
infection, resulting in a widespread restriction of clindamycin prescribing [44]. Regarding safety in pregnancy, of
647 first-trimester exposures to clindamycin, no increased
risk of a birth defect was detected [45].
3.1.4 Erythromycin
Erythromycin is the oral antibiotic of choice for acne
during pregnancy [36]. It is more commonly used in
pregnancy to treat other infections, allowing retrospective
analysis of pregnancy outcomes to be studied [46]. As
previously mentioned, oral erythromycin is FDA pregnancy category B. There is increasing bacterial resistance
to erythromycin and so it should be combined with a topical preparation where possible [47]. Erythromycin estolate
is the preparation that has been most noted to cause hepatotoxicity in pregnancy and it is probably best avoided,
but this can rarely happen with other esters [48].

355

improve the appearance of acne [52]. Antiandrogens such


as spironolactone are contraindicated during pregnancy
because of the theoretical risk of feminization of male
fetuses [53].
Co-cyprindiol 2000/35 (cyproterone acetate 2 mg, ethinylestradiol 35 lg), also known as Dianette (Bayer
Schering Pharma, UK), is not available in the USA but is
licensed in the UK for the treatment of acne that has not
responded to prolonged oral antibacterials [33]. This is also
contraindicated in pregnancy.
3.3 Oral Retinoids
The use of oral retinoids in pregnancy is absolutely contraindicated [54]. This is because of the severe teratogenicity associated with retinoids, namely craniofacial,
cardiac, and thymic malformations [55]. As a result of
these teratogenic effects, the manufacturers of oral isotretinoin have developed pregnancy prevention programs
whereby the use of at least one but preferably two methods
of contraception is recommended [54]. Currently, enrolling
on the pregnancy prevention program is compulsory in the
USA, and in the UK exemptions are only made in exceptional circumstances. Women should be aware that they
should not become pregnant 1 month before, during, or for
1 month after taking isotretinoin.
3.4 Zinc
During the literature review, a paper was found that had
surveyed French dermatologists and found that around
10,000 pregnant women and 2,000 breast-feeding women
were treated for acne using zinc gluconate with only four
serious adverse events reported [56]. In the S3 European
acne guidelines, oral zinc can be considered for the treatment of mild to moderate acne based on a low strength of
recommendation [9]. Topical zinc alone is ineffective for
acne treatment [8].

3.1.5 Azithromycin
3.5 Oral Corticosteroids
Azithromycin is an azalide antibiotic derived from erythromycin [45]. It has been used in the treatment of acne and has
been found to be as effective as doxycycline [49]. Animal
studies have shown that azithromycin crosses the placenta but
there are no adequate and well-controlled studies in pregnant
women. As such, the UK Medicines and Healthcare products
Regulatory Agency (MHRA) have recommended it only be
used if adequate alternatives are not available [50].
3.2 Anti-Androgens
Spironolactone is not licensed for use in acne, although it
has been found to decrease sebum secretion [51] and

In the American Academy of Dermatology guidelines,


expert opinion states that short courses of higher dose oral
corticosteroids may be beneficial in patients with highly
inflammatory disease [8]. The dose range to be used is not
specified. It is well documented that corticosteroid use can
induce acneiform lesions [57], but 0.51 mg/kg/day courses of oral corticosteroids can be used in conjunction with
oral isotretinoin to treat acne fulminans [58]. Prednisolone
has been given FDA pregnancy category C (D if in the first
trimester). Corticosteroids have caused oral clefts in animal
studies [36]. Prospective cohort studies in humans have not
shown a teratogenic effect, but have had limited power

356

[59]. Prolonged or repeated use of corticosteroids in


pregnancy can increase the risk of intrauterine growth
restriction [60]. It is also important to note that dexamethasone and betamethasone readily cross the placenta
compared with prednisolone where 88 % is inactivated
crossing the placenta [60]. One study of 311 first-trimester
exposures to corticosteroids found lower median birth
weight (3,080 vs. 3,290 g; P \ 0.001) and earlier median
gestational age (39 vs. 40 weeks; P \ 0.001) [59].

F. M. Meredith, A. D. Ormerod

the course of the acne but may improve the appearance of


the skin [8]. Hyfrecation of comedones can also be an
effective physical therapy [65].
4.3 Dietary Restriction
Dietary restriction has not been shown to be of benefit in
the treatment of acne [2, 8]. Dietary manipulation should
not be encouraged during pregnancy.
4.4 Other Therapies

4 Non-Pharmacologic Treatment Options


There are many other treatment modalities that have been
used to treat acne. Some are used to treat the inflammatory
lesions; others are aimed at improving any scarring or postinflammatory hyperpigmentation. Cosmetic treatments for
acne scarring are not included in this review and elective
procedures are probably best delayed until after delivery.
4.1 Laser and Blue-Light Treatments
There have been various devices trialed for use in inflammatory acne and for treating scarring [61]. Light therapies
for acne are thought to kill P. acnes and shrink sebaceous
glands, reducing sebum output [62]. In the most recent
European guidelines, a low strength of recommendation was
made for the treatment of mild to moderate papulopustular
acne with blue-light monotherapy. No recommendation was
made for or against treatment with red light, intense-pulsed
light, laser or photodynamic therapy for the same grade of
acne [9]. There are limited data on these therapies and
uncertainty regarding the optimal dosing strategy.
Often maintenance therapy is required with light-based
therapies, but particularly as they carry no risk to the fetus
they represent an attractive option for treatment in pregnancy. The exception is photodynamic therapy where
neither aminolevulinic acid nor methyl aminolevulinate has
been studied for use in pregnant women and should be
avoided [63].
Narrow-band ultraviolet B phototherapy is used for
other indications during pregnancy and there is a single
case report of it being used successfully to treat acne during
pregnancy [64]; however, previous studies have shown
poor long-term efficacy [61].
There are some studies using laser sources to treat noninflammatory acne lesions but the published evidence is
still scarce in this area [9].
4.2 Comedo Extractors
Despite widespread use, comedo extractors have very little
evidence to support their use. They are not thought to alter

Many herbal agents have been used in the treatment of acne


vulgaris but there are few data on their safety and efficacy
available [8] and therefore their use cannot be recommended in pregnancy.

5 Conclusions
There are a limited number of options available for the safe
management of acne in pregnancy. Isotretinoin, which is
the mainstay of treatment for severe and nodulocystic acne,
is absolutely contraindicated in pregnancy.
The options for oral antibiotics are also limited with
erythromycin being the safest option available. Unfortunately, this is also the least effective oral antibiotic to be
used and evidence supporting its efficacy in acne is poor
[9].
Where possible, acne treatments in pregnancy should be
limited to topical treatments [41]. They have the best safety
profile and minimize the levels of systemic absorption, and
therefore have the least risk of fetal exposure. If these are
applied properly with a strong emphasis on adherence,
excellent results can be achieved. Previous reviews have
recommended topical erythromycin, clindamycin, and
benzoyl peroxide as the agents of choice [36, 41, 66, 67].
The purpose of this review is not to create a guideline
but to collate the available data on acne therapies in
pregnancy to help decision making for patients and
clinicians. To this end, we have tried to summarize our
findings in Table 4 and rank therapies based on their
safety profile. With more severe cases of acne, topical
treatments still have an important role in improving
symptoms and minimizing any ongoing scarring. These
may be safely supported by physical treatments including light-based therapies but not photodynamic therapy.
When systemic therapy is required, discussion between
the physician and patient is required to explain potential
risks, benefits, and paucity of evidence of the available
options including oral erythromycin, oral corticosteroids, and zinc as possible choices to augment topical
therapy.

Management of Acne Vulgaris in Pregnancy


Table 4 Summary of authors
views on acne therapies in
pregnancy

In cases of acne fulminans,


after first trimester

Category

Medication

Favorable safety profile

Benzoyl peroxide, azelaic acid, nicotinamide, erythromycin,


clindamycin, zinc, prednisolonea

Safety concerns/inadequate data

Topical retinoids, salicylates, azithromycin

Contraindicated

Tetracyclines, oral retinoids, trimethoprim, anti-androgens

6 Useful Resources

357

FDA http://www.fda.gov/ScienceResearch/SpecialTopi
cs/WomensHealthResearch/ucm134848.htm Information aimed at helping pregnant women make informed
choices about medicine use during their pregnancy.
The Organization of Teratology Information Specialists
(ORTIS) http://www.otispregnancy.org provides education and support to teratology services in North
America. It also provides many links to relevant government and professional bodies.
UK Teratology Information Service (UKTIS) http://
www.uktis.org collects data on all aspects of the toxicity of drugs and chemicals in pregnancy and has
helpful summary sheets available online for many
topical and oral medications.
The UK MHRA http://www.mhra.gov.uk is the government organization that collects, monitors, and reports
safety data on medications in the UK. They produce
drug analysis prints of suspected adverse drug reactions
and side effects that have been reported to them.
The electronic Medicines Compendium (eMC) http://
www.medicines.org.uk is a useful resource that contains patient information leaflets and summaries of
product characteristics

Acknowledgments Both authors have no relevant conflicts of


interest. FMM researched and drafted the initial document, which was
then reviewed and edited by ADO.

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