Cutaneous Disorders of Pregnancy
Cutaneous Disorders of Pregnancy
Cutaneous Disorders of Pregnancy
of Pregnancy
Kelly H. Tyler
Editor
123
Cutaneous Disorders of Pregnancy
Kelly H. Tyler
Editor
Cutaneous Disorders
of Pregnancy
Editor
Kelly H. Tyler, MD
Internal Medicine, Division of Dermatology
Ohio State University
Columbus, OH
USA
This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
To my funny and flexible husband Jaret for
putting up with me through two residencies
and a surprise career change. Also, to my
son Dean who always makes me laugh.
I hope you never lose your zest for life!
Preface
vii
viii Preface
10 years later stating they will be applying for another residency, so they were a bit
confused at first. To make a long story short, I was fortunate enough to match into
the dermatology residency program at the Ohio State, and this book is part of fulfill-
ing my mission of increasing education about skin disease in the female patient. It
was a long, interesting, and rewarding journey, and I want others to benefit from my
experience.
My hope is for this book to provide guidance for anyone caring for a pregnant
patient who has normal but concerning skin changes, a pre-existing dermatologic
condition, or a pregnancy-specific dermatosis. With the proper knowledge and
resources, all healthcare professionals should feel confident providing adequate and
safe treatments that can benefit both the mother and the fetus.
I would like to acknowledge Dr. Benjamin Kaffenberger and Dr. Steven Helms for
generously contributing photos for this book.
I would also like to acknowledge and express my gratitude to all of the authors
who spent countless hours compiling data and composing such eloquent chapters.
ix
Contents
Conclusion�������������������������������������������������������������������������������������������������������� 123
Index������������������������������������������������������������������������������������������������������������������ 125
xi
Contributors
Treating pregnant patients presents a challenge for all physicians and healthcare
professionals, regardless of specialty. Due to concern for side effects on the fetus,
many physicians or practitioners tend to err on the side of caution, often resulting in
undertreatment. Skin disorders in pregnancy can be particularly challenging, not
only because physiologic skin changes in pregnancy that seem abnormal may actu-
ally represent normal variants, but also because dermatology is not always a spe-
cialty that gets adequate attention during routine medical education. Perhaps one of
the more challenging aspects of treating skin disease during pregnancy is that most
data on medication safety in pregnancy are based on incidental exposures, case
reports, and expert opinion, so there are no controlled human studies, and we must
rely on animal data in many cases.
Classification of medication safety in pregnancy and lactation has evolved over
the years, and it underwent a major change in 2015. Historically, we used the Federal
Drug Administration (FDA) pregnancy categories (Table 1.1) as a main source of
information about medication safety in pregnancy. Each medication was assigned a
letter, indicating its level of safety for use in pregnancy. Sixty six percent of drugs
were FDA Pregnancy Category C [1], which is described as: Risk cannot be ruled
out; human studies may or may not show risk; potential benefits may justify poten-
tial risk. That non-specific description, which applied to the majority of medica-
tions, is not reassuring, and most practitioners who did not routinely treat pregnant
patients felt uncomfortable prescribing a category C medication.
This classification system was imprecise because the potential risk of the drug is
not a global risk and often depends on which trimester the exposure happened. The
stages of prenatal development are as follows: pre-implantation – 0–2 weeks,
embryonic/organogenesis – 2–8 weeks, and fetal – 9th week to birth. Avoiding tera-
togenic medications during the embryonic period is the most important, but the
brain, teeth, and bones do remain susceptible after 9 weeks. When prescribing for
women of childbearing age, it is critical to remember that a home pregnancy test
may not be positive until up to 5 weeks after conception, so any woman who is not
on contraception and could potentially become pregnant should be treated with
medications that are safe to use during pregnancy.
xv
xvi Introduction
For most dermatologic conditions, topical medications are the safest choice and
should be considered first-line. Studies of various topicals estimate systemic absorp-
tion to range from less than 4–25% [2]. For topical medications, using them on a
smaller body surface area, using the option with the lowest potency, and avoiding
occlusion will decrease systemic absorption. Systemic medications can be used
when necessary if the practitioner is knowledgeable about safety ratings and high-
risk periods during pregnancy. Common systemic dermatologic medications that
are teratogenic (previous FDA pregnancy category X) and absolutely contraindi-
cated in pregnant patients or those who could become pregnant are isotretinoin,
acitretin, and methotrexate.
The new FDA medication safety labeling, which took effect on 6/30/2015 for
newly approved medications, includes a fetal risk summary, clinical considerations,
and data. Manufacturers of older medications were required to revise labeling and
remove letter categories within 3 years of that date [3]. Although the new system
gives more specific information, reading and interpreting each summary does
require extra work on the part of the treating physician or practitioner. Because
many readers will have more experience with the classic FDA pregnancy medica-
tion categories, most authors have included those ratings in the sections of each
chapter dedicated to treatment.
With proper knowledge of medication safety during pregnancy, physiologic skin
changes in pregnancy, pregnancy-specific dermatoses, and common pre-existing
skin disorders not specific to pregnancy, any healthcare professional can confidently
treat dermatologic conditions in their pregnant patients and avoid unnecessary risks
to the mother and fetus that could result from either inappropriate treatment or
undertreatment. In the chapters that follow, the authors give a thorough review of
the above topics, provide specific information about medication safety for each con-
dition, and present guidelines for safely using dermatologic surgery during
pregnancy.
References
1. Sannerstedt R, Lundborg P, Danielsson BR, et al. Drugs during pregnancy: an issue of risk
classification and information to prescribers. Drug Saf. 1996;14:69–7.
2. Tyler K, Zirwas M. Pregnancy and dermatologic therapy. J Am Acad Dermatol 2013;68(4):663–1.
3. http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/labeling/
ucm093307.htm.
Part I
Pregnancy-Specific Skin Changes
and Disorders
Chapter 1
Physiologic Skin Changes in Pregnancy
Mark A. Bechtel
Introduction
Pregnancy is associated with a variety of physiologic changes that can have a direct
impact on the skin. Metabolic, immunologic, and hormonal alterations during preg-
nancy can impact the appearance and morphology of the skin. These alterations can
affect skin pigmentation, cutaneous vasculature, existing cutaneous lesions, hair,
and nails. Although some changes can be concerning to the patient and health care
providers, most are benign and resolve or improve after delivery. A comprehensive
review of the physiologic changes of the skin during pregnancy is provided in this
chapter.
Pigmentary Changes
One of the most striking physiologic changes of the skin during pregnancy is the
impact on pigmentation. Approximately 90% of pregnant women manifest some
form of hyperpigmentation [1, 2]. Hyperpigmentation becomes more prominent
during the second half of pregnancy and is often in specific areas and patterns [1, 2].
The linea alba darkens to become the linea nigra, which extends from the xiphoid
process to the pubic symphysis [1, 3, 4] (Fig. 1.1). The linea nigra often fades or
resolves following delivery, and the cause is unknown. An accentuated darkening of
normally hyperpigmented regions of skin can occur during pregnancy as well. This
is most apparent in the axillae, genitalia, perineum, and inner thighs [1, 3].
Sometimes darkening of the skin around the areola produces what is termed a
M. A. Bechtel (*)
Department of Internal Medicine, Division of Dermatology, Ohio State University,
Columbus, OH, USA
secondary areola [2, 4]. Darkening of freckles and nevi has been reported during
pregnancy, but there may be insufficient evidence to support this observation [5].
Despite the controversy, biopsies should be obtained promptly from any changing
nevi during pregnancy that raise concern for malignancy [5].
Pigmentary demarcation lines can develop during pregnancy and present as
abrupt transitions from heavily pigmented skin to areas of lighter pigmentation [4].
The demarcation lines are known as Voigt or Futcher lines and present along the
posterior legs or upper arms [3]. Resolution after delivery is usually observed, and
no treatment is needed [4]. There is no clear etiology for the development of demar-
cation lines, but an association with peripheral nerves has been suggested [4].
Increased melanogenesis during pregnancy is complex and may be related to
increased levels of beta and alpha melanocyte stimulating hormone (MSH), estro-
gen, and progesterone [3]; however, increased pigmentation may occur early in
pregnancy before MSH levels become elevated [1]. Increased pigmentation may
also be impacted by increased density of epidermal melanocytes and upregulation
of tyrosinase by human placental lipids [1]. Recently, it has been shown that physi-
ologic estrogen (17-beta estradiol) and progesterone reciprocally regulate melanin
syntheses. Sex steroid effects on human pigment synthesis are mediated by
membrane-bound steroid hormone receptors [6], and estrogen effects are signifi-
cantly attenuated by the presence of progesterone. This may explain why pregnancy-
associated hyperpigmentation primarily occurs in areas with a higher baseline
melanocyte density or increased ultraviolet radiation exposure [6].
Melasma (chloasma or mask of pregnancy) is prominent facial hyperpigmenta-
tion that develops in up to 70% of pregnant patients [3, 7]. The hyperpigmentation
is often symmetric and poorly demarcated. Distribution of melasma may involve the
nose and cheeks (malar), the entire central face (centrofacial), or the ramus of the
mandible (mandibular) [1, 3, 7] (Fig. 1.2). The depth of melanin deposition varies,
which impacts its appearance under a Wood’s lamp. The melanin is deposited in the
epidermis in 70%, dermal melanophages in 10–15%, and both in 20% [7]. Women
1 Physiologic Skin Changes in Pregnancy 5
Fig. 1.2 Melasma.
Prominent poorly
demarcated facial
hyperpigmentation of
melasma develops in up to
70% of pregnant patients.
(Courtesy Benjamin
Kaffenberger, MD)
with darker skin are especially affected. Melasma usually improves postpartum, but
patients need to be advised that it may recur with subsequent pregnancies or possi-
bly flare with use of estrogen-containing oral contraceptives. Postpartum melasma
may persist in 30% of patients despite treatment [7].
High sun protective factor broad spectrum sunscreens with UVA protection may
lessen the severity of melasma. Other than sunscreen, most treatments for melasma
should be deferred until the postpartum period. Hydroquinone, one of the most
common treatments for melasma, has a transcutaneous absorption of 35–45% and
distributes rapidly and widely [8]. This raises concern for use during pregnancy and
lactation, so it is typically avoided. Tretinoin was a previous Federal Drug
Administration (FDA) pregnancy category C (Table 1.1) [9], and studies are con-
flicting on whether it is teratogenic during the first trimester of pregnancy [9]. The
safety data of topical retinoids such as tretinoin and adapalene are limited, and most
experts recommend avoiding these during pregnancy [8]. Due to lack of absorption
in significant quantities, tretinoin and adapalene are likely safe during lactation
[10]. With regard to elective cosmetic laser treatments for melasma, although there
are no adverse fetal complications reported, most health care practitioners choose
not to perform them during pregnancy [7].
6 M. A. Bechtel
Azelaic acid, another common topical treatment for melasma, is a former FDA
pregnancy category B (Table 1.1) drug. In a large double-blind study, azelaic acid
20% had good or excellent results in 65% of patients, similar results to hydroqui-
none [11]. Azelaic acid is therefore considered a safe, reasonable choice to treat
melasma during pregnancy and lactation.
All the above topical treatments are considered safe to treat melasma following
pregnancy and lactation. Additional topical treatments to consider for melasma
postpartum include triple combination creams (hydroquinone, tretinoin, topical ste-
roid) and kojic acid. Glycolic acid peels, laser, intense pulse light, and topical and
oral tranexamic acid are additional therapeutic considerations.
Fig. 1.3 Striae
gravidarum. Prominent
pink striae gravidarum
over the abdomen develop
during the second and third
trimester
fractional photothermolysis, pulse dye lasers, and intense pulse light have been
reported to be beneficial [15]. Recently, the non-ablative fractional laser has demon-
strated some efficacy for striae rubra and striae alba [16].
Molluscum fibrosum gravidarum or skin tags are frequent during the second and
third trimester [1]. They are 1–5 mm flesh colored papules, which are often pedun-
culated and occur on the neck, axillae, groin, and inframammary regions [7].
Lesions often regress postpartum and usually do not require treatment during preg-
nancy. If skin tags persist postpartum and are symptomatic, they can be treated by
cryotherapy or snip excision.
Fig. 1.4 Telogen
effluvium. Postpartum
shedding of hair from the
scalp, telogen effluvium
usually begins 1–5 months
after delivery
Fig. 1.5 Spider
angiomata. Common
during pregnancy, spider
angiomata manifest as
raised telangiectatic puncta
with radiating branches
Vascular Changes
Spider angiomata are one of the most common vascular changes of pregnancy. They
first appear during the second to fifth months of pregnancy as flat or slightly raised
telangiectatic red puncta with surrounding radiating branches [3] (Fig. 1.5). Spider
angiomata are noted in areas drained by the superior vena cava (face, neck, arms,
and hands) [20]. Approximately two-thirds of Caucasian women may develop spi-
der angiomata during pregnancy, but they are less common in black women [1, 3].
They tend to increase in number and size until delivery and then usually fade by
2 months postpartum [21]. Vascular lesions that persist more than several months
after delivery can be treated by fine needle cautery, pulsed dye laser, or intense
pulsed light [20].
Palmar erythema is a common vascular change during pregnancy and may be
early in onset [3]. Approximately two-thirds of Caucasian patients and one-third of
women of color develop palmar erythema [1, 3, 7]. The palmar erythema may pres-
ent as mottled erythema of the palms or mottling of the thenar or hypothenar emi-
nences and finger pads. Palmar erythema may be associated with a burning sensation
[22]. Within 1–2 weeks after delivery, the palmar erythema rapidly resolves [1, 3,
20]. Of note, palmar erythema may also be seen in association with cirrhosis and
lupus erythematosus [20].
Granuloma gravidarum or pyogenic granuloma of pregnancy is a benign prolif-
eration of capillaries during pregnancy which often presents on the gingiva [7].
They may present as asymptomatic erythematous fragile papules or nodules on the
gingival mucosa, but they may occur on the lip or non- mucosal sites [20] (Fig. 1.6).
The most common location is between the teeth or on the buccal or lingual surface
[7]. Plaque deposits or gingivitis may be contributing factors [20]. Because the
lesions typically undergo spontaneous shrinkage following delivery, they often
require only reassurance. Excessive bleeding, tenderness, or irritation may be an
indication for treatment. Electrosurgical desiccation, vascular lasers, or excision can
10 M. A. Bechtel
Fig. 1.6 Granuloma
gravidarum. Granuloma
gravidarum or pyogenic
granuloma of pregnancy
manifest as friable
erythematous vascular
papules or nodules
Glandular Activity
Conclusion
References
1. Geraghty LN, Pomeranz MK. Physiologic changes and dermatoses of pregnancy. Int J
Dermatol. 2011;50(7):771–82.
2. Motosko CC, Bieber AK, Pomeranz MK, et al. Physiologic changes in pregnancy: a review of
the literature. Int J Womens Dermatol. 2017;3(4):219–24.
3. Tyler KH. Physiologic skin changes during pregnancy. Clin Obstet Gynecol. 2015;58:119–24.
4. Bieber AK, Martires KJ, Stein JA, et al. Pigmentation and pregnancy: knowing what is normal.
Obstet Gynecol. 2017;129(1):168–73.
5. Bieber AK, Martires KJ, Driscoll MS, et al. Nevi and pregnancy. J Am Acad Dermatol.
2016;75(4):661–6.
6. Natale CA, Duperret EK, Zhang J, et al. Sex steroids regulate skin pigmentation through
nonclassical membrane-bound receptors. Elife. 2016;5:e15104. https://doi.org/10.7554/
eLife.15104.
12 M. A. Bechtel
7. Kroumpouzos G. Skin disease in pregnancy and puerperium. In: Gabbe SG, Niebyl JR,
Simpson JL, Landon MB, Galan HL, Jauniaux ER, Driscoll DA, editors. Obstetrics: normal
and problem pregnancies. 6th ed. Philadelphia: Elsevier/Saunders; 2012. p. 1084–97.
8. Murase JE, Heller MM, Butler DC. Safety of dermatologic medications in pregnancy and
lactation: part 1. Pregnancy. J Am Acad Dermatol. 2014;70(3):401.e1–14.
9. Tyler KH. Dermatologic therapy in pregnancy. Clin Obstet Gynecol. 2015;58:112–8.
10. Butler DC, Heller MM, Murase JE. Safety of dermatologic medications in pregnancy and
lactation: Part II. Lactation. J Am Acad Dermatol. 2014;70(3):417.e1–10.
11. Balina LM, Graupek K. The treatment of melasma: 20% azelaic acid versus 4% hydroquinone
cream. Int J Dermatol. 1991;30:893–5.
12. Korgavkar K, Wang F. Stretch marks during pregnancy: a review of topical prevention. Br J
Dermatol. 2014;172(3):606–15. https://doi.org/10.1111/bjd.13426.
13. Al-Himdani S, Vd-Din S, Gilmore S, et al. Striae distensae: a comprehensive review and
evidence-based evaluation of prophylaxis and treatment. Br J Dermatol. 2014;170(3):527–47.
14. Rangel O, Aries I, Garcia E, et al. Topical tretinoin 0.1% for pregnancy-related abdominal
striae: an open-label, multicenter, prospective study. Adv Ther. 2001;18(4):181–6.
15. Nabatian AS, Khorasani H. Striae. In: Lebwohl MF, Heymann WR, Berth-Jones J, Coulson I,
editors. Treatment of skin disease: comprehensive therapeutic strategies. 5th ed. Philadelphia:
Elsevier; 2018. p. 794–6.
16. Gokulp H. Long-term results of the treatment of pregnancy-induced striae distensae using a
1550-nm non-ablative fractional laser. J Cosmet Laser Ther. 2017;19(7):378–82.
17. Gizlenti S, Ekmekci JR. The changes in the hair cycle during gestation and the postpartum
period. J Eur Acad Dermatol Venereol. 2014;28:878–81.
18. Kar S, Krishnan A, Shivkumar PV. Pregnancy and skin. J Obstet Gynaecol India.
2012;62(3):268–75.
19. Erpolat S, Eser A, Kaygusuz I, et al. Nail alterations during pregnancy: a clinical study. Int J
Dermatol. 2016;55:1172–5.
20. Soutou B, Aractingi S. Skin disease in pregnancy. Best Pract Res Clin Obstet Gynaecol.
2015;29(5):732–40.
21. Wong RC, Ellis CN. Physiologic skin changes in pregnancy. J Am Acad Dermatol.
1984;10:929–40.
22. Henry F, Quatresooz P, Valverde-Lopez JC, et al. Blood vessel changes during pregnancy: a
review. Am J Clin Dermatol. 2006;7(1):65–9.
23. Osol G, Ko NL, Mandala M. Plasticity of the maternal vasculature during pregnancy. Annu
Rev Physiol. 2019;81:89–111.
24. Kepley JM, Mohiuddin SS. Physiology, maternal changes. Treasure Island: StatPearls; 2019;
https://www.ncbi.nlm.nih.gov/books/NBK539766/.
Chapter 2
Pregnancy Dermatoses
Synonyms
Definition
* Some classifications group these entities with polymorphic eruption of pregnancy (PEP) or as
separate dermatoses.
S. Shearer
Department of Dermatology, Duke University, Durham, NC, USA
e-mail: Sabrina.shearer@duke.edu
A. Blaszczak · J. Kaffenberger (*)
Division of Dermatology, Ohio State University, Gahanna, OH, USA
e-mail: Alecia.blaszczak@osumc.edu; Jessica.kaffenberger@osumc.edu
Epidemiology
Pathogenesis
Despite the prevalence of PEP, its etiology is poorly understood. Early literature
suggested that PEP may be the pre-bullous phase of pemphigoid gestationis (PG);
however, this theory has since been discredited [21]. Because PEP tends to arise in
primigravidas within striae distensae and has a predilection for multiple gestation
pregnancies, investigators have sought a correlation between maternal weight gain
and PEP. However, observational studies have yielded mixed results [5, 10, 13, 18,
19]. Mechanical stress from abdominal weight gain may damage connective tissue
in the striae, exposing an unidentified antigen in the skin and producing an immune-
mediated inflammatory response [21–23]. Increased numbers of antigen presenting
cells and Th lymphocytes have been identified in lesional tissue of patients with
PEP, supporting an antigenic trigger [24]. The predilection for first pregnancies may
be explained in part by an increased likelihood of striae in primigravid women and
the development of immune tolerance in subsequent pregnancies [2, 22].
Fetal deoxyribonucleic acid (DNA) may also act as an antigenic trigger.
Circulating fetal DNA increases in prevalence throughout pregnancy and is found in
>90% of expectant mothers by the late third trimester [25]. Increased vascular per-
meability in the gravid abdominal skin may lead to deposition of chimeric cells and
a subsequent immune response, in a manner paralleling graft-versus-host-disease
[25, 26]. This theory is supported by a skewed CD4:CD8 profile and deposition of
interferon-gamma and interleukin-2 in lesional skin [27].
Various hormonal fluctuations during pregnancy may also influence the develop-
ment of PEP. Suprabasal keratinocytes from lesional skin of patients with PEP have
increased expression of progesterone receptors when compared to nonlesional skin
and controls [28]. Multiple gestation pregnancies may result in even higher
2 Pregnancy Dermatoses 15
circulating levels of progesterone, amplifying the rates of PEP in these patients [22].
Although one early study showed reduced levels of serum cortisol in PEP patients,
these findings have not been replicated [16].
Intradermal eosinophils may play a pathologic role in the development of PEP
[29]. Increased rates of atopy have been reported in some studies [15, 18]. Whether
this represents overlap with atopic eruption of pregnancy or a true association
between PEP and atopy remains to be determined.
Clinical Presentation
PEP typically presents late in pregnancy, with 75–94% of patients presenting in the
third trimester [5, 9, 12–19, 27, 30] and 4–15% presenting in the immediate postpar-
tum period [5, 13, 16–18, 20]. Among women presenting after delivery, the vast
majority develop symptoms in the first 1–2 weeks postpartum [18]. Infrequently,
women may present in the earlier two trimesters. Earlier presentation is more com-
monly associated with multiple gestation pregnancies and atypical clinical pheno-
types [11, 15].
Classically, patients develop papules and wheals initially on the abdomen, aris-
ing within the striae distensae [1, 18, 31] (Fig. 2.1). Rapid centrifugal spread to the
remainder of the trunk, buttocks, and proximal extremities is common. Less fre-
quently, the eruption begins on the extensor surfaces of the limbs and rarely is iso-
lated to the extremities without involvement of the trunk [18, 19]. Involvement of
the umbilicus is rare, which can be helpful in differentiating PEP from PG [16, 17,
32]. Similarly, involvement of the face, palms and soles is uncommon in PEP [13,
15, 17, 18, 21, 32–34]. Mucosal involvement has not been reported.
Pathology
a b
Fig. 2.2 Low power magnification shows perivascular inflammatory infiltrate with minimal
changes in the epidermis (a, H&E 4×). The inflammatory infiltrate is mostly comprised of lympho-
cytes in a perivascular distribution with mild edema (b, H&E 20×). Eosinophils can be seen in
some cases (c, H&E 40×). (Courtesy of Dr. Rami Al-Rohil, MD)
(Ig)M and IgA may be observed perivascularly and along the dermoepidermal junc-
tion [12, 15–18, 20, 39]. Indirect immunofluorescence (IIF) is negative.
Differential Diagnosis
domain of BP-180 is a highly sensitive (96%) and specific (96%) diagnostic test for
PG and should be negative in PEP [42].
The primary morphology of the lesions in specific cases of PEP may guide the
differential diagnosis. Targetoid lesions must be distinguished from erythema mul-
tiforme, in particular EM driven by anogenital herpes simplex virus, which should
be treated prior to vaginal delivery to prevent transmission to the fetus. Wheals
should be differentiated from acute and chronic urticaria. Arthropod assault may
present as papular urticaria. Acute urticaria may rarely be caused by anaphylaxis,
which may be associated with maternal hypotension and shock and can have dire
implications for the mother and fetus. Chronic urticaria may be associated with
maternal hypothyroidism, which is imperative to treat intrapartum to prevent cogni-
tive deficits in the offspring. Chronic urticaria may also be a manifestation of under-
lying infection or malignancy; in fact, a case of an urticarial eruption mimicking
PEP in a patient with acute hepatitis B viral infection has been reported [43].
Eczematous lesions should be differentiated from atopic eruption of pregnancy.
Like PEP, autoimmune progesterone dermatitis may be polymorphic with urticarial,
papulovesicular, targetoid, or eczematous lesions, and a history of premenstrual
flares of dermatitis or positive intradermal skin testing to progesterone can distin-
guish it from PEP [44].
Treatment
Management of patients with PEP is based primarily on the extent of the eruption
and severity of symptoms. First line therapies include emollients, over-the-counter
antipruritics such as menthol and urea, and mid- to high-potency topical corticoste-
roids [1, 12, 13, 18, 19, 31]. Oral antihistamines may be used as an adjuvant therapy
for pruritis and insomnia [18, 19]. Occasionally, in severe cases, oral steroids may be
required. Low doses of oral prednisone may be used and tapered over several weeks
[12, 13, 36]. However, due to late pregnancy risks including premature delivery, pre-
mature rupture of membranes, and eclampsia, caution is advised, and the lowest
effective dose should be used [45]. Use during breastfeeding is permitted, but moth-
ers should be advised to attempt to time feedings 4 hours after the administration of
systemic steroids to minimize steroid concentrations in breast milk [46]. In the
absence of treatment, PEP will spontaneously resolve in the postpartum period [2].
Intramuscular injections of autologous whole blood have been proposed as an
alternative to traditional therapies in women who are medication averse, based on
reports of improvement in chronic urticaria and other dermatologic diseases [47,
48]. Of the few published cases where autologous whole blood injections were suc-
cessfully used, three were in patients who presented earlier in the course of preg-
nancy than expected (14–28 weeks gestational age) [47], raising the possibility of
an alternative diagnosis. One additional patient presented postpartum and experi-
enced resolution several days after treatment was initiated [48], but it is difficult to
2 Pregnancy Dermatoses 19
determine whether the improvement can be attributed to the autologous whole blood
injections, or whether this was the natural course of spontaneous resolution that is
expected in the postpartum period. Further studies are required.
In rare refractory cases, early delivery may be necessary to alleviate PEP [36, 49].
Synonyms
Definition
Epidemiology
AEP is the most common pregnancy dermatosis, accounting for up to 50% of cases
[17, 53, 54]. Prevalence ranges from 0.3% to 2% of all pregnancies [2, 55]. The vast
majority of patients with AEP have an underlying atopic diathesis; 20–40% of
women have a personal history of atopic dermatitis (AD), allergic rhinitis, or asthma
[16, 17, 54], and an additional 50% have a family history of atopy [16]. Of note, the
historic subclassifications pruritic folliculitis of pregnancy (PFP) and prurigo of
pregnancy (PP) may not share an atopic association [50, 52].
* Some classifications group these entities with polymorphic eruption of pregnancy (PEP) or as
separate dermatoses.
20 S. Shearer et al.
Pathogenesis
Clinical Presentation
a b
Fig. 2.3 Atopic eruption of pregnancy. E-type eczematous patches and plaques involving the
trunk (a) and flexural extremities (b) in a 31-year-old primigravid woman. P-type erythematous
papules clustered on the abdomen (c) in a 26-year-old primigravid woman. ((a, b) Reprinted with
permission, Ambros-Rudolph et al. [17]. (c) Reprinted with permission, Roth [186])
of P-type AEP, excoriations are typical, and secondary crusting is common. Scarring
secondary to manipulation of the lesions and resolution with post-inflammatory
hyperpigmentation may occur [51].
Laboratory evaluation is largely unremarkable, with the exception of elevations
in serum IgE in some patients [16, 17].
Although one early case series describing a widespread papular eruption of preg-
nancy reported poor fetal outcomes [60], similar data has not been reproduced, and
the justifications driving the authors’ conclusions have been questioned [2]. In gen-
eral, all subtypes of AEP are thought to have a benign course for both the mother
and child [16, 61, 62]. Although one study found a statistically significant associa-
tion between maternal AD and premature rupture of the membranes, the absolute
risk remained low, and there was no significant increased risk of fetal prematurity or
stillbirth [58].
AEP tends to resolve 2–3 months after delivery, regardless of treatment [51].
However, as up to 40% of women have a personal history of atopic dermatitis, some
patients will have flares of their pre-existing disease postpartum. Recurrence in
future pregnancies is common [17, 50, 51, 53], possibly owing to the underlying
atopic diathesis in many patients.
22 S. Shearer et al.
Pathology
The histopathology of AEP is nonspecific and variable [17, 63]. Specimens typi-
cally demonstrate epidermal acanthosis, hyperkeratosis, parakeratosis, and spongi-
osis. A mild to moderate perivascular lymphohistiocytic infiltrate admixed with
eosinophils may be present. Less commonly, there is dermal edema and lympho-
cytic vasculitis. In cases of PFP, a sterile folliculitis may be observed. Direct and
indirect immunofluorescence are characteristically negative [2, 17].
Differential Diagnosis
Treatment
Synonyms
Definition
Epidemiology
Pathogenesis
Hormonal Estrogen has been linked with ICP. In rat models, administration of
estrogen will promote cholestasis through the impaired function of genes known to
be related to the development of disease, including ABCB11 and ABCC2 [91, 92].
Estrogen has also been linked with cholestasis in women taking estrogen-contain-
ing contraceptives or hormone replacements [93]. Additionally, ICP typically pres-
ents at the end of pregnancy when estrogen levels are highest, and it is more
common in multiple gestation pregnancies, which have higher levels of estrogen
[78]. In addition to estrogen, progesterone has also been linked to ICP. Women
treated early in their pregnancy with progesterone have an increased risk for ICP
[94]. Furthermore, elevated levels of progesterone metabolites have been identified
2 Pregnancy Dermatoses 25
in the serum of affected females [95, 96]. The addition of these progesterone
metabolites to in vitro experiments inhibited the bile salt export pump encoded by
the gene ABCB11, which was previously found to carry mutations in patients with
the disease [97].
Clinical Presentation
ICP typically presents during the third trimester and has spontaneous resolution 1–2
weeks following delivery [99]. Unlike other dermatoses of pregnancy, intrahepatic
cholestasis of pregnancy has no classic primary lesions. Severe pruritus occurs on
the palms and soles, which then often generalizes to affect the entire body, espe-
cially the extremities, buttocks, and abdomen. Diffuse excoriations are seen on
exam. Most patients experience worsening of pruritus at night, which may lead to
insomnia [100]. Patients may also experience symptoms of cholestasis including
jaundice, (often noticed 1–4 weeks following the onset of pruritus), anorexia,
fatigue, dark urine and steatorrhea [101]. Symptoms resolve 1–2 weeks after
delivery.
Diagnosis is confirmed by elevated levels of serum bile acids (>10 μmol/l in a
pregnant woman). Liver function tests are also usually elevated. Rarely, the onset of
pruritus can occur before biochemical changes [102].
Fetal morbidity can be significant with ICP, as damaging bile acids cross the
placenta. Preterm delivery [103], spontaneous abortion [104], fetal distress [105]
and meconium staining of amniotic fluid [103] have been associated with ICP. The
high bile acids can affect cardiomyocytes causing fetal arrhythmias and can impose
a vasoconstrictive effect on the placental chorionic veins leading to fetal distress,
asphyxia, and fetal death [106, 107]. Additionally, the bile acids may affect the
oxytocin receptors which may contribute to preterm labor [108].
The severity of complications correlates with the level of bile acids, with the
most severe complications seen with the highest levels of bile acids [109]. Potential
long-term sequelae for children born from mothers affected by ICP include increased
fasting insulin levels, lower HDL, and higher BMIs [110].
Mothers affected by ICP were found to have a higher incidence of hepatitis C,
nonalcoholic cirrhosis, gallstones and cholecystitis post-partum [111], although a
direct cause and effect is difficult to discern.
26 S. Shearer et al.
Pathology
Histopathology of the skin reveals changes resulting from pruritus and exocoriation.
Liver histopathology reveals acinar cholestasis with bile back-up into the canaliculi
and hepatocytes. The bile ducts are relatively preserved, and there is limited inflam-
mation apparent within the liver microstructure [112].
Differential Diagnosis
Treatment
Mothers must also be counseled that ICP can recur in up to 60–70% of future
pregnancies. Additionally, medications containing high doses of estrogen, such as
certain oral contraceptives, should be avoided to prevent disease flares.
Pemphigoid Gestationis
Synonyms
Definition
Epidemiology
Pathogenesis
tissues is thought to lead to the loss of immunotolerance of the placenta and fetus
allowing for the uptake and processing of placental proteins including Bullous
Pemphigoid (BP)180 [138]. BP180 is a hemidesmosomal protein [139] found in the
amniotic epithelium and umbilical cord of the fetus as well as the skin of the mother
[140, 141]. This loss of maternal-fetal immunotolerance allows for the development
of autoantibodies against the NC16A domain of BP 180 [42, 142]. Although ini-
tially thought to belong to the IgG1 and IgG3 subclass of antibodies [146, 149], it is
now believed that the predominant subclass is IgG4 [150], which is the subclass that
crosses the placenta. This binding, in turn, activates the classical complement path-
way resulting in immune cell infiltration [143]. Over 90% of PG patients also carry
a C4 null allele causing a faulty complement system that impairs immune complex
removal [144]. This immune cell activation and infiltration, especially of eosino-
phils [145], is thought to be the primary contributor to the disruption of the dermal-
epidermal junction causing blister formation [146–148].
In addition to antibody production, alterations in female hormone levels during
pregnancy likely contribute to the disease course. Estrogen is known to rise through-
out pregnancy and increases the production of antibodies, the key mediators of pem-
phigoid gestationis. Conversely, progesterone, which decreases antibody production,
peaks right before delivery and rapidly decreases postpartum, which may help
explain flares of PG shortly after delivery [149, 150]. Changes in hormone levels are
also implicated in disease flares during menstruation and oral contraceptive use
[126, 131].
Clinical Presentation
Pemphigoid gestationis classically occurs during the second or third trimester. It usu-
ally begins with intense pruritus followed by the development of urticarial papules
and plaques. In 90% of patients, the papules and plaques are initially located in the
periumbilical area [131, 151, 152], but with time they will spread centrifugally to
involve other cutaneous surfaces of the abdomen and the extremities, including the
palms and soles (Fig. 2.4). Mucous membranes and the face are usually spared. The
urticarial plaques can further progress to vesicles and tense vesicles or bullae in some
patients [126, 153, 154]. Patients may experience a decrease in symptoms a few
weeks before delivery, followed by a flare shortly after delivery. Following delivery,
the urticarial plaques and vesicles or bullae will slowly subside with the majority of
patients being symptom-free by 6 months [131]. There have been a few reports of
subsequent development of bullous pemphigoid; however, this is uncommon [155].
Clinical findings in the fetus may be present upon delivery because of the trans-
mission of autoantibodies across the placenta. Neonates have skin lesions approxi-
mately 5–10% of the time. Fortunately, skin findings in the neonate are usually mild
urticarial papules and plaques and spontaneously resolve within days to weeks after
delivery [156, 157]. PG is also associated with prematurity and small for gestational
age infants, and these risks correlate with disease severity [158, 159].
2 Pregnancy Dermatoses 29
The risk of recurrence in future pregnancies is high and ranges from 33% to
50%. In multiparous women with a history of pemphigoid gestationis, recurrence
has been associated with more severe disease and earlier onset during subsequent
gestations [151]. Skip pregnancies may also be seen and occur in about 8% of
patients [131], perhaps because of the full compatibility of fetus and mother during
unaffected gestations.
Females with a history of pemphigoid gestationis have an increased risk for the
development of Grave’s disease when compared to the normal population [131],
and family members of patients with pemphigoid gestationis have an increased risk
of other autoimmune diseases [160]. This relationship to other autoimmune dis-
eases is likely secondary to the presence of HLA-DR3 and HLA-DR4, which are
involved in the development of autoimmunity.
Pathology
as they correlate with disease severity [42, 162, 163]. The sensitivity and specificity
of these tests are greater than 95% [42, 142, 147] and therefore, in the presence of
classic skin findings, ELISA for BP180 may allow for a diagnosis without
histopathology.
Differential Diagnosis
Treatment
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2 Pregnancy Dermatoses 39
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186. Roth MM. Atopic eruption of pregnancy: a new disease concept. J Eur Acad Dermatol
Venereol. 2009;23(12):1466–7.
Part II
Pre-Existing Skin Disease in Pregnancy
Chapter 3
Psoriasis
Daisy Danielle Yan and Lisa Pappas-Taffer
Epidemiology
Introduction
half of patients, with approximately 25% of patients remaining stable. Only roughly
25% of the pregnant patients had worsened psoriasis. Among those who improved,
there was a significant improvement, with an 83.8% reduction in psoriasis lesions
from week 10 to 30 [3]. However, post-partum flares are not uncommon (occurring
in 40–90% of patients), and 30–40% of women note the onset of psoriatic arthritis
in either the post-partum or peri-menopausal period [4]. One theory for this waning
and waxing course during pregnancy is the hormone-driven modulation of the
immune system. It has been hypothesized that progesterone can directly affect kera-
tinocytes, which possess estrogen and progesterone receptors [5]. There is also a
shift from Type 1 T helper cell (TH1) to Type 2 T helper cell (TH2) immunity to
prevent fetal rejection during pregnancy, which is thought to explain improvement
in autoimmune TH1-mediated diseases, such as psoriasis.
Pustular psoriasis of pregnancy (PPP) is a subset of generalized pustular pso-
riasis that occurs during the third trimester of pregnancy. PPP was originally
called impetigo herpetiformis (IH), but IH is a misnomer, as PPP is not caused by
bacterial or viral infections. PPP is characterized by coalescent pustules, even-
tual desquamation, and systemic symptoms such as fever, delirium, and diarrhea.
Mother and fetus are at risk of electrolyte imbalances and secondary sepsis in
severe cases. PPP generally resolves upon parturition but can recur in subsequent
pregnancies.
There is a paucity of rigorous data about the impact of psoriasis on pregnancy out-
comes. A systemic review of 9 observational studies reported spontaneous abor-
tion, caesarean delivery, low birth weight, macrosomia, large-for-gestational age,
or prematurity/low birthweight as adverse pregnancy outcomes. However, there
was no consistent relationship across studies linking psoriasis and adverse preg-
nancy outcomes [6]. One reason for this could be a failure to stratify psoriasis by
severity. In patients with mild to moderate psoriasis, 3 prospective cohort studies
found no increased risk for adverse birth outcomes, spontaneous abortions, or fetal
death [7–9]. In patients with moderate to severe psoriasis, there was an increased
risk for low birth weight and spontaneous abortions [7, 10, 11]. Most recently, a
cross-sectional population-based cohort study was performed in which data was
collected prospectively from Denmark and Sweden [12]. 8097 births were identi-
fied in 6103 women with psoriasis and 753 with psoriatic arthritis. An increased
incidence of gestational diabetes, gestational hypertension, eclampsia, and elective
and emergent cesarean section was noted in patients with severe psoriatic disease.
Hence, more severe disease burden appears to correlate with poorer pregnancy
outcomes. For PPP, close monitoring and early treatment is paramount, as placen-
tal insufficiency, intrauterine growth restriction, and fetal demise have been
observed [13].
3 Psoriasis 45
Treatment
For patients with mild to moderate psoriasis who are planning pregnancy or who
become pregnant, the author (LPT) provides patients reassurance that 75% of
patients will have stable to improved disease and that no or scaled back therapy
could be an option. However, for patients with severe disease, the risk of NOT treat-
ing the psoriasis (i.e. poor pregnancy outcomes) may outweigh those of medica-
tions, and often continuation of therapy is advised.
Treatment of psoriasis during pregnancy should be tailored to minimize adverse
effects on both the mother and fetus. Consensus guidelines are helpful but not abso-
lute given the rapid explosion of new medications to treat moderate to severe psoria-
sis in the last 10 years. However, an agreed upon therapeutic ladder includes starting
with topical agents, then phototherapy, then systemic agents.
First line treatment includes emollients and low-to-moderate potency topical ste-
roids [14]. Although topical steroids were previously categorized as Federal Drug
Administration (FDA) pregnancy category C (Table 1.1), large studies have demon-
strated safety with no evidence of increased risk for congenital abnormalities or
pregnancy loss. Extensive use of high potency topical steroids should be avoided,
however, given a possible association with low birth weight with excessive absorp-
tion [15]. Topical therapy is an effective strategy for treating limited disease, typi-
cally 5–10% BSA or less (Fig. 3.1).
Fig. 3.1 Topical steroids are insufficient for widespread psoriasis (greater than 5–10% BSA).
(Photo used with permission of Dr. Joel Gelfand, University of Pennsylvania)
46 D. D. Yan and L. Pappas-Taffer
recommends postponing live vaccines (e.g. rotavirus) until infants are ≥6 months of
age. Non-live vaccinations are still effective and should be delivered without delays.
Regarding lactation, monoclonal antibodies used in biologic therapies have poor
oral bioavailability due to their large molecular size. Therefore, gastrointestinal
absorption is theoretically limited. In several studies, infliximab was undetectable in
the breastmilk of nursing mothers or sera of their newborn children [21]. Hence,
there is no contraindication to nursing while on an anti-TNF agent.
Due to PPP’s potential for life-threatening complications, first line treatment is
prompt initiation of systemic corticosteroids or cyclosporine [22]. For mild cases of
PPP, adequate control can be achieved at corticosteroid dosages of <30 mg/day. For
more severe cases, corticosteroid dosage can be increased to up to 60–80 mg/day.
For PPP, cyclosporine dosage is 2–3 mg/kg body weight/day. Phototherapy, specifi-
cally nbUVB, can be helpful, but acts more often as an adjunctive therapy. Fetal
monitoring and maternal electrolyte, calcium, vitamin D, and albumin levels should
be followed closely.
Other Biologics
A new influx of biologics has joined the traditional arsenal of psoriasis treatments.
These include anti-IL 12/23 agents (ustekinumab), anti-IL-17a agents
(secukinumab, ixekizumab, brodalumab), and anti-IL-23 agents (guselkumab, til-
drakizumab). All anti-TNFs, ustekinumab, and secukinumab were labelled as
FDA pregnancy cateogory B. The remaining newer agents came to market follow-
ing the discontinuation of FDA pregnancy categories. Based on preliminary data,
there are no concerns for congenital malformations, and these newer biologics are
thought to be safe in pregnancy based on animal studies and reports of pregnancy
in patients already being treated with these agents. However, given the small num-
ber of reports, treatment during pregnancy should be considered on a case by case
basis. In contrast, apremilast, the oral PDE-4 inhibitor, carries a previous FDA
pregnancy category C due to an increased risk of miscarriage based on animal
studies [23].
–– Consensus: biologics appear safe, but there are ways to maximize safety
–– Pre-pregnancy planning includes consideration of disease severity, timing of
drug initiation and timing of drug termination
–– Many recommend stopping once pregnancy confirmed
–– Most recommend stopping by or at 30 weeks gestational age
–– Consider agent: Certolizumab or Etanercept preferable
48 D. D. Yan and L. Pappas-Taffer
Therapeutics to Avoid
Psoriasis Summary
underscores the necessity of broaching this topic [27]. Only half of the dermatolo-
gists were aware that the highest risk period of pregnancy was the first trimester,
one-third were up to date on current treatment guidelines, and only 7.89% reported
making a joint treatment decision with a patient’s obstetrician. Reproductive goals
should be an ongoing discussion, and discussion of the risks and benefits of treat-
ment as well as risks of non-treatment is critical. Communication with a patient’s
obstetrician is also paramount.
Generally, skin directed therapy is typically preferred. If initiating anti-TNF
therapy for psoriasis, consider etanercept or certolizumab. Based on severity, con-
tinuation of a patient’s current biologic is an option. Overall, published guidelines
for treatment of psoriasis in pregnancy are useful but not absolute.
References
17. Colla L, Diena D, Rossetti M, Manzione AM, Marozio L, Benedetto C, et al. Immunosuppression
in pregnant women with renal disease: review of the latest evidence in the biologics era. J
Nephrol. 2018;31(3):361–83.
18. Pottinger E, Woolf RT, Exton LS, Burden AD, Nelson-Piercy C, Smith CH. Exposure to
biological therapies during conception and pregnancy: a systematic review. Br J Dermatol.
2018;178(1):95–102.
19. Julsgaard M, Christensen LA, Gibson PR, Gearry RB, Fallingborg J, Hvas CL, et al.
Concentrations of adalimumab and infliximab in mothers and newborns, and effects on infec-
tion. Gastroenterology. 2016;151(1):110–9.
20. Cheent K, Nolan J, Shariq S, Kiho L, Pal A, Arnold J. Case report: fatal case of disseminated
BCG infection in an infant born to a mother taking infliximab for Crohn’s disease. J Crohn’s
Colitis. 2010;4(5):603–5.
21. Lund T, Thomsen SF. Use of TNF-inhibitors and ustekinumab for psoriasis during pregnancy:
a patient series. Dermatol Ther. 2017;30(3):e12454.
22. Trivedi MK, Vaughn AR, Murase JE. Pustular psoriasis of pregnancy: current perspectives. Int
J Women’s Health. 2018;10:109.
23. Otezla (Apremilast) [package insert]. Summit: Celgene Pharmaceutical Companies; 2017.
24. Puig L, Barco D, Alomar A. Treatment of psoriasis with anti-TNF drugs during pregnancy:
case report and review of the literature. Dermatology. 2010;220(1):71–6.
25. Mahadevan U, Wolf DC, Dubinsky M, Cortot A, Lee SD, Siegel CA, et al. Placental transfer of
anti–tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin
Gastroenterol Hepatol. 2013;11(3):286–92.
26. Murase JE, Heller MM, Butler DC. Safety of dermatologic medications in pregnancy and
lactation: part I. Pregnancy. J Am Acad Dermatol. 2014;70(3):401.e1–e14.
27. Maccari F, Fougerousse AC, Esteve E, Frumholtz L, Parier J, Hurabielle C, et al. Crossed
looks on the dermatologist’s position and the patient’s preoccupations as to psoriasis and
pregnancy: preliminary results of the PREGNAN-PSO study. J Eur Acad Dermatol Venereol.
2019;33(5):880–5.
Chapter 4
Autoimmune Connective Tissue Diseases
Daisy Danielle Yan and Lisa Pappas-Taffer
Introduction
Lupus Erythematosus
Epidemiology
Introduction
only occurs in the setting of systemic lupus erythematosus (SLE) flares. In contrast
to ACLE, all other CLE subtypes can occur in the setting of SLE or as isolated skin
disease in the absence of SLE. Various studies have reported that approximately
20% to 25% of newly diagnosed CLE patients will eventually progress to SLE [3].
Hence, 75–80% of CLE patients will never develop SLE but should be routinely
screened. In general, CLE is equally as prevalent as SLE, with incidence rates rang-
ing from 1.43 to 4.30 per 100,000 [4, 5]. Females are disproportionately affected by
lupus, with a ratio of 6:1 for SLE and 3:1 for CLE when compared to men. The age
of onset is primarily during the reproductive years, which makes treatment more
salient. Fortunately, lupus in pregnancy is well-studied with regard to SLE, and we
can extrapolate much of what we know about SLE for CLE.
Compared to a healthy population, SLE patients are at higher risk for preeclampsia,
thrombosis, preterm delivery, fetal growth restriction, and fetal loss [12, 13]. In one
study which aimed to identify risk factors for adverse pregnancy outcomes in SLE,
385 multi-ethnic and multi-racial pregnant females with inactive or stable mild to
moderate SLE were followed prospectively during pregnancy in 8 clinical centers
across the US and Canada [14]. It showed that <5% had severe flares in the second
or third trimesters, and the probability of a negative pregnancy outcome was <8%
4 Autoimmune Connective Tissue Diseases 53
for women without risk factors during the first trimester. Risk factors for adverse
pregnancy outcomes included baseline hypertension, positive lupus anti-coagulant,
active SLE, flares in the second or third trimester, and non-white ethnic origin.
Women of non-white origin had more than double the risk of developing one or
more adverse pregnancy outcomes; women of African (N = 78) and Hispanic
(N = 58) descent had poor fetal outcomes in 27.4% and 20.6% of their pregnancies,
respectively. Serologic data such as complements and anti-dsDNA did not correlate
with poor outcomes. This study was quite reassuring in that it showed that inactive
or stable mild to moderate SLE patients only rarely experience severe disease flares
and overall have favorable pregnancy outcomes. It is unclear why women of non-
white origin had a higher risk for adverse pregnancy outcomes, so this topic war-
rants further research.
Although SLE in pregnancy has been well studied, there are fewer studies evalu-
ating pregnancy outcomes for those with isolated cutaneous disease. There are cur-
rently only two studies in the literature addressing cutaneous lupus erythematosus
(CLE) and pregnancy outcomes. Both demonstrated that pregnancy outcomes in
CLE were more favorable than SLE. The first study, a 2 center prospective cohort
comparative study of CLE (n = 67), SLE (n = 67), and controls (n = 67), found simi-
lar pregnancy outcomes in CLE patients when compared to healthy controls [15]. In
the second study, SLE patients who only had mucocutaneous involvement, such as
malar rash, oral/nasal ulcers, and photosensitivity, had similar pregnancy outcomes
to healthy controls [12].
Treatment
Treatment of CLE
Counselling and ongoing discussion of reproductive goals is crucial with all CLE
patients of childbearing age. Understanding their goals can help in choosing appro-
priate treatment modalities and ensuring optimal disease control for at least 6 months
prior to conception. While SLE patients should be classified as high risk obstetric
patients, CLE patients with no systemic involvement should not [16]. The status of
anti-SSA/SSB and antiphospholipid antibodies should be established given risk for
neonatal lupus and increased risk for maternal and fetal morbidity, respectively.
The first line of treatment for CLE is photoprotection and skin-directed therapy
[1]. Low to medium potency topical steroids and calcineurin inhibitors are recom-
mended, while potent topical and intralesional steroids should be used sparingly.
Calcineurin inhibitors have less absorption than topical steroids. Second line treat-
ment is hydroxychloroquine (HCQ), which has been shown to reduce the risk of
neonatal lupus, prematurity, and intrauterine growth restriction (IUGR) in
SLE. HCQ is continued pre-pregnancy when topical therapy is insufficient, sys-
temic manifestations are present, or the patient has a history of positive a nti-SSA/
SSB antibodies [17, 18]. Of note, there are no reports of fetal ocular toxicity with
54 D. D. Yan and L. Pappas-Taffer
intrauterine HCQ exposure [19]. The third line treatment is azathioprine, which is
added if HCQ is insufficient. Azathioprine can be continued if started pre-pregnancy,
and it is the agent of choice if switching from contraindicated oral agents. Classically,
azathioprine was previously labeled Federal Drug Administration (FDA) pregnancy
category D (Table 1.1), but data from the transplant population is reassuring [20].
There is no evidence of congenital malformations, spontaneous abortions, or still-
births, but the reported case numbers may not be sufficient. Recently, azathioprine
exposure was suggested to impose a slightly increased risk of atrial or ventricular
septal defects in the fetus [21]. Fourth line treatment is intravenous immunoglobu-
lin (IVIG).
Therapies to avoid in pregnancy include chloroquine, methotrexate, mycopheno-
late mofetil, cyclophosphamide, and acitretin [2]. Chloroquine has a higher placen-
tal drug concentration than HCQ, although a Cochrane meta-analysis supports
chloroquine safety in the setting of malaria prophylaxis at lower doses [22].
Methotrexate is an abortifacient, has teratogenic properties, and is a previous FDA
pregnancy category X. Methotrexate needs to be discontinued 3 months prior to
conception. Mycophenolate mofetil is a previous FDA pregnancy category D drug
that is teratogenic, and it needs to be discontinued 6 weeks before conception.
Cyclophosphamide is former FDA pregnancy category D and can cause miscar-
riages [23]. Acitretin, previously FDA pregnancy category X, needs to be discontin-
ued 3 years prior to conception.
Dermatomyositis
Epidemiology
Introduction
Fig. 4.2 Gottron’s
papules, characterized by
erythema along the bony
prominences, are a
pathognomonic sign of
dermatomyositis. Photo
used with permission of
Dr. Victoria Werth,
University of Pennsylvania
Adverse pregnancy outcomes in DM include IUGR, prematurity, and fetal loss, but
there is minimal risk to the fetus if DM is well-controlled pre-conception. Worsened
fetal prognosis is associated with severe maternal disease, flares during pregnancy,
and first onset of disease during pregnancy [26, 29, 30].
56 D. D. Yan and L. Pappas-Taffer
Treatment
Therapies for DM during pregnancy are similar to CLE, but muscle and lung
involvement must be taken into account [1]. Photoprotection is recommended
regardless of disease severity. For mild skin-limited disease, low to medium potency
topical steroids and/or topical calcineurin inhibitors are first line. For recalcitrant
skin disease, HCQ can be added. For muscle and/or lung involvement or skin
involvement refractory to HCQ, either oral corticosteroids or IVIG can be added
[31, 32]. Oral steroids must be dosed at the lowest effective dose for rapid control,
and azathioprine can be added to keep the maintenance steroid dose at less than
20 mg of prednisone per day. IVIG is dosed at 1 to 2 grams per kilogram (g/kg)
divided over 2 to 5 consecutive days monthly. If the treating physician anticipates
that a patient’s DM might require an extended course of corticosteroids, IVIG would
be the preferred agent.
Summary
References
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tion with systemic lupus erythematosus: a nationwide population-based cohort study in Korea.
J Dermatol. 2019.
5. Petersen MP, Möller S, Bygum A, Voss A, Bliddal M. Epidemiology of cutaneous lupus ery-
thematosus and the associated risk of systemic lupus erythematosus: a nationwide cohort study
in Denmark. Lupus. 2018;27(9):1424–30.
6. Chen JS, Roberts CL, Simpson JM, March LM. Pregnancy outcomes in women with rare
autoimmune diseases. Arthrit Rheumatol. 2015;67(12):3314–23.
7. Ruiz-Irastorza G, Khamashta MA, Castellino G, Hughes GR. Systemic lupus erythematosus.
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ated with similar disease manifestations during pregnancy. Lupus. 2015;24(12):1283–92.
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maternal and fetal complications in SLE patients: a prospective study. Immunol Res.
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Arthritis Care Res. 2005;53(1):119–21.
Chapter 5
Atopic Dermatitis in Pregnancy
Blake Friedman and Lionel Bercovitch
Epidemiology
Atopic dermatitis is the most common skin condition in pregnancy, accounting for
approximately 50% of all pregnant patients presenting with skin concerns [1, 2].
Approximately 27% of those diagnosed with atopic dermatitis of pregnancy carry a
personal history of atopy or infantile atopic dermatitis, 50% report a family history
of atopy, and 19% have children diagnosed with infantile atopic dermatitis [2].
However, recent studies suggest that up to 80% of those diagnosed with atopic der-
matitis during pregnancy represent new diagnoses, with atopic dermatitis presenting
for the first time in pregnancy [1, 2]. Of those who carry an existing diagnosis of
atopic dermatitis, studies suggest disease exacerbations will occur in 52% to 61% of
patients [3, 4]. The majority of these patients demonstrate deterioration in the sec-
ond or third trimesters [5]. It should be noted that a small subset of patients with
pre-existing atopic dermatitis demonstrate improvement of atopic dermatitis during
pregnancy, with a recent small study reporting improvement in 4% of patients [3].
B. Friedman
Department of Dermatology, Warren Alpert Medical School of Brown University,
Providence, RI, USA
e-mail: blake_friedman@brown.edu
L. Bercovitch (*)
Department of Dermatology, Warren Alpert Medical School of Brown University,
Providence, RI, USA
Division of Pediatric Dermatology, Hasbro Children’s Hospital, Providence, RI, USA
Department of Medicine, Women and Infannts Hospital, Providence, RI, USA
e-mail: lionel_berccovitch@brown.edu
Clinical Presentation
Diagnosis
Pathogenesis
subset, including Interleukin (IL)4, IL10, and IL13, are important for allograft toler-
ance, allowing for pregnancy maintenance and inhibiting a potentially deleterious
Th1 response [11]. Thus, a switch from cell-mediated to humoral-mediated mecha-
nism (Th1 to Th2 shift) during gestation plays a key role in placental immune toler-
ance [6]. As a result of this important immunologic shift in pregnancy, skin diseases
that are that are Th2-mediated often worsen, whereas skin diseases that are Th1-
mediated often improve during gestation [6]. It is widely accepted that atopic der-
matitis is a Th2 dominant disease. Therefore, the shift towards a Th2 cytokine
predominant state is thought to, at least in part, explain the increased severity and
incidence of atopic dermatitis during pregnancy [6]. It should be noted that the
immune response underlying atopic dermatitis is complicated, with Th1, Th17 and
Th22 cells as well as numerous additional cytokines (i.e. IL25, IL31, and IL33) also
implicated [12]. It is unclear if alterations in expression of these cytokines play a
role in the worsening of atopic dermatitis during pregnancy [13].
In addition to immunologic changes, the pregnant mother is also exposed to
emotional and physiologic stressors that may exacerbate pre-existing atopic derma-
titis [14]. Atopic dermatitis is a complex condition with a known psychologic com-
ponent, with stress and sleep deprivation contributing to (as well as being caused
by) disease exacerbations [13]. Therefore, the stress and sleep pattern disruption
associated with pregnancy may in part account of the worsening of atopic dermatitis
in pregnancy.
The tendency to minimize medical interventions in pregnant patients may also
play a role in the worsening of atopic dermatitis in pregnancy. While formal data on
treatment patterns in pregnancy are lacking, providers and patients often reduce
both topical and systemic interventions in pregnancy to minimize presumed risk to
the fetus [13]. A recent Danish study demonstrated decreased use of both topical
and systemic dermatologic interventions for atopic dermatitis during pregnancy as
compared to prior to pregnancy. Of note, the reason for this reduction in interven-
tions could not be elucidated from the collected data; thus, it is possible that the
minimization of interventions could have been secondary to improvement or resolu-
tion of atopic dermatitis. However, within the studied cohort, there was increased
use of prednisolone during pregnancy, which, the authors concluded, could indicate
undertreatment of atopic dermatitis leading to need for rescue therapy with systemic
treatments [15].
Importance
Given concern that treatment of atopic dermatitis could adversely affect the unborn
fetus, it is not only important to closely evaluate the safety profile of available inter-
ventions but also consider the benefits of medical interventions to the mother and
fetus. In addition to the clear improvement in comfort for the pregnant patient, treat-
ment of atopic dermatitis in pregnancy may prevent deleterious outcomes for both
the mother and fetus. Untreated atopic dermatitis puts the pregnant patient at risk of
62 B. Friedman and L. Bercovitch
Treatment
Basic
In all patients with atopic disease, including pregnant individuals, routine manage-
ment with emollients and use of mild cleansers is encouraged [22]. There is no
evidence in the literature to support the use of any one emollient type; however, use
of an emollient with high lipid content is recommended [13]. All emollients, includ-
ing those containing urea (3–10%) and antipruritic agents (i.e. menthol and polido-
canol), are deemed safe in pregnancy [23]. Patients should be instructed to proceed
with lukewarm baths for hydration coupled with subsequent application of an occlu-
sive emollient after patting the skin dry, which may decrease the necessity for addi-
tional treatments [24, 25]. Adequate cutaneous hydration facilitates transepidermal
penetration of topical corticosteroids should additional therapies be required [5].
5 Atopic Dermatitis in Pregnancy 63
Topical Corticosteroids
Topical corticosteroids represent first line therapy for atopic dermatitis and are con-
sidered safe to use in pregnancy. They are categorized as a previous category C drug
by the Food and Drug Administration (FDA) (Table 1.1) and considered safer than
systemic corticosteroids given the low systemic absorption relative to systemic ste-
roids [5]. While an earlier study demonstrated a significant association between
topical corticosteroid use in pregnancy and orofacial clefting in infants born to
exposed mothers, multiple large case-control studies failed to demonstrate any
increased risk of this birth defect [26–28]. Additionally, studies examining the risk
of preterm delivery failed to demonstrate increased risk in infants born to mothers
with prenatal topical corticosteroid exposure; notably, these studies did note an
inverse dose-dependent relationship between topical corticosteroids use and birth
weight [29, 30]. A recent Cochrane review on the safety of topical corticosteroids in
pregnancy noted a non-significant association between potent or very potent topical
corticosteroid use and fetal low birth weight, but the studies evaluated were noted to
be low-quality evidence [31]. Evidence-based guidelines for topical steroid use dur-
ing pregnancy recommend use of low to medium potency topical steroids if effec-
tive, with high potency topical steroids used only for brief time periods. Of note,
fluticasone propionate should be avoided in the pregnant patient, as it is the only
topical corticosteroid of record not metabolized by the placenta [32]. Further, guide-
lines recommend against use of corticosteroids on areas with thinner skin and, con-
sequently, greater rates of cutaneous absorption [32]. Should use of topical
corticosteroids exceed 200 grams per month, additional treatments, such as photo-
therapy, should be considered [13]. Topical corticosteroids are generally considered
safe in the breastfeeding mother. However, cleaning of the nipples immediately
prior to breastfeeding is recommended [13].
Phototherapy
When atopic dermatitis is not responsive to emollients and topical low dose topical
corticosteroids, providers should consider referral for phototherapy, with best
results obtained using UVA (340–400 nm), broadband UV (UVA & UVB
290–400 nm), or narrow-band UVB (311 nm) [33, 34]. During UVA therapy in
pregnancy, psoralens should be avoided due to concerns for teratogenicity [5].
While UV phototherapy is thought to be safe in pregnancy given relatively superfi-
cial penetration of UV rays, high cumulative doses of UVB (narrowband and broad-
band) has been associated with decreased folic acid, potentially increasing the risk
of fetal neural tube defects, so folic acid supplementation is recommended [35, 36].
64 B. Friedman and L. Bercovitch
Topical Antibiotics
For localized superficial skin infections, topical mupirocin is safe to use in the preg-
nant patient. Systemic absorption of mupirocin is low, and no reports of harmful
effects secondary to use in pregnancy exist in the literature [13]. However, it is not
recommended for furunculosis or cellulitis or widespread impetiginization.
Furthermore, muprocin resistance is becoming more prevalent worldwide.
Systemic Steroids
Cyclosporine
favorable safety profile, cyclosporine is considered one of the best options when
systemic treatments are considered for atopic dermatitis. In fact, a recent position
paper by the European Task Force on Atopic Dermatitis (ETFAD) lists cyclosporine
as their treatment of choice when long term therapy is required in recalcitrant or
severe atopic dermatitis [13]. It is important for the prescribing provider to bear in
mind that while not clearly teratogenic, cyclosporine is nephrotoxic. Thus, treat-
ment courses should be limited to the shortest duration possible, and blood pressure
and renal function monitoring is necessary in the mother while undergoing treat-
ment [13, 22, 51]. Further, the prescribing provider should bear in mind that cyclo-
sporine is contraindicated in breastfeeding mothers because cyclosporine is secreted
in breast milk; thus, alternative treatment strategies would be needed postpartum
should the patient plan to breastfeed [49, 52].
Dupilumab
There are no studies to date evaluating the safety of dupilumab in the pregnant
patient. Dupilumab is an immunoglobulin G4 (IgG4) antibody against IL4alpha, a
subunit present in both the IL4 and the IL13 receptor [53]. As IgG4 has the second
highest transplacental transport of all antibody subtypes, it is likely that dupilumab
crosses the placenta and accumulates in the fetus [54]. However, there are no data to
suggest a teratogenic effect of dupilumab. There are also no data to suggest whether
dupilumab leads to other complications of pregnancy such as premature birth and
spontaneous abortion. Still, the mechanism of action of dupilumab, specifically
blocking Th2 cytokines thought to play a role in the maintenance of pregnancy, does
imply possible consequences to the fetus. In line with this, unpublished data from
Piccinni et al. demonstrated reduced IL4 and IL10 production by T cell clones gen-
erated from the placenta of women with unexplained recurrent spontaneous abor-
tions as compared to the placenta of women with voluntary abortions [11]. Thus,
until more data are available to determine the safety of dupilumab in pregnancy,
alternative systemic treatments with more available safety data should be favored.
Azathioprine
The FDA previously classified azathioprine as pregnancy category D [5]. The use of
azathioprine in pregnancy is controversial, as it freely crosses the placenta and has
been linked to preterm births, intrauterine growth restriction, miscarriage, and low
birth weight [51, 55, 56]. However, these associations may be confounded by the
complicated maternal health status of the patient populations studied [57]. While
azathioprine may carry the above-enumerated risks, it does not appear to cause fetal
anomalies, thought in large part due to the inability of the fetal liver to convert aza-
thioprine into its active metabolites [56, 58]. Of note, no studies to date have
5 Atopic Dermatitis in Pregnancy 67
Systemic Antibiotics
Acyclovir
The FDA classifies acyclovir as previous pregnancy category B. Studies support the
safety of acyclovir use in pregnant and lactating patients, with no increase in infant
toxicities or adverse events seen with in utero exposure or breastfeeding [65–67].
Antihistamines
Most systemic first generation antihistamines are former FDA pregnancy category
B and considered safe for use in pregnancy [22]. However, promethazine and
hydroxyzine are classified as former FDA pregnancy category C due to limited
well-controlled studies demonstrating safety in human populations [68].
Additionally, in-utero exposure to hydroxyzine during the first trimester has been
associated with a mildly increased risk of congenital anomalies as compared to the
general population [41, 69]. While this risk has not been definitively proven, alter-
native first-generation antihistamines are favored in the pregnant patient. Of note,
68 B. Friedman and L. Bercovitch
one study did find an association between diphenhydramine and risk of cleft palate;
however, subsequent studies of antihistamine use in pregnancy have not corrobo-
rated this finding [70]. Further, when administered intravenously or at levels suffi-
cient to cause overdose, diphenhydramine may cause an oxytocin-like effect,
leading to uterine hyperstimulation and distress to the fetus [71, 72]. As such, low
dose chlorpheniramine and diphenhydramine are preferred over other first genera-
tion antihistamines in pregnancy [5]. While the limited data on second-generation
antihistamines also demonstrate no teratogenic effects, first-generation antihista-
mines are recommended given more extensive safety data [68]. Should first-
generation antihistamines be too sedating, second-generation antihistamines can be
considered. However, recent systemic reviews note no clear improvement in atopic
dermatitis-associated pruritus in patients using second generation antihistamines as
monotherapy or in conjunction with topical treatments [73, 74]. Animal studies
examining the effect of second-generation antihistamines in pregnancy suggest no
increased risk of teratogenicity with loratadine and cetirizine; however, in utero
exposure to fexofenadine was associated with adverse effects to the fetus [68].
Therefore, loratadine is favored when second generation antihistamines are used in
pregnancy [5, 75]. While antihistamines are regarded as safe during pregnancy, they
should be used with caution in the last weeks of pregnancy, as they may cause infant
withdrawal symptoms . These symptoms, including irritability, diarrhea, and grand
mal seizures, may persist for up to 4 weeks after birth and are most associated with
high doses of antihistamines taken during the last month of pregnancy [76, 77].
Further, a single study demonstrated an association between antihistamine use dur-
ing the last 2 weeks of pregnancy and retrolental fibroplasia; however, additional
studies have not corroborated this finding [78].
Of note, while first-generation antihistamines are preferred during pregnancy,
second-generation antihistamines, specifically loratadine, are preferred during
breast feeding as they are less sedating, are found in low levels in breast milk, and
are thought to have less of an impact on breast milk production than first generation
antihistamines [5].
Certain treatments with great utility in the non-pregnant patient should be avoided
in the pregnant patient with atopic dermatitis. Methotrexate is classified as former
FDA pregnancy category X as it is teratogenic and associated with numerous fetal
anomalies [79]. This medication should be stopped at least 3 months prior to planned
conception [5]. Mycophenolate mofetil (MMF) is a former FDA pregnancy cate-
gory D and should be avoided in pregnancy given accumulating evidence suggest-
ing teratogenicity of MMF [5, 80]. While psoralens, used in combination with UVA
phototherapy (PUVA), are classified as a previous FDA pregnancy category C, the
literature suggests its avoidance in pregnancy due to a theoretical risk of teratogen-
esis [5].
5 Atopic Dermatitis in Pregnancy 69
Summary
The following table summarizes the treatment options for atopic dermatitis during
pregnancy. Choice of treatment depends on the severity and extent of the derma-
titis, the stage of pregnancy, and whether or not secondary infection is present
(Table 5.1).
Table 5.1 (continued)
Blood pressure and renal function monitoring during treatment
Risks [13, 39]
Nephrotoxic
Inconclusive data
Possible association with prematurity, low birth weight
Breastfeeding considerations [49, 52]
Contraindicated in breast feeding
Alternative/adjunctive treatments
Topical calcineurin inhibitors
Recommendations
Favor topical corticosteroids, given more safety data
Risks:
Unclear risks given limited data on topical form
Breastfeeding considerations [40]
If used in breastfeeding woman, nipple should be spared
Azathioprine (former FDA pregnancy category D)
Recommendations [13]
Consider when patient fails other systemic treatments
Risks [51, 55, 56]
Possible association with IUGR, miscarriage, low birth weight
Breastfeeding considerations [59]
Avoid in breastfeeding mother as secreted in breast milk
Dupilumab (pregnancy category – Not assigned)
Recommendations
Favor more well-studied systemic treatments
Risks:
Unknown effects in pregnant women
Breastfeeding considerations
Unknown effects in lactating women
Antihistamines (former FDA pregnancy category B and C)
Recommendations
First generation antihistamines preferred
Avoid promethazine and hydroxyzine
Favor loratadine if second generation antihistamines
Risks
Infant withdrawal symptoms if used in last weeks of pregnancy
Possible association with retrolental fibroplasia if used in final weeks of pregnancy
Breastfeeding considerations
Second generation antihistamines preferred
Interventions to avoid in pregnancy
Methotrexate (pregnancy category X)
Mycophenolate mofetil (pregnancy category D)
5 Atopic Dermatitis in Pregnancy 71
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74 B. Friedman and L. Bercovitch
Introduction
Author Attribution Casey Spell and Hannah Badon wrote the first draft of this manuscript. Robert
T. Brodell, MD, reviewed and approved the content of this manuscript.
C. A. Spell (*)
University of Mississippi Medical School, Jackson, MS, USA
e-mail: cspell@umc.edu
H. R. Badon · R. T. Brodell
Department of Dermatology, University of Mississippi Medical Center, Jackson, MS, USA
A. Flischel
Northwestern Medical Group, Vernon Hills, IL, USA
inflammatory and glandular skin changes are associated with a gradual shift from
cell-mediated to humoral immune responses throughout gestation. This switch from
Type 1 T helper cells (Th1) to a predominance of Type 2 T helper cells (Th2) is
thought to play a critical role in placental immune tolerance. This immunologic
adjustment comes with a tradeoff leading to a worsening of conditions involving
sebaceous and eccrine glands, while diseases of the apocrine glands tend to improve.
Of course, not all pregnancies follow these general trends [4]. While 90% of women
experience skin changes during pregnancy, acne and rosacea are among the most
distressing [3, 5].
Acne
Epidemiology
Acne has a prevalence ranging from 85–100% in adolescence [6, 7]. While many
patients experience a regression of acne after their teenage years, others have symp-
toms that can persist well into adulthood [6]. Despite acne’s being so common, only
a few studies have focused on acne treatment during pregnancy.
In one French study, 42.3% of 378 pregnant patients examined by dermatologists
were found to have acne. Among these acne patients, 86.6% reported having acne
prior to pregnancy, while another 35.1% reported a relapse of previously “cured”
acne during pregnancy. Another 51.5% reported unremitting acne since adoles-
cence. Among all surveyed patients, 59.7% reported worsening acne symptoms,
9.1% improving symptoms, and 31.2% no change in symptoms through the course
of pregnancy [8]. The clinical course of acne in pregnancy is variable, and reports
are not consistent across other studies [9].
Pathophysiology
Diagnosis
The diagnosis of acne is made by physical examination. Patients present with closed
comedones (whiteheads), open comedones (blackheads), papules, pustules, and
cysts. Differential diagnosis of acne vulgaris includes perioral dermatitis, rosacea,
milia, and keratosis pilaris rubra faceii. Typically, bacterial cultures are negative but,
on occasion, a gram negative bacteria may be identified, especially in patients not
responding to antibiotic treatment. Serologic testing is generally not performed for
acne patients unless polycystic ovarian syndrome is suspected or if patients have a
history of oligomenorrhea, hirsutism, acanthosis nigricans, or a family history of
hyperandrogenism. In these patients, total and free testosterone, dehydroepiandros-
terone sulfate (DHEAS), androstenedione, luteinizing hormone, and follicle-
stimulating hormone, as well as a lipid panel, glucose, and insulin level can be
obtained [14].
Treatment
Acne treatment involves topical, oral, and physical therapies. Some of these options
are limited in pregnant patients. In one study, pregnant patients were most com-
monly treated with topical antibiotics (53.5%), oral zinc gluconate 30 mg/day
(89.9%), and no prescription (5.6%) [8]. Selected systemic antibiotics can also be
utilized with an effort to minimize the risk of harm to mother and fetus.
78 C. A. Spell et al.
Topical agents are considered first line in pregnant patients with acne. Systemic
therapies may be utilized in more severe or refractory acne. Very little research
exists regarding cosmetic procedures during pregnancy.
A system whereby the Federal Drug Administraion (FDA) assigned a letter cat-
egory (A,B,C,D, and X) to each drug (Table 6.1) was replaced by a narrative system
focusing on specified information required in the package insert of each prescrip-
tion drug (Table 6.2) [9]. The new system, unfortunately, requires a high level of
Table 6.1 “Classic” US Food and Drug Administration (FDA) Drug Risk Classification System
for Pregnant Women
Category Definition
A Adequate and well-controlled human studies have failed to demonstrate a risk to the
fetus in the first trimester of pregnancy (and there is no evidence of risk in later
trimesters)
B Animal reproduction studies have failed to demonstrate a risk to the fetus and there
are no adequate and well-controlled studies in pregnant women OR animal studies
have shown an adverse effect, but adequate and well-controlled studies have failed to
demonstrate a risk to the fetus in any trimester
C Animal reproduction studies have shown an adverse effect on the fetus and there are
no adequate and well-controlled studies in humans, but potential benefits may
warrant use of the drug in women despite potential risks
D There is positive evidence of human fetal risks based on adverse reaction data from
investigational or marketing experience or studies in humans, but potential benefits
may warrant use of the drug in pregnant women despite potential risks
X Studies in animals or humans have demonstrated fetal abnormalities and/or there is
evidence of human fetal risk based on adverse reaction data from investigational or
marketing experience and the risks involved in the use of the drug in pregnant women
clearly outweigh potential benefits
1. Azelaic Acid
Azelaic acid is a former FDA pregnancy category B medication. It is a dicarbox-
ylic acid with antimicrobial and anti-inflammatory properties used to suppress the
formation of microcomedones and improve acne [17, 18]. In addition, it is an inhibi-
tor of tyrosinase, which can reduce hyperpigmentation. It has also been known to
cause a transient burning sensation in some patients [19]. Animal studies indicate no
adverse birth outcomes, and less than 4% of applied medication is systemically
absorbed [20]. Azelaic acid is also found in several foods including milk, barley,
rye, and wheat. This drug is considered a safe choice for topical acne treatment dur-
ing pregnancy [18, 19].
2. Benzoyl Peroxide
Benzoyl peroxide (BPO) is a topical preparation with antimicrobial properties
produced as a lotion, gel, wash, cream, and pledgets in concentrations ranging from
2.5 to 10%. It is a former FDA pregnancy category C medication that is commonly
used in pregnancy. However, adequate safety data in pregnant patients is not avail-
able, and we advise patients to avoid applying BPO over large surfaces of skin to
minimize systemic absorption [18, 20].
3. Salicylic Acid
Salicylic acid is a former FDA pregnancy category C medication that provides
comedolytic and anti-inflammatory properties [18]. Systemic use is typically con-
traindicated during the third trimester of pregnancy due to a risk of oligohydramnios
and early closure of the ductus arteriosus. Topical preparations have a systemic
absorption somewhere between 9 and 25%. Pregnant patients should be advised to
avoid using salicylic acid over large surface areas or under occlusive dressings to
minimize systemic absorption [20]. Patients should also be informed that this is a
common ingredient in many non-prescription acne washes.
80 C. A. Spell et al.
4. Glycolic Acid
Glycolic acid is an α-hydroxy acid with comedolytic and keratolytic activity and
can decrease sebum production [21]. The lack of an FDA pregnancy rating and
definitive safety studies should limit the use of this drug, though birth complications
have not been reported [18, 19].
5. Sodium Sulfacetamide
Topical sodium sulfacetamide is a bacteriostatic and anti-inflammatory agent
that inhibits dihydropteroate synthetase and was previously considered FDA preg-
nancy category C [18]. Although sulfur-containing ointments are occasionally used
by pregnant patients, a pregnancy category was never assigned by the FDA [22].
Sodium sulfacetamide lacks adequate data to support or dispute its use during preg-
nancy [20].
6. Topical Antibiotics
Topical antibiotic agents with both bactericidal and anti-inflammatory activity
are used during pregnancy to combat the putative cause of acne: P. acnes [18].
Topical erythromycin and clindamycin are previous FDA pregnancy category B
medications and are generally considered to be safe for use during pregnancy.
Antibiotic resistance of P. acnes can occur when these agents are used as mono-
therapy. Metronidazole is another former FDA category B medication that can be
safely used in pregnant patients. It has anti-inflammatory and immunosuppressive
effects in addition to antimicrobial properties. Studies of metronidazole have
revealed no association with adverse birth outcomes [23]. Topical dapsone is a for-
mer FDA pregnancy category C medication. It has been used during pregnancy to
treat leprosy and dermatitis herpetiformis with no reports of birth defects in current
literature. Oral dapsone has also been used in cases of nodulocystic acne [24].
However, a theoretical risk exists for neonatal hyperbilirubinemia when used near
delivery. Any physician prescribing topical dapsone should consider stopping this
regimen at least one month before delivery. Lastly, tetracycline as a topical acne
preparation is contraindicated in pregnancy [20].
7. Topical Retinoids
Topical retinoids such as tretinoin and adapalene were previously categorized as
FDA pregnancy category C medications. While the percutaneous absorption of tret-
inoin is minimal and does not alter endogenous drug levels, treatment with topical
tretinoin is not recommended since this drug can cross the placenta. There have
been a total of only four reports of birth defects associated with first trimester use
including ear anomalies, limb reduction, and central nervous system abnormalities.
In one study, 133 pregnant patients exposed to tretinoin during the first trimester
showed no statistically significant increase in minor or major birth defects [25].
Adapalene is associated with rare reports of teratogenicity with exposure during the
first trimester. Neither tretinoin nor adapalene has been associated with an increased
risk in birth defects during the second and third trimesters. Topical tazarotene was
6 Acne and Rosacea in Pregnancy 81
1. Antibiotics
Commonly prescribed as second line therapy for acne, systemic antibiotics are
often utilized in non-pregnant patients including tetracyclines, penicillins, macro-
lides (erythromycin and clindamycin), and cephalosporins [18]. Tetracyclines are
considered a former FDA pregnancy category D medication and should be avoided
during pregnancy, especially after 14 weeks gestation. These antibiotics deposit in
the bones and teeth during the second and third trimester resulting in enamel hypo-
plasia and yellow staining of the teeth that may darken over time. Tetracyclines have
also been associated with cases of acute fatty liver disease in mothers during the
third trimester. First trimester use of tetracyclines have not been linked to congenital
anomalies if medication is discontinued when pregnancy is suspected. Erythromycin,
a macrolide, is a previous FDA pregnancy category B medication when used sys-
temically; however, rare cases of hepatotoxicity have been documented with pro-
longed use of erythromycin ethylsuccinate. In addition, a set of Swedish studies
have noted malformations in the cardiovascular system when erythromycin was
used in early pregnancy. Other options that are considered safe for use during late
pregnancy are azithromycin, penicillins, and cephalosporins, each of which was
previously designated FDA pregnancy category B [20].
2. Spironolactone
Spironolactone is a systemic treatment used off-label to treat acne and is a previ-
ous FDA pregnancy category C medication. This drug competitively inhibits
5α-reductase and aldosterone and has been documented to cause feminization in
male rat fetuses as well as delayed sexual maturation of female rat fetuses. Though
these studies were not conducted in humans, spironolactone poses a high theoretical
risk and should be avoided during pregnancy or in those planning for pregnancy [20].
3. Isotretinoin
Isotretinoin is a former FDA pregnancy category X medication and should never
be used in pregnant or lactating patients [20]. This medication is a proven teratogen
that can lead to spontaneous abortion and congenital malformations including cen-
tral nervous system and thymic defects, microtia, stenosis of the external auditory
canal, hydrocephalus, facial and palatal defects, and cardiovascular defects [9, 20,
26]. It is recommended that women trying to conceive stop the use of prescription
retinoids for at least 1 month prior to conception [9]. Isotretinoin should not be
prescribed to patients who are trying to conceive or have the potential to become
pregnant.
82 C. A. Spell et al.
Cosmetic Treatment
1. Phototherapy
Narrowband (NBUVB) and broadband (BBUVB) ultraviolet B phototherapy
are considered safe options for treatment during pregnancy based on data from
treatment of pregnant psoriasis patients [32]. However, more recent studies have
shown that cumulative exposure to NBUVB can decrease serum folic acid levels
required to support the development of the fetal nervous system and prevent
neural tube defects [33]. Given that folic acid requirements increase during
pregnancy, it may be prudent to ensure folic acid supplementation and even
perhaps monitor folic acid levels in pregnant patients treated with UV ther-
apy [18].
2. Lasers
Fractionated CO2 lasers for pitted acne scarring or vascular lesion lasers (595 nm)
for telangiectasias should be safe during pregnancy and lactation but are generally
avoided until after delivery, as are most elective treatments. Several studies refer-
ence the use of CO2 lasers for the treatment of genital condyloma during pregnancy
with no maternal or fetal complications reported [34].
6 Acne and Rosacea in Pregnancy 83
Rosacea
Epidemiology
Pathophysiology
Diagnosis
Treatment
Similar to the management of acne, the mainstay of treatment for rosacea during
pregnancy is the use of selected oral and topical antibiotics. Avoidance of common
clinical triggers is recommended. For cases of papulopustular rosacea, azelaic acid as
well as topical antibiotics including metronidazole and clindamycin are frequently
used [18]. Vascular lesion lasers (595 nm) are recommended for erythematotelangi-
ectatic rosacea but are typically delayed until after pregnancy. Ocular rosacea can be
treated with erythromycin ophthalmic ointment and sulfa eye drops [4]. Cases of
rosacea fulminans during pregnancy have been treated with oral erythromycin and
corticosteroids or systemic azithromycin and topical metronidazole [4, 41].
Conflict of Interest Robert T. Brodell, M.D., discloses the following potential conflicts of inter-
est: MULTI-CENTER CLINICAL TRIALS: Genentech, Janssen Pharmaceuticals, Corrona
Psoriasis Registry, Novartis, and Glaxo-Smith-Kline. Casey Spell, Hannah Badon and Amy
Flischel have no conflicts of interest.
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Part III
Skin Cancer and Dermatologic Surgery
During Pregnancy
Chapter 7
Skin Cancer in Pregnancy
Jennifer Villasenor-Park
Cutaneous growths or tumors occur during pregnancy and can be benign or malig-
nant. The incidence of both benign and malignant cutaneous lesions will likely
increase, as there is a growing trend for women to delay pregnancy [1]. Of these
lesions, some are more frequently associated with pregnancy, while the influence of
pregnancy on the onset, progression and prognosis of other lesions is still
controversial.
Nonmelanoma skin cancer encompasses a variety of cutaneous malignancies
that include keratinocyte carcinomas such as basal cell and squamous cell carcino-
mas, dermatofibromasarcoma protuberans (DFSP), Kaposi sarcoma, Merkel cell
carcinoma, and cutaneous lymphoma. While they occur infrequently during preg-
nancy, they have been described during pregnancy, and their behavior and manage-
ment during pregnancy will be discussed here.
Keratinocyte carcinomas include basal cell carcinomas and squamous cell carci-
nomas and are the most common types of skin cancer. These are increasing in inci-
dence, especially within the Medicare population [2, 3]. However, their incidence
during pregnancy is unknown. Mucosal involvement by squamous cell carcinoma
during pregnancy is well documented and has been reported in the oral mucosa
including the tongue and larynx, vulvar region, and cervix [4–6]. There are several
case reports of basal cell carcinoma occurring during pregnancy. These reports doc-
ument unusual and aggressive behavior of basal cell carcinoma occurring during
pregnancy, including one case of metastatic basal cell carcinoma, that may not
reflect a true effect of pregnancy [7–9]. Interestingly, there are a few reports docu-
menting some association between the use of exogenous hormones and the onset of
J. Villasenor-Park (*)
Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA
of their CTCL shortly after pregnancy, which may be attributed to the relative shift
from a Type 1 T helper cell (TH1) to a Type 2 T helper cell (TH2) cytokine profile
that occurs during pregnancy [54]. Further studies are necessary to determine
whether there is an effect of pregnancy on the prognosis of MF.
The occurrence of nonmelanoma skin cancer during pregnancy is relatively rare,
and while there are few published data regarding their behavior during pregnancy,
appropriate counseling and follow-up are indicated in particular types of nonmela-
noma skin cancer. Aggressive cutaneous malignancies, such as dermatofibrosar-
coma protuberans and Merkel cell carcinoma, should be treated appropriately
during pregnancy and without delay. Additionally, the placenta and the newborn
should be examined carefully for possible transmission, especially in the setting of
widespread Kaposi sarcoma.
reported clinical change in 76% of nevi during pregnancy. In addition, these women
were two times more likely to have nevi with histologic atypia. One patient was
diagnosed with melanoma during pregnancy [71]. Overall, there does not appear to
be any significant differences in the clinical, dermoscopic, or histologic appearance
of melanocytic nevi during pregnancy in women who do not have dysplastic nevus
syndrome. Women with dysplastic nevi should be monitored more closely for
changes in their nevi. Importantly, these data suggest that any features suspicious
for melanoma should not be attributed to physiologic change and should be treated
appropriately.
the predominant receptor type in melanoma [88–92]. Loss of ERβ expression cor-
relates with increased Breslow depth [91, 93]. Immunohistochemical analyses of
melanomas from pregnant and non-pregnant women showed a correlation between
GPER/ERβ-positive melanomas and lower Breslow thickness, lower mitotic rate,
and higher presence of peritumoral lymphocyte infiltration [94]. Zhou et al. showed
more frequent expression of ERβ in pregnant women compared to men; however,
there was no difference observed when compared to nonpregnant women, and there
was no association between ERβ expression and survival [92]. It is still unclear
whether the expression of these receptors and estrogen signaling has a positive or
negative impact in the progression of melanoma or survival [95, 96].
The immunologic milieu in the pregnant patient also contributes to the notion of
poor prognosis in patients with pregnancy associated melanoma. The immunosup-
pressive environment necessary for maintaining the fetus during pregnancy has
been compared to the environment necessary for cancer and its progression [97, 98].
Specifically, the placental villi, which are in constant contact with maternal blood,
do not express Human Leukocyte Antigen (HLA) molecules and therefore do not
trigger a maternal T-cell response. The extravillous trophoblast, which are the pla-
cental cells that interact with the decidua and myometrium, express only select
types of HLA molecules (HLA-C, HLA-E and HLA-G) that do not engage with T
cells and mainly engage with receptors on innate immune cells, including natural
killer cells and macrophages [99]. Additionally, there is a relative shift from a TH1-
predominant to a TH2-predominant immune response during pregnancy, leading to
suppression of the cytotoxic T-lymphocyte response and a less robust cell-mediated
immunity [100]. CD4+CD25+ regulatory T cells (Tregs) are important for maintain-
ing tolerance to the fetus during pregnancy, and their numbers are notably increased
during pregnancy and in cancer [97, 101]. Lastly, uterine natural killer cells (uNKs),
which have reduced cytotoxic activity, are present in increased numbers within the
maternal-fetal interface of the decidua of the pregnant uterus [97]. To date, there has
been no compelling evidence to suggest that the immunologic environment in the
pregnant patient predisposes them to or causes the spread of melanoma.
Table 7.2 Summary of studies showing increased risk of mortality in pregnancy associated
melanoma
Authors Study Population PAM (N) Control (N) Findings Follow-up
Tellez Single center Patients at 41; 19 421 Higher >2 years
et al. retrospective Cleveland diagnosed remainder incidence of follow-up
JAAD case-control Clinic during of study mortality,
2016 study pregnancy population recurrence,
and
metastasis
Byrom Let Meta-analysis 10–338 56% 5–20 years
et al. increased risk
JEADV of mortality
2015 (based on 4
studies)
Moller Population- United 306; 29 3465 2-fold Up to
et al. 2013 based Kingdom patients increased 11 years
retrospective analyzed risk; risk
study PAM – decreased
5 years when
post-partum adjusted for
tumor stage
Stensheim Population- Norway 247 4460 HR 1.52; no Median
et al. JCO based (diagnosed diff when 11.9 years
200 g retrospective during adjusted for
cohort pregnancy) Breslow
thickness and
tumor
location
PAM Pregnancy Associated Melanoma
7 Skin Cancer in Pregnancy 97
thickness and tumor location, and some studies lacked complete data regarding
stage of disease. Stenshiem et al. performed a population-based cohort study using
data from the Cancer Registry and the Medical Birth Registry of Norway comparing
cause-specific survival between pregnant and non-pregnant patients diagnosed with
cancer, including breast cancer, cervical cancer, melanoma, lymphoma and leuke-
mia [102]. Amongst those diagnosed with melanoma during pregnancy, the authors
found a slightly increased risk of cause-specific death (HR, 1.52; P = 0.047). The
authors attributed this slightly increased risk to a delay in diagnosis in pregnant
patients whose doctors may have interpreted changes in the pigmentation of a mole
as a normal physiologic change of pregnancy. When the authors performed a sub-
analysis comparing tumor thickness and tumor location amongst pregnant and age-
matched, non-pregnant controls, this difference was no longer statistically
significant.
Using the national cancer registration and hospital discharge data for women in
England from 1998–2007, Moller et al. conducted a population-based retrospective
study comparing women diagnosed with melanoma within 5 years post-partum
[109]. In their analysis, they found a two-fold increased risk in women who were
diagnosed within 1-year post-partum. Within this cohort of patients, 6 of 29 patients
were advanced stage (stage III or IV), and 7 patients could not be staged. After
adjusting for tumor stage, this association was only slightly attenuated. However, in
patients with melanoma diagnosed beyond 1 year but before 5 years postpartum,
there was no significant increased risk of cause-specific death. It’s unclear whether
this observation in women diagnosed within 1 year postpartum is due to a delay in
diagnosis during pregnancy, a more aggressive type of melanoma, or a true preg-
nancy association.
Byrom et al. conducted a meta-analysis of 4 population-based studies utilizing
multivariable methods reporting hazard ratios (HR) with confidence intervals (CI)
and reported a 56% increased risk of mortality amongst those with pregnancy-
associated melanoma [110]. The statistical methods used in this study were reap-
praised and scrutinized for incomplete data by several authors. Using the same data
used by Byrom et al., a repeat analysis did not find any significant differences in
mortality amongst women diagnosed with pregnancy-associated melanoma
[111, 112].
In 2016, Tellez et al. published a retrospective cohort study using data from a
single institution comparing controls to patients diagnosed with melanoma during
pregnancy or within 1 year postpartum [113]. In their cohort, 41 patients were
included in their analysis, 19 of which were diagnosed during pregnancy. A major-
ity of the patients in this group had advanced stage disease. The authors reported a
20% mortality rate and 5.10 greater odds of death in patients with pregnancy associ-
ated melanoma, which is one of the highest reported in the literature. Inconsistent
reporting on stage of disease and inappropriate statistical methods have been cited
as major flaws in this study [114].
A more recent European observational study published in 2017 used patients
selected from the database of the “International Network on Cancer, Infertility, and
Pregnancy” (INCIP), which relies on voluntary reporting by doctors who work in
98 J. Villasenor-Park
specialized hospitals and are affiliated to the INCIP [115]. Sixty patients were
included in their analysis, and, amongst this group of patients, there was a high
incidence of advanced stage disease. About 50% of patients had regional and meta-
static disease (Stage III-IV), which is high compared to the reported incidence of
advanced-stage melanoma in young patients (1–5%) [116, 117]. It is likely that the
high incidence reported in this study was related to a delay in diagnosis or a referral
bias, as these cases were voluntarily reported by physicians affiliated at tertiary care
hospitals.
Several studies have assessed the characteristics of melanoma in pregnant
patients by evaluating Breslow depth and proliferative activity [81, 102, 105, 106,
118–123]. Two groups did report thicker melanomas in pregnant patients compared
to non-pregnant women; however, these studies did not report a difference in sur-
vival, and one study found a protective effect on survival [81, 119]. There was also
no significant difference in proliferative activity between pregnant and non-pregnant
patients diagnosed with melanoma. In a retrospective cohort study conducted at a
single institution, pathologists compared melanoma tissue from patients with preg-
nancy associated melanoma and non-pregnant patients [124]. Tumor proliferation
rates were assessed by mitotic count (assessed by the number of dermal mitotic
figures/mm2), phosphohistone H3 staining, and Ki-67 staining. Amongst 50 tissue
samples obtained from pregnancy-associated melanoma and 122 tissue samples
obtained from non-pregnancy associated melanoma, there were no significant dif-
ferences in proliferative activity between groups with invasive melanoma. Moreover,
no significant association between pregnancy status and Breslow depth, Clark level,
or ulceration was noted. Fabian et al. also assessed Breslow thickness and mitotic
rate in pregnancy-associated melanoma and compared these rates to non-pregnant
women and men and found no significant differences [125].
In summary, most of the data do not support a worse prognosis, increased thick-
ness, or proliferative rate in patients diagnosed with pregnancy associated melanoma.
Several studies have examined whether pregnancy has a negative influence on sur-
vival if melanoma is diagnosed before or after pregnancy. Examination of 966
women with melanoma diagnosed before pregnancy compared to 4567 women who
did not become pregnant after a melanoma diagnosis showed no difference in sur-
vival after controlling for Breslow depth, tumor site, Clark level, and age [105].
Additionally, Mackie et al. examined 85 women who became pregnant after their
melanoma diagnosis and compared them to 143 women who did not become preg-
nant and found no significant difference in overall survival [119].
With regard to the post-partum period, there are a few studies examining the role
of pregnancy in the prognosis of melanoma. Johansson et al. examined prognosis in
patients with pregnancy associated melanoma up to 5 years postpartum and com-
pared them to controls using data from the Swedish Cancer and Multi-Generation
7 Skin Cancer in Pregnancy 99
The expression of estrogen receptors in melanoma is well established [82, 87, 88,
90, 93]. However, the role of exposure to exogenous estrogens and its impact on
mortality is not known. There have been several studies examining the role of oral
contraceptive pills (OCPs) in the prognosis of melanoma. Early studies reported an
increased risk of melanoma in those taking OCPs and suggested a correlation
between prolonged use of OCPs and increased risk of developing melanoma [125,
126]. However, these studies did not account for potential confounding factors
including a history of sun exposure, and some findings did not reach significance.
Larger studies, including two meta-analyses and a pooled analysis of 10 case con-
trol studies, showed no correlation between length of use of OCPs, age at first use,
or current use and the risk of developing melanoma [127, 128].
The role of HRT in the development of melanoma is less well characterized. One
large randomized control trial from the Women’s Health Initiative examined the
incidence of melanoma in 27,347 postmenopausal women who were randomized to
receive either: (1) conjugated equine estrogen plus medroxyprogesterone or placebo
(if intact uterus) or (2) estrogen alone or placebo (if had hysterectomy). After 6 years
follow-up, there was no detectable difference in the incidence of melanoma between
the groups receiving active hormone compared to the placebo group [129].
A recent analysis of 11 studies previously published examined the role of in vitro
fertilization (IVF) in melanoma risk compared with the general population [130].
This study also examined the role of different types of IVF in parous or nulliparous
women. After analyzing 11 studies that met their criteria, there were no significant
patterns indicating an increased risk of melanoma in those patients undergoing IVF
compared to the general population. However, in patients who were ever parous
either before or after receiving IVF, particularly with use of clomiphene or gonado-
tropins, there appeared to be an increased risk of melanoma [131–133].
Based on available current evidence, there does not appear to be significant data
to suggest any increased risk for developing melanoma in women exposed to exog-
enous forms of hormones. The current guidelines for the treatment of primary cuta-
neous melanoma suggest that exogenous hormones may be used in women
diagnosed with melanoma [134].
100 J. Villasenor-Park
Pregnant patients should be evaluated for any suspicious lesions using the same clini-
cal and dermatoscopic criteria as non-pregnant patients [134]. Pregnant patients
diagnosed with melanoma should be managed in the same way as non-pregnant
patients. Management by a multidisciplinary team consisting of the obstetrician,
neonatologist, oncologist and dermatologist should be the goal in order to adequately
evaluate and treat both the mother and the fetus, particularly if the melanoma is at an
advanced stage [134–136]. Excisional biopsy of suspicious lesions with 2-mm mar-
gins and definitive treatment with appropriate surgical margins based on the depth of
the melanoma are current guidelines for the management of melanoma. Surgical
treatment in the pregnant patient can be safely performed with appropriate precau-
tions including proper positioning of the patient to avoid aortocaval compression.
For staging and risk assessment, sentinel lymph node biopsy should be consid-
ered in patients with melanomas thicker than 0.8 mm and in thinner melanomas
with ulceration, as it is helpful in assessing prognosis and guiding treatment [134].
Sentinel lymph node biopsy with lymphoscintigraphy using a radionuclide with a
short half-life, such as 99-Techneticum nanocolloid, can be safely performed during
pregnancy, as the estimated fetal radiation exposure is less than 0.01 gray (Gy). This
is well below the threshold dose of 0.1–0.2 Gy that is associated with fetal malfor-
mations. Additionally, no adverse effects on the fetus have been described after
sentinel lymph node biopsy during pregnancy [137–139]. As sentinel lymph node
biopsy does not influence survival from melanoma, use of this procedure should be
considered on a case-by-case basis after thorough discussion of the benefits and
risks to the mother and the fetus with a multidisciplinary team.
Treatment of advanced melanoma previously relied on the use of chemotherapy.
There are a few reports of successful use of chemotherapy regimens, particularly
when used during the second and third trimesters [140–142]. In all cases, full-term
delivery should be the goal, if possible, in order to optimize the outcome for the
offspring. With the advent of targeted therapy and immunotherapy, the use of these
treatments has become standard of care for the treatment of advanced melanoma.
However, their use during pregnancy and their effects on the fetus are not well docu-
mented. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade with ipi-
limumab, an Immunoglobulin G1 (IgG1) antibody, can cross the placenta, and
animal studies in monkeys show in an increased rate of miscarriage, still births,
premature births, malformation of the urogenital tract, and neonatal death [143].
There are only a few case reports of successful delivery of a healthy baby following
in utero exposure to ipilumumab during pregnancy [144, 145]. The Programmed
cell death-1 (PD-1) inhibitors such as nivolumab and pembrolizumab, both
Immunoglobulin G4 (IgG4) antibodies, also cross the placenta with the highest risk
for transplacental transfer during the third trimester. Use of PD-1 inhibitors led to
fetal loss in pregnant mice [143]. There are few reports of PD-1 inhibitor use during
pregnancy in humans. Menzer et al. describe the use of a combination of ipilim-
umab and nivolumab in a stage IV melanoma patient during pregnancy with the
resultant delivery of a healthy baby with no evidence of melanoma [145].
7 Skin Cancer in Pregnancy 101
BRAF inhibitors, specifically vemurafenib, have not been studied for their use in
pregnancy; however, only a few case studies have been reported. The earliest case
reported for use of vemurafenib during pregnancy was in 2013 in a 37 year old
woman with metastatic melanoma [146]. She was given vemurafenib during her
second trimester of pregnancy at the 25th week with the hope of prolonging the
duration of gestation until week 34. However, the growth of the fetus rapidly
declined, and the patient underwent caesarian section during 30th week of gestation
due to fetal distress. Since restriction of growth was already observed during the
24th week of gestation before the initiation of vemurafenib therapy, it is unclear
whether the continued decline in growth observed after the initiation of vemurafenib
was due to maternal illness or a toxic effect from vemurafenib. There were no fetal
malformations reported. Another case report describes the successful treatment of a
25 year-old woman, gravida 1, with a history of stage IIA melanoma diagnosed and
treated with wide local excision and a negative sentinel lymph node biopsy 5 years
prior to presentation [147]. She was diagnosed with Stage IV metastatic melanoma
with metastasis to the lungs and treated with vemurafenib starting at 25 weeks of
gestation. She delivered a female infant with a birth weight in the 67th percentile
and APGAR scores of 9 and 9 at 34 weeks of gestation. The neonatal course was
complicated by paroxysmal supraventricular tachycardia requiring admission to the
neonatal intensive care unit (NICU). No congenital malformations or melanoma
were reported in the infant. Finally, de Haan et al. describe a case of a 30 year old
woman with widely metastatic melanoma and a twin pregnancy who was treated
with vemurafenib starting at week 22 of gestation and developed toxic epidermal
necrolysis (TEN) 12 days after commencing treatment with vemurafenib [148]. The
patient delivered at 26 weeks of gestation while under sedation. After a prolonged
stay at the NICU, the twins appeared to be developing normally.
Previous studies on the effect of chemotherapy during pregnancy have shown
that chemotherapy after the first trimester is unlikely to have long-term effects on
the development of the exposed offspring, while prematurity negatively impacts
offspring developmental outcomes [141, 142]. However, in cases where conven-
tional chemotherapy fails to improve prognosis, the use of targeted therapy or
immunotherapy are increasingly being considered.
Summary
Women diagnosed with melanoma before, during, or after pregnancy do not have a
worse prognosis than non-pregnant patients. While hyperpigmentation of the skin
occurs during pregnancy, any suspicious melanocytic lesion should be biopsied,
which can be done safely during pregnancy. Surgical treatment of melanoma during
pregnancy should follow appropriate guidelines and should not be delayed. In
advanced stage patients, treatment by a multidisciplinary team composed of obste-
tricians, oncologists, neonatologists, and dermatologists is important to ensure opti-
mal care and appropriate consideration of risks of therapeutic options for both the
mother and the fetus.
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Chapter 8
Dermatologic Surgery in Pregnancy
Jennifer Villasenor-Park
Introduction
Timing
Timing of the procedure can significantly alter the risk to the fetus. The second tri-
mester (weeks 13–24) is generally regarded as a relatively safe time to undergo a
minimally invasive procedure [1, 2]. The first trimester, during which key organo-
genesis and possible spontaneous abortion are more likely to occur, and third tri-
mester, during which preterm labor can occur, carry much higher risk for
complications compared to the second trimester. However, it is important to weigh
the relative risk for these complications and the risk for under treatment or delay in
treatment of the patient.
J. Villasenor-Park (*)
Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA
Preoperative Considerations
Intraoperative Considerations
Antiseptics
In general, antiseptics considered safe for use during pregnancy include alcohol and
chlorhexidine. Alcohol is commonly used for short procedures, such as skin biop-
sies. While it is percutaneously absorbed, it is rapidly metabolized and does not
accumulate to significant levels in the blood [7]. For longer procedures, including
excisions, chlorhexidine can be safely used during pregnancy [8]. Care should be
taken to avoid sensitive areas such as the eye and ears due to the risk of corneal
injury and ototoxicity [9, 10]. Povidine-iodine is avoided due to reports of neonatal
hypothyroidism. Hexachlorophene is also avoided due to its association with severe
fetal abnormalities [11].
Anesthesia
The anesthetic choice for pregnant patients should also be carefully considered.
Lidocaine, which is widely used in dermatologic procedures, is considered safe for
use during pregnancy in small amounts. There is no evidence to support harm to the
fetus with the use of infiltrated lidocaine in animal studies; however, it does cross
the placenta [12, 13]. The maximum safe dose of local infiltrative anesthesia with
lidocaine is not known, but is suggested by the manufacturer to be 7 mg/kg of lido-
caine with epinephrine and 4.5 mg/kg of lidocaine without epinephrine [13]. Doses
of 3.0–4.5 mg/kg of lidocaine with epinephrine and 1.5–2.0 mg/kg of lidocaine
without epinephrine appear to be safe in children [14, 15]. Although most dermato-
logic procedures rarely exceed these doses, lidocaine toxicity can occur if a large
amount is inadvertently delivered intravascularly or if an idiosyncratic response
occurs. Thus, careful monitoring for signs of lidocaine toxicity is important. Initial
signs of lidocaine toxicity include perioral numbness, facial tingling, slurred or
pressured speech, metallic taste, auditory changes and hallucinations, which may
also accompany hypertension, tachycardia, and premature ventricular contractions.
Cardiac and central nervous system toxicity progresses with increasing dose and
can evolve to seizures, central nervous system depression, and can ultimately lead
to cardiac failure or arrest [16]. Intravenous lipid infusion is used to prevent mortal-
ity secondary to lidocaine toxicity [17]. Bupivacaine and mepivacaine are generally
not used in pregnant patients, as their use has been associated with inhibition of
cardiac conduction, congenital abnormalities, and fetal bradycardia [1, 18]. Rare
cases of methemoglobinemia from high dose prilocaine have been reported [5, 19].
Given its safe use as infiltrative local anesthesia, lidocaine is considered safe dur-
ing pregnancy in the topical form as well [13]. Use of topical benzocaine is avoided
due to the risk of methemoglobinemia in infants and children [20]. Lidocaine 2.5%/
prilocaine 2.5% topical cream is considered safe for use during pregnancy but
should not be used for long periods of time over large areas of the body due to the
risk of methemoglobinemia with high doses of prilocaine [5, 19].
Epinephrine has been shown in one study to be associated with an increased risk
of malformations in children of mothers exposed to systemic epinephrine during the
first trimester [12]. Epinephrine can also decrease blood flow within the uterus, can
potentially trigger uterine spasms, and reduce uterine contractile strength [21].
However, the concentration of epinephrine given via local infiltrative anesthesia is
far below the concentration of epinephrine produced endogenously during stress
and is unlikely to cause clinically significant adverse effects. Additionally, the local
116 J. Villasenor-Park
Several studies have documented minimal significant change in the size, color and
dermatoscopic features of nevi in pregnant women [22–28]. Dermatologists should
use standard clinical and dermatoscopic guidelines when assessing melanocytic
nevi in pregnant women. Therefore, any suspicious features noted in melanocytic
nevi should not be attributed to a normal consequence of pregnancy. Skin biopsy
can be safely conducted during any trimester of pregnancy and should not be
delayed if there are suspicious melanocytic lesions noted during pregnancy. Use of
lidocaine for local infiltrative anesthesia is considered safe for use during pregnancy
[1]. While epinephrine has been associated with uterine artery spasm in animal and
in vitro studies, the concentrations of epinephrine used during dermatologic surgery
are considered safe and can reduce systemic absorption of lidocaine [1]. Diagnostic
excisional biopsy by elliptical (fusiform) excision, punch excision, or deep shave/
saucerization with narrow peripheral margins of 1–3 mm margins around the suspi-
cious lesion is recommended [29].
Wide local excision with local anesthesia using appropriate margins for the treat-
ment of melanoma can be safely conducted during pregnancy and should not be
delayed once a diagnosis of cutaneous melanoma has been made [1, 29]. For patients
with advanced stage melanoma, incorporation of a multidisciplinary group consist-
ing of an obstetrician, dermatologist, surgeon and/or medical oncologist is impor-
tant to provide optimal and appropriate care to pregnant women and is recommended
in the most recent guidelines of care for the management of primary cutaneous
melanoma published by the American Academy of Dermatology [29].
Sentinel lymph node biopsy is considered a safe, low-morbidity procedure that
provides staging and prognostic information for patients with melanomas with a
Breslow thickness of 1.0 mm or more and for thinner melanomas with high-risk
features [30]. Timing of sentinel lymph node biopsy should be carefully considered
to minimize risks to the mother and the fetus. In general, the sentinel lymph node
biopsy may be safely performed during the second and third trimester. Isosulfan
blue or lymphazurin is avoided due to the risk of severe allergic reaction and ana-
phylaxis [31–34]. Methylene blue is also avoided, particularly during the first tri-
mester, due its known association with fetal abnormalities including atresia of the
ileum and jejunum [35]. Use of technetium-99m (99mTc)-labeled radiocolloids in
sentinel lymph node biopsy is considered safe during pregnancy because of its short
half-life, and radioactive exposure delivered to the fetus is <0.01 Gy, which is well
8 Dermatologic Surgery in Pregnancy 117
below the National Council on Radiation Protection and Measurement limits for a
pregnant woman and the threshold dose of 0.1–0.2 Gy that is associated with
increased risk of fetal malformation [1, 36]. In addition, the standard dose can be
lowered without sacrificing radiographic information [37]. Sentinel lymph node
biopsy should be avoided during the first trimester due to the risks associated with
general anesthesia [29].
Treatment of non-melanoma skin cancer, such as basal cell carcinoma and squa-
mous cell carcinoma, should be considered on an individual case-by-case basis, and the
potential risks associated with treatment or delay of treatment should be discussed.
Elective procedures, including cosmetic procedures such as chemical peels and
laser surgery, should be postponed to the postpartum period due to a lack of data
regarding safety during pregnancy unless a compelling medical reason for treatment
exists [5, 38]. Most data are limited to case reports of women treated during a time
when they were not aware they were pregnant [5]. There are, however, several stud-
ies reporting the safe use of CO2 laser therapy in the treatment of genital condyloma
during pregnancy [39–42]. However, one report described the onset of premature
rupture of membranes and subsequent delivery in one patient shortly after laser
therapy and treatment with 85% trichloroacetic acid [43]. Use of other lasers during
pregnancy have also been reported, but none have been studied for their safe use
during pregnancy, so these procedures should be postponed until after pregnancy.
Postoperative Considerations
Acetaminophen is generally safe for use in the postoperative period for pregnant
patients [1]. However, a case of acetaminophen poisoning resulting in fulminant
hepatotoxicity and fetal demise was reported in a pregnant patient taking 9 grams
per day for several days [44]. Patients should be advised to avoid exceeding the
maximum recommended daily dose of 3 grams. Nonsteroidal anti-inflammatory
drugs (NSAIDs) and salicylates are avoided during pregnancy due to their associa-
tion with fetal cryptorchidism, low birth weight, and asthma [45, 46]. Further, the
Federal Drug Administration (FDA) has advised women to discontinue use of
NSAIDs and aspirin in the last 3 months of pregnancy due to the risk of renal injury,
oligohydramnios, and premature close of the ductus arteriosus [1, 45].
Postoperative Infections
Conclusions
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Conclusion
D
Demodex mites, 83 G
Dermatofibrosarcoma protuberans, 91 Glycolic acid, 80
Dermatologic surgery Glycopeptides, 117
anesthesia, 115, 116 Gottron’s papules, 55
Index 127
H M
Hemorrhoid(s), 10 Macrolides, 81
Hemorrhoidal varicosities, 10 Major Histocompatibility Complex (MHC)II
High factor broad spectrum sunscreens, 5 molecules, 27
Hirsutism, 8 Maternal atopic dermatitis, 62
Hormonal therapy, 82 Mechanical tension, 6
Hormone replacement therapy (HRT), 99 Melasma, 4–6
Human chorionic gonadotropin Mepivacaine, 115
(hCG), 76, 90 Merkel cell carcinoma (MCC), 90
Human Leukocyte Antigen (HLA), 94 Merkel cell polyomavirus (MCV), 90
Hydroxychloroquine (HCQ), 53, 56 Methemoglobinemia, 115
Hyperandrogenism, 77 Methotrexate, 48, 68
Hyperpigmentation, 3 Molluscum fibrosum gravidarum, 7
Montgomery tubercles, 11
Mupirocin, 64
I Mycophenolate, 68
Immunogloblulin E (IgE), 60 Mycophenolate mofetil (MMF), 54, 68
Immunoglobulin G1 (IgG1) antibody, 100 Mycosis fungoides (MF), 91
Immunoglobulin G4 (IgG4) antibody, 100
Impetigo herpetiformis (IH), 44
Inferior vena cava (IVC), 114 N
Inflammatory cascade of rosacea, 83 Nail growth, 8
International Network on Cancer, Infertility, Narrative FDA System, safety of drugs during
and Pregnancy (INCIP), 97 pregnancy and lactation, 78
Intradermal eosinophils, 15 Narrowband ultraviolet B phototherapy
Intrahepatic cholestasis of pregnancy (NBUVB), 23, 46, 82
clinical presentation, 25 Neonatal intensive care unit (NICU), 101
definition, 23 Nivolumab, 100
differential diagnosis, 26 Non-melanoma skin cancer, 89–92, 117
epidemiology, 24 Nonsteroidal anti-inflammatory drugs
pathogenesis, 24, 25 (NSAIDs), 117
pathology, 26
treatment, 26, 27
Intrauterine growth restriction (IUGR), 53 O
Intravenous lipid infusion, 115 Ocular rosacea, 84
In-utero corticosteroid, 65 Oral contraceptive pills (OCPs), 99
Ipilimumab, 100
I-Pledge program, 82
Isotretinoin, 81, 82 P
Palmar erythema, 9
Papulopustular rosacea, 84
K Pembrolizumab, 100
Kaposi sarcoma, 90, 92 Pemphigoid gestationis (PG), 14
Keratinocyte carcinomas, 89 clinical presentation, 28, 29
definition, 27
differential diagnosis, 30
L epidemiology, 27
Lasers, 82 pathogenesis, 27, 28
Lidocaine, 115 pathology, 29, 30
Linea alba, 3 treatment, 30
Linea nigra, 3, 4 Penicillin, 67, 81, 117
128 Index