Dermatological disorders unique to pregnancy

Abstract

Pregnancy creates marked alterations in a woman's usual cutaneous anatomy and physiology. Skin changes during pregnancy may range from normal changes that occur with almost all pregnancies through common or pre-existing skin diseases that are not associated with, but influenced by the pregnancy, to eruptions that appear to be specifically associated with pregnancy and the puerperium. In recent years a group of well-defind dermatoses of pregnancy has been generally defined. These are: pruritic urticarial papules and plaques of pregnancy (PUPPP), pemphigoid gestationis (PG), prurigo of pregnancy, intrahepatic cholestasis of pregnancy (ICP) and impetigo herpetiformis. The most common is PUPPP, and the least common is impetigo herpetiformis. These conditions occur usually in the third trimester, however prurigo of pregnancy which has the earliest onset, occur before the third trimester. With the exception of PG the pathogenesis of these diseases is yet unrevealed. Primigravida and multiple gestations were characteristic for PUPPP, abdominal involvement for PUPPP and PG, and a history of affected pregnancies for ICP. This group of pregnancy-specific dermatoses is usually symptomatic and thus may be alarming. Importantly, some of these may be associated with adverse pregnancy outcomes. Pregnant women will have numerous questions about these changes. If well informed, the dermatologist can help pregnant women understand, adjust, and treat these dermatoses.

Full text

73
VOLUME 4, 2009 (73-85)
REVIEW
Dermatological disorders unique to pregnancy
ABSTRACT
Pregnancy creates marked alterations in a woman’s usual cutaneous anatomy and
physiology. Skin changes during pregnancy may range from normal changes that
occur with almost all pregnancies through common or pre-existing skin diseases that
are not associated with, but influenced by the pregnancy, to eruptions that appear
to be specifically associated with pregnancy and the puerperium. In recent years a
group of well-defind dermatoses of pregnancy has been generally defined. These
are: pruritic urticarial papules and plaques of pregnancy (PUPPP), pemphigoid
gestationis (PG), prurigo of pregnancy, intrahepatic cholestasis of pregnancy (ICP)
and impetigo herpetiformis. The most common is PUPPP, and the least common is
impetigo herpetiformis. These conditions occur usually in the third trimester, however
prurigo of pregnancy which has the earliest onset, occur before the third trimester.
With the exception of PG the pathogenesis of these diseases is yet unrevealed.
Primigravida and multiple gestations were characteristic for PUPPP, abdominal
involvement for PUPPP and PG, and a history of affected pregnancies for ICP. This
group of pregnancy-specific dermatoses is usually symptomatic and thus may be
alarming. Importantly, some of these may be associated with adverse pregnancy
outcomes. Pregnant women will have numerous questions about these changes. If
well informed, the dermatologist can help pregnant women understand, adjust, and
treat these dermatoses.
S. GIATRAKOU
1
, E.RALLIS
2
, M. BAKALAKOU
1
.
1
2nd Department of Dermatology and Venereology, “Attikon” General University Hospital,
Medical School, University of Athens, Greece.
2
Department of Dermatology and Venereology, 417 NIMITS Military General Hospital, Athens,
Greece.
Mailing address
Sophia Giatrakou
"Attikon" University Hospital
2
nd
Department of
Dermatology and Venereology
1 Rimini Str., Haidari,
Athens 124 62
E-mail: giatrakou@hotmail.com

74 VOLUME 4, 2009
INTRODUCTION
The dermatoses of pregnancy represent a unique,
heterogeneous group of pathologic skin disturbances,
caused by the gravid state. Pruritis or an itchy skin eruption,
is often the main symptom of dermatosis in pregnancy.
Unfortunately, pruritis in itself is not diagnostically helpful.
It is still necessary to fully evaluate and examine pregnant
women to exclude the possibility of a pre-existing or de novo
skin disorder unrelated to the pregnancy. Correct diagnosis
is important for the choice of treatment and the prognosis of
mother and child, because some dermatoses of pregnancy,
such as pemphigoid gestationis, intrahepatic cholestasis of
pregnancy and impetigo herpetiforms constitute a health
risk. During the past few decades, a significant amount of
new data has provided new insights into the classification,
pathogenesis, treatment, prognosis and fetal risk that are
associated with the specific dermatoses of pregnancy.
PRURITIC URTICARIAL PAPULES AND PLAQUES
OF PREGNANCY (PUPPP)
PUPPP (also referred to as toxemic rash of pregnancy,
polymorphic eruption of pregnancy or PEP, and toxemic
erythema of pregnancy) is the most common of the
pregnancy specific dermatosis
1,2
. The condition occurs in
approximately 1 in 240 pregnant women (0.45-1%). The
onset occurs in the third trimester of the first pregnancy,
but may be delayed until a few days postpartum
1
. This
dermatosis is intensely pruritic, and tends not to recur in
subsequent pregnancies
1,2
(Figure 1, 2).
The cause and the pathogenesis of PUPPP are unclear,
but estrogen and progesterone have been suggested as
causative agents
3
. Because the lesions develop in striae,
it has been suggested that the abdominal distention of
pregnancy elicits an inflammatory response by damaging
the connective tissue
3
.
Recent studies have suggested that PUPPP is associated
with twin pregnancy
4,5
. Weiss and Hell -1992 describe a
familiar tendency and attribute the maternal response to
a circulatory paternal factor
6
. Other recent studies have
suggested that PUPPP may be related in some cases to the
presence of male DNA in the skin of women carrying male
fetuses
7,8
. Male fetal DNA was detected in maternal skin
lesions, pointing to microchimerism as a potential trigger
factor. There are other reports that PUPPP is associated
with the birth of male babies
9
. Also, there is an association
of PEP with multiple gestation pregnancy, excessive fetal
weight and maternal weight gain, resulting in excessive
abdominal distention
1,7
. Thus, there is an increased risk for
Figure 1, 2. PUPPP.The lesions are intensely pruritic and can be quite variable in appearance. They include patchy
or generalized, discrete erythematous urticarial papules and plaques on the abdomen, thighs, and buttocks.
Courtesy of Dr Eustathios Rallis.

DERMATOLOGICAL DISORDERS UNIQUE TO PREGNANCY
75
caesarian section
9
. The onset occurs typically in the later
part of the third trimester of the first pregnancy in which
striae are more common, but sometimes initially appears
in the immediate postpartum period
1,2,7
. The urticarial
papules usually begin within striae, on the abdomen and
thighs and unlike HG, spare the periumbilical region
1,2,9
.
Like HG, face, palms and soles are often spared. The
lesions are intensely pruritic, and can be quite variable
in appearance
1,2
. They include patchy or generalized,
discrete erythematous urticarial papules and plaques on
the abdomen, thighs, arms, legs, and buttocks. (Figure 1,
2) Occasionally, vesicles or targetoid lesions may develop,
but blister formation is not seen, and the eruption spreads
over a matter of days.
PUPPP is a diagnosis of exclusion. It may resemble
the very early (urticarial stage) of Herpes gestationis but
there are not vesicles or bullae. Direct and/or indirect
immunofluorescence (IMF) should be performed if
pemphigoid gestationis is suspected
1
. In PUPPP, direct
and indirect immunofluorescence are generally negative
1-4
.
Direct IMF may reveal minimal nonspecific granular
deposition of IgM and C
3
4
.
The absence of a linear band of C
3
in the basement
membrane differentiates this dermatosis from herpes
gestationis
7,9
. Histopathology typically shows a spongiotic
epidermis with a perivascular inflammatory infiltrate
1-4
.
There may be an increased number of eosinophils (60%)
and edema of the papillary dermis. Laboratory tests are
normal, however serum IgE levels are elevated in 28% of
patients.
Differential diagnosis also includes all similar eruptions
that occur in non pregnant women
1,9
. Thus erythema
multiforme, drug eruptions, contact dermatitis, urticaria,
and insect bites should be excluded.
The pregnant women are relieved to learn that the
condition is not serious. PUPPP poses no risk to the
mother (except pruritus) or fetus, and lasts 1-4 weeks
1-4
.
It resolves postpartum and tends not to recur in subsequent
pregnancies
3
. If there is recurrence, it is less severe. However,
treatment is usually demanded to provide relief from the
intense itching.
In most cases, topical steroids, emollients and oral
antihistamines H
1
, which are first line therapies, will control
the itching
1
. Ointments containing substances such as
betamethasone, mometasone or methylprednisolone can
be regarded as safe during pregnancy, but large amounts
of potent topical steroids over prolonged periods should
probably be regarded similarly to systemic steroids
1,2,10
.
First generation H
1
blockers (old sedators) such as
chlorpenamine, (chlorpheniramine) diphenhydramine,
tripelenamine, cyclizine,meclizine and cyproheyptadine
are safer for use in pregnancy than the others, based
on their longevity
11
. Sometimes hydroxyzine is needed
additional
12
. In some severe cases, systemic steroids,
which are second line therapy may be required
1
. Oral
methylprednisolone 20-40mg daily for 5 days tapering by
5mg every 2 days over the following 2 weeks is very effective.
For systemic treatment during pregnancy prednisone,
prednisolone, and methylprednisolone are regarded as
safer
1
than betamelthasone, dexamethasone, cortisone, and
hydrocortisone, which may be associated with some risk of
malformation, although prospective studies are missing
1,11
.
Corticosteroids, both oral and topical are designated FDA
Pregnancy Category C
2,10
. In animals systemic steroids have
Figure 3. Autoantigens in selected
autoimmune bullous diseases. The
approximate localization of major
autoantigens in selected subepidermal
immunobullous diseases
15
. AECP,
antiepiligrin cicatricial pemphigoid; BP
bullous pemphigoid; BSLE, the bullous
eruption of systemic lupus erythematosus;
CP, cicatricial pemphigoid; EBA,
epidermolysis bullosa acquisita; LABD,
linear IgA bullous dermatosis; PG,
pemphigoid gestationis.
Basal
Keratinocytes
Lamina lucida
Lamina densa
Sublamina densa

76 VOLUME 4, 2009
been associated with cleft palate, placental insufficiency,
spontaneous abortion, and growth retardation
2,10
. In
humans, many normal infants have been born to mothers
who have received systemic corticosteroids throughout
pregnancy, but there have been reports of low birth weight
and congenital cataracts
2,10,13
. In addition, if systemic steroids
are administered for long periods during pregnancy, the
child should be observed for hypoadrenalism
1,2
. Although
few effects from corticosteroids have been observed in
infants, Dr. Reed in his publication related some relatively
recent information about the effects of birth weight and
fetal growth patterns on adult cardiovascular health
10,13
.
Low birth weight and disproportionate fetal growth have
been associated with a predisposition to hypertension,
stroke, and cardiovascular disease. As a result, there may be
long-term consequences to fetal exposure to corticosteroids
that are unobservable until adulthood.
Third line therapy is early delivery but this is generally
avoided
1,8
. Beltrani and Beltrani (1992) described a woman
at 35 weeks whose pruritus was refratory to prednisone
and symptoms were so severe that delivery by caesarian
section was performed
6
. Pruritus began to resolve within
hours and complete resolution was seen in 2 days. Delivery
is the outcome in some cases, but the resolution is not
necessarily related to delivery
8
.
For symptomatic PUPPP that persists after delivery many
doctors recommend against the use of oral antihistamines for
nursing mothers, because antihistamines are excreted in the
milk and may cause drowsiness, and paradoxical excitement
response in infants
2
. Steroids are also excreted in small
amounts into breast milk. No deleterious effects in nursing
infants have been observed; however, prednisolone given
with avoidance of nursing for 3-4 hours is recommended to
minimize the infant’s exposure
10,14
. Topical steroids, with
avoidance of use on the nipple and areola, are generally
considered safe
10
HERPES GESTATIONIS
Herpes gestationis, also called pemphigoid gestationis
(PG) is a rare, intensely itchy, urticarial or polymorphic
or vesiculobullous eruption
15
(Figure 4, 5). It affects
approximately one in 60.000 pregnancies and usually
appears in the second or third trimester
1,2
. The term
pemphigoid gestationis is preferable because this condition
shows many clinical and immunologic similarities with
bullous pemphigoid and has no relationship with herpes
virus infection
1
!
Although the etiology is unknown, pathogenesis is well
studied. All women with a history of H.G. have anti-HLA
antibodies
15,6
. The only source of disparate HLA antigen
is placental. It is hypothesized that HG is caused by a
incompatibility of HLA antigens between the mother and
father, manifested by an immunologic response against
the paternal class II antigens at the placental basement
membrane zone (BMZ) with cross-reaction at BMZ of
the skin .There is cross reaction between placental tissue
and skin
2
.
It is an autoimmune dermatosis of pregnancy caused
by an anti-BMZ serum factor (herpes gestationis –HG-
serum factor) that induces C
3
deposition along the dermal-
epidermal junction
6
.
Figure 4, 5. PG. There is a sudden onset of pruritic urticarial lesions on trunk, especially periumbilically -typical
distribution- with a rapid progression to multiple, generalized bullae, pemphigoid-like eruption
2
. Courtesy of Dr
Eustathios Rallis.

DERMATOLOGICAL DISORDERS UNIQUE TO PREGNANCY
77
The majority of patients have circulating autoantibodies
directed against the BP180 KD antigen
2
in the transmembrane
hemidesmosomal protein (BPAg2 – collagen XVII)
15
. The
non-collagenous segment closest to the plasma membrane
of the basal keratinocyte (NC16A) appears to contain the
BP180/gestational pemphigoid immunoreactive site
15
.
The antibody belongs to the IgG
1
subclass and fixes
complement via the classical pathway. The autoantibody
of gestational pemphigoid binds to the amniotic basement
membrane, resulting in the findings of immune activation
in the placenta and evidence of placental insufficiency.
Women with gestational pemphigoid also show and
increased expression of MHC class II antigen (DR, DP,
DQ) within the villous stroma of chorionic villi
16
. It has
therefore been proposed that GP is a disease initiated
by the aberrant expression of MHC class II antigens (of
paternal haplotype) that serves to initiate an allogeneic
response to placental BMZ, which then cross reacts with
skin
16
. There is a marked increase of HLA-DR3 or HLA-
DR4 antigens and, in 50%, presence of both in affected
women
6
. This is associated with an increased risk for Grave’s
disease, and suggests an inheretited predisposition to the
development of the disease
6,7,15
. Studies show association
with gestational trophoblastic disease (hydatidiform moles
and choriocarcinoma)
15
.
The onset typically occurs in the second or third
trimester (34% each), in the first trimester (18%), and
sometimes 1-2 weeks postpartum (14%)
17
. There is a
Figure 6. Lesions may vary, and include urticarial
papules and plaques, erythema, vesicles, and bullae
18
.
Courtesy of Dr Eustathios Rallis.
Figure 7. PG. Direct IF: Demonstrating deposits of C
3
along the dermo-epidermal junction. Courtesy of Dr
Eustathios Rallis.
Table 1. Bullous pemphigoid and herpes gestationis have many clinical and immunologic similarities, but
there are distinguished differences between them
18
Bullous Pemphigoid Pemphigoid Gestational
Gender: male:female (1:1) only female
Onset: >60 age 15-45
Cause: Unknown, HLA pregnancy, DR3, DR4
Periumbilical lesions: - +
Autoantibodies primarily against: 230 KD hemidesmosome antigen 180 KD hemidesmosome antigen
Hormons influence, pregnancy - +

78 VOLUME 4, 2009
sudden onset of pruritic urticarial lesions on the trunk,
especially periumbilically (typical distribution), with a rapid
progression to a multiple, generalized bullae, pemphigoid-
like eruption
2
(Fig.4, 5).
Common sites of involvement are the abdomen and
extremities. Lesions may vary, and include urticarial papules
and plaques, erythema, vesicles, and bullae
18
(Figure 6).
The face, mucous membranes, palms and soles are often
spared
2
. If involved, it is an atypical distribution. In severe
cases there is burning and itching, the blister can be large,
tense or a flaccid bullae, the exanthema spreads quickly,
and there is nausea, fever and mild headache.
PG has many clinical and immunologic similarities with
bullous pemphigoid. The autoantibodies are directed
against the same target antigens as in bullous pemphigoid,
although more commonly against BP180 antigen than
BP230 antigen (Table 1). Differential diagnosis also includes
PUPPP, allergic contact dermatitis, erythema multiforme,
dermatitis herpetiformis and bullous pemphigoid
18
. The
correct diagnosis is especially important because most
patients with pemphigoid gestationis need treatment with
systemic corticosteroids and are therefore at risk for side
effects from this treatment
1
. The usual histopathologic
findings are a subepidermal vesicle and perivascular
infiltration of lymphocytes, eosinophils, and histiocytes
2
.
Direct immunofluorescence
2
(IMF) reveals C
3
deposits (in
100%) with or without IgG (in 30%) in a linear band along
the basement membrane zone in a diagnostic pattern
2
. The
antibody localizes at the roof of the blister. In salt-split skin
specimens antibody deposition is found along the bottom
of the epidermal fragment
19
. This is similar to the finding
seen in bullous pemphigoid patients (Table 1). Complement
indirect immunofluorescence reveals the circulating anti-
BMZ IgG in all patients
2
. ELISA demonstrates activity of
the disease
19
(Figure 7). IMF is the key for diagnosis and
helps the patient plan for future pregnancies
15
.
The fetus is at risk for prematurity and low birth weight,
because the placenta is also involved (see above, in the
pathogenesis)
2,21
. In cases in which patients have been
treated with systemic corticosteroids the studies have
recorded a much better fetal prognosis
1,21
.
The newborn shows signs of HG with transient lesions
in less than 10%
2
. This occurs by passive transfer of
the antibasement membrane zone antibody across the
placenta. No therapy is required. Despite its often severe
appearance, discomfort and intense pruritus, there is no
significant maternal risk although systemic corticosteroids
are frequently necessary to control maternal signs and
symptoms
1,2,15,21
.
The disease may improve during the later part of
pregnancy and usually resolves spontaneously, several
weeks to months postpartum, but exacerbations at delivery
or during the postpartum period are common
17
. Some cases
have been reported with recurrences more than 10 years
postpartum
1
. Recurrences in subsequent pregnancies are
more severe. Also, there are reports of flares with menses,
oral contraceptives (25%) and subsequent pregnancies
2
.
Rarely, cases evolve into chronic bullous pemphigoid
3
.
Although mild cases, may respond to topical steroids,
first generation antihistamines, and antipruritics, most
patients required systemic steroids
2
(see also PUPPP).
All of the above are first line therapies
1
. Most cases will
be controlled with prednisone 0.5mg/kg. Severe cases
require 1mg/kg or even higher doses of prednisolone with
tapering and typical treatment for 6-10 weeks postpartum
1
.
The usual alternatives and adjuvants to steroids have
been tried in recalcitrant cases, but only cyclosporine has
been useful prior to delivery
2
. In cases in which complete
remission take months, or even years alternative drugs,
contraindicated during pregnancy or lactation, may be
used. Azathioprine, dapsone, sulfapyridine and pyridoxine
may be tried as adjunctive therapy with oral corticosteroids
or alone
1
. Other drugs that may be used are goserelin and
ritodrine, high dose intravenous immune globulin alone
or in combination with cyclosporine or cyclophosphamide
(corticosteroid sparing effect)
1
.
If corticosteroid treatment proves unsuccessful, or is
contraindicated, then plasmapheresis which belongs to
second line therapies should be considered, either during
pregnancy or postpartum
1,20
.
PRURIGO OF PREGNANCY
Prurigo of pregnancy also referred to as "early onset
prurigo of pregnancy", or "Papular eruption of pregnancy"
is the second most common of the pregnancy specific
dermatosis (1:300 incidences) (Figure 8, 9). This condition
includes three variants. The mild and more common variant
of prurigo gestationis is characterized by localized lesions
only (Besnier)
15
. The generalized variant is referred to as
Papular dermatitis (Spangler)
15
. Pruritic folliculitis and
linear IgM disease of pregnancy, also clinically belong in
this group, but are separated by their histopathology or
IF findings
4,15
.
The term prurigo gestationis was first introduced by
Besnier in 1904
4
. At that time “prurigo” was the term used
to describe atopic dermatitis
4
. Eczema of pregnancy, prurigo

DERMATOLOGICAL DISORDERS UNIQUE TO PREGNANCY
79
gestationis, papular dermatitis, and pruritic folliculitis of
pregnancy showed considerable overlap both clinically, and
histopathology
4,22
. Thus, this disease complex is summarized
as atopic eruption of pregnancy (AEP)
4
. One explanation
may be a recent prospective study on the above pruritic skin
diseases in pregnancy that demonstrate a high prevalence
of atopic eczema in all of them
22
.
The cause is unknown, however, many patients have
elevated IgE
4
. To prevent fetal rejection, normal pregnancy
is characterized by a lack of strong maternal cell-mediated
immune function and T-helper 1 (Th1) cytokine production
4
.
Thus, dominant immune response, is the humoral one, with
T-helper 2 (Th2) cytokine production. Atopic dermatitis
overall is considered to be a Th2-dominant disease, thus,
the Th2 shift associated with pregnancy, may favor the
exacerbation of atopic dermatitis.
Other patients have been reported to have cholestasis,
suggesting an overlap with cholestasis of pregnancy
4
. It
is likely that this group is heterogeneous and multiple
pathways may be relevant
4
.
Prurigo of pregnancy usually is accompanied by increased
weight gain of the pregnant woman and is associated with
twin pregnancies
4
.
This disease complex starts significantly earlier than the
other specific dermatosis of pregnancy
4
. Onset is before
the third trimester. The mild and more common variant
of prurigo gestationis, is characterized by small discrete,
pruritic, rapidly excoriated papules on the forearms and
trunk, predominantly on the extensor surface
4
(Figure 8).
Vesicles or bullae do not develop. Lesions may or may
not be follicular and are typically 0.5-1.0cm in size, with
or without a central crust (Figure 9). Prurigo gestationis
is localized to forearms and trunk, but papular dermatitis
is generalized
4
.
Papular dermatitis is a rare dermatitis of late pregnancy,
characterized by a generalized pruritic eruption. Lesionns
consist of soft, red-violet to red-brown papules (3-5mm)
some of which have a centrally hemorrhagic crust,
and sometimes form large patches
15
. There is usually a
history of atopy. Recent studies have shown association of
papular dermatitis with elevated urinary human chorionic
gonadotropin (HCG), decreased plasma hydrocortisone
and a decreased half life of hydrocortisone
4
.
Pruritic folliculitis of pregnancy (Fig.10, 11), begins
between the 4th- 9th week. It resolves 2-3 weeks after
delivery. It is a kind of acne caused by hormonal changes.
Skin lesions commonly involve the trunk and limbs
4
(Figure
11).
The differential diagnosis must include cholestasis of
pregnancy and bacterial folliculitis
25
.
Histopathology findings for purigo gestationis and
papular dermatitis are non specific
4
. There is lymphat-
ic perivascular infiltrate, parakeratosis, and acanthosis.
Imunofluorescense and laboratory tests are negative
4
.
Histopathology findings for Pruritic Folliculitis are charac-
terized by intrafollicular neutrophils, lymphocytes, mono-
Figure 8. Prurigo gestationis. Courtesy of Dr Eustathios
Rallis.
Figure 9. Prurigo gestationis. Lesions may or may not
be follicular with or without a central crust. Courtesy of
Dr Eustathios Rallis.

80 VOLUME 4, 2009
nuclear cells and a variable number of eosinophils
4
. IMF
and labs are negative. The key for diagnosis of Linear IgM
disease is direct IF, which shows a bright linear IgM along
the BMZ. Histopathology is non-specific.
There is no evidence of fetal or maternal risk and no
skin involvement for the newborn.
The disease may last for weeks up to months postpartum.
It resolves spontaneously and recurrence during subsequent
pregnancies is variable
4
.
Treatment includes antipruritics, topical steroids, and
oral steroids in severe cases, (see also PUPPP). As there is
no evidence of maternal or fetal risk, there is no indication
for intervention
15
.
INTRAHEPATIC CHOLESTASIS OF PREGNANCY
(ICP)
Intrahepatic cholestasis of pregnancy (ICP) is a relatively
rare condition (0.02 - 2.4% of pregnancies). The terms
‘obstetric cholestatisis’, ‘icterus gravidarum’ and ‘idiopathic
jaundice of pregnancy’, all refer to the same clinical entity
23
.
It is characterized by pruritus without primary skin lesions,
the variable presence of jaundice, blood chemistries con-
sistent with cholestasis, and resolution after delivery
1-3
. ICP
is the second most common cause of gestational jaundice
(viral hepatitis being first). It is estimated that ICP accounts
for approximately 20% of obstetric jaundice
3
. It is divided
into two forms
23
.
Pruritus gravidarum is the mild form of ICP. This includes
women with pruritus and other biochemical abnormalities,
but without hyperbilirubinemia and jaundice.
Jaundice of pregnancy, is the second form and is char-
acterized by the presence of cholestatic jaundice.
The cause is believed to be an abnormal hepatic excre-
tion of bile acids, induced by endogenous estrogen and
progesterone
23,24,25
. These hormones interfere with bile
acid secretion across the hepatocytes. Another hypoth-
esis is that increased opioidergic neurotransmission or
neuromodulation in the CNS, contributes to the pruritus
of cholestasis
23
.
Genetical, mechanical and hormonal factors (estrogen,
progesterone and their metabolites) may contribute to
pathogenesis of the disease
23
.
A mendelian dominant inheritance pattern associated
with the HLA Aw31B8 haplotype has been proposed
23
.
A positive family history is seen in up to 50% of those af-
fected women, and the incidence is higher in association
with twin pregnancies
23
. Impaired bromsulphalein (BSP)
clearance especially under the influence of estrogen is
frequently seen and mutation (deletion) of the multidrug
resistance MDR3 gene which interferes with canalicular
transport of bile acids was found
23
. Also, low selenium
levels appear to be an important factor
23
.
Most cases develop in the third trimester
3
. ICP is defined
by pruritus without primary skin lesions
23
. The pruritus
usually affects first palms and soles. Then, extends to the
legs and abdomen; followed by secondary excoriations. It
Figure 10. Pruritic folliculitis. It is a kind of acne caused
by hormonal changes. Courtesy of Dr Eustathios Rallis.
Figure 11. Pruritic folliculitis. It is a kind of acne caused
by hormonal changes. Courtesy of Dr Eustathios Rallis.

DERMATOLOGICAL DISORDERS UNIQUE TO PREGNANCY
81
Disorder,
synonyms
Frequency Clinical Characteristics Diagnosis Perinatal
Outcome
Treatment Comments
PUPPP or toxemic
erythema of
pregnancy (PEP)
or toxemic rash.
The most
common
0.45-1%.
Late onset, in 3rd
trimester, intense pruritus,
polymorphous generalized,
papulo-urticarial eruption,
starting within striae.
Predominant abdominal
involvement, periumbilical
sparing.
H&E: non specific.
Spongiotic epidermis,
with lymphocytic
perivascular infiltrate.
IMF: non–specific
LAB: non-specific
No maternal or
fetal risk.
Antipruritics, emollients,
antihistamines, topical or
systemic steroids.
Common in nulliparas, does not
recur in subsequent pregnancy.
Resolves postpartum. Association
with twin, male fetus, weight
gain, caesarian section.
Papular
eruptions,or AEP
a) Prurigo of
pregnancy
b) Papular
dermatitis
c) Pruritic
folliculitis
d) Linear IgM
disease.
The
second
most
common.
Early onset, before 3rd
trimester, pruritic papules
which are localized in
prurigo gestationis , but
generalized in papular
dermatitis. Excoriations
common. Pruritic folliculitis
is acne-like. It is considered,
an exacerbation of
atopic dermatitis or
the first manifestion of
atopic dermatitis during
pregnancy.
a-b)
H&E:
non
specific. Lymphocytic
perivascular infiltrate
parakeratosis,
acanthosis.
IMF:
non–specific
LAB:
c) non-specific, +/- IgE.
PF:sterile folliculitis.
d) Linear IgM disease:
Bright linear IgM
along the BMZ by
direct IΜF.
No maternal
or fetal risk.
Antipruritics, emollients,
antihistamines, topical
steroids, systemic steroids
if severe.
Resolves postpartum and
recurrence in subsequent
pregnancy is variable
Association with twin, high
prevalence of atopic eczema.
Cholestasis
of pregnancy
(ICP), or Icterus
gravidarum.
Not very
common.
Onset in 3rd trimester,
intense generalized
pruritus,only secondary
skin lesions due to pruritis
(excoriations common).
H&E:
non-specific
IMF:
non–specific
LAB:
elevated total
serum bile acid
levels, and other lab
values consistent with
cholestasis.
Increased
risk of
prematurity,
fetal distress,
stillbirths.
Antipruritics, phototherapy,
Cholestyramin
Ursodesoxycholic acid.
Resolves postpartum, recurs
in subsequent pregnancy.
Genetical, mechanical
hormonal factors involved.
Herpes
gestations
Pemphigoid
gestationis (PG).
Rare
1:60.000
Late onset, in 3rd trimester,
sometimes 1-2 weeks
postpartum. Severe
pruritus, vesiculo-bullous
eruption on urticated
erythema. Predominant
abdominal involvement
especially periumbilically.
Generalized, pemphigoid-
like eruption.
H&E:
Subepidermal
blisters. Edema,
infiltrate of
lymphocytes, and
eosinophils.
IMF:
linear deposits of
C3±IgG along DEJ on
direct IMF
LAB:
positive indirect
IMF
Increased
preterm labor
and small for
date b abies.
Transient
neonatal
lesions in
10%.
Antipruritics,
antihistamines, topical
steroids, systemic steroids if
severe. Plasmapheresis.
Association with trophoblastic
disease. Resolves over weeks
postpartum. Exacerbations
and remissions during
pregnancy are common.
Postpartum exacerbations very
commonly recur in subsequent
pregnancies.
Impetigo
herpetiformis,
or generalized
pustular
psoriasis (GPP).
Rare Onset in third trimester,
local, then generalized
erythema with marginal
sterile pustules. Mucous
membranes involved,
systemic symptoms.
H&E:
Microabscesses
(initially sterile) –
pustule of Kogoj.
Maternal
sepsis
common.
Antibiotics, oral steroids,
cyclosporine, induce labor
Possibly pustular psoriasis,
persist for weeks to months
postpartum. May recur with
subsequent pregnancy. No
history of psoriasis.
Table 2
4,6,15
. Differential diagnosis of pruritic skin diseases in pregnancy; AEP, atopic eruption of pregnancy; DEJ, dermoepidermal junction; H&E, hematoxylin-eosin; IMF,
immunofluorescence microscopy; LAB laboratory investigations; PUPPP, pruritic urticarial papules and plaques of pregnancy; PP, prurigo of pregnancy, PF, pruritic foliculitis.

82 VOLUME 4, 2009
is more intense during the night, with or without jaundice
and with no history of exposure to the hepatitis virus or
hepatotoxic drugs. There are also, clinical signs of cholestasis
(dark urine, light color stools, subclinical steatorrhoea and
icterus) in 50% of affected women.
The differential diagnosis must include other pruritic
conditions that may occur by chance during pregnancy
and other causes of jaundice
25
. Thus, pruritic conditions
such as scabies, eczema, urticaria, drug eruptions, prurigo
gestations early cases of PUPPP and pemphigoid gestationis
have to be excluded. The differential diagnosis must also
include viral hepatitis, drug induced hepatitis, and other
causes of jaundice (such as preeclampsia)
25
.
In mild cases the diagnosis is based on exclusion. E-
valuation of pregnant patients with pruritus has to be
followed carefully, with complete medical history and
laboratory tests (see table 3). Histopathologic findings
are non specific and immunofluorescence is negative
1,23
.
Liver function tests may occasionally be consistent with
cholestasis, without an identifiable cause
24
. They include
increased bile acid levels which correlate with the severity
of pruritus, increased direct billirubin, alkaline phosphatase,
γ-glutamyltransferase, cholesterol,lipids, transaminases and
5’ nucleotide
24,25
. However, ultrasound is normal.
Although intense pruritus is the most common conse-
quence of ICP, the risks to the mother include subclinical
steatorrhea, vitamine K deficiency, and an increased preva-
lence of gallstones
2,3,23
. Risks to the fetus include preterm
delivery (40%), meconium staining (45%), fetal distress
(13%), and fetal death (13%,)
2,3,23
. The side effects are
noticed, when bile acid levels are greater than 40μmol/L
23
.
This causes vasoconstriction of placental chorionic veins
and placental insufficiency
2,3,23
. There is no skin involve-
ment of the newborn.
The incidence of prematurity and low birth weight is
increased in the offspring of patients with pruritus gravi-
darum the pregnancies should be followed carefully
23
.
The condition usually resolves postpartum
23
. Induction of
labor is recommended in the 38th week in mild cases and
in the 36th week in severe cases, (after fetal lung maturity).
Pruritus gravidarum is a mild form of cholestatic jaundice
and which recurs in subsequent pregnancy (70%) with
use of birth control pills
23
.
Emollients, cooling lotions or creams, topical antiprurit-
ics, and first generation antihistamines belong to first line
therapies
1,23
(for the use of oral antihistamines during
pregnancy see also the discussion of their use in PUPPP
above).
There are reports that phototherapy with UVB (290-
320nm) or UVA (320-400nm), may also be benefit in some
cases which belong to second line therapies
1,23
.
Third line therapies include ursodeoxycholic acid,
cholestyramine, rest and a low-fat diet
1
. At present, ur-
sodeoxycholic acid is considered to be the drug of choice,
Table 3. Algorithms for differential dia gno sis
of pruritic skin diseases in pregnancy. AEP, A to-
pic Eruption of Pregnancy; H&E, Hematoxylin-
eosin; ICP, Intrahepatic Cholestasis; D.IMF,
Direct Immunofluorescence; LAB, Laboratory
Investigations; PG, Pemphigoid Getsationis;
PP, Postpartum; PUPPP, Pruritic Urticarial
Papules and Plaques of Pregnancy.

DERMATOLOGICAL DISORDERS UNIQUE TO PREGNANCY
83
as it is the only therapy that has been seen to decrease
both maternal pruritus and fetal mortality
4,15,23
. The rec-
ommended dose is 15mg/kg/day. Oral guargum, is a
gel-forming dietary fiber which lowers serum bile acid
levels and reduces pruritus, with less adverse effects than
cholestramine. Also, exogen vitamin K (absorption in ICP
may be impaired), and intravenous S-adenosylmethionine
can be used. In more severe cases, oral corticosteroids are
preferable.
IMPETIGO HERPETIFORMS
Impetigo herpetiforms, also referred to as generalized
pustular psoriasis associated with pregnancy (GPP), is
characterized by a generalized pustular eruption with fe-
ver and leucocytosis, developing during late pregnancy
26
(Figure 12). Many consider this to be a variant of pustular
psoriasis that occurs during pregnancy
26
. It is a rare acute
form of pustular psoriasis and occurs, interestingly, without
a history of psoriasis.
The cause is unclear, but hypocalcermia of pregnancy has
been suggested as a causative agent
15,27
. It is a diagnosis
of exclusion and an unusual manifestation of psoriasis and
pregnancy, which is a triggering factor for severe GPP.
The onset is in the third trimester. It starts locally, with
periumbilical lesions, the hallmark of which are sterile
pu stules that form around the margin of erythematous
patches
6
(Figure 12).
The erythematous lesions characteristically begin at
flexures and extend peripherally.
Pruritus is not severe, but constitutional symptoms are
common
6
. There is increased nausea, vomiting, diarrhea,
chills and fever. Although, the pustules are initially sterile
they may become secondarily infected which can be fol-
lowed by rupture and sepsis. Mucous membranes are
usually involved
6
.
Also, frequently there is hypoalbuminemia and hypocal-
cemia with tetania.
Based upon clinical observations, four distinct patterns
of GPP are proposed
26
:
The Von Zumbusch patter consists of a generalized painful
eruption with fever, which start abruptly and resolve after
several days.
The Annular pattern is characterized by annual lesions,
which enlarge by centrifugal expansion over a period of
hours to days, with central healing.
Exanthematic type is an acute eruption of small pustules.
It usually follows an infection and systemic symptoms
usually do not occur.
Sometimes pustules appear within or at the edge of
existing psoriatic plaques. This is referred to as “Localized
pattern”.
The usual histopathologic findings are infiltration of
neutrophils which dominates to the extent that sterile
macroscopic pustular appear.These are sterile microabscess
and the spongelike epidermal cavity filled with neutrophils
has been termed the spongioform pustule of Κogoj
6
.
Women must be informed about maternal and fetal risk,
because perinatal sepsis is common
6
. Fetal morbidity and
mortality is related to the severity of maternal infection
6
.
Also, there are reports which refer unexplained perinatal
deaths, and births with fetal hydrocephaly
6
.
The disease may persists for several weeks to months
postpartum
6,28
. It may recur with a subsequent pregnancy or
after using estrogen-progesterone oral contraceptives
6
.
If bed rest, emollients, compresses, antibiotics for second-
ary infection, and mild topical corticosteroids are ineffective,
systemic corticosteroids can be used
26
. Following labor
and delivery or termination of pregnancy corticosteroids
can be replaced by retinoids or methotrexate
26
. Most
recently, oral cyclosporine has proven effective for most
variants of psoriasis.
This treatment appears to be the least harmful systemic
treatment for psoriasis during pregnancy and may therefore
Figure 12. Impetigo herpetiforms. Starts with pe-
riu mbilical lesions, the hallmark of which are sterile
pustules that form around the margin of erythematous
patches. Courtesy of Dr Eustathios Rallis.

84 VOLUME 4, 2009
be the treatment of choice
26
. Doses of 4-5mg/kg daily are
prescribed. Concerns about cumulative toxicity, such as
nephrotoxicity are less worrisome in impetigo herpetiforms,
because it may resolve at the end of pregnancy, limiting
the amount of cyclosporine prescribed
26
.
SUMMARY
The specific dermatoses of pregnancy usually are symp-
tomatic and thus may be alarming. Importantly, some of
these may be associated with adverse pregnancy outcomes.
Listed in Table 2 are some of the most important charac-
teristics of the skin conditions that have been described.
There should be a precise knowledge of the diagnosis
and the course of these diseases. The pregnant woman
has to be informed about the risks and possibilities of the
outcome of the disease for her and her baby. The decision
to treat pregnant women with a drug should be made by
the physician and the pregnant women together, on the
best benefit to risk ratio. The pharmacology of the active
component and its safety during pregnancy should be
established. Usually, these diseases resolve postpartum and
recur in subsequent pregnancies. Some diseases include
evidence of fetal or maternal risk. The dermatologist, if
well informed, can help pregnant women understand and
treat the dermatoses of pregnancy.
REFERENCES
1. Wolfgang J. Pregnancy Dermatosis. In: Mark G. Lebwohl,
Warren R. Heymann, J, Bert-Jones J, and Coulson L, edi-
tors Treatment of Skin Disease, Comprehensive thera-
peutic strategies. 2nd edition. New York: Mosby 2006;
179:p.520-525
2. Reed BR. Diseases during pregnancy. Program and abstracts
of the American Academy of Dermatology, Academy
2001; July 29-August 1, 2001; Anaheim, California. Topic
Session 210.
3. Kroumpouzos G, Cohen LM. Dermatoses of pregnancy. J
Am Acad Dermatol. 2001; 45:1-19.
4. Ambros - Rudolph C, Mullegger R, Vaughn-Jones S, et
al. The specific dermatoses of pregnancy revisited and
reclassified: Results of a retrospective two-center study
on 505 pregnant patients, J Am Acad Dermatol 2006;
54:395-404.
5. Bunker CB, Erskine K, Rustin MP, Gilkes JJH Severe polymor-
phic eruption of pregnancy occurring twin pregnancies.
Clin Exp Dermatol 1990; 15:228-230.
6. Cummingham G. Dermatological Disorders. In: Mac Donald
P, Gant N, Leveno K, Gilstrap L, editors. Williams Obstrectics.
19th edition. London: Prentice Hall International Inc; 1993;
56(13):p.1259-1267.
7. Stephanie Regnier, Virginie Fermard, Pierre Levy, et al,
editors. A case-control study of polymorphic eruption of
pregnancy. J Am Acad Dermatol 2008; 58:63-67.
8. Aractingi S, Berkane N, Bertheau P, et al. Fetal DNA in skin
of polymorphic eruptions of pregnancy. Lancet. 1998;
352:1898-1901.
9. Holmes RC, Black MM, Dann J, et al. A comparative study
of toxic erythema of pregnancy and herpes gestationis.
Br J Dermatol 1982; 106:499-510.
10. Reed BR. Dermatological drugs, pregnancy, and lactation. A
conservative guide. Arch Dermatol. 1997; 133:894-898.
11. Sasseville D. Dermatological therapy during pregnancy
and lactation. In: Harahap M, Wallach R, editors. Skin
changes and diseases in pregnancy. New York: Marcel
Dekker; 1996:249-319.
12. Caller JP, Happo R. Pruritic urticarial papules and plaques
of pregnancy (PUPPP). A clinicopathologic study. J Am
Acad Dermatol 1981; 5:401-405.
13. Green LR. Programming of endocrine mechanisms of
cardiovascular control and growth. J Soc Gynecol Investig.
2001; 8:57-68.
14. Vaughan Jones SA, Dunmill MG, Black MM. Pruritic
urticarial papules and plaques of pregnancy (polymor-
phic eruption of pregnancy): two unusual. Br J D. 1996;
135:102-105.
15. Shornick JK. Pregnancy dermatoses. In: Bolognia JL,;Jorizzo
JL, Rapini RP, Horn TD, Mancini AJ, Mascara JM, et al
editors. Dermatology. 2nd edition. New York: Mosby;
2003;29(4):425-432.
16. Kelly SE, Black MM, Fleming S. Pemphigoid gestationis:
a unique mechansism of initiation of an autoimmune
response by MHC class II molecules? J Pathol. 1989;
158:81-82.
17. Shornick JK, Bangert JL, Freeman, Gillian JN. Herpes
gestationis: clinical and histologic feature twenty-eight
cases. J Am Acad Dermatol. 1983; 8:214-224.
18. Jurecka W, Holmes RC, Black MM, et al. An immunoelec-
tron microscopy study of the relationship between herpes
gestationis and polymorphic eruption of pregnancy. Br.
J Dermatol. 1983; 108:147-151.
19. Sitaru C, Powell J, Messer G, et al. Immunoblotting and
enzyme-linked immunosorbent assay for the diagno-
sis of pemphigoid gestationis. Obstet Gynecol. 2004;
109:p.757-763.
20. Van de Weil A, Hart C, Flinkermann J, et al. Plasma exchange
in herpes gestationis. Br Med J 1980; 2:1041-1042.
21. Lawley TL, Sting G, Katz SI. Fetal and maternal risk factors
in herpes gestationisis. Arch Dermatol 1979; 552-555.
22. Vaughan-Jones SA, Hern S, Nelson-Piercy C, Seed PT, Black
MM. A prospective study of 200 women with dermatoses
of pregnancy correlating; clinical findings with hormonal
and immunopathological prtoflles. Br J Dermatol 1999;
141:71-81.
23.Kroumpouzos G. Intrahepatic cholestasis of pregnancy:

DERMATOLOGICAL DISORDERS UNIQUE TO PREGNANCY
85
What’s new. JEADV 2002; 5:316-318..
24. Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholesta-
sis of pregnancy: relationships between bile acid levels
and fetal complication rates. Hepatology 2004; 40:p.287-
288.
25. Brites AD. Intrahepatic cholestasis of pregnancy: changes
in maternal-fetal bile acid balance and improvement by
ursodeoxycholic acid. Hepatol 2002; 1:p.20-28.
26. Lebwohl M, Kerkhof P. Impetigo Herpetiformir. In: Lebwohl
M, Heymann W, Bert-Jones J, and Coulson L editors.
Treatment of skin disease; Comprehensive therapeutic strat-
egies. 2nd edition. New York:Mosby 2006; 188:p.551.
27. Kerkhof P. Papulosquamous and Ecrematous dermato-
sis. Psoriasis pustular variant In: Bolognia JL, Jorizzo JL,
Rapini RP, Horn TD, Mancini AJ, Mascaro JM, et al editors.
Dermatology. New York:Mosby; 2003; 9(3):137-139.