- Email: [email protected]
Polymorphic eruption of pregnancy
Polymorphic Eruption of Pregnancy Drew Taylor MD, Eden Pappo MD, Iris K. Aronson MD PII: DOI: Reference:
S0738-081X(16)30026-8 doi: 10.1016/j.clindermatol.2016.02.011 CID 7023
To appear in:
Clinics in Dermatology
Please cite this article as: Taylor Drew, Pappo Eden, Aronson Iris K., Polymorphic Eruption of Pregnancy, Clinics in Dermatology (2016), doi: 10.1016/j.clindermatol.2016.02.011
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT POLYMORPHIC ERUPTION OF PREGNANCY Drew Taylor, MD, Eden Pappo, MD, Iris K. Aronson, MD
RI P
T
University of Illinois at Chicago College of Medicine, Department of Dermatology, Chicago, IL
Key Words: polymorphic eruption of pregnancy; pruritic urticarial papules and plaques of
Conflicts of Interest: None declared.
NU
Tables: 1
Figures: 3
Reference count: 83
MA
Word Count: 96 (Abstract) / 4,698 (Text)
SC
pregnancy; etiopathogenesis; management
PT
ED
Funding sources: None declared.
CE
Contact Information: Drew Taylor: [email protected]; Iris K. Aronson: [email protected]
AC
Corresponding Author: Eden Pappo, MD
University of Illinois at Chicago College of Medicine, Department of Dermatology Address: 808 S Wood Street, 380CME; M/C 624 Chicago, IL 60612 Telephone: 847-804-0430 E-mail: [email protected]
ACCEPTED MANUSCRIPT ABSTRACT Polymorphic eruption of pregnancy (PEP), a specific dermatosis of pregnancy also known as
RI P
T
pruritic urticarial papules and plaques of pregnancy (PUPPP), is a benign, self-limited skin disorder. Key features include an increased prevalence in primigravidas, onset in the third
SC
trimester, remission near the time of delivery, and association with multiple gestation pregnancy. The clinical features are crucial to diagnosis. Histopathology is non-specific, and
NU
immunofluorescence sutides help differentiate PEP from pemphigoid gestationis. The
MA
pathogenesis of PEP remains elusive, and relvant theoreis are reviewed. There are no
AC
CE
PT
ED
associated maternal or fetal risks, and treatment is largely symptomatic.
ACCEPTED MANUSCRIPT INTRODUCTION Pruritic urticarial papules and plaques of pregnancy (PUPPP) and polymorphic eruption of
RI P
T
pregnancy (PEP) are synonymous terms for a pregnancy-associated skin disorder. Despite the multiple prior names and due to the clinical spectrum reported for this dermatosis, the term
SC
PEP has begun to supplant PUPPP. This article reviews historical aspects culminating in the current name of this disorder, the diagnostic clinical and histopathological features, treatment
NU
options, as well as areas of current research that may shed light on the etiology of this specific
MA
dermatosis of pregnancy.
ED
HISTORICAL PERSPECTIVE
PEP, an erythematous, urticarial eruption of pregnancy, has been described under various
PT
names.1, 2, 3, 4 Previously named entity Toxemic Rash of Pregnancy, first described by Bourne in
CE
1962, showed features of PEP. Bourne described a severely pruritic eruption presenting in late
AC
pregnancy with erythematous papules and plaques within abdominal striae, often with gradual spread, and resolving after delivery.1 The majority (62.5%) of patients were primigravidas, the incidence of the eruption was 1 in 120 patients, and pregnancies were uneventful.1 The term Toxemic Rash of Pregnancy continued to be used in Europe until 1982, even by Holmes and Black, who in that same year in another article proposed abandoning that term as well as PUPPP, and proposing a new name for the entity, Polymorphic Eruption of Pregnancy (PEP).5
Another diagnostic name considered consistent with the clinical entity of PEP is Late-Onset Prurigo of Pregnancy, reported by Nurse in 1968.2 Nurse divided the cases into an early and a
ACCEPTED MANUSCRIPT late type, with the early type consisting of papules affecting the extremities consistent with the papular prurigo eruptions. The late type had the abdominal focus, urticarial papules and
RI P
T
plaques but also targetoid and occasional vesicular lesions.2, 6 Half of the patients were primagravidas, and one case of twins was reported. With the exception of one stillbirth, the
SC
babies were healthy. The late-onset dermatosis is clinically consistent with findings in PEP.7 Due to clinical similarities of pre-bullous herpes gestationis, in the pre-direct immunofluorescence
NU
(DIF) era, Nurse suggested that this entity may be a pre-bullous, or less severe form of herpes
MA
gestationis (HG).2 When DIF became available in 1973, it was recognized as a valuable tool to differentiate various dermatoses of pregnancy. The histopathologic and immunopathologic
ED
correlation became particularly critical in the differentiation of pemphigoid gestationis (PG)
PT
(synonymous with HG) from PEP.3, 7
CE
The term PUPPP was first used in 1979 by Lawley and colleagues.3 The small study included
AC
characteristic onset in the third trimester, cutaneous findings of erythematous urticarial papules and plaques first seen on the abdomen, and spreading to the extremities, mainly the thighs, buttocks and arms. No patient had facial involvement, and vesicles were only rarely noted. The papules were often surrounded by a thin, pale halo. Histopathologic findings and negative DIF were consistent with the current diagnosis of PEP (see below). The majority of patients were in their first pregnancy and all patients had resolution of symptoms within 2 weeks of parturition.3 Lawley et al noted that although the women reported intractable pruritus, excoriated lesions were uncommon. He also differentiated PUPPP from other
ACCEPTED MANUSCRIPT dermatoses of pregnancy and from Spangler’s Papular Dermatitis of Pregnancy which is now
RI P
T
considered a widespread prurigo of pregnancy, an atopic eruption of pregnancy.8
In 1980 Cooper et al aimed to clarify the varying diagnostic terminology, reporting several
SC
patients who fit the overall diagnosis termed Prurigo of Late Pregnancy.4 In 1982, Holmes and Black suggested a classification of pregnancy-specific dermatoses to include PG, PEP and
NU
prurigo of pregnancy (PP), in an attempt to simplify and organize the many entities related to
MA
these diagnoses.6 The main distinction between the latter two categories was that PEP had urticarial primary lesions whereas PP had lesions that were primarily excoriated prurigo
ED
papules. They included in the PEP category Nurse’s Late Onset Prurigo of Pregnancy, Lawley’s PUPPP, and Bourne’s Toxaemic Rash of Pregnancy. The key elements were onset in late
PT
pregnancy, pruritic papules and urticarial plaques within and around abdominal striae with
CE
spread to extremities, and prompt improvement after delivery.6 While Holmes and Black
AC
appreciated the morphologic appropriateness of PUPPP terminology, they felt that the term PEP was more inclusive and concise because of the variable clinical presentation of this entity and “was both clinically accurate and free from misleading connotations”.6 All subsequent classification systems of dermatoses of pregnancy have maintained PEP/PUPPP as a distinct diagnostic entity, separated from atopic and prurigo eruptions as well as from PG.
EPIDEMIOLOGY The incidence of PEP in a single pregnancy has been estimated at 1 in 200 pregnancies (0.5%),9 as well as 1 in 120 pregnancies,1, 4 thus a common pregnancy-specific dermatosis. The average
ACCEPTED MANUSCRIPT age in studies has been reported at 25.4 years10 and 29 years,11 similar to the general population of women giving birth depending on the year of the study. Caucasians are most
T
often affected (88% in one large study).12 Non-Caucasian incident rates are lower depending on
RI P
the population; a large Israeli study found a rate of 0.03%.13 A large study in India found a
SC
higher rate of PEP of 2.3%14 although in another study of patients in Northern India, intrahepatic cholestasis of pregnancy was the most common diagnosis.15 An Iraqi study found
NU
PEP to be the most common dermatosis of pregnancy, at 29.5% of the specific pregnancy
MA
dermatoses,16 whereas a much lower incidence of 1% was reported in a Pakistani study.17
ED
CLINICAL FEATURES These are summarized on the Table.
AC
CE
PT
Table. Key Features of Polymorphous Eruption of Pregnancy. Onset Third trimester or shortly postpartum; less often in other trimesters Resolution Postpartum Clinical findings Variable erythematous, pruritic papules and plaques, beginning in the abdominal striae with distal spread and occasional generalization. May include small vesicles or target-like lesions. Does not tend to recur in subsequent pregnancies or with hormonal exposures Diagnosis Clinical; direct immunofluorescence skin testing to rule out pemphigoid gestationis Maternal characteristics More likely nulliparous or primigravida Fetal characteristics Male predominance Maternal risks Possible increased risk of cesarean section Fetal risks None Management Patient counseling Symptomatic treatment (topical corticosteroids, topical emollients, oral antihistamines) Refractory cases may require systemic corticosteroids
Primigravidas / nulliparous
ACCEPTED MANUSCRIPT There is a high percentage of women with PEP who are either pregnant with their first child or who have never given birth (i.e. the first pregnancy suffered from spontaneous abortion, etc.).
T
In one review, 42% were primigravidas and 68% were nulliparous.10 In larger studies, 70% and
RI P
73% were primigravidas.11, 12 A small study reported an even higher percentage of nulliparous
SC
patients (89%).18
NU
Multiple gestation pregnancy
MA
Several studies have reported an increase in multiple gestation pregnancies in women presenting with PEP, compared to the general population. They showed 16%,11 13%,19 and
ED
9.5%13 of PEP cases associated with multiple gestation pregnancies. In a study from Lebanon, half of the patients (9 of 18) with PEP had multiple gestation pregnancies; of note, the majority
CE
PT
of those pregnancies resulted from in vitro fertilization procedures.18
AC
In a specific investigation of multiple gestations in association with PEP, 2.9% of 8000 twin pregnancies had a diagnosis of PEP, but 14.3% of triplet pregnancies was associated with PEP. 20 In the original PUPPP case series, 28.6% of the cases were multiple gestation pregnancies.3 Other incidence rates of multiple gestation pregnancy in PEP include 9%,21 16%,22 and 10% whereas the control population was 1.6%.23 In the largest PEP study to date, patients with multiple gestation pregnancies had earlier onset of skin lesions.12 A meta-analysis has demonstrated a prevalence of multiple gestation in PEP was 10-fold higher than the prevalence of multiple gestation pregnancy in the United States.24
ACCEPTED MANUSCRIPT Gender of fetus Some authors have reported an increased frequency of male fetuses in PEP cases. In one study,
RI P
T
the sex of the newborn was male in 64.5% of the PEP group, while the percentage was closer to the expected statistic (48.5%) in the control group. This was statistically significant after
SC
multivariate analysis (P=0.026).25 A prospective study observing women with multiple dermatoses of pregnancy found an increased prevalence in women who were carrying male
NU
fetuses compared to female fetuses, with a ratio of 2:1.26 The largest study found an overall
MA
increase in male fetuses, but with no statistical significance.12
ED
Effect on fetus and pregnancy
Maternal and fetal outcomes are not altered if the patient has PEP.6, 13 Throughout the
PT
literature, there are reports that infants of mothers with PEP are born without complications
CE
and without skin lesions, however one case report did note similar cutaneous lesions on the
AC
infant born to a mother diagnosed with PEP.27 Preterm delivery prior to 37 weeks’ gestation in 18.4% of PEP patients, compared to in 5.8% of control group patients has been reported (P=0.02).25 Another large study separating the patients into early and late onset groups based on symptoms before or after 35 weeks, respectively, the early onset group had a statistically significant (P<0.001) lower mean gestational age at time of delivery.12
Rate of cesarean section has also been noted, with one study demonstrating a statistically higher incidence of cesarean section in patients with PEP (40% versus 13.1% in the control group, P= <0.0001).25 The reasons for cesarean section were not reported for all patients. An
ACCEPTED MANUSCRIPT increase in cesarean section (56%) was also noted in another study in which all patients had healthy babies without skin lesions or other complications.18 In addition, the number of
T
hospitalizations for pregnant patients was also higher in the PEP group compared to the control
RI P
group (P= <0.0001).25 In another study, induction of labor was seen significantly more often in
SC
PEP patients, along with lower APGAR scores and higher rate of cesarean section in the PEP group compared to the control group.13 There was also a statistically significant association
MA
NU
between PEP patients versus control with regards to hypertensive disorders.13
PEP infrequently recurs in subsequent pregnancies. Nineteen patients were followed for 5 years
ED
postpartum in which time there were 8 pregnancies as well as oral contraceptive exposure with no repeated episode of PEP.22 However, recurrence was noted in one of four and 3 of 57 PEP
CE
PT
patients in two other studies.4, 10
AC
The data above suggests a possible increase in cesarean section rates and preterm labor in PEP; however, larger studies are needed in order to evaluate these risks. Overall, earlier onset may have greater effect on preterm delivery. PEP has been reported to recur, but infrequently.4, 10
Onset and Resolution PEP begins most often in the third trimester with rates between 79% to 100%,10, 11, 18, 28 with few outliers in the late second trimester or postpartum.10, 11, 12, 18 Second trimester symptoms were rare, and 15-16% of patients did not develop symptoms until the postpartum period. 11,12 Resolution of symptoms generally occurs promptly after delivery. In one study, 33% of patients
ACCEPTED MANUSCRIPT had resolution intrapartum or prior to delivery, 60% had resolution within 1 week of delivery, and less than 1% had symptom resolution several weeks postpartum.28 In another study
T
cutaneous lesions were resolved in 100% of patients within 1-4 weeks of delivery, with a mean
RI P
clearance at 3 weeks postpartum.18 Interestingly, a more atypical PEP presentation is associated
SC
with a longer duration,12 earlier onset,10 multigravida status, and atopy.12
NU
Cutaneous findings
MA
PEP presents as pruritic, urticarial papules and plaques during pregnancy. This finding is consistent throughout the literature, but the variation in presentation suggests PEP as an
ED
appropriate diagnostic term. Aronson et al categorized the clinical findings into three PEP subgroups; type I, characterized primarily by urticarial papules and plaques, type II, which
PT
included broader clinical findings such as erythematous patches, non-urticarial papules (1-
CE
2mm) or vesicles, and type III, a combination of the other two types.10 All three types often
AC
also had some lesions with surrounding blanched halos (Figure 1). Erythema multiforme-like targetoid lesions were noted in 5.3% (histopathology in these cases excluded erythema multiforme).10 However, this categorization did not affect treatment options, response to treatment or outcomes.10, 29
A characteristic clinical finding of PEP is predominant abdominal involvement, often beginning within and around abdominal striae (Figure 2).6, 10 In one study, 48% had primary lesions which began within the abdominal striae;22 however, lesions can be seen in patients without abdominal striae.10 The proximal upper and lower extremities are the most common non-
ACCEPTED MANUSCRIPT abdominal locations.10 In 91% of patients in a large study, the cutaneous symptoms were first seen on the abdomen or the proximal thighs and occasionally both; only 17% had skin lesions
T
stay within this distribution without generalized spread. This group showed 3% of all patients
SC
RI P
lacking any abdominal involvement.12
Mucosal sparing is a clinical aspect consistent throughout the literature. 12, 20 PEP atypical
NU
lesions, including vesicles (Figure 3), complicate the diagnosis, and have been reported in up to
MA
40% of cases.30 In a large retrospective study, 98% presented with the classic pruritic, urticarial plaques and papules. Later in the course, 51% had altered clinical findings including vesicles,
ED
targetoid lesions as well as more eczematous plaques.12 Histopathology of the targetoid lesions does not show multiforme-associated histopathological features, thereby excluding erythema
PT
multiforme from the diagnosis.10, 31 An additional study demonstrated that 27.8% of PEP
CE
patients had atypical lesions including vesicles, eczematous patches, and targetoid lesions. The
findings.18
AC
most common atypical feature was presence of vesicles along with the more typical urticarial
Palms or soles may be involved with papular or vesicular lesions resembling dyshidrotic eczema as well as PG but are affected in less than 2% of patients.10, 11, 12 Facial involvement has varied from 1-2%11, 12 to 12%10 and, when present, is seen in patients with the larger PEP spectrum that includes erythema, vesicles and targetoid lesions.10
ACCEPTED MANUSCRIPT DIAGNOSIS PEP is a disorder with a broad clinical spectrum and diverse clinical features but with absence of
RI P
T
pathognomonic identifying features. Due to the wide clinical spectrum of PEP, laboratory and histopathological investigations need to be utilized to exclude other entities, particularly those
SC
that potentially pose an unfavorable maternal or fetal prognosis. The authors recommend obtaining complete blood count, liver function tests, renal function, thyroid stimulating
NU
hormone, urinalysis, and bile acids. PEP must be differentiated from PG, contact dermatitis,
MA
toxic drug eruptions, viral exanthems, pityriasis rosea, and urticaria.
ED
Histopathology shows a superficial or superficial and deep perivascular dermatitis with lymphohystiocytic vasculitis.32 Eosinophils are often present (60-100%) but to varying
PT
degrees.12, 18 Variable papillary edema, and nuclear dust can be seen.32, 33 In about 33% of cases,
CE
focal spongiosis and parakeratosis are present.34 Additional epidermal changes include
AC
acanthosis, hyperkeratosis, and intraepidermal vesicles.12 Lesions, present for greater than 72 hours, are more likely to display epidermal changes.32 There is no definitive diagnostic histopathologic difference between PEP and atopic eruption of pregnancy (AEP).32
If there is question regarding the diagnosis, two biopsies should be performed: one from lesional skin for hematoxylin and eosin staining and one from perilesional skin for direct immunofluorescence (DIF). DIF can be utilized to differentiate PEP from PG and urticarial vasculitis. In one report, 15 (31%) of 57 patients had nonspecific positive granular deposition of IgM, IgA, or C3 at the dermal-epidermal junction or at the blood vessels.10 The extent of
ACCEPTED MANUSCRIPT immunoglobulin or C3 deposition varied significantly. There was also an association of earlier onset PEP and positive DIF, thus lending insight into a more exuberant inflammatory state in
T
early onset PEP.10 Another study of DIF cases found 2 with IgM, C3 or IgA deposition in a
RI P
nonspecific, granular distribution that was not diagnostic.11 The deposition was noted either at
SC
the dermal-epidermal junction or surrounding blood vessels.11 This is in contrast to the linear C3 deposition that is seen in PG. Consistently negative DIF studies for PEP are reported
NU
throughout the literature.3, 12, 33 Of note, there was no difference in DIF findings between the
MA
three clinical subtypes of PEP.10 Additionally, indirect complement-added immunofluorescence or serological studies may assist in differentiating PG and PEP. Formalin-fixed paraffin-
ED
embedded tissue-based immunohistochemistry for anti-C3d or C4d can be utilized, in place of DIF, for differentiating PEP from PG.35,36 The C4d immunohistochemistry may eliminate the
PT
need for DIF biopsy in the future, thus allowing to obtain only one biopsy. Until these
AC
CE
techniques are further investigated, DIF continues to be the recommendation.
Other more complex tests have been employed to help identify PEP and differentiate it from PG. Using an NC16A domain enzyme-linked immunosorbent assay (ELISA), the diagnoses could be differentiated with sensitivity and specificity of 96%. NC16A ELISA was more sensitive than IIF for both IgG and C3 studies alone, but the combination of IIF and ELISA testing had superior sensitivity (99%).37 Therefore, PG and PEP may be differentiated with high sensitivity and specificity without taking a tissue sample. The test can be completed within 3.5 hours in some laboratories. Finally, immunoelectron microscopy has been negative in PEP.38 Due to cost
ACCEPTED MANUSCRIPT constraints and availability, DIF and IIF will likely remain the most common tests utilized for
RI P
T
diagnosis.
ETIOPATHOGENESIS
SC
The etiopathogenesis of PEP remains elusive. To date, PEP is not believed to be familial or autoimmune, in the usual sense, although a familial case has been reported. 39 Studies of HLA
NU
types have yet to reveal an association.22 There is no pathognomonic identifiable common
MA
denominator, “PEP factor”, as seen in HG. One possibility is that blunt trauma and koebnerization may be a factor in PEP. Complicating these hypotheses is that PEP onset
ED
immediately postpartum has been reported.40, 41 Select theories regarding PEP pathogenesis
PT
are summarized below.
CE
Inflammatory disorder with koebnerization
AC
Histopathology confirms an inflammatory process underlying PEP. Koebnerization of an inflammatory disorder may explain the predilection for areas of blunt trauma, e.g. striae distensae. Stretching of the skin was recently suggested as a precipitating factor for ‘true koebnerization’ seen in vitiligo, psoriasis, and lichen planus.42 Striae development occurs in 90% of women during pregnancy;43 yet, PEP only occurs in 1:200 pregnancies. In addition, PEP is not limited to koebnerized locations, and may disseminate widely to other regions. It has been suggested that this dissemination in PEP may result from cross-reactivity to dermal antigens in normal skin.44
ACCEPTED MANUSCRIPT Excessive maternal weight (>15 kg by definition) is a point of contention in the development of PEP. Excessive maternal weight gain in 78% and 75% of women with PEP has been reported. 12,18
T
A French study documented an increased maternal weight gain of 15 kg in PEP cases compared
RI P
to 12.73 kg in controls,45 whereas another study reported an average weight gain of 18.1 kg in
SC
PEP patients versus 14.6kg in the control group.23 The weight of the infants was also greater in the PEP group, with an average birth weight of 3.6kg versus 3.3kg for the control group.23 Yet
NU
PEP was statistically not related to maternal or fetal weight gain in other studies. 21, 25
MA
undermining excessive weight gain as a necessary feature and important factor in the
ED
development of PEP.
Multiple gestation pregnancies are a well-documented factor in patients who develop PEP.12, 13, Today, one in 30 babies born is a twin. An increased twin rate of 41.66% in PEP
PT
20, 24, 25
CE
compared to that of 1.2% in controls was documented in one study.45 A 10-fold higher
AC
prevalence of multiple gestation pregnancy in patients with PEP was determined by a metaanalysis.24 Increased incidence of multiple gestation and its consequence of increased abdominal distension, larger abdominal circumference and possible increased striae have been suggested to be related to higher incidence of PEP.24 Maternal anthropometric measurements have been utilized to help determine fetal well-being. A maternal abdominal circumference of 89.1 +/- 4.61 cm has been associated with fetal well-being.46 Whether increasd distension, striae and resultant trauma on collagen play a role in the development of PEP is still speculative.
ACCEPTED MANUSCRIPT Hormonal Although a relationship to reproductive hormones should be considered, no consistent
RI P
SC
PEP has not been confirmed since it was first described.26
T
hormonal abnormalities have been reported.4, 22, 47 The role of low maternal serum cortisol in
Lesional skin in PEP displayed progesterone receptor immunoreactivity in the cytoplasm of
NU
suprabasal keratinocytes whereas non-lesional skin did not.48 Placenta-synthesized
MA
progesterone has been shown to potentiate tissue inflammation and is found in increased amounts in multiple gestation pregnancies. Suprabasilar keratinocytes contain progesterone
ED
receptors and thus can be targets of hormonal factors in pregnancy.49 In addition, female sex hormones have been shown to regulate the synthesis of interleukin-6, a pro-inflammatory
CE
PT
cytokine.50
AC
Prolactin has been suggested as a possible factor in development of PEP as its levels rise in pregnancy, and it functions as a modulator of both skin epithelial growth and skin immune functions.51, 52 It affects the innate and adaptive immune system and its receptors have been found in skin,51, 53 suggesting another possible, but speculative, hormonal factor in the development of PEP.
Microchimerism Another hypothetical etiologic mechanism for development of PEP was raised with the discovery of fetal DNA in the skin lesions of PEP patients with male fetuses and absence in non-
ACCEPTED MANUSCRIPT affected mothers with male fetuses.54 The exact mechanism of fetal DNA homing into maternal skin is puzzling, but the authors propose that it is caused by blood chimerism (fetal cells
T
detected in maternal blood throughout pregnancy).55 The fetal lymphocytes may induce a graft-
RI P
versus-host disease-like reaction against the maternal tissues.56 Bianchi et al provides support
SC
for this hypothesis as they have identified male fetal progenitor cells in the maternal blood 27
NU
years postpartum.57 Currently, this hypothesis remains to be confirmed.
MA
Inflammatory mediated
The immunohistologic profile of patients with PEP strongly expresses an HLA-DR genotype,
ED
indicative of an antigenically driven immune hyperactivation;49 however, lack of consistent HLA association is found in other sources.22, 30 Immunohistochemical studies reveal a predominantly
PT
T-helper lymphocytic infiltrate with an increased number of CD1a+, CD54+ (ICAM-1+) dendritic
CE
cells, and CD1a+ epidermal Langerhans cells in lesional skin compared to perilesional skin. 58, 59
AC
This profile may support a delayed hypersensitivity reaction to an unknown antigen. 24 A Lebanese study found a strong correlation between PEP and erythrocyte rhesus (Rh) factor phenotype positivity.18 The study indicated that all 18 patients with PEP were Rh positive, which is a novel potential antigen. Unfortunately, the study made no mention of the phenotype of the fetuses. Rh phenotype is generally only of concern when the mother is phenotypically negative and the fetus is phenotypically positive. The authors wonder whether Rh immunoglobulin (Rhogam) could prevent PEP if the eruption was driven by antibody response to Rh factor. Of note, Blood type and Rhesus positivity were consistent within the affected population as well as the general population in earlier, smaller studies.2
ACCEPTED MANUSCRIPT
Medication-Induced
T
There have been few reports of suspected medication-induced PEP. Six patients were described
RI P
as having developed PEP after treatment with terbutaline for tocolysis.60 In another report, 3 of
SC
15 PEP patients were treated with progesterone and/or ritodrine or albuterol for threatened premature labor 3 weeks before the onset of the eruption.61 Although an interesting
NU
association, the role of terbutaline, ritodrine or albuterol as the cause of PEP in these case
MA
cannot be determined with certainty. Paradoxically, terbutaline in conjunction with
ED
aminophylline has been reported to treat urticarial eruptions.62
Paternal
PT
Paternity is known to play a role in PG,26 but recent evidence may suggest it also may
CE
contribute to the development of PEP. A multiparous woman developed PEP in her fifth
AC
pregnancy. This fetus was fathered by a different man and was also the patient’s first multiple gestation pregnancy, with significant abdominal distention reported.63 This paternity derived theory is also supported by an observation by another group that reported PEP in families where the sisters were married to brothers.39
Autoimmune DIF is consistently negative in PEP for any specific deposition.3, 12, 33 A single study revealed positive anti-basement membrane IgM antibodies on indirect immunofluorescence in five out of 111 patients with PEP.64 Linear IgM deposition at the dermal-epidermal junction
ACCEPTED MANUSCRIPT unassociated with other antibodies has been reported, but etiopathogenesis was considered non-specific as it was associated with a variety of dermatoses.65 Recently, linear deposition
T
solely of IgM at the basement membrane zone has been associated with Waldenstrom
RI P
macroglobulinemia.66-68 Thus sole IgM deposition at the basement membrane zone,
SC
unassociated with Waldenstrom, is rare, and the significance is still undetermined.
NU
Contradicting the autoimmune theory is the fact that PEP does not seem to recur, and if it does,
MA
it is not necessarily more severe or of earlier onset, which is a hallmark of PG, a disease with known autoimmune etiology.44 Also, there exists only a single case of mother and child with
ED
PEP at birth reported in which the neonate developed a similar rash that resolved within 10 days.27 No DIF was obtained, thus it is uncertain as to whether this was truly PEP, a PEP-like
AC
Atopy
CE
PT
case, or another dermatosis.
Pregnancy creates a shift from a Th-1 to a Th-2 cytokine milieu.69 Pregnancy is a relative state of immunosuppression, designed to prevent fetal rejection. It results in a decreased cell mediated immunity, an increase in humoral immunity, and a natural homeostasis between antigenically different tissues. Recent evidence suggests that atopic dermatitis is an autoimmune disease, driven by an IL-4 and IL-13, Th2-centered inflammatory axis.70 Atopy may have pathogenic significance in PEP and may alter the natural course of the eruption. In one study, 55% of patients who developed PEP had a personal or family history of atopy.12 Serum IgE levels were elevated in 28% of the cases and is likely the result of IL-4 (a Th2 cytokine) induced isotype
ACCEPTED MANUSCRIPT switching to IgE production in B-cells.12 This feature is supported by a work, which found a correlation between PEP and concomitant asthma.10 Similarly, urticarial eruptions may be
RI P
T
exacerbated in pregnancy.71
SC
PROGNOSIS
PEP nearly always resolves with parturition, but has been noted to persist for several weeks
NU
postpartum.72 The average duration of PEP eruptions is 4-6 weeks.44, 73 The self-limited nature,
MA
lack of significant fetal or maternal risk, and the rarity of PEP recurrence in subsequent pregnancies should be conveyed to the patient at time of diagnosis to ameliorate patient
ED
anxiety and enhance understanding of PEP. Interdisciplinary communication between dermatology, obstetrics and neonatal pediatrics is critical in management of more severe cases
CE
PT
of PEP.
AC
It is a general consensus that PEP poses a negligible risk to either the mother or fetus; however, a positive non-stress test in 3 patients,10 hypertension and mild preeclampsia as well as hypertension with induction of labor13 have been reported. An increased incidence of cesarean section especially with multiple gestation pregnancies, and rare stillborn births have been reported.13, 22, 25 Although these problems are relatively rare findings, they should be kept in mind and monitored for in patients with PEP.
ACCEPTED MANUSCRIPT TREATMENT Symptomatic treatment consists of cooling baths, frequent application of emollients,
RI P
T
refrigerated menthol-containing topical medications (r the safety of these products in pregnancy when used frequently and over extensive body areas with increased absorption is
SC
unclear and generally not recommended by the authors), light cotton clothing, oral firstgeneration sedating antihistamines (chlorpheniramine and diphenhydramine) and mid-potency
MA
NU
topical corticosteroids.
Severe cases may warrant super-potent topical corticosteroids, limited to a total of 200 grams
ED
over the duration of pregnancy, as amounts greater than 300 grams have been associated with low birth weight.74 A recent report demonstrated that fluticasone 0.05% lotion, a low-medium
PT
potency corticosteroid, applied two times daily had dramatic efficacy within one week. 29 If oral
CE
corticosteroids are needed, prednisolone, 40-60 mg/day, with a quick taper, is favored over
AC
betamethasone given the lower risk of fetal hypothalamic-pituitary-adrenal axis suppression, with a maternal-fetal gradient of 10:1,75 and has been shown to induce prompt resolution of both symptoms and cutaneous eruption.76 While a lower dose of prednisone is preferred, it may not improve symptoms as quickly.22
Given the relatively short duration of PEP, narrowband ultraviolet light B (NBUVB) is rarely employed, but has been reported as effective.77 NBUVB can induce degradation of folate in patients with psoriasis, thus additional folate supplementation must be reinforced in any patient undergoing NBUVB therapy during pregnancy.78
ACCEPTED MANUSCRIPT
An interesting therapeutic strategy, recently reported in Europe, consists of intramuscular
T
injections of autologous whole blood.79 It has been postulated that autologous whole blood, at
RI P
the correct dose, promotes a ‘self-healing process’ within the body.80 This is similar to data
SC
published in 1941, in which women with PEP were injected with blood serum from a woman without PEP.81 Further investigation of this therapeutic modality is required to definitely
MA
NU
comment on this treatment option.
Recalcitrant PEP may resolve with cesarean section.82 PEP is not considered an indication for
ED
early delivery or induction of labor. Of note, all current treatment trials are done in small
CE
CONCLUSIONS
PT
patient populations.83
AC
PEP, synonymous with PUPPP, is a benign, pregnancy-specific dermatosis. It can cause severe pruritus but is not associated with any fetal risks. Key characteristics of PEP include an increased prevalence in primigravidas, onset towards the end of pregnancy, and distribution of lesions within or adjacent abdominal striae. DIF is integral in ruling out PG. While its etiopathogenesis is unknown, several potential theories based on variable evidence exist. Treatment is largely symptomatic, focusing on control of pruritus; however, further research for safe and effective treatment modalities is being conducted.
ACCEPTED MANUSCRIPT
REFERENCES
RI P
T
1. Bourne G. Toxaemic rash of pregnancy. Proc R Soc Med. 1962;55:462-464. 2. Nurse DS. Prurigo of pregnancy. Australas J Dermatol. 1968;9:258-267.
SC
3. Lawley TJ, Hertz KC, Wade TR, et al. Pruritic urticarial papules and plaques of pregnancy. JAMA. 1979;241:1696-1699.
NU
4. Cooper AJ, Fryer JA. Prurigo of late pregnancy. Australas J Dermatol. 1980;21:79-84.
MA
5. 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.
ED
6. Holmes RC, Black MM. The specific dermatoses of pregnancy: a reappraisal with special emphasis on a proposed simplified clinical classification. Clin Exp Dermatol. 1982;7:65-73.
PT
7. Ambros-Rudolph CM. Dermatoses of pregnancy - clues to diagnosis, fetal risk and therapy.
CE
Ann Dermatol. 2011;23:265-275.
AC
8. Ambros-Rudolph CM, Black MM. From prurigo gestationis Besnier to atopic eruption of pregnancy: the confusing nosology of the less well-defined dermatoses of pregnancy has been largely clarified. Clin Dermatol. 2006;24:545-547. 9. Holmes RC, Black MM. The specific dermatoses of pregnancy. J Am Acad Dermatol. 1983;8:405-412. 10. Aronson IK, Bond S, Fiedler VC, et al. Pruritic urticarial papules and plaques of pregnancy: Clinical and immunopathologic observations in 57 patients. J Am Acad Dermatol. 1998;39:933-939.
ACCEPTED MANUSCRIPT 11. Ambros-Rudolph CM, Mullegger RR, Vaughan-Jones SA, et al. The specific dermatoses of
RI P
pregnant patients. J Am Acad Dermatol. 2006;54:395-404.
T
pregnancy revisited and reclassified: results of a retrospective two-center study on 505
12. Rudolph CM, Al-Fares S, Vaughan-Jones SA, et al. Polymorphic eruption of pregnancy:
SC
clinicopathology and potential trigger factors in 181 patients. Br J Dermatol. 2006;154:5460.
NU
13. Ohel I, Levy A, Silberstein T, et al. Pregnancy outcome of patients with pruritic urticarial
MA
papules and plaques of pregnancy. J Matern Fetal Neonatal Med. 2006;19:305-308. 14. Kumari R, Jaisankar TJ, Thappa DM. A clinical study of skin changes in pregnancy. Indian J
ED
Dermatol Venereol Leprol. 2007;73:141.
15. Chander R, Garg T, Kakkar S, et al. Specific Pregnancy Dermatoses in 1430 females from
PT
Northern India. J Dermatol Case Rep. 2011;5:69-73.
CE
16. Hamdi K, Dhaher SA, Alyasin ZT. Specific dermatoses of pregnancy among Iraqi pregnant
AC
women. Iraqi J Comm Med. 2010;3:177-180. 17. Niaz F, Wahid Z, Ahmed I, et al. Frequency of specific dermatoses of pregnancy. J Pak Assoc Dermatol. 2013; 23:256-261. 18. Ghazeeri G, Kibbi AG, Abbas O. Pruritic urticarial papules and plaques of pregnancy: epidemiological, clinical, and histopathological study of 18 cases from Lebanon. Int J Dermatol. 2012;51:1047-1053. 19. Powell FC. Pruritic urticarial papules and plaques of pregnancy and multiple pregnancies. J Am Acad Dermatol. 2000;43:730-731.
ACCEPTED MANUSCRIPT 20. Elling SV, McKenna P, Powell FC. Pruritic urticarial papules and plaques of pregnancy in twin and triplet pregnancies. J Eur Acad Dermatol Venereol. 2000;14:378-381.
RI P
T
21. Roger D VL, Lorette G. Pruritic urticarial papules and plaques of pregnancy are not related to maternal or fetal weight gain. Arch Dermatol. 1990;126:1517.
SC
22. Yancey KB, Hall RP, Lawley TJ. Pruritic urticarial papules and plaques of pregnancy. Clinical experience in twenty-five patients. J Am Acad Dermatol. 1984;10:473-480.
NU
23. Cohen LM, Capeless EL, Krusinski PA, et al. Pruritic urticarial papules and plaques of
Dermatol. 1989;125:1534-1536.
MA
pregnancy and its relationship to maternal-fetal weight gain and twin pregnancy. Arch
ED
24. Kroumpouzos G, Cohen LM. Specific dermatoses of pregnancy: an evidence-based systematic review. Am J Obstet Gynecol. 2003;188:1083-1092.
PT
25. Regnier S, Fermand V, Levy P, et al. A case-control study of polymorphic eruption of
CE
pregnancy. J Am Acad Dermatol. 2008;58:63-67.
AC
26. Vaughan Jones SA, Hern S, Nelson-Piercy C, et al. A prospective study of 200 women with dermatoses of pregnancy correlating clinical findings with hormonal and immunopathological profiles. Br J Dermatol. 1999; 141:71-81. 27. Uhlin SR. Pruritic urticarial papules and plaques of pregnancy. Involvement in mother and infant. Arch Dermatol. 1981;117:238-239. 28. Callen JP, Hanno R. Pruritic urticarial papules and plaques of pregnancy (PUPPP). A clinicopathologic study. J Am Acad Dermatol. 1981;5:401-405.
ACCEPTED MANUSCRIPT 29. Scheinfeld N. Pruritic urticarial papules and plaques of pregnancy wholly abated with one week twice daily application of fluticasone propionate lotion: a case report and review of
RI P
T
the literature. Dermatol Online J. 2008;14:4.
30. Charles-Holmes R. Polymorphic eruption of pregnancy. Semin Dermatol. 1989; 8:18-22.
SC
31. Sirikudta W, Silpa-Archa N. Polymorphic eruption of pregnancy presented with targetoid lesions: a report of two cases. Case Rep Dermatol. 2013;5:138-143.
NU
32. Massone C, Cerroni L, Heidrun N, et al. Histopathological diagnosis of atopic eruption of
Dermatopathol. 2014;36:812-821.
MA
pregnancy and polymorphic eruption of pregnancy: a study on 41 cases. Am J
ED
33. Moreno A, Noguera J, de Moragas JM. Polymorphic eruption of pregnancy: histopathologic study. Acta Derm Venereol. 1985;65:313-318.
PT
34. Weedon D. The vasculopathic reaction pattern. In: Weedon D, ed: Weedon’s Skin Pathology.
CE
3rd ed. London: Churchill Livingstone Elsevier, 2010;195-244.
AC
35. Kwon EJ, Ntiamoah P, Shulman KJ. The utility of C4d immunohistochemistry on formalinfixed paraffin-embedded tissue in the distinction of polymorphic eruption of pregnancy from pemphigoid gestationis. Am J Dermatopathol. 2013; 35:787-791. 36. Pfaltz K, Mertz K, Rose C, et al. C3d immunohistochemistry on formalin-fixed tissue is a valuable tool in the diagnosis of bullous pemphigoid of the skin. J Cutan Pathol. 2010;37:654-658. 37. Powell A, Sakuma-Oyama Y, Oyama N, et al. Usefulness of bp180 nc16a enzyme-linked immunosorbent assay in the serodiagnosis of pemphigoid gestationis and in differentiating
ACCEPTED MANUSCRIPT between pemphigoid gestationis and pruritic urticarial papules and plaques of pregnancy. Arch Dermatol. 2005;141:705-710.
RI P
T
38. Jurecka W HR, Black MM, McKee P, Das AK, Bhogal B. An immunoelectron microscopy study of the relationship between herpes gestationis and polymorphic eruption of pregnancy. Br J
SC
Dermatol. 1983;108:147-151.
Am Acad Dermatol. 1992;26:715-717.
NU
39. Weiss R, Hull P. Familial occurrence of pruritic urticarial papules and plaques of pregnancy. J
MA
40. Park SY, Kim JH, Lee WS. Pruritic urticarial papules and plaques of pregnancy with unique distribution developing in postpartum period. Ann Dermatol. 2013;25:506-508.
ED
41. Buccolo LS, Viera AJ. Pruritic urticarial papules and plaques of pregnancy presenting in the postpartum period: a case report. J Reprod Med. 2005;50:61-63.
PT
42. Verma SB. Striae: stretching the long list of precipitating factors for 'true koebnerization' of
CE
vitiligo, lichen planus and psoriasis. Clin Exp Dermatol. 2009;34:880-883.
AC
43. Korgavkar K, Wang F. Stretch marks during pregnancy: a review of topical prevention. Br J Dermatol. 2015;172:606-615. 44. Ahmadi S, Powell FC. Pruritic urticarial papules and plaques of pregnancy: current status. Australas J Dermatol. 2005;46:53-58. 45. Pauwels C, Bucaille-Fleury L, Recanati G. Pruritic urticarial papules and plaques of pregnancy: relationship to maternal weight gain and twin or triplet pregnancies. Arch Dermatol. 1994;130:801-802. 46. Preedy VR, ed. Handbook of Growth and Growth Monitoring in Health and Disease. New York: Springer Verlag; 2011.
ACCEPTED MANUSCRIPT 47. Alcalay J, Ingber A, Kafri B, et al. Hormonal evaluation and autoimmune background in pruritic urticarial papules and plaques of pregnancy. Am J Obstet Gynecol. 1988;158:417-
RI P
T
420.
48. Callahan TL, Hall JE, Ettner SL, et al. The economic impact of multiple-gestation pregnancies
SC
and the contribution of assisted-reproduction techniques to their incidence. N Engl J Med. 1994;331:244-249.
NU
49. Cohen LM, Kroumpouzos G. Polymorphic eruption of pregnancy. In: Kroumpouzos G, ed:
MA
Text Atlas of Obstetric Dermatology. Philadelphia: Lippincott Williams & Wilkins publishers; 2013:194-204.
ED
50. Telleria CM, Ou J, Sugino N, et al. The expression of interleukin-6 in the pregnant rat corpus
1998;139:3597-3605.
PT
luteum and its regulation by progesterone and glucocorticoid. Endocrinology.
CE
51. Horseman ND, Gregerson KA. Prolactin actions. J Mol Endocrinol. 2014; 52:R95-106.
AC
52. Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol. 2009;114:1326-1331. 53. Peeva E, Zouali M. Spotlight on the role of hormonal factors in the emergence of autoreactive B-lymphocytes. Immunol Lett. 2005;101:123-143. 54. Aractingi S, Berkane N, Bertheau P, et al. Fetal DNA in skin of polymorphic eruptions of pregnancy. Lancet. 1998;352:1898-1901. 55. Ganshirt D, Garritsen HS, Holzgreve W. Fetal cells in maternal blood. Curr Opin Obstet Gynecol. 1995;7:103-108.
ACCEPTED MANUSCRIPT 56. Caproni M, Giomi B, Berti S, et al. Relevance of cellular infiltrate and cytokines in polymorphic eruption of pregnancy (PEP). J Dermatol Sci. 2006;43:67-69.
RI P
T
57. Bianchi DW, Zickwolf GK, Weil GJ, et al. Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum. Proc Natl Acad Sci USA. 1996;93:705-708.
SC
58. Carli P, Tarocchi S, Mello G, et al. Skin immune system activation in pruritic urticarial papules and plaques of pregnancy. Int J Dermatol. 1994;33:884-885.
NU
59. Tarocchi S, Carli P, Caproni M, et al. Polymorphic eruption of pregnancy. Int J Dermatol.
MA
1997;36:448-450.
60. Barron WM, Lindheimer MD, eds. Medical disorders during pregnancy. 2nd ed. St. Louis:
ED
Mosby; 1995.
61. Roger D, Vaillant L, Fignon A, et al. Specific pruritic diseases of pregnancy. A prospective
PT
study of 3192 pregnant women. Arch Dermatol. 1994;130:734-739.
AC
213.
CE
62. Husz S, Toth-Kasa I, Kiss M, et al. Treatment of cold urticaria. Int J Dermatol. 1994;33:210-
63. Powell FC. Parity, polypregnancy, paternity, and PUPPP. Arch Dermatol. 1992; 128:1551. 64. Zurn A, Celebi CR, Bernard P, et al. A prospective immunofluorescence study of 111 cases of pruritic dermatoses of pregnancy: IgM anti-basement membrane zone antibodies as a novel finding. Br J Dermatol. 1992;126:474-478. 65. Helm TN, Valenzuela R. Continuous dermoepidermal junction IgM detected by direct immunofluorescence: a report of nine cases. J Am Acad Dermatol. 1992;26:203-206.
ACCEPTED MANUSCRIPT 66. Cobb MW, Domloge-Hultsch N, Frame JN, et al. Waldenstrom macroglobulinemia with an IgM-kappa antiepidermal basement membrane zone antibody. Arch Dermatol.
RI P
T
1992;128:372-376.
67. Whittaker SJ, Bhogal BS, Black MM. Acquired immunobullous disease: a cutaneous
SC
manifestation of IgM macroglobulinaemia. Br J Dermatol. 1996;135:283-286. 68. Chattopadhyay M, Rytina E, Dada M, et al. Immunobullous dermatosis associated with
NU
Waldenstrom macroglobulinaemia treated with rituximab. Clin Exp Dermatol. 2013;38:866-
MA
869.
69. Howarth PH. ABC of allergies. Pathogenic mechanisms: a rational basis for treatment. BMJ.
ED
1998;316:758-761.
70. Hamilton JD, Suarez-Farinas M, Dhingra N, et al. Dupilumab improves the molecular
PT
signature in skin of patients with moderate-to-severe atopic dermatitis. J Allergy Clin
CE
Immunol. 2014;134:1293-1300.
229.
AC
71. Di Lorenzo G, Mansueto P, Melluso M, et al. [Allergy in pregnancy]. Clin Ter. 1994;145:223-
72. Brzoza Z, Kasperska-Zajac A, Oles E, et al. Pruritic urticarial papules and plaques of pregnancy. Journal Midwifery Womens Health. 2007;52:44-48. 73. Roth MM. Pregnancy dermatoses: diagnosis, management, and controversies. Am J Clin Dermatol. 2011;12:25-41. 74. Chi C, Wang S, Mayon-White R, et al. Pregnancy outcomes after maternal exposure to topical corticosteroids: A UK population-based cohort study. JAMA Dermatol. 2013;149:1274-1280.
ACCEPTED MANUSCRIPT 75. Gabbe SG. Drug therapy in autoimmune diseases. Clin Obstet Gynecol. 1983;26:635-641. 76. Stoller HE. Pruritic urticarial papules and plaques of pregnancy. JAMA. 1980;243:2156.
RI P
T
77. Kroumpouzos G, Cohen LM. Dermatoses of pregnancy. J Am Acad Dermatol. 2001;45:1-19. 78. El-Saie LT, Rabie AR, Kamel MI, et al. Effect of narrowband ultraviolet B phototherapy on
SC
serum folic acid levels in patients with psoriasis. Lasers Med Sci. 2011;26:481-485. 79. Jeon IK, On HR, Oh SH, et al. Three cases of pruritic urticarial papules and plaques of
MA
Acad Dermatol Venereol. 2015;29:797-800
NU
pregnancy (PUPPP) treated with intramuscular injection of autologous whole blood. J Eur
80. Asefi M, Augustin M. [Regulative therapy: treatment with nonspecific stimulants in
ED
dermatology in traditional and modern perspectives]. Forsch Komplementarmed. 1999; 6(Suppl 2):9-13.
PT
81. Costello M. Eruptions of Pregnancy. NY State J Med. 1941;41:849-855.
CE
82. Beltrani VP, Beltrani VS. Pruritic urticarial papules and plaques of pregnancy: a severe case
AC
requiring early delivery for relief of symptoms. J Am Acad Dermatol. 1992;26:266-267. 83. Lehrhoff S, Pomeranz MK. Specific dermatoses of pregnancy and their treatment. Dermatol Ther. 2013;26:274-284.
ACCEPTED MANUSCRIPT FIGURE LEGENDS Figure 1. Pale halos surrounding the erythematous papules are shown on the arm.
RI P
T
Figure 2. Erythematous, urticarial papules and plaques presenting within abdominal striae.
AC
CE
PT
ED
MA
NU
SC
Figure 3. Vesicles and papules on a background of erythema are shown on the arm.
CE AC
Figure 1
PT
ED
MA
NU
SC
RI P
T
ACCEPTED MANUSCRIPT
CE AC
Figure 2
PT
ED
MA
NU
SC
RI P
T
ACCEPTED MANUSCRIPT
ED
MA
NU
SC
RI P
T
ACCEPTED MANUSCRIPT
AC
CE
PT
Figure 3
S0738-081X(16)30026-8 doi: 10.1016/j.clindermatol.2016.02.011 CID 7023
To appear in:
Clinics in Dermatology
Please cite this article as: Taylor Drew, Pappo Eden, Aronson Iris K., Polymorphic Eruption of Pregnancy, Clinics in Dermatology (2016), doi: 10.1016/j.clindermatol.2016.02.011
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT POLYMORPHIC ERUPTION OF PREGNANCY Drew Taylor, MD, Eden Pappo, MD, Iris K. Aronson, MD
RI P
T
University of Illinois at Chicago College of Medicine, Department of Dermatology, Chicago, IL
Key Words: polymorphic eruption of pregnancy; pruritic urticarial papules and plaques of
Conflicts of Interest: None declared.
NU
Tables: 1
Figures: 3
Reference count: 83
MA
Word Count: 96 (Abstract) / 4,698 (Text)
SC
pregnancy; etiopathogenesis; management
PT
ED
Funding sources: None declared.
CE
Contact Information: Drew Taylor: [email protected]; Iris K. Aronson: [email protected]
AC
Corresponding Author: Eden Pappo, MD
University of Illinois at Chicago College of Medicine, Department of Dermatology Address: 808 S Wood Street, 380CME; M/C 624 Chicago, IL 60612 Telephone: 847-804-0430 E-mail: [email protected]
ACCEPTED MANUSCRIPT ABSTRACT Polymorphic eruption of pregnancy (PEP), a specific dermatosis of pregnancy also known as
RI P
T
pruritic urticarial papules and plaques of pregnancy (PUPPP), is a benign, self-limited skin disorder. Key features include an increased prevalence in primigravidas, onset in the third
SC
trimester, remission near the time of delivery, and association with multiple gestation pregnancy. The clinical features are crucial to diagnosis. Histopathology is non-specific, and
NU
immunofluorescence sutides help differentiate PEP from pemphigoid gestationis. The
MA
pathogenesis of PEP remains elusive, and relvant theoreis are reviewed. There are no
AC
CE
PT
ED
associated maternal or fetal risks, and treatment is largely symptomatic.
ACCEPTED MANUSCRIPT INTRODUCTION Pruritic urticarial papules and plaques of pregnancy (PUPPP) and polymorphic eruption of
RI P
T
pregnancy (PEP) are synonymous terms for a pregnancy-associated skin disorder. Despite the multiple prior names and due to the clinical spectrum reported for this dermatosis, the term
SC
PEP has begun to supplant PUPPP. This article reviews historical aspects culminating in the current name of this disorder, the diagnostic clinical and histopathological features, treatment
NU
options, as well as areas of current research that may shed light on the etiology of this specific
MA
dermatosis of pregnancy.
ED
HISTORICAL PERSPECTIVE
PEP, an erythematous, urticarial eruption of pregnancy, has been described under various
PT
names.1, 2, 3, 4 Previously named entity Toxemic Rash of Pregnancy, first described by Bourne in
CE
1962, showed features of PEP. Bourne described a severely pruritic eruption presenting in late
AC
pregnancy with erythematous papules and plaques within abdominal striae, often with gradual spread, and resolving after delivery.1 The majority (62.5%) of patients were primigravidas, the incidence of the eruption was 1 in 120 patients, and pregnancies were uneventful.1 The term Toxemic Rash of Pregnancy continued to be used in Europe until 1982, even by Holmes and Black, who in that same year in another article proposed abandoning that term as well as PUPPP, and proposing a new name for the entity, Polymorphic Eruption of Pregnancy (PEP).5
Another diagnostic name considered consistent with the clinical entity of PEP is Late-Onset Prurigo of Pregnancy, reported by Nurse in 1968.2 Nurse divided the cases into an early and a
ACCEPTED MANUSCRIPT late type, with the early type consisting of papules affecting the extremities consistent with the papular prurigo eruptions. The late type had the abdominal focus, urticarial papules and
RI P
T
plaques but also targetoid and occasional vesicular lesions.2, 6 Half of the patients were primagravidas, and one case of twins was reported. With the exception of one stillbirth, the
SC
babies were healthy. The late-onset dermatosis is clinically consistent with findings in PEP.7 Due to clinical similarities of pre-bullous herpes gestationis, in the pre-direct immunofluorescence
NU
(DIF) era, Nurse suggested that this entity may be a pre-bullous, or less severe form of herpes
MA
gestationis (HG).2 When DIF became available in 1973, it was recognized as a valuable tool to differentiate various dermatoses of pregnancy. The histopathologic and immunopathologic
ED
correlation became particularly critical in the differentiation of pemphigoid gestationis (PG)
PT
(synonymous with HG) from PEP.3, 7
CE
The term PUPPP was first used in 1979 by Lawley and colleagues.3 The small study included
AC
characteristic onset in the third trimester, cutaneous findings of erythematous urticarial papules and plaques first seen on the abdomen, and spreading to the extremities, mainly the thighs, buttocks and arms. No patient had facial involvement, and vesicles were only rarely noted. The papules were often surrounded by a thin, pale halo. Histopathologic findings and negative DIF were consistent with the current diagnosis of PEP (see below). The majority of patients were in their first pregnancy and all patients had resolution of symptoms within 2 weeks of parturition.3 Lawley et al noted that although the women reported intractable pruritus, excoriated lesions were uncommon. He also differentiated PUPPP from other
ACCEPTED MANUSCRIPT dermatoses of pregnancy and from Spangler’s Papular Dermatitis of Pregnancy which is now
RI P
T
considered a widespread prurigo of pregnancy, an atopic eruption of pregnancy.8
In 1980 Cooper et al aimed to clarify the varying diagnostic terminology, reporting several
SC
patients who fit the overall diagnosis termed Prurigo of Late Pregnancy.4 In 1982, Holmes and Black suggested a classification of pregnancy-specific dermatoses to include PG, PEP and
NU
prurigo of pregnancy (PP), in an attempt to simplify and organize the many entities related to
MA
these diagnoses.6 The main distinction between the latter two categories was that PEP had urticarial primary lesions whereas PP had lesions that were primarily excoriated prurigo
ED
papules. They included in the PEP category Nurse’s Late Onset Prurigo of Pregnancy, Lawley’s PUPPP, and Bourne’s Toxaemic Rash of Pregnancy. The key elements were onset in late
PT
pregnancy, pruritic papules and urticarial plaques within and around abdominal striae with
CE
spread to extremities, and prompt improvement after delivery.6 While Holmes and Black
AC
appreciated the morphologic appropriateness of PUPPP terminology, they felt that the term PEP was more inclusive and concise because of the variable clinical presentation of this entity and “was both clinically accurate and free from misleading connotations”.6 All subsequent classification systems of dermatoses of pregnancy have maintained PEP/PUPPP as a distinct diagnostic entity, separated from atopic and prurigo eruptions as well as from PG.
EPIDEMIOLOGY The incidence of PEP in a single pregnancy has been estimated at 1 in 200 pregnancies (0.5%),9 as well as 1 in 120 pregnancies,1, 4 thus a common pregnancy-specific dermatosis. The average
ACCEPTED MANUSCRIPT age in studies has been reported at 25.4 years10 and 29 years,11 similar to the general population of women giving birth depending on the year of the study. Caucasians are most
T
often affected (88% in one large study).12 Non-Caucasian incident rates are lower depending on
RI P
the population; a large Israeli study found a rate of 0.03%.13 A large study in India found a
SC
higher rate of PEP of 2.3%14 although in another study of patients in Northern India, intrahepatic cholestasis of pregnancy was the most common diagnosis.15 An Iraqi study found
NU
PEP to be the most common dermatosis of pregnancy, at 29.5% of the specific pregnancy
MA
dermatoses,16 whereas a much lower incidence of 1% was reported in a Pakistani study.17
ED
CLINICAL FEATURES These are summarized on the Table.
AC
CE
PT
Table. Key Features of Polymorphous Eruption of Pregnancy. Onset Third trimester or shortly postpartum; less often in other trimesters Resolution Postpartum Clinical findings Variable erythematous, pruritic papules and plaques, beginning in the abdominal striae with distal spread and occasional generalization. May include small vesicles or target-like lesions. Does not tend to recur in subsequent pregnancies or with hormonal exposures Diagnosis Clinical; direct immunofluorescence skin testing to rule out pemphigoid gestationis Maternal characteristics More likely nulliparous or primigravida Fetal characteristics Male predominance Maternal risks Possible increased risk of cesarean section Fetal risks None Management Patient counseling Symptomatic treatment (topical corticosteroids, topical emollients, oral antihistamines) Refractory cases may require systemic corticosteroids
Primigravidas / nulliparous
ACCEPTED MANUSCRIPT There is a high percentage of women with PEP who are either pregnant with their first child or who have never given birth (i.e. the first pregnancy suffered from spontaneous abortion, etc.).
T
In one review, 42% were primigravidas and 68% were nulliparous.10 In larger studies, 70% and
RI P
73% were primigravidas.11, 12 A small study reported an even higher percentage of nulliparous
SC
patients (89%).18
NU
Multiple gestation pregnancy
MA
Several studies have reported an increase in multiple gestation pregnancies in women presenting with PEP, compared to the general population. They showed 16%,11 13%,19 and
ED
9.5%13 of PEP cases associated with multiple gestation pregnancies. In a study from Lebanon, half of the patients (9 of 18) with PEP had multiple gestation pregnancies; of note, the majority
CE
PT
of those pregnancies resulted from in vitro fertilization procedures.18
AC
In a specific investigation of multiple gestations in association with PEP, 2.9% of 8000 twin pregnancies had a diagnosis of PEP, but 14.3% of triplet pregnancies was associated with PEP. 20 In the original PUPPP case series, 28.6% of the cases were multiple gestation pregnancies.3 Other incidence rates of multiple gestation pregnancy in PEP include 9%,21 16%,22 and 10% whereas the control population was 1.6%.23 In the largest PEP study to date, patients with multiple gestation pregnancies had earlier onset of skin lesions.12 A meta-analysis has demonstrated a prevalence of multiple gestation in PEP was 10-fold higher than the prevalence of multiple gestation pregnancy in the United States.24
ACCEPTED MANUSCRIPT Gender of fetus Some authors have reported an increased frequency of male fetuses in PEP cases. In one study,
RI P
T
the sex of the newborn was male in 64.5% of the PEP group, while the percentage was closer to the expected statistic (48.5%) in the control group. This was statistically significant after
SC
multivariate analysis (P=0.026).25 A prospective study observing women with multiple dermatoses of pregnancy found an increased prevalence in women who were carrying male
NU
fetuses compared to female fetuses, with a ratio of 2:1.26 The largest study found an overall
MA
increase in male fetuses, but with no statistical significance.12
ED
Effect on fetus and pregnancy
Maternal and fetal outcomes are not altered if the patient has PEP.6, 13 Throughout the
PT
literature, there are reports that infants of mothers with PEP are born without complications
CE
and without skin lesions, however one case report did note similar cutaneous lesions on the
AC
infant born to a mother diagnosed with PEP.27 Preterm delivery prior to 37 weeks’ gestation in 18.4% of PEP patients, compared to in 5.8% of control group patients has been reported (P=0.02).25 Another large study separating the patients into early and late onset groups based on symptoms before or after 35 weeks, respectively, the early onset group had a statistically significant (P<0.001) lower mean gestational age at time of delivery.12
Rate of cesarean section has also been noted, with one study demonstrating a statistically higher incidence of cesarean section in patients with PEP (40% versus 13.1% in the control group, P= <0.0001).25 The reasons for cesarean section were not reported for all patients. An
ACCEPTED MANUSCRIPT increase in cesarean section (56%) was also noted in another study in which all patients had healthy babies without skin lesions or other complications.18 In addition, the number of
T
hospitalizations for pregnant patients was also higher in the PEP group compared to the control
RI P
group (P= <0.0001).25 In another study, induction of labor was seen significantly more often in
SC
PEP patients, along with lower APGAR scores and higher rate of cesarean section in the PEP group compared to the control group.13 There was also a statistically significant association
MA
NU
between PEP patients versus control with regards to hypertensive disorders.13
PEP infrequently recurs in subsequent pregnancies. Nineteen patients were followed for 5 years
ED
postpartum in which time there were 8 pregnancies as well as oral contraceptive exposure with no repeated episode of PEP.22 However, recurrence was noted in one of four and 3 of 57 PEP
CE
PT
patients in two other studies.4, 10
AC
The data above suggests a possible increase in cesarean section rates and preterm labor in PEP; however, larger studies are needed in order to evaluate these risks. Overall, earlier onset may have greater effect on preterm delivery. PEP has been reported to recur, but infrequently.4, 10
Onset and Resolution PEP begins most often in the third trimester with rates between 79% to 100%,10, 11, 18, 28 with few outliers in the late second trimester or postpartum.10, 11, 12, 18 Second trimester symptoms were rare, and 15-16% of patients did not develop symptoms until the postpartum period. 11,12 Resolution of symptoms generally occurs promptly after delivery. In one study, 33% of patients
ACCEPTED MANUSCRIPT had resolution intrapartum or prior to delivery, 60% had resolution within 1 week of delivery, and less than 1% had symptom resolution several weeks postpartum.28 In another study
T
cutaneous lesions were resolved in 100% of patients within 1-4 weeks of delivery, with a mean
RI P
clearance at 3 weeks postpartum.18 Interestingly, a more atypical PEP presentation is associated
SC
with a longer duration,12 earlier onset,10 multigravida status, and atopy.12
NU
Cutaneous findings
MA
PEP presents as pruritic, urticarial papules and plaques during pregnancy. This finding is consistent throughout the literature, but the variation in presentation suggests PEP as an
ED
appropriate diagnostic term. Aronson et al categorized the clinical findings into three PEP subgroups; type I, characterized primarily by urticarial papules and plaques, type II, which
PT
included broader clinical findings such as erythematous patches, non-urticarial papules (1-
CE
2mm) or vesicles, and type III, a combination of the other two types.10 All three types often
AC
also had some lesions with surrounding blanched halos (Figure 1). Erythema multiforme-like targetoid lesions were noted in 5.3% (histopathology in these cases excluded erythema multiforme).10 However, this categorization did not affect treatment options, response to treatment or outcomes.10, 29
A characteristic clinical finding of PEP is predominant abdominal involvement, often beginning within and around abdominal striae (Figure 2).6, 10 In one study, 48% had primary lesions which began within the abdominal striae;22 however, lesions can be seen in patients without abdominal striae.10 The proximal upper and lower extremities are the most common non-
ACCEPTED MANUSCRIPT abdominal locations.10 In 91% of patients in a large study, the cutaneous symptoms were first seen on the abdomen or the proximal thighs and occasionally both; only 17% had skin lesions
T
stay within this distribution without generalized spread. This group showed 3% of all patients
SC
RI P
lacking any abdominal involvement.12
Mucosal sparing is a clinical aspect consistent throughout the literature. 12, 20 PEP atypical
NU
lesions, including vesicles (Figure 3), complicate the diagnosis, and have been reported in up to
MA
40% of cases.30 In a large retrospective study, 98% presented with the classic pruritic, urticarial plaques and papules. Later in the course, 51% had altered clinical findings including vesicles,
ED
targetoid lesions as well as more eczematous plaques.12 Histopathology of the targetoid lesions does not show multiforme-associated histopathological features, thereby excluding erythema
PT
multiforme from the diagnosis.10, 31 An additional study demonstrated that 27.8% of PEP
CE
patients had atypical lesions including vesicles, eczematous patches, and targetoid lesions. The
findings.18
AC
most common atypical feature was presence of vesicles along with the more typical urticarial
Palms or soles may be involved with papular or vesicular lesions resembling dyshidrotic eczema as well as PG but are affected in less than 2% of patients.10, 11, 12 Facial involvement has varied from 1-2%11, 12 to 12%10 and, when present, is seen in patients with the larger PEP spectrum that includes erythema, vesicles and targetoid lesions.10
ACCEPTED MANUSCRIPT DIAGNOSIS PEP is a disorder with a broad clinical spectrum and diverse clinical features but with absence of
RI P
T
pathognomonic identifying features. Due to the wide clinical spectrum of PEP, laboratory and histopathological investigations need to be utilized to exclude other entities, particularly those
SC
that potentially pose an unfavorable maternal or fetal prognosis. The authors recommend obtaining complete blood count, liver function tests, renal function, thyroid stimulating
NU
hormone, urinalysis, and bile acids. PEP must be differentiated from PG, contact dermatitis,
MA
toxic drug eruptions, viral exanthems, pityriasis rosea, and urticaria.
ED
Histopathology shows a superficial or superficial and deep perivascular dermatitis with lymphohystiocytic vasculitis.32 Eosinophils are often present (60-100%) but to varying
PT
degrees.12, 18 Variable papillary edema, and nuclear dust can be seen.32, 33 In about 33% of cases,
CE
focal spongiosis and parakeratosis are present.34 Additional epidermal changes include
AC
acanthosis, hyperkeratosis, and intraepidermal vesicles.12 Lesions, present for greater than 72 hours, are more likely to display epidermal changes.32 There is no definitive diagnostic histopathologic difference between PEP and atopic eruption of pregnancy (AEP).32
If there is question regarding the diagnosis, two biopsies should be performed: one from lesional skin for hematoxylin and eosin staining and one from perilesional skin for direct immunofluorescence (DIF). DIF can be utilized to differentiate PEP from PG and urticarial vasculitis. In one report, 15 (31%) of 57 patients had nonspecific positive granular deposition of IgM, IgA, or C3 at the dermal-epidermal junction or at the blood vessels.10 The extent of
ACCEPTED MANUSCRIPT immunoglobulin or C3 deposition varied significantly. There was also an association of earlier onset PEP and positive DIF, thus lending insight into a more exuberant inflammatory state in
T
early onset PEP.10 Another study of DIF cases found 2 with IgM, C3 or IgA deposition in a
RI P
nonspecific, granular distribution that was not diagnostic.11 The deposition was noted either at
SC
the dermal-epidermal junction or surrounding blood vessels.11 This is in contrast to the linear C3 deposition that is seen in PG. Consistently negative DIF studies for PEP are reported
NU
throughout the literature.3, 12, 33 Of note, there was no difference in DIF findings between the
MA
three clinical subtypes of PEP.10 Additionally, indirect complement-added immunofluorescence or serological studies may assist in differentiating PG and PEP. Formalin-fixed paraffin-
ED
embedded tissue-based immunohistochemistry for anti-C3d or C4d can be utilized, in place of DIF, for differentiating PEP from PG.35,36 The C4d immunohistochemistry may eliminate the
PT
need for DIF biopsy in the future, thus allowing to obtain only one biopsy. Until these
AC
CE
techniques are further investigated, DIF continues to be the recommendation.
Other more complex tests have been employed to help identify PEP and differentiate it from PG. Using an NC16A domain enzyme-linked immunosorbent assay (ELISA), the diagnoses could be differentiated with sensitivity and specificity of 96%. NC16A ELISA was more sensitive than IIF for both IgG and C3 studies alone, but the combination of IIF and ELISA testing had superior sensitivity (99%).37 Therefore, PG and PEP may be differentiated with high sensitivity and specificity without taking a tissue sample. The test can be completed within 3.5 hours in some laboratories. Finally, immunoelectron microscopy has been negative in PEP.38 Due to cost
ACCEPTED MANUSCRIPT constraints and availability, DIF and IIF will likely remain the most common tests utilized for
RI P
T
diagnosis.
ETIOPATHOGENESIS
SC
The etiopathogenesis of PEP remains elusive. To date, PEP is not believed to be familial or autoimmune, in the usual sense, although a familial case has been reported. 39 Studies of HLA
NU
types have yet to reveal an association.22 There is no pathognomonic identifiable common
MA
denominator, “PEP factor”, as seen in HG. One possibility is that blunt trauma and koebnerization may be a factor in PEP. Complicating these hypotheses is that PEP onset
ED
immediately postpartum has been reported.40, 41 Select theories regarding PEP pathogenesis
PT
are summarized below.
CE
Inflammatory disorder with koebnerization
AC
Histopathology confirms an inflammatory process underlying PEP. Koebnerization of an inflammatory disorder may explain the predilection for areas of blunt trauma, e.g. striae distensae. Stretching of the skin was recently suggested as a precipitating factor for ‘true koebnerization’ seen in vitiligo, psoriasis, and lichen planus.42 Striae development occurs in 90% of women during pregnancy;43 yet, PEP only occurs in 1:200 pregnancies. In addition, PEP is not limited to koebnerized locations, and may disseminate widely to other regions. It has been suggested that this dissemination in PEP may result from cross-reactivity to dermal antigens in normal skin.44
ACCEPTED MANUSCRIPT Excessive maternal weight (>15 kg by definition) is a point of contention in the development of PEP. Excessive maternal weight gain in 78% and 75% of women with PEP has been reported. 12,18
T
A French study documented an increased maternal weight gain of 15 kg in PEP cases compared
RI P
to 12.73 kg in controls,45 whereas another study reported an average weight gain of 18.1 kg in
SC
PEP patients versus 14.6kg in the control group.23 The weight of the infants was also greater in the PEP group, with an average birth weight of 3.6kg versus 3.3kg for the control group.23 Yet
NU
PEP was statistically not related to maternal or fetal weight gain in other studies. 21, 25
MA
undermining excessive weight gain as a necessary feature and important factor in the
ED
development of PEP.
Multiple gestation pregnancies are a well-documented factor in patients who develop PEP.12, 13, Today, one in 30 babies born is a twin. An increased twin rate of 41.66% in PEP
PT
20, 24, 25
CE
compared to that of 1.2% in controls was documented in one study.45 A 10-fold higher
AC
prevalence of multiple gestation pregnancy in patients with PEP was determined by a metaanalysis.24 Increased incidence of multiple gestation and its consequence of increased abdominal distension, larger abdominal circumference and possible increased striae have been suggested to be related to higher incidence of PEP.24 Maternal anthropometric measurements have been utilized to help determine fetal well-being. A maternal abdominal circumference of 89.1 +/- 4.61 cm has been associated with fetal well-being.46 Whether increasd distension, striae and resultant trauma on collagen play a role in the development of PEP is still speculative.
ACCEPTED MANUSCRIPT Hormonal Although a relationship to reproductive hormones should be considered, no consistent
RI P
SC
PEP has not been confirmed since it was first described.26
T
hormonal abnormalities have been reported.4, 22, 47 The role of low maternal serum cortisol in
Lesional skin in PEP displayed progesterone receptor immunoreactivity in the cytoplasm of
NU
suprabasal keratinocytes whereas non-lesional skin did not.48 Placenta-synthesized
MA
progesterone has been shown to potentiate tissue inflammation and is found in increased amounts in multiple gestation pregnancies. Suprabasilar keratinocytes contain progesterone
ED
receptors and thus can be targets of hormonal factors in pregnancy.49 In addition, female sex hormones have been shown to regulate the synthesis of interleukin-6, a pro-inflammatory
CE
PT
cytokine.50
AC
Prolactin has been suggested as a possible factor in development of PEP as its levels rise in pregnancy, and it functions as a modulator of both skin epithelial growth and skin immune functions.51, 52 It affects the innate and adaptive immune system and its receptors have been found in skin,51, 53 suggesting another possible, but speculative, hormonal factor in the development of PEP.
Microchimerism Another hypothetical etiologic mechanism for development of PEP was raised with the discovery of fetal DNA in the skin lesions of PEP patients with male fetuses and absence in non-
ACCEPTED MANUSCRIPT affected mothers with male fetuses.54 The exact mechanism of fetal DNA homing into maternal skin is puzzling, but the authors propose that it is caused by blood chimerism (fetal cells
T
detected in maternal blood throughout pregnancy).55 The fetal lymphocytes may induce a graft-
RI P
versus-host disease-like reaction against the maternal tissues.56 Bianchi et al provides support
SC
for this hypothesis as they have identified male fetal progenitor cells in the maternal blood 27
NU
years postpartum.57 Currently, this hypothesis remains to be confirmed.
MA
Inflammatory mediated
The immunohistologic profile of patients with PEP strongly expresses an HLA-DR genotype,
ED
indicative of an antigenically driven immune hyperactivation;49 however, lack of consistent HLA association is found in other sources.22, 30 Immunohistochemical studies reveal a predominantly
PT
T-helper lymphocytic infiltrate with an increased number of CD1a+, CD54+ (ICAM-1+) dendritic
CE
cells, and CD1a+ epidermal Langerhans cells in lesional skin compared to perilesional skin. 58, 59
AC
This profile may support a delayed hypersensitivity reaction to an unknown antigen. 24 A Lebanese study found a strong correlation between PEP and erythrocyte rhesus (Rh) factor phenotype positivity.18 The study indicated that all 18 patients with PEP were Rh positive, which is a novel potential antigen. Unfortunately, the study made no mention of the phenotype of the fetuses. Rh phenotype is generally only of concern when the mother is phenotypically negative and the fetus is phenotypically positive. The authors wonder whether Rh immunoglobulin (Rhogam) could prevent PEP if the eruption was driven by antibody response to Rh factor. Of note, Blood type and Rhesus positivity were consistent within the affected population as well as the general population in earlier, smaller studies.2
ACCEPTED MANUSCRIPT
Medication-Induced
T
There have been few reports of suspected medication-induced PEP. Six patients were described
RI P
as having developed PEP after treatment with terbutaline for tocolysis.60 In another report, 3 of
SC
15 PEP patients were treated with progesterone and/or ritodrine or albuterol for threatened premature labor 3 weeks before the onset of the eruption.61 Although an interesting
NU
association, the role of terbutaline, ritodrine or albuterol as the cause of PEP in these case
MA
cannot be determined with certainty. Paradoxically, terbutaline in conjunction with
ED
aminophylline has been reported to treat urticarial eruptions.62
Paternal
PT
Paternity is known to play a role in PG,26 but recent evidence may suggest it also may
CE
contribute to the development of PEP. A multiparous woman developed PEP in her fifth
AC
pregnancy. This fetus was fathered by a different man and was also the patient’s first multiple gestation pregnancy, with significant abdominal distention reported.63 This paternity derived theory is also supported by an observation by another group that reported PEP in families where the sisters were married to brothers.39
Autoimmune DIF is consistently negative in PEP for any specific deposition.3, 12, 33 A single study revealed positive anti-basement membrane IgM antibodies on indirect immunofluorescence in five out of 111 patients with PEP.64 Linear IgM deposition at the dermal-epidermal junction
ACCEPTED MANUSCRIPT unassociated with other antibodies has been reported, but etiopathogenesis was considered non-specific as it was associated with a variety of dermatoses.65 Recently, linear deposition
T
solely of IgM at the basement membrane zone has been associated with Waldenstrom
RI P
macroglobulinemia.66-68 Thus sole IgM deposition at the basement membrane zone,
SC
unassociated with Waldenstrom, is rare, and the significance is still undetermined.
NU
Contradicting the autoimmune theory is the fact that PEP does not seem to recur, and if it does,
MA
it is not necessarily more severe or of earlier onset, which is a hallmark of PG, a disease with known autoimmune etiology.44 Also, there exists only a single case of mother and child with
ED
PEP at birth reported in which the neonate developed a similar rash that resolved within 10 days.27 No DIF was obtained, thus it is uncertain as to whether this was truly PEP, a PEP-like
AC
Atopy
CE
PT
case, or another dermatosis.
Pregnancy creates a shift from a Th-1 to a Th-2 cytokine milieu.69 Pregnancy is a relative state of immunosuppression, designed to prevent fetal rejection. It results in a decreased cell mediated immunity, an increase in humoral immunity, and a natural homeostasis between antigenically different tissues. Recent evidence suggests that atopic dermatitis is an autoimmune disease, driven by an IL-4 and IL-13, Th2-centered inflammatory axis.70 Atopy may have pathogenic significance in PEP and may alter the natural course of the eruption. In one study, 55% of patients who developed PEP had a personal or family history of atopy.12 Serum IgE levels were elevated in 28% of the cases and is likely the result of IL-4 (a Th2 cytokine) induced isotype
ACCEPTED MANUSCRIPT switching to IgE production in B-cells.12 This feature is supported by a work, which found a correlation between PEP and concomitant asthma.10 Similarly, urticarial eruptions may be
RI P
T
exacerbated in pregnancy.71
SC
PROGNOSIS
PEP nearly always resolves with parturition, but has been noted to persist for several weeks
NU
postpartum.72 The average duration of PEP eruptions is 4-6 weeks.44, 73 The self-limited nature,
MA
lack of significant fetal or maternal risk, and the rarity of PEP recurrence in subsequent pregnancies should be conveyed to the patient at time of diagnosis to ameliorate patient
ED
anxiety and enhance understanding of PEP. Interdisciplinary communication between dermatology, obstetrics and neonatal pediatrics is critical in management of more severe cases
CE
PT
of PEP.
AC
It is a general consensus that PEP poses a negligible risk to either the mother or fetus; however, a positive non-stress test in 3 patients,10 hypertension and mild preeclampsia as well as hypertension with induction of labor13 have been reported. An increased incidence of cesarean section especially with multiple gestation pregnancies, and rare stillborn births have been reported.13, 22, 25 Although these problems are relatively rare findings, they should be kept in mind and monitored for in patients with PEP.
ACCEPTED MANUSCRIPT TREATMENT Symptomatic treatment consists of cooling baths, frequent application of emollients,
RI P
T
refrigerated menthol-containing topical medications (r the safety of these products in pregnancy when used frequently and over extensive body areas with increased absorption is
SC
unclear and generally not recommended by the authors), light cotton clothing, oral firstgeneration sedating antihistamines (chlorpheniramine and diphenhydramine) and mid-potency
MA
NU
topical corticosteroids.
Severe cases may warrant super-potent topical corticosteroids, limited to a total of 200 grams
ED
over the duration of pregnancy, as amounts greater than 300 grams have been associated with low birth weight.74 A recent report demonstrated that fluticasone 0.05% lotion, a low-medium
PT
potency corticosteroid, applied two times daily had dramatic efficacy within one week. 29 If oral
CE
corticosteroids are needed, prednisolone, 40-60 mg/day, with a quick taper, is favored over
AC
betamethasone given the lower risk of fetal hypothalamic-pituitary-adrenal axis suppression, with a maternal-fetal gradient of 10:1,75 and has been shown to induce prompt resolution of both symptoms and cutaneous eruption.76 While a lower dose of prednisone is preferred, it may not improve symptoms as quickly.22
Given the relatively short duration of PEP, narrowband ultraviolet light B (NBUVB) is rarely employed, but has been reported as effective.77 NBUVB can induce degradation of folate in patients with psoriasis, thus additional folate supplementation must be reinforced in any patient undergoing NBUVB therapy during pregnancy.78
ACCEPTED MANUSCRIPT
An interesting therapeutic strategy, recently reported in Europe, consists of intramuscular
T
injections of autologous whole blood.79 It has been postulated that autologous whole blood, at
RI P
the correct dose, promotes a ‘self-healing process’ within the body.80 This is similar to data
SC
published in 1941, in which women with PEP were injected with blood serum from a woman without PEP.81 Further investigation of this therapeutic modality is required to definitely
MA
NU
comment on this treatment option.
Recalcitrant PEP may resolve with cesarean section.82 PEP is not considered an indication for
ED
early delivery or induction of labor. Of note, all current treatment trials are done in small
CE
CONCLUSIONS
PT
patient populations.83
AC
PEP, synonymous with PUPPP, is a benign, pregnancy-specific dermatosis. It can cause severe pruritus but is not associated with any fetal risks. Key characteristics of PEP include an increased prevalence in primigravidas, onset towards the end of pregnancy, and distribution of lesions within or adjacent abdominal striae. DIF is integral in ruling out PG. While its etiopathogenesis is unknown, several potential theories based on variable evidence exist. Treatment is largely symptomatic, focusing on control of pruritus; however, further research for safe and effective treatment modalities is being conducted.
ACCEPTED MANUSCRIPT
REFERENCES
RI P
T
1. Bourne G. Toxaemic rash of pregnancy. Proc R Soc Med. 1962;55:462-464. 2. Nurse DS. Prurigo of pregnancy. Australas J Dermatol. 1968;9:258-267.
SC
3. Lawley TJ, Hertz KC, Wade TR, et al. Pruritic urticarial papules and plaques of pregnancy. JAMA. 1979;241:1696-1699.
NU
4. Cooper AJ, Fryer JA. Prurigo of late pregnancy. Australas J Dermatol. 1980;21:79-84.
MA
5. 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.
ED
6. Holmes RC, Black MM. The specific dermatoses of pregnancy: a reappraisal with special emphasis on a proposed simplified clinical classification. Clin Exp Dermatol. 1982;7:65-73.
PT
7. Ambros-Rudolph CM. Dermatoses of pregnancy - clues to diagnosis, fetal risk and therapy.
CE
Ann Dermatol. 2011;23:265-275.
AC
8. Ambros-Rudolph CM, Black MM. From prurigo gestationis Besnier to atopic eruption of pregnancy: the confusing nosology of the less well-defined dermatoses of pregnancy has been largely clarified. Clin Dermatol. 2006;24:545-547. 9. Holmes RC, Black MM. The specific dermatoses of pregnancy. J Am Acad Dermatol. 1983;8:405-412. 10. Aronson IK, Bond S, Fiedler VC, et al. Pruritic urticarial papules and plaques of pregnancy: Clinical and immunopathologic observations in 57 patients. J Am Acad Dermatol. 1998;39:933-939.
ACCEPTED MANUSCRIPT 11. Ambros-Rudolph CM, Mullegger RR, Vaughan-Jones SA, et al. The specific dermatoses of
RI P
pregnant patients. J Am Acad Dermatol. 2006;54:395-404.
T
pregnancy revisited and reclassified: results of a retrospective two-center study on 505
12. Rudolph CM, Al-Fares S, Vaughan-Jones SA, et al. Polymorphic eruption of pregnancy:
SC
clinicopathology and potential trigger factors in 181 patients. Br J Dermatol. 2006;154:5460.
NU
13. Ohel I, Levy A, Silberstein T, et al. Pregnancy outcome of patients with pruritic urticarial
MA
papules and plaques of pregnancy. J Matern Fetal Neonatal Med. 2006;19:305-308. 14. Kumari R, Jaisankar TJ, Thappa DM. A clinical study of skin changes in pregnancy. Indian J
ED
Dermatol Venereol Leprol. 2007;73:141.
15. Chander R, Garg T, Kakkar S, et al. Specific Pregnancy Dermatoses in 1430 females from
PT
Northern India. J Dermatol Case Rep. 2011;5:69-73.
CE
16. Hamdi K, Dhaher SA, Alyasin ZT. Specific dermatoses of pregnancy among Iraqi pregnant
AC
women. Iraqi J Comm Med. 2010;3:177-180. 17. Niaz F, Wahid Z, Ahmed I, et al. Frequency of specific dermatoses of pregnancy. J Pak Assoc Dermatol. 2013; 23:256-261. 18. Ghazeeri G, Kibbi AG, Abbas O. Pruritic urticarial papules and plaques of pregnancy: epidemiological, clinical, and histopathological study of 18 cases from Lebanon. Int J Dermatol. 2012;51:1047-1053. 19. Powell FC. Pruritic urticarial papules and plaques of pregnancy and multiple pregnancies. J Am Acad Dermatol. 2000;43:730-731.
ACCEPTED MANUSCRIPT 20. Elling SV, McKenna P, Powell FC. Pruritic urticarial papules and plaques of pregnancy in twin and triplet pregnancies. J Eur Acad Dermatol Venereol. 2000;14:378-381.
RI P
T
21. Roger D VL, Lorette G. Pruritic urticarial papules and plaques of pregnancy are not related to maternal or fetal weight gain. Arch Dermatol. 1990;126:1517.
SC
22. Yancey KB, Hall RP, Lawley TJ. Pruritic urticarial papules and plaques of pregnancy. Clinical experience in twenty-five patients. J Am Acad Dermatol. 1984;10:473-480.
NU
23. Cohen LM, Capeless EL, Krusinski PA, et al. Pruritic urticarial papules and plaques of
Dermatol. 1989;125:1534-1536.
MA
pregnancy and its relationship to maternal-fetal weight gain and twin pregnancy. Arch
ED
24. Kroumpouzos G, Cohen LM. Specific dermatoses of pregnancy: an evidence-based systematic review. Am J Obstet Gynecol. 2003;188:1083-1092.
PT
25. Regnier S, Fermand V, Levy P, et al. A case-control study of polymorphic eruption of
CE
pregnancy. J Am Acad Dermatol. 2008;58:63-67.
AC
26. Vaughan Jones SA, Hern S, Nelson-Piercy C, et al. A prospective study of 200 women with dermatoses of pregnancy correlating clinical findings with hormonal and immunopathological profiles. Br J Dermatol. 1999; 141:71-81. 27. Uhlin SR. Pruritic urticarial papules and plaques of pregnancy. Involvement in mother and infant. Arch Dermatol. 1981;117:238-239. 28. Callen JP, Hanno R. Pruritic urticarial papules and plaques of pregnancy (PUPPP). A clinicopathologic study. J Am Acad Dermatol. 1981;5:401-405.
ACCEPTED MANUSCRIPT 29. Scheinfeld N. Pruritic urticarial papules and plaques of pregnancy wholly abated with one week twice daily application of fluticasone propionate lotion: a case report and review of
RI P
T
the literature. Dermatol Online J. 2008;14:4.
30. Charles-Holmes R. Polymorphic eruption of pregnancy. Semin Dermatol. 1989; 8:18-22.
SC
31. Sirikudta W, Silpa-Archa N. Polymorphic eruption of pregnancy presented with targetoid lesions: a report of two cases. Case Rep Dermatol. 2013;5:138-143.
NU
32. Massone C, Cerroni L, Heidrun N, et al. Histopathological diagnosis of atopic eruption of
Dermatopathol. 2014;36:812-821.
MA
pregnancy and polymorphic eruption of pregnancy: a study on 41 cases. Am J
ED
33. Moreno A, Noguera J, de Moragas JM. Polymorphic eruption of pregnancy: histopathologic study. Acta Derm Venereol. 1985;65:313-318.
PT
34. Weedon D. The vasculopathic reaction pattern. In: Weedon D, ed: Weedon’s Skin Pathology.
CE
3rd ed. London: Churchill Livingstone Elsevier, 2010;195-244.
AC
35. Kwon EJ, Ntiamoah P, Shulman KJ. The utility of C4d immunohistochemistry on formalinfixed paraffin-embedded tissue in the distinction of polymorphic eruption of pregnancy from pemphigoid gestationis. Am J Dermatopathol. 2013; 35:787-791. 36. Pfaltz K, Mertz K, Rose C, et al. C3d immunohistochemistry on formalin-fixed tissue is a valuable tool in the diagnosis of bullous pemphigoid of the skin. J Cutan Pathol. 2010;37:654-658. 37. Powell A, Sakuma-Oyama Y, Oyama N, et al. Usefulness of bp180 nc16a enzyme-linked immunosorbent assay in the serodiagnosis of pemphigoid gestationis and in differentiating
ACCEPTED MANUSCRIPT between pemphigoid gestationis and pruritic urticarial papules and plaques of pregnancy. Arch Dermatol. 2005;141:705-710.
RI P
T
38. Jurecka W HR, Black MM, McKee P, Das AK, Bhogal B. An immunoelectron microscopy study of the relationship between herpes gestationis and polymorphic eruption of pregnancy. Br J
SC
Dermatol. 1983;108:147-151.
Am Acad Dermatol. 1992;26:715-717.
NU
39. Weiss R, Hull P. Familial occurrence of pruritic urticarial papules and plaques of pregnancy. J
MA
40. Park SY, Kim JH, Lee WS. Pruritic urticarial papules and plaques of pregnancy with unique distribution developing in postpartum period. Ann Dermatol. 2013;25:506-508.
ED
41. Buccolo LS, Viera AJ. Pruritic urticarial papules and plaques of pregnancy presenting in the postpartum period: a case report. J Reprod Med. 2005;50:61-63.
PT
42. Verma SB. Striae: stretching the long list of precipitating factors for 'true koebnerization' of
CE
vitiligo, lichen planus and psoriasis. Clin Exp Dermatol. 2009;34:880-883.
AC
43. Korgavkar K, Wang F. Stretch marks during pregnancy: a review of topical prevention. Br J Dermatol. 2015;172:606-615. 44. Ahmadi S, Powell FC. Pruritic urticarial papules and plaques of pregnancy: current status. Australas J Dermatol. 2005;46:53-58. 45. Pauwels C, Bucaille-Fleury L, Recanati G. Pruritic urticarial papules and plaques of pregnancy: relationship to maternal weight gain and twin or triplet pregnancies. Arch Dermatol. 1994;130:801-802. 46. Preedy VR, ed. Handbook of Growth and Growth Monitoring in Health and Disease. New York: Springer Verlag; 2011.
ACCEPTED MANUSCRIPT 47. Alcalay J, Ingber A, Kafri B, et al. Hormonal evaluation and autoimmune background in pruritic urticarial papules and plaques of pregnancy. Am J Obstet Gynecol. 1988;158:417-
RI P
T
420.
48. Callahan TL, Hall JE, Ettner SL, et al. The economic impact of multiple-gestation pregnancies
SC
and the contribution of assisted-reproduction techniques to their incidence. N Engl J Med. 1994;331:244-249.
NU
49. Cohen LM, Kroumpouzos G. Polymorphic eruption of pregnancy. In: Kroumpouzos G, ed:
MA
Text Atlas of Obstetric Dermatology. Philadelphia: Lippincott Williams & Wilkins publishers; 2013:194-204.
ED
50. Telleria CM, Ou J, Sugino N, et al. The expression of interleukin-6 in the pregnant rat corpus
1998;139:3597-3605.
PT
luteum and its regulation by progesterone and glucocorticoid. Endocrinology.
CE
51. Horseman ND, Gregerson KA. Prolactin actions. J Mol Endocrinol. 2014; 52:R95-106.
AC
52. Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol. 2009;114:1326-1331. 53. Peeva E, Zouali M. Spotlight on the role of hormonal factors in the emergence of autoreactive B-lymphocytes. Immunol Lett. 2005;101:123-143. 54. Aractingi S, Berkane N, Bertheau P, et al. Fetal DNA in skin of polymorphic eruptions of pregnancy. Lancet. 1998;352:1898-1901. 55. Ganshirt D, Garritsen HS, Holzgreve W. Fetal cells in maternal blood. Curr Opin Obstet Gynecol. 1995;7:103-108.
ACCEPTED MANUSCRIPT 56. Caproni M, Giomi B, Berti S, et al. Relevance of cellular infiltrate and cytokines in polymorphic eruption of pregnancy (PEP). J Dermatol Sci. 2006;43:67-69.
RI P
T
57. Bianchi DW, Zickwolf GK, Weil GJ, et al. Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum. Proc Natl Acad Sci USA. 1996;93:705-708.
SC
58. Carli P, Tarocchi S, Mello G, et al. Skin immune system activation in pruritic urticarial papules and plaques of pregnancy. Int J Dermatol. 1994;33:884-885.
NU
59. Tarocchi S, Carli P, Caproni M, et al. Polymorphic eruption of pregnancy. Int J Dermatol.
MA
1997;36:448-450.
60. Barron WM, Lindheimer MD, eds. Medical disorders during pregnancy. 2nd ed. St. Louis:
ED
Mosby; 1995.
61. Roger D, Vaillant L, Fignon A, et al. Specific pruritic diseases of pregnancy. A prospective
PT
study of 3192 pregnant women. Arch Dermatol. 1994;130:734-739.
AC
213.
CE
62. Husz S, Toth-Kasa I, Kiss M, et al. Treatment of cold urticaria. Int J Dermatol. 1994;33:210-
63. Powell FC. Parity, polypregnancy, paternity, and PUPPP. Arch Dermatol. 1992; 128:1551. 64. Zurn A, Celebi CR, Bernard P, et al. A prospective immunofluorescence study of 111 cases of pruritic dermatoses of pregnancy: IgM anti-basement membrane zone antibodies as a novel finding. Br J Dermatol. 1992;126:474-478. 65. Helm TN, Valenzuela R. Continuous dermoepidermal junction IgM detected by direct immunofluorescence: a report of nine cases. J Am Acad Dermatol. 1992;26:203-206.
ACCEPTED MANUSCRIPT 66. Cobb MW, Domloge-Hultsch N, Frame JN, et al. Waldenstrom macroglobulinemia with an IgM-kappa antiepidermal basement membrane zone antibody. Arch Dermatol.
RI P
T
1992;128:372-376.
67. Whittaker SJ, Bhogal BS, Black MM. Acquired immunobullous disease: a cutaneous
SC
manifestation of IgM macroglobulinaemia. Br J Dermatol. 1996;135:283-286. 68. Chattopadhyay M, Rytina E, Dada M, et al. Immunobullous dermatosis associated with
NU
Waldenstrom macroglobulinaemia treated with rituximab. Clin Exp Dermatol. 2013;38:866-
MA
869.
69. Howarth PH. ABC of allergies. Pathogenic mechanisms: a rational basis for treatment. BMJ.
ED
1998;316:758-761.
70. Hamilton JD, Suarez-Farinas M, Dhingra N, et al. Dupilumab improves the molecular
PT
signature in skin of patients with moderate-to-severe atopic dermatitis. J Allergy Clin
CE
Immunol. 2014;134:1293-1300.
229.
AC
71. Di Lorenzo G, Mansueto P, Melluso M, et al. [Allergy in pregnancy]. Clin Ter. 1994;145:223-
72. Brzoza Z, Kasperska-Zajac A, Oles E, et al. Pruritic urticarial papules and plaques of pregnancy. Journal Midwifery Womens Health. 2007;52:44-48. 73. Roth MM. Pregnancy dermatoses: diagnosis, management, and controversies. Am J Clin Dermatol. 2011;12:25-41. 74. Chi C, Wang S, Mayon-White R, et al. Pregnancy outcomes after maternal exposure to topical corticosteroids: A UK population-based cohort study. JAMA Dermatol. 2013;149:1274-1280.
ACCEPTED MANUSCRIPT 75. Gabbe SG. Drug therapy in autoimmune diseases. Clin Obstet Gynecol. 1983;26:635-641. 76. Stoller HE. Pruritic urticarial papules and plaques of pregnancy. JAMA. 1980;243:2156.
RI P
T
77. Kroumpouzos G, Cohen LM. Dermatoses of pregnancy. J Am Acad Dermatol. 2001;45:1-19. 78. El-Saie LT, Rabie AR, Kamel MI, et al. Effect of narrowband ultraviolet B phototherapy on
SC
serum folic acid levels in patients with psoriasis. Lasers Med Sci. 2011;26:481-485. 79. Jeon IK, On HR, Oh SH, et al. Three cases of pruritic urticarial papules and plaques of
MA
Acad Dermatol Venereol. 2015;29:797-800
NU
pregnancy (PUPPP) treated with intramuscular injection of autologous whole blood. J Eur
80. Asefi M, Augustin M. [Regulative therapy: treatment with nonspecific stimulants in
ED
dermatology in traditional and modern perspectives]. Forsch Komplementarmed. 1999; 6(Suppl 2):9-13.
PT
81. Costello M. Eruptions of Pregnancy. NY State J Med. 1941;41:849-855.
CE
82. Beltrani VP, Beltrani VS. Pruritic urticarial papules and plaques of pregnancy: a severe case
AC
requiring early delivery for relief of symptoms. J Am Acad Dermatol. 1992;26:266-267. 83. Lehrhoff S, Pomeranz MK. Specific dermatoses of pregnancy and their treatment. Dermatol Ther. 2013;26:274-284.
ACCEPTED MANUSCRIPT FIGURE LEGENDS Figure 1. Pale halos surrounding the erythematous papules are shown on the arm.
RI P
T
Figure 2. Erythematous, urticarial papules and plaques presenting within abdominal striae.
AC
CE
PT
ED
MA
NU
SC
Figure 3. Vesicles and papules on a background of erythema are shown on the arm.
CE AC
Figure 1
PT
ED
MA
NU
SC
RI P
T
ACCEPTED MANUSCRIPT
CE AC
Figure 2
PT
ED
MA
NU
SC
RI P
T
ACCEPTED MANUSCRIPT
ED
MA
NU
SC
RI P
T
ACCEPTED MANUSCRIPT
AC
CE
PT
Figure 3