Polymorphic eruption of pregnancy

doi:10.1016/j.clindermatol.2016.02.011

Clinics in Dermatology

Volume 34, Issue 3, May–June 2016, Pages 383-391

https://doi.org/10.1016/j.clindermatol.2016.02.011 Get rights and content

Abstract

Polymorphic eruption of pregnancy (PEP), a specific dermatosis of pregnancy also known as 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 trimester, remission near the time of delivery, and association with multiple gestation pregnancy. The clinical features are crucial to diagnosis. Histopathology is nonspecific, and immunofluorescence studies help differentiate PEP from pemphigoid gestationis. The pathogenesis of PEP remains elusive, and relevant theories are reviewed. There are no associated maternal or fetal risks, and treatment is largely symptomatic.

Introduction

Pruritic urticarial papules and plaques of pregnancy (PUPPP) and polymorphic eruption of 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 PEP has begun to supplant PUPPP. This paper reviews historical aspects culminating in the current name of this disorder, the diagnostic clinical and histopathologic features, and treatment options, as well as areas of current research that may shed light on the etiology of this specific dermatosis of pregnancy.

Section snippets

Historical perspective

PEP, an erythematous, urticarial eruption of pregnancy, has been described under various names.[1], [2], [3], [4] The previously named entity toxemic rash of pregnancy, first described in 1962, showed features of PEP. It was described as a severely pruritic eruption presenting in late 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

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, it is a common pregnancy-specific dermatosis. The average 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 often affected (88% in one large study).¹² Non-Caucasian incident rates are lower depending on the population; a large

Clinical features

Clinical features are summarized in Table 1.

Primigravidas/nulliparous

A high percentage of women with PEP are either pregnant with their first child or have never given birth (eg, the first pregnancy resulted in spontaneous abortion). In one review, 42% were primigravidas and 68% were nulliparous.¹⁰ In larger studies, 70% and 73% were primigravidas.[11], [12] A small study reported an even higher percentage of nulliparous patients (89%).¹⁸

Multiple gestation pregnancy

Several studies have reported an increase in multiple gestation pregnancies in women presenting with PEP, compared with the general population. They found 16%,¹¹ 13%,¹⁹ and 9.5%¹³ of PEP cases associated with multiple gestation pregnancies. In a study from Lebanon, half of the patients (9/18) with PEP had multiple gestation pregnancies; of note, the majority of those pregnancies resulted from in vitro fertilization procedures.¹⁸

In a specific investigation of multiple gestations in association

Gender of fetus

Some authors have reported an increased frequency of male fetuses in PEP cases. In one study, the sex of the newborn was male in 64.5% of the PEP group, whereas the percentage was closer to the expected statistic (48.5%) in the control group. This was statistically significant after multivariate analysis (P = .026).²⁵ A prospective study observing women with multiple dermatoses of pregnancy found an increased prevalence in women who were carrying male fetuses compared with female fetuses, with a

Effect on fetus and pregnancy

Maternal and fetal outcomes are not altered if the patient has PEP.[6], [13] Throughout the literature, there are reports that infants of mothers with PEP are born without complications and without skin lesions; however, one case report did note similar cutaneous lesions on the infant born to a mother diagnosed with PEP.²⁷ Preterm delivery before 37 weeks’ gestation in 18.4% of PEP patients, compared with in 5.8% of control group patients, has been reported (P = .02).²⁵ Another large study

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 had resolution intrapartum or before delivery, 60% had resolution within 1 week of delivery, and

Cutaneous findings

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 appropriate diagnostic term. Clinical findings have been categorized into three PEP subgroups: type I, characterized primarily by urticarial papules and plaques; type II, which included broader clinical findings such as erythematous patches and nonurticarial papules (1–2 mm) or vesicles; and type III, a combination

Diagnosis

PEP is a disorder with a broad clinical spectrum and diverse clinical features but with absence of pathognomonic identifying features. Due to the wide clinical spectrum of PEP, laboratory and histopathologic investigations need to be used to exclude other entities, particularly those that potentially pose an unfavorable maternal or fetal prognosis. The authors recommend obtaining complete blood cell count, liver function tests, renal function tests, thyroid-stimulating hormone level,

Etiopathogenesis

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 types have yet to reveal an association.²² There is no pathognomonic identifiable common denominator, or “PEP factor,” as seen in herpes gestationis. One possibility is that blunt trauma and koebnerization may be a factor in PEP. Complicating these hypotheses is that PEP onset immediately postpartum has been

Inflammatory disorder with koebnerization

Histopathologic examination confirms an inflammatory process underlying PEP. Koebnerization of an inflammatory disorder may explain the predilection for areas of blunt trauma (eg, striae distensae). Stretching of the skin was recently suggested as a precipitating factor for the “true koebnerization” seen in vitiligo, psoriasis, and lichen planus.⁴² Striae development occurs in 90% of women during pregnancy⁴³; yet, PEP only occurs in 1 in 200 pregnancies. In addition, PEP is not limited to

Hormonal

Although a relationship to reproductive hormones should be considered, no consistent hormonal abnormalities have been reported.[4], [22], [47] The role of low maternal serum cortisol in PEP has not been confirmed since it was first described.²⁶

Lesional skin in PEP displayed progesterone receptor immunoreactivity in the cytoplasm of suprabasal keratinocytes, whereas nonlesional skin did not.⁴⁸ Placenta-synthesized progesterone has been reported to potentiate tissue inflammation and is found in

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 nonaffected 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 detected in maternal blood throughout pregnancy).⁵⁵ The fetal lymphocytes may induce a graft-versus-host disease–like reaction against

Inflammatory mediated

The immunohistologic profile of patients with PEP strongly expresses an HLA-DR genotype, indicative of an antigenically driven immune hyperactivation⁴⁹; however, lack of consistent HLA association is found in other sources.[22], [30] Immunohistochemical studies reveal a predominantly T-helper lymphocytic infiltrate with an increased number of CD1 a⁺, CD54⁺ (ICAM-1⁺) dendritic cells and CD1 a⁺ epidermal Langerhans cells in lesional skin compared with perilesional skin.[58], [59] This profile may

Medication induced

There have been few reports of suspected medication-induced PEP. Six patients were described as having developed PEP after treatment with terbutaline for tocolysis.⁶⁰ In another report, 3 of 15 PEP patients were treated with progesterone and ritodrine or albuterol for threatened premature labor 3 weeks before the onset of the eruption.⁶¹ Although an interesting association, the role of terbutaline, ritodrine, or albuterol as the cause of PEP in these case cannot be determined with certainty.

Paternal

Paternity is known to play a role in PG,²⁶ but recent evidence may suggest it also contributes to the development of PEP. A multiparous woman developed PEP in her fifth 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 5 out of 111 patients with PEP.⁶⁴ Linear IgM deposition at the dermal-epidermal junction unassociated with other antibodies has been reported, but etiopathogenesis was considered nonspecific because it was associated with a variety of dermatoses.⁶⁵ Recently, linear deposition solely of IgM at the basement

Atopy

Pregnancy creates a shift from a T helper 1 (T_H1) to a T_H2 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 interleukin 4 (IL-4) and IL-13, T_H2-centered inflammatory axis.⁷⁰ Atopy may have pathogenic

Prognosis

PEP nearly always resolves with parturition but has been noted to persist for several weeks postpartum.⁷² The average duration of PEP eruptions is 4 to 6 weeks.[44], [73] The self-limited nature, lack of significant fetal or maternal risk, and rarity of PEP recurrence in subsequent pregnancies should be conveyed to the patient at time of diagnosis to ameliorate patient anxiety and enhance understanding of PEP. Interdisciplinary communication between dermatology, obstetrics, and neonatal

Treatment

Symptomatic treatment consists of cooling baths, frequent application of emollients, refrigerated menthol-containing topical medications (the safety of these products in pregnancy when used frequently and over extensive body areas with increased absorption is unclear, and their use is generally not recommended by the authors), light cotton clothing, oral first-generation sedating antihistamines (chlorpheniramine and diphenhydramine), and mid-potency topical corticosteroids.

Severe cases may

Conclusions

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 toward the end of pregnancy, and distribution of lesions within or adjacent to abdominal striae. DIF is integral in ruling out PG. Although its etiopathogenesis is unknown, several potential theories based on variable evidence exist. Treatment is largely symptomatic,

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