Pruritic Urticarial Papules and Plaques of Pregnancy Zenon Brzoza, MD, PhD, Alicja Kaspe Kasperskarska-Zajac Zajac,, MD, PhD, Ewa Oles´ , MD, and Barbara Rogala, MD, PhD Pruritic Prurit ic urt urtica icaria riall pap papule uless and pla plaques ques of pre pregna gnancy ncy (PU (PUPPP PPP)) are amon among g the mos mostt com common mon pru prurit ritic ic dermat der matose osess obs observ erved ed in pre pregnan gnantt wom women. en. PUP PUPPP PP appe appears ars mos mostt fre freque quentl ntly y in the thi third rd tri trimes mester ter,, in primig pri migrav ravida idas, s, and in mul multip tiple le ges gestat tation ion pre pregnan gnancies cies.. The eru erupti ption on of cha changes nges occu occurs rs ini initia tially lly on the abdomen and extends over the thighs, legs, back, buttocks, arms, and breasts. Skin changes typical for PUPPP are erythematous, erythematous, urticarial plaques, plaques, and papules. Rash regres regression sion is usuall usually y observ observed ed withi within n 6 weeks postpartum. Immunologic mechanisms, hormonal abnormalities, and abdominal skin distension have been suggested as etiologic mechanisms. PUPPP is thought to be harmless for the mother and fetus and usually requires intervention only for symptom relief. In some cases, laboratory investigation, histologic examination, and immunologic study should be performed to exclude more serious disorders of pregnancy, such as herpes gestationis or intrahepatic cholestasis of pregnancy. This article reviews the epidemiology, clinical manifestation, etiology, differential diagnosis, and treatment of PUPPP. J Midwifery Womens Health 2007; 52:44–48 © 2007 by the American College of Nurse-Midwives. keywords: dermatosis, pregnancy, pruritic urticarial papules and plaques of pregnancy, skin, urticaria
INTRODUCTION
Skin changes reflecting hormonal and metabolic changes duri du ring ng pr preg egna nanc ncy y ca can n be cl clas assi sifie fied d in into to 3 gr grou oups ps:: 1) dermatoses that started before pregnancy; 2) physiologic lesions, such as hyperpigmentation, melasma, striae gravidarum, gravi darum, palmar erythe erythema, ma, etc.; and 3) derma dermatoses toses specific for pregnancy, such as itching in the course of intrahepatic cholestasis of pregnancy (ICP), herpes gestationis (HG), prurigo of pregnancy (PP), and pruriti pruri ticc urticarial papules and plaques of pregnancy (PUPPP). 1 This article reviews the epidemiology, clinical manifestation, etiology, diagnosis, and treatment of PUPPP in the contex contextt of other other skin skin disorde disorders rs affect affecting ing pregna pregnant nt women. women. Most of availa available ble litera literature ture concer concernin ning g this this prob proble lem m is base based d on case case repo report rtss or repo reports rts of sm smal alll numbers of women. EPIDEMIOLOG EPIDEMIOLOGYY OF PUPPP
The The term term “pru “pruri riti ticc urti urtica cari rial al papu papule less and and plaq plaque uess o f pregnancy” was initially proposed by Lawley in 1979. 2 Available literature from that time also refers to “toxemic eryt erythe hema ma of pregn pregnan ancy cy”” and and “lat “latee onse onsett pruri prurigo go of pregnancy.” In the United Kingdom, the name suggested for for such such derm dermat ato osis sis is the the poly polymo morp rphi hicc erup erupti tion on of 1 pregnancy (PEP). PUPPP is a self-limiting disorder, and is supp suppos osed ed to be one one of the the most most comm common on pruri pruriti ticc dermat dermatose osess observ observed ed in pregna pregnant nt women. women. Though Though approx proxim imat atel ely y 1 in 200 200 preg pregna nant nt wome women n suffe suffers rs from from PUPPP, PUPPP, its etio etio logy, like other other urtica urticaria riall change changes, s, re1,3–5 mains unknown. PUPPP appears most frequently in the third trimester
Address correspondence to Zenon Brzoza, MD, PhD, Chair and Clinical Department of Internal Diseases, Allergology and Clinical Immunology, Medical University of Silesia, Katowice, ul. 3 Maja 13-15, 41-800 Zabrze, Poland. E-mail:
[email protected]
44 © 2007 by the American College of Nurse-Midwives Issued by Elsevier Inc.
in primigravidas and in women with wi th multiple multiple gestation 2,6–10 pregnancies (incidence 2.9%–16%). However, in a few cases, cases, an early early (first (first or second second trimester trimester)) or late late (postpartum period) onset has been observed. CLINICAL CLINICAL PRESENTATI PRESENTATION ON
Skin changes typical for PUPPP are erythematous, urticarial plaques, and 1 to 2 m m papules usually surrounded by a narrow and pale halo. halo .2 Vesicles that are not larger than 2 mm can also occur. 1 The eruption of changes in the course of PUPPP PUPPP appear appear initia initially lly on the abdome abdomen, n, particularly in striae atrophicae, then progresses to involve inv olve the the thighs thighs,, leg legs, back, back, buttoc buttocks ks,, arms, arms, and and breasts. breasts.6,7,9 Aronson et al. 6 observed 57 patients with the diagnosis of PUPPP and classified PUPPP into 3 types, depending on the the type type of lesi lesion on:: 1) urti urtica cari rial al papu papule less and and plaq plaque uess (type (type I); 2) nonurt nonurtica icaria riall erythe erythema, ma, papule papules, s, or vesivesicles (type II); and 3) a combination of the two forms (type (type III). III). Fourte Fourteen en of the 57 women women develo developed ped skin changes i changes initially nitially on their arms, wrists, thighs, legs, feet, 6 or face. Interestingly, no patient suffering from type I had her face, palms, or soles involved, whereas women with type II or type III can have lesions in such areas. Trimester onset, parity, and direct immunofluorescence findings did not differ signi significantly among the 3 groups. In Call Callen en and and Hamo’ Hamo’ss8 obse observ rvat atio ion, n, 2 out out of 15 patien patients ts had lesions lesions on their their legs legs only. only. Althoug Although h the eruption does not usually involve the face, palms, and soles, some case studies have described patients patients whose 2,3,7,9,11 soles and palms were covered with rash. Mucous membranes are usually not involved. Pruritus is characteristic for PUPP PU PPP P and its intensity can keep patients 2,7 awake at night. ETIOLOGY
There is little little insight insight into pathogenesis pathogenesis of PUPPP. PUPPP. Some researchers researchers suggest suggest immunologic immunologic mechanisms; mechanisms; others Volume 52, No. 1, January/February 2007 1526-9523/07/$32.00 doi:10.1016/j.jmwh.2006.09.007 •
point to hormonal abnormality.2,8 Distension of abdominal skin has also been considered. However, none of these mechanisms has been supported enough to prove what exactly causes PUPPP. Abdominal Distension
Cohen et al.7 suggested that abdominal distension or reaction to this process might play a pivotal role in the development of PUPPP. They observed a significant increase in maternal weight gain and the newborn birth weight in women who have PUPPP, when compared with women who do not have PUPPP, as well as a higher twin rate in patients with such dermatosis as compared to the general twin rate in their hospital. It was also suggested that lymphohistiocytic inflammatory reaction in PUPPP could be provoked by collagen antigens, exposed as a result of abdominal distension. This hypothesis is supported by the observation that PUPPP occurs more frequently in women with a triplet p regnancy and in patients suffering from polyhydraminos.12 Furthermore, in a case study of a woman with triplets described by Vaughan-Jones et al.,13 the rash onset occurred at 24 weeks’ gestation, which is earlier than it occurs in women who have a singleton fetus. According to the authors’ opinion, at this stage, the patient’s abdomen distension was comparable to 38-week single pregnancy, which accounts for the early onset. Immunologic Mechanisms
Histopathology studies carried out in patients with PUPPP resulted in similar conclusions. Superficial and/or middermal perivascular lymphohistiocytic infiltrate (possibly associated with edema); eosinophils; spongiosis, or small vesicles in the dermis; and parakeratosis, or scale crusts in the epidermis of some patients, have been observed.6,7 Obviously, such histopathologic findings were not specific for PUPPP. In most studies, direct and indirect immunofluorescence tests performed in PUPPP patients proved negative.1,2,6,14,15 In some cases, however, minimal deposits of complement (C3) in the basement membrane zone or perivascular C3 deposits in the dermis were found.2,9 Trattner et al.16 found antiepidermal cell surface antibod-
Zenon Brzoza, MD, PhD, is an assistant at the Clinical Department of Internal Diseases, Allergology and Clinical Immunology, Medical University of Silesia, Katowice, Poland. Alicja Kasperska-Zajac, MD, PhD, is an assistant at the Clinical Department of Internal Diseases, Allergology and Clinical Immunology, Medical University of Silesia, Katowice, Poland. Ewa Oles´, MD, is an assistant at post-graduate training at the Clinical Department of Internal Diseases, Allergology and Clinical Immunology, Medical University of Silesia, Katowice, Poland. Professor Barbara Rogala, MD, PhD, is the Head of Chair and Clinical Department of Internal Diseases, Allergology and Clinical Immunology, Medical University of Silesia, Katowice, Poland.
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ies in a patient suffering from PUPPP. The immunofluorescence tests performed by Aronson et al. 6 revealed the deposition of IgM, IgA, or C3 at dermoepidermal junction or blood vessels among 15 out of 57 examined patients. There were no cases of linear deposits of any immune reactant at the dermoepidermal junction; indirect immunofluorescence examination for circulating IgG antibodies was also negative. 6 In Yancey’s study,9 slightly elevated IgA complexes were observed in 2 out of 10 patients. Alcalay et al. 14 also studied the immunologic aspects of PUPPP pathogenesis; however, they found no specific antibodies in any of 11 patients and the autoimmune mechanism was not proved. Activation of skin immune system was also supposed to underlie PUPPP pathogenesis.16 Activated T cells (human leukocyte antigen [HLA]-DR , CD25 , and leukocyte functioning antigen (LFA-1) ) associated with CD1a were found in the dermis. Additionally, the number of CD54 dendritic cells and CD1a epidermal cells was increased in lesional skin in comparison to perilesional, unaffected skin.15 Some authors postulated maternal response to paternal antigens present in the fetal component of placenta as a PUPPP mechanism; others suggested that placental p roducts could play some role in pathogenesis of PUPPP. 14,17 In addition, it has been postulated that the presence of fetal DNA in maternal skin as a result of fetal cells migration in women carrying a male fetus may be an etiologic factor of PUPPP. 18 In summary, none of the evaluations of immunologic mechanisms done to date have demonstrated changes that are consistently seen in women with clinical manifestations of PUPPP.
Hormonal Changes
The suggested role of hormonal changes in the development of PUPPP has not been confirmed. In most studies, the level of serum -subunit human chorionic gonadotropin (HCG), estradiol, progesterone, cortisol, and urinary estriol in PUPPP patients did not differ from that of the control groups.2,8,14 PROGNOSIS
The rash usually regresses within a week postpartum; however, it can also clear at any time before birth and up to the sixth week postpartum.8 In a few cases, postpartum exacerbation of PUPPP has been observed. 7 PUPPP does not usually reoccur in future pregnancies.2,8 In Aronson’s6 study, only 3 out of 57 patients suffered from PUPPP recurrence in a subsequent pregnancy. Most studies of women with PUPPP confirm the absence of associated maternal and fetal morbidity and mortality in patients, and it is thought that PUPPP is harmless to both the mother and the fetus. 9,14 Neverthe45
Table 1. Dermatoses of Pregnancy That Must be Considered in Differential Diagnostics of Pruritic Urticarial Papules and Plaques of Pregnancy (PUPPP) Dermatoses of Pregnancy
Herpes gestationis (HG)
Pruritus gravidarum: Intrahepatic cholestasis of pregnancy (ICP)
Prurigo of pregnancy (PP)
DIF
Clinical Characteristics
Differential Diagnosis, Laboratory Evaluation
Perinatal Outcome
Treatment
Abdominal urticarial lesions may be clinically indistinguishable from the lesions seen in women who have PUPP, though in HG, bullae and larger vesicles are common. Lesions can be situated on palms and soles. HG associated with exacerbations and reoccurrence during pregnancy may occur postpartum and frequently reoccurs in subsequent pregnancies Intense itching without primary skin eruption. In some cases, symptoms such as anorexia or nausea, and jaundice may appear. Often reoccurs in subsequent pregnancies
Autoimmune development of antibody to the basement membrane zone of the epidermis. In DIF test of lesion and perilesional skin a linear band of C3 deposits and IgG along the basement membrane noted. ELISA evaluation of skin biopsy can to be a valuable tool in differentiating between HG and PUPPP.
Increased risk of preterm birth, transient neonatal lesions.
Antipruritics, topical and/or oral steroids. Cyclophosphamide and methotrexate in refractory cases.
In some patients increased serum bile acids concentration, increased liver enzymes activity. Patients with ICP may have normal lab values.
There is an association between ICP and prematurity, fetal distress, meconium staining, and stillbirth
Grouped excoriated papules cover extensor surface of the extremities and rarely the trunk. Face often involved. Lesions can occur at any time of pregnancy and recur in subsequent pregnancy
Normal serologic tests, nonspecific histopathology, negative immunofluorescence
No maternal risk or fetal morbidity and mortality
Emollients, topical antipruritics, topical or oral steroids as needed, cholestyramine,* ursodeoxycholic acid. Oral antihistamines rarely sufficient. Weekly antenatal NST recommended. Induction at 38 weeks may be recommended. Symptomatic
direct immunofluorescence assay; ELISA
enzyme-linked immunosorbent assay; NST
nonstress test.
*Patients placed on cholestyramine therapy need supplemental vitamin K.
less, in a few case studies, complications potentially associated with the dermatosis have been observed. A patient with PUPPP who delivered twin s (one live birth and one stillborn) has been described.2 In Aronson’s study,6 one out of the 57 pregnancies ended in fetal death at 30 weeks’ gestation. 6 Moreover, spontaneous abortion in the 9th week was noticed in a patient w hose eruption appeared in the 7th week of gestation.6 Lowenstein et al.19 suggested possible association of PUPPP and severe preeclampsia with fetal death. They reported a case of a woman with PUPPP who had a stillbirth. On the other hand, none of the case studies mentioned above had sufficient power or numbers of participants to ascertain a true correlation between morbid outcomes and the presence of PUPPP during pregnancy. DIFFERENTIAL DIAGNOSIS
PUPPP is one of numerous, difficult to differentiate pruritic dermatoses that affect pregnant women (Table 1).20–23 It 46
must be stated that in all cases of unusual skin changes, laboratory investigation, histologic examination, and immunologic studies should be performed to exclude more serious pregnancy disorders. Other skin lesions that have presentations similar to PUPPP are superficial gyrate erythema, superficial urticarial allergic eruption, viral exanthema, and superficial response to arthropod bites.2 TREATMENT
Treatment of PUPPP is focused on the relief of pruritus. The most common agents used are antipruritic agen ts, skin emollients, and topical corticosteroids (Table 2).24 Ref ractory cases may require oral corticosteroid therapy.24 In the study by De Gaetano et al., 3 one patient with PUPPP needed treatment with a long tapering of prednisone. The authors emphasized the need for tapering doses of steroids to treat particularly severe manifestaVolume 52, No. 1, January/February 2007
Table 2. Medications for Treatment of PUPP Medication
Brand Name
High Potency Steroid Betamethasone dipropionate*
Dose
Comments
Diprolene
0.05% bid
Aristocort, Kenalog
0.5% bid to tid
Aristocort, Kenalog
0.1% bid to tid
Elocon
0.1% bid–tid
Low Potency Steroid Hydrocortisone acetate
Cortaid, Corticaine
0.5% or 0.1% bid
Ointment 0.5% (15, 30 grams)† Ointment 0.1% (30 grams) Cream 0.5% (15, 20, 30 grams) Cream 0.1% (15, 20, 30 grams)
Nonsteroid Medication Calamine lotion Oatmeal Sarna lotion
Calamine Aveeno Sarna Lotion
apply tid to qid apply bid to tid apply tid to qid
Diphenhydramine
Benadryl
Hydroxyzine
Atarax
20 –50 mg PO Maximum of 300 mg per day 25–100 mg PO qd to qid
Lotion (120, 240 ml) Over the counter packets or lotion Made of 0.5% camphor, 0.5% menthol, and 0.5% phenol. Effect is cooling of skin Tablets (25, 50 mg)
Triamcinolone acetonide* cream Medium Potency Steroid Triamcinolone acetonide cream
Mometasone furoate
Ointment (15 or 45 grams)† Cream (15 or 45 grams) Lotion (20 or 60 ml) Ointment (15, 20, 28, 57 grams)† Cream (15, 20, 30, 60 grams) Ointment (15, 20, 28, 57 grams)† Cream (15, 60, 80 grams) Lotion (15, 60 ml) Ointment (15 or 45 grams)† Cream (15 or 45 grams) Lotion (30 or 60 ml)
Tablets (10, 25, 50 mg)
*High-potency steroids should be used with caution in pregnancy and for no more than 2 weeks. Known teratogens in animal studies when ingested in the first trimester. Prescribe with physician consultation. †
The ointment provides the most percutaneous absorption. Do not use ointments on skin that is weepy or broken from scratching.
tions of the disease, especially if unresponsive to topical steroids. There are some risks associated with corticosteroid treatment: maternal hyperglycemia, increased risk of infections, fetal intrauterine growth restriction, and an increased risk of early-onset neonatal sepsis. These adverse outcomes are rare, and the use of oral corticosteroids has been shown to be relatively safe in the treatment of maternal asthma, inflammatory bowel disease, and autoimmune disorders.13 In two studies, atypical PUPPP patients were presented, who, despite intensive local and systemic treatment, suffered from intense, resistant, and incapacitating pruritus, which led to premature cesarean delivery. Symptoms were relieved a few days after delivery.25,26 CONCLUSION
Though PUPPP is the most common skin condition seen during pregnancy, many questions pertaining to this disease remain unanswered. This review points to PUPPP as a well-defined entity, the diagnosis of which is based mainly on the clinical presentation (onset, typical localization, and appearance of changes). In women who have unusual presentations, laboratory investigation, histologic examination, and immunologic studies can be Journal of Midwifery & Women’s Health
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performed to exclude more serious pregnancy disorders. These persons should be referred to a dermatologist for diagnostic work-up. Treatment of PUPPP focuses on the mitigation of pruritus. Antihistamines, skin emollients, and topical steroids are the primary agents used. In some cases, a short course of oral corticosteroids may be of value. REFERENCES 1. Holmes RC, Black MM. The specific dermatoses of pregnancy. J Am Acad Dermatol 1983;8:405–12. 2. Lawley TJ, Hertz KC, Wade TR, Ackerman AB, Katz SI. Pruritic urticarial papules and plaques of pregnancy. JAMA 1979; 241:1696–9. 3. De Gaetano JS, De Gaetano HM. Pruritic urticarial papules and plaques of pregnancy: An unusual case. J Am Osteopath Assoc 2002;102:44–6. 4. Kasperska-Zajac A, Brzoza Z, Rogala B. Serum concentration of dehydroepiandrosterone sulphate in female patients with chronic idiopathic urticaria. J Dermatol Sci 2006;41:80–1. 5. Kasperska-Zajac A, Rogala B, Nowakowski M. Assessment of platelet activity as expressed by plasma levels of platelet factor 4 and beta-thromboglobulin in patients with chronic idiopathic urticaria. Exp Dermatol 2005;14:515–8.
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6. Aronson IK, Bond S, Fiedler VC, Vomvouras S, Gruber D, Ruiz C. Pruritic urticarial papules and plaques of pregnancy: Clinical and immunopathologic observations in 57 patients. J Am Acad Dermatol 1998;39:933–9. 7. Cohen LM, Capeless EL, Krusinski PA, Maloney ME. Pruritic urticarial papules and plaques of pregnancy and its relationship to maternal-fetal weight gain and twin pregnancy. Arch Dermatol 1989;125:1534–6. 8. Callen JP, Hanno R. Pruritic urticarial papules and plaques of pregnancy (PUPPP). A clinicopathologic study. J Am Acad Dermatol 1981;5:401–5. 9. Yancey KB, Hall RP, Lawley TJ. Pruritic urticarial papules and plaques of pregnancy. Clinical experience in twenty-five patients. J Am Acad Dermatol 1984;10:473–80. 10. Elling SV, McKenna P, Powell FC. Pruritic urticarial papules and plaques of pregnancy in twin and triplet pregnancies. J Eur Acad Dermatol Venereol 2000;14:378–81.
face antibodies in a patient with pruritic urticarial papules and plaques of pregnancy. J Am Acad Dermatol 1991;24:306–8. 17. Weiss R, Hull P. Familial occurrence of pruritic urticarial papules and plaques of pregnancy. J Am Acad Dermatol 1992;26: 715–7. 18. Aractingi S, Berkane N, Bertheau P, Le Goue C, Dausset J, Uzan S, et al. Fetal DNA in skin of polymorphic eruptions of pregnancy. Lancet 1998;352:1898–1901. 19. Lowenstein L, Solt I, Peleg A, Brenner B, Drugan A. Is there an association between PUPPP and preeclampsia, abruptio placentae and fetal death? [in Hebrew] Harefuah 2004;143:861–2. 20. Sherard GB, Atkinson SM. Focus on primary care: Pruritic dermatological conditions in pregnancy. Obstet Gynecol Surv 2001;56:427–32. 21. Engineer L, Bhol K, Ahmed AR. Pemphigoid gestationis: A review. Am J Obstet Gynecol 2000;183:483–91.
11. High WA, Hoang MP, Miller MD. Pruritic urticarial papules and plaques of pregnancy with unusual and extensive palmoplantar involvement. Obstet Gynecol 2005;105:1261– 4.
22. Kroumpouzos G, Cohen LM. Specific dermatoses of pregnancy: an evidence-based systemic review. Am J Obstet Gynecol 2003;188:1083–92.
12. Beckett MA, Goldberg NS. Pruritic urticarial papules and plaques of pregnancy and skin distension. Arch Dermatol 1991; 127:125–6.
23. Powell AM, Sakuma-Oyama Y, Oyama N, Albert S, Bhogal B, Kaneko F, et al. Usefulness of BP180 NC16a enzyme-linked immunosorbent assay in the serodiagnosis of pemphigoid gestationis and in differentiating between pemphigoid gestationis and pruritic urticarial papules and plaques of pregnancy. Arch Dermatol 2005;141:705–10.
13. Vaughan-Jones SA, Dunnill MG, Black MM. Pruritic urticarial papules and plaques of pregnancy (polymorphic eruption of pregnancy): Two unusual cases. Br J Dermatol 1996;135:102–5. 14. Alcalay J, Ingber A, Kafri B, Segal J, Kaufmann H, Hazaz B, et al. Hormonal evaluation and autoimmune background in pruritic urticarial papules and plaques of pregnancy. Am J Obstet Gynecol 1988;158:417–20. 15. Carli P, Tarocchi S, Mello G, Fabbri P. Skin immune system activation in pruritic urticarlial papules and plaques of pregnancy. Int J Dermatol 1994;33:884–5. 16. Trattner A, Ingber A, Sandbank M. Antiepidermal cell sur-
24. Catanzarite V, Quirk JG Jr. Papular dermatoses of pregnancy. Clin Obstet Gynecol 1990;33:754–8. 25. Rotsztejn H, Krawczyk T, Jaczewski B, Lutosławska J, Oszukowski P. Pruritic urticaria-related papules and plaques of pregnancy: A case report. Ginekol Pol 2001;72:497–9. 26. Beltrani VP, Beltrani VS. Pruritic urticarial papules and plaques of pregnancy: A severe case requiring early delivery for relief of symptoms. J Am Acad Dermatol 1992;26:266–7.
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