Pruritic urticarial papules and plaques of pregnancy: Clinical and immunopathologic observations in 57 patients

Pruritic urticarial papules and plaques of pregnancy: Clinical and immunopathologic observations in 57 patients Iris K. Aronson, MD, Shirley Bond, BS, Virginia C. Fiedler, MD, Stephanie Vomvouras, MD, David Gruber, MD, and Catherine Ruiz, MA Chicago, Illinois Background: Pruritic urticarial papules and plaques of pregnancy (PUPPP) has been described either as a homogeneous or a polymorphic clinical process. Its cause is unknown. Objective: We attempted to characterize the clinical and immunopathologic findings in PUPPP on the basis of long-term clinical and immunopathologic observations. Methods: The clinical and immunopathologic features of 57 patients with PUPPP were evaluated. Results: The clinical features in 57 patients with PUPPP were categorized into three types: mainly urticarial papules and plaques (type I), nonurticarial erythema, papules, or vesicles (type II), and combinations of the two forms (type III). Direct immunofluorescence studies in 48 of the 57 patients showed nonspecific immunoreactants in dermal blood vessels and/or moderate granular deposits at the dermoepidermal junction in 15 patients. Conclusion: Type I PUPPP differed from types II and III in clinical appearance and distribution (absence of face, palm, and sole lesions), but trimester onset, parity, and direct immunofluorescence findings were not significantly different among the three groups. (J Am Acad Dermatol 1998;39:933-9.)

Urticarial and erythematous eruptions of pregnancy have been described by a number of observers, each giving them different names.1-7 Pruritic urticarial papules and plaques of pregnancy (PUPPP) is the term most commonly used in the United States, but because this name does not satisfactorily describe the reported clinical spectrum of this process in Great Britain, polymorphic eruption of pregnancy (PEP) has been suggested as an alternative.7 The majority of reported cases of PUPPP begin in the third trimester and are not associated with fetal morbidity or mortality.1-37 Immunofluorescence staining of lesional biopsy specimens is consistently negative for a linear band of complement

From the Department of Dermatology, University of Illinois College of Medicine. Accepted for publication Aug 10, 1998. Reprint requests: Iris K. Aronson, MD, Department of Dermatology, M/C 624, University of Illinois, College of Medicine, 376 CME, 808 S Wood St, Chicago, IL 60612. Copyright © 1998 by the American Academy of Dermatology, Inc. 0190-9622/98/$5.00 + 0 16/1/93685

or immunoglobulins at the dermoepidermal junction (DEJ), thus differentiating it from herpes gestationis (HG).5,22,38 However, occasionally patients have been described with deposits of C3 or IgM in blood vessel walls or granular deposits of C3 at the DEJ.4,8,9,11,18,19 Linear deposits of IgM at the DEJ39 and antiepidermal cell surface IgG antibodies35 have been reported in single cases. PATIENTS AND METHODS Between 1979 and 1990, 57 patients with the diagnosis of PUPPP were seen. Timing of onset, distribution of lesions, specific clinical appearance, and medical and drug history were noted. Specific inquiry was made into the use of antibiotics in the month before onset of eruption. Several patients were excluded from the PUPPP diagnosis group because they had used antibiotics in the weeks preceding the eruption. After informed consent was obtained, lesional skin biopsy specimens were obtained in 48 of the 57 patients and examined by routine histopathologic studies and immunofluorescence microscopy by means of antihuman IgG, IgM, IgA, C3, and fibrinogen (Behring Diagnostics Inc).

933

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934 Aronson et al Table I. Onset of PUPPP subtypes and gestational age All patients

Total No. of patients Trimester 1 2 3 DIF positive (n = 48)

PUPPP I

57 6 (10.5%) 6 (10.5%) 45 (79%) 15/48 (31%)

PUPPP II

23

PUPPP III

25

1/23 (4%) 1/23 (4%) 21/23 (91)% 7/23 (30%)

DIF positive (n = 48)

9

4/25 (16%) 3/25 (12%) 18/25 (72%) 4/16 (25%)

15/48 (31%)

1/9 (11%) 2/9 (22%) 6/9 (66%) 4/9 (44%)

3/4 (75%) 5/6 (83%) 7/38 (18%)

Table II. Clinical spectrum of PUPPP: Some comparisons

I. Urticarial papules and plaques II. Erythema, nonurticarial 1 to 2 mm papules or vesicles III. Combinations of clinical features of type I and type II * 2 Type I patients and 1 Type III patient also had some targetlike lesions resembling EM, but H&E c/w PUPPP

All patients

Face lesion

Palm lesion

Sole lesion

DIF positive

Third trimester

Parity nulliparous

23 25

0 4

0 2

0 0

7 4

21 (91%) 18 (72%)

17 (74%) 16 (64%)

9

3

4

3

4

6 (66%)

6 (66%)

3

RESULTS

Onset The average age of the patients at onset was 25.4 years (range, 16 to 40 years). Twenty four (42%) of the 57 patients were primagravidas, 16 (28%) were gravida 2, 9 (16%) gravida 3, 4 (7%) gravida 4, 3 (5%) gravida 6, and 1 (1.7%) gravida 7; 68% of the patients were nulliparous. Gestational age at the time of onset of eruption showed variability (Table I); onset occurred in the first and second trimester, as well as in the third. Forty-five of the patients (79%) were in the third trimester, but in type I PUPPP patients, 21 of 23 (91%) had onset of PUPPP in the third trimester, whereas 72% and 66% were third trimester eruptions in the type II and type III patients, respectively. There were no patients who had onset of the eruption postpartum during the study. However, two cases of postpartum PUPPP, one beginning 3 days and the other 5 days postpartum, were seen after the completion of the study and are thus excluded from the analysis. Recurrences of similar eruption in subsequent pregnancy occurred in 3 patients.

Clinical features The eruption began on the abdomen in 43 patients. Sixteen of these patients did not have striae. Of those with striae, all but one had onset in or around the striae. In other patients the initial appearance occurred on the arms in 6, wrists in 2, thighs in 2, leg in 1, feet in 2, and face in 1. The eruption frequently became widespread, involving abdomen, buttocks, upper and lower extremities, chest, and back. Hands were involved in 17, feet in 11, palms in 6, and soles in 3. In addition, the face was involved in 7 patients. The spectrum of morphologic features seen in our patients is presented in Table II and included (1) urticarial papules and plaques (PUPPP type I; Fig 1); (2) erythematous patches that were discrete or confluent and surmounted by tiny (1 to 2 mm) papules or vesicles, or clusters or sheets of 1 to 2 mm erythematous papules, with variable vesicles and excoriations (maculopapular type–type II; Fig 2); and (3) combination of features found in type I and type II noted above (type III; Fig 3). Not infrequently small papules surrounded by a blanched halo were seen on the legs in all three clinical types of patients. Targetlike lesions reminiscent of

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Aronson et al 935

Fig 1. Urticarial plaque and papules of type I PUPPP.

Fig 2. Small (1 to 2 mm) erythematous papules and patchy erythema of type II PUPPP.

erythema multiforme were present in 3 patients, but histologic examination did not reveal erythema multiforme. Of the 7 patients with involvement of the face, 4 were type II (maculopapular type) and 3 were type III (combination of features). No patients with typical type I PUPPP had face, palm, or sole involvement (Table II). Associated medical findings are listed in Table III. Most notably present were asthma (11%) and concomitant use of long-acting theophylline (5%) or terbutaline (5%). Of the 57 pregnancies in this series, one ended in fetal death at 30 weeks gestation (eruption onset at 28 weeks, subsided 2 weeks after delivery of stillborn). Subsequent pregnancy in the same mother, not associated with PUPPP, led to a live, but low birth weight premature infant. Another patient whose eruption appeared at 7 weeks gestation had a spontaneous abortion at 9 weeks. The

Fig 3. Type III PUPPP: Combination of urticarial papules and plaques, nonurticarial papules with tiny (1 mm) blisters and excoriations.

eruption disappeared at the time of the abortion. There were no cases of fetal distress or intrauterine growth retardation in the other fetuses. One set of twins were born. Histopathologic and immunofluorescence microscopy studies Of the 57 patients, 48 had lesional biopsy specimens. Histopathologic examination showed a spectrum of nonspecific findings with slight to moderate perivascular infiltrates of mononuclear cells, some eosinophils, and variable epidermal spongiosis. The direct immunofluorescence (DIF) studies revealed that 15 (31%) had some deposition of IgM, C3, or IgA at DEJ or blood vessels (Table IV; Fig 4). The extent of deposition of immunoglobulins and C3 varied from a few (2) to many (> 6) blood vessels, and the density of granular deposition at the DEJ varied from slight to moderately dense.

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936 Aronson et al

Table III. Associated findings in PUPPP

IV drug abuse Sarcoidosis Hypertension Asthma (taking Theodur-3) Terbutaline

All 57

48 DIF biopsy

15 DIF positive

1 1 2 6

1 1 2 6

1 1 1 0

3

2

1

Table IV. Direct immunofluorescence (DIF) in PUPPP No. of patients

9 4 2 15/48

DIF biopsy findings

+ DEJ + BV + BV only + DEJ only + DIF

BV, Blood vessels; DEJ, dermoepidermal junction.

DISCUSSION

Fig 4. Deposition of C3 in blood vessels in papillary dermis and moderately dense granular deposition at DEJ in patient with PUPPP.

Of the 15 patients with positive DIF deposition, 7 were PUPPP type I, 4 were PUPPP type II (maculopapular type), and 4 were PUPPP type III (combination group; Table II). There was no significant difference in the pattern of immunofluorescence deposition in the 3 clinical types of PUPPP. However, early-onset PUPPP showed an increased incidence of positive DIF (Table I), with first trimester onset 3 of 4 (75%) positive and second trimester onset 5 of 6 (83%) positive. All the findings were “nonspecific” and showed only small granular deposits in blood vessels or minimal to modest granular deposits at the DEJ. There were no cases of linear deposits of any immune reactant at the DEJ, thus eliminating the diagnosis of HG. Indirect immunofluorescence examination of serum for circulating IgG antibody using monkey esophagus was done in 28 patients; results in all cases were negative for circulating IgG antibody directed at the basement membrane.

The most commonly diagnosed pruritic dermatosis of pregnancy is one that presents us with a confusing array of nomenclature and an unknown pathogenetic mechanism. The confusion is created by the broad clinical spectrum and diversity of the cutaneous features. A parallel disease in pregnancy with a wide clinical spectrum and morphologic diversity occurs in HG, but this disease has an identifiable common denominator. A linear band of complement (C3) is always present on DIF examination of lesional or perilesional skin as is the circulating complement fixing “HG factor” (IgG).5,22 These crucial factors have led to advances in an understanding of the cause and pathogenetic mechanisms of HG.38,40,41 The absence of a pathognomonic identifying feature has led to some difference of opinion as to what constitutes the spectrum of PUPPP. Yancey, Hall, and Lawley8 suggested restricting the diagnosis to a clinically homogeneous group of patients in whom the eruption occurred late in the third trimester, began on the abdomen (frequently in the striae) as 1 to 2 mm erythematous papules, coalesced to form urticarial plaques that were only occasionally surmounted by tiny vesicles, and despite the pruritus, lacked excoriations. The primary locations of the eruption were the abdomen, thighs, arms, and buttocks, with facial sparing and

Journal of the American Academy of Dermatology Volume 39, Number 6

infrequent hand and foot lesions. Holmes and Black7 studied a group of 30 patients (and 32 pregnancies), who, although lacking involvement of face, palms, and soles, presented with a wider clinical spectrum. In addition to the papules and plaques previously described, vesicles, excoriation, target lesions, and polycyclic erythema were also present in a significant number of patients. It was this more heterogeneous presentation that led them to suggest the name PEP instead of PUPPP. The clinical spectrum in our patients (Table II) displayed features described by both groups and were divided into three clinical categories. The first, type I PUPPP, demonstrates the defined clinical criteria described by Lawley et al4 and Yancey, Hall, and Lawley8 of urticarial papules and plaques in which vesicles and excoriations were not observed. The second group, type II PUPPP, had predominantly nonurticarial erythema and 1 to 2 mm erythematous papules with variable vesicles and excoriations (maculopapular type). The third group, type III PUPPP, showed a combination of features found in type I and type II. The onset of PUPPP has usually been reported in the third trimester and most frequently in the 35th to 39th week. Postpartum onset has been reported5,8 but we did not see this until after the completion of the study. Earlier onset of PUPPP has been reported at 24 and 25 weeks9,10,33 and at 17 weeks gestation.5 In our group of 57 patients (Table I) 45 (79%) had onset in the third trimester, but in the type I PUPPP, 21 of 23 (91%) occurred in the third trimester. Although the majority of type II and III eruptions also occurred in the third trimester, it did not approach the overwhelming majority seen in the type I PUPPP, and more than 20% of type II and III occurred in the second and first trimesters. The earliest onset, at 7 weeks, occurred in a patient whose eruption (type II) disappeared 2 weeks later at the time of a spontaneous abortion. Whether these episodes were related or coincidental and whether early-onset PUPPP is caused by the same mechanism as later-onset PUPPP is unknown. The distribution of lesions in PUPPP has been a notable clinical feature. The primary locations of the eruption are the abdomen, thighs, arms, and buttocks with notable facial sparing. Callen and Hanno10 described 2 patients in whom only the legs were involved. The face, palms, and soles were not involved in any of the original patients of

Aronson et al 937 Holmes et al,5 and the face was spared although hand and foot lesions were infrequently noted in the patients of Yancey, Hall, and Lawley.8 In our patients (Table II) 6 patients had palmar lesions and 3 had sole lesions. These were usually 1 to 2 mm erythematous papules or vesicles. Facial involvement in PUPPP was reported by Alcalay, David, and Sandbank27 who stated that close observation would most likely reveal more patients with facial eruptions. In our group, head and neck involvement was found in 11 patients, with facial involvement in 7 (Table II). Of these 7, 4 were in the maculopapular group (type II) and 3 were in the overlap group (type III). Thus, the type I PUPPP patients with the exclusively urticarial papules and plaques did not have facial, palmar, or sole lesions (Table II). Recently two patients with palm and sole microvesicles were reported. The clinical features appear consistent with our type II or III PUPPP33 and were specifically noted to present overlap with HG. Whether the clinical differentiation into type I, II, and III PUPPP indicates a different cause or pathogenetic mechanism remains speculative. Irrespective of whether facial, palm, and sole involvement is present in the type II and type III patients, the eruption must be differentiated from contact dermatitis, toxic drug eruptions, viral eruptions, and pityriasis rosea.27,28 An interesting observation was the history of asthma in 6 patients, 3 of whom were taking theophylline. The eruption was type II in 1 patient and type III in 2. The 3 patients with asthma who were receiving no medications had type I PUPPP. In the 3 patients in whom there was association with terbutaline, the eruption was type II in 2 and type I in 1. Whether these medications were involved in the induction of the cutaneous eruption is unknown. In the report of Lawley et al4 of 7 PUPPP cases, 1 patient who was delivered of twins had one stillborn and one normal child. A subsequent twin pregnancy in the same patient, unassociated with PUPPP, was again associated with one live baby and one stillborn. In our group of 57 patients there was 1 stillbirth at 30 weeks. This patient had type I eruption that cleared a few weeks after delivery. Because this is the only fetal death at this stage of pregnancy reported in association with PUPPP (with the exception of the stillbirth in one out of a set of twins) it is statistically impossible to relate that death to PUPPP.

938 Aronson et al There are no specific laboratory abnormalities found in PUPPP. Histopathologically, light microscopy reveals a nonspecific perivascular lymphohistiocytic infiltrate with some edema and eosinophils in the dermis.4,5 Some patients will also have spongiosis or small spongiotic vesicles in the epidermis.4,5 All our patients’ biopsy specimens fall into this spectrum. Of the multiple patients with PUPPP who have been reported1-37 many have had DIF studies. Of these, only a few had immunoreactants in the biopsy specimen.4,8,9,11,18 Of the 48 patients in our group who underwent biopsy, 15 (31%) had immunoreactants in blood vessels or at the DEJ. The presence of immunoglobulin and C3 in blood vessels has usually been associated with circulating immune complexes and vasculitis.42 In the study of Yancey, Hall, and Lawley,8 circulating immune complexes were measured in 10 patients; in only 2 patients were IgA complexes slightly elevated. Thus, the presence of immune reactants in lesional skin of some of our patients may reflect circulating immune complexes, but in most it may represent nonspecific immune reactants often found in skin lesions of various inflammatory dermatoses (personal observation, I. K. A.). The question of whether PUPPP is a homogeneous or heterogeneous process may not be answered looking solely at the clinical features. Type I PUPPP differed from types II and III mainly in clinical appearance and distribution; but trimester onset, parity, and histologic/immunofluorescence findings were not significantly different in the 3 groups. It is possible that the patients within this clinical spectrum may be heterogeneous with respect to pathogenesis as well as clinical appearance. REFERENCES 1. Bourne G. Toxemic rash of pregnancy. Proc R Soc Med 1962;55:462-4. 2. Nurse DS. Prurigo of pregnancy. Aust J Dermatol 1968;9:258-67. 3. Cooper AJ, Fryer JA. Prurigo of late pregnancy. Aust J Dermatol 1980;21:79-84. 4. Lawley TJ, Hertz KC, Wade TR, Ackerman AB, Katz SI. Pruritic urticarial papules and plaques of pregnancy. JAMA 1979;241:1696-9. 5. Holmes RC, Black MM, Dann J, James DCO, Bhogal B. A comparative study of toxic erythema of pregnancy and herpes gestationis. Br J Dermatol 1982;106:499-510. 6. Holmes RC, Black MM. The specific dermatoses of pregnancy; a reappraisal with specific emphasis on a proposed simplified clinical classification. Clin Exp Dermatol 1982;7:65-73.

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7. Holmes RC, Black MM. The specific dermatoses of pregnancy. J Am Acad Dermatol 1983;8:405-12. 8. Yancey KB, Hall RP, Lawley TJ. J Am Acad Dermatol 1984;10:473-80. 9. Alcalay J, Ingber A, David M, Hazaz B, Sandbank M. Pruritic urticarial papules and plaques of pregnancy. J Reprod Med 1985;32:315-6. 10. Callen JP, Hanno R. Pruritic urticarial papules and plaques of pregnancy (PUPPP). J Am Acad Dermatol 1981;5:401-5. 11. Faber WR, Joost ThV, Hausman R, Weenink GH. Late prurigo of pregnancy. Br J Dermatol 1982;106:511-6. 12. Schwartz RA, Hansen RC, Lynch PJ. Pruritic urticarial papules and plaques of pregnancy. Cutis 1981;27:425-7. 13. Noguera J, Moreno A, Moragas JM. Pruritic urticarial papules and plaques of pregnancy (PUPPP). Acta Derm Venereol (Stockh) 1983;63:35-8. 14. Uhlin SR. Pruritic urticarial papules and plaques of pregnancy. Arch Dermatol 1981;117:238-9. 15. Romero R, Olsen TG, Chervenak FA, Hobbins JC. Pruritic urticarial papules and plaques of pregnancy. J Reprod Med 1983;28:615-8. 16. Ahmed AR, Kaplan R. Pruritic urticarial papules of pregnancy. J Am Acad Dermatol 1981;4:679-81. 17. Stoller HE. Pruritic urticarial papules and plaques of pregnancy [letter]. JAMA 1980;243:2156. 18. Alcalay J, Ingber A, Sandbank M. Unusual histopathological findings in polymorphic eruption of pregnancy (PUPPP). Z Hautkr 1987;62:879-81. 19. Alcalay J, Ingber A, Kafri B, Segal J, Kaufmann H, Hazaz B, et al. Hormonal evaluation and autoimmune background in PUPPP. Am J Obstet Gynecol 1988;158: 417-20. 20. Rockl LH, Lurz C. Die PUPPP-Dermatose. Hautarzt 1983;34:179-81. 21. Linasmita V, Sugkraroek S. Pruritic urticarial papules and plaques of pregnancy (PUPPP): report of 2 cases. J Med Assoc Thailand 1984;67:624-8. 22. Jurecka W, Holmes RC, 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 Dermatol 1983;108:147-51. 23. Fox GN. Pruritic urticarial papules and plaques of pregnancy. Am Fam Physician 1986;34:191-5. 24. Hill JA. Pruritic urticarial papules and plaques of pregnancy. J Med Assoc Ga 1985;74:493-5. 25. Moreno A, Noguera J, DeMoragas JM. Polymorphic eruption of pregnancy: histopathologic study. Acta Derm Venereol (Stockh) 1985;65:313-8. 26. 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. 27. Alcalay J, David M, Sandbank M. Facial involvement in pruritic urticarial papules and plaques of pregnancy. J Am Acad Dermatol 1986;15:1048. 28. Carruthers A. Facial involvement in pruritic urticarial papules and plaques of pregnancy. J Am Acad Dermatol 1987;17:302. 29. Bunker CB, Erskine K, Rush MHA, Gilkes JJH. Severe polymorphic eruption of pregnancy occurring in twin pregnancies. Clin Exp Dermatol 1990;15:228-31. 30. Zurn A, Celebi CR, Bernard P, et al. A prospective immunofluorescence study of 111 cases of pruritic dermatoses of pregnancy: IgM anti-basement membrane

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Aronson et al 939 37. Beltrani VP, Beltrani SB. 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. 38. Shornick JK. Herpes gestationis. J Am Acad Dermatol 1987;17:539-56. 39. Alcalay J, Ingber A, Hazzaz B, et al. Linear IgM dermatosis of pregnancy. J Am Acad Dermatol 1988;18: 412-5. 40. Ortonne JP, Hsi BL, Verrando P, et al. Herpes gestationis factor reacts with the amniotic epithelial basement membrane. Br J Dermatol 1987;117:147-54. 41. Morrison LH, Labib RS, Zone JJ, et al. Herpes gestationis autoantibodies recognize a 180-kd epidermal antigen. J Clin Invest 1988;81:2023-6. 42. Kumar V, Beutner EH, Chorzelski TP. Immunopathology of blood vessels. In: Beutner EH, Chorzelski TP, Kumar V, editors. Immunopathology of the skin. New York: John Wiley & Sons; 1987. p. 745-54.

ATTENTION AUTHORS The Editorial Office of the Journal of the American Academy of Dermatology moved from Charleston to the University of Massachusetts Medical Center in Worcester on June 1, 1998. Please send all new submissions to: Jeffrey D. Bernhard, MD, Editor Journal of the American Academy of Dermatology University of Massachusetts Medical Center 55 Lake Ave. North Worcester, MA 01655 Telephone: 508-856-2583 Fax: 508-856-5687