Herpes gestationis: Clinical and histologic features of twenty-eight cases

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III

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Herpes gestationis: Clinical and histologic features of twenty-eight cases Jeff K. Shornick, M.D., Jerry L. Bangert, M.D., Robert G. Freeman, M.D., and James N. Gilliam, M.D.*

Dallas, TX We have studied 28 patients with well-documented herpes gestationis (HG) to determine the frequency of complications and to review the histopathology, immunopathology, and clinical parameters of disease. The frequency of miscarriages and other maternal complications in our series was not extraordinary. Fetal complications were similarly limited. Less than 5% of infants had cutaneous lesions, and no other untoward fetal complications were apparent. Although the clinical features of our patients largely paralleled those typically reported for patients with HG, several variants of disease were noted. We report one woman with immunofluorescence-confirmed HG who had no clinical disease during a subsequent pregnancy. We also identified cases in which the characteristic vesiculobullous lesions of HG never developed. Instead, four women had urticarial papules or plaques throughout their clinical courses. HG was verified in these four women by typical immunottuorescent findings and by recurrent, classical disease during subsequent pregnancies in two. In addition, two women were identified with recurrent HG during pregnancies by different husbands. (J AM AeAD DERMATOL8:214-224, 1983.)

Herpes gestationis (HG) is a rare autoimmune disease which has been estimated to occur in one o f 3 , 0 0 0 t to one of 10,0002 pregnancies. It typically begins in the second or third trimester and is characterized by a severely pruritic eruption consisting of erythematous papules, plaques, and vesiculobullous lesions. The initial lesions are often localized to the periumbilical area but rapidly spread to involve other sites on the trunk or exFrom the Department of Dermatology and the Department of Pathology, University of Texas Health Science Center at Dallas. Supported by Immunodermatology Cerlter Grant AM17363, Immunodermatology Fellowship Grant AM07341, and a Dermatology Foundation grant. Accepted for publication June 23, 1982. Reprint requests to: Dr. Jeff K. Shomick, Dermatology, University of Connecticut Health Center, Farrnington, CT 06032/203-674-3474. *Recipient of a Research Career Development Award from the National Institutes of Health, No. AM00278.

214

tremities. The disease may begin or exacerbate in the postpartum period. During subsequent pregnancies it tends to occur earlier in gestation and to be more severe. Flares associated w i t h menstruation are well documented, 3-5 and several reports note recurrences provoked by birth control pills at variable times after pregnancy. 4'6 W h e t h e r there is an increased incidence of fetal morbidity or mortality is unclear) '5 The best procedure for differentiation o f this disease from other entities which may give a similar clinical or histologic appearance is to stain skin biopsy specimens by the direct immunofluorescence (IF) technic. The characteristic I F finding is the deposition of complement and occasionally immunoglobulin G (IgG) in a linear pattern along the basement membrane zone (BMZ). 7-to An IgG serum antibody may be found by indirect IF even when IgG is not seen by direct examination. 6-9"11 0190-9622/83/020214+ 11501.10/0 © 1983 Am A c a d Dermatol

Volume 8 Number 2 February, 1983

Similar immunologic findings have been noted in the serum and skin of newborns 12,13 even in the absence of clinically apparent disease, s The purpose o f this report is to describe twenty-eight patients who had well-documented HG. Particular attention is directed toward estimating the frequency of miscarriages and fetal complications and a review of the histopathology.

METHODS Patients for this study were identified through contact with three histopathology and immunopathology laboratories, seven dermatology training centers with an interest in immunologically mediated diseases, and a large group of practicing dermatologists. The criteria for inclusion in the study group were: (1) a clinically compatible eruption during pregnancy or the puerperium and (2) IF documentation of disease. All patients were interviewed in person or by telephone and questioned about all pregnancies, involved or uninvolved. Directed histories were obtained regarding spontaneous abortions, obstetric complications, methods of delivery, prematurity, birth weights, and perinatal health. Particular attention was paid to preexistent skin disease and the clinical features of HG: onset, severity, extent, type and time course of lesions, duration, fluctuations in course, exacerbation with delivery, recurrence with menstruation or exposure to oral contraceptives, recurrence in subsequent pregnancies, and the effect of disease on subsequent choice of birth control. All information was verified by a review of records or discussion with the referring dermatologist. Relevant records were obtained and reviewed on twenty-three patients. A history of past medical disease, concurrent medications, allergies or history of atopy, a review of systems, and family history were obtained in all cases. Treatment modalities were confirmed by contact with the appropriate dermatologist or a review of the records. Immunofluorescence reports were obtained in all cases, and histopathology slides were reviewed in twenty-three cases. Tissue blocks were available on only six cases. Histopathology sfides reviewed were the best available sections on each patient, obtained from the referring dermatologist, the histopathology laboratory, or both. SELECTED CASE REPORTS Case 1 A 39-year-old woman developed HG during her sixth pregnancy. Her first pregnancy terminated spontaneously at 2 months' gestation. Her fifth was complicated by delivery of a male infant who died at 6 months

Herpes gestationis

215

of age from congenital heart disease. The patient first presented to her dermatologist with an intensely pruritic rash around the umbilicus during the 37th week of her sixth pregnancy. Within hours of delivery she developed extensive patches of erythema with annular and serpiginous borders on the neck, arms, upper thighs, and feet. The involved areas were studded with small vesicles. There were no mueosal lesions. Her white blood cell count was 12,000 with 1% eosinophils. She was treated with 60 mg of prednisone daily, which was tapered over 4 weeks without recurrence of disease. In the third month of her seventh pregnancy she developed recurrent skin disease in the same pattern and distribution experienced earlier. Her white blood cell count was 11,150 with 6% eosinophils. She was treated with 40 mg of prednisone daily, but was unable to taper her dose below 10 mg daily without an increase in cutaneous involvement. A female infant without cutaneous lesions was born but died of anoxia due to a knot in the umbilical cord. A dramatic flare of the patient's disease necessitated an increase in prednisone to 40 nag daily. It took 4 months to discontinue treatment. Similar clinical courses ensued in her eighth and ninth pregnancies. HG was confirmed when IF revealed a linear deposition of C3, C l q, properdin, and fibrin in the basement membrane zone. A complement-fixing anti-BMZ antibody was present in the serum, blister fluid, and cord blood. A postpartum flare once again required 4 months of systemic therapy. A trial of birth control pills containing 1.0 nag norethindrone and 0.08 mg mestranol resulted in the reappearance of her rash in less than 1 week. A tenth pregnancy was terminated in anticipation of recurrent disease. There was no clinical evidence of HG at the time of the procedure, but a flare occurred on her hands and feet within hours of surgery. This resolved during 2 weeks of treatment with systemic steroids. Mild flares occurred with menstruation for 3 months afterward. Comment. The recurrent course in this woman demonstrates the classical pattern of disease. It also demonstrates how misleading statistics on fetal morbidity or mortality can be. A death from a knot in the umbilical cord during an involved pregnancy is surely unrelated to the presence of HG; that from congenital heart disease occurred before the first pregnancy associated with cutaneous disease. Case 2 A 20-year-old woman developed an extremely pruritic bullous eruption on her lower extremities 4 days postpartum. The eruption never spread beyond her

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Fig. 2. Spongiosis and subepidermal vesiculation. The blister contains numerous neutrophils and eosinophils.

Fig. 1. Epidermal changes typically include spongiosis, liquefaction degeneration, and lining up of neutrophils or eosinophils along the dermoepidermal junction. legs, was unresponsive to antibiotics, and resolved spontaneously over a 4-week period. Her second pregnancy terminated spontaneously in the second month. She had no cutaneous symptoms during or after this pregnancy. In the fifth month of her third pregnancy she experienced the onset of blisters in her umbilicus. Within a week she developed urticarial patches and bullae on the hips, ankles, and hands. Occasional oral lesions and denuded areas of the vaginal mucosa were noted. A biopsy specimen was interpreted as "subacute vesicular dermatitis compatible with herpes gestationis." Immunofluorescence showed linear deposition of C3 and IgG at the dermoepidermal junction. She was initially treated with 40 mg of prednisone daily and then varying doses for the duration of her pregnancy. A postpartum flare required 60 mg of prednisone daily for 16 days, followed by tapering doses over the next 4 months. She had no rash or itching with menstruation or during a 2-year course of treatment with birth control pills containing 0.5 mg norgestrel and 0.05 mg ethinyl estradiol.

The patient divorced and remarried after her third pregnancy. A fourth pregnancy ended with a spontaneous abortion in the third month. There was no evidence of HG during or alter this pregnancy. During a fifth pregnancy her skin remained normal, but within 24 hours of delivery she developed extremely pruritic vesiculobullous lesions in the umbilicus. Her cutaneous disease developed in the same pattern as before, though never to the same extent. No treatment was instituted, and her eruption resolved spontaneously over 4 weeks. There had been no recurrence of disease at the time of writing. Comment. Recurrent disease during subsequent pregnancies by different husbands raises some interesting questions about the pathogenesis of this entity and the potential role of paternal factors in the development of disease. Do paternal antigens represented in the placenta play any role in the development of HG? That disease may occur by different husbands implies that paternal antigens are irrelevant. However, it may be that once "sensitized," recurrent pregnancy by any mate is sufficient to reproduce disease. Case 3 A 30-year-old woman presented in the seventh month of her third pregnancy with a 2-month history of "poison i v y " on her arms and hands. She had previously had no difficulty during two full-term pregnancies and no derrnatoses during a 9-year period of treatment with birth control pills containing norinyl, 1.0 rag, and 0.05 mg mestranol. The eruption gradually spread to her trunk, neck, face, and scalp and was composed of edematous plaques studded with 2- to

Volume 8 Number 2 February, 1983

6-ram vesicles and pustules. Her white blood cell count was 18,200, with 1% eosinophils. Direct immunofluorescence (IF) showed weak staining of the BMZ for IgG and strong staining for C3, C4, and properdin. Repeat IF studies I month before delivery, at the time of parturition, and 1 month later showed similar findings. A full-term male infant was born with several vesicular and pustular lesions on his hands, face, and feet. IF studies showed linear BMZ staining for C3, C4, and properdin. No new Iesions developed after birth, and all lesions resolved in 2 weeks without sequelae. The mother continued a slowly tapering dose of prednisone. Six weeks postpartum she began taking birth control pills (the same contraceptive as prior to her pregnancy, containing 1.0 mg of norethindrone and 0.05 mg of mestranol) but had to discontinue treatment when her skin disease began to recur. Oral contraceptives were stopped after 1 week, and the prednisone was stopped 3 weeks later. An abortion with tubal ligation was performed when she became pregnant for a fourth time. No cutaneous disease developed, and there have been no further episodes of dermatitis to date. Comment. The course of disease in this woman and her inthnt are typical for disease which involves the child. Infants with cutaneous disease do well, without developing new lesions after their initial presentation. It would appear that disease in infants is due to passive transfer of the HG antibody. However, the potential influence of residual maternal hormones must also be considered.

Herpes gestationis

217

the onset of intense pruritus, with lesions identical to those of her previous pregnancy, A pregnancy test, usually positive after 5 weeks, was negative. She was thought to have anovulatory bleeding, and no treatment was instituted. The cause of her dermatitis was not determined, but it resolved over a period of 4 weeks.' There was no recurrence during a 1-year course of birth control pills, although she continued to have mild pruritus with menstruation. Within 1 week of stopping her oral contraceptives there was a mild exacerbation of her skin disease. She did not seek medical consultation, no treatment was instituted, and the eruption resolved over 6 weeks. The patient divorced her first husband 1 year before presenting with urticarial plaques and excoriations on the trunk and thighs. These lesions had first developed during the fourth week of gestation. She decided against treatment and had an induced abortion at 13 weeks. Her dermatosis did not exacerbate, and no treatment was required. Comment. This woman also had disease in subsequent pregnancies by different husbands. Unlike Patient 2, however, the disease in this woman appeared to follow the more typical pattern of earlier, more severe disease during a subsequent gestation. Because of the presence of recurrent HG, we have considered this patient's episode of "anovulatory bleeding" as a spontaneous abortion, even though her pregnancy test was negative. It should be noted that inclusion of this "pregnancy" tends to bias our data toward increased complications with HG. C a s e 11

Case 4 A 17-year-old woman presented in the fifth month of her first pregnancy with a 2-month history of an extremely pruritic, excoriated dermatosis on the trunk and extremities. The eruption began as 1- to 2-ram papules on her wrists but rapidly spread to her extremities, back, abdomen, palms, and soles. Multiple vesicles on edematous, urticarial bases were noted, with confluence over the entire abdomen. Direct IF revealed small amounts of IgG and a rich deposition of C3 and C4 in a linear band along the BMZ. She was started on 40 mg of prednisone daily but was unable to taper her dose below 25 mg daily without recurrence. Her prednisone was increased at the time of delivery, there was no postpartum flare, and all medications were discontinued 6 weeks later. Five months later she presented in the emergency room with vaginal bleeding, 6 weeks after her last menstrual period. Three weeks earlier she experienced

A 25-year-old woman developed intensely pruritic, erythematous papules and plaques in the fifth month of her second pregnancy. A previous pregnancy without associated skin disease had been electively terminated during her first marriage 5 years earlier. Routine histopathology was consistent with HG, and direct IF showed weak staining for IgG and strong staining for C3 at the dermoepidermal junction. Indirect IF was negative for IgG or C3. Within 2 weeks of the initial onset of disease she began to develop numerous 2- to 12-ram vesicles and bullae on the trunk and extremities. There were extensive areas o f confluence into large, flaccid bullae on the buttocks and thighs. Treatment with topical agents was instituted. One week after premature rupture of the membranes at 33 weeks' gestation (10 weeks after the onset of disease) a cesarean section was performed. Systemic steroids were instituted, with compIete resolution of symptoms within 3 days. The steroids were discon-

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Table I, Historical and immunofluorescence findings in twenty-three patients with HG

I.

SA; F; F; M; M; M; F; F; F; Ab D S TL

9th month

Umbilicus

No

Yes

2.

1st husband: ~ SA ~4

4 days postpartum

Umbilicus

No

Yes

2nd husband: SAM 3.

M M M Ab TL

5th month

Hands/arms

Yes

Yes

4.

1st husband: M ~A't

4th month

Palms/soles

No

Yes

2nd husband: Ab 5.

F M F SA F CCC C

6th month

Umbilicus

No

No

6.

M MF

5th month

Umbilicus

No

Yes

7.

SA F F M SAM ~I

4th month

Legs

No

Yes

8.

FMM

6th month

Umbilicus

No

No

9.

MF

7th month

Umbilicus

No

Yes

Mi~ 1st husband: Ab ~M husband: ~t F P,C C

7th month

Umbilicus

No

Yes

5th month

Ankles

No

No

4th month

Feet

No

Yes

10. I 1.

12,

SA F M

Ab: ~ u m ; C: ce,mrea, ~ectiom; D: died (see text); F: female; HM: hydatidiform mole; M: male; P: premature; S: stillbirth; SA: spontaneous ~m; YL tubal hg~tmtt; *: ptegnar,cy associated with HG. tl~y te~t was negative, but ept~xl¢ associated with HG (see text). Counted as a pregnancy for the purposes of this study.

ti:nued after I week of treatment without recurrence of dt~ase. A third pregnancy 2 years later was carded to term, and a cesarean section (with tubal ligation) was done. There was no evidence of cutaneous disease at any poim during gestation or the postpartum period. However, k i n specimens taken at the time of delivery revealed linear complement deposition along the BMZ. In&met IF s ~ i e s using serum and cord blood failed to reveal IgG. or complement-fixing capacity. Repeat direct and i ~ m e t IF stuff~es 6 months later were

parent at any time during gestation or the postpartum period, the presence of linear IgG and C3 deposition on IF suggests that the immunologic basis of disease was intact. Although it is not known what her IF would have shown between pregnancies, no immunoreactants were seen 6 months after her last child was born, suggesting that no immunoreactants were present between pregnancies either. One can only speculate about the factors that may have suppressed clinical disease in this woman.

RESULTS

negative.

Comment, Them have been no reports of HG failing to ~ ' c ~ in a subsequent pregnancy in the years since IF became available. Although no clinical disease was ap-

Histopathology, A review o f the histopathology of twenty-five biopsy specimens from twentythree patients revealed a highly variable spectrum

Volume 8 Number 2 February, 1983

Mucosa [ No

Yes

No

No

Herpes gestationis 219

1)IF

]

m~

C3 Properdin Fibrin IgG C3

Maternal serum, cord blood, blister fluid all positive Not done

IgG C3 C4 Properdin IgG C3 C4

Not done

Not done

Yes

C3

Not done

Yes

C3

Not done

No

C3 Clq C4 C3

Not done

No

IgG C3

Not done

No

C3

Not done

No

IgG C3

Negative

Yes

C3

Maternal serum, blister fluid both positive

No

Blister fluid positive

continued

of changes that seemed to parallel the polymorphic clinical patterns of disease. The pathology in most cases involved both the epidermis and the dermis, although dermal changes were seen most consistently. The most constant epidermal findings included focal areas of liquefaction degeneration or a variable degree of spongiosis (Fig. 1). Liquefaction degeneration was seen in an unexpectantly large number of cases (50%). Intraepidermal spongiotic vesicles were seen in five specimens (20%). Eosinophils were often numerous and were present both within vesicles or singly within spongiotic areas of epidermis. In several instances, intraepidermal vesicles appeared to have begun as subepidermal vesicles with regeneration of epi-

dermis beneath the blister. In a few cases there was individual cell necrosis o f keratinocytes or clusters of keratinocytes. In one case there was extensive necrosis of the full thickness of epidermis. Consistent changes in the papillary dermis included varying amounts of edema and perivascular infiltration by lymphocytes, histiocytes, and eosinophils. Inflammatory ceils were concentrated around the subpapillary vessels but often extended into the midretieular dermis and occasionally even deeper. There was a tendency for eosinophils, neutrophils, and, occasionally, lymphocytes to line up along the basement membrane zone (Fig. 1). Infiltration by eosinophils was the single most consistent finding in our series, being present in twenty-three of the twenty-five cases. The degree of edema varied from barely perceptible to extensive. Vesicle formation was present in only ten specimens. The location of the vesicle was intraepidermal in five cases, subepidermal in three cases, and both intraepidermal and subepidermal in two cases (Fig. 2). Immunottnorescent findings. The clinical and IF features of these patients are summarized in Table I. AU twenty-eight patients had linear deposition of C3 along the basement membrane of lesional or perilesional skin. IgG was identified in nine samples. Other reactants included C4, Clq, properdin, and fibrin. There appeared to be no difference in the clinical expression of disease in those patients who had deposition of complement alone compared to those who had IgG in addition to complement components. Indirect immunofluorescence (IIF) was done on the sera of ten patients and was positive for IgG or the ability to fix complement in six. Blister fluid from three women was similarly tested and was positive for IgG or complement fixation in all. There were too few patients with indirect IF to attempt a correlation with disease severity.

Maternal disease In the twenty-eight patients reported, there were 102 pregnancies, forty-two of which were associated with the cutaneous manifestations of HG. The maternal age at the initial onset of disease ranged from 17 to 39 years. The initial presentation occurred as early as the first pregnancy or as late as

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Table I. Cont'd

Patient

Pregnandes

[

Onset

Initialsite

[ Face [" Palms/soles

13,

SASAMF~

4th month

Arms/legs

No

Yes

14.

HM F M

7th month

Legs

No

No

15.

F

6th month

Arms

No

Yes

16. 17.

MMFM Ist husband: M F 2nd husband: l~I~

4th month

Arms/legs

Yes

Yes

24 hours postpartum

Soles

No

Yes

18.

FM

5th month

Umbilicus

No

Yes

19.

FM

6th month

Umbilicus

No

No

20.

MMM

8th month

Umbilicus

No

Yes

21.

MFSAM

7th month

Arms/legs

No

Yes

22. 23.

l~I 1st husband: M , 2nd husband: HM F

2nd month

Soles

No

Yes

3 days postpartum

Back

No

Yes

24.

MFMFMMSAMM D

24 hours postpartum

Legs

No

Yes

25.

Ab M Ab P,C

4th month

Arms/legs

Yes

Yes

26.

MSAM C P,C

7th month

Umbilicus

No

No

27.

FF

8th month

Arms

No

No

28.

MF P

7th month

Umbilicus

No

Yes

the seventh. The initial onset ranged from the second month of gestation to the fourth day postpartum, but the majority of cases began in the sixth or seventh month. Patients occasionally reported that the initial onset in a previous pregnancy occurred as late as 2 weeks' postpartum; however, we have not been able to document these eruptions as being due to HG. Two women had involvement in pregnancies by different husbands, In one of these patients the disease followed the classical pattern of earlier and intensified disease in a subsequent pregnancy (Case 4), while the other woman had less severe involvement by her second mate (Case 2). Three multiparous women had their initial onset of HG only after a second marriage.

There were thirteen spontaneous abortions in ten women. Only one of the pregnancies that ended in spontaneous abortion was associated with clinical disease. In fact, nine of these miscarriages occurred before the first pregnancy associated with HG. Two more spontaneous abortions without associated skin disease occurred in the same woman between full-term, involved pregnancies (Case 2). There were six induced abortions, three of which were to avoid recurrent HG. There were two hydatidiform moles which were not associated with HG. The initial site of involvement was in or around the umbilicus in twelve patients and on the extremities in fifteen. Only three women had facial involvement. The palms or soles were eventually

Volume 8 Number 2 February, 1983

Herpes gestationis 221

DIF

Mucosa

I

IIF

No

C3

Not done

No

C3

Not done

No

C3 C4

Not done

Yes

C3

Positive for C3

No

C3

Not done

No

C3

Not done

No

C3

Not done

No

C3

Negative

No

C3 C4 C3

Not done

No

Negative

No

IgG C3

Negative

No

IgG C3

IgG C3

No

C3

Not done

No

IgG C3

C3

No

IgG C3 C3

Not done

No

C3

involved in twenty-one. Mucosal lesions were uncommon. Only five women had lesions of the mouth, conjunctiva, vagina, or anal mucosa. The onset was occasionally explosive but more typically was gradual over a 2- to 6-week period. Vesiculobullous lesions usually had their onset in the same area as the initial eruption, but typically they did not appear for several weeks after the onset of disease. Herpes gestationis was often not considered at the initial presentation. Instead, contact dermatitis, bites, and urticaria were usually the first considerations. Extreme pruritus was reported by all twenty-eight women. The unusual severity of pruritus was characteristic and occasionally preceded the onset of cutaneous findings. Pruritus was generalized and episodic in most patients,

while stinging, burning, or pain was only occasionally reported. Arthralgias were noted by two women and episodic fever by one, but the relationship of these complaints to their HG was unclear. Of forty-two pregnancies associated with clinical disease, four were not associated with vesiculobullous lesions. Three of these were associated with large polycyclic or urticarial lesions (Cases 9, 19, and 28) and one with edematous, red papules (Case 20). Patients 9 and 19 had subsequent pregnancies in which typical vesicles and bullae were noted. Two women had all evidence of cutaneous disease resolve prior to delivery. Patient 22 experienced resolution after a short course of prednisone, only to flare postpartum. Patient 19 had all lesions resoNe spontaneously prior to delivery, but had a subsequent pregnancy characterized by extensive disease and a severe exacerbation with delivery. Postpartum exacerbation occurred in thirty-one of forty-two involved pregnancies and usually occurred within the first 12 to 48 hours. There was some variability to this. Some women were on large doses of prednisone at the time of delivery, and it is unclear to what extent their diathesis may have been altered by treatment. Some patients with late flares (after 7 days) probably were responding to a decrease in their medication. Puerperal flares were occasionally quite severe. Prednisone was used during thirty-four involved pregnancies in doses initially between 20 and 80 mg per day. There was extreme variability in the need for protracted treatment. Some women were able to stop prednisone within 5 days of delivery, whereas others needed treatment for up to 18 months. The typical duration of treatment was 6 to 10 weeks following delivery. None of the infants of these women required systemic treatment for cutaneous disease or adrenal suppression due to therapy of the mother. Patient 26 was successfully treated with plasma exchange when adequate control with prednisone became unobtainable. Seven women had a recurrence of pruritus or overt skin disease with menstruation for months to years postpartum. Nine women subsequently used oral contraceptives. Only two of these women

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Journal of the American Academy of Dermatology

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were among those who had an increase in itching or dermatitis with menstrual periods before beginning oral estrogens. Two of those using birth control pills had flares of their HG within 1 week of beginning treatment. One additional woman experienced no difficuky throughout therapy, but she had a flare lasting 6 weeks when the pill was discontinued after 1 year of treatment. The remaining four women had no difficulty during treatment with birth control pills.

Infant disease Of the 102 pregnancies, seventy-nine were carried to parturition, resulting in the birth of fortyseven male and thirty-two female infants. The children born of each woman's first pregnancy in which HG occurred included seventeen male and eleven female children. There were thirteen miscarriages and two hydatidiform moles. One child died at birth with a knot in the umbilical cord, and another child of the same mother died at 6 weeks of age from congenital heart disease (Case 1). Patient 24 had a premature girl die from respiratory distress syndrome 7 years before her first pregnancy associated with HG. Only one of the thirteen spontaneous abortions was associated with clinical HG. All but four occurred before the first involved pregnancy. Of forty pregnancies carried to parturition and associated with HG, only two infants had cutaneous lesions (Cases 3 and 25), All cutaneous signs resolved spontaneously in both infants within 2 weeks. Immunofluorescence studies in one of the infant's skin showed a linear band of C3, C4, and properdin at the dermoepiderrnal junction (Case 3). The circumcised foreskin of another child without skin disease was submitted for IF, and linear deposition of C3 in the BMZ was observed.

Associations with other diseases Seven of our patients had a history of asthma or hay fever. None had ever experienced any signs of vitiligo, alopecia areata, or well-documented thyroid dysfunction. Patient 6 had been treated with thyroid supplementation for 9 years, but available tests do not clearly document preexistent thyroid dysfunction. One woman (Patient 16) had a his-

tory of primary biliary cirrhosis and will be reported on in depth elsewhere. Two women had histories of surgical treatment for ovarian disease prior to the initial onset of HG. There was no history of diabetes in any of these women. The lack of association with diabetes is of particular interest because both diabetes and H G are known to be associated with the combination of HLA antigens DR3 and DR4.14

DISCUSSION Russell and Thome 1 determined the number of patients with HG in a single referral hospital over a period of 35 years and estimated its incidence to be between 1:3,000 and 1:4,000 deIiveries. Kolodny 2 counted the number of patients over an 18-year period at two major university hospitals in St. Louis and estimated the incidence to be closer to 1:10,000. Russell and Thorne did their retrospective study in a large referral hospital in London long before IF became available. It is likely that selective referral artificially increased the incidence of disease in this study. It is also likely that cases were included that would no longer be accepted as HG. Although Kolodny estimated the incidence to be higher than the 1 : 3,000 figure described by Russell and Thome, he was, in fact, able to find only two cases among 113,000 deliveries. Estimating the incidence of a nonreportable disease is subject to many errors. We have collected all of the known cases of HG in the Dallas-Fort Worth area over a 10-year period by contacting all of the practicing dermatologists and the major pathology and immunopathology laboratories in the area. We were able to find six cases during a time period when there were 379,000 birth certificates issued (299,000 to Caucasians). We have also counted the number of cases seen in our own institution in the years since IF became available. Only one case was found in 77,000 births (28,000 Caucasians). We think it is unlikely that we have missed any recognized cases during this time, but we are aware of the limitations of this type of investigation. We estimate the incidence of HG to be much closer to 1 : 50,000 pregnancies than the 1:3,000 to 1 : 10,000 figure commonly quoted.

Volume 8 Number 2 February, 1983

The clinical features of the patients in this group are largely in accord with those of previous reports. HG tends to have its onset in the second or third trimester and tends to occur earlier and to be more severe in subsequent pregnancies. However, patients with well-documented disease have had less severe involvement during subsequent pregnancies, and occasional patients have had no subsequent disease at all. Patient 11 is of particular interest in this respect because of the complete lack of clinical evidence of disease during her third pregnancy. The finding of complement deposition in skin specimens taken at the time of delivery suggests that subclinical disease was present. What immunologic controls allowed her to avert clinical disease must remain purely conjectural. The peculiar proclivity for the rash of HG to begin around the umbilicus is intriguing. There is no evidence that there are unusual antigenic differences in the skin of this area, yet the first appearance of the eruption at this site is greater than chance would allow. Similarly, the tendency to avoid facial skin and mucosal surfaces is curious. It is clear that cases of HG can occur without typical vesiculobullous lesions. The eruption may appear urticarial in one pregnancy only to become more typical in the postpartum period or during a subsequent pregnancy. Immunofluorescence is the key to differentiating HG from other entities in these early or atypical stages of disease. Indeed, it may be difficult to separate HG from urticaria, contact dermatitis, dermatitis herpetiformis, erythema multiforme, bullous drag eruption, or other dermatoses of pregnancy by any other means. Cases of HG reported before immunofluorescence became available are biased toward patients with typical histories and vesiculobullous eruptions. A broader spectrum of disease is appreciated if IF is applied and accepted as definitive. HG has been reported with hydatidiform moles Iz and choriocarcinoma, x6 These tumors in women are of gestational tissue, with both maternal and paternal antigens represented. Although choriocarcinoma is a relatively common tumor in men, no case of a vesiculobullous eruption similar to HG has been reported in a man. Unlike the tumor in women, choriocarcinoma in men is totally de-

Herpes gestationis 223

rived from syngeneic tissue. It is therefore interesting to speculate on the role that paternal antigens might play in HG. Since a fetus is not required for a woman to develop disease, the production of HG must somehow be related to the presence of placental tissue, placental hormones, or other placental "factors." The potential role of paternal antigens is entirely speculative. The appearance of HG in a multiparous woman only after remarriage is probably coincidental. On the other hand, it may be that only certain combinations of male and female "tissue types" will serve to sensitize the host and only the second husband of these women possessed the appropriate contributing factors for the development of HG. If so, the occurrence in other women during subsequent pregnancies by different husbands remains to be explained. There are too few such cases to provide insight into this question. Patient 2 appeared to lose reactivity with her second mate, while Patient 4 did not. Nonetheless, the new finding of these cases during pregnancies by different husbands is important. The occurrence of two hydatidiform moles in our group is also intriguing. The commonly quoted incidence of this tumor in the United States and Europe is 1:2,000 pregnancies. 17 The occurrence of these two cases in our series is probably coincidental. However, the additional occurrence of surgically treated ovarian cysts in two patients leads us to speculate that abnormal ovarian or placental functions might somehow be related to the development of disease. Such possibilities, however, remain unproved. The commonly reported incidence of spontaneous abortions in the general population is 10% to 15% 17 Our group had a 13% rate, clearly within the expected range. The incidence of premature births was also within the expected range. We can find no evidence of increased fetal morbidity or mortality in HG. We suspect that the previously reported increase in fetal risks is due to the tendency for "worst case" patients to be reported and subsequently reviewed. It is possible that the use of prednisone decreases risk, but we have no data to support such a contention. Although subclinical disease is more common,

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clinically apparent skin disease in the newborn occurs about 5% o f the time. This involvement appears to be transient and without sequelae. The finding of complement deposition in the skin of clinically normal infants is not surprising or n e w ) The " H G factor" is an IgG and as such is well known to have the capacity to pass the placental barrier. If there is no cutaneous disease in the newborn, it would appear that no ill effects are borne by the children o f involved pregnancies. SUMMARY Twenty-eight patients with well-documented HG are presented. Our experience with this disease indicates an incidence of 1:50,000 to 1: 60,000 pregnancies in the Caucasian population. The frequency of miscarriages and other maternal complications does not appear to be beyond that reported in the population at large. Fetal risks are minima/, and less than 5% of newborns have transient cutaneous involvement. The uninvolved infant may have deposition of IgG or complement along the BMZ in the absence of clinically apparent disease. Several clinical variants have been identified. Two women had recurrent HG in pregnancies by different husbands. Four patients had IF-confirmed disease in which vesiculobullous lesions did not appear. Two o f these women had subsequent pregnancies in which classical vesiculobullous lesions developed. Another woman with well-documented disease had a subsequent pregnancy without cutaneous involvement, but with positive findings for igG and complement on IF studies. Direct and indirect IF appear to be the most reliable technics for differentiation of this disease from other clinically and histopathologically similar dermatoses that can occur during pregnancy. The importance o f correct diagnosis lies in the predictive ability for involvement during future pregnancies. Most patients choose definitive procedures for birth control when faced with the possibility of recurrent disease. We thank the following persons for referral of patients: Rene Rheinhart, Drs. J, Bikowsky, A. Carruthers,

Journal of the American Academy of Dermatology

M. V. Dahl, W. C. Duncan, S. L. Fort, W, R. Gammon, J. H. Hemdon, Jr., E. I. McBurney, T. J. Meek, A. Menter, L. T. Nesbitt, Jr., R. W. Romero, and J. G. Thompson. REFERENCES 1. Russell B, Thorne NA: Herpes gestationis. Br J Dermatol 69:339-357, 1957. 2. Kolodny RC: Herpes gestationis. A new assessment of incidence, diagnosis and fetal prognosis. Am J Obstet Gynecol 104:39-46, 1969. 3. Lynch FW, Albrecht RJ: Hormonal factors in herpes gestationis. Arch Dermatol 93:446-447, 1966. 4. Honigsmann H, Stingl G, Holubar K, Wolff K: Herpes gestationis: Fine ultrastructural pattern of immunoglobufin deposits in the skin in vivo. J Invest Dermatol 66:389-392, 1976. 5. Lawley TJ, Stingl G, Katz SI: Fetal and maternal risk factors in herpes gestationis. Arch Dermatol 114"552555, 1978. 6. Carruthers JA, Black MM, Ramnarain M: Immunopathological studies in herpes gestationis. Br J Dermatol 96:35-43, 1977. 7. Jordon RE, Heine KG, Tappeiner G, Bushkell LL, Provost TT: The immunopathology of herpes gestationis, Immunofluorescence studies and characterization of "HG factor." J Clin Invest 57:1426-1433, 1976. 8. Katz SI, Hertz KC, Yaoita H: Herpes gestationis: Immunopathology and characterization of the HG factor, J Clin Invest 57:1434-1441, 1976. 9. Carruthers JA, Ewins AR: Herpes gestationis: Studies on the binding characteristics, activity and pathogenetic significance of the complement-fixing factor. Clin Exp Immunol 31:38-44, 1978. 10. Provost TT, Tomasi TB Jr: Evidence for complement activation via the alternate pathway in skin diseases. I. Herpes gestationis, systemic lupus erythematosus, and bullous pemphigoid. J Clin Invest 52:1779-1787, 1973. I1. Harrington CI, Bleehen SS: Herpes gestationis: Immunopathological and ultrastructural studies, Br J Dermatol 100:389-399, 1979. 12. ChorzelskiTP, Jablonska S, Beutner EH, Maciewjowska E, Jarzabek-Chorzelska M: Herpes gestationis with identical lesions in the newborn. Passive transfer of the disease? Arch Dermatol 112:1129-1131, 1976. 13. Katz A, Minta JO, Toole JWP, Medwidsky W: Immunopathologic study of herpes gestationis in mother and infant. Arch Dermatol 113:1069-1072, 1977. 14. Shornick JK, Stastny F, Gilliam JN: High frequency of histocompatibility antigens HLA-DR3 and DR4 in herpes gestationis. J Clin Invest 68:553-555, 1981. 15. Dupont C: Herpes gestationis with hydatidiform mole. Trans St. Johns Hosp Dermatol Soc 60:103, 1974. 16. Tillman WG: Herpes gestationis with hydatidiform mole and chorion epithelioma. Br Med J 1:1471, 1950. 17. Pritchard JA, MacDonald PC, editors: Williams Obstetrics, ed. 15. New York, 1976, Appleton-Century-Crofts, pp. 456-484.