Pemphigoid gestationis – a rare dermatosis of the prenatal period. Case report

Pemfigoid ciężarnych – rzadka dermatoza okresu prenatalnego. Opis przypadku

Marcin M. Skutil, Ryszard Roztoczyński

Department of and Gynaecology, Voivodeship Hospital, Bielsko-Biała, Poland

Przegl Dermatol 2016, 103, 209–213 DOI: 10.5114/dr.2016.60624

ABSTRACT KEY WORDS: Introduction. Most skin lesions during are associated with gestationis, hormonal changes. Pemphigoid (herpes) gestationis (PG) is a signifi- herpes gestationis, dermatoses cant dermatosis of the prenatal period reflecting pathology affecting the of pregnancy. mother and . Objective. The aim of the study was to present a PG case, a rare preg- SŁOWA KLUCZOWE: nancy dermatosis with a severe clinical outcome during the postpartum pemfigoid ciężarnych, period. opryszczka ciążowa, Case report. We present a case of a patient in whom skin lesions with dermatozy ciążowe. tense occurred at the 40th week of pregnancy. Herpes gestatio- nis – a rare skin disease – was diagnosed based on the clinical picture. During the first days of puerperium, because of an aggressive disease course, the patient was transferred to a reference centre for skin disease treatment. She was given therapy, which brought the ex- pected results. Conclusions. Pemphigoid gestationis is a rare and serious dermatosis of the prenatal period. Although the treatment of such diseases is the dermatologists’ task, obstetricians are responsible for diagnosis and for fetal monitoring considering placental pathology.

STRESZCZENIE Wprowadzenie. Większość zmian skórnych w okresie ciąży wiąże się ze zmianami gospodarki hormonalnej. Pemfigoid (opryszczka) ciężar- nych jest ważną dermatozą okresu prenatalnego odzwierciedlającą pa- tologię toczącą się w jednostce matczyno-płodowej. Cel pracy. Przedstawienie przypadku pemfigoidu ciężarnych, rzadkiej dermatozy ciążowej, o ciężkim przebiegu klinicznym w okresie połogu. Opis przypadku. Przedstawiamy przypadek pacjentki, u której w 40. ty­- ADDRESS FOR CORRESPONDENCE: godniu ciąży zaobserwowano zmiany skórne w postaci napiętych pę- Marcin Skutil MD, PhD cherzy, co pozwoliło na podstawie obrazu klinicznego rozpoznać rzad- Ryszard Roztoczyński MD ką chorobę skóry, jaką jest opryszczka ciężarnych. W pierwszych dniach Department of Obstetrics połogu ze względu na agresywny przebieg choroby pacjentka została and Gynaecology przekazana do ośrodka referencyjnego leczenia chorób skóry. Zastoso- Voivodeship Hospital wana tam terapia glikokortykosteroidami przyniosła zamierzony efekt. 101 Armii Krajowej St Wnioski. Pemfigoid ciężarnych jest rzadką dermatozą okresu prenatal- 43-316 Bielsko-Biała, Poland nego, której terapię prowadzą dermatolodzy, a zadaniem położników phone: +48 692 392 528 jest rozpoznanie choroby i monitorowanie stanu płodu z uwzględnie- e-mail: [email protected] niem faktu patologii łożyska.

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INTRODUCTION Pemphigoid gestationis is etiologically an auto- immune disease, and its association with HLA-DR3 The generally accepted classification suggested by and HLA-DR4 haplotypes has been proven. Due to Ambros-Rudolph et al. [1] is used to describe skin di- the fact that early clinical diagnosis presents a certain seases typical for pregnancy. It includes the characte- challenge, skin is helpful but direct immuno- ristics of all types of dermatoses occurring only during fluorescence test (DIF) is necessary to make the final pregnancy, i.e. prurigo of pregnancy, polymorphic diagnosis. The material undergoes pathomorpholo- eruption of pregnancy, pemphigoid gestationis (PG), gical examination and the DIF test is performed. In and intrahepatic cholestasis of pregnancy [1]. a typical course of the disease, cell degeneration of Most pregnancy-specific skin conditions have no the stratum basale (the cause of blistering) and epi- clinical significance and are associated with phy- dermal spongiosis are found in microscopic analysis. siological insulinemia, as well as an increase in es- Deposits of the C3 component of complement along trogen, progesterone and melanotropin concentra- the basement membrane are observed in the DIF test. tions [2]. Complement binding IgG antibodies occur in half of Physiological changes in the prenatal period inc- the affected patients [7]. lude the following: The indirect immunofluorescence test (IIF) of blo- – skin pigmentation in the area of the nipples and od or the fluid obtained from the changes shows the areola (at about 20 weeks of gestation), underarms, presence of IgG antibodies directed against bullous and external genital organs, pemphigoid antigen 2, which is located on hemide- – linea nigra, smosomes along the basement membrane [8]. –  (on the forehead, cheeks and the lower Treatment during pregnancy relies on reduction jaw), of change intensification and is most often individu- – connective tissue changes such as striae distensae alized. If the locally acting drugs are ineffective, in- and skin polyps [3, 4]. travenous pharmacotherapy should be initiated, the The majority of these changes may be reversible, base of which, apart from histamine antagonists, are to a certain extent, after delivery. Vascular changes, . Ciclosporin, which seems safe for the which are partially caused by increased estrogen le- fetus, has also been approved for PG treatment, but it vels, are the effect of widening of the blood vessels, cannot be used during lactation [9, 10]. Prednisolone, their instability, and capillary proliferation occurring the safest of the corticosteroids, is subject to almost on the skin surface. Telangiectasias are more notice- complete placental metabolism [11]. able in women with a fair complexion and occur pre- The disease has periods of remission and exacer- ferentially around the eyes, on the neck, on the chest, bation. Regression of the changes is observed pre- and on the upper limbs. dominantly in the pre-delivery period. However, Exacerbation of these changes occurs in the second blistering is present in about 75% of the patients trimester of pregnancy and disappears about 2 mon- during delivery. Skin changes disappear after about ths after postpartum [5]. Some skin lesions which 2–6 weeks postpartum in the majority of affected pa- occur in pregnant women may reflect complications tients. Dermatosis is a recurrent disease; it can occur of the prenatal period such as intrauterine growth re- in subsequent and run a more severe striction (IUGR), the risk of premature delivery, or course. Menstruation and hormonal contraception even intrauterine fetal death. Therefore, it is crucial are among other provoking factors [12]. A correla- to diagnose dermatoses such as intrahepatic chole- tion has been found between the presence of PG and stasis of pregnancy or in pre- IUGR. Data on such correlation are of low diagnostic gnancy, which is also known as herpes gestationis, value, but they indicate the need for careful fetal mo- to assure proper care of pregnant women. Pemphi- nitoring in that group of patients [13]. goid gestationis occurs relatively rarely, with the es- Moreover, inflammatory processes in the skin also timated incidence of 1/700 to 1/50 000 pregnancies, affect the placental tissue. They are probably the re- according to different sources. The changes develop ason for IUGR and can lead to all the consequences most often in the second trimester of pregnancy, and associated with this disorder [14]. their presence on occasions other than before the de- A similar rash occurring immediately after the livery is rather uncommon [6]. delivery can be observed in about 10% of infants The first changes occur on the skin in the navel born to mothers with PG, as a result of passive area in the form of urticaria with papules and plaqu- transfer of the antibodies from the mother [15]. es, developing into a vesiculobullous rash during di- Pemphigoid gestationis occurs with other autoim- sease progression, and then on the skin of the trunk, mune diseases such as Graves’ disease. Therefore, limbs, palms and soles. After a few weeks, the initial thyroid function tests are recommended in this gro- skin rash evolves into tense blisters, large in diameter. up of patients [16].

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CASE REPORT A The patient, at 37 weeks of gestation, was admit- ted to the Department of Pathology of Pregnancy due to intense skin pruritus and rash around the navel. Based on the data gathered during the interview, the course of pregnancy was assessed as physiological. In the differential diagnosis of the above ailments, in- trahepatic cholestasis of pregnancy and polymorphic eruption of pregnancy were distinguished. In the performed laboratory tests, significant aberrations were not observed. In the IF test an elevated titer B (1 : 160) of antinuclear antibody with a coarse spec- kled pattern was detected. Second-generation antihistamines were admini- stered due to persistent pruritus, improving the gene- ral condition of the patient. Fetal ultrasound (biophy- sical profile, Doppler ultrasound test) was normal. The patient was discharged from the hospital. The patient was readmitted at 40 weeks of gesta- tion due to intensified pruritus and the presence of an erythematous papular rash on the abdomen and small blisters on the upper limbs (Figures 1 A, B). Pemphigoid gestationis was suspected after consul- tation with a dermatologist. As the disease is asso- ciated with placental pathology, labor was induced. Cesarean section was performed due to abnormal cardiotocography. A male infant (weight 3380 g, Ap- gar scores of 9) was delivered. A few hours after the operation, progression of skin lesions, with intense pain and pruritus, was observed (Figure 2). Systemic corticosteroid thera- Figure 1 A, B. Initial lesions py ( 30 mg/day; dexamethasone 12 mg/ Rycina 1 A, B. Zmiany pierwotne day), calcium carbonate and antibiotic therapy resul- ted in slight alleviation of the symptoms. Lactation was inhibited. During postoperative day 1, blisters (1 cm in diameter) occurred and were located ma- inly on the medial thighs and the forearms (Fig- ures 3 and 4 A, B). The therapy proved ineffective, and therefore, on postoperative day 5, the patient was transferred to the reference center for treating skin diseases. Herpes gestationis was clinically diagnosed at the Department of Dermatology. Skin biopsy was Figure 2. Small blisters on the upper limbs performed and treatment including methylpredniso- Rycina 2. Niewielkie pęcherze na kończynach górnych lone (48 mg/day for 4 days), cefuroxime (3 g/day for 10 days), antianemic drugs and anticoagulants was initiated. The IIF test was negative. Skin lesions were treated topically with hydro- cortisone, oxytetracycline hydrochloride, and clo- betasol propionate, resulting in gradual regression of lesions and general improvement of the patient’s condition. The puerperium during the dermatosis treatment was otherwise uneventful. On day 13 of hospitalization, the general condition of the patient was good and she was discharged from hospital. Figure 3. Blisters and lesions with a target sign The patient was advised to continue treatment with Rycina 3. Pęcherze i zmiany typu „tarcza strzelnicza”

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A inhibit nutrient exchange between the mother and the fetus [17]. In the present case, early stages of the dermatosis were not typical and were suggestive of intrahepatic cholestasis of pregnancy. They resolved after treatment with ursodeoxycholic acid, which not only alleviates clinical symptoms but also reduces the risk of fetal complications [18]. Exacerbation of the disease occurred just after delivery and took an aggressive course. The symptomatic treatment pro- ved ineffective. Therapy with high doses of steroids was initiated in the reference center for treatment of dermatosis and brought the expected, satisfactory ef- B fects. Corticosteroids must be used carefully because they can increase the risk of osteoporosis in pregnant patients. Therefore, it is recommended to conduct the symptomatic treatment using topical therapy. In order to alleviate the symptoms, first-generation or second-generation antihistamines such as cetirizi- ne or loratadine (which are classified in category B according to the FDA) should be administered. The only side effect of loratadine may be rarely occurring hypospadias [19–23]. In case of an aggressive course of disease, indivi- Figure 4 A, B. Severe skin lesions with tense blisters dually adjusted prednisolone dosing should be ad- Rycina 4 A, B. Nasilone zmiany z obecnością napiętych pęcherzy ministered (it is most often 0.5 mg/kg/body weight reducing the dose by 5 mg every 3 days), because it is safe for the fetus and entirely metabolized by the methylprednisolone for 5 days, with gradual dose human placenta [15]. If escalating the dose above reduction under ambulatory control of the clinical 7.5 mg is necessary, it is recommended to monitor state. Antianemic drugs and topical application of kidney functions and blood pressure. Since more chloramphenicol ointment were also recommended. severe disease symptoms can occur before delivery, Histopathological results of the biopsy confirmed the it is recommended to increase the dose 7 days befo- initial clinical diagnosis, i.e. herpes gestationis. IgG re the due date. Broad-spectrum antibiotic therapy and IgA deposits at the basement membrane zone should be implemented. Ciclosporin is a safe medi- (+BMZ) and in the same location abundant deposits cation in the therapy for pregnant women [9] but it is of complement component C3 (+++BMZ) were fo- contraindicated during lactation due to possible im- und in tissue examination by DIF test in the biopsy munosuppressive activity and possible induction of of healthy skin near the skin lesion. neutropenia [10]. During puerperium immunosup- pressive medications can be used and plasmaphore- sis can be performed [24]. DISCUSSION The patient remains under dermatological and Skin lesions, which occur in a normal pregnancy, gynecological ambulatory care in a hospital outpa- are usually associated with physiological insulin re- tient clinic. Pruritus occurs in the area of the navel sistance and hyperestrogenism [2]. Also, they are so- and on the medial compartment of both thighs be- metimes symptoms of pregnancy-specific diseases. fore and during menstruation. Neurotic excoriations Pemphigoid gestationis, which frequently occurs on the skin have been noted. with IUGR, is an inflammatory process occurring not only in the skin but also in the trophoblastic tis- CONFLICT OF INTEREST sue. The IUGR is defined as fetal growth below the The authors declare no conflict of interest. expected genetic potential. It results in a significant increase in perinatal mortality and vascular com- References plications such as stroke and myocardial infarction in adulthood. Insufficient fetal development in the 1. Ambros-Rudolph C.M., Müllegger R.R., Vaughan-Jo- nes S.A., Kerl H., Black M.M.: The specific dermatoses of dermatosis is associated with placental vascular pa- pregnancy revisited and reclassified: results of a retrospec- thology. The inflammation in the trophoblastic tis- tive two-center study on 505 pregnant patiens. J Am Acad sue can lead to infarcts and calcification, which can Dermatol 2006, 54, 395-404.

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2. Męczekalski B., Podfigurna-Stopa A., Czyżyk A., Katul- adverse pregnancy outcomes. Br J Dermatol 2009, 160, ski K.: Endokrynologiczne zaburzenia czynności jajników 1222-1228. a ciąża. [in:] B. Męczekalski (ed.). Endokrynologia ciąży. 14. Huilaja L., Mäkikallio K., Sormunen R., Lohi J., Hurska- Wydawnictwo Lekarskie PZWL, Warszawa 2012, 241. ien T., Tasanen K.: Gestational pemphigoid: placental mor- 3. Wong R.C.: Physiologic skin changes in pregnancy. [in:] phology and function. Acta Derm Venereol 2013, 93, 33-38. M. Harahap, R.C. Wallach (ed.). Skin changes and diseases 15. Black M.M., Ambros-Rudolph C., Edwards L., Lynch P.: in pregnancy. New York, 1996, 37. Obstetric and gynecologic dermatology. 3rd ed. Mosby El- 4. Martin A.G., Leal-Khouri S.: Physiologic skin changes as- sevier, London 2008. sociated with pregnancy. Int J Dermatol 1992, 31, 375-378. 16. Semkova K., Black M.: Pemphigoid gestations: current in- 5. Esteve E., Saudeau L., Pierre F., Barruet K., Vaillant L., sights into pathogenesis and treatment. Eur J Obstet Gyne- Lorette G.: Physiological cutaneous signs in normal preg- col Reprod Biol 2009, 145, 138-144. nancy: a study of 60 pregnant women. Ann Dermatol Ven- 17. Grand’Maison S., Durand M., Mahone M.: The effects of erol 1994, 121, 227-231. ursodeoxycholic acid treatment for intrahepatic cholestasis 6. Maharajan A., Aye C., Ratnavel R., Burova E.: Skinserup- of pregnancy on maternal and fetal outcomes: a meta-anal- tions specific to pregnancy: an overview. Obstet Gynecol ysis including non-randomized studies. J Obstet Gynaecol 2013, 15, 233-240. Can 2014, 36, 632-641. 7. Kint A., Geerts M.L., Vanneste B., De Cuyper C.: Herpes 18. Khaliq A., Li XF., Shams M., Sisi P., Acevedo C.A., Whit- gestationis. A histological and electron microscopic study. tle M.J., et al.: Localisation of placenta growth factor (PIGF) Ann Dermatol Venerol 1980, 107, 1133-1142. in human term placenta. Growth Factors 1996, 13, 243-250. 8. Zilikens D.: Pemphigoid gestations: recent advances. JEADV 19. Gilbert C., Mazzota P., Loebstein R., Koren G.: Fetal safe- 2003, 17 (Suppl s3), 7. ty of drugs used in the treatment of allergic rhinitis: a criti- 9. Branche J., Cortot A., Bourreille A., Coffin B., Vos M., Sau- cal review. Drug Saf 2005, 28, 707-719. ssure P. i inni: Cyclosporine treatment of steroid-refractory 20. Schatz M., Zeiger R.S., Harden K., Hoffman C.C., Chilin- ulcerative colitis during pregnancy. Inflamm Bowel Dis gar L., Petitti D.: The safety of asthma and allergy medica- 2009, 15, 1044-1048. tions during pregnancy. J Allergy Clin Immunol 1997, 100, 10. American Academy of Pediatrics: The transfer of drugs 301-306. and other chemicals into human milk. Pediatrics 2001, 108, 21. Seto A., Einarson T., Koren G.: Pregnancy outcome follow- 776-7812. ing first trimester exposure to antihistamines: meta-analy- 11. Murphy V.E., Fittock R.J., Zarzycki P.K., Delahunty M.M., sis. Am J Perintol 1997, 14, 119-124. Smith R., Clifton V.L.: Metabolism of synthetic steroids by 22. Giloba S.M., Strickland M.J., Olshan A.F., Werler M.M., the human placenta. Placenta 2007, 28, 39-46. Correa A.: National Birth Defects Prevention Study. Use 12. Vaughan Jones S.A., Hern S., Nelson-Piercy C., Seed P.T., of antihistamine medications during early pregnancy and Black M.M.: A prospective study of 200 women with der- isolated major malformations. Birth Defects Res A Clin Mol matoses of pregnancy correlating clinical findings with Teratol 2009, 85, 137-150. hormonal and immunopathological profiles. Br J Dermatol 23. Weber-Schoendorfer C., Schaefer C.: The safety of cetiri- 1999, 141, 71-81. zine during pregnancy. Reprod Toxicol 2008, 26, 19-23. 13. Chi C.C., Wang S.H., Charles-Holmes R., Ambros-Ru- 24. Briggs G.G., Freeman R.K., Yaffe S.J.: Drugs in pregnancy dolph C., Powell J., Jenkins R. i inni: Pemphigoid gesta- and lactations. 7th ed. Lippincot Williams & Wilkins, Phila- tions: early onset and formation are associated with delphia, 2005.

Submitted: 22 X 2015 Accepted: 20 V 2016

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