Other dermatoses in pregnancy

Other Dermatoses in Pregnancy

1. What every clinician should know

The dermatoses of pregnancy include skin conditions occurring almost exclusively during the gravid or puerperal state. The cutaneous diseases specific to pregnancy include pemphigoid gestationis (PG) and polymorphic eruption of pregnancy (PEP). Atopic eruption of pregnancy (AEP) has recently been added to the literature to represent several less specific pruritic eruptions. Pustular psoriasis of pregnancy, left out of many current texts on dermatoses of pregnancy, has many characteristics of a true dermatosis of pregnancy. Intrahepatic cholestasis of pregnancy (ICP), though not a dermatosis in the strict sense of the word because there are no primary lesions, is an important cause of itch and secondary skin lesions in pregnancy. These dermatoses will be discussed below.

PG, previously known as herpes gestationis, is the most fully understood of the specific dermatoses of pregnancy. It is a rare autoimmune bullous disease occurring during pregnancy or rarely with trophoblastic tumors. Classically the eruption occurs during the second or third trimester, may diminish weeks before delivery and flares at time of delivery or immediately postpartum. Typically, the rash of PG begins on the abdomen and may surround or directly involve the umbilicus. Initial lesions are urticarial papules and plaques that progress to vesicles and bullae and spread to the extremities (Figure 1). Palms and soles are occasionally involved and rare reports of face and mucous membrane involvement exist.

Figure 1.

Most cases of PG remit in the weeks following delivery, but lesions may recur during menses, with the use of oral contraceptive pills and with subsequent pregnancies. A trend toward more severe eruption and eruption earlier in pregnancy is seen with PG affecting subsequent pregnancies.

AEP encompasses three related, yet incompletely understood entities: eczema in pregnancy, prurigo of pregnancy and pruritic folliculitis of pregnancy. These related dermatoses share several clinical features and importantly do not portend a poor prognosis for the fetus. In addition, the majority of those affected have a family history of atopy and may also have elevated IgE levels.

Eczema in pregnancy usually develops during the first or second trimester and frequently presents in flexural areas with ill defined eczematous patches, with or without excoriated papules. Prurigo of pregnancy and encompassing historical terms such as prurigo gestationis of Besnier, Nurse’s early onset prurigo of pregnancy, Spangler’s papular dermatitis of pregnancy and linear IgM of pregnancy, is a clinical diagnosis. The characteristic findings of prurigo of pregnancy include pruritic erythematous excoriated nodules or papules on the extensor surface of the extremities and trunk (Figure 2).

Figure 2.

The eruption typically resolves within 3 months postpartum. Pruritic folliculitis of pregnancy is a sterile eruption of pruritic follicular papules and pustules. This rare entity is based on the characteristic clinical exam and absence of infectious etiology as confirmed by negative bacterial or fungal cultures. The eruption typically occurs during the third trimester and initially presents on the trunk. Some have likened the appearance to that of steroid induced acne.

Pustular psoriasis of pregnancy (PPP), also known as impetigo herpetiformis, is a very important entity to recognize as it has been associated with placental insufficiency and serious sequelae such as miscarriage, fetal growth restriction and stillbirth. Pustular psoriasis of pregnancy is a diagnosis that is made clinically but should be confirmed by skin biopsy for histologic evaluation.

This rare eruption begins with erythematous plaques with rings or occasionally sheets of pustules at the margins. The plaques enlarge at the periphery as the center develops crusted erosions. Classically the lesions first manifest in the intertriginous region and spread to involve the extremities and the trunk. Of note, hands, feet and face are usually not involved and mucous membrane involvement is rare.

Nail findings such as onycholysis (separation of nail plate from nail bed) and nail pitting have been described in association with PPP. Patients feel unwell and may complain of fatigue, malaise, fevers, chills, nausea, vomiting or diarrhea. Pustular psoriasis of pregnancy tends to remit upon delivery but occasionally flares postpartum. It often recurs with subsequent pregnancies and has been noted to occur with menses and oral contraceptive pills.

ICP is a familiar entity to the obstetrician and will not be covered in detail. However, ICP deserves mention as this disease can cause severe generalized pruritus and may manifest with secondary skin findings as a result of scratching. This entity should remain in the differential diagnosis of the pruritic pregnant patient, as cholestasis can be associated with consequences for the mother and fetus.

2. Diagnosis and differential diagnosis

Establishing the diagnosis

The morphology and location of the specific dermatoses of pregnancy can help differentiate among them. Pemphigoid gestationis (PG) tends to originate on the abdomen and spread centrifugally. Classically, PG begins as urticarial papules and plaques, not sparing the umbilicus that evolve to form vesicles and bullae. PEP also typically presents on the abdomen as urticarial papules and plaques. However, PEP spares the umbilicus and rarely goes on to develop vesicles, though may evolve into eczematous scaly papules and plaques. PG has been reported to affect the palms, soles and face, whereas PEP does not.

Eczema in pregnancy and prurigo of pregnancy tend to start and often remain on the extremities. The excoriated eczematous patches and papules of eczema in pregnancy favor the flexural surface, whereas the excoriated eczematous nodules and papules of prurigo of pregnancy favor the extensor surface. Pruritic folliculitis of pregnancy (PFP), grouped under the heading atopic eruption of pregnancy, is distinguished primarily by its morphology. PFP refers to the eruption of monomorphic sterile follicular pustules and papules, resembling steroid acne.

The unique morphology of pustular psoriasis of pregnancy is readily set apart from the other dermatoses of pregnancy. The classic morphology of pustular psoriasis of pregnancy is that of well demarcated erythematous plaques with a ring of pustules which enlarge at the periphery and evolve to erode and crust over in the center. The initial lesions begin in intertriginous areas and subsequently spread to involve the trunk and extremities. It is important to get a good medication history because acute generalized exanthematous pustulosis (AGEP), an allergic drug eruption, can mimic pustular psoriasis clinically and histologically.

ICP may present with secondary skin changes such as excoriations and excoriated papules from scratching, or may present with pruritus alone. ICP is differentiated from the heterogeneous eruptions of atopic eruption of pregnancy by elevated liver function tests and bile acids, and lack of primary skin lesions.

Timing of onset during the course of pregnancy differs among the specific dermatoses of pregnancy. PG presents during both the second and third trimesters with a characteristic improvement weeks prior to delivery with a subsequent flare at delivery or postpartum. PEP tends to occur later in pregnancy and resolves at the time of delivery or shortly thereafter. Additionally, PG may develop during menses and with use of oral contraceptive pills. PG also routinely recurs with subsequent pregnancies, while PEP does not.

Patients with eczema in pregnancy typically present early on, either first or second trimester. However, prurigo of pregnancy characteristically develops during the third trimester. Pustular psoriasis of pregnancy can occur anytime during pregnancy and usually clears shortly after delivery. ICP occurs predominantly during the third trimester and recurs in subsequent pregnancies half the time.

For PEP and AEP, no lab tests are indicated. If ICP is suspected, total bile acids as well as complete liver function tests should be sent. Total bile acids above 11 micromoles/liter makes the diagnosis. Hepatitis C antibody should also be sent to screen for hepatitis C.

In patients with pustular psoriasis of pregnancy it is essential to closely monitor electrolytes, especially calcium, as hypocalcemia can lead to delirium, seizures and tetany. Urinalysis may reveal hematuria, albuminuria and pyuria, but the significance of these findings is unknown. In addition, an elevated erythrocyte sedimentation rate is commonly found, but blood cultures and skin cultures are sterile in pustular psoriasis of pregnancy.

Skin biopsy and histopathologic evaluation is most useful for the diagnosis of PG and PPP. In PPP, the histology classically reveals subcorneal spongiform pustules filled with neutrophils and perivascular inflammatory infiltrate of lymphocytes and neutrophils. Early PG lesions can have edema in the upper and mid dermis as well as a predominantly perivascular lymphohistiocytic infiltrate with variable numbers of eosinophils. However, this can also be seen in a biopsy of PEP. A second biopsy also is needed for direct immunofluorescence (DIF), the gold standard. DIF shows bright linear deposition of c3 along the basement membrane in all cases.

About 30% of cases will also have IgG deposits detected along the basement membrane. Indirect immunofluorescence may reveal circulating IgG antibodies, but these levels have not been shown to definitively correlate with disease activity. An ELISA for the BP180 NC16a domain is now used to diagnose PG with a sensitivity and specificity in some studies as high as 96%.

3. Management

The goal of treatment is relief of symptoms, while protecting the fetus. For pemphigoid gestationis, mid to high potency topical steroids are recommended as initial therapy for localized disease. Ointments tend to cause less stinging and burning and are more effective, but tend to be messier. Topical antihistamines are not recommended as they can cause allergic contact dermatitis and are often not effective.

Topical doxepin, a tricyclic antidepressant, has not been well studied, but is not recommended due to the theoretical concern for neonatal withdrawal. For PG, the above measures often do not control the pruritus and systemic glucocorticoids are often needed. Initiating oral prednisone at 0.5 mg/kg/day is usually effective and can eventually be tapered and discontinued in some prior to delivery; however, a significant number of patients with PG will require systemic glucocorticoids well into the postpartum state.

The management of atopic eruption of pregnancy is similar to non-pregnant patients with eczema. Symptoms are typically controlled with low to mid potency topical steroids in combination with adequate skin hydration through the use of topical emollients. Oral antihistamines also may be used to control pruritus. Rare case reports of the successful use of UV phototherapy also exist.

For pustular psoriasis of pregnancy, rapid control of disease is desired with use of systemic glucocorticoids or cyclosporine for initial therapy. We suggest an initial dose of oral prednisone of 80 mg, to be slowly tapered upon reaching the desired response, with close monitoring for disease flare. In pustular psoriasis of pregnancy there have been single case reports of treatment success with cyclosporine, infliximab and etretinate. Notably etretinate was used postpartum, as this medication is highly teratogenic and should be avoided completely during pregnancy.

ICP is treated with ursodeoxycholic acid and early delivery.

4. Complications

Pemphigoid gestationis may be associated with mild placental insufficiency and fetuses are at risk for premature birth and fetal growth restriction. Poor prognostic factors include earlier disease onset and the presence of blisters. Rarely newborns will present at the time of delivery with vesicles mild PG. The eruption usually resolved within in several weeks. The mother is at high risk for recurrent and more severe eruption of PG with subsequent pregnancies as well as flares during menses and with the use of oral contraceptive pills. In addition, there is an increased lifetime risk of Grave’s disease.

Serious maternal complications associated with pustular psoriasis of pregnancy such as delirium, tetany and seizures due to hypocalcemia can be avoided. Unfortunately, fetal prognosis may be poor even in appropriately controlled mothers. Although rare, fetal risks such as stillbirth and neonatal death associated with pustular psoriasis of pregnancy necessitate close antenatal monitoring and likely early delivery.

5. Prognosis and outcome

Prurigo of pregnancy, eczema in pregnancy and pruritic folliculitis of pregnancy, entities included under the heading atopic eruption of pregnancy, do not portend a poor prognosis for mother or fetus. Symptomatic treatment of pruritus alone is appropriate.

Pemphigoid gestationis may be associated with mild placental insufficiency and fetuses are at risk for premature birth and fetal growth restriction. Poor prognostic factors include earlier disease onset and the presence of blisters. Rarely newborns will present at the time of delivery with vesicles mild PG. The eruption usually resolves within in several weeks. The mother is at high risk for recurrent and more severe eruption of PG with subsequent pregnancies as well as flares during menses and with the use of oral contraceptive pills. In addition, there is an increased lifetime risk of Grave’s disease.

Maternal prognosis for pustular psoriasis of pregnancy is quite good, even in severe cases. Good maternal outcomes depend on early recognition and rapid initiation of treatment with cyclosporine or oral high dose glucocorticoids. Serious maternal complications associated with pustular psoriasis of pregnancy, such as delirium, tetany and seizures due to hypocalcemia, can be avoided. Unfortunately, fetal prognosis may be poor even in appropriately controlled mothers. Although rare, fetal risks such as stillbirth and neonatal death associated with pustular psoriasis of pregnancy necessitate close antenatal monitoring and likely early delivery.

6. What is the evidence for specific management and treatment recommendations

Holmes, RC. “The specific dermatoses of pregnancy.”. J Am Acad Dermatol. vol. 8. 1983. pp. 405(This is a study of of 64 patients with dermatoses occurring during pregnancy. The authors noted that the terminology of specific dermatoses of pregnancy was very confusing and multiple names for the same clinical disorders existed. They proposed a simplified classification which included; [1] herpes gestationis; [2] polymorphic eruption of pregnancy; [3] prurigo of pregnancy; and [4] pruritic folliculitis of pregnancy.)

Kroumpouzos, G. “Specific dermatoses of pregnancy: An evidence-based systematic review.”. Am J Obstet Gynecol. vol. 188. 2003. pp. 1083(In this systematic review, studies published from 1962-2002 pertaining to herpes gestationis, pruritic urticarial papules and plaques of pregnancy, pruritic folliculitis of pregnancy, prurigo of pregnancy, and intrahepatic cholestasis of pregnancy were reviewed. The authors sought to clarify further the distinguishing clinical features and prognosis of these specific dermatoses of pregnancy. Additionally, a meta-analysis included within this review revealed a higher prevalence of multiple gestation pregnancy among patients with pruritic urticarial papules and plaques of pregnancy. This review also highlighted the successful use of ursodeoxycholic acid in ICP in multiple case series.)

Powell, AM. “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. vol. 141. 2006. pp. 705-10. (In this study of 412 women – 82 with pemphigoid gestationis, 164 with PEP, and166 age- and sex-matched controls – the authors found that the BP180 NC16a ELISA test was 96% sensitive and specific in differentiating PG from PEP.)

Tani, N. “Clinical and immunological profiles of 25 patients with pemphigoid gestationis.”. Br J Dermatol. vol. 172. 2015. pp. 120-9. (In this study, immunologic and clinical analyses of 25 patients with PG were performed. The authors found that PG developed during the second and third trimesters preferentially. Histopathology noted subepidermal blisters rarely. All patients had c3 reactivity at the basement membrane zone (BMZ) on direct immunofluorescence. Ninety-two percent of patients had circulating IgG anti-BMZ with indirect immunofluorescence. Immunoblotting and ELISA of the NC16a domain of BP 180 was positive in 96 and 92 % of patients respectively, supporting the usefulness of this test in establishing the diagnosis of PG.)

Shornick, JK. “Dermatoses of Pregnancy”. Semin Cutan Med Surg. vol. 17. 1998. pp. 172(In this review, the author classifies and describes the skin diseases found uniquely during pregnancy. The author includes herpes gestationis, pruritic urticarial papules and plaques of pregnancy, prurigo of pregnancy, and cholestasis of pregnancy.)

Roth, MM. “Pregnancy Dermatoses; diagnosis, management, and controversies”. Am J Clin Dermatol. vol. 12. 2011. pp. 25(The author reviews the pregnancy dermatoses including PG, ICP, impetigo herpetiformis, polymorphic eruption of pregnancy, and the papular dermatoses of pregnancy, including prurigo of pregnancy, pruritic folliculitis of pregnancy and atopic eruption of pregnancy. The author suggests a new classification schema whereby the dermatoses PG, impetigo herpetiformis and ICP should continue to be identified by characteristic histologic, immunohistologic, and laboratory testing. However, the remaining dermatoses currently diagnosed by clinical criteria alone should be reclassified under the heading polymorphic eruption of pregnancy. The author further proposes that polymorphic eruption of pregnancy be divided into early and late onset types.)

Ambros-Rudolph, CM. “The specific dermatoses of pregnancy revisited and reclassified: Results of a retrospective two center study on 505 pregnant patients.”. J Am Acad Dermatol. vol. 54. 2006. pp. 395(In this retrospective study, data from 505 pregnant patients that presented over a 10-year period (1994-2004) with pruritic dermatoses were analyzed. Eczema in pregnancy was the most common dermatosis and showed considerable overlap with prurigo of pregnancy and pruritic folliculitis of pregnancy. The authors suggest inclusion of these three entities under the heading atopic eruption of pregnancy. The authors found that patients with atopic eruption of pregnancy tended to present earlier in pregnancy than patients with pemphigoid gestationis, polymorphic eruption of pregnancy and intrahepatic cholestasis of pregnancy.)

Oumeish, OY. “Impetigo Herpetiformis.”. Clin Dermatol. vol. 24. 2006. (In this review, the authors summarize the existing literature to date on impetigo herpetiformis. They characterize the disease as a possible variant of generalized pustular psoriasis. In addition, the authors define the clinical and histopathologic characteristics of this dermatosis of pregnancy as well as accepted treatment strategies. Importantly, the authors point out the increased maternal and fetal morbidity of impetigo herpetiformis and need for early recognition and treatment.)

Robinson, A,, Van Voorhees, AS,, Hsu, S. “Treatment of pustular psoriasis: From the Medical Board of the National Psoriasis Foundation.”. J Am Acad Dermatol. vol. 67. 2012. pp. 279-88. (In this review, the authors, as part of a task force of the National Psoriasis Foundation Medical Board, convened to evaluate treatment options for pustular psoriasis. Overall, the group determined that the evidence for treatments in pustular psoriasis is weak, but management should be guided by the extent of involvement and severity of disease. With regard to pustular psoriasis of pregnancy, the authors recommend cyclosporine, oral glucocorticoids or topical agents as first-line treatment options. Cyclosporine is recommended based on the established safety record of its use in pregnant transplant patients.)

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