Dermatoses of Pregnancy

Etiology

Pemphigoid gestationis (PG) involves the formation of autoantibodies against bullous pemphigoid antigens 180 and 230.[4] The disease process begins with an immune response within the placenta, where abnormal expression of antigens occurs. This stimulates maternal antibody production to the abnormal placental antigens. These antibodies bind not only to the placental antigen but also to the antigen in the basement membrane of the skin. The inflammatory cascade of the skin is subsequently activated, causing the splitting of the epidermis and dermis. Tense bullae are formed on the skin, which is a distinct feature of pemphigoid gestationis.[5]

Polymorphic eruption of pregnancy (PEP) is the updated name of the pregnancy dermatosis formerly called pruritic urticarial papules and plaques of pregnancy (PUPPP) in the United States.[6] It commonly begins in the abdominal striae. Although the etiology is poorly understood, it has been suggested that damage to the underlying collagen connective tissue of the skin from abdominal distention may play a role in developing this pregnancy-specific dermatosis. An inflammatory response is activated in the skin of the abdomen, which may spread to the collagen of the skin in other areas of the body.[5] Frequently, PEP is seen in women with multiple gestations or who have gained large amounts of weight during pregnancy. Another proposed etiology is a maternal immune response to fetal antigens in the maternal blood.[5]

Intrahepatic cholestasis of pregnancy (ICP) is caused by the buildup of bile salts within the cells of the liver. This results in elevated levels of bile salts in the blood. The underlying cause of this phenomenon during pregnancy is poorly understood.[7] It is likely due to a combination of genetic, environmental, and endocrine factors. Mutations in biliary transporters could play a genetic role in the etiology of cholestasis. Potential environmental factors include low vitamin D levels and low dietary intake of selenium, as noted by an increased incidence of cholestasis of pregnancy in the winter months. Endocrine factors include elevated levels of estrogen and progesterone metabolites during pregnancy, which can disrupt the influx and efflux of bile acids from liver cells.[8]

Atopic eruption of pregnancy (AEP) is usually seen in pregnant women with a history of atopy.[9] It most likely occurs due to a change in the maternal immune response during pregnancy, including the downregulation of T-helper 1 cytokine production and cell-mediated immune function. There is an increase in T-helper 2 cytokine production and humoral immune response. This shift in the immune response, which is specific to pregnancy, exacerbates the imbalance already seen in people with atopy, resulting in the itching and skin lesions seen with atopic eruption of pregnancy.[5][10]

Pustular psoriasis of pregnancy (PPP), also known as impetigo herpetiformus, is likely a variant of pustular psoriasis seen outside of pregnancy.[5]

Epidemiology

Dermatoses of pregnancy are skin conditions seen in reproductive-aged females throughout the world.

Pemphigoid gestationis (PG) is a rare skin disease of pregnancy. The incidence of pemphigoid gestationis is 1 in 50,000 to 1 in 60,000 pregnancies.[5] The most significant risk factor for PG is having it in a previous pregnancy.

Polymorphic eruption of pregnancy (PEP) affects 1 in 200 pregnancies and typically occurs in the third trimester and in primigravid women. It is a self-limiting skin dermatosis that may also present postpartum. It is seen more commonly when the fetus is male. Seventy-five percent of women with PEP are primiparous.[5]

Intrahepatic cholestasis of pregnancy (ICP) is seen in varying frequencies based on patient population. Araucanian Indian women, indigenous to the South American country of Chili, have the highest incidence at 28%. In Europe, the incidence is 1.5% or less. In the United States, the incidence is as low as 0.32% in white populations to as high as 5.6% in Hispanic groups.[5] Risk factors for developing ICP include personal or family history of ICP, hepatobiliary disease, and advanced maternal age. Risks for severe disease include smoking, previous cholecystectomy, history of ICP in an earlier pregnancy, and pregestational diabetes.[11]

Atopic eruption of pregnancy (AEP) is the most common skin disorder seen in pregnancy, accounting for half of all dermatoses. Most cases present early in pregnancy, in the first trimester. In 75% of patients, AEP begins before the third trimester, which is earlier in pregnancy than the other dermatoses specific to pregnancy.[12] 

Pustular psoriasis of pregnancy (PPP) or impetigo herpetiformus is a very rare dermatosis of pregnancy that is seen most commonly in third-trimester patients.[5] It frequently occurs in primigravidas.[1]

Pathophysiology

Pemphigoid gestationis (PG) is an autoimmune disease similar to bullous pemphigoid. It may rarely occur with hydatiform moles or choriocarcinoma. The immune response begins in the placenta and stimulates maternal antibody production. These antibodies to the placenta then cross-react with antigens in the skin. Autoantibodies react with collagen XVII in the skin, causing splitting of the dermis and epidermis resulting in tense bullae formation. Initially, bullae form in the periumbilical region but then spread to other parts of the trunk and extremities. Itching is very common. PG develops most commonly (34% of the time) in the second and third trimester of pregnancy. However, it may occur in the first trimester 18% of the time and postpartum 14% of the time. The skin lesions frequently resolve in the last few weeks of pregnancy. However, 10% of women have a recurrence of lesions with the use of oral contraceptives, and 75% of women have recurrences postpartum.[5] 

Polymorphic eruption of pregnancy (PEP) is usually seen in primiparous patients in the last trimester or sometimes in the second trimester of pregnancy. The lesions first appear as pruritic, erythematous papules and plaques that begin in the abdominal striae and may later spread to the skin of the breasts, back, arms, or thighs. Sparing of the periumbilical area as well as the face, soles of feet, and palms of hands is characteristic.[5] Recurrence in subsequent pregnancies is rare. Only about 15% of cases begin in the postpartum time frame.[13]

Intrahepatic cholestasis of pregnancy (ICP) starts as pruritus without any primary skin lesions. Typical itching occurs on the palms of the hands and soles of the feet. Secondary skin lesions like linear excoriations, erosions, and scabbing may be present. It frequently recurs during subsequent pregnancies in 45% to 70% of cases.[5]

Atopic eruption of pregnancy (AEP) includes a variety of dermatoses that have been placed in a category together due to shared clinical features. In atopic eczema, the eczematous lesions appear for the first time during pregnancy. They usually occur during the first or second trimester. In the majority, lesions are in flexures or atopic sites. In the remaining, about one-third of the lesions are distributed on the trunk and limbs. In prurigo of pregnancy, groups of excoriated papules are seen on the limbs and trunk. In pruritic folliculitis of pregnancy, occurring in the second or third trimester, erythematous follicular papules resembling steroid-induced acne are seen.[14] The pathophysiology may be due to an exaggerated shift in the immune response, which normally occurs in pregnancy to prevent fetal rejection.[5]

Pustular psoriasis of pregnancy (PPP) may be caused by underlying hypocalcemia, low vitamin D, hyperparathyroidism, genetic variations, or hormonal changes. The underlying pathophysiology is overall poorly understood.[5]

Histopathology

Pemphigoid gestationis (PG) is characterized by eosinophilic spongiosis, eosinophilic epitheliotropism, and dense superficial dermal eosinophils. It is confirmed by histopathology of a skin biopsy and direct immunofluorescence staining.[4] 

Polymorphic eruption of pregnancy (PEP) has non-specific histopathology findings. It variably shows scattered stromal mast cells, polymorphous mononuclear infiltrates with eosinophils, and dermal edema. Histology may manifest with superficial and deep perivascular mononuclear cells with eosinophils in half of cases. In approximately one-third of biopsies, parakeratosis, focal spongiosis, and acanthosis may be seen in the epidermis. Direct immunofluorescence is consistently negative.[1] Superficial or deep perivascular dermatitis and lymphocytic vasculitis may be present. In some cases, nuclear dust may be noted, but no fibrin extravasation.[6]

Intrahepatic cholestasis of pregnancy (ICP) shows abnormal placental histopathology, including increased terminal villous and capillary surface area, increase in the number of syncytial knots, as well as decidual arteriopathy, delayed villous maturation, choriangiosis, and decidual arteriopathy.[15] There are no primary skin lesions with ICP. 

Atopic eruption of pregnancy (AEP) shows subepidermal pustules and perifollicular neutrophilic infiltration on microscopic examination.[9] Epidermal hyperplasia, spongiosis, and parakeratosis may be seen in the skin on histopathology.[6]

Pustular psoriasis of pregnancy (PPP) is usually diagnosed by clinical findings rather than microscopic exams. Multiple tender and sterile pustules are noted on the skin. Blotchy erythema is found underneath these pustules. If biopsied, histopathology shows neutrophilic infiltrates in the dermis and micropustules in the epidermis.[16]

History and Physical

When a new rash occurs during pregnancy, a diagnosis must be made to alert the patient and clinician of potential risks to the mother or fetus. A medical history, including personal and family history as well as obstetrical history, is important since some dermatoses of pregnancy recur in subsequent pregnancies. Specifics about the onset and particular symptoms are important, as well as a detailed skin exam and possibly a skin biopsy. Laboratory evaluations may be needed based on the clinical and history findings.

Pemphigoid gestationis (PG) usually develops in the second or third trimester of pregnancy. The main symptom is severe itching. Skin papules and plaques on the abdomen and back are characteristic. The urticarial papules, plaques, and vesicles appear first in the periumbilical region. Spread to the truck and extremities may occur later, but the face and mucous membranes are typically spared. The initial skin rash turns into vesicles or tense bullae on an erythematous base, with the time between initial rash formation and bullae formation being days to up to 4 weeks. The bullae that develop during pregnancy typically regress spontaneously in the final weeks of pregnancy, before delivery. However, many patients develop flares immediately postpartum. PG may recur during subsequent pregnancies, and about 10 percent of cases will recur while patients take oral contraceptives.[5]

Polymorphic eruption of pregnancy (PEP) is usually present during the third trimester. Urticarial lesions involve the abdominal striae. PEP spares the periumbilical area. The erythematous lesions may be surrounded by pale halos, forming target-like lesions. It is the most frequent pregnancy dermatosis.[14] 

Intrahepatic cholestasis of pregnancy (ICP) presents as generalized pruritus in the late second or third trimester, frequently starting on the palms and soles. The itching is worse at night. There are no visible primary skin lesions. Secondary lesions like excoriations, erosions, and scabbing are seen. Jaundice, pale stools, and steatorrhea may or may not be present. ICP may recur during subsequent pregnancies.[5]

Atopic eruption of pregnancy (AEP) is associated with intense itching. It usually presents in the first or second trimester of pregnancy. It is a clinical diagnosis that is confirmed by ruling out other diagnoses. There are P-type and E-type of skin eruptions. P-type are commonly erythematous groups of small papules or lesions on the extensor surfaces of the extremities and on the trunk. E-type lesions are eczematous lesions that often involve the face, neck, upper chest, and flexural aspects of the extremities, which are common areas affected by eczema. Frequently, patients have a personal or family history of atopy, asthma, or seasonal allergies.[5]

Pustular psoriasis of pregnancy (PPP) or impetigo herpetiformis is a rare finding in pregnancy, but when it occurs, it is frequently seen in the third trimester of pregnancy when circumferential rings of erythematous plaques covered with sterile pustules along the periphery occur in flexural areas. The lesions do not typically itch. These plaques may spread to the trunk and extremities. Hands, feet, and face are generally spared. The plaques may become centrally crusted and eroded. This is a rare disorder of pregnancy but systemic symptoms may be associated, including nausea, vomiting, diarrhea, fever, anorexia, lymphadenopathy malaise, and even seizures. Onycholysis may result. The plaques then spread to involve the trunk and extremities, often sparring the hands, feet, and face.[5]

Evaluation

Pemphigoid gestationis (PG) is diagnosed by skin biopsy for both histology and direct immunofluorescence. More recently, enzyme-linked immunoassay can detect maternal antibodies in the serum.[5]

Polymorphic eruption of pregnancy (PEP) is usually diagnosed based on the clinical presentation and history. Rarely a skin biopsy is needed.[5] No bullae are noted on the skin with PEP.[17]

PG and PEP can be difficult to distinguish clinically, as they both involve urticated papules and plaques. It is important to evaluate and differentiate between these 2 dermatoses of pregnancy, however, because PEP is not associated with pregnancy complications, but PG may be associated with placental insufficiency. In areas of the world where direct immunofluorescence and enzyme-linked immunoassays are not available, a scoring system for differentiating PG and PEP may be helpful.[17]

Intrahepatic cholestasis of pregnancy (ICP) is associated with elevated serum total bile acid levels >11 micromoles/L. If bile acids are >40 micromoles/L, the disease is considered severe. Direct or indirect bilirubin and liver transaminases may be elevated. Ultrasound of the liver may help exclude other causes of transaminitis.[5]

Atopic eruption of pregnancy (AEP) is a diagnosis usually made by clinical presentation; however, a skin biopsy may be used to rule out other conditions.[5] There are no reliable diagnostic criteria for AEP.[12]

Pustular psoriasis of pregnancy (PPP) is frequently diagnosed by skin biopsy.[5] Histology shows spongiform pustules and intraepidermal microabscesses formed by neutrophils. The mean surface area of skin affected is 56%.[18]

Distinct diagnostic studies are only available for cholestasis of pregnancy and pemphigoid gestationis.[6]

Treatment / Management

Pemphigoid gestationis (PG): The main goals of treatment are to minimize itching and decrease blister formation. The first-line treatment is topical steroids such as fluocinonide 0.05% cream or ointment or clobetasol propionate 0.05% cream or ointment. Oral antihistamines, like 10 mg of loratadine daily, may help treat itching. Systemic corticosteroids may be necessary if topical therapy does not achieve an adequate response. Intravenous immune globulin, azathioprine, and dapsone have also been used as therapy. Rituximab has been used for the treatment of postpartum flares.[5]

Polymorphic eruption of pregnancy (PEP): The main goal of treatment is to decrease itching. The lesions frequently resolve on their own in 4 to 6 weeks. Oral antihistamines and topical steroids are commonly used for treatment. Topical hydrocortisone 2.5% ointment or cream, desonide 0.05% ointment or cream, triamcinolone acetonide 0.1% ointment or cream, mometasone furoate 0.1% cream, or fluocinolone acetonide 0.025% ointment may be used. Systemic corticosteroids may be used as a short course if topical treatment is not satisfactory. Common regimens include prednisolone or prednisone 0.5 mg/kg daily for a week, followed by a taper over the subsequent 1 to 2 weeks.[5]

Intrahepatic cholestasis of pregnancy (ICP): Ursodeoxycholic acid (UDCA) is currently the most effective pharmacologic treatment for ICP and has the most benefits. However, the Society for Maternal-Fetal Medicine states that UDCA therapy does not improve fetal outcomes with ICP. It significantly improves maternal pruritis. A starting dose of UDCA of 10 mg/kg to 15 mg/kg per day can be divided into 2 or 3 daily doses. After 1 week, the dose can be increased to a maximum of 21 mg/kg per day to control symptoms. A dose in the range of 450 mg/day to 1200 mg/day reduces total bile acids in cord blood, colostrum, and amniotic fluid.[19][3] Alternative treatment options include oral antihistamines, S-adenosyl-l-methionine, and rifampin. Cholestyramine has a high side-effect profile and does not improve itching but does reduce bile acid resorption.[5] Delivery is recommended at 36 weeks gestation when bile acid levels are ≥100 micromoles/L due to the increased risk of stillbirth. Delivery between 36 and 39 weeks of gestation is recommended when bile acid levels are <100 micromoles/L.[5]

Atopic eruption of pregnancy (AEP): Topical therapies to improve itching and relieve dryness, including urea and 1% to 2% menthol, are initial treatment recommendations. Adequate skin hydration is critical as fundamental therapy. Antihistamines such as chlorpheniramine, loratadine, and cetraizine may also be used.[5] Topical medium to high potency steroids in the amount of 200 mg/month are considered safe in pregnancy. Fluticasone propionate should not be used in pregnancy because the placenta does not metabolize it and can, therefore, reach the fetus in higher concentrations.[12] Oral corticosteroids may be needed when initial treatment is not successful. Prednisone or prednisolone at a maximum dose of 0.5 mg/kg/d for 2 to 3 weeks may be necessary to control symptoms. Broad and narrowband UVB and UVA-1 light therapy have also been utilized.[5][12] Cyclosporin A and azathioprine (off-label use) may be used in pregnancy when the benefits to the mother are deemed to outweigh any potential risk to the fetus. Methotrexate and mycophenolate mofetil use are contraindicated during pregnancy. Janus kinase inhibitors, baricitinib, upadacitinib, and abrocitinib are also contraindicated for use in pregnancy.[12][5]

Pustular psoriasis of pregnancy (PPP): Prednisolone 15 mg to 30 mg daily, a systemic corticosteroid, is the most common treatment for PPP. The dose may be increased to prednisolone 60 mg to 80 mg daily if needed.[5]  Topical betamethasone 0.05% at a dose of 15 g/day to 30 g/day has also been used. Dapsone, H1-receptor antagonists, and colchicine have been tried. Acitretin has been successfully used in postpartum women.[18] Cyclosporine or tumor necrosis inhibitors, infliximab and adalimumab, may be used in very severe cases. Several other medications have been used in pregnancy to treat PPP, but since this disease is so rare, there is limited data on the efficacy and safety in pregnancy. Delivery is curative, so this may be considered, especially when close to term and with refractory disease.[5] 

Differential Diagnosis

The differential diagnosis for dermatoses of pregnancy includes the following:

• Acute urticaria
• Contact dermatitis
• Chronic urticaria
• Drug eruptions
• Erythema multiforme
• Insect bites
• Gallstones
• Biliary disease (cholecystitis and cholangitis)
• Hepatitis
• Acute fatty liver of pregnancy
• Atopic dermatitis
• Scabies pregnancy
• Folliculitis

Prognosis

Pemphigoid gestationis (PG) frequently recurs in subsequent pregnancies, with 50% to 70% of patients having a recurrence in subsequent pregnancies associated with earlier-onset and more severe disease. Preterm birth and fetal growth restriction are infrequently associated with PG. PG usually regresses after delivery, but a postpartum recurrence may occur in 75% to 85% of patients.[1]

Pruritic eruption of pregnancy (PEP) usually lasts 3 to 6 weeks postpartum.[1]

Intrahepatic cholestasis of pregnancy (ICP) is unique to pregnancy and typically resolves spontaneously postpartum.[11] Adverse neonatal effects may be seen, including intrauterine fetal death.

Atopic eruption of pregnancy (AEP) is not associated with any adverse fetal or maternal outcomes. However, the itching may be intense and disruptive.

Pustular psoriasis of pregnancy (PPP) may be associated with fetal death due to placental ischemia. Maternal convulsions may occur due to elevated calcium levels. Recurrences in subsequent pregnancies may start earlier, and the use of oral contraceptive pills may trigger a flare.[1]

Complications

Pemphigoid gestationis (PG) may be associated with fetal growth restriction and preterm delivery.[4] Neonatal pemphigoid gestationis occurs in 10% to 13% of neonates. The mild blistering seen resolves spontaneously within several weeks of birth.[5][4]

Pruritic eruption of pregnancy (PEP) is not associated with any adverse maternal or fetal outcomes. It does not frequently recur in subsequent pregnancies.

Intrahepatic cholestasis of pregnancy (ICP) is associated with poor outcomes for the fetus. Prematurity, respiratory distress, and meconium-stained amniotic fluid are all fetal risks associated with ICP. Stillbirth is an additional fetal risk, especially when bile acid levels are >100 micromoles/L.[5]

Atopic eruption of pregnancy (AEP) commonly occurs in subsequent pregnancies. There are no maternal or fetal risks associated.[5]

Pustular psoriasis of pregnancy (PPP) is associated with maternal electrolyte imbalances, especially low calcium, which can lead to delirium, seizures, or tetany. Fluid losses, dehydration, and sepsis from infections may be associated. PPP may recur in subsequent pregnancies at an earlier stage of pregnancy and a more severe clinical presentation. PPP can also recur during menstruation or when taking birth control pills. Other complications include preterm labor, neonatal demise, fetal growth restriction, premature rupture of membranes, and intrauterine fetal death due to placental insufficiency.[5]