Maria-Magdalena Roth, MD, PhD

During pregnancy, every mother-to-be undergoes radical psychological and physiological changes (endocrinologic, immunologic, metabolic, or vascular) whose influence may trigger various skin manifestations, even during the very first weeks of gestation. These pregnancy-related cutaneous conditions, collectively grouped under the conceptual umbrella of “dermatoses of pregnancy,” can be disentangled into 4 distinct categories:

1. Common, physiologic skin changes that can accompany pregnancy; for example, 

 (also called chloasma, “mask of pregnancy”)

2. Changes in preexisting skin diseases (dermatoses coinciding with pregnancy)-past events with onset not related to a previous pregnancy; for example, atopic dermatitis, lupus erythematosus

3. Dermatoses specific to pregnancy-disorders known to develop only during pregnancy or during the postpartum period; for example, pemphigoid gestationis

4. Disorders related to pregnancy yet considered nonspecific to gestation; for example, impetigo herpetiformis (also called generalized pustular psoriasis of pregnancy)

 
Algorithm approach to the diagnosis and management of dermatoses of pregnancy.

Knowing how to deal with the dermatoses of pregnancy conditions is crucial, because some dermatoses, including pemphigoid gestationis, intrahepatic cholestasis of pregnancy, and impetigo herpetiformis, are associated with considerable potential for negative fetal outcomes such as prematurity, fetal distress, or even stillbirth. Others, such as polymorphic eruption of pregnancy, prurigo of pregnancy, and pruritic folliculitis of pregnancy, although not associated with fetal risks, can be caused by pruritic symptomatology, which is severely distressing for the mother.

This review offers practical clinical guidance and updated treatment strategies for each of these dermatoses of pregnancy and presents an algorithmic approach to pregnant patients who manifest skin-related conditions (

). At end of the article you will also find a 

 summarizing the conditions as well as diagnosis and treatment approaches. In this context, I will use a recent pragmatic, clinically based classification scheme of the specific dermatoses of pregnancy

Late-onset polymorphic eruption of pregnancy

 (polymorphic eruption of pregnancy, pruritic urticarial papules, and plaques of pregnancy)

Early-onset polymorphic eruption of pregnancy

 (comprising the papular dermatoses of pregnancy: prurigo of pregnancy, atopic eruption of pregnancy, and pruritic folliculitis of pregnancy)

 (liver disorder of pregnancy; also known as cholestasis of pregnancy, obstetric cholestasis, recurrent jaundice of pregnancy, idiopathic jaundice of pregnancy, pruritus gravidarum, icterus gravidarum)

 (pregnancy-related dermatosis-generalized pustular psoriasis of pregnancy)

Pemphigoid gestationis (PG)-previously known as herpes gestationis-is a rare autoimmune vesiculobullous disorder with severe pruritic manifestations. The condition occurs mainly in late pregnancy or in the puerperium.

Although PG seems to be characterized by a worldwide distribution rather than by a specific geographic prevalence, existent studies highlight different rates of incidence in various regions of the globe: the estimated incidence in North America is 1 in 50,000 pregnancies, 

 while the incidence is only 1 in 40,000 in the United Kingdom 

(even if, in this latter case, some researchers support incidences as high as up to 1 in 1700 pregnancies).

In this context, it is worth noting that one of the basic tenets shared by these existing studies is the association between PG and the haplotypes HLA-DR3 (in 61%–80% of cases) and HLA-DR4 (in 52%–53% of cases).

 Existing literature suggests that the pathogenically relevant autoantigen is a 180 kDa epidermal protein, also termed “bullous pemphigoid-180,” “bullous pemphigoid antigen 2,” or “type XVII collagen”.

 Bullous pemphigoid antigen 2 is in fact a transmembrane glycoprotein of basal keratinocytes that consists of a large extracellular domain within the lamina lucida of the dermo-epidermal junction. The ectodomain contains more than 1000 amino acids, but the reactivity of the autoantibodies is directed against the 

-terminal 45 amino acids of the 16th noncollagenous domain,

 which is located in the proximity of the cell membrane.

The autoantibodies are circulating, complement-fixing immunoglobulin G (IgG) antibodies of the subclass IgG1, formerly called “herpes gestationis factor,”

 which are also found in the skin and are formed in order to be directed against the bullous pemphigoid antigen 2 in the hemidesmosomes of the basal membrane zone (BMZ). The autoimmune response consists of immune complex deposition and complement activation (via the classical pathway),

 followed by the consecutive chemo-attraction and degranulation of eosinophils. The latter results in tissue damage (destruction of the BMZ) and blister formation.

Strong direct and indirect evidence supports an autoimmune etiology for PG, and the condition has been seen in patients with other conditions that are autoimmune in nature, such as Grave disease, pernicious anemia, and Hashimoto thyroiditis. On the other hand, the recurrence of the disease when using oral contraceptives or during the premenstrual period supports the theory that hormonal factors play an essential role in the pathogenesis of PG.

PG’s initial manifestations occur during the second (34% of patients) or third (34% of patients) trimester of pregnancy. According to Jenkins and colleagues,

 the onset can also occur during the first trimester (in 18% of patients), while only 14% of patients exhibit symptoms during the postpartum period.

The typical evolutionary pattern of PG consists of severe initial pruritus, which precedes the appearance of skin lesions, the latter appearing in the form of erythematous urticarial papules that evolve into plaques.

 
Highly pruritic abdominal rash in a 24-year-old woman’s first pregnancy. A biopsy and direct immunofluorescence confirmed the suspected diagosis of pemphigoid gestationis. (Image courtesy of Dr Scott Ross, ConsultantLive.)             FIGURE 2b             

 
A 16-year-old patient with pemphigoid gestationis during the 38th week of her first pregnancy. Patient was affected with pruritic, hivelike, edematous, bullous lesions on her abdomen and legs. (Image courtesy of Dr Scott Ross, ConsultantLive.) 

 the typical localization of the lesions is in the abdominal region, almost always within or proximate to the umbilicus (

). Atypical patterns of lesions include involvement of the limbs, palms, or soles.

As lesions evolve-within days or weeks-into tense blisters (similar to those of bullous pemphigoid) with a generalized pemphigoid-like pattern of eruption, the diagnosis becomes more obvious. While the entire skin surface can theoretically be involved, the face, palms, soles, and mucous membranes are usually spared.

Histopathologic and immunopathologic tests are the most important tools used to confirm a diagnosis of PG, as routine laboratory tests usually reveal no abnormalities. Histopathologic findings from lesional skin depend on the stage and severity of the disease. In the preblistering stage, edema in the upper and middle dermis can be identified with a predominant perivascular inflammatory infiltrate, composed of lymphocytes, histiocytes, and a variable number of eosinophils. In this stage, epidermal spongiosis and focal necrosis of the keratinocytes can also be observed.

On the other hand, the bullous stage reveals a subepidermal blister, which in fact is nothing but a histopathologic sine qua non feature located in the lamina lucida of the BMZ. In addition, numerous eosinophils are seen along the BMZ and in the bullous spaces.

Direct immunofluorescence (DIF) performed on perilesional skin is considered to be a veritable gold diagnostic standard for pemphigus gestationis; in 100% of cases, it reveals a bright linear deposition of C3 along the BMZ. In addition, in 25% to 30% of cases

) deposition can also be observed. Depending on the applied technique, indirect immunofluorescence (IIF) may show circulating IgG antibodies in 30% to 100% of cases.

 However, it is worth noting that there is no consistent correlation between autoantibody levels and disease severity, and although some authors do describe a correlation between the two

 and immunoblot techniques), others insist that there is no correlation at all.

In the preblistering stage it is almost impossible to distinguish pemphigus gestationis from late-onset polymorphic eruption of pregnancy, mainly due to the fact that both have clinical and histopathological overlap in this early stage. Some clinical aspects, such as the absence of striae gravidarum and the presence of skin lesions involving the umbilical area, may suggest the PG diagnosis. Nevertheless, in order to clearly elucidate it, it is imperative to perform DIF.

Bullous conditions coinciding with pregnancy such as bullous pemphigoid, dermatitis herpetiformis, linear immunoglobulin A disease (Berger disease), bullous systemic lupus erythematosus, erythema multiforme, bullous drug eruptions, or contact dermatitis 5 must also be excluded. In all these cases, the immunopathologic tests (DIF/IIF) play an important role in differentiating PG from other blistering disease states.

Treatment of PG is mandatory, with the dual goals of controlling pruritus and preventing blister formation. The exact therapeutic intervention is, however, dependent on the stage and on the severity of the disease.

In mild preblistering stages of PG, potent topical corticosteroids plus emollients with or without oral antihistamines (eg, loratadine and cetirizine) are sufficient.

 However, when blisters have arisen, the use of systemic corticosteroids is recommended (prednisolone, started at a dosage of 0.5-1 mg/kg/d). When the disease shows signs of improvement (usually in approximately 2 weeks), the use of prednisolone can be tapered (over several weeks) and maintained at the lowest effective dose. The prednisolone dose may be increased around the patient’s due date to prevent the characteristic flare-up of the disease at delivery or immediately postpartum.

For the affected neonates, treatment consists of wound care, because the condition is transient and usually has mild clinical manifestations. No specific treatment is typically required.

The natural course of the disease consists of alternating exacerbations and remissions during pregnancy, with general improvement in the third trimester and flare-up at the time of delivery (in 50%-75% of patients

). PG tends to reoccur in all subsequent pregnancies, usually with an earlier onset and with increased severity compared to the initial pregnancy. Existent literature highlights that only a small number of pregnancies (approximately 5%-8%) are passed over (the so-called skip pregnancies).

After delivery, exacerbations or recurrences have been reported-especially during the premenstrual period or after the use of oral contraceptives.

 For obvious reasons, in these cases, use of oral contraceptives is contraindicated.

In PG there is a passive transfer of IgG1 antibodies from the mother to the fetus, and up to 10% of newborns can develop a mild clinical picture, consisting of urticarial or vesicular skin lesions. All other cases seem to manifest a subclinical disease with no clinical lesions (the immunopathologic tests from the cord blood or neonatal skin do still demonstrate the presence of antibodies).

Of importance is the increased inclination to develop fetal risks such as small-for-gestational-age babies and prematurity, which seem to suggest a low-grade placental insufficiency that is possibly associated with the use of systemic corticosteroids or with the pathophysiologic mechanism of the disease itself.

Adrenal insufficiency must also be taken into consideration in the case of infants whose mothers were treated with systemic corticosteroids at higher dosages over a long period. Nevertheless, Gabbe

 suggested that the maternal-fetal gradient of prednisolone is only 10:1 and, as a consequence, fetal adrenal suppression is a rare sequel.

LATE-ONSET POLYMORPHIC ERUPTION OF PREGNANCY 

 
Late-onset polymorphic eruption of pregnancy at primigravida with onset at 2 weeks postpartum, with intensely pruritic urticarial papules within and/or adjacent to striae gravidarum on the abdomen. 

Late-onset polymorphic eruption of pregnancy (late-onset PEP, also called polymorphic eruption of pregnancy largely in Europe or pruritic urticarial papules and plaques of pregnancy largely in the United States) is a benign, self-limited, pruritic, papulo-urticarial inflammatory disorder that usually affects the primigravida in the last trimester of pregnancy or in the immediate postpartum period (

). In contrast to PG, this disorder has minimal risk of recurrence in subsequent pregnancies.

Articles

During pregnancy, every mother-to-be undergoes radical psychological and physiological changes (endocrinologic, immunologic, metabolic, or vascular) whose influence may trigger various skin manifestations, even during the very first weeks of gestation.

Dermatoses of Pregnancy at a Glance

. Highly pruritic abdominal rash in a 24-year-old woman’s first pregnancy. A biopsy and direct immunofluorescence confirmed the suspected diagosis of pemphigoid gestationis. (Image courtesy of Dr Scott Ross, ConsultantLive.)

. A 16-year-old patient with pemphigoid gestationis during the 38th week of her first pregnancy. Patient was affected with pruritic, hivelike, edematous, bullous lesions on her abdomen and legs. (Image courtesy of Dr Scott Ross, ConsultantLive.)

. Late-onset polymorphic eruption of pregnancy at primigravida with onset at 2 weeks postpartum, with intensely pruritic urticarial papules within and/or adjacent to striae gravidarum on the abdomen (

. Atopic eruption of pregnancy (generalized maculopapular rash and pustules) in a 26-year-old woman presenting at 30 weeks gestation of her first pregnancy. 
 (Reprinted from Dermatology Nursing, 2009, Volume 21, Number 2, pp. 70-74, 81. Reprinted with permission of the publisher, Jannetti Publications, Inc., East Holly Avenue, Box 56, Pitman, NJ 08071-0056; Phone (856) 256-2300; FAX (856) 589-7463; 

. Impetigo herpetiformis in the postpartum period: erythematous plaques with polycyclic edges covered with widespread, tiny, green-yellow pustules on the abdomen (

Figure 2a. Highly pruritic abdominal rash in a 24-year-old woman’s first pregnancy. A biopsy and direct immunofluorescence confirmed the suspected diagosis of pemphigoid gestationis. (Image courtesy of Dr Scott Ross, ConsultantLive.)

Maria-Magdalena Roth, MD, PhD

Articles

Dermatoses of Pregnancy at a Glance

Dermatoses of Pregnancy: Figures & Captions