Complex endocrinologic, immunologic, metabolic and vascular changes associated with pregnancy may influence the skin in various ways. Skin findings in pregnancy can roughly be classified as physiologic skin changes, alterations in pre-existing skin diseases, and the specific dermatoses of pregnancy. Physiologic skin changes in pregnancy include changes in pigmentation, alterations of the connective tissue, vascular system, and endocrine function as well as changes in hair and nails (Table 1)1. Pregnancy is also known to influence the course of pre-existing skin diseases in both positive and negative ways2. A typical example is psoriasis, a classical Th1-associated disease, which often improves in pregnancy, only to worsen after delivery. A special case in this context is impetigo herpetiformis, which today is regarded as a variant of generalized pustular psoriasis presenting in pregnancy, accompanied by systemic signs such as fever, chills, vomiting, diarrhea and tetanic seizures due to hypocalcemia. Diseases primarily associated with a Th2-immune response, such as lupus erythematosus and other autoimmune dermatoses, in contrast, characteristically deteriorate during pregnancy and improve after delivery. This is thought to be due to a temporary imbalance that develops between the differential cytokine secretion profiles and the preferential cellular or humoral dominated Th1 and Th2 mediated immune responses in order to prevent rejection of the fetus. Another disease typically affected in its course by pregnancy is acne, which most often improves, but can also be quite tenacious ("acne gravidarum"). Nevi tend to darken and enlarge, especially on the abdomen and breasts. The assumption that pregnancy has deleterious effects on the course of melanoma has not been substantiated; however, diagnostic and therapeutic decisions are often delayed in pregnancy leading to a more advanced tumor stage and hence worse prognosis.

The specific dermatoses of pregnancy represent a heterogeneous group of severely pruritic inflammatory dermatoses associated exclusively with pregnancy and/or the immediate postpartum period. The rarity of these diseases, their variable clinical morphology, the lack of unequivocal diagnostic tests (with the exception of immunofluorescence in pemphigoid gestationis) as well as limited treatment options have led to confusing terminologies and have made their management difficult over decades. This article addresses the specific dermatoses of pregnancy in particular as a new classification has been recently established based on the results of a retrospective two-centre study on more than 500 pregnant patients3.

The first specific dermatosis of pregnancy reported was pemphigoid gestationis, which Milton described in 1872 under the name herpes gestationis4. The term "herpes" referred to the characteristic "creeping" blister formation. Only after the introduction of immunofluorescence microscopy and the discovery of specific linear complement deposition along the dermo-epidermal junction zone (DEJ) in 1973 could this disease entity be differentiated from the other dermatoses of pregnancy. In 1904 Besnier described another pregnancy-related disease which he termed prurigo gestationis5. The original description as well as illustration resemble today's picture of atopic dermatitis; of interest, at that time, what we define today as atopic dermatitis was known as prurigo. Costello (1941) employed this term and designated all pregnancy-related dermatoses which were not herpes gestationis as prurigo gestationis of Besnier and reported an incidence of 2%6. In the further course of time the disease was also referred to as early onset prurigo of pregnancy or prurigo of pregnancy7. Bourne (1962) described a further pregnancy-related dermatosis under the name toxemic rash of pregnancy, which appears on the abdomen often of small women with excessive weight gain and prominent striae, corresponding to today's polymorphic eruption of pregnancy8. Other synonyms followed such as late onset prurigo of pregnancy, toxic erythema of pregnancy and pruritic urticarial papules and plaques of pregnancy (PUPPP)7,9,10. Also in 1962, Spangler et al. described an entity whose existence is rightly questioned today. He differentiated a papular dermatitis from prurigo gestationis, which is clinically similar, on the grounds of biochemical alterations (raised levels of β-HCG in urine, lowered plasma cortisol levels) and reported a dramatically increased fetal death rate (early miscarriage and miscarriage in previous pregnancies were included!)11. In over 40 years, with the exception of one further case report by the same authors, no further case corresponding to the original description has surfaced. Even a recent large prospective study with extensive laboratory analyses could not detect a manifestation corresponding to "papular dermatitis"12. The first simplified classification of dermatoses of pregnancy was presented by Holmes et al. in 1982 and included pemphigoid gestationis, polymorphic eruption of pregnancy and prurigo of pregnancy9. One year later they added a further dermatosis, pruritic folliculitis of pregnancy13,14. Whereas in the USA the terms herpes gestationis and PUPPP are still preferred, in Europe the names pemphigoid gestationis (points to the autoimmune pathogenesis and avoids association with herpes virus) and polymorphic eruption of pregnancy (points to the morphological spectrum) are widely accepted. The classification of Holmes and Black stood the test of time for two decades; in 1998 Shornick proposed a further adaptation15. He postulated that folliculitis of pregnancy was not an entity on its own but belonged to the spectrum of prurigo of pregnancy. He further introduced intrahepatic cholestasis of pregnancy into the classification of specific dermatoses of pregnancy. This disease had previously not appeared in the classification, as it displays only secondary skin changes. It seems sensible to include it in such as classification, as it is an important differential diagnostic consideration associated with potential fetal risk which can increase if the diagnosis is delayed or overlooked. Whereas pemphigoid gestationis, polymorphic eruption of pregnancy and intrahepatic cholestasis of pregnancy are accepted as independent entities, prurigo of pregnancy according to Holmes and Black as well as to Shornick is included only as a questionable independent entity. Even though it has been repeatedly suggested since the first description by Besnier that there might be a link to atopy, Holmes and Black were the first to postulate that it might merely be the result of pruritus in atopic pregnant women13. In a recent retrospective study on over 500 pregnant patients with pruritus, we were able to demonstrate conspicuous overlaps in clinical presentation and histopathology between female patients with atopic dermatitis, prurigo of pregnancy and pruritic folliculitis of pregnancy (together 50% of our patient collective), thus leading us to group them together under the term atopic eruption of pregnancy3. This results in a new classification of specific dermatoses of pregnancy as follows: pemphigoid gestationis, polymorphic eruption of pregnancy, intrahepatic cholestasis of pregnancy, and atopic eruption of pregnancy (Table 2, 3).

Pemphigoid gestationis is a rare, self-limited autoimmune bullous disorder that presents mainly in late pregnancy or the immediate postpartum period but can appear in any of the three trimesters. Beyond pregnancy it can also very rarely occur in association with trophoblastic tumors (choriocarcinoma, hydatidiform mole). Its incidence varies from 1:2.000 to 1:50.000~60.000 pregnancies depending on the prevalence of the HLA-haplotypes DR3 and DR416. There is also an increased risk to develop other autoimmune diseases, in particular Grave's disease. Pemphigoid gestationis tends to recur in subsequent pregnancies, with usually earlier onset and increasing severity. Only very rarely (5%) a pregnancy may be passed over ("skip pregnancies").

Pathogenetically, circulating complement fixing IgG antibodies of the subclass IgG1 (formerly known as "herpes gestationis factor") bind to a 180-kDa protein, BP-180 or bullous pemphigoid antigen 2 in the hemidesmosomes of the DEJ, leading to tissue damage and blister formation17. The immune response is even more highly restricted to the NC16A domain as it is in bullous pemphigoid. Of interest, the primary site of autoimmunity seems not to be the skin, but the placenta, as antibodies bind not only to the BMZ of the epidermis, but also to that of chorionic and amniotic epithelia, both equally of ectodermal origin. Aberrant expression of MHC class II molecules on the chorionic villi suggests an allogenic immune reaction to a placental matrix antigen, thought to be of paternal origin.

Polymorphic eruption of pregnancy is a benign, self-limited pruritic inflammatory disorder that usually affects primigravidae in the last weeks of pregnancy or immediately postpartum (15%)22. Its incidence is about 1:160 pregnancies and the condition is associated with excessive maternal weight gain and multiple pregnancies22,23.

The pathogenesis of polymorphic eruption of pregnancy remains unclear. The main theories proposed by now focus on abdominal distension, hormonal and immunological factors24. The fact that polymorphic eruption of pregnancy starts within striae distensae at the time of greatest abdominal distension favors connective tissue damage due to overstretching to play a central role. The increase of CD1a cells in the inflammatory infiltrate could confirm the theory that previously inert structures develop antigenic character, thus triggering the inflammatory process. Hormonal and immunological changes have not definitively been shown to play a role; nor has an association with increased birth weight or male sex of the newborn been confirmed12,22.

Intrahepatic cholestasis of pregnancy is a reversible form of hormonally triggered cholestasis that typically develops in genetically predisposed individuals in late pregnancy. In contrast to the other dermatoses of pregnancy, it presents with pruritus and exclusively secondary skin lesions due to scratching. The incidence of intrahepatic cholestasis of pregnancy shows a striking geographical pattern; while its prevalence in Middle Europe is around 0.2~2.4%, it is particularly frequent in Scandinavia and South America, with highest rates in Chile (15~28%)25. Intrahepatic cholestasis of pregnancy runs in families and tends to recur in subsequent pregnancies (45~70%)25,26.

Pathogenetically, there is a defect in the excretion of bile salts resulting in elevated bile acids in the serum. This leads to severe pruritus in the mother, and, as toxic bile acids can pass into fetal circulation, may have deleterious effects on the fetus due to acute placental anoxia and cardiac depression. The reason for this defect seems to be multifactorial with genetic, hormonal, and exogenous factors being involved25. Endemic clustering and familial occurrence has pointed towards a genetic background; recently, mutations of certain genes encoding for transport proteins necessary for bile excretion (e.g., the ABCB4 [MDR 3] gene) have been identified in some intrahepatic cholestasis of pregnancy patients27. With normal hormone levels, this defect has no clinical implications; it only becomes evident with highest concentrations as in late pregnancy and/or with hormonal contraception. Furthermore, estrogen and progesterone metabolites have been seen to be cholestatic themselves28. Some authors also discuss additional environmental and dietary factors influencing the manifestation of intrahepatic cholestasis of pregnancy such as decreased serum selenium levels, for instance29.

Atopic eruption of pregnancy is a benign pruritic disorder of pregnancy which includes eczematous and/or papular lesions in patients with an atopic diathesis after exclusion of the other dermatoses of pregnancy. It is the most common dermatosis in pregnancy, accounting for 50% of patients, starts usually early, in 75% before the third trimester, and tends to recur in subsequent pregnancies due to the atopic background3.

The pathogenesis of AEP is thought to be triggered by pregnancy-specific immunological changes; a reduced cellular immunity and reduced production of Th1 cytokines (IL-2, interferon gamma, IL-12) stands in contrast to the dominant humoral immunity and increased secretion of Th2 cytokines (IL-4, IL-10)41. Thus, the exacerbation of pre-existing atopic dermatitis as well as the first manifestation of atopic skin changes can be explained by a dominant Th2 immune response that is typical for pregnancy.