Specific dermatoses of pregnancy: advances and controversies

Abstract

Specific dermatoses of pregnancy include herpes (pemphigoid) gestationis, polymorphic eruption of pregnancy (also known as pruritic urticarial papules and plaques of pregnancy), prurigo of pregnancy and pruritic folliculitis of pregnancy. This article focuses on what is currently known about the epidemiology, clinical characteristics, etiopathogenesis and management of these disorders. Moreover, it discusses the intrahepatic cholestasis of pregnancy and ‘atopic eruption of pregnancy’, which were recently reclassified as specific dermatoses of pregnancy, as well as debates related to the prevalence and diagnostic criteria of the latter. Finally, it addresses the suggested overlap between ‘atopic eruption of pregnancy’ and specific dermatoses of pregnancy, such as prurigo and pruritic folliculitis.

Keywords::

• atopic dermatitis
• cholestasis
• herpes gestationis
• polymorphic eruption of pregnancy
• prurigo of pregnancy
• pruritic folliculitis of pregnancy

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Release date: November 24, 2010; Expiration date: November 24, 2011

Learning objectives

Upon completion of this activity, participants should be able to:

• • Describe the presentation and prevalence of AD in pregnancy

• • Identify risk factors for ICP

• • Describe helpful treatment modalities for ICP

• • Describe clinical characteristics of herpes (pemphigoid) gestationis (HG)

• • Identify best management approaches to HG

Financial & competing interests disclosure

EDITOR

Elisa Manzotti,Editorial Director, Future Science Group, London, UK

Disclosure:Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Desiree Lie,MD, MSEd, Clinical Professor; Director of Research and Faculty Development, Department of Family Medicine, University of California, Irvine at Orange, CA, USA

Disclosure:Désirée Lie, MD, MSEd, has disclosed the following relevant financial relationship: Served as a nonproduct speaker for: “Topics in Health” for Merck Speaker Services.

AUTHOR

George Kroumpouzos, MD, PhD,Department of Dermatology, Brown Medical School, Providence, RI, USA, and Dermatology Clinic, South Shore Medical Center, Atrius Healthcare System, Norwell, MA, USA

Disclosure:George Kroumpouzos, MD, PhD, has disclosed no relevant financial relationships.

Skin diseases in pregnancy can be categorized into the following categories: skin diseases affected or induced by pregnancy, the most common being atopic dermatitis (AD); conditions that manifest with pruritus, such as intrahepatic cholestasis of pregnancy (ICP); and specific dermatoses of pregnancy, which include herpes (pemphigoid) gestationis (HG), polymorphic eruption of pregnancy (PEP; also known as pruritic urticarial papules and plaques of pregnancy), prurigo of pregnancy (PP) and pruritic folliculitis of pregnancy (PFP). This article provides an update on specific dermatoses of pregnancy, ICP and AD. The established and recently proposed classifications are discussed (Table 1) [1]. The concept of ‘atopic eruption of pregnancy’ (AEP), which was introduced in the recent classification, has been debated, and controversies regarding the diagnostic criteria, especially IgE elevation, and epidemiology of AD in pregnancy are discussed [2]. The proposed associations between AD and specific dermatoses of pregnancy, such as PP and PFP of pregnancy. are analytically reviewed [1]. An emphasis is placed on etiopathogenesis and maternal and fetal/neonatal risks.

Atopic dermatitis

Epidemiology & clinical features

Two large studies indicated an unexpectedly high incidence of AD in gestation, including ‘new eczema’ (eczema presenting during gestation for the first time) [1,3]. AD is the most common pregnancy dermatosis, accounting for 36–49.7% of total cases. A recent study indicated that 46% of females with AD experience deterioration of the disease in pregnancy or in relation to their menstrual cycle [4]. According to other studies, approximately 25% of female patients with AD experience improvement, and more than 50% deterioration of the disease in pregnancy, and may even develop AD for the first time in gestation [5,6]. There is a history of atopy in 27% of pregnant females with AD, a family history of atopy in 50% of cases and infantile eczema in 19% of the offspring [7]. The clinical features of gestational AD are identical to those seen in nonpregnant females. Eczematous lesions can develop bacterial (typically from Staphylococcus aureus) or herpetic superinfection (eczema herpeticum) in pregnancy. Up to 2% of breastfeeding mothers develop eczema of the areola or nipple, and approximately half of these will satisfy criteria for AD [6].

Diagnosis & etiopathogenesis

The criteria used for the diagnosis of AD in pregnancy in two recent studies, which also included total serum IgE elevations (uncontrolled), did not differ from those used in nonpregnant females [8]. Nevertheless, it has been debated whether total serum IgE measurements may be used as one of the minor criteria for gestational AD, because the regulation of IgE in normal pregnancy has not been adequately clarified [2]. Furthermore, in a recent study there were no statistically significant differences in the total IgE levels between the patient group who experienced deterioration of AD in pregnancy and the patient group who did not [4]. The reasons why AD worsens during pregnancy remain unclear. Some authors suggested that the placental Th-2 drive, which is associated with an increase in IL-4 during gestation, may be critical to the induction of IgE that could be relevant to atopic disease in pregnancy [9]. Nevertheless, a recent study indicated that it is more the intrinsic (‘nonallergic’/constitutional) than the extrinsic (IgE-associated) eczema that is affected by pregnancy [4]. The intrinsic AD fulfills the most common diagnostic criteria for AD [8]. Patients with intrinsic AD, as opposed to those with the extrinsic type, have no associated respiratory disease (bronchial asthma or allergic rhinitis), show normal total serum IgE levels, no specific IgE and negative skin prick tests to aeroallergens or foods (peer review of eczema types can be found in [10]). Experimental studies indicate that estrogens may affect mast cell activation, while progesterone suppressed histamine release and potentiated IgE induction in animal studies [11].

Management

Dry skin care remains an integral part of eczema management, and topical steroids are the mainstay of treatment [3]. Mid- or high-potency topical steroids can be used for severe symptomatic AD in small surface areas; their use on large body surface areas is associated with systemic absorption and risks similar to those observed with systemic steroids. A short course of oral steroid may be used in the third trimester for severe symptomatic or recalcitrant AD. Oral steroids have been associated with cleft lip and palate defects in mice, and fetal growth retardation in patients who used oral steroids for asthma. Nevertheless, it remains unknown whether the effects of maternal disease (asthma) contributed more to fetal retardation than those of oral steroids. Topical calcineurin inhibitors (pimecrolimus and tacrolimus) are Pregnancy Category C and should be used with caution in pregnancy, although their bioavailability is limited (<5%) and their use has not been associated with fetal anomalies; accepted practice is to restrict use to localized areas only in poorly controlled AD that has not responded to UVB [6]. Systemic antihistamines, such as diphenhydramine (Category B), are safe during gestation and often required for pruritus control. Narrow-band UVB is an effective treatment for severe AD, and should be considered the safest second-line treatment for gestational AD. If systemic agents are needed for severe or recalcitrant eczema, cyclosporine is the safest option and should be used for the shortest duration possible. Systemic antibiotics, such as erythromycin base or penicillin, are safe during gestation and should be administered in superinfected AD. Prompt acyclovir treatment is warranted if there is strong clinical suspicion of eczema herpeticum.

Complications

There is no evidence to suggest that eczema affects fetal outcome. Pregnant women who use large amounts of topical corticosteroids over large body surface areas should be warned of the possibility of low birthweight babies. Fetal risks, such as premature delivery, intrauterine growth retardation and miscarriage, which are associated with fetal herpes simplex infection, are minimized when eczema herpeticum is treated promptly with acyclovir. Genetic as well as pre- and peri-natal influences, such as black and Asian race/ethnicity, male gender, higher gestational age at birth and maternal history of eczema, have been associated with an increased risk of AD in the first 6 months of life [12]. Maternal atopy poses a higher risk for infantile AD than paternal atopy [13], and the maternal, but not paternal, total IgE level correlated with elevated infant IgE levels and infant atopy in one study [14]. The influence of breastfeeding on AD in the infant has been contentious. Some studies showed no effect on the development of AD [15], whereas others showed significantly lower [16] or increased prevalence [17] of infantile eczema with each additional month of breastfeeding. The influence of maternal food antigen (particularly cow’s milk and egg) avoidance during pregnancy and lactation on the incidence of infantile AD has also been debated [18,19]. Maternal smoking may be implicated in the development of AD during pregnancy and lactation [20].

Challenges & controversies

It has been debated whether serum IgE elevation may be used as a minor criterium for AD in pregnancy, because the regulation of IgE in normal pregnancy has not been adequately clarified, and total serum IgE cannot be used as a diagnostic criterion without an appropriate control group of pregnant females [2,21]. Since the original report of diagnostic criteria for AD by Hanifin and Rajka [8], which mentioned that only high IgE levels (e.g., >2000 units/ml) may add considerable support to the diagnosis of AD, these criteria have been extensively revised. Now several authorities consider the detection of allergen-specific IgE, rather than total IgE, as one of the criteria of atopy [22]. To make things even more complex, maternal serum IgE during pregnancy can be affected by ethnic, genetic, lifestyle and psychosocial stress [23]. The prevalence of the intrinsic (‘nonallergic’) versus extrinsic (IgE-associated) type of AD during gestation is unknown, although a recent small study demonstrated that it is more the intrinsic than the extrinsic eczema that is affected by pregnancy [4]. The findings of this study seem consistent with those of the studies [1,3] that showed predominantly mild IgE elevations in AD in pregnancy (median IgE elevation 156 kU/l; normal <100 kU/l). It can be concluded from the above that the diagnostic criteria for gestational AD need to be refined. The unexpected high prevalence of eczema in pregnancy [1,3] may have been biased by the inclusion of serum IgE elevations in the diagnostic criteria [2], and needs to be confirmed by further studies after a consensus on the diagnostic criteria of gestational AD is reached. It needs to be clarified whether ‘eczematiform’ lesions, rather than ‘true’ eczema, develop in pregnancy. Furthermore, PEP also showed IgE elevations (uncontrolled) in these studies [1,3], and the high prevalence of AEP might have been biased by the inclusion of PEP patients with ‘eczematiform’ features in the AEP group. Moreover, it needs to be investigated whether patients with ‘new eczema’ in pregnancy represent cases of extrinsic and/or intrinsic eczema, and whether they will continue to experience eczema flares after pregnancy.

Intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy is defined as pruritus with onset in pregnancy, which is associated with abnormal liver function in the absence of other liver disease, and which resolves typically in the immediate postpartum period [24]. The reclassification of ICP in specific dermatoses of pregnancy [1] was subsequently debated [2], as ICP is not a dermatosis. ICP always needs to be differentiated from specific dermatoses of pregnancy in daily clinical practice (Box 1).

Epidemiology & clinical features

Intrahepatic cholestasis of pregnancy is the most common pregnancy-induced liver disorder, and typically presents in the third trimester (80% of cases occur after 30 weeks’ gestation) [25,26]. The prevalence of ICP varies widely with geographical location and ethnicity, the highest being in Chile (1.5–4%), Bolivia and Scandinavia (1–2%); the disease is less prevalent in Europe (0.1–2%), Australia (0.2–1.5%) and the USA (<0.1%) [24,27]. Surveys in Bolivia and Chile show that ICP is significantly more prevalent in women of Indian descent (Araucanian and Aimaras groups). A higher prevalence has been reported in twin pregnancies (20–22%) and subsequent to in vitro fertilization treatment (2.7 vs 0.7%) [24]. ICP is characterized by pruritus, elevation of serum total bile acids (TBAs) and mild elevations of other liver function tests, and increased rates of adverse fetal outcomes. Pruritus typically develops without jaundice (pruritus gravidarum) and occasionally in conjunction with jaundice (intrahepatic jaundice of pregnancy or obstetric cholestasis). There is a family history of ICP in approximately half of the cases, and associations with multiple gestation pregnancy and hepatitis C have been reported [25,28]. Hepatitis C seropositivity increases the risk of ICP, and has been associated with early onset of the disease. Associations with other pregnancy-related disorders, such as pre-eclampsia, acute fatty liver of pregnancy and gestational diabetes, indicate that these disorders may increase the risk for ICP [24]. ICP can recur in 40–60% of subsequent pregnancies or with oral contraceptives [29]. Disease severity in subsequent pregnancies cannot be predicted by the course in previous pregnancies [24].

Pruritus may precede or lag behind the laboratory abnormalities of the disease. It worsens as the pregnancy advances, and typically resolves within 48 h of delivery. It usually affects the palms and soles and extends to the legs and abdomen, but often becomes generalized or affects other areas. There are no dermatological signs other than excoriation marks, and the absence of primary skin lesions helps to differentiate ICP from specific dermatoses of pregnancy (Box 1). Constitutional symptoms, such as anorexia and malaise, may be present, as well as mild nausea and discomfort in the upper right quadrant. Mild jaundice (10–15%) can develop 2–4 weeks after the onset of pruritus, and may be associated with subclinical steatorrhea and increased risk of intra- and post-partum hemorrhage [29]. Unlike the pruritus, jaundice does not worsen with advancing gestation [24]. ICP may be preceded by a urinary tract infection that may precipitate the onset of this syndrome. Up to half of patients develop dark urine and light-colored stools, and steatorrhea may occur.

Diagnosis & etiopathogenesis

Elevation of serum TBAs, primarily the conjugated fraction, is the most sensitive biochemical marker of ICP [28,29], and the most suitable parameter for monitoring the disease. The serum cholic acid level increases, and an increase in the ratio of cholic acid to chenodeoxycholic acid is considered to be the most sensitive indicator for the early diagnosis of ICP. A decreased glycine-to-taurine ratio is typically seen. Biochemical abnormalities are those of a cholestatic syndrome, and include a mild elevation of transaminases, alkaline phosphatase, cholesterol and triglycerides; the conjugated bilirubin is elevated (2–5 mg/dl) in jaundiced patients. Malabsorption of fat may cause vitamin K deficiency and a prolonged prothrombin time. The laboratory abnormalities of ICP normally resolve within 2–8 weeks postpartum.

The etiopathogenesis of ICP is complex, and current investigations suggest interactions among hormonal, immunologic, genetic, environmental and alimentary factors [25]. Estrogens interfere with bile acid secretion, and progestins inhibit hepatic glucuronyltransferase. Enhanced cell-mediated (Th1 type) reaction [30], as well as increased IFN-γ, natural killer cells and natural killer T cells, and decreased T cells in decidual parietalis have been reported [31]. Genetic factors have been suggested by the clustering of ICP within families and certain ethnic groups, worldwide variations and a higher prevalence in mothers of patients with progressive familial intrahepatic cholestasis or benign recurrent intrahepatic cholestasis. Notably, several women with ICP have been positive for mutations in the ABCB4 gene, which encodes the multidrug resistance protein 3 [32], a canalicular phosphatidylcholine translocase. Environmental factors that may be implicated in the etiology of ICP include: reduced serum selenium levels; an increased incidence of ICP in the winter months; associations with hepatitis C and urinary tract infections; a higher incidence of drug sensitivities, especially to antibiotics, in the ICP population [24]; and increased gut permeability (‘leaky gut’) [33].

Management

The aims of pharmacologic treatment are to reduce symptoms and biochemical abnormalities in the mother and improve fetal outcome. Treatment with topical antipruritic medications, emollients and oral antihistamines is minimally helpful. Epomediol, silymarine, S-adenosyl-L-methionine, activated charcoal, phenobarbital and guar gum have met limited success [25,34,35]. UVB has been variably helpful (anecdotal). Dexamethasone inhibition of fetoplacental estrogen synthesis has shown promising results [36,37], but in a recent randomized placebo-controlled trial [38], dexamethasone produced no alleviation of pruritus or reduction of serum levels of alanine aminotransferase, and was less effective than ursodeoxycholic acid (UDCA) in reducing TBAs and bilirubin. Furthermore, repeated high doses of dexamethasone have been associated with decreased birthweight and abnormal neuronal development [39,40]. Cholestyramine (up to 18 g/day) can be effective in mild-to-moderate ICP, but needs to be administered for several days before pruritus control can be achieved, and is often associated with a rebound of pruritus after the first week of treatment [25]. Furthermore, cholestyramine has no effect on serum TBAs and other biochemical abnormalities of ICP [34], and has not been reported to improve fetal outcome. As cholestyramine can deplete the levels of vitamin K, it should be administered in conjunction with weekly vitamin K supplementation [25] so that the risk of hemorrhage for the mother and fetus is minimized.

Ursodeoxycholic acid is currently the most effective pharmacologic treatment for ICP and has the most benefit for mother and fetus. UDCA reduces TBAs in cord blood, colostrum and amniotic fluid. UDCA exerts its beneficial effects in a multitude of mechanisms [41–44]. The author’s meta-analysis [29] of randomized controlled trials demonstrated that UDCA (450–1200 mg/day) is highly effective in alleviating the pruritus and normalizing the laboratory abnormalities associated with ICP [28,45]. UDCA has been more effective than S-adenosyl-L-methionine [45,46], and has shown a synergistic effect with it [45,47,48]. Other authors have reported a synergistic effect of UDCA with rifampicin, but further confirmation is required [49]. Compared with cholestyramine, UDCA is safer, works faster, has a more sustained effect on pruritus and shows higher efficacy in improving the liver function abnormalities of ICP [25]. In addition, babies are delivered closer to term by patients treated with UDCA than those treated with cholestyramine [50]. UDCA has been safe for both mother and fetus, and may decrease the fetal risks associated with ICP [51], as well as exert a cardioprotective effect on the fetus [52].

Complications

Maternal risks include intra- and post-partum hemorrhage secondary to vitamin K malabsorption, and a higher risk for gallstones and recurrence of ICP with oral contraceptives, particularly those with a high estrogen content. Fetal risks include fetal distress (22–33%), stillbirth (0.4–4.1%), preterm delivery (44%) associated with an increased prevalence of cesarean section, and meconium staining (16–58%) [24,53]. Acute onset of fetal compromise (22%) and intrauterine demise (2%) have been well-documented complications. The frequency of these risks in a British study was lower than historically reported [54]. Untreated ICP is associated with increased perinatal mortality (11–20% in older studies) [55]; the perinatal mortality was reduced to less than 3.5% in recent studies that employed policies of active management [24]. A 2.5-fold increase in neonatal respiratory distress syndrome has been reported [56]. Early onset of pruritus and high TBA levels have been associated with preterm delivery and poor neonatal outcome [57]. A study from Sweden found a correlation between maternal serum TBA levels and fetal complication rates [58].

Most authors believe that the fetal complications are related to bile acid accumulation in the fetal compartment. Decreased fetal elimination of toxic bile acids can cause vasoconstriction of placental chorionic veins and increased myometrial contractility; the latter may be implicated in preterm delivery [59]. Bile acids increase colonic motility, and their presence in meconium may explain the observed umbilical vein constriction that meconium causes. Interestingly, meconium staining of amniotic fluid has been reported in all cases affected by intrauterine death. Experimental studies demonstrated that elevated levels of the bile acid taurocholate in the fetal circulation may cause fetal dysrhythmia and sudden intrauterine fetal death. Researchers have shown an association between neonatal respiratory distress syndrome and maternal serum TBAs, and suggested that bile acids may cause ‘bile acid pneumonia’ in near-term neonates [60]. Exposure time and TBAs are important independent factors for predicting respiratory distress syndrome and fetal asphyxia [60,61]. Malabsorption of vitamin K increases the risk of intracranial hemorrhage, and most authors suggest prophylactic administration of vitamin K. Most authors support starting treatment with UDCA, which has been shown to decrease fetal risks, in all patients with ICP after confirmation of the diagnosis.

The risk of serious fetal complications makes intensive fetal surveillance mandatory, although it remains unclear which clinical and/or laboratory parameters predict intrauterine death [62]. At present, no test reliably predicts the risk of fetal demise. Many different protocols for intensified surveillance have been proposed [55,63,64]. Some authors recommend fetal surveillance, including weekly nonstress cardiotocography or biophysical assessment, from the 34th week of gestation [55]. If gestational age is less than 36 weeks, one should monitor fetal well-being, TBAs and liver function tests, and consider delivery at 36–37 weeks with fetal maturity or continue surveillance if liver function tests improve. Delivery around 36 weeks or earlier, if lung maturity is achieved and cervix favorable, should be considered for severe cases with jaundice, progressive elevations in serum TBAs and suspected fetal distress [64]. If gestational age is more than 36 weeks, amniocentesis and delivery should be considered if cervix is favorable and fetal lung maturity satisfactory. A recent literature review advocated the induction of labor between 37 and 38 weeks’ gestation in order to reduce the incidence of stillbirth, as the vast majority of stillbirths cluster around the 38th week of gestation [65]. There is a general agreement that all women with ICP should deliver no later than at 37–38 weeks of gestation [62]. Most authors consider the iatrogenic risks associated with active management (greater incidence of failed induction and instrumental delivery) less serious than the risk of intrauterine death posed by intensive surveillance and spontaneous onset of labor. Nevertheless, a British study indicated substantial iatrogenic risks, and that there is insufficient data to support the practice of ‘early’ induction of labor (37 weeks) aimed at reducing late stillbirth [42].

Challenges & controversies

Genetic research has not led to better prediction of the course of ICP, but genetic risk profiling may help stratify cases at the time of diagnosis that are associated with increased fetal risks [53]. The active obstetrical management at term has been debated, and the most suitable monitoring modalities need to be determined. At present, there are no laboratory and/or clinical parameters that can reliably predict the risk of fetal demise. It needs to be clarified which fetuses are at highest risk, and which pregnancies may most benefit from active management.

Specific dermatoses of pregnancy

The classification of specific dermatoses of pregnancy into HG, PEP (pruritic urticarial papules and plaques of pregnancy), prurigo gestationis and PFP has been accepted by most authors (Table 1)[66]. A recent reclassification [1] that included ICP in the specific dermatoses of pregnancy and grouped AD, prurigo gestationis and PFP under AEP (Table 1) was debated [2] (see sections on AD and ICP). The differential diagnosis of specific dermatoses of pregnancy is shown in Box 1.

Herpes (pemphigoid) gestationis

Epidemiology & clinical features

The prevalence of HG ranges from one in 7000 to one in 50,000 pregnancies. Although there is a lack of population studies, HG may be more common in Caucasian individuals [67,68]. HG may exceptionally present itself as paraneoplastic syndrome of choriocarcinoma or molar pregnancy [69], and in these cases the course of the cutaneous disease parallels that of the tumor. The disease starts typically in the second or third trimester (mean onset at 21 weeks) or the immediate postpartum period (14–25% of cases) [70]; onset of HG as late as 35 days postpartum has been reported [71]. HG starts in more than half of cases in the umbilicus and/or periumbilical area, with severely pruritic urticarial papules and plaques that may become targetoid or polycyclic, and spread onto other areas of the trunk and extremities, often involving palms and soles [72]. A generalized bullous eruption follows within days to weeks. Tense bullae develop in both urticarial lesions and clinically normal skin, and typically heal without scarring. The bullous eruption can affect palms and soles, but only exceptionally the face, neck and mucous membranes. Pustules are rarely encountered. HG runs a variable clinical course. There is often a relative quiescence in late pregnancy, followed by a flare at the time of delivery or in the immediate postpartum period in 75% of cases.

Herpes (pemphigoid) gestationis usually subsides spontaneously even without treatment through the weeks to months after parturition, but a protracted course has been reported in exceptional cases; the medium duration of postpartum flares is 28 weeks [71]. A ‘conversion’ to bullous pemphigoid (BP) has been reported [73,74]. Chronic HG, defined as lasting more than 6 months postpartum, has been reported in fewer than 20 cases [72,74–79]. HG often recurs in subsequent pregnancies, usually appearing more severe and earlier in gestation, and lasting longer postpartum [68]. ‘Skip pregnancies’, however, have been reported (8%) [71,80] and were attributed to a male consort change or expression of identical HLA-DR antigens by mother and fetus [80]. Nevertheless, several ‘skipped pregnancies’, despite constant paternity and nonidentical HLA-DR alleles, have been reported [81,82]. Premenstrual exacerbations have been reported, and may last for months to years. Recurrence with oral contraceptives has been documented in as many as half of patients with a history of HG who subsequently took oral contraceptives [80,83]. Recurrence typically starts within days to weeks after initiation of oral contraceptive use and disappears after their withdrawal [68]. The effects of breastfeeding and prolactin on the postpartum duration of HG have been poorly clarified, although breastfeeding may help reduce the postpartum duration of the disease [80,83].

Diagnosis & etiopathogenesis

Histopathology of early urticarial lesions shows a spongiotic epidermis, marked papillary dermal edema with teardrop-shaped dermal papillae and a mixed perivascular lymphohistiocytic infiltrate with numerous eosinophils [26]. A subepidermal blister with a large number of eosinophils in the blister cavity develops during the bullous phase of HG as a result of focal necrosis of basal keratinocytes [70,71]; this type of necrosis is seen less often in BP. Direct immunofluorescence (DIF) of lesional, perilesional and uninvolved skin typically shows heavy linear C3 deposition along the basement membrane zone (BMZ) in virtually all patients [26]. IgG deposition is found in approximately 25–50% of cases. DIF differentiates HG from PEP (negative in PEP). DIF may remain positive for 6 months to 4 years after clinical remission [80]. Salt-split skin testing shows that the antibody binds to the roof of the vesicle. Conventional indirect immunofluorescence detects C3 in patients’ sera in more than 90% of cases and IgG in less than 25% of cases. However, IgG is positive in all patients’ sera when a three-step, complement-binding indirect immunofluorescence is used [68]. Similar linear deposition of C3 and IgG has been observed in the skin of neonates of affected mothers and along the BMZ of amniotic epithelium [68]. Immunoelectron microscopy demonstrates that the deposits of C3 and IgG are localized to the upper lamina lucida beneath the plasma membrane.

Immunopathologically, HG is closely related to the BP group of diseases. Genetic susceptibility is evidenced by associations with MHC class II HLA antigens DR3 (61–85%), DR4 (52%) or both (43–45%), and the detection of the C4 null allele in most patients [70]. Anti-HLA antibodies are found in 85% of patients with a history of HG, compared with 25% in a control group of normal multiparous women, but their significance remains uncertain [68]. The pathogenically relevant antibody in HG belongs to the IgG1 subclass and can activate complement through the classical pathway. However, a study by Patton et al. demonstrated predominance of the IgG4 subclass in lesional skin, a finding that mimics classic BP [84]. The major pathogenic antigen is the BP antigen 2 (collagen XVII), a 180-kd hemidesmosomal glycoprotein [85]. Reactivity against both BP antigen 2 (180-kd) and antigen 1 (240-kd) has been detected in 10% of patients. Autoantibodies recognize epitopes in the noncollagenous domain (NC16A) of the transmembrane BP-180 antigen [86], although other epitopes on the intracellular and/or extracellular domains of the BP-180 antigen may occasionally be targeted [87]. Epitopes within the NC16A domain pathogenically relevant for blister induction have been identified with immunoadsorption [88]. A case of HG with predominantly oral lesions and IgA autoantibodies targeting the C-terminus of BP-180 antigen was reported [89]. Serum antibody titers with conventional indirect immunofluorescence do not correlate with the course of disease and may remain low-positive even after the eruption resolves. Serum autoantibody levels, however, paralleled disease activity when BP-180 NC16A-ELISA was used [90], which indicates that ELISA can serve as a monitor marker and guide treatment decisions. ELISA has shown higher sensitivity and specificity than indirect immunofluorescence in several studies [91], and was very useful in differentiating HG from PEP [92].

Early studies demonstrated that the antigen-specific T lymphocytes express a Th1 cytokine profile [93], but a subsequent study showed a population of Th2-type cells in the inflammatory infiltrate in lesional skin that may be implicated in the very early stages of the disease [94]. Several authors postulated that an immunologic response occurs against aberrant expression of MHC class II molecules of probable paternal origin in the placenta or, alternatively, an allogeneic reaction of placental stromal cells to 180-kd antigen in the context of paternal MHC molecules that can bypass antigen-specific helper responses; the antibody subsequently cross-reacts with the homologous maternal antigen in the BMZ of the skin [89,95]. Nevertheless, a recent study demonstrated that BP-180 is expressed by both syncytial and cytotrophoblastic cells of human placenta and epithelial cells of the amniotic membrane during the first trimester of pregnancy, and the clinical symptoms of HG occur after the expression of autoantigen in the placenta [96]. Therefore, exposure to the antigen alone cannot be the trigger for the induction of HG. The earlier onset of HG in subsequent pregnancies could be explained by the presence of autoantigen in the placenta during the first trimester.

Management

Oral corticosteroids remain the mainstay of treatment in HG, and the vast majority of patients respond to oral steroids within a few days. Potent topical steroids may be helpful only in early urticarial lesions or premenstrual flares, but can be associated with systemic absorption and local side effects. Most patients are started at low prednisone doses (20–40 mg daily in divided doses), and dosage is then titrated according to clinical response. In severe cases, prednisone doses as high as 180 mg/day have been used, although high doses of steroids may represent a risk factor for premature rupture of membranes, preterm delivery, maternal side effects and intrauterine growth retardation [97]. Once new blister formation has been suppressed, prednisone should be tapered preterm to lower doses (5–10 mg/day) or even discontinued. The dosage should be increased or steroid therapy resumed shortly after delivery to control the anticipated flare of the disease. Prednisone is considered relatively safe during gestation, but other steroids, such as betamethasone and dexamethasone, which can cross the placenta, are toxic for the fetus and should be avoided [70]. Postpartum prednisone at doses of up to 20 mg/day allows safe breastfeeding.

Alternative treatments need to be considered in postpartum recalcitrant or chronic HG because of the serious adverse effects of long-term steroid therapy. Minocycline or doxycycline, in combination with nicotinamide, have been successfully used in nonbreastfeeding mothers with refractory HG [98,99]. High-dose intravenously administered IgG in combination with cyclosporine or other immunosuppressant medications has shown some success [75,100]. Several cases of recalcitrant HG have been treated with cyclophosphamide, azathioprine, plasmapheresis, immunoapheresis, chemical oophorectomy with goserelin, ritodrine and rituximab [29,72,78,101–103]. Immunosuppressive and anti-inflammatory agents, such as pyridoxine, sulfapyridine, gold, methotrexate or dapsone, have been used postpartum in refractory cases [26,29,72,104], but are rarely used nowadays because they have been neither consistently effective nor safe, and their use is limited to non-nursing patients. Most authors advocate against early delivery because the fetal risks seem to be mild. The pregnant patient should be counseled that there is no evidence that any treatment can prevent the fetal risks associated with HG, which seem milder than previously thought. Fetal surveillance should include monitoring for growth retardation with periodic ultrasounds, and in case growth restriction is confirmed, obstetric management and decisions on early delivery should follow the guidelines for small-for-gestational age infants [70].

Complications

The mother is at an increased risk of Graves’ disease (10–11% of patients, compared with 0.4% in controls), which does not develop simultaneously with HG [68,70]. Other maternal risks include only those associated with side effects of pharmacologic treatments. Associations with small-for-gestational age weight at birth and preterm delivery (20%) have been reported [105], as well as a borderline increase in spontaneous abortions [71]. A case of fetal cerebral hemorrhage and a case of neonatal convulsions associated with HG in the neonate have been reported [106]. A recent study indicated that early onset of HG and blister formation are associated with adverse pregnancy outcomes [107]. The fetal risks may not decrease with treatment and are thought to be due to low-grade placental insufficiency [29,68]. Huilaja et al. suggested that BP-180 autoantibodies may induce epithelial–stromal microseparation in placenta, which may lead to minor functional failure and explain the mild fetal complications seen in some HG newborns [96]. Neonatal HG is mild and occurs in up to 10% of cases [108]. Neonatal disease develops as a result of passive transplacental transfer of HG antibody and typically resolves spontaneously in the course of days to weeks after onset, even before the maternal antibodies clear from the neonate’s blood. Interestingly, the titer of pathogenic antibody transferred to the neonate is almost the same as that found in the mother [109]. There is a significant risk of skin infection in neonatal HG that should be treated promptly. Infants born to affected mothers who were treated with high and/or long courses of systemic steroids should be examined by a neonatologist for adrenal insufficiency [97].

Challenges & controversies

Although there has been controversy about the fetal risks in HG, most recent studies indicate that these risks are manageable and the fetal/neonatal prognosis remains good. The role of paternal antigens remains controversial, and whether the high prevalence of anti-HLA antibodies supports the theory of ‘paternal factor’ remains unclear. Because of the rarity of HG, a stratification of pregnancies to low- or high-risk for fetal complications has not been possible. For the same reason, planning prospective studies on the treatment of disease has not been feasible, and therefore guidelines on management cannot be established. However, a better understanding of the pathogenesis of the disease has been achieved, and may help develop new therapeutic options. Collective data from epidemiologic studies in different ethnic groups are needed in order to clarify questions related to genetic predisposition and factors that may trigger recalcitrant or chronic HG [70].

Polymorphic eruption of pregnancy (pruritic urticarial papules & plaques of pregnancy)

Epidemiology & clinical features

Polymorphic eruption of pregnancy is the most common specific dermatosis of pregnancy, and affects between one in 160 and one in 240 pregnancies. The term ‘pruritic urticarial papules and plaques of pregnancy’ is still used in American and Australian literature. PEP has been primarily reported in Caucasian females, and its prevalence in other ethnic groups is not well studied. It occurs predominantly in primigravidas (80%) in the third trimester (mean onset at 35 weeks), and less often in other trimesters or postpartum [110,111]. High prevalence (55%) of family and/or personal history of atopy and allergic asthma (11%) have been reported and need to be further investigated [111,112]. PEP has been associated with a predominance of male infants (55%) in two studies [3,112]. This pruritic eruption starts on the abdomen and proximal thighs in 91% of cases, and 80% of patients will subsequently develop involvement of upper extremities and other areas of the trunk. Lesions usually spare the face, neck, palms and soles. The lesions characteristically start within or adjacent to the abdominal striae (striae gravidarum) in two-thirds of cases, and typically demonstrate periumbilical sparing [26,29]. The lesions are usually urticarial (49%), but the eruption often becomes polymorphous, showing vesicular (17%), targetoid (6%), polycyclic (6%) or purpuric lesions [112]. Excoriations and eczematous features (22%) are common [112]. Dyshidrosis-like lesions on the palms and soles, predominance of confluent vesicular lesions on the extremities, koebnerization and photodistribution have been exceptionally reported [113–115]. Generalized PEP with extensive desquamation may resemble a toxic erythema. The presence of polymorphous lesions may increase with disease duration, and an association between nonurticarial morphology and disease duration of more than 6 weeks has been reported [112]. The eruption resolves spontaneously or with delivery.

Diagnosis & etiopathogenesis

Skin histopathology is usually nonspecific, and demonstrates epidermal changes (spongiosis, parakeratosis, acanthosis and exocytosis), especially in older lesions or those with polymorphous morphology, as well as upper dermal edema and a perivascular or dermal lymphohistiocytic infiltrate with variable numbers of eosinophils [26]. Eosinophil infiltration is prominent in a third of cases, but is overall less prominent than in HG [116]. DIF and serologic screenings for circulating autoantibodies have been almost invariably negative, and a decrease in serum cortisol in one study [3] has not been corroborated by others.

The etiopathogenesis of PEP has not been clarified. Immunohistochemical studies have not provided us with consistent results. One study demonstrated an infiltrate composed primarily of T-helper lymphocytes, as well as activated T cells in the dermis, dermal dendritic cells and epidermal Langerhans cells in lesional skin [117]. This profile, as well as the strong HLA-DR expression, may indicate an activation of the skin immune system to an unknown antigen. Caproni et al. demonstrated a predominant role of Th1-oriented CD8⁺ lymphocytes in PEP compared with a predominant Th2 profile (CD4 cells) in HG [118], and suggested that the Th1 pattern in PEP may indicate the involvement of a graft-versus-host-like reaction in the pathogenesis of PEP. The authors, however, had shown in a previous study a stronger expression of HLA-DR by a wider spectrum of cells, and the T cells express a more heterogeneous profile as they are able to secrete Th1- and Th2-like cytokines [94]. The eosinophil involvement was greater in HG compared with PEP in one study [119], but this was not found in another study in which only two out of six HG patients had urticarial lesions [118].

Several hypotheses regarding trigger factors in PEP have been proposed. The characteristic localization of lesions to abdominal striae and associations with multiple gestation pregnancy [29,120], abnormal weight gains in the mother and fetus [121] and maternal obesity [122] made several authors postulate that the rapid abdominal wall distention in primigravidas during the latter part of pregnancy may damage the connective tissue within striae, and thus provoke an inflammatory reaction [120,121]. Nevertheless, the association with excessive maternal and fetal weight gains has been debated [123,124]. A meta-analysis by the author that revealed a tenfold higher prevalence of multiple gestation pregnancy in patients with PEP [29] and a retrospective study [120] lend support to this hypothesis. Furthermore, multiple gestation pregnancy, as frequently seen in patients with PEP, is associated with high levels of progesterone that can aggravate the inflammatory process at the tissue level, possibly through expression of progesterone receptors by keratinocytes. A study that showed increased progesterone receptor reactivity in skin lesions of PEP supports the role of hormonal factors in the pathogenesis of disease [125]. Other authors suggested that in the third trimester, the aging placenta may release in the maternal circulation a hormonal substance that induces fibroblast proliferation in maternal skin, but the evidence for this theory is scarce [126].

An unexpectedly high prevalence (55%) of personal and/or family history of atopy was found in a recent study [112], but has not been corroborated by other studies. The authors reported IgE elevation in 28% of PEP cases (uncontrolled), but the significance and specificity of IgE elevations in pregnancy remain unclear [2]. Finally, a small study demonstrated male fetal DNA in skin lesions of PEP [127], and the authors postulated that it can result from fetal cell migration to maternal skin secondary to peripheral blood chimerism, a phenomenon that is known to start early in gestation and increases as pregnancy progresses. This theory is supported by other studies that show the presence of male fetal progenitor cells in maternal circulation for up to 27 years postpartum [128], and a case of recurrent PEP-like lesions in a female 28 years after her last pregnancy [129]. Although the precise link between microchimerism and PEP remains unknown, an immunohistochemical study demonstrated predominance of CD8⁺ T cells in lesions of PEP, which could be chimeric, and proposed them as an initiator factor, with Th1-like molecules and eosinophils as effector mechanisms [118].

Management

Mild-to-moderate PEP can be treated symptomatically with general measures (cooling baths, emollients and wet soaks to the skin), antipruritic topical medications, mid-potency topical steroids and first-generation oral antihistamines that are considered safe in gestation (chlorpheniramine and diphenhydramine). In cases of severe pruritus and/or when the eruption becomes generalized, a short course of an oral steroid, such as prednisone or prednisolone, may be required, and appears to be relatively safe in the latter part of gestation. The risk of fetal adrenal suppression secondary to a short course of oral steroid is considered low, as evidenced by the fact that the maternal–fetal gradient of prednisolone is 10:1 [130]. UVB has been used successfully by the author [29]. The pregnant female needs to be counseled that PEP is limited in duration, does not usually recur in subsequent pregnancies and does not pose any substantial risks to the fetus or mother.

Complications

The perinatal outcome has been favorable, with fetal deaths being extremely uncommon and possibly coincidental [3,131]. A recent study indicated an association with hypertensive disorders [122], but there is scarce evidence of this association in the literature [131]. In the same study, higher rates of labor induction and subsequent cesarean section were noted in the PEP group, but PEP was not an independent risk factor for cesarean delivery in multivariate analysis. A higher rate of cesarean section was also reported in another study [124].

Challenges & controversies

The etiopathogenesis of PEP remains elusive, but the associations with multiple gestation pregnancy and excessive maternal weight gain, the preponderance of male fetuses and detection of male fetal DNA in maternal skin lesions have opened a new area of investigation in this field. Prospective studies are needed to confirm reported association with atopy. The association with cesarean section in two recent studies needs to be clarified, and may help to identify early in gestation those PEP pregnancies that may necessitate labor induction.

Prurigo of pregnancy

Epidemiology & clinical features

Prurigo of pregnancy affects approximately one in 300 to one in 450 pregnancies. The incidence of PP in non-Caucasian females is unknown. Although PP has been reported in all trimesters, it usually starts at approximately 25–30 weeks’ gestation and persists until delivery. It manifests itself with grouped, intensely pruritic papules over the extensor surfaces of the extremities, and occasionally on the abdomen and elsewhere; with disease progression, the trunk and extremities are equally involved. Excoriations and crusting secondary to scratching are invariably seen [26]. Nodular lesions similar to those of prurigo nodularis in nonpregnant females are often present. The disease usually resolves in the immediate postpartum period, although lesions may occasionally persist for up to 3 months. Recurrence with subsequent pregnancies is variable.

Diagnosis & etiopathogenesis

Prurigo of pregnancy lacks specific histopathologic features and DIF is negative. Serologic tests may show elevated serum IgE levels in a third of patients [3]. PP has been associated with ICP [132] or family history of ICP [133]. It has been speculated that PP and ICP are closely related entities [3], and may be different levels of severity of the same condition [134]. Holmes and Black were the first to suggest that PP may not be a distinct entity, and could result from pruritus gravidarum in women with an atopic predisposition [66]. Subsequently, Black’s group reported an association with personal or family history of AD (four out of 12 patients), and elevation of serum IgE (five out of 12 patients; uncontrolled) [3]. The group recently suggested that PP should be classified under AEP [1], although four out of 49 PP patients in the most recent study of the group fulfilled only minor criteria of atopy [8]. Nevertheless, there has been no history of AD or established atopic background in some PP patients [3,29,133], and associations with ICP have been reported [132,133]. The association with atopy has not been confirmed by other groups, and the importance of mild serum IgE elevations in pregnancy has been debated [2], as the IgE regulation in pregnancy is complex and still poorly understood. The above may indicate the heterogeneity of pathogenetic mechanisms involved in PP.

Management

Treatment for symptomatic relief typically requires moderately potent topical steroids, if necessary intralesional or under occlusion, and oral antihistamines that are safe in gestation [26]. Cooling baths and antipruritic topical medications, such as aqueous cream with 1–2% menthol, are helpful with pruritus. A short course of oral steroid may be necessary in cases of recalcitrant pruritus [3]. The pregnant patient should be counseled that PP has not been associated with fetal risks.

Complications

Fetal outcome is not affected in PP, and the birthweight remains normal. The disease has not been associated with any maternal risks if pharmacologic treatment is administered in a safe way, and may recur in subsequent pregnancies.

Challenges & controversies

As PP remains one of the less well-defined pregnancy dermatoses, its etiology and clinical associations can only be clarified with prospective large-scale clinical studies. The associations with atopic disease/background and ICP warrant further investigation.

Pruritic folliculitis of pregnancy

Epidemiology & clinical features

Pruritic folliculitis of pregnancy is a rare specific dermatosis of pregnancy (more than 30 cases reported). Its incidence in various ethnic groups is unknown. PFP, originally reported by Zoberman and Farmer [135], presents with sparse mildly to moderately pruritic, follicular and/or acneiform-looking, erythematous papules and pustules that predominantly affect the trunk [136]. The eruption resolves spontaneously by delivery or 1 month postpartum, and may recur in subsequent pregnancies [135].

Diagnosis & etiopathogenesis

Histopathology is that of sterile folliculitis, with special stains for microorganisms being negative. The inflammatory infiltrate contains lymphocytes and neutrophils, as well as sparse eosinophils, plasma cells and giant cells. DIF and serology are negative, and levels of sex hormones are normal for gestational age. The etiopathogenesis of PFP is unknown. There is no evidence of immunologic abnormalities [136]. It has been suggested [137] that PFP may be a form of hormonally induced acne, similar to steroid acne, based on clinical similarities, an association with increased serum androgen levels [137] and the fact that one patient with PFP had a similar eruption while on danazol [135]. Nevertheless, PFP lacks a comedonal component that is typically seen in steroid acne, and measurement of serum androgen levels in a series of PFP patients showed no increase when compared with controls [138]. However, it is possible that PFP may result from end-organ hypersensitivity to normal pregnancy levels of sex hormones. An association with ICP [139] may have been coincidental. Other authors [133] have postulated that PFP can be a variant of PEP, but the clinicopathologic features of PFP differ from those of PEP. A recent study classified PFP under AEP on the basis of PFP in a patient with a personal and family history of eczema. Nevertheless, out of more than 30 PFP cases that have been reported, only one has been associated with a history of atopy [1]. A suggestion that PFP can be caused by Pityrosporum[140] was debated [141].

Management

Pruritic folliculitis of pregnancy has been treated with benzoyl peroxide, mild-to-moderate topical steroids, other topical antipruritic medications and narrow-band UVB [135,142]. The pregnant patient should be counseled that PFP resolves spontaneously by delivery or postpartum, and has not been associated with any adverse prognostic effect on the mother or fetus.

Complications

Associations with a decreased birthweight and a male-to-female ratio of 2:1 in the largest series of PFP [3] are difficult to confirm retrospectively because of the rarity of the condition. Cases of preterm delivery with cesarean section [142] and threatened preterm labor [133] have been reported, but no fetal distress or other fetal risks.

Challenges & controversies

Pruritic folliculitis of pregnancy is a rare, ill-defined, specific dermatosis of pregnancy, the etiology of which remains elusive, and its status as a distinct entity has been challenged. Because of the rarity of the disease, clinical associations, such as the association with atopy, have not been confirmed.

Expert commentary

Recent large studies have not addressed whether it is intrinsic (‘nonallergic’) and/or extrinsic (IgE-associated) eczema that is affected by pregnancy [1,3]. The median IgE elevation in these studies was mild, thus suggestive of intrinsic/constitutional eczema. This is supported by a small study that indicated that it is the intrinsic eczema that is affected by pregnancy, and found no statistically significant differences in the total serum IgE levels between the patient group that experienced deterioration of symptoms in pregnancy and the patient group that did not [4]. This data indicates that the etiopathogenesis of AD in pregnancy may not be primarily related to the induction of IgE and/or it is the intrinsic eczema that is mostly affected by pregnancy. Based on the above, and since the IgE regulation in pregnancy remains unknown, total serum IgE measurements may not be used as diagnostic criterion for gestational AD, and studies into allergen-specific IgE levels are required. These studies will examine whether there is a role for environmental and/or food allergens in the pathogenesis of gestational AD. Despite a proposed reclassification of PP and PFP under AEP based primarily on the clinical history of these patients [1], there are still differences among these disorders, and the notion of AEP encompassing other specific dermatoses of pregnancy remains contentious, especially since some PP patients and the vast majority of PFP patients did not have an atopic background. The suggestion of an overlap among these entities is valid, but the question of whether to lump or split them still remains [2]. These issues cannot be addressed satisfactorily until the diagnostic criteria for gestational AD are refined and more light is shed into its etiopathogenesis and IgE regulation in pregnancy. Future research studies in the genetics of atopy may help stratify pregnancies to low- or high-risk for AD deterioration. Large-scale prospective studies are required to establish the etiopathogenesis of PEP and HG, optimal obstetric management in ICP and guidelines on management of HG.

Five-year view

There is a growing notion that an overlap between clinical entities, such as AEP, PP and PFP, may occur. In order to validate this concept, the diagnostic criteria for AD in pregnancy first need to be refined. It is expected that some issues will be further clarified – that is, how often pregnancy induces ‘new eczema’, whether it is instrinsic and/or extrinsic (IgE-associated) eczema that are affected by gestation, and whether pregnant patients with ‘new eczema’ may continue to experience AD flares after pregnancy. IgE regulation during pregnancy is currently unknown, and further studies will help elucidate this, as well as determine whether mild IgE elevations, such as those seen in AD and occasionally other gestational dermatoses, are related to atopy or, instead, to ‘non-atopy relevant’ mechanisms. In the years to come, we may know better whether there is a role for environmental and/or food allergens in the pathogenesis of gestational AD. The obstetric management guidelines for ICP will be further refined, and a consensus among groups should be expected. The etiopathogenesis of PEP and less well-defined entities, such as PP and PFP, may be further clarified through prospective large-scale studies, which will also help elucidate the relationship between these dermatoses and AD.

Table 1. Established and recent classifications of specific dermatoses of pregnancy.

Established classification [66]	Recent reclassification [1]
Herpes (pemphigoid) gestationis	Herpes (pemphigoid) gestationis
Polymorphic eruption of pregnancy^†	Polymorphic eruption of pregnancy
Prurigo of pregnancy	Atopic eruption of pregnancy^‡
Pruritic folliculitis of pregnancy	Intrahepatic cholestasis of pregnancy

^†Also called pruritic urticarial papules and plaques of pregnancy.

^‡Atopic eruption of pregnancy includes atopic dermatitis in pregnancy, prurigo of pregnancy and pruritic folliculitis of pregnancy.

Box 1. The differential diagnosis of the entities discussed.

Atopic dermatitis

• • Intrahepatic cholestasis of pregnancy

• • Polymorphic eruption of pregnancy

• • Prurigo of pregnancy

• • Pruritic folliculitis of pregnancy

• • Drug eruption

• • Infestations (i.e., scabies)

Intrahepatic cholestasis of pregnancy

• • Atopic dermatitis

• • Systemic disease with pruritus but no eruption (lymphoma, liver, renal and thyroid disease)

• • Polymorphic eruption of pregnancy

• • Prurigo of pregnancy

• • Pruritic folliculitis of pregnancy

• • Hyperemesis gravidarum complicated with cholestasis

• • Striae gravidarum with pruritus but no eruption

Herpes (pemphigoid) gestationis

• • Polymorphic eruption of pregnancy

• • Bullous disease

• • Drug eruption

• • Erythema multiforme

Polymorphic eruption of pregnancy

• • Atopic dermatitis

• • Drug eruption

• • Intrahepatic cholestasis of pregnancy

• • Prurigo of pregnancy

• • Pruritic folliculitis of pregnancy

Prurigo of pregnancy

• • Atopic dermatitis

• • Intrahepatic cholestasis of pregnancy

• • Pruritic folliculitis of pregnancy

• • Prurigo nodularis

Pruritic folliculitis of pregnancy

• • Infectious folliculitis

• • Atopic dermatitis

• • Polymorphic eruption of pregnancy

• • Prurigo of pregnancy

• • Impetigo herpetiformis

Key issues

• • Atopic dermatitis (AD, ‘atopic eruption of pregnancy’) is the most common pregnancy dermatosis. The high prevalence of AD, especially ‘new eczema’, in pregnancy in recent studies needs to be confirmed by future studies, as the diagnostic criteria for gestational eczema have not been adequately defined.

• • Increased levels of serum bile acids is the hallmark of intrahepatic cholestasis of pregnancy (ICP). Ursodeoxycholic acid is first-line treatment, and may decrease fetal risks in ICP (distress, stillbirth and preterm delivery). A consensus on the obstetric management in ICP has not been reached.

• • Positive direct skin immunofluorescence is the hallmark of herpes (pemphigoid) gestationis (HG), and systemic steroids is first-line treatment for the disease. Fetal risks in HG include small-for-gestational age infants, preterm delivery and neonatal pemphigoid gestationis.

• • Polymorphic eruption of pregnancy (PEP) most commonly starts in the abdominal striae and shows periumbilical sparing. It occurs primarily in primigravidas and is associated with multiple gestation pregnancy.

• • PEP, prurigo (PP) and pruritic folliculitis of pregnancy (PFP) present with no maternal or fetal risks, and their etiopathogenesis remains elusive. It has been suggested that PP and PFP may be classified under ‘atopic eruption of pregnancy’.

• • Dermatologists, obstetricians and primary care practicioners should be aware of the clinical characteristics of these disorders and the potential maternal/fetal risks associated with them.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Specific dermatoses of pregnancy: advances and controversies

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

	1	2	3	4	5
1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
4. The activity was presented objectively and free of commercial bias.

1. A 28-year-old woman who is pregnant for the first time has a history of atopic dermatitis (AD). Which of the following best describes the likelihood of deterioration of the condition during pregnancy?

• □ A 15%

• □ B 25%

• □ C 36%

• □ D 46%

2. A 34-year-old woman with a family history of intrahepatic cholestasis of pregnancy (ICP) is concerned about her own risk of developing ICP during pregnancy. Which of the following is least likely to be a risk factor for ICP in her future pregnancy?

• □ A Twin pregnancy

• □ BIn vitro fertilization

• □ C Hepatitis B seropositivity

• □ D Family history of ICP

3. Which of the following is considered the least efficacious treatment for pruritis and liver function in women with mild to moderate ICP?

• □ A Cholestyramine

• □ B Dexamethasone

• □ C Ursodeoxycholic acid

• □ D Epomediol

4. A 32-year-old pregnant white woman develops periumbilical pruritic targetoid urticarial papules and plaques that spread to the trunk and palms and soles during the 21st to 22nd gestational week. The rash subsides in the third trimester, but she experiences a flare at delivery and in the immediate postpartum period. Which of the following is the most likely diagnosis?

• □ A Herpes gestationis

• □ B Polymorphic eruption of pregnancy

• □ C Intrahepatic cholestasis of pregnancy

• □ D Pruritic folliculitis of pregnancy

5. Which of the following is considered the safest and most appropriate treatment for herpes gestationis?

• □ A Prednisone

• □ B Dexamethasone

• □ C Betamethasone

• □ D Any of the above