Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015) 1e9
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Skin disease in pregnancy de me decine a, b, *, 1, Boutros Soutou, MD, Faculte lim Aractingi, MD, PhD, Faculte de me decine c, d, 2 Se Facult e de m edecine, Universite saint-Joseph, 11-5076 Riad el Solh, Beirut, Lebanon Centre Hospitalier du Nord, 100 Jdeidet Zgharta, Lebanon c ^pital Cochin Tarnier, 89, rue d'Assas, Facult e de m edecine, Paris 5 descartes, Service de Dermatologie, Ho 75006 Paris, France d Equipe Cellules souches foetales, Inserm UMR S 938 & UPMC, CDR St Antoine, 27, rue de Chaligny, 75012 Paris, France a
b
Keywords: pregnancy skin abnormality polymorphic eruption of pregnancy atopic eruption of pregnancy pemphigoid gestationis impetigo herpetiformis
Skin manifestations during pregnancy are common and diversified. This review will focus on the most important entities to be recognized by obstetricians. These are, on the one hand, physiological changes, where unnecessary investigations should be avoided, and on the other, the specific dermatoses of pregnancy. These develop electively in pregnancy, and they are currently grouped into three disorders: polymorphic eruption of pregnancy, atopic eczema of pregnancy, and pemphigoid gestationis. Arguments for recognition of these are presented including detection of anti-BP180 antibodies. Follow-up and treatment depend on the precise diagnosis. Risks in fetal prognosis may occur in rare pemphigoid gestationis cases. © 2015 Elsevier Ltd. All rights reserved.
Skin disease in pregnancy Dermatological manifestations associated with pregnancy can be grouped into five categories: (i) physiological changes, (ii) pregnancy-specific dermatoses, (iii) cutaneous infections affecting fetal outcome, (iv) various intercurrent dermatoses affected by or affecting pregnancy, and (v) side effects of topical cutaneous treatments and fetal risk of such treatments. These manifestations, mainly
Saint-Joseph, 11-5076 Riad el Solh, Beirut, Lebanon. * Corresponding author. Universite E-mail addresses: [email protected] (B. Soutou), [email protected] (S. Aractingi). 1 Tel.: þ961 3 741478; Fax: þ961 6 555290. 2 Tel.: þ33 1 58 41 18 13; Fax: þ33 1 58 41 17 65. http://dx.doi.org/10.1016/j.bpobgyn.2015.03.005 1521-6934/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Soutou B, Aractingi S, Skin disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.03.005
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physiologic changes and specific dermatoses, will be the focus of this review. They are important to recognize as diagnostic studies and monitoring are mandatory in some disorders while workup is unnecessary in others. Cutaneous physiological changes during pregnancy During pregnancy, the following three main precipitating factors induce the development of skin changes: (i) the increase in the level of circulating hormones, (ii) the intravascular volume expansion, and (iii) the compression from the enlarging uterus. In the skin, almost all cell types such as keratinocytes, melanocytes, fibroblasts, inflammatory cells, and components such as pilosebaceous units, sweat glands, and blood vessels express receptors to the various previously cited secreted molecules. The main subsequent modifications result in an increase in keratinocyte proliferation, angiogenesis, melanogenesis, collagen synthesis, and an increase in T helper 2 (Th2) lymphocytes and regulatory T cells. According to the cell type targeted, the modifications of the skin are divided into pigmentary, vascular, structural, and adnexal changes. These changes are called physiological due to the following reasons: they correspond to the expected consequences of the new hormonal, metabolic, immune, and vascular status of a pregnant woman; they affect the majority of these women; they commonly appear early on in the period of pregnancy; and they tend to resolve spontaneously after delivery. Pigmentary changes Hyperpigmentation is the most frequent skin modification found in pregnancy. Estrogens and progesterone synergistically stimulate melanogenesis. In addition, the increased levels of melanocytestimulating hormone have a direct effect on the skin. Hyperpigmentation manifests early in the first trimester, mainly affecting women with darker complexion and body areas of normally darker pigmentation. After delivery, it fades variably from one patient to another. The most commonly affected sites are the areolae and/or nipples, the periumbilical area and the linea nigra, the anogenital region, the axillae, and the thighs [1]. Naevi, freckles, and recent scars also may darken. Facial hyperpigmentation, or melasma, most commonly manifests on the forehead, the cheeks, the upper lip, and the chin, consisting of greyebrown plaques. Many risks factors are clearly associated with melasma including dark skin type, Amerindian ancestry, chronic sun exposure, hormonal stimuli, and antidepressant/anxiolytic use [2]. It begins after the third month; it usually regresses in the postpartum period, but it can recur for years after with sun exposure, oral contraception, or future pregnancies. Treatment of melasma is preferred after the end of lactation as some molecules used such as hydroquinone and tretinoin can be teratogenic. Meanwhile, preventive measures including mainly sun avoidance and sunscreen protection are the most effective [3]. Vascular changes During pregnancy, there is activation of endothelium and decreased vascular smooth muscle tone leading to reduced peripheral vascular resistance. At the same time, intravascular volume expansion and compression from the enlarging gravid uterus cause venous congestion. All these factors explain the different vascular changes of skin during pregnancy. Spider telangiectasias (spider angiomas) These lesions typically begin, at the end of the first trimester, in the area of skin drained by the superior vena cava (face, neck, arms, and hands). They present as a punctiform central redness (corresponding to a dilated afferent arteriole) with radiating capillaries and surrounding erythema. These lesions increase in number through pregnancy especially in women with lighter complexions [4]. If the number of spider angiomas increases abnormally, the liver status should be checked as estrogen catabolism decreases in liver diseases. Spider telangiectasias often disappear within weeks after delivery. Persistent lesions can be effectively treated with fine-needle cautery, pulsed dye laser, or intense pulse light system. Please cite this article in press as: Soutou B, Aractingi S, Skin disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.03.005
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Palmar erythema This sign also appears during the first trimester, more frequently in white women, and fades within 1 week post partum. The following two patterns are distinguished: (a) diffuse mottled erythema of the entire palms, and (b) erythema restricted to the thenar and hypothenar eminences, the metacarpophalangeal joints, and the finger pads. Palmar erythema is attributed to venous engorgement, but hyperthyroidism, cirrhosis, lupus, and salbutamol intake are differential diagnoses that should be kept in mind [5]. Vasomotor instability During pregnancy, women frequently experience episodes of pallor, facial flushing, hot-and-cold sensations, and cutis marmorata (reticulate bluish erythema of the lower legs when exposed to cold). Venous congestion signs Varicosities appear in 40% of pregnant women starting from the second month [4]. Additional precipitating factors are genetic predisposition and prolonged standing. Leg raising and elastic stockings are effective methods of prevention. - Those localized on the legs, the pelvis, and the perineum may have a small risk of thrombosis [5]. They usually regress post partum. Lesions persisting 3 months post partum may be treated with sclerosing agents and laser. - Hemorrhoids with pain and bleeding occur in 40% of patients, mainly associated with constipation, high birth weight of the newborn, and prolonged straining during delivery. Hemorrhoids are common during the last trimester of pregnancy and the first month post partum [6]. Preventing constipation with laxatives and fibers has a beneficial effect [7]. - The Jacquemier sign (varicosities of the vestibule and vagina) and the Chadwick sign (bluish tint of the mucosa) are two early diagnostic signs of pregnancy [8]. Nonpitting edema of the legs but also possibly of the face and the eyelids is due to fluid leakage in the extracellular milieu when the venous hydrostatic pressure increases. It is very frequent in the morning during the last few months of pregnancy [4,9]. It should be noted that persistent edema of the face and the hands may be indicative of preeclampsia. Purpura of the legs is also possible in the second half of pregnancy due to excessive fragility of skin capillaries induced by venous hypertension in lower limbs. Purpura should always warrant a check of the platelet count, as it is an unusual physiological sign of pregnancy. Vascular proliferation signs Hyperplasia of the interdental papillae of the gingival mucosa is frequently observed during the third trimester of pregnancy [8]. It can be mild and asymptomatic or severe with intense pain and bleeding. Poor dental hygiene, periodontal disease, local irritants, and nutritional deficiencies are triggering factors. Healing is progressive in the postpartum period. Epulis gravidarum, misnamed pyogenic granulomas, represents asymptomatic erythematous fragile nodules of the gingival mucosa corresponding to hyperplasia of mucosal capillaries and fibroblasts or of the skin itself. Triggers are physical trauma and irritation (plaque deposits and gingivitis). Epulis regresses within months after delivery and recurs in later pregnancies. Considerable bleeding allows surgical excision.
Structural changes Striae distensae In the third trimester, striae begin as linear red to purple bands. They develop on the abdomen, the breasts, the thighs, the inguinal folds, and the arms. They fade gradually and leave white atrophic bands. Risk factors in primiparous women are young maternal age, elevated maternal body mass index (BMI), excessive maternal weight gain, macrosomia, and personal and familial history of striae. Causes Please cite this article in press as: Soutou B, Aractingi S, Skin disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.03.005
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seem multiple including mechanical stretching of the skin and hormonal reduction of elastic fibers through steroids, estrogens, and relaxin. A recent genome-wide association study (GWAS) suggested an association with mutations of genes encoding for elastic microfibrils [10]. All preventive measures have been failures [11,12]. The appearance of recent purplish striae may improve with pulsed dye laser or 0.1% tretinoin cream, two treatments reserved for at least 3 months post partum [13,14]. Acrochordons Skin tags grow during the second half of pregnancy. They correspond to small pedunculate lightly pigmented polyps on the neck, the axillary, the inframammary, and the inguinal folds. They have no malignant potential. They often shrink after delivery. Otherwise, removal is simple with snipping, cryotherapy, or cautery. Adnexal changes Hair During pregnancy, fewer anagen (growing) hair follicles enter the telogen (shedding) phase. Scalp and body hair will increase in number, thickness, and brightness, especially on the face, the arms, and the legs. This pattern reverses within 6 months post partum [5]. Two to four weeks after delivery, the scalp hair enters a prolonged telogen phase and sheds profusely (telogen effluvium) during 3e4 months. Later on, hair completely grows within 6e15 months [15]. However, anemia, iron deficiency, and thyroid dysfunction should be evaluated if any doubt is present. Nails Nails grow faster and become brittle. Other manifestations are uncommon and reversible (subungual thickening, longitudinal melanonychia (brown pigmentation arranged lengthwise along the nail unit), transversal grooves (linear narrow depressions of the nail), and distal onycholysis) [5]. Sebaceous glands As an early sign of pregnancy, sebaceous glands enlarge on the areola and appear as multiple brown papules (Montgomery's glands), starting from the sixth week of gestation. They regress spontaneously after delivery [5,15]. Facial skin may become greasy in the third trimester due to increased sebaceous glands activity. Acne frequently develops during pregnancy. The diagnosis is easy but the treatment should exclude cyclins and retinoids. Erythromycin and benzoyl peroxide can be prescribed. Sudoral glands Eccrine sweat gland activity increases through pregnancy with subsequent hyperhidrosis and miliaria (pruriginous inflammation of the glands) [15]. Apocrine gland activity seems to decrease. Specific dermatoses of pregnancy The specific dermatoses of pregnancy strictly occur during or immediately after pregnancy. The pathophysiology of dermatoses of pregnancy remains poorly understood. Furthermore, their previous classification has led to a confusing set of names and acronyms. Currently, the three specific dermatoses of pregnancy are as follows: polymorphic eruption of pregnancy (PEP), atopic eczema of pregnancy (AEP), and pemphigoid gestationis (PG). Intrahepatic cholestasis of pregnancy and impetigo herpetiformis (IH) are not, strictly speaking, specific dermatoses of pregnancy. However, their knowledge is essential when considering fetal and maternal risks. Polymorphic eruption of pregnancy PEP is a pruritic disorder that predominantly affects women in the third trimester of their first pregnancy [16e18]. Earlier or postpartum onsets are possible. Incidence may vary between 0.06% and Please cite this article in press as: Soutou B, Aractingi S, Skin disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.03.005
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0.8% of pregnancies [16,17,19]. Intensely pruritic urticarial papules and plaques appear first on the lower abdomen, particularly on the striae distensae and typically sparing the periumbilical area. The eruption may spread to the rest of the trunk and extremities (Fig. 1). However, the face, palms, and soles are rarely affected [19]. In approximately 50% of cases, eczematous, vesicular, or target-like lesions can also be seen [20]. Histology is not specific. It variably shows dermal edema and polymorphous mononuclear infiltrate with eosinophils found in half of cases. Spongiosis, acanthosis, and parakeratosis are the main epidermal changes [20]. Direct immunofluorescence is constantly negative. Pathogenic mechanisms are still unclear. However, many interesting findings can be mentioned: - There are no hormonal abnormalities, no human leukocyte antigen (HLA) associations, and no profiles of autoimmunity. - Twin or triplet pregnancy with further abdominal skin distension, and probably higher maternal weight gain and newborn birth weight, could have some role in the development of PEP over striae distensae [21]. However, the hypothesis of skin inflammation secondary to mechanical distension cannot be considered as a unique valid explanation as PEP may affect other cutaneous areas not subject to such distension. - The presence of fetal keratinocytes in skin lesions probably corresponds to a secondary repair phenomenon more than a primary source of inflammation [22,23]. Significant associations were found with higher rates of male fetuses, cesarean delivery, and multiple pregnancies [18,24]. However, PEP does not influence the outcome of pregnancy. Spontaneous remission occurs within 3e6 weeks after delivery. The recurrence rate in later pregnancies is low. Treatment with a once-daily application of potent or ultrapotent topical steroids relieves symptoms. Emollients and antihistamines may add some favorable effect when pruritus is very intense. If PEP is widespread, systemic steroids, for example, prednisolone 20e30 mg, will usually suppress cutaneous inflammation. Atopic eczema of pregnancy AEP appears to be the most frequent of specific dermatoses in pregnancy [18]. Unlike PEP, the eruption starts in 76% of patients during the first and second trimesters. Diagnostic criteria are not very specific. Indeed, these correspond to pruritic dermatosis with a background of personal or familial atopy. High immunoglobulin E (IgE) serum levels and previously known dry skin are not mandatory. Lesions are featured as pruritic eruption of eczema-like lesions flares in the same sites of atopic eczema, mainly the inside of the knees and elbows (Fig. 2). However, in almost a third of cases, elementary lesions consist of papular and nodular prurigo of the extremities. Histology has no distinguishing features. Direct immunofluorescence is negative. High serum levels of IgE are present in 20e70% of cases [25].
Fig. 1. Polymorphic eruption of pregnancy. Urticarial papules on the skin of the abdomen of a patient in the third trimester of her first pregnancy.
Please cite this article in press as: Soutou B, Aractingi S, Skin disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.03.005
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Fig. 2. Atopic eczema of pregnancy. Papulovesicular plaque with pruritus on the elbow fold during a flare in a pregnant patient.
Immunity mechanisms change during pregnancy with a switch toward a dominant humoral immune response and an increased release of Th2 cytokines (interleukin (IL)-4 and IL-10). This may partly explain de novo flares and acute exacerbations of pre-existing atopic dermatitis [26,27]. The role of a genetic background for atopy and the implication of filaggrin gene mutations require more investigation. Maternal outcome is favorable even in severe and extended flares of AEP. Recurrences can occur in later pregnancies. Fetal prognosis is not altered, but the offspring of affected pregnancies are at a risk of developing atopic eczema during childhood [27]. As in atopic dermatitis, Treatment consists of topical steroids to cure flares and emollients applied on a regular basis in order to improve skin dryness. Ultraviolet B (UVB) phototherapy that appears to be safe in pregnancy can control severe and steroid-resistant eruptions. Pemphigoid gestationis PG is an autoimmune skin disease, immunologically similar to bullous pemphigoid, but epidemiologically related to pregnancy, postpartum, and rarely hydatidiform moles. The incidence ranges at approximately one in 7000 [17,25,28]. PG usually affects multiparous women in their second or third trimester. Onset in postpartum or the first trimester is also reported. Intense pruritus precedes skin eruption. Later on, urticarial pruritic papules, sometimes displaying an annular pattern, appear typically on the periumbilical skin. Then, they spread to the trunk and the extremities sparing the face and the mucosa (Fig. 3). Later on, bullae can rise either on edematous plaques or on normal unaffected skin. However, the presence of bullae remains rare. Most of the PG cases are non-bullous, showing pruritic urticarial papules and eczema-like plaques, of variable progression, without mucosal involvement, clinically similar to PEP's manifestations. Histology shows spongiotic epidermis, subepidermal vesicles, dermal edema with a mild perivascular infiltrate of lymphocytes, histiocytes, and many eosinophils. These features are not very specific and can also be seen in PEP. Diagnosis relies on direct immunofluorescence. It shows a linear Please cite this article in press as: Soutou B, Aractingi S, Skin disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.03.005
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Fig. 3. Pemphigoid gestationis. Annular urticarial plaques involving the periumbilical skin of a patient in the second trimester of her second pregnancy.
deposit of C3 (±IgG) along the basement membrane zone. In 69-90% of patients, indirect immunofluorescence detects IgG1 autoantibodies (herpes gestationis factor) targeting the hemidesmosomes of the basal membrane. Western blotting shows circulating autoantibodies against either BPAg2 (180kD) antigen alone or more rarely BPAg1 (230kD) and BPAg2 together. Lately, two tests have been suggested to replace direct immunofluorescence to diagnose PG: - Autoantibodies of PG have a common antigenic site with the noncollagenic domain NC16a of BPAg2. A specific and sensitive ELISA can depict anti-BPAg1-NC16a antibodies [29]. - Routine immunochemistry for anti-C4d in formalin-fixed paraffin-embedded tissue shows very specifically in PG linear C4d immunoreactant deposition along the basement membrane zone [30]. Serum titers of circulating IgG antibodies detected by conventional indirect immunofluorescence correlate neither with disease activity nor with pregnancy outcome [18,31]. PG is in part related to a genetic background; approximately 45% of women with PG (vs. 3% of the controls) display the HLA-DR3 allele. Moreover, 90% of PG women have a null C4 allele [32,33]. Furthermore, an abnormal expression of HLA class II antigens has been shown in the trophoblasts of PG-affected women [34]. Therefore, the proposed hypothesis is that a response of the maternal immune system against paternal HLA antigens abnormally expressed on placenta will also target the collagen XVII present in the basal membrane zone of the skin by cross-reaction. Such a hypothesis can explain PG being specific to one partner and not another [35]. Maternal and fetal prognoses are good in PG despite some known overrisks of cesarean section, prematurity, and low birth weight [28,36,37]. Obstetricians should be aware of the risk of intrauterine growth retardation in PG. This risk is low, but it increases if PG appears early in the second trimester and when bullous lesions are numerous. Ultrasound measurements should then be performed regularly. Neonatal vesicles may appear in newborns of affected mother, but such eruption is infrequent, usually mild, self-limited, and related to the transient passage of maternal antibodies. PG usually regresses after delivery. A postpartum flare is however reported in 75e85% of cases. Very rarely, some cases may have an autonomous course for several years after pregnancy. Recurrences in later pregnancies are frequent (50e70%), with earlier onset and more severe form. Cases were also reported with subsequent use of oral contraceptives. There is no absolute consensus for the treatment of PG. However, similar to bullous pemphigoid, we consider that first-line treatment in PG is actually ultrapotent topical steroids [38e40]. In resistant cases, systemic steroids at a daily dose of 0.5 mg/kg are necessary to control the disease. Please cite this article in press as: Soutou B, Aractingi S, Skin disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.03.005
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Intrahepatic cholestasis of pregnancy (ICP) (refer to chapter on liver disease in pregnancy) ICP is not strictly a skin disease as there are no primary skin lesions. ICP manifests by isolated nocturnal itching mainly during the third trimester. Usually, skin appears normal. Excoriations and prurigo secondary to scratching are the only possible skin manifestations. Impetigo herpetiformis IH is a very rare skin disorder sometimes reported outside pregnancy. Misnamed, IH is neither a bacterial nor a herpesvirus infection. Onset occurs in primigravidae in their third trimester. Erythematous plaques, secondarily bordered with sterile pustules, appear in the folds and extend centrifugally. Fever, nausea, vomiting, and diarrhea are common. Hypoalbuminemia, secondary hypocalcemia, or low serum levels of vitamin D should be systematically sought. True hypocalcemia remains rare, and it is usually the reflection of the hypoalbuminemia. Some authors consider IH as a flare of generalized pustular psoriasis triggered by pregnancy. This remains controversial as a personal history of psoriasis is reported in only a third of patients. Maternal risk is linked to poor management and/or to hypercalcemia-induced convulsions. Fetal death is possible due to placental ischemia. Recurrence in successive pregnancies may start earlier. Oral contraceptives can also trigger a flare. Topical or systemic steroids and cyclosporine in resistant cases are the mainstay of treatment [41].
Practice points Two recommendations are essential when dealing with skin disorders during pregnancy. First, we should be able to recognize the dermatoses of pregnancy, and if there is any uncertainty of the diagnosis, or if the pattern is suggestive of PG, then a skin biopsy is indicated. Otherwise, excessive, unnecessary biopsies will be performed. Second, all the dermatoses of pregnancy will improve with either topical or systemic steroids. Steroid treatment is safe throughout pregnancy.
Research agenda Cutaneous biology and interactions between skin components and hormones secreted during pregnancy An investigation into the role of fetal stem cells in the maternal circulation on tissue repair and tumor development.
Conflicts of interest None. References ve E, Saudeau L, Pierre F, et al. Signes cutane s lors des grossesses normales. Etude ne re ol [1] Este de 60 cas. Ann Dermatol Ve 2004;121:227e31. [2] Handel AC, Lima PB, Tonolli VM, et al. Risk factors for facial melasma in women: a case-control study. Br J Dermatol 2014 Apr 19. http://dx.doi.org/10.1111/bjd.13059 [Epub ahead of print]. [3] Sheth VM, Pandya AG. Melasma: a comprehensive update. Part II. J Am Acad Dermatol 2011;65:699e714. [4] Henry F, Quatresooz P, Valverde-Lopez JC, et al. Blood vessel changes during pregnancy: a review. Am J Clin Dermatol 2006;7:65e9. [5] Elling SV, Powell FC. Physiological changes in the skin during pregnancy. Clin Dermatol 1997;15:35e43.
Please cite this article in press as: Soutou B, Aractingi S, Skin disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.03.005
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[6] Poskus T, Buzinskiene_ D, Drasutiene G, et al. Haemorrhoids and anal fissures during pregnancy and after childbirth: a prospective cohort study. BJOG 2014 May 9. http://dx.doi.org/10.1111/1471-0528.12838 [Epub ahead of print]. [7] Alonso-Coello P, Guyatt G, Heels-Ansdell D, et al. Laxatives for the treatment of hemorrhoids. Cochrane Database Syst Rev 2005;4:CD004649. *[8] Torgerson RR, Marnach ML, Bruce AJ, et al. Oral and vulvar changes in pregnancy. Clin Dermatol 2006;24:122e32. [9] Kroumpouzos G, Cohen LM. Dermatoses of pregnancy. J Am Acad Dermatol 2001;45:1e19. [10] Tung JY, Kiefer AK, Mullins M, et al. Genome-wide association analysis implicates elastic microfibrils in the development of nonsyndromic striae distensae. J Invest Dermatol 2013;133:2628e31. *[11] Brennan M, Young G, Devane D. Topical preparations for preventing stretch marks in pregnancy. Cochrane Database Syst Rev 2012 Nov 14;11:CD000066. http://dx.doi.org/10.1002/14651858.CD000066.pub2. Madera Gonza ndez JA, lez D, Padilla Castillo M, et al. Use of a specific anti-stretch mark cream for preventing [12] García Herna or reducing the severity of striae gravidarum. Randomized, double-blind, controlled trial. Int J Cosmet Sci 2013;35:233e7. [13] Rangel O, Arias I, García E, et al. Topical tretinoin 0.1% for pregnancy-related abdominal striae: an open-label, multicenter, prospective study. Adv Ther 2001;18:181e6. nez GP, Flores F, Berman B, et al. Treatment of striae rubra and striae alba with the 585-nm pulsed-dye laser. Der[14] Jime matol Surg 2003;29:362e5. die Me dico-Chirurgicale (Dermatologie). Editions [15] Roger D, Boudrie JL, Vaillant L, et al. Peau et Grossesse. In: Encyclope dicales Elsevier SAS; 2001. 200198-858-A-10. Scientifiques et Me [16] Holmes RC, Black MM. The specific dermatoses of pregnancy. J Am Acad Dermatol 1983;8:405e12. *[17] Roger D, Vaillant L, Fignon A, et al. Specific pruritic diseases of pregnancy: a prospective study of 192 pregnant women. Arch Dermatol 1994;30:734e9. *[18] Vaughan Jones SA, Hern S, Nelson-Piercy C, et al. A prospective study of 200 women with dermatoses of pregnancy correlating clinical findings with hormonal and immunopathological profiles. Br J Dermatol 1999;141:71e81. [19] Ghazeeri G, Kibbi AG, Abbas O. Pruritic urticarial papules and plaques of pregnancy: epidemiological, clinical, and histopathological study of 18 cases from Lebanon. Int J Dermatol 2012;51:1047e53. *[20] Rudolph CM, Al-Fares S, Vaughan-Jones SA, et al. Polymorphic eruption of pregnancy: clinicopathology and potential trigger factors in 181 patients. Br J Dermatol 2006;154:54e60. [21] Cohen LM, Capeless EL, Krusinski PA, et al. Pruritic urticaria papules and plaques of pregnancy and its relationship to maternal-fetal weight gain and twin pregnancy. JAMA Dermatol 1989;125:1534e6. [22] Aractingi S, Berkane N, Bertheau P, et al. Fetal DNA in skin of polymorphic eruption of pregnancy. Lancet 1998;352: 1898e901. [23] Nguyen Huu S, Dubernard G, Aractingi S, et al. Feto-maternal cell trafficking: a transfer of pregnancy associated progenitor cells. Stem Cell Rev 2006;2:111e6. *[24] Regnier S, Fermand V, Levy P, et al. A case-control study of polymorphic eruption of pregnancy. J Am Acad Dermatol 2008; 58:63e7. *[25] Ambros-Rudolph CM, Müllegger RR, Vaughan-Jones SA, et al. The specific dermatoses of pregnancy revisited and reclassified: Results of a retrospective two-center study on 505 pregnant patients. J Am Acad Dermatol 2006;54: 395e404. [26] García-Gonz alez E, Ahued-Ahued R, Arroyo E, et al. Immunology of the cutaneous disorders of pregnancy. Int J Dermatol 1999;38:721e9. [27] Ambros-Rudolph CM. Dermatoses of pregnancy - Clues to diagnosis, fetal risk and therapy. Ann Dermatol 2011;23: 265e75. [28] Jenkins RE, Hern S, Black MM. Clinical features and management of 87 patients with pemphigoid gestationis. Clin Exp Dermatol 1999;24:255e9. *[29] Powell MB, Sakuma-Oyama Y, Oyama N, et al. Usefulness of BP180 NC16a enzyme-linked immunosorbent assay in the serodiagnosis of pemphigoid gestationis and in differentiating between pemphigoid gestationis and pruritic urticarial papules and plaques of pregnancy. JAMA Dermatol 2005;141:705e10. *[30] Kwon EJ, Ntiamoah P, Shulman KJ. The utility of C4d immunohistochemistry on formalin-fixed paraffin-embedded tissue in the distinction of polymorphic eruption of pregnancy from pemphigoid gestationis. Am J Dermatopathol 2013;35: 787e91. [31] Chi CC, Wang SH, Charles-Holmes R, et al. Pemphigoid gestationis: early onset and blister formation are associated with adverse pregnancy outcomes. Br J Dermatol 2009;160:1222e8. [32] Shornick JK, Artlett CM, Jenkins RE, et al. Complement polymorphism in herpes gestationis: association with C4 null allele. J Am Acad Dermatol 1993;29:545e9. [33] Shornick JK, Jenkins RE, Briggs DC, et al. Anti-HLA antibodies in pemphigoid gestationis (herpes gestationis). Br J Dermatol 1993;129:257e9. [34] Borthwick GM, Sunderland CA, Holmes RC, et al. Abnormal expression of HLA-DR antigen in the placenta of a patient with pemphigoid gestationis. J Reprod Immunol 1984;6:393e6. [35] Villegas M, Goff HW, Kraus EW, et al. Blisters during pregnancy-just with the second husband. J Fam Pract 2006;55: 953e6. [36] Mascaro Jr JM, Lecha M, Mascaro JM. Fetal morbidity in herpes gestationis. Arch Dermatol 1995;131:1209e10. rature. Ann Dermatol Venereol 2011;138:209e13. [37] Ingen-Housz-Oro S. Pemphigoïde de la grossesse: revue de la litte [38] Guillaume JC, Donnard JC, Schnebelen MP, et al. Local corticosteroid therapy in a severe form of pemphigoid gestationis. Ann Dermatol Venereol 1996;123:31. [39] Valeyrie L, Lebrun-Vignes B, Bodak N, et al. Pemphigoid gestationis: treatment by topical class I corticosteroid. Ann Dermatol Venereol 2001;128:638e40. *[40] Saidi W, JolyP. Topical or systemic corticosteroids in patients with pemphigoid gestationis and polymorphic eruption of pregnancy. Ann Dermatol Venereol 2008;135:865e6. [41] Imai N, Watanabe R, Fujiwara H, et al. Successful treatment of impetigo herpetiformis with oral cyclosporine during pregnancy. JAMA Dermatol 2002;138:128e9.
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Skin disease in pregnancy de me decine a, b, *, 1, Boutros Soutou, MD, Faculte lim Aractingi, MD, PhD, Faculte de me decine c, d, 2 Se Facult e de m edecine, Universite saint-Joseph, 11-5076 Riad el Solh, Beirut, Lebanon Centre Hospitalier du Nord, 100 Jdeidet Zgharta, Lebanon c ^pital Cochin Tarnier, 89, rue d'Assas, Facult e de m edecine, Paris 5 descartes, Service de Dermatologie, Ho 75006 Paris, France d Equipe Cellules souches foetales, Inserm UMR S 938 & UPMC, CDR St Antoine, 27, rue de Chaligny, 75012 Paris, France a
b
Keywords: pregnancy skin abnormality polymorphic eruption of pregnancy atopic eruption of pregnancy pemphigoid gestationis impetigo herpetiformis
Skin manifestations during pregnancy are common and diversified. This review will focus on the most important entities to be recognized by obstetricians. These are, on the one hand, physiological changes, where unnecessary investigations should be avoided, and on the other, the specific dermatoses of pregnancy. These develop electively in pregnancy, and they are currently grouped into three disorders: polymorphic eruption of pregnancy, atopic eczema of pregnancy, and pemphigoid gestationis. Arguments for recognition of these are presented including detection of anti-BP180 antibodies. Follow-up and treatment depend on the precise diagnosis. Risks in fetal prognosis may occur in rare pemphigoid gestationis cases. © 2015 Elsevier Ltd. All rights reserved.
Skin disease in pregnancy Dermatological manifestations associated with pregnancy can be grouped into five categories: (i) physiological changes, (ii) pregnancy-specific dermatoses, (iii) cutaneous infections affecting fetal outcome, (iv) various intercurrent dermatoses affected by or affecting pregnancy, and (v) side effects of topical cutaneous treatments and fetal risk of such treatments. These manifestations, mainly
Saint-Joseph, 11-5076 Riad el Solh, Beirut, Lebanon. * Corresponding author. Universite E-mail addresses: [email protected] (B. Soutou), [email protected] (S. Aractingi). 1 Tel.: þ961 3 741478; Fax: þ961 6 555290. 2 Tel.: þ33 1 58 41 18 13; Fax: þ33 1 58 41 17 65. http://dx.doi.org/10.1016/j.bpobgyn.2015.03.005 1521-6934/© 2015 Elsevier Ltd. All rights reserved.
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physiologic changes and specific dermatoses, will be the focus of this review. They are important to recognize as diagnostic studies and monitoring are mandatory in some disorders while workup is unnecessary in others. Cutaneous physiological changes during pregnancy During pregnancy, the following three main precipitating factors induce the development of skin changes: (i) the increase in the level of circulating hormones, (ii) the intravascular volume expansion, and (iii) the compression from the enlarging uterus. In the skin, almost all cell types such as keratinocytes, melanocytes, fibroblasts, inflammatory cells, and components such as pilosebaceous units, sweat glands, and blood vessels express receptors to the various previously cited secreted molecules. The main subsequent modifications result in an increase in keratinocyte proliferation, angiogenesis, melanogenesis, collagen synthesis, and an increase in T helper 2 (Th2) lymphocytes and regulatory T cells. According to the cell type targeted, the modifications of the skin are divided into pigmentary, vascular, structural, and adnexal changes. These changes are called physiological due to the following reasons: they correspond to the expected consequences of the new hormonal, metabolic, immune, and vascular status of a pregnant woman; they affect the majority of these women; they commonly appear early on in the period of pregnancy; and they tend to resolve spontaneously after delivery. Pigmentary changes Hyperpigmentation is the most frequent skin modification found in pregnancy. Estrogens and progesterone synergistically stimulate melanogenesis. In addition, the increased levels of melanocytestimulating hormone have a direct effect on the skin. Hyperpigmentation manifests early in the first trimester, mainly affecting women with darker complexion and body areas of normally darker pigmentation. After delivery, it fades variably from one patient to another. The most commonly affected sites are the areolae and/or nipples, the periumbilical area and the linea nigra, the anogenital region, the axillae, and the thighs [1]. Naevi, freckles, and recent scars also may darken. Facial hyperpigmentation, or melasma, most commonly manifests on the forehead, the cheeks, the upper lip, and the chin, consisting of greyebrown plaques. Many risks factors are clearly associated with melasma including dark skin type, Amerindian ancestry, chronic sun exposure, hormonal stimuli, and antidepressant/anxiolytic use [2]. It begins after the third month; it usually regresses in the postpartum period, but it can recur for years after with sun exposure, oral contraception, or future pregnancies. Treatment of melasma is preferred after the end of lactation as some molecules used such as hydroquinone and tretinoin can be teratogenic. Meanwhile, preventive measures including mainly sun avoidance and sunscreen protection are the most effective [3]. Vascular changes During pregnancy, there is activation of endothelium and decreased vascular smooth muscle tone leading to reduced peripheral vascular resistance. At the same time, intravascular volume expansion and compression from the enlarging gravid uterus cause venous congestion. All these factors explain the different vascular changes of skin during pregnancy. Spider telangiectasias (spider angiomas) These lesions typically begin, at the end of the first trimester, in the area of skin drained by the superior vena cava (face, neck, arms, and hands). They present as a punctiform central redness (corresponding to a dilated afferent arteriole) with radiating capillaries and surrounding erythema. These lesions increase in number through pregnancy especially in women with lighter complexions [4]. If the number of spider angiomas increases abnormally, the liver status should be checked as estrogen catabolism decreases in liver diseases. Spider telangiectasias often disappear within weeks after delivery. Persistent lesions can be effectively treated with fine-needle cautery, pulsed dye laser, or intense pulse light system. Please cite this article in press as: Soutou B, Aractingi S, Skin disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.03.005
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Palmar erythema This sign also appears during the first trimester, more frequently in white women, and fades within 1 week post partum. The following two patterns are distinguished: (a) diffuse mottled erythema of the entire palms, and (b) erythema restricted to the thenar and hypothenar eminences, the metacarpophalangeal joints, and the finger pads. Palmar erythema is attributed to venous engorgement, but hyperthyroidism, cirrhosis, lupus, and salbutamol intake are differential diagnoses that should be kept in mind [5]. Vasomotor instability During pregnancy, women frequently experience episodes of pallor, facial flushing, hot-and-cold sensations, and cutis marmorata (reticulate bluish erythema of the lower legs when exposed to cold). Venous congestion signs Varicosities appear in 40% of pregnant women starting from the second month [4]. Additional precipitating factors are genetic predisposition and prolonged standing. Leg raising and elastic stockings are effective methods of prevention. - Those localized on the legs, the pelvis, and the perineum may have a small risk of thrombosis [5]. They usually regress post partum. Lesions persisting 3 months post partum may be treated with sclerosing agents and laser. - Hemorrhoids with pain and bleeding occur in 40% of patients, mainly associated with constipation, high birth weight of the newborn, and prolonged straining during delivery. Hemorrhoids are common during the last trimester of pregnancy and the first month post partum [6]. Preventing constipation with laxatives and fibers has a beneficial effect [7]. - The Jacquemier sign (varicosities of the vestibule and vagina) and the Chadwick sign (bluish tint of the mucosa) are two early diagnostic signs of pregnancy [8]. Nonpitting edema of the legs but also possibly of the face and the eyelids is due to fluid leakage in the extracellular milieu when the venous hydrostatic pressure increases. It is very frequent in the morning during the last few months of pregnancy [4,9]. It should be noted that persistent edema of the face and the hands may be indicative of preeclampsia. Purpura of the legs is also possible in the second half of pregnancy due to excessive fragility of skin capillaries induced by venous hypertension in lower limbs. Purpura should always warrant a check of the platelet count, as it is an unusual physiological sign of pregnancy. Vascular proliferation signs Hyperplasia of the interdental papillae of the gingival mucosa is frequently observed during the third trimester of pregnancy [8]. It can be mild and asymptomatic or severe with intense pain and bleeding. Poor dental hygiene, periodontal disease, local irritants, and nutritional deficiencies are triggering factors. Healing is progressive in the postpartum period. Epulis gravidarum, misnamed pyogenic granulomas, represents asymptomatic erythematous fragile nodules of the gingival mucosa corresponding to hyperplasia of mucosal capillaries and fibroblasts or of the skin itself. Triggers are physical trauma and irritation (plaque deposits and gingivitis). Epulis regresses within months after delivery and recurs in later pregnancies. Considerable bleeding allows surgical excision.
Structural changes Striae distensae In the third trimester, striae begin as linear red to purple bands. They develop on the abdomen, the breasts, the thighs, the inguinal folds, and the arms. They fade gradually and leave white atrophic bands. Risk factors in primiparous women are young maternal age, elevated maternal body mass index (BMI), excessive maternal weight gain, macrosomia, and personal and familial history of striae. Causes Please cite this article in press as: Soutou B, Aractingi S, Skin disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.03.005
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seem multiple including mechanical stretching of the skin and hormonal reduction of elastic fibers through steroids, estrogens, and relaxin. A recent genome-wide association study (GWAS) suggested an association with mutations of genes encoding for elastic microfibrils [10]. All preventive measures have been failures [11,12]. The appearance of recent purplish striae may improve with pulsed dye laser or 0.1% tretinoin cream, two treatments reserved for at least 3 months post partum [13,14]. Acrochordons Skin tags grow during the second half of pregnancy. They correspond to small pedunculate lightly pigmented polyps on the neck, the axillary, the inframammary, and the inguinal folds. They have no malignant potential. They often shrink after delivery. Otherwise, removal is simple with snipping, cryotherapy, or cautery. Adnexal changes Hair During pregnancy, fewer anagen (growing) hair follicles enter the telogen (shedding) phase. Scalp and body hair will increase in number, thickness, and brightness, especially on the face, the arms, and the legs. This pattern reverses within 6 months post partum [5]. Two to four weeks after delivery, the scalp hair enters a prolonged telogen phase and sheds profusely (telogen effluvium) during 3e4 months. Later on, hair completely grows within 6e15 months [15]. However, anemia, iron deficiency, and thyroid dysfunction should be evaluated if any doubt is present. Nails Nails grow faster and become brittle. Other manifestations are uncommon and reversible (subungual thickening, longitudinal melanonychia (brown pigmentation arranged lengthwise along the nail unit), transversal grooves (linear narrow depressions of the nail), and distal onycholysis) [5]. Sebaceous glands As an early sign of pregnancy, sebaceous glands enlarge on the areola and appear as multiple brown papules (Montgomery's glands), starting from the sixth week of gestation. They regress spontaneously after delivery [5,15]. Facial skin may become greasy in the third trimester due to increased sebaceous glands activity. Acne frequently develops during pregnancy. The diagnosis is easy but the treatment should exclude cyclins and retinoids. Erythromycin and benzoyl peroxide can be prescribed. Sudoral glands Eccrine sweat gland activity increases through pregnancy with subsequent hyperhidrosis and miliaria (pruriginous inflammation of the glands) [15]. Apocrine gland activity seems to decrease. Specific dermatoses of pregnancy The specific dermatoses of pregnancy strictly occur during or immediately after pregnancy. The pathophysiology of dermatoses of pregnancy remains poorly understood. Furthermore, their previous classification has led to a confusing set of names and acronyms. Currently, the three specific dermatoses of pregnancy are as follows: polymorphic eruption of pregnancy (PEP), atopic eczema of pregnancy (AEP), and pemphigoid gestationis (PG). Intrahepatic cholestasis of pregnancy and impetigo herpetiformis (IH) are not, strictly speaking, specific dermatoses of pregnancy. However, their knowledge is essential when considering fetal and maternal risks. Polymorphic eruption of pregnancy PEP is a pruritic disorder that predominantly affects women in the third trimester of their first pregnancy [16e18]. Earlier or postpartum onsets are possible. Incidence may vary between 0.06% and Please cite this article in press as: Soutou B, Aractingi S, Skin disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.03.005
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0.8% of pregnancies [16,17,19]. Intensely pruritic urticarial papules and plaques appear first on the lower abdomen, particularly on the striae distensae and typically sparing the periumbilical area. The eruption may spread to the rest of the trunk and extremities (Fig. 1). However, the face, palms, and soles are rarely affected [19]. In approximately 50% of cases, eczematous, vesicular, or target-like lesions can also be seen [20]. Histology is not specific. It variably shows dermal edema and polymorphous mononuclear infiltrate with eosinophils found in half of cases. Spongiosis, acanthosis, and parakeratosis are the main epidermal changes [20]. Direct immunofluorescence is constantly negative. Pathogenic mechanisms are still unclear. However, many interesting findings can be mentioned: - There are no hormonal abnormalities, no human leukocyte antigen (HLA) associations, and no profiles of autoimmunity. - Twin or triplet pregnancy with further abdominal skin distension, and probably higher maternal weight gain and newborn birth weight, could have some role in the development of PEP over striae distensae [21]. However, the hypothesis of skin inflammation secondary to mechanical distension cannot be considered as a unique valid explanation as PEP may affect other cutaneous areas not subject to such distension. - The presence of fetal keratinocytes in skin lesions probably corresponds to a secondary repair phenomenon more than a primary source of inflammation [22,23]. Significant associations were found with higher rates of male fetuses, cesarean delivery, and multiple pregnancies [18,24]. However, PEP does not influence the outcome of pregnancy. Spontaneous remission occurs within 3e6 weeks after delivery. The recurrence rate in later pregnancies is low. Treatment with a once-daily application of potent or ultrapotent topical steroids relieves symptoms. Emollients and antihistamines may add some favorable effect when pruritus is very intense. If PEP is widespread, systemic steroids, for example, prednisolone 20e30 mg, will usually suppress cutaneous inflammation. Atopic eczema of pregnancy AEP appears to be the most frequent of specific dermatoses in pregnancy [18]. Unlike PEP, the eruption starts in 76% of patients during the first and second trimesters. Diagnostic criteria are not very specific. Indeed, these correspond to pruritic dermatosis with a background of personal or familial atopy. High immunoglobulin E (IgE) serum levels and previously known dry skin are not mandatory. Lesions are featured as pruritic eruption of eczema-like lesions flares in the same sites of atopic eczema, mainly the inside of the knees and elbows (Fig. 2). However, in almost a third of cases, elementary lesions consist of papular and nodular prurigo of the extremities. Histology has no distinguishing features. Direct immunofluorescence is negative. High serum levels of IgE are present in 20e70% of cases [25].
Fig. 1. Polymorphic eruption of pregnancy. Urticarial papules on the skin of the abdomen of a patient in the third trimester of her first pregnancy.
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Fig. 2. Atopic eczema of pregnancy. Papulovesicular plaque with pruritus on the elbow fold during a flare in a pregnant patient.
Immunity mechanisms change during pregnancy with a switch toward a dominant humoral immune response and an increased release of Th2 cytokines (interleukin (IL)-4 and IL-10). This may partly explain de novo flares and acute exacerbations of pre-existing atopic dermatitis [26,27]. The role of a genetic background for atopy and the implication of filaggrin gene mutations require more investigation. Maternal outcome is favorable even in severe and extended flares of AEP. Recurrences can occur in later pregnancies. Fetal prognosis is not altered, but the offspring of affected pregnancies are at a risk of developing atopic eczema during childhood [27]. As in atopic dermatitis, Treatment consists of topical steroids to cure flares and emollients applied on a regular basis in order to improve skin dryness. Ultraviolet B (UVB) phototherapy that appears to be safe in pregnancy can control severe and steroid-resistant eruptions. Pemphigoid gestationis PG is an autoimmune skin disease, immunologically similar to bullous pemphigoid, but epidemiologically related to pregnancy, postpartum, and rarely hydatidiform moles. The incidence ranges at approximately one in 7000 [17,25,28]. PG usually affects multiparous women in their second or third trimester. Onset in postpartum or the first trimester is also reported. Intense pruritus precedes skin eruption. Later on, urticarial pruritic papules, sometimes displaying an annular pattern, appear typically on the periumbilical skin. Then, they spread to the trunk and the extremities sparing the face and the mucosa (Fig. 3). Later on, bullae can rise either on edematous plaques or on normal unaffected skin. However, the presence of bullae remains rare. Most of the PG cases are non-bullous, showing pruritic urticarial papules and eczema-like plaques, of variable progression, without mucosal involvement, clinically similar to PEP's manifestations. Histology shows spongiotic epidermis, subepidermal vesicles, dermal edema with a mild perivascular infiltrate of lymphocytes, histiocytes, and many eosinophils. These features are not very specific and can also be seen in PEP. Diagnosis relies on direct immunofluorescence. It shows a linear Please cite this article in press as: Soutou B, Aractingi S, Skin disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.03.005
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Fig. 3. Pemphigoid gestationis. Annular urticarial plaques involving the periumbilical skin of a patient in the second trimester of her second pregnancy.
deposit of C3 (±IgG) along the basement membrane zone. In 69-90% of patients, indirect immunofluorescence detects IgG1 autoantibodies (herpes gestationis factor) targeting the hemidesmosomes of the basal membrane. Western blotting shows circulating autoantibodies against either BPAg2 (180kD) antigen alone or more rarely BPAg1 (230kD) and BPAg2 together. Lately, two tests have been suggested to replace direct immunofluorescence to diagnose PG: - Autoantibodies of PG have a common antigenic site with the noncollagenic domain NC16a of BPAg2. A specific and sensitive ELISA can depict anti-BPAg1-NC16a antibodies [29]. - Routine immunochemistry for anti-C4d in formalin-fixed paraffin-embedded tissue shows very specifically in PG linear C4d immunoreactant deposition along the basement membrane zone [30]. Serum titers of circulating IgG antibodies detected by conventional indirect immunofluorescence correlate neither with disease activity nor with pregnancy outcome [18,31]. PG is in part related to a genetic background; approximately 45% of women with PG (vs. 3% of the controls) display the HLA-DR3 allele. Moreover, 90% of PG women have a null C4 allele [32,33]. Furthermore, an abnormal expression of HLA class II antigens has been shown in the trophoblasts of PG-affected women [34]. Therefore, the proposed hypothesis is that a response of the maternal immune system against paternal HLA antigens abnormally expressed on placenta will also target the collagen XVII present in the basal membrane zone of the skin by cross-reaction. Such a hypothesis can explain PG being specific to one partner and not another [35]. Maternal and fetal prognoses are good in PG despite some known overrisks of cesarean section, prematurity, and low birth weight [28,36,37]. Obstetricians should be aware of the risk of intrauterine growth retardation in PG. This risk is low, but it increases if PG appears early in the second trimester and when bullous lesions are numerous. Ultrasound measurements should then be performed regularly. Neonatal vesicles may appear in newborns of affected mother, but such eruption is infrequent, usually mild, self-limited, and related to the transient passage of maternal antibodies. PG usually regresses after delivery. A postpartum flare is however reported in 75e85% of cases. Very rarely, some cases may have an autonomous course for several years after pregnancy. Recurrences in later pregnancies are frequent (50e70%), with earlier onset and more severe form. Cases were also reported with subsequent use of oral contraceptives. There is no absolute consensus for the treatment of PG. However, similar to bullous pemphigoid, we consider that first-line treatment in PG is actually ultrapotent topical steroids [38e40]. In resistant cases, systemic steroids at a daily dose of 0.5 mg/kg are necessary to control the disease. Please cite this article in press as: Soutou B, Aractingi S, Skin disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.03.005
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Intrahepatic cholestasis of pregnancy (ICP) (refer to chapter on liver disease in pregnancy) ICP is not strictly a skin disease as there are no primary skin lesions. ICP manifests by isolated nocturnal itching mainly during the third trimester. Usually, skin appears normal. Excoriations and prurigo secondary to scratching are the only possible skin manifestations. Impetigo herpetiformis IH is a very rare skin disorder sometimes reported outside pregnancy. Misnamed, IH is neither a bacterial nor a herpesvirus infection. Onset occurs in primigravidae in their third trimester. Erythematous plaques, secondarily bordered with sterile pustules, appear in the folds and extend centrifugally. Fever, nausea, vomiting, and diarrhea are common. Hypoalbuminemia, secondary hypocalcemia, or low serum levels of vitamin D should be systematically sought. True hypocalcemia remains rare, and it is usually the reflection of the hypoalbuminemia. Some authors consider IH as a flare of generalized pustular psoriasis triggered by pregnancy. This remains controversial as a personal history of psoriasis is reported in only a third of patients. Maternal risk is linked to poor management and/or to hypercalcemia-induced convulsions. Fetal death is possible due to placental ischemia. Recurrence in successive pregnancies may start earlier. Oral contraceptives can also trigger a flare. Topical or systemic steroids and cyclosporine in resistant cases are the mainstay of treatment [41].
Practice points Two recommendations are essential when dealing with skin disorders during pregnancy. First, we should be able to recognize the dermatoses of pregnancy, and if there is any uncertainty of the diagnosis, or if the pattern is suggestive of PG, then a skin biopsy is indicated. Otherwise, excessive, unnecessary biopsies will be performed. Second, all the dermatoses of pregnancy will improve with either topical or systemic steroids. Steroid treatment is safe throughout pregnancy.
Research agenda Cutaneous biology and interactions between skin components and hormones secreted during pregnancy An investigation into the role of fetal stem cells in the maternal circulation on tissue repair and tumor development.
Conflicts of interest None. References ve E, Saudeau L, Pierre F, et al. Signes cutane s lors des grossesses normales. Etude ne re ol [1] Este de 60 cas. Ann Dermatol Ve 2004;121:227e31. [2] Handel AC, Lima PB, Tonolli VM, et al. Risk factors for facial melasma in women: a case-control study. Br J Dermatol 2014 Apr 19. http://dx.doi.org/10.1111/bjd.13059 [Epub ahead of print]. [3] Sheth VM, Pandya AG. Melasma: a comprehensive update. Part II. J Am Acad Dermatol 2011;65:699e714. [4] Henry F, Quatresooz P, Valverde-Lopez JC, et al. Blood vessel changes during pregnancy: a review. Am J Clin Dermatol 2006;7:65e9. [5] Elling SV, Powell FC. Physiological changes in the skin during pregnancy. Clin Dermatol 1997;15:35e43.
Please cite this article in press as: Soutou B, Aractingi S, Skin disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.03.005
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[6] Poskus T, Buzinskiene_ D, Drasutiene G, et al. Haemorrhoids and anal fissures during pregnancy and after childbirth: a prospective cohort study. BJOG 2014 May 9. http://dx.doi.org/10.1111/1471-0528.12838 [Epub ahead of print]. [7] Alonso-Coello P, Guyatt G, Heels-Ansdell D, et al. Laxatives for the treatment of hemorrhoids. Cochrane Database Syst Rev 2005;4:CD004649. *[8] Torgerson RR, Marnach ML, Bruce AJ, et al. Oral and vulvar changes in pregnancy. Clin Dermatol 2006;24:122e32. [9] Kroumpouzos G, Cohen LM. Dermatoses of pregnancy. J Am Acad Dermatol 2001;45:1e19. [10] Tung JY, Kiefer AK, Mullins M, et al. Genome-wide association analysis implicates elastic microfibrils in the development of nonsyndromic striae distensae. J Invest Dermatol 2013;133:2628e31. *[11] Brennan M, Young G, Devane D. Topical preparations for preventing stretch marks in pregnancy. Cochrane Database Syst Rev 2012 Nov 14;11:CD000066. http://dx.doi.org/10.1002/14651858.CD000066.pub2. Madera Gonza ndez JA, lez D, Padilla Castillo M, et al. Use of a specific anti-stretch mark cream for preventing [12] García Herna or reducing the severity of striae gravidarum. Randomized, double-blind, controlled trial. Int J Cosmet Sci 2013;35:233e7. [13] Rangel O, Arias I, García E, et al. Topical tretinoin 0.1% for pregnancy-related abdominal striae: an open-label, multicenter, prospective study. Adv Ther 2001;18:181e6. nez GP, Flores F, Berman B, et al. Treatment of striae rubra and striae alba with the 585-nm pulsed-dye laser. Der[14] Jime matol Surg 2003;29:362e5. die Me dico-Chirurgicale (Dermatologie). Editions [15] Roger D, Boudrie JL, Vaillant L, et al. Peau et Grossesse. In: Encyclope dicales Elsevier SAS; 2001. 200198-858-A-10. Scientifiques et Me [16] Holmes RC, Black MM. The specific dermatoses of pregnancy. J Am Acad Dermatol 1983;8:405e12. *[17] Roger D, Vaillant L, Fignon A, et al. Specific pruritic diseases of pregnancy: a prospective study of 192 pregnant women. Arch Dermatol 1994;30:734e9. *[18] Vaughan Jones SA, Hern S, Nelson-Piercy C, et al. A prospective study of 200 women with dermatoses of pregnancy correlating clinical findings with hormonal and immunopathological profiles. Br J Dermatol 1999;141:71e81. [19] Ghazeeri G, Kibbi AG, Abbas O. Pruritic urticarial papules and plaques of pregnancy: epidemiological, clinical, and histopathological study of 18 cases from Lebanon. Int J Dermatol 2012;51:1047e53. *[20] Rudolph CM, Al-Fares S, Vaughan-Jones SA, et al. Polymorphic eruption of pregnancy: clinicopathology and potential trigger factors in 181 patients. Br J Dermatol 2006;154:54e60. [21] Cohen LM, Capeless EL, Krusinski PA, et al. Pruritic urticaria papules and plaques of pregnancy and its relationship to maternal-fetal weight gain and twin pregnancy. JAMA Dermatol 1989;125:1534e6. [22] Aractingi S, Berkane N, Bertheau P, et al. Fetal DNA in skin of polymorphic eruption of pregnancy. Lancet 1998;352: 1898e901. [23] Nguyen Huu S, Dubernard G, Aractingi S, et al. Feto-maternal cell trafficking: a transfer of pregnancy associated progenitor cells. Stem Cell Rev 2006;2:111e6. *[24] Regnier S, Fermand V, Levy P, et al. A case-control study of polymorphic eruption of pregnancy. J Am Acad Dermatol 2008; 58:63e7. *[25] Ambros-Rudolph CM, Müllegger RR, Vaughan-Jones SA, et al. The specific dermatoses of pregnancy revisited and reclassified: Results of a retrospective two-center study on 505 pregnant patients. J Am Acad Dermatol 2006;54: 395e404. [26] García-Gonz alez E, Ahued-Ahued R, Arroyo E, et al. Immunology of the cutaneous disorders of pregnancy. Int J Dermatol 1999;38:721e9. [27] Ambros-Rudolph CM. Dermatoses of pregnancy - Clues to diagnosis, fetal risk and therapy. Ann Dermatol 2011;23: 265e75. [28] Jenkins RE, Hern S, Black MM. Clinical features and management of 87 patients with pemphigoid gestationis. Clin Exp Dermatol 1999;24:255e9. *[29] Powell MB, Sakuma-Oyama Y, Oyama N, et al. Usefulness of BP180 NC16a enzyme-linked immunosorbent assay in the serodiagnosis of pemphigoid gestationis and in differentiating between pemphigoid gestationis and pruritic urticarial papules and plaques of pregnancy. JAMA Dermatol 2005;141:705e10. *[30] Kwon EJ, Ntiamoah P, Shulman KJ. The utility of C4d immunohistochemistry on formalin-fixed paraffin-embedded tissue in the distinction of polymorphic eruption of pregnancy from pemphigoid gestationis. Am J Dermatopathol 2013;35: 787e91. [31] Chi CC, Wang SH, Charles-Holmes R, et al. Pemphigoid gestationis: early onset and blister formation are associated with adverse pregnancy outcomes. Br J Dermatol 2009;160:1222e8. [32] Shornick JK, Artlett CM, Jenkins RE, et al. Complement polymorphism in herpes gestationis: association with C4 null allele. J Am Acad Dermatol 1993;29:545e9. [33] Shornick JK, Jenkins RE, Briggs DC, et al. Anti-HLA antibodies in pemphigoid gestationis (herpes gestationis). Br J Dermatol 1993;129:257e9. [34] Borthwick GM, Sunderland CA, Holmes RC, et al. Abnormal expression of HLA-DR antigen in the placenta of a patient with pemphigoid gestationis. J Reprod Immunol 1984;6:393e6. [35] Villegas M, Goff HW, Kraus EW, et al. Blisters during pregnancy-just with the second husband. J Fam Pract 2006;55: 953e6. [36] Mascaro Jr JM, Lecha M, Mascaro JM. Fetal morbidity in herpes gestationis. Arch Dermatol 1995;131:1209e10. rature. Ann Dermatol Venereol 2011;138:209e13. [37] Ingen-Housz-Oro S. Pemphigoïde de la grossesse: revue de la litte [38] Guillaume JC, Donnard JC, Schnebelen MP, et al. Local corticosteroid therapy in a severe form of pemphigoid gestationis. Ann Dermatol Venereol 1996;123:31. [39] Valeyrie L, Lebrun-Vignes B, Bodak N, et al. Pemphigoid gestationis: treatment by topical class I corticosteroid. Ann Dermatol Venereol 2001;128:638e40. *[40] Saidi W, JolyP. Topical or systemic corticosteroids in patients with pemphigoid gestationis and polymorphic eruption of pregnancy. Ann Dermatol Venereol 2008;135:865e6. [41] Imai N, Watanabe R, Fujiwara H, et al. Successful treatment of impetigo herpetiformis with oral cyclosporine during pregnancy. JAMA Dermatol 2002;138:128e9.
Please cite this article in press as: Soutou B, Aractingi S, Skin disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.03.005
