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Home , Dermatoses of pregnancy, Fetal distress, Melasma, Prurigo gestationis

DOI: 10.1111/tog.12051 Review The Obstetrician & Gynaecologist http://onlinetog.org

Skin eruptions specific to : an overview

a, b Ajaya Maharajan MBBS DGO MRCOG, * Christina Aye BMBCh MA Hons MRCOG, c d Ravi Ratnavel DM(Oxon) FRCP(UK), Ekaterina Burova FRCP CMSc (equ. PhD) aConsultant in and Gynaecology, Luton and Dunstable University Hospital, Lewsey Road, Luton, Bedfordshire LU4 0DZ, UK bST5 in Obstetrics and Gynaecology, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK cConsultant Dermatologist, Buckinghamshire Health Care, Mandeville Road, Aylesbury, Buckinghamshire HP21 8AL, UK dConsultant Dermatologist, Skin Cancer Lead for Bedford Hospital, Bedford Hospital NHS Trust, South Wing, Kempston Road, Bedford MK42 9DJ, UK *Correspondence: Ajaya Maharajan. Email: [email protected]

Accepted on 31 January 2013

Key content Learning objectives  Pregnancy results in various physiological skin changes.  To understand the physiological skin changes in pregnancy. As a consequence, some common dermatoses can present more  To identify the skin conditions that require appropriate referral. frequently in pregnant women. In addition, there are a number  To be able to take a history, to diagnose the skin eruptions unique to of skin eruptions unique to pregnancy. pregnancy, undertake appropriate investigations and first-line  The aetiology of physiological skin changes in pregnancy is management, and understand the criteria for referral to a uncertain but is thought to be due to hormonal and physical dermatologist. changes of pregnancy. Keywords: atopic eruption of pregnancy / intrahepatic cholestasis  The four are: atopic eruption of pregnancy / pemphigoid gestastionis / polymorphic eruption of of pregnancy, pemphigoid gestationis, polymorphic pregnancy / skin eruptions eruption of pregnancy and intrahepatic cholestasis of pregnancy.

Please cite this paper as: Maharajan A, Aye C, Ratnavel R, Burova E. Skin eruptions specific to pregnancy: an overview. The Obstetrician & Gynaecologist 2013; DOI: 10.1111/tog.12051.

Introduction the exact aetiology is uncertain. Box 1 summarises these changes.2,3 Pregnancy is a physiological state that is associated with specific Almost all women notice an increase in skin pigmentation dermatoses and modification of common dermatoses. Various during pregnancy, which is more noticeable in dark-skinned hormonal, immunological and haemodynamic factors that are individuals. This usually fades post-delivery, but often does specific to pregnancy influence the status of the skin. There not disappear completely. has been reported in 75% have been a number of attempts to create a universal of expectant , predominantly in the second or third classification, however, more recently, a clinically approved trimester. The condition is distressing and often persists for classification by Ambros-Rudolph and Mullegger€ has been months and years postpartum. Treatment can prove widely accepted.1 The classification recognises atopic eruption challenging, with limited response to topical bleaching of pregnancy, pemphigoid gestationis, polymorphic eruption creams, (not licensed in the UK), of pregnancy and intrahepatic cholestasis of pregnancy to be and steroids, as well as chemical peels, treatments and unique to pregnancy. This review provides an explanation of .4 All of the above treatments are the possible aetiology of the physiological skin changes and contraindicated in pregnancy and . Avoidance skin eruptions specific to pregnancy, their diagnosis, of excessive sunlight exposure and the use of broad-spectrum management and implications. sunscreens are therefore essential to prevent both initial development and exacerbation of melasma.5 Physiological skin changes in pregnancy (striae gravidarum) are also a common concern. These develop as linear red–purplish areas resulting Most physiological skin changes are recognised to be due from the stretching of skin in the second trimester. Striae to hormonal (increased estrogen, progesterone and gravidarum (Figure 1) occur predominantly on the -stimulating hormone) and physical factors but abdomen, breasts, thighs, lower back, buttocks and upper

ª 2013 Royal College of Obstetricians and Gynaecologists 1 Skin eruptions specific to pregnancy arms. They are caused by the rupture of dermal elastic fibres, which explains their irreversible nature. However, they often fade in the postnatal period to thin, atrophic, hypopigmented scars. Risk factors include personal or family history, dark-skinned women and excessive abdominal distension in pregnancy. Use of emollients is helpful, but there is no evidence that preparations such as vitamin E cream, tea tree oil and so on have any special value.

Box 1. Physiological skin changes in pregnancy

Pigmentation

 (abdomen)  Nipples  Axillae  Genitalia  Perineum Figure 1. Striae gravidarum  Secondary areola (pigmented area appears around the primary areola commonly during the fifth month) people.3 They are more common in fair-skinned individuals  Melasma (chloasma gravidarum or pregnancy mask): and the usual sites include areas around the eyes, neck, face, - Forehead upper chest, hands and arms. They appear in the second - Malar distribution - Mandibular area trimester and the majority will disappear by the third postnatal month.6 If treatment is required for those on the lower Glands extremities, sclerotherapy or laser treatment can be used.7,8  Eccrine All gland activity is affected during pregnancy. However, - increased eccrine gland secretions towards the third trimester - Hyperhidrosis can cause prickly heat (miliaria) and hyperhidrosis which can  Apocrine contribute to pruritus.3 - Decreased activity (improves conditions such as hidradenitis Changes are noted not only in the skin, but also in the other suppurativa) ectodermal structures, such as hair and nails. Increased hair  Sebaceous growth, antenatally, is thought to be due to prolongation of the 9 - Activity increased in third trimester but effects on variable anagen phase. Acute telogen effluvium, a generalised hair - Montgomery tubercles (follicles) may develop (hypertrophic shedding with diffuse non-scarring alopecia, characteristically sebaceous glands, non-pigmented elevations in the primary areola) occurs 3–6 months postpartum. Generally, recovery is spontaneous Vasculature and occurs within 9–12 months, and rarely does hair density 9  Spider naevi fail to recover completely.  Telangiectasia Nails tend to grow faster during pregnancy and can become  Palmar dystrophic, brittle, soft and/or pigmented.2 Mucosal changes  Varicosities: include pigmentation, hyperaemia and hypertrophy, which can - Saphenous lead to bleeding.2 Pruritus in the absence of an underlying - Vulval/vestibular/vaginal - Haemorrhoidal haematological orbiochemical disorderisa commoncomplaint, 10  Vasomotor instability, such as, flushing affecting up to 18% of . Common sites affected  Increased hydrostatic pressure, such as, purpura include the scalp and abdominal skin. It can start as early as the  Increased capillary permeability, such as, oedema in extremities and third month and peaks a month before delivery. The recurrence face rate in subsequent pregnancies is thought to be up to 80%. Connective tissue Dermographism (Figure 2) and urticaria are also common  Striae gravidarum in the last half of pregnancy.9 It is important nevertheless to  Skin tags (epithelial polyps) exclude other possible cases of pruritus, such as , allergic contact , drug-induced pruritus and an Vascular changes are thought to be partly due to the exacerbation of an . The presence of skin increase in estrogen, causing dilatation, instability, congestion excoriations and a glossy, polished appearance of the and proliferation of vessels that can be seen on or patient’s nails should make the physician suspect pruritus. through the skin. The prevalence of the spider naevi is noted to It is essential for the clinician to establish whether any be higher, 66%, in Caucasians compared with 11% in black skin-related complaint is due to a pre-existing dermatological

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Dermatoses of pregnancy The ability to distinguish between dermatoses of pregnancy is of utmost importance, as some (intrahepatic cholestasis of pregnancy and pemphigoid gestationis) can cause morbidity and mortality of and , such as intrauterine growth restriction, preterm delivery and . Table 1 summarises the four dermatoses of pregnancy featured in this review. Patient information about dermatoses can be downloaded from the British Association of Dermatologists, the American Academy of and the New Zealand Dermatological Society websites.

Intrahepatic cholestasis of pregnancy Intrahepatic cholestasis of pregnancy is also known as obstetric cholestasis, cholestasis of pregnancy, jaundice of Figure 2. Dermatographism pregnancy or pruritus/ gravidarum. Unlike other dermatoses, this condition presents initially condition, exacerbated by pregnancy, or represents a new with itching and results in secondary skin changes as a result skin problem. A focused, detailed history (Box 2) and of pruritus. In England, intrahepatic cholestasis of pregnancy examination (Box 3) are key to determine whether further is recorded to be 0.7% in multi-ethnic populations11 and in investigations or a referral are indicated. One needs to be 1.2–1.5% of women of Indian–Asian or Pakistani–Asian aware that scratching and ulceration can alter the origin.12 Its prevalence is known to be determined by genetic, characteristics of the primary lesion. Pictorial records may hormonal and environmental factors, and varies between be useful to monitor progression and response to treatment. populations worldwide. It is responsible for some of the most intense itching. Box 2. History taking: specific questions to ask Cholestasis-related pruritus is most severe at night and mainly affects the hands, feet and pressure sites.  Duration of the disease Post-inflammatory caused by scratching  Distribution and progression of the condition may occur on the back with sparing in the middle. Pruritus  Exacerbating or relieving factors  Associated symptoms like itching, burning, pain, weeping and redness disturbs the sleeping pattern, thus severely affecting the  Family history of skin disorders quality of life and general health of a pregnant woman.  Social history, such as, job, travel Obstetric cholestasis has been linked to stillbirth,  Past medical history, such as, asthma, hay fever premature birth, meconium passage, , delivery  Drug history and allergies  Past dermatological problems by and postpartum haemorrhage, but some 13  Previous treatments tried for this condition of this evidence is of poor quality. Monitoring of liver  Impact of condition on quality of life function and bile acids in patients with suspected obstetric cholestasis is crucial as it allows monitoring and exclusion of other conditions. Consideration should be given to carrying Box 3. Examination out investigations such as a viral screen, liver autoimmune and pre- screen and liver ultrasound to rule out Distribution  Site other causes.  Symmetry: If liver function improves or worsens very rapidly then this - Symmetry suggests endogenous cause condition becomes less likely and other diagnoses need to be - Non-symmetry suggests an exogenous cause e.g. infection, irritant sought. It is not possible at present to predict poor outcome or from deranged biochemistry levels and therefore there are no Description of primary lesion specific cut-off points for delivery.13 However, a link between  Shape outcome and bile acid levels is suspected and is the focus of  Size current research.  Colour No evidence-based antenatal surveillance techniques are  Margin available currently in prevention of stillbirth and perinatal  Surface  Type of lesion – , pustule, wheal, vesicle, bulla complications as ultrasound scans and are not reliable in preventing intrauterine death which is usually

ª 2013 Royal College of Obstetricians and Gynaecologists 3 4 kneutosspeci eruptions Skin fi opregnancy to c

Table 1. Dermatoses of pregnancy

Dermatoses of pregnancy Areas affected Risk factors Recurrence risk Management Pregnancy outcome

Intrahepatic cholestasis Scalp, anus, vulva and Indian–Asian or 60–70% in future Ursodeoxycholic acid ? Increased risk of stillbirth of pregnancy abdominal skin Pakistani–Asian pregnancies Topical emollients ? Increased risk of PPH ethnic origin, previous Sedating antihistamines ? Increased risk of fetal distress obstetric cholestasis ? Water-soluble vitamin K Increased risk of premature birth (mostly iatrogenic), meconium passage and caesarean section Atopic eruption of Face, neck, chest and Family history of atopy Limited data Topical emollients No on mother or fetus pregnancy extensor surfaces of the Topical anti-pruritics limbs and trunk Topical steroids Antihistamines Ultraviolet light Topical acne treatment Polymorphic eruption Abdominal striae with Nulliparity, multiple Rarely recurs Topical steroids (first-line) No adverse effect on mother or fetus of pregnancy periumbilical sparing pregnancies Topical emollients Can progress to trunk Any cause of Antihistamines and extremities, sparing overdistension of skin Oral steroids palms, soles and face Pemphigoid gestationis Appears around umbilicus Recognised correlation with May recur in Topical/oral corticosteroids IUGR ª unlike PEP the haplotypes HLA-DR3 subsequent Antihistamines ? Preterm labour 03RylCleeo bttiin n Gynaecologists and Obstetricians of College Royal 2013 Can progress to trunk, and HLA-DR4 pregnancies, with Antibiotics Self-limiting skin lesions in neonate extremities, palms and Other autoimmune earlier onset and Immunophoresis soles with conditions increasing severity Immunosuppressants mucosal sparing Also may recur with oral contraception/ menstruation

IUGR = intrauterine growth restriction; PEP = polymorphic eruption of pregnancy; PPH = Postpartum haemorrhage; ? = limited evidence Maharajan et al. sudden.13 The role of monitoring fetal movements has not been assessed in women suffering from obstetric cholestasis. Early intervention such as induction of labour is not routinely recommended.13 Postnatal resolution of liver function should be carried out after 10 days as biochemistry may worsen in the immediate postnatal period.13 Recurrence risk is thought to be 45–90%.13 Ursodeoxycholic acid is reported to be the only known effective treatment of intrahepatic cholestasis, which not only reduces maternal pruritus and liver function, but is also said to improve prognosis for the fetus, although the data are not robust.14 It is reported to have a good safety profile at the dose of 15 mg/kg a day as a single dose or in two divided doses.14,15 It is licensed in the UK for the treatment of gallstones and biliary cirrhosis at the dose of 8–12 mg/kg in two divided doses or as a single dose, and pregnancy and lactation are on the list of contraindications. Topical emollients may be used which may provide some relief from pruritus although no good-quality evidence exists to support their use. Sedating antihistamines may help with sleep at night but are unlikely to have a major Figure 3. Atopic eruption of pregnancy in a 12 weeks pregnant effect on pruritus. It has been suggested that a discussion woman with the woman should be had about the use of water-soluble vitamin K to prevent clotting abnormalities related to the hepatic effects of obstetric cholestasis. and requires no further investigations as long as other However, there is a small theoretical risk of neonatal dermatoses of pregnancy have been ruled out. haemolytic anaemia, hyperbilirubinaemia and kernicterus.13 Histopathology is non-specific and immunofluorescence is The patient’s consent for unlicensed treatments needs to negative. Improvement is seen following delivery with no be obtained. postnatal exacerbation. There are limited data on its recurrence in the next pregnancy. Atopic eruption of Atopic eruption of pregnancy pregnancy is relatively benign and causes no adverse effects Atopic eruption of pregnancy (Figure 3) is also known as on the mother or fetus. (Besnier), Nurse’s early-onset prurigo of Treatment of atopic eruption of pregnancy is pregnancy, pruritic of pregnancy or eczema symptomatic. Oatmeal baths, emollients, topical in pregnancy. antipruritics such as 1% menthol in aqueous cream and Atopic eruption of pregnancy is known to be a benign calamine in aqueous cream, topical steroids and oral condition and the most common dermatosis of pregnancy antihistamines, and ultraviolet light may help to alleviate with an incidence of 1 in 300.5 There is a higher incidence of symptoms. Wearing soft light clothes and staying in a cool atopic eruption of pregnancy in women with a family history environment is recommended. Topical benzoyl peroxide of atopy. The pathogenesis of this condition is thought to be preparations and erythromycin with zinc acetate lotion are linked to pregnancy-specific immunological changes. sometimes effective in atopic eruption of pregnancy, which Reduced cellular immunity and reduced production of Th1 some clinicians consider to be hormone-induced acne.18 cytokines (interleukin[IL]-2, IL-12, interferon gamma) stand in contrast to the dominant humoral immunity and Polymorphic eruption of pregnancy increased secretion of Th2 cytokines (IL-4, IL-10).16 In Polymorphic eruption of pregnancy (Figure 4) is also known 80% of cases atopic eruption of pregnancy occurs as the as pruritic urticarial and plaques of pregnancy, toxic primary condition and in the rest of patients as an erythema of pregnancy, Bourne’s toxaemic of exacerbation of a pre-existing complaint. It predominantly pregnancy, linear IgM dermatosis of pregnancy and Nurse’s affects women in the second and third trimester, but may also late-onset prurigo. occur as early as the first trimester.17 It is a benign, self-limiting, pruritic inflammatory disorder It presents as erythematous, excoriated nodules or papules of pregnancy with the reported incidence being between 1 in on the face, neck, chest and extensor surfaces of the limbs 160 and 1 in 300 pregnancies, usually presenting in the third and trunk.17 The diagnosis is based on clinical presentation trimester or immediately postpartum. Risk factors include

ª 2013 Royal College of Obstetricians and Gynaecologists 5 Skin eruptions specific to pregnancy nulliparity, multiple pregnancies and any other cause of Pemphigoid gestationis overdistension of the abdominal skin in pregnancy. Pemphigoid gestationis (Figure 5) is also known as The condition initially presents with pruritic, pregnancy-related , gestational erythematous papules commonly located within the pemphigoid and herpes gestationis. abdominal striae and with periumbilical sparing. It The incidence of this dermatosis is very rare, affecting progresses to the trunk and extremities, sparing the palms between 1 in 1700 and 1 in 50 000 pregnancies, and it occurs and soles in the majority of cases, and does not affect the face. any time after the second trimester and, rarely, immediately The lesions can coalesce to form plaques or wheals, often after . resembling target lesions.19 Most of the time it resolves The rash usually appears around the umbilicus as urticarial within 4–6 weeks from the time of onset. papules and plaques, which join to form bullae, extending to The cause of polymorphic eruption of pregnancy is involve the trunk, extremities, palms and soles with mucosal unknown and may be multifactorial. One hypothesis sparing. Large, tense can form after a few weeks suggests that stretching of the abdomen causes damage around the edge of the rash or in otherwise unaffected areas to the connective tissue, provoking an inflammatory of the skin. reponse.20 No association is noted with hormonal or It is believed to be an autoimmune condition with immunological changes. antibodies against target antigen (proteins of and Most cases are diagnosed clinically without the need for the skin). There is a recognised correlation with the invasive testing. However, skin biopsies may be needed if haplotypes HLA-DR3 and HLA-DR4. A skin biopsy is there is no response to initial treatment, or there is doubt as necessary to make the diagnosis. Two samples must be to the diagnosis. Histology shows lymphocytic with taken from perilesional skin: one for histology and the other eosinophils and oedema of the papillary . Early for direct immunofluorescence studies. Histology reveals biopsies show a prominent dermal oedema, and later degenerative changes in the basal cells resulting in the biopsies reveal epidermal changes such as spongiosis, and being located first in the and subsequently hyper- and parakeratosis.21 Negative direct and indirect between the Malphigian layer and the subepidermal immunofluorescence studies help in differential diagnosis basement membrane. There is associated spongiosis. Direct with pemphigoid gestationis. immunofluorescence studies reveal C3 deposition along the This dermatosis is usually self-limiting and treatment is basement membrane. Complement fixing IgG antibodies are predominantly for symptom control to relieve pruritus and seen in 50% of patients.22 Indirect immunofluorescence reduce inflammation. Topical steroids are often used as the (blood or blister fluid) reveals circulating IgG against BP180 first line of treatment and oral steroids are virtually never or bullous pemphigoid antigen 2 in the hemidesmosomes of required. Antihistamines and emollients may also be the basal membrane zone.23 beneficial. Induction of labour is not necessary or Treatment focuses on symptom control with the use of recommended, as polymorphic eruption of pregnancy has topical and oral corticosteroids and antihistamines. Therapy no impact on maternal or fetal outcome. Recurrence in may need to be altered prior to delivery to prevent a flare-up. subsequent pregnancies is rare. Drug treatment will depend on individual circumstances.

Figure 4. Polymorphic eruptions in pregnancy Figure 5. Pemphigoid gestationis

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Oral steroids can be indicated for symptomatic relief of  Pemphigoid gestationis. symptoms if topical corticosteroids are not sufficient for  Intrahepatic cholestasis of pregnancy. disease control. Pregnant women are at increased risk of Women who should be referred to a dermatologist include osteoporosis so steriods should be used with caution. those with: Typically prednisolone 30–40 mg (0.5 mg/kg bodyweight)  Pemphigoid gestationis. reduced by 5 mg every 3 days to 0. It is essential to monitor  Polymorphic eruption of pregnancy, atopic eruption of glucose and electrolytes while on treatment. Various other pregnancy or a localised area of itching or skin eruption systemic treatments, including some antibiotics, can be where initial management fails. helpful in recalcitrant disease. Alendronic acid is  Skin eruptions associated with systemic symptoms. contraindicated in pregnancy. Cyclosporin appears to be safe in pregnancy. Recent data show no increased risk of Ideally, patients with any skin eruption should be seen in a malformation, preterm labour or low birthweight babies and joint obstetric/dermatology clinic. thereby its use during pregnancy can be considered safe and effective.24 The American Academy of Pediatrics25 considers cyclosporine contraindicated during breastfeeding owing to Conclusion the potential for immunosuppression and neutropenia. It Pregnancy results in a variety of physiological and is used with monitoring of renal function and blood pressure pathological changes to the skin. The latter can be divided if it proves impossible to maintain disease control with less into two categories – those that can occur outside pregnancy than 7.5 mg prednisolone. Immunosuppressants as and those that are unique to pregnancy. Idiopathic pruritus steroid-sparing agents may be helpful for severe cases without obvious skin eruption is a common problem. post-delivery. Cases unresponsive to systemic Diagnosis and management are dependent upon a 26 corticosteroids may benefit from immunophoresis. structured history and examination, and understanding of Exacerbations and remissions are characteristic. The serious and/or common dermatoses that may require referral course of the disease shows frequent improvement towards to a dermatologist. delivery followed by a flare-up at the time of delivery (75% of 21 patients). Increased blistering can occur around delivery. If Disclosure of interests the blister count increases as the expected date approaches, None declared. the dose of prednisolone may need to be introduced/ increased for 7 days with monitoring. A postnatal flare-up is also common and usually resolves within 2 to 6 weeks. References Unlike polymorphic eruption of pregnancy, pemphigoid 1 Ambros-Rudolph CM, Mullegger€ RR, Vaughan-Jones SA, Kerl H, gestationis may recur in subsequent pregnancies, with earlier Black MM. The specific dermatoses of pregnancy revisited and onset and increasing severity, and also with use of oral reclassified: results of a retrospective two-center study on 505 contraception or during menstruation.27 There have been pregnant patients. J Am Acad Dermatol 2006;54:395–404. reported cases of intrauterine growth restriction with this 2 Wong RC. Physiologic skin changes in pregnancy. In: Harahap M, Wallach RC, editors. Skin Changes and Diseases in Pregnancy. New dermatosis, so antenatal fetal surveillance is crucial to watch York, NY: Marcel Dekker, Inc; 1996. p. 37. out for this complication.28 It is prudent to increase 3 Martin AG, Leal-Khouri S. Physiologic skin changes associated with frequency of scanning to monthly if there is suspicion of pregnancy. Int J Dermatol 1992;31:375. intrauterine growth retardation. There is conflicting evidence 4 Victor FC, Gelber J, Rao B. Melasma: a review. J Cutan Med Surg 2004;8:97. about any increased risk of preterm labour with this 5 Kroumpouzos G, Cohen LM. Dermatoses of pregnancy. J Am Acad condition.27,28 One in ten newborns may develop mild, Dermatol 2001;45:1–19. self-limiting skin lesions due to a passive transfer of 6 Esteve E, Saudeau L, Pierre F, Barruet K, Vaillant L, Lorette G. 10 [Physiological cutaneous signs in normal pregnancy: a study of 60 antibodies to the fetus. pregnant women]. [Article in French] Ann Dermatol Venereol Pemphigoid gestationis is described in association with 1994;121:227–31. other autoimmune diseases, including Graves’ disease and so 7 Kern P. Sclerotherapy of varicose leg veins. Technique, indications and consideration should be given to screening for this with complications. Int Angiol 2002;21:40. 29 8 Ross V, Domankevitz Y. Laser leg vein treatment: a brief overview. J thyroid function tests. Cosmet Laser Ther 2003;5:192. 9 Winton GB, Lewis CW. Dermatoses of pregnancy. J Am Acad Dermatol 1982;6:977. Referral criteria to secondary care 10 Black MM, Ambros-Rudolph C, Edwards L, Lynch P, editors. Obstetric and Gynaecologic Dermatology. 3rd ed. London: Mosby Elsevier; In general women should be referred to an obstetric 2008. consultant if they have symptoms and signs of the 11 Kenyon AP, Tribe RM, Nelson-Piercy C, Girling JC, Williamson C, Seed following dermatoses in pregnancy: PT, et al. Pruritus in pregnancy: a study of anatomical distribution and

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prevalence in relation to the development of obstetric cholestasis. 21 P~aunescu MM, Feier V, P~aunescu M, Dorneanu F, Sisak A, Obstet Med 2010;3:25–9. Ambros-Rudolph CM. Dermatoses of pregnancy. Acta 12 Abedin P, Weaver JB, Egginton E. Intrahepatic cholestasis of pregnancy: Dermatovenerol Alp Panonica Adriat 2008;17:4–11. prevalence and ethnic distribution. Ethn Health 1999;4:35–7. 22 Kint A, Geerts ML, Vanneste B, De Cuyper C. Herpes gestationis. A 13 Royal College of Obstetricians and Gynaecologists. Obstetric histological and electron microscopic study. Ann Dermatol Venereol Cholestasis. Green-Top Guideline No. 43. London: RCOG; 2011. 1980;107:1133–42. 14 Palma J, Reyes H, Ribalta J, Hernandez I, Sandoval L, Almuna R, et al. 23 Zilikens D. Pemphigoid gestationis: recent advances. J Eur Acad Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: a Dermatol Venereol 2003;17 Suppl 3:7. randomized, double-blind study controlled with placebo. J Hepatol 24 Branche J, Cortot A, Bourreille A, Coffin B, Vos M, Saussure P, et al. 1997;27:1022–8. Cyclosporine treatment of steroid-refractory ulcerative colitis during 15 Kondrackiene J, Beuers U, Kupcinskas L. Efficacy and safety of pregnancy. Inflamm Bowel Dis 2009;15:1044–8. ursodeoxycholic acid versus cholestyramine in intrahepatic cholestasis 25 American Academy of . The transfer of drugs and of pregnancy. Gastroenterology 2005;129:895–901. other chemicals into human milk. Pediatrics 108, 776–789 16 Garcia-Gonzalez E, Ahued-Ahued R, Arroyo E, Montes-De-Oca D, (2001). Granados J. Immunology of the cutaneous disorders of pregnancy. 26 Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. Int J Dermatol 1999;38:721–9. 7th ed. Philadelphia: Lippincot Williams & Wilkins; 2005. 17 Vaughan Jones SA, Black MM. Pregnancy dermatoses. J Am Acad 27 Vaughan Jones SA, Hern S, Nelson-Piercy C, Seed PT, Black MM. A Dermatol 1999;40:233. prospective study of 200 women with dermatoses of pregnancy 18 Wilkinson SM, Buckler H, Wilkinson H, O’Driscoll J, Roberts MM. correlating clinical findings with hormonal and immunopathological Androgen levels in pruritic folliculitis of pregnancy. Clin Exp Dermatol profiles. Br J Dermatol 1999;141:71–81. 1995;20:234–6. 28 Chi CC, Wang SH, Charles-Holmes R, Ambros-Rudolph C, Powell J, 19 Aronson IK, Bond S, Fiedler VC. Pruritic urticarial papules and plaques Jenkins R et al. Pemphigoid gestationis: early onset and blister of pregnancy: clinical and immunopathologic observations in 57 formation are associated with adverse pregnancy outcomes. patients. J Am Acad Dermatol 1998;39:933. Br J Dermatol 2009;160:1222–8. 20 Cohen LM, Capeless EL, Krusinski PA, Maloney ME. Pruritic urticarial 29 Semkova K, Black M. Pemphigoid gestationis: current insights into papules and plaques of pregnancy and its relationship to maternal-fetal pathogenesis and treatment. Eur J Obstet Gynecol Reprod Biol weight gain and twin pregnancy. Arch Dermatol 1989;125:1534. 2009;145:138.

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