¹School of Medicine, ² Department of Dermatology, The University of Texas Medical Branch, Galveston, TX, USA

ABSTRACT
Acute bacterial skin and skin-structure infections (ABSSSIs), often caused by aerobic gram-positive cocci, are most often mild-tomoderate infections that can easily be treated in an outpatient setting. With the rates of these infections substantially increasing in the past decade, owing in part to the emergence of community acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), alternative options for the treatment of ABSSSIs are necessary. This editorial reviews the mechanism of action, efficacy, bacterial coverage, and potential side effect profiles for dalbavancin and oritavancin, both semisynthetic lipoglycopeptide antibiotics, and tedizolid, an oxazolidinone. Dalbavancin, oritavancin, and tedizolid have been extremely valuable additions to treatment options for ABSSSIs due to the convenient dosing regimen and the fact that there are fewer resistant organisms to these therapies at this time.

Key Words:
acute bacterial skin and skin-structure infections, antibiotics, glycopeptide, dalbavancin, oritavancin, tedizolid

Introduction

Acute bacterial skin and skin-structure infections (ABSSSIs), often caused by aerobic gram-positive cocci, are estimated to cause more than 15 million infections and 870,000 hospital admissions annually in the United States.1 SSSIs are most often mild-to-moderate infections that can easily be treated in an outpatient setting. Rates of these infections have substantially increased in the past decade, owing in part to the emergence of community acquired methicillin-resistant Staphylococcus aureus (CA-MRSA).² The economic burden of SSSIs remains substantial and is driven by the high costs of hospitalization, which is often required for severe SSSIs since the agents used to treat these infections require daily intravenous (IV) administration for multiple days.³ Early clinical detection of severe or necrotizing SSSIs is difficult because the disease is often indistinguishable from its milder counterparts early in the disease course. Signs of a severe infection include pain disproportionate to the clinical findings, violaceous bullae, cutaneous hemorrhage, skin sloughing, skin anesthesia, rapid progression, and gas in the tissue.⁴ Additionally, it is recommended that patients with SSSIs accompanied by signs and symptoms of systemic toxicity, such as hypotension, fever, hypothermia, tachycardia, increased creatinine level, decreased serum bicarbonate, increased creatinine phosphokinase, marked left shift, or C-reactive protein >13 mg/L, be considered for hospitalization.⁴

Glycopeptide antibiotics, such as vancomycin, have been used in treatment of SSSIs for over half a century and are still used extensively today; however, reduced vancomycin susceptibility in CA-MRSA strains as well as difficulty in therapeutic drug monitoring compromise the clinical efficacy of vancomycin.^2,5 Second generation semisynthetic lipoglycopeptide derivatives such as dalbavancin and oritavancin, which possess a broader spectrum of activity and improved pharmacokinetic properties, will be discussed in this article. The new glycopeptide antibiotics provide efficacious alternatives for the treatment of complicated ABSSSIs.¹ A major benefit is management in an outpatient setting, which could significantly decrease or omit the costs and risks of hospitalization, as well as eliminating the need for laboratory monitoring.¹

Oxazolidinones are another important class of antibiotics used in the treatment of ABSSSIs, particularly vancomycin resistant Enterococcus(VRE) infections. Historically, linezolid has been the antibiotic of choice; however, tedizolid is a novel oxazolidinone that offers enhanced antimicrobial potency, low rates of bacterial resistance, and potential safety advantages. Additionally, the recommended dosing of once per day may be more convenient and is associated with higher compliance than twice per day dosing for linezolid.⁶

To maintain effectiveness of new antibiotics, their use should be limited to ABSSSIs where the bacteria are susceptible to the new medication and are resistant to other more cost effective options. Although tedizolid, dalbavancin, and oritavancin have been approved for SSSIs caused by MRSA, they probably should not be used as a first-line treatment when there are less expensive and more easily accessible antibiotics, such as trimethoprimsulfamethoxazole or doxycycline, that are very effective for MRSA infections.⁷

Glycopeptide Therapeutics – Dalbavancin and
Oritavancin

Dalbavancin is a long-acting IV semisynthetic lipoglycopeptide antibiotic with bactericidal activity against gram-positive cocci, including MRSA.^6-10 It is the first US FDA approved drug for adults with ABSSSIs that requires only 2 IV doses administered 1 week apart: the first dose is 1000 mg IV infused over 30 minutes, followed 1 week later by the second dose of 500 mg IV.^6-10

Dalbavancin is effective for treatment of adult patients with ABSSSI caused by susceptible isolates of gram-positive organisms. Susceptible gram-positive organisms include Staphylococcus aureus (S. aureus), including MRSA and MSSA, and Streptococcus groups (S. pyogenes, S. agalactiae, and S. anginosus).^6-11 In vitro studies suggest it may also be effective against vancomycinsusceptible Enterococcus faecium and Enterococcus faecalis (E. faecalis), as well as vancomycin-intermediate S. aureus; however, clinical importance has not been established.^6,11 The safety and efficacy in pediatric patients 18 years of age and younger has not been demonstrated.^8,11 However, vancomycin has been successfully used in treating these bacterial infections in the pediatric patient population.11 Dalbavancin is pregnancy category C meaning there has been some fetal toxicity in animals, but no adequate human studies.^6,8,11

The adverse effects most commonly experienced include nausea, diarrhea, and headaches, reported in 5% or less of patients.^6-8,10,11 Infrequent serious hypersensitivity reactions, including anaphylaxis, have been reported and caution should be exercised with patients who have a known allergy to other glycopeptides.^8,10 Additionally, rapid IV infusion could cause infusion-related reactions (pruritus, urticaria, and flushing).^6-8,10 Slowing or interrupting the infusion may be helpful if this occurs.⁷

Oritavancin is a long-acting IV semisynthetic lipoglycopeptide antibiotic with potent activity against gram-positive pathogens, including MRSA.³ Oritavancin is bactericidal and has an extended plasma half-life.^3,11,12 It is the first single-dose antibacterial drug approved by the US FDA for treatment of adult patients with ABSSIs.¹² The recommended single dose is 1200 mg IV infused over 3 hours.^7,11 Dose adjustment for advanced age, decreased renal function, or moderate hepatic impairment is not required.^3,7

Oritavancin is approved for use in adults with ABSSSIs caused by susceptible gram-positive microorganisms. Susceptible grampositive microorganisms include S. aureus (including MRSA and MSSA), various Streptococcus groups (S. pyogenes, S. agalactiae, S. dysgalactiae, and S. anginosus), and E. faecalis (vancomycinsusceptible isolates only).¹¹ The safety and efficacy have not been established in patients 18 years of age and younger.¹¹ Oritavancin is pregnancy category C.¹¹

The adverse effects most often reported include nausea, headache, vomiting and diarrhea, all occurring in less than 10% of patients.^3,7,11,12Osteomyelitis is a rare adverse event occurring in 0.3% of patients.^11,12 If osteomyelitis is suspected an antibacterial agent other than oritavancin should be used.^11,12 Infrequent reports of serious hypersensitivity reactions have occurred.^3,11 It is important to be aware of patients who have a history of allergies to other glycopeptides, including vancomycin.¹¹ Additionally, infusion-related reactions (pruritus, urticaria, flushing) have been experienced, as with other glycopeptides.^3,11,12 If this occurs, slowing or interrupting the infusion should be considered.¹¹

The current therapeutic options for the treatment of ABSSSIs require multidose and multiday regimens, with some patients requiring dosage adjustments for renal insufficiency or monitoring of plasma drug concentration.³ Multiday regimens may require patients to be hospitalized over their course of treatment, which increases the risk of nosocomial complications.³ Additionally, oral antibiotic regimens have an increased rate of noncompliance, which increases the potential for pathogen resistance. Oritavancin achieves a sustained clinical response with a single dose and does not require dosage adjustments for renal insufficiency. Oritavancin and dalbavancin could potentially reduce or eliminate hospital stays, improve treatment compliance, reduce utilization of health care resources, and add flexibility to the treatment of these serious infections. Despite the advantages, other more cost effective antibiotics with a history of effective use in treatment of ABSSSIs should be considered before deciding to treat with dalbavancin or oritavancin.

Oxazolidinone Therapeutic – Tedizolid Phosphate

The oxazolidinones are a synthetic class of agents now commonly relied on for the treatment of ABSSSIs, including more serious infections like MRSA and VRE.¹³ With increasing utilization of linezolid, resistant pathogens have begun to emerge.¹³ Tedizolid phosphate is a second-generation oxazolidinone antibiotic that offers enhanced antimicrobial potency and low rates of bacterial resistance.^13-15 Available in both IV and oral forms, tedizolid exhibits bacteriostatic activity by binding the 50S subunit of the bacterial ribosome, resulting in inhibition of bacterial protein synthesis.^11,13-15 The recommended dosage is 200 mg once daily for 6 days,^6,7,14,16 which may offer increased convenience and compliance when compared to twice daily linezolid.

Clinical studies have proven tedizolid phosphate to be effective against susceptible isolates of gram-positive organisms including S. aureus (including MRSA and MSSA), various Streptococcus groups (S. pyogenes, S. agalactiae, and S. anginosus), and E. faecalis (including VRE).^6,7,11,13-16 In vitro studies have suggested it may also exhibit activity against some strains of Staphylococci and Enterococci that are not susceptible to vancomycin or linezolid; however, the clinical importance of this data has not been established.^{6,11,13,14,16} The safety and effectiveness in pediatric patients 18 years of age or younger has not been demonstrated; whereas, linezolid is indicated for use in pediatric patients.^11,16 Tedizolid phosphate is pregnancy category C.^6,11,16

Structural differences between tedizolid and linezolid are thought to contribute to tedizolid’s decreased rates of resistance and enhanced potency.^13,14 Bacteria confer resistance to linezolid by acquiring the chloramphenicol-florfenicol resistance gene, which can be horizontally transferred.^13,15 However, because of structural distinctions, tedizolid has decreased vulnerability to this resistance mechanism.^13,15 Interactions with the ribosomal subunit are thought to contribute to the increased potency of tedizolid.^13,15

Another potential advantage of tedizolid compared to linezolid is an improved safety profile.^14,15 The most common adverse effects are similar to those seen with linezolid and include nausea, headache, diarrhea, vomiting, and dizziness, each occurring in less than 8% of patients.^6,7,14-16 Toxicity linked to duration of treatment with linezolid includes peripheral and optic neuropathy as well as hematologic toxicity and thrombocytopenia.^13,16 Tedizolid has not had reports of peripheral and optic neuropathy.^13,16 Although tedizolid exposure has been limited to 21 days or less in patients, a rat study using tedizolid doses up to 10-fold greater than human doses did not induce a neuropathy.¹³ This data indicates a possible safety advantage of tedizolid. Additionally, at recommended doses, tedizolid has not been associated with hematologic toxicity or thrombocytopenia¹³; however, higher doses or longer treatment durations might increase the risk. Linezolid has been associated with the occurrence of myelosuppression, especially in patients who have underlying hematologic abnormalities or renal insufficiency, which requires complete blood counts to be monitored weekly.¹³ An additional concern exists for the oxazolidinone class, which has been shown to act as weak, reversible monoamine oxidase (MAO) inhibitors in some in vitro studies.^6,13 However, based on two randomized, double-blind, placebo-controlled crossover studies, as well as another study including both humans and animals, tedizolid failed to interact with serotonergic drugs, adrenergic agents, or result in MAO inhibitor activity.^6,13,16 Data from post marketing experience will be beneficial to confirm the encouraging results that are currently available.

Conclusion

Dalbavancin, oritavancin, and tedizolid have been extremely valuable additions to treatment options for ABSSSIs due to the convenient dosing regimen and the fact that there are fewer resistant organisms to therapy at this time. In practice, other antibiotics with a history of effective use for ABSSSIs, which also cost less, should be considered first in order to prevent bacterial resistance.

References

1. Chambers HF. Pharmacology and the treatment of complicated skin and skin-structure infections. N Engl J Med. 2014 Jun 5;370(23):2238-9.
2. Holmes NE, Howden BP. What’s new in the treatment of serious MRSA infection? Curr Opin Infect Dis. 2014 Dec;27(6):471-8.
3. Corey GR, Kabler H, Mehra P, et al. Single-dose oritavancin in the treatment of acute bacterial skin infections. N Engl J Med. 2014 Jun 5;370(23):2180-90.
4. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005 Nov 15;41(10):1373-406.
5. Tacconelli E, Kern WV. New antibiotics for skin and skin-structure infections. Lancet Infect Dis. 2014 Aug;14(8):659-61.
6. Two new drugs for skin and skin structure infections. Med Lett Drugs Ther. 2014 Aug 18;56(1449):73-5.
7. New MRSA drugs: tedizolid, dalbavancin, and oritavancin. Duke Antimicrobial Stewardship Outreach Network (DASON): Infection Prevention News. 2014 Aug; 2(8).
8. Dalvanceô (dalbavancin) for injection, for intravenous use [Prescribing information]. Chicago, IL: Durata Therapeutics U.S. Limited; revised May 2014.
9. Dalvanceô for acute bacterial skin and skin structure infections (ABSSSI). J Drugs Dermatol. 2014 Jun;13(6):772.
10. Boucher HW, Wilcox M, Talbot GH, et al. Once-weekly dalbavancin versus daily conventional therapy for skin infection. N Engl J Med. 2014 Jun 5; 370(23):2169-79.
11. Hussar DA, Nguyen A. Dalbavancin, tedizolid phosphate, oritavancin diphosphate, and vedolizumab. J Am Pharm Assoc (2003). 2014 Nov-Dec; 54(6):658-62.
12. Markham A. Oritavancin: first global approval. Drugs. 2014 Oct;74(15):1823-8.
13. Rybak JM, Marx K, Martin CA. Early experience with tedizolid: clinical efficacy, pharmacodynamics, and resistance. Pharmacotherapy. 2014 Nov; 34(11):1198-208.
14. Moran GJ, Fang E, Corey GR, et al. Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2014 Aug;14(8):696-705.
15. O’Riordan W, Green S, Mehra P, et al. Tedizolid phosphate for the management of acute bacterial skin and skin structure infections: efficacy summary. Clin Infect Dis. 2014 Jan;58 Suppl 1:S43-50.
16. Sivextro^® (tedizolid phosphate) for injection, for intravenous use; tablet, for oral use [Prescribing information]. Lexington, MA: Cubist Pharmaceuticals U.S; revised March 2015.

Department of Dermatology, University of Texas Medical Branch, Galveston, TX, USA

ABSTRACT
The pregnancy-specific skin disorders are pruritic, inflammatory eruptions. The current classification by Ambros-Rudolph et al. includes four entities: pemphigoid gestationis (PG), polymorphic eruption of pregnancy (PEP), atopic eruption of pregnancy (AEP), and intrahepatic cholestasis of pregnancy (ICP). Although these disorders are all characterized by intense pruritus during pregnancy, they can be distinguished by timing, morphology, histopathology, treatment and potential for fetal complications. Diagnosis is made by clinical presentation, histology, and immunofluorescence. PEP and AEP typically resolve without sequelae; however, PG may lead to prematurity and low birth weight, and ICP is associated with an increased risk of prematurity, fetal distress, and intrauterine fetal demise. The potential for serious fetal complications necessitates a thorough evaluation of pregnancy-related pruritus. This article will discuss the skin disorders specific to pregnancy, with a focus on clinical presentation, potential for fetal complications, pathogenesis, diagnosis, and treatment.

Key Words:
atopic eruption, intrahepatic cholestasis, pemphigoid gestationis, polymorphic eruption, pregnancy complications, pruritus, skin disease

Introduction

While pregnancy may result in a number of skin changes, there are pruritic eruptions that occur specific to pregnancy and the postpartum period.^1-3 In 1983, Holmes and Black proposed a classification of pregnancy-specific skin disorders, which included pemphigoid gestationis, polymorphic eruption of pregnancy, prurigo of pregnancy, and pruritic folliculitis of pregnancy.⁴ In 1998, Shornick proposed the addition of intrahepatic cholestasis of pregnancy.⁵ The current classification was proposed by Ambros-Rudolph et al. in 2006 on the basis of a large retrospective study of 505 patients, and includes four entities: pemphigoid gestastionis, polymorphic eruption of pregnancy, atopic eruption of pregnancy (encompassing prurigo of pregnancy and pruritic folliculitis of pregnancy), and intrahepatic cholestasis of pregnancy.²

A major etiology of skin changes in pregnancy involves alterations in the maternal immune system. To prevent fetal rejection, an imbalance is created between cellular and humoral immunity.^1-3 T helper type 2 (Th2) cytokine production is favored over Th1, enhancing humoral immunity and stunting cell-mediated immunity. The changes in maternal hormones are also believed to have an effect, as many skin disorders develop during the third trimester.³

This article will discuss the skin disorders specific to pregnancy, with a focus on clinical presentation, potential for fetal complications, pathogenesis, diagnosis, and treatment.

Discussion

Pemphigoid Gestationis

Pemphigoid gestationis (PG), previously known as herpes gestationis, is the most rare of the pregnancy-specific disorders, with incidence of 1:2,000 to 1:60,000, varying with the prevalence of human leukocyte antigens (HLA)-DR3 and HLA-DR4.^1,3 PG initially presents with pruritic, erythematous urticarial papules and plaques that progress to a vesiculobullous eruption. PG characteristically involves the umbilicus, and often spreads to the chest, back, and extremities.^3,4,6 Palms and soles can be affected, but not typically the face and mucosa.^3,4 The eruption develops most often in the third trimester.³ The course fluctuates throughout pregnancy and, in 75% of patients, a flare occurs at delivery.¹ PG usually clears spontaneously within a few months after delivery. Recurrence during subsequent pregnancies is common, and is often characterized by earlier presentation and increased severity.^1,3 There have also been reports of flares during menstruation or with the use of oral contraceptives.^1,6,7 There is an increased incidence of prematurity and small-for-gestational age infants, especially with more severe maternal disease, marked by blister formation and onset before the third trimester.^1,3 Approximately 10% of infants develop a transient, bullous eruption due to the transfer of antibodies via the placenta.^1,3,4

Autoimmune diseases commonly present during pregnancy due to the immunosuppression required to maintain fetal life. PG is an autoimmune condition in which antibodies develop against the NC16A domain of collagen XVII (BPAG2, BP180), which is present in the amniotic, placental, and umbilical cord tissues, in addition to the basement membrane of the skin.³ The antibodies activate the complement cascade leading to inflammation and bullae formation.^1,3,8 Immunoglobulin G (IgG) is the main crossreacting antibody seen in PG, specifically IgG4.^3,8 Women who present with this disorder are at a higher risk of autoimmune disease, particularly Grave’s disease.¹ An association with HLADR3 and HLA-DR4 has been observed.³

Histologically, pre-bullous PG is characterized by dermal edema and perivascular inflammation with lymphocytes, histiocytes, and eosinophils. A sub-epidermal split is observed in the vesiculobullous lesions, with an eosinophil-predominant infiltrate.^1,4,6 Direct immunofluorescence of peri-lesional skin shows linear deposition of complement 3 (C3) along the basement membrane zone in all patients.^1,3 Some patients also have IgG deposition along the basement membrane.¹ Enzyme-linked immunosorbent assay (ELISA) detects the specific antibodies against collagen XVII, which correlates with disease activity and can be monitored to assess treatment effectiveness.^1,3

Treatment of PG is focused on managing pruritus and bullae formation.^1,3 In mild cases, topical corticosteroids and antihistamines are effective. In severe bullous PG, it is appropriate to use systemic corticosteroids. The dose can be decreased after adequate control is attained, however, it is often increased prior to delivery due to the high risk of flare.³ Use of systemic corticosteroids does not increase fetal risk, and may actually decrease risk due to control of placental inflammation.⁹

Polymorphic Eruption of Pregnancy

Polymorphic eruption of pregnancy (PEP), previously called pruritic urticarial papules and plaques of pregnancy, is a benign, pruritic inflammatory disorder that affects approximately 1 in 160 pregnancies.^1,4,10 It is typically observed during the late third trimester or immediate postpartum period of first pregnancies, and the risk is increased with multiple gestations and rapid weight gain. Urticarial papules and plaques first appear within striae distensae on the abdomen, and unlike PG, spare the umbilicus. The eruption commonly spreads to the thighs and buttocks, and rarely may generalize.^1-3,10 One-to-two millimeter vesicles may develop, but in contrast to PG, bullae are not observed.¹ Target lesions and widespread erythema may also be present.⁴ The eruption is self-limited and clears spontaneously in 4-6 weeks without relation to delivery. It does not typically recur; however, there have been recurrences with earlier presentation of the lesions in subsequent pregnancies that are multiple gestations. No adverse fetal outcomes have been described.^1,3

It is theorized that connective tissue damage from excessive stretching plays a major role in the pathogenesis of the disorder. The stretching may elicit an immune response to the damaged connective tissue antigen.^1,3

Histological findings are similar to PG. In early PEP, a superficial to mid-dermal perivascular infiltrate of lymphocytes, histiocytes, and sporadic eosinophils is observed with edema of the dermis. Later stages of PEP demonstrate epidermal spongiosis.^1,3,4,6 Immunofluorescence is negative, distinguishing PEP from PG.^1-3,10

Treatment of PEP is based on symptomatic relief with the use of topical corticosteroids and antihistamines. If the rash becomes generalized, a short systemic corticosteroid taper can be used.^1,3

Atopic Eruption of Pregnancy

Atopic eruption of pregnancy (AEP) is the most common pregnancy-specific skin disorder, accounting for almost 50% of cases. It has also been referred to by several other names including prurigo of pregnancy, prurigo gestationis, early-onset prurigo of pregnancy, Spangler’s papular dermatitis of pregnancy, pruritic folliculitis of pregnancy, and eczema of pregnancy.^1-3 AEP is a benign disorder characterized by a pruritic eczematous or papular eruption.¹ It usually presents before the third trimester, in contrast to the other dermatoses of pregnancy.^1,4 Two-thirds of AEP cases are characterized by eczematous skin changes in the common atopic sites such as neck and flexor surfaces. The remaining cases are characterized by a papular eruption of the abdomen and extremities.¹ Lesions typically respond well to treatment and spontaneously clear postpartum; however, AEP is likely to recur in future pregnancies.^1,3 The fetus is unaffected, but is at increased risk for atopic dermatitis as an infant.¹

It is thought that the pathogenesis of atopic eruption of pregnancy is initiated by pregnancy-related immune system changes.^1,3 There is a shift towards humoral immunity, with increased Th2 activation.¹ Patients who develop AEP may have an existing predisposition to atopic dermatitis, but 80% of the patients develop these skin changes for the first time during their pregnancy.¹ A family history of atopic dermatitis is frequently observed.³

AEP is commonly a diagnosis of exclusion, as diagnostic testing is nonspecific. Serum IgE levels are elevated in 20-70% of patients.¹ Other pregnancy-specific skin disorders, particularly ICP, must be excluded. Additionally, pruritic eruptions not specific to pregnancy, such as scabies and drug eruptions, must be considered in the differential diagnosis of AEP.

Topical corticosteroids are the mainstay of treatment. In severe cases, systemic corticosteroids and antihistamines may be indicated for short-term use. Phototherapy can also be considered.¹

Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy (ICP), known previously as obstetric cholestasis, cholestasis of pregnancy and jaundice of pregnancy, is a reversible cholestasis that appears to be hormonally triggered towards the end of pregnancy in predisposed women. It is characterized by pruritus of acute onset that often starts on the palms and soles and then generalizes. On exam, there are only secondary lesions, such as excoriations and prurigo nodules. Ten percent develop jaundice due to concomitant extrahepatic cholestasis. After delivery, pruritus resolves within a few weeks. There is a risk of recurrence in future pregnancies and with the use of oral contraceptives.^1,11

Recognition of ICP is critical due to its association with serious sequelae. Potential fetal complications include prematurity, intrauterine fetal distress, and intrauterine fetal demise.^1,11 Fetal complication rates correlate with total bile acids in maternal serum, but do not increase significantly until bile acid levels exceed 40 µmol/L.¹² In cases of severe ICP complicated by jaundice, there is risk of maternal or fetal hemorrhage due to malabsorption of vitamin K.^1,11

The severe pruritus present in ICP is due to elevated conjugated bile salts in the blood caused by impaired secretion, a multifactorial process influenced by genetics, environment and hormones.¹ There is a higher incidence of ICP in twin pregnancy.¹¹

ICP is diagnosed by elevated bile acid level. Hyperbilirubinemia is noted in only the most severe cases, about 10-20%, and liver function tests can be normal in 30%. Histology is nonspecific and immunofluorescence is negative.^1,11

Treatment targets serum bile acid levels to reduce fetal risk and control maternal symptoms.^1,11 Recommended treatment is ursodeoxycholic acid (UDCA).^1,3,11 Other drugs have been found to decrease pruritus but not fetal risk, including antihistamines, S-adenosyl-L-methionine, dexamethasone, and cholestyramine.¹ Anion exchange resins, such as cholestyramine, can cause a vitamin K deficiency independent of ICP and, therefore, should be avoided.¹¹

Conclusion

The four skin disorders specific to pregnancy, pemphigoid gestationis, polymorphic eruption of pregnancy, atopic eruption of pregnancy, and intrahepatic cholestasis of pregnancy, can be distinguished by clinical presentation, histopatholgy, pathogenesis, and potential for fetal complication. Only pemphigoid gestationis and intrahepatic cholestasis of pregnancy are associated with significant risk to the fetus. As these dermatoses are all characterized by pruritus, careful evaluation of any pregnancy related pruritus is essential to appropriately treat the mother and manage any potential risk to the fetus.

References

1. Ambros-Rudolph CM. Dermatoses of pregnancy – clues to diagnosis, fetal risk and therapy. Ann Dermatol. 2011 Aug;23(3):265-75.
2. Ambros-Rudolph CM, Mullegger 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 Mar;54(3):395-404.
3. Warshauer E, Mercurio M. Update on dermatoses of pregnancy. Int J Dermatol. 2013 Jan;52(1):6-13.
4. Holmes RC, Black MM. The specific dermatoses of pregnancy. J Am Acad Dermatol. 1983 Mar;8(3):405-12.
5. Shornick JK. Dermatoses of pregnancy. Semin Cutan Med Surg. 1998 Sep;17(3):172-81.
6. Shornick JK, Bangert JL, Freeman RG, et al. Herpes gestationis: clinical and histologic features of twenty-eight cases. J Am Acad Dermatol. 1983 Feb;8(2):214-24.
7. Lawley TJ, Stingl G, Katz SI. Fetal and maternal risk factors in herpes gestationis. Arch Dermatol. 1978 Apr;114(4):552-5.
8. Patton T, Plunkett RW, Beutner EH, et al. IgG4 as the predominant IgG subclass in pemphigoides gestationis. J Cutan Pathol. 2006 Apr;33(4):299-302.
9. 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 Jun;160(6):1222-8.
10. 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 Sep;51(9):1047-53.
11. Lammert F, Marschall HU, Glantz A, et al. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol. 2000 Dec;33(6):1012-21.
12. Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates. Hepatology. 2004 Aug;40(2):467-74.