Pemphigoid (Herpes) Gestationis
Pemphigoid (herpes) gestationis (PG; see Chapter 59) is an intensely pruritic, vesiculobullous eruption of mid- to late pregnancy and the immediate postpartum period. PG classically begins during the second or third trimester, and is manifest by the abrupt appearance of severely pruritic urticarial lesions on a background of normal or erythematous skin. PG is associated with an increased incidence of small-for-gestational age births and premature delivery. PG is immunologically mediated, and linear deposition of C3 with or without IgG are found at the dermal–epidermal junction by direct immunofluorescence (DIF).7
Intrahepatic Cholestasis of Pregnancy
Nomenclature and Epidemiology
The terms obstetric cholestasis, cholestasis of pregnancy, recurrent jaundice of pregnancy, cholestatic jaundice of pregnancy, idiopathic jaundice of pregnancy, prurigo gravidarum, and icterus gravidarum all refer to the same clinical entity, intrahepatic cholestasis of pregnancy (ICP), characterized by a reversible form of cholestasis in late pregnancy. Svanborg and Ohlsson first recognized ICP as a distinct entity, separate from other causes of jaundice during pregnancy in 1939.8 Jaundice develops in approximately 1 in 1,500 pregnant women. With an estimated incidence of 70 cases per 10,000 pregnancies in the United States, ICP ranks second only to viral hepatitis in terms of etiology of jaundice in pregnant women.9 Mild cases of ICP, in which pruritus is not accompanied by jaundice, were previously referred to as prurigo gravidarum.
ICP is most common in Scandinavia and South America. The highest reported incidence rates are in Chile (14%–16%), whereas much lower rates are seen among pregnant women in the United States (less than 0.1%–0.7%), Canada (0.1%), Australia (0.2%–1.5%), and Central Europe (0.1%–1.5%).9
Although the precise pathogenesis remains unclear, the interplay of hormonal, genetic, environmental, and alimentary factors is thought to induce a biochemical cholestasis in susceptible individuals. A prominent role for hormonal alterations is suggested by the following observations: (1) ICP is a disease of late pregnancy (corresponding to the period of highest placental hormone levels); (2) ICP spontaneously remits at delivery when hormone concentrations normalize; (3) twin and triplet pregnancies, characterized by greater rises in hormone concentrations, have been linked to ICP; and, (4) ICP recurs during subsequent pregnancies in an estimated 45%–70% of patients.9,10
Geographic variation and familial clustering indicate a genetic predisposition. ICP appears to be a polygenetic condition. Candidate genes include those mutated in a variety of other forms of inherited cholestasis: ABCB4 (multidrug resistance gene3), ABCB11 (Bsep), and ATP8B1 (FIC1). A recent decline in prevalence rates in Chile, reports of higher incidence rates during the winter months, and reports of relative reductions of selenium levels in some ICP patients all point toward etiologic roles for environmental and alimentary factors.9,11 At least one study confirmed a higher risk of hepatitis C virus infection among women with ICP.12
Patients classically present during the third trimester with moderate-to-severe pruritus, which may be either localized to the palms and soles or generalized. Pruritus begins during the first and second trimester in 10% and 25% of cases, respectively. Intense pruritus is oftentimes associated with secondary excoriations, although primary cutaneous lesions are invariably absent. Initially, patients may complain of nocturnal pruritus only, and symptoms generally are more severe at night throughout the course of illness. Constitutional symptoms such as fatigue, nausea, vomiting, or anorexia may accompany the pruritus. Progression to clinical jaundice, dark urine, or lightly colored stools occurs in approximately one in five patients. Pruritus generally precedes the onset of these symptoms by 1–4 weeks.9
A hallmark of ICP is that symptoms and associated biochemical abnormalities typically resolve within 2–4 weeks of delivery. Recurrences during subsequent pregnancies occur in an estimated 45%–70% of patients. Some women experience recurrent ICP after exposure to oral contraceptives or to contraceptive aids, such as synthetic estrogens and progestational agents.
Maternal outcomes are generally favorable, although women with severe cases are predisposed to postpartum hemorrhage secondary to vitamin K depletion. Additionally, affected women have a tendency toward the later development of cholelithiasis or gallbladder disease. Fetal risks in ICP include increased rates of prematurity, intrapartal fetal distress, and fetal death. These complications generally correlate with higher bile acid levels and are thought attributable to acute placental anoxia and an increased incidence of meconium-stained amniotic fluid. Such fetal complications may be reduced with treatment and induction of labor after fetal pulmonary maturation has been documented.9
Elevation in serum bile acids is the single most sensitive indicator of ICP. In healthy pregnant women, total bile acids (TBAs) are slightly elevated above baseline and levels as high as 11.0 μM are accepted as normal in late pregnancy. Clearly defined biochemical indices of ICP have not yet been established. However, Brites et al13 identified the following common features of ICP: (1) serum TBA concentrations greater than 11.0 μM (normal range, 4.6–8.7 μM); (2) cholic acid–chenodeoxycholic acid ratio greater than 1.5 (normal range, 0.7–1.5) or cholic acid proportion of TBAs greater than 42%; (3) glycine conjugates–taurine conjugates of bile acids ratio less than 1.0 (normal range, 0.9–2.0) or glycocholic acid concentration greater than 2.0 μM (normal range, 0.6–1.5 μM).13 Degree of pruritus and disease severity generally correlate with bile acid concentrations.
Mild perturbations in liver function tests, including elevated transaminases, alkaline phosphatase, 5′-nucleotidase, cholesterol, triglycerides, phospholipids, and lipoprotein X are commonly found. Among these parameters, alanine transaminase is particularly sensitive, as an elevation in this enzyme is not a feature of healthy pregnancies, but is commonly seen in ICP. γ-Glutamyl transferase, which is generally low in late gestation, is typically normal or slightly elevated in ICP. Direct (or conjugated) fractions of bilirubin are most commonly elevated in ICP. Albumin may be slightly reduced, whereas α2-globulins and β-globulins are appreciably elevated. However, routine liver tests alone are not a sufficient basis for the diagnosis of ICP.13
Cutaneous biopsy does not aid in the diagnosis of ICP. Although generally unnecessary, hepatic biopsy reveals intrahepatic cholestasis with dilated, plugged bile canaliculi and deposits of bile pigment in centrilobular hepatocytes.9
Distinction from other causes of pruritus in the pregnant woman can be challenging. The presence of primary lesions points away from a diagnosis of ICP, which lacks primary lesions. Other causes of liver derangement and jaundice, such as viral and nonviral hepatitis, medications, hepatobiliary obstruction, and other intrahepatic diseases (i.e., primary biliary cirrhosis) must be ruled out. Finally, it must be remembered that hyperthyroidism, allergic reactions, polycythemia vera, lymphoma, pediculosis, and scabies may each manifest as generalized pruritus in pregnant as in nonpregnant women.
Therapy aims to reduce serum bile acid levels and thereby prolong pregnancy, ameliorate maternal symptoms and reduce fetal risks. An interdisciplinary approach characterized by intense fetal surveillance is essential to the management of ICP. Although obstetric management varies, the need for weekly fetal monitoring beginning by the thirty-fourth week of gestation is widely accepted. Additionally, most authors recommend early induction of labor, commonly at 37–38 weeks’ gestation, but as soon as there is evidence of fetal pulmonary maturity in severe cases.9
In mild cases, adequate relief of maternal symptoms can be achieved with bland emollients and topical antipruritic agents. Antihistamines and Ultraviolet B (UVB) phototherapy are variably effective.7 Several uncontrolled trials have suggested that the anion exchange resin, cholestyramine, may effectively reduce symptoms in up to 70% of patients with mild ICP. However, the lack of randomized, placebo-controlled cholestyramine trials precludes definite conclusions about the efficacy of this agent. Furthermore, cholestyramine must be administered for several days before taking effect. Its efficacy in treating severe cases has been disappointing, and, importantly, it may precipitate vitamin K and thereby trigger a coagulopathy.14,15 Other systemic therapies such as dexamethasone, S-adenosylmethionine, and plasmapheresis have been reported to sometimes reduce maternal symptoms.7,9,16,17 However, these agents do not reverse the associated biochemical abnormalities, and thus, do not reduce fetal risks.
Ursodeoxycholic acid (UDCA), a naturally occurring hydrophilic bile acid, is the only treatment that has been shown to reduce maternal symptoms and fetal risk. UDCA exerts a hepatoprotective effect through augmentation of the excretion of hydrophobic bile acids, sulfated progesterone metabolites, and other hepatotoxic compounds. UDCA decreases bile acid levels in colostrum, cord blood, and amniotic fluid. The results of several small, randomized, placebo-controlled trials demonstrate that when administered at doses between 450 mg and 1,200 mg daily, UDCA is well tolerated and highly effective in controlling the clinical and liver function abnormalities that define ICP.15 Enhanced efficacy may be achieved by coadministration with S-adenosylmethionine.18 Randomized, controlled trials comparing UDCA head-to-head with either dexamethasone19 or cholestyramine20 demonstrated UDCA's superior efficacy.
Pustular Psoriasis of Pregnancy (Impetigo Herpetiformis)
Von Hebra first used the designation impetigo herpetiformis in 1872 to describe an acute pustular eruption with usual onset during the third trimester of pregnancy. It is now generally regarded as a variant of pustular psoriasis attributable to hormonal alterations during pregnancy; however, some authors maintain that it is a distinct clinical entity.21,22
Pustular psoriasis of pregnancy is characterized by an acute eruption occurring as early as the first, but generally during the third, trimester of an otherwise uneventful pregnancy. The condition manifests as erythematous patches whose margins are studded with subcorneal pustules (Fig. 108-4). The eruption typically originates in flexural areas but spreads centrifugally and sometimes generalizes. Subungual lesions may result in onycholysis. Rarely, mucous membrane involvement may lead to painful erosions. The face, palms, and soles are commonly spared. The rash may be pruritic or painful. Onset of the eruption is accompanied by such constitutional symptoms as fever, chills, malaise, diarrhea, nausea, and arthralgias. Rarely, tetany, delirium, and convulsions occur if hypocalcemia is severe.1
Pustular psoriasis of pregnancy. Erythematous patches are studded with subcorneal pustules.
Although generally regarded as a form of pustular psoriasis (see Chapter 18), absence of a positive family history, abrupt resolution of symptoms at delivery, and a tendency to only recur during subsequent pregnancies distinguish this entity from generalized pustular psoriasis. Moreover, factors known to trigger pustular psoriatic flares, such as infection, exposure to culprit drugs, or abrupt discontinuation of systemic corticosteroids are lacking in virtually all patients with pustular psoriasis of pregnancy.1,22
Histopathologic examination reveals classic features of pustular psoriasis (see Chapter 18). The most common laboratory derangements include leukocytosis, neutrophilia, an elevated erythrocyte sedimentation rate, hypoferric anemia, and hypoalbuminemia. Less commonly, calcium, phosphate, and vitamin D levels are decreased. Serum parathormone levels are rarely decreased. Cultures of pustule contents and peripheral blood are negative unless secondarily infected.1
Pustular psoriasis of pregnancy classically presents during the last trimester, but there are reports of cases occurring as early as the first trimester, during the puerperium, in nonpregnant women taking oral contraceptives, and in postmenopausal women. Symptoms are invariably progressive throughout pregnancy. A cardinal feature of this disorder is the rapid resolution of symptoms after delivery. Recurrences in subsequent pregnancies are common and characteristically are more severe with onset earlier in gestation.1 Several reports of subsequent menstrual exacerbation occurring either during or immediately preceding menses exist in the literature.23
More widespread disease generally portends a worse prognosis. Life-threatening maternal complications are infrequent today, but may result from profound hypocalcemia and bacterial sepsis. The most feared complications are placental insufficiency and consequent stillbirth or neonatal death. For these reasons, early induction of labor is often contemplated.21
Box 108-1 outlines the differential diagnosis of pustular psoriasis of pregnancy.
Box 108-1 Differential Diagnosis of Pustular Psoriasis of Pregnancy ||Download (.pdf)
Box 108-1 Differential Diagnosis of Pustular Psoriasis of Pregnancy
- Pustular drug eruption (acute generalized exanthematous pustulosis)
- Pemphigoid gestationis
- Pemphigus vulgaris
- Dermatitis herpetiformis
- Subcorneal pustular dermatosis
- Pustular eruption in inflammatory bowel disease
Always Rule Out
- Infectious causes of pustular eruptions
Resolution after delivery is the norm. However, given its consistently progressive course, treatment is indicated to reduce the risk of fetal and maternal complications during pregnancy. Topical treatments include wet dressings and topical corticosteroids, but are rarely effective as monotherapy. Systemic corticosteroids are the mainstay of therapy during pregnancy. Cyclosporine, which is categorized as pregnancy category “C,” has been successfully used at doses between 5 mg/kg and 10 mg/kg daily to treat cases refractory to high-dose systemic corticosteroids.24,25 Narrowband UVB combined with topical steroids has been reported to be successful.26 Infliximab, a TNF-α blocking agent has been successfully used without adverse effect on the fetus.27 Although careful consideration of the benefits and risks of TNF-blockade during pregnancy must be considered, these agents (including etanercept, infliximab, and adalimumab) are Class B and may have a role in the management of cases refractory to other therapies.
In all, cases, fluid status and electrolytes should be monitored with rapid correction of imbalances. Fetal monitoring is essential as decelerations in fetal heart rate may be the earliest sign of fetal hypoxemia. Maternal cardiac and renal functions may be compromised with disease progression and therefore should be monitored as well. Induction of labor is an option when symptoms do not remit despite supportive and pharmacologic therapy. The therapeutic armamentarium available after pregnancy termination or after delivery in a non-nursing mother can be extended to include oral psoralen and ultraviolet A (PUVA), oral retinoids, clofazimine, methotrexate, sulfapyridine, and sulfones.28