The Importance of Serum Bile Acid Level Analysis and Treatment with Ursodeoxycholic Acid in Intrahepatic Cholestasis of Pregnancy a Case Series from Central Europe

OBSERVATION The Importance of Serum Bile Acid Level Analysis and Treatment With Ursodeoxycholic Acid in Intrahepatic Cholestasis of Pregnancy A Case Series From Central Europe

Christina M. Ambros-Rudolph, MD; Martin Glatz, MD; Michael Trauner, MD; Helmut Kerl, MD; Robert R. Mu¨llegger, MD

Background: Intrahepatic cholestasis of pregnancy (ICP) with impaired fetal prognosis. Only 10 cases (77%) had is a severely pruritic form of reversible cholestasis that is other liver function test result abnormalities. Fetal dis- associated with significant fetal risks. Because precise di- tress occurred in 3 pregnancies (23%). In the 10 cases agnostic and therapeutic guidelines are lacking, we per- treated with ursodeoxycholic acid, 3 (30%) involved pre- formed a retrospective investigation of dermatologic and term deliveries compared with a 100% preterm delivery biochemical features, treatment, and neonatal outcome in rate in the cases not treated with ursodeoxycholic acid. patients with ICP seen from 2000 through 2005 at a university-based dermatologic hospital in central Europe. Conclusions: Severe pruritus with or without skin changes in the second half of pregnancy should alert the Observations: The 13 observed cases of ICP (11 pa- physician to the possibility of ICP. Elevated total serum tients) represented 6% of all pregnancy-associated der- bile acid levels are the clue to diagnosis, which should matoses at our department. Intrahepatic cholestasis of preg- be established as early as possible. Close obstetric sur- nancy started at a mean±SD of 30±4 weeks’ gestation, with veillance and prompt treatment with ursodeoxycholic pruritus as the leading symptom, followed by secondary acid are warranted. skin lesions in 11 cases (85%). Total serum bile acid levels were markedly elevated in all patients and correlated Arch Dermatol. 2007;143:757-762

NTRAHEPATIC CHOLESTASIS OF nancy is often neglected. In the case of ICP, pregnancy (ICP) or obstetric cho- dermatologists may not have been alerted lestasis is a rare form of revers- to the problem enough, since most of the ible cholestasis occurring in the pertinent literature has been published in second half of pregnancy and is hepatologic or obstetric journals. As a con- Ione of the specific dermatoses of preg- sequence, the dermatologic characteriza- nancy, along with pemphigoid gestatio- tion of ICP is vague and precise diagnos- nis, polymorphic eruption of pregnancy, tic and therapeutic guidelines are lacking. and atopic eruption of pregnancy.1 Pruri- This leads to delayed diagnosis and treat- tus is typical for all 4 specific dermatoses ment and threatens fetal prognosis. of pregnancy, and their clinical presenta- The purposes of this study were to re- tion often overlaps. Intrahepatic cholesta- port our experience with 13 recent cases sis of pregnancy may be associated with of ICP seen at a university-based derma- significant fetal risks, including prema- tologic hospital in central Europe with em- ture births in 19% to 60% of deliveries, in- phasis on clinical presentation, diagnos- trapartal fetal distress in 22% to 33% of af- tic clues, treatment, and fetal outcome and fected pregnancies, and stillbirths in 1% to review the literature. to 2%.2 Thus, prompt diagnosis and specific treatment are warranted to prevent METHODS fetal impairment. The difficult clinical diagnosis can be substantiated by the find- Between 2000 and 2005, 228 pregnant pa- Author Affiliations: ing of elevated total serum bile acid lev- tients with skin disorders were seen at the De- Departments of Dermatology els.2 While various therapies have been partment of Dermatology, Medical University (Drs Ambros-Rudolph, Glatz, of Graz, Graz, Austria, and entered into the da- Kerl, and Mu¨ llegger) and applied, including antihistamines and cho- tabase of our specialized dermatologic preg- Internal Medicine (Dr Trauner), lestyramine resin, only ursodeoxycholic nancy clinic. Among those 228 patients, 13 Medical University of Graz, acid has been shown to improve fetal prog- cases of ICP could be identified and were ret- Graz, Austria. nosis.2 Unfortunately, pruritus in preg- rospectively studied by medical chart review.

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 1. Characteristics of 13 Cases (11 Patients) With Intrahepatic Cholestasis of Pregnancy

Case No./ Pruritus Onset of Time of Bile Acid Abnormal Time of Neonatal Age of Gravida/ in Previous Pruritus, Skin Diagnosis, Levels, Routine LFT Delivery, Mode of Fetal Sex/ Patient, y Para Pregnancies wk Lesions wk µmol/L Findings Treatment wk Delivery Outcome Weight, g 1*/27 1/0 − 24 Prurigo 29 21.0 No Ursodeoxycholic acid 38 SP Unimpaired F/2100 2*/29 2/1 Yes 24 Prurigo 31 22.0 No Ursodeoxycholic acid 40 IND Unimpaired F/2090 3*/32 3/2 Yes 32 Prurigo 35 28.2 Yes Ursodeoxycholic acid 38 SP Unimpaired M/2100 4/27 1/0 − 32 None 32 11.3 Yes Ursodeoxycholic acid 40 SP Unimpaired F/3140 5/21 2/1 Yes 35 None 37 32.0 Yes Topical corticosteroid 37 IND Prematurity F/3430 6/41 4/3 Yes 24 Prurigo 35 50.0 Yes Cholestyramine resin, 35 SP Prematurity M/2690 antihistamines 7/16 1/0 − 25 Prurigo 31 50.4 Yes Topical steroid 31 IND Prematurity, FD M/1610 8/34 3/1 No 35 Prurigo 37 42.8 No Ursodeoxycholic acid 40 SP Unimpaired M/3545 9/32 1/0 − 32 Excor 36 16.0 Yes Ursodeoxycholic acid 39 SP Unimpaired F/3600 10/44 3/2 Yes 32 Excor 36 35.2 Yes Ursodeoxycholic acid 37 SP Prematurity M/3135 11/24 5/2 Yes 29 Excor 36 138.0 Yes Ursodeoxycholic acid 37 C Prematurity, FD M/2900 12/22 2/1 Yes 29 Prurigo 33 95.0 Yes Ursodeoxycholic acid 35 IND Prematurity, FD F/2550 13/40 1/0 − 35 Excor 39 18.0 Yes Ursodeoxycholic acid 40 SP Unimpaired M/3040

Abbreviations: C, cesarean; Excor, excoriations; FD, fetal distress; IND, induction; LFT, liver function test; Prurigo, prurigo nodularis; SP, spontaneous; −, patient did not have a previous pregnancy. SI Conversion factor: To convert bile acid to micrograms per milliliter, divide by 2.448. *One patient presented with intrahepatic cholestasis of pregnancy in 3 successive pregnancies.

Approval from the Medical University of Graz ethics commit- weeks) with sudden severe, generalized pruritus, often tee was obtained for this study. The diagnosis of ICP was based pronounced on the palms and soles, but without pri- on the following criteria: (1) generalized pruritus with or with- mary skin lesions. In 2 cases (15%) that had the shortest out skin changes starting in the second half of pregnancy; (2) disease duration until the time of diagnosis, pruritus re- Ͼ 2 elevated total serum bile acid levels ( 11 µmol/L) (to con- mained the only symptom; all other cases developed sec- vert to micrograms per milliliter, divide by 2.448); and (3) ex- clusion of other dermatologic and/or internal conditions known ondary skin changes due to scratching over the next few to cause pruritus. The clinical parameters evaluated included weeks. Skin lesions varied from subtle excoriations (31%) age, ethnicity, and medical history (particularly, personal and/or to prurigo nodularis lesions (54%), and mostly in- family history of pregnancy-associated pruritus, time of dis- volved the distal limbs (Figure). None of the patients ease onset, presenting signs and symptoms, disease duration, presented with jaundice. treatment, and maternal outcome). Laboratory results re- Diagnosis was established at a mean±SD of 34±3 viewed in all patients included levels of total serum bile acids, weeks’ gestation (range, 29-39 weeks). At that time, oral aspartate aminotransferase, alanine aminotransferase, ␥-glu- therapy with ursodeoxycholic acid was started in 10 (77%) tamyl transferase, total serum alkaline phosphatase, and total of 13 cases at a dose of 15 mg/kg per day after informed serum bilirubin. Scrutinized obstetric parameters were gesta- consent was obtained. Pruritus improved in all patients tion, parity, time and mode of delivery, presence of fetal distress (pathological cardiotocogram and meconium-stained am- within 5 to 7 days, and treatment with ursodeoxycholic niotic fluid), neonatal sex, and weight. Data for at least 1 acid was continued until delivery (mean±SD, 4±3 weeks; follow-up visit after delivery were available in all patients. range, 1-9 weeks). No adverse effects were observed except for very mild and transient diarrhea in 1 patient (10%). Two patients were treated with topical cortico- RESULTS steroids with only minimal effect. In 1 patient, neither administration of oral antihistamines for 14 days nor cho- CLINICAL CHARACTERISTICS AND THERAPY lestyramine resin for 6 days proved beneficial. In these 3 patients, pruritus resolved completely only after deliv- The 13 observed cases of ICP (mean patient age, 30 years; ery, within a maximum of 5 days. range, 16-44 years) comprised 6% of the total 228 patients with pregnancy-associated dermatoses seen at our department (Table 1). Ten patients (91%) were cen- LABORATORY FINDINGS tral Europeans, and 1 patient (9%), who was seen for ICP in 3 successive pregnancies, was Egyptian. One patient Total serum bile acid levels at the time of diagnosis were (9%) had a family history of pregnancy-associated pru- notably elevated in all patients (mean, 43.1 µmol/L; range, ritus, and 7 (88%) of the 8 multiparous women re- 11.3-138.0 µmol/L), whereas associated biochemical liver ported pruritus and identical skin changes in previous alterations were noted in only 10 cases (77%) (Table 2). pregnancies. Medical history was otherwise unremark- These included elevated serum concentrations of aspar- able. None of the patients had received progesterone treat- tate aminotransferase (62%), alanine aminotransferase ment or antibiotics during pregnancy, and all had nega- (46%), and ␥-glutamyl transferase (23%). An increased tive serologic findings for hepatitis B and C. The disease total serum bilirubin level was observed in only 2 pa- started during the second half of pregnancy in all patients (15%), although clinically undetectable, with a high- tients (mean±SD, 30±4 weeks’ gestation; range, 24-35 est value of 2.1 mg/dL (35.9 µmol/L) (normal range, 0.1-

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Figure. Skin changes of intrahepatic cholestasis of pregnancy vary from subtle linear scratch marks (A) to pronounced excoriations and prurigo nodules, most commonly on the shins (B); severe manifestation of intrahepatic cholestasis of pregnancy with extensive, partly superinfected prurigo nodules in a primigravida woman 5 weeks after the onset of pruritus, before ursodeoxycholic acid treatment (C), and the same patient 4 weeks after initiation of ursodeoxycholic acid treatment (15 mg/kg per day) with only postinflammatory hyperpigmentation (D).

Table 2. Liver Function Tests in 13 Cases of Intrahepatic Cholestasis of Pregnancy

No. (%) of Pregnancies Laboratory Test With Abnormal Values Mean Value (Range) Reference Range* Total serum bile acids 13 (100) 43.1 (11.3-138) µmol/L 0-6 µmol/L Alkaline phosphatase 13 (100) 270 (166-783) U/L 35-105 U/L Aspartate aminotransferase 8 (62) 64 (11-217) U/L 0-30 U/L Alanine aminotransferase 6 (46) 109 (8-514) U/L 0-35 U/L ␥-Glutamyl transferase 3 (23) 24 (18-54) U/L 0-38 U/L Total bilirubin 2 (15) 0.8 (0.3-2.1) mg/dL 0.1-1.2 mg/dL

SI conversion factor: To convert bilirubin to micromoles per liter, multiply by 17.1. *During normal pregnancy, liver function test results may be up to 20% lower than in nonpregnant women,3 except for alkaline phosphatase, which is usually higher, and total serum bile acids (to convert to micrograms per milliliter, divided by 2.448), for which levels of up to 11 µmol/L are accepted as normal.4

1.2 mg/dL [1.7-20.5 µmol/L]). Total serum alkaline experienced spontaneous delivery at 37 weeks’ gesta- phosphatase levels were elevated in all patients, but al- tion. Interestingly, time of delivery was not correlated with kaline phosphatase was most likely of placental origin, the time of initiation of ursodeoxycholic acid. In con- as usual in pregnancy,2 although isoenzymes were not trast to this subgroup of patients, all 3 patients who were determined. not treated with ursodeoxycholic acid experienced pre- Levels of total serum bile acids were correlated with term delivery at a mean of 34 weeks’ gestation. In 1 of fetal prognosis as determined by the t test; pregnancies these cases (case 7), labor had to be induced at 31 weeks’ complicated by fetal distress or prematurity exhibited sig- gestation because of severe fetal distress (pathological car- nificantly higher total bile acid levels than those with un- diotocogram and heavily meconium-stained amniotic impaired fetal outcome (mean, 61.1 µmol/L vs mean, 21.8 fluid). In the other 2 patients, one experienced sponta- µmol/L; P=.04). No statistically significant correlation neous delivery at 35 weeks’ gestation and a mature fetus was found for all other clinical, biochemical, or obstet- was induced at 37 weeks’ gestation in the other. Of the ric parameters investigated in this study. babies born in this case series, 7 (54%) were male and 6 (46%) were female. Body weight was adequate for ges- OBSTETRIC CHARACTERISTICS tational age in all of them. No abnormalities were identified that could be associated with ICP or its treatment. All 13 cases were single pregnancies. Premature deliv- Follow-up for up to 17 weeks postpartum showed nor- ery (before week 38 of pregnancy) occurred in 3 (30%) mal growth and development in all infants. of the 10 patients treated with ursodeoxycholic acid (Table 1), at a mean of 36 weeks’ gestation. In 2 of them (cases 11 and 12), fetal distress with pathological cardi- COMMENT otocogram led to induction of labor or cesarean delivery at 35 and 37 weeks’ gestation, respectively. These 2 pa- We found a high frequency of ICP in this central Euro- tients had the highest pretreatment levels of total serum pean case series (6% of all pregnancy-associated derma- bile acids measured within this series. The third patient toses). In all 13 cases, ICP exclusively occurred in the

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 second half of pregnancy, with sudden severe, general- endotoxins and the enterohepatic circulation of chole- ized pruritus and then excoriations or prurigo nodu- static metabolites of sex hormones and bile salts. laris developing with disease progression. Elevated total Intrahepatic cholestasis of pregnancy typically ap- serum bile acid levels were diagnostic in all cases, pears in the late second or third trimester of pregnancy, whereas other liver function parameters were normal in as it did in our patients. The usual scenario is the sud- one third or more of patients. The rate of preterm deliv- den onset of incapacitating pruritus, which often starts eries and fetal distress was significantly increased and on the palms and soles but then becomes generalized. correlated with levels of total serum bile acids. Therapy Of our cases, 2 (15%) that were presented shortly after with ursodeoxycholic acid not only stopped maternal the onset of pruritus had no further signs; the others all pruritus very effectively but also improved the rate of presented with secondary skin changes due to scratch- prematurity. ing, which varied from excoriations to prurigo nodu- The frequency of ICP shows striking geographic and laris lesions. Although jaundice has often been believed ethnic differences. While ICP is most common in South to be a common finding in ICP, it did not occur in any America, with the highest incidence rates observed in of our patients. Also Rioseco and colleagues13 noted jaun- Chile (16%) (particularly among Araucanian Indian dice in only 10% of patients with ICP, complicating the women [28%]) and Bolivia (9%), rates of only 0.1% to most severe and prolonged episodes. If present, jaun- 1.5% have been described for Europe and North America, dice may be associated with steatorrhea and subsequent with “hot spots” in Scandinavia and the Baltic states vitamin K deficiency with increased risk for intrapar- (1%-2%).2 Nevertheless, ICP represents an important tum and postpartum hemorrhage.2 dermatologic health issue, as reflected by the relatively The differential diagnoses of ICP include primarily the high proportion of 6% of patients with ICP among all other specific dermatoses of pregnancy. The categoriza- pregnancy-associated dermatoses in the present study. tion of these dermatoses has been controversial for de- The pathogenesis of ICP is multifactorial. A recur- cades. For instance, ICP has not been considered in this rence of ICP in 45% to 70% of subsequent pregnancies list until 1998.14 Also, the classification of prurigo of preg- and a positive family history in up to 50% have been re- nancy and pruritic folliculitis of pregnancy was not defi- ported and may point to a genetic background of the dis- nite because of a lack of a clear clinical and etiopatho- ease.5,6 In our series, recurrence was noted in 7 (88%) of genetic definition. In a large study of more than 500 8 multiparous women, and 1 patient (9%) had a posi- pregnant patients with pruritus, we recently demon- tive family history. Other postulated causes such as pro- strated significant overlap between these skin changes gesterone treatment, antibiotic treatment following uri- and eczema in pregnancy both clinically and histopatho- nary tract infection, or hepatitis C infection2,7 were not logically.1 We therefore introduced the term atopic erup- present in our patients. Historically, ICP has been asso- tion of pregnancy (AEP) to cover these dermatoses. Atopic ciated with the cholestatic effect of estradiol metabo- eruption of pregnancy is defined as exacerbation or the lites, in particular 17-␤-estradiol glucuronide. Proges- first occurrence of eczematous or papular skin changes terone metabolites, however, play an even more important during pregnancy in atopic individuals and is not asso- role in its pathogenesis.8 The serum profile in ICP dif- ciated with impaired fetal outcome.1 The distinction be- fers considerably from that seen in normal pregnancy.2 tween ICP and AEP, in particular its prurigo type, can Excess of monosulfated or disulfated progesterone me- be challenging. The most important diagnostic clue to tabolites (in particular, the 3␣- and 5␣-isomers) in the discriminate ICP from AEP is gestational age. While ICP urine of patients with ICP may be related to malfunc- manifests in late pregnancy, the onset of AEP is consid- tion of biliary canalicular transporters normally respon- erably earlier, with 75% of cases occurring before the third sible for their secretion from hepatocytes into bile.8 Sev- trimester.1 Additional atopic skin features and fre- eral of these transporters have recently been characterized. quently elevated IgE levels further support the diagno- Mutations in the ABCB4 gene, encoding a member of the sis of AEP. The differentiation from pemphigoid gesta- ATP-binding cassette family of membrane transporters, tionis and polymorphic eruption of pregnancy is usually and variants in the ATP8B1 gene have been identified in straightforward because they always present with char- a small number of patients with ICP.7 Genetically linked acteristic morphologic primary skin change. Other dif- mild malfunction of canalicular transporters, which causes ferential diagnostic considerations include drug reac- no problems in nonpregnant individuals or in the non- tions, scabies, and viral rashes, for which history, pregnant state, may lead to clinical symptoms of cho- associated symptoms, and/or blood cell count can be help- lestasis when the transporters’ capacity to secrete sub- ful clues to the correct diagnosis. Intrahepatic cholesta- strates is exceeded, as occurs with the high levels of sex sis of pregnancy with jaundice should be distinguished hormones produced in pregnancy.9 Environmental fac- from acute liver of pregnancy, pre-eclampsia compli- tors may also play a role, as suggested by the peak inci- cated by increased levels of liver enzymes, hyperemesis dence of ICP in winter or the decreased prevalence in Swe- gravidarum, viral hepatitis, hyperbilirubinemic states, den and Chile in association with improved selenium drug-induced jaundice, and obstructive biliary disease, supply over the past decades.10,11 Only recently, an in- as well as hemolytic and metabolic diseases.15 creased intestinal permeability (“leaky gut”), which has Most important for the diagnosis of ICP is a notable been demonstrated in several liver diseases, was also de- (Ͼ11-µmol/L) elevation of total serum bile acid levels.2 tected in patients with ICP. Reyes and coworkers12 pos- Total serum bile acid levels are slightly higher in preg- tulated that a leaky gut may play a role in the pathogen- nant than in nonpregnant women (mean±SD, 6.6±0.3 esis of ICP by enhancing the absorption of bacterial µmol/L vs 5.7±0.4 µmol/L),16 and levels up to 11.0 µmol/L

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 are accepted as normal in late gestation.4 We and others therapy.2 Although not licensed for this indication in most could demonstrate elevated liver enzymes (20%-60%), countries, ursodeoxycholic acid, a naturally occurring hy- in particular alanine aminotransferase, and ␥-glutamyl drophilic nontoxic bile acid, is the treatment of choice transferase levels (30%) in ICP.13,17 Because serum trans- for patients with ICP,18,26,31,32 and has been successfully aminase levels are normal or even lower and ␥-glutamyl used to improve clinical and liver function abnormali- transferase is usually lower in healthy pregnancies,3 any ties in a variety of cholestatic liver diseases.2 It stimu- rise should lead to further tests. Since at least one third lates the excretion of hydrophobic bile acids, other po- of patients have normal liver function test results, se- tentially hepatotoxic compounds, and sulfated rum bile acid level analysis is mandatory when ICP is sus- progesterone metabolites. Although the exact mecha- pected. An upper abdominal ultrasound may be consid- nism of action in ICP is still not fully understood, there ered in patients with ICP with abdominal symptoms to is evidence that it corrects the maternal serum bile acid exclude concomitant cholelithiasis, whereas liver or skin profile,4 decreases the passage of maternal bile acids to biopsies are unnecessary.2 the fetoplacental unit, and improves the function of the Fetal risks in ICP include spontaneous preterm de- bile acid transport system across the trophoblast,22 thus livery, meconium staining of amniotic fluid, and abnor- representing a valuable contribution to fetal well-being mal intrapartum heart rate in more than one third of and outcome.31 Ursodeoxycholic acid is safe for both cases.18 Perinatal morbidity attributable to prematurity mother and fetus and is the only treatment that can re- has been detected in 10% to 15% of neonates.18 The most duce the risk of premature delivery with perinatal mor- concerning consequence is the 3- to 5-fold increased risk bidity.18,26 In the present study, ursodeoxycholic acid was for fetal death in utero.19 The cause of fetal distress and used to treat 10 of 13 cases. Of these 10 cases, 3 (30%) stillbirth in ICP is not fully understood, but acute pla- involved preterm deliveries compared with a 100% pre- cental anoxia due to abnormal uterine contractility and term delivery rate in the 3 cases not treated with ur- vasoconstriction of chorionic veins as well as impaired sodeoxycholic acid. With the exception of 1 patient who fetal cardiomyocyte function because of elevated bile acid experienced transient, mild diarrhea, ursodeoxycholic levels seem to play a central role.20,21 An increased flux acid was tolerated without adverse effects in all our of bile acids from the mother to the fetus and a reduced patients. ability of the fetus to eliminate bile acids across the pla- In conclusion, pruritus in pregnancy, particularly in centa have been observed,22,23 and high bile acid levels the last trimester, must never be neglected, and its workup have been found to be associated with more frequent oc- should always include laboratory assessment of total se- currence of fetal distress,24 in particular with levels ex- rum bile acid levels to exclude or confirm ICP. Because ceeding 40 µmol/L.25 Also among our patients, fetal risk ICP may be associated with severe fetal risks, including increased with higher levels of total serum bile acids. We premature birth, intrapartal fetal distress, and stillbirth, observed no stillbirths, but the rate of preterm delivery early diagnosis, close obstetric surveillance, and prompt was 46% and of fetal distress, 23%. An association be- treatment with ursodeoxycholic acid are essential. Der- tween early onset of pruritus and prematurity, as noted matologists have an important role in detecting and treat- by others,26 was not observed among our patients. Neo- ing ICP and therefore need to be familiar with its diag- natal weight was adequate for gestational age in all of our nostic criteria and therapeutic options. cases, irrespective of ursodeoxycholic acid treatment, ar- guing against a role for chronic placental insufficiency. Thus, neither growth nor development of the infants ap- Accepted for Publication: November 11, 2006. pear to be influenced by the disease or its treatment. Ob- Correspondence: Christina M. Ambros-Rudolph, MD, stetric management of patients with ICP should include Department of Dermatology, Medical University of Graz, weekly cardiotocogram examination, starting at least at Auenbruggerplatz 8, A-8036 Graz, Austria (christina 34 weeks’ gestation. Because most intrauterine deaths [email protected]). occur after 37 weeks’ gestation,26,27 elective delivery at Author Contributions: Study concept and design: Ambros- 37 weeks’ has been discussed to prevent intrauterine Rudolph. Acquisition of data: Ambros-Rudolph, Kerl, and deaths.28 The obstetric challenge is to weigh the risk of Mu¨ llegger. Analysis and interpretation of data: Ambros- such a premature delivery against the risk of sudden Rudolph, Glatz, and Trauner. Drafting of the manuscript: death in utero. Ambros-Rudolph. Critical revision of the manuscript for Treatment of ICP should ideally decrease maternal bile important intellectual content: Glatz, Trauner, Kerl, and acid levels to prolong the pregnancy and reduce both fe- Mu¨ llegger. Statistical analysis: Ambros-Rudolph. Admin- tal risk and maternal symptoms. Systemic treatment with istrative, technical, and material support: Glatz. Study su- antihistamines, epomediol, silymarin, phenobarbital, or pervision: Ambros-Rudolph, Trauner, and Mu¨ llegger. activated charcoal have had only limited success.2 The Financial Disclosure: None reported. role of S-adenosylmethionine is unclear,2 while suppres- sion of fetoplacental estrogen production with dexameth- REFERENCES asone was effective in a small uncontrolled trial.29 An- ion exchange resins, such as cholestyramine resin, have 1. Ambros-Rudolph CM, Mu¨llegger RR, Vaughan-Jones SA, et al. 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