Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of as yet undefined etiology and pathogenesis. ICP is characterized by pruritus and elevated serum bile acids (≥10 μmol/L) with onset in the second half of pregnancy and persisting until delivery. Family clustering and varying incidence in different geographic regions suggest an underlying genetic explanation.1 Although essentially benign from a maternal viewpoint, ICP is associated with increased fetal risks, such as preterm delivery in 19% to 60%,2–4 fetal distress in 22%-41%,3, 5–8 and intrauterine fetal death in 1% to 4% of affected pregnancies.3, 6, 9 Fetal complication rates are related to maternal serum bile acid levels, and increase when bile acid levels exceed 40 μmol/L.10 Previous studies have indicated that it is possible to reduce pruritus and some surrogate parameters of cholestasis by pharmacologic treatment. Agents such as phenobarbital, anion exchangers, S-adenosyl methionine, and others have been tested but not introduced into clinical practice due to uncertain efficacy and/or intolerable side effects.11–13 However, small studies with ursodeoxycholic acid (UDCA) and dexamethasone indicate that pharmacologic treatment may provide relief from pruritus and reduce serum bile acid and liver enzyme levels. UDCA has been tested in two randomized, placebo-controlled studies, with 8 patients in each group.14, 15 The effects of dexamethasone were investigated in an uncontrolled study of 10 women.16 These studies were not able to prove the effectiveness of any of these treatments. Thus, we performed a randomized, placebo-controlled trial aiming at comparing the effects of UDCA and dexamethasone on: (i) alleviation of pruritus, (ii) improvement in serum liver tests, and (iii) the possible reduction of fetal complication rates after a treatment period of 3 weeks in women with ICP.
Intrahepatic cholestasis of pregnancy (ICP) is characterized by troublesome maternal pruritus, elevated serum bile acids (≥10 μmol/L) and increased fetal risk. Recently we determined a cutoff level of serum bile acids, ≥40 μmol/L, to be associated with impaired fetal outcome. We have now studied the effects of ursodeoxycholic acid (UDCA) and dexamethasone on pruritus, biochemical markers of cholestasis, and fetal complication rates in a double-blind, placebo-controlled trial. For this purpose, 130 women with ICP were randomly allocated to UDCA (1 g/day for three weeks), or dexamethasone (12 mg/day for 1 week and placebo during weeks 2 and 3), or placebo for 3 weeks. Pruritus and biochemical markers of cholestasis were analyzed at inclusion and after 3 weeks of treatment. Fetal complications (spontaneous preterm delivery; asphyxial events; and meconium staining of amniotic fluid, placenta, and membranes) were registered at delivery. An intention-to-treat analysis showed significant reduction of alanine aminotransferase (ALT) (P = .01) and bilirubin (P = .002) in the UDCA group only. In a subgroup analysis of ICP women with serum bile acids ≥40 μmol/L at inclusion (n = 34), UDCA had significant effects on pruritus (−75%), bile acids (−79%), ALT (−80%), and bilirubin (−50%) as well, but not on fetal complication rates. Dexamethasone yielded no alleviation of pruritus or reduction of ALT and was less effective than UDCA at reducing bile acids and bilirubin. In conclusion, 3 weeks of UDCA treatment improved some biochemical markers of ICP irrespective of disease severity, whereas significant relief from pruritus and marked reduction of serum bile acids were only found in patients with severe ICP. (HEPATOLOGY 2005;42:1399–1405.)
Patients and Methods
Between February 1, 1999, and January 31, 2002, all pregnant women in the Västra Götaland region of Sweden were prospectively screened for ICP, defined as otherwise unexplained pruritus of pregnancy combined with fasting bile acid levels ≥10 μmol/L. There were 1,500,462 inhabitants in the region in February 2001, and 45,485 pregnancies leading to deliveries during the study period. In Sweden, all pregnancies are monitored by midwives in local prenatal clinics. If complications occur, women are referred to the nearest department of obstetrics for further care. All 106 prenatal clinics and all 6 departments of obstetrics in the region participated in the study.
During the study period, 937 women (2.1%) complained of generalized pruritus during pregnancy and were, after giving written consent, included in the observational part of the ICP study. A study protocol recording data on heredity, prior pregnancies, skin disorders, allergic conditions, and hepatic, biliary, and metabolic conditions was given to each patient. Puncture of an antecubital vein was performed after a 12-hour fast to determine serum bile acids on a weekly basis until parturition. If serum bile acids exceeded 10 μmol/L at any time, the woman was diagnosed with ICP and referred to the nearest department of obstetrics for further care. ICP was detected in 693 women (1.5%). The results of the observational part of our ICP study have recently been published.10
Women with ICP and a gestational age less than 37 weeks were invited to participate in a double-blind, placebo-controlled study comparing treatment effects of UDCA and dexamethasone. Exclusion criteria were diabetes, pre-eclampsia, intrauterine growth restriction, liver disease (including viral hepatitis), and history of manic disorders or bleeding gastric ulcer. After exclusion, 425 women were eligible for the study.
Women who chose to participate were consecutively enrolled after giving written consent. In a double-blind fashion, they were randomly allocated to 1 of 3 groups. The first group received UDCA, 1 g/day as a single dose, for 3 weeks. The second group was allocated to dexamethasone, 12 mg/day as a single dose for 1 week, and placebo during weeks 2 and 3. The third group was given placebo for 3 weeks. UDCA capsules, placebo capsules, and empty capsules to be filled with dexamethasone, all of identical appearance, were supplied by Dr. Falk Pharma (Freiburg, Germany). The hospital pharmacy at Sahlgrenska University Hospital, Göteborg, filled the empty capsules with dexamethasone, packed study drugs in anonymous tins marked with a study code, and was responsible for randomization. The study drugs were randomized in blocks of 6 treatments, containing 2 each of UDCA, dexamethasone, and placebo. Staff at the 6 participating centers were instructed to hand out the treatments consecutively, starting with the lowest study code number. When all 6 treatments in the block were dispensed or when 6 months had elapsed, a new block was distributed.
The primary outcome variable was the rate of the following fetal complications, registered at delivery and compared between groups: spontaneous preterm delivery (<37 weeks) in singleton pregnancies, asphyxial events (operative delivery due to asphyxia, postpartum pH <7.05 in umbilical arterial blood or Apgar score <7 at 5 minutes), and meconium staining of amniotic fluid, placenta, and membranes. Changes of biochemical markers and pruritus were secondary variables for evaluation. Differences between groups regarding other obstetric variables such as total prematurity rate (including preterm inductions of labor and preterm Caesarean sections), total elective delivery rate (inductions of labor and planned Caesareans), and maternal blood loss during vaginal delivery were also registered.
Blood samples were analyzed for bile acids, aminotransferases, and bilirubin at inclusion, after 2-3 days, after 4-5 days and after 1, 2, and 3 weeks of treatment. If the pregnancy continued after completed treatment, the same variables were analyzed weekly until parturition.
Treatment effects on biochemical markers of cholestasis and pruritus were evaluated as the differences between values at inclusion and after 3 weeks of treatment. Total serum bile acid concentrations were analyzed with an enzymatic, colorimetric method (Enzabile, Biostat Diagnostic Systems, Stockport, UK). Aminotransferases and serum bilirubin levels were analyzed with standard laboratory methods. Pruritus was estimated on a 100-mm–long visual analog scale with the endpoints “no pruritus at all” (0 mm) and “worst possible pruritus” (100 mm). Fetal well-being was monitored by cardiotocography at each sampling occasion.
The results of the serum analyses were open to the managing obstetricians, who were not given any specific instructions regarding timing of deliveries. The study was approved by the Swedish Medical Products Agency and the Ethics Committee of the Faculty of Medicine at the University of Göteborg. All enrolled women gave written informed consent, according to the Helsinki declaration.
Means, standard deviations, medians, and ranges were calculated for descriptive purposes.
The Wilcoxon signed rank test was used for ordinal variables and for tests over time within groups. Changes over time between all 3 groups were analyzed by the Kruskal-Wallis test, and the Mann-Whitney U test was used for pairwise comparisons. Comparisons of patient characteristics and fetal and maternal outcome were tested with the chi-square test or Student′s t test, as appropriate. P values less than .05 were considered statistically significant.
Our estimation of the number of patients needed to treat to observe differences in fetal complication rates between the UDCA, dexamethasone, and placebo groups was based on fetal complication rates previously reported in the literature.2–9 Based on a possible drug-related reduction of the fetal complication rate by 33%, a significance level of 0.05, a two-tailed analysis, and a power of 80%, 240 patients (80 in each arm) were needed to treat.
A subgroup analysis of changes in laboratory parameters and pruritus during treatment was performed in ICP women with serum bile acids ≥40 μmol/L at inclusion. This analysis was based on the data from our recent observational study10 in which complication rates did not increase until serum bile acid values exceeded 40 μmol/L.
A total of 130 women met the inclusion criteria and chose to participate in the treatment study. A total of 47 were randomized to UDCA, 36 to dexamethasone, and 47 to placebo. There were no differences between groups regarding parity or previous history of ICP. Mean values (±SD) of pruritus onset; maternal and gestational age; and levels of bile acids, alanine aminotransferase (ALT), and bilirubin at inclusion did not differ between groups, nor did median values of pruritus intensity (Table 1).
|Variable||All included n = 130||UDCA n = 47||Dexamethasone n = 36||Placebo n = 47||P Value|
|Previous pregnancies (n)||118||36||32||50||n.s.|
|ICP in previous pregnancies (n)||76 (64%)||24 (67%)||19 (59%)||33 (66%)||n.s.|
|Onset of pruritus (weeks)||27.7 ± 6.3||26.5 ± 6.7||28.1 ± 6.6||28.7 ± 5.5||n.s.|
|Maternal age (years)||30.2 ± 4.8||33.2 ± 5.1||29.5 ± 4.5||30.0 ± 4.7||n.s.|
|Gestational age (weeks)||33.7 ± 3.0||33.3 ± 3.2||33.8 ± 2.6||34 ± 3.2||n.s.|
|Bile acids (μmol/L)||34.8 ± 40.7||39.7 ± 47.7||32.6 ± 29.8||31.6 ± 40.8||n.s.|
|≥40 μmol/L (n)||34 (26%)||12 (26%)||11 (31%)||11 (23%)||n.s.|
|ALT (U/L)||176 ± 197||186 ± 174||174 ± 216||168 ± 210||n.s.|
|>42 U/L* (n)||88 (68%)||35 (74%)||23 (64%)||30 (64%)||n.s.|
|Bilirubin (μmol/L)||13.0 (9.0)||13.4 ± 8.7||13.4 ± 10.5||12.4 ± 8.4||n.s.|
|>21 μmol/L* (n)||16 (12%)||5 (11%)||7 (19%)||4 (9%)||n.s.|
The majority of the women (96 of 130) had bile acid levels of 10-39 μmol/L at inclusion. A severe form of ICP with bile acid levels ≥40 μmol/L was identified in 34 women (12 women in the UDCA group and in 11 women in the dexamethasone and placebo groups, respectively).
Treatment Effects on Maternal and Fetal Complication Rates.
Fetal and maternal complication rates are presented in Table 2. The results are presented as intention-to-treat (ITT) analysis (Table 2A) and as a subgroup analysis in women with severe ICP (Table 2B). Spontaneous preterm deliveries in singleton pregnancies and total prematurity rate and meconium staining of amniotic fluid, placenta, and membranes were approximately doubled in the severe ICP group, whereas the rates of asphyxial events and total elective delivery did not differ when these parameters in the ITT group were compared with those of women with severe ICP. Treatment with UDCA or dexamethasone did not improve any outcome variable in the ITT analysis group or in the subgroup of women with severe ICP.
|All Included n = 130||UDCA n = 47||Dexamethasone n = 36||Placebo n = 47||P Value|
|Preterm delivery*||24 (18.5%)||8 (17%)||9 (25%)||7(14.9%)||n.s.|
|Asphyxial events†||8 (6.2%)||2 (4.3%)||4 (11.1%)||2 (4.3%)||n.s.|
|Meconium passage||48 (36.9%)||18 (38.3%)||13 (36.1%)||17 (34%)||n.s.|
|Green staining of placenta/membranes||31 (23.8%)||14 (29.8%)||8 (22.2%)||9 (19.1%)||n.s.|
|Prematurity, total‡||34 (26.2%)||12 (25.5%)||11 (30.6)||11 (23.4%)||n.s.|
|Elective delivery, total§||45 (34.6%)||15 (31.9%)||12 (33.3%)||18 (38.3%)||n.s.|
|All n = 34 (%)||UDCA n = 12 (%)||Dexamethasone n = 11 (%)||Placebo n = 11 (%)||P Value|
|Preterm delivery*||12 (35.3)||4 (33.3)||3(27.3)||5 (45.5)||n.s.|
|Asphyxial events†||2 (5.9)||0||1 (9.1)||1 (9.1)||n.s.|
|Meconium passage||17 (50)||6 (50)||5 (45.5)||6 (54.5)||n.s.|
|Green staining of placenta/membranes||15 (44.1)||6 (50)||4 (36.4)||5 (45.5)||n.s.|
|Prematurity, total‡||17 (50)||6 (50)||4 (36.4)||7 (63.6)||n.s.|
|Elective delivery, total§||12 (35.3)||5 (41.7)||3 (27.3)||4 (36.4)||n.s.|
Treatment Effects on Biochemical Markers and Pruritus.
Changes in bile acids, ALT, bilirubin, and pruritus during treatment with UDCA, dexamethasone, and placebo are presented in Fig. 1 as an ITT analysis including all women (filled lines) and as a subanalysis of women with bile acid levels ≥40 μmol/L at inclusion (dotted lines).
ITT analysis (n = 130) revealed significant reductions in ALT (Fig 1B, P = .01) and bilirubin (Fig. 1C, P = .002) in the UDCA group compared with the placebo group. Changes in bile acids and pruritus did not reach statistical significance. Overall, no significant changes were revealed during treatment with dexamethasone or placebo by ITT analysis.
In women presenting with severe ICP (≥40 μmol/L) at inclusion (n = 34), serum bile acid levels were reduced by treatment both in the UDCA (−79%) and in the dexamethasone (−45%) groups, compared with placebo (+13%) (P = .001 and P = .01, respectively). The reduction was more pronounced in the UDCA group than in the dexamethasone group (P = .001; Fig. 1A). In the UDCA group, serum bile acid levels increased from 101 ± 58 μmol/L to 153 ± 111 μmol/L during the first 2-3 days of treatment. After 4-5 days the values decreased to 115 ± 105 μmol/L, and further to 83 ± 77; 36 ± 52; and 21 ± 13 μmol/L after 1, 2, and 3 weeks of treatment, respectively. The initial decrease of bile acids in the dexamethasone group was rapid but transient, from 71 ± 22 to 26 ± 26 μmol/L after the first week of treatment, but rising again to 39 ± 22 μmol/L after 3 weeks of treatment.
A reduction in ALT was only found in the UDCA group (UDCA vs. dexamethasone: P = .002, UDCA vs. placebo: P = .01, Fig. 1B). A reduction in bilirubin was observed both in the UDCA group and in the dexamethasone groups vs. placebo (P < .001 and P = .001, respectively; Fig. 1C). Pruritus was alleviated only in the UDCA group and differed significantly from the dexamethasone group (P = .01) and the placebo group at the end of treatment (P = .001; Fig. 1D). In the UDCA group, pruritus scores paralleled bile acid levels. Median pruritus score on a visual analog scale was 74 mm at inclusion, increasing to 79 mm after 2-3 days of treatment. There was a subsequent decrease to 72 mm after 4-5 days of treatment and further to 55, 27, and 18 mm after 1, 2, and 3 weeks of treatment, respectively.
Tolerability and Duration of Treatment.
The duration of treatment is illustrated in Table 3. A total of 80 women completed the 3-week treatment period. One woman in each group discontinued because of side effects within 3 days (UDCA, 1 patient after 3 days because of diarrhea; dexamethasone, 1 patient after 2 days because of nausea, dizziness, and stomach pain; placebo, 1 patient after 1 day because of severe headache). One woman in each group was randomized to treatment but did not start medication because of fear of side effects. The remaining women discontinued their treatment because of spontaneous or planned delivery.
|All n = 130||UDCA n = 47||Dexamethasone n = 36||Placebo n = 47||P Value|
One case of intrauterine fetal death occurred during the study period. The subject was a 26-year-old woman undergoing her first pregnancy, who was medicated with clomipramine, 10 mg daily, due to a long-term depressive disorder with anxiety and panic attacks. Her pruritus started in week 33, and she was allocated to treatment in week 36. Bile acid levels were 16 μmol/L both at inclusion and after 2 weeks of treatment. cardiotocography was normal at check-up visits after 1 and 2 weeks of treatment. Two days after her last check-up, spontaneous labor began. Intrauterine fetal death was diagnosed in the delivery ward, and the patient delivered a stillborn baby (birth weight, 3650 g). The amniotic fluid was heavily meconium stained. No autopsy was performed. The incident was reported to the Swedish Medical Products Agency as an adverse event. When the study code was broken, it was revealed that this woman had taken placebo capsules.
Intrahepatic cholestasis of pregnancy has been reported to be associated with maternal pruritus and increased fetal risk, including intrauterine fetal death.2–9 This double-blind, placebo-controlled study was designed to compare the effects of UDCA and dexamethasone on fetal outcome, biochemical markers of cholestasis, and maternal pruritus in women diagnosed with ICP. Based on an ITT analysis, the only observed significant effects of any treatment were UDCA-induced reductions of serum bilirubin and ALT levels. The study was unable to demonstrate differences between treatment groups regarding fetal complication rates. According to power calculations based on previously published fetal complication rates in women with ICP, 240 women should have been included, 80 in each arm. Only 130 of 425 eligible women, according to inclusion criteria, accepted participation. The most common explanation for not entering the study was fear of negative treatment effects on the fetus, which may be the major obstacle to clinical studies of pharmacologic agents in pregnant women, presumably not only in Sweden. It is noteworthy that even if 240 women had been included, it would have been insufficient to reveal treatment effects on fetal outcome because the overall number of fetal complications was substantially lower in our ICP study population than in any previous report.2–10
However, because the observational part of our ICP study recently demonstrated that fetal complication rates do not increase until bile acid levels exceed 40 μmol/L,10 the subgroup of women presenting with bile acid levels ≥40 μmol/L at randomization was analyzed separately. This subgroup analysis revealed that treatment with UDCA actually improved all biochemical markers of cholestasis as well as pruritus, and that treatment with UDCA was more effective than treatment with dexamethasone or placebo. Mean bile acid levels decreased by 79% in the UDCA group, compared with a 45% decrease in the dexamethasone group and a 13% increase in the placebo group (UDCA vs. dexamethasone, P = .001; UDCA vs. placebo, P = .001). In this subgroup analysis, the UDCA-induced reductions of ALT (by 80%) and bilirubin (by 50%) were more pronounced than in the ITT analysis and also differed significantly from the ALT and bilirubin reductions observed in the dexamethasone (ALT, −17%; bilirubin, −22%) and placebo groups (ALT, −18%; bilirubin, −11%; for ALT, UDCA vs. dexamethasone: P = .002; UDCA vs, placebo: P = .01). However, although the relative incidence of a number of fetal complications such as preterm delivery, meconium passage and green-staining of placenta/membranes was approximately twice as high in women with bile acids exceeding 40 μmol/L compared with women with bile acid levels <40 μmol/L (Table 2), the subanalysis did not reveal any difference in the outcome related to treatment with UDCA or dexamethasone.
The efficacy of UDCA in ICP pregnancies has been previously investigated in 2 small randomized, placebo-controlled ICP trials, both with 8 patients in the UDCA group and treatment periods of 20 days. One study showed a reduction of all investigated variables (pruritus, bile acids, bilirubin, and alkaline phosphatase [ALP]) in the UDCA group, but also a significant reduction in pruritus and ALP in the placebo group.14 The other study showed a decrease of aminotransferases, bilirubin, and pruritus in the UDCA group, but no reduction of bile acids,15 which is in line with the results of our study. Efficacy in reducing maternal serum bile acid levels seems to be an important quality when choosing a drug for the treatment of ICP because bile acid levels have been demonstrated to have a dose-dependent association with fetal complication rates.10 In conflict with a previous report on dexamethasone therapy in ICP women,16 we found the effects on pruritus and biochemical markers of cholestasis to be transient in the dexamethasone group. A rapid decrease in pruritus and bile acids was seen after the first week of treatment, but was followed by an increase.
An interesting detail was the observation of an increase of total serum bile acid levels during the first 2-3 days of treatment in the UDCA group, decreasing close to baseline after 4-5 days of treatment, after which a steady decrease occurred. This phenomenon was interpreted as a dose-dependent medication effect, initially adding supraphysiological levels of UDCA to the total maternal bile acid pool. Interestingly, the pruritus scores paralleled the serum bile acid levels, increasing in the first days of treatment and then gradually decreasing. Thus, from a clinical viewpoint, the efficacy of UDCA treatment in bile acid level reduction in ICP cannot be evaluated earlier than after 1 week of treatment.
The fact that the randomized groups differed in size (dexamethasone n = 36, UDCA and placebo n = 47, respectively) is surprising. The random allocation to the study medication was strictly double blind, and the randomization procedure was performed by a professional authority. However, boxes containing the study medication had to be replaced at the study centers every 6 months, regardless of whether all study medications had been used or not. Some study centers did not include more than 1 or 2 patients durinig every 6-month period of, leading to a large amount of study medication not being used, which might have had an impact on the differences of randomization groups.
In this study, both UDCA and dexamethasone were well tolerated, with similar discontinuation rates. The reason for choosing only 1 week of active treatment followed by 2 weeks of placebo in the dexamethasone group was that this is the only dose regimen of dexamethasone treatment in ICP pregnancies previously reported in the literature.16 Furthermore, questions have recently been raised concerning potentially harmful effects of corticosteroids on the developing fetal brain. This has lead to a more restrictive approach to corticosteroid treatment during pregnancy,17, 18 The data from the present study showed that dexamethasone was less effective than UDCA regarding all studied variables. Therefore we conclude that UDCA is currently the best pharmacologic treatment option for women with ICP.
Proof of the efficacy of UDCA, in particular the effect on fetal complication rates, nevertheless remains to be elicited from investigations of an even larger study population. We propose a serum bile acid level of ≥40 μmol/L as the lower limit for inclusion of patients.
In conclusion, ITT analysis showed that UDCA reduced ALT and bilirubin, but not bile acids or pruritus, in women with ICP. In patients with bile acid levels exceeding 40 μmol/L, treatment with UDCA was more effective in alleviating pruritus and reducing bile acids, aminotransferases, and bilirubin, compared with treatment with dexamethasone and placebo. However, no differences in fetal or maternal complication rates could be detected. Although this is as yet the largest treatment study of ICP, the sample size was still too small to answer the important question of whether fetal complications in ICP can be reduced by pharmacologic treatment. Nevertheless, our data may help to define inclusion criteria for an even larger, multicenter, double-blind, placebo-controlled study of UDCA for the treatment of ICP in the future.
We thank all collegues and midwives in the Västra Götaland region for enrolling and taking care of study patients. Study nurse Ann Christiansson was of invaluable help. Special thanks to Anders Odén and Emma Jaensson for their help with the statistical calculations.