GASTROENTEROLOGY 2012;143:1492–1501

CLINICAL—LIVER

Efficacy of Ursodeoxycholic Acid in Treating Intrahepatic Cholestasis of

Pregnancy: A Meta-analysis
YANNICK BACQ,* LOÏC SENTILHES,‡ HUMBERTO B. REYES,§ ANNA GLANTZ,储 JURATE KONDRACKIENE,¶
TOMAS BINDER,# PIER LUIGI NICASTRI,** ANNA LOCATELLI,‡‡ ANNAROSA FLOREANI,§§ ISMAEL HERNANDEZ,§ and
VINCENT DI MARTINO储 储
*Service d’Hépatogastroentérologie, CHRU de Tours, Tours, France; ‡Department of Obstetrics and Gynecology, Angers University Hospital, Angers, France;
§
Department of Experimental Medicine, University of Chile, Santiago, Chile; 储Department of Obstetrics and Gynecology, Sahlgrenska University, Goteborg, Sweden;
¶
Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania; #Department of Obstetrics and gynecology, Medical School Charles
University, Prague, Czech Republic; **Department of Obstetrics and gynecology, University of Bari, Bari, Italy; ‡‡Department of Obstetrics and gynecology, ISBM San
CLINICAL LIVER

Gerardo, Monza, Italy; §§Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy; and 储 储UPRES EA 4266 Université de Franche
Comté et Service d’Hépatologie, CHRU de Besançon, Besançon, France

This article has an accompanying continuing medical education activity on page e13. Learning Objective: Upon
completion of the CME activity, successful learners will be able to prescribe a medical treatment for intrahepatic
cholestasis of pregnancy (ICP).

BACKGROUND & AIMS: We performed a meta-analysis CONCLUSIONS: Based on a meta-analysis, UDCA is

to evaluate the effects of ursodeoxycholic acid (UDCA) on
pruritus, liver test results, and outcomes of babies born to
women with intrahepatic cholestasis of pregnancy (ICP).
METHODS: We performed a systematic review of 9 pub-
lished, randomized controlled trials (3 double blinded) that
compared the effects of UDCA to other drugs, placebo, or no
specific treatment (controls) in patients with ICP. We ana-
lyzed data from 454 patients: 207 received only UDCA, 70
received only placebo, 42 received cholestyramine, 36 re-
ceived dexamethasone for 1 week and then placebo for 2
weeks, 65 received S-adenosyl-methionine, and 34 received
no specific treatment. To achieve consistency among end
points, a standard questionnaire was sent to all correspond-
ing authors. For each end point, we performed pooled anal-
ysis that compared the effects of UDCA with those of all
controls and UDCA with those of placebos. RESULTS: In
pooled analyses that compared UDCA with all controls,
UDCA was associated with total resolution of pruritus (odds
ratio [OR], 0.23; 95% confidence interval [CI], 0.07– 0.74; P ⬍
.01), reduced pruritis (OR, 0.27; 95% CI, 0.13– 0.55; P ⬍
.0001), normalization of serum levels of alanine aminotrans-
ferase (ALT) (OR, 0.23; 95% CI, 0.10 – 0.50; P ⬍ .001), de-
creased serum level of ALT (OR, 0.24; 95% CI, 0.11– 0.52; P ⬍
.0001), reduced serum levels of bile acids (OR, 0.37; 95% CI,
0.19 – 0.75; P ⬍ .001), fewer premature births (OR, 0.44; 95%
CI, 0.24 – 0.79; P ⬍ .01), reduced fetal distress (OR, 0.46; 95%
CI, 0.25– 0.86; P ⬍ .01), less frequent respiratory distress
syndrome (OR, 0.30; 95% CI, 0.12– 0.74; P ⬍ .01), and fewer
neonates in the intensive care unit (OR, 0.49; 95% CI, 0.25–
0.98; P ⫽ .046). In pooled analyses that compared the effects
of UDCA with placebo, UDCA reduced pruritus (OR, 0.21;
95% CI, 0.07– 0.62; P ⬍ .01), normalized (OR, 0.18; 95% CI,
0.06 – 0.52; P ⬍ .001) or decreased serum levels of ALT (OR,
0.12; 95% CI, 0.05– 0.31; P ⬍ .0001), and reduced serum
levels of bile acids (OR, 0.30; 95% CI, 0.12– 0.73; P ⬍ .01).
effective in reducing pruritus and improving liver test
results in patients with ICP; UDCA therapy might also
benefit fetal outcomes.
Keywords: Liver Disease; Preterm Birth; Drug; Newborn.
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I ntrahepatic cholestasis of pregnancy (ICP) is character-
ized by pruritus associated with elevated serum bile
acid and/or serum alanine aminotransferase (ALT) levels,
with spontaneous improvement after delivery.1,2 ICP has
been reported all over the world, but its prevalence greatly
varies according to country and ethnic groups.3 The high-
est levels of prevalence were reported in the 1970s in Chile
and Bolivia, with prevalence from 11.8% to 27.6% accord-
ing to ethnic origin.4,5 In other countries, the levels of
prevalence are usually between 0.5% and 1.5%,3 although
in the United States the prevalence has been found to be
much higher in some populations of Latin origin.6 Pruri-
Abbreviations used in this paper: ALT, alanine aminotransferase; CI,
confidence interval; ICP, intrahepatic cholestasis of pregnancy; IUFD,
intrauterine fetal death; NICU, neonatal intensive care unit; OR, odds
ratio; RCTs, randomized controlled trials; RDS, respiratory distress syn-
drome; UDCA, ursodeoxycholic acid.
© 2012 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2012.08.004
December 2012
tus is often a very unpleasant symptom, and cholestasis
may have deleterious consequences for the fetus by in-
creasing the risk of prematurity, fetal distress, and intra-
uterine fetal death (IUFD), which may suddenly occur at
the end of pregnancy.7 No specific biochemical tests or
modalities of fetal monitoring for the prediction of IUFD
are currently recommended.8 Consequently, labor is com-
monly induced in these patients because of the severity of
the pruritus or to prevent IUFD.3,9 However, the induc-
tion of labor may induce morbidity in the mother by
increasing complications following a failed induction.
The fetus is also at risk of complications related to pre-
maturity, such as neonatal respiratory distress syndrome
(RDS) or hospitalization in neonatology.8,10 Therefore,
pharmacologic treatment is clearly required in such pa-
tients to improve pruritus, prevent fetal complications,
and delay the delivery that definitely eliminates the pru-
ritus and the risk of IUFD. Such pharmacologic treatment
must be safe for the mother and the baby. In this context,
ursodeoxycholic acid (UDCA) appeared to be the most
efficient pharmacologic treatment.3,11–14 The aim of this
systematic review was to evaluate the efficacy of UDCA in
improving pruritus and liver tests, as well as preventing
poor fetal outcomes in women suffering from ICP.
Patients and Methods
Meta-analyses were conducted according to a predeter-
mined protocol following the recommendations of Sacks et al15
but were limited to English language randomized controlled
trials (RCTs). To collect data for the meta-analyses, a standard-
ized questionnaire was sent to the corresponding author of each
of the selected RCTs.
Study Objective and Definition of End Points
The study aimed to identify the effects of UDCA on
maternal and fetal conditions in patients suffering from ICP. To
avoid heterogeneity in the definitions of the end points and
allow further analyses, we sent to each corresponding author
queries regarding each outcome measure, including details of
their definitions. The queries were related to the number of
mothers or newborns in UDCA and control groups and con-
cerned the following end points: (1) total resolution of pruritus,
(2) improvement of pruritus (total resolution or reduction of
pruritus score of more than 50%), (3) normalization of serum
ALT, (4) more than 50% decrease in serum ALT levels, (5) more
than 50% decrease in serum total bile acid concentrations, (6)
total prematurity (spontaneous or iatrogenic delivery before 37
weeks gestation), (7) spontaneous prematurity, (8) fetal distress
(meconium staining and/or fetal asphyxia), (9) IUFD, (10) neo-
natal RDS, (11) Apgar score ⬍7 at 5 minutes, and (12) hospi-
talization in neonatal intensive care unit (NICU). Maternal and
fetal adverse effects reported in the UDCA group or control
groups were also collected. For pruritus and liver tests (serum
ALT and bile acids), the meta-analysis was based on changes
between baseline and day 14 or between baseline and day 21 if
data were not available at day 14. For some outcome measures,
the corresponding authors allowed us to record and report
unpublished data from their trials.
UDCA FOR ICP 1493
Literature Search
Retrieval of studies was performed independently by 3
authors (Y.B., V.D.M., and L.S.) combining MEDLINE on
PubMed, the Cochrane Library database, and manual searches.
The key words “intrahepatic cholestasis of pregnancy,” “choles-
tasis,” “pregnancy,” “ursodesoxycholic acid,” “UDCA,” and “ur-
sodiol” were used as free text words and/or combined with
“randomized controlled clinical trials” or “clinical trials.” Gen-
eral reviews, meta-analyses, and references from published RCTs
were also manually searched for the periodicals devoted to in-
ternal medicine, hepatology, therapeutics, and obstetrics. The
search was completed in October 2010.
Criteria for Inclusion
We selected RCTs published as full papers in English in
peer-reviewed journals. The intervention analyzed was the use of
CLINICAL LIVER
UDCA alone. Control groups could include several interventions
such as placebo, cholestyramine, dexamethasone, S-adenosyl-
methionine, or no specific treatment.
Criteria for Exclusion
Nonrandomized trials and trials that did not use UDCA
in at least 1 studied group were excluded.
Selection and Data Extraction Bias
All RCTs considered for inclusion were analyzed inde-
pendently by 3 observers (Y.B., V.D.M., and L.S.), with any
disagreement being discussed by all 3 observers. The decision as
to inclusion or exclusion was independent of the results.
Statistical Methods
The response rate was calculated based on the intention-
to-treat method and using the data collected by the answers to
the questionnaire. When we failed to contact the corresponding
author, we used the published data. For the 4 end points related
to the fetal outcome (fetal distress, RDS, Apgar score, and
hospitalization in NICU), the calculations were based on live
births, ie, after excluding cases of IUFD. For each end point, we
performed pooled analysis comparing UDCA versus all controls
including placebo and pooled analysis restricted to RCTs com-
paring UDCA versus placebo. We used the DerSimonian and
Laird model for random effects meta-analysis to obtain sum-
mary estimates across studies.16 Results were expressed by the
combined weight-adjusted odds ratios (OR), with their 95%
confidence interval (95% CI). A P value (from directional zero
effect test) of .05 or less was considered statistically significant.
We tested for heterogeneity by using the Cochran’s Q test, which
follows a ␹2 distribution to make inferences about the null
hypothesis of homogeneity (considered significant at P ⬍ .100).
For each end point, in case of heterogeneity, the study, or
studies, showing the greatest difference between the 2 groups in
favor of UDCA was/were removed from the meta-analysis. This
report follows the PRISMA guidelines17 and the Cochrane col-
laboration guidelines for reporting meta-analyses (available at
www.cochrane.org).
Results
Studied Population
Nine RCTs including 489 patients with ICP were
selected and analyzed.18 –26 Out of the 489 patients, 35
patients who received an association of UDCA and S-
 1494 BACQ ET AL GASTROENTEROLOGY Vol. 143, No. 6

Table 1. Characteristics of the Selected Randomized Controlled Trials

Number of multiple Number of Number of Planned
First author Double pregnancies in the patients in each patients in UDCA dose duration of
(reference) Year blinded study Controls control group UDCA group (mg/d) treatment
Diafera A18 1996 Yes 0 Placebo 8 8 600 20 Days
Nicastri PL19 1998 No 0 SAMe 8 8 600 20 Days
SAMe⫹UDCAa 8
Placebo (vitamin) 8
Palma J20 1997 Yes 1 Placebo 7 8 1000 Until delivery
Floreani A21 1996 No 0 SAMe 10 10 450 Until delivery
Roncaglia N22 2004 No 3 SAMe 22 24 600 Until delivery
Glantz A23 2005 Yes 7 Placebo 47 47 1000 21 Days
Dexamethasone 36
Kondrackiene J24 2005 No 5 (including 1 triple) Cholestyramine 42 42 750 14 Days
Binder T25 2006 No 0 SAMe 25 26 750 Until delivery
SAMe⫹UDCAa 27
Liu Y26 2006 No 0 Low fat ⫹ vitamin C 34 34 900 14 Days
CLINICAL LIVER

SAMe, S-adenosyl-methionine; UDCA, ursodeoxycholic acid.

aThe control groups using SAMe⫹UDCA were excluded from the meta-analysis.

adenosyl-methionine were excluded from the meta-analy-
sis. Out of the remaining 454 patients, 207 received
UDCA alone, 70 received the placebo alone, 42 received
cholestyramine, 36 received dexamethasone for 1 week
and then placebo for 2 weeks, 65 received S-adenosyl-
methionine, and 34 received no treatment. We sent our
standardized questionnaire to each corresponding author
of the 9 RCTs, and we received 8 answers. For the remain-
ing RCT, we used the data available in the published
article.26 For 2 studies, the data regarding the pruritus
outcome and liver tests were available at day 21 (instead of
day 14).18,19
The main characteristics of these 9 RCTs are given in
Table 1. Three RCTs were double blinded.18,20,23 The di-
agnosis of ICP was always based on the presence of pru-
ritus and abnormal liver tests (ie, serum ALT and bile acid
levels). Four RCTs included patients with multiple preg-
nancies (Table 1). There was no difference in the fre-
quency of multiple pregnancies among the UDCA (7/
207; 3.4%), all control (7/247; 2.8%), or placebo (2/70;
2.9%) groups. The results regarding each outcome mea-
sure given by the selected studies, including the studies
secondarily removed because of heterogeneity, are given
in Tables 2 and 3. The results of pooled analyses,
including the test of heterogeneity, are summarized in
Table 4.
Effect of UDCA on Maternal Clinical and
Biochemical Parameters
Pruritus. A total resolution of pruritus was observed
with UDCA, all controls, and placebo in 41.6% (72/173),
6.1% (12/213), and 8.6% (6/70) of cases, respectively. It was
more frequently observed with UDCA than in all controls
(weight-adjusted OR, 0.23; 95% CI, 0.07– 0.74; P ⬍ .01). In
studies comparing UDCA versus placebo, the total resolu-
tion of pruritus was not more frequent in the UDCA groups
(OR, 0.39; 95% CI, 0.17–1.32; P ⫽ .13).
An improvement of pruritus was observed with UDCA,
all controls, and placebo in 61.3% (106/173), 26.8% (57/
213), and 25.7% (18/70) of cases, respectively. In pooled
analyses, UDCA significantly improved pruritus when
compared both with all controls (OR, 0.27; 95% CI, 0.13–
0.55; P ⬍ .0001) and placebo (OR, 0.21; 95% CI, 0.07– 0.62;
P ⬍ .01) (Figure 1).
Serum ALT. A normalization of serum ALT levels
was observed with UDCA, all controls, and placebo in
27.8% (48/173), 9.4% (20/213), and 14.3% (10/70) of cases,
respectively. The pooled analysis demonstrated that the
rate of serum ALT normalization was higher in the UDCA
groups than in both all control (OR, 0.23; 95% CI, 0.10 –
0.50; P ⬍ .001) and placebo (OR, 0.18; 95% CI, 0.06 – 0.52;
P ⬍ .001) groups.
A decrease in serum ALT levels was observed with
UDCA, all controls, and placebo in 65.9% (114/173),
25.4% (54/213), and 20.0% (14/70) of cases, respectively.
Weight-adjusted pooled analysis showed that a decrease
in serum ALT levels was more frequent in the UDCA
groups than in both all control (OR, 0.24; 95% CI, 0.11–
0.52; P ⬍ .0001) and placebo (OR, 0.12; 95% CI, 0.05– 0.31;
P ⬍ .0001) groups (Figure 2).
Serum total bile acids. A decrease in serum total
bile acid concentrations (with or without normalization)
was observed with UDCA, all controls, and placebo in
54.3% (94/173), 24.4% (52/213), and 18.6% (13/70) of
cases, respectively. Weight-adjusted pooled analysis show-
ed that this decrease was more frequent in the UDCA
groups than in both all control (OR, 0.37; 95% CI, 0.19 –
0.75; P ⬍ .001) and placebo (OR, 0.30; 95% CI, 0.12– 0.73;
P ⬍ .01) groups.
Effect of UDCA on Fetal Outcome
Prematurity. The rate of total prematurity was
15.9% (33/207), 33.6% (83/247), and 40.0% (28/70) for
UDCA, all control, and placebo groups, respectively.
Weight-adjusted pooled analysis showed this rate to be
lower in UDCA groups than in all control groups (OR,
0.44; 95% CI, 0.24 – 0.79; P ⬍ .01) (Figure 3). The total
December 2012 UDCA FOR ICP 1495

Table 2. Meta-analytical Data of Mother Outcome Parameters From RCTs Comparing UDCA vs All Controls and UDCA vs
Placebo
Meta-analyses comparing Meta-analyses comparing
No. of patients UDCA vs all controls UDCA vs placebo

Outcome parameters and UDCA All control Random effect Random effect
studies groups treatments Placebo OR (95% CI) weight for OR (%) OR (95% CI) weight for OR (%)
Total resolution of pruritus
Diafera (1996)18 0/8 0/8 0/8 1.00 (0.02⫺56.46) 7.07 1.00 (0.02⫺56.47) 9.06
Palma (1997)20 4/8 0/7 0/7 0.07 (0.00⫺1.55) 10.70 0.07 (0.00⫺1.55) 14.88
Nicastri (1998)19 6/8 10/16 5/8 0.62 (0.11⫺3.60) 23.66 0.60 (0.08⫺4.38) 37.56
Glantz (2005)23 3/47 2/83 1/47 0.39 (0.07⫺2.06) 25.07 0.41 (0.06⫺2.90) 38.50
Roncaglia (2004)22 4/24 1/22 — 0.32 (0.05⫺2.22) 21.05 — —
Binder (2006)25 22/26 0/25 — 0.00 (0.00⫺0.08) Removed — —
Floreani (1996)21 10/10 0/10 — 0.00 (0.00⫺0.13) Removed — —
Kondrackiene (2005)24 23/42 0/42 — 0.00 (0.0⫺0.17) 12.46 — —
Liu (2006)26 NA NA — NA NA — —

CLINICAL LIVER
Improvement of pruritus
Diafera (1996)18 8/8 8/8 8/8 1.00 (0.02⫺56.46) 3.08 1.00 (0.02⫺56.46) 6.89
Palma (1997)20 8/8 1/7 1/7 0.01 (0.00⫺0.39) Removed 0.01 (0.00⫺0.39) 9.79
Nicastri (1998)19 7/8 10/16 5/8 0.32 (0.04⫺2.41) 10.28 0.31 (0.03⫺2.86) 21.38
Glantz (2005)23 14/47 12/83 4/47 0.40 (0.17⫺0.96) 27.63 0.24 (0.08⫺0.75) 61.94
Roncaglia (2004)22 7/24 5/22 — 0.73 (0.20⫺2.65) 18.83 — —
Binder (2006)25 24/26 11/25 — 0.08 (0.02⫺0.37) 15.38 — —
Floreani (1996)21 10/10 2/10 — 0.01 (0.00⫺033) Removed — —
Kondrackiene (2005)24 28/42 8/42 — 0.13 (0.05⫺0.33) 24.80 — —
Liu (2006)26 NA NA — NA NA — —
Normalization of serum ALT
Diafera (1996)18 7/8 4/8 4/8 0.20 (0.02⫺1.78) 12.30 0.20 (0.02⫺1.78) 21.30
Palma (1997)20 5/8 0/7 0/7 0.04 (0.00⫺1.00) 6.12 0.04 (0.00⫺1.00) 10.85
Nicastri (1998)19 8/8 6/16 2/8 0.04 (0.00⫺0.74) 6.70 0.02 (0.00⫺0.56) 10.58
Glantz (2005)23 11/47 10/83 4/47 0.45 (0.18⫺1.14) 51.12 0.33 (0.10⫺1.06) 57.28
Roncaglia (2004)22 3/24 0/22 — 0.14 (0.01⫺2.80) 6.68 — —
Binder (2006)25 1/26 0/25 — 0.33 (0.01⫺8.57) 5.82 — —
Floreani (1996)21 0/10 0/10 — 1.00 (0.02⫺55.27) 3.85 — —
Kondrackiene (2005)24 13/42 0/42 — 0.03 (0.00⫺0.45) 7.41 — —
Liu (2006)26 NA NA — NA NA — —
Decrease of serum ALT
Diafera (1996)18 8/8 5/8 5/8 0.09 (0.00⫺2.16) 5.39 0.09 (0.00⫺2.16) 8.48
Palma (1997)20 7/8 0/7 0/7 0.01 (0.00⫺0.38) Removed 0.01 (0.00⫺0.38) 7.48
Nicastri (1998)19 8/8 10/16 4/8 0.10 (0.00⫺1.94) 5.82 0.06 (0.00⫺1.36) 8.56
Glantz (2005)23 20/47 17/83 5/47 0.35 (0.16⫺0.77) 32.25 0.17 (0.06⫺0.50) 75.48
Roncaglia (2004)22 6/24 3/22 — 0.51 (0.12⫺2.17) 17.96 — —
Binder (2006)25 24/26 3/25 — 0.02 (0.00⫺0.09) Removed — —
Floreani (1996)21 8/10 7/10 — 0.63 (0.09⫺4.20) 12.40 — —
Kondrackiene (2005)24 33/42 9/42 — 0.08 (0.03⫺0.22) 26.18 — —
Liu (2006)26 NA NA — NA NA — —
Decrease of serum bile acid
concentrations
Diafera (1996)18 8/8 2/8 2/8 0.02 (0.00⫺0.56) Removed 0.02 (0.00⫺0.56) 7.52
Palma (1997)20 4/8 2/7 2/7 0.45 (0.06⫺3.31) 10.21 0.45 (0.06⫺3.31) 19.18
Nicastri (1998)19 7/8 11/16 4/8 0.41 (0.06⫺3.17) 9.87 0.20 (0.02⫺1.78) 15.91
Glantz (2005)23 11/47 15/83 5/47 0.72 (0.30⫺1.70) 31.22 0.41 (0.14⫺1.24) 57.39
Roncaglia (2004)22 5/24 3/22 — 0.64 (0.14⫺2.80) 16.17 — —
Binder (2006)25 24/26 6/25 — 0.03 (0.00⫺0.16) Removed — —
Floreani (1996)21 10/10 5/10 — 0.05 (0.00⫺1.03) 4.73 — —
Kondrackiene (2005)24 25/42 8/42 — 0.17 (0.06⫺0.44) 27.81 — —
Liu (2006)26 NA NA — NA NA — —

NOTE. Empty cases (—) are not applicable. Removed, study removed from the meta-analysis to avoid heterogeneity.
UDCA, ursodeoxycholic acid; NA, data nonavailable after queries to authors; OR, odds ratio.

prematurity rate was not different between UDCA and control, and placebo groups, respectively. Weight-adjusted
placebo groups (OR, 0.59; 95% CI, 0.19 –1.77; P ⫽ .43). pooled analysis showed that there was no difference in the
The rate of spontaneous prematurity was 8.7% (15/ rate of spontaneous prematurity between UDCA and all
173), 19.3% (41/213), and 18.6% (13/70) for UDCA, all control groups (OR, 0.51; 95% CI, 0.22–1.20; P ⫽ .15) or
 1496 BACQ ET AL GASTROENTEROLOGY Vol. 143, No. 6

Table 3. Meta-analytical Data of Fetal Outcome Parameters From RCTs Comparing UDCA vs All Controls and UDCA vs
Placebo
Meta-analyses comparing Meta-analyses comparing
No. of patients or babies UDCA vs all controls UDCA vs placebo

Outcome parameters and All control Random effect Random effect

studies UDCA treatments Placebo OR (95% CI) weight for OR (%) OR (95% CI) weight for OR (%)

Total prematurity
Diafera (1996)18 0/8 8/8 8/8 0.00 (0.00⫺0.20) Removed 0.00 (0.00⫺0.20) Removed
Palma (1997)20 2/8 5/7 5/7 0.17 (0.02⫺1.41) 6.81 0.17 (0.02⫺1.14) 21.29
Nicastri (1998)19 12/8 7/16 4/8 0.49 (0.01⫺2.79) 9.09 0.38 (0.05⫺2.73) 23.46
Glantz (2005)23 2/47 22/83 11/47 0.96 (0.43⫺2.15) 23.20 1.12 (0.44⫺2.82) 55.25
Roncaglia (2004)22 3/24 8/22 — 0.28 (0.68⫺1.14) 12.40 — —
Binder (2006)25 2/26 11/25 — 0.13 (0.03⫺0.58) 11.23 — —
Floreani (1996)21 5/10 4/10 — 1.44 (0.27⫺7.79) 9.58 — —
Kondrackiene (2005)24 3/42 5/42 — 0.60 (0.15⫺2.48) 12.38 — —
Liu (2006)26 4/34 13/34 — 0.24 (0.07⫺0.78) 15.31 — —
Spontaneous prematurity
Diafera (1996)18 0/8 4/8 4/8 0.06 (0.00⫺1.36) 6.39 0.06 (0.00⫺1.36) 9.93
Palma (1997)20 1/8 1/7 1/7 0.87 (0.07⫺10.51) 9.38 0.87 (0.07⫺10.51) 15.16
CLINICAL LIVER

Nicastri (1998)19 1/8 3/16 1/8 0.77 (0.09⫺6.37) 12.15 1.00 (0.08⫺11.93) 15.34
Glantz (2005)23 9/47 16/83 7/47 1.01 (0.41⫺2.46) 31.42 1.33 (0.46⫺3.82) 59.58
Roncaglia (2004)22 0/24 8/22 — 0.03 (0.00⫺0.65) 7.21 — —
Binder (2006)25 0/26 4/25 — 0.09 (0.00⫺1.77) 6.99 — —
Floreani (1996)21 1/10 0/10 — 3.32 (0.12⫺91.60) 5.79 — —
Kondrackiene (2005)24 3/42 5/42 — 0.60 (0.15⫺2.48) 20.67 — —
Liu (2006)26 NA NA — NA NA — —
Fetal distressa
Diafera (1996)18 0/8 3/8 3/8 0.09 (0.00⫺2.16) 3.46 0.09 (0.00⫺2.16) 9.12
Palma (1997)20 1/9 3/6 3/6 0.17 (0.02⫺1.73) 6.03 0.17 (0.02⫺1.73) 15.93
Nicastri (1998)19 2/8 3/16 2/8 1.48 (0.23⫺9.66) 8.24 1.00 (0.13⫺7.87) 18.75
Glantz (2005)23 18/49 30/85 17/48 1.07 (0.52⫺2.21) 23.14 1.06 (0.47⫺2.40) 56.20
Roncaglia (2004)22 2/25 5/22 — 0.38 (0.08⫺1.89) 10.27 — —
Binder (2006)25 3/26 5/25 — 0.56 (0.13⫺2.40) 11.67 — —
Floreani (1996)21 0/10 0/10 — 1.00 (0.02⫺55.27) 2.22 — —
Kondrackiene (2005)24 8/46 14/44 — 0.46 (0.18⫺1.23) 18.47 — —
Liu (2006)26 6/34 21/34 — 0.14 (0.05⫺0.43) 15.50 — —
Respiratory distress
syndromea
Diafera (1996)18 0/8 1/8 1/8 0.29 (0.01⫺8.37) 7.33 0.29 (0.01⫺8.37) 28.50
Palma (1997)20 0/9 0/6 0/6 0.68 (0.01⫺39.07) 5.03 0.68 (0.01⫺39.07) 19.52
Nicastri (1998)19 1/8 1/16 1/8 2.07 (0.18⫺23.36) 13.97 1.0 (0.08⫺11.93) 51.97
Glantz (2005)23 NA NA NA NA NA NA NA
Roncaglia (2004)22 0/25 2/24 — 0.18 (0.01⫺3.3.87) 8.61 — —
Binder (2006)25 2/26 9/25 — 0.18 (0.04⫺0.82) 35.26 — —
Floreani (1996)21 0/10 0/10 — 1.00 (0.02⫺55.27) 5.10 — —
Kondrackiene (2005)24 NA NA — NA NA — —
Liu (2006)26 1/34 7/34 — 0.16 (0.03⫺1.02) 24.70 — —
Apgar score ⬍7 at 5
minutesa
Diafera (1996)18 0/8 4/8 4/8 0.06 (0.00⫺1.36) 5.51 0.06 (0.00⫺1.36) 22.60
Palma (1997)20 0/9 0/6 0/6 0.68 (0.01⫺39.07) 3.31 0.68 (0.01⫺39.07) 13.60
Nicastri (1998)19 0/8 2/16 2/8 0.34 (0.01⫺7.98) 5.45 0.15 (0.01⫺3.77) 21.68
Glantza (2005)23 1/49 3/85 1/48 0.73 (0.10⫺5.10) 14.32 0.98 (0.10⫺9.75) 42.12
Roncaglia (2004)22 2/24 1/22 — 1.67 (0.20⫺13.66) 12.25 — —
Binder (2006)25 2/26 5/25 — 0.38 (0.08⫺1.90) 21.01 — —
Floreani (1996)21 0/10 0/10 — 1.00 (0.02⫺55.27) 3.37 — —
Kondrackiene (2005)24 4/46 7/44 — 0.53 (0.16⫺1.85) 34.77 — —
Liu (2006)26 NA NA — NA NA — —
Hospitalization in neonatal
intensive care unita
Diafera (1996)18 0/8 1/8 1/8 0.29 (0.01⫺8.37) 4.21 0.29 (0.01⫺8.37) 37.24
Palma (1997)20 0/9 0/6 0/6 0.68 (0.01⫺30.07) 2.88 0.68 (0.01⫺30.07) 25.51
Nicastri (1998)19 0/8 1/16 1/8 0.61 (0.02⫺16.61) 4.31 0.29 (0.01⫺8.37) 37.24
Glantz (2005)23 NA NA NA NA NA NA NA
Roncaglia (2004)22 3/25 7/24 — 0.36 (0.09⫺1.49) 23.57 — —
Binder (2006)25 3/26 4/25 — 0.71 (0.16⫺3.24) 20.56 — —
Floreani (1996)21 0/10 0/10 — 1.00 (0.02⫺55.27) 2.93 — —
Kondrackiene (2005)24 6/46 11/44 — 0.47 (0.16⫺1.36) 41.55 — —
Liu (2006)26 NA NA — NA NA — —

NOTE. Empty cases (—) are nonapplicable data. Removed, study removed from the meta-analysis to avoid heterogeneity.
UDCA, ursodeoxycholic acid; NA, data nonavailable after queries to authors; OR, odds ratio.
aFor these parameters, the analysis was based on the number of live newborns (or live fetuses) and did not include the 2 cases of IUFD.

UDCA and placebo groups (OR, 0.88; 95% CI, 0.32–2.43;
P ⫽ .93).
Fetal distress. The rate of fetal distress was 18.6%
(40/215), 33.30% (84/252), and 35.7% (25/70) for UDCA,
all control, and placebo groups, respectively. Weight-ad-
justed pooled analysis showed this rate was lower in
UDCA groups than in all control groups (OR, 0.46; 95%
CI, 0.25– 0.86; P ⬍ .01) (Figure 3), but there was no
difference between UDCA and placebo groups (OR, 0.63;
95% CI: 0.23–1.72; P ⫽ .50).
December 2012 UDCA FOR ICP 1497

Table 4. Summary of Pooled Analyses Before and After Resolving Heterogeneity

Pooled analyses including all studies Pooled analyses with selected studiesa

Heterogeneity Heterogeneity
Outcome parameter Combined OR (95% CI) (Cochran’s Q test) Combined OR (95% CI) (Cochran’s Q test)
Total resolution of pruritus
UDCA vs all controls 0.09 (0.02⫺0.40); P ⬍ .0001 18.94; P ⬍ .01 0.23 (0.07⫺0.74); P ⬍ .01 7.45; P ⫽ .19
UDCA vs placebo 0.39 (0.12⫺1.32); P ⫽ .13 1.61; P ⫽ .66
Improvement of pruritus
UDCA vs all controls 0.19 (0.08⫺0.45); P ⬍ .0001 14.42; P ⫽ .04 0.27 (0.13⫺0.55); P ⬍ .0001 8.38; P ⫽ .14
UDCA vs placebo 0.21 (0.07⫺0.62); P ⬍ .01 3.30; P ⫽ .35
Normalization of serum ALT
UDCA vs all controls 0.23 (0.10⫺0.50); P ⬍ .001 7.47; P ⫽ .38
UDCA vs placebo 0.18 (0.06⫺0.52); P ⬍ .001 3.39; P ⫽ .34
Decrease in serum ALT levels
UDCA vs all controls 0.13 (0.05⫺0.36); P ⬍ .0001 19.26; P ⬍ .01 0.24 (0.11⫺0.52); P ⬍ .0001 8.13; P ⫽ .15
UDCA vs placebo 0.12 (0.05⫺0.31); P ⬍ .0001 2.34; P ⫽ .51

CLINICAL LIVER
Decrease in serum bile acid
concentrations
UDCA vs all controls 0.22 (0.09⫺0.54); P ⬍ .0001 17.72; P ⫽ .01 0.37 (0.19⫺0.75); P ⬍ .001 7.05; P ⫽ .22
UDCA vs placebo 3.32 (1.38⫺8.06); P ⬍ .01 3.11; P ⫽ .38
Total prematurity
UDCA vs all controls 0.37 (0.18⫺0.75); P ⬍ .001 16.02; P ⫽ .04 0.44 (0.24⫺0.79); P ⬍ .01 10.35; P ⫽ .17
UDCA vs placebo 0.25 (0.04⫺1.45); P ⫽ .20 9.55; P ⫽ .02 0.59 (0.19⫺1.77); P ⫽ .43 3.03; P ⫽ .22
Spontaneous prematurity
UDCA vs all controls 0.51 (0.22⫺1.20); P ⫽ .15 9.74; P ⫽ .20
UDCA vs placebo 0.88 (0.32⫺2.43); P ⫽ .93 3.42; P ⫽ .33
Fetal distress
UDCA vs all controls 0.46 (0.25⫺0.86); P ⬍ .01 12.70; P ⫽ .12
UDCA vs placebo 0.63 (0.23⫺1.72); P ⫽ .50 3.97; P ⫽ .26
Respiratory distress syndrome
UDCA vs all controls 0.30 (0.12⫺0.74); P ⬍ .01 3.93; P ⫽ .69
UDCA vs placebo 0.66 (0.11⫺3.91); P ⫽ .64 0.33; P ⫽ .85
Apgar score ⬍7 at 5 minutes
UDCA vs all controls 0.53 (0.25⫺1.10); P ⫽ .09 3.48; P ⫽ .84
UDCA vs placebo 0.33 (0.07⫺1.47); P ⫽ .15 2.37; P ⫽ .50
Hospitalization in neonatal intensive
care unit
UDCA vs all controls 0.49 (0.25⫺0.98); P ⫽ .04 0.67; P ⫽ .10
UDCA vs placebo 0.36 (0.05⫺2.81); P ⫽ .33 0.12; P ⫽ .94

UDCA, ursodeoxycholic acid; OR, odds ratio.

aIncase of heterogeneity (P ⬍ .100 for the Cochran Q test), the study (or eventually the 2 studies) showing the greatest difference between the
2 groups in favor of UDCA was/were removed from the meta-analysis (see Patients and Methods section and Tables 2 and 3).

RDS. The rate of RDS was 3.3% (4/120), 16.3%
(20/123), and 9.1% (2/22) for UDCA, all control, and
placebo groups, respectively. Weight-adjusted pooled
analysis showed this rate was lower in UDCA groups than
in all control groups (OR, 0.30; 95% CI, 0.12– 0.74; P ⬍
.01) (Figure 3) but was not different between UDCA and
placebo groups (OR, 0.66; 95% CI, 0.11–3.91; P ⫽ .64).
Apgar score. The rate of Apgar score ⬍7 at 5
minutes was 5.0% (9/181), 10.1% (22/218), and 10.0%
(7/70) for UDCA, all control, and placebo groups, respec-
tively. Weight-adjusted pooled analysis showed that this
rate was not significantly different between UDCA and all
control groups (OR, 0.53; 95% CI, 0.25–1.11; P ⫽ .09) or
between UDCA and placebo groups (OR, 0.33; 95% CI,
0.07–1.47; P ⫽ .15).
Hospitalization in NICU. The rate of hospitalization
in NICU was 9.1% (12/132), 18.1% (24/133), and 9.1% (2/22)
for UDCA, all control, and placebo groups, respectively.
Weight-adjusted pooled analysis showed hospitalization in
NICU to be less frequent in UDCA groups than in all control
groups (OR, 0.49; 95% CI, 0.25– 0.98; P ⫽ .046) (Figure 3).
There was no difference in this rate between UDCA and
placebo groups (OR, 0.36; 95% CI, 0.05–2.81; P ⫽ .33).
IUFD. Two cases of IUFD were observed in the
selected RCTs, each of them in a placebo group.20,23 The
small number of events did not allow specific analysis on
this point.
Maternal and Fetal Adverse Effects
Maternal adverse effects were observed in 1% (2/
207), 5.7% (14/247), and 1.4% (1/70) of cases in UDCA, all
control, and placebo groups, respectively. Weight-adjusted
pooled analysis showed that the number of maternal
adverse effects was not different between UDCA and all
control groups (OR, 0.70; 95% CI, 0.23–2.12; P ⫽ .53) or
between UDCA and placebo groups (OR, 1.27; 95% CI,
0.26 – 6.19; P ⫽ .76). The adverse effects reported in UDCA
groups were diarrhea (n ⫽ 1) and transient nausea and
 1498 BACQ ET AL
CLINICAL LIVER
vomiting (n ⫽ 1). No fetal adverse effects were observed in
any group of these RCTs.
Discussion
Although UDCA appears as the most efficient
treatment of ICP, the evidence of its benefit on pruritus is
still debated, and the only previous meta-analysis failed to
provide significant results.27 Moreover, the role of UDCA
in preventing severe fetal outcome has never been dem-
onstrated.28 In the previously published systematic review
on this topic led by Burrows et al (update available on
www.cochrane.org), the authors concluded that “inconsis-
tent and inadequate reporting of results precluded pool-
ing the results of small studies.”27 However, this review
was based only on data from the published papers and
was hampered by missing information and by the hetero-
geneity of the end points used between trials.27 Because large
Figure 2. Decrease in serum
ALT levels under UDCA therapy
in patients with ICP. (A) RCTs
comparing UDCA vs all controls.
(B) RCTs comparing UDCA vs
placebo.
GASTROENTEROLOGY Vol. 143, No. 6
Figure 1. Improvement of pru-
ritus under UDCA therapy in pa-
tients with ICP. (A) RCTs com-
paring UDCA vs all controls.
(B) RCTs comparing UDCA vs
placebo.
RCTs are difficult to carry out with pregnant women, par-
ticularly in a relatively rare disease such as ICP, we decided to
perform a new systematic review with meta-analyses using
data from a standardized questionnaire sent to each corre-
sponding author of the published RCTs. This enabled us to
collect exhaustive information with homogenized defini-
tions of end points from 8 of the 9 published RCTs to date
and to perform specific meta-analyses on 12 outcome mea-
sures, in an individual data-based fashion.
Our study provides 3 relevant findings: (1) it demonstrates
that UDCA is efficient for improving pruritus and liver tests
in women with ICP; (2) it provides specific analyses on fetal
outcome that strongly suggest a benefit of UDCA; and (3) it
confirms the good safety profile of UDCA.
Our results clearly demonstrated the benefit of UDCA
on both liver tests studied (serum ALT and serum bile
acid concentrations). These results were robust because
December 2012
Figure 3. Effects of UDCA ther-
apy on fetal outcome in ICP:
RCTs comparing UDCA vs all
controls. (A) Effects on total pre-
maturity. (B) Effects on fetal dis-
tress. (C) Effects on respiratory
distress syndrome. (D) Effects
on hospitalization in neonatal in-
tensive care unit.
the benefit of UDCA was significant when compared with
all control treatments, as well as with placebo, despite the
small sample size in the latter comparison. The effect of
UDCA on total serum bile acid levels should be particu-
larly relevant for the prognosis of the fetus.29 The effect of
UDCA on pruritus (both for total resolution and im-
provement) was significant when comparing UDCA ver-
sus all control treatments. The improvement of pruritus
was also significant when comparing UDCA versus pla-
cebo. However, the effect of UDCA versus placebo was no
longer significant when considering the total resolution
of pruritus, which is a less subjective but more stringent
outcome measure. This result was possibly the conse-
quence of a type 2 error. This beneficial effect of UDCA on
pruritus is of great importance for clinical practice. In-
UDCA FOR ICP 1499
CLINICAL LIVER
deed, although ICP is a benign disease for the mother (ie,
with no risk of liver failure), it is worthwhile for the
clinician to have efficient treatment at their disposal for
this very painful symptom. The need for efficient treat-
ment against pruritus may have made practitioners reluc-
tant to conduct large studies of UDCA versus placebo,
thus hampering a definitive evidence-based demonstra-
tion of the positive effect of UDCA.
Despite this difficult context for providing evidence-
based results, our meta-analysis has the merit to strongly
suggest that UDCA is beneficial for fetal outcome. Indeed,
in this meta-analysis, the use of UDCA was associated
with a decrease of total prematurity; fetal distress; RDS;
and, as a consequence, a decrease of the number of hos-
pitalizations in NICU in comparison with other treat-
 1500 BACQ ET AL
ments. Among these fetal outcome parameters, the de-
creases of total prematurity is of importance because it is
likely that it contributes to the improvement of the other
fetal outcome parameters that are expected consequences
of the prematurity. Moreover, although no statistical dif-
ference was found regarding the rate of Apgar score ⬍7 at
5 minutes, the data showed there was a trend in favor of
UDCA for this parameter, which is a well-known predictor
of the neurologic development in infants.30 The benefit of
UDCA was not significant for any of these items in studies
comparing UDCA versus placebo, probably because of a
type 2 error.
Finally, this systematic review confirms that UDCA is
well tolerated and that maternal adverse effects are rare
and minor. Moreover, no fetal adverse effects were ob-
CLINICAL LIVER
served in any group of these RCTs included in this meta-
analysis and, to our knowledge, in any ICP studies or cases
reported. Long-term data regarding the safety of UDCA in
later childhood are lacking, but a follow-up of 26 children
(1 infant, 12 preschool children, and 13 school children
aged up to 12 years) showed that these children developed
normally.13
The mechanism of this beneficial effect of UDCA in
patients suffering from ICP and their fetus remains spec-
ulative. As with chronic liver disease, UDCA, a hydrophilic
bile acid, may decrease liver damage in the mother by
affording a cytoprotection against the hepatotoxic effects
of the hydrophobic bile acids and by improving the trans-
port and secretion of hepatobiliary bile acid.31 In ICP, the
most important mechanism seems to be the stimulation
of impaired hepatocellular secretion.32,33 UDCA may also
have a specific effect by improving the transport of bile
acid across the placenta.34,35 The improvement of pruritus
under UDCA therapy in patients with ICP contrasts with
the absence of a significant effect in patients with primary
biliary cirrhosis.36 However, ICP is a disease with a short
duration, whereas primary biliary cirrhosis is a chronic
disease with inflammatory and fibrotic damage of the
interlobular bile ducts; additionally, the mechanism of
pruritus may be different between these 2 cholestatic liver
diseases. The improvement of fetal outcome could directly
result in a decrease of maternal bile acid concentrations
related to UDCA because a relationship has already been
found between maternal bile acid concentrations and
some fetal complications like fetal distress or RDS.29,37
This improvement may also be, at least in part, secondary
to the improvement of the maternal condition. Indeed,
when the the pruritus and liver test results improved
under medical treatment, the obstetrical team may have
chosen to delay the delivery, which may, in turn, contrib-
ute to the decrease of the rate of prematurity.
Our study acknowledges several limitations. First, for
some specific outcome measures, the positive effect of
UDCA compared with control treatments was no longer
significant when restricting the comparison to placebo.
This was observed for the total resolution of pruritus as
well as for all the studied parameters regarding fetal
outcome. The discrepancies were possibly because of type
GASTROENTEROLOGY Vol. 143, No. 6
2 error, and the small number of women receiving placebo
can be explained by the context of pregnancy, the uncom-
fortable symptoms, and the reluctance of the obstetrical
team to leave the mother without efficient treatments.
Second, for some outcome measures, pooled analyses pro-
vided heterogeneity for which we failed to find 1 relevant
source (as available in Table 1). Thus, in case of hetero-
geneity, we pragmatically chose to exclude the outlying
studies (ie, with the more marked positive differences)
favoring UDCA for each end point considered in the
analysis. By using this method, we avoided, as much as
possible, the impact of positive studies with ORs that may
be considered as overestimated, perhaps resulting from
imperfect study design, and participating in publication
biases. The combined ORs before and after removing
these outlying studies from analyses had the same statis-
tical significance (Table 4). Third, we failed to demon-
strate a positive effect of UDCA on IUFD, which is the
most feared consequence of ICP but which, fortunately, is
a rare event. In this systematic review, IUFD was indeed
too rare to allow any specific analyses. It only occurred in
women receiving placebo, but no conclusion can be drawn
concerning this dramatic event because some cases of
IUFD have also been reported in women with ICP receiv-
ing UDCA.38
In conclusion, this systematic review supports the use
of UDCA as initial treatment in patients with ICP because
UDCA improves liver tests and is currently the most
efficient treatment of pruritus in these patients. The re-
sults of this meta-analysis also suggest that UDCA is
beneficial for fetal outcome.
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Received November 23, 2011. Accepted August 7, 2012.
Reprint requests
Address requests for reprints to: Yannick Bacq, MD, Service
d’Hépatogastroentérologie, CHRU de Tours, 37044 Tours Cedex,
France. e-mail: bacq@med.univ-tours.fr; fax: (33) 2 47478428.
Acknowledgments
The authors thank Adam Smith for reviewing the English text.
Conflicts of interest
The authors disclose no conflicts.