Key words
cholestasis of pregnancy - pruritus - bile acids - antenatal care - induction of labor
- fetal death
Introduction
Intrahepatic cholestasis of pregnancy (ICP) is a reversible liver disease that involves
disturbed secretion of biliary substances and pruritus in previously healthy skin.
This disorder is usually characterised by its reversible and benign course. It consists
diagnostically of maternal pruritus with elevated bile acids and/or elevated transaminases
in the serum, usually from the late second or third trimester. There are no primary
skin changes though intense scratching can lead to secondary excoriations.
The pruritus ceases immediately postpartum, usually within a few days, and the elevated
liver function tests should normalise within a few weeks. Recurrence is frequent at
up to 70% in subsequent pregnancies. There is currently no guideline in Germany on
intrahepatic cholestasis of pregnancy. Treatment with ursodeoxycholic acid (UDCA)
can significantly reduce the maternal pruritus and the elevated bile acids.
Epidemiology
ICP is subject to considerable geographic and ethnic variation. In Germany, roughly
0.7 – 1% of all pregnancies are affected. Throughout Europe, the highest incidence
is found in Scandinavian countries. The incidence can be much higher in South America
and China [1], [2], [3], [4]. A seasonal increase in incidence in the winter months has been described [5].
Pathogenesis and Risk Factors
Pathogenesis and Risk Factors
The pathogenesis of ICP is so far not fully understood. It was first described by
Ahlfeld in 1883 [6]. Genetic [7], [8], [9], hormonal [10] and environmental [5] factors are involved in the aetiology. The disease occurs more often in multiparous
women and multiple pregnancies [2], [3], [11], [12]. Other risk factors are maternal age > 35 years and low selenium [13], [14] and vitamin D levels [15], [16]. An increased risk was also reported in women with chronic hepatitis C infection
[17], [18]. The incidence appears to be increased after assisted reproduction treatment as
raised bile acids are found more often in these women [19]. Because of hormonal triggering with accumulation of progesterone metabolites there
is a disturbance of hepatocyte bile acid secretion with a cholestatic effect. Certain
sulphated progesterone metabolites such as PM2DiS, PM3S and PM3DiS appear to play
an important part in the pathogenesis of ICP and pruritus [20]. For instance, vaginal progesterone replacement increased the incidence of ICP compared
with controls (0.75 vs. 0.23%, aOR 3.16, 95% CI 2.23 – 4.49, p < 0.01) [21]. Cholestasis parameters can increase and pruritus can occur with oral contraceptives
with a high oestrogen content [22]. This should also be borne in mind when contraceptives are re-prescribed. The WHO
recommends progestogen mono- or depot preparations, progestogen-containing IUDs
or etonogestrel implants for these women. Combined oral contraceptives can be prescribed
after a strict benefit-risk assessment provided the benefit outweighs the risk [23] ([Table 1]).
Table 1 Maternal risk factors.
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Maternal risk factors
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Maternal age (> 35 years)
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Low selenium level
|
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Low vitamin D level
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Chronic HCV infection
|
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Polymorphisms in bile transporters (e.g. ABCB4, ABCB11, etc.)
|
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Multiple pregnancy
|
Pruritus as the main symptom occurs particularly in the third trimester as the highest
concentrations of oestrogen and progesterone metabolites in the course of the pregnancy
are reached then. The function of the two important transport proteins BSEP (bile
salt export pump, bile acid transporter) and MDR3 (multidrug resistance associated
protein 3, phospholipid transporter) is reduced [24] ([Table 2]).
Table 2 Symptoms.
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Clinical features
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Pruritus
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Effects of scratching (e.g., excoriations, prurigo nodularis)
|
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Mental stress (insomnia, fatigue)
|
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Malabsorption (steatorrhoea, vitamin K deficiency, rarely peripartum haemorrhage)
|
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Dyslipidaemia
|
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Upper abdominal discomfort
|
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Nausea
|
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Anorexia
|
In pregnancy there is a physiological rise and a change in the composition of the
bile acids. In women with ICP the concentration of cholic acid (CA) increases proportionally
compared with that of chenodeoxycholic acid (CDCA). In normal pregnancies the ratio
of CDCA to CA is the same, possibly with slight predominance of CDCA [25]. There is also a shift to the taurine-conjugated bile acids and thus to a reduction
in the glycine-taurine ratio [26]. At the same time, a foeto-maternal bile acid concentration gradient develops [25]. In addition, a maternal immunological imbalance has been described in association
with ICP.
The pathogenesis is also influenced by molecular genetic factors that affect the mechanisms
of the bile acid receptor and bile acid transport. Genetic variations are found in
ca. 10 – 15% of cases of ICP [27]. The most frequent genetic abnormality at 16% involves mutations in the ABCB4 gene,
which codes for MDR3 (multidrug resistance-associated protein 3), responsible for
the transmembrane transport of phospholipids into bile [7], [27]. In 5% there is a mutation of the ABCB11 gene, which codes for the liver-specific
protein BSEP (bile salt export pump). This can result in liver cell damage due to
accumulation of toxic bile acids in the hepatocytes as transport of bile acids from
the hepatocytes into bile is impaired due to the mutation [27], [29]. This gene mutation is also associated with an increased risk of
hepatocellular carcinoma (HCC) [27]. The altered genes can be diagnosed by means of Sanger sequencing and NGS panel
sequencing. Genetic testing after a pregnancy with these clinical features could be
considered in an individual case with regard to the late consequences. Other genes
that play a part in ICP are ATP8B1, TJP2, ABCC2, NR1H4, FGF19 and SLC4A2 [13], [27], [30], [31], and the development of cholestasis is due to the complex variability, differences
in penetrance and a variety of environmental factors [13]. It can be assumed that certain pregnancy-associated changes such as the altered
oestrogen and progesterone levels and pre-existing raised bile acid levels lead to
increased expression of the disorder in genetically predisposed women [32].
It is important to note at this point that intrahepatic cholestasis of pregnancy is
a diagnosis of exclusion and the laboratory and clinical changes must cease completely
after delivery. If elevated liver and cholestasis parameters persist, further investigation
by a hepatologist is important as primary biliary cholangitis (PBC), primary sclerosing
cholangitis (PSC), autoimmune hepatitis (AIH) or familial cholestasis syndromes can
be associated with similar laboratory abnormalities and clinical symptoms (pruritus)
in pregnancy ([Table 3]).
Table 3 Differential diagnosis.
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Differential diagnosis
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Viral hepatitis (A – E)
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Pre-existing liver disease (PBC, PSC)
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Obstructive jaundice
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Fatty liver of pregnancy
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HELLP/PE
|
Complications and Prognosis
Complications and Prognosis
Placental insufficiency or foetal arrhythmias resulting in intrauterine foetal death
(1.5%) are feared complications [9], [22], [33]. Moreover, depending on the bile acid concentration, premature delivery, often induced
[33], foetal stress with meconium-containing amniotic fluid or respiratory distress syndrome
(RDS) and thus the need for neonatal intensive care, can occur in up to 25% [22], [33], [34], [35], [36]. The risk for foetal morbidity and mortality correlates with the level of the bile
acids [13], [36], which accumulate in the foetal compartment [26]. The risk for the foetus appears to be
caused by increased myocardial and contractile complications [37], [38], [39], [40]. In addition, pathological vasoconstrictor mechanisms acting on the foeto-placental
vessels due to bile acids are suspected [32]. Uterine contractility can increase [42] through increased expression of oxytocin receptors in the myometrium caused by bile
acids [41]. The risk for intrauterine foetal death rises significantly and is more than doubled
in women with a bile acid concentration of over 100 µmol/l [36], [43], [44]. The risk for IUFT also increases with pregnancy age.
Geenes et al. showed a significantly increased risk for IUFT in 713 women at a bile
acid concentration of ≥ 40 µmol compared with the control group with a normal pregnancy
(1.5 vs. 0.5%; adjusted OR 2.58, 95% CI 1.03 – 6.49). An increased rate of premature
deliveries was also described compared with the control group (non-adjusted OR 7.39,
95% CI 5.33 – 10.25), especially iatrogenically induced [33].
In the meta-analysis by Ovadia et al. a significantly increased rate of IUFT was seen
only at bile acid concentrations above 100 µmol/l (3.44%, 95% CI 2.05 – 5.37) while
only a tendency was observed at a concentration up to 40 µmol/l (0.13%, 95% CI 0.02 – 0.38)
and at 40 – 99 µmol/l (0.28%, 95% CI 0.08 – 0.72). The large meta-analysis also showed
that women with ICP have a significantly increased risk of both spontaneous (OR 3.47,
95% CI 3.06 – 3.95) and iatrogenically induced premature delivery (OR 3.65, 95% CI
1.94 – 6.85). The prevalence was high in all three groups (< 40 µmol/l [16.5%, 95%
CI 15.1 – 18.0]; 40 – 99 µmol/l [19.1%, 95% CI 17.1 – 21.1]; ≥ 100 µmol/l [30.5%,
95% CI 26.8 – 34.6]). In addition, neonates of women with ICP had a significantly
higher rate of meconium-stained amniotic fluid (OR 2.60, 95% CI 1.62 – 4.16) and also
had to be admitted more often to a neonatal intensive care unit (OR 2.12, 95% CI 1.48 – 3.03)
[36].
A systematic review based on 1200 singleton pregnancies found perinatal mortality
of 6.8% at maternal bile acid concentrations of ≥ 100 µmol/l compared with 0.3% at
bile acid concentrations of ≥ 40 µmol/l. The preterm delivery rate and the rate of
meconium-stained amniotic fluid were also significantly increased [45]. Due to the vasoconstrictor effect of the meconium, acute foetal danger may occur
as a result of reduced placental perfusion [46]. Pregnancy-associated comorbidities such as pre-eclampsia and gestational diabetes
can increase the risk for intrauterine foetal death even in women with lower bile
acid concentrations [36], [43]. The risk of preterm delivery increases for women above bile acid concentrations
of over 40 µmol/l [36].
In a French cohort with 140 women a significantly increased risk was also found for
respiratory distress syndrome (RDS) in neonates of women with ICP (17.1 vs. 4.6%,
p < 0.001; crude OR 4.46 (95% CI 2.49 – 8.03) [35].
Clinical Features
The disorder manifests towards the end of the first trimester in 10%, in the second
trimester in 25% and predominantly in the third trimester in 65% of cases [47]. The main symptom is new-onset severe cholestatic pruritus. This is accompanied
by jaundice as a result of extrahepatic cholestasis in fewer than 10% [48]. The pruritus usually starts in the extremities, can become generalised over the
entire integument and can be very troublesome for the pregnant woman [13]. Typically, the palms of the hands and soles of the feet are most affected. This
can occur before any skin or laboratory manifestation. It is suspected that this pruritus
is attributable to the direct pruritogenic effect of bile acids in the skin [5], though the serum concentration of the bile acids does not correlate with the severity
of the pruritus [49], [50]. The subjective perception of pruritus can vary greatly individually. Other nonspecific
symptoms are right-sided upper abdominal pain due to stretching of the liver capsule,
nausea and anorexia. In very rare cases, secondary steatorrhoea and vitamin K deficiency
may develop. There are usually no primary skin changes. Secondary effects in the skin
produced by intensive scratching may appear. The association between the pruritus
and the laboratory changes remains unclear as these may precede the itching but may
also only occur subsequently [13].
Women with ICP are affected more often by dyslipidaemia, gestational diabetes and
foetal macrosomia and pre-eclampsia [12], [15], [22], [51], [52], [53], [54]. In a recently published study, an increased incidence of pre-eclampsia was found
in women with ICP (7.78 vs. 2.41%, aOR 3.74, 95% CI 12.0 – 7.02, p < 0.0001), and
also in women with a twin pregnancy. The earlier in pregnancy the ICP occurred, the
higher was the association with pre-eclampsia. On average, affected women developed
pre-eclampsia about 30 days after the diagnosis (29.7 ± 24 days) [52].
The incidence of intrauterine foetal death in pregnant women with ICP depends on the
serum bile acid concentration and is ca. 1,5%.
As a rule, the disorder resolves completely in the mother within a few days to 6 weeks
postpartum and the liver tests normalise. A protracted postpartum course occurs rarely.
If the liver function tests are still abnormal 6 weeks postpartum, other causes of
liver dysfunction must be considered. Recurrence in subsequent pregnancy is common,
occurring in up to 70% [17]. There is an increased lifetime risk in the mother for hepatobiliary disease [17], such as gallstone disorders and cholangitis [55] and for cardiovascular and immunological diseases such as diabetes mellitus, hypothyroidism
or Crohnʼs disease [51].
Diagnosis
ICP is a diagnosis of exclusion. Elevated transaminases in combination with elevated
bile acids and pruritus confirm the suspected diagnosis. It must be ensured that the
bile acids in the serum are measured in the fasting state as oral food ingestion leads
to a rise in this parameter. The bile acids play an important part in fat digestion
and as a solubiliser and inhibitor of cholesterol synthesis. The primary bile acids
cholic acid (CA), and chenodeoxycholic acid (CDCA), which are present in conjugated
compounds, are the most important representatives. They are excreted as lithocholic
and deoxycholic acid. Because of their hydrophobic structure, they could play a clinically
important part as a toxic metabolite in the pathomechanism of cholestasis [56].
The transaminases can be increased 2 – 10-fold in 20 – 60% [48]. The ratio of ASAT/ALAT is usually < 1 [47], [57]. The bile acid concentration in the serum is regarded as the most sensitive parameter.
In late pregnancy, depending on the laboratory, a concentration of up to 11 µmol/l
is considered normal [26]. Hyperbilirubinaemia occurs in only 10 – 20%. The partial thromboplastin time (pTT)
can be prolonged because of possible vitamin K deficiency [5]. The enzyme autotaxin has been described as a highly sensitive predictive marker
for cholestasis of pregnancy but it is not available in routine clinical practice
[50].
Liver ultrasonography usually appears normal in women with ICP. Nevertheless, posthepatic
biliary obstruction should be excluded by abdominal ultrasound, especially as the
incidence of ICP is increased in patients with cholelithiasis [48]. In any case, however, this should be done postpartum at the latest if the symptoms
persist longer than 4 – 6 weeks after delivery. Since microscopic liver changes are
usually nonspecific, liver biopsy for histological confirmation is not indicated.
As well as other pregnancy-related dermatoses, viral hepatitis in particular (e.g.,
hepatitis viruses A – E), pre-existing liver disease such as primary biliary cholangitis
(PBC) or primary sclerosing cholangitis (PSC), obstructive jaundice and pre-eclampsia/HELLP
syndrome and acute fatty liver of pregnancy should be excluded in the differential
diagnosis. Certain genetic causes for ICP are also associated with an increased risk
for gallstones, cholecystitis or
cholangitis and with the development of liver fibrosis and malignant disease.
For this reason, affected persons, especially those with severe disease, should be
offered genetic counselling and genetic testing if appropriate [27].
Treatment
The primary aim of treatment is to reduce the clinical symptoms by reducing the laboratory
test results while reducing foetal complications also.
The agent of choice is ursodeoxycholic acid (UDCA), a tertiary, hydrophilic bile acid
that occurs physiologically [43]. Absorption takes place both passively via diffusion in the jejunum and ileum and
actively in the distal ileum [58]. A dose of 13 – 15 mg/kg body weight/d [2], [59] is recommended. The starting dose should be 500 mg and the maximum daily dose is
2 g [60]. In a meta-analysis, pruritus was reduced significantly with this compared with
placebo (OR 0.21, 95% CI 0.07 – 0.62, p < 0.01), the transaminases were normalised
(OR 0.18, 95% CI 0.06 – 0.52, p < 0.001) or reduced (OR 0.12, 95% CI 0.05 – 0.31,
p < 0.0001) and the bile acids were reduced (OR 0.30, 95% CI 0.12 – 0.73, p < 0.01).
The authors concluded that the use of UDCA would also be able to improve the perinatal
outcome [61]. However, this was not confirmed in the recently published PITCHES study with 605
women, though the study was underpowered for patients with severe forms of ICP [43]. It is of particular importance that UDCA can also reduce the bile acids in amniotic
fluid and cord blood [25], [62]. Since the drug is not licensed in pregnancy, it requires separate informed consent
(off-label use). UDCA was used successfully in many thousands of pregnant women and
significant side effects did not occur apart from mild diarrhoea [61].
Treatment with UDCA can increase the measured bile acids in the serum. UDCA accounts
for approximately 60% of total bile acids [63]. This should be noted so as to avoid misinterpretation and resulting indication
for delivery.
According to a Cochrane review from 2013 statistically significantly fewer preterm
deliveries were seen in women on treatment with UDCA compared with placebo (RR 0.46,
95% CI 0.28 – 0.73). The results were not significant with regard to fewer signs of
foetal stress and less meconium in the amniotic fluid and higher birth weight in the
UDCA group [64].
Two more meta-analyses also reported a reduction in the rate of preterm deliveries
[65], [79].
Cholestyramine can be used as an alternative, but this proved inferior to UDCA in
a randomised study [66]. Reduced fat absorption with cholestyramine therapy can cause vitamin K deficiency
and subsequently an increased bleeding tendency in mother and child. Vitamin K can
be given intravenously to reduce the risk of peripartum haemorrhage in severe cases
[3].
Other treatment options are S-adenosylmethionine (SAM) [47], [61], which can be used in dosages of about 1000 mg/day as second-line therapy, especially
for persistent pruritus. In a randomised controlled study by Roncaglia et al. SAM
proved less effective than UDCA as regards reducing the serum levels of bile acids,
transaminases and bilirubin. The improvement in the pruritus was similar [67]. This is also confirmed by a meta-analysis from 2016, in which UDCA was more effective
than SAM in the treatment of ICP and significantly and effectively reduced the pruritus
score, bile acids and rate of preterm delivery [68]. Combined treatment with both medications in 89 pregnant women with mild ICP (bile
acid concentration < 40 µmol/l) was shown to be equivalent with regard to an unfavourable
perinatal outcome [69].
Rifampicin in dosages of 150 – 300 (up to a maximum of 600) mg/d can be considered
as third-line therapy. This bactericidal tuberculostatic drug exhibits anticholestatic
mechanisms [59]. The intensity of the pruritus can diminish and the cholestasis parameters can be
reduced by combined treatment with UDCA [70].
A Cochrane analysis from 2019 of pharmacological interventions concluded that treatment
with UDCA reduces pruritus symptoms only slightly. A reduction in the foetal risks
remains unclear. There is insufficient evidence for other pharmacological therapies,
for example SAM, dexamethasone, cholestyramine and others [71].
Supportive treatment with moisturising and cooling effects, e.g. with menthol ingredients,
is possible and may provide relief [13]. If a patient is found to have a genetic disease-associated variant of ABCB4, lifelong
treatment by UDCA must be discussed [27].
Management
There are no uniform recommendations internationally on monitoring a pregnant woman
with ICP [72]. Since last year, the S2k guideline on induction of delivery includes recommendations
on the procedure in cases of intrahepatic cholestasis of pregnancy [73].
The severity of the maternal symptoms and the risks to the child from an iatrogenic
preterm delivery must be weighed against the risk of acute placental insufficiency
and subsequent intrauterine foetal death in the third trimester with expectant management.
During the pregnancy, weekly laboratory measurement of the transaminases, bilirubin
and bile acids is indicated to monitor treatment so as to identify possible short-term
progression of the ICP [74]. If outpatient treatment is unsuccessful, the patient must be admitted to hospital
for foetal monitoring and appropriate treatment adjustment.
Termination of pregnancy must be considered depending on the age of the pregnancy
at bile acid concentrations above 40 µmol/l. If treatment is unsuccessful, premature
delivery appears to be the only possible intervention that can prevent an unfavourable
perinatal outcome. UDCA alone was unable to significantly reduce the occurrence of
IUFT, the preterm delivery rate and foetal stress [43].
The extent to which maternal bile acids influence foetal heart rate alterations in
women with and without ICP is currently being investigated in a prospective pilot
study (Bile Acid Effects in Fetal Arrhythmia Study, “BEATS”) [75].
Delivery of pregnant women with ICP after 36 weeks proved to be the optimal procedure
in a statistical decision analysis of pre- and postpartum decision-making factors
[76].
In a large American retrospective study the perinatal mortality with delivery after
36 weeks was much lower compared with a wait-and-see approach (4.7 vs. 19.2 per 10 000
deliveries out of a total of 1.6 million deliveries) [77].
Since severe ICP with maternal jaundice and highly elevated bile acids of ≥ 100 µmol
is associated with high perinatal mortality, early inpatient foeto-maternal monitoring
and delivery after 35 – 36 weeks should be discussed despite the paucity of data [45]. There is no absolute indication for caesarean section.
Since definite predictive factors, especially for the risk of IUFT are lacking, the
bile acid concentration remains the most important factor in decision-making, even
though IUFT can occur suddenly without warning as the most severe though rare complication.
Management should be tailored individually all the more.
Since December 2020 the new S2k guideline on induction of delivery provides recommendations
on management at term of pregnant women with ICP [73]. According to this, induction of delivery must be recommended from 38 + 0 weeks if ICP is present (expert consensus; consensus strength
+++). It is also stated that induction of delivery should be recommended from 37 + 0 weeks and that induction of delivery can be recommended
even in the period from 34 + 0 to 36 + 6 weeks when the bile acid concentration is
above > 100 µmol/l (expert consensus; consensus strength +++).
Comment: The graduation in the German-language recommendations is divided according
to the respective binding strength of the recommendations. “Must” stands for a strong
recommendation with highly binding character and “should” for a regular recommendation
with moderately binding character [73].
A very discriminating recommendation based on constantly updated literature searches
can be found at www.icpsupport.org
[60]. The sometimes different treatment recommendations regarding the times in the German
S2k guideline are explained by the unclear data internationally and should be noted
([Fig. 1]).
Fig. 1 Management of women with ICP according to www.icpsupport.org
[60], modified and adapted to the German recommendations of [73].
[Fig. 1] is based on the RCOG Green-top Guideline No. 43 from 2011 which is continually updated
according to the most recent findings (see also Mitchell et al., 2021 [78] and Ovadia et al. 2021 [79]). When this article went to press, the RCOG had not yet updated its recommendations.
Once their new recommendations are published, this Figure will be updated promptly
and will be available at www.icpsupport.org.
In future, progesterone metabolites could be a predictive marker for ICP; these can
be found in raised concentrations in early pregnancy and show an association with
pruritus [20].
The decision for expectant management or active termination of pregnancy can only
be made with consideration of the pregnant womanʼs individual risk profile based on
the subjective pruritus stress, laboratory test results and their course, additional
risks (gestational diabetes, pre-eclampsia) and additional foetal diagnostics (CTG,
biometry/Doppler ultrasonography) and may require interdisciplinary consultation and
care of the pregnant woman by obstetricians, neonatologists and hepatologists.
Summary
Intrahepatic cholestasis of pregnancy (ICP) is a rare but potentially serious complication
of pregnancy, the main symptom of which is intense pruritus with elevated serum levels
of bile acids. These are regarded as a predictor for poor perinatal outcome including
intrauterine death. Ursodeoxycholic acid (UDCA) has become established as the treatment
of choice in clinical management to achieve a significant improvement in symptoms
and reduce the cholestasis. Pregnant women with severe intrahepatic cholestasis should
always be managed in a perinatal centre with close interdisciplinary monitoring and
treatment involving perinatologists and hepatologists to minimise the markedly increased
perinatal morbidity and mortality as well as maternal symptoms.
