Intrahepatic cholestasis of pregnancy: Diagnosis and management

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Abbreviations

ALT

alanine aminotransferase

ICP

intrahepatic cholestasis of pregnancy

IUFD

intrauterine fetal death

RCT

randomized controlled trial

UDCA

ursodeoxycholic acid.

Intrahepatic cholestasis of pregnancy (ICP) is a liver disease unique to pregnancy. It is characterized by pruritus associated with elevated serum bile acids and/or aminotransferase levels. ICP usually manifests during the second or third trimester of pregnancy and spontaneously improves after delivery.1 ICP has been identified worldwide, but its prevalence varies considerably depending on country and ethnicity.2 The highest rates of prevalence reported were those in Bolivia and in Chile in the 1970s. In the United States, the prevalence has been estimated to range from 0.3% in Connecticut to 5.6% in Los Angeles (in a predominantly Latina population).3 In Europe, the prevalence is about 0.5% to 1.5%.2

Pathophysiology

ICP is a complex disease that has been shown to be primarily associated with hormonal and genetic factors.4 The role of estrogens has been clearly established in ICP and animal studies have shown that estrogens are cholestatic. Progesterone probably also plays a role, and oral administration of natural progesterone in cases of threatened preterm labor increases the risk of ICP.1 A multigenic disease, mutations of genes encoding several proteins involved in the hepatobiliary transport have been associated with ICP. Heterozygous mutations in gene ABCB4 (adenosine triphosphate‐binding cassette, subfamily B, member 4), which encodes the hepatic phospholipid transporter MDR3 (multidrug resistance 3), have been found in patients with ICP.4, 5 Mutations in genes ATP8B1, ABCB11, or NRH1HA encoding familial intrahepatic cholestasis 1 protein (FIC1), the bile salt export pump, or farnesoid X receptor (a regulator of bile acid synthesis and transport in the hepatocyte), respectively, have less frequently been found in patients with ICP.4 In addition, environmental factors may be involved in the expression of the disease.4

Clinical Presentation and Diagnosis

Pruritus is the main symptom of ICP and is very uncomfortable and often difficult for patients to tolerate. It is often generalized but predominantly affects the palms and soles. It is more severe at night and interferes with sleep. The intensity of the pruritus can be monitored using either a prefixed score (Table 1) or a 100‐mm visual analogue scale.5 Pruritus disappears spontaneously within the first few days after delivery. Clinical examination findings are normal except for evidence of scratching. Patients may have jaundice in more severe forms (less than 10%). ICP with jaundice but without pruritus is very rare.1 Patients do not experience fever, abdominal pain, or encephalopathy. Ultrasound examination may reveal gallstones in the gallbladder, but there should be no evidence to suggest biliary obstruction such as dilation of the biliary tract.

Table 1.

Monitoring of the Intensity of Pruritus in Patients With ICP Using a Prefixed Score.

Score 0: Absence of pruritus

Score 1: Occasional pruritus (not every day)

Score 2: Discontinuous pruritus every day, prevailing asymptomatic lapses (i.e., pruritus is present less than 50% of time)

Score 3: Discontinuous pruritus every day, prevailing symptomatic lapses (i.e., pruritus is present more than 50% of time)

Score 4: Permanent pruritus (day and night)

Measurement of aminotransferase activity, especially alanine aminotransferase (ALT), provides a very sensitive test for the diagnosis of ICP.1 Patients with ICP may exhibit very significant increases in serum ALT activity, suggesting acute viral hepatitis, which should be ruled out by suitable serologic tests.1 The serum bile acid concentrations also are usually elevated, and the cutoff values chosen for diagnosis of ICP are usually values of more than 10 µmol/L. Normal bile acid concentrations do not exclude the diagnosis. It should be noted that the determination of the serum bile acid concentration is not a routine test and is not available in all centers. Measurement of serum bile acid concentrations is especially useful for the diagnosis of ICP in patients with pruritus when ALT levels are in normal limits. In some patients with ICP, pruritus may precede liver test abnormalities. In contrast to ALT, serum bile acid determinations may be of interest for fetal prognosis. Indeed, a relationship between maternal serum bile acid levels and fetal distress has been found in severe ICP, which is defined as serum bile acid concentrations of more than 40 µmol/L.6, 7, 8 The serum bile acid concentration and serum ALT activity decrease rapidly after delivery—and as a rule return to normal within a few weeks. Remarkably, serum gamma‐glutamyltransferase activity, which is increased in most hepatobiliary diseases, is normal or only slightly increased in ICP.1 Alkaline phosphatase levels increase during the second and third trimesters in normal pregnancy, mainly as a result of the production of the placental isoenzyme, so this is not a useful test for the diagnosis of cholestasis during pregnancy. The prothrombin time is usually normal, and there is no liver failure. Prolonged prothrombin time, if present, is caused by vitamin K deficiency and should be treated before delivery to prevent postpartum hemorrhage.

Liver biopsy is rarely necessary for the diagnosis of ICP; however, if it is carried out, the histopathology is characterized by pure cholestasis, with bile plugs sometimes visible in the hepatocytes and canaliculi.

Diagnosis of ICP is usually based on pruritus occurring during pregnancy that is associated with elevated serum aminotransferase and/or serum bile acids, after other causes of liver test abnormalities have been excluded.9 ICP may rarely be associated with another liver disease unique to pregnancy, such as preeclampsia or acute fatty liver of pregnancy, which also may occur during late pregnancy.5 Intercurrent causes of liver diseases during pregnancy include acute viral hepatitis or cytomegalovirus infection, as well as drug liver injury. Urinary tract infection may cause cholestasis or be associated with ICP. Chronic liver diseases may occasionally worsen during pregnancy or be detected by chance during pregnancy. Consequently, liver function tests should be carried out after delivery to check for any persistent abnormalities that should lead to further diagnostic investigations and appropriate follow‐up.

Maternal Outcome

The maternal prognosis during pregnancy and postpartum is good, without severe maternal morbidity. Cholestasis frequently recurs in subsequent pregnancies (60%‐70%). The administration of oral contraceptives to women with a history of ICP rarely results in cholestasis, and ICP is not a contraindication for oral contraceptives. Oral contraception (either combined contraceptives with a low dose of estrogen or progestin‐only contraceptives) can be initiated after the liver test values have normalized. The patient should be informed of the possibility of pruritus during such contraception, and routine liver tests should be checked after 3 or 6 months of oral contraception.

As a rule, long‐term maternal prognosis is good. However, two recent longitudinal population‐based studies from Finland and Sweden found that patients with ICP have substantially increased risks for later gallstone‐related diseases, nonalcoholic liver cirrhosis, and hepatitis C.10, 11 The results of these studies highlight the importance of carrying out hepatitis C serology tests in all patients with ICP and confirming that serum liver tests have returned to normal after delivery.

Fetal Outcome

ICP does carry a risk for the fetus, especially in severe cases.7 Total (i.e., spontaneous and induced) prematurity, consisting mainly of late preterm deliveries (34 0/7‐36 6/7 weeks of gestation), is more frequent in patients with ICP than in the general population. The rate of prematurity varies greatly from study to study, depending on the rate of multiple pregnancies, which is increased in patients with ICP, and the obstetric management of ICP at the end of the pregnancy. The active management and induction of labor, undertaken because of the risk of intrauterine fetal death (IUFD), may be responsible for higher prematurity rates. Indeed, IUFD remains the most feared complication of ICP but rarely occurs before the last month of pregnancy; its prevalence may currently be estimated to be between 1% and 2%.8, 12

Medical Treatment

Vitamin K should be supplemented if the prothrombin time is prolonged.9 The efficacy of topical emollients to improve pruritus is unknown. However, they are safe in pregnancy and may be useful in some patients.9, 13

Ursodeoxycholic acid (UDCA) is currently the most effective treatment of pruritus in ICP.9, 12 UDCA also improves the liver tests. The results of a meta‐analysis also suggest that UDCA therapy is beneficial for fetal outcome12 (Table 2). No side effects of UDCA have been reported for mothers or babies. The authors of this study usually prescribe 500 mg twice a day (or 15 mg/kg per day) until delivery. The mechanism underlying the beneficial effect of UDCA is unclear. UDCA, which is a hydrophilic bile acid, may decrease signs of cholestasis in the mother by providing cytoprotection against the hepatotoxic effects of the hydrophobic bile acids and by improving the hepatobiliary bile acid transport. UDCA may also have a specific effect by improving the transport of bile acid across the placenta.12

Table 2.

Efficacy of UDCA in Treating ICP: Meta‐Analysis of Nine RCTs.

Outcome parameters	UDCA versus All Controls or Placebo	Rate	Combined OR (95% CI)
Total resolution of pruritus	UDCA versus all controls	41.6% versus 6.1%	0.23 (0.07‐0.74); P < .01
	UDCA versus placebo	41.6% versus 8.6%	0.39 (0.12‐1.32); P = 0.13
Improvement of pruritus	UDCA versus all controls	61.3% versus 26.8%	0.27 (0.13‐0.55); P < 0.0001
	UDCA versus placebo	61.3% versus 25.7%	0.21 (0.07‐0.62); P < 0.01
Normalization of serum ALT levels	UDCA versus all controls	27.8% versus 9.4%	0.23 (0.10‐0.50); P < 0.001
	UDCA versus placebo	27.8% versus 14.3%	0.18 (0.06‐0.52); P < 0.001
Decrease in serum ALT levelsa	UDCA versus all controls	65.9% versus 25.4%	0.24 (0.11‐0.52); P < 0.0001
	UDCA versus placebo	65.9% versus 20.0%	0.12 (0.05‐0.31); P < 0.0001
Decrease in serum bile acid concentrationsb	UDCA versus all controls	54.3% versus 24.4%	0.37 (0.19‐0.75); P < 0.001
	UDCA versus placebo	54.3% versus 18.6%	3.32 (1.38‐8.06); P < 0.01
Total prematurityc	UDCA versus all controls	15.9% versus 33.6%	0.44 (0.24‐0.79); P < 0.01
	UDCA versus placebo	15.9% versus 40.0%	0.59 (0.19‐1.77); P = 0.43
Spontaneous prematurity	UDCA versus all controls	8.7% versus 19.3%	0.51 (0.22‐1.20); P = 0.15
	UDCA versus placebo	8.7% versus 18.6%	0.88 (0.32‐2.43); P = 0.93
Fetal distressd	UDCA versus all controls	18.6% versus 33.3%	0.46 (0.25‐0.86); P < 0.01
	UDCA versus placebo	18.6% versus 35.7%	0.63 (0.23‐1.72); P = 0.50
Respiratory distress syndrome	UDCA versus all controls	3.3% versus 16.3%	0.30 (0.12‐0.74); P < 0.01
	UDCA versus placebo	3.3% versus 9.1%	0.66 (0.11‐3.91); P = 0.64
Apgar score < 7 at 5 minutes	UDCA versus all controls	5.0% versus 10.1%	0.53 (0.25‐1.10); P = 0.09
	UDCA versus placebo	5.0% versus 10.0%	0.33 (0.07‐1.47); P = 0.15
Hospitalization in neonatal intensive care unit	UDCA versus all controls	9.1% versus 18.1%	0.49 (0.25‐0.98); P = 0.04
	UDCA versus placebo	9.1% versus 9.1%	0.36 (0.05‐2.81); P = 0.33

This table has been adapted from Bacq et al.12

Abbreviations: CI, confidence interval; OR, odds ratio; UDCA, ursodeoxycholic acid;

^aMore than 50% decrease in serum ALT levels.

^bMore than 50% decrease in serum total bile acid concentrations.

^cSpontaneous or iatrogenic delivery before 37 weeks' gestation.

^dMeconium staining and/or fetal asphyxia.

Cholestyramine, which decreases the ileal absorption and increases the fecal excretion of bile acids, has been used in ICP. Nevertheless, cholestyramine is less effective than ursodeoxycholic acid in improving pruritus and liver tests and is also associated with more side effects.14

Obstetric Management

Active management has usually been recommended to prevent the risk of IUFD, and routine deliveries at 37 to 38 weeks of gestation are commonplace in maternity units.5, 8, 15 Fortunately, IUFD is a rare event, and there is no consensus for the best gestational age for delivery. Moreover, the usefulness of a policy of the induction of labor has never been demonstrated by appropriate randomized controlled trials (RCTs). In the absence of evidence‐based recommendations, the timing of delivery should be discussed on an individual basis after weighing the risk related to prematurity, and the maternal morbidity (increase risk of cesarean section) related to inducing labor, against the risk of sudden IUFD, which thus far remains unpredictable.9, 13 Moreover, from 37 weeks' gestation, a serum bile acid concentration higher than 40 µmol/L should lead caregivers to envisage measures to ensure prompt delivery.

ICP:The Patient's Perspective

A summary of tips for the patient affected by ICP is given in Table 3.

Table 3.

Tips for Patients Affected by ICP

• Diagnosis of ICP should be considered when a pregnant women presents with a generalized pruritus (itching) during the second or third trimester.

• Diagnosis of ICP should be confirmed by blood tests (liver function tests and bile acids, if available) and other liver diseases should be excluded.

• Ursodeoxycholic acid is the most effective treatment of pruritus in ICP and is prescribed until delivery.

• ICP carries a risk for the fetus, especially in severe cases. Sudden intrauterine fetal death (IUFD) is a rare event (1%‐2%), but is unpredictable and remains the most feared complication of ICP.

• Active management, i.e., routine deliveries at 37‐38 weeks of gestation, has been proposed to prevent the risk of IUFD. The obstetric team should discuss the risk related to prematurity and the maternal morbidity related to inducing labor against the risk of sudden IUFD with patients.

• ICP is not a contraindication to breastfeeding.

• Patients should be followed after delivery to ensure resolution of pruritus and to carry out blood tests (liver function tests and bile acids, if available).

• An appointment with a medical practitioner may be proposed 2 and 3 months after delivery to check persistent liver abnormalities that should lead to appropriate follow‐up. This is also the time to discuss contraceptives choice and the risk of recurrence in subsequent pregnancies.