ICP Overview for Healthcare Professionals
ICP Overview for providers

Overview of Intrahepatic Cholestasis of Pregnancy (ICP)

Intrahepatic Cholestasis of Pregnancy (ICP) is a pregnancy-specific liver disorder in which bile transport through the liver is altered leading to elevated serum bile acids. The hallmark symptom is pruritus. Classically, pruritus involves the palms and the soles but in many women itching is severe and generalized, and some do not experience itching on the palms or soles. The majority of cases occur in the second and third trimesters, but there have been cases reported in the literature as early as five weeks.1 This diagnosis should be considered even in patients with itching in the first trimester.

Primary Symptom

Pruritus

Moderate to severe pruritus is the hallmark symptom of ICP, and in most cases is the only symptom reported. The most common presentation is pruritus which is worse on the hands and feet and becomes more intense at night. In many women, the pruritis becomes generalized, or occurs in locations other than hands and feet. In most cases Intrahepatic Cholestasis of Pregnancy is not associated with a rash, but excoriations can occur with severe itching.

Severity of pruritus does not correlate with severity of the disease and may precede any abnormal laboratory findings.2 Lysophosphatidic acid is increased as a result of increased autotaxin activity in patients with ICP and may be a mediator of pruritus as it correlates well with the intensity of pruritus.3

Other Symptoms

  • RUQ Pain with or without the presence of gallstones or sludge.4 One study found that 13% of women with ICP have gallstones concurrently.5 Reasons for RUQ pain are as yet unclear.
  • Pale stool and/or steatorrhea6
  • Dark urine7
  • Fatigue/malaise7
  • Nausea/lack of appetite7
  • Mild depression

Etiology

The etiology of ICP is complex and not fully understood. Several factors are known or suspected to contribute.

Genetics

Several genes have been identified which appear to contribute to ICP. Many of the genes contribute to the functionality of the bile salt export protein (BSEP). Heterozygosity for all known mutations puts the patient at risk of developing ICP.8,9,10 However, not all heterozygous women will develop ICP, so in practice some forms appear to follow a dominant mode of inheritance, where others appear to follow a recessive mode of inheritance. Multiple mutations may cause a more severe form of the disorder,11 and first trimester onset may be associated with a specific mutation.12

Hormonal influences

It has generally been assumed that elevated levels of estrogen is responsible for contributing to ICP.13,14 However, more recent investigations have found that progesterone may be as much at fault.15,16,17 The role of hormones is also supported by the observation that assisted reproductive technology and multifetal pregnancies increase the risk of developing ICP.15,18,19

Prior Liver Disorders

Intrahepatic Cholestasis of Pregnancy risk is increased in patients with other liver disorders such as Hepatitis C and autoimmune hepatitis.20 In severe or early onset cases, evaluation by a hepatologist may be considered to determine if there is an underlying cause for ICP.

Exogenous factors

Insufficient selenium intake and pregnancy during winter months has been associated with higher rates of ICP in some populations.21 In these populations, improved nutrition has been accompanied by a decrease of ICP incidence in winter months, though no causal relationship has been established. Patients with ICP have higher rates of drug-induced cholestasis.22

Diagnosis

Total bile acids (TBA)/Serum bile acids

TBA over 10 μmol/L indicates ICP.23,24 Pruritis may precede any abnormal laboratory findings.2 Normal bile acids do not rule out a diagnosis of ICP. If symptoms persist, TBA should be repeated for diagnosis.

  • Of note, many of the bile acid tests will have a reference range that is not a pregnancy reference range. The level of 10 μmol/L can be used even on tests with a different reference range as this level for diagnosis has been confirmed in studies comparing the level of bile acid elevation between a cholestasis pregnancy and a non-cholestasis pregnancy
  • There are fractionated bile acid tests on the market that have been validated for diagnosis at a lower reference range (usually either 6.8 or 8.6). These tests are not necessary for diagnosis and a total bile acid test can be used.24
  • Bile acid testing can be performed any time during the day and does not need to be performed after fasting.24 Recent studies have shown that many patients would have a missed diagnosis had testing been performed fasting.25 Since the severity of elevation of bile acids determines the risk of complications in an ICP pregnancy, it has been suggested that non-fasting levels would give a more accurate representation of the highest bile acids throughout the day. In this recent study, many of the most severe cases with bile acids over 100 µmol/L in a non-fasting state would have had much lower levels if fasting and the true risks would have not been discovered.25 Delivery timing should be based on the highest bile acid during a pregnancy.

Hepatic panel

Transaminases are elevated in approximately 60% of cases and may provide more timely results.24 ALT is considered the most sensitive of the transaminases for diagnosis of ICP, followed by AST.26 Bilirubin and GGT are normal in most patients.7 However, normal liver function tests do not rule out Intrahepatic Cholestasis of Pregnancy.

Maternal Effects

The main maternal effect of Intrahepatic Cholestasis of Pregnancy (ICP) is pruritus which can be severe and debilitating. ICP is also linked with an increased risk of gestational diabetes and pre-eclampsia.27,28,29

Prior studies had shown an increased risk of maternal hemorrhage at the time of delivery.30 However recent observations in treated populations have shown that coagulopathy is rare in this group.7,31

Fetal Effects

Preterm labor and delivery

The prevalence of spontaneous preterm delivery may be as high as 20-40% without active management but appears to be reduced with active management.27,30,32,33,34,35,36 The risk of preterm labor has been shown in some studies to be increased when ICP presents prior to the 30th week of gestation,37 and in patients with severe ICP (defined as >40 μmol/L TBA),38 and further increased when TBA exceeds 100 μmol/L.39 The increased incidence of preterm labor may be due, at least in part, to increased sensitivity to oxytocin as a result of exposure to bile acids.40

Meconium staining of the amniotic fluids (MSAF)

At 37 weeks gestation the incidence of MSAF is significantly higher than controls at the same gestational age (17.9 as compared to 2.9%).41 Higher TBA is associated with greater risk of MSAF and appears to increase linearly.36,38,42

Respiratory distress syndrome (RDS) and asphyxial events

RDS and asphyxial events are more common in ICP when adjusted for gestational age.37,38,43,44,45,46 Major predictors for risk are gestational age at diagnosis and total bile acid levels. These risks are present even in the presence of documented pulmonary maturity.37,47,48 Bile acids may enter the lungs, interfering with surfactant in a process sometimes termed bile acid pneumonia.49,50 Increased bile acids may also induce an inflammatory response in lung tissues.51

Fetal distress/CTG abnormalities

Fetal distress is common in cases of ICP (21-44%) and does not appear to correlate well with TBA in most studies.32,33,35,37,52,53,54,55 Arrhythmias most commonly include decelerations, tachycardia, and bradycardia.

Stillbirth (Intrauterine fetal demise/IUFD)

Stillbirth is the most troubling of the potential complications of Intrahepatic Cholestasis of Pregnancy. The mechanisms by which it occurs are not fully understood. The main theories are either a development of a fetal arrhythmia or vasospasm of the placental vessels due to the elevated bile acids.24 It is known that stillbirth can occur without warning and cannot always be predicted with fetal surveillance.56,57,58,59 In one case study, IUFD occurred in the midst of reassuring monitoring.56

A recent meta-analysis by Ovadia et al in 2019 was better able to quantify the risk of stillbirth dependent on bile acid levels.60 It has been established in prior studies that increasing bile acid levels lead to an increase in stillbirth risk. In the meta-analysis, the risk of stillbirth was 0.13% with bile acids under 40 μmol/L, 0.28% with bile acids 40-99 μmol/L and 3.44% with bile acids over 100 μmol/L. 25.3% of women with bile acids under 100 delivered preterm, and about 63% before 38 weeks. The authors note that no conclusions on risk can be made past 39 weeks of gestation as too few participants remained pregnant. It is known there is a dramatic increase in stillbirth for bile acids over 100, therefore these pregnancies need more aggressive management. Overall, the results were reassuring for lower bile acids acknowledging that most were delivered by 38 weeks.

Management

Medication

Ursodeoxycholic acid (UDCA) is considered the first line treatment for Intrahepatic Cholestasis of Pregnancy (ICP) as indicated by SMFM.24 Dosing should start at 10-15 mg/kg per day in divided doses. The medication can be increased up to 21 mg/kg per day if bile acid levels are not controlled on lower doses or maternal pruritus is not improved.24 A prior meta-analysis has shown that UDCA is superior to other medications at relieving maternal symptoms, and improves laboratory parameters.33,61,62

There is less evidence that UDCA improves fetal outcomes. There are several laboratory investigations which provide insights into ways in which UDCA may confer benefits to the fetus. UDCA appears to protect fetal heart cells from the changes which can be induced by bile acids,63 prevents changes to the placenta which may be induced by bile acids,64,65 and corrects the placenta’s ability to transport bile acids away from the fetus, at least in part via upregulation of breast cancer resistant protein (BCRP).66,67,68 UDCA also upregulates placental expression of ABCG2 which may protect the fetus from detrimental effects of bile acids and progesterone metabolites.69

A recent randomized, placebo-controlled trial of the use of Ursodiol did not find a difference of a composite outcome of perinatal death, preterm delivery or NICU admission with the treatment.70 This study was not able to be powered to detect solely a reduction in stillbirth rates. These findings make the true fetal benefit of this medication less clear.24

A more recent meta-analysis published in 2021 looked at the RCT data in conjunction with other studies in the literature and was able to show that the use of ursodeoxycholic acid reduced spontaneous preterm birth in singleton pregnancies. This study was not able to be powered to detect the effects of the medication solely on stillbirth due to its rare occurrence and so it can not be concluded that Ursodiol is able to reduce stillbirth.86 Ursodiol has been proven to be safe in pregnancy33,62 and given that it might have benefit, it is still recommended for use by SMFM.24

Other medications have been studied for use in Intrahepatic Cholestasis of Pregnancy. Rifampin and S-Adenosyl-L-methionine (SAMe) have been studied as treatments for cholestasis and can be considered in addition to ursodeoxycholic acid treatment in refractory cases.71,72  Cholestyramine is no longer recommended for use in ICP as it has no effect on maternal biochemical abnormalities and has limited effectiveness in relieving maternal symptoms. 52,73

Elective early delivery

Stillbirths in cholestasis of pregnancy tend to cluster between 37-39 weeks of gestation and early delivery has been recommended to decrease the risk of stillbirth.74,75

The two governing boards (Society for Maternal Fetal Medicine and American College of Obstetrics and Gynecology) in the United States agree on the following recommendations.24,76

  • Bile acids over 100 μmol/L: Delivery at 36 0/7 weeks; Delivery prior to 36 weeks (34-36 weeks) may occur with unremitting maternal pruritus, a prior history of a stillbirth before 36 weeks gestation due to ICP or preexisting or acute hepatic disease with worsening liver function.
  • Bile acids 40-99 μmol/L : Delivery at 36 0/7-39 0/7 weeks with delivery in the EARLIER portion of the window
  • Bile acids less than 40μmol/L : Delivery 36 0/7-39 0/7 weeks

The changes in the SMFM guidelines are largely based on the article by Ovadia et al.60 Prior studies had determined that an optimal delivery strategy was delivery between 36-37 weeks.77,78 The new delivery windows allows for a less aggressive approach to pregnancies with mild elevations in bile acids as the meta-analysis clarified that the majority of the stillbirth risk occurs in pregnancies with levels over 100 μmol/L. However, it must be noted that many of the pregnancies in the Ovadia meta-analysis were delivered early and SMFM acknowledges that this might have mitigated some of the stillbirth risk.24 A conversation between provider and patient should discuss the risks and benefits to decisions on delivery timing.

In 2017, a US-based retrospective cohort study examined severe ICP pregnancies (defined as BA over 40 μmol/L). Delivery at 36-37 weeks was the optimal strategy for this group, and did not adversely affect other maternal or neonatal outcomes. This supports delivery in the earlier portion of the window for women with bile acids greater than 40 μmol/L.79

For a more detailed discussion of how delivery recommendations have been developed based on the research and literature, please see delivery timing page.

Monitoring Bile Acids

Most US labs have a turn around time of 4-7 days for bile acids, which makes it difficult to base management decisions solely based upon bile acid levels. SMFM recommends following bile acids throughout the pregnancy, especially for determination of delivery timing.24 They do not recommend weekly bile acid tests but do recommend testing frequently enough to formulate a delivery plan. Also, ursodeoxycholic acid doses can be adjusted based on bile acid levels.

Fetal surveillance

Stillbirths in Intrahepatic Cholestasis of Pregnancy are thought to be an acute event and fetal surveillance has not been shown to prevent stillbirth.56,57,58,59 However, surveillance can possibly detect fetal distress in cases of ICP, in which cases timely intervention can occur.24,80

SMFM endorses antepartum surveillance starting at a reasonable timeframe when delivery would be considered.24 There is no set schedule or recommendations for what this testing should entail.

Betamethasone

Betamethasone administration is recommended for any pregnancies with planned delivery prior to 37 weeks gestation by SMFM.24 It is a well-documented risk that babies with Intrahepatic Cholestasis of Pregnancy have a higher risk of RDS compared to matched gestational age infants.

Follow Up Care

In most cases, symptoms will disappear within 48 hours of delivery.  Follow up testing is recommended for all patients at 3-6 months postpartum with a CMP and possibly a bile acid level.81 If laboratory parameters do not return to normal within 6 months, referral to hepatology should be pursued to determine if there is an underlying condition which may have contributed to the development of ICP.82

There is minimal risk for long term maternal effects from Intrahepatic Cholestasis of Pregnancy. Recently it has been suggested that women who suffered from ICP may be at a slightly increased risk for developing biliary tree cancer, diabetes, and autoimmune diseases.83 The risk of cancer is thought to be a consequence of the relationship between cholelithiasis and the development of ICP and not a process of ICP itself. A large study found that long term liver-related diseases were rare, with the exception of cholelithiasis and cholecystitis.82

One study examined 18 female and 27 male children of women who were affected by ICP in their pregnancies. In this study a small but significant risk of metabolic disorders such as increased hip girth or diabetes was found. The pregnancies in this study received neither medication nor active management.84 However two larger studies examining 187 women95 and 138 men born to women who were affected by ICP failed to find any impact on the long term health of the offspring.85

Healthcare Professional Brochure Printable PDF

Resource for ICP familiesMaternal 911 online multi-module course designed to provide updated education to all health care providers working at the bedside of a pregnant woman. Continuing Medical Education credits will be awarded upon successful completion of the modules and simulation drills from Michigan State University College of Human Medicine.

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