Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a reversible type of hormonally influenced cholestasis. It frequently develops in late pregnancy in individuals who are genetically predisposed.[1] It is the most common pregnancy-related liver disorder.[2, 3] It is characterized by generalized itching, often commencing with pruritus of the palms of the hands and soles of the feet, with no other skin manifestations. It most often presents in the late second or early third trimester of pregnancy.

Approximately 1% of pregnancies in the United States are affected by this condition. ICP has no clear etiology, and it is believed to be a multifactorial disorder with environmental, hormonal, and genetic contributions. The diagnosis is based on physical examination and laboratory findings, but, in general, ICP is a diagnosis of exclusion. Once the diagnosis of ICP is made, treatment should be initiated immediately. Maternal outcomes for patients diagnosed with ICP are good, with few, if any, long-term sequelae; however, fetal outcomes can be devastating. Thus, early recognition, treatment, and timely delivery are imperative.

See Diagnosing Dermatoses in Pregnant Patients: 8 Cases to Test Your Skills, a Critical Images slideshow, for help identifying several types of cutaneous eruptions associated with pregnancy.

Affected individuals have a defect involving the excretion of bile salts, which leads to increased serum bile acids. These are deposited within the skin, causing intense pruritus.[1] The cause of ICP is unknown but is thought to be multifactorial with genetic, hormonal, and environmental involvement. Family clustering and varying incidence in different geographic regions speaks strongly for a genetic etiology of ICP[4] ; for example, certain populations in Chile experience a far higher incidence of ICP than in the United States. In addition, ICP has a high recurrence rate suggesting that certain people are innately susceptible to ICP.

Up to 15% of ICP cases are associated with the adenosine triphosphate binding cassette, subfamily B, member 4 (ABCB4/abcb4) gene.[2, 5] This gene, also known as multidrug resistant protein 3 (MDR3), encodes the transporter for phospholipids across the canalicular membrane of hepatocytes. Up to 10 different MDR3 mutations have been identified and any one of these mutations may result in loss of function and, therefore, raise bile acid levels.[6, 7, 8, 9] MDR3 is also associated with progressive familial intrahepatic cholestasis.[10, 11] Therefore, a careful and focused family history of a patient diagnosed with ICP, looking for a personal or family history of ICP or gallstones and cholestasis with oral contraceptive pill (OCP) use is important.

Changes induced by these genetic mutations lead to an increased sensitivity to estrogen.[12] Estrogen has a known role in causing cholestasis, and, thus, cholestasis can arise from estrogen-containing OCPs.[4] All steroids, estrogen, progesterone, and corticosteroids are increased during pregnancy 1,000-fold at term compared with the nonpregnant state.[5] Sex hormones exert cholestatic effects via inhibition of the hepatocellular bile salt export pump.[2] Another mechanism for sex hormone interaction involves the association of higher sex hormone levels with impaired sulfation. The hepatic transport mechanisms for biliary excretion can be saturated by sulfated progesterone metabolites.[2]

Individuals with a sensitivity to estrogen should be monitored closely during pregnancy for signs and symptoms of ICP, especially in the third trimester when estrogen levels are at their highest.[13] Similarly, those with multiple gestations are at an increased risk for developing ICP, owing to increased levels of estrogen above those seen with singleton gestations.

Environmental factors are also thought to contribute to the development of ICP. Many patients have more mild recurrence in subsequent pregnancies, which suggests that environmental factors play a role in the development and severity of ICP.[14] For example, limited studies have shown that selenium deficiency can play a role in ICP.[14] Selenium acts as a cofactor of several enzymes in the oxidative metabolism in the liver but the role of selenium in bile secretion has yet to be defined.[15] Seasonal variation is also noted, with more severe cases in the winter months.[16] Thus, consultation with a dietician and discussion of timing for subsequent pregnancies is prudent in patients with a history of ICP.

Recent studies have implemented 2 bile acids, taurocholic and taurodeoxycholic aids, as being the specific ones elevated in ICP. Interestingly, these are also the bile acids significantly decreased by ursodeoxycholic acid (UCDA), which is currently the main pharmacological treatment. The significance of these findings remains to be fully elucidated.[17, 18]

A study by Abu-Hayyeh et al found that sulfated progesterone metabolites are a prognostic indicator for ICP and can help predict onset of ICP and distinguish it from benign pruritus gravidarum.[19]

Frequency

United States

The incidence of ICP varies greatly not only throughout the world, but throughout different regions in the United States as well. Evidence of family clustering and prevalence in certain ethnic groups may partially explain the geographic variation in incidence. For example, the Chilean population overall has a 16% incidence of ICP, and a subpopulation in Chile, the Araucanos Indians, has an incidence of 28%.[20]

While ICP is more common in South Asia, South America, and the Scandinavian countries, the incidence in the United States varies greatly. The United States has a heterogeneous population, and thus the incidence has a wide range, 0.32-5.6%.[12, 21, 22] ICP also shows seasonal variation, occurring more frequently in the winter months.[23] Other risk factors for ICP include advanced maternal age, a personal or family history of cholestasis with oral contraceptive use, and multiparity.[24] In addition, women with twin pregnancies are 5 times more likely to develop ICP than women with a singleton pregnancy.[13]

Mortality/Morbidity

From a maternal viewpoint, the main consideration is intense pruritus, which may become so intolerable that delivery is considered as early as 35-37 weeks.[25] The fetal viewpoint is more concerning, as even with modern treatment the risk for fetal demise can range from 2-11 %. Thus, many would advocate induction at 37 weeks.[25, 26] Other authors believe that a significant rise in bile acids or persistent increases in transaminases despite adequate UCDA treatment should prompt consideration for delivery.[26, 27, 28, 29, 30]

One of the more worrisome aspects of ICP is the possibility of sudden fetal death, sometimes within hours of normal fetal heart rate tracings.[25, 31] Possible explanations for this are taurocholate crossing into the fetal compartment and causing fetal arrhythmias and decreased contractility.[25, 32] This has been documented in the rat model. Other studies have noted an increased P-R interval in human fetuses affected by ICP.[33] Still others have found human chorionic vein constriction when exposed to the bile acid cholate. This is postulated as a possible cause of acute fetal asphyxia. Some authors have postulated a role for impaired fetal adrenal function.[34]

With this risk for sudden fetal death, the dilemma becomes how to monitor and when to deliver. Since fetal death rarely occurs before 36 weeks’ gestation,[35, 36, 37] many authors, as noted above, favor delivery when 37 weeks gestation is reached. Twice-weekly nonstress testing is also usually recommended. Some evidence suggests that umbilical artery Doppler test results become abnormal in these pregnancies prior to abnormal nonstress tests, so the use of this modality for monitoring can also be considered.[38]

Two recent publications seem to come to opposite conclusions. Authors who looked at the literature supporting the American College of Obstetrics and Gynecology (ACOG) recommendation for active management in ICP pregnancies concluded that this was based on less-than-ideal evidence.[39] However, Geenes et al reports a prospective cohort study noting significant increased risks of adverse prenatal outcomes in severe intrahepatic cholestasis.[40] The differences may be attributable to looking at ICP as a whole versus the subset of severe ICP. Some have suggested that profiling with primary bile acids, especially taurochenodeoxycholic acid (TCA) and glycocholic acid (GCA), which are significantly elevated in the severe ICP group, may help stratify ICP further and assist with these management dilemmas.[41]

Intrauterine fetal demise is also associated with ICP, especially if the total bile acid level is elevated and/or jaundice is present, but it rarely occurs prior to 36 weeks’ gestation.[35, 36, 37] In a study by Glantz et al, fetal complications including preterm delivery, meconium staining of the amniotic fluid and the placenta, and fetal asphyxia were related to bile acid concentration with the critical level of 40 micromol/L or greater.[42]

A study by Kawakita et al found that in women with ICP, total bile acid level ≥100 μmol/L was associated with increased risk of stillbirth. The authors also added that TBA ≥40 μmol/L was associated with increased risk of meconium-stained amniotic fluid.[43]

In summary, the current consensus favors twice-weekly nonstress testing with or without Doppler testing and induction at 37 weeks.

Intrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus that usually occurs in the second or third trimester; however, ICP may occur as early as the first trimester. ICP-related pruritus without a rash may affect all areas of the body but characteristically starts in the soles of the feet and palms of the hands and progresses to the trunk and face.[44] Pruritus associated with ICP is often worse at night and the pruritus may be so severe that it can affect the patient’s quality of life, even leading to suicidal ideation.[16] Steatorrhea and vitamin K deficiency may also occur due to fat malabsorption.[44] If the vitamin K deficiency is not corrected by the time of delivery, a postpartum hemorrhage may ensue.

ICP is characterized by profound itching often beginning with the palms of the hands and soles of the feet without evidence of a rash.

Jaundice may occur in 17-75% of cases of intrahepatic cholestasis of pregnancy (ICP) but typically develops 1-4 weeks after the onset of pruritus.[24, 45, 46, 47] Multiple laboratory abnormalities can be seen in ICP. The most specific and sensitive marker of ICP is total serum bile acid (BA) levels greater than 10 micromol/L.[48] In addition to the elevation in serum BA levels, the cholic acid level is significantly increased and the chenodeoxycholic acid level is mildly increased, leading to elevation in the cholic/chenodeoxycholic acid level ratio.[49, 50] The elevation of aminotransferases associated with ICP varies from a mild increase to a 10- to 25-fold increase.[48]

Total bilirubin levels are also increased but usually the values are less than 5 mg/dL. Alkaline phosphatase (AP) is elevated in ICP up to 4-fold, but this is not helpful for diagnosis of the disorder since AP is elevated in pregnancy due to production by the placenta. Mild elevation of gamma glutamyltransferase (GGT) is seen with ICP but occurs in fewer than 30% of cases.[16] If GGT is elevated in cases of ICP, the patient is more likely to have a genetic component of the liver disease.[15]

BA levels have been suggested to be used for diagnosis and management of ICP but there is no uniform agreement on the criteria for diagnosing ICP. Most laboratories have a turnover time of 3-4 days for BA level results, making management decisions based solely on BA levels difficult. Davis et al asserted that alanine aminotransferase (ALT) is the most sensitive of the conventional liver tests for diagnosis of ICP in the presence of pruritus without a rash.[51] Palma et al also used ALT and aspartate aminotransferase (AST) values greater than 40 IU/L as partial criteria for the diagnosis of ICP.[48]

Recommended laboratory studies for the diagnosis of ICP include total serum bile acid levels, cholic acid, chenodeoxycholic acid (to evaluate the cholic/chenodeoxycholic acid ratio), total bilirubin, transaminases, GGT, PT, PTT, and INR. These laboratory studies are used in conjunction with physical examination and symptoms to make a diagnosis of ICP. Once a diagnosis of ICP has been made, total bile acid levels can be followed every 2-3 weeks to guide therapy and timing of delivery. In addition, coagulation studies and transaminase levels should be monitored to measure progression of the disease.

Diagnosis of ICP may thus be made in the presence of pruritus without a rash in the absence of other liver disease in a gravid patient beyond 25 weeks’ gestation with the elevation of serum BA and/or aminotransferases levels.

Liver biopsy is not required to make the diagnosis of ICP. However, if liver biopsy is performed, it is common to demonstrate bile plugs without evidence of inflammation and bile pigment in hepatocytes.[44]

A study by Kremer et al reported that increased serum autotaxin activity represents a highly sensitive, specific and robust diagnostic marker of ICP and can distinguish ICP from other pruritic disorders of pregnancy and pregnancy-related liver diseases.[52]

Antenatal testing, including umbilical artery Doppler studies, biophysical profile (BPP), and nonstress tests, have all been performed to reduce the risk of stillbirth.[53, 54, 55] One study demonstrated that increased fetal testing and scheduled induction with documentation of fetal lung maturity in patients with ICP lessened perinatal mortality rates compared with patients who were not tested.[56]  Another study concluded that bile acids above 100 μmol/L were associated with increased mortality despite twice-weekly antenatal testing.[57] A study by Kohari et al examined the effectiveness of an intensive surveillance system for women with total bile acids >40 μmol/L at < 36 weeks. The intensive surveillance included inpatient admission and continuous FHR monitoring with delivery between 36 and 37 weeks. The authors noted a significant reduction in the stillbirth rate with this intensive surveillance strategy.[58]

Delivery is commonly recommended at 37 weeks’ without an amniocentesis for fetal lung maturity due to increased risk of fetal mortality, or after an amniocentesis for delivery prior to 37 weeks’ gestation. If meconium is present at the time of amniocentesis, delivery is indicated regardless of the fetal lung maturity results. Delivery can proceed without an amniocentesis if the fetal monitoring is nonreassuring. Some providers are now waiting until 38-39 weeks gestation to deliver if there is resolution of pruritus symptoms with treatment and bile acid levels are not significantly elevated (less than 40 micromol/L). 

A retrospective case-control study by Furrer et al found no differences in postpartum blood loss in women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and with a planned delivery at 38 weeks of gestation.[59]

Many pharmacological agents have been used in the treatment of intrahepatic cholestasis of pregnancy (ICP). These include phenobarbital (100 mg qd), hydroxyzine (25-50 mg qd), glutathione precursor S-adenosyl methionine (SAME) (800 mg qd IV or 1600 mg qd orally), cholestyramine (8-16 g/d) and dexamethasone (12 mg 4 times daily for 7 days followed by a tapering dose). All these agents showed some limited clinical benefit (eg, phenobarbital relieved pruritus in 50% of patients but showed no reduction of liver enzymes or bile salts) but also had significant adverse effects.[60] Vitamin K deficiency was observed with the use of cholestyramine in high doses.[49, 61, 62, 63, 64, 65, 66] Dexamethasone demonstrated limited benefits in cases of ICP with significant side effects.[65, 67]

Ursodeoxycholic acid (UDCA) improves clinical symptoms and liver parameters in a number of cholestatic liver disorders.[66, 68, 69, 70] The mechanism of UDCA is unknown. One putative action of UDCA is that the drug inserts a key translocator or transporter protein, improving bile salt export from the liver and theoretically reducing the risk to the fetus.[71]

UDCA remains the drug of choice for the treatment of ICP. UDCA at a daily dose ranging from 600-2000 mg was effective at reducing pruritus, decreasing the total serum bile acid levels, ALT values, and bilirubin levels and allowing delivery closer to term (37.8 ± 0.9 wk vs 33.8 ± 7.1 wk).[72, 73] UDCA also improved the cholic acid/chenodeoxycholic acid ratio seen in ICP.[74, 75, 76] UDCA has no significant maternal adverse effects. An infant follow-up study of 26 children over a 12-year period showed no long-term sequelae.[77] Based on a meta-analysis, UDCA is effective in reducing pruritus and improving liver test results in patients with ICP, and may also improve fetal outcomes.[78]

Antihistamines are commonly administered in conjunction with UDCA to alleviate pruritus symptoms. Diphenhydramine or Hydroxyzine can help treat the insomnia that typically accompanies severe pruritus. 

Patients with intrahepatic cholestasis of pregnancy (ICP) should have regular antenatal testing (starting at 32-34 weeks) with consideration for Doppler flow studies of the umbilical artery.

The recurrence rate for ICP is believed to be 45-70%.[16] In patients with a history of ICP, oral contraceptives containing estrogen should be used with caution and at the lowest possible dose. Exogenous estrogen in these patients can lead to cholestasis outside of pregnancy. Conversely, patients who exhibit cholestasis with the use of OCPs should be evaluated for ICP during pregnancy.

The past consensus has been that ICP is a contraindication for OCP use. However, some authors suggest that the newer low-dose pills can be safely used as long as liver function test results are followed and patients are aware of possible recurrence risks.[79]

For all patients with ICP, serum bile acid levels and liver function tests should be drawn 3-6 months postpartum. If bile acid levels remain elevated at 6 months’ postpartum, further evaluation is indicated to rule out an underlying genetic disorder or chronic liver disease. There is no data about the advisability of monitoring patients with a history of ICP during subsequent pregnancies. As recurrence rates are high for ICP, especially those with a genetic predisposition, the authors recommend a baseline bile acid level and liver enzymes and repeat levels if symptoms occur. Patients should be closely monitored for pruritus throughout pregnancy and UDCA should be initiated at the first signs of ICP even prior to receipt of the laboratory results. 

ICP presents greater risk to the fetus than to the mother.[80] ICP increases the rate of preterm delivery with the associated mortality and morbidity. In addition, the fetus is at an increased risk for stillbirth. The major concern for the mother is for postpartum hemorrhage if her vitamin K level is low, leading to an increase in prothrombin time.