Background
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.
Pathophysiology
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]
Epidemiology
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.
