Intrahepatic cholestasis of pregnancy (ICP) is a reversible liver disease that occurs in the second and third trimesters of pregnancy.¹ The presenting symptom is pruritus (severe itching), primarily of the palms of hands and the soles of feet associated with elevated bile acids (≥10 umol/L).¹ In addition, 60% of women with ICP have elevated transaminases, and 25% have increased bilirubin, both of which normalize quickly after delivery.² As reports range widely, the incidence of ICP is variable, ranging from 0.1 to 6% worldwide.^3–5 In North America and Western Europe, the incidence is 0.1% to 1.5%.¹ Patients with ICP are monitored closely, as it is associated with increased risk of preterm delivery (19%–60%),^4,6,7 intrapartum fetal distress (22%–41%), meconium-stained fluid at time of delivery,¹ respiratory distress syndrome (RDS),⁸ and intrauterine fetal demise (IUFD) (0.75%–1.6%).^1,6,9,10 However, standard antepartum testing (nonstress tests, biophysical profiles) are not predictive of ICP-related morbidity and mortality.^11,12

Although ICP is still thought of as a disease process specific to pregnancy, with resolution occurring shortly after delivery, it has recently been found that mothers with ICP may have increased risk of gallstone formation, nonalcoholic liver cirrhosis, nonalcoholic pancreatitis, and hepatitis C, suggesting that these patients may need more follow-up than initially assumed.¹³ Certainly, patients with persistent symptoms, laboratory abnormalities, or both after delivery should undergo further workup for underlying causes. Patients should also be counseled that there is a risk of recurrence (as high as 60%) of developing ICP in future pregnancies, which may be suggestive of a genetic component to the condition in some women.^9,14

Multiple small studies have shown geographic variation in the incidence of ICP, suggesting differing susceptibility in certain ethnic groups. In the United States, the prevalence of ICP ranges from 0.32% to 5.6%, with higher rates in areas with predominately Hispanic populations.^15,16 The possible association of ICP with Hispanic heritage is further suggested by the fact that the highest incidences are reported in Chile and Bolivia (6%–27%).¹⁷

Aside from possible increased susceptibility due to ethnic background, vitamin deficiencies (most notably selenium or vitamin D) have been reported to increase the risk of ICP. Additionally, women who have ICP during pregnancy may be at an increased risk for underlying hepatic function. In fact, several studies have shown that the incidence of ICP is significantly higher in women with preexisting hepatitis C virus (HCV).^13,18,19 It should also be noted that women who have had ICP in a prior pregnancy are at increased risk for developing ICP in subsequent pregnancies.²⁰

INTRAHEPATIC CHOLESTASIS

Although the exact cause of ICP is unknown, it results from the incomplete clearance of bile acids, with subsequent accumulation in the plasma. Initially, it was assumed that the bile acids themselves caused pruritus; however, bile acid levels do not correlate to self-reported itching scores.²¹ Recently, a bile acid–induced sensory nerve-signaling pathway, TGR5, has been identified, which is thought to possibly lead to increased pruritus.²² It has been shown that progesterone sulfate levels are more likely to correlate with the degree of pruritus.²² In addition, an elevation in liver transaminases is common in women with ICP. Even at low concentrations, bile acids are cytotoxic. Thus an increase in bile acids leads to liver damage, likely resulting in transaminitis.^23,24

HORMONAL CHANGES OF PREGNANCY

Pregnancy itself may increase the risk of developing ICP due to normal, physiologic changes. It is suggested that changes in sex steroid levels during pregnancy may contribute to impaired bile acid management.²⁴ For example, progesterone metabolites can cross-talk with bile acid–signaling pathways.²⁵ In addition, ICP is most commonly seen in the late second and third trimesters, when serum estrogen concentration is at its peak.¹⁷ It occurs more often in twin gestations, which are characterized by higher levels of circulating estrogen than their singleton counterparts.¹⁴ With respect to progesterone, sulfated progesterone metabolites may saturate the hepatic transport system that is also used for biliary excretion. In a small French study, 64% of women with ICP were treated with oral progesterone for premature birth prevention.⁴ It was determined that the onset of pruritus was statistically earlier in women who had been taking progesterone than those who had not, suggesting that exogenous progesterone may be a factor in the development of ICP.⁴

VITAMIN DEFICIENCIES

Several small studies have also reported increased incidence in women with low selenium or vitamin D levels.^26,27 It is has been suggested that low selenium alters oxidative metabolism in the liver.²⁶ It is unclear why vitamin D levels may play a role in ICP development.

HEPATITIS C

The association of ICP and HCV has not been fully explained. It has been suggested that HCV downregulates the expression of a transporter (ABC multidrug resistance-protein 2), which hinders the liver’s ability to prevent the buildup of substances such as bile acids.²⁸ There also may be a connection between a HCV-induced defect in the ABCB11 gene, which encodes a bile salt exporter pump, and development of ICP.²⁹ In addition to targeting specific receptors, one study found that hepatitis modifies hepatocytes and biliary endothelial cells, preventing the excretion of bile acids.¹⁹ If ICP develops in patients with hepatitis, it often presents at an earlier gestational age. It is thought that preexisting damage to the liver makes a patient more susceptible to developing ICP.¹⁹

GENETIC PREDISPOSITION

Current research is focused on identifying genetic mutations in the hepatocellular transport system that cause bile acid buildup, leading to ICP. For example, ABCB4 (adenosine triphosphate-binding cassette, subfamily B, member 4), which encodes the multidrug resistance protein 3, a canalicular phospholipid translocator, has been shown to be involved in a subtype of progressive familial intrahepatic cholestasis.³⁰ There have been reports of heterozygous mutations in this transporter in women with ICP.³⁰ A defect in ABCB11, a member of the ABC transporter superfamily and a highly specific transporter of conjugated bile acids into canaliculus, causes abnormal section.³¹ A European study identified six single nucleotide polymorphisms (SNPs) significantly associated with an increased risk of ICP.³¹

The role of transporter defects in ICP is not always clear-cut. For example, in one study, a defect in the transporting ATPase made by ATP8B1, which results in abnormal excretion of amniophospholipids, was associated with ICP.³² However, a larger study did not confirm this initial finding; its role in the disease process has yet to be determined.^32–34 A study done using microarray technology found 20 genes that may be linked to ICP.³⁴ Continued work must be done to clearly identify the role that genes, and the resulting mutations, may play in ICP.

Based on literature reviews, the estimated incidence of IUFD in women with ICP is 1.74%.³⁵ By comparison, the rate of IUFD in the general population occurring ≥28 weeks gestation is 0.0031%.³⁶ A Swedish large cohort study demonstrated that higher bile acid levels (>40 umol/L) are more strongly associated with fetal complications.³⁷ The degree of bile acid elevation at the time of diagnosis of ICP has been significantly linked to IUFD (OR, 1.26; 95% CI 1.01–1.57; p = 0.39).¹ One study has shown that perinatal death is most common in ICP patients with bile acid levels ≥100 umol/L at the time of diagnosis (9.5%, n = 2/21).¹ Maternal treatment to reduce bile acid levels may provide symptomatic relief, but it has not been proven to improve fetal outcomes.^38,39

Bile acids are transported across the placenta, as umbilical cord bile acid levels have been found to have a positive correlation with both the highest-measured maternal bile acid levels and maternal bile acid levels at the time of delivery.¹ Research in animal models has shown that bile acids adversely affect cardiomyocytes leading to arrhythmia, which may cause IUFD.^40,41 In addition, when isolated human placental chorionic veins are exposed to bile acids, vasoconstriction occurs.⁴² The resulting fetal distress and asphyxia may lead to fetal demise. A DNA microarray study found the placentas of women with mild and severe ICP differentially express genes when compared to placentas from normal pregnancies.⁴³ These placentas display differences in the expression of proteins linked with blood coagulation and platelet and chaperone activation, among other signs.⁴⁴ Research has yet to be done linking these specific placental abnormalities to IUFD, and yet it is logical that a disruption of vasculature between mother and fetus could result in fetal death.

Due to the risk of IUFD, iatrogenic preterm birth is the primary cause of early delivery in patients with ICP. As the majority of IUFDs occur after 37 weeks gestation and there is an increased rate of complication in ICP pregnancies carried to >40 weeks gestation,^1,45 most guidelines recommend induction of labor prior to 40 weeks gestation, regardless of the severity of ICP.^46–48 Due to the higher rate of complications in women with severe ICP (bile acids ≥100 umol/L), these patients are often induced in late preterm gestations, generally between 34 and 37 weeks.¹ In this case, the risk of IUFD may outweigh the associated risks of preterm delivery. However, in women with mild to moderate ICP (BA ≥10–99 umol/L), the incidence of complications is lower. Therefore the morbidity of a late preterm delivery must be weighed against the lower likelihood of IUFD.^49,50

The need for delivery <37 weeks gestation in women without severe ICP has not been proven.¹ However, a study done using a decision-analytic model showed that immediate delivery at 36 weeks without prior steroid administration for fetal lung maturity is the optimal delivery timing for decreasing risk of IUFD.³⁵ The generalizability of this study is limited, as it did not specify maternal bile acid levels at the time of diagnosis. Although there is no consensus, given that risk of IUFD seems to increase at term in patients with ICP, iatrogenic preterm birth may be a consideration for some women with ICP.

Preterm birth also may be independently associated with ICP, as bile acids have been shown to increase the sensitivity and expression of oxytocin receptors in human myometrium.^51,52 A retrospective study performed in the Netherlands found that higher bile acid levels are significantly associated with spontaneous preterm birth, with an adjusted odds ratio (OR) of 1.15 (95% CI, 1.06–1.25).¹

In a small retrospective cohort study, RDS was found in 28.6% of neonates born to mothers with ICP, compared to 14% in the control group, despite a slightly higher than average gestational age in the control group (35.6 vs. 35.1 weeks).⁸ The probability of RDS occurring rises as maternal bile acid levels increase.⁸ The hypothesis behind this relationship is that placental clearance of fetal bile acids is impaired in women with ICP, leading to an accumulation of these toxic compounds in the fetus.⁵³ In the lungs, this disrupts the normal functioning of phospholipase A2, which is needed to synthesize surfactant.⁵⁴ Reduced surfactant then results in an increased likelihood of developing RDS.

(Table 32-1)

ICP is a diagnosis of exclusion. It is defined as an elevation in total bile acids in a pregnant woman with pruritus and in the absence of an alternative etiology. The differential diagnosis for ICP includes other causes of pruritus that are not necessarily related to pregnancy. Conditions causing both pruritus and rash would certainly suggest an alternative etiology, as rash is generally not associated with ICP. For example, pemphigoid gestationis, an autoimmune reaction to complement-fixing immunoglobulin G (IgG) antibodies, can present with itching of the palms and soles. However, in that case, lesions quickly develop and erupt into bullae. In addition, bile acids are not elevated in this condition.

In women with suspected ICP who have elevated transaminases, other causes for abnormal liver function tests need to be ruled out. Pregnancy-associated conditions, such as preeclampsia and HELLP syndrome, may have elevated liver enzymes but are also generally associated with hypertension and proteinuria. Acute fatty liver of pregnancy should also be considered. While women with ICP generally appear well, women with acute fatty liver of pregnancy are ill and may complain of nausea, vomiting, headache, abdominal pain, and polydipsia and are more likely to have associated coagulopathy, renal impairment, preeclampsia, and hypoglycemia.

Preexisting hepatic impairment may also be a consideration in women with elevated liver function tests. Viral hepatitis may be a concern, although these patients will typically present with jaundice, abdominal pain, nausea, and vomiting. Biliary obstruction may be another possibility, but patients with this diagnosis will usually also have complaints of right upper quadrant pain.