Intrahepatic cholestasis of pregnancy

Abstract

Intrahepatic cholestasis of pregnancy is a pregnancy-specific liver disorder. It is characterized by pruritus, jaundice, and elevated serum bile acids, mainly in the third trimester, with different fetal outcomes. The pathophysiology involves abnormal bile acid metabolism, with deposition of bile acids in the maternal tissues and the placenta. It is commonly (∼70% of cases) accompanied by elevated maternal serum total bile acids. Abnormal liver function tests (transaminase levels in the 60–200 range U/l and alkaline phosphatase 200–400 U/l range) are typically present, but hyperbilirubinemia with clinical jaundice is rare. The etiology of intrahepatic cholestasis of pregnancy is complex and not fully understood, but it is likely to result from the cholestatic effects of reproductive hormones and their metabolites.

Introduction

Intrahepatic cholestasis of pregnancy (ICP), which is also known as obstetric cholestasis, was originally described in 1883 by Ahlfeld as recurrent jaundice in pregnancy that resolved following delivery. Over the years, ICP has also been described as jaundice in pregnancy, recurrent jaundice in pregnancy, idiopathic jaundice of pregnancy, obstetric hepatosis, hepatosis gestationalis, or obstetric cholestasis ¹. Apart from the severe maternal symptomatology, the chief perinatal risk is intrauterine fetal death, which is typically very poorly predicted by fetal surveillance. Late preterm birth (34–36 weeks), fetal intolerance of labor, and meconium-stained fluid are also more common in these pregnancies. Maternal symptoms resolve promptly after delivery, but there is a 40–70% recurrence rate in subsequent pregnancies ².

The livers of postmenopausal women with a history of ICP well tolerated the short-term exposure to oral and transdermal estradiol, although the doses used were higher than those in routine clinical use. The response of serum levels of sex hormone-binding globulin to oral estradiol was slightly reduced in the ICP group. Transdermal estradiol had no effect on C-reactive protein or sex hormone-binding globulin. A number of liver and biliary diseases were found to be associated with ICP ³.

Epidemiology

The incidence of ICP varies widely with geographical location and ethnicity. It is most common in Chile, where early reports have described an overall incidence of 10%, with higher rates found in women of Araucanian Indian descent. However, this has decreased to ∼1.5–4% ^4,5. The reasons for this decline are unclear, but do not appear to reflect changing diagnostic criteria, which have become more inclusive in recent studies.

ICP is more common in the winter months in Finland, Sweden, Chile, and Portugal ⁶. A higher incidence is found in twin pregnancies and following in-vitro fertilization treatment ⁷. One study has suggested that it is more common in women older than 35 years of age ⁸.

Etiology and pathogenesis

Over the last decade, it has become increasingly apparent that the etiology of ICP is multifactorial, involving genetic and hormonal factors. Hormonal factors may lead to transient decompensation of the heterozygous state for genes encoding hepatobiliary transport proteins that fail during pregnancy, leading to ICP ⁹.

Estrogens and progesterone

ICP occurs mainly during the third trimester, when serum concentrations of estrogens and progesterone reach their peak. ICP is also more common in twin pregnancies, which are associated with higher levels of hormones than singleton pregnancies ¹⁰. All hormones are metabolized by the liver, and an excess of metabolites influences the activity of biliary canalicular transporters. The function of hepatocellular transporters such as ABCB11 and ABSB4 has been shown to be impaired at the post-transcriptional level in vitro by high loads of estrogen glucuronides and progesterone ¹¹. In addition, estrogens impair basolateral as well as canalicular bile acid transporter expression of liver cells in vitro by transcriptional mechanisms ^12,13.

Genetic factors

There is increasing evidence that interaction between genetically determined dysfunction in the canalicular ABC transporters and high levels of sex hormones produced in pregnancy can predispose toward the development of ICP ¹⁴. Genetic factors could explain familial cases and the higher incidence in some ethnic groups. Also supporting genetic factors are the high rate of recurrence of ICP in subsequent pregnancies and the susceptibility of affected women to progesterone ¹⁵.

Other factors

Some characteristics of ICP, such as incomplete recurrence at subsequent pregnancies, the decrease in prevalence, and seasonal variations, suggest that environmental factors may contribute toward the pathogenesis of this disorder ¹⁶.

Clinical features

Maternal presentation

The most common presenting symptom of ICP is pruritus, which usually presents in the third trimester. This increases progressively as the pregnancy advances and usually resolves after delivery. It most frequently affects the palms of the hands and soles of the feet, but without dermatological features other than excoriation marks. Approximately 80% of affected women present after 30 weeks of gestation, but ICP may be presented as early as 8 weeks.

The relationship between onset of pruritus and development of hepatic dysfunction is not clear. It has been reported that itch may be present either before or after an abnormal liver function is detected. Clinical jaundice is rare with ICP, and if it does occur, it tends to be mild, with bilirubin levels rarely exceeding 100 μmol/l, and does not deteriorate with advancing gestation. Constitutional symptoms including anorexia, malaise, and abdominal pain may be present. Pale stools and dark urine have been reported and steatorrhea may occur. There is also an association between steatorrhea and an increased risk of postpartum hemorrhage as a result of malabsorption of vitamin K.

Fetal disease

There are consistent reports of adverse fetal outcomes in association with the condition, although most studies are not sufficiently large to allow accurate quantification of the frequency of the complications. Many studies have attempted to correlate maternal serum biochemistry with fetal outcomes. The sensitivity of bile acids is used as a predictive marker of fetal risk in several studies.

Meconium staining of the amniotic fluid

The incidence of meconium staining of amniotic fluid (MSAF) in normal-term pregnancies is ∼15% and is considered to be a sign of fetal distress. In ICP, MSAF has been reported in 16–58% of all cases and up to 100% of cases affected by intrauterine death. The frequency of MSAF is greater in pregnancies with higher reported levels of maternal serum bile acids.

Cardiotocography abnormalities

Both antepartum and intrapartum cardiotocograpic abnormalities have been reported in association with ICP, including reduced fetal heart rate variability, tachycardia, and bradycardia ¹⁷.

Preterm labor

There is an increased risk of spontaneous preterm labor, which has been reported in as many as 60% of deliveries in some studies, but most studies report rates of 30–40% in ICP cases without active management. The rate of this complication was significantly higher in ICP pregnancies with maternal fasting serum bile acids greater than 40 μmol/l in the larger study of Swedish ICP cases.

Respiratory distress syndrome

Studies have shown that there is an increased risk of respiratory distress syndrome with either induction of labor or elective cesarean section at 37 weeks’ gestation. It should be noted that the risk of neonatal respiratory distress is considerably higher with elective cesarean section, and it should be borne in mind that labor is induced in the majority of women with ICP. Also, there are some data to suggest that neonatal respiratory distress following ICP may be a consequence of the disease process.

Sudden intrauterine death

Older studies using biochemical abnormalities to diagnose ICP have reported a perinatal mortality rate of 10–15%.This has been reduced to 3.5% or less in more recent studies using policies of active management. The term active management may encompass many different clinical practices, including increased fetal monitoring, frequent biochemical testing, pharmacotherapy with ursodeoxycholic acid (UDCA), or delivery at 37–38 weeks’ gestation. These management protocols are based on evidence showing that stillbirths in ICP tend to cluster around 37–39 weeks ¹⁸.

Other findings

Several studies have shown that there is no increase in the number of small for gestational age infants born to women with ICP.

Investigations

The diagnosis of ICP is one of exclusion, and alternative causes of hepatic impairment or pruritus should be considered before the diagnosis is made.

Liver function tests

In ICP, alanine aminotransferase and aspartate aminotransferase may increase before or after serum bile acids. Alanine aminotransferase is considered to be a more sensitive marker of ICP; there is a 2–10-fold increase in serum levels that is generally more marked than the increase in aspartate aminotransferase. Bilirubin is normal in the majority of ICP cases and is of limited value in diagnosis or follow-up.

Bile acids

The primary bile acids, cholic acid and chenodeoxycholic acid are the end products of hepatic cholesterol metabolism and represent the major route for the excretion of cholesterol. UDCA is a tertiary bile acid as it results from bacterial modification, followed by hepatic metabolism. It is normally detectable in trace amounts in normal serum. Serum bile acid measurement is now considered to be the most suitable biochemical marker for both the diagnosis and the monitoring of ICP.

Other serum biochemistry

Lipids

Many studies have reported deranged lipid profiles in association with ICP, especially LDL and cholesterol.

Glucose

ICP is usually associated with impaired glucose tolerance.

Clotting

A prolonged prothrombin time is reported in 20% of patients.

Liver biopsy

Several studies have reported that there is a normal liver structure, with no evidence of liver cell damage, and only mildly dilated bile ducts, bile stasis in canaliculi, bile plugs, and mild portal tract inflammation in liver biopsies from women with ICP.

Management options

Fetal monitoring

There are several case reports of normal cardiotocography and/or normal fetal movements in the hours preceding fetal loss ¹⁹. However, these forms of fetal surveillance do not prevent intrauterine death. However, they may be reassuring to women with ICP and the clinicians responsible for their care at the time they are performed ²⁰.

Elective delivery

Some studies have reported good outcomes with a policy of induction of labor at 37 or 38 weeks’ gestation.

Drugs

Ursodeoxycholic acid

UDCA is a naturally occurring hydrophilic bile acid that constitutes less than 3% of the physiological bile acid pool in humans. It has been used with positive effects in the management of primary biliary cirrhosis and other cholestatic disorders for several years, and is gaining popularity as a treatment for ICP.

Dexamethasone

Dexamethasone inhibits placental estrogen synthesis by reducing the secretion of the precursor, dehydroepiandrosterone sulfate, from the fetal adrenal glands.

Rifampicin

Although there are no published studies reporting the use of rifampicin in ICP, it has been used with good results in several other liver diseases, including gallstones and primary biliary cirrhosis.

Vitamin K

ICP is associated with a risk of malabsorption of fat-soluble vitamins because of reduced enterohepatic circulation of bile acids and the subsequent reduction of uptake in the terminal ileum. Therefore, many clinicians advice treatment of women with oral vitamin K to protect against the theoretical risk of fetal antepartum and maternal postpartum hemorrhage.

Prognosis

Most women have no lasting hepatic damage, but ICP recurs in the majority of cases, with variations in intensity in subsequent pregnancies. Recurrence is less likely following multiple pregnancies. Women with a history of ICP may also develop symptoms if taking the combined oral contraceptive pill or in the second half of the menstrual cycle ²¹. Additional studies in ICP populations from different countries are required to further characterize the genetic background in these patients. UDCA is currently considered as first-line therapy for ICP. Future prospective controlled studies may provide a better understanding of the underlying pathophysiological mechanisms of fetal risk, identify the most suitable monitoring modalities, and clarify the obstetrical management near term.

Acknowledgements

Conflicts of interest

There are no conflicts of interest.