Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific complication typically occurring during the mid-to-late stages of pregnancy. It is primarily characterized by pruritus, elevated serum total bile acid levels, and rapid symptom resolution with gradual normalization of biochemical markers postpartum. While ICP is a benign condition for the pregnant woman, it is associated with adverse perinatal outcomes such as preterm birth, meconium-stained amniotic fluid, unpredictable intrauterine fetal death, and neonatal asphyxia, increasing perinatal morbidity, mortality, and cesarean delivery rates.
Etiology
The exact pathogenesis of ICP remains unclear, but it may involve factors such as female hormones, genetics, immune mechanisms, and environmental influences.
Estrogen
ICP predominantly occurs in late pregnancy and is more common in cases of multiple pregnancies, a history of ovarian hyperstimulation, and oral contraceptive use, all of which are associated with elevated estrogen levels. High estrogen levels may be related to abnormal estrogen metabolism and heightened hepatic sensitivity to the physiological increase in estrogen during pregnancy. Estrogen has been reported to reduce Na+-K+-ATPase activity, leading to disorders in bile acid metabolism, increase the cholesterol-to-phospholipid ratio in hepatic cell membranes, thereby obstructing bile flow, or act on estrogen receptors on hepatic cell surfaces, altering protein synthesis and leading to bile acid reflux.
Genetic and Environmental Factors
Epidemiological studies have shown that the incidence of ICP varies with seasons, being higher in winter compared to summer. Geographic variation, familial clustering, and recurrence rates are observed as well. Regions such as Chile, Sweden, and the United Kingdom report higher incidence rates. Women with a family history of ICP or a personal history of ICP have a significantly increased risk of developing the condition.
Impact on Maternal and Fetal Health
Maternal Impact
The impact on the mother is generally mild. However, in cases where ICP is accompanied by significant steatorrhea, the absorption of fat-soluble vitamin K may be impaired, increasing the risk of postpartum hemorrhage.
Fetal and Neonatal Impact
The toxicity of bile acids significantly elevates perinatal morbidity and mortality, leading to fetal hypoxia, fetal distress, preterm birth, meconium-stained amniotic fluid, neonatal asphyxia, intracranial hemorrhage, neonatal respiratory distress syndrome, and other complications. The most severe consequence is the unpredictable occurrence of sudden intrauterine fetal death.
Clinical Manifestations
Pruritus
Pruritus without skin lesions is the initial symptom of ICP, occurring in over 70% of cases during late pregnancy, though it may also appear in mid-pregnancy in some cases. The severity of pruritus varies, is often persistent, and tends to be milder during the day and more intense at night. Pruritus typically starts on the palms and soles before spreading to the proximal limbs and, in some cases, the face. It usually appears before abnormal laboratory results and subsides within 24–48 hours postpartum.
Jaundice
Mild jaundice develops in 10%–15% of cases, usually appearing 2–4 weeks after the onset of pruritus. It does not typically worsen as pregnancy progresses and resolves within 1–2 weeks after delivery.
Skin Scratches
ICP does not cause primary skin lesions, but scratch marks may be observed due to pruritus. No abnormalities are detected on skin tissue biopsies.
Other Symptoms
Some pregnant women report nausea, vomiting, loss of appetite, abdominal pain, and mild steatorrhea, though these symptoms are usually mild and infrequent, and their overall well-being remains unaffected.
Diagnosis
The diagnosis of ICP is primarily based on typical clinical symptoms and laboratory findings and is considered a diagnosis of exclusion. It is recommended to perform routine virological tests and hepatobiliary ultrasound to rule out other causes of liver dysfunction or pruritus.
Clinical Features
The onset of pruritus occurs during mid-to-late pregnancy, with mild cases of jaundice in some individuals. Symptoms of pruritus rapidly resolve after delivery.
Laboratory Tests
Serum Bile Acid Measurement
Serum total bile acid (TBA) levels are the primary laboratory indicator for diagnosing ICP. They are also critical for monitoring disease progression, treatment response, and predicting perinatal outcomes. A fasting TBA level ≥10 μmol/L or a random TBA level ≥19 μmol/L strongly suggests ICP.
Liver Function Tests
Most ICP patients exhibit mild-to-moderate elevations in aspartate transaminase (AST) and alanine transaminase (ALT) levels, ranging from 2 to 10 times the normal value, generally not exceeding 1,000 U/L. ALT levels are more sensitive than AST. Some patients may show elevated γ-glutamyl transferase and bilirubin levels, with increased bilirubin being predominantly direct bilirubin. Liver function typically returns to normal within 4–6 weeks postpartum.
Virological Tests
Testing for hepatitis viruses, Epstein-Barr virus, and cytomegalovirus infections is necessary to exclude viral infections.
Liver Ultrasound
While no specific hepatic changes are observed in ICP patients, hepatobiliary ultrasound is recommended to exclude underlying liver and gallbladder diseases.
ICP Severity Grading
Grading the severity of ICP assists in clinical management. TBA levels are closely associated with perinatal outcomes, and ICP is classified based on peak TBA levels during pregnancy:
- Mild ICP: Fasting 10 ≤ TBA < 40 μmol/L or Random 19 ≤ TBA < 40 μmol/L.
- Severe ICP: 40 ≤ TBA < 100 μmol/L.
- Very Severe ICP: TBA ≥ 100 μmol/L.
Differential Diagnosis
ICP needs to be differentiated from conditions causing pruritus without cholestasis or diseases leading to liver dysfunction. The main differential diagnoses include the following:
Pruritus
Conditions such as eczema, urticaria, pregnancy-specific dermatoses, allergic reactions, pruritic folliculitis, or uremic pruritus should be considered for differentiation.
Liver Dysfunction
Viral hepatitis, hepatolithiasis, acute fatty liver of pregnancy, preeclampsia, and HELLP syndrome need to be distinguished from ICP.
Treatment
The treatment principles include alleviating pruritus, improving liver function, reducing TBA levels, prolonging the gestational period, appropriately timing delivery, and optimizing maternal and fetal outcomes.
Maternal and Fetal Monitoring
General Management
For mild ICP cases, liver function and serum total bile acid levels should be monitored every 1–2 weeks until delivery. In moderate to severe ICP cases, the frequency of biochemical testing can be adjusted as needed to assess disease severity and treatment response.
Fetal Monitoring
Fetal well-being should be closely monitored through methods such as fetal movement assessments, electronic fetal heart rate monitoring, and ultrasound. Fetal movement is the simplest way to evaluate intrauterine status; decreased or absent movements indicate fetal hypoxia and require immediate medical attention. From 32 weeks of gestation, non-stress tests (NSTs) can be performed. Obstetric ultrasound is primarily used to monitor fetal growth and, when intrauterine fetal status is uncertain, to calculate biophysical profiles.
Bile Acid Lowering Therapy
Medications may alleviate maternal symptoms, improve biochemical markers of cholestasis, and contribute to better perinatal outcomes. Commonly used drugs include:
- Ursodeoxycholic Acid (UDCA): UDCA is a primary medication for ICP treatment. It helps relieve pruritus, lower serum bile acid levels, prolong gestation, and improve maternal and fetal outcomes. The usual dosage is 1 g daily or 10–15 mg per kg per day, divided into 3–4 doses orally, and should be discontinued postpartum. Liver function and TBA levels should be regularly monitored during treatment.
- S-adenosylmethionine (SAMe): SAMe is used as adjunct therapy for ICP and can be administered orally or intravenously at a dose of 1 g daily, given in divided doses.
Adjunctive Treatments
Fetal Lung Maturity Induction
Dexamethasone may be used for patients at risk of preterm birth.
Pruritus Relief
Calamine lotion, menthol-containing products, and antihistamines can alleviate pruritus.
Postpartum Hemorrhage Prevention
Uterine contractions should be enhanced during delivery. When significant steatorrhea or prolonged prothrombin time is present, vitamin K supplementation (5–10 mg daily, orally or intramuscularly) may be required.
Hepatoprotective Therapy
Hepatoprotective medications may be considered in cases of elevated liver enzyme levels.
Sedation: Sedatives may be provided at night for patients with poor sleep.
Obstetric Management
Sudden intrauterine fetal death is a possible but unpredictable complication of ICP. However, recent studies suggest that fetal death is closely associated with TBA levels ≥100 μmol/L. The ultimate aim of ICP management during pregnancy is to determine the optimal timing for delivery to achieve favorable perinatal outcomes.
For patients with TBA ≥100 μmol/L, prompt consideration should be given to terminating the pregnancy. For patients with TBA <100 μmol/L, routine monitoring of serum total bile acid levels is recommended, and the timing of delivery should be carefully evaluated.
Disease Severity
Severe cases with early onset or prolonged duration may not permit extended expectant management.
Time to Delivery:
Mild ICP
Delivery is recommended at 38–40 weeks’ gestation.
Severe ICP
Delivery is suggested between 36–38 weeks.
Very Severe ICP
Delivery may be considered as early as 35–36 weeks.
For patients with additional high-risk factors or specific conditions (e.g., twin pregnancy, gestational diabetes, preeclampsia, history of stillbirths, deteriorating liver function), the timing of delivery should be individually determined based on gestational age, disease severity, and treatment response.
Mode of Delivery
ICP is not an absolute indication for cesarean delivery. For mild ICP without other indications for cesarean birth, vaginal delivery may be attempted under close monitoring. Labor should be carefully observed, with vigilant monitoring of uterine contractions and fetal heart rate, and neonatal resuscitation should be readily available. If fetal distress is suspected, the indication for cesarean delivery should be broadened appropriately.
Cesarean delivery may be considered under the following circumstances:
- Severe or very severe ICP.
- A history of ICP with associated stillbirths, neonatal asphyxia, or death in prior pregnancies.
- Significant placental dysfunction or strong suspicion of fetal distress.
- Complications such as multiple pregnancies, severe preeclampsia, or other contraindications to vaginal delivery.