Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder distinguished by pruritus and elevated serum bile acids and/or aminotransferase levels. Typically manifesting in the second or third trimester, ICP resolves spontaneously after childbirth. Recognized globally, the prevalence of ICP varies significantly across different geographical regions and ethnicities. While its occurrence in the United States ranges from 0.3% to 5.6%, with higher rates observed in Latina populations in Los Angeles, European prevalence is estimated between 0.5% and 1.5%. Historically, Bolivia and Chile reported the highest incidence rates in the 1970s.
Pathophysiology of ICP
The development of ICP is multifactorial, primarily attributed to hormonal and genetic influences. Estrogens are known to induce cholestasis, a finding supported by animal studies. Progesterone is also implicated, as evidenced by an increased ICP risk associated with oral progesterone administration for threatened preterm labor. Genetically, ICP is complex, with mutations in genes encoding hepatobiliary transport proteins being significant. Mutations in ABCB4, the gene for multidrug resistance 3 (MDR3), a hepatic phospholipid transporter, are frequently observed in ICP patients. Less commonly, mutations in ATP8B1, ABCB11, or NRH1HA, which encode familial intrahepatic cholestasis 1 protein (FIC1), the bile salt export pump, and farnesoid X receptor (FXR), respectively, are also found. Environmental factors may further modulate the expression of ICP.
Clinical Presentation and Diagnosis of ICP
Pruritus, or intense itching, is the hallmark symptom of ICP. This discomfort is often generalized, but predominantly affects the palms and soles, typically worsening at night and disrupting sleep. The severity of pruritus can be quantified using a prefixed score (Table 1) or a visual analogue scale. Postpartum, pruritus resolves within days. Physical examination is usually unremarkable except for scratch marks. Jaundice occurs in less than 10% of cases with severe ICP; ICP presenting with jaundice but without pruritus is exceedingly rare. Patients do not present with fever, abdominal pain, or encephalopathy. While ultrasound may detect gallstones, there should be no signs of biliary obstruction such as biliary tract dilation.
Table 1. Monitoring Pruritus Intensity in ICP with Prefixed Score
| Score | Pruritus Intensity |
|---|---|
| 0 | Absence of pruritus |
| 1 | Occasional pruritus (not daily) |
| 2 | Discontinuous daily pruritus, asymptomatic periods >50% |
| 3 | Discontinuous daily pruritus, symptomatic periods >50% |
| 4 | Permanent pruritus (day and night) |
Alanine aminotransferase (ALT) activity measurement is a highly sensitive diagnostic test for ICP. Significantly elevated serum ALT levels may mimic acute viral hepatitis, necessitating serologic tests for differentiation. Serum bile acid concentrations are also typically elevated, with diagnostic cutoffs often exceeding 10 µmol/L. However, normal bile acid levels do not rule out ICP. It is important to note that serum bile acid concentration measurement is not universally available. This test is particularly useful for diagnosing ICP in pruritic patients with normal ALT levels. In some instances, pruritus may precede liver test abnormalities. Serum bile acid levels, unlike ALT, are valuable for fetal prognosis, as elevated maternal serum bile acids, especially above 40 µmol/L (severe ICP), are associated with fetal distress. Both serum bile acid concentration and ALT activity rapidly normalize postpartum, usually within weeks. Gamma-glutamyltransferase activity, typically elevated in hepatobiliary diseases, remains normal or only mildly increased in ICP. Alkaline phosphatase levels are naturally elevated in the second and third trimesters due to placental isoenzyme production, rendering it unhelpful for Icp Diagnosis. Prothrombin time is generally normal, and liver failure is absent. Prolonged prothrombin time suggests vitamin K deficiency, requiring pre-delivery treatment to prevent postpartum hemorrhage.
Liver biopsy is rarely needed for ICP diagnosis. If performed, histopathology reveals pure cholestasis, sometimes with bile plugs in hepatocytes and canaliculi.
The diagnosis of ICP is primarily based on pregnancy-related pruritus combined with elevated serum aminotransferase and/or bile acids, after excluding other causes of abnormal liver function. Differential diagnosis includes other pregnancy-specific liver diseases like preeclampsia and acute fatty liver of pregnancy, as well as intercurrent conditions such as viral hepatitis, cytomegalovirus infection, and drug-induced liver injury. Urinary tract infections may also induce cholestasis or coexist with ICP. Pre-existing chronic liver diseases may worsen or be incidentally detected during pregnancy. Postpartum liver function tests are crucial to identify persistent abnormalities requiring further investigation and follow-up.
Maternal Outcome in ICP
Maternal prognosis for ICP is generally favorable during and after pregnancy, with low severe morbidity. However, ICP recurrence in subsequent pregnancies is common (60%-70%). Oral contraceptive use post-ICP rarely induces cholestasis, and ICP is not a contraindication to oral contraceptives. After liver function normalization, low-dose estrogen or progestin-only contraceptives can be initiated with monitoring for pruritus and routine liver function tests after 3-6 months.
Long-term maternal prognosis is typically good. However, recent studies indicate increased long-term risks of gallstone-related diseases, nonalcoholic liver cirrhosis, and hepatitis C in women with a history of ICP. Therefore, hepatitis C serology and confirmation of normalized postpartum liver function are important in ICP management.
Fetal Outcome in ICP
ICP poses risks to the fetus, particularly in severe cases. Prematurity, especially late preterm deliveries (34 0/7 – 36 6/7 weeks), is more frequent in ICP pregnancies. Prematurity rates vary across studies due to factors like multiple pregnancies (more common in ICP) and obstetric management strategies. Active management and induced labor, often performed to mitigate intrauterine fetal death (IUFD) risk, may contribute to higher prematurity rates. IUFD remains the most concerning fetal complication, though rare, estimated at 1%-2%, and typically occurs in the last month of pregnancy.
Medical Treatment for ICP
Vitamin K supplementation is recommended if prothrombin time is prolonged. Topical emollients for pruritus relief have unknown efficacy but are safe during pregnancy and may be helpful for some patients.
Ursodeoxycholic acid (UDCA) is the most effective current treatment for ICP-related pruritus and also improves liver function tests. Meta-analysis suggests UDCA benefits fetal outcomes (Table 2). UDCA has no reported maternal or fetal side effects. A typical prescription is 500 mg twice daily (or 15 mg/kg daily) until delivery. UDCA, a hydrophilic bile acid, may protect against hydrophobic bile acid toxicity and improve hepatobiliary bile acid transport, potentially also enhancing placental bile acid transport.
Table 2. UDCA Efficacy in ICP Treatment: Meta-Analysis of Nine RCTs
| Outcome parameters | UDCA vs. Controls/Placebo | Rate | Combined OR (95% CI) |
|---|---|---|---|
| Total pruritus resolution | UDCA vs. all controls | 41.6% vs 6.1% | 0.23 (0.07–0.74); P |
| UDCA vs. placebo | 41.6% vs 8.6% | 0.39 (0.12–1.32); P = 0.13 | |
| Pruritus improvement | UDCA vs. all controls | 61.3% vs 26.8% | 0.27 (0.13–0.55); P |
| UDCA vs. placebo | 61.3% vs 25.7% | 0.21 (0.07–0.62); P | |
| Serum ALT normalization | UDCA vs. all controls | 27.8% vs 9.4% | 0.23 (0.10–0.50); P |
| UDCA vs. placebo | 27.8% vs 14.3% | 0.18 (0.06–0.52); P | |
| Serum ALT decrease[a] | UDCA vs. all controls | 65.9% vs 25.4% | 0.24 (0.11–0.52); P |
| UDCA vs. placebo | 65.9% vs 20.0% | 0.12 (0.05–0.31); P | |
| Serum bile acid decrease[b] | UDCA vs. all controls | 54.3% vs 24.4% | 0.37 (0.19–0.75); P |
| UDCA vs. placebo | 54.3% vs 18.6% | 3.32 (1.38–8.06); P | |
| Total prematurity[c] | UDCA vs. all controls | 15.9% vs 33.6% | 0.44 (0.24–0.79); P |
| UDCA vs. placebo | 15.9% vs 40.0% | 0.59 (0.19–1.77); P = 0.43 | |
| Spontaneous prematurity | UDCA vs. all controls | 8.7% vs 19.3% | 0.51 (0.22–1.20); P = 0.15 |
| UDCA vs. placebo | 8.7% vs 18.6% | 0.88 (0.32–2.43); P = 0.93 | |
| Fetal distress[d] | UDCA vs. all controls | 18.6% vs 33.3% | 0.46 (0.25–0.86); P |
| UDCA vs. placebo | 18.6% vs 35.7% | 0.63 (0.23–1.72); P = 0.50 | |
| Respiratory distress syndrome | UDCA vs. all controls | 3.3% vs 16.3% | 0.30 (0.12–0.74); P |
| UDCA vs. placebo | 3.3% vs 9.1% | 0.66 (0.11–3.91); P = 0.64 | |
| Apgar score | UDCA vs. all controls | 5.0% vs 10.1% | 0.53 (0.25–1.10); P = 0.09 |
| UDCA vs. placebo | 5.0% vs 10.0% | 0.33 (0.07–1.47); P = 0.15 | |
| Neonatal intensive care unit admission | UDCA vs. all controls | 9.1% vs 18.1% | 0.49 (0.25–0.98); P = 0.04 |
| UDCA vs. placebo | 9.1% vs 9.1% | 0.36 (0.05–2.81); P = 0.33 |
Cholestyramine, which reduces bile acid absorption, is less effective than UDCA for pruritus and liver function improvement and has more side effects.
Obstetric Management of ICP
Active obstetric management, involving routine deliveries at 37-38 weeks, is commonly recommended to prevent IUFD. However, IUFD is rare, and the optimal gestational age for delivery is debated. The benefit of routine labor induction is not evidence-based. Delivery timing should be individualized, balancing prematurity and induction risks against unpredictable IUFD risk. From 37 weeks onward, serum bile acid levels exceeding 40 µmol/L should prompt consideration for expedited delivery.
ICP: Patient Tips
Key advice for patients diagnosed with ICP is summarized in Table 3.
Table 3. Tips for ICP Patients
| Tip |
|---|
| ICP diagnosis should be considered for pregnant women with generalized pruritus in the second or third trimester. |
| ICP diagnosis confirmation requires blood tests (liver function and bile acids) and exclusion of other liver diseases. |
| Ursodeoxycholic acid is the most effective pruritus treatment in ICP, prescribed until delivery. |
| ICP poses fetal risks, especially in severe cases. IUFD risk is rare (1%-2%) but unpredictable and the most feared complication. |
| Active management (routine delivery at 37-38 weeks) is proposed for IUFD prevention. Obstetric team discussions should balance risks. |
| ICP is not a contraindication to breastfeeding. |
| Postpartum follow-up is needed to ensure pruritus resolution and blood test normalization. |
| Medical appointments 2-3 months postpartum may be needed to check for persistent liver abnormalities and discuss contraception/recurrence risk. |
Potential conflict of interest: Yannick Bacq was speaker for Aptalis Pharma.
