Intrahepatic cholestasis of pregnancy (ICP), sometimes referred to as obstetric cholestasis, is a liver condition specific to pregnancy. It’s primarily recognized by intense itching, known as pruritus, accompanied by elevated levels of bile acids and/or liver enzymes (aminotransferases) in the blood. Typically emerging in the second or third trimester, ICP symptoms spontaneously resolve after childbirth.1 While ICP is observed globally, its occurrence varies significantly across different geographical regions and ethnicities.2 Notably high prevalence rates were documented in Bolivia and Chile in the 1970s. In the United States, estimates range from 0.3% in Connecticut to 5.6% in Los Angeles, particularly within Latina populations.3 Across Europe, prevalence generally falls between 0.5% and 1.5%.2
Pathophysiology of ICP
ICP is considered a multifaceted condition, predominantly linked to hormonal shifts and genetic predispositions.4 Estrogen’s role in ICP is well-documented, with studies indicating its cholestatic effects. Progesterone is also believed to contribute; the administration of natural progesterone for threatened preterm labor has been associated with an increased ICP risk.1 Genetically, ICP is complex, with mutations in genes responsible for hepatobiliary transport proteins being implicated. Heterozygous mutations in the ABCB4 gene, which codes for the MDR3 phospholipid transporter in the liver, are commonly found in ICP patients.4, 5 Less frequently, mutations in ATP8B1, ABCB11, or NRH1HA genes, which encode proteins like familial intrahepatic cholestasis 1 protein (FIC1), the bile salt export pump, and the farnesoid X receptor (FXR), respectively, have been observed in ICP cases.4 Environmental factors might also play a role in the manifestation of ICP.4
Clinical Presentation and ICP Diagnosis
Pruritus is the hallmark symptom of ICP. This intense itching can be profoundly uncomfortable and often challenging for pregnant individuals to endure. Typically generalized, it is most pronounced on the palms of the hands and soles of the feet. Characteristically, pruritus worsens at night, significantly disrupting sleep. Patients may describe the itch as relentless, sometimes unbearable, and not always relieved by typical anti-itch remedies. The severity of pruritus can be assessed using a scoring system, like the prefixed score in Table 1, or a visual analogue scale.5 It’s important to note that this itching spontaneously resolves within days after delivery.
Clinical examination in ICP patients usually reveals normal findings, aside from potential scratch marks due to the itching. Jaundice, a yellowing of the skin and eyes, may occur in more severe cases, but this is relatively infrequent, affecting less than 10% of ICP patients. It’s exceedingly rare to have ICP with jaundice but without the preceding symptom of pruritus.1 Patients typically do not present with fever, abdominal pain, or encephalopathy. Ultrasound examinations might incidentally detect gallstones, but there should be no indications of biliary obstruction, such as dilation of the bile ducts.
Table 1: Visual representation of pruritus intensity levels in ICP, ranging from absence to permanent itching, aiding in diagnosis and monitoring.
Diagnostically, alanine aminotransferase (ALT) measurement is a highly sensitive test for ICP.1 ICP can cause substantial elevations in serum ALT levels, sometimes mimicking acute viral hepatitis, which necessitates exclusion through serologic testing.1 Serum bile acid concentrations are also typically elevated in ICP, with diagnostic thresholds often set above 10 µmol/L. However, normal bile acid levels do not entirely rule out ICP. It’s important to consider that bile acid concentration measurement isn’t a standard routine test and may not be available in all healthcare facilities. Measuring serum bile acid concentrations becomes particularly valuable in diagnosing ICP in patients experiencing pruritus but with normal ALT levels. Interestingly, in some ICP cases, pruritus can precede abnormalities in liver function tests.
Serum bile acid levels, unlike ALT, can also offer insights into fetal prognosis. A correlation between elevated maternal serum bile acid levels and fetal distress has been observed in severe ICP, defined by bile acid concentrations exceeding 40 µmol/L.6, 7, 8 Both serum bile acid concentration and ALT activity rapidly decrease post-delivery, usually returning to normal within weeks. Notably, gamma-glutamyltransferase (GGT) activity, typically elevated in most hepatobiliary diseases, remains normal or only mildly increased in ICP.1 Alkaline phosphatase levels naturally increase during the second and third trimesters of pregnancy due to placental isoenzyme production, making it less useful for diagnosing cholestasis in pregnancy. Prothrombin time is generally normal, and liver failure is not a feature of ICP. Prolonged prothrombin time, if present, indicates vitamin K deficiency and requires pre-delivery treatment to prevent postpartum hemorrhage.
Liver biopsy is rarely needed for ICP diagnosis. When performed, it typically reveals pure cholestasis, sometimes with bile plugs visible in hepatocytes and canaliculi.
The diagnosis of ICP is primarily based on the presence of pruritus during pregnancy, coupled with elevated serum aminotransferase and/or bile acid levels, after excluding other potential causes of abnormal liver function tests.9 It is important to differentiate ICP from other liver conditions that can occur during pregnancy. Rarely, ICP may coexist with other pregnancy-specific liver diseases like preeclampsia or acute fatty liver of pregnancy, both of which can also manifest in late pregnancy.5 Other liver diseases unrelated to pregnancy, such as acute viral hepatitis, cytomegalovirus infection, or drug-induced liver injury, should also be considered in the differential diagnosis. Urinary tract infections can sometimes cause cholestasis or occur concurrently with ICP. Pre-existing chronic liver diseases may also worsen during pregnancy or be incidentally detected. Therefore, liver function tests should be conducted postpartum to identify any persistent abnormalities requiring further investigation and follow-up.
Maternal Outcome in ICP
The maternal prognosis for ICP during pregnancy and after delivery is generally favorable, with no significant long-term maternal health complications. However, cholestasis has a high recurrence rate in subsequent pregnancies, estimated at 60%–70%. For women with a history of ICP, oral contraceptive use rarely triggers cholestasis, and ICP is not considered a contraindication to oral contraceptives. Oral contraception, including low-dose estrogen combined or progestin-only options, can be initiated once liver function tests have normalized postpartum. Patients should be informed about the possibility of pruritus during oral contraceptive use, and routine liver function tests are recommended 3 to 6 months after starting.
Generally, the long-term maternal prognosis remains positive. However, recent population-based studies from Finland and Sweden have indicated that women with a history of ICP have a notably increased risk of developing gallstone-related diseases, nonalcoholic liver cirrhosis, and hepatitis C later in life.10, 11 These findings underscore the importance of hepatitis C serology testing in all women with ICP and confirming the normalization of liver function tests after delivery.
Fetal Outcome in ICP
ICP poses risks to the fetus, particularly in severe cases.7 Premature birth, both spontaneous and induced, is more common in pregnancies affected by ICP compared to the general population. This is predominantly seen as late preterm deliveries, occurring between 34 0/7 and 36 6/7 weeks of gestation. The reported prematurity rates vary considerably across studies, influenced by factors like the frequency of multiple pregnancies, which is slightly higher in ICP, and the clinical management approaches for ICP towards the end of pregnancy. Active management strategies, including the induction of labor due to concerns about intrauterine fetal death (IUFD), might contribute to higher prematurity rates. IUFD remains the most serious concern associated with ICP, although it is relatively rare, particularly before the last month of pregnancy. Current estimates place the prevalence of IUFD in ICP pregnancies between 1% and 2%.8, 12
Medical Treatment for ICP
Vitamin K supplementation is recommended if prothrombin time is prolonged.9 Topical emollients are safe during pregnancy and may provide symptomatic relief for pruritus in some individuals, although their effectiveness is not definitively established.9, 13
Ursodeoxycholic acid (UDCA) is currently the most effective treatment for pruritus associated with ICP.9, 12 UDCA also leads to improvements in liver function tests. Meta-analysis suggests that UDCA therapy may also have benefits for fetal outcomes12 as shown in Table 2. UDCA is considered safe for both mothers and babies, with no reported side effects. A typical prescription is 500 mg twice daily or 15 mg/kg per day until delivery. The exact mechanism of UDCA in ICP is not fully understood. As a hydrophilic bile acid, it may protect liver cells from the toxic effects of hydrophobic bile acids and improve bile acid transport in the liver. UDCA might also enhance bile acid transport across the placenta.12
Table 2: Data summarizing the efficacy of UDCA treatment for ICP across multiple randomized controlled trials, highlighting positive outcomes for both maternal symptoms and fetal health indicators.
Cholestyramine, another medication that reduces bile acid absorption and increases fecal excretion, has been used in ICP. However, cholestyramine is generally less effective than UDCA in alleviating pruritus and improving liver function, and it is associated with a higher incidence of side effects.14
Obstetric Management of ICP
Active obstetric management is generally recommended to mitigate the risk of IUFD. Routine delivery between 37 and 38 weeks of gestation is common practice in many maternity units.5, 8, 15 While IUFD is a rare occurrence, there is no definitive consensus on the optimal gestational age for delivery in ICP pregnancies. The benefit of routine labor induction has not been confirmed through randomized controlled trials (RCTs). In the absence of clear evidence-based guidelines, the timing of delivery should be individualized. This decision-making process involves carefully considering the risks associated with prematurity and the potential maternal complications (like increased cesarean section risk) related to labor induction, against the unpredictable risk of sudden IUFD.9, 13 However, from 37 weeks of gestation onwards, a serum bile acid concentration exceeding 40 µmol/L should prompt consideration for expedited delivery.
ICP: Patient-Focused Guidance
Key advice for patients diagnosed with ICP is summarized in Table 3.
Table 3: Essential guidelines and recommendations for pregnant individuals diagnosed with ICP, covering diagnosis, treatment, fetal risks, management strategies, and postpartum care.
Potential conflict of interest: Yannick Bacq was speaker for Aptalis Pharma.
