Cholestasis of pregnancy (jaundice of pregnancy, obstetric cholestasis, and prurigo gravidarum)

Are You Confident of the Diagnosis?

Intrahepatic cholestasis of pregnancy (ICP) is defined by: (1) generalized pruritus, with or without jaundice, with no history of exposure to hepatitis or hepatotoxic drugs, (2) the absence of primary lesions on the skin (Figure 1), (3) biochemical abnormalities consistent with cholestasis, (4) disappearance of signs and symptoms following pregnancy, and (5) recurrence during subsequent gestations. Patients typically present in the third trimester of pregnancy, but onset as early as 8 weeks has been reported. In 50% of patients the onset has been noted to coincide with a urinary tract infection.


Palms are typically pruritic in patients with ICP. Note the lack of primary lesions.

Characteristic features on physical examination

The presenting symptom is intense, generalized pruritus that is worse at night and particularly localized to the trunk, palms, and soles. The physical examination usually reveals no rash other than excoriations due to scratching. Twenty percent of patients will develop jaundice within 2-4 weeks of the onset of pruritus, and 50% will develop dark urine and light-colored stools. Steatorrhea can also be a sign which is typically followed by vitamin K deficiency.

Symptoms tend to last the duration of the pregnancy after onset, but may wax and wane. They usually disappear 24-48 hours after delivery, with jaundice resolving 1-2 weeks after delivery. Recurrence occurs in subsequent pregnancies and with oral contraceptives in most patients.

Diagnosis confirmation

The diagnosis of ICP is confirmed by the presence of increased total serum or urine bile acids. Bile acids may range from 3-100 times normal levels, and may be the only identifiable abnormality in patients without jaundice. Direct bilirubin may be slightly increased. Serum abnormalities do not parallel fetal risk, however, and are only useful to confirm the presence or absence of disease. Alkaline phosphatase, gamma-glutamyl transferase (GGT), cholesterol, lipids, and liver transaminases may be slightly increased, but these levels should not be relied upon to establish the diagnosis, as they may be erratic in normal pregnancies. Liver ultrasound is normal. Skin biopsies are normal and non-diagnostic.

The differential diagnosis includes viral hepatitis, gallbladder disease, drug hepatotoxicity, primary biliary cirrhosis, uremia, and prurituc urticarial papules and plaques of pregnancy.

Who is at Risk for Developing this Disease?

ICP occurs in approximately 0.02-2.4% of pregnancies worldwide. It is thought to be uncommon in Asian or Black individuals, but is particularly prevalent in Scandinavia, northern Europe and Chile due to dietary factors. There is a positive family history in 50% of cases, and the incidence is increased in twin pregnancies.

What is the Cause of the Disease?

A genetic component is suspected, as there are familial cases of ICP and a high recurrence rate of ICP in subsequent pregnancies. Additionally, some studies have shown patients with ICP are more likely to have genetic mutations in hepatocyte proteins involved in bile secretion. Such proteins are also inhibited by high levels of hormone metabolites in pregnancy, which may explain the clinical manifestations occuring only during the gravid state.


It is postulated that the relative fall in hepatic blood flow during pregnancy results in decreased clearance of estrogens, with subsquent increased biliary cholesterol concentration and secretion as well as impaired hepatic transport of bilirubin and bile salts.

Systemic Implications and Complications

If the disease is severe or prolonged, depletion of vitamin K due to malabsorption may lead to bleeding abnormalities in the mother and fetus, which may result in postpartum hemorrhage and fetal intracranial hemorrhage, respectively. There is also an increased incidence of stillbirth, meconium staining and premature labor (up to 45% of cases), fetal stress, and fetal death (reportedly as high as 13%).

Intensive antepartum fetal monitoring is recommended, and induction between 37 and 38 weeks has been shown to significantly reduce morbidity and mortality. Early recognition and treatment of ICP may decrease the incidence of complications. Reduction of serum bile salts reduces incidence of preterm labor.

Recurrences usually occur during subsequent gestations. Due to recurrence of the disease with oral contraceptives, hormonal contraception may be contraindicated in women with a history of ICP.

Treatment Options

Ursodeoxycholic acid (USDO) has been shown to control symptoms of ICP and reduce the risk of adverse fetal outcomes. As a result, this is the drugy of choice. The recommended dose is 14-16mg/kg/day (450-1200mg) daily.

Cholestyramine and phenobarbitol have been reported to be beneficial for modest elevations of bile acids, although their benefit is disputed. Cholestyramine can bring a 70% response rate but is slow acting and but can precipitate vitamin K. A total of 8 to 16g/day in 3-4 divided doses is often helpful in relieving pruritus. It is most effective if started as soon as the pruritus is noted, before it becomes severe. It often takes up to 2 weeks to work.

Cholestyramine causes a sensation of bloating and often results in constipation. Cholestyramine also can interfere with the absorption of other ingested medications, including prenatal vitamins.

Phenobarbital at 100mg daily given at bedtime has shown some benefit for ICP. Phenobarbital induces hepatic microsomal enzymes, increasing bile salt secretion and bile flow. This medication usually takes more than 1 week to be effective. It has not been shown to change the serum concentration of bile acids.

S-adenyl-methionine (SAM-e), a glutathione precursor can also be used at doses of 800mg daily IV or 1600mg daily orally. In a small study of 32 women, SAM-e combined with USDO showed the most improvement when compared to either drug alone. No side effect for mother and fetus have been noted.

If ICP lasts longer than several weeks, vitamin K absorption may be impaired, increasing maternal and fetal prothrombin time. It may be necessary to administer intramuscular vitamin K to the mother.

Physical modalities include phototherapy using ultraviolet B (UVB) radiation, which may help to relieve pruritus but does not decrease concentration of bile salts.

Optimal Therapeutic Approach for this Disease

Start patient on ursodeoxycholic acid as soon as the diagnosis is made. If patient does not respond consider adding SAM-e to USDO. Move to elective delivery around 37-38 week gestational age. Monitor maternal and fetal prothrombin time and administer intramuscular vitamin K to mother if needed. Monitor mother and fetus closely and counsel mother on possible recurrence of disease with hormonal contraception and pregnancies. Chose alternative method of contraception if possible.

Patient Management

Monitor mother and fetus closely before and after delivery for bleeding diathesis and prothrombin time. Counsel mother on possible recurrence of disease with hormonal contraception and pregnancies. Chose alternative method of contraception if possible

Unusual Clinical Scenarios to Consider in Patient Management

Check all suspect patients for occult urinary tract infections.

What is the Evidence?

Shornick , JK, Bolognia , JL, Jorizzo , JL, Rapini , RP. “Pregnancy Dermatoses”. Dermatology. 2003. pp. 425-32.

Bremmer , M, Driscoll , MS, Colgan , R. “Six skin disorders of pregnancy: a management guide”. OBG Management . vol. 22. 2010. pp. 24-33.

Reyes , H. “The spectrum of liver and gastrointestinal disease seen in cholestasis of pregnancy”. Gastroenerol Clin N AM . vol. 21. 1992. pp. 905-21.

Holmes , RC, Black , MM. “The specific dermatoses of pregnancy”. J Am Acad Dermatol . vol. 8. 1983. pp. 405-12.

Rustgi , VK. “Liver disease in pregnancy”. Med Clin N Am . vol. 73. 1989. pp. 1041-7.

Al-Fares , SI, Vaughan Jones , SA, Black , MM. “The specific dermatoses of pregnancy: a re-appraisal”. JEADV . vol. 15. 2001. pp. 197-206.

Nicastri , PL, Diaferia , A, Tartagni , M, Loizzi, , P, Fanelli , M. “A randomised placebo-controlled trial of ursodeoxycholic acid and S-adenosylmethionine in the treatment of intrahepatic cholestasis of pregnancy”. Intl J Ob/Gyn . vol. 105. 1998. pp. 1205-07. (The above articles and book chapter clearly define the diagostic and therapeutic pearls for cholestasis of pregnancy. The Bremmer et al. article is is a brief summary of the main dermatosis of pregnancy with a user-friendly table that aids in sorting the diagnostic clues and treatment pearls. The Nicastri et al. paper is the only article to fully elucidate using SAM-e in the treatment of intrahepatic cholestasis of pregnancy.)