Intrahepatic cholestasis of pregnancy is a disease that is induced by pregnancy and resolves following delivery. It has been referred to as recurrent jaundice of pregnancy, cholestatic hepatosis, and icterus gravidarum and is characterized clinically by pruritus, icterus, or both. Its incidence is probably about 1 in 500 to 1000 pregnancies. The cause is unknown although it was previously assumed to be stimulated in susceptible persons by the high estrogen concentrations of pregnancy. Others have proposed that there is a defect in secretion of sulfated progesterone metabolites. There is evidence that obstetrical cholestasis is related to the many gene mutations that control hepatocellular transport systems.
Most women with cholestasis develop pruritus in late pregnancy, although the syndrome occasionally occurs in the second trimester. Generalized pruritus is usually the presenting symptom, but there are no accompanying skin changes unless there are excoriations from scratching. A minority of women, perhaps 10 percent, develop jaundice within several days following pruritus. There are no constitutional symptoms.
Bile acids are cleared incompletely by the liver and accumulate in plasma of women with cholestasis. Serum concentration of total bile acids may be elevated 10- to 100-fold. Hyperbilirubinemia results from retention of conjugated pigment, but total plasma concentrations rarely exceed 4 to 5 mg/dL. The serum alkaline phosphatase level is usually elevated more so than for normal pregnancy. Serum transaminase activities are normal-to-moderately elevated but seldom exceed 250 U/L. Liver biopsy shows mild cholestasis with intracellular bile pigments and canalicular bile plugging without necrosis. These changes disappear after delivery but often recur in subsequent pregnancies or when an oral estrogen-containing contraceptive is taken.
The differential diagnosis should include both obstetric and nonobstetric causes of liver dysfunction. Preeclampsia must be excluded but is unlikely if there is no proteinuria and hypertension. Ultrasound examination can serve to exclude cholelithiasis or biliary obstruction. Acute viral hepatitis is ruled out based on only modest elevations in the serum transaminase levels. However, women with chronic hepatitis C infection have approximately a 20-fold increased risk to develop cholestasis of pregnancy.
Pruritus associated with cholestasis is caused by elevated serum bile salts and may be quite troublesome. Orally administered antihistamines and topical emollients may provide some relief. Cholestyramine, which binds bile salts, may be effective at relieving pruritus; however, our observations have been that this effect is modest at best. Additionally, absorption of fat-soluble vitamins is further impaired with cholestyramine administration and may result in vitamin-K deficiency. Fetal coagulopathy with resultant intracranial hemorrhage has been reported in this setting.
Ursodeoxycholic acid has been reported to quickly relieve pruritus and lower serum hepatic enzyme levels in women with obstetric cholestasis. It has been demonstrated that ursodeoxycholic acid therapy provides superior relief of pruritus when compared to cholestyramine. Other agents reported to help relieve the pruritus include dexamethasone and naltrexone, an opioid antagonist.
EFFECT OF CHOLESTASIS ON PREGNANCY OUTCOME
Although early reports suggested that perinatal mortality was increased in women with cholestasis, more recent publications have failed to confirm this risk. Preterm birth and meconium-stained amniotic fluid have also been reported to occur with increased frequency in women with cholestasis. Although it is not clear if increased fetal surveillance improves pregnancy outcomes, antenatal testing in these women is reasonable given the ambiguity of the data available.
For further reading in Williams Obstetrics, 23rd ed.,
see Chapter 50, “Hepatic, Gallbladder, and Pancreatic Disorders.”