Intrahepatic Cholestasis of Pregnancy
Vol.3 No.3
by David Larson
Yale Medical Student

Introduction

Intrahepatic cholestasis of pregnancy (ICP) is a temporary condition caused by maternal liver dysfunction during pregnancy.  It is characterized by intense generalized pruritus (itchiness) which usually begins in the third trimester.  Though it may cause extreme discomfort, cholestasis of pregnancy is generally regarded as benign to the mother.1  It has, however, been associated with an increased incidence of stillbirth.2-5  The condition resolves shortly after delivery.6   ICP is also known as cholestatic jaundice of pregnancy, cholestatic hepatosis, icterus gravidarum, and obstetric cholestasis.2

 

Statistics

Cholestasis of pregnancy is a relatively rare condition affecting pregnant women.  Though it has been reported to occur in as many as 4% of pregnancies in Chile7 and in over 1% of pregnancies in Scandinavia,8 the rate of occurrence in the U.S. is believed to be less than 1 in 1,000 (0.1%).2, 9   It appears to be genetically linked;10 more than one-third of patients have a family history of the disease (e.g. mothers or sisters).11  When the condition occurs in a pregnancy, it recurs in 60-70% of future pregnancies1,3,12 and occurs in every pregnancy of about 25% of affected women.9  However, the severity of ICP may vary from one pregnancy to the next13 and may skip pregnancies entirely.9  The condition is also up to four times as common in twin or triplet pregnancies than in singleton pregnancies.9, 12  ICP has a mild association with previous miscarriage while it has been shown to have no association with obesity, infertility, maternal diabetes, or chronic illness.14

 

Causes

The term cholestasis refers to a condition in which there is abnormal flow of bile from the liver into the intestine.   Bile is a fluid created in the liver that contains, among other substances, bile salts and bilirubin.  Bile salts aid in emulsifying and absorbing fats in the intestine.  Bilirubin is an end product of the breakdown of hemoglobin—the main functional protein found in red blood cells.  When the flow of bile is impaired, the blood levels of bile acids and bilirubin increase.  The increased levels of bile acids in the blood are thought to cause the pruritus16 and the increased level of bilirubin in the blood may cause jaundice—a yellowish staining of the skin and the sclerae (whites of the eyes).

 

Intrahepatic refers to the fact that the primary problem is in the liver itself, rather than in another location like the bile duct (as might be caused by a lodged gallstone).  While the exact cause is not known, it is widely accepted that in affected women, the membranes of the liver cells are somehow altered by the high estrogen level in the blood during pregnancy.7  It is thought that the altered membranes are impaired in their function of transporting bile out of the liver so that bile salts and other liver products begin to build up in the blood.2  The idea of increased estrogen sensitivity is supported by cases of ICP that have arisen in non-pregnant women taking oral contraceptives that contain estrogen.8

 

Symptoms

The classic symptom of intrahepatic cholestasis of pregnancy is intense generalized pruritus.   The itching usually begins to be manifested in the third trimester, but may occur any time from before 20 weeks up until term.3,4  It ranges in intensity from mild to virtually intolerable.4  It is usually noticed first at night and then progresses to become constant.  Though the pruritus is found throughout the body, it is often most severe on the palms and the soles.  Insomnia often accompanies the itching and the patient may scratch her skin to the point it becomes excoriated (scratched and crusted over).1,2,13,16  Though the term “itchy” may conjure notions of mere annoyance, it should be understood that the pruritus associated with ICP has been described as “disabling,”16 “severe and incapacitating,”17 and on rare occasions, has even lead to threats of suicide.1  After delivery, the symptoms usually decrease within 48 hours of delivery and disappear completely within 4 weeks postpartum.3,11,13  Cholestasis of pregnancy does not cause permanent liver impairment—once the baby is delivered, the liver returns to normal function.1

 

Cholestasis of pregnancy is also the leading cause of jaundice in pregnant women. The yellowing skin and sclerae may be worrisome and may intensify the pruritus.  However, it usually is not very severe, has no other harmful effects, and disappears, along with the ICP, soon after delivery.2,9

 

Laboratory Tests

There are several laboratory tests which can be done to confirm a diagnosis of cholestasis of pregnancy.  Maternal blood levels of bile salts must be at least three times the normal level to diagnose ICP; however, the levels may be 10-100 times normal.2,13  Blood tests can also reveal increased levels of ALT, AST, and alkaline phosphatase—liver enzymes that indicate general liver dysfunction.  While ALT/AST levels may be normal or slightly elevated, alk phos levels are almost always higher than normal (though this may be due, in part, to the alk phos added to the mother’s blood from the placenta). However, if the liver enzymes are extremely elevated, other causes such as viral hepatitis should be considered.13  In the absence of bile acid tests, elevated ALT, AST and/or alk phos levels in the setting of intense pruritus are generally adequate to diagnose cholestasis of pregnancy. 

 

Complications

Though cholestasis of pregnancy appears to have no serious health risks to the mother, it has been shown to be associated with somewhat increased risks to the fetus.  The most concerning complication in ICP is increased rate of fetal death.  One review of over 1,000 reported cases showed a rate of stillbirth and fetal death at delivery to be 10%.5  Virtually all of the deaths occur at 36 weeks gestational age or more (normal term delivery is at 40 weeks).2-4

 

The cause of stillbirth related to ICP is unclear.  Because of the presence of meconium† associated with the stillbirths, it is thought that the meconium itself may cause a decrease in oxygen available to the fetus.17  Some authors have thought that the deaths may be related to an increased incidence of post-partum hemorrhage.9,18  Regardless, it is widely accepted that the deaths are due to a sudden episode of decreased oxygen rather than a chronic or long-term deficiency.17

 

Treatment

There are two primary objectives in treating cholestasis of pregnancy:  alleviating the pruritis and ensuring that the child is born safely.

 

Pruritis

The primary methods of treating pruritis related to ICP have been the administration of cholestyramine and phenobarbital. 

 

Cholestyramine inhibits reabsorption of bile acids from the intestine into the blood.  Some studies have found it is effective in decreasing pruritis.2  However, other studies have found it to cause little, if any, improvement in symptoms.11,19   In addition, cholestyramine is known to cause problems absorbing vitamin K (a necessary vitamin for blood coagulation factors),13,18 and often has undesirable side effects like constipation and bloating.13

 

Phenobarbital is a barbiturate that has sedative properties in addition to its anti-pruritic (anti-itching) effect.  Again, its use is controversial—some physicians have found it to be effective,2,13 whereas others have seen no improvement with its use.11,19

 

There are a few other treatments that have been attempted, but none have been proven to be safe and effective.  Anti-histamines, such as Benadryl, have been tried with little success.16  Steroids have been tried with promising effectiveness,20 but have been associated with maternal liver damage.21  Even charcoal has been attempted, but to little avail.22  A new agent, called UDCA, has been tested with some success, but its safety has not yet been established.4,10,23

 

Fetal Death

Fetal death in cholestasis of pregnancy is a real risk.  The primary objective of treatment is to make sure the baby is born before stillbirth occurs.  Close monitoring of the pregnancy with frequent blood levels, non-stress tests, and even amniocenteses are currently recommended,2,5,24 but they have shown to have mixed effectiveness.  Since the cause of death of the fetus is regarded as a sudden event, problems are often detected only when it is too late, even with vigilant monitoring.5,18,24  Because nearly all of the deaths occur very late in the pregnancy, the current recommendation, and most effective means of treatment, is to induce labor when the fetus’ lungs are mature, regardless of any other test results.4,5,11,17,18  While the fetal death rate for untreated patients is around 10%, studies in which patients are induced before term have found a fetal mortality rate to be 0-2%.5,14  Since there have been no reports of other permanent injury to the child other than stillbirth, the danger from ICP is eliminated when the child is safely delivered.

 

When cholestasis of pregnancy was first described, it was viewed as a benign condition.  Since then, it has been widely established that ICP poses a significantly increased risk to the fetus.  Nevertheless, many physicians still perceive this condition as harmless and merely adopt a “watch and wait” policy.  Because many obstetricians may see very few pregnancies with ICP in their careers, and most of those end without complication (even without treatment), they may be reluctant to induce labor when fetal monitoring shows no abnormalities.  It is hoped, however, that they learn from the sad experience of other physicians who have published their data that the condition indeed poses serious risks and should be treated accordingly.4,9

 

Conclusion

While intrahepatic cholestasis of pregnancy can cause tremendous maternal discomfort and may lead to fetal death, current management techniques have been shown to substantially decrease the risks to the fetus.  Pregnant women who experience extreme generalized pruritis (itching all over their body) should contact their physician.  Expecting mothers who had a previous case of ICP or who has a family history of the condition should inform their physician and educate themselves to determine the best course of treatment.

 

 


† Meconium is the baby’s first bowel movement, which may occur in the uterus.

 

 

References

1.  Feldman M et al. (Reily C, Portis M). Sleisenger & Fordtran's Gastrointestinal and Liver Disease Pathophysiology/Diagnosis/Management c1998 W.B. Saunders Co., 1253-1257.

 

2.  Wilson B, Haverkamp A. Cholestatic jaundice of pregnancy: new perspectives. Obstetrics & Gynecology 1979, 54(5):650-652.

 

3.  Laatikainen T, Ikonen E. Serum bile acids in cholestasis of pregnancy. Obstetrics & Gynecology 1977, 50(3):313-318.

 

4.  Davies M et al. Fetal mortality associated with cholestasis of pregnancy and the potential benefit of therapy with ursodeoxycholic acid. Gut 1995, 37(4):580-584.

 

5.  Fisk N, Storey B. Fetal outcome in obstetric cholestasis. 1988 Nov, British Journal of Obstetrics and Gynaecology 1988, 95:1137-1143.

 

6.  Arfwedson H. General pruritus in pregnancy: symptom of liver dysfunction. Obstetrics & Gynecology 1956, 7:274-276.

 

7.  Reyes H. The enigma of intrahepatic cholestasis of pregnancy: lessons from Chile.  Hepatology 1982, 2(1):87-96.

 

8.  Berg B, Helm G, Petersohn L, Tryding N. Cholestasis of pregnancy: clinical and laboratory studies. Acta Obstetricia et Gynecologica Scandinavica 1986, 65:107-113.

 

9.  Johnston W, Baskett T. Obstetric cholestasis. American Journal of Obstetrics and Gynecology 1979, 133:299-301.

 

10.  Holzbach RT. Gallbladder stasis: consequence of long-term parenteral hyperalimentation and risk factor for cholelithiasis.  Gastroenterology 1983, 84(5):1055-8.

 

11.  Shaw D, Frohlich J, Wittman B, Willms M. A prospective study of 18 patients with cholestasis of pregnancy. American Journal of Obstetrics and Gynecology 1982, 142(6):621-625.

 

12.  Gonzalez MC, Reyes H, Arrese M et al. Intrahepatic cholestasis of pregnancy in twin pregnancies. Journal of Hepatology 1989, 9:84.

 

13.  Gabbe S et al. (Samuels P, Landon M). Obstetrics—Normal and Problem Pregnancies c1996 Churchill Livingstone, Inc., 1121-1123.

 

14.  Heinonen S, Kirkinen P. Pregnancy outcome with intrahepatic cholestasis. Obstetrics & Gynecology 1999, 94(2):189-193.

 

15.  Anderson JB, Turner GM, Williamson RCN. Fulminant ulcerative colitis in late pregnancy and the puerperium. Proceedings of the Royal Society of Medicine 1987, 80:492.

 

16.  McDonald J. Cholestasis of pregnancy. Journal of Gastroenterology and Hepatology 1999, 14:515-518.

 

17.  Alsulyman O, Ouzounian J, Ames-Castro M, Goodwin M. Intrahepatic cholestasis of pregnancy: Perinatal outcome associated with expectant management. American Journal of Obstetrics and Gynecology 1996, 175(4):957-960.

 

18.  Matos A, Bernardes J, Ayres-de-Campos D, Patrício, B. Antepartum fetal cerebral hemorrhage not predicted by current surveillance methods in cholestasis of pregnancy. Obstetrics and Gynecology 1997, 89(5):803-804.

 

19.  Laatikainen T.   Effect of cholestyramine and phenobarbital on pruritus and serum bile acid levels in cholestasis of pregnancy. American Journal of Obstetrics and Gynecology 1978, 72(5):501-506.

 

20.  Hirvioj M, Tuimala R, Vuori J.  The treatment of intrahepatic cholestasis of pregnancy by dexamethasone.  British Journal of Obstetrics and Gynaecology 1992, 99:109-111.

 

21.  Kretowicz E, McIntyre H.  Intrahepatic cholestasis of pregnancy, worsening after dexamethasone.  Australian and New Zealand Journal of Obstetrics and Gynaecology 1994, 34:211-213.

 

22. Kaaja R, Kontula K, Raiha A, Laatikainen T. Treatment of cholestasis of pregnancy with peroral activated charcoal. A preliminary study. Scandinavian Journal of Gastroenterology 1994, 29(2):178-81.

 

23. Diaferia A, Nicastri P, Tartagni M, Loizzi P, Iacovizzi C, Di Leo A. Ursodeoxycholic acid therapy in pregnant women with cholestasis. International Journal of Gynaecology & Obstetrics 1996, 52(2):133-40.

 

24.  Rioseco A, Ivankovic M, Manzur A, Hamed F, Kato S, Parer J, Germain M. Intrahepatic cholestasis of pregnancy: A retrospective case-control study of perinatal outcome. American Journal of Obstetrics and Gynecology 1994, 170(3):890-895.

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