INTRAHEPATIC CHOLESTASIS OF PREGNANCY

doi:10.1016/S1089-3261(05)70087-8

Clinics in Liver Disease

Volume 3, Issue 3, 1 August 1999, Pages 603-632

https://doi.org/10.1016/S1089-3261(05)70087-8 Get rights and content

Intrahepatic cholestasis of pregnancy (IHCP) is the most common liver disorder unique to pregnancy and is second only to viral hepatitis as a cause of jaundice.34, 35, 67, 117 Intrahepatic cholestasis of pregnancy is one of the primary disorders of the liver that adversely affects maternal well-being and fetal outcome. Early identification of this condition and careful interdisciplinary management can improve outcomes in the mother and child.

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HISTORY

In 1883 Ahlfeld² reported generalized pruritus, mild jaundice, and intrahepatic cholestasis in late pregnancy, as did Eppinger³² in 1937 and Thorling¹³³ in 1955. In 1954, Svanborg reported seven women with similar symptoms and with fatigue and mild abdominal pain; the symptoms resolved rapidly postpartum but tended to recur in successive pregnancies.¹³²

EPIDEMIOLOGY

The true incidence and spectrum of IHCP are unknown. The prevalence of IHCP seems to vary significantly according to country and ethnic origin. The reported prevalence is approximately 1% to 4% of pregnant women in Chile,107, 108, 114 Bolivia, Scandinavian, the Mediterranean countries, Portugal,17, 18 Poland,¹¹⁸ Australia,¹²⁹ Canada,¹²⁶ and China.¹⁰⁰ The current prevalence is unknown for most of these regions because many reports have not been updated.⁶² In Chile, IHCP has been reported in

ETIOLOGY

The cause of IHCP remains unclear. Early studies in rats with bile fistulae drew attention to the decrease in basal bile flow following administration of ethinyl estradiol.⁶¹ Today, the consensus is that IHCP probably arises from a genetic predisposition for increased sensitivity to normally produced estrogens and progestogens and altered membrane composition of bile ducts and hepatocytes. Alternatively, or in addition, cholestasis may be a response to the production of abnormal metabolites.

URSODEOXYCHOLIC ACID

Ursodeoxycholic acid (UDCA), a minor naturally occurring hydrophilic bile salt, increases the hydrophilic properties of the bile acid pool, thereby preventing damage to plasma membranes by hydrophobic bile salts.⁴⁰ Ursodeoxycholic acid reduces concentrations in serum of sulfated metabolites of progesterone and bile acids.8, 80, 81 Ursodeoxycholic acid stimulates biliary transport systems involved in clearing steroid monosulphates and disulfates⁹² and leads to reduced concentrations of bile

ROLE OF THE FETUS AND PLACENTA

The liver of the healthy fetus has limited capacity to handle and remove bile acids from plasma and deliver them to the canalicular membrane because of the immature status of the bile acid transporters. Consequently, in a normal pregnancy concentrations of serum bile acids are higher in the fetus than in the mother. However, in animal models of cholestasis some evidence exists for maturation of the liver and ileal transporters in early neonatal life. As an example, although bile duct ligation

CLINICAL AND LABORATORY FEATURES

Pruritus (pruritus gravidaram) typically develops in the third trimester of pregnancy. Itching is prominent on the extremities and trunk, becomes progressively severe to term, and is relieved within days following delivery. Pruritus occurring before 33 weeks tends to be severe and is more likely to cause distress for the woman who has to endure a longer period before fetal maturity and delivery. Intrahepatic cholestasis of pregnancy is uncommon in the first trimester, usually occurring then in

RECURRENCE OF INTRAHEPATIC CHOLESTASIS OF PREGNANCY

Rates of recurrence, defined by pruritus, vary according to regions of high and low prevalence for IHCP. In the prospective study from France, pruritus recurred in 45% of multipara and in five of eight primapara who became pregnant again.⁸ However, pruritus was not noted in any of the 44 French women who had taken estrogens as oral contraceptive therapy prior to the pregnancy that evolved into IHCP.⁸ Recurrent IHCP is much more likely (>85%) in multiparous patients with a previous history of

DIFFERENTIAL DIAGNOSIS

Intrahepatic cholestasis of pregnancy remains a disorder that requires diagnosis by exclusion of other conditions that feature pruritus without cholestasis or pruritus with cholestasis in liver disorders peculiar to pregnancy (Table 3) or coincidental to pregnancy (Table 4). Other liver disorders may be coincidental to IHCP, especially in high-prevalence countries. The presentation of many parenchymal diseases of the liver can be delayed until development of cholestasis, with pruritus,

MANAGEMENT

The management of IHCP is dictated by the increased risks of fetal distress, spontaneous preterm delivery, and sudden fetal death,3, 8, 34, 35 as well as the need to control the pruritus.³⁵ The treatment of IHCP remains empirical because the exact cause remains unclear.

The consensus is that provision should be made to induce labor as soon as fetal lung maturity has been established. Accordingly, estimations of lung maturity and maternal levels of total bile acids should be performed regularly,

RECOMMENDATIONS CONCERNING ORAL CONTRACEPTION

Although estrogens have been linked to IHCP, pruritus and the development of abnormal liver tests are not inevitable with their use in oral contraception. Accordingly, the oral contraceptive pill is not absolutely contraindicated for women who have a prior history of IHCP.⁸ Such women should be advised that oral contraceptives can result in pruritus and elevated liver enzyme tests (serum ALT and AST). Accordingly, these women may begin using an oral contraceptive containing low-dose estrogen⁸

RECOMMENDATIONS FOR FUTURE PREGNANCIES

Women who have experienced IHCP should be advised that the chance of recurrence is high (45% to 70%) but not inevitable.⁸ Occasionally, IHCP may skip one pregnancy.⁸ Also, the severity of IHCP during any one pregnancy gives no indication of future severity or of protection from future intrauterine death.⁸ Although intrauterine death cannot be predicted accurately and can occur in any woman with IHCP, high levels of total serum bile acids should be considered as a forewarning of potential death

SUMMARY

Intrahepatic cholestasis of pregnancy is one of the primary disorders of the liver that adversely affects maternal well-being and fetal outcome. Early identification of this condition, careful interdisciplinary monitoring, and prompt delivery at fetal maturity can improve outcomes in the mother and child. Although the cause is unclear, IHCP probably arises from a genetic predisposition for increased sensitivity to estrogens and progestogens and altered membrane composition and expression of

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