Editorials

Intrahepatic cholestasis of pregnancy

BMJ 1994; 309 doi: http://dx.doi.org/10.1136/bmj.309.6964.1243 (Published 12 November 1994) Cite this as: BMJ 1994;309:1243
  1. E A Fagan

    Intrahepatic cholestasis of pregnancy is one of the few disorders that adversely affect maternal wellbeing and fetal outcome. Early diagnosis and timely intervention can reduce perinatal mortality.

    The condition is the most common liver disorder peculiar to pregnancy and is second to viral hepatitis as a cause of jaundice in the third trimester. It is rarely reported except in Chile, Bolivia, Scandinavia, and China.1 Its true incidence and range are unknown. Generalised pruritus, mild jaundice, and intrahepatic cholestasis in late pregnancy were reported by Ahlfeld in 18832 and later by Eppinger3 and Thorling.4 Svanborg also described fatigue and mild abdominal pain and suggested that the condition resolved rapidly after birth but tended to recur in successive pregnancies.5 Pruritus typically develops after 20 weeks of pregnancy; is prominent on the arms, legs, and trunk; and progresses until delivery. Jaundice may develop two to four weeks later without progressing.

    The pathogenesis of intrahepatic cholestasis of pregnancy is unclear. Multiple factors probably interact with a genetic predisposition to alter the membrane composition of bile ducts and hepatocytes and increase their sensitivity to sex steroids.1 In cholestasis, itching has been linked to increased availability of opiate receptors in the brain to bind their agonist ligands.6 A family history (autosomal dominant and possibly X linked) is commonly associated with haplotypes HLA-B8 and HLA-Bw16. Fathers transmit the susceptibility to daughters. Hormonal factors are implicated because intrahepatic cholestasis worsens with multiple pregnancies and can recur with menstruation and oestrogen treatment. Cholestasis and pruritus may resolve after high dose S-adenosyl-L-methionine, suggesting a metabolic defect. Seasonal variation in countries with a high prevalence suggests that environmental factors could have a role.

    Reports tend to contrast the low maternal mortality with the high perinatal mortality, but maternal morbidity can be considerable. Nocturnal itching causes insomnia and fatigue. Anorexia, malaise, mild epigastric discomfort, steatorrhoea, and dark urine are common. Malabsorption of fat can lead to weight loss and vitamin deficiency, particularly vitamin K deficiency, which may account for some cases of uterine and intracranial haemorrhage.

    Jaundice is an uncommon presenting feature. Serum concentrations of conjugated bilirubin and activities of alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase are rarely higher than three times the normal values. Other causes of pruritus and jaundice require exclusion, especially gall stones, primary biliary cirrhosis, sclerosing cholangitis, viral hepatitis, autoimmune chronic active hepatitis, and drug hepatotoxicity. Severe pain, hepatomegaly, splenomegaly, or fever suggests other causes. Ultrasonographic imaging helps to exclude gall stones and biliary disease and to locate the gall bladder, which is exceptionally large in intrahepatic cholestasis of pregnancy, before percutaneous biopsy. Histological confirmation of acinar cholestasis and bile plugs is unnecessary except in atypical cases when symptoms start before 20 weeks, jaundice precedes pruritus, and itching persists after delivery.

    Women with intrahepatic cholestasis of pregnancy, a history of familial cholestasis, or jaundice exacerbated by oestrogens should be followed up closely throughout pregnancy. Serial measurements of maternal serum concentrations of bile acids, albumin, and alkaline phosphatase are essential. Steatorrhoea can be overlooked unless body weight and faecal fats are measured objectively. Supplementation of fat soluble vitamins, particularly vitamin K, may be required.

    Maternal outcome is good. Itching and jaundice resolve rapidly after delivery but may recur with subsequent pregnancies, menstruation, and oestrogen treatment. Substances for relieving itching, such as cholestyramine, phenobarbitone, charcoal, ultraviolet light, evening primrose oil, intravenous S-adenosyl-L-methionine, and epomediol, have proved disappointing in trials but may benefit individual women. Cholestyramine binds bile acids, anionic drugs, and fat soluble vitamins, and vitamin K1 may be needed to reduce the risk of postpartum haemorrhage. The use of phenobarbitone and antihistamines can aggravate the respiratory difficulties of a preterm baby by causing sedation. Ursodeoxycholic acid, a naturally occurring hydrophilic bile salt, has been shown in small studies to reduce biochemical abnormalities and itching without adversely affecting the newborn baby.7,8 It can relieve itching in chronic cholestatic syndromes, but in Britain its use is contraindicated in pregnancy. Bile acids cross the placenta, and concern remains over their potential teratogenicity in some animal studies, though in these studies they were given in early pregnancy.

    The management of intrahepatic cholestasis in pregnancy is is overshadowed by the increased risks of fetal distress, spontaneous preterm delivery, and death.1,9 The causes of these are unknown. Risks are unrelated to the severity of symptoms and increase near term. Close monitoring of fetal wellbeing is essential, although no single test reliably predicts the risk of intrauterine death. Raised serum concentrations of maternal bile acids correlate with the severity of pruritus and risk of fetal distress.10 Some obstetricians recommend regular non-stress and contraction stress tests. Delivery should ideally take place around 38 weeks after serial estimations of fetal lung maturity and maternal serum concentrations of total bile acids. Delivery around 36 weeks should be considered for severe intrahepatic cholestasis of pregnancy with jaundice and progressive increases in serum bile acid concentrations if fetal distress is suspected and lung maturity has been confirmed.1,9 The intrapartum fetal heart rate seems an unreliable indicator of fetal distress in intrahepatic cholestasis of pregnancy.9 Giving vitamin K1 to the baby immediately after birth may help prevent intracranial bleeding.

    Recent reports of optimistic fetal outcomes are mostly from experienced referral centres in countries with a high prevalence of the condition.1,9 Maternal and fetal wellbeing are likely to improve with a better understanding of the pathogenetic mechanisms associated with bile acid metabolism, pruritus, and cholestasis. Treatment will be hampered by insufficient data on drug toxicity during late pregnancy in humans.

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