Editorials

Obstetric cholestasis

May have serious consequences for the fetus, and needs to be taken seriously

Obstetric cholestasis (or intrahepatic cholestasis of pregnancy) remains widely disregarded as an important clinical problem, with many obstetricians still considering its main symptom, pruritus, a natural association of pregnancy. Obstetric cholestasis is associated with cholesterol gallstones. It may be extremely stressful for the mother but also carries risks for the baby.

Clinical studies clearly show that when obstetric cholestasis complicates pregnancies it may lead to premature births in up to 60%, fetal distress in up to 33%, and intrauterine death in up to 2% of patients.¹ The cause of fetal death is acute anoxia.² The incidence of obstetric cholestasis varies from 0.1% to 1.5% of pregnancies in Europe and 9.2%-15.6% in South American countries such as Bolivia or Chile. It is particularly high in the native Araucanian population in Chile, where the proportion of affected pregnancies reaches nearly 28%.³ The low quoted incidence of obstetric cholestasis in Europe may reflect an underestimation of the problem, and growing awareness of the condition will probably increase the numbers. For example, early studies from North America, published in 1962, showed its incidence to be less than 0.1%, whereas a study published 17 years later estimated the incidence to be around 0.7%.¹

The aetiology of obstetric cholestasis is undoubtedly multifactorial, with genetic, environmental, and hormonal factors having important roles. Historically obstetric cholestasis has been associated with the cholestatic effect of oestradiol metabolites, in particular 17- oestradiol glucuronide. Progesterone metabolites, however, play an even more important part in its pathogenesis. Patients with obstetric cholestasis have a significantly increased ratio of 3  to 3  hydroxysteroids and large amounts of mono or disulphated progesterone metabolites excreted in their urine.⁴ Excess of these metabolites in the urine in obstetric cholestasis may be related to malfunction of biliary canalicular transporters normally responsible for their secretion from hepatocytes into bile. Several of these transporters have recently been characterised. These include proteins responsible for bile canalicular secretion of bile acids (bile salt export pump), organic anions (multidrug resistant protein 2) or phospholipids (multidrug resistance protein 3).

Recent findings have shown that obstetric cholestasis occurs more commonly in mothers of patients with rare, inborn cholestatic syndromes such as progressive familial intrahepatic cholestasis type 3 or recurrent familial intrahepatic cholestasis, both related to dysfunction of biliary transporters. This suggests that mothers heterozygous for mutations in genes coding for transporter proteins are predisposed to obstetric cholestasis. For example, in the family of an infant with progressive familial intrahepatic cholestasis type 3 both maternally and paternally related women who were heterozygous for the multidrug resistance protein 3 mutation suffered from obstetric cholestasis.⁵ The infant's condition was caused by a mutation associated with dysfunction of the bile canalicular phospholipid transporter multidrug resistance protein 3, which causes raised levels of gamma glutamyl transpeptidase,

In another patient with obstetric cholestasis and raised gamma glutamyl transpeptidase but without a family history of progressive familial intrahepatic cholestasis, we found that a single amino acid substitution disrupted multidrug resistance protein trafficking to the membrane of transfected cells.⁶ A recent study from Finland showed a significantly higher incidence of obstetric cholestasis among mothers and sisters of patients with obstetric cholestasis, confirming a genetic predisposition to this condition.⁷

Thus it is plausible to speculate that mild malfunction of canalicular transporters, which causes no problem outside pregnancy, may lead to clinical symptoms of cholestasis when the transporter's capacity to secrete substrates is exceededas occurs with the high levels of sex hormones produced in pregnancy. It is possible that fetal inheritance of the "loss of function" mutation in a gene that codes for a protein which transports bile acids across the placenta to the mother could predispose it to the effects of raised serum bile acids. Animal studies have implicated bile acids in the pathophysiology of intrauterine death and spontaneous prematurity in obstetric cholestasis. ^{8 9} Therefore inheritance of such a mutation would predispose the fetus to these complications.

Obstetric cholestasis classically manifests itself in the second or third trimester of pregnancy with generalised pruritus, most pronounced in palms and soles. Jaundice is relatively uncommon, complicating only the most severe and prolonged episodes. Routine liver function tests show raised transaminases in 60% of patients and raised bilirubin concentrations in only 25%. Serum bile acids are raised in the vast majority of patients.

The recent demonstration of an association between obstetric cholestasis and mutation of multidrug resistance protein 3 (causing raised levels of serum gamma glutamyl transpeptidase) prompted us to determine the proportion of our patients with obstetric cholestasis who had raised gamma glutamyl transpeptidase values: these were a third of all patients with obstetric cholestasis.¹⁰

Ursodeoxycholic acid, though not licensed for use in pregnancy, is increasingly used in patients with obstetric cholestasis.^11-13 This hydrophilic bile acid was found to normalise the ratio of 3  to 3  hydroxysteroid in patients with obstetric cholestasis and decrease the accumulation of bile acids, in particular cholate, in the fetus. ^{4 12 14} Ursodeoxycholic acid is effective in reducing pruritus and abnormalities in liver function tests. ^{11 12} No concerns have emerged about potential adverse events, and the only side effect noted so far is occasional, mild diarrhoea.

The occurrence of pruritus in pregnant women should be the subject of routine inquiry, and when present acted on. Confirmation of obstetric cholestasis with blood tests should alter management. Affected patients can be offered treatment with ursodeoxycholic acid, not only to relieve pruritus but also to protect against accumulation of biliary constituents of maternal origin in the fetus, which may contribute to the risk of fetal distress or even stillbirth. Because obstetric cholestasis is associated with increased risk of stillbirth it is our policy that pregnancy should not be allowed to continue beyond the 37th week of gestation. In affected mothers the symptoms classically disappear within a day to two after delivery, with rapid normalisation of liver function values and serum bile acid concentrations. Persistent abnormalities should prompt a search for underlying liver disease.

Piotr Milkiewicz, registrar. 
Elwyn Elias, consultant hepatologist. 

Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, Birmingham B15 2TH

Catherine Williamson, Wellcome advanced clinical fellow. 

Maternal and Fetal Disease Group, Imperial College School of Medicine, London W12 0NN

Judith Weaver, consultant obstetrician. 

Birmingham Women's Hospital, Birmingham B15 2TG