Metformin in Intrahepatic Cholestasis of Pregnancy (METRIC)

This is a pilot study aimed at comparing the effect of metformin versus ursodeoxycholic acid in women with intrahepatic cholestasis in pregnancy. The study will be conducted in three NHS hospital sites, over an 18 month period.

Intrahepatic cholestasis is a condition that affects pregnant women. It is characterised by itching, usually in the third trimester of pregnancy and is associated with an increase in the liver enzymes and bile salts. This can be associated with maternal and neonatal morbidity, and rarely perinatal mortality. The investigators propose to assess and compare the effect of Metformin versus Ursodeoxycholic acid on lowering liver enzymes and bile salts, improving maternal morbidity and improving neonatal outcomes. This study is a pilot study that will be conducted at 3 NHS hospital sites where patients will randomly assigned to receive either Metformin or Ursodeoxycholic acid. There will be 20 patient in each arm. Recruitment will commence in February 2017 and will run for an 18 month period.

Metformin Hydrochloride (HCl) Tablets, is an oral antihyperglycemic drug used in the management of type 2 diabetes

Ursodeoxycholic acid (UDCA) is used to treat gallstones and primary biliary cirrhosis. UDCA is also used to treat obstetric cholestasis (OC), a liver condition that occurs specifically in pregnancy.

Normalisation of Bile acids and liver enzymes - both parameters are the cornerstone for a diagnosis of intrahepatic cholestasis. They have been separated into two outcomes due to to the different laboratory indices of measurement. Results will be aggregated together to report number of patients with abnormal results

Normalisation of liver enzymes Alanine transaminase Aspartate transaminase Bilirubin (total) Gamma glutamyl transferase Results will be aggregated together to report the number of patients with abnormal liver enzymes

Inclusion Criteria: 20+0 to 40 weeks' gestation on day of randomisation Itching with a raised serum bile acid above the upper limit of normal Normal anomaly scan at 20 weeks Aged 18 years or over Able to give written informed consent No known pre-existing liver disease Exclusion Criteria: Decision already made for delivery within the next 48 hours Known allergy to any component of the ursodeoxycholic acid or metformin tablets Patients already on metformin for other conditions

Elfituri A, Ali A, Shehata H. Managing Recurring Obstetric Cholestasis With Metformin. Obstet Gynecol. 2016 Dec;128(6):1320-1323. doi: 10.1097/AOG.0000000000001748.

Walker KF, Chappell LC, Hague WM, Middleton P, Thornton JG. Pharmacological interventions for treating intrahepatic cholestasis of pregnancy. Cochrane Database Syst Rev. 2020 Jul 27;7(7):CD000493. doi: 10.1002/14651858.CD000493.pub3.