British Journal of Obstetrics and Gynaecology February 1992, Vol. 99, pp. 109-1 11
OBSTETRICS
The treatment of intrahepatic cholestasis of pregnancy by dexamethasone M A R J A - L I I SA H I R V I 0 J A RISTO TUIMALA Department of Obstetrics and Gynecology University of Tampere, Finland JUHANI VUORI Deaconess Institute of Oulu, Finland
ABSTRACT Objective To investigate whether dexamethasone supression of fetoplacental oestrogen production can reduce obstetric cholestasis. Design Observational study. Setting Department of Obstetrics and Gynaecology, University of Tampere, Finland. Subjects 10 women, at between 28 and 37 weeks gestation, with intrahepatic cholestasis of pregnancy. Interventions Treatment with 12 mg oral dexamethasone daily for 7 days, after which the therapy was gradually discontinued over 3 days. Main outcome measures Serum oestriol, oestradiol, total bile acids and ALAT were measured before and during therapy and on days 4 and 7 and ALAT also on day 12. Differences were tested by paired t test. Results Itching disappeared or was relieved in all patients. Serum oestriol level fell significantly by day 1 of treatment, serum oestradiol and total bile acid levels by day 4 and ALAT by day 12 from the beginning of the therapy. Conclusion Dexamethasone is a drug of choice in the treatment of intrahepatic colestasis of pregnancy.
In the Scandinavian countries the prevalence of intrahepatic cholestasis of pregnancy, the most common liver disorder during pregnancy, is 1-1.5% (Heikkinen 1982; Berg et al. 1986). This condition is characterized by intensive itching, elevated serum transaminase and bile acid levels and sometimes stillbirth, which is thought to be associated with high bile acid concentrations (Heikkinen 1982: Laatikainen & Ikonen 1975; Laatikainen & Ikonen 1977). The treatment of intrahepatic cholestasis has been in the main symptomatic, including phenobarbitone, cholestyramine and antihistamines, but no specific effective therapy has yet been found. During pregnancy the main circulating oestrogen is oestriol and about 90% of the total amount is derived from the fetus and placenta. About 50% of the serum oestradiol comes from the fetoplacental unit. Fetal adrenals provide dehydroepiandrosterone (DHEAS) as a precursor for the placental production of oestrogens (Siiteri & MacDonald 1966; Madden et a / . 1978). Dexamethasone penetrates the placenta and is known to reduce DHEAS secretion from fetal adrenals, resulting also in a reduction in oestrogen production (Simmer et (11. 1974; Simmer et al. 1975; Kauppila et al. 1976; Kauppila et al. 1979). In obstetric cholestasis increased circulating oestrogen concentrations associated with a normal pregnancy lead to intrahepatic cholestasis because of abnormal hepatic reactivity. The aim of the present investigation was to establish whether the suppression of fetoplacental oestrogen production by dexamethasone treatment reduced obstetric cholestasis. Correspondence: Risto Tuimala, Tayks, Teiskontie 35, SF-33520 Tampere, Finland.
Subjects and methods Ten women, at between 28 and 37 weeks gestation, with intrahepatic cholestasis of pregnancy were involved in the study. They were given oral dexamethasone, 12 mg daily for 7 days, after which the therapy was gradually discontinued over 3 days. Serum oestriol and oestradiol levels were determined before and on days 1 , 4 and 7 of therapy. Serum total bile acids and serum alanine aminotransferase (ALAT) levels were measured before therapy and on days 4 and 7, ALAT was measured again 12 days after the beginning of therapy. Venous blood samples were obtained at 08.00 h before breakfast. Serum ALAT, total bile acids and oestradiol were determined immediately, the samples for oestriol measurement were centrifugated and stored at -20°C. Serum oestriol was determined with the total oestriol ('251) RIA Kit test (Farmos, Oulunsalo, Finland), a radioimmunoassay for the quantitative measurement of total (free and conjugated) oestriol in human serum. Serum oestradiol was measured with '251-oestradiol direct RIA Kit test (Baxter Dade AG, Dudingen, Switzerland), which is used for the direct quantitative determination of 17-P-oestradiol levels in serum and plasma, based on the competitive binding radioimmunoassay principles. Serum total bile acids were determined with Enzabile test from Nycomed (Nycomed AS, Pharma, Oslo, Norway), an enzymatic, colorimetric determination method of total 3-ahydroxy bile acids in serum, gastric juice and faeces. Serum ALAT was determined using the standard automated ultraviolet kinetic method with the composition of reagents
109
110
M . - L . H l K V I O J A ET A L .
thasone treatment in all the patients (Fig. 1). Circulating oestrio1 levels fell significantly (P
OBSTETRICS
The treatment of intrahepatic cholestasis of pregnancy by dexamethasone M A R J A - L I I SA H I R V I 0 J A RISTO TUIMALA Department of Obstetrics and Gynecology University of Tampere, Finland JUHANI VUORI Deaconess Institute of Oulu, Finland
ABSTRACT Objective To investigate whether dexamethasone supression of fetoplacental oestrogen production can reduce obstetric cholestasis. Design Observational study. Setting Department of Obstetrics and Gynaecology, University of Tampere, Finland. Subjects 10 women, at between 28 and 37 weeks gestation, with intrahepatic cholestasis of pregnancy. Interventions Treatment with 12 mg oral dexamethasone daily for 7 days, after which the therapy was gradually discontinued over 3 days. Main outcome measures Serum oestriol, oestradiol, total bile acids and ALAT were measured before and during therapy and on days 4 and 7 and ALAT also on day 12. Differences were tested by paired t test. Results Itching disappeared or was relieved in all patients. Serum oestriol level fell significantly by day 1 of treatment, serum oestradiol and total bile acid levels by day 4 and ALAT by day 12 from the beginning of the therapy. Conclusion Dexamethasone is a drug of choice in the treatment of intrahepatic colestasis of pregnancy.
In the Scandinavian countries the prevalence of intrahepatic cholestasis of pregnancy, the most common liver disorder during pregnancy, is 1-1.5% (Heikkinen 1982; Berg et al. 1986). This condition is characterized by intensive itching, elevated serum transaminase and bile acid levels and sometimes stillbirth, which is thought to be associated with high bile acid concentrations (Heikkinen 1982: Laatikainen & Ikonen 1975; Laatikainen & Ikonen 1977). The treatment of intrahepatic cholestasis has been in the main symptomatic, including phenobarbitone, cholestyramine and antihistamines, but no specific effective therapy has yet been found. During pregnancy the main circulating oestrogen is oestriol and about 90% of the total amount is derived from the fetus and placenta. About 50% of the serum oestradiol comes from the fetoplacental unit. Fetal adrenals provide dehydroepiandrosterone (DHEAS) as a precursor for the placental production of oestrogens (Siiteri & MacDonald 1966; Madden et a / . 1978). Dexamethasone penetrates the placenta and is known to reduce DHEAS secretion from fetal adrenals, resulting also in a reduction in oestrogen production (Simmer et (11. 1974; Simmer et al. 1975; Kauppila et al. 1976; Kauppila et al. 1979). In obstetric cholestasis increased circulating oestrogen concentrations associated with a normal pregnancy lead to intrahepatic cholestasis because of abnormal hepatic reactivity. The aim of the present investigation was to establish whether the suppression of fetoplacental oestrogen production by dexamethasone treatment reduced obstetric cholestasis. Correspondence: Risto Tuimala, Tayks, Teiskontie 35, SF-33520 Tampere, Finland.
Subjects and methods Ten women, at between 28 and 37 weeks gestation, with intrahepatic cholestasis of pregnancy were involved in the study. They were given oral dexamethasone, 12 mg daily for 7 days, after which the therapy was gradually discontinued over 3 days. Serum oestriol and oestradiol levels were determined before and on days 1 , 4 and 7 of therapy. Serum total bile acids and serum alanine aminotransferase (ALAT) levels were measured before therapy and on days 4 and 7, ALAT was measured again 12 days after the beginning of therapy. Venous blood samples were obtained at 08.00 h before breakfast. Serum ALAT, total bile acids and oestradiol were determined immediately, the samples for oestriol measurement were centrifugated and stored at -20°C. Serum oestriol was determined with the total oestriol ('251) RIA Kit test (Farmos, Oulunsalo, Finland), a radioimmunoassay for the quantitative measurement of total (free and conjugated) oestriol in human serum. Serum oestradiol was measured with '251-oestradiol direct RIA Kit test (Baxter Dade AG, Dudingen, Switzerland), which is used for the direct quantitative determination of 17-P-oestradiol levels in serum and plasma, based on the competitive binding radioimmunoassay principles. Serum total bile acids were determined with Enzabile test from Nycomed (Nycomed AS, Pharma, Oslo, Norway), an enzymatic, colorimetric determination method of total 3-ahydroxy bile acids in serum, gastric juice and faeces. Serum ALAT was determined using the standard automated ultraviolet kinetic method with the composition of reagents
109
110
M . - L . H l K V I O J A ET A L .
thasone treatment in all the patients (Fig. 1). Circulating oestrio1 levels fell significantly (P
