Diagnosis
A diagnosis of cholestasis is established in the
presence of raised (above 14) bile acids and itching.
There may also be a two to four fold increase in transaminases
and a small rise in bilirubin levels. Alkaline phosphatase
is raised in normal pregnancy (normal values 133-418
iu/l in the third trimester ( 1)
as it is produced by the placenta. Therefore at present
its contribution to the diagnosis is debatable. A careful
history may reveal cyclical itching or itching whilst
on the oral contraceptive pill or during a previous
pregnancy.
Differential diagnosis
Care must be taken to exclude other underlying liver
disorders especially in the presence of markedly raised
liver function or jaundice. A past or family history
of liver disease should be sought and risk factors
for hepatitis and liver disease in general, such as
drugs and alcohol, should be identified. A full hepatitis
screen should include cytomegalovirus and Epstein Barr
virus as well as serology for types A B and C. An upper
abdominal ultrasound may be useful although the presence
of gallstones may be incidental. Autoimmune liver disease
may present with similar biochemistry or itching and
may be diagnosed by testing for anti-smooth muscle
antibodies (chronic active hepatitis) and anti-mitochondrial
antibodies (primary biliary cirrhosis).
The mainstay of current management is early delivery,
which may help to reduce the stillbirth rate (2).
The majority of stillbirths occur at term, and the
current recommendation is to induce delivery by 37-38
weeks.
Management
Unfortunately the situation is analogous to diabetic
pregnancies in that sudden stillbirth may occur without
evidence of prior fetal compromise. There is usually
no evidence of placental insufficiency. Doppler umbilical
artery velocimetry has not been shown to correlate
with bile acid or alanine aminotransferase levels (3).
However in the absence of an agreed protocol for fetal
surveillance, a suggested regime would include fortnightly
growth scans with weekly liquor and Doppler estimations
and cardiotocography two or three times a week (4).
In some cases inpatient monitoring may be appropriate
although no studies to date examine the outcome with
inpatient versus outpatient care. Maternal liver function,
bile acids and clotting (PT/APTT) should be checked
at least weekly.
Ursodeoxycholic acid (Urso)
This improves maternal itching and normalises biochemistry
(5).
Only one randomised controlled trial of its usage in
cholestasis exists in the literature (6).
This was stopped prematurely because of one stillbirth,
which was found to be in the control group. Of the
15 patients who completed the trial there were no adverse
effects in the mothers or their babies. There were
5 premature deliveries and one stillbirth in the control
group but none in the trial group.
Urso works by normalising the bile acid pool (7),
stimulating bile flow and competing for bile acid receptors.
Clinically it improves maternal pruritis, lowers maternal
bile acids and corrects the abnormal ratio of progesterone
metabolites (8).
It also lowers bile acids in cord blood and amniotic
fluid (9)
although bile acids in meconium remain unchanged (10).
Although unlicensed in pregnancy it is increasingly
being used (8-12mg/kg in two daily divided doses).
Other drugs
One small trial looked at dexamethasone usage (11).
There is certainly a role for dexamethasone for fetal
lung maturity in those cases where delivery is anticipated
before 36 weeks. S-adnosylmethionine has also been
used (12,13)
and compared to ursodeoxycholic acid (14).
Vitamin K should be given to women with deranged clotting
as a result of cholestasis, and in addition should
be considered for all women with cholestasis to help
prevent primary post partum haemorrhage and haemorrhagic
disease of the newborn.
Postpartum
Symptoms and biochemistry should resolve within one
to two weeks postpartum. All women should be followed
up and in the absence of normalisation of biochemistry,
they should be investigated for an alternative cause
of their raised liver function.
All women with cholestasis should avoid the oral contraceptive
pill as this can cause a similar condition. They should
also be warned that the recurrence rate in subsequent
pregnancies is high. There is no evidence to date that
hormone replacement therapy is harmful
References
1.Girling JC, Dow E, Smith JH. Liver function tests
in pre-eclampsia: importance of comparison with a reference
range derived from a normal pregnancy. Br J Obstet
Gynaecol 1997; 104: 246-50, Abstract
2. Rioseco AJ. Ivankovic MB. Manzur A. Hamed F. Kato
SR. Parer JT. Germain AM. Intrahepatic cholestasis
of pregnancy: a retrospective case-control study of
perinatal outcome. American Journal of Obstetrics & Gynecology.
1994;170(3):890-5, Abstract
3. Zimmermann P, Koskinen J, Vaalamo P, Ranta T. Doppler
umbilical artery velocimetry in pregnancies complicated
by intrahepatic cholestasis. Journal of Perinatal Medicine
1991; 19(5):351-5, Abstract
4.Kelly A, Nelson-Piercy C. Obstetric cholestasis:PACE
review. The Obstetrician and Gynaecologist 2000;2(3)
29-31
5. Palma J, Reyes H, Ribalta J et al. Effects of ursodeoxycholic
acid in patients with intrahepatic cholestasis of pregnancy.
Hepatology 1992; 15:1043-7, Abstract
6.Palma J. Reyes H. Ribalta J. Hernandez I. Sandoval
L. Almuna R. Liepins J. Lira F. Sedano M. Silva O.
Toha D. Silva JJ. Ursodeoxycholic acid in the treatment
of cholestasis of pregnancy: a randomized, double-blind
study controlled with placebo. Journal of Hepatology.
1997; 27(6): 1022-8, Abstract
7.Brites D, Rodrigues CMP, Oliveira N, Da Conceicao
Cardoso M, Graca LM. Correction of maternal serum bile
acid profile during ursodeoxycholic acid therapy in
cholestasis of pregnancy. Journal of Hepatology. 1998;
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8. Meng LJ. Reyes H. Axelson M. Palma J. Hernandez
I. Ribalta J. Sjovall J. Progesterone metabolites and
bile acids in serum of patients with intrahepatic cholestasis
of pregnancy: effect of ursodeoxycholic acid therapy.
Hepatology. 1997;26(6):1573-9, Abstract
9.Mazzella G, Nichola R, Francesco A et al Ursodeoxycholic
acid administration in patients with cholestasis of
pregnancy: Effects on primary bile acids in babies
and mothers. Hepatology. 2001;33(3):504-508, Abstract
10. Rodrigues CMP, Marin JJG, Brites D. Bile acid
patterns in meconium are influenced by cholestasis
of pregnancy and not altered by ursodeoxycholic acid.Gut
1999;45(3):446-452., Abstract
11.Hirvioja M-L, Tuimala R, Vuori J. The treatment
of intrahepatic cholestasis of pregnancy by dexamethasone.
Br J Obstet Gynaecol 1992; 99:109-11, Abstract
12. Frezza M, Centini G, Caareri G et al. S-Adenosylmethionine
for the treatment of intrahepatic cholestasis of pregnancy.
Results of a controlled clinical trial. Hepatogastroenterology.
1990; 37(12):122-5, Abstract
13. Ribalta J. Reyes H. Gonzalez MC. Iglesias J. Arrese
M. Poniachik J. Molina C. Segovia N. S-adenosyl-L-methionine
in the treatment of patients with intrahepatic cholestasis
of pregnancy: a randomized, double-blind, placebo-controlled
study with negative results. Hepatology.1991;13(6):1084-9, Abstract
14. Floreani A. Paternoster D. Melis A. Grella PV.
S-adenosylmethionine versus ursodeoxycholic acid in
the treatment of intrahepatic cholestasis of pregnancy:
preliminary results of a controlled trial. European
Journal of Obstetrics, Gynecology, & Reproductive
Biology.1996; 67(2):109-13, Abstract
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