Abnormal Liver Function Tests in The Symptomatic Pregnant Patient: The Local Experience in Singapore

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204

Annals Academy of Medicine


Liver Disease in PregnancyHY Wong et al
Introduction
The diagnostic work-up of abnormal liver function tests
(LFT) in pregnancy is challenging, as the conditions peculiar
to pregnancy have to be considered in addition to the causes
affecting the non-pregnant population.
1,2
The spectrum of
disease is varied and the abnormal LFT can be mild with no
long-term consequence, or it can be severe, leading to both
maternal and foetal mortality.
3
As such, gastroenterologists
and obstetricians are often faced with the dilemma of
whether the abnormal LFT is related to pregnancy and
whether immediate obstetric intervention is necessary.
Knowing the distribution of the various probable causes of
abnormal LFT in the pregnant population would therefore
be useful in guiding clinical practice.
Of pregnancy-related causes of abnormal LFT in the
third trimester, acute fatty liver of pregnancy, haemolysis,
elevated liver enzymes and low platelets (HELLP)
syndrome, pre-eclampsia toxaemia (PET) and partial
HELLP syndrome can potentially be fatal, but the LFT
abnormalities usually resolve after delivery.
4
We also looked
at the LFT in patients with these diagnoses postpartum to
study the time course to resolution.
1
Registrar
3
Senior Consultant
Gastroenterology Unit, Department of General Medicine
Tan Tock Seng Hospital
2
Visiting Consultant
Department of Maternal Fetal Medicine
KK Womens and Childrens Hospital
Address for Reprints: Dr HY Wong, Gastroenterology Unit, Department of General Medicine, Tan Tock Seng Hospital, 11 J alan Tan Tock Seng, Singapore
308433.
Abstract
Introduction: The causes of abnormal liver function tests in pregnancy are varied and may or
may not be pregnancy related. Often, the diagnosis can be difficult. This study looked at the
causes of deranged liver function tests in obstetric patients with significant symptoms and signs.
Materials and Methods: Data from 50 cases of abnormal liver function tests in pregnant patients,
who presented from 1998 to 2001, were analysed. Their presenting symptoms included persistent
vomiting (48%), pruritis (14%), jaundice (26%), upper abdominal discomfort (24%) and
hypertension (46%). Results: Pregnancy-related causes accounted for 84% of the abnormal liver
function tests. Abnormal liver function tests occurred more frequently in the first (34%) and
third (58%) trimesters than in the second trimester (8%). Hyperemesis gravidarum (94%) and
partial haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome (31%) were the
commonest causes in the first and third trimesters respectively. Hepatitis B flare resulted in 2
maternal deaths. Seven patients with pre-eclampsia toxaemia, acute fatty liver of pregnancy or
partial/complete HELLP syndrome had their liver function tests measured sequentially before
and after delivery. All of them showed rapid improvement postpartum with their alanine
aminotransferase (ALT) dropping 50% within 3 days. Conclusions: The majority of patients
with abnormal liver function tests had a cause related to pregnancy, and pregnancy-related
causes in the third trimester improved rapidly postpartum. Hepatitis B flare was a significant
non-obstetric cause leading to maternal mortality. This diagnosis must therefore be considered
in ethnic groups where the incidence of chronic hepatitis B infection is high, especially in chronic
hepatitis B carriers with suspected pregnancy-related disease who deteriorate postpartum.
Ann Acad Med Singapore 2004;33:204-8
Key words: HELLP syndrome, Hepatitis B, Liver function tests, Pre-eclampsia, Pregnancy
Abnormal Liver Function Tests in the Symptomatic Pregnant Patient:
The Local Experience in Singapore
HY Wong,
1
BA (Hons), BM BCh, MRCP (UK), J YL Tan,
2
MBBS, MRCP (Ire), CC Lim,
3
FAMS, MBBS, FRCP (Edin)
Original Article
March 2004, Vol. 33 No. 2
205 Liver Disease in PregnancyHY Wong et al
Materials and Methods
This is a retrospective study of patients, at a major
obstetric hospital in Singapore from 1998 to 2001, who
were referred to the obstetric physician and had abnormal
LFT. The medical records of these patients were obtained
and information relating to the episode of abnormal LFT
were analysed. Routine LFT are not done in all patients in
this hospital and performed only in the presence of symptoms
or abnormalities on physical examination. This comprised
persistent vomiting (48%), pruritis (14%), jaundice (26%),
upper abdominal discomfort (24%) and hypertension (46%).
The definition of abnormal LFT pertained to values
higher than the normal range as defined by the local
laboratory (bilirubin >24 mol/L, alkaline phosphatase
(ALP) >103 U/L, gamma-glutamyltranspeptidase (GGT)
>26 U/L, ALT >51 U/L, aspartate aminotransferase (AST)
>33 U/L). Hyperemesis gravidarum was defined as
persistent vomiting with the onset occurring before 13
weeks of gestation, and of such severity that the patient is
unable to retain solids and liquids and requires hospital
admission for intravenous hydration.
5
In this study, the
diagnosis of HELLP syndrome required the presence of the
following criteria: ALT greater than and haptoglobin less
than the range defined by the local laboratory (haptoglobin
<0.37 g/L) and platelets of less than 100 x 10
9
/L. If the
patients had a raised ALT but only 1 of the 2 remaining
criteria, they were diagnosed as having partial HELLP
syndrome. PET was defined as the development of
hypertension after 20 weeks gestation according to the
Australasian Society for the Study of Hypertension in
Pregnancy criteria.
6
There are no established diagnostic
criteria for acute fatty liver of pregnancy. Although liver
biopsy is the gold standard for the diagnosis of acute fatty
liver of pregnancy, the diagnosis can be made in most cases
clinically with liver biopsies indicated only for patients
with atypical presentations.
3,4,7,8
The diagnosis of acute
fatty liver of pregnancy in our study was made on clinical
grounds in patients with acute hepatic failure in the third
trimester who had reduced synthetic function of the liver
with coagulopathy and impaired renal function as prominent
features as discussed by Castro et al.
8
In addition, non-
obstetric causes of acute hepatic failure such as hepatitis A,
hepatitis B, hepatitis C and drug-induced hepatitis were
excluded in these patients. Lastly, their clinical parameters
improved after delivery. The diagnosis of intrahepatic
cholestasis of pregnancy was made on clinical grounds as
described by Davidson.
9
These patients presented with
pruritis as a prominent symptom without skin lesions in late
pregnancy. The pruritis generally begins in the palms and
soles, and may extend to the trunk. The pruritis resolves
within days of delivery. Serum bile acids were not assessed
in our patients as this test is not available locally.
Results
Patient Demographics
There were 48 patients seen during the study period with
49 pregnancies associated with abnormal LFT and the
presence of significant symptoms and signs. One woman
had 2 pregnancies during the study period with abnormal
LFT for which 2 different causes were found. Another
woman had 2 different causes for the abnormal LFT during
the same pregnancy. The median age for the whole study
group was 31 years (range, 19 to 40 years). Forty-six per
cent of this population was primiparous. The ethnic
distribution was as follows: Chinese (34%), Malay (38%),
Indian (20%) and minority ethnic groups (4%).
Causes of Abnormal LFT
The causes of abnormal LFT are shown in Table 1. The
majority of LFT abnormalities in this study were related to
pregnancy (84%). Most episodes of abnormal LFT occurred
in the first (34%) and third (58%) trimesters. In contrast, the
occurrence of abnormal LFT was uncommon during the
second trimester (8%). The commonest cause of abnormal
LFT in the first trimester was hyperemesis gravidarum
(94%). The causes of abnormal LFT in the third trimester
were the most varied, with partial HELLP syndrome (31%)
and PET (21%) comprising the commonest diagnoses. The
only patient with drug-induced hepatitis was on isoniazid
and rifampicin for treatment of pulmonary tuberculosis.
There were 2 deaths in this study which were due to
hepatitis B flare. Both patients had emergency Caesarean
sections as their abnormal LFT were thought to be related
to pregnancy, but their liver impairment did not recover and
they died subsequently. The first patient was diagnosed to
be a chronic hepatitis B carrier during routine antenatal
Table 1. Causes of Abnormal LFT in the Study Population Stratified
According to Trimester
Diagnosis No. %
1st trimester Hyperemesis gravidarum 16 94
Typhoid 1 6
2nd trimester Hyperemesis gravidarum 2 50
Choledocholisthesis 2 50
3rd trimester Acute fatty liver of pregnancy 2 7
Drug induced 1 3
HELLP syndrome 3 10
Hepatitis B flare 3 10
Unknown 1 3
Intrahepatic cholestasis of 4 14
pregnancy
PET 6 21
Partial HELLP syndrome 9 31
HELLP: haemolysis, elevated liver enzymes, low platelets;
PET: pre-eclampsia toxaemia
206
Annals Academy of Medicine
Liver Disease in PregnancyHY Wong et al
screening. In the third trimester, she developed jaundice
associated with disseminated intravascular coagulation
and renal impairment. She was suspected to have acute
fatty liver of pregnancy with a differential diagnosis of
hepatitis B flare. The foetus was delivered immediately as
this is the treatment of choice for acute fatty liver of
pregnancy. However, the patient deteriorated post-delivery
with worsening LFT and renal function, not typical of acute
fatty liver of pregnancy. With the exclusion of acute fatty
liver of pregnancy, the diagnosis of a hepatitis B flare was
made. Her HBsAg was positive, HBeAg was negative and
Anti-HBeAb was positive. Her HBV DNA test result was
subsequently available and was 1295.0 MEq/mL. She
could have had a pre-core mutant infection or a fatal
seroconversion reaction. The patient was referred for liver
transplantation, but she deteriorated rapidly with cerebral
oedema and septic shock, and died before liver
transplantation could be initiated. The second patient was
a chronic hepatitis B carrier diagnosed to have PET as she
had proteinuria, a raised uric acid and severe hypertension
requiring IV hydralazine. Following an emergency
Caesarean section, her blood pressure normalised and her
LFT improved and she was discharged 3 days postpartum.
She was re-admitted 2 weeks later with vomiting, jaundice
and drowsiness. There was a marked deterioration in her
LFT and she lapsed into fulminant liver failure rapidly. The
diagnosis of a hepatitis B flare was made only after the
second rise in her LFT. Her HBsAg and HBeAg were
positive and HBV DNA was 66.3 MEq/mL. She was
referred for liver transplantation, but she developed
septicaemia which led to her death before liver
transplantation could be made. The diagnosis of hepatitis
B was difficult to make in this case as she had co-existing
PET which improved postpartum.
Our patients with PET, HELLP, partial HELLP and
acute fatty liver of pregnancy were treated by urgent
delivery of the foetus. Apart from the patient described
above who had co-existing PET and hepatitis B flare, and
1 patient with PET who absconded from the ward and was
subsequently lost to follow-up, the remaining 18 patients
recovered uneventfully after delivery of the foetus.
Laboratory Tests
The median LFT for the 3 commonest diagnoses of
hyperemesis gravidarum, PET and partial HELLP are
listed in Table 2. Postpartum LFT were measured
sequentially in 7 patients of whom 3 had partial HELLP
syndrome, 2 had acute fatty liver of pregnancy, 1 had
HELLP syndrome and the last had PET. The median time
taken for the ALT to fall to 50% of the highest recorded
level was 2 days (range, 1 to 3 days).
Discussion
There have been numerous publications on the specific
causes of abnormal LFT in pregnancy
4,8-11
but this study
focuses on the probable diagnoses that a physician would
expect when faced with a pregnant woman with symptoms
and signs associated with an abnormal LFT. It is therefore
pertinent that the study looked at patients who had their
LFT tested only when indicated clinically rather than as a
result of blanket screening, because the use of laboratory
investigations in the appropriate clinical setting reflects our
local medical practice at present.
Hyperemesis gravidarum was by far the commonest
cause of raised LFT during the first trimester in our study.
Abnormal LFT have been reported previously in 16% to
25% of patients with severe hyperemesis gravidarum who
required hospitalisation.
12,13
Elevations in ALT are usually
mild and less than 4 times the upper limit of normal.
13
The
ALT levels in our patients with hyperemesis gravidarum
were similar, with a median value of 103 U/L. However,
there have been occasional case reports of ALT rising more
than 1000 U/L in patients with hyperemesis gravidarum.
14
The cause of LFT abnormalities in hyperemesis gravidarum
is not known, but is thought to be related to fasting and poor
nutrition.
12
However, Morali and Braverman
13
reported
that the degree of ketonuria and level of LFT abnormality
did not correlate in patients with hyperemesis gravidarum,
suggesting that other mechanisms may be responsible.
Many definitions of the clinical parameters of HELLP
Table 2. The Median (Range) LFT for Patients With Hyperemesis Gravidarum, PET and Partial HELLP Syndrome
Hyperemesis gravidarum (n =18) PET (n =6) Partial HELLP syndrome (n =9)
Total bilirubin (mol/L) 21.5 (11-90) 14 (6-16) 15 (8-222)
ALP (U/L) 51.5 (34-90) 203.5 (67-314) 195 (86-276)
GGT (U/L) 45 (12-154) 17 (7-59) 35 (2-286)
ALT (U/L) 103.5 (44-405) 115 (20-342) 149 (22-1048)
AST (U/L) 73 (25-154) 66 (30-407) 81 (44-735)
Albumin (g/L) 36 (31-45) 28.5 (22-32) 31.5 (21-34)
ALT: alanine aminotransferase; ALP: alkaline phosphatase; AST: aspartate aminotransferase; GGT: gamma-glutamyltranspeptidase;
HELLP: haemolysis, elevated liver enzymes, low platelets; LFT: liver function tests; PET: pre-eclampsia toxaemia
March 2004, Vol. 33 No. 2
207 Liver Disease in PregnancyHY Wong et al
syndrome have been proposed in the literature. We have
chosen to use a decreased haptoglobin in our study as an
indicator of haemolysis rather than a raised LDH, raised
total bilirubin or a falling haematocrit used in previous
studies.
15
The reasons are that LDH and total bilirubin are
also raised as a result of liver impairment.
16
Furthermore, it
is difficult to attribute a falling haematocrit to haemolysis
alone as blood loss following delivery, especially Caesarean
section, can contribute to a falling haematocrit. A reduced
haptoglobin may be a better indicator of haemolysis as
Wilkie et al
17
reported reduced levels of haptoglobin in all
25 patients with HELLP syndrome in their study. In contrast,
in 5 patients with HELLP syndrome where they measured
LDH isoenzymes, elevated plasma LDH in 4 patients were
of liver origin rather than from haemolysis.
PET, partial HELLP and HELLP are thought to be
related entities with different clinical manifestations of the
same underlying disease process. Liver biopsies of patients
with HELLP syndrome showed fibrin deposition in the
periportal sinusoids and hepatocellular necrosis
18
similar
to that found in pre-eclampsia.
19
The mortality with PET is
lower than that of HELLP syndrome, with rates of less than
1% and 1% to 3%, respectively.
4
The clinical distinction
between patients with full blown HELLP syndrome and
partial HELLP syndrome also carries prognostic
significance. Audibert et al
20
reported that patients with
HELLP syndrome developed more complications than
patients with partial HELLP syndrome. PET and partial
HELLP syndrome were the commonest causes of raised
LFT in our study population during the third trimester,
occurring with a frequency of 21% and 31%, respectively.
The median ALT for PET and partial HELLP were 115 U/L
and 149 U/L, respectively, in our study. The rise in
aminotransferases is usually not severe, with mean levels
of 60 U/L in pre-eclampsia and 150 U/L in HELLP reported
previously.
4
In their series of 28 patients with acute fatty liver disease
of pregnancy, Castro et al
8
reported that the cardinal
features were that of impaired coagulation and renal
impairment. However, HELLP too can lead to disseminated
intravascular coagulation and renal impairment with a
reported incidence of 21% and 7.7%, respectively.
11
Indeed,
it has been suggested that acute fatty liver of pregnancy
may form the extreme end of the spectrum of pre-eclamptic
disease. This is supported by the findings of Minakami et
al,
21
in which liver biopsies were taken from 41 patients
with acute fatty liver of pregnancy, HELLP syndrome, PET
with normal AST and PET with raised AST, and the liver
tissue stained with oil red O. All liver biopsy specimens
showed microvesicular fat droplets in varying degrees
suggesting a common pathology. Interestingly, patients
with HELLP and acute fatty liver of pregnancy tended to
have a higher liver fat density than patients with PET, but
it was not possible to distinguish these diagnoses
histologically.
We found that the large majority of abnormal LFT in
pregnancy was related to the pregnancy. This occurred
primarily in the first and third trimesters. However, despite
the observation that 83% of abnormal LFT in the third
trimester was related to pregnancy, the non-obstetric causes
were important as the deaths in our study were secondary
to hepatitis B flare. Both patients had raised LFT in the third
trimester which were initially thought to be due to acute
fatty liver disease of pregnancy and PET respectively as
discussed previously. Lin et al
22
reported in their study that
5 out of 30 patients who were hepatitis B carriers sero-
converted in the first 3 months postpartum. In contrast none
of the patients in the control group seroconverted. This
increased rate of seroconversion may be related to
postpartum immune rebound.
23
The level of endogenous
cortisol in pregnancy rises in the second trimester, reaching
levels of 2 to 3 times normal in the third trimester. Following
delivery, the cortisol falls rapidly to pre-pregnancy levels.
24
This phenomenon is reminiscent of that following
withdrawal of corticosteroids in non-pregnant individuals
with chronic hepatitis B. A similar phenomenon has been
observed with chronic hepatitis C carriers in whom the
histopathological grading was found to be more severe in
patients postpartum than in controls.
25
In patients with
abnormal LFT due to an attempt at hepatitis B sero-
conversion during the third trimester, emergency delivery
of the foetus reduces circulating cortisol rapidly and this
may ironically worsen the seroconversion reaction as may
have been the case in both maternal deaths in our study.
The diagnosis of the pre-eclamptic diseases and acute
fatty liver of pregnancy may be difficult to distinguish from
hepatitis B flare as illustrated in our cases. Moreover,
patients with chronic liver disease may have co-existing
pre-eclamptic disease, as it has been reported that patients
with chronic active hepatitis have an increased risk of
developing PET.
26
A major difference between obstetric
and non-obstetric causes of abnormal LFT is that acute
fatty liver of pregnancy and the pre-eclamptic diseases
respond well to delivery of the foetus.
4
Our study showed
that patients with acute fatty liver of pregnancy, HELLP
syndrome, partial HELLP syndrome and PET had rapid
improvement in the LFT postpartum, whereas patients with
hepatitis B flare deteriorated rapidly postpartum. As hepatitis
B is common in the Asia-Pacific region with a prevalence
of the carrier state of greater than 10%,
27
a high index of
suspicion for a hepatitis B flare is required in patients with
suspected pregnancy-related liver disease from these
countries when their LFT do not improve rapidly within a
few days postpartum.
208
Annals Academy of Medicine
Liver Disease in PregnancyHY Wong et al
REFERENCES
1. Knox TA. Evaluation of abnormal liver function in pregnancy. Semin
Perinatol 1998;22:98-103.
2. Riely CA. Hepatic disease in pregnancy. Am J Med 1994;96:18S-22S.
3. Riely CA. Liver disease in the pregnant patient. Am J Gastroenterol
1999;94:1728-32.
4. Knox TA, Olans LB. Liver disease in pregnancy. N Engl J Med
1996;335:569-76.
5. Tan J YL, Loh KC, Yeo GSH, Chee YC. Transient hyperthyroidism of
hyperemesis gravidarum. Br J Obstet Gynaecol 2002;109:683-8.
6. Australasian Society for the Study of Hypertension in Pregnancy.
Consensus Statement management of hypertension in pregnancy,
executive summary. Med J Aust 1993;158:700-2.
7. Riely CA, Latham PS, Romero R, Duffy TP. Acute fatty liver of
pregnancy. A reassessment based on observations in nine patients. Ann
Intern Med 1987;106:703-6.
8. Castro MA, Fassett MJ , Reynolds TB, Shaw KJ , Goodwin TM. Reversible
peripartumliver failure: a new perspective on the diagnosis, treatment,
Although we do not advocate checking LFT in
asymptomatic pregnant patients, it may be worthwhile
performing screening LFT in asymptomatic hepatitis B
carriers, because of the possible effects of pregnancy as
discussed previously. In addition, these patients should
have their e status evaluated if this was not done recently.
For patients with abnormal LFT on screening, a baseline
HBV DNA should be done as subsequent measurements of
HBV DNA may be useful in distinguishing pregnancy-
related causes of abnormal LFT from a hepatitis B flare.
However, many questions regarding this special group of
pregnant patients remain unanswered. For example, what
is the optimal frequency of LFT evaluation in pregnant
hepatitis B carriers with abnormal LFT? Is lamivudine
indicated in pregnant patients with a hepatitis B flare?
Large prospective trials are needed to answer these complex
yet important clinical questions.
Conclusion
Knowing the likely causes of an abnormal LFT in the
various stages of pregnancy helps allay much anxiety and
allows appropriate obstetric planning with regards to the
timing of delivery. Extra caution should be exercised in
interpreting the abnormal LFT of a HBsAg positive obstetric
patient bearing in mind the consequence of a more serious
outcome in a seroconversion reaction occurring in the
immediate postpartum period. Early referral to a hepatologist
would be important in the management of hepatitis B flare
in pregnancy.
and cause of acute fatty liver of pregnancy, based on 28 consecutive
cases. Am J Obstet Gynecol 1999;181:389-95.
9. Davidson KM. Intrahepatic cholestasis of pregnancy. Semin Perinatol
1998;22:104-11.
10. Hunt CM, Sharara AI. Liver disease in pregnancy. Am Fam Physician
1999;59:829-36.
11. Sibai BM, Ramadan MK, Usta I, Salama M, Mercer BM, Friedman SA.
Maternal morbidity and mortality in 442 pregnancies with haemolysis,
elevated liver enzymes, and low platelets (HELLP syndrome). Am J
Obstet Gynecol 1993;169:1000-6.
12. Adams R, Gordon J , Combes B. Hyperemesis gravidarum. I. Evidence
of hepatic dysfunction. Obstet Gynecol 1968;31:569-74.
13. Morali GA, Braverman DZ. Abnormal liver enzymes and ketouria in
hyperemesis gravidarum. J Clin Gastroenterol 1990;12:303-5.
14. Conchillo J M, Koek GH. Hyperemesis gravidarum and severe liver
enzyme elevation. J Hepatol 2002;37:162-6.
15. Saphier CJ , Repke J T. Haemolysis, Elevated Liver Enzymes, and Low
Platelets (HELLP) Syndrome: a review of diagnosis and management.
Semin Perinatol 1998;22:118-33.
16. Zakim D, Boyer TD, editors. Hepatology: A Textbook of Liver Disease.
Philadelphia: WB Saunders Co, 1996.
17. Wilkie G, Schutz E, Armstrong VW, Kuhn W. Haptoglobin as a sensitive
marker of haemolysis in HELLP syndrome. Int J Gynecol Obstet
1992;39:29-34.
18. Aarnoudse J G, Houthoff HJ , Weits J , Vellenga E, Huisjes HJ . A
syndrome of liver damage and intravascular coagulation in the last
trimester of normotensive pregnancy: a clinical and histopathological
study. Br J Obstet Gynaecol 1986;93:145-55.
19. Crawford J M. The liver and the biliary tree. In: Cotrans RS, Kumar V,
Robbins, editors. Robbins Pathologic Basis of Disease. 5
th
ed.
Philadelphia: WB Saunders, 1994:875.
20. Audibert F, Friedman SA, Frangich AY, Sibai BM. Clinical utility of
strict diagnostic criteria for the HELLP (haemolysis, elevated liver
enzymes, and low platelets) syndrome. Am J Obstet Gynecol
1996;175:460-4.
21. Minakami H, Oka N, Sato T, Tamada T, Yasuda Y, Hirota N. Preeclampsia:
a microvesicular fat disease of the liver? Am J Obstet Gynecol
1988;159:1043-7.
22. Lin HH, Chen PJ , Chen DS, Sung J L, Yang KH, Young YC, et al.
Postpartum subsidence of hepatitis B viral replication in HBeAg-
positive carrier mothers. J Med Virol 1989;29:1-6.
23. Hidaka Y, Amino N, Iwatani Y, Kaneda T, Matsuda N, Morimoto Y, et
al. Changes in natural killer cell activity in normal pregnant and post-
partumwomen: increases in the first and second post-partumperiod and
decrease in late pregnancy. J Reprod Immunol 1991;20:73-83.
24. Carr BR, Parker CR J r, Madden J D, MacDonald PC, Porter
J C. Maternal plasma adenocorticotropin and cortisol relationships
throughout human pregnancy. AmJ Obstet Gynecol 1981;139:416-22.
25. Fontaine H, Nalpas B, Carnot C, Brechot C, Pol S. Effect of pregnancy
on chronic hepatitis C: a case-control study. Lancet 2000;356:1328-9.
26. Steven MM, Buckley J , Mackay I. Pregnancy in chronic active hepatitis.
Q J Med 1979;48:519-31.
27. Core Working Party for Asia-Pacific Consensus on hepatitis B and C.
Consensus statement on the prevention and management of hepatitis B
and hepatitis C in the Asia-Pacific region. J Gastroenterol Hepatol
2000;15:825-41.

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