Table Of ContentJAUNDICE DURING PREGNANCY
WITH SPECIAL EMPHASIS ON
RECURRENT JAUNDICE DURING PREGNANCY
AND ITS DIFFERENTIAL DIAGNOSIS
BY
URS PETER HAEMMERLI
Springer Science+Business Media, LLC
ALSO PUBLISHED AS SUPPLEMENT No. 444 TO AcrA MEDICA SCANDlNAVICA 1966.
ISBN 978-0-387-90001-8 ISBN 978-1-4757-5621-0 (eBook)
DOI 10.1007/978-1-4757-5621-0
All rights reserved. especially that of nanslation into foreign languages
It is also forbidden to reproduce this book. either whole or in part. by phoromechanical means
(photostat. microfilm and/or microcard or any other means)
without written permission from the Publishers
© 1967 by Springer Science+Business Media New York
Originally published by Springer-Verlag New York Inc. in 1967.
Library of Congress Catalog Card Number 67-21050
Title No. 1430
INDEX
FOREWORD 7
1. THE LIVER IN NORMAL PREGNANCY 9
Liver palpation. . . . . . 9
Spider angiomas and palmar erythema 9
Histological changes in liver biopsies 10
Liver blood flow . . . . . . . . . . 10
Hemoglobin and serum iron . . . . . 11
Total leucocyte and differential count. 11
Prothrombin time 11
Urinary bile components 11
Serum bilirubin . . . 11
Bromsulfalein retention . 12
Galactose tolerance test . 12
Serum alkaline phosphatase 12
Serum transaminases and other enzymes . 13
Serum cholesterol and serum lipids . . . 14
Total serum proteins and serum electrophoresis 14
Serum turbidity and flocculation tests 15
Conclusions . . . . . . . . . . . 15
II. JAUNDICE DURING PREGNANCY . . . • . • 17
1) Incidence of jaundice durip.g pregnancy 17
2) Classification of jaundice during pregnancy 17
3) Frequency distribution of different diseases causing jaundice during
pregnancy . . . . . . . . . . . . . . . . . '. 20
4) Review of literature on jaundice during pregnancy . . 23
Infectious hepatitis during pregnancy . . . . . . . 23
Susceptability of pregnant women to viral hepatitis 23
Incidence of hepatitis in relation to stage of pregnancy 25
Mortality from hepatitis during pregnancy . 26
Clinical course of hepatitis during pregnancy . . . . 27
Sequellae from hepatitis during pregnancy . . . . . 28
Child survival from mothers with hepatitis during pregnancy 29
Transplacentar infection with hepatitis virus and incidence of
malformation in babies of mothers with hepatitis during preg-
nancy. . . . . . . . . . . . . . . . . . . . . . . .. 30
Jaundice in liver cirrhosis during plegnancy . . . . . . . .. 31
Drug-induced intrahepatic cholestasis during pregnancy . . .. 32
Obstructive jaundice due to choledocholithiasis during pregnancy 33
Effect of pregnancy in chronic idiopathic hyperbilirubinemias
(Dubin-Johnson syndrome, Rotor syndrome, Gilbert-Meulen-
gracht syndrome) . . . . . . . . . . . 33
Hemolytic jaundice during pregnancy 34
Rare causes of jaundice during pregnancy 35
Jaundice in severe pyelonephritis during pregnancy 35
Jaundice during pregnancy due to toxicity of drugs used in treat-
ment of pyelonephritis (Tetracycline toxicity) 35
Jaundice due to delayed chloroform poisoning 36
Intrahepatic cholestasis of pregnancy . 36
Acute fatty metamorphosis of pregnancy 37
Jaundice in hyperemesis gravidarum . 39
Jaundice in vomiting of late pregnancy 40
Jaundice in toxemia of pregnancy . . 40
5) Indications for interruption of pregnancy because of jaundice 41
III. RECURRENT JAUNDICE DURING PREGNANCY . . .'. . 43
1) Historical note . . . . . . . . . . . . . . . 43
2) Recurrent intrahepatic cholestasis of pregnancy 44
Nomenclature . . . . . . . . . . . 44
Material for review of world literature . . . 47
Liver biopsies . . . . . . . . . . . . . . 48
Gross anatomical findings and radiological gallbladder examinations 50
Symptoms and signs . . . . . . . . . 55
Laboratory data . . . . . . . . . . . , 57
Laboratory data before and after delivery . 63
Obstetrical course, incidence of premature deliveries and child
survival . . . . . . . . . . . . . . . . . . . . . . . .. 64
Clinical course of successive pregnancies in the individual patient 67
Treatment .. . . . . . . . . . . . . . . . . . . . . .. 69
Antecedent or underlying hepato-biliary or gastrointestinal disease 69
Familial occurrence of intrahepatic cholestasis of pregnancy 70
Non-recurrent intrahepatic cholestasis of pregnancy.. . . 70
Pruritus gravidarum . . . . . . . . . . . . . . . . 73
3) Differential diagnosis of recurrent intrahepatic cholestasis during
pregnancy . . . . . . . . . . . . . . . . . . . . . . 75
Recurrent jaundice during pregnancy due to recurrent viral hepa-
titis or due to exacerbation of chronic anicteric hepatitis . .. 75
Recurrent jaundice during pregnancy due to incipient primary
biliary cirrhosis .................... 77
4
Recurrent jaundice during pregnancy due to post-hepatitic hyper-
bilirubinemia . . . . . . . . . . . . . . . . . . . . 77
Recurrent jaundice during pregnancy due to gallstones in the
common bile duct . . . . . . . . . . . . . . . . . . .. 78
Recurrent jaundice during pregnancy due to familial non-hemolytic
jaundice. . . . . . . . . . . . . . . . . . . . . . 78
Recurrent jaundice during pregnancy due to hemolysis . . .. 79
Recurrent jaundice with hemoglobinuria during pregnancy . .. 80
Recurrent jaundice during pregnancy due to. severe pyelonephritis 80
Recurrent jaundice during pregnancy due to hyperemesis
gravidarum . . . . . . . . . . . . . . 80
Recurrent jaundice during pregnancy with different etiology of
jaundice during successive pregnancies . . . . . . . . . . 81
Recurrent jaundice during pregnancy due to unclassified causes 82
Misquoted cases of recurrent jaundice during pregnancy in the
literature . . . . . . . . . . . . . . . . . . . . . 83
4) Classification of recurrent jaundice during pregnancy . . . 84
5) Other diseases with recurrent jaundice and complete recovery in
the anicteric interval . . . . . . . . . . 84
Idiopathic recurrent cholestasis . . . . . 85
Recurrent jaundice during menstruation 86
6) Pathogenesis of intrahepatic cholestasis of pregnancy 86
SUMMARY. • 92
REFERENCES 99
5
FOREWORD
During the years 1959 to 1964 we had part will be devoted to a description
the occasion to observe personally 5 and definition of recurrent intrahepatic
patients with recurrent intrahepatic cholestasis of pregnancy on the basis of
cholestasis of pregnancy and to follow all verified cases in the world literature
them through multiple gestations. These i~cluding our own patients and to a
cases, together with a sixth case dis description of all other disorders which
covered in the hospital files, have been may present as recurrent jaundice dur
described in detail elsewhere (Haem ing pregnancy. We believe that the
merli and Wyss). The perusal of the literature in the third part is as complete
literature during the preparation of that as it possibly can be. The first two parts
manuscript soon revealed, that not all had to be somewhat restricted in con
cases of recurrent jaundice during tent, and while they-as we hope-will
pregnancy could be due to recurrent present a fair summary of the present
jaundice of pregnancy i.e. the cholestatic state of knowledge, not all papers cover
form. It also became apparent that an ing the respective topics could be in
attempt at a differential diagnosis of cluded.
recurrent jaundice during pregnancy Our interest in jaundice during preg
has never been made and that many nancy has been stimulated during our
conflicting statements in the literature work as medical consultant and gastro
on recurrent jaundice during pregnancy enterologist to the Department of Ob
originate in the lack of clear definitions. stetrics, Ziirich University Hospital, and
The present paper attempts to fill this I wish to gratefully acknowledge the
need. In order to achieve our purpose it continuing help and encouragement re
has become necessary to present in a ceived from its chief, Professor E. R.
first part a brief review of the changes Held, his co-worker Dr. H. I. Wyss, and
in so-called liver function tests during from my chief, Professor P. H. Rossier,
uncomplicated pregnancy and in a head of the Department of Medicine,
second part a general review of jaundice Ziirich University Hospital.
during pregnancy. The third and main
7
I. The liver in normal pregnancy
The liver performs its function well Lichtman 1953, Thorling 1955, Hoynck
during gestation. Tests and laboratory Van Papendrecht 1957, Richman 1960
detenninations usually employed to and Friedberg 1960, 1962, 1963. A fair
evaluate liver function and liver disease summing-up has been made by Cross in
deviate, however, not infrequently from 1929: "The liver is the largest, the most
the nonnal in healthy pregnant women. abused, the most neglected, one of the
These disturbances are rarely severe, most important, and the least understood
surpassing the accepted upper limit of organ of the body".
nonnal for non-pregnant females only
slightly. They are on the main more Liver palpation
common in the later weeks of gestation Palpation of the liver can be difficult
and are usually rectified after delivery. in the later weeks of gestation, when the
The knowledge of the "physiological" liver may be forced upwards, backwards
derangements is important for any and to the right by the enlarged uterus.
physician evaluating a women with A nonnal liver is rarely palpable to
jaundice during pregnancy. In the non wards term. When it is felt, liver disease
pregnant state there exists for every test or congestive heart failure should be
an accepted division line between a suspected.
nonnal and a pathological result. It is
probably wise to follow Friedberg's sug Spider angiomas and palmar erythema
gestion to fonn a third intennediary Bean et aI. carefully examined all women
group of test results in pregnant women: in a prenatal clinic during one year.
those lying above the upper limit of They found spider angiomas in 66.6 %
nonnal for non-pregnant subjects, but of 484 white and in 11.4 % of 759 negro
lying below the highest observed values pregnant females. The control incidence
in uncomplicated pregnancies. As only a was 12 % among 58 non-pregnant
certain percentage of pregnant females white females with children and 14.9 %
surpass the non-pregnant norm, this among 295 white soldiers. In the same
intennediary group may then be truely pregnancy groups 62.5 % of white and
"nonnal", or may have a pathological 35 % of negro females had palmar
significance. erythema. There was an overlap in the
Reviews of liver function in uncom occurrence of spider angiomas and
plicated pregnancy have been attempted palmar erythema in about two thirds of
by Holmer 1927, Vignes 1935, Dietel each group. Spider angiomas occurred as
1936, Williams 1952, Dieckmann 1952, early as the second month of gestation
9
with a sharp incidence rise between the was considered normal. In 1947 Nixon
2nd and 5th month and but a slow rise et al. biopsied 9 pregnant females and
thereafter. During pregnancy the single found only minor nonspecific histological
spider angioma may increase in size and changes. These consisted in an occa
new ones may appear in the second and sional variation in the shape of liver
third trimester. Most disappear after cells, in an increase in the number of
delivery. large nuclei, in some irregularities of the
Bean et al.'s study is the result of a nuclei, and in an increased glycogen
meticulous search for these skin changes. content of the cytoplasm. In the same
It is not surprising that they are usu year Dietel obtained 31 surgical liver
ally not noted by the more hasty ob biopsies during pregnancy and found
server and that they are rarely men only a slight increase in the number of
tioned in obstetric textbooks. binucleated liver cells when compared
with 50 non-pregnant controls.
Histological changes in liver biopsies All these authors agree that histologi
In 1907 Hofbauer described as typical cal liver changes during pregnancy are
histological changes of the liver during minor and nonspecific and that a
pregnancy: centrolobular fatty degener "Schwangerschaftsleber" does not exist.
ation, decreased glycogen content,
centrolobular bile stasis and ectasia of Liver blood flow
the centrolobular veins and capillaries. Liver blood flow is within the normal
He coined the term "Schwangerschafts range in pregnancy. Using the brom
leber". His opinion was based on 4 post sulfalein technic and hepatic vein cathe
mortem examinations of pregnant terization Munnell and Taylor found a
women dying at term: three from pul mean liver blood flow of 1,554 ml per
monary emboli and one from exsangui minute per 1.73 sq.m. of body surface in
nation during delivery. This concept 15 pregnant females (range 1,075-
was challenged in 1910 by Schickele but 2,465) compared to a mean of 1,548 ml
still kept appearing in the literature up per minute (range 1,177-1,900) in 15
to 1945. It is now clear that Hofbauer's nonpregnant controls.
observations were due to unrelated and This is noteworthy because in preg
terminal pathology in his 4 cases. nancy plasma volume and blood volume
In 1945 Ingerslev and Teilum per rise by 50 to 60 % and cardiac output
formed liver biopsies in 17 females dur increases by 30 to 50 % reaching a
ing delivery. They found some variation maximum in the 7th pregnancy month
in the size of liver cells and nuclei, oc and returning to normal towards term.
casionally small lymphocytic infiltrations (Tysoe and Lowenstein.) Liver blood
in the portal spaces, and sometimes a flow comprises 35 % of cardiac output
mild vacuolar accumulation of fat in the in nonpregnant females and only 28 %
centrolobular area which was more of cardiac output in pregnancy. The ex
pronounced than in their 6 nonpregnant cess blood volume is shunted through
controls. Otherwise the liver histology the placenta.
10
Hemoglobin and serum iron Prothrombin time
Young et al. demonstrated a fall in The prothrombin time remains normal
hemoglobin levels during pregnancy in in all cases of uncomplicated pregnancy
219 serially examined patients. Hoch et (Ikonen).
al. found in addition a fall in serum iron
Urinary bile components
levels, but could .not demonstrate a cor
relation between hemoglobin and serum Although most textbooks state that
iron. In a more detailed study of 176 urinary urobilinogen and urobilin may
patients Niesert observed an average fall be increased in the later stages of preg
in hemoglobin from 95 % to 85 %, a nancy, few exact studies have been per
fluctuating, but on the whole constant formed. Merletti in 1902 observed "as
serum iron level, an increase in total a rule" a two to three fold increase of
iron binding capacity and a correspond urobilin in the last trimester. In normal
ing fall in iron saturation. Ikonen found pregnancies at term Arfwedson found
the serum iron levels widely dispersed "pathological bile components" in ·5 %
(range 59-294 microgm per 100 ml) in of 100 patients, Dieckmann et al. a
his 84 normal pregnancies. positive urine bilirubin test in 14.5 %
Anemia during the last trimester of of 85 patients and Labo et al. a positive
pregnancy is generally considered to be urine urobilin test in 8.3 % of 75 pa
present only when the hemoglobin level tients. On the other hand Cross reported
falls to below 10 gm per 100 ml. The bilirubin, urobilin and urobilinogen tests
fall in hemoglobin and hematocrit is to be all normal in 61 uncomplicated
explained by the rise in plasma volume pregnancies.
which is only partially compensated by
Serum bilirubin
a minor rise in red cell volume. (Tysoe
and Lowenstein.) Total serum bilirubin levels were re
ported to be normal during uncompli
cated pregnancy by Cross in 61 patients,
Total leucocyte and differential count by Cantarow et al. in 34 patients, by
Kuvin and Brecher found a normal Dieckmann et al. in 85 patients, by Wet
white cell count and morphology in stone et al. in 56 patients and by Thor
only 46 % of 88 pregnancies. 20 % have ling in 202 patients. The latter author
an increase of total white cells above gives a mean of 0.3 mg per 100 ml with
10,000 per cu. mm and counts of 15,000 a range of 0.1 to 1.1 mg per 100 ml.
per cu. mm are still considered normal Other authors report a mild serum
in the last trimester. Abnormal differ bilirubin increase in a small percentage
ential counts are also common. There of normal pregnancies, e.g. Eufinger and
is an increase in both segmented and Bader. Ikonen found bilirubin levels of
nonsegmented neutrophils. Not infre 1.0 to 2.0 mg per 100 ml in 2 % of 100
quently myelocytes and metamyelocytes patients, Arfwedson in 6 % of 100 pa
may be seen which are not necessarily tients and McNair and Jaynes in 4.3 %
part of the "shift to the left". of 564 patients. Among Friedberg's 120
11
