CHAPTER VI: NON-VIRAL ICTERIC DISORDERS IN PREGNANCY

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  • CHAPTER VI

    NON-VIRAL ICTERIC DISORDERS IN PREGNANCY

    Jaundice in late Pregnancy

    This group of icteric pregnant women forms the main body of the series, 38 patients, Cases 35 to 72. The term late pregnancy in the title of this chapter may appear to be somewhat misleading, in view of the fact that the onset in some cases occurred in a relatively early stage of pregnancy. Rut, although the group may not be uniform from the standpoint of aetiology, the clinical signs and symptoms in its different members are so similar that, for practical pur- poses, they are best described in the group as a whole. The title was suggested by the fact that the onset of jaundice occurred towards the end of pregnancy in the great majority of cases. Howerer, a closer analysis of the histories shows symptoms other than jaundice to have become manifest in several instances appreciably earlier in the course of gestation than one might hare expected. There is, in fact, no little difficulty in dating the onset of the condition exactly. The only source of information available is the history, which cannot be relied upon to the day. Dates may well be inaccurate by as much as a week or so in either direction. However, as will be illustrated in the following, this inaccuracy is of no importance whatsoever to a general interpretatioii of the condition.

    CLINICAL SIGNS AND SYMPTOMS

    Some of the signs and symptoms in each case are giren in Table 10 (mild symptoms are marked (+)). Their incidence is shown in Table 12. As these figures offer no indication from a qualitative standpoint, some comments are called for.

    Lassitztde.-This symptom occurs commonly. I t is, however, extremely difficult to assess-not least when associated with pregnancy. Its diagnostic value may be considered small, but it is none the less of interest. In the authors experience of these patients, the fatigue is too extreme to be purely physiologic lassitude. Nor does the disturbance to sleep caused by pruritus offer a satisfactory ex- planation, though i t may be a contributory factor. The symptom may be so severe that, as in Case 51, the patient has not the strength to get up although

  • JAUNDICE IN PREGNANCY 65

    the other symptoms are not particularly marked. It may also persist after delivery, for some months, as in Cases 36, 51, 60, 62 and 69. This is exemplified by Case 51 ; some 5 months after delivery the patient attended hospital for her fatigue. Examination showed both haematologic and hepatologic conditions to be fully normal. The lassitude is of the asthenic type so commonly found after other diseases of the liver-such as viral hepatitis-which may with reason be regarded as due to cerebral lesions ( THORLING 1950, 1950, and others).

    Anorexia, Nausea and Vomiting.-Anorexia has not been found to any great extent and was frequently absent in patients with both the other symptoms. Nausea and vomiting have as a rule been coexistent. I n general these symptoms were only slight or very moderate. I n only one instance, Case 67, could their intensity be compared to that of the pernicious vomiting of pregnancy (for case report see page 77).

    Epigastric Pain.-All grades and varieties of epigastralgia are represented in the 9 cases in which this symptom occurred. The pain is described in some instances as a dull ache, in others as laminating, in most mild. Severe pain appears to have been present only in Case 67. Typical biliary colic did not occur. I n a few cases, however, the pain was referred to the right shoulder or to the back and bile-duct disease was suspected-for a time a t least. Epigastric pain, then, may give rise to diagnostic problems.

    Stools.-Tables 10 and 12 show diarrhoea to have occurred in 13 cases. The term diarrhoea, implying frequent loose stools, appears to be too drastic in the majority of the cases. I n no case were they of a character suggestive of a specific intestinal infection, and culture of the faeces was not thought to be indicated. They appear only in one case to have been spurting or as thin as water. Their colour is described as pale yellow or clay-coloured. This latter description is common even in cases in which diarrhoea did not occur. I n two such cases, bile pigments were demonstrated in the faeces; in view of this, and despite the history, one cannot assume them to be acholic stools suggestive of total obstruc- tion of the bile ducts. I n Case 60 the attacks of diarrhoea were clearly synchro- nized with meals, an example of the gastrocolic reflex. On the information avail- able, it is not possible to say whether or not this phenomenon is widespread.

    Przwitus and the Skin.-In this, as in the two groups of patients described earlier, pruritus was an extremely common symptom. It was wholly absent in only 3 of 38 cases. In many of the patients it was very severe, and in some their immediate reason for seeking medical advice. Scratches were observed in 14 of the 35 patients; and in a further 16 instances, although there were no scratches, the patients sleep was disturbed. Thew figures give some indication of the intensity of the itching, and it seems quite clear that in these cases the condition was what might be called pathologic pruritus. The clinical features of this itching did not differ from those associated with various other types of internal diseases. It increased in intensity towards evening. It was usually

    5 - 551613 Zeif Thorling

  • 66

    I1

    28 29 30 31 32

    F F D F D

    LEIF THORLISG

    Table 10. Clinical Signs and Symptoms in 46 For group classifications

    111 IV

    33 34 35

    F F F

    -_ -- 36 37 38 39 40 41

    F F F F F F

    42 43 44 45

    F F F F

    V I VI Month of pregnancy I Case number

    Group 2

    Ti- I - T ( + : I (+: -

    T (+: I ( + : -

    I - - T I -

    l -

    + ( + I + + + + + ( + ) - + + -

    + - + t

    + - + - Lassitude

    Anorexia

    Nausea

    Vomiting

    Epigastric pains

    Diarrhoea

    Arthralgia, Muscle pains ~~

    Sore throat

    Pruritus + + + + ( + I + [ + ) + - + - +

    Fever - - ( + ) - - - + - - - ( + I - - 1 - + I -

    Dark urine + + - + + + + + ? ? - + + I - + I + + + + + + + + ? ? + + - - - + - - ? ? -

    - - + - - - I - ( + ) - - Palp. liver I -

    Palp. spleen l - Liver tend. - -(+b - 1 - - I +

    I I - I - - I - _ - _ _

    situated on the hands-particularly between the fingers, the soles of the feet, the lower leg and the arms. Very frequently, however, it was generalized and the face was the only portion of the body on which the author failed to find it. This symptom usually appeared early in the course of the disease, as will be discussed -in more detail in the following.

  • JAUNDICE I N PREGNANCY

    L6 47 48 49

    F D F F

    67

    50 51 62 53 64 56 56 57 68 69 60

    F F D F F D F B F F F

    Pregnant Women with Non-Viral Icteric Disorders. 888 Table 6, p. 38. ( -t ) = mildness.

    + + + + + + + + + + + + - - + + + + - + + - + + - + + + + + I

    VII I VIII I IX I x

    + + + + + + + + + + i. + - + + + + + + - + + + +

    61 62 63 64 65 66 67 68 69 70 71 72

    F F F F F B F F F F l- F F ? + + ? I + + + + + ? + + - ? + ? + + ? + - - + + ? - + - ? -

    + - - + + - - - - - - - + - - - + - - I + - - - + - - - - - -

    + + + - - ? + + + ( + I - + + + - - - ? + + + - I - + + + ( + I ( + ) - - + - - - + + - ( + ) - - - - - -

    Apart from the scratches, in some cases combined with lichenization, other skin lesions were observed in only 3 cases. Transient urticaria was noted in Case 68; reddish papules the size of confetti with horny centres occurred in Case 54 ; and in case 37 papulo-vesicular efflorescences were disseminated over the trunk and extremities. In the latter case, the diagnosis of herpes gestationis

  • LEIF THORLING 68

    I, 85 !I Fever . . . . . . 30 Sore throat. . . . 37 1 1 Pruritus . . . . . 34 I Dark urine . . . .

    , Palpable liver . . . 0 ! Liver tenderness .

    Palpable spleen . .

    Table. 12. Incidence of Clinical Signs and Symptoms in 38 Women with 'Jaundice in Late Pegnancy'.

    38 0 36 0 38 84 36 100 37 37 37

    Symptoms and signs

    I

    Lassitude . . . . Anorexia . . . . . Nausea. . . . . . Vomiting. . . . . Arthralgia and/or muscle pains . . .

    Epigastric pains . . Diarrhoea . . . .

    Number of

    cases

    33 37 38 38

    30 38 38

    Initial. per cent

    61 19 21 21

    0 18 16

    Total

    per cent ' 1 course. I' Symptoms and signs Total

    course. per cent

    (3) 8

    90 100 41 19

    O I

    was considered, but the long duration of the condition and the favourable out- come for both mother and child afforded no confirmation. It may be of interest to note that the patient's mother and maternal aunt had both suffered intense itching during their pregnancies.

    In every instance the itching subsided a t the time of, or shortly after, delivery and in some even before the onset of labour.

    One might imagine the combination of pregnancy and liver disease to furnish ideal conditions for the manifestation of spider iiaevi (cf. BEAN 1945 and others). In the 16 patients whom the author examined personally and systemati- cally for such skin lesions, one single spider was found in two instances, Cases 51 and 72. The first of these patients could not say whether i t had been present earlier, and in the second i t appeared between two examinations. I n the remain- ing cases in the series there are occasional notes to the effect that lesions of this type were absent, otherwise they are not mentioned. However, the fact that repeated examinations were made of the skin for the presence of scratches, et cetera, leads one to suppose that spider naevi were absent in these cases too. The author feels justified in assuming this type of skin lesion not to be charac- teristic of the condition. The same appears to apply to palmar erythema, which was not observed in any of the 16 patients examined systematically.

    While collecting the control series, a patient with numerous spider angiomata on the upper half of the trunk was found. She was in the 9th month of pregnancy and had observed these skin lesions one month previously. They had increased successively. As fa r as she could remember, no lesions of this type had attended her first pregnancy. She felt well, had no itching, no albuminuria, and her blood pressure was normal. The serum bilirubin level was 0.3 mg per cent, negative direct reaction; alkaline phosphatases 7 units; cephalin flocculation test 0; and the thymol turbidity test 0.04 ext. coeff., in other words, the values were fully normal. These observations should not necessarily be taken to indicate the presence of liver disease. The same view is expressed by BEAN (1945).

  • JAUNDICE IN PREGNANCY 69

    Physical Abdominal Findings.-The positive palpatory findings in 16 cases may be taken as suggestive of enlargement of the liver. In these cases, the liver edge was usually felt immediately below the costal margin. I n Cases 51 and 52 the liver was felt digitally slightly more than 3 cm below the costal margin on examination the day after delivery. Negative palpatory findings do not, of course, rule out the presence of enlargement of the liver. This applies particu- larly in patients in the final stages of pregnancy. From the standpoint of diag- nosis, one may say only that a palpable liver may or may not be part of the syndrome. As regards liver diseases in general, i t is said that a palpable or percussible decrease in the size of the liver is an unfavourable prognostic sign. No such finding was made in the two cases of greatest clinical severity, Nos. 64 and 67. However, both the patients survived. There was no relation between the palpatory findings and the presence of pain in the abdomen.

    Liver tenderness was not particularly marked. I n some instances there was slight tenderness in the epigastrium or under the right costal margin, occasion- ally brought on by jolts. In Case 51 the tenderness was definitely localized to the region of the gall-bladder, even after delivery. However, continued observa- tion and roentgen examination of the gall-bladder revealed no disease in that organ.

    It will be seen in Table 10 that the spleen was not palpable in any case. This does not, of course, imply that the syndrome may not be attended by sple- nomegaly. Palpation and percussion of the spleen are difficult examinations, particularly so in late pregnancy. I n 6 cases, however, the spleen was also exam- ined roentgenographically. It was found to be of normal size in Cases 49, 52, and 72 on the 12th day after delivery. I n Case 64 the lower pole of the spleen was seen 2 cm below the costal margin, but the upper pole could not be deter- mined 17 days after delivery. I n Case 51, the size of the spleen was 17 X 6 cm 14 days after delivery; the lower pole lying 3 cm below the costal margin, On examination 5 months later, it measured 13 X 6 em. In the last two cases, one might reasonably suppose the spleen to be palapble. But, although the author was aware of the roentgenographic findings, palpation failed to verify them. This suggests that in such cases the spleen is soft. However, although i t appears possible that splenomegaly may attend the syndrome, its presence is not in- variable.

    LABORATORY FINDINGS

    The greatest deviations from normal to these tests in each case are given in Table 13, and the figures are summarized in Table 14. The alkaline phosphatase values will be found in Fig. 10, with the exception of Case 51 in which the increase was so marked that it could not be fitted into the diagram.

  • 70 LEIF THORLING

    Table 13. Greatest Deviation from Normal in Laboratory

    sented. It is of interest to note that the direct reaction in the 19 patients exam- ined was always positive, even in the case showing the smallest increase in serum bilirubin (1.3 mg per cent). Bilirubinuria was a common finding, al- though there were several exceptions. I n these, the histories contained reports of dark urine (two cases unknown). The duration of this symptom is, however, strikingly short and the result of an isolated laboratory test is of help only as an indication of the conditions that particular day. This is illustrated by some of the case reports in the following.

    Flocculation Tests.-The reaction to the thymol turbidity test has invariably been negative on repeated examination (see case reports below). The same applies to the zinc sulphate turbidity test. The cephalin flocculation test gave a reaction of 3 + in only one of the 16 cases examined; this was Case 43, and 4 subsequent examinations gave wholly negative results. In the Takata-Ara test, slight flocculation occurred commonly in one or more tubes. Maximal flocculation in a t least one tube was observed in Cases 39 and 40.

    Citric Acid of the Serum.-The citric acid content of the serum was within normal limits in all but one case (No. 57) , in which a slight increase was noted. The tests were not performed on serum taken during labour; according to LEKKER (1934) the serum a t that time may show an increase in citric acids.

    Alkaline Yhospltatases.-As is seen in Fig. 10, an increase in alkaline phos- phatases is characteristic of the syndrome. The values observed are definitely above the limit normal to the final stages of pregnancy. I n one instance, Case 51, extremely high values were noted in repeated examinations. It appears, also, that the post-delivery decrease is slower in these cases than in normal preg- nancy. This will be discussed in more detail in the following.

  • JAUNDICE IN PREGNANCY 71

    501 511 621

    3.0 2.4 1 1 5 + + 1 2

    0.06 0.03 0.13 0.05 0 0

    - - -

    100 89 100 1 15 140 21

    Testa in 38 Women with Jaundice in Late Pregnancy.

    15 61 2.7 +

    3 4 0.17 0.19

    0 - -

    18 115 91 95 13 21 40

    130 4.0

    + +

    0.05 0.09

    0 -

    31 17 20

    19

    4

    100 27

    1.3 3.0 + +

    0.03 0.03 0.20

    0 0 - - -

    92 87 29 18

    14

    1

    111 41

    5.6 +

    0.13 0.22 0

    - -

    109 36

    18

    3

    30 106 22

    23 36 2.6 + +

    0.05 0.02 0.03 0.29

    0 0 - -

    70 92 17 18 17

    18

    25 116 20

    120

    1 3

    -

    53 19

    19

    16 96 16

    12 23 3.3 +

    3 1 3 0.06

    - 23

    110 58 96 31 25 20

    Units

    41

    40

    38

    36

    34

    31

    30

    18

    1b

    14

    11

    10

    18

    16

    - 0 - 0

    0 - - -

    0 - -

    0 - 0 - 0 0 0 0

    0 - - 0 0

    0 0 0 0 - O W - 0 a o - 0

    0

    00 ao

    0

  • 72 LEIB THORLING

    Table 14. Summarized Results of Laboratory Tests in Cases of Jaundice in Late Pregnancy.

    I Serum Icterus index 13 138 33

    bilirubin mg. per cent 1 19 I 9.2 1 3.7 Thymol IJnits 19 4 2.4

    turbidity Ext. coeff. I 19 I 0.17 I 0.07 1 12 1 0.29 1 0.17 Ext. coeff. Zinc sulphate turb

    I Number of abnormal

    responses

    Cephalin flocculation I I 1 Takata-Ara I 28 I 2

    Prothrombin Index < 70 3

    1

    18

    I 9 1 I I

    Citric acid, serum

    Direct reaction

    Normal limit Blin.

    12 I 8 1.3 1.0

    I s 0.20 1 0.02 ~ ~

    0.05 1 0.30 I

    Protlirombin Index.-A prothroinbin index below 70 was observed in 3 cases. I n Case 55 the index rapidly returned to normal after delivery, during which haemorrhage was estimated at 900 g ; no other complications occurred, and there was no cutaneous bleeding. The two other cases, Nos. 64 and 67, are the severest in the whole series and delivery was attended by copious haemor- rhage. In Case 67 cutaneous bleeding also occurred. This laboratory test appears to be of great help to prognosis both in this condition as in certain other liver diseases.

    Haemotologic Findings (these are not given in detail).-In 22 cases a moder- ate normo- or hypochromic anaemia was observed. The hypotonic fragility of the blood was tested in 9 cases, 5 with and 4 without anaemia. The results were in every instance normal, initial haeniolysis a t 0.54 to 0.44 and complete haemoly- sis a t 0.36 to 0.30 per cent saline. It is possible that this syndrome is sometimes attended by anaemia. Information available, however, does not allow any con- clusions. Case 40, 41 and 43 are more complex as regards the haematologic findings; they are described in more detail in the following chapter. Of the remaining 8 cases, 7 showed no anaemia and one is unknown.

  • JAUNDICE IN PREGNANCY 73

    CLINICAL FEATURES AND COURSE I n assessing the clinical features and course of the condition, such symptoms

    as lassitude and anorexia must be disregarded. Descriptions of these symptoms -however troublesome they may in fact be-are far too inaccurate for them to be placed chronologically in the evolution of the disease. Their exclusion is of minor importance to a general interpretation, as lassitude, for instance, occurs so very frequently even in the pre-icteric stage (see Tables 10 and 12).

    The author has confined his investigation to jaundice, pruritus, and various abdominal symptoms. The series may be assessed in two different ways, (A) characteristic combinations of symptoms, and (B) the relation of the syndrome to the course of pregnancy and labour.

    A. Characteristic Combinations of Symptoms (The reader is referred to Fig. 11)

    In this respect, the series may be classified as follows:

    a. Jaundice +pruritus +abdominal symptoms . . . . 25 cases b. Jaundice+pruritus . . . . . . . . . . . . . . . 10 cases c. Jaundice +abdominal symptoms . . . . . . . . . 3 cases

    This grouping may afford some indication as to the types of symptom com- plexes which may be anticipated, as far as one can judge from this series. How- ever, the classification is only schematic and of little value to prognosis. All grades of jaundice are found in each group, as also an increase in alkaline phosphatases. Symptoms such as lassitude, may be of some severity irrespective of the type of combination of other symptoms.

    The time of onset of the symptoms is not always easy to date exactly. It may be marked by nausea and slight vomiting early in pregnancy, as in Case 61, and regarded at first as ordinary physiologic vomiting. The same may apply to pruritus, as in Cases 36 and 45. Pruritus is wholly predominant in the symptomatology of the pre-icteric stage. The itching occurred in 35 patients, and in 34 of them it preceded manifest jaundice. The length of the pre-icteric phase may vary widely. If i t can be counted in days in cases of viral hepatitis, it should be counted in weeks in this syndrome. The following approximate figures may give some indication as to the length of the period in this series: mean 7 weeks, maximum 26 and minimum 1 week.

    The following case reports illustrate the three groups. Some data are given in diagrammatic form at the end of the reports. The group classifications are explained in Table 5, page 38.

    a. Case 57.-Para I, 25 years. Group B. No history of bile-duct or liver disease. Pregrancy: Fairly troublesonie vomiting in the 2nd to 4th months. Subsequently free from symptoms until the 36th week when albuminuria was observed. The patient was

  • 74 LEIF THORLING

    I

    + Dir rswilon + - - - - - per

  • JAUNDICE I N PREGNANCY 75

    Thymol curb Erc.

    Zn-sulph Esc

    Cephalin f l ~ c r

    jaundice. At the same time lassitude developed. The abdominal symptoms subsided after a few days, before the onset of labour. No pruritus. Delivery in the 39th week. The foetus was dead, in the first degree of maceration, with the umbilical cord strangulating the neck. No evidence of blood group incompatibility (the patient and her husband both belonged to ORh,Rh,). No further damage to the foetus was seen at autopsy.

    011 0 0 7 007 0 10 0.15

    006 0.05 0 11 0 19

    0 0 0 0 0

    I

    O-0

    Uniu

    Alkaline phaph.tases =O-

    10 -

    + + 0 B P. mm Hg. lMAl0

    In addition to the grouping above, the series may also be classified according to the degree of clinical severity. It should be noted that no deaths occurred. Two cases, Nos. 64 and 67, must be regarded as very severe and the patients' state critical. The bilirubinaemia values were highest in these two instances. I n the rest of the series there was no definite relation between, e.g. the serum bilirubin level and the severity of the disease. Thus, the lassitude may be marked or the itching intense in the presence of only mild jaundice. I n other words, it is not possible to correlate the intensity of the disease with the result of any given laboratory test ; consequently, no figures can be given to elucidate this problem. The fact that some patients were hospitalized for long periods, others only for a short time or not at all, also fails to provide any guide. The clinician has still to resort to the jaundice as the basis of prognisis. He has no other choice as regards objective signs. Experience has shown i t to be of no little value as a basis for evaluation, although i t is deficient in many respects. Various types of tolerance tests have also been used to advantage, though they are subject to the same limitations as the serum bilirubin determinations. I n the present series one might wonder if the behaviour of the alkaline phosphatases were of help in this respect. The answer is no. But the determination of the prothrombin index proved valuable ; in the two most severe cases, mentioned above, the index was strikingly low.

    11% l13/s5

  • 76 LEIF THORLING

    20

    Hemoglobin zn: W.b c. m 1000

    Albuminurn

    From the clinical standpoint, one can say only that the course of the 36 cases was mild or moderate, and that no deaths occurred. The two severe cases will, however, be described in more detail since this type of patient is fairly rare.

    - 7s 60 5 1 61 69 66 59 60 79

    18 11 6 1

    + + + + + + o 0

    Cone 64.-Para I, 28 years. Group F. Previously in good health ; no history of bile-duct or liver disease. Pregnancy: The course was normal until the 23rd week, when itching developed and later increased, not subsiding until after delivery. In the 35th week the patient was examined a t an out-patient department of prenatal care. There \\-as no al- buminuria. The blood pressure had been normal on earlier occasions, so no examination was made. The same day, lassitude developed; the next day, nausea and vomiting twice, and she twice passed pale yellow stools. On the third day she noted that her urine mas dark and that scanty haemorrhages occurred. This latter observation prompted her to attend hospital; her condition a t that time was fairly good. The subsequent course was extremely rapid. Labour started within a few hours and was over 24 hours later. Delivery was attended by copious haemorrhages from a flaccid and enlarged uterus. Shock de- veloped and the patient was in a state of near coma for the following 12 hours. During that time she was given 1000 ml blood in addition to glucose intravenously, and her con- dition showed steady improvement. Roentgen examination of the spleen revealed the presence of splenomegaly. The weight of the baby was 1,400 g ; successfully treated in the pedriatic clinic. At the age of 8 nionths, however, the child died suddenly; endomyocardial fibrosis was found a t autopsy-The placenta was filled with infarctions.

    58 128 78 42 IS 12 I

  • JAUNDICE IN PREGNANCY 77

    W.b.r In l#x) Index

    1#) Serum biliNbin 60

    20

    Billrubmuria

    Thymol curb. Unli

    ~0i.1 protein p, ,f Bleeding tendency

    Case 67.-Para I, 25 years. Group F. No history of viral hepatitis. Not known whether or not she suffered from bile-duct disease. Pregnancy: Gestation was normal until the 35th week when constipation was accompanied by pain in the epigastric region radiating towards the back. Loss of appetite and lassitude developed. Some days later she vomited after every meal, and at the beginning of the 37th week jaundice was observed. No itching throughout the period. The day after admission to hospital the patient was de- livered of a dead foetus. Delivery was complicated by copious haemorrhages from a flaccid uterus, and at the same time there was extensive cutaneous bleeding. The patient's mental state was impaired for a long period. Details are given in the diagram.-Autopsy of the foetus: weight 2,550 g, no perceptible histologic changes in the liver. Death was due to intracranial haemorrhage-The placenta showed numerous haemorrhages of recent and earlier date.

    i

    18 40 15 31 9 4 3 5 9 9 6 -

    D\o/o.o \O

    - -

    O-o-O-o - \- + + + + 0 0 0 0 0 0

    1 1 1 1 3 3 3

    4.b 6 1

    I Abdomml sympt I - I - I

    Plairlcl. in loo0

    Hemo;lob.; pzr cent

    Albummuria

    N P.N. m; per cent

    8.P mm Hg

    50 65 loo 100 51 0

    1 0 1 10.5 10910.7 10.8 11.5 9.1 9.3 7.3 8.0 9.4 9.7

    0 0 0 0 0 0 0 0 0 0 0 0

    83 cn

    . , '%ll%%lgY&. !yy. , . . ,

    The course of the disease in these two cases is marked initially by a n ap- parently innocuous phase which is changed by the advent of labour with great rapidity to a critical state accompanied by a strong tendency to haemorrhage. Hypertension appears to have been present prior to labour; in Case 64 this was combined with albuminuria, but not in Case 67. I n both instances there was a transient rise in non-protein nitrogen. Both albuminuria a n d an increase in non-protein nitrogen may occur in any form of severe liver insufficiency, particularly when the insufficiency is precipitated by copious bleeding. Hyper- tension, on the other hand, is not associated with that condition. It should be

  • 78 LEIF THORLIXG

    Index 5 0 .

    Serum bnlwubin ''1

    10

    Bhrubmuru

    noted that in Case 67 the tendency to haemorrhage may have been caused by a deficiency of prothrombin or by thrombocytopenia. The platelets were not examined in Case 64 ; this patient also showed hypoprothrombinaemia. Both patients were given blood transfusions and vitamin K. The return of the prothrombin index to normal was strikingly rapid ; whether or not this was due to the therapeutic measures is discussed later on. Finally, i t may be mentioned that both patients suffered from leukocytosis without fever prior to labour and before the malignant state was established.

    o\

    + -

    + + + + + + + + O + + 0

    B. Relation of the Syndrome to the Course of Pregnancy and Labour

    As is seen in Fig. 11, the onset of labour led in 29 patients to a definite improvement. Various symptoms, such as jaundice, itching, and abdominal dis- orders, usually subsided within a week of delivery-in some instances even more rapidly. This is illustrated in earlier case reports. In the two severe cases, Nos. 64 and 67, the symptoms persisted for a considerably longer period. The same applies in Case 38, but in this instance there was an infected pseudomucinous cystadeiioma of the right ovary which necessitated operative intervention. This may have delayed recovery. In case 49, in which the itching was present for three weeks before the premature delivery, jaundice did not become mani- fest until the onset of labour. Case 63 is also of interest in this connection. After slightly more than 3 weeks' itching, the last being attended by marked lassitude, delirery occurred earlier than expected ; the baby was alive and weighed 3,000 g. The itching gradually decreased but jaundice was not observed until the patient had been discharged from the obstetric department ; she was referred to a hospital for infectious diseases with the tentative diagnosis of viral hepatitis. The abdominal symptoms in this instance were of short duration and mild, being characterized by moderate nausea. For further data, see diagram below.

    Thymol turb Unit 1 3 3 2 ~ 1 6 2 1 1 3 1

    Fig. 1 1 . Clinical Course of 5 Cases of Jaundice in Early Pregnancy (Cases 27-34) and 35 Cases of 'Jaundice in Late Pregnancy'. (Cases 35-73).

    -= Various symptoms except - - - - - = Jaundice and . . . . . = Pruritus. Mildness is marked by wid esspaeing. SA = Spontaneous Abortion. J = Delivery. Below the arrow birth weight of the infant.

  • so LEIF THORLING

    Thymol curb Err

    Zn Idph E.t

    I n four cases the disease had run its full course before the onset of labour. I n two other cases, in which the time of delivery is not known, the course of the disease seems to have been similar. The following case reports exemplify this evolution.

    I .~ 0 0) - 0 09

    01s 016 . ._ ._ ~.

    00s 006 0 01 0 05 0 05

    Case 35.-Para 11, 35 years. Group F. No history of bile-duct or liver disease. Operated upon 5 years earlier for Grave's disease. Thyroid gland had to he substituted. Hay fever during the last 8 years. The first pregnancy 5 years earlier was not attended by complications. Present Pvegnancy: No vomiting or nausea a t the start of pregnancy. I n the 15th week loose stools were passed. In the 18th week lassitude, epigastralgia and, siniultaneously, dark urine and itching. Admitted to hospital in the 20th week when jaundice was observed. Apart from persistent fatigue she was free from symptoms on discharge two weeks later. The further course of gestation was normal, delivery in 43rd week.

    I Week of pregnancy 1 15 17 19 21 11 25 27 1'3 11 I

    Prurll",

    lndcr Serum 10 "\ bilirubin

    10 0

    I I

    The condition in the next patient may be said to be an intermediary form, in that jaundice disappeared before labour but the itching persisted until after delivery.

    Case 46.-Para 11, 28 years. Group F. No history of bile-duct or liver disease. The first pregnancy was complicated by pruritus but no visible jaundice. Presetat Pregnancy: Fairly troublesome vomiting during the first 3 months. Pruritus developed in the 22nd week and jaundice was observed in the 34th week. At that time the patient vomited once but had no other abdominal symptoms. Jaundice subsided 10 days before delivery, but the itching persisted until 10 days after that date.

    - Um1r

    Alkaline lo / O . phorphrrarcr o-o -0 -

    0

    Bhrubmurm t + 0 0 Albummuria 0 0 0 0 0 0

    Time ~n days I5 10 2 1 20 15 10 I 0 5 10 IS 10 25

  • JAUNDICE IN PREGNANCY 81

    Thus, we see that the syndrome shows a strong predilection for the final stage of pregnancy-as has already been pointed out. In the great majority of patients, delivery leads to spontaneous healing. One may also find occasional cases in which the condition runs a similar course but in which the process heals before the onset of labour. Between these two extremes another type may be found in which the patient becomes free from jaundice, but not itching, before delivery. Finally, in one case the onset of jaundice did not occur until after delivery but pruritus was present before that date.

    TIME OF ONSET OF LABOUR AND ITS CAUSE

    In Fig. 11 one sees that a strikingly large number of deliveries occurred ,earlier than anticipated. This was of no major importance in the majority of cases. We all know that the period of gestation may normally vary within fairly wide limits. When the delivery is not obviously premature, no great significance is attached to the fact that it occurs a week or so earlier than expected. However, it may be of interest to see whether the syndrome under discussion has a tendency to precipitate labour.

    A control series of 39 normal pregnant women was investigated at the time of onset of labour on the principles laid down in Chapter 11. The length of gesta- tion in both series is given in weeks as from the last normal menstruation. Results are given in Table 15.

    Table 15. Length of Gestation in 39 Normal Controls as Compared to 36 Patients with Jaundice in Late Pregnancy.

    Week of pregnancy 1301 31 I32 I33 I34 I36 I37 I38 I39 I40 141 142 I43 I44 IS:a

    Controls . . . . . . . . . I - 1 - 1--[-1-[11 11-1 1 1 6 1 8 1161 4 13 139 Jaundiced . . . . . . . . 1 - - - 1 1 1 3 7 ~ 3 6 8 3 1 2 - 3 6

    In the patients with jaundice, the average length of gestation was 38.4 weeks, in the control series 41.5 weeks. The quotient difference/standard error is 3.1 0.46 = 6.7, which gives P < 0.001. The difference is significant. Jaundice in late pregnancy appears, then, to precipitate delivery. This is also indicated by the fact that no less than 30 of 36 deliveries in the jaundice series occurred before the 41st week, whereas the corresponding figure in the control series is 8 of 39 deliveries.

    The cause of the onset of labour has been studied briefly in the present series.

    1 xa analysis of the fourfold table gives xa = 29.7 and P < 0.001. 6 - 557673 Leif Thorling

  • 82 LEIF THORLING

    The syndrome has already been seen to have a tendency to provoke labour. This was particularly marked in the severe cases (Nos. 64 and 67) as was the copious haemorrhage. Haemorrhages of between 500 and 900 g occurred in Cases 36, 37, 55, 58, 59, and 62. I n Case 71 the placenta was detached manually and bleeding amounted to some 600 g. No shock was observed in these cases. Subinvolution occurred in Case 48 and 38. I n the latter case, which was also complicated by a pseudomucinous cystadenoma, shock developed and was re- lieved by a transfusion of blood. I n Case 41 no major haemorrhage was noted, but shock developed the day after delivery. I n Case 57 abrasio had to be per- formed a fortnight after delivery. We see, then, that some abnormalities were observed in 13 of 36 cases but, with the exception of Cases 64 and 67, they had no serious consequences.

    Data as to the appearance of the placenta are available in 28 cases; of these, all but two were normal. The two exceptions were Cases 64 and 67, described earlier, in which the placenta showed numerous infarctions.

    THE INFANTS

    The weight at birth is known in 36 cases. I n Case 54, the patient gave birth to twins, weighing 2,460 and 2,540 g, both alive. The weight of the remaining 35 infants has been compared to that of the 39 in the control series. The figures are given in Fig. 12 and Table 16.

    1s 1b 3

    10 9 -

    7 7 7 - - 3

    1 I

    Fig. 12. Infants Birth Weight in 39 Normal Pregnancies and 34 Cases of 'Jaundice in Late Pregnancy'.

    0 = Kormal. I- Jaundice.

    These figures show that the average weight at birth of infants to jaundiced mothers is less than that in the control group. This discrepancy in the two series cannot be due to sampling variation (0.01 < P < 0.02).

    Premature delivery, i.e. birth weight less than 2,500 g, occurred in three

  • JAUNDICE IN PREGFANCY 83

    Mother jaundiced . . . . Mother healthy. . . . .

    Total I Birth weight 5300045 I z30OOg 8

    instances, Cases 48, 49 and 64 ; all the infants lived. Two stillbirths took place, Cases 67 and 72 ; the cause of death was intracranial haemorrhage and strangnla- tion by the umbilical cord respectively. All the deliveries passed in hospital and there is no record of any abnormalities in the remaining 31 cases.

    A follow-up examination gave the following results. Of the three premature infants, one died a t the age of 8 months (Case 64). The mother was one of the two severe cases. The infant, a girl, developed normally until one evening she was listless, the following day she had fever, intractable shock developed and two hours later she was dead. No inflammatory changes were found at autopsy. The heart was enlarged and of firm consistency. The walls were definitely thicker than normal. The valves normal. Histologic examination revealed fibrosis of the myocardium and the endocardia1 connective tissues. Moderate oedema was present in the lungs. The liver was enlarged and dark red; one part was lighter in colour with fairly extensive fatty infiltration. Diagnosis: Endomyo- cardial fibrosis.

    The other two premature infants have developed normally; one is now 1 and the other 4 years old.

    Of the 31 full-termed infants, i.e. weight at birth more than 2,500 g, two have died. In Case 62 the infant died at the age of 3 weeks. Autopsy showed subtotal atelectasis of the right lung secondary to aspiration, and a cyst the size of a walnut in the left lung. I n Case 40, the child died of miliary tuberculosis a t 16 months.

    On being questioned, the mothers reported the remaining 29 children to have shown no abnormalities, and their development was normal during the period of observation given below.

    Period of Observation Case No.

    6 months 38, 46, 60, 63, 70. 6 months to 1 year 41, 61, 62, 64, 68. 68.

    1 to 1* yeera 37, 44, 46, 60. 69. 71.

    2 t o 3 39, 61. 66. 3 t o 4 42. 43. 67, 69. 4 t o 6 36, 63.

    1+ to 2 36, 66.

  • 84 LEIF THORLINQ

    This raises the problem of the extent to which jaundice in late pregnancy may have contributed to the 5 deaths among the children. It is clear that in Case 40, in which the foetus was full-termed and the cause of death miliary tuberculosis, there is no reason to assume any causal connection. I n Case 62, the infant had a cyst of the lung; this may have been due to the disease in the mother, but it cannot be proved. The strangulation by the umbilical cord in the still-born foetus in Case 72 is a complication which cannot be related to the state of the mothers health.

    Case 64 is of particular interest. Endocardia1 fibrosis is a fairly rare disease and its cause is not yet fully clarified (cf. HALLIDAY (1954)). EDMONDS et al. (1951) claim that i t may be due to a n antenatal lesion. One can base no con- clusions on a single case, of course, but its occurrence might act as a stimulus to further investigation of this problem.

    There remains only one death among 36 children which can definitely be attributed to the syndrome of jaundice in late pregnancy, Case 67.

    PROGNOSIS

    As has been mentioned earlier, there were no deaths in this series. However, according to the literature, a fatal outcome may be anticipated. It is also indicated by the sudden change from an innocuous to a critical state in the two severe cases in this series, Cases 64 and 67.

    A follow-up examination was made in 34 cases, Table 17. The period of observation varies; i t is given in each case in months as from the time of delivery. Indications of disease of the bile-ducts and liver are taken from the patients histories. The gall-bladder was examined roentgenographically. The results of some laboratory tests are also given, if normal they are marked n.

    As can be seen from the table, prognosis was favourable in every instance, as judged by the histories. The fat intolerance reported in 6 cases has apparently not troubled the patients unduly. Furthermore, i t cannot definitely be regarded as a sequela to the jaundice in pregnancy in every case. I n Case 45 it I Q ~ present prior to pregnancy. Case 44, however, shows that it may be a result of the jaundice and also that it may be of transient character. Further, it appears that there is no relation between the fat intolerance and the roentgenographic findings. I n Case 46, the roentgen examination was unsuccessful in that the gall-bladder was incompletely contrast-filled. The examination was carried out 2 weeks before delivery. I n Cases 59 and 70, gall-stones were demonstrated. They seem, however, to have had no effect on the jaundice complicating pregnancy. The laboratory tests have all shown conditions to return to normal. As has been mentioned earlier, lassitude may persist for an appreciable period after delivery.

  • JAUNDICE IN PREGNANCY 85

    Table 17. Findings at Follow-Up Examinations in 34 Cases of 'Jaundice in Late Pregnancy'.

    n = normal. In Case 46 the result of roentgen examination was uncertain.

    CaSe number

    35

    36

    37 38

    39

    40

    41

    42 43

    44

    45 46

    48

    49 50 51

    52

    53

    54 55

    56

    57 58 59 60 61 62

    63

    64 66

    68

    70 71 72

    Time of heenration in months

    60

    {2 13 6

    ( 6 2"' 35

    (t 14 { 1: 37 38

    1

    {4: 1 15

    {i { 6:

    9 20

    { 6; 48 12 43 2 36

    { i 2 32

    {1: 5 17 11

    idicationb 01 iver or bile h o t disease

    no

    no

    no no

    Fat intd.

    no no no no no no

    Fat intol.

    no Fat into].

    no

    Fat intol.

    no no

    Fat intol. no no no no no no no no no no Yes no no

    Fat intol. no no no no no no Yes no no

    ,, ,,

    3. 99

    serum bilirubin

    n. n. n.

    n.

    n.

    n. n. n.

    n. n. n.

    n.

    n. n. n. n.

    n. n.

    n. n. n.

    n. n.

    n.

    n.

    n.

    n.

    Thymol turb. test

    n. n. n.

    n.

    n.

    n. n. n.

    n. n. n.

    n.

    n. n. n. n.

    n. n.

    n. n. n.

    n. n.

    n.

    n.

    n.

    n.

    A&. phos- phatsses

    n.

    n.

    n.

    n. n.

    n. 15 n.

    n.

    n. n.

    n.

    n.

    n.

    fallstones on X-ray

    no

    no

    no

    operated

    operated no no

    no (no)

    operated no no

    no

    Yes

    no

    Yes

    no

  • 8G LEIF THORLING

    PRECEDING AND SUBSEQUENT PREGNANCIES Certain types of jaundice are known to recur in succeeding pregnancies. The

    same applies to pruritus of pregnancy. Of these 38 patients, 26 are multiparous and in 25 of them data as to the occurrence of jaundice and/or pruritus is available. They will be found in Fig. 13.

    The figure needs no explanation. But it should, perhaps, be pointed out that in three cases both the jaundice and the itching attended two successive preg- nancies. I n one of them, Case 39, it will be seen that two preceding pregnancies were not complicated by these states. It is commonly found that a preceding or subsequent pregnancy was attended only by itching. Case 58 is of particular interest in this connection ; the first pregnancy was complicated by jaundice alone, and the second only by pruritus.

    In this series, the tendency to recurrence is shown not to be invariable. Mul- tiparas may suffer only once from these complications. However, jaundice is a complication which may entail certain consequences to both mother and child. It may be of interest to see how great the danger of recurrence in later preg- nancy may be.

    The series comprises 20 women with jaundice and pruritus, and 2 with only jaundice who had had either one or both these symptoms earlier, later under- going one or more pregnancies. These 22 women have since had 27 pregnancies, 19 of which were complicated by itching. On this basis, the danger of pruritus in a subsequent pregnancy can be estimated at about 70 per cent. The 95 per cent confidence interval of this percentage is 50 to 86 per cent. This means that if a large number of pregnant women with jaundice and/or pruritus were examined as regards the following pregnancy, the percentage of women with pruritus in that pregnancy might be expected to be at least 50 per cent.

    CONCLUSIONS

    1. Jaundice in late pregnancy is a syndrome characterized by lassitude, ab- dominal disturbances which are generally mild if present, no fever, and a high incidence of pruritus.

    2. Pruritus usually precedes the jaundice by some weeks. 3. Delivery generally leads to spontaneous recovery. The syndrome may also

    disappear before delivery. In exceptional cases, it appears that jaundice may not become manifest until after delivery.

    4. The clinical course is generally mild or moderate. A sudden change to a critical state may, however, be anticipated. These patients should be given treatment and kept under careful observation, even if jaundice is not particu- larly marked. The long-term prognosis is favourable.

  • Cese number

    28

    29

    30

    31

    33

    35

    36

    37

    39

    41

    42

    43

    44

    45

    46

    48

    60

    51

    53

    54

    56

    68

    61

    62

    65

    66

    69

    70

    71

    12

    -

    JAUNDICE IN P R W N A N C Y

    Actual observation A

    Jaundice

    Pruritus

    No complications

    87

    Fig. 13. Complications of Pregnancies in Multiparoua Women. Five c w n of Hyperemesis Gravidarum above the line. and 26 of Jaundice in Late Pregnancy b l o w it.

  • 88 LEIF THORLING

    5. The laboratory findings are characterized by bilirubinaemia with a positive direct reaction ; bilirubinuria, frequently very transient ; an increase in alka- line phosphatases to values higher than those of normal pregnancy; normal reaction to the thymol turbidity and cephalin flocculation tests. A decrease in the prothrombin index and the presence of leukocystosis are ominous signs. The Takata-Bra test and determination of the citric acid content of the serum are of little value to diagnosis.

    6. The syndrome shows a strong tendency to recur in succeeding pregnancies. In occasional cases both jaundice and pruritus recur, and in a t least 50 per cent of cases pruritus alone.

    7. The onset of labour commonly occurs earlier than expected. This does not usually imply that the weight a t birth of the infants is comparable to premature delivery, though the possibility should be borne in mind.

    8. Prognosis for the full-term infant appears to be favourable. (One case of endo-myocardial fibrosis.) The foetuses of premature delivery may be stillborn or, if alive, subject to the complications usual in that condition.

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