NON-VIRAL ICTERIC DISORDERS IN PREGNANCY
29 3 8 42 4 6 5 7 67 - 3 0 3 9 4 3 4 7 5 ~ 1 6 8 - 3 1 33
3 2 34135 41 45 49 60 7017-
40 44 48 5 9 69 7
Jaundice in Early Pregnancy
The time of onset in relation to the stage of pregnancy in cases other than those of viral origin will be found in Fig. 9. The signs and symptoms in each case are given in Table 10, p. 66. An attempt has been made to grade the in- tensity of certain symptoms, mildness being marked (+), et cetera. As can be seen in Fig. 9, the cases fall into 2 groups: a small group of 8 cases in which the onset occurred in the first trimester, and a larger one in which i t took place in the last two trimesters. One might be tempted to classify these as jaundice in early pregnancy and that in late pregnancy. However, Table 10 shows fairly clearly that the symptomatology of the first group, as opposed to the second, is characterized mainly by nausea and vomiting. Two exceptions to this rule, Cases 27 and 34, will be discussed separately.
A. THE HYPEREMESIS OF PREGNANCY
The symptom complex in Cases 28 to 33 shows the nausea and vomiting to be of the predominant character usually associated with hyperemesis gravidarum. The date of onset endorses this diagnosis. The presence of jaundice and dark
56 LEIF THORLISG
Alk. phosphitasel. Unit
N P N. m i per tent
ur ine , although not uncommon i n th i s f o r m of gestosis, are the only f e a t u r e s at var iance wi th the s igns and s y m p t o m s usua l ly associated wi th th i s condition. Their presence may be taken to suggest several differential diagnost ic possibili- ties. T h i s appl ies to the cases i n the present series, repor ted below.
11 9 14 9 11
0 0 0 0 0 0
33 51 63133 25 12 10 25
( T h e g r o u p classifications are explained in Table 5, page 38. V a r i o u s data are compiled i n d iagrammat ic form at t h e end
of each case repor t . )
Case ,?&?.--Para 11, 33 years. Group F. KO history of bile-duct or liver disease. The patient reports emesis of sonic severity during her first pregnancy. Hospitalization was not considered necessary. No itching. Preseiat Pregizniiql: During the 5th week of gesta- tion, increasing nausea, voniiting, and lcss of appetite developed. Froin the 8th week to the end of gestation she had to attend hospital repeatedly. H e r fatigue incrthased and during the 13th to 20th weeks her niental depression was such as to lead to thoughts of suicide. She lost weight. Almost siniultaneously with the appearance of jaundice in the 12th week, itching started and persisted until shortly after delivery in the 35th week. Her liver was somewhat enlarged during the second manifestation of jaundice in the 17th week. No fever was present, and the pulse rate was generally high. Bilirubinuria was observed on inore than one occasion, as also a positive reaction to Hay's test. Uro- bilinuria was present throughout. Apart from transient asphyxia after delivery, the baby was normal, weight 3,130 g, and has sincc developed normally. The mother recovered but the sccretion of milk ceased after 6 weeks.
Index Serum bilirubin
Thimol turb Unn 2 2 2 2
('11s dg.-Para TIT, 31 years. Group F. No history of bile-duct or liver disc je. Her first pregnancy was coniplicated by voniiting in the early stages, and pruritus during the greater part of gestation. Vomiting occurred during her second pregnancy. Hospitali- zation was never necessary. Pt-esmt PrPgna?te?j: Increasing nausea, voniiting, loss of appetite and fatigue during the 5th week. These syniptonis subsided after one week's treatment in hospital, during which jaundice was not observed. Jtching derelopcd in the 9th week, and in the 10th jaundice was noted (grade +). Voniiting again increased. In
JAUNDICE Ilr; PREGNANCY 57
N.P.N. mg per wnc' 35
'% B.P. mm Hg. i
the 15th week, after one week's hospitalization during which bilirubinuria was observed, the syniptoms gradually disappeared. The roiniting and itching ceased. Delivery in the 35th week was free froiii complications. The infant weighed 2,620 g, and was reported to be in good health by the niother 3 years later.
1 Week olpngnancy s 7 9 1 1 1) i s 1 7 19 11 11 Is 17 19 31 33 3s I 7 IP 43
I Albumhurl. I Tr. + O 0 I I
Index 10 Serum blllrubln 10
Thyme1 curb. Unit
\ - - /\o 3 4 4
B.P. mm Hg.
0 0 0 0 0
This patient becanie pregnant again 3 years later. On this occasion she again had severe vomiting in the early stages, but no jaundice. Later in the course of pregnancy itching developed, but subsided after delivery.
Case 31.-Para 111, 32 years. Group F. No history of bile-duct or liver disease. Under treatment for rheumatoid arthritis for the last 6 months. Both earlier pregnancies were complicated by what the patient reported as violent vomiting during the early stages, and itching throughout the greater part of gestation. Present Pregnancy: Increasing
fatigue, loss of appetite and nausea from the 6th week. At ahout the same time, itching dweloped. Voiiiiting started in the 8th week, the urine gradually became dark and jaundice was inanifest in the 9th week. Transient pain in the epigastriuni and sonie tender- ness helow the right costal niargin, a t which point the liver could be felt. KO fever and no Ieukocytosis. Urohilinuria and hiliruhinuria werp ohserved and the reaction to Hay's test was positive. Gestation was interrupted in the 10th week by a spontaneous abortion, after which the jaundice and itching gradually subsided-as did the other syruptoins. Roentgen exantination of the gall-hladder showed conditions to lie normal. The patient has since been free froni symptonis.
r'(ise 32.-Para I, 34 years. Gronp 1). Xo history of hile-duct or liver disease. Prey- nctnq: Increasing fatigue, nausea and voiiiiting froni the 8th week. Itching present during this period. Dark urine and manifest jaundice in the l l t h week. Admitted to hospital two days later for a period of 13 days. Urohilinuria was observed and the reaction to Hay's test was positive. No hiliruhinuria noted. Hypotonic fragility of thr blood 0.44 to 0.22 per cent saline. No fever. The symptoms subsided fairly rapidly and the further course of gestation was free froiii coiitplications. Delivery in the 41st week, infant weighed 3,070 g, and was reported to he in good health hy the inother 8 tiionths later.
( ' u s e ,?.?.-Para 11, 22 years. Group F. So history of hile-duct or liver disease. Sinct, the age of 8 the patient has had n noii-tuherculous disease of the hip-joint of unknown aetiologp. H e r first pregnancy was complicated hy mild vomiting of the type known as tiiorning sickness, and by itching during the last month. Pre,wat I'regnnncy: Increasing fatigue, nausea and vomiting from the l l t h week. This was followed by a short period of itching and the almost sittiultaneous nppearance of dark urine and inanifest jaundice. Was hospitalized for 11 days during which the syniptonis subsided appreciahly. Uro- hilinuria was observed, but no hilirubinuria. Positive reaction to Hay's test. No fever. The further course of gestation was free from complications and delivery occurred in the 41st week. The infant's weight a t birth was 3,700 g: the mother reported it to he in good health 4 years later.
One year later, the patient becnnte pregnant again. She was troubled hy vomiting, though not so severely as during her preceding pregnanry. Periodically she noted manifest jaundice and dark urine. Throughout gestntion she was never free from nausea and vomiting, and during the last two months itching developed. She hecame asymptomatic itntiiediately after delivery.
B P mm nI
0 0 0 ' 0 0 0 0 0 0 0
'I% '% "xi
JATSDICE 1X P R E G S A S C T 59
As mentioned earlier, histologic changes in the liver of varying severity are comnionly found in pregnancy complicated by pernicious vomiting. The most important clinical sign of such changes is manifest jaundice-although not invariably present. According to the literature, a slight rise in bilirubin con- centration is commonly found in this condition ( HEYKEMANN 1928, HEROLD 1939, and others). The combination of pernicious vomiting and jaundice is, however, considered an alarming state which may in certain circumstances justify proyocative abortion.
Among these six cases there were no maternal deaths. One spontaneous abor- tion occurred, and in two instances delivery was definitely earlier than ex- pected. All fire children are reported to have developed normally, and the mothers have recovered.
Clinical Findings.-With the exception of the high incidence of pruritus (5 of 6 cases), there were no exceptional clinical signs. Scratches were observed in one case, and in two other instances the patients sleep was disturbed. The author has questioned 200 women in whom the course of pregnancy was ap- parently normal. i.e. complicated only by slight, physiologic vomiting in the early stages, or by none a t all. I n no instance did itching develop at this stage of pregnancy. This suggests that the itching in the 5 cases of jaundice was related to the pathologic state associated with the hyperemesis of pregnancy. As is discussed in more detail later on in this study, there is reason to assume a causal connection between the deranged liver function and the itching. As a working hypothesis, a t least, one may be justified in regarding this symptom as deriving from the liver.
The combination of vomiting, manifest jaundice, and itching was observed in 5 of the cases. I n three of them, Cases 29, 31 and 32, the itching started a t an early stage before jaundice was observed. In another instance, Case 28, pruritus persisted throughout pregnancy, despite the fact that jaundice was absent during a considerable period. It should, however, be noted that the patient was never wholly free of nausea and vomiting although these symptoms were appreciably less severe during the jaundice-free interval. Around the 30th week the vomiting again became more violent and moderate jaundice reappeared, but both these symptoms subsided before parturition. The itching, however, persisted until after the spontaneous premature delivery. In Case 30 there was no pruritus during the icteric stage, but it appeared in the final phase of gesta- tion when the patient was not jaundiced. It is difficult to say whether or not there was in this case a relation between the late itching and the early manifesta- tion of jaundice. I n view of the evolution in the preceding case, i t is not entirely ruled out.
I n this respect, the conditions attending preceding and subsequent pregnancies
60 I.EIF THORLING
+ + + + + + + + + + __ + - - + + - - - + - + + - + + + + + +
Table 11. Recurrence of Certain Complications in 5 Subjects Suffering from Hyperemesis Gravidarum in the Present Pregnancy.
- + + - + + + + +
I Case number Pregnancy number
Vomiting . . . . . . . . . Jaundice . . . . . . . . . Pruritus . . . . . . . . .
28 I 29 1 30 I 31 1 33 I
in multiparous patients are of interest. Table 11 shows the incidence of vomiting, jaundice and pruritus in each pregnancy. The intensity of the vomiting can only be judged on the patient's report. When it appeared to her to be severe, this is indicated by +. However, in no instance was hospitalization considered necessary. The boundary between emesis and hyperemesis in pregnancy is dif- ficult to establish, and one wonders how many of the patients \vould have been sent to hospital during the pregnancy in question had not jaundice become manifest. We see in the table, however, that none of these patients' various pregnancies was entirely free from complication by one or more of the three above conditions.
Laboratory Data.-An increase in alkaline phosphatases was observed in three cases, Nos. 28, 29, and 33. In two others, Cases 31 and 32, they were within normal limits. The values in the control series are given iii Fig. 2, page 28; this shows the values in Cases 28, 29 and 33 to be higher than those in the normal cases a t the corresponding stage of pregnancy. It appears reasonable to consider this increase as deriving from the gestosis and in all probability secondary to the entailing disturbance in the function of the liver. In no case were therc signs of bile-duct disease. In the only instance of abdominal pain (Case 31) which might have been taken as suggestive of such a condition, the roentgeno- gram of the gall-bladder showed norinal appearances and the alkaline phospha- tases were not increased. One wonders why in this case, as well as in Case 32. there was no increase in alkaline phosphatases. The most probable explanation is that in this, as in diseases of the liver in general, certain signs are absent a t a given stage in the evolution of the condition or never appear a t all for reasons as yet only partly known. I n view of the special conditions attending pregnancy. some significance may attach to the fact that the onset occurred earlier in the course of pregnancy in the two cases with normal alkaline phosphatases than in those with increased values.
A marked increase in the citric acid content of the serum was noted in Case 31; in Case 33 i t was normal. According to SJosTRoar (l%i) and others, a high concentration is suggestive of daniage to the liver of the type associated with viral hepatitis. However, the clinical findings and the absence of a positive
JAUNDICE Ih PREGXAHCY 61
reaction to the thymol turbidity test conflict with this diagnosis. The fact that the patient underwent a spontaneous abortion may possibly have affected the citric acid (cf. LENNER 1934). In only one instance, Case 30, was the cephalin flocculation test performed, giving the result 3 f . The Takata-Ara test was carried out in five cases, in which only slight flocculation was observed; the reaction was never definitely positive. These findings may be attributed to the changes in serum proteins commonly associated with the pernicious vomiting of pregnancy. Although the total protein content of the serum is not always decreased quantitatively, qualitative changes may be demonstrable, i.e. electro- phoretically (cf. VEIT 1952). The results of these two tests appear to be of little help in differentiating this condition from viral hepatitis.
The fact that the thymol reaction was in no instance positive is of some interest. It is worthy of special notice in Case 28, in which the clinical signs were severe and the period of observation long. This is not in accordance with the findings of FRIEDBERQER et al. (1951) and GRAEF (1952), who claim that they observed positive tests in severe cases of hyperemesis gravidarum. Their cases are not reported in detail. It may be that the present authors cases were not sufficiently severe, or that some of their patients had viral hepatitis.
Being an internist, the present author has very little practical experience in the field of obstetrics. The usual obstetric textbooks and the literature studied by the author make no mention of pruritus as being associated commonly with the hyperemesis of pregnancy-not even when that condition is complicated by jaundice. This may be due to the fact that the patients were not questioned as to this symptom, or that no causal connection was believed to exist. Another possible explanation may be that individual factors in the authors cases gave rise to the unusual symptom complex. It should be noted that the histories of these patients contained no suggestion of earlier bile-duct or liver disease which might have led to a change in reaction to the new hepatic strain, i.e. by defective healing of earlier hepatic damage et cetera. The only exception to this rule is Case 31, in which the patient had rheumatoid arthritis. LOWREN (1953) and others have described both disorders of the liver function and histologic lesions in the liver in the presence of that condition. They state that a positive thymol reaction is one of several signs of such changes; the reaction to this test in Case 31 was not positive. Even if one cannot in this case entirely rule out rheumatoid arthritis as a causative factor (the only instance of spontaneous abortion), the remaining cases have still to be accounted for. Many theories have been put forward as to the genesis of gestosis; these include one of allergic origin. I n view of this and the presence of pruritus, the patients were questioned as to other allergic manifestations (cf. Chapter XI). None were reported.
o:! I.EIF THORIJKG
There is yet another possible explanation, that the cases in this series repre- sent a variant form of gestosis. The author finds no grounds for such an as- sumption. It is, for instance, usual though by no nieans obligatory that severe vomiting attends subsequent pregnancies in the same patient. The saiiie applies to pruritus gravidarum and to certain forms of jaundice. In the cases on which this study is based, these three complications are combined in different ways in different pregnancies, but they all appear to derive from one muse-gestosis and the entailing damage to the liver.
Data recorded in the literature give one the inipression that liver lesions, or a t least their clinical manifestations, are symptoms of fairly late onset. Their genesis limy be twofold: (1) primarily caused by gestosis, and (2) secondarily caused by a iintritional deficiency resulting from persistelit vomiting. The latter supposition is based on aninial experiments already inentioiied in Chapter IV. In this connection it should be noted that in Cases 29, 3 1 , and 32. the itching was present before jaundice was manifest, and in two of them (Sos. 31 and 32) at a stage when the vomiting was of physiologic character-if such R thing exists. In Case 30 the development was extremely rapid, and jaundice appeared on the third day. These clinical observations indicate gestosis as the iiiaiii eaiise of the liver disturbances. It is nnreasonable to assume that nutritional insuf- ficiency should produce symptoms in so short a time. Hut shoiild it be so, this voiidition would siipersede the gestosis as regards the liwr, ant1 thcrapy \vould have to be directed against both.
B. MISCELLANEOUS CASES (use P7.--Parn 111, 27 years. Group B. This patient is also reported as Case 2; she
had typical infectious hepatitis 2 years earlier during her first pregnancy which ended in niisearriage, probably not related to the coinplicating hepatitis. She becaiiie pregnant :gain B year later and had fairly troublesoine vomiting though no jaundice in the early stage. The pregnancy ended in iniscarriage in the 7th month. Present Prepancy: In xhout the 2nd week, nausea, voniiting, colicky pain and diarrhoea developed. The voiiiiting WHS not so severe a s that teriiied hypereniesis gravidaruin. At the saiiw tinir, slight jaundice appeared and the urine be vain^ dark. She stayed in bed hut showed no notc- worthy iniproveinent ; af ter a week she was admitted to hospital. Seruni bilirubin i d e s 12, alkaline phosphatases 5 units, thyiiiol turbidity test showed a niaxiniuiii of 5 units. No fever. No itching. She was discharged free from jaundice 10 days later. The further course of pregnancy was threatened by ~niscarriagc. but in thr 10th month n well-devel- oped infant weighing 3,130 g was delirered.
A follow-up exainination was carried out 2 years later. Both thp abdominal and h-~lecystographic findings wrrr normal. Seruni bilirubin 0.6 nig per cent, nlkaline phosphatases 2.6 units, cephalin flocculation test 1+, thyniol turbidity test 0.10 (rxtinc- tion coefficient). The Takata-Am test was negative.
Coninacnts.-Two years earlier, the patient had had i t 1 1 attack of iiifectioiis hepatitis ; no exposure to inoculatioiial infection was known to iinderlie thta
JAUNDICE I S PREGSASCP U3
last period of jaundice. The negative reaction to the t h p o l test and the normal findings of the follow-up examination are not suggestive of chronic hepatitis. I n all likelihood, a liver complication was secondary to the vomiting, though the latter was not of the degree usually termed hyperemesis gravidarum.
Case 34.-Para IV, 38 years. Group F. No history of bile-duct or liver disease. Exposure to inoculational infection known. The course of the earlier pregnancies is unknown, apart froiii one attack of pyelitis. Present PrPgnancy: In the 8th week she was given sick-leave for swelling and pain in the joints of the fingers. In 10th week fatigue and loss of appetite developed. In the 11th week there was fever for 3 days, 38 C. At about the saiiie t h e she experienced pain in the epigastriuni but no voniiting occurred. The urine was dark. She was adinitted to hospital in the 12th week. Good general condi- tion. No fever. No leukocytosis. Seruiii bilirubin index 32, alkaline phosphatases 7 units, thymol turbidity test 2 units. Nornial cho1ecgstograiii.-Spontaneous abortion occurred in the 14th week
Comments.-The history, in conjunction with the negative reaction to the thymol turbidity test on repeated examination, is not suggestive of viral hepati- tis. Some other infection appears to have been the factor provoking the liver symptoms (see Chapter VII ) . The patient was not available for a follow-up examination and the data in the history are insuffici~ntly detailed to permit of any definite conclusion.
Conclusions Based on some Unusual Features in this Series
1. Jaundice may be an early sign of liver disorder in the presence of hyper- emesis gravidarum.
2. A combination of pruritus and physiologic vomiting in early pregnancy indicates liver disturbances and may give warning of impending hyperemesis.
3. Pruritus, persisting once the vomiting and, possibly, the jaundice have subsided, is an indication of a state of instability in the liver.
4. Elevated alkaline phosphatases may be found, a t least in cases of jaundice. I n the absence of other definite clinical signs and symptoms they do not indicate any bile-duct disease demanding surgical treatment. This sign may be absent.
5. Reactions to the thymol turbidity test were negative in this series; the test appears to be helpful in differentiating this condition from viral hepatitis. The cephalin flocculation test and the Takata-Ara test, as also the determination of the citric acid content of the serum, are of little value in that respect.
6. Data concerning the presence or absence of vomiting, jaundice and pruritus in earlier pregnancies are of importance to differential diagnosis. If present, they suggest the jaundice to be due to gestosis rather than viral hepatitis.