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Maternal mortality due to the hepatorenal syndrome of pre-eclampsia
EUROP. J. OBSTET. GYNEC. REPROD. BIOL., 1979,9/S, 0 Elsevier/North-Holland Biomedical Press
299-306
Maternal mortality due to the hepatorenal syndrome of pre-eclampsia A case report
P.W.J. van Dongen I, T.K.A.B.
Eskes *, J.S.F. Gimbrbe
2 and P. Snel 3
’ Departments of Obstetricsand Gynecology, 2 Intensive Care and 3 Gastroenterology, St. Radboud Ziekenhuis, Nijmegen, The Netherlands Accepted for publication 16 March 1979 VAN DONGEN, P.W.J., ESKES, T.K.A.B., CIMBRERE, J.S.F., and SNEL, P. (1979): Maternal mortality due to the hepatorenal syndrome of pre-eclampsia. A case report. Europ. J. Obstet. Gynec. reprod, Biol., 915, 299-306. A maternal death in the 23rd wk of pregnancy is described. The patient was gravida 8, with 6 previous abortions and one growth-retarded term infant. The clinical symptoms and biochemical findings strongly suggest that the mode of death was septic shock, with the hepatorenal syndrome due to pre-eclampsia as the underlying cause. hepatorenal syndrome; pregnancy; pre-eclampsia; maternal mortality
of epigastric pain and frontal headache of 2 days’ duration. She had been under prenatal care in the hospital outpatient clinic because of a poor reproductive history: her first 6 pregnancies had ended in abortion between the 6th and 10th weeks of amenorrhea. Two of these abortions had been classified as missed abortions. Her 7th pregnancy had resulted in delivery of a growth-retarded (2600 g) infant at 40 wk amenorrhea. During this pregnancy, she had been treated with insulin and a high carbohydrate, low sodium diet (Stoot, 1978). No disturbances of liver or kidney function had been observed during this pregnancy. The same management had been instituted early in the present (8th) pregnancy. Her total weight gain had been 8 kg; however, 3 kg of the total had occurred in the 3rd week prior to admission. Hypertension or proteinuria had not been present on any of the clinic visits, and liver and renal function tests had been within normal limits.
Introduction
The term ‘maternal mortality’ denotes deaths due to delivery and complications of pregnancy, childbirth and the puerperium (WHO, 1965; Bout, 1971). The analysis of a maternal death should result in the identification of the mode of death (the immediate cause of death) and the underlying cause (the disease or condition which initiated the train of morbid events leading to death) (WHO, 1965). An important objective of such an analysis is the determination of whether the death resulted from obstetric factors, medical or surgical problems related to the pregnancy, or incidental disease or trauma.
Case report
A 31-yr-old woman was admitted to the hospital in the 23rd wk of her 8th pregnancy, with complaints 299
300
P. W.J. van Dongen et al.: Maternal mortality and hepatorenaI syndrome
On admission, 1 wk after the last clinic visit, she appeared markedly dehydrated and was vomiting continuously and heavily. She exhibited obvious distress due to epigastric pain, which, she related, penetrated to the back and was only bearable in the left lateral position with her knees flexed. On examination, the uterine size was compatible with the duration of amenorrhea (23 wk) and there was no uterine tenderness. The right hypochondrium and costovertebral angle were quite tender. The rest of the abdominal examination was unremarkable. The patient was afebrile. Her blood pressure was 170/105 mm Hg, whereas the highest blood pressure recorded in the prenatal clinic had been 120/70 mm Hg. The laboratory data on admission are summarized in Table I. The urine output was 1500 ml/24 h. Serum transaminase values were elevated, and bilirubin and alkaline phosphatase were slightly above the normal upper limits. Serum urea, uric acid and creatinine were normal. Coagulation studies showed marked thrombocytopenia. The urine was dark and teacolored; however, the reaction for bilirubin was negative, and that for urobilin, only weakly positive. Proteinuria and acetonuria were present. Shortly after admission, a surgical consultant sug-
TABLE I
Clinical and laboratory third hospital days
Hb (mmol/l) Leucocytes (X103/tl) Thrombocytes (X103/J) F.D.P. &g/ml) Fibrinogen (g/l) P.T. (%) Urea (mmol/l) Creatinine (Mmol/l) Uric acid &mol/l) SGPT (U/l) SGOT (U/l) LDH (U/l) Bilirubin total (clmol/l) Bilirubin direct (%) Alk. phosphatase
MARCH
1
1977 2
3
4
5
6
mm Hg FHTneg
Fig. 1. Blood pressure during clinical observation.
gested the diagnosis of cholecystitis. An additional urologic cause for the costovertebral angle pain seemed unlikely. The tendon reflexes were not increased, and an EEG showed varying and ‘drowsing’ patterns. On the second hospital day, further deterioration
U ; umol/
I
of v. KH 260145
12000
data on the first and
Day 1 Temp. (‘C) BP (mm Hg)
KH 260145
37.4 170/105
8.8 20.2 20 65 3.86 62 3.6 61 230 750 580 2070 30 12 90
Day 3 37.2 110/90 125170 150/l 10 7.0 50 15 255 3.65 76 8.5 140 520 2200 1900 8000 110 52 1200
Nov. 1976
Fig.
2.
4
6
8
10
12 14 March
16 1977
18
2u
Liver function tests before and after delivery.
22
2:
301
P. W.J. van Dongen et al.: Maternal mortality and hepatorenal syndrome TABLE II
Medication before and during admission
I. Medication before admission Insulin (Monotard) Ferrous fumarate Prochlorperazine (Stemetil) II. Medication during admission A. Antepartum Hydromorphonchloride-atropine sulfate (Novolaudon) Butylscopolamlne chloride (Buscopan) Diazoxide (Hyperstat) Diazepam (Valium) Lactulose (Duphalac) Pethidine Pentazocine (Fortral) Piritramide (Dipidolor) Nitroglycerine Dopamine chloride Insulin (Actrapid) Parenteral fluids glucose 20% ) albumin B. Postpartum Antirhesus (D) lmmunoglobulin Ergometrine maleate (Ermetrme) Insulin (Actrapid) Pirltramide (Dipidolor) Dopamine chloride Nitroglycerine Parentrovite I + II Lactulose (Duphalac) Flucloxacillin sodium (Floxapen) Haloperidol (Serenase; Haldol) Chlordiazepoxide (Librium) Phytomenadione (vit. Kl) (Konakion) Folic acid Cyanocobalamin Arginine monochloride Isoproterenol sulfate Ampicillin (Penbritin) Gentamycin sulfate (Garamycin) Pancuronium chloride (Pavulon) Diazepam (Valium) Chloramphenicol (Globenicol) Atropine sulfate Prednisolone sodium succinate (Di-Adreson-F) Chlorpromazine (Largactil) Parenteral fluids glucose 20% } albumin
Dose
Route of administration
12 U/day 200 mg t.i.d.
S.C.
Day
5 mg
oral suPP.
daily -1
2 mg/0.3 mg (7X) 20 mg (1X) 300 mg/20 min (1X) 5 mg (2x1 15 ml 100 mg 30 mg (4X) 15 mg (1X) 10 dr/min 50 mg/12 h 12 u
suPP. i.v. i.v. i.m. oral i.m. i.m. iv. i.v. i.v. i.v.
l-2 1 2 2 3 3 3 3-4 3-4 3-4 4
i.v.
4
i.m. i.m. i.m. iv. i.v. iv. iv. oral iv. i.m. i.m. i.m. i.m. i.m. i.v. i.v. iv. i.v. i.v. iv. local i.m. i.v. i.m.
4 4 4-10 4-9 4-23 4;7; 12-20-22 4-23 4-10; 16-19 6-23 8 8;14 10 1 l-23 11-23 12-13 12-14; 20-22 19-23 19; 21 19-23 19; 23 22 22 22 23
i.v.
4-23
1 amp. 0.15 mg 12 U b.i.d. 1.5 mg 50 mg/12 h 10 dr/min lamp.I+II 15 ml b.i.d. 500 mg q.i.d. 2.5 mg 25 mg 10mg 15 mg q.d. 100 pg/wk 20 mmol/lf h 10 mg/24 h 500 mg q.i.d. 80 mg q.d. 1 mg/h 10mg eye ointment 0.25 mg 50 mg 25 mg (2X)
302
P. W.J. van Dongen et al.: Maternal mortality and hepatorenal syndrome
Fig. 3. Liver scan. The scale (top) indicates increasing counts from left to right. There is almost no activity detected in the hepatic region in contrast to the activity over the stomach and spleen.
I lP-+==---+-t
=dn 3 2
Fig. 4. The course of serum uric acid (UA), creatinine, urea and electrolytes during observation. D = dialysis.
of liver function was evident, and the thrombocyte count remained low. The blood pressure increased to 200/l 15 mm Hg (Fig. 1). Diazoxide was given because of the extreme hypertension, and thereafter the blood pressure decreased to 110/90 mm Hg. Fetal heart tones had disappeared before the diazoxide was given. FolIowing diazoxide, the headache was markedly improved; however, the epigastric pain remained despite analgesics (Table II). Oligurla of 50 ml/24 h developed on the 3rd hospital day in spite of adequate intravenous fluid therapy. There was further deterioration in the parameters of liver and kidney function, as’ shown in Table I and Fig. 2. Serum and urinary amylase were within normal limits. Because of the evidence of increasing hepatic necrosis, coagulopathy and oliguria, the
patient was transferred to the medical intensive care unit (Dr. J.S.F. Gimbrere). On the 4th hospital day, the patient delivered spontaneously a macerated female fetus weighing 490 g (25th percentile for gestational age; Kloosterman, 1973). There were no congenital anomalies. The placenta weighed only 130 g, and old and fresh infarcts were apparent on both macroscopic and microscopic examination. After delivery, the transaminase values decreased rapidly, whereas the bilirubin levels increased (Fig. 2). The hepatitis Bs antigen was reported as negative. A liver scan at this time showed no activity over the right lobe, and minimal activity over the central lobe
P. W-J. van Dongen et al.: Maternal mortality and hepatorenal syndrome KH 260145
1977
MARCH
2
4
Thrombocytes 1x103/u1)
6
0
10
12
14
16
18
20
22
24
26
dc=lwery
300-
.
200-
/
IOO-
f\
/
’
/ a’
Hb
TT
10
(mmol/l)
:
:;
.
*.
8 1, .-
T/-W
‘.
I
6 I
PT
100
.
c%1 50 0I
Fig. 5. The course of prothrombin time (PT), thrombocytes and hemoglobin (Hb). v = one unit of blood given.
TABLE III
Symptoms and findings
Day 1. Epigastric pain Frontal headache Nausea; vomiting Dehydration Hypertension Abnormal liver functions Normal renal functions Proteinuria Granular casts Negative urine culture Fetus alive No fever Thrombocytopenia L&ucocytosis
303
Jaundice Increasing abnormal liver functions Thrombocytopenia F.D.P. rising Leucocytosis Micturition good No vomiting Fetal death HBsAg negative Proteinuria Increasing jaundice Oliguria Decreasing Hb concentration Thrombocytopenia Normal serum and urine amylase Intensive care unit 4. Constricted peripheral circulation Delivery of dead fetus, female, 490 g Placenta 130 g 5. Serum transaminases decreasing Alkaline phosphatase stable 6. Psychotic 7. Blood culture: E. coli Urine culture: negative Liver scan failed 8. Increasing jaundice 12. Septic shock E. coli in blood and urine Liver scan performed 14. Atelectasis Thoracocentesis: 940 ml pleural fluid Nephrology 18. Atelectasis Thoracocentesis: 500 ml pleural fluid Restless and confused lntenrive care unit 19. Intubation 20. Septic shock Constricted peripheral circulation E. coli in pleural fluid and blood 23. Hemoptysis Bradycardia Hypotension Des th Total 9 dialyses and 10 U of blood given.
Recause of anuria and uremia, the patient was dialyzed 9 times (Fig. 4). The further course of the disease up to death is shown in Table III. The patient’s husband refused permission for postmortem examination. (Fig. 3).
304
P. W.J. van Dongen et al.: Maternal mortality and hepatorenal syndrome
Discussion The possibilities considered in the differential diagnosis are shown sequentially in Table IV. Cholecystitis was considered on admission, but was ruled out because of the minimal increase in alkaline phosphatase and the hypertension. Pyelonephritis was excluded because of the clinical symptoms, repeatedly negative urine cultures (until the 12th hospital day), the absence of fever and of leucocyturia. Fulminant viral hepatitis was excluded because of the negative hepatitis Bs antigen, and the clinical course, Atypical appendicitis with pylephlebitis was excluded because of a history of appendectomy some years in the past. The acute and severe epigastric pain was not typical of acute yellow atrophy of the liver (Sheehan’s syndrome) (Sheehan and Sutherland, 1940; MacKenna et al., 1977). This, entity begins typically with complaints of nausea, vomiting, headache, hematemesis and jaundice (Table IV). This diagnosis was, however, considered as a leading possibility because of the laboratory results. - Tetracycline administered during pregnancy, especially when given intravenously, can produce symptoms and findings resembling those seen in the present case. Tetracycline is a general inhibitor of cell metabolism, especially in the liver (Sherlock, 1968). However, no tetracycline had been administered to this patient. The only possibly hepatotoxic drug given had been one prochlorperazine suppository (Table II). - The obstruction of hepatic venous outflow (BuddChiari syndrome) is most often caused by thrombosis of the hepatic veinleading to ascites, hepatomegaly and abdominal diseomfort (Meindok and Langer, 1976). An acute form leading quickly to death has been described, In this syndome, the liver scan is very characteristic, and shows an increased uptake in the caudate lobe and normal or decreased uptake in the right and left lobes (Hungerford et al., 1976). In our patient, however, the liver scan showed almost complete destruction of the liver parenchyma (Fig. 3). - Thrombotic thrombocytopenic purpura (TTP) is characterized by thrombocytopenia, hemolytic
P. W.J. van Dongen et al.: Maternal mortality and hepatorenal syndrome
anemia and renal dysfunction (Byrnes and Khurana, 1977). Schistocytes are present in the peripheral blood smear. In our patient, no clear or potential signs of hemolysis were present except for the high bilirubin levels. Since the bilirubinemia was of the indirect reacting type, the destruction of the liver seemed to be the more likely cause, and the possibility of TTP could be dismissed. - The remaining possibility seems to be the preeclampsia/eclampsia syndrome with liver dysfunction and subcapsular hepatic hemorrhage without rupture. The suddenly acquired hypertension, weight gain of 3 kg in 3 wk, proteinuria, history of a growth-reduced infant in a previous pregnancy and (eventually) infarcted placenta, all point to this syndrome. The occurrence in the 23rd wk of but not unknown. pregnancy is unusual Castaneda et al. (1970) described the diagnosis of subcapsular hepatic hemorrhage in pregnancy by means of a liver scan. They noted always a defect in the right lobe of the liver. The review of Bis and Waxman (1976) included 32 patients with subcapsular hematoma of the liver during pregnancy. The lesion was situated in the right lobe in 26 cases, and in the left lobe in 4 instances. In 2 cases, both lobes were involved. In all cases, histologic examination revealed periportal deposition of fibrin in the sinusoids with hemorrhages. This picture is characteristic of (pre-) 1972; Sheehan and Lynch, eclampsia (Sophian, 1973). The liver scan of our patient fits well with the diagnosis of a subcapsular hepatic hematoma (Fig. 3). The clinical picture of pre-eclampsia with subcap sular hemorrhage of the liver has been described by a number of authors in an identical way: (pre-)eclamp tic complaints in a multigravida, with hypertension present before liver involvement becomes apparent (Haller et al., 1951; Castaneda et al., 1970; Baumwol and Park, 1976; Bis and Waxman, 1976; Hibbard, 1976; Long et al., 1977). The first symptom of liver involvement has usually been griping epigastric pain leading to an initial impression of cholecystitis or cholelithiasis. Proteinuria develops (if not already present), followed by leucocytosis, jaundice, oliguria, and increasing serum transaminase levels. The diagnosis is eventually established as hepatorenal syndrome (Summerskill, 1971). An enlarged liver with a damaged parenchyma is
305
vulnerable. With convulsions or vomiting, the intraabdominal pressure is suddenly increased; the diaphragm depresses the liver and, with the flexion of the body, the liver is compressed between the rigid rib cage and the spine. A subcapsular hemorrhage and even a rupture may occur. (Pre-)eclamptic patients are also predisposed to disseminated intravascular coagulation, with or without clinical bleeding (Page, 1972). In retrospect, some remarks can be made regarding additions or alternatives in the medical management which might have altered the outcome in this case: Laparotomy or laparoscopy might have been helpful at an early stage in the clinical course, when only a thrombocytopenia was present and no other coagulation factors were severely disturbed (Fig. 5). As a result, the diagnosis might have been established much earlier. Although the initial echoscopic examination did not give a clear picture of the liver, the examination was never repeated. The sepsis due to E. coli, present in retrospect on the 7th hospital day, should have been diagnosed earlier and treated appropriately (Gimbrbre, 1977). Sepsis due to staphylococcus was suspected instead, and treatment directed against this organism. The E. coli sepsis was recognized only on the 19th hospital day, and proper antibiotic therapy was thus delayed until this time (Table II). Table II shows also that this patient was treated with 30 (!) different drugs. Could drug toxicity have played a decisive role in the outcome? The decrease in serum transaminase levels (Fig. 2) was interpreted as real improvement. The increase in serum urea (Fig. 4) was also taken to represent evidence of a functioning liver. Retrospectively, largescale destruction of liver parenchyma seems the more probable explanation for both phenomena. Serum transaminase values exceeding 300 U/l almost always signify destruction of liver parenchyma (Croughs and Hemker, 1976). The serum bilirubin did not fall post partum as did the transaminases; this dissociation is a very bad prognostic sign, indicating nearly complete destruction of the liver (Croughs and Hemker, 1976). This case clearly fits the WHO (1965) definition of a maternal mortality, being due to a complication of pregnancy. The mode of death in this case was septic shock, and the underlying cause, hepatorenal syn-
306
P. W.J. van Dongen et al.: Maternal mortality and hepatorenal syndrome
drome due to pre-eclampsia. Thus, our patient died as a result of an obstetric condition, and not as a consequence of coincident medical disease. The importance of the detailed analysis of each maternal mortality, and assessment of immediate and underlying cause, is that it often permits judgement in retrospect as to whether the death might have been avoided or not. Further, the analysis often suggests modifications in clinical management which may contribute constructively in prospective cases containing similar elements. We have attempted to analyse our case in this fashion. Final judgement regarding avoidability cannot be reached in this case because of the absence of a postmortem examination and, thus, the ability to state whether any viable liver parenchyma remained. For the reasons given above, however, the possibility remains that this mortality might have been averted had the eventual mode of death, E. coli sepsis, been recognized earlier and treated vigorously. However, as an abscess in the postulated liver hematoma cannot be ruled out, it might be possible that the antibiotic treatment in the final phase was sufficient to suppress the bacteriemia but insufficient to prevent endotoxin release from the infected hepatic subcapsular hematoma.
Acknowledgement
The authors highly appreciate the valuable help of Ch.B. Martin in preparing this paper.
References Baumwol, M. and Park, W. (1976): An acute abdomen: spontaneous rupture of liver during pregnancy. Brit. J. Surg., 63, 718. Bis, A. and Waxman, B. (1976): Rupture of the liver associated with pregnancy: a review of the literature and report of two cases. Obstet. Gynec. Surv., 31,763. Bout, J. (1971): Moedersterfte in Nederland. Thesis, Free University, Amsterdam. Byrnes, J.J. and Khurana, M. (1977): Treatment of throm-
botic thrombocytopenic
purpura with plasma. New Engl.
J. Med., 297, 1386.
Castaneda, H., Garcia-Romero, H. and Canto, M. (1970): Hepatic haemorrhage in toxaemia of pregnancy. Amer. J, Obstet. Gynec., 107, 578. Croughs, R.J.M. and Hemker, H.E. (1976): De fysiologische basis van klinisch laboratoriumonderzoek, Vol. 1. Oosthoek, Scheltema en Holkema, Utrecht. Gimbrere, J.S.F. (1977): Septic shock. Neth. J. Med., 20, 184. Haller, A.P., Abels, D.W. and Straus, R. (1951): Spontaneous rupture of the liver in a patient with non-convulsive eclampsia. Amer. J. Obstet. Gynec., 62, 1170. Hibbard, L.T. (1976): Spontaneous rupture of the liver in pregnancy: a report of eight cases. Amer. J. Obstet. Gynec., 126, 334. Hungerford, G.D., Hamlyn, A.N., Lunzer, M.R., Dick, R. and Sherlock, Sh. (1976): Pseudometastases in the liver: a presention of the Budd-Chiari syndrome. Radiology, 120, 627. Kloosterman, G.J. (1973): Intra-uteriene Groeicurven. De Voortpianting van de Mens, p. 255. Centen, Bussum. Long, R.G., Scheuer, P.J. and Sherlock, Sh. (1977): Preeclampsia presenting with deep jaundice. J. chin.Path., 30, 212. MacKenna, J., Pupkin, M., Crenshaw, C., McLeod, M. and Parker, R.T. (1977): Acute fatty metamorphosis of the liver. Amer. J. Obstet. Gynec., 127,400. Meindok, H. and Langer, B. (1976): Liver scan in BuddChiari syndrome. J. nucl. Med., 17,365. Page, E.W. (1972): On the pathogenesis of pre-eclampsia and eclampsia. J. Obstet. Gynec. Brit. Cwlth., 79,883. Sheehan, H.L. and Lynch, J.B. (1973): Pathology of Z’oxaemia of Pregnancy, 413 pp. Churchill-Livingstone, Edinburgh. Sheehan, H.L. and Sutherland, A.M. (1940): The pathology of acute yellow atrophy and delayed chloroform poisoning. J. Obstet. Gynaec. Brit. Emp., 47, 49. Sherlock, Sh. (1968): Diseasesof the Liver and Biliary System, 4th edn. Blackwell Scientific Publications, Oxford and Edinburgh. Sophian, J. (1972): Pregnancy Nephropathy, Vol. 2, 309 pp. Butterworth, London. Stoot, J.E.C.M. (1978): Aangeboren Afwiikingen van de Uterus en Gestoorde Voortplanting. Thesis, Nijmegen, The Netherlands. Summerskill, W.H.J. (1971): The liver, the Kidney and the Hepatorenal Syndrome, 95 pp. A Sear1 monograph, Sear1 Diagnostic. W.H.O. (1965): International Classificationof Disease (revision), Vol. 1. World Health Organization, Geneva.
299-306
Maternal mortality due to the hepatorenal syndrome of pre-eclampsia A case report
P.W.J. van Dongen I, T.K.A.B.
Eskes *, J.S.F. Gimbrbe
2 and P. Snel 3
’ Departments of Obstetricsand Gynecology, 2 Intensive Care and 3 Gastroenterology, St. Radboud Ziekenhuis, Nijmegen, The Netherlands Accepted for publication 16 March 1979 VAN DONGEN, P.W.J., ESKES, T.K.A.B., CIMBRERE, J.S.F., and SNEL, P. (1979): Maternal mortality due to the hepatorenal syndrome of pre-eclampsia. A case report. Europ. J. Obstet. Gynec. reprod, Biol., 915, 299-306. A maternal death in the 23rd wk of pregnancy is described. The patient was gravida 8, with 6 previous abortions and one growth-retarded term infant. The clinical symptoms and biochemical findings strongly suggest that the mode of death was septic shock, with the hepatorenal syndrome due to pre-eclampsia as the underlying cause. hepatorenal syndrome; pregnancy; pre-eclampsia; maternal mortality
of epigastric pain and frontal headache of 2 days’ duration. She had been under prenatal care in the hospital outpatient clinic because of a poor reproductive history: her first 6 pregnancies had ended in abortion between the 6th and 10th weeks of amenorrhea. Two of these abortions had been classified as missed abortions. Her 7th pregnancy had resulted in delivery of a growth-retarded (2600 g) infant at 40 wk amenorrhea. During this pregnancy, she had been treated with insulin and a high carbohydrate, low sodium diet (Stoot, 1978). No disturbances of liver or kidney function had been observed during this pregnancy. The same management had been instituted early in the present (8th) pregnancy. Her total weight gain had been 8 kg; however, 3 kg of the total had occurred in the 3rd week prior to admission. Hypertension or proteinuria had not been present on any of the clinic visits, and liver and renal function tests had been within normal limits.
Introduction
The term ‘maternal mortality’ denotes deaths due to delivery and complications of pregnancy, childbirth and the puerperium (WHO, 1965; Bout, 1971). The analysis of a maternal death should result in the identification of the mode of death (the immediate cause of death) and the underlying cause (the disease or condition which initiated the train of morbid events leading to death) (WHO, 1965). An important objective of such an analysis is the determination of whether the death resulted from obstetric factors, medical or surgical problems related to the pregnancy, or incidental disease or trauma.
Case report
A 31-yr-old woman was admitted to the hospital in the 23rd wk of her 8th pregnancy, with complaints 299
300
P. W.J. van Dongen et al.: Maternal mortality and hepatorenaI syndrome
On admission, 1 wk after the last clinic visit, she appeared markedly dehydrated and was vomiting continuously and heavily. She exhibited obvious distress due to epigastric pain, which, she related, penetrated to the back and was only bearable in the left lateral position with her knees flexed. On examination, the uterine size was compatible with the duration of amenorrhea (23 wk) and there was no uterine tenderness. The right hypochondrium and costovertebral angle were quite tender. The rest of the abdominal examination was unremarkable. The patient was afebrile. Her blood pressure was 170/105 mm Hg, whereas the highest blood pressure recorded in the prenatal clinic had been 120/70 mm Hg. The laboratory data on admission are summarized in Table I. The urine output was 1500 ml/24 h. Serum transaminase values were elevated, and bilirubin and alkaline phosphatase were slightly above the normal upper limits. Serum urea, uric acid and creatinine were normal. Coagulation studies showed marked thrombocytopenia. The urine was dark and teacolored; however, the reaction for bilirubin was negative, and that for urobilin, only weakly positive. Proteinuria and acetonuria were present. Shortly after admission, a surgical consultant sug-
TABLE I
Clinical and laboratory third hospital days
Hb (mmol/l) Leucocytes (X103/tl) Thrombocytes (X103/J) F.D.P. &g/ml) Fibrinogen (g/l) P.T. (%) Urea (mmol/l) Creatinine (Mmol/l) Uric acid &mol/l) SGPT (U/l) SGOT (U/l) LDH (U/l) Bilirubin total (clmol/l) Bilirubin direct (%) Alk. phosphatase
MARCH
1
1977 2
3
4
5
6
mm Hg FHTneg
Fig. 1. Blood pressure during clinical observation.
gested the diagnosis of cholecystitis. An additional urologic cause for the costovertebral angle pain seemed unlikely. The tendon reflexes were not increased, and an EEG showed varying and ‘drowsing’ patterns. On the second hospital day, further deterioration
U ; umol/
I
of v. KH 260145
12000
data on the first and
Day 1 Temp. (‘C) BP (mm Hg)
KH 260145
37.4 170/105
8.8 20.2 20 65 3.86 62 3.6 61 230 750 580 2070 30 12 90
Day 3 37.2 110/90 125170 150/l 10 7.0 50 15 255 3.65 76 8.5 140 520 2200 1900 8000 110 52 1200
Nov. 1976
Fig.
2.
4
6
8
10
12 14 March
16 1977
18
2u
Liver function tests before and after delivery.
22
2:
301
P. W.J. van Dongen et al.: Maternal mortality and hepatorenal syndrome TABLE II
Medication before and during admission
I. Medication before admission Insulin (Monotard) Ferrous fumarate Prochlorperazine (Stemetil) II. Medication during admission A. Antepartum Hydromorphonchloride-atropine sulfate (Novolaudon) Butylscopolamlne chloride (Buscopan) Diazoxide (Hyperstat) Diazepam (Valium) Lactulose (Duphalac) Pethidine Pentazocine (Fortral) Piritramide (Dipidolor) Nitroglycerine Dopamine chloride Insulin (Actrapid) Parenteral fluids glucose 20% ) albumin B. Postpartum Antirhesus (D) lmmunoglobulin Ergometrine maleate (Ermetrme) Insulin (Actrapid) Pirltramide (Dipidolor) Dopamine chloride Nitroglycerine Parentrovite I + II Lactulose (Duphalac) Flucloxacillin sodium (Floxapen) Haloperidol (Serenase; Haldol) Chlordiazepoxide (Librium) Phytomenadione (vit. Kl) (Konakion) Folic acid Cyanocobalamin Arginine monochloride Isoproterenol sulfate Ampicillin (Penbritin) Gentamycin sulfate (Garamycin) Pancuronium chloride (Pavulon) Diazepam (Valium) Chloramphenicol (Globenicol) Atropine sulfate Prednisolone sodium succinate (Di-Adreson-F) Chlorpromazine (Largactil) Parenteral fluids glucose 20% } albumin
Dose
Route of administration
12 U/day 200 mg t.i.d.
S.C.
Day
5 mg
oral suPP.
daily -1
2 mg/0.3 mg (7X) 20 mg (1X) 300 mg/20 min (1X) 5 mg (2x1 15 ml 100 mg 30 mg (4X) 15 mg (1X) 10 dr/min 50 mg/12 h 12 u
suPP. i.v. i.v. i.m. oral i.m. i.m. iv. i.v. i.v. i.v.
l-2 1 2 2 3 3 3 3-4 3-4 3-4 4
i.v.
4
i.m. i.m. i.m. iv. i.v. iv. iv. oral iv. i.m. i.m. i.m. i.m. i.m. i.v. i.v. iv. i.v. i.v. iv. local i.m. i.v. i.m.
4 4 4-10 4-9 4-23 4;7; 12-20-22 4-23 4-10; 16-19 6-23 8 8;14 10 1 l-23 11-23 12-13 12-14; 20-22 19-23 19; 21 19-23 19; 23 22 22 22 23
i.v.
4-23
1 amp. 0.15 mg 12 U b.i.d. 1.5 mg 50 mg/12 h 10 dr/min lamp.I+II 15 ml b.i.d. 500 mg q.i.d. 2.5 mg 25 mg 10mg 15 mg q.d. 100 pg/wk 20 mmol/lf h 10 mg/24 h 500 mg q.i.d. 80 mg q.d. 1 mg/h 10mg eye ointment 0.25 mg 50 mg 25 mg (2X)
302
P. W.J. van Dongen et al.: Maternal mortality and hepatorenal syndrome
Fig. 3. Liver scan. The scale (top) indicates increasing counts from left to right. There is almost no activity detected in the hepatic region in contrast to the activity over the stomach and spleen.
I lP-+==---+-t
=dn 3 2
Fig. 4. The course of serum uric acid (UA), creatinine, urea and electrolytes during observation. D = dialysis.
of liver function was evident, and the thrombocyte count remained low. The blood pressure increased to 200/l 15 mm Hg (Fig. 1). Diazoxide was given because of the extreme hypertension, and thereafter the blood pressure decreased to 110/90 mm Hg. Fetal heart tones had disappeared before the diazoxide was given. FolIowing diazoxide, the headache was markedly improved; however, the epigastric pain remained despite analgesics (Table II). Oligurla of 50 ml/24 h developed on the 3rd hospital day in spite of adequate intravenous fluid therapy. There was further deterioration in the parameters of liver and kidney function, as’ shown in Table I and Fig. 2. Serum and urinary amylase were within normal limits. Because of the evidence of increasing hepatic necrosis, coagulopathy and oliguria, the
patient was transferred to the medical intensive care unit (Dr. J.S.F. Gimbrere). On the 4th hospital day, the patient delivered spontaneously a macerated female fetus weighing 490 g (25th percentile for gestational age; Kloosterman, 1973). There were no congenital anomalies. The placenta weighed only 130 g, and old and fresh infarcts were apparent on both macroscopic and microscopic examination. After delivery, the transaminase values decreased rapidly, whereas the bilirubin levels increased (Fig. 2). The hepatitis Bs antigen was reported as negative. A liver scan at this time showed no activity over the right lobe, and minimal activity over the central lobe
P. W-J. van Dongen et al.: Maternal mortality and hepatorenal syndrome KH 260145
1977
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Fig. 5. The course of prothrombin time (PT), thrombocytes and hemoglobin (Hb). v = one unit of blood given.
TABLE III
Symptoms and findings
Day 1. Epigastric pain Frontal headache Nausea; vomiting Dehydration Hypertension Abnormal liver functions Normal renal functions Proteinuria Granular casts Negative urine culture Fetus alive No fever Thrombocytopenia L&ucocytosis
303
Jaundice Increasing abnormal liver functions Thrombocytopenia F.D.P. rising Leucocytosis Micturition good No vomiting Fetal death HBsAg negative Proteinuria Increasing jaundice Oliguria Decreasing Hb concentration Thrombocytopenia Normal serum and urine amylase Intensive care unit 4. Constricted peripheral circulation Delivery of dead fetus, female, 490 g Placenta 130 g 5. Serum transaminases decreasing Alkaline phosphatase stable 6. Psychotic 7. Blood culture: E. coli Urine culture: negative Liver scan failed 8. Increasing jaundice 12. Septic shock E. coli in blood and urine Liver scan performed 14. Atelectasis Thoracocentesis: 940 ml pleural fluid Nephrology 18. Atelectasis Thoracocentesis: 500 ml pleural fluid Restless and confused lntenrive care unit 19. Intubation 20. Septic shock Constricted peripheral circulation E. coli in pleural fluid and blood 23. Hemoptysis Bradycardia Hypotension Des th Total 9 dialyses and 10 U of blood given.
Recause of anuria and uremia, the patient was dialyzed 9 times (Fig. 4). The further course of the disease up to death is shown in Table III. The patient’s husband refused permission for postmortem examination. (Fig. 3).
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P. W.J. van Dongen et al.: Maternal mortality and hepatorenal syndrome
Discussion The possibilities considered in the differential diagnosis are shown sequentially in Table IV. Cholecystitis was considered on admission, but was ruled out because of the minimal increase in alkaline phosphatase and the hypertension. Pyelonephritis was excluded because of the clinical symptoms, repeatedly negative urine cultures (until the 12th hospital day), the absence of fever and of leucocyturia. Fulminant viral hepatitis was excluded because of the negative hepatitis Bs antigen, and the clinical course, Atypical appendicitis with pylephlebitis was excluded because of a history of appendectomy some years in the past. The acute and severe epigastric pain was not typical of acute yellow atrophy of the liver (Sheehan’s syndrome) (Sheehan and Sutherland, 1940; MacKenna et al., 1977). This, entity begins typically with complaints of nausea, vomiting, headache, hematemesis and jaundice (Table IV). This diagnosis was, however, considered as a leading possibility because of the laboratory results. - Tetracycline administered during pregnancy, especially when given intravenously, can produce symptoms and findings resembling those seen in the present case. Tetracycline is a general inhibitor of cell metabolism, especially in the liver (Sherlock, 1968). However, no tetracycline had been administered to this patient. The only possibly hepatotoxic drug given had been one prochlorperazine suppository (Table II). - The obstruction of hepatic venous outflow (BuddChiari syndrome) is most often caused by thrombosis of the hepatic veinleading to ascites, hepatomegaly and abdominal diseomfort (Meindok and Langer, 1976). An acute form leading quickly to death has been described, In this syndome, the liver scan is very characteristic, and shows an increased uptake in the caudate lobe and normal or decreased uptake in the right and left lobes (Hungerford et al., 1976). In our patient, however, the liver scan showed almost complete destruction of the liver parenchyma (Fig. 3). - Thrombotic thrombocytopenic purpura (TTP) is characterized by thrombocytopenia, hemolytic
P. W.J. van Dongen et al.: Maternal mortality and hepatorenal syndrome
anemia and renal dysfunction (Byrnes and Khurana, 1977). Schistocytes are present in the peripheral blood smear. In our patient, no clear or potential signs of hemolysis were present except for the high bilirubin levels. Since the bilirubinemia was of the indirect reacting type, the destruction of the liver seemed to be the more likely cause, and the possibility of TTP could be dismissed. - The remaining possibility seems to be the preeclampsia/eclampsia syndrome with liver dysfunction and subcapsular hepatic hemorrhage without rupture. The suddenly acquired hypertension, weight gain of 3 kg in 3 wk, proteinuria, history of a growth-reduced infant in a previous pregnancy and (eventually) infarcted placenta, all point to this syndrome. The occurrence in the 23rd wk of but not unknown. pregnancy is unusual Castaneda et al. (1970) described the diagnosis of subcapsular hepatic hemorrhage in pregnancy by means of a liver scan. They noted always a defect in the right lobe of the liver. The review of Bis and Waxman (1976) included 32 patients with subcapsular hematoma of the liver during pregnancy. The lesion was situated in the right lobe in 26 cases, and in the left lobe in 4 instances. In 2 cases, both lobes were involved. In all cases, histologic examination revealed periportal deposition of fibrin in the sinusoids with hemorrhages. This picture is characteristic of (pre-) 1972; Sheehan and Lynch, eclampsia (Sophian, 1973). The liver scan of our patient fits well with the diagnosis of a subcapsular hepatic hematoma (Fig. 3). The clinical picture of pre-eclampsia with subcap sular hemorrhage of the liver has been described by a number of authors in an identical way: (pre-)eclamp tic complaints in a multigravida, with hypertension present before liver involvement becomes apparent (Haller et al., 1951; Castaneda et al., 1970; Baumwol and Park, 1976; Bis and Waxman, 1976; Hibbard, 1976; Long et al., 1977). The first symptom of liver involvement has usually been griping epigastric pain leading to an initial impression of cholecystitis or cholelithiasis. Proteinuria develops (if not already present), followed by leucocytosis, jaundice, oliguria, and increasing serum transaminase levels. The diagnosis is eventually established as hepatorenal syndrome (Summerskill, 1971). An enlarged liver with a damaged parenchyma is
305
vulnerable. With convulsions or vomiting, the intraabdominal pressure is suddenly increased; the diaphragm depresses the liver and, with the flexion of the body, the liver is compressed between the rigid rib cage and the spine. A subcapsular hemorrhage and even a rupture may occur. (Pre-)eclamptic patients are also predisposed to disseminated intravascular coagulation, with or without clinical bleeding (Page, 1972). In retrospect, some remarks can be made regarding additions or alternatives in the medical management which might have altered the outcome in this case: Laparotomy or laparoscopy might have been helpful at an early stage in the clinical course, when only a thrombocytopenia was present and no other coagulation factors were severely disturbed (Fig. 5). As a result, the diagnosis might have been established much earlier. Although the initial echoscopic examination did not give a clear picture of the liver, the examination was never repeated. The sepsis due to E. coli, present in retrospect on the 7th hospital day, should have been diagnosed earlier and treated appropriately (Gimbrbre, 1977). Sepsis due to staphylococcus was suspected instead, and treatment directed against this organism. The E. coli sepsis was recognized only on the 19th hospital day, and proper antibiotic therapy was thus delayed until this time (Table II). Table II shows also that this patient was treated with 30 (!) different drugs. Could drug toxicity have played a decisive role in the outcome? The decrease in serum transaminase levels (Fig. 2) was interpreted as real improvement. The increase in serum urea (Fig. 4) was also taken to represent evidence of a functioning liver. Retrospectively, largescale destruction of liver parenchyma seems the more probable explanation for both phenomena. Serum transaminase values exceeding 300 U/l almost always signify destruction of liver parenchyma (Croughs and Hemker, 1976). The serum bilirubin did not fall post partum as did the transaminases; this dissociation is a very bad prognostic sign, indicating nearly complete destruction of the liver (Croughs and Hemker, 1976). This case clearly fits the WHO (1965) definition of a maternal mortality, being due to a complication of pregnancy. The mode of death in this case was septic shock, and the underlying cause, hepatorenal syn-
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P. W.J. van Dongen et al.: Maternal mortality and hepatorenal syndrome
drome due to pre-eclampsia. Thus, our patient died as a result of an obstetric condition, and not as a consequence of coincident medical disease. The importance of the detailed analysis of each maternal mortality, and assessment of immediate and underlying cause, is that it often permits judgement in retrospect as to whether the death might have been avoided or not. Further, the analysis often suggests modifications in clinical management which may contribute constructively in prospective cases containing similar elements. We have attempted to analyse our case in this fashion. Final judgement regarding avoidability cannot be reached in this case because of the absence of a postmortem examination and, thus, the ability to state whether any viable liver parenchyma remained. For the reasons given above, however, the possibility remains that this mortality might have been averted had the eventual mode of death, E. coli sepsis, been recognized earlier and treated vigorously. However, as an abscess in the postulated liver hematoma cannot be ruled out, it might be possible that the antibiotic treatment in the final phase was sufficient to suppress the bacteriemia but insufficient to prevent endotoxin release from the infected hepatic subcapsular hematoma.
Acknowledgement
The authors highly appreciate the valuable help of Ch.B. Martin in preparing this paper.
References Baumwol, M. and Park, W. (1976): An acute abdomen: spontaneous rupture of liver during pregnancy. Brit. J. Surg., 63, 718. Bis, A. and Waxman, B. (1976): Rupture of the liver associated with pregnancy: a review of the literature and report of two cases. Obstet. Gynec. Surv., 31,763. Bout, J. (1971): Moedersterfte in Nederland. Thesis, Free University, Amsterdam. Byrnes, J.J. and Khurana, M. (1977): Treatment of throm-
botic thrombocytopenic
purpura with plasma. New Engl.
J. Med., 297, 1386.
Castaneda, H., Garcia-Romero, H. and Canto, M. (1970): Hepatic haemorrhage in toxaemia of pregnancy. Amer. J, Obstet. Gynec., 107, 578. Croughs, R.J.M. and Hemker, H.E. (1976): De fysiologische basis van klinisch laboratoriumonderzoek, Vol. 1. Oosthoek, Scheltema en Holkema, Utrecht. Gimbrere, J.S.F. (1977): Septic shock. Neth. J. Med., 20, 184. Haller, A.P., Abels, D.W. and Straus, R. (1951): Spontaneous rupture of the liver in a patient with non-convulsive eclampsia. Amer. J. Obstet. Gynec., 62, 1170. Hibbard, L.T. (1976): Spontaneous rupture of the liver in pregnancy: a report of eight cases. Amer. J. Obstet. Gynec., 126, 334. Hungerford, G.D., Hamlyn, A.N., Lunzer, M.R., Dick, R. and Sherlock, Sh. (1976): Pseudometastases in the liver: a presention of the Budd-Chiari syndrome. Radiology, 120, 627. Kloosterman, G.J. (1973): Intra-uteriene Groeicurven. De Voortpianting van de Mens, p. 255. Centen, Bussum. Long, R.G., Scheuer, P.J. and Sherlock, Sh. (1977): Preeclampsia presenting with deep jaundice. J. chin.Path., 30, 212. MacKenna, J., Pupkin, M., Crenshaw, C., McLeod, M. and Parker, R.T. (1977): Acute fatty metamorphosis of the liver. Amer. J. Obstet. Gynec., 127,400. Meindok, H. and Langer, B. (1976): Liver scan in BuddChiari syndrome. J. nucl. Med., 17,365. Page, E.W. (1972): On the pathogenesis of pre-eclampsia and eclampsia. J. Obstet. Gynec. Brit. Cwlth., 79,883. Sheehan, H.L. and Lynch, J.B. (1973): Pathology of Z’oxaemia of Pregnancy, 413 pp. Churchill-Livingstone, Edinburgh. Sheehan, H.L. and Sutherland, A.M. (1940): The pathology of acute yellow atrophy and delayed chloroform poisoning. J. Obstet. Gynaec. Brit. Emp., 47, 49. Sherlock, Sh. (1968): Diseasesof the Liver and Biliary System, 4th edn. Blackwell Scientific Publications, Oxford and Edinburgh. Sophian, J. (1972): Pregnancy Nephropathy, Vol. 2, 309 pp. Butterworth, London. Stoot, J.E.C.M. (1978): Aangeboren Afwiikingen van de Uterus en Gestoorde Voortplanting. Thesis, Nijmegen, The Netherlands. Summerskill, W.H.J. (1971): The liver, the Kidney and the Hepatorenal Syndrome, 95 pp. A Sear1 monograph, Sear1 Diagnostic. W.H.O. (1965): International Classificationof Disease (revision), Vol. 1. World Health Organization, Geneva.