Int J Gynaecol Obstet 17:73-77, 1979
Viral Hepatitis Complicating Pregnancy: Mortality Trends in Saudi Arabia A. P. Gelpi Department of Medicine, Stanford University School of Medicine, Stanford, California, and the Palo Alto Medical Clinic, Palo Alto, California, USA
ABSTRACT Gelpi AP (Dept of Medicine, Stanford University School of Medicine, Stanford, CA, and the Palo Alto Medical Clinic, Palt Alto, CA, USA). Viral hepatitis complicating pregnancy: mortality trends in Saudi Arabia. Int J Gynaecol Obstet 17:73-77, 1979 The striking mortality in viral hepatitis associated with pregnancy, regularly observed in developing countries, has shown a significant decrease in Saudi Arabia during a period of unprecedented economic growth. However, the risk of fatal hepatitis in the pregnant Saudi woman remains approximately four times that for the nonpregnant woman. The explanation for the observed mortality trend is not apparent, but is unlikely to be the result of improved nutritional status of the population alone, or because of treatment of severe hepatitis with adrenal corticosteroids. Disseminated intravascular coagulation may be one factor that decisively influences the outcome of hepatitis in the pregnant woman.
not helpful in predicting an unfavorable course. Data from both the retrospective and prospective studies are used to trace changes in the character of viral hepatitis complicating pregnancy in the population of a developing country. T h e discriminative value of certain laboratory tests in estimating the risk of death among patients with hepatitis is reported. Data are also presented on the effects of adrenal corticosteroid therapy in preventing fatality among high-risk patients with hepatitis and on the effects of viral hepatitis on the outcome of pregnancy in respect to fetal salvage. T h e differential pattern of hepatitis mortality between males a n d females is discussed. T h e relationship of nonpregnant a n d pregnant females to socioeconomic a n d pathophysiologic factors is examined. Selected publications of the past ten years are reviewed.
MATERIALS A N D M E T H O D S INTRODUCTION An earlier report of viral hepatitis in Saudi women (10) emphasized the high mortality associated with pregnancy and the significant fetal wastage. This retrospective report represented experience obtained over a ten-year period, 1953-1962. Beginning in 1963, a prospective study of hepatitis complicating pregnancy was undertaken. T h e aim was to assess the predictive value of certain laboratory procedures for identifying patients at mortal risk with viral hepatitis and to evaluate the effects of adrenal corticosteroid therapy in the management of patients with hepatitis who were believed to be at high mortal risk. In the retrospective study, it appeared that those patients who presented with coma, hyperpyrexia, bleeding diatheses and ascites or edema were likely to have a difficult course, ending in death. With the exception of the determination of prothrombin time, other tests of hepatic function or indicators of hepatocellular necrosis were
All available medical records of both male and female patients, who were admitted between J a n u ary 1, 1963, a n d December 3 1 , 1975, to the D h a h r a n Health Center, which serves employees and dependents of the Arabian American Oil C o m p a n y in Dhahran, Saudi Arabia, a n d who were discharged with the diagnosis of viral hepatitis, were considered for inclusion in this study. For comparison with the retrospective study, only those patients who were aged 15 years and older and who were Saudi Arabians were further evaluated in regard to mortality, laboratory data, effects of adrenal corticosteroid therapy and the outcome of pregnancy with respect to fetal salvage. Because of previous experience with hepatitis among pregnant Saudi women, a high proportion of Saudi women with viral hepatitis were hospitalized at the D h a h r a n Health Center for close observation. O n the other hand, the majority of Saudi males with hepatitis diagnosed during the prospective study were managed as outpatients or admitted to ancillary, convalescent facilities. Ad-
IntJ Gynaecol Obstet 17
74
Gelpi
orally. Therapy was continued until there was clear evidence of recovery, verified by the usual clinical criteria and supporting laboratory values, or until death. It was not possible to test blood samples from these patients for the presence of hepatitis B antigen because the serodiagnositc procedure was not available at the D h a h r a n Health Center laboratories during the course of this investigation.
mission to the D h a h r a n Health Center was generally dictated by the occurrence of hepatitis of more than the usual severity or hepatitis complicated by some other medical problem. Traditional criteria for the diagnosis of viral hepatitis included the absence of any history of prior medication (to exclude drug-induced hepatitis) and the absence of clinical and laboratory features, or both, usually associated with cholestatic jaundice of pregnancy or extrahepatic biliary tract obstruction. T h e possibility that instances of acute fatty metamorphosis of the liver were included in the small group of pregnant women who died could not be excluded. T h e diagnostic advantage afforded by liver biopsy could not be employed to provide the distinction between this entity and viral hepatitis because of the usual prolongation of the prothrombin time a n d the risk of hemorrhage in the critically ill patient.
RESULTS During the prospective study, a total of 74 women and 36 men meeting the criteria of acute viral hepatitis were hospitalized at the D h a h r a n Health Center. T h e ratio of pregnant to nonpregnant women was 41:33 (124), which closely approximated the ratio of 54:42 (1.29) from the 1953-1962 series, an indication of comparable selection of female patients between the two series. Further comparison (Table I) reveals a striking reduction in the mortality for women (X2 = 14.7, p < 10 - 5 ). But the reduction in mortality appears essentially to be caused by an increased in survival for the group in the third trimester of pregnancy or puerperium (x 2 = 13.0, p < 10 - 3 ). However, the risk of fatal hepatitis among pregnant patients, a compared to nonpregnant ones, remains virtually unchanged: 0.463/ 0.119 = 3.89 (1953-1962), as opposed to 0.122/0.30 = 4.06 (1963-1975). Furthermore, the mortality risk for the group in the third trimester or puerperium compared with the group in the first and second trimester of pregnancy had not changed appreciably: 0.708/0.267 = 2.65 (1953-1962), as opposed to 0.143/0.056 = 2.55 (1963-1975). However, the risk for third trimester pregnancy/puerperium patients, as compared with nonpregnant ones, had decreased slightly, 0.708/0.119 = 5.95 (19531962), as opposed to 0.143/0.030 = 4.76 (19621975). From 1963 through 1967, there were five deaths among 39 women, but from 1968 through
Conventional laboratory tests used for diagnostic a n d prognostic evaluation included for the serum glutamic oxaloacetic transaminase (SGOT) and the prothrombin time. T h e normal value for the S G O T was 40 I U / m l , and for the prothrombin time, 12-14 seconds. Both of these tests were selected for consideration as discriminants of the severity of hepatitis, the former because of its traditional utility in assessing the degree of hepatocellular necrosis, and the latter because previous experience among Saudi women with hepatitis had confirmed its reliability in predicting a fatal course of hepatitis (10). In highrisk patients, those in the third trimester of pregnancy or the puerperium, daily prothrombin determinations were done. Any patient showing signs of clinical deterioration (an initial prothrombin time of 20 seconds or longer) or a progressive increase in the prothrombin time to and above 20 seconds was considered for adrenal corticosteroid therapy. Such treatment consisted of the intravenous administration of 200 m g / d a y of hydrocortisone sodium succinate, 60 m g / d a y of prednisolone in divided intramuscular doses or 40-60 m g / d a y of prednisone
Table I. Hepatitis mortality at the Dhahran Health Center. Females Male Interval
1953-1962 1963-1975
No. 25 (552) a 2(36)
Nonpregnant % 4.5 5.6
Pregnant: 1st-2nd trimester
No.
%
No.
5(42) 1(33)
11.9 3.0
8(30) 1 (18)
% 26.7 5.6
Pregnant: 3rd trimester/puerperium No.
17 (24) 3(21)
' Numbers in parentheses represent totals in each group. ' Includes two pregnant patients with uncertain duration of gestation and with one death.
InlJ Gynaecol Obstet 17
% 70.8 14.3
Total No.
55 (648) 8 (110) b
% 8.5 7.3
Hepatitis complicating pregnancy
1975, there was only one death among 35 consecutive women. In the 1963-1975 series, 14 subjects were treated with adrenal corticosteroids: twelve of these patients were pregnant and six of the 14 died, a death rate of 43%. Two of the fatal cases were comatose on admission, and the course of hepatitis in these patients was not likely to have been altered by the administration of corticosteroids. O n e patient who developed coma following admission survived, and this person was not treated with corticosteroids. Among the remaining eight patients treated with corticosteroids, the usual indications for such management were a moderate-to-marked increase in the one-stage prothrombin time or unfavorable prognostic signs, which included profound anorexia and a changing sensorium, as well as those previously cited. In any case, corticosteroid treatment for highrisk patients did not appear to reduce mortality to any significant extent. Comparison with a similar group of high-risk patients seen during the interval 1953-1962 provided no evidence of a beneficial effect from corticosteroids; within this group no patient with a peak prothrombin time of 25 seconds or more survived. In the 1963-1975 group, there were seven patients with prothrombin times in excess of 25 seconds. All received corticosteroids; only two survived. In the group of women whose parturitions were directly related to hepatitis, data on the outcome of the pregnancies were available for 11 patients. There were no abortions but there were two stillbirths. This contrasts with experience from the 1953-1962 series in which 15 of 43 pregnancies terminated in an abortion or stillbirth; this difference, however, is not statistically significant. In order to assess the discriminative value of the S G O T a n d the prothrombin time determinations for predicting the severity of hepatitis among the four groups of patients (males, nonpregnant females, females in the first and second trimesters of pregnancy a n d females in the third trimester or early postpartum period), peak values for each of the tests were tabulated for each patient. In the majority of
75
patients, several determinations of the S G O T a n d the prothrombin time were carried out during hospitalization. T h e cases for which only one S G O T or prothrombin determination was recorded in the medical records were also included in the tabulation. Two patients had serum enzyme determinations other than for the S G O T to confirm the presence of hepatocellular disease, a n d there were several who lacked either determinations for S G O T or prothrombin time and were, therefore, not included in the tabulation. Finally, determinations of S G O T and prothrombin times from those who succumbed to hepatitis were not included in the tabulation. There appeared to be trends in severity, as evidenced by comparison of the mean peak S G O T determination between the two groups of pregnant women, and of the prothrombin times between the nonpregnant and pregnant women (Table II). However, an analysis of variance revealed no significant discriminant value for either test in separating the four groups in terms of anticipated severity and expected mortality. Thus, the actual comparative risk of death that had been observed between pregnant and nonpregnant women with hepatitis was not matched by parallel aberrations in the two laboratory parameters that were considered in this study. Over the past ten years, publications from Africa (4, 6, 14, 18), the Middle East (3, 10), South Asia (1, 2, 5, 15) a n d Latin America (7, 17) have implicated viral hepatitis as an important cause of mortality during pregnancy a n d have emphasized the increasing risk during late pregnancy and the puerperium. T h e cumulative experience reflected in the literature shows a significant increase in mortality associated with viral hepatitis between nonpregnant and pregnant status a n d from the first and second trimester of pregnancy to late pregnancy a n d puerperium.
DISCUSSION Several reports that have emphasized the great risk of hepatitis occurring during pregnancy have
Table II. Mean peak serum glutamic oxaloacetic transaminase (SGOT) and prothrombin time (PT) among Saudi Arabians with viral hepatitis. SGOT in lU/ml Group Males Nonpregnant females Females in 1 s t - 2 n d trimester Females in 3rd trimester/puerperium
No. 34 29 15 16
PT in sec
Mean
SD
No.
1026 1134 788 1318
±705 ±991 ±661 ±1087
30 30 16 18
Mean 18.1 16.2 18.7 18.6
SD ±6.4 ±2.1 ±8.2 ±6.2
IntJ Gynaecol Obstet 17
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concluded that malnutrition plays an important role in determining the outcome of hepatitis (2, 3, 6, 18). T h e hypothesis that malnutrition adversely affects the course of viral hepatitis does not explain the increased mortality risk in relation to pregnancy as compared with nonpregnant status, nor does it take into account the gradient of increasing severity and mortality from early through late pregnancy and the puerperium. Finally, despite the a b u n d a n t evidence that viral hepatitis is a definite risk for the pregnant woman, there is little evidence that the outcome of other systemic viral infections, with the exception of certain outbreaks of pandemic influenza, is adversely affected by pregnancy (8, 12). D a t a on the course of viral hepatitis in pregnancy from Saudia Arabia, spanning the course of 23 years, provide the first indication that a trend of improvement in the outcome of hepatitis associated with pregnancy could be related to changing socioeconomic conditions. Within the period encompassed by this longitudinal study, there has been startling economic development in Saudi Arabia a n d in neighboring oil-producing countries, which has been accompanied by social reforms, improving educational opportunities, importation and distribution of luxury foods, proliferation of health-care facilities a n d the application of public health measures that have promoted maternal-child health programs. These dramatic events are nowhere more evident t h a n in the eastern, oil-producing area of Saudi Arabia. It would be tempting to conclude that the improvement in the quality of life and in the general health of the Saudi population has reduced the mortality from hepatitis in pregnancy. However, the relative risk of dying of hepatitis in pregnancy has not changed appreciably; therefore, the differential mortality from hepatitis observed between pregnant and nonpregnant women is likely to reflect a true susceptibility to more severe disease during the gestational period. An important consideration regarding the concurrence of pregnancy and hepatitis is the hypercoagulable state that appears to accompany normal pregnancy (13), and evidence of incipient intravascular coagulation that has been observed in uncomplicated viral hepatitis (9). T h e more florid disseminated intravascular coagulation (DIC), which often complicates fulminant hepatitis (16), has also been observed. T h e association of moderately severe hepatitis with pregnancy might therefore provide the conditions for accelerated intravascular coagulation, with catastrophic consequences for the patient. O n e possible explanation for the favorable trend in the mortality observed among Saudi women with hepatitis lies in the selective bias wherein all women
IntJ Gynaecol Obstet 17
with hepatitis, however mild, were admitted to the hospital during the prospective study, from 1963 through 1975. This should be reflected in a comparative increase in the n u m b e r of women hospitalized during the latter period. However, the average number of admissions per year during the retrospective study was 11, as compared with six during the prospective study. This difference may simply reflect an overall decrease in the incidence of viral hepatitis in the Saudi population, with decreasing numbers of women hospitalized for hepatitis despite the inclusion of milder cases for hospital admission. T h e most conclusive evidence of the favorable trend in the course of hepatitis among Saudi women comes from the final eight years of the prospective study: there was only one fatal case of hepatitis, a death rate of 3%. Neither of the laboratory parameters that were evaluated in this report, the S G O T and the prothrombin time, provided discrimination a m o n g the four groups of patients in regard to severity of hepatitis. However, marked elevations of the prothrombin times were associated with a high mortality, as had been observed in the retrospective study of hepatitis in Saudi Arabians, and noted in other publications. T h e use of adrenal corticosteroids in the management of viral hepatitis remains a matter of controversy. At least one recent report suggests that corticosteroids may actually have an adverse effect on the course of hepatitis (11). T h e effect of corticosteroids on the course of hepatitis in Saudi women, and on the mortality pattern in pregnancy complicated by hepatitis, cannot be determined from the data provided in this report. Too few patients qualified for treatment with corticosteroids, according to the protocol employed in the prospective study, and two of the six patients who died of hepatitis were comatose on admission and prior to the administration of corticosteroids. T w o patients with m a x i m u m prothrombin times in excess of 25 seconds survived, possibly salvaged by the administration of corticosteroids. T h e compiled data from a number of recent publications concerning the course of hepatitis complicating pregnancy conclusively demonstrate an increasing risk of death associated with pregnancy, which is most evident during late pregnancy and puerperium. These and other sources have furnished evidence of significant fetal loss directly related to the occurrence of hepatitis during pregnancy, and, in addition, they have emphasized significant perinatal loss and prematurity. There has been a notable decrease in the mortality, due to viral hepatitis in a population of Saudi
Hepatitis complicating pregnancy
Arabians observed over a 23-year period. This decrease is primarily the result of improved survival of pregnant women with hepatitis. T h e earlier high death rate that had been observed in Saudi women parallels those that have been more recently encountered in populations of other developing countries. In Saudi Arabia, the relative risk of fatal outcome among pregnant women has not changed significantly despite the substantial decrease in the overall mortality among women with viral hepatitis. These data, together with observations from other publications on the differential risk of hepatitis from early through late pregnancy, suggest that changing socioeconomic conditions do not completely explain the change in mortality observed among Saudi women. Pregnancy itself seems to be an important determinant of severity and the risk of death with viral hepatitis. Pregnancy complicated by hepatitis may be associated with an increased tendency for disseminated intravascular coagulation, which is greater than that anticipated for uncomplicated pregnancy or for moderatley severe hepatitis alone. Finally, there is a high rate of fetal loss associated with hepatitis-complicated pregnancy in populations of developing countries, and, in general, this trend parallels the high mortality among mothers with viral hepatitis. In cases of hepatitis, marked elevations of the prothrombin time, twice or more the normal values, are usually associated with fatal outcomes. However, excluding those patients with fatal hepatitis, mean peak prothrombin times do not appear to correlate with presumed severity and observed differential mortality between groups of pregnant and nonpregnant women. Administration of adrenal corticosteroids to women with viral hepatitis who were believed to be at greatest risk for fatal termination has not been demonstrated to have significantly influenced the outcome of hepatitis.
ACKNOWLEDGMENT Funding and facilities for this study were provided entirely by the Arabian America Oil Company, Dhahran, Saudi Arabia.
77
REFERENCES 1. Adams WH, Shrestha SM, Pai DN: Coagulation studies of viral hepatitis occurring during pregnancy. Am J Med Sci 272:139, 1976. 2. Bhalerao VR, Desi VP, Pai DN: Viral hepatitis in pregnancy. Ind J Public Health 25:165, 1974. 3. Borhanmanesh F, Haghighi P, Kekmat K, Rezaizadeh K: Viral hepatitis during pregnancy: severity and effect on gestation. Gastroenterology 6"4:304, 1973. 4. Christie AB, Allam AA, Aref MK, El Montasser IH, ElNageh M: Pregnancy hepatitis in Libya. Lancet 2:827, 1976. 5. D'Cruz IA, Balani SG, Iyer LS: Infectious hepatitis and pregnancy. Obstet Gynecol 3/:449, 1968. 6. Delons S, Berbich A, Reynaud R, Lebon P: Contribution to the study of severe icterus of the pregnant woman in Morocco. Rev Medichochir Mal Foie 43:117, 1968. 7. Espinosa de Los Reyes V, Garcia RS, Valenzuela AJ: Hepatitis and pregnancy. Ginecol Obstet Mex 30:635, 1971. 8. Finland M: Influenza complicating pregnancy. In Obstetric and Perinatal Infections (ed D Charles, M Finland), p 355. Lea & Febiger, Philadelphia, 1973. 9. Gallus AS, Lucas CR, Hirsh J: Coagulation studies in patients with acute infectious hepatitis. Br J Haematol 22: 761, 1972. 10. Gelpi AP: Fatal hepatitis in Saudi Arabian women. Am J Gastroenterol 53:41, 1970. 11. Gregory PB, Kanuer MC, Kempson RL, Miller R: Steroid therapy in severe viral hepatitis: a randomized trial. N Engl J Med 2S4:681, 1976. 121. Horstmann DM: Viral infections in pregnancy. Yale J Biol Med 42:99, 1969. 13. Hyde E, Joyce D, Gurevich V, Flute PT, Barbera S: Intravascular coagulation during pregnancy and the puerperium. J Obstet Gynaecol Br Commonw 00:1059, 1973. 14. Morrow RH, Smetana HF, Sai FT, Edgcomb J H : Unusual features of viral hepatitis in Accra, Ghana. Ann Intern Med 6.9:1250, 1968. 15. Narayana Rao AV, Sita Devi C, Savirthri P, Seshirekha E: Infectious hepatitis in pregnancy and puerperium—a study of 60 cases. Indian J Med Sci 23:271, 1969. 16. Rake MO, Flute PT, Pannell G, Williams R: Intravascular coagulation in acute hepatic necrosis. Lancet /:533, 1970. 17. Shiroma M, Hutzler RU, De Alcantara LG, Meira JA, Ferreira J M , Amato Neto V: Viral hepatitis in pregnancy. Rev Hosp Clin Fac Med Sao Paulo 24:349, 1969. 18. Tsega E: Viral hepatitis during pregnancy in Ethiopia. East Afr Med J 53:270, 1976.
Address for reprints: A. P. Gelpi Room S-169 Stanford University Medical Center Stanford, CA 94305 USA
InlJ Gynaecol Obstet 17
Viral Hepatitis Complicating Pregnancy: Mortality Trends in Saudi Arabia A. P. Gelpi Department of Medicine, Stanford University School of Medicine, Stanford, California, and the Palo Alto Medical Clinic, Palo Alto, California, USA
ABSTRACT Gelpi AP (Dept of Medicine, Stanford University School of Medicine, Stanford, CA, and the Palo Alto Medical Clinic, Palt Alto, CA, USA). Viral hepatitis complicating pregnancy: mortality trends in Saudi Arabia. Int J Gynaecol Obstet 17:73-77, 1979 The striking mortality in viral hepatitis associated with pregnancy, regularly observed in developing countries, has shown a significant decrease in Saudi Arabia during a period of unprecedented economic growth. However, the risk of fatal hepatitis in the pregnant Saudi woman remains approximately four times that for the nonpregnant woman. The explanation for the observed mortality trend is not apparent, but is unlikely to be the result of improved nutritional status of the population alone, or because of treatment of severe hepatitis with adrenal corticosteroids. Disseminated intravascular coagulation may be one factor that decisively influences the outcome of hepatitis in the pregnant woman.
not helpful in predicting an unfavorable course. Data from both the retrospective and prospective studies are used to trace changes in the character of viral hepatitis complicating pregnancy in the population of a developing country. T h e discriminative value of certain laboratory tests in estimating the risk of death among patients with hepatitis is reported. Data are also presented on the effects of adrenal corticosteroid therapy in preventing fatality among high-risk patients with hepatitis and on the effects of viral hepatitis on the outcome of pregnancy in respect to fetal salvage. T h e differential pattern of hepatitis mortality between males a n d females is discussed. T h e relationship of nonpregnant a n d pregnant females to socioeconomic a n d pathophysiologic factors is examined. Selected publications of the past ten years are reviewed.
MATERIALS A N D M E T H O D S INTRODUCTION An earlier report of viral hepatitis in Saudi women (10) emphasized the high mortality associated with pregnancy and the significant fetal wastage. This retrospective report represented experience obtained over a ten-year period, 1953-1962. Beginning in 1963, a prospective study of hepatitis complicating pregnancy was undertaken. T h e aim was to assess the predictive value of certain laboratory procedures for identifying patients at mortal risk with viral hepatitis and to evaluate the effects of adrenal corticosteroid therapy in the management of patients with hepatitis who were believed to be at high mortal risk. In the retrospective study, it appeared that those patients who presented with coma, hyperpyrexia, bleeding diatheses and ascites or edema were likely to have a difficult course, ending in death. With the exception of the determination of prothrombin time, other tests of hepatic function or indicators of hepatocellular necrosis were
All available medical records of both male and female patients, who were admitted between J a n u ary 1, 1963, a n d December 3 1 , 1975, to the D h a h r a n Health Center, which serves employees and dependents of the Arabian American Oil C o m p a n y in Dhahran, Saudi Arabia, a n d who were discharged with the diagnosis of viral hepatitis, were considered for inclusion in this study. For comparison with the retrospective study, only those patients who were aged 15 years and older and who were Saudi Arabians were further evaluated in regard to mortality, laboratory data, effects of adrenal corticosteroid therapy and the outcome of pregnancy with respect to fetal salvage. Because of previous experience with hepatitis among pregnant Saudi women, a high proportion of Saudi women with viral hepatitis were hospitalized at the D h a h r a n Health Center for close observation. O n the other hand, the majority of Saudi males with hepatitis diagnosed during the prospective study were managed as outpatients or admitted to ancillary, convalescent facilities. Ad-
IntJ Gynaecol Obstet 17
74
Gelpi
orally. Therapy was continued until there was clear evidence of recovery, verified by the usual clinical criteria and supporting laboratory values, or until death. It was not possible to test blood samples from these patients for the presence of hepatitis B antigen because the serodiagnositc procedure was not available at the D h a h r a n Health Center laboratories during the course of this investigation.
mission to the D h a h r a n Health Center was generally dictated by the occurrence of hepatitis of more than the usual severity or hepatitis complicated by some other medical problem. Traditional criteria for the diagnosis of viral hepatitis included the absence of any history of prior medication (to exclude drug-induced hepatitis) and the absence of clinical and laboratory features, or both, usually associated with cholestatic jaundice of pregnancy or extrahepatic biliary tract obstruction. T h e possibility that instances of acute fatty metamorphosis of the liver were included in the small group of pregnant women who died could not be excluded. T h e diagnostic advantage afforded by liver biopsy could not be employed to provide the distinction between this entity and viral hepatitis because of the usual prolongation of the prothrombin time a n d the risk of hemorrhage in the critically ill patient.
RESULTS During the prospective study, a total of 74 women and 36 men meeting the criteria of acute viral hepatitis were hospitalized at the D h a h r a n Health Center. T h e ratio of pregnant to nonpregnant women was 41:33 (124), which closely approximated the ratio of 54:42 (1.29) from the 1953-1962 series, an indication of comparable selection of female patients between the two series. Further comparison (Table I) reveals a striking reduction in the mortality for women (X2 = 14.7, p < 10 - 5 ). But the reduction in mortality appears essentially to be caused by an increased in survival for the group in the third trimester of pregnancy or puerperium (x 2 = 13.0, p < 10 - 3 ). However, the risk of fatal hepatitis among pregnant patients, a compared to nonpregnant ones, remains virtually unchanged: 0.463/ 0.119 = 3.89 (1953-1962), as opposed to 0.122/0.30 = 4.06 (1963-1975). Furthermore, the mortality risk for the group in the third trimester or puerperium compared with the group in the first and second trimester of pregnancy had not changed appreciably: 0.708/0.267 = 2.65 (1953-1962), as opposed to 0.143/0.056 = 2.55 (1963-1975). However, the risk for third trimester pregnancy/puerperium patients, as compared with nonpregnant ones, had decreased slightly, 0.708/0.119 = 5.95 (19531962), as opposed to 0.143/0.030 = 4.76 (19621975). From 1963 through 1967, there were five deaths among 39 women, but from 1968 through
Conventional laboratory tests used for diagnostic a n d prognostic evaluation included for the serum glutamic oxaloacetic transaminase (SGOT) and the prothrombin time. T h e normal value for the S G O T was 40 I U / m l , and for the prothrombin time, 12-14 seconds. Both of these tests were selected for consideration as discriminants of the severity of hepatitis, the former because of its traditional utility in assessing the degree of hepatocellular necrosis, and the latter because previous experience among Saudi women with hepatitis had confirmed its reliability in predicting a fatal course of hepatitis (10). In highrisk patients, those in the third trimester of pregnancy or the puerperium, daily prothrombin determinations were done. Any patient showing signs of clinical deterioration (an initial prothrombin time of 20 seconds or longer) or a progressive increase in the prothrombin time to and above 20 seconds was considered for adrenal corticosteroid therapy. Such treatment consisted of the intravenous administration of 200 m g / d a y of hydrocortisone sodium succinate, 60 m g / d a y of prednisolone in divided intramuscular doses or 40-60 m g / d a y of prednisone
Table I. Hepatitis mortality at the Dhahran Health Center. Females Male Interval
1953-1962 1963-1975
No. 25 (552) a 2(36)
Nonpregnant % 4.5 5.6
Pregnant: 1st-2nd trimester
No.
%
No.
5(42) 1(33)
11.9 3.0
8(30) 1 (18)
% 26.7 5.6
Pregnant: 3rd trimester/puerperium No.
17 (24) 3(21)
' Numbers in parentheses represent totals in each group. ' Includes two pregnant patients with uncertain duration of gestation and with one death.
InlJ Gynaecol Obstet 17
% 70.8 14.3
Total No.
55 (648) 8 (110) b
% 8.5 7.3
Hepatitis complicating pregnancy
1975, there was only one death among 35 consecutive women. In the 1963-1975 series, 14 subjects were treated with adrenal corticosteroids: twelve of these patients were pregnant and six of the 14 died, a death rate of 43%. Two of the fatal cases were comatose on admission, and the course of hepatitis in these patients was not likely to have been altered by the administration of corticosteroids. O n e patient who developed coma following admission survived, and this person was not treated with corticosteroids. Among the remaining eight patients treated with corticosteroids, the usual indications for such management were a moderate-to-marked increase in the one-stage prothrombin time or unfavorable prognostic signs, which included profound anorexia and a changing sensorium, as well as those previously cited. In any case, corticosteroid treatment for highrisk patients did not appear to reduce mortality to any significant extent. Comparison with a similar group of high-risk patients seen during the interval 1953-1962 provided no evidence of a beneficial effect from corticosteroids; within this group no patient with a peak prothrombin time of 25 seconds or more survived. In the 1963-1975 group, there were seven patients with prothrombin times in excess of 25 seconds. All received corticosteroids; only two survived. In the group of women whose parturitions were directly related to hepatitis, data on the outcome of the pregnancies were available for 11 patients. There were no abortions but there were two stillbirths. This contrasts with experience from the 1953-1962 series in which 15 of 43 pregnancies terminated in an abortion or stillbirth; this difference, however, is not statistically significant. In order to assess the discriminative value of the S G O T a n d the prothrombin time determinations for predicting the severity of hepatitis among the four groups of patients (males, nonpregnant females, females in the first and second trimesters of pregnancy a n d females in the third trimester or early postpartum period), peak values for each of the tests were tabulated for each patient. In the majority of
75
patients, several determinations of the S G O T a n d the prothrombin time were carried out during hospitalization. T h e cases for which only one S G O T or prothrombin determination was recorded in the medical records were also included in the tabulation. Two patients had serum enzyme determinations other than for the S G O T to confirm the presence of hepatocellular disease, a n d there were several who lacked either determinations for S G O T or prothrombin time and were, therefore, not included in the tabulation. Finally, determinations of S G O T and prothrombin times from those who succumbed to hepatitis were not included in the tabulation. There appeared to be trends in severity, as evidenced by comparison of the mean peak S G O T determination between the two groups of pregnant women, and of the prothrombin times between the nonpregnant and pregnant women (Table II). However, an analysis of variance revealed no significant discriminant value for either test in separating the four groups in terms of anticipated severity and expected mortality. Thus, the actual comparative risk of death that had been observed between pregnant and nonpregnant women with hepatitis was not matched by parallel aberrations in the two laboratory parameters that were considered in this study. Over the past ten years, publications from Africa (4, 6, 14, 18), the Middle East (3, 10), South Asia (1, 2, 5, 15) a n d Latin America (7, 17) have implicated viral hepatitis as an important cause of mortality during pregnancy a n d have emphasized the increasing risk during late pregnancy and the puerperium. T h e cumulative experience reflected in the literature shows a significant increase in mortality associated with viral hepatitis between nonpregnant and pregnant status a n d from the first and second trimester of pregnancy to late pregnancy a n d puerperium.
DISCUSSION Several reports that have emphasized the great risk of hepatitis occurring during pregnancy have
Table II. Mean peak serum glutamic oxaloacetic transaminase (SGOT) and prothrombin time (PT) among Saudi Arabians with viral hepatitis. SGOT in lU/ml Group Males Nonpregnant females Females in 1 s t - 2 n d trimester Females in 3rd trimester/puerperium
No. 34 29 15 16
PT in sec
Mean
SD
No.
1026 1134 788 1318
±705 ±991 ±661 ±1087
30 30 16 18
Mean 18.1 16.2 18.7 18.6
SD ±6.4 ±2.1 ±8.2 ±6.2
IntJ Gynaecol Obstet 17
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Gelpi
concluded that malnutrition plays an important role in determining the outcome of hepatitis (2, 3, 6, 18). T h e hypothesis that malnutrition adversely affects the course of viral hepatitis does not explain the increased mortality risk in relation to pregnancy as compared with nonpregnant status, nor does it take into account the gradient of increasing severity and mortality from early through late pregnancy and the puerperium. Finally, despite the a b u n d a n t evidence that viral hepatitis is a definite risk for the pregnant woman, there is little evidence that the outcome of other systemic viral infections, with the exception of certain outbreaks of pandemic influenza, is adversely affected by pregnancy (8, 12). D a t a on the course of viral hepatitis in pregnancy from Saudia Arabia, spanning the course of 23 years, provide the first indication that a trend of improvement in the outcome of hepatitis associated with pregnancy could be related to changing socioeconomic conditions. Within the period encompassed by this longitudinal study, there has been startling economic development in Saudi Arabia a n d in neighboring oil-producing countries, which has been accompanied by social reforms, improving educational opportunities, importation and distribution of luxury foods, proliferation of health-care facilities a n d the application of public health measures that have promoted maternal-child health programs. These dramatic events are nowhere more evident t h a n in the eastern, oil-producing area of Saudi Arabia. It would be tempting to conclude that the improvement in the quality of life and in the general health of the Saudi population has reduced the mortality from hepatitis in pregnancy. However, the relative risk of dying of hepatitis in pregnancy has not changed appreciably; therefore, the differential mortality from hepatitis observed between pregnant and nonpregnant women is likely to reflect a true susceptibility to more severe disease during the gestational period. An important consideration regarding the concurrence of pregnancy and hepatitis is the hypercoagulable state that appears to accompany normal pregnancy (13), and evidence of incipient intravascular coagulation that has been observed in uncomplicated viral hepatitis (9). T h e more florid disseminated intravascular coagulation (DIC), which often complicates fulminant hepatitis (16), has also been observed. T h e association of moderately severe hepatitis with pregnancy might therefore provide the conditions for accelerated intravascular coagulation, with catastrophic consequences for the patient. O n e possible explanation for the favorable trend in the mortality observed among Saudi women with hepatitis lies in the selective bias wherein all women
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with hepatitis, however mild, were admitted to the hospital during the prospective study, from 1963 through 1975. This should be reflected in a comparative increase in the n u m b e r of women hospitalized during the latter period. However, the average number of admissions per year during the retrospective study was 11, as compared with six during the prospective study. This difference may simply reflect an overall decrease in the incidence of viral hepatitis in the Saudi population, with decreasing numbers of women hospitalized for hepatitis despite the inclusion of milder cases for hospital admission. T h e most conclusive evidence of the favorable trend in the course of hepatitis among Saudi women comes from the final eight years of the prospective study: there was only one fatal case of hepatitis, a death rate of 3%. Neither of the laboratory parameters that were evaluated in this report, the S G O T and the prothrombin time, provided discrimination a m o n g the four groups of patients in regard to severity of hepatitis. However, marked elevations of the prothrombin times were associated with a high mortality, as had been observed in the retrospective study of hepatitis in Saudi Arabians, and noted in other publications. T h e use of adrenal corticosteroids in the management of viral hepatitis remains a matter of controversy. At least one recent report suggests that corticosteroids may actually have an adverse effect on the course of hepatitis (11). T h e effect of corticosteroids on the course of hepatitis in Saudi women, and on the mortality pattern in pregnancy complicated by hepatitis, cannot be determined from the data provided in this report. Too few patients qualified for treatment with corticosteroids, according to the protocol employed in the prospective study, and two of the six patients who died of hepatitis were comatose on admission and prior to the administration of corticosteroids. T w o patients with m a x i m u m prothrombin times in excess of 25 seconds survived, possibly salvaged by the administration of corticosteroids. T h e compiled data from a number of recent publications concerning the course of hepatitis complicating pregnancy conclusively demonstrate an increasing risk of death associated with pregnancy, which is most evident during late pregnancy and puerperium. These and other sources have furnished evidence of significant fetal loss directly related to the occurrence of hepatitis during pregnancy, and, in addition, they have emphasized significant perinatal loss and prematurity. There has been a notable decrease in the mortality, due to viral hepatitis in a population of Saudi
Hepatitis complicating pregnancy
Arabians observed over a 23-year period. This decrease is primarily the result of improved survival of pregnant women with hepatitis. T h e earlier high death rate that had been observed in Saudi women parallels those that have been more recently encountered in populations of other developing countries. In Saudi Arabia, the relative risk of fatal outcome among pregnant women has not changed significantly despite the substantial decrease in the overall mortality among women with viral hepatitis. These data, together with observations from other publications on the differential risk of hepatitis from early through late pregnancy, suggest that changing socioeconomic conditions do not completely explain the change in mortality observed among Saudi women. Pregnancy itself seems to be an important determinant of severity and the risk of death with viral hepatitis. Pregnancy complicated by hepatitis may be associated with an increased tendency for disseminated intravascular coagulation, which is greater than that anticipated for uncomplicated pregnancy or for moderatley severe hepatitis alone. Finally, there is a high rate of fetal loss associated with hepatitis-complicated pregnancy in populations of developing countries, and, in general, this trend parallels the high mortality among mothers with viral hepatitis. In cases of hepatitis, marked elevations of the prothrombin time, twice or more the normal values, are usually associated with fatal outcomes. However, excluding those patients with fatal hepatitis, mean peak prothrombin times do not appear to correlate with presumed severity and observed differential mortality between groups of pregnant and nonpregnant women. Administration of adrenal corticosteroids to women with viral hepatitis who were believed to be at greatest risk for fatal termination has not been demonstrated to have significantly influenced the outcome of hepatitis.
ACKNOWLEDGMENT Funding and facilities for this study were provided entirely by the Arabian America Oil Company, Dhahran, Saudi Arabia.
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Address for reprints: A. P. Gelpi Room S-169 Stanford University Medical Center Stanford, CA 94305 USA
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