Aetiology, clinical course and outcome of sporadic acute viral hepatitis in pregnancy

Aetiology, clinical course and outcome of sporadicacute viral hepatitis in pregnancy*M. S. Khuroo1 and S. Kamili2 1Section of Gastroenterology, Department of Medicine, King Faisal Specialist Hospital & Research Centre,

Riyadh, Saudi Arabia; 2Experimental Pathology Section, Hepatitis Branch, Division of Viral and Rickettsial Diseases, US Centres for Disease Control and

Prevention, Atlanta, GA, USA

Received June 2002; Accepted for publication September 2002

SUMMARY. Hepatitis E causes large-scale epidemics in

endemic areas. The disease, during epidemics, has increased

incidence and severity in pregnant women. Sporadic acute

viral hepatitis (AVH) is common in endemic areas. The

relationship of sporadic AVH and pregnancy has not been

well studied. Over a 3-year period we prospectively studied

76 pregnant women and 337 non-pregnant women of

childbearing age with sporadic acute viral hepatitis for ae-

tiology, clinical course and outcome of disease. The aetiology

in sporadic AVH was hepatitis A virus (HAV) in six (1.5%),

hepatitis B virus (HBV) in 62 (15%), hepatitis C virus (HCV)

in seven (1.7%), hepatitis D virus (HDV) co-infection in six

(1.5%), hepatitis E virus (HEV) in 205 (49.6%), and hepatitis

non-A-to-E (HNAE) in 127 (30.7%). Sixty-five (85.5%)

pregnant women and 140 (41.5%) nonpregnant women

had hepatitis E. The proportion of pregnant women was

31.7% in HEV group and 5.3% in non-HEV group

[P < 0.001; OR ¼ 8.3 (95%C1 4.2–16.3)]. The prevalence

of HEV in pregnant women in first trimester (76.9%), second

trimester (88.9%), third trimester (83.8%) and puerperium

(100%) did not differ significantly (P ¼ 0.09). Forty-seven

(61.8%) of the 76 pregnant women developed fulminant

hepatic failure (FHF), 69.2% in HEV group and 10% in non-

HEV group (P < 0.001). Thirty-four (10.1%) nonpregnant

women developed fulminant hepatic failure, 10% in HEV

group and 9.7% in non-HEV group (P ¼ 0.86). FHF had

occurred in four (40%) of 10 patients with HE in first

trimester as against 41 (74.5%) of 55 patients in second

trimester and beyond (P ¼ 0.015). Amongst the major

complications of fulminant hepatic failure, cerebral oedema

(53.2%) and disseminated intravascular coagulation

(21.3%) occurred more often in pregnant women than in

nonpregnant women (29.4% and 2.8%; P ¼ 0.03 and

0.016, respectively) while infections occurred more often in

nonpregnant women (36.1%) than in pregnant women

(10.6%; P ¼ 0.003). Fifty (61.7%) patients with FHF died

[25 (53.2%) pregnant women and 25 (69.5%) nonpregnant

women (P ¼ 0.06)]. Cerebral oedema and HEV aetiology

were independent variables of survival in patients with FHF.

Patients with cerebral oedema had worse prognosis and

patients with HEV aetiology had best chances of survival.

Hence HEV was the most common cause of sporadic AVH in

this endemic area. High proportion of pregnant women and

increased severity of disease in pregnancy were limited to

patients with hepatitis E. Sporadic AVH caused by agents

other than HEV did not show any special predilection to or

increased severity in pregnancy. FHF in pregnant women

caused by HEV was an explosive disease with short pre-

encephalopathy period, rapid development of cerebral

oedema and high occurrence of disseminated intravascular

coagulation and may represent a severe manifestation of a

Schwartzmann-like phenomenon.

Keywords: fulminant hepatic failure, hepatitis E, hepatitis E

virus, liver diseases in pregnancy, pregnancy, viral hepatitis.

Abbreviations: AVH, acute viral hepatitis; HEV, hepatitis E virus; FHF, fulminant hepatic failure; HNAE, hepatitis non-A-E; HAV, hepatitis A

virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis delta virus.

*This work was done at the Department of Gastroenterology Sher-I-Kashmir Institute of Medicine Srinagar, Kashmir, India.

Correspondence (present address): Prof. M.S. Khuroo, Consultant Hepatologist, Head, Gastroenterology (MBC 46), Department of Medicine,

Post Box 3354, King Faisal Specialist Hospital & Research Centre, Riyadh 11211 Saudi Arabia. E-mail: [email protected]

Journal of Viral Hepatitis, 2003, 10, 61–69

� 2003 Blackwell Publishing Ltd

INTRODUCTION

Hepatitis E (HE) is an enterically transmitted acute viral

hepatitis (AVH) and is aetiologically associated with the

recently identified hepatitis E virus (HEV) [1]. HEV causes

large-scale epidemics in developing countries, involving tens

of thousands of cases [2]. The disease, in its epidemic form,

causes considerable morbidity and mortality and poses a

major health problem in endemic areas [3,4]. Epidemics

are caused by contaminated drinking water sources [5].

Secondary waves of hepatitis usually do not occur following

epidemics, suggesting that person-to-person transmission is

not a major factor in the evolution of the outbreaks [6].

There is a high attack rate in adults with a lower attack rate

in children below 14 years [2]. HE has been reported in the

developed countries as an imported disease in travellers to

endemic areas and recently as a cause of a small percentage

of cases of sporadic and fulminant hepatic failure (FHF) in

persons who had not visited endemic areas [7,8]. Seropre-

valence data reveal a global distribution of the disease [9].

The infection is prevalent in a wide range of animal species

and it has been suggested that human infection may have a

zoonotic origin [10]. A recombinant vaccine against HEV

has passed through phase I study and phase II & III trials are

under way [11].

HE has high incidence and severity in pregnant women

[12]. In fact, the major cause of mortality in the epidemics is

the high rate of FHF in pregnant women. Vertical trans-

mission commonly occurs with high fetal and neonatal

morbidity and mortality [13]. The reason for the increased

incidence and severity of HE in pregnancy is not known. The

epidemiology of sporadic AVH and its association with

pregnancy has not been well studied. Most of the studies

addressing this issue were done when serological tests for

HEV were not available and all patients negative for acute

markers of HAV and HBV were classified as non-A, non-B

hepatitis [14–21]. In fact, only about one half of such cases

are aetiolologically related to HEV and remaining cases are

caused by unknown putative viral agents, hepatitis non-A-E

(HNAE) [19]. The proportion of cases of sporadic AVH in

pregnancy caused by HEV and other hepatitis viruses is not

known. Whether hepatitis viruses other than HEV have

increased incidence and severity in pregnancy in developing

countries is also not known. How does FHF in pregnancy

differ from those in nonpregnant women? Answers to

these questions may help in understanding the reason for

increased incidence and severity of AVH in pregnancy in

developing countries. The present study reports on a large

cohort of pregnant women with sporadic AVH from an

endemic area.

PATIENTS AND METHODS

The study included all consecutive patients of sporadic

AVH in pregnancy attending the Liver Unit of Gastroen-

terology Department at Sheri Kashmir Institute of Medical

Sciences, Srinagar, Kashmir, India from January 1993 to

January 1996. During the same period, all cases of sporadic

AVH in nonpregnant women of childbearing age (15–

45 years) were studied. Patients reported from outbreaks or

epidemics of hepatitis or those who had visited such areas

in the last 3 months were excluded. All patients had clin-

ical examination, urinary test for chorionic gonadotropin

and pelvic ultrasound examination to detect pregnancy and

to evaluate age of gestation in pregnant women. Clinical

history and physical examination were recorded on a pro-

forma and 10 ml blood sample was collected for bio-

chemical and serological tests. A serum sample was stored

at )70 �C for subsequent virological assays. Patient

admission to hospital and management was determined by

severity of liver disease as assessed by clinical and bio-

chemical parameters. All patients with FHF were admitted

to intensive care unit and received standard supportive care

with monitoring of clinical, biochemical and haemody-

namic parameters. None of the patients received a liver

transplant, as this facility was not available at our centre.

Pregnant women had conservative and expectant approach

and no attempts were made to terminate pregnancy or

induce labour unless otherwise indicated on standard

obstetric practices.

The criteria for the diagnosis of AVH were (i) recent onset

of jaundice in the absence of prior history of jaundice or

chronic liver disease; (ii) no other cause to account for

jaundice, including drug hepatitis, severe infections, chole-

static jaundice of pregnancy, eclampsia, Hemolysis Elevate

Liver enzymes and Low Platelet (HELLP) syndrome, acute

fatty liver of pregnancy, etc. (if any of the above diagnoses

was entertained, appropriate clinical examination, imaging

tools and laboratory tests were utilized to substantiate the

diagnosis); (iii) serum bilirubin of 2.0 mg/dL or more, with

an increase in transaminases two and a half times above the

upper limit of normal [serum aspartate aminotransferase

(AST), 6–18 IU/L; serum alanine aminotransferase (ALT),

3–26 IU/L); (iv) liver biopsy in selected group of patients

substantiating diagnosis of acute viral hepatitis. Liver biop-

sies were performed in all fatal cases (postmortem) and in

those with suspected fatty liver of pregnancy. Cholestatic

viral hepatitis was diagnosed when clinical (itching, clay

stools and dark urine) and biochemical (serum alkaline

phosphatase three times above the upper limit of normal)

features of intrahepatic cholestasis lasted for over 6 weeks.

Fulminant hepatic failure was defined as the occurrence

of hepatic encephalopathy in a patient with AVH within

8 weeks of onset of the disease. Encephalopathy was classi-

fied into four grades as per defined criteria Cerebral oedema

in such patients was diagnosed when features of decere-

bration occurred, along with other clinical signs of high

intracranial pressure. Disseminated intravascular coagula-

tion (DIC) was diagnosed when bleeding occurred from

multiple anatomical sites (skin, mucosa, venipuncture sites,

� 2003 Blackwell Publishing Ltd, Journal of Viral Hepatitis, 10, 61–69

62 M. S. Khuroo & S. Kamili

etc.) along with low levels of fibrinogen (< 2 g/L), thrombo-

cytopenia (< 100 · 109/L), and high levels of fibrin degra-

dation products. Infections were diagnosed on clinical,

radiological and microbiological evidences. Acute renal

failure was diagnosed when urine output dropped below

400 ml/day and serum creatinine rose to 3.0 mg/dL or

above. Fatal hepatitis meant death in a case of FHF.

Serology for hepatitis viruses was performed by enzyme-

linked immunosorbant assays (ELISA) for markers of HAV

(IgM anti-HAV), HBV (HBsAg and IgM anti-HBc), HCV

(anti-HCV second generation) and HDV (IgG and IgM anti-

HDV) using commercially available kits from Abbott

Laboratories (North Chicago, IL, USA). The assays were

performed according to manufacturer’s instructions. Sera

from all patients were also tested by ELISA for IgG and IgM

antibodies to HEV by a kit using two recombinant HEV

antigens corresponding to structural region of the HEV

(Diagnostic Biotechnology, Singapore). All repeatedly

reactive samples were further tested by synthetic peptide

based ELISA using an immunoreactive peptide in ORF3 of

the HEV genome. Only reactive samples in the both ELISA

systems were accepted for diagnosis of HEV infection. All

sera were tested by Polymerase chain reaction (PCR) for

HEV RNA and sera negative for acute markers of hepatitis A

to E were tested for HCV RNA by PCR. The detection of HEV

RNA was performed by reverse transcription nested PCR

using primer sets 3043/3044 and HEV-1/HEV-3. The pri-

mer sequences and the conditions for PCR have been

previously described. HCV RNA was detected by reverse-

transcription nested PCR using primer from the 5¢nontranslated region. To avoid bias, all sera were tested

under code. Confirmed positive and negative controls were

run with all PCR amplification reactions to ensure faithful

amplifications. Strict application of containment measures

was used to avoid false positives. Results of any PCR reac-

tions were considered valid only if they were consistent in at

least two independent experiments that included RNA

extraction step as well [3,13,22].

On the basis of above viral markers, AVH was classified as:

HA (presence of IgM anti-HAV), Acute Hepatitis B (AHB)

(presence of HBsAg and IgM anti-HBc), acute hepatitis on a

HB carrier (presence of HBsAg with negative IgM anti-HBc),

HD (presence of IgG or IgM anti-HDV and HBsAg), HCV

infection (presence of anti-HCV and/or HCV RNA), HEV

(presence of IgM anti-HEV and/or HEV RNA) and hepatitis

non-A–E (HNAE) (negative of above viral markers).

Statistical methods

Comparisons of categorical variables were analysed using

either Fisher’s exact test when any of the expected value was

<5 or v2-test for all others. Comparisons of continuous

variables were analysed using Student’s t-test for normally

distributed variables and Mann–Whitney U-test for non-

normally distributed variables. Variables with skewed devi-

ation (serum bilirubin and ALT) were normalised using log

transformation for analysis. In patients with FHF, all con-

tinuous variables found significant on univariate analysis

were dichotomized for best discrimination between survivors

and nonsurvivors. Logistic regression analysis, using SAS

software statistical package (SA Institute Inc., Cary, NC,

USA) was used to identify which of the variables independ-

ently predicted prognosis in patients with FHF. Odd’s ratios

were computed from the coefficients and their 95% confid-

ence intervals were calculated. All values are expressed as

mean ± SD. A P-value of < 0.05 was considered significant

[23,24].

RESULTS

During the study period, a total of 76 consecutive pregnant

women with sporadic AVH were enrolled. Thirteen (17.1%)

patients were in the first trimester, 18 (23.7%) patients in the

second trimester, 37 (48.7%) patients in the third trimester

and eight (10.5%) patients in the puerperium. During the

same period a total of 337 consecutive nonpregnant women of

childbearing age (15–45 years) with sporadic AVH were

studied. The aetiologies of sporadic AVH were: HAV in six

(1.5%), HBV in 62 (15%), HCV in seven (1.7%), HDV coin-

fection in six (1.5%), HEV in 205 (49.6%) and HNAE in 127

(30.7%). The proportion of pregnant women in HEV group

was 31.7% (65 of 205 patients) and 5.3% in non-HEV group

(11 of 208 patients) [P < 0.001; OR ¼ 8.3 (95%CI 4.2–

16.3)].

The clinical, biochemical parameters and aetiology of

sporadic AVH in pregnant vs nonpregnant women is shown

in Table 1. The two groups did not differ significantly in mean

age. Pregnant women with AVH presented to the hospital

earlier (P ¼ 0.01) and had lower serum bilirubin than non-

pregnant women with AVH (P < 0.001), however, serum

ALT, AST and Alkaline Phosphatase (ALP) in the two groups

did not differ significantly. Cholestatic hepatitis developed in

45 (10.9%) patients; 10 (13.2%) in pregnant women and 35

(10.4%) in nonpregnant women [P ¼ 0.2; OR ¼ 1.3 (95%CI

0.5–1.0)]. The aetiology of AVH in the two groups differed

significantly. HEV was the predominant (85.5%) cause of

AVH in pregnant women [P < 0.001, OR ¼ 8.3(95%CI

4.2–16.3)], followed by HNAE in 11.9% and HBV in 2.9%. In

contrast, aetiology of AVH in nonpregnant women, in order

of frequency, was HEV (41.5%), HNAE (35%), HBV (17.8%),

HCV (2.1%), HDV coinfection (1.8%) and HAV (1.8%). The

prevalence of HEV in first trimester [76.9% (10/13)], second

trimester [88.9% (16/18)%], third trimester [83.8% (31/37)]

and puerperium [100% (8/8)] did not differ significantly from

each other (P ¼ 0.09).

Eighty-one (19.6%) of the 413 AVH patients developed

FHF. The rate of FHF was significantly higher in pregnant

women [61.8% (37/76)] than nonpregnant women [10.1%

(34/337)] [P < 0.001, OR ¼ 14.4 (95%CI 8.0–25.8)]. The

rate of FHF in first trimester was 30.8% (4/13), which was


Viral hepatitis in pregnancy 63

significantly lower than in second trimester [66.7% (12/

18)], third trimester [62.2% (23/37)] and puerperium

[100% (8/8)] (P ¼ 0.015 for all). The clinical, biochemical

parameters and aetiology of FHF in pregnant vs nonpreg-

nant women is shown in Table 2. The pre-encephalopthy

period in pregnant women with FHF was significantly

shorter than those with nonpregnant women (P ¼ 0.001).

Pregnant women with FHF developed more often cerebral

oedema and disseminated intravascular coagulation than

those with nonpregnant women. In contrast, nonpregnant

women with FHF, developed systemic infections more often

than those with pregnant women. The mortality of pregnant

women with FHF, was lower (53.2%) than those with

nonpregnant women (69.5%); however, this difference did

not reach statistical significance.

None of the patients with HA, HC and HD co-infection

developed FHF. The rates of FHF in patients with various

aetiologies were as follows: HBV 8.1% (5/62) [0% (0/2) in

pregnant women and 8.3% (5/60) in nonpregnant women],

HEV 28.7% (59/205) [69.2% (45/65) pregnant women and

10% (14/140) in nonpregnant women] and HNAE 13.4%

(17/127) [22.2% (2/9) in pregnant women and 12.7% (15/

118) in nonpregnant women]. The rate of FHF in pregnant

women with HE (69.2%) was significantly higher than those

with HB and HNAE (18.1%; P ¼ 0.001). In contrast, rate of

FHF in nonpregnant women with HE (10%) was similar to

those with HB and HNAE (10.6%; P ¼ 0.86).

Hepatitis E virus was the aetiological cause of FHF in 45

(95.7%) of 47 pregnant women. In contrast, aetiology of

FHF in nonpregnant women was HNAE (44.1%), HEV

(41.2%), and HBV (14.7%) [P < 0.001, OR ¼ 32.1(95%CI

6.7–154.5)].

The clinical variables that influenced survival in 81

patients with FHF are shown in Table 3. Short pre-

encephalopathy period, nonpregnant state, non-HEV aetiol-

ogy, higher grades of encephalopathy, cerebral oedema,

infections and acute renal failure were detected in a higher

proportion of patients who died, in comparison with those

who survived. Age, trimester of pregnancy, gastro-intestinal

bleed, disseminated intravascular coagulation and bio-

chemical tests among survivors and nonsurvivors were

similar. Multiple stepwise logistic regression was performed

Table 1 Clinical, biochemical and aetiological profile of sporadic viral hepatitis in pregnant women vs nonpregnant women

Pregnant women Nonpregnant women P-value OR (95% Cl )

Number of patients 76 337

Age in years

Mean + 1SD 27.7 + 5.5 28.9 + 7.1 0.311

Range 16–45 18–42

Duration of disease at presentation (days)

Mean + 1SD 5.6 + 4.3 9.5 + 5.2 0.014

Range 1–12 3–18

Clinical disease (no. of patients)

Non-fulminant 29 303 < 0.001 14.4 (8.0–25.8)

Fulminant 47 34

Hepatic profile serum bilirubin (mg/dL)

Mean + 1SD 12.1 + 6.9 19.9 + 10.9 0.00014

Range 0.8–32.5 3.5–46.0

Serum ALT(U/I)

Mean + 1SD 446.5 + 354 348 + 1630 0.1446

Range 72–1670 58–5927

Serum ALP(U/I)

Mean + 1SD 557.5 + 179.7 535 + 193.9 0.7269

Range 213–935 310–999

Aetiology (no. of patients) < 0.001 8.3 (4.2–16.3)

HAV 0 6

HBV 2 60

HCV 0 7

HDV (co-inf ) 0 6

HEV 65 140

HNAE 9 118



to discriminate survivors and nonsurvivors. The only

dependant predictors of outcome were cerebral oedema and

HEV aetiology. Patients with cerebral oedema had worse

prognosis and patients with HEV aetiology had best chances

of survival.

Table 4 shows the outcome of pregnancies in 76 pregnant

women with AVH. Four pregnancies ended in abortion or

still birth, in 18 pregnancies mother died without delivery of

the fetus/baby and in 54 pregnancies pregnancy continued

unaffected by AVH or normal delivery occurred during the

disease course.

DISCUSSION

Viral hepatitis in pregnancy has been a matter of considerable

debate. Studies from the west have shown that AVH has no

special predilection to pregnancy and the disease in pregnant

women has similar clinical course to those in nonpregnant

women [25–30]. In contrast, viral hepatitis in developing

countries has increased incidence and severity in pregnancy

[12, 14–22]. This may be related to differing aetiologies of

AVH and FHF in developed and developing countries. The

aetiology of AVH in the western countries includes HAV

(40%), HBV (30%), HCV (25%) and HNAE (2%)[31]. FHF in

such countries is related to hepatitis viruses in 50–70% of

patients and caused by HAV (17%), HBV (27%) and HNAE

(55%) [32]. HE is seen as imported disease or as isolated case

reports in patients who have not travelled to endemic areas

and constitutes < 1% of all cases of sporadic AVH [7,8].

Aetiology of sporadic AVH in developing countries is different

from that in the west [22]. HEV is the most common cause of

sporadic AVH (40%). Remaining cases are related, in order of

Table 2 Clinical, biochemical and aetiological profile of fulminant hepatic failure in pregnant women vs nonpregnant women

Pregnant women Nonpregnant women P-value OR (95%CI)

Number 47 34

Age

Mean + 1SD 28.74 + 5.76 28.82 + 6.57 0.954

Range 16–45 18–40

Duration of disease at admission (days)

Mean + 1SD 8.93 + 11.0 18.84+20.67 0.0254

Range 2–60 3–75

Pre-encephalopathy period (days)

Mean + 1SD 5.83 + 5.81 19.53 + 21.89 0.0018

Range 1–30 2–85

Aetiology (no. of patients) < 0.001 32.1 (6.7–154.5)

HBV 0 5

HEV 45 14

HNAE 2 15

Hepatic profile serum bilirubin (mg/dL)

Mean + 1SD 14.6 + 5.99 21.44 + 10.79 0.0028

Range 6.8–32.5 6.0–46.0

Serum ALT(U/I)

Mean + 1SD 523.7 + 349 348 + 1863 0.179

Range 118–1216 110–5927

Serum ALP(U/I)

Mean + 1SD 563.8 + 161.6 537.5 + 202.3 0.709

Range 347–838 310–999

Complications

Cerebral oedema 25 10 0.033 2.7 (0.6–12.9)

G.I.bleed 5 7 0.2 2.2 (0.6–7.5)

Infections 5 13 0.0034 8.5 (1.6–16.5)

Renal failure 6 6 0.2 1.5 (0.2–2.1)

D.I.C 10 1 0.016 8.9 (1.1–72.6)

Mortality (no. of patients) 25 25 0.063 2.4 (0.4–16.2)



Univariate analysis

Pf vsNPF Live Dead P-value

Total 31 50

Age

Mean + SD 29.2 + 6.2 28.8 + 6.1 0.8

Range 18–45 16–45

PEP (days)

Mean + SD 5.3 + 2.9 12.8 + 17.4 0.0048

Range 2–12 16–45

< 56 31 43 0.0001

> 56 0 7

< 7 27 21 0.0013

8–28 4 18

> 28 0 11

< 84 24 38 0.288

> 84 0 4

Pregnancy

Yes 22 25 0.0134

No 9 25

Aetiology

HEV 29 30

non-HEV 2 20

PSE grade

Mean + SD 2.8 + 0.9 3.2 + 0.9 0.0247

1 13 14 0.0239

2 7 3

3 5 10

4 6 23

Cerebral oedema

Yes 5 29 0.0002

No 26 21

Infection

Yes 3 15 0.032

No 28 35

GI bleed

Yes 2 10 0.094

No 29 40

Renal failure

Yes 1 11 0.02

No 30 39

DIC

Yes 4 7 0.893

No 27 43

Bilirubin

Mean + SD 14.9 + 6.1 17.3 + 9.9 0.096

PT(sec)

Mean + SD 18.1 + 3.0 20.6 + 12.4 0.098

ALT

Mean + SD 161 + 249 245 + 346 0.269

ALP

Mean + SD 254 + 169 236 + 173 0.0987

Table 3 Demographic and clinical

profile of patients with fulminant

hepatic failure



frequency, to HNAE (25%), HBV (22%), HCV (9%) and HAV

(4%). FHF is aetiologically related to hepatitis viruses in over

95% of cases and aetiologically related to HNAE (37%), HBV

(18%), HCV (5%) and HAV (3%). The data from the present

study confirmed these earlier observations. HEV was the most

common cause of sporadic AVH and FHF. HAV was an

insignificant cause of sporadic AVH and FHF in adult females,

as exposure to HAV occurs very early in life and prevalence of

antibodies to HAV is over 95% by the end of first decade of life.

In the present study, pregnant women constituted 76

(18.4%) of the 413 women (15–45 years) with sporadic

AVH. Census data from this community showed that preg-

nant women constitute only 3.0% of the female population

in this age group [2,4]. Thus pregnant women were repre-

sented six times more often in the group with sporadic AVH

than the general population. We and others have recorded

high proportion of pregnant women in sporadic AVH in

earlier studies. Tsega et al. studied 110 Ethiopian patients

with sporadic AVH [20]. Of the 66 women in the repro-

ductive age range (15–45 years), 32 (48%) were pregnant;

five were in the first trimester, nine were in second and 18

were in the third trimester. We studied 293 patients with

sporadic AVH from an endemic area [12]. Pregnant women

constituted 27 (28.7%) of the 94 women in the reproductive

age group, three in the first trimester, five in the second

trimester and 19 in the third trimester. An important finding

in the present study is that a high proportion of pregnant

women in sporadic AVH were limited to the HEV group

(31.7%) and not in those patients with non-HEV aetiology

(5.3%). These data are in conformity with our previous data

collected during an epidemic of HE. During this epidemic,

pregnant women constituted 41.8% (36 of 86 cases) women

in the childbearing age with HE and the attack rate of HE in

pregnant women was 17.3% as against 2.1% in nonpreg-

nant women of childbearing age. These data suggested that

increased proportion of pregnant women in sporadic AVH

was due to increased attack rate of HEV in pregnant women,

similar to that seen during the epidemics of HE. Sporadic

AVH caused by other hepatitis viruses did not have

increased attack rate in pregnant women.

The rate of FHF in sporadic AVH in the present study was

19.6%, being significantly higher (61.8%) in pregnant

women than in nonpregnant women (10.1%). FHF in

patients with sporadic AVH in the west is around 1% and

occurs with equal frequency in pregnant and nonpregnant

women. A number of studies from the developing countries

have shown high rate of FHF in sporadic AVH, being sig-

nificantly higher in pregnant women than nonpregnant

women [12,14–20]. This difference in the rate of FHF

between the west and the east may be in part due to bias-

reporting of only severe cases of hepatitis presenting to the

hospitals from the developing countries. However, the high

rate of FHF in pregnant women is a distinct phenomenon

seen only in the developing countries. Our data showed that

the higher rate of FHF in pregnant women was limited to

those caused by HEV. Forty-five (69.2%) of the 65 pregnant

women with sporadic AVH caused by HEV had developed

FHF, whereas only two (18.2%) of the 11 pregnant women

with sporadic AVH caused by viruses other than HEV

(HBV ¼ 2 and HNAE ¼ 9) had developed FHF. FHF in

sporadic AVH in nonpregnant women caused by HBV

(8.3%), HEV (10%) and HNAE (12.7%) did not differ signi-

ficantly from each other and from those of pregnant women

with non-HEV aetiology (18.2%). During epidemics of HE,

FHF occurs in 25% pregnant women in contrast to 1.9% in

men and nonpregnant women of the corresponding age

groups [12]. These data suggest that increased severity of

sporadic AVH in pregnant women in the developing coun-

tries occurs exclusively in HEV group and is not seen in AVH

caused by other hepatitis viruses.

Pregnant women with AVH had shorter duration of illness

and lower serum bilirubin than nonpregnant women with

Table 4 Outcome of pregnancy in patients with sporadic viral hepatitis

First Second Third Puerperium

Fulminant

Non

fulminant Fulminant

Non

fulminant Fulminant

Non

fulminant Fulminant

No. of cases 4 (3*) 9 12 (7*) 6 23 (12*) 14 8 (3*)

Aetiology

HE 4 6 11 5 22 9 8

Other than HE 0 3 1 1 1 5 0

Outcome of pregnancy

abortion/still birth

1 1 1 0 1 0 0

Mother died undelivered 3 0 6 0 9 0 0

Pregnancy continued

or normal delivery

0 8 5 6 13 14 8**

*Fatal cases.

**Delivered prior to fulminant hepatic failure.



AVH. Also pregnant women with FHF had shorter duration

of disease, shorter pre-encephalopathy period, lower serum

bilirubin and more frequent development of cerebral oedema

than nonpregnant women with FHF. This suggests that HE

in pregnant women is an explosive disease with rapid pro-

gression of symptoms, development of encephalopathy and

cerebral oedema. However the most remarkable feature of

FHF caused by HEV in pregnant women was the occurrence

of DIC in 10 (22.2%) of 45 patients. Singh et al. studied

coagulation factors in 30 patients with acute viral hepatitis

with or without hepatic encephalopathy from Agra, India

[33]. DIC with significant clinical bleeding was seen in 10 of

15 patients with FHF. Six (60%) of these 10 patients were

in advanced stage of pregnancy, and pregnancy constitu-

ted the most significant prognostic factor for occurrence of

DIC. In other studies on FHF from developing countries,

bleeding disorder has been found the most common cause of

death in pregnant women with FHF. The pathogenesis of

DIC in pregnant women with FHF is not known, however,

it may give an important clue to the pathogenesis of

increased severity of HEV in pregnant women. Considering

the explosive nature of HEV in pregnancy with DIC, it may

represent a severe manifestation of a Schwartzmann-like

phenomenon.

Prognostic factors for FHF in the present study were cer-

ebral oedema and HEV aetiology. Patients with cerebral

oedema had a worse prognosis and patients with HE had the

best chances of survival. Pregnant women with FHF had

significantly better survival than nonpregnant women as

shown in the univariate analysis, however, pregnancy was

not found to be a significant prognostic factor in multivariate

analysis. One study from India identified four variables that

independently predicted outcome in patients with FHF, these

were age > 40 years, presence of cerebral oedema at the

time of hospitalization, serum bilirubin > 15 mg/dL and

prothrombin time > 25 s over controls. In this study all

patients with FHF were not tested for HEV aetiology and thus

HEV aetiology could not be tested for independently as a

prognostic factor [4]. Studies from the west have incrimin-

ated the cause of FHF and pre-encephalopathy period as

important prognostic predictors in patients with FHF [32]. In

these reports, FHF caused by HNAE agents and drugs have

worse prognosis, and patients with short pre-encephalopa-

thy period had the best chance of recovery. These differences

might be attributable to the heterogeneous causes of FHF in

the west, whereas hepatitis viruses were the predominant

cause of FHF in our patients.

REFERENCES

1 Reyes GR, Purdy MA, Kim JP et al. Isolation of a cDNA from

the virus responsible for enterically transmitted non-A,

non-B hepatitis. Science 1990; 247: 1335–1339.

2 Khuroo MS. Study of an epidemic of non-A, non-B hepatitis.

Possibility of another human hepatitis virus distinct from

post-transfusion non-A, non-B hepatitis. Am J Med 1980;

68: 818–823.

3 Khuroo MS. Acute liver failure in India. Hepatology 1997;

26: 244–246.

4 Achaya SK, Dasarathy S, Kumar TL et al. Fulminant

hepatitis in a tropical population: clinical course, cause, and

early predictors of outcome. Hepatology 1996; 23: 1448–

1455.

5 Khuroo MS, Hepatitis E: the enterically transmitted non-A,

non-B hepatitis. Indian J Gastroenterol 1991; 10: 96–100.

6 Arankalle VA, Chadha MS, Mehendale SM, Tungatkar SP.

Epidemic hepatitis E: serological evidence for lack of intra-

familial spread. Indian J Gastroenterol 2000; 19: 24–28.

7 Centers for Disease Control and Prevention. Hepatitis E

among US travelers, 1989–92. MMWR Morb. Mortal. Wkly

Rep. 1993; 42: 1–4.

8 Heath TC, Burrow JN, Currie et al. Locally acquired hepatitis

E in the Northern territory of Australia. Med J Aust 1995;

162: 318–319.

9 Aggarwal R, Krawczynski K. Hepatitis E: an overview

and recent advances in clinical and laboratory research.

J Gastroenterol Hepatol 2000; 15: 9–20.

10 Meng XJ, Dea S, Engle RE et al. Prevalence of antibodies to

the hepatitis E virus in pigs from countries where hepatitis E

is common or is rare in the human population. J Med Virol

1999; 59: 297–302.

11 Emerson SU, Purcell RH. Recombinant vaccines for

hepatitis E. Trends Mol Med 2001; 7: 462–466.

12 Khuroo MS, Teli MR, Skidmore S, Sofi MA, Khuroo MI.

Incidence and severity of viral hepatitis in pregnancy. Am J

Med 1981; 70: 252–255.

13 Khuroo MS, Kamili S, Jameel S. Vertical transmission of

hepatitis E virus. Lancet 1995; 345: 1025–1026.

14 Nayak NC, Panda SK, Datta R et al. Etiology and outcome of

acute viral hepatitis in pregnancy. J Gastroenterol Hepatol

1989; 4: 345–352.

15 Khuroo MS, Duerrmeyer W, Zargar SA, Ahanger MA, Shah

MA. Acute sporadic non-A, non-B hepatitis in India. Am J

Epidemiol 1983; 118: 360–364.

16 Jaiswal SP, Jain AK, Naik G, Soni N, Chitnis DS. Viral hepatitis

in pregnancy. Int J Gynaecol Obst 2001; 72: 103–108.

17 Gebreel AO. Hepatitis in pregnancy in Libya. Ann Trop Med

Parasitol 1983; 77: 321–322.

18 Nouasria B, Bernau AJ, Benhamou JP et al. Fulminant viral

hepatitis and pregnancy in Algeria and France. Ann Trop

Med Parasitol 1986; 80: 623–629.

19 Mallia CP, Nancekivell AF. Fulminant virus hepatitis in late

pregnancy. Ann Trop Med Parasitol 1982; 76: 143–146.

20 Tsega E, Hansson BG, Krawczynski K, Nordenfelt E.

Acute sporadic viral hepatitis in Ethiopia: causes, risk

factors, and effects on pregnancy. Clin Infect Dis 1992; 14:

961–965.

21 Ghabrah TM, Strickland GT, Tsarev S et al. Acute viral

hepatitis in Saudi Arabia: Seroepidemiological analysis, Risk

factors, Clinical Manifestations and evidence for a sixth

Hepatitis Agent. Clin Infect Dis 1995; 21: 621–627.

22 Khuroo MS, Rustgi VK, Dawson GJ et al. Spectrum of

hepatitis E virus infection in India. J Med Virol 1994; 43:

281–286.



23 Campbell MJ, Machin D. Medical statistics: a common sense

approach. Chichester, England: John Wiley, 1992.

24 Fleiss JL. Confidence intervals for the odds ratio in case-

control studies: the state of the art. J Chronic Dis 1979; 32:

69–77.

25 Knox TA, Olans LB. Liver disease in pregnancy. N Engl J Med

1996; 335: 569–576.

26 Wilkinson ML. Diagnosis and management of liver disease

in pregnancy. Adv Intern Med 1990; 35: 289–310.

27 Mishra L, Seeff LB. Viral hepatitis, A through E, complicating

pregnancy. Gastroenterol Clin N America 1992; 21: 873–887.

28 Pastorek JG II. The ABCs of hepatitis in pregnancy. Clin Obst

Gynecol 1993; 36: 843–854.

29 Rustgi VK, Hoofnagle. Viral hepatitis during pregnancy.

Semin Liver Dis 1987; 7: 40–46.

30 Magriples U. Hepatitis in pregnancy. [Journal Article] Semin

Perinatol 1998; 22: 112–7.

31 Centers for Disease Control. Summary of notifable diseases,

US, 1991. MMWR 1992; 40 (53): 1–12.

32 Hoofnagle JH, Carithers RL, Shapiro C, Ascher N. Fulminant

hepatic failure: summary of a workshop. Hepatology 1995;

21: 240–252.

33 Singh R, Singh MM, Hazra DK et al. A study of dissemi-

nated intravascular coagulopathy in hepatic coma compli-

cating acute viral hepatitis. Angiology 1983; 34 (7):

470–479.



Documents

Aetiology, clinical course and outcome of sporadic acute viral hepatitis in pregnancy