Viral Hepatitis in Pregnancy

Dr. Rita Luthra
Director, Women's Health & Education Center

Viral hepatitis complicates 0.2% of all pregnancies. It is one of the most serious infections that can occur in pregnant women. Six different forms of viral hepatitis have now been defined. The most common viral agents causing hepatitis in pregnancy are hepatitis A virus, hepatitis B virus, hepatitis C (non-A, non-B hepatitis virus), and Epstein-Barr virus. Delta agent hepatitis has also received increasing attention as a cause of hepatitis.

This chapter addresses various types of hepatitis, their implications during pregnancy, the risk of perinatal transmission and treatment. The immunization recommendations of the Centers for Disease Control and Prevention (CDC) are also discussed with special focus on health care workers (1).

Natural History, Epidemiology of Viral Hepatitis:

1. Hepatitis A:

Approximately one third cases of acute hepatitis are caused by hepatitis A virus. It may occur sporadically or in epidemics. The virus usually is transmitted by person-to person contact through fecal-oral contamination. Poor hygiene, poor sanitation and intimate personal and sexual contact facilitate transmission. Hepatitis A is caused by an RNA virus, belongs to picornavirus group. Its incubation period ranges from 15 to 50 days; the mean is 28-30 days. Excretion of virus in stool normally begins approximately 2 weeks prior to the onset of clinical symptoms and is complete within 3 weeks following clinical symptoms. No known carrier state exists for the virus. Both blood and stool are infectious during the 2-6 week incubation period. Hepatitis A is endemic in Southeast Asia, Africa, Central America, Greenland, Mexico and Middle East.

Serious complications of hepatitis A are uncommon. Among all acutely ill patients who require hospitalization, the overall fatality rate does not exceed 2-1,000 cases in the USA. Hepatitis A immune globulin is recommended for household contacts and contacts in day care centers and custodial institutions. It should be given as soon as possible, if given after more than 2 weeks of exposure, it is ineffective. A vaccine is available, which may be taken during pregnancy.

Specific Tests: the diagnosis of acute hepatitis A is confirmed by detecting IgM antibodies to the virus. IgG antibodies to hepatitis A virus will persist in patients with previous exposure to the virus.

2. Hepatitis B:

Hepatitis B infection occurs throughout the world. In the United States, it is responsible for 40-50% of all cases of hepatitis. Acute hepatitis B occurs in 1-2/1,000 pregnancies. Chronic hepatitis is present in 5-15/1,000 pregnancies, but is more prevalent among certain ethnic groups (Asians, Insuits). Hepatitis B is caused by a small DNA virus. The intact virus is termed the Dane particle. Hepatitis B surface antigen (HBsAg) is present on the surface of the virus and also circulates freely in the serum in spherical and filamentous forms. The middle portion of the Dane particle contains hepatitis B core antigen (HBcAg). The core antigen is present in hepatocytes and does not circulate in the serum. Hepatitis B e antigen (HBeAg) is encoded by the same portion of the viral genome that codes for the core antigen. The presence of HBeAg indicates an extremely high viral inoculum and active virus replication. The incubation period of hepatitis B is 6 weeks to 6 months.

Hepatitis B is transmitted by parenteral and sexual contact. Individuals at greatest risk of becoming infected are those who have multiple sexual partners, inject drugs percutaneously, or have sexual partners who engage in these risk-taking behaviors. Other important risk factors are receipt of blood products and household or institutional contact. The mortality associated with acute hepatitis B is approximately 1%. Of patients who become infected, 85-90% experience complete resolution of their physical findings and develop protective levels of the antibody. The other 10-15% of patients becomes chronically infected; they continue to have detectable serum levels of HBsAg but are asymptomatic and have no biochemical evidence of hepatic dysfunction. In 15-30% of those chronically infected, viral replication continues and is manifested by persistence of the e-antigen and active viral DNA synthesis. These individuals are at risk for the subsequent development of chronic or persistent hepatitis and cirrhosis, and approximately 4,000 to 5,000 die annually of complications of chronic liver disease, including hepatocellular carcinoma.

The virus is contained in most body secretions. Because hepatitis B virus is highly pathogenic and infectious perinatal transmission of infection occurs with disturbing regularity. About 10-20% of women who are seropositive for HBsAg transmit the virus to their neonates in the absence of immunoprophylaxis. In the women who are seropositive for both HBsAg and HBeAg, the frequency of vertical transmission increases to about 90%. When maternal infection occurs in the first trimester, up to 10% of neonates will be seropositive for HBsAg. In women acutely infected in the third trimester, 80-90% of offspring will be infected. Between 85-90% of perinatal transmission of hepatitis B virus occur as a consequence of intrapartum exposure of the infant to contaminated blood and genital tract secretions. The remaining cases result from hematogenous transplacental dissemination, breast feeding, and close postnatal contact between the infant and the infected parent (5).

Infants of women who are HBsAg positive at the time of delivery should receive both hepatitis B immune globulin (HBIG) and hepatitis B vaccine within 12 hours of birth, followed by two more injections of hepatitis B vaccine in the first 6 months of life.

Specific Tests: in the acute stage the surface antigen and the IgM antibody to the core antigen is present. The presence of e-antigen is indicative of an exceptionally high viral inoculum and active virus replication, and implies high degree of infectivity. Chronic hepatitis B virus infection is characterized by the persistence of the surface antigen in the liver and serum. The time of infection can be evaluated by measuring IgG and IgM antibodies to HBcAg. Typically the IgG hepatitis B core antibody (HBcAb) appears 6 months of more after infection, with the IgM moiety being predominant at that time. Anti-HBc (IgM) may be helpful in HBsAg negative patients in whom hepatitis B is strongly suspected.

3. Hepatitis C:

Hepatitis C virus (previously termed non-A, non-B hepatitis) is a single-stranded RNA virus that appears to infect as much as 0.6% of the pregnant population. The principle risk factor for acquiring hepatitis C virus are the same as for hepatitis B. The incubation period is usually 7-8 weeks but may vary from 3-21 weeks. A chronic state for hepatitis C exists. Approximately 50% of patients with acute hepatitis C develop biochemical evidence of chronic liver disease. Of these individuals, at least 20% subsequently have chronic active hepatitis or cirrhosis. Approximately 7-8% of hepatitis C virus-positive women transmit hepatitis C virus to their offspring. Vertical transmission of hepatitis C may be more likely if the mother also is infected with human immunodeficiency virus (HIV).

Currently, no method has been found to prevent prenatal transmission. Many experts believe that hepatitis C virus-positive women should not breastfeed because there is a 2-3% risk of vertical transmission. Unlike hepatitis B, antibodies to hepatitis C are not protective.

Specific Tests: it is confirmed by identifying the antibody to hepatitis C virus. However antibody may not be present until 6-16 weeks after the onset of clinical illness. Hepatitis C viral RNA can be detected by polymerase chain reaction assay of serum soon after infection as well as in chronic disease.

4. Hepatitis D

Hepatitis D requires hepatitis B virus for replication and expression and so occurs only in people already infected with hepatitis B. In acute hepatitis B, once HBsAg clears the bloodstream, so does hepatitis D. Approximately 20-25% of chronic hepatitis B virus carriers ultimately are coinfected with hepatitis D virus. In acute hepatitis D, immunoglobulin M (IgM) antibodies against hepatitis D predominate, whereas IgG antibodies may be found in chronic infections. 70-80% patients infected by chronic hepatitis D ultimately develop cirrhosis and portal hypertension, 15% of whom suffer an unusually rapid progression to cirrhosis within 2 years of the initial onset of acute illness. Mortality due to hepatic failure is about 25%.

Vertical transmission of hepatitis D virus has been documented. Transmission is uncommon, however, because the measures used to prevent perinatal infection with hepatitis B virus are almost uniformly effective in preventing infection by hepatitis D.

Specific Tests: identification of the IgM antibody to hepatitis D virus. D antigenemia usually persists in patients with chronic hepatitis D despite the appearance of the IgG antibody to the virus. Thus, as in hepatitis C and HIV infection, viremia and end-organ damage can continue despite the presence of the antibody to the virus.

5. Hepatitis E:

The epidemiologic features of hepatitis E are similar to those of hepatitis A. Although the disease has been reported rarely in the United States, it is endemic in several developing countries, similar to those mentioned for hepatitis A. In India and Burma it is reported that 10-18% of pregnant women with hepatitis E died as a complication of their infection. Acute hepatitis E can be a serious disease; it usually is self-limiting and does not result in carrier state. Hepatitis E is transmitted via contaminated food and water, and vertical transmission has been reported.

Specific Tests: the diagnosis of infection with hepatitis E is by documentation of virus-specific antibodies.

6. Hepatitis G:

Hepatitis G infection is more likely in people already infected with hepatitis B or C or who have a history of intravenous drug use and HIV. Vertical transmission is high and hepatitis G probably does not cause chronic active hepatitis or cirrhosis.

Specific Tests: the diagnosis of infection with hepatitis G is by documentation of virus- specific antibodies.

Clinical Manifestations:

The clinical picture of hepatitis is highly variable; most patients have asymptomatic infection, while a few may present with fulminating disease and die within few days. The usual subjective symptoms in patients with acute hepatitis are malaise, fatigue, anorexia, nausea and right upper quadrant or epigastric pain. Typical findings include jaundice, upper abdominal tenderness, and hepatomegaly. Many cases of hepatitis do no have jaundice. The patient's urine usually is darkened, and the stool may be acholic. In cases of fulminating hepatitis signs of coagulopathy and encephalopathy may be evident.

In the cases of hepatitis A or E, there may be history of recent travel to an endemic area or exposure to an infected person. Hepatitis B, C, D, or G typically ensues after parenteral exposure to contaminated blood or sexual contact with an infected partner. The initial phase of infection, patients with hepatitis D are indistinguishable from individuals with acute hepatitis B. The patients infected with hepatitis B, C or D virus whose acute symptoms resolve, some become chronic carrier of viral antigens. The same may be true for hepatitis G. Although most viral hepatitis carriers initially are asymptomatic, up to one third subsequently develop chronic active or persistent hepatitis or cirrhosis. Once cirrhosis ensues, patients demonstrate the typical sings of end-stage liver disease, such as jaundice, muscle wasting, ascites, spider angioma, palmar erythema, and hepatic encephalopathy. Hepatitis C is probably the leading cause of hepatocellular carcinoma in the United States.

Diagnosis:

The diagnosis is made using the previously described serologic markers. Jaundice, a primary symptom of hepatitis infection, also occurs with numerous other disorders. The differential diagnosis of viral hepatitis should include the following clinical conditions (2). In acute hepatitis marked increase in the serum concentration of alanine aminotransferase (ALT, previously SGPT) and asparate aminotransferase (AST, previously SGOT) is seen. In addition, the serum bilirubin concentration often is increased. Patients who are severely ill, coagulation abnormalities and hyperammonemia also may be present. Initial evaluation includes the tests for: anti-HA IgM, HBsAg and HC PCR. In selected patients, additional testing can include anti-HBc IgM, HD PCR, anti-HE, and anti-HG. Liver biopsy is rarely indicated in pregnancy.

Differential Diagnosis of Jaundice in Pregnancy:

Condition	Distinguishing Characteristic
Viral hepatitis	Mild to marked elevation in serum transaminases Positive viral serology Prominent inflammatory infiltrate with hepatocellular disarray
Acute fatty liver of pregnancy	Minimal elevation in transaminases Little if any inflammatory infiltrate with prominent microvesicular fat deposition
Toxic injury	History of drug exposure (eg; tetracycline, isoniazid, erythromycin, alpha methyldopa)
Cholestasis of pregnancy	Pruritis Elevation of bile salts Cholestasis with little inflammation
Severe Preeclampsia	Hypertension, edema, proteinuria, oliguria Elevated blood urea nitrogen, creatinine, uric acid, transaminases, and lactate dehydrogenase Thrombocytopenia
Mononucleosis	Flue-like illnessPositive heterophile antibodyElevated transaminases
Cytomegalovirus (CMV) hepatitis	CMV antibodies Positive viral culture or polymerase chain reaction Elevated transaminases
Autoimmune hepatitis	Antinuclear antibodies, liver-kidney microsomal antibodies Elevated transaminases

Management:

Supportive Treatment:Bed-rest should be instituted during the acute phase of the illness. If nausea, vomiting or anorexia is prominent, intravenous hydration and general supportive measures are instituted. Fluid and electrolyte abnormalities should be corrected. If a coagulopathy is present, administration of erythrocytes, platelets, and clotting factors such as fresh frozen plasma or cryoprecipitate may be necessary. Infected women should avoid intimate contact with household members and sexual partners until these individuals receive appropriate prophylaxis outlines as follows.

Specific Immunotherapy:

1. Hepatitis A: currently no antiviral agent is available for treatment of acute hepatitis A. An inactivated-virus vaccine that is safe in pregnancy is available. Women at risk for infection with hepatitis A, such as those traveling to endemic areas, should be vaccinated. For post-exposure prophylaxis, a single intramuscular dose of 1 mL should be administered as soon as possible. Administration of immune globulin more than 2 weeks after exposure is not effective in preventing or ameliorating the severity of hepatitis A. Immune globulin does not pose a risk to either a pregnant woman or her fetus, and therefore preparation should be administered during pregnancy if indicated.

2. Hepatitis B: although interferon alfa has been shown to alter the natural history of acute hepatitis B, C and D, it should be avoided in pregnancy. Prevention of infection is of paramount importance. Specific immunotherapy with hepatitis B immune globulin (HBIG) has been effective.

   Vaccination: pregnancy is not a contraindication to vaccination. In fact, susceptible pregnant women who are at risk for hepatitis B infection should be specifically targeted for vaccination. Currently available vaccines prepared from yeast cultures by using recombinant DNA technology, poses no risk of transmission of HIV infection. They are highly immunogenic and result in sero-conversion in more than 95% of recipients. Individuals who have been exposed to hepatitis B virus before they are vaccinated should receive passive immunization with HBIG and undergo the immunization series. When exposure has occurred as a result of sexual contact, the patient should receive a single dose of HBIG within 14 days of contact. The preparation is administered intramuscularly in a dose of 0.06 mL/kg. For prophylaxis after percutaneous or mucous membrane injury, treatment should include an initial injection of HBIG, followed by a second dose 1 month later.

   Perinatal Management: the maternal course of viral hepatitis is unaltered by pregnancy, but the incidence of premature labor and delivery is increased. The Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists recommend hepatitis B virus screening for all pregnant women (3). The combination of passive and active immunization has been particularly effective in reducing the frequency of perinatal transmission of hepatitis B virus. Several investigations conducted in Asian nations have shown that passive and active immunization of the newborn is 85-95% effective in preventing perinatal transmission of hepatitis B virus. Pregnant women should be routinely tested for HBsAg during an early prenatal visit. Women in high-risk groups who initially test negative for hepatitis B virus should be targeted for vaccination if they have not been vaccinated previously. Seropositive women should be encouraged to inform their children and sexual partners of the need for testing and vaccination. Serum transaminases should be measured in seropositive women to detect biochemical evidence of chronic active hepatitis. If the test results are abnormal or if the liver is palpable, the patient should be evaluated further to determine whether the disease is acute or chronic. The physician responsible for the care of a newborn delivered to a mother with chronic hepatitis B should be informed of the mother's carrier status so that the appropriate doses of hepatitis B virus vaccine and HBIG can be given as soon as possible following delivery. Fetal infection in utero is rare, but the neonate may be exposed to the virus at delivery and the virus may be spread by breast-feeding (4).

3. Hepatitis C and D: treatment with interferon alfa produced clinical improvement in 28-46% of patients with chronic hepatitis C and D. The relapse rate is shown to be about 50% with in 6 months.