Pregnancy and Viral Hepatitis

Etiology

Hepatitis A

Hepatitis A virus (HAV) is a positive-sense, single-stranded RNA virus belonging to the family Picornaviridae with a single serotype worldwide.[3] The virus is mainly transmitted through the fecal-oral route and is most prevalent in developing countries with poor hygiene and sanitation due to food and water contamination. The virus can be transmitted through sexual contact and rarely through blood exposure in injecting drug users during a blood transfusion. The average incubation period for HAV is 30 days. HAV has the highest concentration in the feces, serum, and saliva, respectively. HAV is also transmitted through sexual contact. Chronic sequelae among persons infected with HAV have not been reported. Intrauterine and perinatal transmission of HAV is a rare occurrence.[4][5] 

Hepatitis B

Hepatitis B virus (HBV) is an enveloped, partially double-stranded virus with a circular DNA genome belonging to the family Hepadnavirus. Chronic HBV infection is associated with cirrhosis and hepatocellular carcinoma. HBV does not cross the placenta and cannot infect the fetus unless there have been breaks in the maternal-fetal barrier. Perinatal transmission accounts for more than 50% of cases worldwide. Pregnant women with chronic HBV and positive HBV E antigen (HBeAg) have a 90% likelihood of their newborns being infected with HBV.[6] Other modes of transmission include sexual intercourse, body fluids, and blood transfusion.

Hepatitis C

Hepatitis C virus (HCV) is a partially double-stranded, plus-sense RNA virus with 11 major genotypes and 15 subtypes.[7] Acute HCV infection occurs during the first 6 months after exposure. Failure to clear the HCV after 6 months would progress to chronic HCV. HCV is a significant cause of cirrhosis and hepatocellular carcinoma worldwide. The primary mode of transmission of HCV is mostly through parental transmission, which includes infected blood transmission, intravenous drug users sharing needles, sexual contact, and mother-to-child transmission.[8] Vertical (mother-to-child) transmission is the leading cause of HCV infection in children. Perinatal transmission of HCV is mainly during the last month of pregnancy or delivery. Invasive procedures, eg, amniocentesis and chronic villus sampling, break the maternal-fetal barrier. This increases the risk of vertical transmission of HCV during pregnancy and delivery.

Hepatitis D

Hepatitis D (HDV) is caused by the hepatitis delta virus, a single-stranded, circular RNA, and a defective virus with an incomplete RNA requiring the assistance of the HBV, specifically HBV surface antigen (HBsAg), to be infectious.[9] HDV is transmitted chiefly through the same route as HBV. The parenteral mode is the primary transmission mode, and vertical transmission during pregnancy is rare. Coinfection of HDV and HBV leads to severe acute infection. Superinfection of the HDV on chronic HBV leads to higher progression to chronic HDV. 

Hepatitis E

Hepatitis E virus (HEV) is an icosahedral, nonenveloped virus with a single-stranded, positive RNA virus classified into the family Hepeviridae and the genus Orthohepeviurs. About 7 genotypes of the HEV have been identified, and genotypes 1 to 4 are known to affect humans.[10] The main transmission route for HEV infection is the fecal-oral route and is most prevalent in developing countries with poor sanitation. Vertical transmission of the HEV varies between 23.3% and 50%. Sporadic cases not associated with travel have been reported in developed countries, and this is mainly caused by genotype 3, which is primarily attributed to the immunocompromised state.[11] HEV has rarely been reported to be transmitted through sexual intercourse.

Epidemiology

Hepatitis A

HAV is most prevalent in developing countries. 1:1000 pregnant women are infected with acute HAV. The disease is mainly self-limited, with a mortality of 0.3% to 0.6%.[12]

Hepatitis B

HBV affects more than 250 million individuals worldwide and is the most common cause of chronic hepatitis worldwide. Approximately 65 million women of childbearing age are infected with chronic HBV. About 800,000 to 1.4 million people are infected with HBV in the United States. A 0.7% to 0.9% prevalence of chronic HBV infection among pregnant women in the United States has been noted.[13]

Hepatitis C

HCV affects more than 170 million people worldwide. About 8% of pregnant women are infected with HCV. The estimated prevalence of antenatal HCV infection in the United States is 1% to 2.5%.[14]

Hepatitis D

HDV affects 15 to 20 million people worldwide with HBV carriers. New studies estimate the prevalence of HDV to be closer to 62 to 72 million. The prevalence of HDV in the United States is estimated to range from 2% to 50%, depending on the patient population.[15] The prevalence of HDV in a study in Pakistan revealed an estimated 20.63% of pregnant women with chronic HBV infection.

Hepatitis E

HEV affects about 20.1 million new infections. HEV infection is prevalent in developing countries. HEV infection accounts for 70,000 deaths and 3000 stillbirths yearly.[16] Pregnant women in the second and third trimesters are mostly affected during epidemics. The mortality rate is as high as 5% to 25%, and a higher mortality rate is associated with pregnant women who progressed to fulminant hepatitis. 

History and Physical

Acute viral hepatitis in pregnancy could be asymptomatic or have mild clinical disease. Patients may present with nonspecific symptoms, eg, jaundice, nausea, anorexia, abdominal pain or discomfort, fatigue, malaise, myalgia, and dark urine. Clinical symptoms are unable to differentiate the various viral hepatitides. Pregnant women with chronic HBV and HCV infection may progress to decompensated cirrhosis and develop ascites, hepatic encephalopathy, coagulopathy, thrombocytopenia, spontaneous bacterial peritonitis, and esophageal variceal bleeding.[17] The most common presentation of viral hepatitis is jaundice. Other nonspecific symptoms include fever, myalgia, abdominal pain, nausea, vomiting, and to mention a few.

Evaluation

The liver function test is assessed as the initial biomarker elevated in acute viral hepatitis. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) are elevated during the acute episode. ALT is elevated 2-to-100 fold depending on the severity of the acute viral hepatitis. International normalized ratio (INR), prothrombin time (PT), albumin, and ammonia are evaluated for acute and chronic viral hepatitis infections. 

Hepatitis A

Pregnant women who had contact with persons with acute HAV should be screened for acute HAV infection. HAV viral infection is diagnosed by detecting the immunoglobulin M antibody to the hepatitis A (anti-HAV IgM) virus in pregnant women and the fetus/newborn.

Hepatitis B

Vertical transmission of HBV from infected mothers to their fetuses or newborns results in a 90% likelihood of the newborn getting infected if the pregnant woman has chronic HBV and is positive for HBeAg.[6] The United States Preventive Services recommended universal screening for HBV infection during pregnancy at the first prenatal visit, as well as the Task Force (USPSTF) and the American Congress of Obstetricians and Gynecologists (ACOG). Thus, every pregnant woman should be screened for the HBV surface antigen at the initial visit. This is to decrease the mother-to-child transmission of HBV. HBV DNA should be measured during the second trimester at weeks 26 to 28.[18]

Hepatitis C

Transmission is associated with higher levels of HCV RNA in pregnant women. The American College of Obstetricians and Gynecologists (ACOG) and the Centers for Disease Control and Prevention (CDC) recommend risk-based screening for HCV in pregnant women. The anti-HCV antibody is tested as a screening tool during pregnancy.

Hepatitis D

World Health Organization (WHO) recommends screening pregnant women infected with HBV for HDV. Serum immunoglobulin M anti-HDAg is detected during active infection.

Hepatitis E

Pregnant women in the second and third trimesters are mostly affected during epidemics. The mortality rate is as high as 5% to 25%. There is a higher mortality rate in pregnant women who progressed to fulminant hepatitis. Anti-HEV IgM is tested during pregnancy for suspected cases.

Treatment / Management

Hepatitis A

Administer hepatitis A immunoglobulin to pregnant women who had contact with persons with acute HAV infection and newborns infected during the third trimester. Newborns are to receive hepatitis A immunoglobulin within 48 hours of birth, as recommended by the Centers for Disease Control (CDC) and the American College of Pediatric Association.[19] A minimal risk of transmission of HAV via breastmilk is present. The benefit of breastfeeding greatly outweighs stopping breastfeeding. No contraindication to breastfeeding for mothers infected with HAV has been established. 

Hepatitis B

Pregnant women with immune active HBeAg-positive immune-active phase, cirrhosis, and advanced fibrosis should be treated in pregnancy.[18] Hepatitis B immunoglobulin and hepatitis B vaccine should be administered within 12 to 24 hours of birth to all babies of HBsAg mothers or those with unknown/undocumented HBsAg status, followed by 2 other doses of vaccination at 1 month and 6 months. This is regardless of whether maternal antiviral therapy was administered during the pregnancy. Low birth weight neonates weighing less than 2 kg and preterm neonates should receive Hepatitis B immunoglobulin at birth 1 month, 3 months, and 7 months.[20]

Implementing this approach has reduced the risk of exposure from 90% to 5% to 10% in exposed neonates. Decreasing vertical HBV transmission through cesarean section is not recommended as the sole indication.[21] Using antiviral therapy, eg, tenofovir, telbivudine, or lamivudine after 28 to 32 weeks of gestation in HBV-infected pregnant women with high viral load (>200,000 IU/mL or >6-8 log 10 copies/mL) has been associated with <3% risk of transmission. The new WHO guidelines recommend treatment for HBV-infected pregnant women with high viral load >200,000 IU/mL and HBeAg-positive.[22](A1)

Tenofovir is the preferred antiviral therapy with a lower risk of resistance and is associated with low mineral bone loss in neonates.[23] The administration of both hepatitis B immunoglobulin and hepatitis B vaccine HBV vaccine within 12 to 24 hours of birth to reduce in-utero infection has been recommended by the European Association for the Study of Liver Disease and the SMFM.[24] Fetal exposure risk has not been increased with the use of these antiviral medications during pregnancy.[25] Breastfeeding is encouraged after newborns receive the appropriate immunoprophylaxis by the American College of Pediatrics, Centers for Disease Control and Prevention (CDC), ACOG, and SMFM.(B2)

Hepatitis C

ACOG and the SMFM recommend against doing a cesarean section solely to reduce HCV transmission during pregnancy. Chronic HCV is treated with direct antiviral agents before pregnancy. The safety profile in pregnancy for women taking direct antiviral agents has not yet been established. Direct antiviral agent treatment is mostly deferred until postpartum.[26] Currently, there is no immunization for HCV-infected mothers and infants. No contraindication to breastfeeding has been identified in HCV-infected mothers and infants.

Hepatitis D

HDV infection is treated with long-term alpha interferon and PEGylated interferon, both of which are contraindicated during pregnancy. Due to perinatal prevention and treatment of HBV infection, transmission of HDV has largely decreased.

Hepatitis E

Hepatitis E viral infection is associated with a severe disease course. HEV recombinant protein vaccine was noted to be effective in decreasing HEV transmission in developing countries. This is currently unavailable in developed countries. Safety and efficacy in pregnant women have not been studied. No contraindication to breastfeeding has been identified in mothers infected with the HEV.

Differential Diagnosis

The differential diagnosis of pregnancy and viral hepatitis includes:

• Acute fatty liver of pregnancy
• Hyperemesis gravidarum
• Intrahepatic cholestasis of pregnancy
• Severe preeclampsia
• HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count)
• Herpes simplex virus hepatitis
• Epstein-Barr viral hepatitis.

Prognosis

Chronic sequelae among persons infected with HAV have not been reported. The 2nd and 3rd trimesters are associated with higher mortality of 5% to 25% in HEV infection. Pregnant women are likely to progress to fulminant hepatitis. 

Complications

Hepatitis A

HAV has been associated with gestational complications, including premature contractions, placental separation, premature rupture of membranes, and vaginal bleeding. These have been reported in a study evaluating the impact of acute HAV in pregnancy.[27] Fetal ascites and meconium peritonitis, which is a rare occurrence, have been reported.[4]

Hepatitis B

The adverse effect of HBV on pregnancy is rare in patients with acute or chronic HBV infection. Increased maternal and perinatal death is associated with the HBV infection during pregnancy. The most common cause of maternal mortality of HBV-related cirrhosis was variceal hemorrhage.[28] Placenta abruption, preterm birth, gestational hypertension, and fetal growth restriction have been associated with chronic HBV during pregnancy. Chronic HBV in pregnancy increases the risk of progression to cirrhosis.

Hepatitis C 

Fetal growth restriction, brachial plexus injury, fetal distress, cephalohematoma, neonatal seizures, and intraventricular hemorrhage are gestational complications observed in HCV-infected pregnant women.[29]

Hepatitis D

Chronic HDV is associated with a high risk of severe chronic liver disease in pregnant women.

Hepatitis E

Obstetric complications reported in studies include premature rupture of membranes, antepartum and postpartum hemorrhage, disseminated intravascular coagulation (DIC), intrauterine fetal deaths, spontaneous abortions, stillbirths, and complications of fulminant hepatitis.[30] Fetal complications from the HEV include preterm and low birth weights.