Pregnancy and Viral Hepatitis

Etiology

Hepatitis A

Hepatitis A virus is a positive-sense, single-stranded RNA virus belonging to the family Picornaviridae.[3] There is a single serotype worldwide.

The virus is mostly transmitted through the fecal-oral route. This is most prevalent in developing countries with poor hygiene and sanitation, which results in 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 hepatitis A is 30 days. Hepatitis A virus has the highest concentration in the feces, serum, and saliva, respectively. Hepatitis A is also transmitted through sexual contact. There has been no report of chronic sequelae among persons infected with hepatitis A. Intrauterine and perinatal transmission of Hepatitis A is a rare occurrence.[4][5] 

Hepatitis B

Hepatitis B virus (HBV) is an enveloped virus, partially double-stranded virus, circular DNA genome, and belonging to the family Hepadnavirus. Chronic hepatitis B infection is associated with cirrhosis and hepatocellular carcinoma.

Hepatitis B virus 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 hepatitis B and positive hepatitis B virus E antigen (HBeAg) have a 90% likelihood of their newborns being infected with the hepatitis B virus.[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 different subtypes.[7]

Acute hepatitis C infection occurs during the first 6 months after exposure. Failure to clear the Hepatitis C virus after 6 months would progress to chronic hepatitis C.Hepatitis C is a major cause of cirrhosis and hepatocellular carcinoma worldwide.

The major 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 mostly during the last month of pregnancy or delivery.

Invasive procedures such as amniocentesis and chronic villus sampling break the maternal-fetal barrier. This increases the risk of vertical transmission of the hepatitis C virus during pregnancy and delivery.

Hepatitis D

Hepatitis D is caused by the hepatitis delta virus (HDV), a single-stranded, circular RNA and a defective virus with an incomplete RNA requiring the assistance of the Hepatitis B virus, specifically hepatitis B surface antigen (HBsAg), to be infectious.[9]

Hepatitis D is mostly transmitted through the same route as the Hepatitis B virus. The parenteral mode is the major mode of transmission, and vertical transmission during pregnancy is rare.

Coinfection of Hepatitis D virus and Hepatitis B virus leads to severe acute infection. Superinfection of Hepatitis D virus on chronic HBV leads to higher progression to chronic Hepatitis D. 

Hepatitis E

Hepatitis E virus (HEV) is an icosahedral, non-enveloped virus with a single-stranded, positive RNA virus classified into the family Hepeviridae and the genus Orthohepeviurs. There about 7 genotypes of the Hepatitis E virus, and genotypes 1-4 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 Hepatitis E virus varies between 23.3% and 50%.

Sporadic case not associated with travel has been reported in developed countries, and this is mostly caused by genotype 3, which is mostly attributed to the immunocompromised state.[11]

Hepatitis E virus has rarely been reported to be transmitted through sexual intercourse.

Epidemiology

Hepatitis A

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

Hepatitis B

Hepatitis B affects more than 250 million individuals worldwide and is the most common cause of chronic hepatitis worldwide. Sixty-five million women of childbearing age are infected with chronic hepatitis B virus. About 800,000 to 1.4 million people are infected with the Hepatitis B virus in the United States.

There is a 0.7% to 0.9% prevalence of chronic hepatitis B infection among pregnant women in the United States.[13]

Hepatitis C

Hepatitis C virus 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

Hepatitis D virus affects 15 to 20 million people worldwide with hepatitis B virus carriers. New studies estimate the prevalence of Hepatitis D to be closer to 62 to 72 million.

The prevalence of HDV in the US 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% in pregnant women with chronic hepatitis B virus infection.

Hepatitis E

Hepatitis E virus affects about 20.1 million new infections. Hepatitis E viral infection is prevalent in developing countries.

Hepatitis E viral 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 as high as 5% to 25%. There is a higher mortality rate in 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 such as 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 hepatitis B and C viral infection may progress to decompensated cirrhosis and develop ascites, hepatic encephalopathy, coagulopathy, and esophageal variceal bleeding.

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 hepatitis A should be screened for acute hepatitis A virus infection. Hepatitis A 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 Hepatitis B virus from infected mothers to their fetuses or newborns results in a 90% likelihood of the newborn getting infected if the pregnant woman has chronic hepatitis B and positive for Hepatitis B virus E antigen (HBeAg).[6]

The U.S. Preventive Services have recommended universal screening for hepatitis B virus infection during pregnancy at the first prenatal visit and Task Force (USPSTF) and the American Congress of Obstetricians and Gynecologists (ACOG).

Thus every pregnant woman should be screened for the hepatitis B surface antigen at the initial visit. This is to decrease the mother-to-child transmission of the hepatitis B virus. 

Hepatitis C

Transmission is associated with pregnant women with higher levels of HCV RNA.

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 the screening tool during pregnancy.

Hepatitis D

World Health Organization (WHO) recommends screening pregnant women infected with Hepatitis B virus for Hepatitis D virus. 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 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 hepatitis A viral 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.[17]

There is a minimal risk of transmission of Hepatitis A virus via breastmilk. The benefit of breastfeeding greatly outweighs stopping breastfeeding. There is no contraindication to breastfeeding for mothers infected with hepatitis A. 

Hepatitis B

Hepatitis B immunoglobulin and Hepatitis B vaccine should be administered within 12 to 24 hours of birth to all babies of Hepatitis surface antigen positive (HBsAg) mothers or those with unknown/undocumented HBsAg status. This is regardless of whether maternal antiviral therapy was administered during the pregnancy.

The implementation of this approach has reduced the risk of exposure from 90% to 5% to 10% in exposed neonates. Decreasing vertical hepatitis B virus transmission through cesarean section is not recommended as the sole indication.[18](A1)

Using antiviral therapy such as tenofovir, telbivudine, or lamivudine after 28 to 32 weeks of gestation in Hepatitis B virus-infected pregnant women with high viral load (>6-8 log 10 copies/mL) has been associated with less than 3% risk of transmission.

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 both the European Association for the Study of Liver Disease and Society for Maternal-Fetal Medicine (SMFM).[19](B2)

Fetal exposure risk has not been increased with the use of these antiviral medications during pregnancy.[20] Breastfeeding is encouraged after newborns receive the appropriate immunoprophylaxis by the American College of Pediatrics, Centers for Disease Control and Prevention (CDC), ACOG, and Society for Materno-Fetal Medicine (SMFM).

Hepatitis C

ACOG and Society for Maternal-Fetal Medicine (SMFM) recommend against doing cesarean section solely to reduce HCV transmission during pregnancy.

Chronic hepatitis C 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 agents treatment is mostly deferred until postpartum.[21] Currently, there is no immunization for hepatitis C virus-infected mothers and infants.

There is no contraindication for breastfeeding in hepatitis C virus-infected mothers and infants.

Hepatitis D

Hepatitis D virus infection is treated with long-term alpha interferon and PEGylated interferon. These are both contraindicated during pregnancy.

Transmission of the Hepatitis D virus has largely decreased due to perinatal prevention and treatment of Hepatitis B virus infection.

Hepatitis E

Hepatitis E viral infection is associated with a severe disease course. Hepatitis E virus 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.

There is no contraindication to breastfeeding in mothers infected with the hepatitis E virus.

Differential Diagnosis

Differential diagnosis 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, and Epstein-Barr viral hepatitis.

Prognosis

There has been no report of chronic sequelae among persons infected with hepatitis A. The 2nd and 3rd trimesters are associated with higher mortality of 5% to 25% in Hepatitis E virus infection. Pregnant women are likely to progress to fulminant hepatitis. 

Complications

Hepatitis A

Hepatitis A 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 hepatitis A on pregnancy.[22]

Fetal ascites and meconium peritonitis, which is a rare occurrence, have been reported.[4]

Hepatitis B

The adverse effect of the Hepatitis B virus on pregnancy is rare in patients with acute or chronic HBV infection.

There is increased maternal and perinatal death associated with the Hepatitis B virus infection during pregnancy. 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.[23]

Hepatitis D

Chronic hepatitis D 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.[24]

Fetal complications from Hepatitis E virus include preterm and low birth weights.