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Hepatitis B Virus (HBV) in Pregnancy

Hepatitis B is caused by the hepatitis B virus (HBV). HBV is a double-stranded DNA virus in the Hepadnaviridae family that primarily affects the liver. The illustration below shows an HBV virion, also known as a Dane particle. The virus consists of an outer lipid envelope, and a protein core that encapsulates a small partially double stranded genome and HBV DNA polymerase.

The HBV DNA encodes for:

  • HBV polymerase (an enzyme with reverse transcriptase activity)  [4]
  • Hepatitis B core antigen (HBcAg),
  • Pre-core protein which is cleaved in the endoplasmic reticulum of  the infected cell and secreted as hepatitis B e antigen (HBeAg) [1]
  • Large, middle, and small surface antigens (HBsAg) [2]
  • The X protein (HBxAg) . Appears to be required for initiation and
    maintenance of virus replication after infection[3]

Infection

The average incubation period is 90 days from time of exposure to the onset of symptoms, but may vary from 6 weeks to 6 months [5,6,7,8].In infected persons HBV is found in highest concentrations in the blood, and lower concentrations in saliva, semen, vaginal secretions, and wound exudates. HBV can remain viable for >7 days on environmental surfaces at room temperature. Acutely infected individuals develop clinically apparent hepatitis with loss of appetite, nausea, vomiting, fever, abdominal pain and jaundice [5]. Some may have dark urine and gray stool [6] . About one half of acute HBV infections in adults are symptomatic . About 1% of cases result in acute liver failure and death.

Sexual transmission accounts for most adult HBV infections in the United States [5]. Approximately 25% of the regular sexual contacts of infected individuals will themselves become seropositive. [6] Mother to child transmission is the predominate mode of transmission in areas of the world with a high prevalence of HBV such as Asia and the South Pacific [9].

In patients with acute hepatitis B vertical transmission occurs in up to 10% of neonates when infection occurs in the first trimester and in 80 -90% of neonates when acute infection occurs in the third trimester [6].In women who are seropositive for both HBsAg and HBeAg vertical transmission is approximately 90%. 10-20% of women seropositive for HBsAg transmit the virus to their neonates in the absence of immunoprophylaxis [6]. Immunoprophylaxis failure against vertical transmission appears to occur more frequently in mothers who are HBeAg-positive and or have high viral loads [10,11] . Although the presence of HBeAg  generally  indicates the person has high levels of virus and greater infectiousness the absence of e-antigen does not exclude active viral replication [33]. Maternal HBV-DNA level has been demonstrated to be the strongest predictor of neonatal immunoprophylaxis failure, with a lower prophylaxis effective rate directly related to a higher maternal viral load [28]
 


Sequelae

Chronic infection occurs in about 90% of infected infants, 30% of infected children aged <5 years , and 2%--6% of adults. Among persons with chronic HBV infection, the risk of death from cirrhosis or hepatocellular carcinoma is 15%--25%. [5] Worldwide, some 240 million people have chronic hepatitis B virus with the highest rates of infection in Africa and Asia [25]. More than 780 000 people die every year due to complications of hepatitis B, including cirrhosis and liver cancer [20]

HBV infection does not appear to be a cause of birth defects, but there seems to be a higher incidence of low birth weight among infants born to mothers with acute infection during pregnancy [13]. In one small study acute maternal hepatitis (type B or nontype B) had no effect on the incidence of congenital malformations, stillbirths, abortions, or intrauterine malnutrition. However, acute hepatitis did increase the incidence of prematurity [12].
 


 


Who to Test

The Centers for Disease Control and Prevention (CDC) Recommends:[5,14]

  • "Test all pregnant women at the first prenatal visit for hepatitis B surface antigen (HBsAg) even if they have been previously vaccinated or tested"
  • Women admitted for delivery who have not had prenatal HBsAg testing should have blood drawn for testing [15].
  • “More than 90% of women found to be HBsAg-positive on routine screening will be HBV carriers, routine follow-up testing later in pregnancy is not necessary for the purpose of screening. In special situations, such as when the mother is thought to have acute hepatitis, when there has been a history of exposure to hepatitis, or when particularly high-risk behavior such as parenteral drug abuse has occurred during the pregnancy, an additional HBsAg test can be ordered during the third trimester” [16]

Interpretation of Hepatitis B Panel Test Results

Tests

Results

Interpretation

HBsAg
Total anti-HBc
IgM anti-HBc
anti-HBs

negative
negative
negative
negative

   
Never infected
susceptible
  

HBsAg
Total anti-HBc
IgM anti-HBc
anti-HBs

positive
negative
negative
negative

  
 Early acute infection; transient (up to 18 days) after vaccination
   

HBsAg
Total anti-HBc
IgM anti-HBc
anti-HBs

positive
positive
positive
negative

Acute infection

HBsAg
Total anti-HBc
IgM anti-HBc

anti-HBs

negative
positive
positive

negative

  
Acute resolving infection
  

HBsAg
Total anti-HBc
IgM anti-HBc
anti-HBs

negative
positive
negative
positive


Recovered from past infection.
 Immune
   

HBsAg
Total anti-HBc
IgM anti-HBc
anti-HBs

positive
positive
negative
negative


Chronic infection

HBsAg
Total anti-HBc
IgM anti-HBc
anti-HBs

negative
positive
negative
negative

False positive (i.e., susceptible); past infection; "low-level" chronic infection§; passive transfer to infant born to HBsAg-positive mother

HBsAg
Total anti-HBc
IgM anti-HBc
anti-HBs

negative
negative
negative
positive

Immune due to vaccination (if concentration is >10 mIU/mL) ;

passive transfer after HBIG administration

§ Persons positive for only anti-HBc are unlikely to be infectious except under unusual circumstances involving direct percutaneous exposure to large quantities of blood (e.g., blood transfusion and organ transplantation).

Source: Workowski KA, Bolan GA; Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015 Jun 5;64(RR-03):1-137. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6403a1.htm Accessed 11/17/2015

  • To verify the presence of chronic HBV infection, persons with hepatitis B surface antigen (HBsAg) should be retested.

    • The presence of  HBsAg indicates ongoing HBV infection, and in newly infected persons, HBsAg is the only serologic marker detected during the first 3--5 weeks after infection. In persons who recover from HBV infection, HBsAg is usually eliminated from the blood in  3--4 months, and hepatitis B surface antibody (anti-HBs) develops indicating recovery [15].
      • Antibody to HBsAg (anti-HBs) is produced after a resolved infection and is the only HBV antibody marker present after vaccination.
    • The absence of IgM hepatitis B core antibody (anti-HBc) or the persistence of HBsAg for 6 months indicates chronic HBV infection [19]
  • Pregnant women who are HBsAg positive should be reported to the local or state health department to ensure that they are entered into a case-management system and that timely and appropriate prophylaxis is provided to their infants.
  • Information concerning the pregnant woman's HBsAg status should be provided to the hospital in which delivery is planned and to the health-care provider who will care for the newborn.
  • Women who are HBsAg positive should be provided with, or referred for, appropriate counseling and long term medical management.
  • In addition, household and sex contacts of women who are HBsAg positive should be vaccinated.
     

Prevention

Currently available HBV vaccines are prepared from yeast cultures by inserting a plasmid containing the gene for HBsAg into  yeast (Saccharomyces cerevisiae). Yeast cells then produce HBsAg, which is collected and purified. "HBV infection cannot result from use of the recombinant vaccine, since no potentially infectious viral DNA or complete viral particles are produced  "[19] .

 Pregnant women at risk for HBV infection should receive hepatitis B vaccination [14,18 ]

  • Pregnancy is not a contraindication to vaccination. 
  • For vaccination of adults 20 years of age and older:
    •  1-mL dose by intramuscular injection into the deltoid muscle, at initial visit, then one month and six months after the first dose, for a total of three doses
    • Consult package inserts for details.

Postexposure Prophylaxis for Susceptible Pregnant Women [14, 21]

Management of the exposed person depends on the HBsAg status of the source and the vaccination and anti-HBs response status of the exposed person.

    After Exposure to Persons Who Have Acute Hepatitis B
    When exposure has occurred as a result of sexual contact within 14 days after the most recent sexual contact administer

      • A course of HBV vaccine into the deltoid as above
      • A dose of Hepatitis B immune globulin (HBIG) 0.06 mL/kg IM into the contralateral arm.
        • For prophylaxis after percutaneous or mucous membrane injury, a second dose of HBIG should be given 1 month later.
           
Guidelines for postexposure prophylaxis* of persons with nonoccupational exposure† to blood or body fluids that contain blood, by exposure type and vaccination status
Source of exposure Treatment
Unvaccinated person§ Previously vaccinated person¶
HBsAg-positive source
Percutaneous (e.g., bite or needlestick) or mucosal exposure to HBsAg-positive blood or body fluids Administer hepatitis B vaccine series and HBIG Administer hepatitis B vaccine booster dose
Sex or needle-sharing contact of an HBsAg-positive person Administer hepatitis B vaccine series and HBIG Administer hepatitis B vaccine booster dose
Victim of sexual assault/abuse by a perpetrator who is HBsAg positive Administer hepatitis B vaccine series and HBIG Administer hepatitis B vaccine booster dose
Source with unknown HBsAg status
 Victim of sexual assault/abuse by a perpetrator with unknown HBsAg status Administer hepatitis B vaccine series No treatment
Percutaneous (e.g., bite or needlestick) or mucosal exposure to potentially infectious blood or body fluids from a source with unknown HBsAg status Administer hepatitis B vaccine series No treatment
Sex or needle-sharing contact of person with unknown HBsAg status Administer hepatitis B vaccine series No treatment
Source: CDC. Postexposure prophylaxis to prevent hepatitis B virus infection. MMWR Recomm Rep 2006;55(No. RR-16).
Abbreviations: HBIG = hepatitis B immune globulin. HBsAg = hepatitis B surface antigen.
* When indicated, immunoprophylaxis should be initiated as soon as possible, preferably within 24 hours. Studies are limited on the maximum interval after exposure during which postexposure prophylaxis is effective, but the interval is unlikely to exceed 7 days for percutaneous exposures or 14 days for sexual exposures. The hepatitis B vaccine series should be completed.
† These guidelines apply to nonoccupational exposures. Guidelines for management of occupational exposures have been published separately and also can be used for management of nonoccupational exposures, if feasible. Source: CDC. CDC guidance for evaluating health-care personnel for hepatitis B virus protection and for administering postexposure management. MMWR Recomm Rep 2013;62(No. RR-10).
§ A person who is in the process of being vaccinated but who has not completed the vaccine series should complete the series and receive treatment as indicated.
¶ A person who has written documentation of a complete hepatitis B vaccine series and who did not receive postvaccination testing.

SEE ALSO:

 


http://www.cdc.gov/vaccines/pubs/pinkbook/hepb.html

Newborns Born to Hepatitis B Carriers [6,7]

  • Newborns born to hepatitis B carriers should receive hepatitis vaccine AND hepatitis B immune globulin (HBIG) within 12 hours of birth.

Antepartum

The CDC recommends pregnant Hepatitis B carriers should be advised to [5, 14]

  • Obtain vaccination against hepatitis viruses A as indicated.
  • Abstain form alcohol use
  • Avoid hepatotoxic drugs such as acetaminophen (Tylenol) that may worsen liver damage.
  • Not donate blood, body organs, or other tissue.
  • Not share any personal items that may have blood on them (e.g., toothbrushes and razors) and refrain from premastication of food.
  • Inform the infant’s pediatrician, OB/GYN, and labor staff that they are a hepatitis B carrier.
  • Make sure their baby receives hepatitis B vaccine at birth, one month, and six months of age as well as H-BIG at birth.
  • Be seen at least annually by their regular medical doctor.
  • Discuss the risk for transmission with their partner and discuss the need for counseling and testing
  • Sex partners of persons with HBsAg should be counseled to use latex condoms (32) to protect themselves from sexual exposure to infectious body fluids (e.g., semen and vaginal secretions), unless they have been demonstrated to be immune after vaccination (anti-HBs ≥10 mIU/mL) or previously infected (anti-HBc positive).


The National Institute for Health and Care Excellence (NICE) recommends that adults who are HBsAg positive  [17]:

  • Should be referred to a hepatologist , gastroenterologist , or infectious disease specialist with an interest in hepatology
  • Should have the following tests:
    • Hepatitis B e antigen (HBeAg)/antibody (anti-HBe) status, HBV DNA level, anti-HBc lgM ,hepatitis C virus antibody (anti-HCV), hepatitis delta virus antibody (anti-HDV), HIV antibody (anti-HIV), lgG antibody to hepatitis A virus (anti-HAV),
    • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), serum albumin, total bilirubin, total globulins
    • Complete blood count (CBC) and prothrombin time (PT)
    • Hepatic ultrasound transient elastography (TE)

Society for Maternal-Fetal Medicine (SMFM) recommends when a positive HBsAg test result is obtained [30]

  • Baseline liver function tests (LFTS)  and baseline quantitative HBV-DNA level should be drawn
  • If the baseline HBV DNA  testing is negative, it may be repeated in the third trimester.  HBV-DNA testing during pregnancy can be deferred until the third trimester, especially if the initial LFT results are normal or results prior to pregnancy are available.
  • Consider referral to a maternal-fetal medicine subspecialist or an infectious diseases specialist or hepatologist with experience managing hepatitis B to coordinate care and surveillance for the woman during and after pregnancy.

The Asian Pacific Association for the Study of the Liver (APASL ) recommends [31 ]

  • Maternal HBeAg, HBV DNA status, and  alanine aminotransferase (ALT),  level should be checked during pregnancy

Invasive Prenatal  Testing


The Society of Obstetricians and Gynecologists of Canada (SOGC)  [32]

  • Non-invasive methods of prenatal risk screening that provide the highest sensitivity with the lowest false-positive rate should be used to minimize the number of amniocenteses performed.
  • Every effort should be made to avoid inserting the needle through, or very close to, the placenta.
  • Little information is available on other prenatal diagnostic and therapeutic invasive procedures; the risks and benefits of such procedures should therefore be assessed prior to their use
  • "The rate of neonatal hepatitis B infection attributable to amniocentesis ranges up to 1.4% in newborns of mothers positive for hepatitis B surface antigen. However, the rate of neonatal infection attributable to amniocentesis in newborns of mothers with a positive hepatitis B e antigen status may be as high as 16%.
    • Although there is no statistically significant difference between the rates of infection in newborns exposed to amniocentesis or not exposed to amniocentesis in these two maternal populations, knowledge of the mother’s hepatitis B e antigen status may be valuable in counseling women about the risks associated with amniocentesis. "

 

Society for Maternal-Fetal Medicine (SMFM) recommends [30]

  • For HBV-infected women who have an indication for genetic testing, invasive testing (e.g. amniocentesis or chorionic villus sampling) may be offered.
  • Counseling should include the fact that the risk for maternal-fetal transmission may increase with HBV viral load >7 log 10 copies/mL

Treatment

The treatment of acute HBV infection is supportive. Patients should be hospitalized if they have coagulopathy, encephalopathy , or severe debilitation [6]. 

Two major groups of antiviral treatment for the treatment of chronic HBV infection include interferon alpha (IFNa, or PEG-IFNa) and nucleoside or nucleotide analogues such as lamivudine, adefovir, entecavir telbivudine, and tenofovir. Patents are generally  considered for treatment when they have HBV DNA levels above 2000 IU/ml*, serum alanine aminotransferase levels above the upper limit of normal, and severity of liver disease at least moderate fibrosis [19.]

 Interferon does not appear to adversely affect the embryo or fetus. However, studies are limited, and the potential benefits of interferon use during pregnancy should clearly outweigh possible hazards [26, 27].
 


* 1 IU/mL ~ 5.3 copies/mL
Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. World Health Organization 2015
http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf?ua=1


Several authorities and organizations recommend HBV-targeted maternal antiviral therapy should be considered for the purpose of decreasing the risk of intrauterine fetal infection and adding to the effectiveness of HBIg and vaccination in women with high viral loads during pregnancy  (17,29,30,31,34)

Pan CQ, et. al.,  recommend antiviral therapy for women with a viral HBV DNA> 6 log10 copies/mL ( 200,000 IU/mL), women with a previous child who failed HBIG and vaccine immunoprophylaxis,  and in some cases of HBV positive women with threatened preterm labor [34].

Society for Maternal-Fetal Medicine (SMFM) recommends antiviral therapy should be considered In pregnant women with HBV infection and viral load >6-8 log 10 copies/mL [30]

The Asian Pacific Association for the Study of the Liver (APASL ) recommends short-term maternal nucleotide or  nucleoside analogues (NA) starting from 28 to 32 weeks of gestation  for those mothers with HBV DNA above 6–7 log10 IU/ml (B2).  Since, the HBV transmission could occur even with lower maternal HBV DNA levels, NAs could be administered after discussion with the patient, even in patients with lower DNA levels. The NAs could be stopped at birth and when breastfeeding starts, if there is no contraindication to stopping NAs [31]

Antiviral Therapy

Nucleos(t)ide analogues (NA) for the prevention of mother-to-child transmission of hepatitis B  are generally started in the third trimester (28 weeks) . The most commonly used NAs and dose for each have been  [35-44]  :

  • Lamivudine (LAM) 100 to 150 mg orally per day
  • Telbivudine (LdT)  600 mg orally per day
  • Tenofovir disoproxil fumarate (TDF) 300 mg orally per day
    • Tenofovir is  the preferred antiviral  by several authorities because of its better resistance profile and more extensive safety data in pregnant, HBV positive women [28,30,31]

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals  Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy.

Pregnant women who are HBsAg positive should be reported to the local or state health department to ensure that they are entered into a case-management system and that timely and appropriate treatment  and prophylaxis is provided to patients and their infants.


Delivery

Although cesarean delivery has been proposed as a means of reducing mother to child transmission (MCT) of HBV [10, 22] Convincing benefit was not be demonstrated in one meta-analysis. [23]. Delivery by cesarean section for the purpose of reducing MCT of HBV is not  presently recommended by either the CDC [1,14] or the ACOG [6].


Breast feeding

With appropriate hepatitis B immunoprophylaxis, breast-feeding does not appear to  pose additional risk for transmission from infected hepatitis B virus carriers to their infants [24,25].  Ehrhardt S, et al. report that current data do not support the contraindication to the use of lamivudine or tenofovir disoproxil during breastfeeding. In addition, these drugs may  may need to be continued for at least short period of time after delivery to prevent maternal flares of liver inflammation [45] The World Health Organization recommends that women who have  HIV infection should continue their antiviral drugs during breast feeding ( tenofovir and lamivudine included)  [25].

 FOR PATIENTS:


Reviewed by Mark Curran, M.D. F.A.C.O.G.



 

References

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