Available online on 15.12.2023 at http://jddtonline.info

Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

Copyright   © 2023 The  Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited

Open Access  Full Text Article                                                                                                                                                         Review Article

Management and Elimination of mother-to-child transmission of hepatitis B virus: A therapeutical Approach

Vankodoth Sireesha *¹, Ch. Abhiram ², Y. Sneha ², Syed Mohiuddin ², T. Rama Rao³

1.  Assistant Professor, Pharm D Department, CMR College of Pharmacy, Medchal, Hyderabad, India

2.  Pharm D Student, CMR College of Pharmacy, Medchal, Hyderabad, India

3.  Principal, Professor, CMR College of Pharmacy, Medchal, Hyderabad, India

 

 

Introduction

Hepatitis is an inflammation liver. Viral hepatitis is the most common type of hepatitis. It is caused by one of several hepatitis viruses A, B, C, D, E. Hepatitis B is potentially life- threatening liver infection caused by the hepatitis B virus (HBV). It can cause chronic infection and put people at high risk of death from cirrhosis and liver cancer. Chronic hepatitis B virus infection is an important global health problem. According to World Health Organization estimated that globally, in 2015, 300 million people were suffering with chronic HBV^1, 2. Most of them contract their infections during pregnancy or in early childhood, particularly in locations with high endemicity.³ An estimation of 1.5 million new infections are seen annually. According to previous studies, 90% of newborns have a chance to become chronic carriers after infection with HBV and in children less than 3-year-old the chance is up to 50%, but in adults the chance is up to 5%. For this reason, vertical transmission, also called mother to child transmission (MTCT), during pregnancy or perinatal periods, has been recognized as the most important phase for the prevention of chronic HBV infection.⁴

Strategies for preventing HBV infection during pregnancy include vaccination, combined with hepatitis B immunoglobulin (HBIG) administration, and nucleoside/nucleotide analogs. These methods have reduced carrier rate in pregnant women with high HBV DNA, but eradicating MTCT remains a challenge due to 10% of individuals affected by intrauterine infection and immunoprophylaxis failure.⁵

The risk of maternal-infant transmission is related to the HBV replicative status of the mother which correlates with the presence of HBeAg as 90% of HBeAg -positive mothers transmit HBV infection compared to only 10%-20% of HBeAg - negative mothers. Studies have shown that the rate of HBeAg seroconversion during the first 20 years of life is relatively slow, leaving many women of childbearing age who have contracted HBV infection in their early childhood still highly infectious to their infants⁶. There are several odd reasons why managing HBV infection during pregnancy is challenging such as: (1) passive-active immunoprophylaxis failure in several newborns, (2) HBIG injection- its effects and necessity in mothers, (3) safety of utilizing nucleoside/nucleotide analogues for antiviral prevention, (4) different delivery ways and its benefits, (5) safety of breastfeeding⁷.

Mother to Child Transmission (MTCT)

The transmission of infections from mother to offspring is traditionally known as perinatal infection. For a newborn infant whose mother is positive with HBeAg, in the absence of immunoprophylaxis, the risk of chronic HBV infection is 70%-90% by the age of 6 months.  Perinatal transmission of HBV results in a high frequency of chronic infection, up to 90% in infants born to HBeAg-positive women⁸. Transplacental transmission of HBV include maternal HBeAg positivity and HBV DNA level⁹. The three possible ways an infant get infected to HBV from an infected are:

1. Transplacental transmission of HBV in utero
2. Natal transmission during delivery
3. Postnatal transmission through breast milk

Pre-natal transmission

The pre-natal (intrauterine) route of HBV transmission is currently considered as an important culprit behind this post-exposure prophylaxis (PEP) which failed to block the MTCT of the virus¹⁰. 

Exact mechanism for prenatal transmission of HBV is unknown yet, however various possibilities are hypothesized including:

1. A Breach in the placental barrier: There will be a transplacental leakage of HBeAg- positive maternal blood flow, which will cause disruption of placental barrier due to induced uterine contractions during pregnancy, which is one of the most common ways to cause HBV intrauterine infection.
2. Placental infection and trans-placental transmission of HBV: Placental infection in a fetus with intrauterine HBV infection can be of 2 types, i.e., route for transmission of HBV from mother to fetus or secondary fetal infections by other routes. To differentiate these 2 outcomes, researchers have measured the gradient of placental infection between the mother side and fetal side of placenta and concluded that in majority of the cases, transplacental infection is the mechanism for HBV intrauterine infection¹¹.
3. From recent studies, researchers have revealed that HBV-DNA in the eggs of infected females and also in the sperms of HBV infected males. Therefore, it is possible for the fetus to get effected by the HBV at conception.
4. Other possibility is the intrauterine trans-mission of HBV to fetus, not from the maternal blood but the vaginal secretion of the mother which leads to this type of transmission¹².

Natal transmission:

Natal transmission usually takes place at the time of birth where the transmission of HBV takes place and passes to the infant and it is believed to be a result of exposure to maternal blood and also maternal cervical secretion which contain the virus. It is observed that there are still some controversies which are affecting the mode of delivery on MTCT. Some researchers have recommended cesarean section in case of high maternal HBV-DNA levels, whereas others believe that mode of delivery does not influence the rate of HBV as all the infants will be provided with HBIG and HBV vaccine at the recommended schedule¹³.

Postnatal transmission 

This type of transmission takes place when feeding the infants with Breastmilk. But, feeding their infants with this milk affects no additional risk is transmitted (HBV) provided that appropriate immunoprophylaxis is commenced at birth and continued as scheduled. There is no need of delaying the breastmilk to the infant until the child is received with all the doses of HBV vaccine¹⁴.

 

Mechanism of MTCT of HBV

The mechanism of MTCT is important for the management of chronic HBV infection. Perinatal transmission is the main mode of HBV transmission. There are three possible routes for transmission of HBV: transplacental transmission in utero (intrauterine transmission), natal transmission during delivery (intrapartum transmission) and postnatal transmission through breastmilk (postpartum transmission) ¹⁵.

Intrauterine transmission:

It is considered as the most important reason for the failure of passive-active immunoprophylaxis in prevention of MTCT. The precise mode of HBV intrauterine transfer is still unknown¹⁶.

1. Serum fluid transmission- It occurs usually in conditions of placenta damage caused by contraction of uterine muscle such as threatened abortion, invasive procedures into the uterus like amniocentesis during pregnancy or specific infections like Toxoplasma, Rubella, Cytomegalovirus and Herpes Simplex infections.
2. Cellular transmission- It refers to transmission of HBV from maternal side to fetal side through placenta cells and transfer the infected peripheral blood mononuclear cell from the circulatory systems of mother to infant.
3. Genetic transmission- When germ cells like oocytes and sperm are susceptible to HBV infection and the virus is passed on to the embryo, this form of transmission occurs.

Intrapartum transmission:

It describes transmission that occurs during childbirth and is regarded as the most significant method of HBV MTCT in the state of nature. When the mother's body fluids or blood pass through the maternal vaginal canal during delivery, the newborn baby may be exposed to HBV-containing bodily fluids or blood¹⁷. Additionally, if premature labour is imminent, uterine contractions may lacerate the placenta, allowing maternal blood to enter the foetus' bloodstream.

Puerperal transmission:

HBV infection caused by contact with body fluids, blood, breast milk, or other close contacts with the mother after delivery is referred to as puerperal transmission. After universal passive- active immunoprophylaxis of newborns from HBsAg-positive mothers was carried out, it becomes a subordinate to other transmission pathways that are previously discussed because its incidence is minimal.

Strategies for Preventing MTCT of HBV   

By preventing MTCT we can reduce the global burden of chronic HBV. On the basis of its mechanism, MTCT of HBV is often prevented. These tactics support prenatal care for women and postpartum care for both moms and their newborns¹⁸.

Immunoprophylaxis provided to newborns:

The incidence of perinatal HBV transmission is apparently decreased by immunoprophylaxis given to newborns. Numerous research, including reviews, have shown that the hepatitis B vaccine with HBIG is more effective at lowering the prevalence of MTCT than the hepatitis B vaccine alone in preventing MTCT of HBV in HBsAg positive women. Infants whose mothers are HBsAg-positive will benefit more from this procedure, according to WHO standards, especially if they are HBsAg-positive themselves. Universal passive-active immunoprophylaxis of infants has significantly reduced the transmission rate of HBV by 85– 95 percent. The Hepatitis B vaccine and HBIG should be administered to newborns of HBsAg- positive mothers within 12 hours of delivery, according to recommendations from the WHO and the complete process should be completed within 6 months after the baby was born i.e., in the 1^st month and at the 6^th month respectively. However, infants born to HBsAg-positive mothers must take immunizations, but those born to HBeAg-negative must administer HBIG until the vaccine is proven effective. 

Recent studies have demonstrated that giving mothers who were both HBsAg and HBeAg positive three to four doses of the Hepatitis B vaccine without HBIG has an efficacy up to 90%. Also, some studies have shown that vaccination without HBIG can prevent vertical transmission in 66-90% of cases. These reports are useful for alternatively using Hepatitis B vaccine alone with these conditions of HBIG. MTCT of HBV may still occur in 1–15% of newborns from moms who test positive for HBsAg despite the conventional passive-active immunoprophylaxis approach in neonates. Intrauterine infections are a major factor in HBV vaccine failure¹⁹.

Antiviral prophylaxis with nucleoside/nucleotide analogs:

The most significant risk factor for MTCT of HBV is thought to be high HBV DNA levels and HBeAg positive status in pregnant women, as was previously mentioned. Due to the combination of the HBIG and HBV vaccine, the HBV transmission rate in babies born to HBeAg positive mothers is reduced from over 90% to about 3-7%.²⁰ However, some researchers have revealed that the failure rate of immunoprophylaxis in infants born to mothers with high HBV and HBeAg levels reaches 8–32%. Therefore, reducing maternal HBV DNA levels during pregnancy is the best course of action for preventing MTCT in mothers with high viremia.Telbivudine and tenofovir are two oral anti-HBV medications that have been classified as pregnancy category B medicines. The most effective antiviral medication for treating chronic HBV patients while they are pregnant is lamivudine, which is also the safest option. 

Therefore, the most recent treatments for Hepatitis B infection in pregnant women are Lamivudine, Telbivudine, and Tenofovir²¹. Infected pregnant women with HIV have had success using tenofovir. Tenofovir is anticipated to be successful in preventing MTCT of HBV due to its high antiviral activity. Passive-active prophylaxis was administered to all babies. According to newly developed guidelines from the European Association for the Study of the Liver (EASL) and the Asian Pacific Association for the Study of the Liver (APASL), treating pregnant women with high viremia with antiviral drugs like tenofovir or telbivudine at 28–32 weeks of gestation will be both safe and effective in preventing MTCT given in the fig. 1. These findings have shown that pregnant women with high viremia should also receive neonatal immunoprophylaxis. However, there is still a study gap to determine the ideal HBV DNA threshold for antiviral therapy²². 

 

 

 

 

Figure 1: Management of MTCT of HBV in pregnancy. ALT, alanine aminotransferase; HBV, hepatitis B virus; LFT, liver function test; HBsAg, Hepatitis B surface antigen; HBsAb, hepatitis B surface antibody; HBIG, hepatitis B immunoglobulin; INR, international normalized ratio².

 

Periodical administration of HBIG during pregnancy

It is still debatable whether or not pregnant women with HBsAg positivity who get periodic HBIG treatment during the third trimester of pregnancy are able to prevent HBV MTCT. Researchers who hold this opinion think that administering HBIG intramuscularly in numerous small doses will directly neutralise maternal HBV to give passive immunisation. Also, by binding with HBsAg, it might stimulate the immune system and reduce HBV replication to a certain extent. Researchers discovered that in HBV carrier mothers who received HBIG during pregnancy, there was no discernible decrease in maternal HBV DNA. Additionally, none of their newborns tested positive for HBsAb. There was no difference in the prevalence of HBsAb positivity in infants older than 7 months between mothers who received HBIG treatment during pregnancy and those who did not, even in cases where infants' HBsAb was discovered.

Various delivery methods and procedures

The delivery strategy to lower the MTCT of HBV incidence has not yet been determined. In the past it was observed that Infant mucosal membrane contact with maternal fluids or blood during pregnancy was still thought to enhance the risk of HBV MTCT upon vaginal delivery. However, the probability of MTCT of HBV was reduced by caesarean birth²³. Contrarily, several research came to the opposite conclusion and found no difference between caesarean and vaginal birth in the incidence of MTCT. It was formerly shown that infants delivered via various methods did not have significantly different HBsAg levels after 12 months. There is insufficient evidence to prove that caesarean birth is superior to vaginal delivery in preventing the MTCT of HBV because these results were contradictory. Caesarean delivery is not advised for HBsAg-positive mothers due to the benefits of vaginal delivery and the favorable effects of passive-active immunoprophylaxis on newborns.²⁴

Several strategies are being examined to lower the prevalence of HBV infection during labour. Following delivery, the measures include quickly cleansing the neonates' mouths, respiratory tracts, and skin ²⁵. The likelihood of the foetus being exposed to maternal fluids, serums, and vaginal secretions will be reduced as a result of this process.²⁶

Conclusions

The chance to prevent MTCT of HBV presented by HBV infection during pregnancy is not only unique but also significant. The majority of the data is derived from open-labeled and non- randomized retrospective or prospective research because randomised trials are not practical in pregnant women for ethical and other reasons. 90% of babies are successfully protected from MTCT of HBV with the standard passive-active immunoprophylaxis with HBIG plus HBV vaccine in neonates within 12 hours after birth. MTCT of HBV affects up to 9% of newborns as a result of perinatal transmission of HBV linked to high levels of viremia in mothers. For high viremia, it is reasonable to administer antiviral medications such tenofovir or telbivudine. Breastfeeding is recommended in HBsAg-positive mothers, according to standard active- passive immunoprophylaxis regimen. Some topics are still debatable, including whether mothers receiving antiviral therapy should nurse their children, whether pregnant women should receive HBIG injections, and whether antiviral medications may have long-term negative consequences on both HBV-positive mothers and their children.

 

 

Acknowledgements: 

The authors are thankful to  the Principal   and  Management of CMR college of  Pharmacy Medchal, Hyderabad for providing facilities to complete this manuscript.

Conflict of Interest:

The authors declare no conflicts of interest.

Funding source:

The authors received no funding for preparation of this manuscript.

References

1 Goyal A, Murray JM, The impact of vaccination and antiviral therapy on hepatitis B and hepatitis D epidemiology, PLoS One 9 (2014) e110143. https://doi.org/10.1371/journal.pone.0110143 PMid:25313681 PMCid:PMC4196970

2 Yi P, Chen R, Huang Y, Zhou RR, Fan XG. Management of mother-to-child transmission of hepatitis B virus: Propositions and challenges. Journal of Clinical Virology, 2016 Apr; 77:32-9. https://doi.org/10.1016/j.jcv.2016.02.003 PMid:26895227

3 Janahi EM. Prevalence and Risk Factors of Hepatitis B Virus Infection in Bahrain, 2000 through 2010. Ray R, editor. PLoS ONE. 2014 Feb 3; 9 (2):e87599. https://doi.org/10.1371/journal.pone.0087599 PMid:24498341 PMCid:PMC3911996

4 https://apps.who.int/iris/bitstream/handle/10665/255016/9789241565455-eng.pdf 

5 Chen CJ, Iloeje UH, Yang Hwai-I. Long-term outcomes in hepatitis B: the REVEAL-HBV study. Clinics in Liver Disease. 2007 Nov 1; 11 (4):797-816, viii. https://pubmed.ncbi.nlm.nih.gov/17981229 https://doi.org/10.1016/j.cld.2007.08.005 PMid:17981229

6 Zhang HW, Yin JH, Li YT, Li CZ, Ren H, Gu CY, et al. Risk factors for acute hepatitis B and its progression to chronic hepatitis in Shanghai, China. Gut. 2008 Jul 30; 57 (12):1713-20. https://gut.bmj.com/content/57/12/1713 https://doi.org/10.1136/gut.2008.157149 PMid:18755887 PMCid:PMC2582333

7 Borgia G, Gentile I. Vertical transmission of hepatitis B virus: challenges and solutions. International Journal of Women's Health. 2014 Jun; 605. https://doi.org/10.2147/IJWH.S51138 PMid:24966696 PMCid:PMC4062549

8 Kumar M, Singh T, Sinha S. Chronic Hepatitis B Virus Infection and Pregnancy. Journal of Clinical and Experimental Hepatology. 2012 Dec; 2 (4):366-81. https://doi.org/10.1016/j.jceh.2012.09.001 PMid:25755458 PMCid:PMC3940289

9 Umar M, Hamama-tul-Bushra, Umar S, Khan HA. HBV Perinatal Transmission. International Journal of Hepatology.2013; 2013:875791. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659463/ https://doi.org/10.1155/2013/875791 PMid:23738081 PMCid:PMC3659463

10 Yang J, Zeng X, Men Y, Zhao L. Elective caesarean section versus vaginal delivery for preventing mother to child transmission of hepatitis B virus - a systematic review. Virology Journal. 2008; 5(1):100. https://rd.springer.com/content/pdf/10.1186%2F1743-422X-5-100.pdf https://doi.org/10.1186/1743-422X-5-100 PMid:18755018 PMCid:PMC2535601

11Nelson NP, Jamieson DJ, Murphy TV. Prevention of Perinatal Hepatitis B Virus Transmission. Journal of the Pediatric Infectious Diseases Society. 2014 Sep 1; 3 (Suppl 1):S7-12. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164184/ https://doi.org/10.1093/jpids/piu064 PMid:25232477 PMCid:PMC4164184

12 Chang MH. Chen DS. Prevention of Hepatitis B. Cold Spring Harbor Perspectives in Medicine. 2015 Mar 1; 5 (3): a021493 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355249/ https://doi.org/10.1101/cshperspect.a021493 PMid:25732034 PMCid:PMC4355249

13 World Health Organization. Vaccine- preventable diseases: monitoring system. Global summary. Geneva: WHO. 2007.

14 Tripathi N, Mousa OY. Hepatitis B. PubMed. Treasure Island (FL): Stat Pearls Publishing; 2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK555945/ 

15 Thakur V, Guptan Rc, Kazim Sn, Malhotra V, Sarin Sk. Profile, spectrum and significance of HBV genotypes in chronic liver disease patients in the Indian subcontinent. Journal of Gastroenterology and Hepatology. 2002 Feb; 17 (2):165-70. https://doi.org/10.1046/j.1440-1746.2002.02605.x PMid:11966946

16 Li XM. Interruption of HBV intrauterine transmission: A clinical study. World Journal of Gastroenterology. 2003; 9 (7):1501. https://doi.org/10.3748/wjg.v9.i7.1501 PMid:12854150 PMCid:PMC4615491

17 Ayoub WS, Cohen E. Hepatitis B Management in the Pregnant Patient: An Update. Journal of Clinical and Translational Hepatology. 2016 Sep 28; 4 (3):241-7. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075007/ https://doi.org/10.14218/JCTH.2016.00014 PMid:27777892 PMCid:PMC5075007

18 Puri P. Acute Exacerbation of Chronic Hepatitis B: The Dilemma of Differentiation from Acute Viral Hepatitis B. Journal of Clinical and Experimental Hepatology. 2013 Dec; 3 (4):301-12. https://doi.org/10.1016/j.jceh.2013.08.014 PMid:25755518 PMCid:PMC3940633

19 Xu Q. A randomized controlled clinical trial: Interruption of intrauterine transmission of hepatitis B virus infection with HBIG. World Journal of Gastroenterology. 2006; 12 (21):3434. https://doi.org/10.3748/wjg.v12.i21.3434 PMid:16733865 PMCid:PMC4087879

20 WHO, Guidelines for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection, WHO Guidelines Approved by the Guidelines Review Committee, Geneva, 2015.

21 Fung J, Lai CL, Seto WK, Yuen MF. Nucleoside/nucleotide analogues in the treatment of chronic hepatitis B. Journal of Antimicrobial Chemotherapy. 2011 Dec 1; 66 (12):2715-25. Available from: https://academic.oup.com/jac/article/66/12/2715/698352  https://doi.org/10.1093/jac/dkr388 PMid:21965435

22 Mast EE, Margolis HS, Fiore AE, Brink EW, Goldstein ST, Wang S, et al. A Comprehensive Immunization Strategy to Eliminate Transmission of Hepatitis B Virus Infection in the United States: Recommendations of the Advisory Committee on Immunization Practices (ACIP): Part 1: Immunization of Infants, Children, and Adolescents. Morbidity and mortality weekly report. 2005 Jan 1;

23Aslam A, Campoverde Reyes KJ, Malladi VR, Ishtiaq R, Lau DTY. Management of chronic hepatitis B during pregnancy. Gastroenterology Report. 2018 Nov 1; 6 (4):257-62. https://doi.org/10.1093/gastro/goy025 PMid:30430013 PMCid:PMC6225824

24 Dionne-Odom J, Tita AT, Silverman NS, #38: Hepatitis B in pregnancy screening, treatment, and prevention of vertical transmission, Am. J. Obstet. Gynecol. 214 (2016) 6-14. https://doi.org/10.1016/j.ajog.2015.09.100 PMid:26454123

25 Poordad F, Chee GM. Viral Resistance in Hepatitis B: Prevalence and Management. 2010 Feb 1; 12 (1):62-9. https://doi.org/10.1007/s11894-009-0088-1 PMid:20425486 PMCid:PMC2832900

26 Liang TJ. Hepatitis B: the virus and disease. Hepatology (Baltimore, Md). 2009 May; 49:S13-21. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19399811  https://doi.org/10.1002/hep.22881 PMid:19399811 PMCid:PMC2809016