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REVIEW ARTICLE Table of Contents   
Year : 2007  |  Volume : 4  |  Issue : 1  |  Page : 12-23
Hepatitis B virus and pregnancy


Laboratory of Clinical and Molecular Hepatology, Molecular Genetics and Biology of Complex Diseases Department, Institute of Medical Research. A. Lanari, University of Buenos Aires, CONICET, Ciudad Autonoma de Buenos Aires, Argentina

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   Abstract 

Hepatitis B virus (HBV) infection is very common, with over 350 million chronically infected people worldwide. This review plans to answer some key questions regarding hepatitis B infection during pregnancy, in order to provide healthcare professionals with updated information on the current knowledge in this field. The focus is on the following topics: the main risk factors associated with vertical transmission of HBV in pregnant women who are chronically infected, the influence of pregnancy on HBV viral load, and the effect of pregnancy on the clinical course of chronic hepatitis B. Some recommendations have also been made that may be effective in decreasing the vertical transmission rates of chronic viral hepatitis.

Keywords: Acute liver disease, chronic liver disease, hepatitis B, pregnancy, viral hepatitis

How to cite this article:
Sookoian S. Hepatitis B virus and pregnancy. Hep B Annual 2007;4:12-23

How to cite this URL:
Sookoian S. Hepatitis B virus and pregnancy. Hep B Annual [serial online] 2007 [cited 2021 Oct 16];4:12-23. Available from: https://www.hepatitisbannual.org/text.asp?2007/4/1/12/45086



   Acute Hepatitis B during Pregnancy Top


Acute viral hepatitis is the most common cause of jaundice in pregnancy. [1],[2] The course of most viral hepatitis infections (e.g., hepatitis A, B, C, and D) is unaffected by pregnancy; however, a more severe course of viral hepatitis in pregnancy has been observed in patients with hepatitis E. [1] Hepatitis B virus (HBV) has a high rate of vertical transmission, causing fetal and neonatal hepatitis. Additionally, mother-to-child transmission of HBV infection predisposes to carriage, liver cirrhosis, and hepatocellular carcinoma in young adults. Thus, acute hepatitis B in pregnancy presents risks not only for the mother but also for the newborn.

Some special characteristics of HBV need to be considered in order to understand the behavior of acute hepatitis B. HBV is a double-stranded DNA virus of the Hepadnaviridae family. Its incubation period, from time of exposure to onset of symptoms, is 6 weeks to 6 months. HBV is found in highest concentrations in the blood, with lower concentrations in semen, vaginal secretions, and wound exudates. Perinatal transmission of HBV occurs if the mother has had acute HBV infection during late pregnancy or in the first months postpartum or if the mother is a chronic HBsAg carrier. Sixty percent of pregnant women who acquire acute HBV infections at or near delivery will transmit the HBV to their offspring. [3] Furthermore, intrauterine HBV infection has been suggested to be caused by transplacental transmission, which cannot be blocked by hepatitis B vaccine. A case-control study that included 402 newborn infants from 402 HBsAg-positive pregnant women showed that there is a significant association between intrauterine HBV transmission and HBV infection in villous capillary endothelial cells in the placenta (OR = 18.46, P = 0.0002). [4] In fact, the authors state that the main risk factors for intrauterine HBV infection are maternal serum HBeAg positivity, history of threatened preterm labor, and HBV in the placenta (especially the villous capillary endothelial cells).

Acute hepatitis B in pregnancy is not associated with increased abortion rate, stillbirth, or congenital malformation. However, prematurity seems to be increased if hepatitis is acquired in the last trimester. [5] Finally, HBV infection does not appear to be teratogenic. However, there appears to be a higher incidence of low birth weight among infants born to mothers with acute HBV infection during pregnancy. [6],[7]


   Prevention and Vaccination Top


Several aspects should be considered while making universal recommendations for acute viral hepatitis B in pregnancy. First of all, testing for the HBV is generally a standard, routine test performed in all pregnant women at or before their first antenatal visit, (usually before 12 to 14 weeks of pregnancy). [8] Second, pregnant women who think they may have been exposed to hepatitis B should be given an injection of hepatitis B immunoglobulin (HBIG) against the virus (ideally within 72 h of exposure) as well as hepatitis B vaccine (within 7 days of exposure). A second hepatitis B vaccination needs to be given about 1 month later, with a third injection at around 6 months after the first vaccination (or 5 months after the second vaccination). Besides, pregnant women who are identified as being at risk for HBV infection during pregnancy (e.g., those who have had more than one sex partner during the previous 6 months, been evaluated or treated for a sexually transmitted disease, have a history of recent or current injection-drug use, or have had an HBsAg-positive sex partner) should be vaccinated. [9]

At present, it is thought that administering the hepatitis B vaccine to pregnant women is relatively safe, even though sufficient research evidence is not available to completely confirm its safety for the unborn baby. However, the risks of a woman becoming infected with HBV, and possibly infecting her baby, are thought to outweigh the small risks from the vaccination. [3] Besides, limited data indicate no apparent risk of adverse effects to developing fetuses when hepatitis B vaccine is administered to pregnant women. Additionally, the current vaccines contain noninfectious HBsAg and should cause no risk to the fetus. [10] Pregnant women at risk for HBV infection during pregnancy should be counseled regarding the other methods for prevention of HBV infection. [10]


   Breastfeeding Recommendations Top


Mothers who carry the HBV are encouraged to breastfeed their babies. [11] It is recommended that the baby breastfeeds after the administration of the HBIG but not necessarily before the first hepatitis B vaccination. The hepatitis B vaccination can be delayed by more than 24 h after the baby's birth but definitely needs to be given before the baby is 7 days old. [12] Caution is however advised, since transmission of HBV through breast milk has been reported in some studies. [13],[14]


   Chronic Hepatitis B during Pregnancy Top


Women with chronic viral hepatitis generally do quite well during pregnancy, provided that they have not progressed to decompensated cirrhosis. As a general rule, a stable liver is associated with a safe pregnancy. However, there is concern about how preexisting chronic liver disease may affect the pregnancy and the unborn baby.


   Vertical Transmission of Hepatitis B in Pregnant Women with Chronic Hepatitis Top


Vertical transmission of HBV is the main cause of chronic HBV infection in endemic areas. When the mother is a chronic HBsAg carrier (with serum positive for viral DNA), the risk of the neonate becoming a chronic carrier is close to 80-90%. [15] On the contrary, if the mother's serum is negative for viral DNA, the transmission rate is about 10-30% only. [16] There are three possible routes of transmission of hepatitis virus from infected mothers to infants: transplacental transmission in the uterus (antenatal transmission), transmission during delivery, and postnatal transmission from mothers to infants during child care or through breastfeeding. [17] The baby usually first encounters the hepatitis virus upon entering the birth canal. However, several reports demonstrate that in the case of HBV infection uterine infection too plays an important role. [18] Besides, most researchers believe that the mechanism of intrauterine HBV infection is transplacental infection. In fact, it has been suggested that transplacental leakage of HBeAg-positive maternal blood, which is induced by uterine contractions during pregnancy and the disruption of placental barriers, is the most likely mechanism responsible for intrauterine HBV infection. [19] In addition, it has been shown that the main risk factors for intrauterine HBV infection are maternal serum HBeAg positivity, history of threatened preterm labor, and the presence of HBV in the placenta (especially in the villous capillary endothelial cells). [4] The presence of HBsAg in cord blood may indicate intrauterine infection. Unfortunately, intrauterine transmission of HBV can be a possible cause of vaccination failure and spread of HBV.

An interesting finding is the fact that some of the fetuses that have contact with HBV antigens early in embryonic development may became immunologically tolerant to HBV antigens. [20]

Finally, in chronic HBV infection, high maternal viremia and intrapartum exposure to virus-contaminated maternal blood increases the risk of virus transmission during vaginal deliveries. The main risk factor for vertical transmission of HBV seems to be the mother's viral load. Accordingly, maternal HBV-DNA seems to be a stronger independent predictor of persistent infection than HBeAg status. In effect, vertical transmission was most frequently seen in HBeAg-positive mothers who had very high levels of viremia. [21] Additionally, it was reported that among HBeAg-negative mothers, the odds ratio for having a persistently infected infant was 19.2 (95% confidence interval, 2.3 to 176.6) in mothers with high vs low levels of serum HBV-DNA. [22] Thus, perinatal exposure to high levels of maternal HBV-DNA is the most important determinant of infection outcome in the infant. However, at the same time it has been suggested that the outcome of HBV infection in newborns depends not only on the host's immunocompetence and on the viremia level in maternal blood, but also on the heterogeneity of HBV. Transmission of mixed HBV populations appears to be associated with an early immunoelimination of the virus, while infection with wild-type HBV alone contributes to the induction of chronicity. [23] Specific allelic mutations in maternal HBV and the level of maternal viremia are potential predictors of vertical breakthrough infection. [24]

However, there is a paucity of information on how pregnancy influences viremia levels in women with chronic HBV infection. In a retrospective study that analyzed the changes in HBV-DNA levels during and after 55 pregnancies in HBsAg-positive women, it was shown that although the majority of HBeAg-negative women had low and relatively stable HBV-DNA during pregnancy, viremia was also relatively high in some HBeAg-negative mothers, and both viremia and ALT increased significantly late in pregnancy or shortly after delivery. [21] The authors also found that HBV-DNA increased by a mean of 0.4 log late in pregnancy or in the early postpartum period and that HBV-DNA ranged from 1010 copies/ml in HBeAg-positive, to undetectable (< 100 copies/ml) in HBeAg-negative mothers. With regard to chronic HBV infection during pregnancy, it was shown that both viral load and ALT increase significantly late in pregnancy or shortly after delivery. [21] However, it is important to note that ALT levels have low sensitivity as a surrogate marker for high HBV-DNA levels; it has been reported that there is no correlation between ALT and HBV-DNA levels. [25]

Although cesarean delivery has been proposed as a means of reducing mother-to-child transmission of HBV, [26] the mode of delivery does not appear to have a significant effect on the interruption of this form of HBV transmission. [27] In fact, delivery by cesarean for the purpose of reducing vertical transmission of HBV is presently not recommended by the CDC (Center for Disease Control), [28] the American Academy of Pediatrics, or the American College of Obstetricians and Gynecologists. [28],[29]


   Recommendations to Decrease Vertical Transmission Rates of Chronic Viral Hepatitis Top


1. HBsAg screening

Testing for the HBV (HBsAg) is generally a standard, routine test performed on all pregnant women at or before her first antenatal visit (usually before about 12 to 14 weeks of the pregnancy). [10],[17]

2. Management of infants born to women who are HBsAg positive

An unvaccinated baby whose mother is a hepatitis B carrier has an up to 40% chance of becoming infected with the virus during the first 18 months of life; 90% of such babies can become long-term carriers and be infectious to others, besides being at risk of developing chronic liver disease and liver cancer in later life. Therefore, all infants born to HBsAg-positive women should receive both hepatitis B vaccine and hepatitis B immunoglobulin (HBIG) (0.5 ml) within 12 h of birth; the two should be administered at different injection sites. [12],[30] Administered in standard doses, HBIG provides passively acquired anti-HBs and temporary protection (i.e., for 3-6 months). The vaccine series should be completed according to the recommended schedule for infants born to HBsAg-positive mothers. The final dose in the vaccine series should not be administered before the age of 24 weeks (164 days). [15] For preterm infants weighing < 2000 gm, the initial vaccine dose (birth dose) should not be counted as part of the vaccine series because of the potentially reduced immunogenicity of hepatitis B vaccine in these infants; three additional doses of vaccine (i.e., a total of four doses) should be administered, beginning when the infant reaches the age of 1 month. [10]

The hepatitis B vaccination can be delayed by more than 24 h after the baby's birth but it should definitely be administered before the baby is 7 days old. Although not indicated in the manufacturer's package labeling, HBsAg containing combination vaccines may be used for infants aged ≥6 weeks, born to HBsAg positive mothers, to complete the vaccine series after receipt of a birth dose of single-antigen hepatitis B vaccine and HBIG. [8] A recent meta-analysis that evaluated the effects of hepatitis B vaccine and immunoglobulin in newborn infants of mothers positive for HBsAg showed that there was no significant difference between recombinant vaccine and plasma-derived vaccine on hepatitis B infections (relative risk 1.00; 95% CI 0.70 to 1.42). [15] However, more infants who received recombinant vaccine achieved antibody levels to hepatitis surface antigen > 10 IU/l.

Unfortunately, failure of postnatal immunoprophylaxis for hepatitis B has been reported and specific allelic mutations in maternal HBV and level of maternal viremia were potential predictors of vertical breakthrough infection. [24] Actually, it seems that S variants emerge or are selected under the immune pressure generated by the host or by administration of HBIG and hepatitis B vaccination. [31]

Mothers who carry the HBV are encouraged to breastfeed their babies. However, it is recommended that the baby breastfeeds after the administration of HBIG but not necessarily before the first hepatitis B vaccination (HBV). [11],[30]

As HBV transmission through breast milk has been reported in some studies, [13],[14] several groups do not recommend breastfeeding on the basis of the published data. [32],[33] Finally, keeping in mind that HBV is commonly transmitted by blood-to-blood routes, it is recommended that mothers should be told that when breastfeeding they should take good care of their nipples, ensuring proper latch-on and allowing the nipples to dry before covering to avoid cracking or bleeding.


   Use of Antiviral Therapy in the Mother to Prevent Vertical Transmission of HBV Top


The fact that vertical transmission of HBV may occasionally occur despite vaccination of the child has prompted physicians to treat viremic patients with nucleoside analogues to prevent mother-to-child transmission. In this regard, some authors have observed that in highly viremic HBsAg-positive mothers, reduction of viremia by lamivudine therapy in the last month of pregnancy could be an effective and safe measure to reduce the risk of child vaccination breakthrough. [34],[35] Moreover, no side effects were observed ,either in the mother or in the babies, an observation that had already been made earlier while studying the safety, pharmacokinetics, and antiretroviral activity of lamivudine alone and in combination with zidovudine in pregnant women infected with human HIV-1. [36] Nonetheless, in spite of the reported encouraging results in controlling vertical transmission with optimum maternal therapy and neonatal vaccination, some authors have reported that lamivudine therapy might not prevent perinatal transmission. [37] Finally, it is necessary to keep in mind that lamivudine or any other nucleoside should be used with caution during the first trimester of pregnancy in view of the possible lethal effects during embryogenesis. [38]

As a general rule, there is no reason for the occurrence of adverse pregnancy outcomes in compensated chronic HBV carriers. However, there have been a few case reports and studies indicating an increased incidence of maternal and neonatal morbidity in HBV infection, for instance, premature delivery before 34 weeks and raised incidence of antepartum hemorrhage, [39] fetal distress, and meconium peritonitis. [5],[13],[34] Additionally, it has been suggested that there exists an association between the HBsAg carrier state in mothers and chromosomal abnormalities in their newborns, [40] an observation that has not been replicated. One interesting finding is the association between gestational diabetes mellitus and HBsAg carrier status observed by Lao et al. [41] and Tse et al. [39] both studies were in Chinese women. The authors hypothesize that this phenomenon may be explained by the increased level of proinflammatory cytokines induced by chronic HBV infection, in particular by the effect of the tumor necrosis factor-α.

 
   References Top

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Correspondence Address:
Silvia Sookoian
Laboratory of Clinical and Molecular Hepatology, Molecular Genetics and Biology of Complex Diseases, Department. Institute of Medical Research, A. Lanari, University of Buenos Aires-CONICET, Combatiente de Malvinas 3150, 1427 - Ciudad Autónoma de Buenos Airesm
Argentina
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-9747.45086

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