Currently, there are approximately 350 million people infected with hepatitis B virus (HBV) worldwide, 50% of whom are infected during the perinatal or infant period, especially in countries where HBV is endemic. This is due to the high rate of HBeAg positivity in women of childbearing age in these areas, which makes the probability of mother-to-child transmission of HBV high, and the younger the age of HBV infection, the higher the chance of becoming a chronic carrier. Thus, effective mother-to-child interruption is an important tool to reduce the global burden of chronic HBV infection. Active and passive immunization of newborns with hepatitis B vaccine and hepatitis B immunoglobulin is a safe and effective measure to prevent mother-to-child transmission of HBV, but even with these immunization measures, 5-10% of infants born to HBeAg-positive pregnant women are still infected with HBV, so research on measures to interrupt mother-to-child transmission is urgent.
Chronic hepatitis B infection in pregnant women is different from the general population and requires consideration of many special issues: the impact of hepatitis B virus infection on the pregnant mother and fetus, the impact of pregnancy on hepatitis B virus replication, whether HBV antiviral treatment should be administered during pregnancy, the impact of such treatment on the mother and fetus, what immunizations the newborn should receive, and whether breastfeeding is possible after delivery.
The effect of hepatitis B virus infection on pregnancy
Acute hepatitis B infection during pregnancy may not be much different from that of the general population. Of course, acute HBV infection during pregnancy must be differentiated from other liver diseases during pregnancy, such as intrahepatic cholestasis and acute fatty liver during pregnancy, if symptoms such as jaundice, hemolysis and elevated ALT are present. Acute HBV infection during pregnancy does not increase mortality and has no teratogenic implications. However, hepatitis B virus infection can lead to a significantly higher incidence of low birth weight babies and preterm birth. The incidence of mother-to-child transmission of acute hepatitis B virus infection in early pregnancy is 10%, while the incidence of mother-to-child transmission increases significantly in late pregnancy.
Consideration needs to be given to whether amniocentesis is contraindicated in cases of active hepatitis B infection during pregnancy. In a study that included 21 HBsAg-positive pregnant women with a clear indication for amniocentesis performed at a mean gestational age of 19.5 weeks, none of the infants born with the recommended dose of HBIG and hepatitis B vaccination were HBsAg-positive at 1-12 months of follow-up.
In another prospective study that included 43 HBsAg-positive pregnant women who underwent amniocentesis, all amniocentesis fluid and cord blood were analyzed for HBsAg and HBVDNA. In this study, 32% of the preamniotic fluid was positive for HBsAg and 27% of the cord blood was positive for HBsAg, but all cord blood was undetectable for HBVDNA. Although the results were mixed, the authors of both studies concluded that the rate of mother-to-child transmission of HBV due to amniocentesis is quite low.
Effect of Pregnancy on Hepatitis B Virus Infection
In general, chronic hepatitis B infection in women of childbearing age has no significant effect on the course of pregnancy. However, adrenocorticotropic hormone levels are high during pregnancy and this may lead to high HBV virus replication; however, high estrogen levels during pregnancy have been found to inhibit HBV replication in animal studies. The results of one study showed no significant difference in viral replication of HBV during pregnancy, although there was a trend toward elevated ALT in late pregnancy and the perinatal period. We know that a proportion of women develop HBeAg seroconversion during the initial months after delivery. The study found seroconversion rates of 12.5% to 17%.
The study’s interpretation of this result suggests that this may be related to a significant reduction in postpartum cortisol, just as withdrawal treatment with hormones can induce seroconversion… Although, HBV infection during pregnancy can often be tolerated, there are still reports of perinatal hepatitis flare-ups. Late gestation with lamivudine does not prevent hepatitis flare-ups. Postpartum clearance of HBeAg is not correlated with maternal age or the presence of mutations in the C gene promoter. Pregnant women with HBV infection should be monitored closely for HBV in the postpartum period for early detection of hepatitis flare-ups or seroconversion of HBeAg.
Of course, the burden on the liver may be further aggravated by some other co-morbidities during pregnancy. For example, overlapping infection of HBV and HIV. In sub-Saharan Africa, where HBV is endemic, 13% of HIV-infected pregnant women are co-infected with HBV, and data from Texas, USA, show that 455 HIV-infected obstetric patients were followed up for up to 11 years, showing that 1.55% were co-infected with HBV.
It is important to note that these patients had lower CD4 cell counts than patients with overlapping HIV and HCV infections, and lower CD4 cell counts than patients with HIV infection only. The prognosis is poor when primary liver cancer is combined during pregnancy. Related reports show that most fetuses survive, although some cases of intrauterine death occur; however, maternal mortality is high, suggesting a significant adverse effect of pregnancy on malignancy. A joint data set reported that 20 of 33 pregnant women died within a few days after the presentation of HCC, while most of the rest also died within a few months. These data suggest that, as with other liver tumors, estrogen may accelerate the progression of HCC. In addition, immunosuppression during pregnancy may also be a factor in accelerating tumor progression.
Treatment of HBV infection during pregnancy
Two principles are observed regarding the use of antiviral therapy during pregnancy in HBV-infected pregnant women: treatment of mothers with chronic hepatitis B and prevention of perinatal mother-to-child transmission of HBV.
Most pregnant women with HBV infection have mild symptoms of liver disease. In addition, interferon, lamivudine, adefovir, and entecavir were identified as class C drugs for pregnancy, and tenbivudine and tenofovir as class B. This is mainly because there is a paucity of data on the gestational toxicity and teratogenicity of human applications of these drugs. Thus, in most cases, treatment is recommended to be taken postnatally to avoid possible toxicity of the drugs to the fetus. The standard postnatal treatment regimen follows the measures outlined in several guidelines for HBV treatment.
There has been a long and sufficient experience with lamivudine for either HIV infection or chronic HBV infection. Data from the American Registry of Antiretroviral Drugs in Pregnancy (ARADP) in 2006 showed no significant difference in birth defects in newborns born to pregnant women who used lamivudine during pregnancy compared to the general population.
In one cohort study, there were no cases of fetal birth defects and no cases of perinatal mother-to-child transmission. This compares favorably with previous results of mother-to-child transmission following active and passive immunization in the same population. 35 of 38 women had undetectable HBV, 10 (26.3%) had seroconversion to HBeAg, and 2 women who chose to discontinue lamivudine treatment developed hepatitis activity (ALT elevation) within 6 months. This study was relatively small and the authors believe that more data may be needed, but this study at least provides a basis for the safety of lamivudine use during pregnancy. Comparable study data are lacking for other HBV antivirals.
At this point, there is no standard protocol for the management of pregnancy in women with HBV infection during antiviral therapy. One option is to discontinue treatment immediately upon confirmation of pregnancy. This option is appropriate for women who have only mild hepatitis and who are at relatively low risk of having a hepatitis flare or progression of liver disease. Another option includes continuing treatment under close monitoring or changing to lamivudine to continue treatment after being informed of the risk of drug resistance.
Perinatal mother-to-child transmission of HBV and its interruption
Perinatal mother-to-child transmission of HBV leads to a chronic rate of HBV infection with a nearly 90% probability of infants born to pregnant women with HBeAg. It is now well recognized that most perinatal MTCT occurs at or near birth and that neonatal vaccination prevents 80-95% of mother-to-child transmission. The risk of mother-to-child transmission of HBV at delivery includes exposure of the infant to cervical secretions and maternal blood. Trans-placental transmission (intrauterine transmission) also contributes to the occurrence of mother-to-child transmission of HBV, as even immunization of the newborn does not prevent this part of the infection from occurring. Risk factors for transplacental transmission include maternal HBeAg positivity, HBsAg titers, and HBVDNA levels. Studies have shown a correlation between maternal HBVDNA >10^8copies/ml and significantly higher intrauterine transmission.
The finding of HBV in placental chorionic vascular endothelial cells and trophoblast cells supports the hypothesis that disruption of the placental barrier is one of the mechanisms by which intrauterine infection occurs. Preterm birth and spontaneous abortion put the mother-to-child transmission of HBV at increased risk due to possible exposure to maternal and placental blood. Recently, genes for some cytokines, such as polymorphisms in genes encoding gamma interferon and tumor necrosis factor, have been found to be associated with the risk of intrauterine infection with HBV. Interruption of perinatal mother-to-child transmission is key to reducing the rate of chronic hepatitis B infection in individuals and groups, as well as reducing the global burden of chronic hepatitis B infection.
Mode of delivery has also been identified as a potential risk factor for the occurrence of mother-to-child transmission. The 1998 study in China included 447 newborns born to HBsAg-positive pregnant women, 24.9% (96/385) of whom were delivered vaginally.