Since the widespread use of the hepatitis B vaccine, great progress has been made in controlling the transmission of the hepatitis B virus in China, and horizontal transmission among newborns has been controlled. Universal vaccination of newborns with hepatitis B vaccine for several years has been able to reduce the rate of surface antigen positivity in preschool children to less than 1% or even 0.5% in some large cities. However, there are still some problems in mother-to-child transmission in newborns, and how to interrupt mother-to-child transmission of HBV is an important issue that needs to be addressed urgently.
Interruption of transmission during delivery: HBIG injection immediately after birth
The timing of HBIG injection is critical and should be given immediately after birth, the sooner the better, especially if the virus in the mother’s blood is large.
Mother-to-child transmission is one of the important modes of transmission of HBV. Currently, giving newborns hepatitis B immunoglobulin (HBIG) + hepatitis B vaccine is a better way to interrupt mother-to-child transmission. The common method is to inject 100-200 IU of HBIG into one deltoid muscle and 10 μg of hepatitis B vaccine into the other deltoid muscle after birth, followed by another 10 μg of hepatitis B vaccine at 1 and 6 months of age.
Because the hepatitis B virus enters the newborn mainly during delivery, if HBIG is injected immediately after birth, the HBIG can neutralize the virus as soon as it enters the body. If the injection is late, the virus will have already entered the liver of the newborn and HBIG will no longer be able to work.
Therefore, the timing of HBIG injection is critical and should be given immediately after birth, the sooner the better, especially if the virus in the mother’s blood is large. The reference to prescribing injection within 24 h is not appropriate.
Interruption of intrauterine transmission: application of antiviral drugs is more effective
The effectiveness of HBIG injections in mothers for the prevention of mother-to-child transmission of HBV is inconclusive and therefore not recommended. Antiviral drugs are more effective in chronic HBV carriers, but their application should be determined by the level of HBV DNA in their blood and the patient’s wishes.
Diagnostic criteria for intrauterine transmission
For in utero transmission of HBV, there are no uniform diagnostic criteria, and there are four main ones as follows.
(1) At birth, HBsAg (+) in cord blood or peripheral blood of the newborn. The disadvantage of this criterion is that cord blood is more likely to be contaminated by maternal blood, and peripheral blood is less likely to be contaminated, but there is still the possibility of maternal blood entering the newborn. In other words, the strong contraction of the uterus during delivery may squeeze the mother’s blood into the newborn. In this case, HBIG and hepatitis B vaccine are fully effective when administered to the newborn immediately after birth. Therefore, it is inappropriate to use HBsAg (+) in the infant’s peripheral blood at birth as a criterion for intrauterine transmission.
(2) At birth, the newborn’s cord blood or peripheral blood HBsAg (+) is still positive on retest 1 month later. Again, this criterion does not completely exclude the possibility of maternal blood being mixed during delivery.
(3) Newborns with HBsAg (+) up to 6 months of age after regular HBIG and hepatitis B vaccine prophylaxis after birth. This criterion is more appropriate because the possibility of being infected at birth is ruled out after formal prophylaxis after birth.
(4) HBV DNA (+) in the liver tissue of the fetus. This can confirm the diagnosis, but livers of newborns are difficult to obtain, and livers of induced fetuses, although available, can only be used for research applications.
The frequency of HBV transmission in utero has been reported differently and varies widely. In general, it seems to be closely related mainly to the concentration of HBV DNA in the mother’s blood.
Timing and route of intrauterine transmission
The timing of in utero transmission of HBV is extremely important because it is related to the time at which interruption is performed. Currently, it appears that intrauterine transmission occurs mainly at the end of pregnancy. However, it is also possible, although less likely, in mid- and even early gestation.
Yan YP et al. reported the rate of placental HBV infection: 4.2% (1/24) in early pregnancy, 16.7% (1/6) in midterm, and 44.6% (45/101) in late pregnancy; the rate of fetal infection: 1/6 in midterm (induced) and 7.92% (8/101) in neonates. The relationship between placental infection and fetal infection: 6/45 with intrauterine infection in those with placental infection and 2/56 with intrauterine infection in those with uninfected placenta. The gestational age of induced fetuses studied for the presence of HBV DNA in the fetal liver was mostly after 28 weeks. This indicates that fetal infection is mainly through the placenta (placenta is infected first and then infects the fetus), and the rate of infection increases the later the gestation. However, the fetus may also be infected in the middle of pregnancy, and the fetus may also be infected in those whose placenta is not infected.
An et al. studied HBV DNA in the liver of fetuses induced by mothers with HBsAg (+) and found that the gestational age was 15 weeks in one case of free replication and 17, 24 & 28 weeks in three cases of integrated type. This indicates that the fetus can be infected from the 15th week of gestation, and the status of the fetus before the 15th week is unknown. This is because all fetuses before 15 weeks are aborted (scraped) fetuses and do not have access to the liver.
Methods of interruption of intrauterine transmission There are currently two main approaches.
Maternal HBIG injection
Injections of 200 IU of HBIG are generally advocated three times a month during the last 3 months of pregnancy (usually starting from the 28th week of gestation). The newborn is given HBIG + hepatitis B vaccine as a routine prophylaxis after birth. It has even been suggested that HBIG injections in mothers have the potential to reduce the amount of HBV DNA in the serum. In fact, there are many reports of HBIG being ineffective.
In conclusion, although there is no conclusive evidence on the effectiveness of HBIG injections in mothers for the prevention of mother-to-child transmission of HBV, this method is not recommended if HBIG injections do not definitively reduce the level of HBV DNA in the mother’s blood (by at least 2log10 copies/ml) or if there is another mechanism. Therefore, clinicians should observe the efficacy of HBIG while also observing the changes in HBV DNA in the mother’s blood before and after HBIG injection or investigate other mechanisms in order to finally determine whether it is indeed effective.
Antiviral drugs for mothers
Among the antiviral drugs, interferons have adverse effects on the fetus and should not be used. Among the nucleoside (acid) analogues, adefovir and entecavir have teratogenic effects on animal fetuses and should not be used.
Although lamivudine has adverse effects on animal fetus, a large amount of clinical materials prove that it is safe for human fetus. Tebivudine has no teratogenic effect on animal fetus, and a small amount of clinical material also proves that it is safe for human fetus. Tenofovir has no teratogenic effect on animal fetus, and a large amount of clinical materials also prove that it is safe for human fetus. Therefore, lamivudine, telbivudine and tenofovir can all be used for the interruption of mother-to-child transmission of HBV.
Studies have shown that the incidence of neonatal malformations of lamivudine and tenofovir used during pregnancy is not higher than the general incidence of neonatal teratogenicity, so both can be used for the blockade of mother-to-child transmission of HBV. The effect of blockade varies depending on the duration of drug administration and the amount of HBV DNA in the mother’s blood.
In conclusion, for chronic HBV carriers, the application and timing of antiviral drugs should be decided according to the level of HBV DNA in their blood on the one hand, such as for those with 108 copies/ml), lamivudine or telbivudine must be applied, and the earlier it is applied, the better (preferably starting before the beginning of pregnancy, until the HBV DNA is negative before pregnancy), and for those with moderate amounts of HBV DNA, it must also be applied. On the other hand, the decision should be made according to the patient’s wishes, and for those who want their newborn to be absolutely free of infection, it is best to start before pregnancy and wait until the HBV DNA is negative, but the possibility of trans-ovarian transmission cannot be completely excluded, although it is extremely rare, such as If the patient requires absolute freedom from neonatal malformations, it is best to start late in pregnancy (28 weeks), but it must also be made clear to the patient that malformations can occur during pregnancy for other reasons (e.g., subclinical rubella). As to when to discontinue the drug, it may be considered after delivery, but the patient must be closely monitored to prevent deterioration of the disease. For patients with chronic hepatitis B (elevated serum transaminases) requiring treatment, lamivudine or telbivudine is applied whenever needed.
It is important to emphasize that the question of whether antiviral drugs can be used in pregnant women is not mentioned in many “guidelines” and is not stated in the drug instructions. Therefore, it is important to provide detailed information to the patient and obtain informed consent before application, and it is advisable to indicate in the medical record that the patient requested the use to avoid unnecessary disputes.
Interruption of transmission after delivery: breastfeeding is safe
HBsAg and HBV DNA can be detected in breast milk, but breast milk cannot transmit HBV virus, so breastfeeding is safe.