Chronic infection of hepatitis B virus (HBV) remains an important health problem worldwide because of its serious sequelae such as liver cirrhosis and liver cancers. Mother-to-infant transmission of HBV is a main cause of chronic infection in hepatitis B endemic regions. By the end of 2016, 186 countries have implemented universal vaccination against hepatitis B in all infants.1 Moreover, most countries recommend administration of passive [hepatitis B immunoglobulin (HBIG)] and active (hepatitis B vaccine) immunoprophylaxis in neonates born to mothers with positive hepatitis B surface antigen (HBsAg) within 12 or 24 hours after birth. After the immunoprophylaxis, mother-to-infant transmission of HBV in offsprings of HBV-infected mothers with negative hepatitis B e antigen (HBeAg) has reduced from 10%–30% to <0.1%, while the transmission rate from HBeAg-positive mothers has reduced from 70%–90% to 4%–12% (Table 1).2–10
The major risk factor for mother-to-infant transmission of HBV is maternal high viral loads. Recent studies demonstrated that oral antivirals (lamivudine, telbivudine, or tenofovir) used in pregnant women with positive HBeAg or high viral loads, together with the neonatal use of HBIG and hepatitis B vaccine on the 0, 1, and 6 months schedule, can almost completely prevent mother-to-infant transmission (Table 2),11–18 although some reports showed that the differences had no statistical significance because of the limited subject numbers14 or very low infection rates in infants of mothers without antiviral theraoy.16,18 However, several issues merit further investigations to optimize the antiviral therapy during pregnancy.
HBV DNA threshold for antiviral therapy during pregnancy
In theory, the HBV DNA threshold for antiviral therapy during pregnancy should be a level that can cause mother-to-infant transmission after the neonatal passive and active immunoprophylaxis. Studies showed that maternal HBV DNA level that can cause perinatal infection is somewhat varied. HBV DNA quantification with Roche reagents in Australia, the United States, and Hong Kong of China revealed that the perinatal infection occurred only in infants born to mothers with HBV DNA >2 × 107 IU/mL (108 copies/mL).2,7,10 The data based on detection reagents made in mainland China showed that HBV DNA level >2 × 105 IU/mL (106 copies/mL) is a high risk factor for transmission,4–6 but with Abbott RealTime HBV DNA assay, the mother-to-infant transmission occurred only in infants of mothers with HBV DNA >107 IU/mL, and did not occur in infants of mothers with HBV DNA <107 IU/mL.19 The variation for HBV DNA levels that can cause the transmission is likely associated with the different performance of commercially available reagents.
Meanwhile, the HBV DNA threshold for antiviral therapy during pregnancy to prevent mother-to-infant transmission of HBV applied in different guidelines is also varied. The American Association for the Study of Liver Diseases (AASLD) used >2 × 105 IU/mL (106 copies/mL) as the threshold.20 The European Association for the Study of the Liver (EASL) switched to >2 × 105 IU/mL (106 copies/mL) in 2017 from >106-7 IU/mL in and before 2015.21–23 The Asian Pacific Association for the Study of the Liver recommended >106-7 IU/mL as the therapy cutoff.24 The Chinese Societies of Hepatology and Infectious Diseases set up >2 × 106 IU/mL (107 copies/mL).25
Given the substantial imbalance of the global economics, it is infeasible to quantify HBV DNA with Roche or Abbott reagents across the world. Each country needs to study its own antiviral therapy threshold based on the most commonly used reagents. In addition, it is required to assess the conformity of different quantification reagents made by different companies. Nevertheless, antiviral therapy is not required when maternal HBV DNA level is ≤2 × 105 IU/mL (106 copies/mL),20 because there is almost no mother-to-infant transmission after neonatal passive–active immunoprophylaxis.4–6
Probability of positive HBeAg as a marker for antiviral therapy during pregnancy
Although the HBV DNA level is a direct marker of viral replication, the assay cannot be widely performed in resource-limited countries and regions. It has been confirmed that the presence of HBeAg is very well correlated with high HBV DNA levels.26–31 HBeAg can be tested by conventional qualitative enzyme-linked immunosorbent assay without particular equipment, and thus detection of HBeAg is applicable in resource-limited regions.
In Asia, the median HBV DNA levels in HBsAg-positive pregnant women with negative HBeAg are 2.6–2.7 log10 IU/mL or 2.7 log10 copies/mL, and the proportion of >106 IU/mL or >106 copies/mL is only 0.5–1.8%, while the median HBV DNA levels in positive HBeAg women are 7.7–8.1 log10 IU/mL or 7.4 log10 copies/mL.26–28 The data obtained in Europe and America are similar,29–31 indicating that positive HBeAg can reliably represent high viral loads and negative HBeAg, low viral loads (<106 IU/mL).
However, studies in Africans infected with HBV showed different scenarios. In South Africa, high viral load is mainly seen in HBeAg-positive pregnant women32; however, in Senegal, Gambia, and Nigeria, ∼50% of the infected individuals with HBV DNA ≥106 IU/mL are HBeAg negative.33–35 These findings indicate that, if positive HBeAg serves as a marker of high viral loads, nearly half of the pregnant women with high viral load would not be treated. The different picture of HBeAg as a high viral marker in Africa requires further demonstration. On the other hand, under the circumstances that the quantification of HBV DNA is infeasible, HBeAg test can still detect ∼50% of the pregnant women with high viral load, which can help determine the antiviral treatment.
Timing for antiviral therapy during pregnancy
A large number of studies have demonstrated that antiviral therapy started from 28–32 weeks of gestation can almost completely prevent mother-to-infant transmission of HBV,12–16,18 indicating that earlier use of antivirals, from the first or second trimester, cannot further increase the protection efficacy, which was demonstrated by the investigations.36–38 Thus, the proposal that antiviral therapy started from 24–28 weeks of gestation merits rethinking.23,25 The current evidence does not support to start antiviral therapy before 28 weeks of gestation.
Studies showed that oral antiviral therapy started at 28–32 weeks of gestation can reduce the median maternal HBV DNA levels from 107-8 IU/mL before treatment to <104-5 IU/mL at delivery,12–16,18 a level at which almost no transmission occurs after neonatal immunoprophylaxis. This is similar to the situation in infants born to mothers with negative HBeAg.1–10 Since neonatal immunoprophylaxis cannot prevent intrauterine HBV transmission, the findings of no HBV transmission in children born to HBeAg-negative carrier mothers and in those born to HBeAg-positive mothers treated with antivirals suggest that intrauterine transmission of HBV is extremely rare, at least in mothers with negative HBeAg or low viral loads and in mothers with high viral loads before 28–32 weeks of gestation. Longitudinal observations showed that the presence of HBsAg and/or HBV DNA in the umbilical cord blood just indicates neonatal exposure to, rather than infection with, HBV.39 The total absence of anti-HBc IgM in the newborn infants of HBV-infected mothers provides evidence against the concept of intrauterine infection.39,40 Currently, there is no sufficient evidence to define intrauterine transmission of HBV.41 Therefore, the mechanism of antiviral therapy for preventing mother-to-infant transmission of HBV is likely to reduce the neonatal viral exposure during the birth process by inhibiting maternal high viremia and is less likely to prevent intrauterine transmission.
From the viewpoint of fetal safety and economics, it is best to use antivirals during pregnancy for as short duration as possible, so long as there is no HBV transmission. As the antiviral therapy started at 28–32 weeks of gestation can almost prevent all perinatal infection,12–16,18 it appears to be reasonable to delay the use of antivirals, such as starting from 33–34 weeks of gestation, which merits further study. A quick way is to determine the shortest period of time to reduce HBV DNA from high levels to below the transmission level (2 × 105 IU/mL in EASL and AASLD,20,23 106-7 IU/mL in APSAL,24 and 2 × 106 IU/mL in China25) by the antivirals. As such, an optimal length of treatment during pregnancy can be determined.
Safety of antivirals for fetuses and infants
It is generally considered that intrauterine exposure to tenofovir, telbivudine, or lamivudine has no adverse effects on the fetuses/neonates. However, a summary of the published literatures showed that the severe adverse events appeared to be increased in the fetuses/neonates who had been exposed to antivirals in utero.18 More recently, it was reported that the frequency of premature birth in antiviral therapy pregnant women was higher than that in untreated pregnant women (13.1% vs. 2.9%), although the difference had no statistical significance (P = 0.208).42 Severe congenital malformation (congenital megacolon, anotia, biliary atresia), cerebral palsy, severe muscularly developmental abnormalities, and stillbirth were reported in fetuses/infants born to anti-HBV-treated mothers.17,18,43,44 In a randomized trial including 96 pregnant women who received TDF and 88 pregnant women who did not receive antivirals, one fetal death and one neonatal death occurred in the therapy group, but none occurred in the control group.15 Although the link between two severe adverse events and tenofovir therapy could not be ascertained, the association could not also be completely ruled out. The repeated occurrence of severe adverse events in fetuses/neonates born to treated mothers, but not in those born to untreated mothers, suggest the need to further observe the safety of antivirals for fetuses/infants.
Because the frequency of serious adverse events in fetuses/infants born to mothers treated with antivirals is low, it is difficult to get a concrete conclusion from controlled or cohort studies with limited number of study subjects. Evidence based on the real-world data with much larger samples will help address the relationship between these antiviral drugs and serious adverse effects on fetuses/infants.
In addition, the assessment of infant development in children who had intrauterine exposure to telbivudine showed that the psychomotor development indexes at 1–2 years of age were lower than in children without the exposure.45 The infants with intrauterine exposure to tenofovir had decreased bone mineral content at 6 months of age.46 These results indicate that further studies are needed to determine the long-term effects of the antivirals on the development of infants.
Since the antivirals against hepatitis B can be excreted in breast milk and the safety of antivirals for infants during breastfeeding has not been extensively studied, the drug labels recommend avoidance of breastfeeding when taking these antivirals. As a result, physicians usually recommended the mothers not breastfeeding their babies, and mothers also did not breastfeed their babies.
However, studies showed that the plasma concentration of tenofovir and lamivudine in neonates and infants who were breastfed was only 2%–27% of the maternal plasma concentration,47 which should be much lower than the concentration of intrauterine exposure during pregnancy. This suggests that these antivirals in breast milk are unlikely to cause significant toxicity for neonates and infants. The preliminary data showed that breastfed infants born to mothers with antiviral therapy did not show obvious adverse effects.14,18 Therefore, based on currently available information, breastfeeding should not be contraindicated in HBV-infected women on antiviral treatment, as both EASL and AASLD proposed in their guidelines.20,23 Nevertheless, more evidence is required to support the proposal of breastfeeding.
Timing for discontinuation of antivirals
Different guidelines vary on the time of discontinuation of antiviral therapy started during pregnancy for preventing mother-to-infant transmission of HBV. The ESAL proposed that the TDF started during pregnancy should continue for up to 12 weeks after delivery,23 while the ASSLD did not propose the exact time of the discontinuation, and just objectively stated that “Antiviral therapy was discontinued at birth to 3 months postpartum in most of the studies”.20 Virtually, the issue on the time of discontinuation of antivirals after delivery has not been extensively studied.
It appears that there is no worry about the postnatal infection of HBV in infants following discontinuation of antivirals, because they have already received passive and active immunoprophylaxis after birth. The primary concern of discontinuation of antivirals upon delivery might be associated with maternal hepatitis flare or severe hepatitis, because childbirth increases the burden on the women and can cause dramatic changes of various hormones, both of which appear to be harmful for liver. However, so far no hepatic failure has been reported after the discontinuation of antivirals started in the trimester of pregnancy, indicating that discontinuation of antivirals after relatively short period of time is less likely to cause severe hepatitis flares or hepatic decompensation. The findings that discontinuation of antivirals within 1–2 months did not result in such severe consequences,12–18 suggesting that extending therapy up to 3 months postpartum is not necessary. Moreover, preliminary data showed that discontinuation of drugs upon delivery did not result in severe maternal outcomes.14,48 Thus, it appears that discontinuation of antivirals upon delivery is safe for mothers. Anyway, more study is required on this issue.
Management of abnormal liver functions after discontinuation of antivirals
Rebounds of serum HBV DNA level following discontinuation of antivirals appears to be unavoidable, and around 20% of the women may have abnormal liver functions [alanine aminotransferase (ALT) >40 U/L].18 However, 20%–25% of the HBV-infected pregnant women who did not receive antiviral during pregnancy also underwent postpartum hepatitis flares,18,49 suggesting that the hepatitis flare is less likely associated with the discontinuation of antivirals. Overall, the liver functions are mildly impaired, and can recover in a couple of weeks without specific treatment.18,49 To date, no hepatic decompensation or failure has been reported in women who received antiviral therapy from the third trimester and discontinued therapy 1–3 months postpartum. Therefore, when hepatitis flare occurs after drug discontinuation, conservative management should be the first consideration, rather than to restart antiviral therapy. Antiviral therapy should strictly adhere to indications proposed in the guidelines.20
With the administration of antivirals started from 28–32 weeks of gestation in pregnant women with positive HBeAg or high viral loads, together with the neonatal passive–active immunoprophylaxis, the mother-to-infant transmission of HBV can almost completely be prevented. However, the optimal management of pregnant women requires more carefully designed studies. The safety of fetal exposure to antivirals needs more evidence.
This work was supported by the Science and Technology Department of Jiangsu Province (BK20161105) and the National Natural Science Foundation of China (81672002), China.
Conflicts of Interest
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