Does currently recommended maternal antiviral prophylaxis against mother-to-child transmission of hepatitis B virus require enhancement?

Yi-Hua Zhou and Hong Zhao both contributed to the conception, drafting and revision of this work. We read with interest the article entitled “Enhancing interventions for prevention-of-mother-to-child- transmission (PMTCT) of hepatitis B virus (HBV)” by Matthews et al.,[1]Matthews P.C. Ocama P. Wang S. El-Sayed M. Turkova A. Ford D. et al.Enhancing interventions for prevention-of-mother-to-child-transmission (PMTCT) of hepatitis B virus (HBV).JHEP Reports. 2023; https://doi.org/10.1016/j.jhepr.2023.100777Abstract Full Text Full Text PDF Google Scholar who comprehensively reviewed the measures for preventing MTCT of HBV. We consider that the proposals on the maternal administration of anti-HBV agents (nucleos/tide analogue, NA) against MTCT of HBV should be cautious. Matthews et al. proposed that maternal HBV DNA thresholds for antiviral prophylaxis may reduce from the current >2 × 105 (>200,000) IU/ml to ∼104 or even to 2 × 103 (>2,000), assuming that undetectable HBV DNA levels would mitigate any quantifiable transmission risk, based on the ‘undetectable = untransmissable’ (U U) paradigm for HIV.[1]Matthews P.C. Ocama P. Wang S. El-Sayed M. Turkova A. Ford D. et al.Enhancing interventions for prevention-of-mother-to-child-transmission (PMTCT) of hepatitis B virus (HBV).JHEP Reports. 2023; https://doi.org/10.1016/j.jhepr.2023.100777Abstract Full Text Full Text PDF Google Scholar However, HBV infection is different from HIV infection. All HIV-infected women, regardless of pregnancy, require antiretroviral therapy (ART), but most HBV-infected women at childbearing age are in immunotolerance phase and do not require antiviral therapy. Moreover, since there is no effective vaccine or immunoglobulin against HIV, maternal ART is the most important measure to prevent MTCT. By contrast, MTCT of HBV can be efficiently prevented by combined immunoprophylaxis with hepatitis B immunoglobulin (HBIG) and hepatitis B vaccine in neonates. Numerous studies demonstrated that, after the immunoprophylaxis, almost all infants of mothers with HBV DNA ≤2 × 106 IU/ml are protected against chronic HBV infection, and the lowest maternal HBV DNA level that causes immunoprophylaxis failure is >2 × 106 IU/ml [Supplementary Table S1 and S2]. Thus, the currently recommended maternal HBV DNA threshold (>2 × 105 IU/ml) for antiviral prophylaxis against MTCT of HBV is conservative. Currently, maternal antiviral prophylaxis against MTCT of HBV usually starts from the third trimester (gestation 28–32 weeks). Matthews et al. proposed that maternal antiviral administration may start earlier in pregnancy, potentially as soon as maternal HBsAg-positive status is confirmed.[1]Matthews P.C. Ocama P. Wang S. El-Sayed M. Turkova A. Ford D. et al.Enhancing interventions for prevention-of-mother-to-child-transmission (PMTCT) of hepatitis B virus (HBV).JHEP Reports. 2023; https://doi.org/10.1016/j.jhepr.2023.100777Abstract Full Text Full Text PDF Google Scholar However, studies demonstrated that maternal administration of anti-HBV agents (including tenofovir disoproxil fumarate [TDF], and other anti-HBV agents) earlier than the third trimester did not further reduce MTCT of HBV.[2]Pan C.Q. Yi W. Liu M. Wan G. Hu Y.H. Zhou M.F. Lamivudine therapy during the second vs the third trimester for preventing transmission of chronic hepatitis B.J Viral Hepat. 2017; 24: 246-252Crossref PubMed Scopus (29) Google Scholar,[3]Pan X. Chen J. Zhou L. Ou X. He F. Liu Y. et al.Efficacy and safety of continuous antiviral therapy from preconception to prevent perinatal transmission of hepatitis B virus.Sci Rep. 2020; 1013631Crossref Scopus (3) Google Scholar In practice, after administration of antiviral in mothers with high viral loads and the immunoprophylaxis in neonates, MTCT of HBV is almost completely blocked;2Pan C.Q. Yi W. Liu M. Wan G. Hu Y.H. Zhou M.F. Lamivudine therapy during the second vs the third trimester for preventing transmission of chronic hepatitis B.J Viral Hepat. 2017; 24: 246-252Crossref PubMed Scopus (29) Google Scholar, 3Pan X. Chen J. Zhou L. Ou X. He F. Liu Y. et al.Efficacy and safety of continuous antiviral therapy from preconception to prevent perinatal transmission of hepatitis B virus.Sci Rep. 2020; 1013631Crossref Scopus (3) Google Scholar, 4Pan C.Q. Duan Z. Dai E. Zhang S. Han G. Wang Y. et al.Tenofovir to prevent hepatitis B transmission in mothers with high viral load.N Engl J Med. 2016; 374: 2324-2334Crossref PubMed Scopus (404) Google Scholar, 5Hu Y. Xu C. Xu B. Hu L. Liu Q. Chen J. et al.Safety and efficacy of telbivudine in late pregnancy to prevent mother-to-child transmission of hepatitis B virus: A multicenter prospective cohort study.J Viral Hepat. 2018; 25: 429-437Crossref PubMed Scopus (57) Google Scholar, 6Han G.R. Jiang H.X. Wang C.M. Ding Y. Wang G.J. Yue X. et al.Long-term safety and efficacy of telbivudine in infants born to mothers treated during the second or third trimesters of pregnancy.J Viral Hepat. 2017; 24: 514-521Crossref PubMed Scopus (31) Google Scholar MTCT rate is as low as 0–<1%, rather than 0–6% mentioned in their article.[1]Matthews P.C. Ocama P. Wang S. El-Sayed M. Turkova A. Ford D. et al.Enhancing interventions for prevention-of-mother-to-child-transmission (PMTCT) of hepatitis B virus (HBV).JHEP Reports. 2023; https://doi.org/10.1016/j.jhepr.2023.100777Abstract Full Text Full Text PDF Google Scholar Thus, earlier administration of antiviral agents during pregnancy is less likely to further reduce MTCT of HBV. It is generally considered that intrauterine NA exposure has no influence on the development of fetuses. However, severe congenital malformation (biliary atresia, congenital megacolon, and anotia), cerebral palsy, severe muscularly developmental abnormalities, fetal death, stillbirth, infant sudden death were repeatedly reported in fetuses/infants born to mothers who were treated with anti-HBV agents during pregnancy.4Pan C.Q. Duan Z. Dai E. Zhang S. Han G. Wang Y. et al.Tenofovir to prevent hepatitis B transmission in mothers with high viral load.N Engl J Med. 2016; 374: 2324-2334Crossref PubMed Scopus (404) Google Scholar, 5Hu Y. Xu C. Xu B. Hu L. Liu Q. Chen J. et al.Safety and efficacy of telbivudine in late pregnancy to prevent mother-to-child transmission of hepatitis B virus: A multicenter prospective cohort study.J Viral Hepat. 2018; 25: 429-437Crossref PubMed Scopus (57) Google Scholar, 6Han G.R. Jiang H.X. Wang C.M. Ding Y. Wang G.J. Yue X. et al.Long-term safety and efficacy of telbivudine in infants born to mothers treated during the second or third trimesters of pregnancy.J Viral Hepat. 2017; 24: 514-521Crossref PubMed Scopus (31) Google Scholar, 7Wang R. Fang S. Sun Q. Zhou Y.H. Congenital biliary atresia in an infant born to hepatitis B mother treated with telbivudine before and during pregnancy.Dig Liver Dis. 2018; 50: 1097-1098Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar In addition, the frequency of premature birth in antiviral therapy pregnant women was higher than that in untreated pregnant women (13.1% [8/61] vs. 2.9% [1/34]).[8]He T. Bai Y. Cai H. Ou X. Liu M. Yi W. et al.Safety and efficacy of lamivudine or telbivudine started in early pregnancy for mothers with active chronic hepatitis B.Hepatol Int. 2018; 12: 118-125Crossref PubMed Scopus (17) Google Scholar More recently, studies showed that, of 182 pregnant women who had received TDF before perception or within gestation week 12, 10 (5.5%) underwent miscarriages, 3 (1.6%) stillbirth, and 2 (1.1%) inductions of labor due to severe malformations, and of 417 pregnant women who had received telbivudine before perception or in the first trimester, 10 (2.4%) underwent miscarriages, 6 (1.4%) stillbirth, and 3 (0.7%) inductions of labor due to severe malformations.[9]Li Z. Xie B. Yi N. Cai H. Yi W. Gao X. Efficacy and safety of tenofovir disoproxil fumarate or telbivudine used throughout pregnancy for the prevention of mother-to-child transmission of hepatitis B virus: A cohort study.Eur J Obstet Gynecol Reprod Biol. 2022; 276: 102-106Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Thus, the relationship between maternal NA administration and these severe adverse events cannot be completely excluded. A shortest period of fetal NA exposure is desirable as long as MTCT of HBV is prevented. The safety data of maternal ART in HIV-infected pregnant women cannot be directly used in the maternal anti-HBV therapy. Maternal HIV infection can cause adverse pregnancy outcomes and congenital fetal abnormalities. In theory, maternal ART may decrease the congenital fetal abnormalities after HIV viral loads were significantly inhibited. But maternal ART during pregnancy does not decrease congenital fetal abnormalities in infants, suggesting the potential adverse effects of maternal ART on fetuses. Actually, maternal ART may have other adverse pregnancy outcomes.[10]Jiang W. Ronen K. Osborn L. Drake A.L. Unger J.A. Matemo D. et al.Predictors of adverse pregnancy outcomes among Kenyan women with HIV on antiretroviral treatment in pregnancy.AIDS. 2022; 36: 1007-1019Crossref PubMed Scopus (1) Google Scholar The cornerstone of preventing MTCT of HBV is to use both HBIG and hepatitis B vaccine in neonates. There is almost no concern on the safety of HBIG and hepatitis B vaccine. After timely immunoprophylaxis, MTCT rates in children of HBV-infected mothers with negative and positive HBeAg have been reduced from 10–30% to nearly 0% and from 70–90% to 5–10% respectively. Administration of anti-HBV agents in mothers with high viral loads or positive HBeAg is a supplement measure. The currently recommended neonatal combined immunoprophylaxis and antiviral prophylaxis in pregnant women with HBV DNA >2 × 105 or positive HBeAg, started from gestation 28–32 weeks, can almost completely prevent MTCT of HBV. Lowering the current viral load threshold and starting maternal prophylaxis before the third trimester are less likely to further reduce MTCT of HBV, but may potentially have additional adverse pregnancy and neonatal outcomes. We declare no competing interests. This study was supported by grants from the Health Commission of Nanjing City (ZKX20021), Science and Technology Department of Jiangsu Province (BK20221169), and Jiangsu Province Center for Innovation in Obstetrics and Gynecology (CXZX202229). The following is/are the supplementary data to this article. Download .docx (.03 MB) Help with docx files