Improving integrated perinatal care for women with hepatitis B in China
BMJ 2024; 386 doi: https://doi.org/10.1136/bmj-2023-078643 (Published 30 August 2024) Cite this as: BMJ 2024;386:e078643Read the collection: Promoting women's health in China
- Yunshan Chen, consultant1,
- Rong Fan, professor2,
- Lele Wang, consultant1,
- Abraham (Nick) Morse, adjunct assistant professor3,
- Huishu Liu, professor1
- 1Guangzhou Key Laboratory of Maternal-Fetal Medicine, Department of Obstetrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
- 2Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
- 3Department of Community Medicine, Tufts University School of Medicine, Boston, USA
- Correspondence to: H Liu huishuliu{at}hotmail.com
Key messages
China has made steady progress in improving integrated perinatal care towards the goal of eliminating perinatal transmission of hepatitis B
Better severity stratification for the management of hepatitis B in pregnancy improves care and helps mitigate challenges caused by regional imbalances in incidence and management capabilities
Advancements in the quality and accessibility of counselling and education improve adherence to the treatment recommended by the perinatal care algorithm
Seamless multidisciplinary care and inter-institutional referral is critical to ensure effective care coordination for pregnant women with hepatitis B
Hepatitis B virus infection is a public health issue globally, with a worldwide prevalence of nearly 3.8% and 1.5 million new infections each year.1 In China, a highly endemic area, more than 10 million women of childbearing age had hepatitis B in 2021.2 Mother-to-child transmission (MTCT) is the predominant mode of transmission, accounting for 90% of new infections.3 Thus, the management of hepatitis B during pregnancy is of particular concern.
Although the prevalence of hepatitis B in pregnancy in China fell by 25% between 2015 and 2020, approximately 1 000 000 women with hepatitis B still give birth each year (fig 1).3 With China moving away from its one child policy, older women, who have a higher prevalence of hepatitis B, are now more likely to become pregnant (fig 2).2
Prevalence of hepatitis B virus infection in pregnant women in different regions of China (2015-20). Data from China’s National Notifiable Disease Reporting System (NNDRS) and the Management Information System of the National Integrated Prevention of Mother-to-Child Transmission of HIV, Syphilis, and Hepatitis B (iPMTCT) programme.23
Reducing hepatitis B in pregnancy is essential for maternal and fetal safety. Because more than 90% of newborn hepatitis B infections progress to chronic infections and are difficult to cure, preventing MTCT is the key to eventually eliminating hepatitis B.4 Hepatitis B also increases the risk of maternal complications.5 Globally, severe hepatitis flares account for 6% of admissions to intensive care in pregnancy and increase the risk of adverse pregnancy outcomes.6
Several strategies have been implemented in China to prevent MTCT, and most areas of China have MTCT rates of 1% or less.4 Other high endemic regions such as South East Asia and Africa still have rates above 1%.7 Globally, there is still some way to go in achieving the World Health Organization’s 2030 goal of reducing the rate to less than 0.1%.1 As China is responsible for nearly a third of the worldwide burden of hepatitis B,4 the effectiveness of China’s perinatal care programmes for reducing MTCT are fundamental to the global goal of eliminating hepatitis B by 2030 and can provide important learning opportunities for other regions.
Perinatal care for hepatitis B in China
Strategies for elimination
To eliminate MTCT of hepatitis B, China has expanded free prenatal blood testing for hepatitis B surface antigen (HBsAg), free combined vaccination with hepatitis B vaccine and hepatitis B immunoglobulin, and antiviral treatment for women with high viral load, as recommended in current guidelines.34 Since 2015, the national comprehensive prevention of MTCT plan (PMTCT, which covers hepatitis B, HIV, and syphilis) has expanded nationwide, and the government has invested ¥1.4bn (£150m; $190m; €180m) annually to provide free screening and comprehensive intervention services for hepatitis B in pregnancy, covering 97.7% of China (11 516 counties).4
Combined vaccination (vaccine and immunoglobulin) is considered the most effective measure for preventing MTCT of hepatitis B.1 A series of regulations for hepatitis B vaccination was implemented in China in 1982 and was integrated into WHO’s expanded immunisation programme in 2002. In 2005, a free hepatitis B vaccination programme was adopted by the Chinese government. Hepatitis B immunoglobulin has also been provided free of charge to pregnant women who test positive for HBsAg in the PMTCT programme since 2011.7
Antiviral treatment is given to pregnant women with high hepatitis B viral load in China. Despite combined vaccination, patients who test positive for HBeAg (hepatitis B e-antigen; generally a measure of infectious disease) with high viral load (DNA level ≥200 000 copies/ml) still have MTCT rates of 5-10%.6 Based on key clinical trials of antiviral treatment for hepatitis B in China, tenofovir disoproxil fumarate (TDF) and telbivudine were added to the Chinese national medical insurance formulary of antiviral drugs to prevent MTCT in 2017.24 Tenofovir alafenamide fumarate, a new antiviral formulation for treatment of hepatitis B resistant to TDF was approved in China in December 2018.4
Achievements
These widely implemented strategies and ongoing government funding have reduced MTCT of hepatitis B in China. Coverage of combined vaccination at birth for babies exposed to hepatitis B in pregnancy increased from 22.2% in 1992 to 95.6% in 2015 and 99.7% in 2020.34 Before combined vaccination, the MTCT rate of hepatitis B in China was approximately 50%, with as many as 9.9 % of children <5 years testing positive for HBsAg.2 By 2015, the MTCT rate had dropped to 3% after combined vaccination.4 After antiviral treatment capabilities were made available in most of China, the MTCT prevention rate significantly improved: from 90% in 2010 to 99.7% in 2020.4
The pooled seroprevalence of HBsAg in China decreased from 8.2% in 1973-92 to 5.7% in 1993-2005 and 3.6% in 2006-21. Seroprevalence in children under 5 declined from 5% in 1973 to 0.6% in 2021, and death related to hepatitis B fell from 0.02% in 2000 to 0.011% in 2020.2 The prevalence of hepatitis B among pregnant women fell from 7.3% in 2015 to 5.44% in 2020,3 with related maternal mortality in pregnancy of 0.001%.24
Future goals and integrated algorithm design
To achieve the 2030 WHO goal of eliminating hepatitis B, China has issued an action plan.238 This plan proposes three targets in pregnancy: a detection and treatment rate of 95%, timely combined vaccination coverage of 95% of cases, and an MTCT rate below 1% country wide.4
A national integrated management algorithm for hepatitis B in pregnancy was designed in 2019 through the efforts of experts from the China Foundation for Hepatitis Prevention and Control in the fields of infectious diseases, hepatology, immunology, obstetrics, and public health.9 This algorithm covers screening, severity stratification, monitoring, antiviral treatment, neonatal immunoprophylaxis, and postvaccination follow-up (fig 3). The SHIELD app, based on this algorithm, provides a real time patient-hospital-community health integration platform for counselling, education, and communication in multidisciplinary treatment and follow-up.10
Integrated algorithm of perinatal care for women with hepatitis B virus infection in China. This care algorithm covers comprehensive management of hepatitis B in pregnancy including prenatal screening, severity stratification, monitoring, antiviral treatment, neonatal immunoprophylaxis, discontinuation of antivirals and postvaccination follow-up.9
Practical challenges
Regional imbalances
Substantial differences in the prevalence of hepatitis B in pregnancy are seen across China (fig 1, fig 4). The country’s large migrant populations in urban areas make the infection patterns more complex. Discrepancies in management capabilities also exist across regions and medical institutions, which might influence the prevalence of hepatitis B in different regions.3 In a survey of rural medical clinics in China, only 56% of clinicians could diagnose hepatitis B accurately, 78% could not completely explain the serological results, and 36% of cases were not correctly uploaded to the National Notifiable Disease Reporting System.11
Adherence to the care algorithm
Meticulous adherence to all aspects of the algorithm is necessary for prevention of MTCT. One barrier to adherence seems to be persistent concerns among both health professionals and patients about the risk of fetal birth defects from antiviral treatment.1 A survey of pregnant women in China showed that awareness of specialised interventions for hepatitis B in pregnancy was less than 50%, and less than 20% of pregnant women would choose to actively seek treatment because of inadequate understanding about the risks of MTCT and concerns about the safety of antiviral treatment.1213
For medical providers, especially in rural communities, knowledge gaps and stigma also affect the quality of care. A study among 149 community health centres in China found inadequate education and training regarding interventions for hepatitis B in 80% of centres, which affected adherence to treatment.14 Stigma around hepatitis B is still common among healthcare providers, with 34% reporting taking extra safety and hygiene precautions when interacting with patients with the infection.15
Care coordination
Effective implementation of the national algorithm also requires coordination through a multidisciplinary team of specialty providers. Pregnancies managed by a multidisciplinary team were 3.7 times more likely to have a timely diagnosis of liver dysfunction.16 In practice, this care coordination is still insufficient in many regions. One survey showed that only 70% of pregnant women with hepatitis B visited a liver specialist as part of their care.17 Communication gaps and treatment fragmentation exist in different departments and between medical institutions for specialised hepatitis B care in pregnancy.4
Suggestions for improving integrated perinatal care for hepatitis B
Optimise severity stratification
To tackle the regional and institutional imbalances of care for hepatitis B in pregnancy, broad support for optimised MTCT prevention services must be achieved. Simplification of severity stratification models is recommended to assure more widely available access to testing and treatment.18
In WHO’s Regional Framework for the Triple Elimination of Mother-to-Child Transmission of HIV, Hepatitis B, and Syphilis in Asia and the Pacific (2018-2030) a simple tiered approach is proposed to introduce a comprehensive care package of interventions for prevention of MTCT, considering differing health system capacities.19 This simplified and tiered approach would refer patients with more advanced hepatitis B to more sophisticated institutions to optimise the management process.18
The detailed stratification of maternal and infant interventions for prevention of MTCT based on severity of hepatitis B relies on laboratory tests (including quantification of DNA in the blood to monitor viral load, HBeAg to monitor infection, and alanine transaminase to monitor liver function) and the presence of cirrhosis (fig 5).9
Stratification algorithm for prevention of MTCT of hepatitis B. Based on guidelines from China and WHO, this stratification algorithm aims to prevent MTCT based on the severity of hepatitis B. Free screening should be implemented as early as possible. Management of antiviral treatment relies on serological examinations and liver cirrhosis manifestations in screening and monitoring during pregnancy. Liver function abnormalities caused by factors other than hepatitis B (such as medication or pregnancy complications) need to be excluded. *If monitoring shows increased viral load or ALT, the mode and timing of antiviral treatment should be reassessed. ALT=alanine transaminase.
Comprehensive patient counselling and education
More focus on counselling for women with hepatitis B in pregnancy might be useful to enhance adherence to treatment. Modern methods of counselling that might help improve hepatitis B care outcomes have been tried, such as internet promotion and mobile apps, with positive outcomes.6 The SHIELD app is a successful example.20 It was first introduced in diverse health settings across China, involving over 30 000 pregnant women from 178 hospitals, including general hospitals, infectious disease hospitals, and maternal and child health centres. The SHIELD programme then successfully implemented an intense intervention package in all community health centres and hospitals in the Baoan district of Shenzhen (a total of 4.5 million people). The MTCT rate was much lower among participants who were compliant with SHIELD (0.03%-0.16%) than among those who were non-compliant (1.91%-3.16%, P < 0.001).10
People with hepatitis B and their family members need to be aware of susceptibility to viral transmission and should participate in the prevention of MTCT.18 Multiple modes of education at family and community levels are recommended to enhance the public’s awareness of hepatitis B, reduce discrimination, and enhance public social support in China.9 A scoping review in China showed that more public service campaigns and school based education programmes could familiarise the public with the realities of hepatitis B and the imperative to reduce MTCT in pregnancy.15 Meanwhile, education for medical providers and pregnant women about the safety of antiviral drugs through the internet, training lessons, and public service campaigns, were found to be helpful to facilitate adherence.4
Seamless multidisciplinary care and referral
The necessity of improving care coordination and multidisciplinary care has been mentioned in national strategies such as the Outline for Women’s Development in China (2021-2030) and the Action Plan for Eliminating Mother to Child Transmission of HBV (2022-2025).8 Comprehensive care coordination requires seamless cooperation and communication between obstetricians in women and children’s hospitals, hepatologists or infectious disease specialists in general hospitals, and general practitioners in community hospitals.6
Availability of all relevant information is the key to ensuring seamless multidisciplinary care and referral management for hepatitis B in pregnancy. Strategies to promote better communication between patients and specialists in obstetrics, hepatology, and infectious disease need be developed. Tools like the SHIELD app can be a key resource for data sharing among medical providers and pregnant women with hepatitis B. In one study, the real time use of SHIELD increased multidisciplinary hepatitis B treatment and reduced the MTCT rate to an average of 0.23%.10
In recent years, one-stop multidisciplinary care for the elimination of MTCT has shown advantages in China. Specialised clinics for eliminating MTCT integrate prenatal examination and specialised hepatitis B interventions, providing reliable referrals and follow-up services that are less disruptive to the patient.9 One study showed that such clinics increased the successful treatment rate of high hepatitis B viral load in pregnancy from 28% in 2018 to 84% in 2020.21
Efforts to improve multidisciplinary care, severity stratification, and referral need be supported by governmental budgets and reimbursements. A cost effectiveness evaluation model suggests that implementing antiviral treatment of hepatitis B with multidisciplinary care in pregnancy could potentially prevent approximately 1.1 million neonatal hepatitis B infections by 2030. This strategy would be cost effective in around 70% of countries, particularly if there was a reduction in treatment costs.22 Studies conducted in China and Thailand have shown that the cost effectiveness of multidisciplinary hepatitis B treatment is influenced by factors such as gross domestic product and reimbursement rates, especially in resource limited areas.2324
Scientific research needed to guide evidence based care
More research into the effectiveness of the hepatitis B treatment algorithm is needed to further optimise integrated perinatal care (box 1).
Future scientific research areas for hepatitis B in pregnancy
Screening and assessment
New tools and biomarkers for severity stratification
Develop and validate point of care testing for screening
Expanding screening strategy to the population
Antiviral treatment
Formal evaluation of safety and benefits of antivirals
Evidence for benefits of antivirals at varying viral loads
Optimal time to start antiviral treatment in pregnancy
Risks of hepatitis flare after discontinuation
Safety assessment of long term antiviral treatment
Vaccination and immunoglobulin
Develop more effective hepatitis B vaccines
Assess feasibility and acceptability of vaccination before pregnancy
Optimise the combined vaccination programme (dose and time)
Obstetric management
Assess the relative risks for adverse outcomes in pregnancy
Effects of delivery mode and timing
Adherence and coordination
Optimum approaches to education and counselling in different settings
Optimise education and multidisciplinary care using information technology
Extend coverage of PMTCT programmes
Identify the social and financial barriers in eliminating hepatitis B
Effective ways to eliminate discrimination in pregnancy
Methods for family counselling and engagement
The safety and effectiveness of hepatitis B treatments need more validation in large cohort studies or randomised controlled trials. The optimal time to start antiviral treatment in pregnancy to prevent MTCT is also controversial.6 Although the recombinant hepatitis B vaccine derived from Merck’s technology has been widely used in China since the 1990s,9 more effective hepatitis B vaccines, such as a multi-protein hepatitis B vaccine, need to be developed to improve protection for newborns exposed to hepatitis B in utero.25 Optimisation of combined hepatitis B vaccines and immunoglobulin also need more large cohort studies to understand the effect of earlier use of hepatitis B vaccine on preventing MTCT.26
Obstetric management of women with hepatitis B needs more basic and translational research to improve outcomes in pregnancy.59 The Chinese Center for Disease Control has created and improved a management information system for the prevention of MTCT, which covers all districts and counties in the country.27 This system, along with strong basic science resources and PMTCT network support, real time monitoring, supervision evaluation, and continuous epidemiological study will continue to build a research foundation for eliminating MTCT of hepatitis B.
Research on increasing adherence to treatment and optimising care coordination needs to continue. Social and financial barriers for women with hepatitis B, their partners, and their families need further study to enhance MTCT prevention strategies.1821
Conclusion
Improving perinatal care for women with hepatitis B and eliminating MTCT will require multiple parallel initiatives including optimisation of severity stratification through a national algorithm, more focus on professional counselling and education, seamless multidisciplinary care and facilitation of referral to specialised care. Progress in scientific research is also required to improve perinatal safety and optimise MTCT strategies for pregnant women with hepatitis B.
Acknowledgments
We thank Sitang Gong and Liandong Zuo for policy support, and Di Mao, Chaoming Yue, Pin Li, Zheng Zheng, Jia Yu, and Li Yang for literature review and data preparation.
Footnotes
Contributors and sources: CY and LH focus on perinatal maternal safety and infectious diseases during pregnancy. FR is a hepatologist specialising in the clinical treatment of hepatitis B related disease. AM focuses on the safe management of pregnancy and delivery. LH has a rich research experience in the field of perinatal medicine, high risk pregnancy management, and vertical infection transmission prevention. CY, LH, and WL conceived the paper and wrote the first draft, all other authors offered critical comments. All authors contributed extensively to further refining, editing, and proofing, and have approved the final version of the article. LH is the guarantor.
Patient involvement: No patients were involved.
Competing interests: We have read and understood BMJ policy on declaration of interests and have no interests to declare.
This article is part of a collection proposed by Peking University, led by Jie Qiao. Open access fees were funded by individual institutions. The BMJ commissioned, peer reviewed, edited, and made the decision to publish. Jin-Ling Tang and Jocalyn Clark were the lead editors for The BMJ.
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