The Science of Treating Hepatitis B in Pregnancy
A groundbreaking medical strategy is transforming how we protect newborns from chronic hepatitis B infection.
For the millions of women worldwide living with chronic hepatitis B, pregnancy introduces a complex medical challenge: how to safely manage their condition while protecting their unborn child from infection. Mother-to-child transmission is the primary route of hepatitis B infection globally, with up to 90% of exposed infants developing chronic infections when mothers have high viral loads 8 . This article explores how nucleoside/nucleotide analogues (NAs)—powerful antiviral medications—have revolutionized care for pregnant women with hepatitis B, offering hope for interrupting this cycle of transmission and moving closer to the World Health Organization's goal of eliminating viral hepatitis by 2030.
Chronic hepatitis B virus (HBV) infection affects approximately 257 million people globally, with mother-to-child transmission remaining a significant public health concern 8 . When a pregnant person has hepatitis B, the virus can pass to the baby during childbirth, a phenomenon known as vertical transmission. Without preventive measures, transmission rates range from 10-90%, depending on the mother's viral load and infection status 8 .
The risk of progression to chronic infection is inversely related to the age at acquisition. While only 2-6% of infected adults develop chronic hepatitis B, approximately 90% of infected infants will develop chronic infections 6 . These children face lifelong risks of serious liver complications, including cirrhosis and hepatocellular carcinoma (liver cancer) 6 7 .
Understanding hepatitis B management requires familiarity with its natural progression, typically through several phases:
Characterized by high viral loads but normal liver enzymes, typically seen in younger patients
The immune system attacks infected liver cells, causing inflammation and potential liver damage
Low viral replication and minimal liver inflammation 8
Treatment decisions during pregnancy depend on which phase the patient is in, with antiviral therapy primarily considered for those in the immune active phase or with high viral loads threatening transmission to the baby.
Nucleoside/nucleotide analogues are antiviral medications that work by inhibiting the replication of hepatitis B virus DNA. They accomplish this by mimicking the natural building blocks of DNA, which the virus uses to copy itself. When the virus incorporates these analogues into its genetic material, the chain terminates, preventing successful viral replication 1 .
HBV uses its DNA polymerase to replicate genetic material inside liver cells.
NAs mimic natural nucleotides and are incorporated into the growing DNA chain.
The analogues lack necessary components for further elongation, halting replication.
With replication blocked, viral load decreases, reducing liver damage and transmission risk.
Several NAs have been approved for hepatitis B treatment, though not all are recommended during pregnancy:
These medications have transformed hepatitis B management by effectively suppressing viral replication, reducing liver inflammation, and decreasing the risk of long-term complications. The key advantage of modern NAs like tenofovir and entecavir is their high potency and high barrier to resistance, meaning the virus is less likely to develop mutations that make the medications ineffective 1 .
Managing hepatitis B in pregnancy requires balancing maternal health against fetal protection, with treatment strategies varying by trimester and disease severity.
For women of childbearing age with hepatitis B, preconception planning is ideal. Treatment decisions should consider:
When possible, women with mild disease may delay treatment until after delivery to avoid medication exposure during pregnancy. For those requiring immediate treatment, selecting agents with established safety profiles in pregnancy is crucial 5 .
The approach to hepatitis B treatment during pregnancy depends on both maternal health needs and transmission prevention:
The American Association for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver (EASL), and Asian Pacific Association for the Study of the Liver (APASL) all recommend considering antiviral prophylaxis in the third trimester for pregnant women with HBV DNA levels exceeding 200,000 IU/mL 4 8 .
| Organization | When to Start | Viral Load Threshold | Infant Prophylaxis |
|---|---|---|---|
| APASL (2016) | 28-32 weeks | >6-7 log₁₀ IU/mL (~600,000-2,000,000 IU/mL) | HBV vaccine + HBIG |
| EASL (2017) | 24-28 weeks | >200,000 IU/mL | HBV vaccine + HBIG |
| AASLD (2018) | 28-32 weeks | >200,000 IU/mL | HBV vaccine + HBIG |
| WHO (2024) | Second trimester | >200,000 IU/mL or positive HBeAg | HBV vaccine |
Tenofovir has emerged as the preferred antiviral during pregnancy due to its favorable safety profile and high efficacy 3 8 . Safety data come primarily from:
The available evidence suggests that tenofovir does not significantly increase the risk of congenital anomalies compared to the background rate of 2.72% reported by the CDC birth defect surveillance system 5 .
| Medication | FDA Pregnancy Category | 1st Trimester Exposure (Birth Defects/Live Births) | Safety Evidence |
|---|---|---|---|
| Tenofovir | B | 27/1219 (2.2%) | Extensive data, preferred choice |
| Lamivudine | C | 122/3966 (3.1%) | Extensive data, higher resistance |
| Telbivudine | B | 0/8 | Limited data |
| Entecavir | C | 1/30 | Limited data, not recommended |
A landmark 2024 study published in JAMA (Journal of the American Medical Association) challenged conventional protocols for preventing mother-to-child transmission of hepatitis B 9 . This randomized, noninferiority trial investigated whether earlier initiation of tenofovir could eliminate the need for hepatitis B immune globulin (HBIG) in infants—an expensive, temperature-dependent medication often unavailable in resource-limited areas.
The research team recruited 280 pregnant women from seven tertiary hospitals in China between June 2018 and February 2021. All participants were:
Participants were randomly assigned to one of two groups:
The study was "unblinded," meaning both participants and researchers knew which treatment was being administered. Medication adherence was monitored through pill counts, with infants followed for 28 weeks to determine transmission rates 9 .
The findings were striking. In the intention-to-treat analysis:
The between-group difference was 0.76%, with the upper limit of the 90% confidence interval at 1.74%—well below the predetermined noninferiority margin of 3% 9 . This means the experimental approach was statistically no worse than standard care.
Perhaps even more compelling, in the per-protocol analysis (excluding protocol violations), both groups had 0% transmission rates 9 . This demonstrates that initiating tenofovir at 16 weeks gestation effectively suppressed maternal viral load to such an extent that HBIG became unnecessary for preventing transmission.
Secondary outcomes revealed additional benefits:
| Outcome Measure | Experimental Group (TDF at 16 weeks) | Standard Care Group (TDF at 28 weeks + HBIG) | Statistical Significance |
|---|---|---|---|
| MTCT Rate (ITT Analysis) | 0.76% (1/131) | 0% (0/142) | Noninferior |
| MTCT Rate (Per-Protocol) | 0% (0/124) | 0% (0/141) | Noninferior |
| Mothers with HBV DNA <200,000 IU/mL at Delivery | Statistically higher | Lower | Significant |
| Congenital Defects/Malformations | 2.3% (3/131) | 6.3% (9/142) | Not significant |
Initiating tenofovir at 16 weeks gestation provides comparable protection against mother-to-child transmission as standard care (starting at 28 weeks with HBIG), potentially eliminating the need for HBIG and simplifying treatment protocols, especially in resource-limited settings.
Advancements in hepatitis B treatment rely on specialized tools and biomarkers that help researchers and clinicians monitor disease progression and treatment response. The following table highlights key reagents and biomarkers essential for studying nucleoside/nucleotide analogues in pregnancy:
| Research Tool/Biomarker | Function/Application |
|---|---|
| HBV DNA Quantitative Testing | Measures viral load in international units per milliliter (IU/mL); primary marker for treatment decisions and monitoring response 3 8 |
| Hepatitis B Surface Antigen (HBsAg) | Determines infection status; its persistence for >6 months indicates chronic infection 6 8 |
| Hepatitis B e Antigen (HBeAg) | Marker of high viral replication and infectivity; positive status significantly increases transmission risk 8 9 |
| Quantitative HBsAg | Emerging role in predicting transmission risk and treatment response; potentially more stable than viral load measurements 7 8 |
| HBV Core-Related Antigen (HBcrAg) | Novel biomarker correlating with transcriptional activity of covalently closed circular DNA (cccDNA); predicts disease progression and HCC risk 7 |
| HBV RNA | Reflects replicative activity of cccDNA; helps identify clinical phases of infection 7 |
| Tenofovir Disoproxil Fumarate | First-line nucleoside/nucleotide analogue with high barrier to resistance; preferred choice for pregnancy due to safety profile 3 9 |
The paradigm for hepatitis B management in pregnancy is rapidly evolving. Recent evidence supports expanding treatment eligibility, with the 2025 Canadian Association for the Study of the Liver (CASL) guidelines now recommending antiviral treatment for:
The groundbreaking JAMA trial 9 suggests we may be moving toward simplified, more accessible protocols that maintain efficacy while reducing costs and infrastructure requirements—particularly important for resource-limited regions where HBIG availability remains challenging.
Novel biomarkers like quantitative HBsAg, HBcrAg, and HBV RNA promise more personalized risk stratification and treatment approaches in the future 7 .
The management of chronic hepatitis B during pregnancy has undergone a remarkable transformation. Nucleoside/nucleotide analogues, particularly tenofovir, have emerged as powerful tools that protect both maternal health and infant outcomes. The latest clinical evidence demonstrates that earlier initiation of antiviral therapy can achieve comparable protection against transmission while potentially simplifying treatment protocols by eliminating the need for HBIG.
As research continues to refine our approach, the prospect of eliminating mother-to-child transmission of hepatitis B—once a distant dream—becomes increasingly attainable. Through continued innovation in antiviral therapies and implementation of evidence-based guidelines, we move closer to a future where no child suffers from chronic hepatitis B infection.