Published online Oct 27, 2026. doi: 10.4254/wjh.124577
Revised: August 7, 2026
Accepted: September 21, 2026
Published online: October 27, 2026
Processing time: 121 Days and 20.4 Hours
Managing pregnant women with a low hepatitis B virus (HBV) viral load (HBV DNA < 2 × 105 IU/mL) remains challenging, particularly in monitoring viral dynamics and determining the timing of antiviral therapy.
To identify the risk factors for HBV DNA elevation during pregnancy and to develop a predictive model to guide individualized management and reduce mother-to-child transmission (MTCT) risk.
This retrospective multicenter control study included 430 pregnant women with low HBV DNA loads (< 2 × 105 IU/mL) from three tertiary hospitals in China (2019-2023). Participants were stratified by HBV DNA changes from mid-to-late pregnancy. Logistic regression was used to identify independent risk factors, and a predictive model was constructed and validated.
The elevated HBV DNA group had a higher maternal age (P = 0.008), hepatitis B virus e antigen positivity, and baseline HBV DNA level ≥ 100 IU/mL (P < 0.001). Multivariate analysis confirmed maternal age [odds ratio (OR) = 1.09] and baseline HBV DNA level ≥ 100 IU/mL (OR = 4.06) as independent risk factors. The model showed moderate predictive accuracy (area under the curve = 0.71, 95% confidence interval: 0.66-0.76) with 69.6% sensitivity and 68.0% specificity. Stratified analysis revealed only 20.26% of women with baseline HBV DNA ≤ 100 IU/mL experienced elevation, whereas 35.48% with baseline > 1 × 104 IU/mL reached high-risk levels.
Maternal age and baseline HBV DNA level of ≥ 100 IU/mL were identified as critical predictors of viral elevation during pregnancy. The predictive model offers moderate predictive accuracy and clinical utility, supporting tailored surveillance for low viral load chronic hepatitis B pregnancies to further reduce MTCT risk.
Core Tip: This study identifies maternal age and baseline hepatitis B virus DNA ≥ 100 IU/mL as independent predictors of viral load elevation during pregnancy. We developed and validated a nomogram-based model with good discrimination (area under the curve 0.71) and excellent calibration, offering a practical bedside tool for early risk stratification in routine antenatal care. This approach enables timely intervention and personalized monitoring, potentially reducing mothertochild transmission and improving pregnancy outcomes in chronic hepatitis B carriers.
- Citation: Chen Z, Chen H, Jie B, Peng T, Lin Y, Geng Y, Shen Y, Deng Y, Xie D, Yang L, Ouyang S. Risk factors and predictive model for hepatitis B virus deoxyribonucleic acid elevation in mid-to-late pregnancy with low viremia. World J Hepatol 2026; 18(10): 124577
- URL: https://www.wjgnet.com/1948-5182/full/v18/i10/124577.htm
- DOI: https://dx.doi.org/10.4254/wjh.124577
Hepatitis B virus (HBV) infection is a major public health challenge worldwide, primarily because of its highly contagious nature. Although comprehensive data from 2018 revealed that 3.5% of the global population is chronically infected with HBV[1], the prevalence of HBV infection has declined. This reduction can be attributed to the widespread imple
The World Health Organization’s (WHO) target of eliminating hepatitis B by 2030 presents a formidable challenge. In China, initiatives such as HBV screening during pregnancy and complementary HBV vaccination for newborns have played a pivotal role in decreasing the prevalence of HBV. However, the number of hepatitis B cases remains high because of the large population base in China. In its “Action Plan for the Elimination of Mother-To-Child Transmission (MTCT) of human immunodeficiency virus (HIV), Syphilis, and Hepatitis B (2022-2025)”, the National Health Com
Numerous recent studies have suggested that a heightened HBV DNA level is a major risk factor for MTCT[4-7]. Consequently, existing domestic and international guidelines recommend antiviral therapy to mothers with HBV DNA levels equal or greater than 2 × 105 IU/mL during pregnancy. This measure was designed to hinder the transmission of the virus from mother to child, aligning with the specific characteristics of MTCT. In patients with HBV DNA levels below 2 × 105 IU/mL, there is currently insufficient evidence to suggest an increased risk of MTCT or to recommend antiviral or dynamic retesting. Therefore, this study investigated the risk factors associated with elevated HBV DNA levels in pregnant women with viral loads below the current prophylactic antiviral treatment threshold for (PMTCT; i.e., < 2 × 105 IU/mL), and aimed to develop a predictive model based on early-pregnancy HBV DNA levels to stratify the MTCT risk in this population. Hereinafter, this viral load level is collectively referred to as “low viral load” for brevity. This model provides a theoretical foundation for managing these women and optimizing preventive strategies, enabling clinicians to identify high-risk individuals and implement timely interventions.
This study adopted a multicenter, retrospective study design. The study population comprised HBV-infected pregnant women who received prenatal care and delivered at the First, Third, and Fifth Affiliated Hospitals of Guangzhou Medical University between July 2019 and May 2023. Baseline data were collected during 12-24 weeks of gestation, and follow-up continued from 24 weeks of gestation until delivery. Based on whether HBV DNA levels showed dynamic elevation relative to baseline during the second or third trimester, participants were categorized into an elevated group and a non-elevated group. Comparative analyses between the two groups were conducted to explore the potential risk factors. A clinical prediction model was then developed to inform follow-up care and management of pregnant women with low HBV viral load.
Inclusion criteria were as follows: Age between 18 years and 55 years; complete clinical records including at least two HBV DNA test results spaced more than four weeks apart; demonstrated HBV DNA levels < 2 × 105 IU/mL between 12 weeks and 24 weeks of gestation, persistent hepatitis B surface antigen (HBsAg) positivity for at least six months, and met the diagnostic criteria for CHB according to the Guidelines for the Prevention and Treatment of CHB (2022 edition)[8]. Exclusion criteria included receipt of antiviral therapy prior to pregnancy or before 24 weeks of gestation; presence of severe systemic diseases such as cardiovascular, renal, respiratory, or neurological complications; diagnosis of auto
HBV DNA quantification was performed using the Roche Cobas 6800 System (Roche Diagnostics, Mannheim, Germany) with the real-time PCR assay on serum samples collected at baseline (12-24 weeks of gestation) and during follow-up (≥ 24 weeks until delivery). The assay has a lower limit of detection of 10 IU/mL and a lower limit of quantification of 20 IU/mL, with a linear quantification range of 10 to 1.0 × 109 IU/mL. All procedures were conducted according to the manufacturer’s instructions.
(1) Basic characteristics: Parity, pre-pregnancy body mass index (BMI), and age. BMI = weight (kg)/height squared (m2); (2) Serological virology: HBV DNA and hepatitis B virus e antigen (HBeAg); (3) Biochemical parameters: Total bile acid, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, direct bilirubin, indirect bilirubin, total protein, albumin, globulin, hemoglobin, platelets, white blood cells, total cholesterol, triglyceride (TG), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, glycated hemoglobin (HbA1c), creatinine (Cr), prothrombin time, activated partial thromboplastin time, and international normalized ratio; and (4) Telephone follow-up was conducted for pregnant women classified as high risk. Information collected during follow-up included whether antiviral therapy was administered during pregnancy and the specific timing of initiation, hepatitis B vaccination status, HBsAg status of the newborn (categorized as positive or negative), and duration of breastfeeding.
Statistical analyses were performed using SPSS (version 27.0; IBM, New York, United States) and R version 4.3.3. The baseline characteristics were summarized using descriptive statistics, with categorical variables presented as percentages. Group comparisons employed χ2 or Fisher’s exact tests for categorical variables and Mann-Whitney U tests for continuous measures, with statistically significant variables (P < 0.05) subsequently entered into multivariate logistic regression using forward stepwise selection (entry α = 0.05, removal α = 0.10). Significant independent predictors identified through this process were then incorporated to develop logistic regression prediction models, the performance of which was evaluated through discrimination [area under the curve (AUC) with 95% confidence interval (CI)], calibration (Hosmer-Lemeshow test), and clinical utility (decision curve analysis, DCA). Optimal cut-off values were determined by maximizing Youden’s index, and model robustness was assessed by bootstrap resampling with 1000 iterations. All statistical tests were two-tailed, with a significance level of P < 0.05.
A total of 606 pregnant women with hepatitis B who received prenatal care and delivered at the First, Third, and Fifth Affiliated Hospitals of Guangzhou Medical University between 2019 and 2023 were enrolled. After applying the predetermined exclusion criteria (n = 176), 430 eligible participants were included in the analysis. Based on HBV DNA dynamics after 24 weeks of gestation, the participants were stratified according to the 2019 Chinese Medical Association guidelines for CHB management. A total of 158 patients (36.74%) were assigned to the elevation group, while 272 patients (63.26%) were assigned to the non-elevation group (Figure 1).
The median age of the enrolled cases was 31 years, and the elevated group was slightly older than the non-elevated group [32.00 (29.00, 35.00) years vs 31.00 (28.00, 34.00) years, P = 0.075]. The study cohort comprised of 54.88% primiparas (236/430) and 45.12% multiparas (194/430), with the majority of primiparous women. Comparative analysis revealed a lower proportion of primiparas in the elevated HBV DNA group (51.9%, 82/158) than in the non-elevated group (56.62%, 154/272). Comparative analysis demonstrated marginally elevated median BMI in the elevation group vs the non-elevation group [20.85 (18.99, 22.79) kg/m2 vs 20.55 (19.10, 22.67) kg/m2], with the majority (68.37%, 294/430) maintaining normal BMI values. However, none of these differences were statistically significant (P > 0.05) (Table 1).
| Factor | Total cases (n = 430) | Non-elevation group (n = 272) | Elevation group (n = 158) | P value |
| Parity | 0.343 | |||
| Primiparous | 236 (54.88) | 154 (56.62) | 82 (51.90) | |
| Multiparous | 194 (45.12) | 118 (43.38) | 76 (48.10) | |
| BMI (kg/m2) | 20.59 (19.05, 22.71) | 20.55 (19.10, 22.67) | 20.85 (18.99, 22.79) | 0.623 |
| < 18.5 | 73 (16.98) | 42 (15.44) | 31 (19.62) | 0.652 |
| 18.5 ≤ BMI < 24 | 294 (68.37) | 188 (69.12) | 106 (67.09) | |
| 24 ≤ BMI < 28 | 53 (12.33) | 36 (13.24) | 17 (10.76) | |
| ≥ 28 | 10 (2.32) | 6 (2.20) | 4 (2.53) | |
| Age | 31.00 (28.00, 34.00) | 31.00 (28.00, 34.00) | 32.00 (29.00, 35.00) | 0.075 |
| ≤ 30 | 179 (41.63) | 120 (44.12) | 59 (37.34) | |
| > 30 | 251 (58.37) | 152 (55.88) | 99 (62.66) |
In terms of virological markers, the elevated group exhibited a significantly higher HBeAg positivity rate than the non-elevated group (10.13% vs 4.41%, P = 0.021), as well as a higher proportion of individuals with HBV DNA ≥ 100 IU/mL (70.25% vs 33.46%, P < 0.001). Conversely, TG levels were significantly higher in the non-elevated group than in the elevated group [1.44 (1.17, 1.87) mmol/L vs 1.28 (1.03, 1.68) mmol/L, P = 0.025]. Comparative analysis demonstrated no significant between-group differences in hepatic (bilirubin, transaminases), hematological (complete blood count, coagulation parameters), or metabolic (HbA1c, serum Cr) indices (all P > 0.05; Table 2).
| Factor | Total cases (n = 430) | Non-elevated groups | Elevated groups (n = 158) | P value |
| HBeAg | 0.021 | |||
| Negative | 402 (93.49) | 260 (95.59) | 142 (89.87) | |
| Positive | 28 (6.51) | 12 (4.41) | 16 (10.13) | |
| HBV DNA (IU/mL) | < 0.001 | |||
| < 100 | 228 (53.02) | 181 (66.54) | 47 (29.75) | |
| ≥ 100 | 202 (46.98) | 91 (33.46) | 111 (70.25) | |
| TBA, µmol/L | 2.60 (1.46, 4.25) | 2.60 (1.40, 4.00) | 2.65 (1.80, 4.45) | 0.454 |
| TBIL, µmol/L | 5.75 (4.38, 7.62) | 5.80 (4.25, 7.80) | 5.65 (4.38, 7.50) | 0.530 |
| DBIL, µmol/L | 2.50 (1.91, 3.12) | 2.50 (2.00, 3.20) | 2.50 (1.90, 3.10) | 0.697 |
| IBIL, µmol/L | 3.10 (2.20, 4.70) | 3.10 (2.20, 4.95) | 3.10 (2.15, 4.55) | 0.636 |
| AST, U/L | 15.50 (13.50, 19.60) | 15.40 (13.20, 19.60) | 16.20 (13.60, 19.60) | 0.643 |
| AST < 19 | 251 (58.37) | 159 (58.46) | 92 (58.23) | 0.352 |
| AST ≥ 19 | 100 (23.26) | 58 (21.32) | 42 (26.58) | |
| ALT, U/L | 13.60 (9.80, 18.88) | 13.60 (9.75, 18.75) | 13.50 (9.75, 18.91) | 0.915 |
| ALT < 19 | 232 (53.95) | 140 (51.47) | 92 (58.23) | 0.958 |
| ALT ≥ 19 | 75 (17.44) | 45 (16.54) | 30 (18.99) | |
| TP, g/L | 65.71 ± 4.29 | 65.43 ± 3.85 | 66.04 ± 4.81 | 0.555 |
| ALB, g/L | 36.10 ± 3.81 | 36.11 ± 3.76 | 35.80 ± 3.92 | 0.980 |
| GLB, g/L | 30.30 ± 3.20 | 29.95 ± 318 | 30.68 ± 3.22 | 0.343 |
| HGB, g/L | 120.00 (113.00, 127.00) | 120.00 (113.00, 127.75) | 120.00 (113.50, 126.00) | 0.662 |
| PLT, × 109/L | 230.00 (201.00, 263.25) | 232.00 (201.00, 264.00) | 226.00 (201.50, 263.00) | 0.644 |
| WBC, × 109/L | 8.61 (7.54, 10.20) | 8.60 (7.58, 10.39) | 8.61 (7.36, 9.82) | 0.455 |
| TC, mmol/L | 4.73 (4.12, 5.26) | 4.69 (4.13, 5.23) | 4.83 (4.06, 5.33) | 0.622 |
| TG, mmol/L | 1.39 (1.12, 1.82) | 1.44 (1.17, 1.87) | 1.28 (1.03, 1.68) | 0.025 |
| HDL-C, mmol/L | 1.71 ± 0.29 | 1.70 ± 0.28 | 1.72 ± 0.61 | 0.678 |
| LDL-C, mmol/L | 2.36 (2.02, 2.76) | 2.36 (2.10, 2.70) | 2.38 (1.90, 2.81) | 0.920 |
| HbA1c, % | 5.10 (5.00, 5.30) | 5.10 (5.00, 5.30) | 5.10 (4.90, 5.30) | 0.429 |
| < 6.0 | 276 (64.19) | 177 (65.07) | 99 (62.66) | 0.060 |
| ≥ 6.0 | 2 (0.47) | 0 (0) | 2 (1.27) | |
| Cr, µmol/L | 49.00 (44.00, 54.00) | 48.70 (43.00, 54.00) | 50.00 (44.00, 55.00) | 0.333 |
| PT, seconds | 12.50 (11.10, 12.90) | 12.40 (11.20, 12.88) | 12.50 (11.05, 13.000 | 0.339 |
| APTT, seconds | 32.40 (28.80, 34.70) | 32.45 (28.85, 34.78) | 32.20 (28.80, 34.70) | 0.883 |
| INR | 0.95 (0.92, 0.99) | 0.95 (0.92, 0.99) | 0.96 (0.92, 0.99) | 0.380 |
Potential determinants of HBV DNA elevation were assessed using univariate logistic regression analysis, incorporating baseline characteristics with established biological relevance to viral load fluctuations. Two liver function markers, AST and ALT, demonstrated some association with HBV DNA elevation [odds ratio (OR) > 1] but did not reach statistical significance (P > 0.05). In contrast, age, HBeAg positivity, and HBV DNA level ≥ 100 IU/mL were statistically significant in the univariate analysis (Table 3). These factors, along with other potential influences on HBV DNA elevation, were subsequently included in multivariate logistic regression analysis. After adjusting for OR, the results indicated that HBV DNA level ≥ 100 IU/mL (OR = 4.06, 95%CI: 2.40-6.87, P < 0.001) and age (OR = 1.09, 95%CI: 1.02-1.15, P = 0.008) were independent risk factors for HBV DNA elevation (Figure 2).
| Factor | Β | SE | Wald | OR (95%CI) | P value |
| Parity | 0.133 | 0.150 | 0.786 | 1.14 (0.85-1.53) | 0.375 |
| BMI (kg/m2) | 0.014 | 0.034 | 0.174 | 1.01 (0.95-1.09) | 0.677 |
| Age | 0.049 | 0.024 | 4.393 | 1.05 (1.00-1.10) | 0.036 |
| HBeAg positive | 0.893 | 0.396 | 5.083 | 2.44 (1.12-5.30) | 0.024 |
| HBV DNA ≥ 100 IU/mL | 1.547 | 0.216 | 51.139 | 4.70 (3.07-7.18) | < 0.001 |
| TBA, µmol/L | 0.027 | 0.037 | 0.508 | 1.03 (0.95-1.11) | 0.476 |
| TBIL, µmol/L | -0.008 | 0.031 | 0.060 | 0.99 (0.93-1.05) | 0.807 |
| DBIL, µmol/L | -0.023 | 0.098 | 0.057 | 0.98 (0.81-1.18) | 0.812 |
| IBIL, µmol/L | -0.022 | 0.033 | 0.423 | 0.98 (0.92-1.04) | 0.515 |
| AST ≥ 19 U/L | 0.224 | 0.241 | 0.865 | 1.25 (0.78-2.01) | 0.352 |
| ALT ≥ 19 U/L | 0.014 | 0.271 | 0.003 | 1.01 (0.60-1.73) | 0.958 |
| TP, g/L | 0.034 | 0.056 | 0.359 | 1.03 (0.93-1.15) | 0.549 |
| ALB, g/L | -0.002 | 0.058 | 0.001 | 1.00 (0.89-1.12) | 0.979 |
| GLB, g/L | 0.073 | 0.076 | 0.913 | 1.08 (0.93-1.25) | 0.339 |
| HGB, g/L | 0.009 | 0.009 | 1.036 | 1.01 (0.99-1.03) | 0.309 |
| PLT, × 109/L | 0.000 | 0.002 | 0.007 | 1.00 (0.99-1.01) | 0.933 |
| WBC, × 109/L | -0.036 | 0.054 | 0.445 | 0.96 (0.87-1.07) | 0.505 |
| TC, mmol/L | 0.042 | 0.139 | 0.091 | 1.04 (0.79-1.37) | 0.763 |
| TG, mmol/L | -0.475 | 0.251 | 3.596 | 0.62 (0.38-1.02) | 0.058 |
| HDL-C, mmol/L | 0.206 | 0.493 | 0.175 | 1.23 (0.47-3.23) | 0.676 |
| LDL-C, mmol/L | -0.047 | 0.147 | 0.102 | 0.95 (0.72-1.27) | 0.750 |
| HbA1c, % | -0.413 | 0.344 | 1.443 | 0.66 (0.34-1.30) | 0.230 |
| Cr, µmol/L | 0.009 | 0.015 | 0.345 | 1.01 (0.98-1.04) | 0.557 |
| PT, seconds | 0.097 | 0.111 | 0.773 | 1.10 (0.89-1.37) | 0.379 |
| APTT, seconds | -0.015 | 0.021 | 0.488 | 0.99 (0.95-1.03) | 0.485 |
| INR | 2.882 | 2.072 | 1.934 | 17.85 (0.31-1036.05) | 0.164 |
A nomogram was constructed by incorporating the two independent risk factors as core predictors into a prediction model, with elevation of HBV DNA in pregnant women with low viral load during mid-to-late pregnancy as the outcome event. The regression coefficients (β) for each variable were calculated as follows: Age = 0.467 (P = 0.010) and HBV DNA ≥ 100 IU/mL = 1.399 (P < 0.001). The resulting regression equation was Logit (P/1-P) = -3.01 + 0.052 × age (years) + 1.555 × HBV DNA ≥ 100 IU/mL. The nomogram is shown in Figure 3A.
Internal validation of the prediction model was performed using the bootstrap method, with 1000 resamples for validation and evaluation of model performance. The receiver operating characteristic curve was plotted and the AUC was calculated to be 0.71 (95%CI: 0.66-0.76), with a cut-off value of 0.45. The model demonstrated a sensitivity of 69.62% and specificity of 68.01%. An AUC > 0.7 indicates moderate discriminative ability between the two groups, suggests that the model performs better than random guessing and demonstrates a reasonable level of reliability in classification accuracy (Figure 3B).
The goodness-of-fit of the model was assessed using the Hosmer-Lemeshow test. The test results showed a χ2 value of 3.5709, with eight degrees of freedom (df = 8), and a P value of 0.893 (P > 0.05), indicating that the model fits well. Internal validation and calibration curve analysis yielded a corrected C-index of 0.708, indicating good concordance. The calibration curve is shown in Figure 3C. The calibration curve closely approximated the ideal curve, suggesting strong consistency between the predicted and observed values. The clinical DCA was plotted to assess the clinical applicability of the model (Figure 3D).
The Y-axis represents the net benefit, and the X-axis indicates the threshold probability. The green horizontal solid line (none) represents the scenario where no clinical intervention was performed for all patients and none of the patients experienced HBV DNA elevation. The blue solid line (All) represents the scenario in which all patients receive clinical intervention, and all patients experience HBV DNA elevation. The solid red line represents the DCA of the internal validation cohort of the model. This red line lies above the intersection of the ALL and None curves, indicating that the prediction model has good clinical effectiveness. The red curve of our model exceeded both reference curves, indicating favorable clinical applicability (Figure 3D).
Stratified statistical analysis was performed on baseline HBV DNA levels among all enrolled pregnant women. In the cohort with baseline HBV DNA < 100 IU/mL, 20.26% experienced an elevation in HBV DNA levels during mid-to-late pregnancy, although elevations rarely reached high-risk thresholds (≥ 2 × 105 IU/mL). Among the women with baseline HBV DNA levels between 100 IU/mL and 1 × 104 IU/mL, 54.07% demonstrated HBV DNA elevation, with 4.65% progressing to high-risk levels. In those with baseline HBV DNA ≥ 1 × 104 IU/mL, 35.48% experienced elevations to high-risk levels, indicating the potential need for antiviral therapy, whereas an additional 25.81% exhibited increases in HBV DNA during pregnancy that did not reach high-risk levels (Table 4).
| Range of change in HBV DNA1 | HBV DNA < 100 (n = 227) | 100 ≤ HBV DNA < 1 × 104 (n = 172) | HBV DNA ≥ 1 × 104 (n = 31) |
| Rising and ≥ 2 × 105 | 0 (0) | 8 (4.65) | 11 (35.48) |
| Rising but < 2 × 105 | 46 (20.26) | 85 (49.42) | 8 (25.81) |
| Decreasing or unchanged | 181 (79.74) | 79 (45.93) | 12 (38.71) |
In October 2024, telephone follow-up was conducted for 19 pregnant women whose HBV DNA levels increased to high-risk levels during mid-to-late pregnancy along with their newborns. Among them, 18 patients completed the follow-up successfully, while 1 patient was lost due to inability to establish contact. Of the participants, 27.78% (5/18) received MTCT prophylaxis, with a mean gestational age at initiation of antiviral therapy of 29.6 weeks. All newborns tested negative for HBsAg. The average age of the newborns at the time of follow-up was 3.78 years, and all had completed the standard hepatitis B immunization schedule. A total of 94.74% of the mothers opted for breastfeeding, with a mean duration of 5.95 months (Table 5).
| Case number | Prevention of MTCT during pregnancy | Timing of MTCT | Standard hepatitis B vaccination | Breastfeeding duration | HBsAg |
| 1 | No | - | Finish | 1 month | Negative |
| 2 | No | - | Finish | 12 months | Negative |
| 3 | No | - | Finish | 1 month | Negative |
| 4 | Yes | 32 weeks of gestation | Finish | 8 months | Negative |
| 5 | No | - | Finish | 3 months | Negative |
| 6 | No | - | Finish | 4 months | Negative |
| 7 | No | - | Finish | 0 months | Negative |
| 8 | Yes | 28 weeks of gestation | Finish | 5 months | Negative |
| 9 | Yes | 26 weeks of gestation | Finish | 8 months | Negative |
| 10 | Yes | 31 weeks of gestation | Finish | 8 months | Negative |
| 11 | - | - | - | - | - |
| 12 | No | - | Finish | 2 months | Negative |
| 13 | Yes | 31 weeks of gestation | Finish | 24 months | Negative |
| 14 | No | - | Finish | 7 months | Negative |
| 15 | No | - | Finish | 9 months | Negative |
| 16 | No | - | Finish | 8 months | Negative |
| 17 | No | - | Finish | 1 month | Negative |
| 18 | No | - | Finish | 5 days | Negative |
| 19 | No | - | Finish | 6 months | Negative |
HBV infection remains a major global public health challenge. Current clinical guidelines designate HBV DNA quantification as a key criterion for the initiation of antiviral therapy. China’s HBV epidemic is primarily driven by vertical transmission, making the establishment of the optimal antiviral initiation timing during gestation a critical clinical priority. According to the latest 2024 edition of the Guidelines for the PMTCT of HBV[9], for pregnant women at ≥ 24 weeks of gestation with HBV DNA levels between 1 × 104 IU/mL and 2 × 104 IU/mL, initiation of antiviral therapy should be considered after thorough counseling. Our study revealed that pregnant women with CHB and low baseline viral loads (< 1 × 104 IU/mL) still carry a substantial risk of HBV DNA elevation during late pregnancy, with an occurrence rate of 54.07%. Notably, current clinical guidelines lack standardized protocols for therapeutic management of this specific patient population.
Pregnancy is a distinct physiological state in which the maternal immune system undergoes adaptive shifts from immunological rejection to the fetus. While these adjustments foster immune tolerance, which is critical for fetal survival, they may concurrently diminish the maternal immune response to HBV. This altered immune environment could contribute to the increased risk of HBV DNA elevation in certain subgroups, such as older mothers or those with higher baseline viral loads, highlighting the need for targeted monitoring and intervention strategies. Univariate and multi
Our study further revealed that maternal age is another factor influencing HBV DNA levels during pregnancy. Advanced age is associated with a gradual decline in the function of multiple organ systems, including the immune system. Immunosenescence reduces the body's ability to clear persistent viral infections, particularly through the diminished activity of cytotoxic T lymphocytes, thereby promoting the chronicity of HBV infection. In the context of pregnancy, advanced maternal age is widely recognized as a risk factor for various pregnancy-related complications, including gestational hypertension and gestational diabetes, as well as comorbidities such as chronic hepatitis and cardiovascular disease[13-15]. It is also linked to adverse maternal outcomes, such as postpartum hemorrhage and postpartum hepatitis, and can negatively affect fetal health, increasing the risk of preterm birth and low birth weight[16]. These pregnancy-related complications can intensify oxidative stress and inflammatory responses in the body, leading to DNA damage in somatic cells and mitochondrial dysfunction. Such disruptions in cellular homeostasis alter hepatic metabolism, thereby providing energy and biosynthetic substrates that favor HBV replication and indirectly contributing to elevated HBV DNA levels. Furthermore, epigenetic modifications-such as DNA methylation and histone modifications-may be more pronounced in women of advanced maternal age compared to those of optimal reproductive age[17,18]. These epigenetic alterations can influence the transcriptional regulation of viral genes and modulate the HBV replication dynamics.
Age and baseline HBV DNA ≥ 100 IU/mL were incorporated into a logistic regression-based predictive model, which demonstrated moderate discriminatory power (AUC = 0.71) and good calibration. For a typical pregnant woman aged 34 years with baseline HBV DNA ≥ 100 IU/mL, the model estimates an approximately 58% risk of viral elevation during mid-to-late pregnancy. This level of risk stratification enables clinicians to identify high-risk individuals who may benefit from intensified monitoring, while sparing low-risk patients from unnecessary follow-up. Such personalized surveillance strategies are particularly valuable in real-world clinical practice, where resources for HBV DNA quantification and specialist consultations are often limited.
Extensive research has consistently shown that antiviral treatment administered during pregnancy is both highly effective and safe, significantly decreasing MTCT rates and thereby curbing the incidence of HBV infection in neonates[19-22]. Our investigation revealed that among pregnant women with baseline HBV DNA levels of < 100 IU/mL in early pregnancy, even if viral load fluctuations occur throughout gestation, the probability of escalating to clinically significant thresholds remains negligible (Table 4). Therefore, for this specific population, the frequency of liver function tests and HBV DNA surveillance could be appropriately reduced or the duration between follow-up evaluations could be safely prolonged.
Although current clinical guidelines do not recommend antiviral treatment for patients with HBV DNA levels between 100 and 1 × 104 IU/mL, a subset of these individuals still progress to high-risk viral load levels. We suggest that the monitoring frequency of this group should be increased. Previous domestic and international studies have demonstrated that when maternal HBV DNA levels range from 1 × 104 IU/mL to 2 × 105 IU/mL prior to delivery, the risk of MTCT persists despite neonatal immunoprophylaxis, with a reported transmission rate of 0.6%[23]. This is notably higher than the 0.23% MTCT rate reported in Chinese studies[24]. Accordingly, the 2024 WHO guidelines now recommend that antiviral therapy be considered with informed consent for pregnant women at ≥ 24 weeks of gestation whose HBV DNA levels fall within this intermediate range.
Our findings further support this recommendation by showing that 35.48% of women with a low viral load in early pregnancy may experience HBV DNA elevation to this risk range during the second or third trimester. Therefore, even in women presenting with low viral loads during early gestation, close monitoring of HBV DNA levels and liver function markers is warranted and follow-up intervals should be appropriately intensified. Nevertheless, several limitations should be acknowledged. The lack of an external validation cohort is the most notable, as internal validation alone is insufficient to guarantee the model's generalizability across diverse populations. External validation in independent cohorts from different geographic regions is essential before our model can be confidently applied in routine clinical practice. Additionally, the retrospective design and the single-province, tertiary-hospital setting may limit the representativeness of our study population. Prospective studies with external validation are therefore needed to confirm and extend our findings. Additionally, the inclusion of women up to 55 years of age may be considered broad for a pregnant population. While this cutoff was adopted to maximize generalizability and avoid unnecessary exclusions of advanced-age pregnancies, we acknowledge that it extends beyond the typical reproductive age range. Nevertheless, the median age of our cohort was 31 years, and the proportion of participants aged > 40 years was extremely low, suggesting that this criterion had minimal impact on the overall findings. Future studies may consider applying stricter age restrictions to better reflect the typical childbearing population.
Future research should focus on determining the optimal timing for antiviral therapy initiation, its effect on reducing MTCT, and its potential impact on maternal complications and neonatal outcomes. These topics are expected to become focal points in the field of HBV management during pregnancy.
In conclusion, maternal age and early-pregnancy HBV DNA ≥ 100 IU/mL independently predict HBV DNA elevation during mid-to-late pregnancy in women with low viral load. The predictive model derived from these factors provides a practical tool for individualized risk stratification, enabling clinicians to tailor surveillance intensity and optimize PMTCT. However, external validation in independent cohorts is required before the model can be widely implemented in routine clinical practice.
We thank the enrolled patients for their support with this study.
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