The full content of Annals is available to subscribers

Subscribe/Learn More  >
Original Research |

Prevention of Vertical Transmission of Hepatitis B: An Observational StudyPrevention of Vertical Transmission of Hepatitis B

Ai Kubo, PhD*; Lyle Shlager, MD*; Amy R. Marks, MPH; Dena Lakritz, RN, MPH; Colette Beaumont, RN, MSN; Kim Gabellini, RN, MS; and Douglas A. Corley, MD, PhD
[+] Article, Author, and Disclosure Information

* Drs. Kubo and Shlager are lead coauthors of this article.

This article was published online first at www.annals.org on 27 May 2014.

From Kaiser Permanente Division of Research and Oakland Medical Center, Oakland, and Kaiser Permanente San Francisco Medical Center, San Francisco, California.

Disclaimer: The content of this publication does not necessarily reflect the views or policies of the National Institutes of Health, and the mention of trade names, commercial products, or organizations does not necessarily imply endorsement by the U.S. government. The authors assume full responsibility for the accuracy and completeness of the ideas presented.

Financial Support: By the Kaiser Permanente Community Benefit (grant CN-09LShla-01-H). Dr. Kubo is also supported by the National Cancer Institute and the National Institutes of Health Office of Research on Women's Health (career development award K07CA166143-01A1) and the National Center for Advancing Translational Sciences of the National Institutes of Health (KL2TR000143).

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-2529.

Reproducible Research Statement: Study protocol: Available from Dr. Kubo (e-mail, ai.kubo@kp.org). Statistical code and data set: Not available.

Requests for Single Reprints: Ai Kubo, PhD, Kaiser Permanente Division of Research, 2000 Broadway, Oakland, CA 94612; e-mail, ai.kubo@kp.org.

Current Author Addresses: Drs. Kubo and Corley and Ms. Marks: Kaiser Permanente Division of Research, 2000 Broadway, Oakland, CA 94612.

Dr. Shlager: Kaiser Permanente San Francisco Medical Center, 2350 Geary Boulevard, San Francisco, CA 94115.

Ms. Lakritz, Ms. Beaumont, and Ms. Gabellini: Kaiser Permanente Oakland Medical Center, 3505 Broadway, Oakland, CA 94611.

Author Contributions: Conception and design: A. Kubo, L. Shlager, D. Lakritz, D.A. Corley.

Analysis and interpretation of the data: A. Kubo, L. Shlager, A.R. Marks, D. Lakritz, C. Beaumont, K. Gabellini, D.A. Corley.

Drafting of the article: A. Kubo, L. Shlager, A.R. Marks, D. Lakritz, D.A. Corley.

Critical revision of the article for important intellectual content: A. Kubo, L. Shlager, A.R. Marks, D. Lakritz, K. Gabellini, D.A. Corley.

Final approval of the article: A. Kubo, L. Shlager, D. Lakritz, K. Gabellini, D.A. Corley,

Provision of study materials or patients: C. Beaumont.

Statistical expertise: A.R. Marks, D.A. Corley.

Obtaining of funding: A. Kubo, L. Shlager, D.A. Corley.

Administrative, technical, or logistic support: A.R. Marks, D. Lakritz, K. Gabellini.

Collection and assembly of data: A. Kubo, A.R. Marks, D. Lakritz, C. Beaumont, K. Gabellini, D.A. Corley.

Ann Intern Med. 2014;160(12):828-835. doi:10.7326/M13-2529
Text Size: A A A

Background: For mothers with chronic hepatitis B virus (HBV) infection, the Centers for Disease Control and Prevention recommends immunoprophylaxis to decrease perinatal transmission. However, its effectiveness and risk factors for failure have not been well-studied in community practice.

Objective: To investigate the effectiveness of a contemporary immunoprophylaxis protocol.

Design: Observational study.

Setting: An HBV perinatal immunoprophylaxis program within Kaiser Permanente Northern California.

Patients: 4446 infants born to 3253 HBV-positive mothers between 1997 and 2010.

Measurements: Adherence to immunoprophylaxis, follow-up testing rates, maternal risk factors for HBV transmission, and transmission rates.

Results: The infant infection rate was 0.75 per 100 births from 1997 to 2010 (Poisson 95% CI, 0.48 to 1.10). Rates per 100 births were 3.37 (CI, 2.08 to 5.14) for e antigen–positive mothers and 0.04 (CI, 0.001 to 0.24) for e antigen–negative mothers. Among mothers with viral load testing, the lowest level associated with transmission was 6.32 × 107 IU/mL. Infection rates per 100 births were 3.61 (CI, 0.75 to 10.56) among the 83 births to mothers with viral loads of 5 × 107 IU/mL or greater and 0 among the 831 births to mothers with viral loads less than 5 × 107 IU/mL, regardless of e antigen status.

Limitations: Testing for HBV immunity and infection was less complete in earlier years. Viral load testing was only consistently available starting in 2007.

Conclusion: Prenatal HBV screening followed by postnatal prophylaxis is highly effective in preventing vertical transmission of HBV. A negative e antigen status or a viral load less than 5 × 107 IU/mL (90.9% of women tested) identifies women at extremely low risk for transmission after immunoprophylaxis who are unlikely to benefit from further interventions.

Primary Funding Source: Kaiser Permanente Community Benefit and National Institutes of Health.


Grahic Jump Location
Figure 1.

Proportion of infants receiving HBIg within 12 h after birth plus 3 hepatitis B vaccines within 7, 8, and 12 mo, 1997–2010.

An individual hepatitis B vaccination may or may not have been on time. In 2001, the program coordinators began calling the infants’ providers before the 6-mo appointment to remind them to administer the final vaccine and postvaccination serologic tests. This policy probably caused the increase in the proportion of infants who received HBIg and all 3 vaccine doses by month 7 between 2001 and 2003. HBIg = hepatitis B immunoglobulin.

Grahic Jump Location
Grahic Jump Location
Figure 2.

HBV-positive rate among all children tested (= 3353) and by maternal e antigen testing status (624 positive and 2317 negative).

HBsAg = hepatitis B surface antigen.

Grahic Jump Location




Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).


Submit a Comment/Letter
To the Editor
Posted on June 3, 2014
Pierre Sellier, M.D., Ph.D., Amanda Lopes, MD, Jean-François Bergmann, MD, PhD
Lariboisière Hospital
Conflict of Interest: None Declared
From an observational study (1), Kubo and colleagues’ found that the infant infection rate was 0 among the 831 births to mothers with viral loads less than 5 X 107 IU/mL, regardless of e antigen status. The authors concluded that a negative e antigen status or a viral load less than 5 X 107 IU/mL identifies women at extremely low risk for transmission after immune-prophylaxis, who are unlikely to benefit from further interventions.
However, several limitations have to be underlined in this study: first, viral load was (almost systematically) tested only from 1 July 2007 through 2010. Of the mothers who gave birth to a total of 1185 infants, 1100 (93%) were tested for viral load and 1008 (85%) were tested for both e antigen and viral load. Among the 1185 infants, 904 retained KPNC membership through the post-vaccination testing period and only 837 (76.1%) could be tested for HBs Ag. Loss to follow-up with no bias reduces power because the effective sample size is reduced. Taking into account the uncertainty would result in wider confidence intervals (2).
Second, the observed infection rate among children by maternal viral load (3.9% from maternal viral load ≥ 5 X 107 IU/mL) is obviously low, compared with those reported in Asian studies, ranging from 8 to 30% despite passive-active immunization (3), justifying, the infection rate being related to maternal viral load (4, 5), adding a nucleos(t)ide analogue during the third trimester of pregnancy in order to decrease it. The “high viral loads” in the 76 mothers were ≥ 5 X 107 IU/mL but possibly lower than those observed during the “immune tolerant” phase of HBV infection.
Third, this study did not allow defining the best strategy concerning “intermediate” maternal viral loads, between 105 IU/mL and 107 IU/mL, as vertical transmission of HBV could occur in 2.9% (4) to 13.6% (5), always with maternal positive e antigen status. The relationship between the maternal pre-labour viral loads and the vertical transmission of HBV having to be considered as a step-by-step phenomenon, rather than an on-off phenomenon, with a well defined cut-off, a study focusing on the benefit from additional antiviral treatment in this setting is needed. Although of great interest, this study had too peremptory conclusions.
Author's Response
Posted on August 5, 2014
Ai Kubo, PhD
Kaiser Permanente
Conflict of Interest: None Declared
We concur with the point raised by Sellier et al. that our study was limited by the facts that not all patients had viral load data and there was loss to follow up. Given the improvement in technology, viral load testing became a routine among infected pregnant women only after July 2007. In addition, as in any prospective study, loss to follow up is inevitable. These points were acknowledged in the limitation section, but nevertheless, this represents the largest study to date examining the effectiveness of HBV immunoprophylaxis with availability of viral load data.

We also agree with the author's recommendation for additional research. Such research, however, requires efforts at identifying a target population who is likely to potentially benefit, and at the same time, excluding populations from costly intervention studies who are unlikely to benefit. Thus, although there is likely a linear relationship between risk of transmission and viral load, as the authors note, we believe that it is reasonable within the context of our study to identify a viral load below which no transmission occurred within our population. This allows future researchers to have potential anchor points for inclusion and exclusion criteria for studies that might evaluated whether agents such as nucleoside analogues are of benefit to those still with residual risk.
Submit a Comment/Letter

Summary for Patients

Clinical Slide Sets

Terms of Use

The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.


Buy Now for $32.00

to gain full access to the content and tools.

Want to Subscribe?

Learn more about subscription options

Related Articles
Topic Collections
PubMed Articles
Forgot your password?
Enter your username and email address. We'll send you a reminder to the email address on record.