Prevention of Vertical Transmission of Hepatitis B within a North Carolina Hospital System

Introduction

Hepatitis B virus (HBV) is a major contributor to liver-related disease on a global scale; an estimated 257 million people were living with HBV as of 2015 and nearly one million deaths are attributed to HBV annually.¹ Hepatitis B is transmitted in numerous ways, including from birthing person to child. Vertical transmission at time of birth can result in devastating outcomes for neonates, with 90% of vertically infected infants going on to develop chronic infection and 25% of those infants dying premature deaths from liver disease.^2,3 Prevention vertical transmission of HBV is essential in avoiding these outcomes and fortunately is possible with evidence-based interventions such as a birth dose vaccine and antiviral therapy for selected pregnant individuals.

The current guidelines provided by the American Association for the Study of Liver Diseases (AASLD) recommend that all neonates born to birthing people with positive hepatitis B surface antigen (HBsAg) testing receive both active (HBV vaccination) and passive (hepatitis B immunoglobin [HBIG]) immunoprophylaxis within 12 hours of birth.⁴ These preventive measures have reduced the rate of vertical transmission of hepatitis B from over 90% to less than 10%. Breakthrough transmission is possible despite vaccination, however, and more commonly occurs in people giving birth at high-risk for vertical transmission, defined specifically by a high HBV viral load (≥200,000 IU/mL). If a pregnant person is found to have high-risk disease, the AASLD recommends the use of anti-viral prophylaxis during the third trimester in order to prevent cases of breakthrough transmission.^6,7,8 Currently the AASLD only defines high-risk HBV infection by high HBV viral load, excluding other laboratory tests that may be helpful in further defining risk. HBeAg testing could assist in determining risk status, yet only alongside HBV viral load, as the two are not perfectly correlated.⁵ Current guidelines also recommend that follow-up testing be performed for all HBV-exposed infants at 9–12 months of life; infants should be tested for HbsAg to ensure they are not infected, as well as HBV surface antibody (HbsAb) to ensure protection via immunization. However, oftentimes this testing of exposed infants is overlooked within our decentralized, fragmented medical system.

While hepatitis B birth dose vaccination and HBIG have been widely adopted in the United States since 1991⁹, AASLD guidelines for evaluation of risk status are not as routinely followed, with birthing person antiviral prophylaxis being newer and perhaps less widely adopted. Recognizing the possibility of poor neonatal outcomes if prevention of vertical transmission is not addressed, evaluation of timely prophylaxis and assessment of risk status is essential. Our aim was to assess compliance with AASLD guidelines at a tertiary referral hospital in North Carolina, and to suggest future quality improvement initiatives to improve care for this population.

Materials and Methods

This was a single-center retrospective chart review investigating all HBV-positive individuals who gave birth within a teritiary hospital system in North Carolina between April 1, 2014 and December 31, 2019. The patient population was identified from within the Carolina Data Warehouse with assistance from the North Carolina Translational and Clinical Sciences Institute (NC TraCS). Participants were included in the analysis if they were 1) pregnant and 2) had confirmed HBV infection during pregnancy (based on the following ICD codes: ICD-9 070.30 (Viral hepatitis B without mention of hepatic coma, acute or unspecified, without mention of hepatitis data), ICD-10 B18.1 (Chronic viral hepatitis B without delta-agent), ICD-10 B19.1 (Unspecified viral hepatitis B). After participants were identified and HBsAg testing was confirmed to be positive, electronic medical records were assessed for data elements including: birthing person age, birthing person HIV status, gestational age at delivery, type of delivery, birth weight, APGAR scores, time to neonatal HBV vaccination, time to neonatal HBIG administration, birthing person HBV viral load and HbeAg status, and receipt of tenofovir.

Time to neonatal HBV vaccination and time to neonatal HBIG administration were calculated as the number of hours since birth, and timely vaccination was defined as within 12 hours of birth per AASLD guidelines. Cases in which neonates did not receive timely birth dose vaccination and/or HBIG were further reviewed. A preterm delivery was defined as one at <37 weeks’ gestation.

Assessment of birthing person risk status was only analyzed for birthing persons who delivered in January 2016 or afterwards, in accordance with AASLD recommendations that were published on November 13, 2015. High-risk HBV was defined as HBV viral load ≥200,000 IU/mL. HBeAg positivity was also assessed. The proportion of individuals with HBV viral load and HBeAg testing was determined for those who delivered in 2016 or beyond. We also calculated the proportion of HBsAg-positive participants who had known high-risk HBV and the proportion of birthing persons at high-risk who received tenofovir therapy. As mainstay therapy for HBV prophylaxis, appropriate tenofovir regimen includes initiation of therapy at 28–32 weeks gestation, at a dosage of 300 mg daily per AASLD guidelines, continuing until delivery. Data was compiled in Excel and analyzed in aggregate. We received IRB approval from the University of North Carolina at Chapel Hill to conduct this study.

Discussion

This study demonstrated that a tertiary hospital in North Carolina was generally compliant with AASLD guidelines regarding prevention of vertical transmission of hepatitis B. Data collection identified 99 birthing persons as being hepatitis B positive at time of birth. The average birthing person age for these 99 individuals was 33.7 years with a standard deviation 5.14. At time of delivery for these 99 birthing persons, 68% had spontaneous vaginal delivery and 25% had caesarean section. The average gestational age for the neonates was 39 weeks and 6 days, +/− 15 days. Out of the 99 births, 7 were premature. The average birth weight for neonates was 3149 grams, +/− 587 grams.

Of the 99 birthing person/infant dyads included in this study, the tertiary hospital provided timely and appropriate care to the majority of neonates in the form of birth dose HBV vaccination and HBIG administration within 12 hours of birth. All infants (100%) received timely HBIG and nearly all (98%) infants received timely birth dose vaccine. The two infants that did not receive timely birth dose vaccination were noted to be premature and weighed less than 2 kilograms at birth, receiving birth dose vaccination at one month of age or at time of hospital discharge, respectively. While birth dose vaccine is delayed to one month of age (or hospital discharge) for HBV-unexposed infants weighing <2kg at birth, all HBV-exposed neonates are recommended to receive birth dose vaccination within 12 hours, regardless of weight.¹⁰ A future quality improvement initiative will ensure that neonatologists and newborn providers are aware of this recommendation.

This study also investigated risk status of HBV-infected individuals. Of the 99 people assessed, twenty delivered before 2016, leaving 79 for assessment of risk status (Figure 1). Within this subset, 46 of 79 (58.2%) of birthing persons had documented HBV viral load testing. Assessment of risk status allows for the identification of individuals at high-risk of vertical transmission so that they can be provided with antivirals, such as tenofovir, per the 2015 AASLD recommendations.⁴ Of the 46 individuals with HBV viral load testing, four had viral loads ≥200,000 IU/mL. Three of the four birthing persons (75%) who were considered at high-risk of vertical transmission appropriately received tenofovir. HBV viral load testing is essential in all pregnant individuals, as, without evaluation of risk, providers are unable to identify those who would benefit from antiviral prophylaxis. Given that almost half of the pregnant participants did not undergo HBV viral load testing, there is room for improvement within this tertiary healthcare system to comply with AASLD guidelines. We are conducting a larger follow-up study and quality improvement initiative to address this low compliance. While the majority of birthing people who were identified as having high-risk disease did receive antivirals (3/4 or 75%), it remains uncertain how many birthing persons truly had high-risk disease in this cohort since not all underwent testing. Of note, we were also unable to evaluate the 20 HBV-infected pregnant individuals who delivered prior to 2016, as recommendations had not yet been distributed regarding risk testing and anti-viral prophylaxis.

Figure 1: Cascade of care for pregnant birthing persons assessed after 2016.

Of 79 HBsAg+ individuals, 46 underwent viral load testing. Four birthing persons were identified as having hight-risk HBV (viral load ≥ 200,000/IUmL) and three of these individuals were started on tenofovir.

Interestingly, more pregnant persons had HBeAg testing (49/57, 62%) than HBV viral load testing in our cohort. Each of the four pregnant individuals considered high-risk by HBV viral load had HBeAg antigen testing, and three were found to be positive. Aside from these four, 7 additional individuals had a positive HBeAg status, but a viral load under 200,000 IU/mL. The current testing scheme may miss pregnant individuals who are HbeAg-positive and at high risk of vertical transmission despite having a viral load below the cutoff of 200,000 IU/mL. Thus, perhaps AASLD guidelines should be revised to either include HBeAg in risk status testing or lower the viral load cutoff for antiviral prophylaxis.

Neonatal follow-up testing, which is recommended for all HBV-exposed neonates, includes HBsAg (to ensure the infant is not infected) and HBV surface antibody (to ensure the infant is protected against the disease through vaccination) at 9–12 months of age.¹⁰ Within the context of this study, we could not evaluate infant testing, as many postpartum individuals and neonates were not followed within the health system studied, or did not have any further evaluation recorded. However, we plan to address the recommendation for such infant testing in discharge paperwork as part of a future initiative. While not assessed in this study, it is also imperative that HBV-positive pregnant individuals have appropriate follow-up care, particularly with gastrointestinal or infectious disease specialty services. To achieve this, improved communication between these specialty services must be established.

As mentioned, our plan for a quality improvement initiative will incorporate several elements to increase awareness of current AASLD recommendations. This includes a flowchart to direct management of both birthing person and neonate with factors such as risk status testing, tenofovir prophylaxis, and follow-up for birthing person/neonate dyads (Figure 2). We will reinforce these quality improvement efforts through electronic medical record (EMR) alerts in individuals who should be considered for evaluation, EMR order-sets for recommended high-risk testing, EMR smart phrases for appropriate follow-up testing of post-partum individuals and exposed neonates, and education for pediatric and obstetrics/gynecology providers regarding this issue.

Figure 2: Recommendation flowchart for prevention of vertical transmission of HBV in HBsAg+birthing persons and exposed neonate dyads.

The strength of this study lies in its evaluation of hospital compliance with AASLD guidelines for the prevention of vertical transmission of HBV. To our knowledge, this is one of the first studies to evaluate compliance with AASLD guidelines since the recommendation of antiviral prophylaxis was published in 2015. However, this study had several notable limitations. This study was limited by a small sample size; however, we included patients over a nearly six-year period (limited by the date of initiation of the Epic electronic medical record system within the studied health system). Limitations also include its single-center data extraction as a retrospective chart review, thus restricting external validity. Additionally, follow-up data for HBV-exposed postpartum individuals and their HBV-exposed neonates was incomplete as mentioned.

Conclusion

This study provides an assessment of current practices regarding prevention of vertical transmission of HBV compared to published guidelines. The tertiary hospital studied generally implemented recommended measures for the prevention of vertical transmission of hepatitis B, but there is room for improvement in the assessment of birthing person risk status. The vast majority of HBV-exposed infants in this cohort received timely vaccination, but educational initiatives are needed to ensure that even low-birth weight infants receive timely vaccination. Additionally, striving for 100% of HBsAg-positive pregnant individuals to undergo additional risk assessment is essential in order to ensure that infants are not infected via breakthrough transmission despite vaccination. Finally, follow-up for HBV-infected birthing persons and HBV-exposed neonates should be prioritized. Achieving full compliance with AASLD guidelines is possible through distributing easily accessible guidelines such as our flowchart, providing dedicated education to pediatric and obstetrics faculty/trainees, and assessing adoption of these recommendations over time via PDSA cycles. With this quality improvement initiative we hope to ensure that all providers within this hospital system are aware of these life-saving measures, and that this process may be adopted by other healthcare systems as well.