Categories: HEALTH

Incidence and predictors of postpartum alanine aminotransferase elevation in mothers with chronic hepatitis B: a prospective study protocol | BMC Gastroenterology

research environment

This single-center cohort study will recruit mothers with chronic hepatitis B and healthy mothers at a university medical center in China. Patients were screened and eligible to participate in the study if they met the following inclusion and exclusion criteria:

Inclusion criteria

1.
HBsAg (+) group: Pregnant women aged 20 to 35 years old, HBsAg positive for more than 6 months, single pregnancy, gestational age 12 to 24 weeks, HBV DNA>2000 IU/mL, ALT normal for 2 consecutive times (at least 30 days apart) ), liver stiffness measurement (LSM) < 7.4Kpa and controlled attenuation parameter (CAP) < 259 dB/m;
2.
Healthy pregnant women group: 20 to 35-year-old HBsAg and HBcAb-negative pregnant women who were treated in the Fifth Affiliated Hospital of Guangzhou Medical University during the same period, had a single pregnancy, and had two consecutive normal ALTs (at least 30 days apart), LSM < 7.4Kpa and CAP < 259 dB/m. (Basically matched with the age, body mass index (BMI), and parity of pregnant mothers in the HBsAg (+) group)

Exclusion criteria

1.
Co-infection with human immunodeficiency virus (HIV), hepatitis D virus (HDV), hepatitis C virus (HCV), and syphilis;
2.
Previous pregnancy has a history of miscarriage or congenital malformations;
3.
Treatment experience (unless antiviral drugs were used to prevent mother-to-child transmission in a previous pregnancy and were discontinued more than 6 months before this pregnancy);
4.
Have a history of renal insufficiency; Have evidence of liver cancer or decompensation, estimated creatinine clearance (CLCr) < 80ml/L;
5.
Clinical symptoms of threatened abortion; Ultrasound evidence of fetal malformation;
6.
Concomitant use of nephrotoxic drugs, steroids, cytotoxic drugs, nonsteroidal anti-inflammatory drugs, or immunomodulators; Recipients of solid organ or bone marrow transplants; or disease at the discretion of the investigator, including severe renal, cardiovascular, Lung or neurological disease;
7.
The biological father of the fetus is infected with chronic hepatitis B;
8.
Elevated ALT during pregnancy before admission;
9.
Thyroid dysfunction;
10.
Chronic liver disease other than hepatitis B;
eleven.
Complications of previous pregnancy, such as intrahepatic cholestasis of pregnancy (ICP), gestational hypertension, gestational diabetes, gestational proteinuria, etc.

Subjects who meet any of the exclusion criteria will be excluded from participation in this study. Written informed consent must be obtained from all participating pregnant women before commencing any screening activity.

research proposal

This study is a single-center, prospective, open-label cohort study, ranging from 12 to 24 weeks of pregnancy to the 24th week of postpartum. Eligible pregnant women who registered for delivery at the Fifth Affiliated Hospital of Guangzhou Medical University were all enrolled. At 20-24 weeks of pregnancy, the patients were divided into HBsAg (+) group and healthy pregnant women group according to HBsAg status. Patients were monitored every 4 weeks before delivery and then every 6, 12, and 24 weeks postpartum (Fig. 1). Patient recruitment for the study begins on June 1, 2022 and is expected to be completed on June 1, 2023.

picture. 1

Patient registration and assessment

recruitment

Subjects were recruited through the Department of Infectious Diseases and Obstetrics Clinic of the Fifth Affiliated Hospital of Guangzhou Medical University. Recruitment begins in June 2022. According to published literature (7,9,15), the frequency of postpartum ALT elevations in HBV-infected pregnant women is estimated to be 11.6-30.6%. We calculated the sample size for the HBsAg (+) group of the current study (assuming p = 26%, q = 10%, type I error α = 0.05, test efficiency 1-β = 0.9) and set the number of patients to approximately 120. The healthy mother group plans to enroll 240 subjects (hepatitis B mothers: healthy mothers in a ratio of 1:2). The total number of subjects in the study was 360. We estimate that approximately 5-10% of subjects may drop out of the study. The total number of patients with completed data at the end of the study will be 108 in the HBsAg (+) group and 216 in the healthy pregnant group. The sample size is sufficient to observe adverse events with an incidence rate of 3% or greater.

experimental intervention

Although our study is observational, due to compliance with practice guidelines recommended by national professional societies, mothers with elevated HBV levels will receive antiviral therapy during pregnancy and all infants will receive HBIG and HBV vaccines. These medical products are independently prescribed for study participants as part of a standard-of-care treatment strategy that is not determined in advance by our study protocol. These treatments are applied based on clinical practice. However, we will evaluate the safety of the intervention in mothers and newborns. Trial-specific interventions will not be implemented in the study.

1) Antiviral treatment

In the HBsAg (+) group, antiviral therapy was initiated if the HBV-DNA level was greater than 200,000 IU/mL from 24 to 28 weeks of gestation until delivery. During antiviral treatment, subjects with confirmed CLCr <50ml/min will receive an adjusted dose of the study drug based on renal function and will be closely monitored every 4 weeks.

2) Infant immunization

All newborns of pregnant women with HBsAg (+) will receive a first dose of hepatitis B vaccine (10 µg) and hepatitis B immune globulin (HBIG, 100IU) within 12 hours of birth. The second and third hepatitis B vaccine injections will be given intramuscularly at 1 month and 6 months of age respectively. As with all healthy pregnant women, their newborns will receive the same hepatitis B immunoprophylaxis regimen and schedule, without the need for HBIG injections at birth.

Laboratory evaluation

Laboratory tests included the following: liver function and biochemistry, HBV serology, HBV DNA, and HBV genotype. Imaging tests will include transient elastography (TE) and ultrasound. We also evaluated HBV viral mutations, including pre-S, BCP, and PC.

study endpoint

The primary endpoints were the proportion of HBsAg(+) pregnant women with elevated ALT within 24 weeks postpartum and the frequency of HBsAg(+) pregnant women with sustained ALT elevation beyond 12 weeks. Secondary endpoints include the proportion, peak and period of ALT elevation in healthy pregnant women within 24 weeks postpartum; and comparison of secondary endpoints between the HBsAg (+) pregnant women group and the healthy pregnant women group.

data collection

The following variables for the baseline will be collected:

1.
age.
2.
BMI.
3.
History of hepatitis B.
4.
Reproductive history.
5.
complication.
6.
Medications you have taken before.
7.
Baseline laboratory data: including total bilirubin, ALT, aspartate aminotransferase (AST), and TE. In addition, HBsAg (+) group was also tested for HBsAg, HBsAb, HBeAg, HBeAb, HBcAb, HBV DNA, genotype, pre-S, BCP, and PC.

Follow-up data collected during the follow-up period are shown in Table 1 .

Table 1 Patient follow-up schedule and data collection

Data management

Metadata originating from patients will be de-identified and uploaded to a privacy-preserving research database. Once uploaded, the data cannot be changed. Only the PI and research assistants on the current project have access to the data.

patient and public engagement

Patients or the public were not involved in the design, conduct, reporting, or dissemination plans of the current study.

statistical methods

Statistical analysis was performed using SPSS version 23.0 (IBM, New York, USA) statistical analysis software. Demographic and baseline measurements will be summarized using standard descriptive methods and stratified by study group. Maternal baseline data will include a summary of previous pregnancies, log10 HBV DNA levels, and ALT levels. Baseline data for the infant will include a summary of weight, height, head circumference, gestational age, mode of delivery (cesarean section vs. virgin birth), Apgar score, HBsAg positivity at birth, and HBeAg positivity at birth. The aforementioned baseline variables were elevated ALT and postpartum ALT was normal between the two groups. Quantitative data will be summarized as mean (SD) or median (range), and differences between groups will be compared by Student’s t-test. Categorical data will be presented as counts or percentages and compared by chi-square or nonparametric tests. Predictors of ALT flare will be further analyzed by multivariate analysis of HBsAg-positive pregnancies, and area under the ROC curve will be used to predict ALT rise. A mixed linear model was established through repeated measures and missing value analysis to analyze the changing trend of postpartum ALT. A nested case-control study will be used to analyze baseline risk factors for ALT elevation (with further subgroup analysis for mild and severe ALT elevation). We considered the results to be statistically significant when the P value was < 0.05.

Research ethics approval

The research project will be conducted in compliance with the ethical principles of the Declaration of Helsinki. The current proposal (Proposal Number: V1.2-2022MAY13) has been peer reviewed when applying for research funding from the “Belt and Road” Foreign Experts Innovation Talent Exchange Project funded by the Ministry of Science and Technology of China (G2022030048L). The Ethics Committee of the Fifth Affiliated Hospital of Guangzhou Medical University approved this study on May 23, 2022 (approval number GYWY-Y2022-56). The study is still open for enrollment. The results of this study will be submitted for publication in a peer-reviewed journal.

Confidential

The investigator or a member of the study team designated by the investigator will be responsible for communicating with subjects, including explaining the purpose, methods, benefits, and risks of the study. The research team will also explain to subjects their rights to participate in the study and their right to withdraw from the study at any time for any reason. Patients who withdraw from the study program will receive standard care. Patient rights and quality of care will not be affected. Fully informed patient consent will be provided. All records of patients participating in the study will be kept confidential and data will be de-identified before analysis or publication in a peer-reviewed journal.