The current prospective cohort study was approved by the institutional ethics review committee of the Third Affiliated Hospital of Guangzhou Medical University, and was carried out in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Informed written consent was obtained from each patient in the present study. The present study was registered in ClinicalTrials.gov (No. NCT03181607). We had access to the study data and had reviewed and approved the final manuscript.
This multicenter cohort study was conducted between January 2017 and December 2018. Pregnant women with chronic HBV infection, who visited six hospitals in China and met the following inclusion criteria and exclusion criteria, were enrolled on a voluntary basis. The inclusion criteria were as follows: (a) a history of HBV infection ≥ 6 months; (b) positive for HBsAg; (c) for patients already administrated with antiviral treatment in preconceptional period, the therapy could not be discontinued; for patients never administrated with antiviral treatment, ALT ≥ 2 times the upper limit of normal (ULN), or HBV DNA level ≥ 104 IU/ml (positive for HBeAg) or HBV DNA level ≥ 103 IU/ml (negative for HBeAg), traditional protecting liver and reducing enzyme treatment failed; (d) good compliance of patients.
The exclusion criteria were as follows: (a) patients with antibodies against HIV, HCV, HDV, or other forms of chronic liver disease; (b) evidence of hepatocellular carcinoma, decompensated liver disease, auto-immune hepatitis, or significant renal, cardiovascular, respiratory or neurological comorbidity; (c) concurrent treatment with nephrotoxic drugs, glucocorticoids, cytotoxic drugs, non-steroidal anti-inflammatory drugs, or immune modulators; (d) ultra-sonographic evidence of fetal malformation, abnormal fetal development or placental abnormality; (e) clinical signs of threatened miscarriage; (f) a history of complicated pregnancy; (g) drug discontinuance by themselves.
As shown in Fig. 1, according to the inclusion criteria and exclusion criteria, 136 eligible pregnancy women with chronic HBV infection were enrolled in our study. They were assigned to the following four groups. In group A, patients with active CHB received an oral dose of 300 mg of tenofovir disoproxil fumarate (TDF, GlaxoSmithKline) or 600 mg of telbivudine (LDT, Novartis China) once per day due to ever abnormal liver function. When their liver enzyme turned to be normal prior to pregnancy, they took TDF or LDT continuously during their entire pregnancy. In group B and group C, pregnancies with CHB showed abnormal liver function in early pregnancy (less than 24 gestational weeks) and in late pregnancy (more than 24 gestational weeks), respectively. Then they began to take TDF (300 mg/times) or LDT (600 mg/times) every day, respectively. In group D, the pregnant women showed high HBV DNA level (≥ 106 IU/ml) and normal liver function. To reduce HBV DNA level and risk of MTCT, they were treated with TDF (orally 300 mg/times, Qd) or LDT (orally 600 mg/times, Qd) during the late pregnancy.
During pregnancy, all patients were followed up every 4 weeks to monitor adverse events and laboratory results (liver function tests, HBV DNA level, hematologic tests, etc.). Following delivery, patients in Groups A, B and C continued to receive TDF/LDT therapy, and patients in Group D stopped receiving TDF/LDT therapy. All these patients were also followed up every 4 weeks in the first 3 months of delivery. They subsequently were followed up at 24th week and 28th week postpartum, respectively.
All infants received 100 IU of hepatitis B immune globulin (HBIG, Hualan Biotechnology Co., Ltd. Xinxiang City, Henan Province, China) and 10 μg of the recombined hepatitis B vaccine (RHBV, Shenzhen Kangtai Biotechnology Co., Ltd., Shenzhen City, Guangdong Province, China) intramuscularly within 1–24 h after birth. The same dose of HBIG was administrated at age of 4 weeks. The same dose of recombined hepatitis B vaccine was given at week 4 and week 24.
All mothers and their infants were followed up to 7 months postpartum.
The primary outcome included the efficacy and the safety of antiviral therapy for mothers. We analyzed maternal HBV DNA level and alanine transaminase (ALT) at delivery and 7 months postpartum. To measure the safety of antiviral therapy on the mothers, adverse complications of mothers were analyzed.
The secondary outcome included the effectiveness of blocking MTCT of HBV and the safety of TDF/LDT for the offspring. Fetal development indicators such as birth weight, body length and congenital abnormalities at birth and at age of 6 months were evaluated to assess the safety of antiviral therapy with respect to fetal complications. HBV antigen and antibody status of infants were assayed at age of 7 months to assess the effectiveness of blocking MTCT of HBV.
All data were analyzed using SPSS v22.00 statistical analysis software (SPSS Inc, Chicago, IL). Descriptive variables were expressed as mean ± standard deviation (SD) or percentage. Analysis of variance (ANOVA) test and χ2 test were used to compare quantitative and categorical variables, respectively. Differences were considered statistically significant at a P value < 0.05.