Journal of Infection (2017) 75, 146e154

www.elsevierhealth.com/journals/jinf

Clinical course and perinatal transmission of

chronic hepatitis B during pregnancy: A
real-world prospective cohort study
Zhi-Xian Chen a,e, Gui-Fang Gu b,e, Zhao-Lian Bian c,e,
Wei-Hua Cai c, Yi Shen d, Yan-Li Hao c, Sheng Zhang d,
Jian-Guo Shao c, Gang Qin c,d,*

a
Department of Clinical Pharmacy, Nantong Health College of Jiangsu Province, China
b
Department of Obstetrics and Gynaecology, Nantong Third People’s Hospital, Nantong University,
Jiangsu, China
c
Center for Liver Diseases, Nantong Third People’s Hospital, Nantong University, Jiangsu, China
d
Department of Epidemiology and Biostatistics, School of Public Health, Nantong University, Jiangsu,
China

Accepted 11 May 2017

Available online 24 May 2017

KEYWORDS Summary Objective: To determine the clinical course and perinatal transmission of chronic
Hepatitis B virus; hepatitis B during pregnancy in a real life setting.
Pregnancy; Methods: A total of 221 singleton pregnant women with detectable HBV-DNA levels (!103
Telbivudine; copies/mL) were enrolled during January 2011 to June 2015. Forty-three high viraemic patients
Perinatal transmission; (!106 copies/mL) received telbivudine in the 2nd or 3rd trimester according to their intention,
Occult infection while 89 high viraemic and 79 low viraemic (!103 and <106 copies/mL) patients were the control
cohorts. Primary endpoint was the pregnancy outcomes and secondary endpoint the perinatal
transmission including intrauterine infection, immunoprophylaxis failure and occult infection.
Results: In all, 209 patients completed pregnancy with 209 infants, while 2 in telbivudine-
treated cohort had unexplained late stillbirths. Twenty-nine (70.7%) of telbivudine-treated pa-
tients and 3 (3.4%) of untreated high viraemic controls achieved undetectable HBV-DNA levels
prior delivery. At 7 months postpartum, immunoprophylaxis failure was significantly lower
(2.4%) in telbivudine-treated cohort, compared with 16.9% and 10.1% in untreated high and
low viraemic cohorts, respectively.

* Corresponding author. Center for Liver Diseases, Nantong Third People’s Hospital, Department of Epidemiology and Biostatistics, School
of Public Health, Nantong University, 9 Se-Yuan Road, Nantong, Jiangsu 226019, China. Fax: þ86 513 8551 2674.
E-mail addresses: ntchenzhixian@hotmail.com (Z.-X. Chen), jj6668@126.com (G.-F. Gu), bianzhaolian1998@ntu.edu.cn (Z.-L. Bian),
ntcty@sina.com (W.-H. Cai), sunny@ntu.edu.cn (Y. Shen), 863157552@qq.com (Y.-L. Hao), 1372170612@qq.com (S. Zhang),
shaojianguo4144@ntu.edu.cn (J.-G. Shao), tonygqin@ntu.edu.cn (G. Qin).
e
These authors contributed equally to this work.

http://dx.doi.org/10.1016/j.jinf.2017.05.012
0163-4453/ª 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
CHB pregnant patient cohorts
Conclusions: Low viraemic patients may also need antiviral therapy since they bear moderate
risk for perinatal transmission of HBV. However, more multicenter, large-scale studies are
required before antepartum antiviral therapy is routinely recommended in patients with detect-
able viral loads.
ª 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Worldwide 240 million people are chronic hepatitis B virus
(HBV) carriers, with perinatal transmission, or vertical
transmission or mother-to-child transmission, remaining
the primary pathway of infection. The activeepassive
immunoprophylaxis strategy has reduced perinatal trans-
mission rates to 10e15%. Maternal hepatitis B e antigen
(HBeAg) positivity and high HBV-DNA levels are associated
with increased transmission despite universal immunopro-
phylaxis program.1 Antepartum antiviral therapy for
chronic hepatitis B (CHB) patients with high viral loads in
late pregnancy has been proposed and supported by several
studies conducted in the last decade,2,3 although safety
and cost-effectiveness modeling data is limited.4,5
Among five oral anti-HBV nucleos(t)ide analogs (NAs),
telbivudine (LdT) and tenofovir disoproxil fumarate (TDF)
are classified as category B for pregnancy according to the
United States Food and Drug Administration (FDA). Telbi-
vudine therapy in high viraemic mothers during late
pregnancy has been demonstrated to decrease perinatal
transmission of HBV.2 However, there is limited data con-
cerning telbivudine therapy initiated from the second
trimester and transmission rate for CHB pregnant patients
with low viral load.
We conducted this hospital-based prospective cohort
study to explore the maternal and infant outcomes of HBV-
infected pregnant women with detectable HBV-DNA (!103
copies/mL), as well as the efficacy and safety of telbivu-
dine therapy in reducing perinatal transmission or immuno-
prophylaxis failure.
Materials and methods
Population
HBV-infected pregnant women were prospectively enrolled
from Nantong Third People’s Hospital, Nantong University
(either at the center for liver diseases or the obstetric
outpatient practice) from January 2011 to June 2015.
According to standard prenatal care at our hospital, all
pregnant women are screened in the first trimester for
hepatitis B surface antigen (HBsAg), hepatitis B e antigen
(HBeAg), tests for hepatitis C virus (HCV), human immuno-
deficiency virus (HIV) and ToRCH (toxoplasmosis; other,
syphilis, varicella-zoster, parvovirus B19; rubella; cytomeg-
alovirus, CMV; and herpes simplex virus, HSV) infection.6
Those with positive HBsAg were further screened for HBV-
DNA levels. HBV markers (HBV-M) were detected using the
enzyme-linked immunosorbent assay kit (Abbott Labs,
North Chicago, USA). HBV-DNA was detected by the real-
time quantitative PCR amplification kit (lower detection
limit of 103 copies/mL, Kehua Biological Company,
Shanghai, China) according to the manufacturer’s
instructions.
147
All recruited participants in this study fulfilled the
following criteria: (i) 18e45 of age; (ii) HBV-DNA !103
copies/mL at study entry; (iii) no antiviral treatment
(AVT, NAs or interferon-alpha, IFN-a) in the previous year;
(iv) no evidence of decompensated liver cirrhosis; (v) no ev-
idence of other infection (mentioned above); (vi) exclusion
of other liver diseases such as nonalcoholic fatty liver dis-
eases (NAFLDs), alcoholic liver diseases (ALDs) or autoim-
mune liver diseases (AILDs); (vii) absence of preexisting
chronic diseases such as hypertension, diabetes mellitus
or chronic renal diseases; (viii) no miscarriage or threat-
ened miscarriage in early pregnancy; (ix) agree to
participate.
Methods
Baseline maternal demographics (e.g. age and medical
history) were collected from questionnaires completed by
participants at their prenatal visit during the first trimester.
Body mass index (BMI) was calculated according to the
World Health Organization (WHO) definition.7 Laboratory
tests including serum alanine transaminase (ALT), creatine
kinase (CK) and HBV-DNA levels were conducted at base-
line, in the second trimester and antepartum.
Low viraemic patients (baseline HBV-DNA !103 and
<106 copies/mL) were classified as group A. Telbivudine
(Novartis, Swiss) 600 mg/day oral therapy was recommen-
ded at 13e32 weeks gestation, as suggested elsewhere,8
for high viraemic patients (HBV-DNA !106 copies/mL). Pa-
tients who declined or accepted telbivudine therapy were
classified as group B or group C, respectively. This study
was conducted during Jan 2011 to Jun 2016. All partici-
pants were followed-up until the end of pregnancy and
their children for at least six months. The compliance,
tolerability, biochemical and virologic data, obstetric com-
plications and outcomes were reviewed. Primary preg-
nancy outcomes were: full-term birth, preterm birth
(PTB, <37 gestational weeks), or stillbirth (after 20
completed gestational weeks). Obstetric complications
included intrahepatic cholestasis of pregnancy (ICP),
pregnancy-induced hypertension syndrome (PIH) and
gestational diabetes (GDM). The efficacy measures for tel-
bivudine included ALT normalization and undetectable
HBV-DNA prior to delivery.
Neonatal outcomes including birth weight, low birth
weight (LBW, <2500 g), Apgar score and birth defect were
collected. All infants received 200 IU of hepatitis B immune
globulin (HBIG) and 10 mg of HBV vaccine intramuscularly
within 6 h after birth, then two additional vaccinations at 1
and 6 months of age. Mothers in group A and B were
encouraged to breastfeed. In contrast, mothers in group C
were advised not to breastfeed infants when they were
receiving telbivudine treatment. These patients made their
own decision to stop or continue telbivudine after delivery
148
based on suggestion provided by physicians and desire to
breastfeed. Serum HBV-DNA and HBV-M from the infants’
venous blood were measured at birth (prior to immunopro-
phylaxis) and again at month 7, as suggested elsewhere.2
Intrauterine infection, not preventable by immunopro-
phylaxis,8 was defined as positive HBsAg in peripheral blood
of the infants at birth and consistently positive at 7 months
of age.9 Intrapartum contamination of HBV, was defined as
transient presence of HBV-DNA/HBsAg after delivery, i.e.
positive HBsAg and/or HBV-DNA in the peripheral blood of
newborn infants at birth and negative conversion until 7
months of age.10 Immunoprophylaxis failure (with intra-
uterine infection as the main cause) was defined as positive
HBsAg in the peripheral blood of infants at 7 months of
Figure 1 Flowchart of patients enrollment. HBV, hepatitis B virus; LdT, telbivudine; PTB, preterm birth; HBIG, hepatitis B
immune globulin.
Z.-X. Chen et al.
age.11 Overt HBV infection was defined as positive HBsAg
in the peripheral blood of infants at 7 months of age; occult
HBV infection was defined as negative HBsAg but positive
HBV-DNA in the peripheral blood of infants at 7 months of
age.12
The study protocol conformed to the Declaration of
Helsinki and was duly approved by the institutional review
board of Nantong Third People’s Hospital, Nantong Univer-
sity. Potential benefits and risks of telbivudine therapy
were explained to the participants. The cost for follow-up
tests of HBV-M and HBV-DNA was waived for these patients.
Written informed consents for inclusion in this study were
obtained from all participants.
CHB pregnant patient cohorts 149

Statistical methods declined telbivudine therapy (group B) served as controls.

Continuous variables were summarized as median (range)
or mean (#standard deviation) and student’s t test was
used for in-between group comparisons. Categorical vari-
ables were summarized as number/percentage and chi-
squared or fisher’s test were used for in-between group
comparisons. A P-value of <0.05 was considered as the
level of significance. All analyses were conducted with
Stata software version 13.0 (StataCorp, USA).
Results
Maternal characteristics and outcomes
In total, 377 pregnant women with positive HBsAg were
screened from January 2011 to June 2015. After 166
patients were excluded according to the exclusion criteria,
211 participants were enrolled (Fig. 1). The demographic
and clinical data are summarized in Table 1. Overall, the
median age was 27 years (range 18e42) and 60% (126/
172) of patients were HBeAg-positive. Seventy-nine low vir-
aemic patients (group A) and 89 high viraemic patients who
Forty-three high viraemic patients who received telbivu-
dine starting from the second or third trimester were the
treatment group (group C). Telbivudine was initiated at
the median gestational age (GA) of 24 (13e32) weeks.
The median duration of telbivudine use before delivery
was 17 (8e27) weeks. Patients in group A had lower rates
in HBeAg positivity and ALT abnormality. The baseline char-
acteristics including ALT, HBV-DNA levels of group B and
group C were similar.
Telbivudine therapy was well tolerated by the patients.
A few patients in group C experienced insomnia (4/43,
9.3%), nausea (3/43, 7%), and mild CK elevation ($2 ULN,
2/43, 4.7%), not significantly different from the untreated
groups. No one withdrew from the therapy. Moreover, a
significant decline in HBV-DNA level (decrease !3 log10
copies/mL from baseline) was achieved prior delivery in
37 patients in group C, compared with group A or B
(90.2% vs. 2.5% and 3.4%, P <0.001). The proportion of pa-
tients with undetectable HBV-DNA before delivery was
much higher in group C than those in group A or B (70.7%
vs. 3.8% and 5.6%, P <0.001). There were no significant dif-
ferences among the three groups with respect of ALT
normalization rates prior delivery (Table 1).

Table 1 Maternal characteristics and outcomes.

Group A Group B Group C P
(n Z 79) (n Z 89) (n Z 43) Group B vs C
Age (yr) 27.2 # 5.5 26.2 # 4.5 28.1 # 6.7 >0.05
Parity 27 (34.2%) 22 (23.4%) 11 (26.8%) >0.05
Previous PTB 2 (2.5%) 2 (2.1%) 1 (2.4%) >0.05
Previous abortion 15 (19.0%) 19 (20.2%) 13 (31.7%) >0.05
HBeAgþ 22 (27.8%) 74 (78.7%) 30 (73.2%) >0.05
Compensated cirrhosis 0 1 (1.1%) 2 (4.7%) >0.05
Gestation age at LdT initiation
2nd trimester e e 23 (56.1%)
3rd trimester e e 18 (43.9%)
ICP 2 (2.5%) 3 (3.4%) 1 (2.3%) >0.05
GDM 0 0 0 >0.05
PIH 2 (2.5%) 1 (1.1%) 0 >0.05
Baseline
HBV-DNA (log10 copies/mL) 4.2 # 0.8 7.2 # 0.6 7.2 # 0.7 >0.05
ALT (U/L) 47.8 # 57.9 85.0 # 86.3 89.3 # 104.2 >0.05
>40U/L 12 (15.2%) 21 (22.3%) 11 (26.8%) >0.05
CK (U/L) 22.5 # 13.2 22.9 # 10.8 19.9 # 15.2 >0.05
Before delivery
n 77 89 41
HBV-DNA decline ! 3 log10 2 (2.5%) 3 (3.4%) 37 (90.2%) <0.001
copies/mL from baseline
Undetectable HBV-DNA 3 (3.8%) 5 (5.6%) 29 (70.7%) <0.001
ALT (U/L) 19.3 # 7.5 35.5 # 34.7 30.8 # 27.3 >0.05
>40U/L 4 (5.1%) 15 (16.9%) 5 (12.2%) >0.05
CK (U/L) 20.7 # 14.4 23.6 # 12.7 26.4 # 20.1 >0.05
GA 39.29 # 1.23 39.21 # 1.11 39.24 # 1.21 >0.05
Cesarean section 53 (67.1%) 52 (58.4%) 28 (68.3%) >0.05
Breast feeding 55 (69.6%) 63 (70.8%) 3 (7.3%) <0.001
Abbreviations: BMI, body mass index; PTB, preterm birth; ICP, intrahepatic cholestasis of pregnancy; GDM, gestational diabetes; PIH,
pregnancy-induced hypertension syndrome; CK, creatine kinase; GA, gestational age.
Values are reported as mean # SD, compared with t test; or number (percentage), compared with c2 or fisher’s test.
150 Z.-X. Chen et al.

There were no severe obstetric complications during
pregnancy. Five women had ICP and two women had PIH,
without significant adverse consequence. The median GA at
delivery was 39 (36e41) weeks and 133 (64%) women had
caesarian section whereas others delivered vaginally. In
seven patients, telbivudine was discontinued within 1e3
months after delivery, whereas other women continued
telbivudine or switched to other antiviral therapy until the
end of the study period. Majority (around 70%) of mothers
in group A and B chose breastfeeding while only three
mothers in group C breast feed their infants after discon-
tinuing telbivudine therapy for one month (Table 1).
Fetal and neonatal characteristics and outcomes
The characteristics and outcomes of 211 pregnancies are
summarized in Table 2. There was one preterm delivery (at
week 34) in group A and the infant had low birth weight
(2200 g). All infants had good Apgar scores (!8 at 5 min)
except one with a score of 7 in group B. No congenital ab-
normalities were identified on neonatal examination.
In group C, only one infant was positive for HBsAg and
HBV-DNA from birth to 7 months of age. In group B, 15
infants were positive for HBsAg at birth, among whom one
had HBsAg negative conversion at 7 months of age (intra-
partum contamination). In addition, one infant in group B
was negative for HBsAg and HBV-DNA at birth but had
positive conversion at 7 months. Thus the intrauterine HBV
infection rates were 15.73% (14/89) and 2.24% (1/41) in
group B and group C, respectively (P Z0.04), while the im-
munoprophylaxis failure rates were 16.85% (15/89) and
2.24% (1/41) in these two groups, respectively (P Z0.02).
The intrauterine infection rate (8/79, 10.13%) and immuno-
prophylaxis failure rate (8/79, 10.13%) in group A were
lower than those in group B, but the differences were not
significant. In our study, only three cases of occult HBV
infection had been identified, 1 in group A and 2 in group
B (Table 2). The demographic and clinical data of the 27 in-
fants considered HBV infection and their paired mothers
were summarized in Table 3.
In the telbivudine-treated group, two women aged 25-
and 27-year, respectively had unexplained late stillbirth
(without observed congenital defects). Neither patient had
abnormal pregnancy history or complications during the
current pregnancy. Their ALT levels were high at the
baseline. Telbivudine was administered during the third
trimester and their ALT levels normalized soon. However,
fetal deaths occurred at around 36 weeks of gestation
without any clinical sign. Specific causes, such obese,
infection, obstetric or hepatic complications, could not
be identified in these two patients (Table 4).
Discussion
To date, antiviral treatment in pregnant women with high
HBV-DNA levels to prevent perinatal transmission has been
recommended by several societies and experts,13e15 while
World Health Organization (WHO) guidelines postponed
such recommendation with caution.16 In China, antiviral
therapy has been well-accepted for treatment of pregnant
patients with active CHB. However, there has been no

Table 2 Fetal and neonatal characteristics and outcomes.

Group A Group B Group C P
(n Z 79) (n Z 89) (n Z 43) Group B vs C
Live births 79 89 41
Preterm birth 2 (2.5%) 5 (5.6%) 2 (4.9) >0.05
Defect or malformation 0 0 0 >0.05
Birth weight (g) 3320 # 351 3324 # 359 3358 # 372 >0.05
LBW 2 (2.5%) 0 0 >0.05
Apgar !8 at 5min 79 (100%) 88 (98.87%) 41 (100%) >0.05
At birth
HBsAgþ HBVDNAþ 4 (5.1%) 12 (16.85%) 1 (2.44%)
HBsAgþ HBVDNA% 4 (5.1%) 3 (%) 0
HBsAg% HBVDNAþ 2 (2.5%) 0 0
After 7 m
HBsAgþ HBVDNAþ 8 (10.1%) 15 (16.85%) 1 (2.44%)
HBsAgþ HBVDNA% 0 0 0
HBsAg% HBVDNAþ 1 (1.3%) 2 (2.25%) 0
HBsAbþ 56 (70.9%) 66 (74.16%) 36 (87.80%) >0.05
Overt infection
Intrauterine infection 8 (10%) 14 (15.73%) 1 (2.24%) 0.04
Intrapartum contamination 0 1 (1.12%) 0 >0.05
Immunoprophylaxis failure 8 (10%) 15 (16.85%) 1 (2.24%) 0.02
Occult infection 1 (1.3%) 2 (2.25%) 0 >0.05
Total chronic HBV infection 9 (12.5%) 17 (19.10%) 1 (2.24%) 0.01
Stillbirth 0 0 2 (4.65%) 0.10
Abbreviations: LBW, low birth weight; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.
Values are reported as mean # SD, compared with t test, or number (percentage), compared with c2 test, unless otherwise indicated.
 CHB pregnant patient cohorts
Table 3 Clinical features of 27 infants with HBV infection and their paired mothers.
Case Mother Infant Infection type
Age (yr) GA HBeAg ALT HBV-DNA Delivery Feeding Sex Birth HBV-M HBV-DNA HBV-M HBV-DNA
(wk) Prior to delivery mode mode weight At birth At 7 months
(g)
A5 24 39 þ 17 5.37 & 105 VD Bottle F 3250 þ % % % þ 5.97 & 104 þ % % % þ 1.74 & 105 Intrauterine infection
A34 24 39 % 13 9.63 & 103 VD Breast F 3500 þ % % þ þ <103 þ % % þ þ 4.l9 & 103 Intrauterine infection
A36 33 39 % 24 6.62 & 104 CS Breast M 3450 % % % þ þ 1.41 & 103 % % % þ þ 6.29 & 103 Occult infection
A38 26 38 % 13 1.29 & 103 VD Breast M 3250 þ % % þ þ <103 þ % % þ þ 5.54 & 104 Intrauterine infection
A40 25 40 % 29 2.20 & 104 VD Breast F 3800 þ % % þ þ 3.22 & 103 þ % % þ þ 2.08 & 103 Intrauterine infection
A45 25 39 þ 27 2.23 & 104 VD Breast M 3550 þ % % þ þ 2.28 & 103 þ % % þ þ 3.96 & 105 Intrauterine infection
A58 27 38 % 18 4.62 & 103 CS Bottle F 3500 þ % % þ þ <103 þ % % þ þ 2.22 & 104 Intrauterine infection
A62 23 37 % 19 1.88 & 105 CS Breast F 3650 þ % % þ þ <103 þ % % þ þ <103 Intrauterine infection
A68 29 39 þ 20 3.67 & 104 VD Breast M 3700 þ % % þ þ 5.09 & 103 þ % % þ þ 6.82 & 104 Intrauterine infection
B1 37 41 þ 15 4.99 & 106 VD Breast M 3100 þ % þ % þ 2.01 & 103 þ % þ % þ 5.89 & 105 Intrauterine infection
B3 24 39 þ 13 1.20 & 107 CS Breast M 3300 þ % þ % þ <103 þ % þ % þ 1.44 & 104 Intrauterine infection
B19 32 38 þ 35 4.47 & 107 CS Breast M 3400 þ % % % þ 1.08 & 103 þ % % þ þ 7.41 & 104 Intrauterine infection
B25 20 38 þ 23 1.15 & 106 CS Bottle M 2850 % % þ % þ <103 þ % % % þ 2.42 & 103 Immunoprophylaxis
failure
B28 25 39 þ 24 9.57 & 107 VD Breast M 3200 þ%þ%þ 5.92 & 104 %%%%þ <103 Intrapartum
contamination
B30 25 39 þ 11 3.16 & 107 VD Bottle M 3200 þ % þ % þ 1.51 & 103 þ%þ%þ 2.04 & 107 Intrauterine infection
B31 30 38 % 50 2.69 & 106 CS Breast M 3300 % % þ % þ 1.49 & 103 -%þ%þ 6.02 & 103 Occult infection
B36 21 39 þ 20 7.42 & 107 CS Breast F 3700 þ % þ % þ 1.48 & 103 þ%þ%þ 6.50 & 105 Intrauterine infection
B37 21 39 þ 12 2.23 & 107 VD Breast M 3600 þ % þ % þ 7.21 & 104 þ%þ%þ 4.81 & 105 Intrauterine infection
B48 24 37 þ 37 2.94 & 107 VD Breast F 2650 þ % þ % þ <103 þ%þ%þ 5.50 & 103 Intrauterine infection
B52 24 40 þ 22 1.10 & 107 VD Breast F 3400 þ % þ % þ 2.95 & 105 þ%þ%þ 3.08 & 106 Intrauterine infection
B65 28 37 þ 132 1.50 & 106 CS Breast M 3400 þ % þ % þ 3.64 & 103 þ%þ%þ 1.99 & 105 Intrauterine infection
B69 27 39 þ 27 1.04 & 106 CS Breast F 3300 % % % % þ <103 þ%þþþ 9.25 & 105 Immunoprophylaxis
failure
B73 31 38 þ 16 9.93 & 106 CS Breast F 3100 þ % þ % þ 8.33 & 104 þ % þ % þ 3.08 & 105 Intrauterine infection
B74 26 39 þ 34 1.94 & 107 CS Bottle M 3350 þ % þ % þ 5.49 & 103 þ % % þ þ 2.26 & 103 Intrauterine infection
B80 27 39 þ 27 1.09 & 107 VD Breast M 3450 % % þ % þ <103 % þ þ % þ 4.47 & 103 Occult infection
B85 26 40 þ 29 3.62 & 107 VD Bottle M 3300 þ % þ % þ 1.21 & 105 þ % þ % þ 2.60 & 107 Intrauterine infection
B86 22 38 þ 32 1.33 & 108 CS Bottle F 3400 þ % þ % þ 4.38 & 105 þ % þ % þ 9.03 & 106 Intrauterine infection
B88 34 39 þ 33 5.44 & 106 CS Breast F 3050 þ % þ % þ <103 þ % þ % þ 8.42 & 103 Intrauterine infection
C24 26 38 þ 10 <103 CS Bottle M 2950 þ % þ % þ 1.96 & 103 þ % þ % þ 3.33 & 106 Intrauterine infection
Abbreviations: GA, gestational age; ALT, U/L, HBV-DNA, copies/mL; HBV-M, HBV markers (including HBsAg, HBsAb, HBeAg, anti-HBe, and anti-HBc in order); M, male; F, female; CS,
cesarean section; VD, vaginal delivery.

151
152 Z.-X. Chen et al.

initiated the AVT during the second trimester. Our study re-
Table 4 Clinical Features of 2 patients with stillbirths.
vealed a rate of 70% with undetectable HBV-DNA after me-
C7 C11 dian treatment duration of 17 weeks, higher than that of
Age 25 27 around 30% after treatment of 8e10 weeks.2
Pre-pregnancy BMI 23.30 22.65 Of note, the potential benefits of antiviral therapy
Parity Yes No should be weighed against the risks of adverse effects to
Previous PTB No No the mother and fetus. In general, some adverse events of
Previous abortion No No potentially beneficial drugs may be serious but rare, making
Previous stillbirth No No their effects difficult to identify or quantify, even in
Liver cirrhosis No No randomized controlled trials. The safety of in-utero expo-
ICP No No sure to telbivudine is still insufficient. Almost no severe
GDM No No adverse event was reported in the references by other
PIH No No mainland Chinese authors.2,21e23 In our study, two patients
HBeAg þ þ in the telbivudine-treated group had unexplained still-
Baseline HBV-DNA (copies/mL) 3.93 & 107 4.20 & 107 births. Actually, the estimated stillbirth rate in Eastern
Baseline ALT (U/L) 406 103 Asia in 2015 is 7.2 per 1000 births.24 In contrast, congenital
GA (wk) of LdT initiation 29 1/7 27 3/7 deformities such as deafness or polydactyly in infants of
Sex of fetus F M TDF-treated mothers have been reported previously.25,26
GA (wk) of stillbirth 36 4/7 35 2/7 Recently, Pan et al. reported five cases of treatment failure
in TDF-treated group (5 of 97 women), including one case of
Abbreviations: BMI, body mass index; PTB, preterm birth; ICP,
stillbirth at 36 weeks of gestation and one case of newborn
intrahepatic cholestasis of pregnancy; GDM, gestational dia-
betes; PIH, pregnancy-induced hypertension syndrome; GA,
death.27 Although it is currently difficult to conclude
gestational age; F, female; M, male. whether these adverse events were drug related or not,
these findings may raise warning signals for the antiviral
therapy during pregnancy.
consensus regarding whether antiviral therapy is appro- Concerning the effect of delivery mode on perinatal
priate as prophylaxis of perinatal transmission of HBV, transmission, there was a higher rate of caesarean section
especially for patients with immune-tolerant infection or in the telbivudine-treated patients. Whether elective
inactive carriers. Although quite a few studies on the anti- caesarean section could reduce the vertical transmission
viral therapy during pregnancy were conducted in mainland rate when compared with urgent caesarean section or
China, Chinese Society of Hepatology (CSH) has not recom- vaginal delivery remains unknown.28,29 No significant differ-
mended antiviral prophylaxis until late 2015.17 In contrast, ence in perinatal transmission between caesarean section
the guidelines from the Chinese Society of Obstetrics and and vaginal delivery was found in our study. Admittedly,
Gynecology recommends against antiviral therapy as pro- the high caesarian section rates in China (around 50%) are
phylaxis of perinatal transmission of HBV.18 Our study pro- mainly due to “social influence” rather than medical or ob-
vides a large cohort examining the clinical course of CHB stetric indication.30 Regarding the feeding mode for HBV-
pregnant patients with low or high viral load, as well as infected mothers, breastfeeding is considered safe and
of patients with or without telbivudine treatment in mid low risk for transmission, especially when immunoprophy-
to late pregnancy. This study design which allowed patient laxis was appropriately administered.31 American Associa-
selection of therapy simulated the decision-making process tion for the Study of Liver Diseases (AASLD) guidelines
of AVT for pregnant women in the real-world setting. even suggest that breastfeeding is not contraindicated for
There is limited data on perinatal transmission rates in HBV-infected mothers who are receiving antiviral ther-
CHB patients with low HBV-DNA levels. One previous study apy.14 However, long-term safety data in infants who
reported that perinatal transmission only occurred when were breastfed by mothers under antiviral treatment are
the mothers’ HBV-DNA levels were as high as >150 pg/mL limited. Therefore, in our study it is not encouraged for
(equivalent to around 4 & 107 copies/mL).19 Children born mothers to breastfeed their babies while receiving antiviral
to HBeAg-negative mothers seemed to be at quite low risk treatment.
(<1%) for chronic HBV infection after the immunoprophy- Admittedly, there are several limitations in this single-
laxis program.1,20 In this study, we recruited 79 CHB pa- center study. First, the antiviral treatment was not
tients with low viral load (!103 and <106 copies/mL). randomly assigned. Maternal general and virologic charac-
Eight infants (10%), born to three HBeAg-positive and five teristics were comparable between telbivudine untreated
HBeAg-negative mothers, had confirmed immunoprophy- (group B) and telbivudine treated patients (group C),
laxis failure. Our results suggest that mothers with low minimizing the selection bias in this study. Second, the
HBV-DNA levels may still be at moderate risk to transmit small sample size of our treatment group limited the ability
HBV to their children, no matter their HBeAg status. to detect statistically significant differences. The target
There is no consensus with respect of the optimal disease (HBV infection) was not immediately life-
starting point for antiviral therapy to achieve viral load threatening as HIV infection, thus much pregnant women
below a level associated with immunoprophylaxis failure declined the treatment option. Moreover, a recent study
prior delivery. For patients with high viral load, our results revealed that 42% of infants born to CHB mothers devel-
are consistent with other studies on the efficacy of oped occult HBV infection which was not prevented by
telbivudine in reducing perinatal transmission.2,8,21 It routine activeepassive immunoprophylaxis.12 The PCR
should be noted that half of the patients in group C method used here for HBV-DNA detection was another
CHB pregnant patient cohorts
limitation of this study. The cut-off value by this PCR assay
could not accurately determine the occult infection.
Hence, long-term follow-up of these infants is planned in
our study. Last, this study did not include treatment-
experienced patients. Hence, our results may not be appli-
cable to general CHB patients.
In conclusion, the results of our study suggest that
telbivudine use in the second or third trimester of preg-
nancy for high viraemic mothers is effective in reducing
perinatal transmission. The patients with low viral load
might also be appropriate target population for antiviral
therapy. Meanwhile, the real influence of telbivudine on
fetus remains to be explored. Therefore, more multicenter,
large-scale studies are required before antiviral therapy is
routinely recommended in women with detectable viral
loads to prevent perinatal transmission of HBV.
Funding
This study was supported in part by grant number
BE2015655 from the Jiangsu provincial Department of
Science and Technology, China, by Qing Lan Project from
Jiangsu provincial Department of Education, China, by
“226” Talents Project from Nantong Municipal Government,
Jiangsu Province, China, and by grant number HS2016002
from the Nantong municipal Bureau of Science and Technol-
ogy, Jiangsu Province, China. The funding agreement
ensured the authors’ independence in designing the study,
interpreting the data, writing, and publishing the report.
Author contributions
Z.-X. C, G.-F. G. and G. Q. conceived and designed the
experiments. G.-F. G., Z.-L. B., W.-H. C., J.-G. S. and G. Q.
counseled the women at clinical departments. Z.-X. C. Y.-L.
H, Y. S., S. Z., and G. Q. were responsible for data
collection, statistical analysis. Z.-X. C. and G. Q. prepared
the manuscript. All authors read and approved the final
manuscript.
Potential conflicts of interest
All authors report no potential conflicts.
Acknowledgments
We thank all participants in this study and the staff from
the Center for Liver Diseases and Department of Obstetrics
and Gynaecology, Nantong Third People’s Hospital, Nantong
University for their work on patients enrollment and follow-
up.
References
1. Chen HL, Lin LH, Hu FC, Lee JT, Lin WT, Yang YJ, et al. Effects
of maternal screening and universal immunization to prevent
mother-to-infant transmission of HBV. Gastroenterology
2012;142(4):773e81.
2. Han GR, Cao MK, Zhao W, Jiang HX, Wang CM, Bai SF, et al. A pro-
spective and open-label study for the efficacy and safety of
153
telbivudine in pregnancy for the prevention of perinatal transmis-
sion of hepatitis B virus infection. J Hepatol 2011;55(6):1215e21.
3. Zhang LJ, Wang L. Blocking intrauterine infection by telbivu-
dine in pregnant chronic hepatitis B patients. Zhonghua gan
zang bing za zhi 2009;17(8):561e3.
4. Wang L, Kourtis AP, Ellington S, Legardy-Williams J, Bulterys M.
Safety of tenofovir during pregnancy for the mother and fetus:
a systematic review. Clin Infect Dis 2013;57(12):1773e81.
5. Fan L, Owusu-Edusei Jr K, Schillie SF, Murphy TV. Cost-effec-
tiveness of active-passive prophylaxis and antiviral prophylaxis
during pregnancy to prevent perinatal hepatitis B virus infec-
tion. Hepatology 2016;63(5):1471e80.
6. Cui AM, Cheng XY, Shao JG, Li HB, Wang XL, Shen Y, et al.
Maternal hepatitis B virus carrier status and pregnancy out-
comes: a prospective cohort study. BMC Pregnancy Childbirth
2016;16(1):87.
7. Shen Y, Zhang J, Cai H, Shao JG, Zhang YY, Liu YM, et al. Iden-
tifying patients with chronic hepatitis B at high risk of type 2
diabetes mellitus: a cross-sectional study with pair-matched
controls. BMC Gastroenterol 2015;15:32.
8. Pan CQ, Han GR, Jiang HX, Zhao W, Cao MK, Wang CM, et al.
Telbivudine prevents vertical transmission from HBeAg-positive
women with chronic hepatitis B. Clin Gastroenterol Hepatol
2012;10(5):520e6.
9. Shao ZJ, Xu DZ, Xu JQ, Li JH, Yan YP, Men K, et al. Maternal
hepatitis B virus (HBV) DNA positivity and sexual intercourse
are associated with HBV intrauterine transmission in China: a
prospective case-control study. J Gastroenterol Hepatol
2007;22(2):165e70.
10. Gentile I, Borgia G. Vertical transmission of hepatitis B virus:
challenges and solutions. Int J Womens Health 2014;6:605e11.
11. Zou H, Chen Y, Duan Z, Zhang H, Pan C. Virologic factors asso-
ciated with failure to passive-active immunoprophylaxis in in-
fants born to HBsAg-positive mothers. J Viral Hepat 2012;
19(2):e18e25.
12. Pande C, Sarin SK, Patra S, Kumar A, Mishra S, Srivastava S,
et al. Hepatitis B vaccination with or without hepatitis B immu-
noglobulin at birth to babies born of HBsAg-positive mothers
prevents overt HBV transmission but may not prevent occult
HBV infection in babies: a randomized controlled trial. J Viral
Hepat 2013;20(11):801e10.
13. European Association For The Study Of The Liver. EASL clinical
practice guidelines: management of chronic hepatitis B virus
infection. J Hepatol 2012;57(1):167e85.
14. Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM,
Murad MH, et al. AASLD guidelines for treatment of chronic
hepatitis B. Hepatology 2016;63(1):261e83.
15. Society for Maternal-Fetal Medicine, Dionne-Odom J, Tita AT,
Silverman NS. #38: hepatitis B in pregnancy screening, treat-
ment, and prevention of vertical transmission. Am J Obstet Gy-
necol 2016;214(1):6e14.
16. Guidelines for the Prevention. Care and treatment of persons
with chronic hepatitis B infection. Geneva: WHO Guidelines
Approved by the Guidelines Review Committee; 2015.
17. Hou JL, Wei L. The guideline of prevention and treatment for
chronic hepatitis B: a 2015 update. Zhonghua gan zang bing
za zhi 2015;23(12):888e905.
18. Yang HX, Hu YL. The clinical guideline of prevention for
mother-to-child transmission of hepatitis B virus. Zhong Hua
Fu Chan Ke Za Zhi 2013;48(2):151e4.
19. del Canho R, Grosheide PM, Mazel JA, Heijtink RA, Hop WC,
Gerards LJ, et al. Ten-year neonatal hepatitis B vaccination
program, The Netherlands, 1982e1992: protective efficacy
and long-term immunogenicity. Vaccine 1997;15(15):1624e30.
20. Sun KX, Li J, Zhu FC, Liu JX, Li RC, Zhai XJ, et al. A predictive
value of quantitative HBsAg for serum HBV DNA level among
HBeAg-positive pregnant women. Vaccine 2012;30(36):
5335e40.
154
21. Zhang H, Pan CQ, Pang Q, Tian R, Yan M, Liu X. Telbivudine or
lamivudine use in late pregnancy safely reduces perinatal
transmission of hepatitis B virus in real-life practice. Hepatol-
ogy 2014;60(2):468e76.
22. Yu MM, Jiang Q, Ji Y, Wu KH, Ju LL, Tang X, et al. Comparison of
telbivudine versus lamivudine in interrupting perinatal trans-
mission of hepatitis B virus. J Clin Virol 2014;61(1):55e60.
23. Wu Q, Huang H, Sun X, Pan M, He Y, Tan S, et al. Telbivudine
prevents vertical transmission of hepatitis B virus from women
with high viral loads: a prospective long-term study. Clin Gas-
troenterol Hepatol 2015;13(6):1170e6.
24. Blencowe H, Cousens S, Jassir FB, Say L, Chou D, Mathers C,
et al. National, regional, and worldwide estimates of stillbirth
rates in 2015, with trends from 2000: a systematic analysis.
Lancet Glob Health 2016;4(2):e98e108.
25. Greenup AJ, Tan PK, Nguyen V, Glass A, Davison S,
Chatterjee U, et al. Efficacy and safety of tenofovir disoproxil
fumarate in pregnancy to prevent perinatal transmission of
hepatitis B virus. J Hepatol 2014;61(3):502e7.
Z.-X. Chen et al.
26. Chen HL, Lee CN, Chang CH, Ni YH, Shyu MK, Chen SM, et al.
Efficacy of maternal tenofovir disoproxil fumarate in interrupt-
ing mother-to-infant transmission of hepatitis B virus. Hepatol-
ogy 2015;62(2):375e86.
27. Pan CQ, Duan Z, Dai E, Zhang S, Han G, Wang Y, et al. Tenofovir
to prevent hepatitis B transmission in mothers with high viral
load. New Engl J Med 2016;374(24):2324e34.
28. Hu Y, Chen J, Wen J, Xu C, Zhang S, Xu B, et al. Effect of elective
cesarean section on the risk of mother-to-child transmission of
hepatitis B virus. BMC Pregnancy Childbirth 2013;13:119.
29. Pan CQ, Zou HB, Chen Y, Zhang X, Zhang H, Li J, et al. Cesarean
section reduces perinatal transmission of hepatitis B virus
infection from hepatitis B surface antigen-positive women to
their infants. Clin Gastroenterol Hepatol 2013;11(10):
1349e55.
30. Hellerstein S, Feldman S, Duan T. China’s 50% caesarean deliv-
ery rate: is it too high? BJOG 2015;122(2):160e4.
31. Buchanan C, Tran TT. Management of chronic hepatitis B in
pregnancy. Clin Liver Dis 2010;14(3):495e504.