Li, Yue-Bo Yang, Hong-Ying Hou, Zhong-Jie Shi, Hui-Min Shen, Ben-Qi
Teng, Ai-Min Li, Ling Zou, Department of Obstetrics and Gynecology,
The Third Affiliated Hospital, Sun Yat -Sen University, Guangzhou
510630, Guangdong Province, China
Min-Feng Shi, Maternity Hospital, School of Medicine, Zhejiang
University, Hangzhou 310006, Zhejiang Province, China
Supported by the Science and Research Foundations of Sun Yat -Sen
University and Guangzhou Science Committee, No.1999-J-005-01
Correspondence to: Xiao-Mao Li, Department of Obstetrics and
Gynecology, The Third Affiliated Hospital, Sun Yat -Sen University,
Guangzhou 510630, Guangdong Province, China.
AIM: To investigate the effect of hepatitis B virus (HBV)
specific immunoglobin (HBIG) and lamivudine on HBV intrauterine
transmission in HBsAg positive pregnant women.
Each subject in the HBIG group (56 cases) was given 200 IU HBIG
intramuscularly (im.) every 4 weeks from 28-week (wk) of gestation,
while each subject in the lamivudine group (43 cases) received 100
mg lamivudine orally (po.) every day from 28-wk of gestation until
the 30th day after labor. Subjects in the control group
(52 cases) received no specific treatment. Blood specimens were
tested for HBsAg, HBeAg, and HBV-DNA in all maternities at 28-wk of
gestation, before delivery, and in their newborns 24 hours before
the administration of immune prophylaxis.
Reductions of HBV DNA in both treatments were significant (P<0.05).
The rate of neonatal intrauterine HBV infection was significantly
lower in HBIG group (16.1 %) and lamivudine group (16.3 %) compared
with control group (32.7 %) (P<0.05), but there was no
significant difference between HBIG group and lamivudine group (P>0.05).
No side effects were found in all the pregnant women or their
The risk of HBV intrauterine infection can be effectively reduced by
administration of HBIG or Lamivudine in the 3rd trimester
of HBsAg positive pregnant women.
XM, Yang YB, Hou HY, Shi ZJ, Shen HM, Teng BQ, Li AM, Shi MF, Zou L.
Interruption of HBV intrauterine transmission: A clinical study.
World J Gastroenterol 2003;
It is of vital importance to interrupt the transmission of viral
hepatitis B from mother to fetus in control of its prevalence[1-3],
including HBV intrauterine infection[4-7]. This study
investigated the effect of administration of HBIG (im.) and
lamivudine (po.) on the interruption of HBV intrauterine infection
from the 3rd trimester of gestation.
One hundred and fifty one pairs of women and their newborns
who followed the antepartum care were selected and admitted for
labor in our hospital from January of 1999 to December of 2001.
These pregnant women were HBsAg positive, with normal liver and
kidney function. Serial tests were negative for HAV, HCV, HDV and
HEV in these women and no other severe complications were found and
no other drugs, including the ones that were studied, anti-virus,
cytotoxic, steroid hormones, or immune regulating drugs were
administrated. The patients were randomly allocated into 3 groups.
There were 56 patients in the HBIG group (22 were both HBsAg and
HBeAg positive) and 43 in the lamivudine group (33 were both HBsAg
and HBeAg positive). There were 52 patients in the control group (17
were both HBsAg and HBeAg positive). No significant differences were
found in age, race, time of gestation and parturition, gestational
age, way of delivery, and incidence of threatened abortion,
threatened labor or pregnancy-induced hypertension syndrome (PIH).
The 151 pregnant women delivered 151 newborns.
Patients in the HBIG group were administered HBIG 200IU
intramuscularly (im.) from 28-wk of gestation, once every 4 weeks
till labor. Patients in the lamivudine group were administered 100
mg (po.) lamivudine orally daily till the 30th day after labor.
Patients in the control group were given no specific treatment.
Blood specimens were tested for HBsAg, HBeAg, and HBV-DNA in all the
subjects at 28-wk and before delivery, and their newborns (blood
from the femoral vein) 24 hours before administration of immune
and HBeAg were assessed by ELISA, the assay kits were produced by
Zhongshan Biological and Engineering Co. Ltd. HBV-DNA was assessed
by fluorogenic quantitative polymerase chain reaction (FQ-PCR), and
the assay kits were produced by Da抋n
Gene Diagnosis Center, Sun Yat-Sen University.
administration of positive and/or active prophylaxis at 24 hours
after delivery, intrauterine HBV infection would be considered if
HBsAg and/or HBeAg were tested positive in neonatal peripheral
The t-test and x2 test were used to analyze our
data using Excel software. Statistical significance was set at P<0.05.
HBV DNA values were expressed as
and neonatal intrauterine HBV infection rates were expressed as
percentage of total cases in each group.
Changes of HBsAg, HBeAg and HBV DNA
HBsAg turned negative in 1 case of the HBIG group, but HBeAg
turned negative in no case. HBsAg and HBeAg turned negative in 1
case of the lamivudine group. No cases turned negative of HBsAg or
HBeAg in the control group.
administration of agents, there was no significant difference in the
values of HBV DNA among
3 groups (P>0.05). But there was significant difference
between the values of HBV DNA in HBIG group and lamivudine group
after administration of either reagent respectively (both values
reduced, P<0.05). The reduction of value before and after
administration of the reagents was significantly different between
the administered groups and control group (P<0.05). (Table
1 Comparison of HBV
DNA values before and after administration of the reagents
HBV DNA before
HBV DNA before
value of log10 HBV DNA before
and after administration
of agents (copies/ml)
vs other groups; bP>0.05 between HBIG group and
lamivudine group; cP<0.05 vs HBIG group or
lamivudine group; dP<0.05 (before vs after
of HBV intrauterine infection
Three newborns were HBsAg positive, and 7 cases were HBeAg
positive, one of them was doubly positive for HBsAg and HBeAg in
HBIG group. Corresponding cases in lamivudine group and control
group were 1, 7, and 1, or 8, 11, and 2 respectively. The infection
rates of HBIG, lamivudine, and control groups were 16.1 %, 16.3 %,
and 32.7 %, respectively. There were significant differences between
the incidence of HBV intrauterine infection in either reagent
administrated group and control group (P<0.05), while
there was no significant difference between HBIG group and
lamivudine group (P>0.05). (Table 2).
2 Incidence of
neonatal intrauterine infection in 3 groups
between HBIG group and lamivudine group; bP<0.05
vs HBIG group or lamivudine group.
There were no incidences of fever, rigor, rash, or other
complaints and dysfunction of the liver and kidney in subjects
throughout administration and follow-ups. There were no significant
differences in gestational age, severity of postpartum hemorrhage,
rate of cesarean section, neonatal weight, neonatal height,
circumference of neonatal head and
Apgar score (P>0.05).
There are several thoughts about the mechanisms of HBV
intrauterine transmission, including placental infection,
placental exudation and transudation[9-11], peripheral
blood monocyte (PBMC) infection, fraternal
transmission, etc. Infection through placenta is the most active
pathway in maternity-fetus transmission. It is suggested that
infection mainly occurs in the 3rd trimester. This might be resulted
from the fact that the layer of trophoblastic cells becomes thinner
and turns into chorion-vessel membrane, which makes it easier for
HBV to pass the placental barrier. The organs of
fetus during this period have already developed, therefore, it is
safe for the administration of reagents. So we chose this period to
begin the interruption of infection. Lamivudine (po.) or HBIG (im.)
was administered from 28-wk of gestation.
factors, such as threatened abortion, threatened premature labor and
TORCH (toxoplasmosis, others, rubella, cytomegalovirus, herpes)
infection, were the highly risk factors for HBV intrauterine
infection. It is generally considered that
intrauterine infection might be the general effect of maternity and
virus. In this study, there were no significant differences among
the 3 groups in the highly risk factors (threatened abortion,
threatened premature labor) or age, time of gestation and delivery,
pregnant complication, medical or surgical complication, gestational
age at labor or way of delivery.
has been clinically accepted to administer joint immune reagents (HBIG
together with HBV vaccine) to neonates with high risks, but the
immune failure rate is still about 10-20 %[15,16], the
main reason is intrauterine infection. So, it is important to study
the mechanism of HBV intrauterine infection, and we further
investigated the intrauterine prevention and interruption of HBV
HBIG is a
highly effective immune globulin, which is purified
from highly effective plasma or serum taken from healthy individuals
after the use of HBV vaccine. HBs antibody can bind HBsAg, activate
the complimentary system at the same time and strengthen humoral
immune, clear HBV, and reduce the number of virus in the maternal
blood. It can prevent and decrease the incidence of normal cell
infection and might reduce HBV copy in the body. Placenta has the
function of transmitting antibody in the form of IgG to the fetus.
It is suggested that after maternal administration of HBIG (im.),
HBsAb can be transmitted to fetus, which makes it possible for the
fetus to obtain the protection of intrauterine passive immunization
and to prevent
intrauterine infection. The results of this study
suggest that regular administration of HBIG (im.) to HBV positive
pregnant women might reduce the amount of HBV DNA in blood, and
neonatal intrauterine infection rate also reduced significantly when
compared with control group.
polymerase of HBV has many functions in the process of virus
replication. After infection
of liver cells by HBV, the incomplete double strand DNA integrates
into a complete one, enters the nuclei, forming super helix covalent
closed circular DNA (cccDNA). cccDNA is extremely stable, and is the
resource of viral DNA and directs the formation of viral protein.
The whole mRNA replicated from cccDNA model can form a single strand
minus-DNA by reverse-transcription of the HBV DNA polymerase. This
DNA can form incomplete double strand DNA through DNA polymerase.
The latter can also integrate with antigen proteins in the endoplast,
forming new, contagious mature viral particles and be released into
blood, or migrate into the nuclei to supply cccDNA there. The
multiple functions of HBV polymerase enable it to become one of the
most prosperous anti-virus targets.
Lamivudine is a potent anti-virus nucleotide analogue to HBV
and HIV. Through competitive inhibition of HBV DNA polymerase and
formation of new HBV DNA strand, it can terminate the synthesis of
new strand[19,20]. After several days of the
administration of lamivudine, the level of HBV DNA drops
dramatically, and throughout the treatment, HBV DNA will be
suppressed continuously. It can reduce the necrosis and inflammation
of the liver and bring ALT level to normal without significant side
effects or malformation-causing effects[21-31]. We found
the amount of HBV DNA in blood and the rate of neonatal intrauterine
infection after administration of lamivudine in the 3rd trimester
were significantly lower than that in control group. This suggests
that administration of lamivudine of HBV positive pregnant women in
the 3rd trimester can effectively decrease the rate of intrauterine
passive antibody, the main effect of HBIG is to neutralize HBV in
the body, prevent and decrease infection of normal cells;
while lamivudine is a potent anti-virus agent, which can suppress
the replication of HBV actively, decrease HBV level during
pregnancy. Our data showed that the neonatal infection rates, after
these two reagents were used in the 3rd trimester to interrupt
intrauterine HBV infection, were 16.1 % and 16.3 %, respectively,
with no significant difference between these 2 groups (P>0.05).
But compared with control group, the infection rates of both groups
were significantly lower. These data indicate that both of them are
safe and effective in the interruption of intrauterine HBV
found in our previous studies that HBV DNA level in maternal serum
was an important factor for intrauterine infection.
Especially when HBV DNA is ≥108 copies/ml, it has significant
correlation with neonatal HBV infection.
Administration of HBIG in combination with lamivudine in these
patients might decrease the neonatal HBV infection rate more
effectively. Further studies are required to improve our
understanding about this problem.
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