Liver International 2009; 29(s1): 133–139

Hepatitis B and pregnancy: an underestimated issue

Keywords Abstract
hepatitis B – immunoprophylaxis – neonate – Hepatitis B infection during pregnancy presents a unique set of management
perinatal – pregnancy issues. Aspects of care that must be considered include maternal and fetal effects of
hepatitis B, effects of pregnancy itself on the course of hepatitis B infection and its
Correspondence
complications, treatment of hepatitis B during pregnancy and prevention of
Maureen M. Jonas, Children’s Hospital Boston, perinatal infection. There are insufficient studies to date regarding these concerns;
Center for Childhood Liver Disease, Division of most are from the Far East, and many have important limitations, but some have
Gastroenterology, 300 Longwood Avenue, yielded valuable data. Pregnant women with acute hepatitis B virus (HBV)
Boston, MA 02115, USA infection typically have a course not very different from that in the general adult
Tel: 1617 355 5837 population, but the risk of transmission of HBV to neonates increases the later in
Fax: 1617 730 0716
gestation the acute infection occurs. Chronic HBV infection is usually mild in
pregnant women, but may flare shortly after delivery. The risk of perinatal
Received 30 June 2008 transmission is highest in women with high levels of viraemia; this may be a factor
Accepted 10 November 2008 in the small but reproducible failure rate of current immunoprophylaxis strategies.
Obstetrical policies must be assessed with respect to detection of maternal
DOI:10.1111/j.1478-3231.2008.01933.x infection and liver disease, as well as with respect to perinatal transmission risk.
In addition to the usual issues of drug efficacy and safety in the affected
individuals, effects on the developing fetus must be considered. This paper reviews
the current experience in each of these areas, and highlights the need for further
investigation into this critical but often underestimated topic.

Of the estimated 350 million individuals chronically Similar data are not available for European countries,
infected with hepatitis B virus (HBV) worldwide, it is but are expected to mirror those in the general
generally accepted that at least 50% acquired their populations of each nation, especially as determined
infections either perinatally or in early childhood, by the numbers and countries of origin of immigrants
especially in countries where HBV is endemic (1). This (3, 4). In areas of high endemicity, such as China,
is attributed to the high rates of HBeAg-positive other Far East countries and Africa, rates are propor-
infections in women of child-bearing age in these parts tionately higher. In the USA, testing for HBsAg is
of the world, and the efficient transmission of infec- recommended for every pregnant woman, regardless
tion from these women to their newborns. It has long of previous testing or vaccination (5). Women who
been recognized that prevention of perinatal transmis- have not had this testing and those with risk factors for
sion is a high priority in the attempt to decrease the HBV acquisition should be tested at presentation for
global burden of chronic HBV. Immunoprophylaxis delivery. In Europe, there is no consistent policy with
with hepatitis B immune globulin (HBIG) and hepa- respect to testing of women for HBV infection during
titis B vaccine is known to be safe and effective, but pregnancy, and many countries rely on historical ‘risk
applied variably in different geographical regions. factors’ to determine indications for screening. How-
Even with proper vaccination, 5–10% of infants of ever, a recent report from Denmark indicates that
HBeAg-positive women become infected, and so there approximately 50% of infected pregnant women
is opportunity for improvement in prevention strate- would not have been identified using this strategy (6),
gies. In addition, the interaction of HBV infection and a proportion that closely resembles that found in a
pregnancy itself is an area for further study. comparable study in an urban US hospital a number
The prevalence of chronic HBV infection in preg- of years ago (7). In addition, changing immigration
nant women in urban areas of the USA varies by race patterns in Europe indicate that HBV prevalence will
and ethnicity (2). As expected, the highest rate (6%) is vary greatly at a regional level within each country, and
in Asian women. The rates in black, white and it has been suggested that there is a need to provide a
Hispanic women are 1, 0.6 and 0.14% respectively. more general immunization programme to protect the

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Hepatitis B and pregnancy Jonas

population at large (8). The benefits of detection of sampled from 72 infants delivered from HBsAg-posi-
infected pregnant women include not only identifica- tive women who did not undergo amniocentesis. Of
tion of infants who require prophylaxis, but of women these, 18% contained HBsAg and 4% contained HBV
who might need treatment, and sexual and household DNA. The authors of both studies concluded that the
contacts who will benefit from testing, counselling, risk of HBV transmission by amniocentesis is low.
vaccination or therapy if indicated.
Effect of pregnancy on hepatitis B
Effect of hepatitis B on pregnancy In general, women with chronic hepatitis B do well
during pregnancy. However, pregnancy is associated
Susceptible women who develop acute hepatitis B
with high levels of adrenal corticosteroids, which
during pregnancy may have an illness indistinguish-
might be expected to increase levels of viraemia, and
able from that in the general population. Acute HBV
oestrogen, which has been demonstrated in laboratory
infection must be differentiated from other acute liver
animals to decrease HBV replication. In one study, no
diseases that occur during pregnancy such as intrahe-
significant differences in HBV viraemia were noted
patic cholestasis or acute fatty liver of pregnancy if
during pregnancy, although alanine aminotransferase
jaundice is present, or haemolysis, elevated liver en-
(ALT) levels tended to increase late in pregnancy and
zymes and low platelets syndrome if jaundice is absent.
in the post-partum period (13). It has been known for
It does not appear that acute HBV infection increases
some time that a proportion of women have hepatitis
mortality during pregnancy, or that it has teratogenic
flares with or without HBeAg seroconversion within
effects. However, a higher incidence of low birth
the first months after delivery (14). Seroconversion
weight and prematurity has been reported. In addi-
rates of 12.5% (15) to 17% (14) have been described. It
tion, acute HBV early in pregnancy is associated with a
has been postulated that the rapid decrease in cortisol
10% perinatal transmission rate, and the rate increases
levels characteristic of the post-partum state is analo-
substantially with HBV infection in the third trimester.
gous to the steroid withdrawal therapy that has been
The effects of chronic HBV infection on pregnancy
used to elicit seroconversion (15, 16). Although usual-
outcomes have not been clearly defined. One large
ly this is well tolerated, cases of exacerbation of
study demonstrated no differences in gestational age at
hepatitis (16) and even fulminant hepatic failure (17)
delivery, birth weight, incidence of prematurity, neo-
have been described in the peripartum period. Exacer-
natal jaundice, congenital anomalies or perinatal mor-
bation of hepatitis was not prevented by administra-
tality comparing HBsAg-positive women with controls
tion of lamivudine in the third trimester (16). Factors
(9). However, a relatively recent study described an
that do not appear to be associated with likelihood of
association of maternal HBV infection (HBsAg posi-
postpartum HBeAg clearance include maternal age,
tive) with gestational diabetes mellitus and antepar-
parity and presence of precore or basal core promoter
tum haemorrhage (10). There was a suggested
mutations (15). In one report, a low maternal HBeAg
association with preterm delivery.
level was strongly associated with postpartum HBeAg
Consideration of active HBV infection during preg-
clearance (15). It appears prudent to monitor HBV-
nancy raises the question of whether amniocentesis is
infected women closely for several months after deliv-
contraindicated in this setting. In one series of 21
ery for hepatitis flares and seroconversion.
mother–infant pairs, in which the mothers were
HBsAg positive (but only one HBeAg positive) and
underwent amniocentesis for accepted indications at a Hepatitis B virus and human
mean of 19.5 weeks gestation, none of the infants were immunodeficiency virus co-infection during
HBsAg positive at 1 or 12 months of age (11); they had pregnancy
received the HBIG and HBV vaccine as recommended. There are few reports of HBV co-infection with the
In another study, a prospective longitudinal analysis of human immunodeficiency virus (HIV) in pregnant
outcomes in 47 HBsAg-positive women who presented women. In sub-Saharan Africa, where HBV is ende-
for amniocentesis (12), all the amniotic fluid samples mic, 13% of HIV-infected pregnant women also have
and cord blood samples from the infants were analysed HBV. In the only American series, 1.5% of 455 HIV-
for HBsAg and HBV DNA. In this cohort, 32% of the infected obstetrical patients followed in Texas over 11
amniotic fluid samples were HBsAg positive, but HBV years were HBV co-infected (18). Of note, these
DNA was undetectable in all. Although cord blood women had lower CD4 counts when compared with
from 27% of the infants contained HBsAg, none women with both HIV and HCV or those with HIV
contained HBV DNA. As a control, cord blood was alone. In addition, women with HBV were compared

134
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Jonas Hepatitis B and pregnancy

with those who had serological evidence of previous the several available HBV guidelines, will apply. How-
infection and natural immunity. The women with ever, if maternal liver disease requires treatment, or if a
chronic HBV had lower median CD4 counts than pregnancy occurs in a woman already receiving a
those who had cleared previous HBV infection. The medication for HBV, decisions must be made about
authors raised the question of whether HBV co-infec- treatment course.
tion conferred additional immune suppression in this There is a long history of use of lamivudine during
group. pregnancy, both for women with HIV infection and
for those with chronic HBV. Data from the Antiretro-
Hepatocellular carcinoma and pregnancy viral Pregnancy Registry 2006 (24) indicate that the
rate of birth defects among women exposed to lami-
There are rare recorded cases of hepatocellular carci- vudine was similar to that in the general population.
noma (HCC) in pregnancy. In several reports, fetal In one cohort of 38 HBV-infected women who became
outcome was often satisfactory although some intra- pregnant while taking lamivudine and elected to
uterine deaths were recorded. Maternal mortality was continue the treatment throughout the pregnancy,
high, suggesting an adverse effect of pregnancy on the there were no pregnancy complications, no instances
outcome of this malignancy. Twenty of the 33 reported of fetal injury and no cases of perinatal HBV transmis-
women in a combined series died within a few days of sion (25). This compared favourably to historical rates
the initial presentation (19, 20) and most others of HBV transmission from the same population in
succumbed within months. It has been suggested that which active and passive immunization was used
oestrogen may accelerate the evolution of HCC as it routinely. In addition, 35 of the 38 women were no
does for other liver tumours. In addition, gestational longer viraemic with HBV, and 10 (26.3%) had HBeAg
immune suppression may be an enabling factor in seroconversion. Two women who elected to discon-
tumour progression (21). tinue lamivudine during their pregnancies developed
active hepatitis (abnormal ALT) within 6 months (25).
Vaccination against hepatitis B virus during This study was small, and the authors concede that
pregnancy more data are needed, but there is some support for
Vaccination against HBV is both safe and efficacious the safety of lamivudine in this group. There are no
during pregnancy (22, 23). In addition, passive trans- comparable studies of other antiviral agents for HBV.
fer of maternal antibody to newborns has been At this point, there are no standards regarding
demonstrated, although without the addition of active managing HBV in women who become pregnant while
vaccination, titres in the infants were noted to wane receiving antiviral therapy. One option is discontinua-
over time (22), as would be expected. tion of treatment as soon as the pregnancy is recog-
nized. This is an option only for those with mild
hepatitis, with a low risk of serious flare or disease
Treatment for hepatitis B virus during progression. Other possibilities include continued
pregnancy careful monitoring or change of therapy to lamivu-
There are two principal indications for administration dine, either temporarily or permanently, acknowled-
of antiviral agents to HBV-infected pregnant women: ging the risk of development of resistance.
treatment of chronic hepatitis in the mothers and
prevention of perinatal HBV transmission to the new-
borns. Perinatal hepatitis B virus transmission
Most women with chronic HBV infection have mild Perinatal transmission of HBV results in a high fre-
liver disease during pregnancy, although hepatitis may quency of chronic infection, up to 90% in infants born
flare after delivery, as described above. In addition, to HBeAg-positive women. It is widely accepted that
interferon, lamivudine, adefovir and entecavir are most perinatal transmission occurs at or near the time
classified by the Food and Drug Administration as of birth, because neonatal vaccination prevents new-
Class C, and telbivudine and tenofovir as Class B. In born infection in about 80–95% of cases. Theoretical
most cases, this is because there are insufficient data in risks for HBV transmission at delivery include exposure
humans to demonstrate teratogenic or embryotoxic to cervical secretions and maternal blood. Transplacen-
effects. For these reasons, in most instances, it is tal (intra-uterine) transmission is presumed to cause
reasonable to defer therapy until after delivery, to the minority of infections not prevented by prompt
avoid fetal exposure to the therapeutic agents. After immunization. Risk factors for transplacental transmis-
delivery, standard therapy indications, as expressed in sion of HBV include maternal HBeAg positivity, HBsAg

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Hepatitis B and pregnancy Jonas

titre and HBV DNA level (26). In one study, a maternal opean countries, as the World Health Organization
HBV DNA level of Z108 copies/ml was associated with has recommended, depends on many factors, such
increased likelihood of intra-uterine transmission (27). as perceived prevalence and risk, changing immigra-
HBV is found in the villous capillary endothelial cells tion patterns, cost–benefit analyses and budgetary
(26) and the trophoblasts (28) of the placenta, support- priorities.
ing the hypothesis that breach of the placental barrier is Immunoprophylaxis provided to newborns clearly
a mechanism for intra-uterine infection. Threatened reduces the incidence of perinatal HBV transmission.
preterm labour or spontaneous abortion, with the In a recent meta-analysis of clinical trials (36), the
possible mixing of maternal and fetal blood, appears to relative risk of neonatal HBV infection in those who
increase the risk of HBV transmission (29). Recently, received HBV vaccine (plasma-derived or recombi-
polymorphisms in some cytokine genes, such as those nant) was 0.28 [95% confidence interval (CI) 0.2–0.4]
encoding for interferon-g and tumour necrosis factor- compared with those who received placebo or no
a, have been correlated with risk of intra-uterine intervention. Compared with vaccine alone, the addi-
infection with HBV (30, 31). Prevention of perinatal tion of HBIG to the regimen further reduced the
transmission is considered critical in the attempt to relative risk (0.54, 95% CI 0.41–0.73) when compared
decrease individual and population morbidity from with active prophylaxis only. Nonetheless, there are
chronic hepatitis B infection as well as the global clearly a substantial number of newborn infections,
burden of hepatitis B. even with prompt administration of active and passive
Mode of delivery has been examined as a potential vaccination. The estimates vary, and depend on ma-
risk factor for HBV transmission. In a report from ternal HBeAg status, but most studies demonstrate
China in 1988, of 447 infants born to HBsAg-positive anywhere from 1% (37) to 10% (36) chronic HBV
women, 24.9% (96/385) of newborns delivered vagin- infection in infants who were appropriately immu-
ally were HBV infected at birth, compared with nized. Clearly, with millions of at-risk pregnancies
o 10% (6/62) delivered by caesarean section (32). each year throughout the world, significant numbers
Both groups received HBV vaccine. These authors of perinatally acquired chronic HBV infection are still
advised caesarean section delivery for mothers with occurring.
high levels of viraemia. However, a later study com- The major target for neutralizing anti-HBs is the a
pared outcomes among three groups: 144 infants born determinant of the surface antigen protein. Mutations
by spontaneous vaginal delivery, 40 by forceps or in the S gene of HBV causing conformational changes
vacuum extraction and 117 by caesarean section (33). in the a determinant have been detected in humans
All infants received the HBIG and HBV vaccine at the infected with HBV, and concern has been expressed
recommended schedule. Chronic HBV infection was that these variants might replicate in the presence of
detected in the infants in 7.3, 7.7 and 6.8%, respec- vaccine-induced anti-HBs or anti-HBs contained in
tively, and response rates to immunization were simi- HBIG (38, 39). At this point, no evidence suggests that
lar in all groups. The authors concluded that mode of S gene immunization escape mutants pose a threat to
delivery does not influence the likelihood of HBV programmes using hepatitis B vaccines (40), but
transmission. At this point, most obstetrical algo- perhaps enhanced surveillance to detect the emergence
rithms do not include change in the planned mode of of these variants will be necessary for monitoring the
delivery for HBsAg-positive women regardless of effectiveness of current vaccination strategies.
HBeAg status or level of viraemia. One approach to prevention of perinatal HBV
In the USA, all pregnant women are supposed to be transmission is provision of HBIG during pregnancy.
tested for HBsAg, regardless of assessed risk and Several reports have documented the results of this
previous testing. Neonates born to HBsAg-positive intervention, demonstrating varying efficacy (27,
women should receive HBIG and vaccine before dis- 41–43). Unfortunately, the studies are quite hetero-
charge (5) and be followed to determine the adequacy geneous, using different doses and routes of HBIG
of immune response and the vaccine failures. All administration, and utilizing different outcomes to
infants, regardless of maternal HBsAg status, should determine neonatal infection, such as HBV DNA in
receive HBV vaccine in the first months of life. In cord blood, or HBsAg in the infants at 6 months of
Taiwan, all infants have been receiving the HBV age. In some studies, only HBeAg-positive mothers
vaccine for almost 20 years, with a significant impact were included, and in others HBeAg status was not
on perinatal transmission and childhood and adoles- specified. Three of the four reports, however, docu-
cent infection and its complications (34, 35). Whether mented a beneficial effect (27, 41, 43), while in one no
universal immunization will be adopted in all Eur- obvious difference was noted (42). One of the studies

136
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Jonas Hepatitis B and pregnancy

included examination of the effect of maternal HBIG proportion of HBV-infected women (48, 49). Because
receipt on the results of newborn vaccination, and many infants became infected before the availability of
found that maternal treatment with HBIG was asso- immunization, there was concern about the additional
ciated with higher seroprotection (development of risk that breastfeeding might confer. However, around
antibody to HBsAg, anti-HBs) rates in their offspring the same time, Beasley et al. (50) reported 53% HBV
than observed in those whose mothers were not infection in breastfed vs 60% in formula-fed infants.
treated (41). Although a decrease in the perinatal More recently, several studies have documented no
HBV transmission rate was documented only in difference in rates of perinatal infection between
HBeAg-positive women, the beneficial effect on devel- breastfed and formula-fed vaccinated infants, which
opment of anti-HBs was seen in infants of both was between 0 and 5% in both groups, although many
HBeAg-positive and HBeAg-negative women (41). of the women in these studies were HBeAg negative
Because the risk of intra-uterine and perinatal trans- (51, 52). These data support the recommendation of
mission of HBV is clearly related to the level of maternal the American Academy of Pediatrics that HBV infec-
viraemia (26, 44), another strategy to interrupt this tion not be considered a contraindication to breast-
process is maternal treatment with a nucleoside analo- feeding of infants who receive the HBIG and HBV
gue late in pregnancy. As stated above, the only HBV vaccine as advised (53). In addition, it appears that
drug with a record of safe use in pregnant women is breastfeeding does not interfere with the immune
lamivudine. van Zonneveld et al. (45) treated eight response to the HBV vaccine. In one group of 230
pregnant women with high HBV DNA levels with infants, the rate of anti-HBs at 1 year of age was 80.9%
150 mg lamivudine daily from gestational week 34 until in breastfed compared with 73.2% in formula-fed
delivery. The infants received both active and passive infants who received the HBV vaccine alone, and 90.9
immunization at birth. The HBV DNA levels declined at vs 90.3% in those who received the HBV vaccine and
least 1 log in five of the eight women, after 6–40 days. HBIG (54). It may be prudent, however, to counsel
Although four of the infants were HBsAg positive at against breastfeeding by women receiving antiviral
birth, all but one was negative by 12 months of age agents, because the safety of these drugs during lacta-
(12.5% transmission). The rate of chronic HBV infec- tion has not been demonstrated.
tion in a comparable group of 24 historical controls was
28%. The largest study was a randomized, double-blind,
placebo-controlled trial in 114 highly viraemic women, Summary
68 of whom received lamivudine 100 mg daily beginning It has long been recognized that perinatal transmission
at week 32 (46). Again, all infants received HBIG and of HBV accounts for the majority of chronic infec-
vaccine in the standard regimen. Viral load reduction to tions worldwide, and strategies to affect HBV burden
o 1000 mEq/ml was achieved in 98% of the lamivu- should incorporate methods to decrease this mode of
dine-treated mothers and 31% of controls. At 1 year of acquisition. Many individuals chronically infected
age, 18% of infants of lamivudine-treated mothers were with HBV are women of child-bearing potential, and
HBsAg positive, compared with 39% of those whose while it is the minority who have serious liver disease
mothers received placebo. In addition, there was a requiring intervention during pregnancy, care of this
greater incidence of anti-HBs positivity in infants whose special population is understudied and merits consid-
mothers had been treated with lamivudine, 84 vs. 61% eration. Management of HBV during pregnancy in-
in controls. No adverse effects of lamivudine were noted cludes recognition of maternal virological status,
in either the mothers or their infants. assessment of liver disease and minimization of risk
At this point, there is no consensus regarding using for perinatal transmission of infection. This may
HBIG or a nucleoside analogue in pregnant women to include simple monitoring, changes in obstetrical care
prevent perinatal transmission. One proposed algo- or administration of antiviral therapy in late preg-
rithm includes consideration of both the level of nancy or throughout pregnancy. Passive and active
maternal viraemia and the history of a previous child immunoprophylaxis and monitoring for infection or
becoming infected with HBV perinatally (47). immunity in newborns is an integral part of this
management. Opportunities exist for case detection
and prevention in household and sexual partners as
Breastfeeding by hepatitis B virus-infected well. The unique aspects of this management, with
women consequences for both mothers and newborns, and the
Decades ago, studies from the Far East demonstrated relative lack of data, make this a critical medical
that HBsAg could be detected in breast milk in a large challenge.

c 2009 John Wiley & Sons A/S 137
Hepatitis B and pregnancy Jonas

Conflicts of interest 15. Lin HH, Wu WY, Kao JH, et al. Hepatitis B post-partum e
antigen clearance in hepatitis B carrier mothers: correlation with
The author declares no conflicts of interest.
viral characteristics. J Gastroenterol Hepatol 2006; 21: 605–9.
16. ter Borg MJ, Leemans WF, de Man RA, Janssen HLA.
Exacerbation of chronic hepatitis B infection after delivery.
References J Vir Hepat 2008; 15: 37–41.
17. Yang Y-B, Li X-M, Shi Z-J, Ma L. Pregnant woman
1. Alter MJ. Epidemiology of hepatitis B in Europe and world-
with fulminant hepatic failure caused by hepatitis B virus
wide. J Hepatol 2003; 39(Suppl. 1): 64–9.
infection: a case report. World J Gastroenterol 2004; 10:
2. Euler GL, Wooten KG, Baughman AL, Williams WW. Hepa-
2305–6.
titis B surface antigen prevalence among pregnant women in
18. Santiago-Munoz P, Roberts S, Sheffield J, McElwee B, Wendel
urban areas: implications for testing, reporting, and prevent-
JGD. Prevalence of hepatitis B and C in pregnant women who
ing perinatal transmission. Pediatrics 2003; 111: 1192–7.
are infected with human immunodeficiency virus. Am J
3. Hahne S, Ramsay M, Balogun K, Edmunds WJ, Mortimer P.
Obstet Gynecol 2005; 193(Suppl. 1): 1270–3.
Incidence and routes of transmission of hepatitis B virus in
19. Cobey FC, Salem RR. A review of liver masses in pregnancy
England and Wales, 1995–2000: implications for immunisa-
and a proposed algorithm for their diagnosis and manage-
tion policy. J Clin Virol 2004; 29: 211–20.
ment. Am J Surg 2004; 187: 181–91.
4. Healy CM, Cafferkey MT, Butler KM, et al. Antenatal
20. de la Rosa MA, Nicolás-Pérez D, Muñiz-Montes JR, et al.
hepatitis B screening – is there a need for a national policy?
Evolution and management of a hepatocellular carcinoma
Irish Med J 2001; 94: 111–2.
5. Centers for Disease Control. A comprehensive immunization during pregnancy. J Obstet Gynaecol Res 2006; 32: 437–9.
21. Lau WY, Leung WT, Ho S, et al. Hepatocellular carcinoma
strategy to eliminate transmission of hepatitis B virus infec-
tion in the United States. Recommendations of the Advisory during pregnancy and its comparison with other pregnancy-
Committee on immunization practices. Part 1: childhood associated malignancies. Cancer 1995; 75: 2669–76.
immunization. Morb Mortality Wkly Rep 2005; 54(RR-16): 22. Gupta I, Ratho RK. Immunogenicity and safety of two
1–32. schedules of hepatitis B vaccination during pregnancy.
6. Cowan SA, Bagdonaite J, Qureshi K. Universal hepatitis B J Obstet Gynaecol Res 2003; 29: 84–6.
screening of pregnant women in Denmark ascertains sub- 23. Levy M, Koren G. Hepatitis B vaccine in pregnancy: maternal
stantial additional infections: results from the first five and fetal safety. Am J Perinatol 1991; 8: 227–32.
months. Eurosurveillance 2006; 11: pii–2969. 24. The Antiretroviral Pregnancy Registry Steering Committee.
7. Jonas MM, Schiff ER, O’Sullivan MJ, et al. Failure of the Antiretroviral pregnancy registry international interim re-
centers for disease control criteria to identify hepatitis B port for 1 January 1989 through 31 January 2006. Registry
infection in a large municipal obstetrical population. Ann coordinating center; 2006, Wilmington, NC. Report no.:
Intern Med 1987; 107: 335–7. http://www.apregistry.com/forms/apr_report_106.pdf
8. Zuckerman J, van Hattum J, Cafferkey M, et al. Should 25. Su G-G, Pan K-H, Zhao N-F, et al. Efficacy and safety of
hepatitis B vaccination be introduced into childhood im- lamivudine treatment for chronic hepatitis B in pregnancy.
munisation programmes in northern Europe? Lancet Infect. World J Gastroenterol 2004; 10: 910–2.
Dis 2007; 7: 410–9. 26. Xu DZ, Yan YP, Choi BC, et al. Risk factors and mechanism of
9. Wong S, Chan LY, Yu V, et al. Hepatitis B carrier and perinatal transplacental transmission of hepatitis B virus: a case–
outcome in singleton pregnancy. Am J Perinatol 1999; 16: control study. J Med Virol 2002; 67: 20–6.
485–8. 27. Li X-M, Shi M-F, Yang Y-B, et al. Effect of hepatitis B
10. Tse KY, Lo LF, Lao T. The impact of maternal HBsAg carrier immunoglobulin on interruption of HBV intrauterine infec-
status on pregnancy outcomes: a case–control study. J tion. World J Gastroenterol 2004; 10: 3215–7.
Hepatol 2005; 43: 771–5. 28. Bai H, Zhang L, Ma L, et al. Relationship of hepatitis B virus
11. Alexander JM, Ramus R, Jackson G, Sercely B, Wendel Jr G. infection of placental barrier and hepatitis B virus intra-
Risk of hepatitis B transmission after amniocentesis in chronic uterine transmission mechanism. World J Gastroenterol 2007;
hepatitis B carriers. Infect Dis Obstet Gynecol 1999; 7: 283–6. 13: 3625–30.
12. Towers CV, Asrat T, Rumney P. The presence of hepatitis B 29. Lin HH, Lee TY, Chen DS, et al. Transplacental leakage of
surface antigen and deoxyribonucleic acid in amniotic fluid HBeAg-positive maternal blood as the most likely route in
and cord blood. Am J Obstet Gynecol 2001; 184: 1514–8. causing intrauterine infection with hepatitis B virus. J Pediatr
13. Söderström A, Norkrans G, Lindh M. Hepatitis B virus DNA 1987; 111: 877–81.
during pregnancy and post partum: aspects on vertical 30. Zhu QR, Ge YL, Gu SQ, et al. Relationship between cytokines
transmission. Scand J Infect Dis 2003; 35: 814–9. gene polymorphism and susceptibility to hepatitis B virus
14. Lin HH, Chen PJ, Chen DS, et al. Postpartum subsidence of intrauterine infection. Chin Med J 2005; 118: 1604–9.
hepatitis B viral replication in HBeAg-positive carrier 31. Yu H, Zhu QR, Gu SQ, et al. Relationship between
mothers. J Med Virol 1989; 29: 1–6. IFN-gamma gene polymorphism and susceptibility to

138
c 2009 John Wiley & Sons A/S
Jonas Hepatitis B and pregnancy

intrauterine HBV infection. World J Gastroenterol 2006; 12: 43. Xu Q, Xiao L, Lu X-B, Zhang Y-X, Cai X. A randomized
2928–31. controlled clinical trial: interruption of intrauterine trans-
32. Lee S-D, Tsai K-S, Wu T-C, et al. Role of caesarean section in mission of hepatitis B virus infection with HBIG. World J
prevention of mother-infant transmission of hepatitis B Gastroenterol 2006; 12: 3434–7.
virus. Lancet 1988; 2: 833–4. 44. Burk RD, Hwang LY, Ho GY, et al. Outcome of perinatal
33. Wang J, Zhu Q, Zhang X. Effect of delivery mode on hepatitis B virus exposure is dependent on maternal virus
maternal–infant transmission of hepatitis B virus by immu- load. J Infect Dis 1994; 170: 1418–23.
noprophylaxis. Chin Med J 2002; 115: 1510–2. 45. van Zonneveld M, van Nunen AB, Niesters HGM, et al.
34. Chang MH, Chen CJ, Lai MS, et al. Universal hepatitis B Lamivudine treatment during pregnancy to prevent perinatal
vaccination in Taiwan and the incidence of hepatocellular transmission of hepatitis B virus infection. J Virol Hepatol
carcinoma in children. Taiwan Childhood Hepatoma Study 2003; 10: 294–7.
Group. N Engl J Med 1997; 336: 1906–7. 46. Xu WM, Cui YT, Wang L, et al. Efficacy and safety of
35. Chen H-L, Chang C-J, Kong M-S, et al. Pediatric fulminant lamivudine in late pregnancy for the prevention of mother–
hepatic failure in endemic areas of hepatitis B infection: 15 child transmission of hepatitis B: a multicentre, randomized,
years after universal hepatitis B vaccination. Hepatology 2004; double-blind, placebo-controlled study [abstract]. Hepatol-
39: 58–63. ogy 2004; 40: 272A.
36. Lee C, Gong Y, Brok J, Boxall EH, Gluud C. Effect of hepatitis 47. Tran TT, Keeffe EB. Management of the pregnant hepatitis B
B immunisation in newborn infants of mothers positive for patient. Curr Hep B Rep 2008; 2: 43–8.
hepatitis B surface antigen: systematic review and meta- 48. Wong VC, Lee AKY, Ip HMH. Transmission of hepatitis B
analysis. BMJ 2006; 332: 328–36. antigens from symptom free carrier mothers to the fetus and
37. del Canho R, Grosheide PM, Mazel JA, et al. Ten-year the infant. Br J Obstet Gynaecol 1980; 87: 958–65.
neonatal hepatitis B vaccination program, The Netherlands, 49. Lee AK, Ip HM, Wong VC. Mechanisms of maternal–fetal
1982–1992: protective efficacy and long-term immunogeni- transmission of hepatitis B virus. J Infect Dis 1978; 138:
city. Vaccine 1997; 15: 1624–30. 668–71.
38. Hsu HY, Chang MH, Liaw SH, Ni YH, Chen HL. Changes of 50. Beasley RP, Stevens CE, Shiao IS, Meng HC, et al. Evidence
hepatitis B surface antigen variants in carrier children before against breastfeeding as a mechanism for vertical transmis-
and after universal vaccination in Taiwan. Hepatology 1999; sion of hepatitis B. Lancet 1975; 2: 740–1.
30: 1312–7. 51. De Martino M, Appendino C, Resti M, et al. Should hepatitis
39. Zuckerman AJ. Effect of hepatitis B virus mutants on efficacy B surface antigen positive mothers breast feed? Arch Dis Child
of vaccination. Lancet 2000; 355: 1382–4. 1985; 60: 972–4.
40. Mele A, Tancredi F, Romano L, et al. Effectiveness of hepatitis 52. Hill JB, Sheffield JS, Kim MJ, et al. Risk of hepatitis B
B vaccination in babies born to hepatitis B surface antigen- transmission in breast-fed infants of chronic hepatitis B
positive mothers in Italy. J Infect Dis 2001; 184: 905–8. carriers. Obstet Gynecol 2002; 99: 1049–52.
41. Xiao XM, Li AZ, Chen X, Zhu YK, Miao J. Prevention of 53. Gartner LM, Morton J, Lawrence RA, et al. American
vertical hepatitis B transmission by hepatitis B immunoglo- Academy of Pediatrics Section on Breastfeeding. Breastfeed-
bulin in the third trimester of pregnancy. Int J Gynecol Obstet ing and the use of human milk. Pediatrics 2005; 115:
2007; 96: 167–70. 496–506.
42. Yuan J, Lin J, Xu A, et al. Antepartum immunoprophylaxis of 54. Wang JS, Zhu QR, Wang XH. Breastfeeding does not
three doses of hepatitis B immunoglobulin is not effective: a pose any additional risk of immunoprophylaxis failure on
single-centre randomized study. J Virol Hepatol 2006; 13: infants of HBV carrier mothers. Int J Clin Pract 2003; 57:
597–604. 100–2.

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