Journal of Hepatology 43 (2005) 771–775

www.elsevier.com/locate/jhep

The impact of maternal HBsAg carrier status

on pregnancy outcomes: A case–control study
Ka Yu Tse*, Lai Fong Ho, Terence Lao
Department of Obstetrics and Gynaecology, Queen Mary Hospital, The University of Hong Kong, 102, Pokfulum Road, Hong Kong, Hong Kong

Background/Aims: To examine the impact of maternal HBsAg carrier status on pregnancy outcomes.
Methods: Two hundred and fifty-three carriers of hepatitis B surface antigen (HBsAg) with singleton pregnancy,
were retrospectively compared with 253 controls matched for age and parity and year of delivery.
Results: On univariable analysis, HBsAg carriers had higher incidences of threatened preterm labour at !37 weeks
(11.9% vs. 6.3%, PZ0.030), preterm birth at !34 weeks (4.7% vs. 1.2%, PZ0.033), gestational diabetes mellitus
(19.0% vs. 11.1%, PZ0.012) and antepartum haemorrhage (11.5% vs. 5.5%, PZ0.026). Their infants had lower Apgar
scores at the 1st (8.47G1.67 vs. 8.87G1.07, PZ0.001) and 5th minute (9.56G1.29 vs. 9.80G0.54, PZ0.007), and
increased incidence of intraventricular haemorrhage (4.7% vs. 0.8%, PZ0.007). On multivariable analysis, the
association between HBsAg carrier state with antepartum haemorrhage, gestational diabetes mellitus and threatened
preterm labour were confirmed.
Conclusions: HBsAg carriers have increased risk of gestational diabetes mellitus, antepartum haemorrhage, and
threatened preterm labour. This may be related to the chronic inflammatory state in these subjects. The role of chronic
HBV infection in pregnancy complications has to be further elucidated.
q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Keywords: Chronic hepatitis B infection; Pregnancy outcomes

1. Introduction maternal serum ferritin found in association with gestation

Hepatitis B is endemic in Southeast Asia. The prevalence
rate of chronic hepatitis B virus (HBV) infection is up to
20% in the populations of the Asia-Pacific region [1]. In
Hong Kong, the overall prevalence of chronic HBV
infection in the obstetric population is 10.0% [2].
Consequently, all pregnant women are screened for hepatitis
B surface antigen (HBsAg) at the first antenatal visit.
Despite its prevalence, there are little data on the effect of
maternal chronic HBV infection on pregnancy outcomes. Of
the handful of studies that have examined this issue, the
findings appeared inconclusive [3–12]. On the other hand,
a recent study from our centre suggested that maternal
HBsAg carrier status was the explanation for the increased
Received 14 August 2004; received in revised form 3 May 2005; accepted 9
May 2005; available online 29 June 2005
* Corresponding author. Tel.: C852 2855 3914; fax: C852 2517 3278.
E-mail address: tsekayu@graduate.hku.hk (K.Y. Tse).
diabetes mellitus [13]. As serum ferritin acts as an acute
phase reactant, the findings of this study suggest, an
increased chronic inflammatory state in the HBV infected
women. In view of the proposed association between
systemic inflammatory state and pregnancy complications
[14,15], we have performed a retrospective case–control
study to examine again the impact of chronic HBV infection
on antenatal and perinatal outcomes.
2. Methods
Our hospital is a tertiary referral center catering mainly for high-risk
parturients and those with underlying medical diseases, multiple obstetric
risk factors, and fetal abnormalities. All pregnant women attending
the antenatal clinic have routine blood taking to screen for HBsAg by
enzyme-linked immunosorbent assay (ELISA). Liver biochemical tests for
the HBsAg carriers were not routinely performed unless symptoms or
clinical features suggestive of active liver disease were present. Similarly,
HBeAg status and viral load were not assessed. Since the impact of
maternal HBsAg carriage on adverse pregnancy outcome remains unclear,
we could not estimate the required sample size with confidence. Hence, we

0168-8278/$30.00 q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.jhep.2005.05.023
772 K.Y. Tse et al. / Journal of Hepatology 43 (2005) 771–775

studied the patients delivered over a three-year period between January Table 1
2000 and 2002 who had positive HBsAg screening (cases) identified Maternal demographic parameters with respect to HBsAg status
through the Obstetric Specialty Clinical Information System (OBSCIS) and
the Central Management System (CMS), which are the two computerized HBsAg Cve HBsAg Kve
database systems used by the Hong Kong Hospital Authority to collect (nZ253) (nZ253)
inpatient data on diagnoses and procedures. Only singleton pregnancies
were selected. The delivery rate in our hospital at this period was around Weight at booking (kg)* 55.54G8.31 55.38G8.56
1200 per year. For each case, a control without HBsAg, matched for age Height (cm)* 157.98G5.22 159.91G23.66
and parity, was identified and selected from the Delivery Suite Registry at BMI (kg/m2)* 20.70G2.91 20.61G3.02
random. Hb at booking (g/dL)* 12.25G1.09 12.28G1.16
The clinical records of the cases and controls were retrieved for data Ethnicity
extraction. Demographic information, including age, gravidity, parity, Chinese 243 (96.1%) 237 (93.7%)
ethnicity, past health, weight and weight gain, height, calculated body mass
Filipino 5 (2.0%) 8 (3.2%)
index, antenatal complications, labour outcomes and mode of delivery,
were retrieved from the obstetric records. Perinatal information including Other Asians 5 (2.0%) 8 (3.2%)
birth weight, Apgar scores, gestational age, perinatal complications like History of stillbirth/NND 5 (2.0%) 5 (2.0%)
birth trauma and neonatal jaundice was extracted from the neonatal records. IVF pregnancy 7 (2.8%) 6 (2.4%)
Data were analysed with the use of SPSS 11.5 (Statistical Package for Past health
the Social Sciences, for Windows, Chicago). Differences in continuous Hypertension 1 (0.4%) 2 (0.8%)
variables were analysed by t-test and those in categorical variables were Diabetes mellitus 1 (0.4%) 0 (0.0%)
analysed by Chi-square test or Fisher’s exact test where appropriate in the Autoimmune disease 2 (0.8%) 3 (1.2%)
initial univariable analysis. Subsequently, multivariable regression analysis Liver disease 2 (0.8%) 1 (0.4%)
was used to determine the independent role of HBsAg carriage in the
Thyroid disease 8 (3.2%) 7 (2.8%)
complications that were significantly increased in the HBsAg carriers,
adjusting for the confounding effects of the other factors that were also Thalassaemia trait 13 (5.1%) 11 (4.4%)
found to be significantly different between the two groups. A P-value of less Cardiac disease 7 (2.8%) 10 (4.0%)
than 0.05 is considered as significant. Respiratory disease 3 (1.2%) 5 (2.0%)
Haematological disease 2 (0.8%) 2 (0.8%)
Epilepsy 0 (0.0%) 3 (1.2%)
Genital tract abnormality 2 (0.8%) 1 (0.4%)
Renal disease 4 (1.6%) 2 (0.8%)
3. Results
Late syphilis 1 (0.4%) 0 (0.0%)

Among the 3348 singleton pregnancies delivered in this
period, 253 HBsAg carriers (7.6%) and 253 HBsAg
negative control mothers were identified. In the cohort,
94.9% of the patients were Chinese, the mean age was
30.4G5.5 years and 58.9% of them were primiparas. There
was no significant difference in the demographic character-
istics like BMI and haemoglobin level at booking, or
medical history, between the cases and controls (Table 1).
Among the HBsAg carriers, the weight gain in those
patients with gestational diabetes mellitus (GDM) was
significantly less than those with those without GDM (9.78
vs. 11.74 kg, PZ0.050, 95% CI K3.92 to 0.00). Among the
HBsAg non-carriers, the weight gain was also less in those
with GDM compared with those without GDM, though the
difference was not statistically significant because of the
sample size (9.35 vs. 10.60 kg, PZ0.199, 95% CI K3.19 to
0.69). And among the GDM patients, the HBsAg carriers
had more weight gain than the HBsAg non-carriers, but the
difference was not statistically significant (9.78 vs. 9.35 kg,
PZ0.732, 95% CI K2.07 to 2.93).
In the case group, there was a significantly higher
incidence of gestational diabetes mellitus (19.0% vs. 11.1%,
PZ0.012, OR 1.89, 95% CI 1.14–3.13), as well as that of
antepartum haemorrhage overall (11.5% vs. 5.5%, PZ
0.025, OR 2.21, 95% CI 1.14–4.29). However, further
analysis showed the rates of placenta praevia (3.2%
vs. 0.8%, PZ0.106), placental abruption (2.8% vs. 0.4%,
PZ0.068) and antepartum haemorrhage of unknown origin
(5.9% vs. 4.4%, PZ0.547), were not significantly different
individually. The incidence of threatened preterm labour
was two-fold higher in the case group (11.9% vs. 6.3%,
*Results are expressed in number (%) or meanGSD as indicated.
PZ0.030, OR 1.99, 95% CI 1.06–3.76). This was
associated with a significantly higher incidence of preterm
birth at !34 weeks (4.7% vs. 1.2%, PZ0.033, OR 4.15,
95% CI 1.16–14.89). But statistical significance was not
reached for birth at !32 weeks (2.4% vs. 0.4%, PZ0.122,
OR 6.12, 95% CI 0.732–51.22) or !37 weeks (12.3% vs.
7.5%, PZ0.074, OR 1.72, 95% CI 0.94–3.13). Although the
incidence of pre-eclampsia was higher in the case group
(4.4% vs. 2.8%), this difference was not statistically
significant (Table 2). There was no increased risk of
prelabour rupture of membranes (PROM) in the case group,
and no relationship was noted between preterm birth and
premature prelabour rupture of the membranes (PPROM).
The effects of HBsAg status on the pregnancy and
neonatal outcomes were also analysed (Table 3). Although,
the mean gestational age was slightly but significantly
shorter in the case group (38.28G2.66 weeks vs. 38.68G
1.59 weeks, PZ0.043), there was no significant difference
in the mean birth weight. The Apgar scores at 1st and 5th
minutes were significantly lower in the case group than
those in the control group, being 8.47G1.67 vs. 8.87G1.07
at 1st minute (PZ0.001), and 9.56G1.29 vs. 9.80G0.54 at
5th minute (PZ0.007). However, apart from intraventri-
cular haemorrhage (4.7% vs. 0.8%, PZ0.007, OR 6.25,
95% CI 1.38–28.21), there was no significant increase in
perinatal complications such as meconium aspiration
syndrome and neonatal jaundice in the case group.
Multivariable analysis was performed to examine the
relationship between HBsAg status and the main pregnancy
 K.Y. Tse et al. / Journal of Hepatology 43 (2005) 771–775 773

Table 2 Table 3
Antenatal course and complications with respect to HBsAg status Pregnancy outcomes and neonatal complications with respect to
HBsAg status
HBsAg Cve HBsAg Kve P value
(nZ253) (nZ253) HBsAg Cve HBsAg Kve P value
(nZ253) (nZ253)
Pregnancy weight gain 11.31G5.88 10.45G4.87 0.089
(kg) Gestational age 38.28G2.66 38.68G1.59 0.043
Hb before delivery (g/dL) 11.52G1.07 11.66G1.08 0.174 Mode of delivery
Pre-eclampsia 11 (4.4%) 7 (2.8%) 0.337 Emergency 49 (19.4%) 37 (14.6%) 0.156
Gestational diabetes 48 (19.0%) 28 (11.1%) 0.012 caesarean section
IUGR 3 (1.2%) 6 (2.4%) 0.504 Elective caesarean 21 (8.3%) 22 (8.7%) 0.873
Thrombocytopenia 5 (2.0%) 3 (1.2%) 0.724 section
Genital tract infection 34 (13.4%) 25 (9.9%) 0.213 Normal spon- 134 (53.0%) 146 (57.7%) 0.283
PROM 35 (13.8%) 42 (16.6%) 0.386 taneous delivery
PPROM 4 (1.6%) 7 (2.8%) 0.544 Instrumental 48 (19.0%) 47 (18.6%) 0.909
Antepartum haemorrhage 29 (11.5%) 14 (5.5%) 0.025 delivery
Placenta praevia 8 (3.2%) 2 (0.8%) 0.106 Birthweight (kg) 3126.49G583.57 3135.25G428.47 0.847
Placental abruption 7 (2.8%) 1 (0.4%) 0.068 Placental weight (kg) 605.50G142.53 601.43G113.78 0.724
APH of unknown origin 15 (5.9%) 11 (4.4%) 0.547 Apgar score at 1st 8.47G1.67 8.87G1.07 0.001
Threatened preterm labour 30 (11.9%) 16 (6.3%) 0.030 minute
Preterm birth Apgar score at 5th 9.56G1.29 9.80G0.54 0.007
!37 weeks 31 (12.3%) 19 (7.5%) 0.074 minute
!34 weeks 12 (4.7%) 3 (1.2%) 0.033 Fetal distress 27 (10.7%) 20 (7.9%) 0.284
!32 weeks 6 (2.4%) 1 (0.4%) 0.122 Chorioamnionitis 6 (2.4%) 7 (2.8%) 0.779
Maternal morbidity 88 (34.8%) 48 (19.0%) !0.001 Meconium aspiration 3 (1.2%) 3 (1.2%) 1.000
syndrome
Hb, haemoblobin; IUGR, intra-uterine growth restriction; PROM, Clinical sepsis 17 (6.7%) 13 (5.1%) 0.451
prelabour rupture of membranes; PPROM, premature prelabour rupture of Neonatal jaundice 58 (22.9%) 68 (26.9%) 0.304
membranes; APH, antepartum haemorrhage. Results are expressed in Intraventricular 12 (4.7%) 2 (0.8%) 0.007
number (%) or meanGSD as indicated. haemorrhage
Necrotising 1 (0.4%) 0 (0.0%) 0.500
complications including antepartum haemorrhage, gesta- enterocolitis
tional diabetes mellitus, pre-eclampsia, PPROM, threatened Congenital 20 (7.9%) 16 (6.3%) 0.489
abnormality
preterm labour and preterm delivery at !34 weeks, taking
Metabolic disturbance 8 (3.2%) 6 (2.4%) 0.588
into account the confounding factors of age R35, weight Respiratory disease 16 (6.3%) 10 (4.0%) 0.227
R70 kg, and nulliparity. HBsAg carrier status was Perinatal morbidity 2 (0.8%) 0 (0.0%) 0.499
significantly associated with gestational diabetes mellitus
Results are expressed in number (%) or meanGSD as indicated.
(PZ0.008, OR 2.04, 95% CI 1.21–3.44), antepartum
haemorrhage (PZ0.023, OR 2.18, 95% CI 1.11–4.26), pregnancy outcomes in the carriers [4–6], there have been
and threatened preterm labour (PZ0.046, OR 2.007, 95% case reports and studies indicating an increased incidence of
CI 1.01–3.97). But the association with preterm delivery maternal and neonatal morbidity in HBV infection such as
at !34 weeks failed to reach statistical significance (PZ fetal distress, premature delivery and meconium peritonitis
0.060, OR 3.52, CI 0.95–13.06). Neither pre-eclampsia nor
[7–13]. The underlying explanation for this phenomenon is
PROM had significant relationship with HBsAg carrier
not clear, but factors such as ethnic difference and the
status. Adjusting for the effects of parity, maternal weight,
disease activity in the HBsAg carriers could have been
maternal age, and preterm birth at !37 weeks, HBsAg
contributing.
carrier status is not associated with fetal intraventricular
To examine the impact of HBsAg carrier status on
haemorrhage.
pregnancy outcomes, our cases were matched with controls
for age and parity because age and parity have important
effects on pregnancy outcomes [14,15]. We have demon-
4. Discussion strated a positive association between gestational diabetes
mellitus and HBsAg carrier status, confirming the findings
The screening for maternal HBsAg carriage had been a of a previous observation [16]. In addition, the incidence of
routine antenatal investigation in Hong Kong since the early antepartum haemorrhage overall was raised in the HBsAg
1980s, and the result is known to the obstetric and nursing carriers. This was related to increases in both the incidence
staff for the timely administration of hepatitis B immuno- of placenta praevia and placental abruption, but the
globulin to the newborns [3]. Otherwise, the management of difference of each of these complications failed to reach
the maternal carriers was similar to that of the other statistical significance likely because of the small number of
parturients. Although other reports on the effects of chronic subjects. HBsAg carriers were also at increased risk of
HBV infection indicated no association with adverse delivery before 34 weeks, but this may have been related to
774 K.Y. Tse et al. / Journal of Hepatology 43 (2005) 771–775
some underlying factor since the association failed to
achieve statistical significance in logistic regression
analysis. The Apgar scores at 1st and 5th minutes were
lower in the newborn of the HBsAg carriers, and there was
higher risk of intraventricular haemorrhage as well, which
was probably related to the higher incidence of preterm
delivery.
The reports of hepatitis B-related adult-onset Still’s
disease, polyarteritis nodosa, glomerulonephritis and vas-
culitis [17–20], indicate that chronic HBV infection may be
associated with a systemic inflammatory state that plays a
causative role in these autoimmune diseases. Chronic HBV
infection is associated with increased levels of pro-
inflammatory cytokines such as IL-2, IL-6, IL-10, macro-
phage migration inhibitory factor, and tumour necrosis
factor-alpha (TNF-a), which are more pronounced during
active hepatitis [21,22]. Our findings of the association
between the HBsAg carrier status with gestational diabetes
mellitus, antepartum haemorrhage, and the trend towards
preterm birth could have, therefore, represented the effect of
an accentuation of the normal systemic inflammatory
response seen in pregnancy [23].
There is evidence that an exaggerated systematic
inflammatory response could lead to certain obstetric
complications. In pre-eclampsia, excessive inflammatory
response is responsible for its pathogenesis [24,25]. It is
believed that apoptotic placental debris shed from the
syncytial surface of the placenta, and maternal clearance of
this debris from the circulation, in turn, constitutes a
systemic inflammatory response [26]. The pathogenesis of
gestational diabetes mellitus is related to insulin resistance
[27], which in turn is influenced by chronic subclinical
inflammation in which immune markers are raised [28,29].
TNF-a and its soluble receptors (sTNFR-1 and -2) were
found to be elevated in patients with GDM [30]. It has
been demonstrated that the levels of TNF and its receptors
were raised in patients with chronic HBV infection
[31,32]. Similarly, many studies have shown that increased
serum concentrations of pro-inflammatory cytokines that
include IL-2 receptors, IL-6, IL-8, TNF-a and thrombin
play an important role in premature labour and prelabour
rupture of membranes [33–36]. Therefore, the additional
systemic inflammatory response induced by chronic HBV
infection could be the central explanation of the findings in
our study.
As with previous studies, we found that within a high risk
obstetric population, chronic HBV infection did not result in
adverse perinatal outcomes except for lower Apgar scores.
This could be related to the improvement in neonatal care.
Nevertheless, positive HBsAg carrier status can be a risk
factor on maternal and neonatal well being especially in the
developing countries with a high rate of HBsAg carriage.
More research is warranted to elucidate the potential role of
chronic HBV infection in pregnancy complications in
populations with a high rate of chronic HBV infection.
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