Placenta 35 (2014) 539e545

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Placenta
journal homepage: www.elsevier.com/locate/placenta

The risk of placental abruption and placenta previa in pregnant

women with chronic hepatitis B viral infection: A systematic review
and meta-analysis
Q.T. Huang a, c, 1, J.H. Chen a, 1, M. Zhong a, *, Y.Y. Xu a, C.X. Cai a, S.S. Wei a, L.L. Hang a,
Q. Liu b, Y.H. Yu a
a
Division of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, China
b
Cancer Research Center, Shantou University Medical College, Shantou 515041, China
c
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto M5T 3H7, Canada

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: Several epidemiological studies have found a positive association between chronic hepa-
Accepted 24 May 2014 titis B virus (CHB) infection and the risk of placental abruption and placenta previa, but various studies
have reported conicting ndings. The objective was to systematically review the literature to determine
Keywords: a possible association between CHB infection and these two placental complications.
Placental abruption Methods: We conducted a computerized search in electronic database through March 1, 2014, supple-
Placenta previa
mented with a manual search of reference lists, to identify original published research on placental
HBV
abruption and placenta previa rates in women with CHB infection. Data were independently extracted,
Placental complications
and relative risks were calculated. The meta-analysis was performed using Stata version 10.0 software.
Results: Five studies involving 9088 placenta previa cases were identied. No signicant association
between CHB infection and placenta previa was identied (OR 0.98, 95% CI 0.60e1.62). Five studies
involving 15571 placental abruption cases were identied. No signicant association between CHB
infection and placental abruption was identied (OR 1.42, 95% CI, 0.93e2.15).
Discussion: The immune response against the virus represents a key factor in determining infection
outcomes. No observation of signicant increased risk of the placental complications could be partially
explained by the complex immune response during CHB infection.
Conclusions: Our meta-analysis found no evidence of signicant associations between CHB infection and
increased risk of placental abruption as well as placenta previa. Further well-designed studies were
warranted to assess any potential association between CHB infection and increased risk of placental
abruption as well as placenta previa.
2014 Elsevier Ltd. All rights reserved.

1. Introduction studies have found a positive association between chronic hepatitis

Chronic infection with the hepatitis B virus (HBV) can be found
in 10% or more among the Asian and Chinese populations [1].
Consequently, maternal HBV infection is one of the commonest
infections encountered during pregnancy.
Placental abruption and placenta previa are two most common
placental complications which are major contributors to maternal
and neonatal morbidity and mortality [2,3]. Several epidemiological
* Corresponding author. Fax: 86 (0)20 627 87 560.
E-mail address: zhongm1960@163.com (M. Zhong).
1
These authors contributed equally to this manuscript.
B virus (CHB) infection and the risk of these two placental compli-
cations [4e7], but the magnitude of this association varied: two
studies found signicant higher risk of placental previa [4,7], while 3
studies demonstrated an increased but not signicant trend of these
placental complications with maternal CHB infection [5e7]. Other
studies have reported conicting ndings: a trend toward reduction
of placental abruption and placenta previa in women with CHB
infection [8e10]. The explanation for this discrepancy is that the
smaller studies individually lack sufficient power to detect the
increased risks. Thus, the possible role of CHB infection in the
pathogenesis of placental abruption and placenta previa remains an
important but unresolved issue. Previous studies demonstrated that

http://dx.doi.org/10.1016/j.placenta.2014.05.007
0143-4004/ 2014 Elsevier Ltd. All rights reserved.
540 Q.T. Huang et al. / Placenta 35 (2014) 539e545

inammation could induce dysfunction of trophoblasts and
contribute to defective deep placentation and the associated
placental complications [11,27]. Recently, Lou et al. [12] found that
HBV X protein could promote pro-inammatory cytokine secretion
and repressed anti-inammatory cytokine secretion in human T
cells. Therefore, it is plausible that inammation caused by CHB
infection is partially responsible for the increased risk of placental
abruption and placenta previa.
To address these issues, we have undertaken a systematic re-
view of the literature and performed meta-analyses to investigate
whether maternal CHB infection was associated with an increased
risk of placental abruption and placenta previa.
2. Methods
2.1. Data sources and search strategy
Two independent investigators searched PubMed and Embase
databases from 1966 to March 1, 2014 using the combinations of
terms hepatitis B or hepatitis B surface antigen (HBsAg) and
pregnancy outcome or prenatal outcome or perinatal outcome
or placental abruption or placenta previa or placenta or
placental. We sifted through potentially relevant articles, rstly
by titles and abstracts, and then we retrieved the full texts of articles
for detailed review. Further, we scanned the reference lists of the
articles that met the inclusion criteria in our analysis, and searched
for those articles or citations in the Web of Knowledge, Google
Scholar and Google to obtain additional studies.
2.2. Inclusion and exclusion criteria
Articles were included if they used a cohort or case-control
design and reported a quantitative association between CHB
infection during pregnancy and the risk of placental abruption as
well as placenta previa among pregnant women versus a non-
CHB control group. For studies that enrolled overlapping popu-
lation, only more recently published studies and/or those with
larger sample sizes were included. Studies included in this
analysis dened CHB infection status during pregnancy by the
presence or absence of hepatitis B surface antigen (HBsAg) in
blood during the rst prenatal care visit, on admission to the
labor ward, or before delivery. The diagnosis of placental
abruption and placenta previa were performed according to the
recommended clinical practice.
2.3. Data extraction
A form designed a priori was used to extract the information
from the included studies. Two independent investigators per-
formed the data extraction. A third investigator examined the re-
sults, and a consensus was considered as agreement between at
least two out of the three investigators. Placental abruption and
placenta previa were the outcomes measured. Data were recorded
as follows: rst author's last name, year of publication and country
of origin; number of participants with CHB infection and total
number of participants; ascertainment of CHB infection; assess-
ment of placental abruption and placenta previa; and statistical
adjustments for confounding factors.
2.4. Assessment of methodological quality
Two independent investigators evaluated the quality of each
study using the NewcastleeOttawa.
Quality Assessment Scale (NOS) [13] (Table 1). A supplementary
table was added to give a detailed appraisal of methodological
quality of included studies (Table S1). In our analysis, studies of low,
intermediate and high quality were dened with NOS scores of
1e3, 4e6, and 7e9, respectively.
2.5. Statistical analysis
The pooled odds ratio (OR) with 95% confidence intervals (CIs)
between CHB infection and placental abruption as well as placenta
previa was used to estimate the effect sizes.
Heterogeneity was assessed by the Higgins'I2 (I2) measurement,
with signicance indicated by P < 0.1. We used a peto model to pool
the OR across studies. In the presence of signicant heterogeneity
(I2>50%), we excluded studies that caused heterogeneity based on
Galbraith plot [14] and performed a new meta-analyses using peto
method. The publication bias was investigated by two methods.
Visual detection was used to analyze the funnel plots [15]. Quan-
titative analysis was performed by the Begg's regression

Table 1
Summary information for the included studies.

Reference Design Location Group Subjects Baseline comparison between HbsAg and HbsAg group Placental Quality
complications scaling
Similarity Dissimilarity
described (NOS)

Lu YP 2012 [5] Case-control China HbsAg 183 Age, height, BMI, parity, NA PA, PP 8
HbsAg 265 gestational age, times of
pregnancy, past health
Connell LE 2011 [9] Cohort USA HbsAg 1458 BMI, marital status The HBsAg group had PA, PP 7
HbsAg- 1668911 lower weight and height,
but higher proportion of
Germany origin
Lobstein S 2011 [4] Cohort USA HbsAg 39 Age The HBsAg group had PA, PP 7
HbsAg 8154 higher proportion of
married, smoker and parity
Thungsuk R 2008 [6] Case-control Thailand HbsAg 154 BMI at booking, hematocrit NA PP 6
HbsAg 170 at booking, past health
Lert-amornpong Case-control Thailand HbsAg 164 Age, parity, past health NA PP 8
2007 [8] HbsAg 162
Tse KY 2005 [7] Case-control China HbsAg 253 Age, hematocrit at booking NA PA, PP 8
HbsAg 253
Wong SF 1999 [10] Cohort China HbsAg 824 Age, weight at booking, NA PA, PP 8
HbsAg 6281 hematocrit at booking,
parity, history of contraception

NA, not available; PP, placenta previa; PA, placental abruption.

 Q.T. Huang et al. / Placenta 35 (2014) 539e545
asymmetry test. All analyses were carried out using Stata software
version 10.0. Statistical signicance was set at P < 0.05, and 95% CIs
were quoted throughout.
3. Results
3.1. Characteristics of the subjects in the selected studies
The detailed search procedures are summarized in Fig. 1. The full
text of the 18 identied articles was retrieved for detailed evalua-
tion. Nine of these articles were further excluded because they did
not meet the inclusion criteria. Finally, the remaining 7 indepen-
dent studies were used in the current analysis. The seven studies
included in the present analysis were published between 1999 and
2012. Of these studies, 5 studies [5e7,9,10] both reported the
incidence of placental abruption and placenta previa, 2 studies only
reported the incidence of the placenta previa [4,8] (Table 1). Of
these studies, two were conducted in USA [4,9], three in China
[5,7,10], two in Thailand [6,8]. The CHB infection status was deter-
mined by the presence or absence of HBsAg during pregnancy, and
the diagnosis of placental abruption and placenta previa were
determined through routine clinical practices. According to the
NOS, six studies were of high quality [4,5,7e10] and one was of
intermediate quality [6].
Fig. 1. Flow chart of the literature search and article selection.
541
3.2. Main analysis of placental abruption
The pooled ORs from the 2 case control studies and 3 cohort
studies are shown in Fig. 2. The meta-analysis of the 5 studies
suggested no signicant association between CHB infection and
placental abruption (OR 1.42, 95% CI 0.89e2.25) without sig-
nicant heterogeneity among these studies (I2 13.9%, P 0.325).
An inspection of the funnel plot did not reveal an asymmetry,
which suggested there was no publication bias; the P value for
Begg's regression asymmetry test was 1.00, which indicates a low
probability of publication bias (Fig. 3).
3.3. Main analysis of placenta previa
The pooled ORs from the 4 case control studies and 3 cohort
studies are shown in Fig. 4. The meta-analysis of the 7 studies
suggested no signicant association between CHB infection and
placenta previa (OR 1.24, 95% CI 0.77e1.99) with marked sig-
nicant between-study heterogeneity (I2 69.1%, P 0.004). I2 was
reduced by removing two studies [4,5] which contributed for the
most heterogeneity among the studies according to the Galbraith
plot (Fig. 5). After two studies were removed, the pooled ORs from
the 3 case control studies and 2 cohort studies are shown in Fig. 6.
The meta-analysis of the 5 studies suggested no signicant
542 Q.T. Huang et al. / Placenta 35 (2014) 539e545

Fig. 2. Forest plots for the meta-analysis of the association between chronic hepatitis B infection and placental abruption.

association between CHB infection and placental abruption

(OR 0.98, 95% CI 0.60e1.62) without signicant heterogeneity
among these studies (I2 41.0%, P 0.148). An inspection of the
funnel plot did not reveal an asymmetry, which suggested there
was no publication bias; the P value for Begg's regression asym-
metry test was 0.806, which indicates a low probability of publi-
cation bias (Fig. 7).

4. Discussion

While maternal asymptomatic infection with HBV has been

Fig. 3. Funnel plot for all studies evaluating the association between chronic hepatitis
B infection and placental abruption.
associated with increased antepartum hemorrhage [16], gestational
diabetes mellitus [17], preterm birth [18], and fetal growth re-
striction [16], one intriguing finding was on the occurrence of the
placental complications including placental abruption and placenta
previa. While several epidemiological studies have found a positive
association between CHB infection and the risk of placental
abruption as well as placenta previa, the magnitude of this asso-
ciation varies and other studies have reported conicting ndings:
a trend toward reduction of placental abruption and placenta
previa in women with CHB infection [8e10]. Given the large
number of women world-wide with CHB infection [19,20], any
potential causal association between CHB infection and the

Fig. 4. Forest plots for the meta-analysis of the association between chronic hepatitis B infection and placenta previa.
 Q.T. Huang et al. / Placenta 35 (2014) 539e545
Fig. 5. Identication of studies acting as sources of heterogeneity in placenta previa by
Galbraith plot. Each circle represents a separate study.
placental complications could have a profound public health. Our
meta-analysis found no evidence of signicant association between
CHB infection and an increased risk of placental abruption and
placenta previa.
Some recent studies had conrmed an independent association
between CHB infection and gestational diabetes mellitus [7,21]. It
was postulated that the association between CHB infection and the
development of gestational diabetes mellitus involved increased
insulin resistance induced by chronic subclinical inammation
[22e24]. Moreover, a higher prevalence of preterm delivery had
been observed in women with CHB infection by several epidemi-
ological studies [5,16]. As inammation was one of the most com-
mon risk factors for preterm labor [25,26]. Therefore, it is plausible
that low grade inammation induced by CHB infection is partially
responsible for the increased risk of gestational diabetes mellitus
and preterm delivery. In this meta-analysis, we also observed
higher frequency of preterm birth in the studies which reported a
trend toward increase of placental abruption and placenta previa in
women with CHB infection [5,7,8].
Numerous studies have shown that trophoblast cells play
important roles during placental development [27,28]. Placental
trophoblasts are not only structural and biochemical barriers
Fig. 6. Forest plots for the meta-analysis of the association between chronic hepatitis B infection and placenta previa (after removing two studies which contributed for the most
heterogeneity among the studies).
543
Fig. 7. Funnel plot for all studies evaluating the association between chronic hepatitis
B infection and placenta previa (after removing two studies which contributed for the
most heterogeneity among the studies).
between the maternal and the fetal compartment during preg-
nancy, but also important for its capacity to generate angiogenesis
and growth factors to promote vascularization of the placenta
during its development. A recent publication demonstrated that
inammation could decrease extravillous trophoblast invasion
[29], thus contributing to defective deep placentation and the
associated placental complications [11]. Originally, we speculated
that there was increased risk of the placental complications in
women with CHB infection. However, our meta-analysis found no
such evidence of this association. This could be partially explained
by the complex immune response during hepatitis B virus infec-
tion [30]. Of note, the immune response against the virus repre-
sents a key factor in determining infection outcome from immune
tolerance, chronic inammation to life threatening complications
[31e33]. Migration and invasive capacity of trophoblasts were
closely associated with proper placental implantation and spiral
arteries remodeling [11]. Previous evidences have suggested that
abnormal implantation and impaired spiral arteries remodeling
were involved in the pathogenesis of placenta previa and
544 Q.T. Huang et al. / Placenta 35 (2014) 539e545
placental abruption [11,27]. It had been showed that hepatitis B
virus X protein could enhance migration and invasive capacity in
some types of cancer cells [34,35]. Thus, it is plausible that a
higher migration and invasive capacity of trophoblasts could be
observed in women with CHB infection. On the other hand, sub-
clinical inammation caused by CHB infection could induce tro-
phoblasts' dysfunction and might be responsible for the abnormal
implantation and impaired spiral arteries remodeling. However,
up till now only few studies had explored impact of hepatitis B
virus on the trophoblasts' function [36,37]. Therefore, knowledge
on this eld was largely unknown.
To the best of our knowledge, this is the first systematic review
and meta-analysis to synthesize currently available observational
studies investigating the impact of CHB infection on the placental
complications. To some extent, several limitations of this meta-
analysis should be noted. First, the small sample sizes made it
impossible to explore other placental complications such as
placenta accrete/increta in the present study. In the future, more
original studies are needed to make our conclusions more reliable
and accurate. Second, this meta-analysis is unable to solve prob-
lems with some confounding factors which are inherent in the
included studies. Some important confounders such as smoking
and previous pregnancy history have not been measured with
sufcient precision in most of published studies. However, they are
the most potential confounders of the association between CHB
infection and the placental complications. Third, none of the
studies selected in our meta-analysis provided the degree of HBV
load. Therefore, we were unable to conduct a dose-response anal-
ysis to assess the relationship between these variables more
precisely.
Despite these limitations, this meta-analysis also demonstrated
some advantages. First, no publication bias was detected indicating
that the whole pooled results should be unbiased. Second, the
quality of included studies in the present meta-analysis was satis-
factory and met our inclusion criterion.
5. Conclusion
In conclusion, this meta-analysis evaluated the association be-
tween CHB infection and the placental complications and sug-
gested that CHB infection might be not associated with an
increased risk of placental complications including placental
abruption and placenta previa. Further well-designed studies tak-
ing potential confounding factors into account may eventually
provide a better, comprehensive understanding of the association
between CHB infection and placental abruption as well as placenta
previa.
Conict of interest
None to declare.
Author contributions
Conceived and designed the experiments: QTH JHC. Performed
the experiments: SSW GXC. Analyzed the data: SSW YYX LLH QL.
Contributed reagents/materials/analysis tools: MZ YHY. Wrote the
paper: QTH SSW. All of the authors have read the paper and
approved for publication.
Acknowledgments
This work was supported by the President Grant from Nanfang
Hospital (2012C026) to Dr. Qi Tao, HUANG.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.placenta.2014.05.007.
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