European Journal of Obstetrics & Gynecology and Reproductive Biology 201 (2016) 711

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European Journal of Obstetrics & Gynecology and

Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

Placenta previa with early opening of the uterine isthmus is associated

with high risk of bleeding during pregnancy, and massive
haemorrhage during caesarean delivery
M. Goto a, J. Hasegawa a,b,*, T. Arakaki a, H. Takita a, T. Oba a, M. Nakamura a, A. Sekizawa a
a
Department of Obstetrics and Gynaecology, Showa University School of Medicine, Tokyo, Japan
b
Department of Obstetrics and Gynaecology, St. Marianna University School of Medicine, Kanagawa, Japan

A R T I C L E I N F O A B S T R A C T

Article history: Objective: To demonstrate the relationship between the timing of opening of the uterine isthmus and
Received 14 September 2015 bleeding during pregnancy and caesarean section in patients with placenta previa.
Received in revised form 25 December 2015 Methods: A prospective observational study was conducted at a single perinatal centre. All patients with
Accepted 8 March 2016
placenta previa, diagnosed between 20 and 22 weeks of gestation, who were followed up at the study
hospital and underwent caesarean section were enrolled.
Keywords: The condition of the uterine isthmus was examined every 2 weeks. The timing (in gestational weeks)
Placenta previa
of complete opening of the uterine isthmus was determined. Patients were divided into two groups:
Uterine isthmus
patients in whom the uterine isthmus opened before 25 weeks of gestation (EO-previa), and patients in
Caesarean section
Haemorrhage whom the uterine isthmus opened after 25 weeks of gestation (LO-previa). The frequency of bleeding
Atonic bleeding during pregnancy and the amount of intra-operative bleeding were compared between the two groups.
Ultrasound Results: Forty-four cases of EO-previa and 55 cases of LO-previa were analysed. Complete placenta
previa at delivery was observed more frequently in the EO-previa group than in the LO-previa group
(88.6% vs 47.3%, p < 0.001). An emergency caesarean section due to active bleeding was performed more
frequently in the EO-previa group (48%) than in the LO-previa group (25%) (p = 0.021). The frequency of
massive haemorrage (>2500 ml) during caesarean section was higher in the EO-previa group than in the
LO-previa group (25% vs 9%, p = 0.033).
Conclusion: Placenta previa was associated with a high risk of bleeding leading to emergency caesarean
section during pregnancy, and massive haemorrhage during caesarean section in patients in whom the
uterine isthmus opened before 25 weeks of gestation.
2016 Elsevier Ireland Ltd. All rights reserved.

Introduction lack of a clear zone [2,3] are currently considered to be sonographic

Placenta previa is a major cause of massive haemorrhage during
pregnancy and delivery. However, massive haemorrhage does not
occur in all cases of placenta previa, and the prediction of cases that
are at high risk for massive haemorrhage is important for
management of the condition. As such, there has been a great
deal of discussion regarding the prediction of cases at high risk of
placenta previa through sonographic evaluation. Short cervical
length [1], placenta lacunae, sponge-like echo in the cervix, and the
* Corresponding author at: Department of Obstetrics and Gynaecology, St.
Marianna University School of Medicine, 2-16-1 Sugao Miyamaeku, Kawasaki 216-
8511, Kanagawa, Japan. Tel.: +81 449778111.
E-mail address: hasejun@oak.dti.ne.jp (J. Hasegawa).
risk factors for massive bleeding.
The uterine isthmus is usually closed during early pregnancy,
but opens with advancing gestation. This phenomenon also occurs
in patients with placenta previa. Consequently, it was hypothe-
sized that patients with placenta previa in whom the uterine
isthmus opens earlier are more likely to experience complications,
such as sudden bleeding during pregnancy and massive haemor-
rhage during caesarean section, because changes in the lower part
of the uterus that occur during slight contractions may lead to
separation of the placenta and the decidua during pregnancy, and
because atonic bleeding may occur frequently when the uterine
isthmus is dilated and expanded for a long period of time (from
earlier gestation to delivery by caesarean section).
This study distinguished the uterine isthmus from the uterine
cervix by precise ultrasound examinations. The aim of this study
was to demonstrate the relationship between the timing of

http://dx.doi.org/10.1016/j.ejogrb.2016.03.012
0301-2115/ 2016 Elsevier Ireland Ltd. All rights reserved.

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8 M. Goto et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 201 (2016) 711
opening of the uterine isthmus and bleeding during pregnancy and
caesarean section in patients with placenta previa.
Materials and methods
A prospective cohort study was performed at Showa University
Hospital, Tokyo, Japan between 2009 and 2014. The study
population included all patients with placenta previa, diagnosed
between 20 and 22 weeks of gestation, who were followed up at
the study hospital and underwent caesarean section.
Placenta previa was diagnosed by experienced obstetricians
based on a transvaginal ultrasonic nding of placental tissue
covering the lowest ostium of the uterine cavity (amniotic cavity)
between 20 and 22 weeks of gestation. During the ultrasound
examination, the pregnant patients were placed in a supine
position after urination. Ultrasound examination was taken when
uterine contraction was not investigated. The uterine cervix was
dened as same as the endocervical mucosa (cervical gland), which
was usually visualized as a leaf-like echo area with low
echogenicity compared with the surrounding tissues. The uterine
isthmus was dened as the region from the highest point of the
cervical gland to the lowest point of the internal ostium of
uterine cavity.
Following a diagnosis of placenta previa, the uterine isthmus,
the uterine cervix and the location of the placenta were observed
by transvaginal ultrasound every 2 weeks. As the uterine isthmus
opens with advancing gestation, the timing (in gestational weeks)
of opening was detected and recorded. An open isthmus was
dened as a completely opened isthmus (i.e. an isthmus region was
undetectable); if this condition was not met, the isthmus was
considered to be closed (Figs. 1 and 2).
The subjects were divided into two groups: those in whom the
uterine isthmus opened before 25 weeks of gestation (early opening
isthmus; EO-previa) and those in whom the uterine isthmus opened
after 25 weeks of gestation (late opening isthmus; LO-previa). The
frequency of bleeding during pregnancy, and the amount of bleeding
Fig. 1. Placenta previa with open isthmus. The uterine cervix was dened as same as the endocervical mucosa (cervical gland ~~), which was usually visualized as a
leaf-like echo area with low echogenicity compared with the surrounding tissues.
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during caesarean section were compared between the two groups.
Three authors (M.G., T.A. and H.T.) used ultrasound images to
determine if the isthmus was open. When one author reported a
different diagnosis from the other two authors, the diagnosis made
by the two authors was taken.
When a hysterectomy was performed following a caesarean
section, the amount of bleeding during the hysterectomy was
included. In the present study, massive haemorrhage was dened
as more than 2500 ml during surgery.
Elective caesarean sections were planned between 36 and
37 weeks of gestation. Emergency caesarean sections were
performed before planned caesarean sections in the case of more
than 100 ml of bleeding, uncontrollable uterine contractions or
premature rupture of membranes.
All statistical analyses were performed using Statistical Package
for Social Science Version 20.0J (IBM Corp., Armonk, NY, USA).
Continuous variables were reported as median (range) and
compared using the MannWhitney U-test. Categorical variables
were reported as percentages and compared using Fishers exact
test. Signicant variables associated with EO-previa on univariate
analysis, including complete placenta previa, were used in the
multivariable analysis. p < 0.05 was considered to indicate
statistical signicance.
This study was approved by the hospital ethics committee.
Informed consent was obtained in writing from all patients before
they underwent ultrasound scans.
Results
Two hundred and ninety cases of suspected placenta previa
were identied between 20 and 22 weeks of gestation. The
suspected placenta previa resolved at delivery in 189 cases, so this
study included 101 patients with placenta previa. Two cases were
excluded: one case in which intra-uterine fetal death occurred due
to another perinatal complication, and one case of a twin
pregnancy. Thus, 99 cases were classied into two groups based
 M. Goto et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 201 (2016) 711 9

Fig. 2. Placenta previa with closed isthmus. The uterine cervix was dened as same as the endocervical mucosa (cervical gland ~~). The uterine isthmus was dened as the
region from the highest point of the cervical gland to the lowest point of the internal ostium of the uterine cavity (between ~ and ).

on the timing of opening of the uterine isthmus. The three authors Table 1
Background characteristics between groups.
agreed on the diagnosis of an open or closed isthmus for 96% of
ultrasound images (607/635). Forty-four cases were classied as Opening of uterine isthmus p-Value
EO-previa and 55 cases were classied as LO-previa. The opening of Before 25 weeks After 25 weeks
the uterine isthmus occurred after a median gestation period of of gestation of gestation
22 weeks (range 2024 weeks) in the EO-previa group, and (n = 44) (n = 55)
30 weeks (range 2537 weeks) in the LO-previa group. There were Opening of isthmus, 22 (2024) 30 (2537)
no cases in which the isthmus opened gradually during gestational weeks
transvaginal investigation with or without fundal pressure test. Maternal age (years) 35 (2649) 36 (2542) 0.772
Gravida 1 (04) 1 (04) 0.158
The background characteristics of patients in the EO-previa
Parity 1 (02) 0 (02) 0.327
and LO-previa groups are shown in Table 1. There were no Primipara 45.5% (20) 54.5% (30) 0.369
signicant differences between the two groups, and cervical Previous caesarean section 22.7% (10) 9.1% (5) 0.110
length at 28 weeks of gestation did not differ between the two Cervical length at 34 (1846) 34 (1846) 0.984
groups. 28 weeks (mm)
Placenta on anterior wall 20.5% (9) 10.9% (6) 0.188
The fetal and maternal outcomes in terms of bleeding are
shown in Table 2. There was no signicant difference in the Data presented as median (range) or % (n).

Table 2
Clinical outcomes between groups.

Opening of uterine isthmus p-Value

Before 25 weeks of gestation (n = 44) After 25 weeks of gestation (n = 55)

During pregnancy
Bleeding during pregnancy 64% (28) 49% (27) 0.148
Emergency caesarean section due to bleeding 48% (21) 25% (14) 0.021
Caesarean section due to PROM or uterine contractions 4.6% (2) 3.6% (2) 0.663

During caesarean section

Complete placenta previa at delivery 88.6% (39) 47.3% (26) <0.001
Amount of bleeding during operation (ml) 1823 (3256050) 1510 (3957580) 0.013
Massive bleeding during operation (>2500 ml) 25% (11) 9% (5) 0.033
Placenta accreta 11.4% (5) 1.8% (1) 0.085

Neonatal outcomes
Gestational weeks at delivery 36 w 0 d (25 w 5 d37 w 5 d) 36 w 5 d (25 w 3 d38 w 0 d) 0.305
Neonatal birth weight (g) 2499 (9213211) 2574 (8333893) 0.281
Apgar score
1 min 7 (19) 8 (19) 0.073
5 min 9 (410) 9 (210) 0.260
Umbilical artery pH 7.31 (7.17.39) 7.31 (7.167.54) 0.727

PROM, premature rupture of membrances; w, weeks; d, days.

Data presented as median (range) or % (n).

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10 M. Goto et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 201 (2016) 711
Table 3
Results of the multivariate analysis for emergency caesarean section due to
bleeding, and massive bleeding during caesarean section.
Odds ratio
(95% condence
interval)
Emergency caesarean section due to bleeding
Early-opening 2.7 (1.16.2)
uterine isthmus
Massive bleeding during caesarean section
Early-opening 3.3 (1.110.5)
uterine isthmus
Covariate: complete previa.
Emergency caesarean section due to bleeding was dened as a caesarean section
performed before a planned caesarean section due to uncontrollable bleeding of
more than 100 ml. Massive bleeding was dened as more than 2500 ml of bleeding
during surgery.
frequency of bleeding during pregnancy in the two groups (EO-
previa, 64%; LO-previa, 49%). An emergency caesarean section was
performed due to active bleeding before the planned caesarean
section in 48% and 25% of the EO-previa and LO-previa cases,
respectively (p = 0.021). Complete placenta previa was observed
more often in the EO-previa group than the LO-previa group (88.6%
vs 47.3%, p < 0.001). The median amount of bleeding during
caesarean section was 1823 ml in the EO-previa group and 1510 ml
in the LO-previa group (p = 0.013). The frequency of massive
haemorrhage during caesarean section was higher in the EO-previa
group than the LO-previa group (25% vs 9%, p = 0.033).
In the EO-previa group, the adjusted odds ratio for emergency
caesarean section due to bleeding was 2.7 [95% condence interval
(CI) 1.16.2], while that for massive haemorrhage was 3.3 (95% CI
1.110.5) (Table 3).
Discussion
This study found that the frequency of emergency caesarean
section due to active bleeding during pregnancy, and the amount of
bleeding during caesarean section were signicantly higher in the
EO-previa group than the LO-previa group, whereas the frequency
of bleeding during pregnancy did not differ between the two
groups.
The uterine isthmus opens gradually with advancing gestation.
It has been reported that only one-quarter of the uterine isthmus is
open at 13 weeks of gestation [4]. In a previous investigation, the
authors found that the uterine isthmus was completely open at
20 weeks of gestation in half of cases with normal placenta.
However, the present study found that the uterine isthmus was
completely open in 19% (19/99) of patients in the study population.
In cases of LO-previa, as the uterine isthmus is not open at
20 weeks of gestation, the placenta may develop predominantly in
the lower uterine body instead of in the uterine isthmus.
Consequently, it is hypothesized that the decidual tissue of the
uterine isthmus does not receive rich blood ow in patients with
LO-previa. However, in patients with EO-previa, as the placenta in
the uterine isthmus is likely to be developed from early gestation,
blood-rich decidua may form in the uterine isthmus. With uterine
contractions that occur with advancing gestation, decidua with a
rich blood ow is likely to undergo destructive changes, resulting
in bleeding during pregnancy. Consequently, emergency caesarean
section is required more frequently in patients with EO-previa than
in patients with LO-previa.
EO-previa was also associated with a high frequency of massive
haemorrhage during caesarean section. It was assumed that the
placenta widely covered the uterine isthmus which is difcult for
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the spiral artery to contract. Thus, atonic bleeding following
placental separation is more likely to occur in patients with EO-
previa. In previous studies, the length of the uterine cervix was
p-Value associated with massive haemorrhage and the frequency of
emergency caesarean section in patients with placenta previa
[1,5,6]. Fukushima et al. [6] investigated cases of placenta previa
that were categorized based on a cervical length of 30 mm, and
0.023
demonstrated that a shorter cervical length was a risk factor for
both massive intra-operative blood loss and placental adherence.
Mimura et al. [1] also concluded that a short cervical length, which
0.039
indicated the presence of an extended lower uterine segment, was
associated with massive bleeding during caesarean section
because the condition is likely to involve atonic bleeding after
placental removal. Similar to previous studies that investigated the
association with the uterine cervix, this study found that massive
haemorrhage occurred frequently during caesarean section in
patients with EO-previa due to weak contraction at the isthmus
following placental separation. However, it was assumed that
there was less extension of the lower uterine segment and the
attached area of the isthmus in patients with LO-previa than in
patients with EO-previa.
A limitation of the present study is the determination of when
the isthmus opened. Although there were no cases in which the
isthmus opened gradually during transvaginal investigation, the
effects of uterine contraction are considerable for such timing. As
ultrasound evaluations were performed every 2 weeks, a margin
of error of up to 2 weeks should be tolerated. In this study,
outcomes were compared between patients in whom the isthmus
opened before and after 25 weeks of gestation. Accurate
ultrasound diagnosis of placenta previa should be made after
opening of the isthmus, because the opening isthmus has a large
effect on placental migration. The authors believe that uterine
isthmus ndings following a diagnosis of placenta previa could
provide useful information for further management of placenta
previa.
Conclusion
Patients with placenta previa in whom the uterine isthmus
opened early showed a high risk for bleeding during pregnancy,
and massive haemorrhage during caesarean section, irrespective of
placental adherence and placental location (i.e. complete or
incomplete placenta previa). The results of this study, which
began accumulating data in the mid-gestational period, could lead
to improvements in fetal and maternal outcomes.
Conict of interest
None declared.
Funding
None.
Ethical approval
The study protocol was approved by the Institutional Review
Board of Showa University School of Medicine. Written informed
consent form was obtained from all patients.
References
[1] Mimura T, Hasegawa J, Nakamura M, et al. Correlation between the cervical
length and the amount of bleeding during cesarean section in placenta previa. J
Obstet Gynaecol Res 2011;37:8305.
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[3] Saitoh M, Ishihara K, Sekiya T, Araki T. Anticipation of uterine bleeding in
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[4] Hasegawa J, Nakamura M, Hamada S, Ichizuka K, Sekizawa A, Okai T. Opening of
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