Hypertension Research

20
Bleeding complications in preeclampsia
In Pregnancy

ORIGINAL ARTICLE Reprint request to:

Hironobu Hyodo, M.D., Ph.D.,

Risk factors for bleeding Department of Obstetrics and

Gynecology, Tokyo Metropolitan
Bokutoh Hospital, 4-23-15
complications of postoperative Kotobashi, Sumida-ku, Tokyo
130-8575, Japan.

prophylactic anticoagulation E-mail: hyodo-tky@umin.ac.jp

Key words:
therapy after cesarean section in bleeding complication, cesarean
section, heparin, preeclampsia,

preeclampsia cases prophylactic anticoagulant

Received: March 29, 2018

Revised: July 3, 2018
Naoya Tsujimoto1,2, Hironobu Hyodo2, Sorahiro Sunagawa2,3, Accepted: July 4, 2018
J-STAGE Advance published date:
Koji Kugu2 July 31, 2018

1
DOI:10.14390/jsshp.HRP2018-002
Department of Obstetrics and Gynecology, The University of Tokyo Hospital, Tokyo,
Japan, 2Department of Obstetrics and Gynecology, Tokyo Metropolitan Bokutoh Hospital,
Tokyo, Japan, 3Department of Obstetrics and Gynecology, Okinawa Prefectural Nanbu
Medical Center and Children’s Medical Center, Haebaru, Okinawa, Japan

Aim: This study aimed to identify risk factors for bleeding complications of postoperative prophylactic anticoagulation
after cesarean section in preeclampsia cases.
Methods: A total of 68 cases of preeclampsia or superimposed preeclampsia at a tertiary perinatal center in Tokyo
between 2012 and 2017 were recruited for this study. Bleeding complications were defined as subcutaneous,
subfascial, or intraperitoneal hematoma detected by ultrasonography or computed tomography. Associations of
clinical and laboratory data with bleeding complications were assessed by univariate and multivariate analyses.
Results: Bleeding complications were recorded in nine cases: subcutaneous hematoma in four cases, subfascial
hematoma in four cases, and intraperitoneal hematoma in one case. Univariate analysis revealed preoperative
platelet count and 24-h urine protein level to be associated with bleeding complications. Moreover, multivariate
logistic regression analysis revealed preoperative platelet count (odds ratio, 0.867; 95% confidential interval,
0.756–0.994; P = 0.04) and 24-h urine protein level (odds ratio, 1.498; 95% confidential interval, 1.031–2.176;
P = 0.03) to be independent risk factors for bleeding complications.
Conclusion: Preoperative platelet count and 24-h urine protein level may help to identify patients at increased
risk for bleeding complications.

Venous thromboembolism (VTE), which includes deep
vein thrombosis (DVT) and pulmonary embolism (PE),
is a leading cause of maternal morbidity and mortality
in Japan.1) Not only pregnancy itself, but other factors
during pregnancy and postpartum increase the risk
of VTE. Among these, cesarean section is one of the
most important risk factors.2) In Japan, the incidences
of DVT and PE after cesarean section are 0.04% and
0.06%, respectively, and cesarean section increases
the risk of developing DVT and PE by 5- and 22-fold,
respectively.2,3) As cesarean section has become more
common in Japan, preventing VTE after the procedure is
becoming all the more important.
Preeclampsia, a clinical entity included in hypertensive
disorders of pregnancy (HDP), is characterized by
hypertension, proteinuria, and multiple organ
complications. Although the exact pathogenesis of
preeclampsia is still unknown, it is thought to involve
endothelial dysfunction resulting from an imbalance of
pro-angiogenic and anti-angiogenic factors.4) As maternal
endothelial damage activates the coagulation system,
cesarean section in preeclampsia may increase the risk
of VTE.5) Consideration of prophylactic anticoagulation
therapy for women with preeclampsia after cesarean
section is recommended by the guidelines of the Japan
Society of Obstetrics and Gynecology (JSOG) and

20 Hypertens Res Pregnancy 2018; 6: 20–25 Hypertension Research in Pregnancy © 2018 Japan Society for the Study of Hypertension in Pregnancy

Japan Association of Obstetricians and Gynecologists
(JAOG).6)
While preeclampsia causes a hypercoagulable state,
it is often complicated by liver dysfunction, renal
dysfunction, uncontrolled hypertension, and disseminated
intravascular coagulation (DIC).4) These complications
may increase the risk of bleeding events associated with
anticoagulation therapy. In a previous survey conducted
in 66 hospitals in Japan, 9% of hospitals reported
accidental complications associated with anticoagulation
therapy.7)
In order to reduce the risk of bleeding events, the
Japan Society for the Study of Hypertension in Pregnancy
(JSSHP) recommends evaluating body mass index (BMI),
renal function, and blood pressure of women with HDP
before prophylactic anticoagulation therapy.8) However,
there is insufficient clinical evidence on preventive
anticoagulation therapy for preeclamptic women who
are at higher risk for bleeding complications. Thus, this
study assessed risk factors for bleeding complications
of prophylactic anticoagulation therapy after cesarean
section in preeclampsia cases.
Materials and methods
A retrospective study was conducted at Tokyo
Metropolitan Bokutoh Hospital, a tertiary perinatal center
in Tokyo. The Diagnosis Procedure Combination (DPC)
database was used to identify cases of HDP in which
cesarean section was performed between June 2012 and
May 2017. Medical records were reviewed to confirm
whether the diagnosis of preeclampsia or superimposed
preeclampsia was correct according to JSSHP criteria.8)
Cases of fetal growth restriction without any other
maternal features of preeclampsia were excluded. This
study was approved by the institutional review board of
Tokyo Metropolitan Bokutoh Hospital.
Pharmacological and non-pharmacological methods
were used to prevent VTE. Compression stockings
were worn during the perioperative period. Intermittent
pneumatic compression devices were set postoperatively
and removed by postoperative day 1. As a prophylactic
anticoagulant, 5,000 units of unfractionated heparin
(UFH) was administered subcutaneously; once six h
after the operation and/or at 6 a.m. on postoperative day
1, and every 12 h afterwards for two days. UFH was
discontinued when bleeding complications were observed
during anticoagulation therapy.
All cases were divided into two groups based on
the presence or absence of postoperative bleeding
complications. Bleeding complications were defined as
subcutaneous, subfascial, and intraperitoneal hematoma
detected by ultrasonography or computed tomography.
It was left to the doctors’ discretion whether to perform
N. Tsujimoto et al.
imaging examinations when signs and symptoms
suggesting bleeding complications were noted. The
following factors were analyzed and compared between
the two groups: age, preoperative BMI, use of
intravenous antihypertensive agents, intraoperative blood
loss, symptomatic VTE, and preoperative laboratory
data such as serum alanine aminotransferase (ALT),
aspartate aminotransferase (AST), creatinine, platelet
count, activated partial thromboplastin time (APTT),
prothrombin time (PT) activity, fibrinogen, 24-h urine
protein level, 24-h urine volume, and creatinine clearance.
Exclusion criteria
The following cases were excluded from this study:
1) lack of data on factors of interest; 2) lack of
postoperative UFH; 3) discontinuation, dose reduction,
or extended-interval dosing of UFH due to reasons
other than bleeding complications during prophylactic
anticoagulation therapy.
Statistical analysis
Continuous variables are presented as median and
interquartile range (IQR), and categorical variables as
number and percent. Continuous variables were analyzed
with the Mann-Whitney U-test, and categorical variables
were analyzed with Fisher’s exact test. Variables
with statistical differences were selected to perform
multivariate logistic regression analysis for independent
risk factors. Box-Cox transformations were performed on
the selected variables to account for non-normality. P <
0.05 was considered statistically significant. All statistical
analyses were performed using JMP 14 (SAS Institute
Inc., Cary, NC, USA).
Results
Preeclampsia and superimposed preeclampsia accounted
for 6.1% (94/1,536) of the total cesarean sections
performed in the 5-year study period. Prophylactic
anticoagulation therapy was not performed in one case
due to decreased renal function. Postoperative bleeding
complications were recorded in 11 of 93 cases (11.8%).
Among the 93 cases, data were lacking in 21. The
discontinuation, dose reduction, or extended-interval
dosing of heparin was recorded in four cases. The final
study population consisted of nine cases in the bleeding
group and 59 in the non-bleeding group (Figure 1).
Bleeding complications included four subcutaneous
hematomas, four subfascial hematomas, and one
intraperitoneal hematoma. These complications were
detected within four days after cesarean section.
Reoperation to remove the hematoma was performed
in two cases of subfascial hematoma. An interventional
radiology procedure was performed to arrest bleeding
Hypertens Res Pregnancy 2018; 6: 20–25 21
Bleeding complications in preeclampsia
Figure 1. Selection of study population.
Cesarean sections were performed in 1,536 cases during the 5-year study period. Prophylactic anticoagulation therapy
was performed in 93 cases of preeclampsia or superimposed preeclampsia. The final study population consisted of nine
cases in the bleeding group and 59 cases in the non-bleeding group.
from the left superior vesical artery in one case of
intraperitoneal hematoma.
Univariate analysis revealed that preoperative platelet
counts were significantly lower in the bleeding group
(P = 0.03) and that levels of preoperative 24-h urine
protein were significantly higher in the bleeding group
(P = 0.04), as compared to the non-bleeding group
(Table 1A). Although cases in the bleeding group tended
to have low BMIs and high serum levels of AST and
creatinine, there were no significant differences in these
factors between the two groups. In multivariate logistic
regression analysis, both preoperative platelet count
(odds ratio, 0.867; 95% confidential interval, 0.756–
0.994; P = 0.04) and 24-h urine protein level (odds ratio,
1.498; 95% confidential interval, 1.031–2.176; P = 0.03)
were independent risk factors for bleeding complications.
Discussion
The incidence of bleeding complications in cases of
preeclampsia and superimposed preeclampsia treated with
postoperative prophylactic anticoagulation therapy was
11.8% (11/93) in this study. Only a few reports have been
published on bleeding complications during postoperative
anticoagulation therapy that focused on preeclamptic
women7). The incidence of bleeding events has been
22 Hypertens Res Pregnancy 2018; 6: 20–25
reported to range from 0.7–1.4%9,10) in preeclamptic
cases administered postoperative prophylactic UFH. The
following reasons may account for the discrepancy in
incidence of bleeding complications between previous
studies and the present study. First, the definition of
bleeding complications in the present study differed
from those of the previous reports. Because it was left
to the doctors’ discretion whether imaging examinations
were performed and the hematomas detected by
imaging examinations were regarded as bleeding
complications regardless of size, the present study
may have overestimated the incidence of bleeding
complications. Second, the previous reports did not limit
their subjects to preeclamptic women; all women after
cesarean section received heparin, excluding those at risk
of developing bleeding complications. On the other hand,
the present study limited subjects to preeclamptic women
and found a higher incidence of bleeding complications.
This may suggest that women with preeclampsia
undergoing cesarean section are at increased risk of
developing bleeding complications after prophylactic
anticoagulation therapy.
Conservative treatment may be reasonable for cases
of subcutaneous hematoma, but some cases of active
bleeding, severe pain, or severe anemia may require
invasive treatment such as reoperation or interventional
 N. Tsujimoto et al.

Table 1. Univariate (A) and multivariate (B) analyses of bleeding complications

A
Bleeding group Non-bleeding group
P value
(n = 9) (n = 59)
Age (years) 36 (34.0–37) 36 (33.5–38) 0.70
BMI (kg /m2) 23.5 (23.00–25.2) 26.8 (24.05–29.0) 0.06
Use of intravenous antihypertensive agents (n) 3 (33.3%) 24 (40.7%) 1.00
Intraoperative blood loss (ml) 475 (385–657) 700 (437–905) 0.17
Symptomatic VTE (n) 0 (0%) 0 (0%) 1.00
ALT (IU/l) 27 (14.0–40.0) 15 (9.5–24.5) 0.07
AST (IU/l) 30 (19–40.0) 21 (16–28.5) 0.10
Cre (mg /dl) 0.8 (0.7–0.9) 0.7 (0.6–0.8) 0.09
Plt (104 /μl) 16.2 (12.5–16.7) 19.3 (16.0–24.0) 0.03
APTT (sec) 32.9 (27.5–33.3) 28.7 (27.0–30.1) 0.13
PT activity below the lower limit of normal ( < 75%) (n) 0 (0%) 0 (0%) 1.00
Fib (mg /dl) 388 (343.0–440.0) 410 (337.5–473.5) 0.62
24-h urine protein (g) 5.248 (3.339–6.719) 2.373 (0.748–5.591) 0.04
24-h urine volume (ml) 1,850 (1,600–2,800) 1,600 (1,200–2,100) 0.37
Cre clearance (ml /min) 89.2 (80.7–93.1) 100.9 (78.0–126.7) 0.30

B
Odds ratio 95% CI P value
4
Plt (10 /μl) 0.867 0.756–0.994 0.04
24-h urine protein excretion (g) 1.498 1.031–2.176 0.03
Continuous variables are presented as median and interquartile range, and categorical variables as number and
percent. Box-Cox transformations were performed on variables (Plt and 24-h urine protein excretion level) for the
multivariate analysis.
BMI, body mass index; VTE, venous thromboembolism; ALT, alanine aminotransferase; AST, aspartate
aminotransferase; Cre, creatinine; Plt, platelet; APTT, activated partial thromboplastin time; PT, prothrombin time;
Fib, fibrinogen; CI, confidence interval.

radiology procedures. Intra-abdominal bleeding and
hematoma have been reported as the leading indication
for reoperation after cesarean section.11) However, it
is sometimes difficult to detect the bleeding point in
reoperation due to poor visualization of the surgical
field.12) In the present study, reoperation was performed
to remove hematomas and to relieve pain arising
from compression by hematomas, rather than to
achieve hemostasis. Currently, interventional radiology
is preferred as a minimally invasive treatment and due
to its high success rate in achieving hemostasis.12) In
this study, interventional radiology was used to stop
bleeding from the left superior vesical artery in one case
of intraperitoneal hematoma.
The relationship between proteinuria and adverse
maternal outcomes in preeclampsia has been reported
in many studies.13–16) Although some of these studies
reported that heavy proteinuria increases adverse maternal
outcomes including reoperation, blood transfusion, acute
renal failure, and thrombocytopenia,13,14) others suggest
that the extent of proteinuria is not associated with
adverse maternal outcomes.15,16) The present study found
24-h urine protein level to be an independent risk factor
for bleeding events. The extent of proteinuria, which may
reflect renal endothelial damage, may also reflect vascular
vulnerability, which can lead to bleeding events.
Preeclamptic women tend to have lower platelet
counts than normal pregnant women.17) A previous
report suggested that increased platelet turnover caused
by endothelial injury may be one of the reasons for the
lower platelet count.17) Once preeclampsia is complicated
by HELLP syndrome, consumption of platelets may
increase and promote hemorrhagic tendency. Although
thrombocytopenia is defined as a platelet count less than
100,000/ μl according to the diagnostic standard proposed
by Sibai et al.,18) the results of the present study suggest
that preeclamptic women should be recognized as being
at high risk for bleeding complications by anticoagulant
therapy even when preoperative platelet counts are not
abnormally low.
According to Japanese drug manufacturers, heparin
should not be administered or should be administered

Hypertens Res Pregnancy 2018; 6: 20–25 23

Bleeding complications in preeclampsia
with caution to patients with severe hypertension because
heparin may cause injured vessels to bleed. The JSSHP
also recommends that prophylactic anticoagulants should
not be used or postponed in women with poorly controlled
hypertension.8) In the present study, a significant
difference was not observed in the use of intravenous
antihypertensive agents, which was used as a surrogate
variable for severe hypertension because antihypertensive
agents were intravenously administered in all severe
hypertension cases. Since blood pressure was under
control in all cases after the initiation of intravenous
injection therapy, the use of intravenous antihypertensive
agents may not have reflected uncontrolled hypertension.
Cases of preeclampsia which required discontinuation,
dose reduction, or extended-interval dosing of heparin
for reasons other than bleeding were excluded from this
study. Most of these cases had reduced renal function,
which was the reason for their exclusion. This may
explain the lack of a significant difference in renal
function between the bleeding and non-bleeding groups.
Because the clearance of heparin from blood could be
delayed in patients with renal impairment,19) heparin
should be administered carefully to such patients.
However, there have been no guidelines or proposals
on optimizing heparin administration for preeclamptic
women with renal impairment. A survey involving 66
hospitals revealed that prophylactic anticoagulation
therapy was modified and optimized for women with
HDP in only half of the hospitals.7) In the present study,
the optimization of heparin administration for cases of
renal impairment was left to the attending physicians’
discretion.
One of the limitations of this study is its retrospective
design. Moreover, the exclusion of many cases decreased
the statistical power of the analysis. Excluded cases
included 21 cases with missing data, particularly with
respect to the 24-h urine collection test. The spot urinary
protein/creatinine ratio (P/C) is currently used widely as
a rapid alternative test to the 24-h urine collection test.20)
Thus, further studies using the P/C ratio may be helpful
for evaluating the relationship between proteinuria and
bleeding complications in emergent cases. Second,
the number of bleeding complications may have been
underestimated since whether or not to perform imaging
examinations was left to the doctors’ discretion. The
third limitation relates to the dosage and administration
of prophylactic anticoagulants. UFH was administered
as an anticoagulant, but low-molecular-weight heparins
(LMWH) are now widely used as an alternative for
prophylactic anticoagulation therapy.21) The advantages
of LMWH over UFH include lower risks of bleeding
complications, heparin-induced thrombocytopenia,
and osteoporosis.22) Although the Royal College of
Obstetricians and Gynaecologists (RCOG) reported
24 Hypertens Res Pregnancy 2018; 6: 20–25
contraindications for LMWH use as an anticoagulant, this
recommendation is based on evidence from non-pregnant
populations.21) Further studies may be needed to assess
the impact of anticoagulants other than UFH on bleeding
complications in preeclampsia.
In conclusion, preoperative platelet count and degree
of proteinuria should be considered when prophylactic
anticoagulation therapy is performed in women with
preeclampsia after cesarean section. Even after initiating
anticoagulation therapy, patients should be followed
carefully with physical examinations, blood tests,
and ultrasounds for the early detection of bleeding
complications.
Acknowledgement
None.
Conflict of interest
The authors hereby declare that there are no conflicts of
interest regarding the contents of this article.
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