CONTINUING MEDICAL EDUCATION JPOG NOV/DEC 2015 257

Management of Venous
2 SKP

Thromboembolism
in Pregnancy
Tam Wing Hung, MBChB (CUHK), MD (CUHK), FRCOG, FHKCOG, FHKAM (O&G)

INTRODUCTION
Pregnancy is a proinflammatory state
with activation of endothelial cells while
operative delivery and genital tract in-
jury can result in endothelial damage.
Venous dilatation and compression of
pelvic veins by the gravid uterus en-
courages venous formation in the lower
limbs. The increased levels of coagu-
lant factors such as factors VII and VIII,
fibrinogen, von Willebrand factor and
decreased levels of free protein S favor
coagulation while increased synthesis of
plasminogen activator inhibitors 1 and 2
prohibit fibrinolysis (Table 1). All compo-
nents of the classic Virchow’s triad are
present in pregnancy.

EPIDEMIOLOGY
Venous thromboembolism (VTE) is still a
major cause of maternal death in many
developed countries.2-4 It has been the
leading direct cause of maternal death in
the UK since 1985, accounting for 1.94
deaths per 100,000 maternities; but the
figures show a recent reduction to 0.79
per 100,000 maternities in the latest tri-
ennium (Confidential Enquiry into Ma-
ternal and Child Health, 2011). Maternal
mortality of 1.1 to 2.3 per 100,000 mater-
nities was reported in the US. 2,4,5 A lower
figure is reported was Sweden and the
Venous thromboembolism (VTE) is still a major cause of maternal death in many developed
countries.
mortality appears to have declined from
1.0 to 0.4 per 100,000 live births from the
1970s to 1990s. 6
The overall incidence of pregnan-
cy-related VTE reported worldwide is 1 to
2/1,000 and pregnancy increases a wom-
an’s VTE risk by 4 to 10 times in general.
Data from the US Agency for Healthcare
Research and Quality showed VTE rate
of 1.72 per 1,000 deliveries.5 The risk
was 38% higher for women aged above
35 and was 64% higher among black
women.5 Recent data from the National
Hospital Discharge Survey database and

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 258 JPOG NOV/DEC 2015
Table 1. Changes in the Coagulant Factors in Pregnancy (ACOG Practice
Bulletin no.123)1
Coagulant Factors
Procoagulants
Fibrinogen
Factor VII
Factor VIII
Factor X
Von Willebrand factor
Plasminogen activator inhibitor-1
Plasminogen activator inhibitor-2
Factor II
Factor V
Factor IX
Anticoagulants
Free Protein S
Protein C
Antithrombin III
⇑ increase ; ⇓ decrease; ⇔ no change
the US Agency for Healthcare Research
and Quality consistently suggest an in-
creasing trend in pregnancy related VTE
in the US. 5,7,8
The latest figure from the
US Agency for Healthcare Research and
Quality reported a 14% increase in the
rate of overall VTE-associated pregnan-
cy hospitalisations, pulmonary embo-
lism (PE); antepartum and postpartum
hospitalisations with VTE increased by
17% and 47%, respectively, from 1994
to 2009.8 A temporal increase in the like-
lihood of a VTE diagnosis in pregnancy
was observed for antepartum hospital-
isations from 2006 to 2009 when com-
pared with antepartum hospitalisations
in 1994 to 1997 (adjusted odds ratio,
1.62;95% CI,1.48-1.78). 8
In Scotland, VTE incidence rose
from 1.37 to 1.83 per 1,000 deliveries,
JPOG_NovDec_2015_CME_ID.indd 258
CONTINUING MEDICAL EDUCATION
2010.11 A recent study from Japan also
reported an increasing trend in PE related
to pregnancy and gynaecological surgery
Changes in Pregnancy during 1991 and 2000. PE occurred in 0.2
per 1,000 maternities and the rate is 22
times higher after CS. The mortality rate
⇑
was 2.5 per 100,000 deliveries.12 In Korea,
⇑ a nationwide survey using data from the
⇑ Korean Health Insurance Review and As-
⇑ sessment Service database also showed
⇑ an increasing trend of pregnancy associ-
ated VTE from 0.7 to 1.1 per 10,000 deliv-
⇑
eries from 2006 to 2010 and is associated
⇑ with increasing maternal age.13
⇔
⇔ CLINICAL PRESENTATION AND
⇔ RISK FACTORS
VTE can be presented as leg pain, leg
swelling, lower abdominal pain, low-
⇓ grade pyrexia, dyspnoea, chest pain,
⇔ haemoptysis and collapse. In a recent
⇔ meta-analysis including 27 publications,
57.5% of VTE occurred postpartum,
while 21.3%, 22.7% and 56.0% of VTE
occurred during the 1st, 2nd and 3rd tri-
antenatal deep vein thrombosis (DVT) mesters in pregnancy; DVT was reported
from 0.88 to 1.22 per 1,000 deliveries to occur in the left, right and both lower
and PE from 0.15 to 0.30 per 1,000 deliv- limbs in 73%, 22% and 5% of the cases,
eries. Postnatal DVT, on the other hand, respectively.14 In Caucasians, the ma-
declined from 0.42 to 0.27 per 1,000 de- jority of VTE related pregnancy present
liveries. The use of thromboprophylaxis as iliofemoral thrombosis, predominant-
following emergency caesarean section ly affecting the left lower limb possibly
(CS) may explain such reduction in the because the right iliac artery crosses
postnatal period. 9
anatomically and compresses onto the
Earlier observations showed that left iliac vein. However, the study also
VTE was rare among Asians, especially showed that distal DVT could be a com-
those living in the tropical region. How- mon presentation of VTE among Chi-
ever, a study conducted by a tertiary unit nese in pregnancy.10 Similar findings of
in Hong Kong reported an incidence of predominantly distal DVTs were reported
1.6 per 1,000 deliveries, but the clinical in asymptomatic non-obstetric patients
presentation and patterns are different.10
at the postoperative period.15-18 Most of
An epidemiology study from the Guang- the clots resolved without anticoagu-
dong province in the southern part of lant while a small proportion did propa-
China showed a prevalence rate of 1.3 gate.15,16 The discrepancy in the pattern
per 1,000 maternities between 2005 and of presentation could be related to the
9/11/15 3:51 pm
 CONTINUING MEDICAL EDUCATION
vigilance in searching for below-knee
DVT in the unit, as it is still debatable
whether below-knee DVT should be de-
tected.19
Previous VTE, immobility, obesity
(BMI >30), smoking, assisted reproduc-
tion, pre-eclampsia, preterm delivery
and caesarean sections significantly in-
crease the risk of pregnancy-related VTE
by 2.7 to 24.8 times. Other significant
risk factors include thrombophilia, med-
ical conditions such as lupus, heart dis-
ease, sickle cell disease, fluid and elec-
trolyte imbalance, postpartum infection,
and transfusion. The risk factor with the
highest odds ratio, 51.8 (38.7-69.2), was
thrombophilia.5
DIAGNOSIS AND TREATMENT
OF ACUTE VTE
The Royal College of Obstetricians and
Gynaecologists (RCOG) suggest that
woman with signs and symptoms of VTE
should undergo compression ultrasound
(CUS) with Doppler as soon as possible
and treatment with low-molecular-weight
heparin (LMWH) until the diagnosis is ex-
cluded by objective testing.17 LMWH can
be discontinued if ultrasound is negative
and there is a low level of clinical sus-
picion. However, woman should remain
anticoagulated if a high level of clinical
suspicion still exists; a repeat CUS or an
alternative diagnostic test is required.
Magnetic resonance venography can be
considered when iliac vein thrombosis is
suspected.1,20
In a situation where clinical sus-
picion of acute PE exists, a chest x-ray
(CXR) should be performed. 1,20,21
CUS
should be performed when CXR is nor-
mal.20 If both tests are negative with per-
sistent clinical suspicion of acute PE,
ventilation–perfusion (V/Q) lung scan or
a computed tomography pulmonary an-
JPOG_NovDec_2015_CME_ID.indd 259
Table 2. Fetal Radiation and Maternal Doses Associated With Imaging for
the Diagnosis of Pulmonary Embolism.20
Radiological Procedure Fetal Dose (mSv)
Chest x-ray 0.001-0.01
Ventilation scan 99mTc 0.01-0.1
Perfusion scan 99m
Tc 0.1-0.6
Single slice CTPA 0.03-0.06
Multi slice CTPA 0.003-0.1
Pulmonary angiography >0.5
giogram (CTPA) should be performed.
On the other hand, the American Tho-
racic Society and the Society of Thoracic
Radiology (ATS/STR) committee on Pul-
monary Embolism in Pregnancy suggest
proceeding to imaging of the pulmonary
vasculature directly instead of CUS in
pregnant women with suspected PE
without signs and symptoms of DVT.21
Both RCOG and ACOG have no
preference on V/Q lung scan over
CTPA. 1,20
Hence the choice between
V/Q scan and CTPA will depend on local
availability and guidelines. RCOG also
recommends that the ventilation com-
ponent of the V/Q scan can be omitted
in order to minimize the radiation dose
for the fetus. CTPA may have advan-
tages over V/Q scan because of better
sensitivity and specificity, and a lower
radiation dose to the fetus. 17
CTPA carries a fetal radiation expo-
sure of approximately 0.013 mSv, com-
pared to 0.026 for single detector row
CT, and at least 0.11 mSv for perfusion
component of the V/Q scan 21 (Table 2).
On the contrary, ATS/STR recom-
mend V/Q scan over CTPA in pregnant
women with suspected PE and a normal
CXR.21 However, in case the CXR is ab-
normal in pregnant women with suspect-
ed PE, CTPA is preferred instead of V/Q
JPOG NOV/DEC 2015 259
Maternal Dose (mSv)
<0.01
0.5
0.6-1
1.6-4.0
2-6
5-30
scan. The committee also recommends
CTPA over digital subtraction angiog-
raphy (DSA) in case the V/Q scan is
non-diagnostic.21
RCOG suggests that women with
suspected PE should be advised that
V/Q scan carries a slightly increased risk
of childhood cancer compared to CTPA
(1/280,000 vs < 1/1,000,000) but carries
a lower risk of maternal breast cancer
(lifetime risk increased by up to 13.6%
with CTPA based on a background risk
of 1/200).20
Although D-dimer can be a useful
tool to exclude VTE in the non-pregnant
population, D-dimer could neither predict
nor exclude VTE as its level increases
progressively during pregnancy. Recent
studies have shown a modest but steady
rise in D-dimer concentration during the
trimesters in both Chinese and UK popu-
lations. More than 70% and almost 100%
of these women had D-dimer level com-
parable to the cut-off for a positive test
for non-pregnant women by the 2nd and
3rd trimesters.24,25 Both RCOG and ATS/
STR conclude that D-dimer should not
be performed to diagnose acute VTE
and be used to exclude PE.20,21
Subcutaneous adjusted dose
LMWH is the preferred choice for treat-
ing women with acute VTE in pregnancy
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 260 JPOG NOV/DEC 2015
Table 3. Initial Doses and Regimens of Low Molecular Weight Heparin in Treating Acute VTE Recommended by
ACOG, ACCP and RCOG.1,20,28
ACOG 2010
/ACCP 2012
Enoxaparin 1 mg/kg Q12h
Dalteparin 200 IU/kg QD
or
100 IU/kg Q12h
Tinzaparin
as the drug does not cross the placenta
and is safe for the fetus. In general, a
twice-daily dosage regimen is recom-
mended for enoxaparin and dalteparin
because of the changes in the pharma-
cokinetics of LMWH during pregnan-
cy. A recent study also suggests that
once-daily administration of tinzaparin
can be an alternative to the commonly
used twice-daily regimen (Table 3). A
multicentre study reviewing 254 preg-
nant women treated with tinzaparin (175
units/kg) once daily for VTE reported a
low recurrence rate of 2%.26 A patient
who developed PE whilst receiving
treatment for DVT and two women who
suffered from recurrent PE were sub-
sequently managed with a higher daily
dose of tinzaparin without complication;
two other cases recurred only after ces-
sation of treatment.26
Monitoring of anti-Xa activity for pa-
tients on LMWH for treatment of acute
VTE in pregnancy or postpartum is not
necessary except in women at extremes
of body weight (<50 kg and ≥90 kg) or
with other complicating factors (eg, renal
impairment or recurrent VTE).20 Routine
platelet count monitoring is not neces-
sary except when unfractionated hep-
arin (UFH) is used. Compared to UFH,
JPOG_NovDec_2015_CME_ID.indd 260
CONTINUING MEDICAL EDUCATION
RCOG 2010
Early Pregnancy Weight (kg)
<50 50-69
40 mg bd 60 mg bd
5,000 IU bd 6,000 IU bd
175 IU/kg once daily
LMWH is associated with a substantially
lower risk of thrombocytopenia, haemor-
rhage, and osteoporosis.27
Both RCOG and American College
of Chest Physicians (ACCP) do not rec-
ommend the use of vitamin K antago-
nists to treat acute VTE in pregnancy and
recommend LMWH over adjusted dose
UFH. 20,28
In massive PE, where the patient
collapses, RCOG guidelines suggest that
a team of experienced clinicians should
be involved in deciding the treatment
course whether it be intravenous (IV)
UFH, thrombolytic therapy or surgical
embolectomy. 20
IV UFH is the preferred
treatment in massive PE with cardiovas-
cular compromise.
There has been no study to as-
sess the optimal duration of antico-
agulant therapy for the treatment VTE
during pregnancy. A minimal duration
of 3 months is based on the evidence
from studies in non-pregnant patients.
RCOG/ACCP suggest that therapeutic
anticoagulant therapy should be con-
tinued for at least 6 weeks postpartum
together with a minimum total duration
of 3 months. 20,28
Women taking LMWH for mainte-
nance therapy should be advised to with-
70-89 >90
80 mg bd 100 mg bd
8,000 IU bd 10,000 IU bd
hold injection once they have symptoms of
labour. Both RCOG and ACCP recommend
discontinuation of LMWH at least 24 hours
prior to induction of labour or caesarean
section (or expected time of neuraxial an-
esthesia).20,28 RCOG, ACCP, ACOG and the
American Society of Regional Anesthesia
and Pain Medicine guidelines recommend
withholding neuraxial blockage for 10-12
hours after the last prophylactic dose of
LMWH or 24 hours after the last therapeu-
tic dose of LMWH. 1,20,28,29
Danaparoid (heparinoid com-
posed of heparin sulphate, dermatan
sulphate and chondroitin sulphate) and
Fondaparinux (a synthetic pentasaccha-
ride acts through specific inhibition of
factor Xa via antithrombin) are seldom
used during pregnancy, therefore, clini-
cal experience in this regard is limited.
Animal experiments and human case
reports suggest minimal transport of
danaparoid across the placenta. On the
contrary, anti-Xa activity about 10% of
that in maternal plasma was found in the
umbilical cord plasma in five newborns
of mothers treated with fondaparinux.
Both RCOG and ACCP suggest limiting
their use to heparin induced thrombocy-
topenia (HIT) and skin allergy to hepa-
rin. However, danaparoid was withdrawn
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 CONTINUING MEDICAL EDUCATION JPOG NOV/DEC 2015 261

Table 4. RCOG Guideline for Thromboprophylaxis in Women with Previous VTE and/or Thrombophilia.35

Risk History Prophylaxis

Very high Previous VTE on long-term warfarin
Antithrombin deficiency
Antiphospholipid syndrome with previous VTE
High Previous recurrent or unprovoked VTE
Previous oestrogen-provoked (pill or pregnancy) VTE
Previous VTE + thrombophilia
Previous VTE + family history of VTE
Asymptomatic thrombophilia (combined defects,
homozygous FVL)
Immediate Single previous VTE associated with transient risk
factor no longer present without thrombophilia,
family history or other risk factors
Asymptomatic thrombophilia (except antithrombin
deficiency, combined defects, homozygous FVL)
Antenatal high dose LMWH and at least 6 weeks
Postnatal LMWH/warfarin
Requires specialist management by experts in
haemostasis and pregnancy
Antenatal 6 weeks postnatal prophylactic LMWH
Consider antenatal LMWH (but not routinely
recommended)
Recommend 6 weeks postnatal prophylactic
LMWH
Recommend 7 days (or 6 weeks if family history or
other risk factors) postnatal prophylactic LMWH

from the US market in 2002.20,28 Newer
anticoagulants, namely oral direct throm-
bin (eg, dabigatran) and anti-Xa (eg, ri-
varoxaban, apixaban) inhibitors should
be avoided during pregnancy. 28
Both
dabigatran and its prodrug were found
to have significant placental transfer in a
study based on perfusion model. 30
This
may suggest a potential adverse effect
on the fetal coagulation.
In order to reduce the risk of post-
thrombotic syndrome, women with DVT
should be advised to wear class II compres-
sion stocking on the affected leg for 2 years
if swelling persists after the acute event.20
PREVENTION OF VTE
Women should be assessed for the risk
of thrombosis, either in early pregnan-
cy or before pregnancy, and should be
reassessed if circumstances change
or if hospital admission is required. All
women should be educated on general
measures like weight control, hydration,
leg care and mobility. Women at high risk
of VTE in pregnancy, eg, previous VTE,
should be offered pre-pregnancy coun-
selling to discuss thromboprophylaxis.
Women with a prior history of VTE have
a relative risk of 3.5 times recurrence
during subsequent pregnancies. 31
The
absolute risk of recurrent VTE during
pregnancy without the use of antithrom-
botic prophylaxis is between 2.4% and
7.5%. 32,33
The rate of recurrence was
15.5% if the first VTE was unprovoked,
related to pregnancy or oral contracep-
tive use, whereas no recurrence oc-
curred if the first VTE was related to other
transient risk factors.
32
The RCOG guideline ranks women
with a history of VTE into very high, high
and moderate risk on the basis of any
associating factors of previous VTE, the
presence of thrombophilia and/or family
history of VTE to recommend the choice
of thromboprophylaxis during preg-
nancy and puerperium (Table 4). ACCP
also has a similar recommendation on
thromboprophylaxis.28 However, there
are neither large prospective trials nor
randomized clinical trials that compare
different doses of thromboprophylaxis in
pregnant women with prior VTE.
Despite the fact that there have not
been any large randomized-controlled
trials to prove that either antenatal or
postnatal thromboprophylaxis is effec-
tive,34 successive reports from the con-
fidential enquiry into maternal deaths
have suggested that VTE related mortali-
ty is preventable.
RCOG defined certain antenatal
clinical risk factors of VTE and suggests
considering antenatal LMWH prophylax-
is in case there are three or such more
risk factors.35 RCOG also recommends
at least 7 days postnatal prophylaxic
LMWH for women who have intrapartum

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 262 JPOG NOV/DEC 2015 CONTINUING MEDICAL EDUCATION

Table 5. Clinical Risk Factors and their Adjusted Odds Ratio.36 high-risk patients in whom significant risk
factors persist following delivery, ACCP
Risk Factor for VTE Adjusted Odds Ratio (95%CI) suggest extended prophylaxis (up to 6
weeks after delivery) following discharge
Age >35 1.4-1.7
from the hospital. For all pregnant women
BMI >30 1.7-5.3
with prior VTE, they suggest postpartum
Parity ≥3 1.6-2.9 prophylaxis for 6 weeks with prophylactic-
Smoker 1.7-3.4 or intermediate-dose LMWH (Table 6) or
Immobility 7.7-10.1 vitamin K antagonists.28
Testing for heritable thrombophilia
Gross varicose veins 2.4
in selected patients may be helpful to
Preeclampsia 3-5.8
identify women at risk. Testing selected
Multiple pregnancy 1.6-4.2 patients may give an indication of risk of
Assisted reproductive techniques 2.6-4.3 recurrence following completion of anti-
coagulant therapy, eg, those presenting
with VTE at an early age (<40 years)
and who are from apparent thrombo-
Table 6. Recommendations to Prevent a First or Recurrent Pregnancy-related sis-prone families (ie, more than two
VTE (Prophylaxis Could be Prophylactic or Intermediate Dose LMWH).35
other symptomatic family members).37
This may also influence decisions re-
Weight Enoxaparin Dalteparin Tinzaparin
garding the duration of anticoagulation.
(75 IU/kg/day)
The British Committee for Standards in
<50 20 mg daily 2,500 IU daily 3,500 IU daily Haematology suggests a more discrim-
50-90 40 mg daily† 5,000 IU daily† 4,500 unit daily† inative approach in screening heritable
91-130 60 mg daily* 7,500 IU daily* 7,000 unit daily thrombophilas. Women with a previous
VTE due to a minor provoking factor, eg,
131-170 80 mg daily* 10,000 IU daily* 9,000 unit daily*
travel, should be screened and consid-
>170 0.6 mg/kg/day* 75 IU/kg/day* 75 IU/kg/day* ered for prophylaxis if a thrombophilia is
Intermediate 40 mg Q12 h †
5,000 IU Q12 h †
4,500 IU Q12 h †
found. Moreover, asymptomatic women
dose for women with a family history of venous throm-
(50-90 kg)
bosis may be tested if an event in a
*
may be given in two divided doses
†
Prophylactic and intermediate dosages recommended by ACCP 2012.28 first-degree relative was unprovoked or
provoked by pregnancy, COC exposure
or a minor risk factor. The result will be
caesarean section, asymptomatic inher- pneumatic compression) for women at in- more relevant if the first-degree relative
ited or acquired thrombophilia, BMI>40 creased risk of VTE after caesarean sec- has known thrombophilia.37 The commit-
kg/m2, prolonged hospital admission or tion because of the presence of one major tee does not support testing for unse-
medical comorbidities. The duration of or at least two minor risk factors. ACCP 28
lected patients with upper limb venous
thromboprophylaxis should be extend- also recommends prophylactic LMWH thrombosis, patients with central venous
ed if there are more than three factors or combined with elastic stockings and/or catheter-related thrombosis, after a first
they persist. 35
Table 5 lists some of the intermittent pneumatic compression over episode of cerebral vein thrombosis, ret-
risk factors with their adjusted OR.36 LMWH alone in women at very high risk inal vein occlusion or after a first episode
Similarly, ACCP also recommends for VTE and who have multiple addition- of intra-abdominal vein thrombosis, as
prophylactic LMWH or mechanical proph- al risk factors for thromboembolism that they are of uncertain predictive value for
ylaxis (elastic stockings or intermittent persist in the puerperium. For selected
28
recurrence.

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 CONTINUING MEDICAL EDUCATION JPOG NOV/DEC 2015 263

CONCLUSION
VTE is a common cause of maternal
mortality. Although with the more fre-
quent use of thromboprophylaxis there
appears to be a reduction in the inci-
dence of VTE in Western countries, this
trend appears to be rising in several
Asian countries. There are insufficient
large studies to address the effect of
evidence on which to base recommen-
dations for thromboprophylaxis during
pregnancy and the early postnatal peri-
od. Therefore, recommendations on the
prevention of VTE with thromboprophy-
laxis are predominantly based on con-
sensus from expert opinion. Because
of the high case fatality associated
with PE, all obstetric units should have
guidelines on the objective test for diag-
nosis and a protocol with anticoagulant
treatment.

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