Problem based review: pulmonary embolism in pregnancy Problem-Based Review

Acute Medicine 2013; 12(4): 239-245
239
Problem-Based Review
Problem based review: pulmonary
embolism in pregnancy
F Neuberger & N Wennike
Abstract
Pulmonary embolism (PE) in pregnancy carries a significant mortality. Pregnant patients often present via the acute
medical take with symptoms of possible PE and require timely assessment and investigation. The symptoms of PE
are sometimes very difficult to differentiate from those of normal pregnancy and the vast majority of patients will
require imaging. The radiation risks to mother and foetus from imaging may cause considerable anxiety (to both patients
and healthcare providers) and need to be explained to patients in the context of a potentially life-threatening condition
so they can be actively involved in decision-making on how best to proceed. When PE is diagnosed in pregnancy, there
are obstetric considerations around the time of delivery and women should receive specialist follow-up.
Keywords
pulmonary embolism, pregnancy.
Key Points
• PE is a major cause of maternal death in the UK and carries a significant mortality if untreated.
• Diagnosis or exclusion of PE based on symptoms or signs alone is very difficult in pregnancy making objective diagnosis
essential.
• Thrombophilia screens should not routinely be carried out on women presenting with PE while they are pregnant.
• Novel Oral Anticoagulants (NOACs) are not licensed for use during pregnancy or by women who are breast-feeding.
Introduction
A pregnant patient with breathlessness is frequently
encountered on the acute medical take, and can
present a challenge to Acute Physicians. Venous
thromboembolism (VTE) is up to ten times more
common in pregnant women compared with nonpregnant women of the same age1 and is still a major
cause of direct maternal death in the UK.2 Clinical
assessment of pregnant women with suspected PE is
challenging, as symptoms of PE can mimic those of
normal pregnancy.3
There are a range of clinical scoring systems,
laboratory and radiological investigations available to the
clinician, many of which are not validated in pregnancy.
Acute Physicians need to be aware of the limitations of
clinical assessment in assessing pregnant women with
suspected PE. They must also be knowledgeable about
each of the investigations which may be proposed for a
pregnant woman, to enable an informed decision to be
made about how best to proceed.
This review will focus on the assessment,
investigation and treatment of pregnant women with
suspected PE.
What is the scale of the problem of PE
in pregnancy?
The Confidential Enquiry into Maternal and Child
Health (CEMACH) report from 2007,4 identified
thromboembolism as the major direct cause (i.e.
condition attributed directly to the pregnancy itself)
of maternal death in the UK. Treatment received
© 2013 Rila Publications Ltd.
by patients was considered substandard in the
majority of cases of thromboembolism. The major
deficiencies were poor risk assessment of patients,
failure to recognise symptoms of thromboembolism,
underinvestigation due to perceived risks of radiation
exposure and failure to administer appropriate
treatment.
The incidence of PE in pregnancy is somewhere
between 1 in 1000 and 1 in 10,000 pregnancies.3
It is a common misconception that the incidence
of PE increases with each subsequent trimester; at
least half of VTE in pregnancy occurs in the first
twenty weeks.5 Hypercoagulability and venous
stasis in pregnancy are the major risk factors; other
factors e.g. dehydration secondary to hyperemesis
gravidarum may also contribute. The incidence
of PE rises further in the postpartum period6and
remains elevated for up to six weeks after delivery.
The mortality rate for untreated pulmonary
embolism in pregnancy is up to 30%, making it
important to rapidly identify and treat this condition.3
Case history
A 26-year-old female teacher was referred by her GP to the
Acute Medical Unit (AMU) with two weeks of progressive
shortness of breath and retrosternal chest pain. She was 30
weeks pregnant. She had a past medical history of Polycystic
Ovarian Syndrome (PCOS) and mild asthma. She took
a salbutamol inhaler less than once per week and had no
known drug allergies. She had never smoked, drank no
Dr Francesca Neuberger
MBChB MRCP (UK)
Dr Nic Wennike
BSc MBBS MRCP (UK)
Consultant Acute Physician
Musgrove Park Hospital
Parkfield Drive
Taunton
Correspondence:
Dr Francesca Neuberger
StR 6 Acute and General
Medicine
Severn Deanery
Email: [email protected]
doctors.net.uk
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Problem based review: pulmonary embolism in pregnancy
alcohol, and participated in triathlons in her spare time. She
lived with her husband and healthy four year-old daughter.
On initial assessment she had a pulse of 90 per minute,
blood pressure of 140/80mmHg, temperature 36.5°C,
respiratory rate-26 per minute and saturations of 98% on
air. She was alert and orientated, with normal heart sounds
and a clear chest on auscultation. Her calves were soft.
How should a pregnant patient with
suspected PE be assessed clinically?
Clinical assessment alone has a low sensitivity and
specificity in the diagnosis of VTE in pregnancy.
Women with PE may not present with the classic
symptoms of chest pain, dyspnoea, haemoptysis or
collapse, and conversely, women may experience a
degree of dyspnoea, leg swelling and tachycardia as
part of a normal pregnancy. In a study of 38 pregnant
women with confirmed PE, the four most common
presenting complaints were dyspnoea (62%), pleuritic
chest pain (55%), cough (24%) and sweating (18%).5
Of the ‘classic’ features of PE, there is no single
feature that has a strong predictive value for PE in
pregnancy. In a study of 304 women8 with suspected
PE who were pregnant or postpartum, patients
were assessed for six features: chest pain, dyspnoea,
desaturation, tachycardia, increased A-a gradient
and PaO2 <65mmHg. No association was found
between an individual feature and diagnosis of PE or
any cluster of features in this study.
In non-pregnant patients, scoring systems such
as the Well’s Score can help guide risk stratification
and investigation of patients with suspected PE.
Pregnant women were excluded from the analysis
for validation of the Well’s Score9 and to date, no
validated scoring system exists for pregnant women.
In patients with suspected PE who go on to
have imaging, the majority will have negative
investigations. In a study of 120 consecutive
women with suspected PE undergoing ventilation/
perfusion(V/Q) scanning, only 2 showed high
probability of PE, and the majority were normal.10
This highlights the limitations of clinical assessment
in this group of patients.
Patients with suspected PE in pregnancy may
present to medical or obstetric teams. Patients who are
of advanced gestation with a viable foetus should be
under the care of an obstetric team, with ready access
to facilities and expertise for an emergency Caesarean
Section (CS), should a patient’s clinical picture alter
rapidly, for example with cardiopulmonary arrest
secondary to PE. For women in early pregnancy,
where the foetus is not viable, care under a medical
team with input from obstetrics is preferable.
Should a D-dimer be used in the
assessment of PE in pregnant women?
The physiological changes of normal pregnancy
cause a progressive rise in D-dimer. A quarter of
women will have a positive D-dimer in the second
trimester and half of women in the third trimester.
In the non-pregnant population, a negative
D-dimer is useful in excluding VTE where the
Well’s score indicates that VTE is ‘unlikely’.
Pregnancy places a patient in a high risk category
and thus D-dimer testing is not useful or indicated
in pregnancy. This is endorsed by the Royal College
of Obstetricians and Gynaecologists.11
If a D-dimer level is checked and is negative, it
can be tempting to be falsely reassured. However,
the diagnostic pathways for VTE that use D-dimer
measurement have only been developed to exclude
PE in low risk patients with a negative D-dimer,
and should not be extrapolated to include high risk
patients, such as those who are pregnant.
What investigations should the
pregnant patient with suspected PE
undergo?
The use of electrocardiography (ECG) and arterial
blood gas analysis (ABG) are well-described in
assessing patients with cardiorespiratory symptoms
and should be performed in the vast majority of
cases. It should be noted that while normal arterial
blood gas values do not change significantly in
pregnancy, the arterial oxygen tension drops by up
to 2kPa when a pregnant woman lies flat, therefore
the sample should be taken with the patient sitting.12
Hyperventilation and respiratory alkalosis may be
a normal finding in the later stages of pregnancy
(due to progesterone-mediated stimulation of the
respiratory centre) and typical SI, QIII, TIII on an
ECG may be a normal finding in pregnancy.
An objective investigation to confirm or refute
the diagnosis of PE is vital given the life-threatening
nature of PE in pregnancy and the limitations of
clinical assessment and bedside testing. A reluctance
to request basic imaging such as a chest X-ray has
been implicated in the failures to accurately diagnose
and manage these patients in the CEMACH report.
A diagnosis of PE has implications for maternal
and foetal health, and if these patients are underinvestigated, the implications can be catastrophic.
Pregnant women with suspected PE need to be given
accurate information regarding the risks and benefits
of each investigation in a way they can understand,
so they can actively be involved in the decisionmaking process.
A chest X-ray is useful because it may
identify alternative causes of symptoms such as
a pneumothorax, lobar collapse or pneumonia.
CXR carries a very low risk of radiation exposure
in pregnancy (equivalent to 9 days of background
radiation in the UK), is readily available and should
be performed in all breathless pregnant patients. A
normal chest X-ray does not exclude PE, but may
encourage a clinician to choose VQ scanning in
preference to CTPA as the subsequent investigation.
Two studies of pregnant women with suspected PE
have shown that the rate of diagnostic V/Q results
(i.e. normal or high probability) is between 94% and
96% when the initial CXR was normal.13,14
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Problem based review: pulmonary embolism in pregnancy
The radiation risk from imaging should be
considered in terms of the radiation dose to the
mother and radiation dose to the foetus. The risk
to a foetus of prenatal death, abnormal mental
development and malformations from radiation
exposure is considered to be relevant above 50mGy15
(particularly in the very early stages of pregnancy),
and requires specific discussion with the mother
when it is greater than this.To put this in context,
the foetal radiation dose from a single chest X-ray is
approximately 0.002mGy.15
Should pregnant women with suspected
PE have a Doppler US of both legs in the
absence of any clinical signs of DVT?
There is currently no direct evidence to support
the use of bilateral Doppler ultrasound examination
of the legs veins to diagnose PE in pregnancy.16
However, Doppler ultrasound does not involve
ionising radiation, therefore if a patient presents
with symptoms of a DVT, the diagnosis of venous
thromboembolism can be reached without exposing
the patient and foetus to ionising radiation.
In the non-pregnant population, it is estimated
that 70% of patients with PE have proximal DVT,
but in pregnant women with PE, the proportion
with DVT is unknown.17 Assessing pregnant
women with suspected DVT can be difficult, as
there is a higher incidence of iliac vein thrombosis
which is not routinely assessed during Doppler
US examinations. Furthermore, there is a not
insignificant risk (approximately 3%) of a false
positive Doppler US in pregnancy with attendant
risks of unnecessary anticoagulation. Interestingly,
75-96% of DVTs in pregnant women affect the left
leg rather that the right (compared with 55% in the
non-pregnant population), which is thought to be
due to compression of the left common iliac vein by
the mass effect of the gravid uterus or by the crossing
right iliac artery.3
In the general population with suspected PE, it
has been calculated that 11 patients would need to
have Doppler ultrasound of their legs to diagnose
VTE, negating the need for further investigations.18
In pregnant women with suspected PE, the number
of patients that would need to be tested would be
several times higher due to the lower prevalence of
PE within this group.
In summary, if a patient has symptoms or clinical
signs of a DVT, she should have a Doppler ultrasound
examination of her legs as the next investigation. In
the absence of clinical evidence of DVT, some patients
and clinicians may choose Doppler ultrasound of
the legs as the next investigation, accepting the risk
that organising an extra test may delay definitive
investigations and is very likely to be negative.
The risks and benefits of bilateral Doppler
ultrasound examination of the leg veins were
explained to our patient. She was keen to avoid
ionising radiation, and went on to have this
investigation. The study was negative for DVT.
What investigations should be
performed next in the work-up of a
pregnant patient with suspected PE?
A CTPA or V/Q scan may both be considered as the
next most appropriate investigation. V/Q scanning
is not readily available in all hospitals, particularly
out of hours, and not all radiology departments will
have expertise in interpreting results, making CTPA
the preferred investigation in such circumstances.
However, where V/Q scanning is available, it is often
advocated as the next investigation of choice.
V/Q scanning is a frequently used test for PE
in the non-pregnant population, with reports
being categorised as ‘high probability’, ‘normal’ or
‘indeterminate’. The implication of an indeterminate
Investigation
Pros
Cons
Doppler Ultrasound scan of leg veins
- No radiation exposure
- May give indirect evidence of PE
- May delay definitive investigations
for PE
- A negative result is unhelpful
- Labour intensive
- Risk of false positives
CXR
- Readily available
- Very low radiation dose
- May pick up other pathology (e.g.
pneumothorax, pneumonia) and/or
highlight patients unsuitable for V/Q
scanning
- Doesn’t confirm or exclude PE
CTPA
- May pick up other pathology
- Radiation to maternal breast/lung
(and foetus)
Perfusion scanning
- Reduced overall radiation dose
compared with CTPA
- Risk of indeterminate scan result
- Only suitable for patients with a
normal CXR
- May not be available locally
- Radiation to foetus (and maternal
breast/lung)
Figure 1. Pros and cons of investigations for PE in pregnancy.
© 2013 Rila Publications Ltd.
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Problem based review: pulmonary embolism in pregnancy
Figure 2. Diagnostic algorithm for suspected PE in Pregnancy (American Thoracic Society 2011).16
maternal dose
lung
breast
CTPA
39.5mGy
10-60mGy
V/Q
5.7-13.5mGy
0.98-1.07mGy
Figure 3. Maternal radiation doses associated with
diagnostic tests for pulmonary embolism.26
scan result is that a further investigation (usually a
CTPA) is required to confirm or exclude a diagnosis
of PE. In the general hospital population, there is a
high risk of indeterminate scans (up to 70%), which
makes this test less popular among clinicians. In the
pregnant population, the vast majority of patients
are young with no respiratory comorbidities and
normal CXRs, making the risk of an indeterminate
scan far lower. In the pregnant population, 75%
of patients have a normal scan and 5% have a ‘high
probability’scan result, leaving only 20% of patients
with‘indeterminate’ scan results.17
The radiation exposure from a V/Q scan is detailed
in Figure 3 (the range of values results from a variety
of imaging protocols and equipment being used). All
radiation carries a potential but generally small risk,
which must be balanced against the considerable risk
of maternal and foetal death if there is a failure to
diagnose and adequately treat PE.
There is a lack of evidence regarding the effects
of ionising radiation from investigations for PE in
pregnancy and complications for mother and foetus.
The foetal radiation dose from CTPA increases from
0.03mGy in early pregnancy to 0.66mGy in the third
trimester. The corresponding values for V/Q scanning
are between 0.32mGy and 0.74mGy for V/Q
according to the American Thoracic Society.16 The
maximal dose of radiation to the foetus from either
investigation falls well below the 50mGy threshold
that is associated with increased risk of prenatal death,
malformations and abnormal mental development.
The average foetal radiation doses from V/Q scanning
are slightly higher than from CTPA. To minimise
the radiation dose associated with V/Q scanning, it
is possible to perform a half-dose perfusion scan, and
only proceeding to ventilation imaging if a defect is
identified on the perfusion scan.19
The radiation dose to the mother from CTPA and
V/Q scanning is also of concern to both clinicians and
patients. The radiation doses to the lung and breast
from each investigation are outlined in figure 3. It has
been calculated that the lifetime risk of breast cancer from 20mGy radiation is 1/1200 women at age
20, 1/2000 women at age 30, 1/3500 women at age
40. The lifetime risk of breast cancer is 1/820 and the
overall excess lifetime relative risk following a CTPA
is only 1.004. The issue of radiation to maternal breast
and lung and associated increased risk of malignancies again needs to be considered in the context of a
life-threatening illness, and the radiation risk balanced
against the morbidity and mortality associated with
undiagnosed and untreated PE.
Radiologists should be aware of the higher rate
of sub-optimal CTPA studies on pregnant women
when compared with an age-matched non-pregnant
controlled group.21 Pregnant women have significantly
decreased pulmonary arterial enhancement compared
to non-pregnant patients, probably due to the increase
in cardiac output in pregnancy.22 This should be
taken into consideration when choosing an imaging
protocol.
Clinicians should gain informed consent from
their patient in this situation for imaging involving
ionising radiation. The risks and benefits of any
imaging proposed should be explained to the patient
in a way she can understand, and the patient should
be given the opportunity to ask questions. The
explanation should focus on the risk of undiagnosed
PE to the mother and foetus balanced against the
potential risk of radiation exposure to mother and
foetus. The patient can be reassured that the radiation
exposure from a chest X-ray is not significant, and
while there is little direct evidence regarding the safety
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Problem based review: pulmonary embolism in pregnancy
Subcutaneous
dose
Early pregnancy weight (Kg)
<50
50-69
70-89
>90
Enoxaparin
40mg bd
60mg bd
80mg bd
100mg bd
Dalteparin
5,000iu bd
6,000iu bd
8,000iu bd
10,000iu bd
Tinzaparin
175 units/Kg once daily (all weights)
Figure 4. Calculation of heparin dose during pregnancy.11
of CTPA and V/Q scanning in pregnancy, the risk of
undiagnosed PE to mother and foetus is clear and
significant.
Unstable patients require urgent imaging to
be arranged if they present out of hours. A bedside
echocardiogram is the initial investigation of choice
for patients who are too unstable for transfer, followed
by a CTPA as the definitive investigation. For women
with a viable foetus, where possible, it is preferable
Image 1. Perfusion scan showing multiple perfusion defects
© 2013 Rila Publications Ltd.
to obtain diagnostic imaging to confirm or exclude
the diagnosis of PE as prior use of anticoagulation
significantly increases the risk of haemorrhage during
urgent delivery.
Case Continued
Following a normal CXR our patient went on to have a halfdose Q scan, which showed multiple perfusion defects that
were unmatched on ventilation scanning (see image 1).
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Problem based review: pulmonary embolism in pregnancy
What is the treatment for PE in
pregnancy?
Patients with PE require anticoagulation, which
has special considerations in pregnancy. Vitamin
K antagonists, such as Warfarin, are associated with
teratogenesis and risk of haemorrhage, particularly
at the time of delivery, and are not recommended
during pregnancy. The Royal College of Obstetricians
and Gynaecologists recommend low molecular weight
heparin (LWMH) in preference to unfractionated
heparin. LWMH does not cross the placenta and
has fewer side effects such as osteoporosis, allergic
reactions and heparin-induced thrombocytopaenia
than unfractionated heparin. Dosing of LMWH is
often different during pregnancy, is weight-based and
should be calculated from the patient’s early pregnancy
weight e.g. for enoxaparin, the dose during pregnancy
is 1mg/kg BD rather than the standard treatment dose
of 1.5mg/kg OD recommended outside of pregnancy.
Patients may prefer treatment with tinzaparin,
because it can be given once daily, though there is less
published outcome data for this option. (figure 4)
Before starting anticoagulants, patients should
have blood taken for a full blood count, coagulation
screen, urea and electrolytes and liver function tests as
a minimum. Performing a thrombophilia screen prior
to therapy is not routinely recommended according
to the RCOG guidelines, as it will not affect the
immediate management and results can be difficult
to interpret. The physiological effects of pregnancy
can interfere with clotting screen results. For example
the levels of protein S fall, making the diagnosis
of protein S deficiency difficult. The presence of
extensive thrombus may also affect coagulation screen
testing, as antithrombin levels are reduced when
extensive thrombus is present, which makes results
misleading. The advice from the RCOG is that results
of thrombophilia screens taken in this situation should
be interpreted by clinicians with expertise in this area,
usually haematologists.
Patients with PE should be anticoagulated with
LMWH for the remainder of the pregnancy but this
should be stopped for a minimum of 24 hours prior to
planned delivery, or as soon as a patient has symptoms
of labour. There should be a minimum of 24 hours
without anticoagulation before any spinal anaesthetic
or analgesic attempts are made.
Decisions regarding the most appropriate
management for a patient with PE in pregnancy
need to be made on an individual basis, with the
best available evidence. The NICE clinical guideline
14424 gives detailed guidance in the assessment and
management of patients with VTE, but does not
include pregnant women.
What is the treatment for massive lifethreatening PE?
Management of massive life-threatening PE in
pregnancy is a medical and obstetric emergency and
requires multidisciplinary management including
experienced physicians, obstetricians, intensivists
and radiologists. Obstetric teams looking after
such patients are advised to call the medical team
immediately and an urgent portable echocardiogram
or CTPA should be arranged within one hour of
presentation.11
Therapeutic options for massive life-threatening
PE in pregnancy include intravenous unfractionated
heparin, thrombolytic therapy, catheter-directed
thrombolytic therapy or thoracotomy and surgical
embolectomy. At present, the data regarding the
treatments options are limited. Intravenous unfractionated heparin is the preferred treatment for massive PE in pregnancy11 due to its rapid onset of action
and extensive experience of use in this situation. Intravenous thrombolysis should be considered if there
is haemodynamic compromise associated with massive PE. This should be followed by an intravenous
infusion of unfractionated heparin. From a review of
172 patients, intravenous thrombolysis was associated
with maternal haemorrhage rate of 1% to 6%, which
is comparable with non-pregnant patients receiving
thrombolytics. Out of 172 patients, there were three
foetal deaths and two maternal deaths. The maternal
deaths were not secondary to haemorrhage, and no
maternal intracranial haemorrhages were reported.23
The data for catheter-directed thrombolytic therapy
and surgical embolectomy for PE in pregnancy are
very sparse, but these treatments should be considered in patients with haemodynamic compromise
who are not suitable for thrombolysis, depending on
the local availability. For very unstable patients, the
risk of transfer to a tertiary centre is likely to exceed
potential benefits.
What further treatment should be provided following discharge from hospital?
Patients should be anticoagulated for at least six
weeks postnatally11 and a minimum of three months
anticoagulation should be given in total. The decision
regarding the length of period of anticoagulation
will be based on personal and family history of VTE,
results of any thrombophilia tests and any other risk
factors. Women should be advised that both heparin
and warfarin are acceptable forms of anticoagulation
during breastfeeding, and women can choose
between them based on their perception of the
acceptability of frequent blood tests for patients on
warfarin and regular subcutaneous injections for
those receiving heparin. The novel oral anticoagulants
(NOACs), such as rivoroxaban, apixaban and
dabigatran, are not currently licensed for use during
pregnancy or by women who are breastfeeding.
Women who have co-existing DVT alongside
PE, should be advised to wear graduated elastic
compression stockings on the affected leg for at
least two year to reduce the risk of post-thrombotic
syndrome. Women who have VTE during pregnancy
should have expert follow up, at an obstetric medicine
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Problem based review: pulmonary embolism in pregnancy
or joint obstetric haematology clinic where possible.
At this stage, thrombophilia testing can be considered
and recommendations made for future pregnancies
depending on an individual’s risk of future events.
Patients should also have an echocardiogram and
respiratory follow-up, to assess for pulmonary
hypertension, which may precede the development of
chronic thromboembolic hypertension (CTEPH).25
Case Conclusion
Our patient was given enoxaparin sodium 1mg/kg SC BD
for the remainder of her pregnancy. She had labour induced
at 38 weeks gestation with anticoagulation up until 24
hours prior to induction. She had a healthy female infant via
normal vaginal delivery weighing 6 pounds and 7 ounces.
She recommenced LMWH with once daily dosing following
delivery and was followed up by haematology, obstetrics and
respiratory medicine.
Conflict of interest
This study was funded entirely by the authors and
they have no conflict of interest with any third party.
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