Women are at an increased risk of venous thromboembolism (VTE) during pregnancy and postpartum. The risk is increased 4-5 times during pregnancy and 20 times postpartum. VTE accounts for approximately 10% of maternal deaths. Deep vein thrombosis and pulmonary embolism are the most common types of VTE during pregnancy. Risk factors include inherited thrombophilias, acquired conditions, and factors related to pregnancy and delivery. Treatment involves anticoagulation with low molecular weight heparin or unfractionated heparin.
1. Name: Siti Nurul Afiqah binti Johari
ID No.: 10-6-95
VENOUS THROMBOEMBOLISM IN PREGNANCY
Women are at an increased risk of both venous and arterial thromboembolism during
pregnancy. Compared to women who are not pregnant, the risk of arterial thromboembolism
(strokes and heart attacks) is increased 3- to 4-fold and the risk of venous thromboembolism
(VTE) is increased 4- to 5-fold. Postpartum, the risk is even higher (20-fold). The overall
prevalence of thromboembolic events during pregnancy is approximately 2 per 1000
deliveries. Approximately 20% of these events are arterial, and the other 80% are venous.
VTE accounts for 1.1 deaths per 100 000 deliveries, or 10% of all maternal deaths.
Approximately 80% of venous thromboembolic events during pregnancy are deep vein
thrombosis (DVT) and 20% are pulmonary emboli. Approximately one third of pregnancy-
related DVT and half of pregnancy-related pulmonary emboli occur after delivery. When
DVT occurs during pregnancy, it is more likely to be proximal, massive,and in the left lower
extremity. Distal thrombosis are as likely to occur on the right as on the left, but proximal
thrombosis occurring under the influence of estrogen are more likely to be on the left. This
left-sided predominance is thought to be attributable to a relative stenosis of the left common
iliac vein where it lies between the lumbar vertebral body and the right common iliac artery,
but the true mechanism is unknown. Pelvic vein thrombosis, which account for less than 1%
of all cases of DVT, are rare outside of pregnancy or pelvic surgery yet account for
approximately 10% of DVT during pregnancy and the postpartum period.
Pregnant women are probably at an increased risk for VTE as a result of hormonally induced
decreased venous capacitance and decreased venous outflow, possibly as a result of
mechanical obstruction by the uterus, and questionably as a result of decreased mobility.
These factors, along with vascular injury, are important, especially during the postpartum
period, but the risk of VTE is as high during the first trimester as it is during the second and
third trimesters. Therefore, the risk of VTE increases before many of the anatomic changes of
pregnancy take place, suggesting that; overall, the most important reason for the increased
risk of VTE during pregnancy is hypercoagulability.
Normal pregnancy is accompanied by increased concentrations of factors VII, VIII, X, and
von Willebrand factor and by pronounced increases in fibrinogen. Factors II, V, and IX are
relatively unchanged. Free protein S, the active, unbound form, is decreased during pregnancy
secondary to increased levels of its binding protein, the complement component C4b.
Plasminogen activator inhibitor type 1 (PAI-1) levels increase 5-fold. Levels of PAI-2,
produced by the placenta, increase dramatically during the third trimester. Markers of
thrombin generation such as prothrombin F1+2 and thrombin-antithrombin (TAT) complexes
are increased. These changes, which may not completely return to baseline until more than 8
weeks postpartum, begin with conception. So does the risk of thrombosis.
The hypercoagulability of pregnancy has likely evolved to protect women from hemorrhage
at the time of miscarriage or childbirth. Indeed, in the developing world, the leading cause of
maternal death is still hemorrhage, but in Western Europe and the United States, where
hemorrhage is successfully treated or prevented, the leading cause of maternal death is
thromboembolic disease.
2. Risk Factors for Thrombosis in Pregnancy
There are a number of known risk factors, some hereditary and others acquired. In 80% of
patients, at least one risk factor can be identified. Notably, the antenatalperiod is known to be
a weak risk factor and the postpartum period a moderate risk factor.
Often more than one risk factor is present and these should be actively identified when
assessing the patient for VTE during and post-pregnancy.
Inherited factors
Factor V Leiden mutation (most common).
Prothrombin gene G20210A mutation.
Antithrombin III deficiency.
Protein C deficiency.
Protein S deficiency.
Hyperhomocysteinaemia.
Dysfibrinogenaemia.
Disorders of plasminogen and plasminogen activation.
Strong family history.
Acquired factors
Obesity - body mass index (BMI) ≥30 kg/m2
.
Immobilization (>4 days of bed rest).
Previous thrombotic event.
Smoking.
Trauma.
Inflammatory disorders such as inflammatory bowel disease.
Cancer.
Estrogen therapy (including contraception and hormone replacement therapy).
Sepsis, including urinary tract infections.
Gross varicose veins.
Antiphospholipid syndrome.
Nephrotic syndrome.
Paroxysmal nocturnal haemoglobinuria.
Cerebrovascular event.
Polycythaemia vera.
Sickle cell disease.
Lupus.
Anemia.
Diabetes.
Hypertension.
Long-haul travel of ≥4 hours.
Factors specific to pregnancy and delivery complications
Venous stasis.
Maternal age of ≥35 years.
Multiparity.
Gestation <36 weeks.
Instrument-assisted or caesarean delivery.
Haemorrhage (antepartum and postpartum)
Pre-eclampsia.
3. Prolonged labour.
Hyperemesis.
Postpartum infection.
Clinical Presentation
Presentation is similar to non-pregnant patients with DVT or PE.
DVT: leg pain and discomfort (the left is more commonly affected), swelling,
tenderness, edema, increased temperature and a raised white cell count. There may
also be abdominal pain. The difficulty is that some of these symptoms may be found
in normal pregnancies. The patient may also be asymptomatic with a retrospective
diagnosis being made following a PE.
PE: dyspnea, pleuritic chest pain, hemoptysis, faintness, collapse. The patient may
have focal signs in the chest, tachypnea, a raised jugular venous pressure (JVP) and
there may be ECG changes (S1Q3T3). Arterial blood gases with the patient sitting
down may show respiratory alkalosis and hypoxemia. There may also be symptoms
or signs of a DVT.
Differential Diagnosis
DVT: swelling and lower leg discomfort are not unusual in a normal pregnancy.
Other possibilities include muscle strain, a ruptured Baker’s cyst, cellulitis,
superficial thrombophlebitis, ruptured plantaris tendon and trauma.
PE: potentially extensive but specifically rule out chest infection and an intra-
abdominal bleed (look for abdominal signs, shoulder tip pain from diaphragmatic
irritation and a low JVP).
Diagnostic Approach of VTE
The two most common initial symptoms, present in more than 80% of women with
pregnancy-related DVT, are pain and swelling in an extremity. When signs or symptoms
suggest new onset DVT, the recommended initial diagnostic test is compression
ultrasonography of the proximal veins. When results are equivocal or an iliac vein thrombosis
is suspected, magnetic resonance venography (MRV) may be used.
4. The diagnosis of new onset pulmonary embolism (PE) is similar to that in the non-pregnant
individual. Ventilation/perfusion (V/Q) scanning gives relatively low radiation exposure to
the fetus. With an indeterminate study in a woman without a DVT, a confirmatory test, such
as angiography or spiral computed tomography (spiral CT), is necessary to prevent the
woman from unnecessary exposure to anticoagulation during the rest of her pregnancy, at
delivery, or in future pregnancies.
5. Management of VTE
Massive life-threatening PE:
Collapsed, shocked patients need to be managed by an experienced multidisciplinary
team involving senior obstetricians, physicians and radiologists.
An urgent portable echocardiogram or CTPA within one hour of presentation should
be arranged.
If massive PE is confirmed or, in extreme circumstances prior to confirmation,
immediate thrombolysis should be considered.
Intravenous unfractionated heparin is the preferred treatment.
General points
In a woman with a past history of VTE or with a known inherited thrombophilia, it is
best to refer her prior to a planned pregnancy for optimum prophylaxis throughout the
pregnancy. Refer all women who are on warfarin, as this will have to be stopped or
replaced by heparin before the seventh week of conception, depending on her risk of
VTE.
Medical anticoagulation is the treatment of choice for acute VTE. Subsequently,
surgical interventions may be considered: patients suffering from recurrent PEs
despite adequate anticoagulation (or where there is an absolute contra-indication to
anticoagulation) may benefit from placement of a temporary caval filter and, in those
cases where there is limb or life-threatening embolus, a surgical embolectomy or
thrombus fragmentation may be attempted.
Anticoagulation is by far the most common treatment option. Heparin is the most
frequently used drug, being non-toxic to the fetus (it does not cross the placental
barrier). However, its main disadvantages are that it has to be parentally administered
and, in the long-term, may give rise to heparin-induced osteoporosis and
thrombocytopenia. In some patients, it can also provoke a painful, localized allergic
reaction on administration. Warfarin is the other treatment option in the postnatal
patient but it must be avoided antenatally, as it is teratogenic and can also cause
placental abruption and fetal/neonatal hemorrhage.
In clinically suspected DVT or PE, treatment with unfractionated heparin or LMWH
should be given until the diagnosis is excluded by objective testing, unless treatment
is strongly contraindicated.
Initiating treatment
There are severaldifferent types of heparin to choose from:
LMWH: this is the drug of choice. It has been shown to be more effective than
unfractionated heparin with lower mortality and fewer hemorrhagic complications in
the initial treatment of DVT in non-pregnant subjects. LMWHs are as effective as
unfractionated heparin for treatment of PE. The exact dose will depend on the
manufacturer's recommendations but this is based on the patient's early pregnancy
weight and should be administered subcutaneously twice daily. There should be clear
local guidelines for the dosage of LMWH to be used.
Intravenous unfractionated heparin: this is an extensively used drug in the acute
management of VTE, particularly massive PE with cardiovascular compromise. It is
initiated with a loading dose of 5,000 international units (IU) followed by a
continuous infusion of 1,000-2,000 IU/hour depending on activated partial
thromboplastin time (aPTT) measurements (daily - at least), the first of which is taken
six hours after the loading dose. Thus, there is the benefit of accurate drug
6. administration but it has been demonstrated that there are a number of difficulties
with accurate aPTT measurement (when the sample is taken and in the laboratory),
particularly late in pregnancy when interpretation of the results can be problematic.
Prolonged use in pregnancy may give rise to the problems described above.
Subcutaneous unfractionated heparin: this has been shown to be as effective as the
intravenous form. It is administered as a 5,000 IU bolus and subsequent 15,000-
20,000 IU doses at 12-hourly intervals. The aPTT needs to be checked and is best
done midway between the 12-hourly doses, once every 24 hours. A target of 1.5-2.5
times the control should be aimed for.
Additionally, the leg should be elevated and a graduated elastic compression stocking applied
to reduce oedema. Mobilisation with graduated elastic compression stockings should be
encouraged.
Maintenance therapy
Pregnancy
Heparins are the maintenance treatment of choice. Dose-adjusted subcutaneous,
unfractionated heparin or subcutaneous LMWH are effective alternatives to oral
anticoagulants in maintenance treatment of VTE.
Subcutaneous LMWH appears to have advantages over aPTT-monitored
unfractionated heparin in the maintenance treatment of VTE in pregnancy. The
simplified therapeutic regimen for LMWH tends to be more convenient for patients,
minimising blood tests (routine platelet counts are not required and levels of anti-Xa
will only need to be monitored where there are extremes of weight: <50 kg or >90 kg)
and allowing outpatient treatment. Women should be taught to self-inject and can
then be managed as outpatients until delivery.
If unfractionated heparin is used, monitor the platelet count at least every other day
for the first 14 days or until treatment is stopped (whichever comes first).
Seek specialist advice if the patient develops heparin-induced thrombocytopenia or a heparin
allergy and requires continuing anticoagulant therapy. She should be managed with the
heparinoid, danaparoid sodium or fondaparinux, under specialist supervision.
Labour
When the patient thinks she is going into labour, she should stop injecting and get in touch
with the delivery ward staff that will manage the anticoagulation throughout labour and
immediately post-delivery. Alternatively, planned elective induction of labour or caesarean
section at least 12 hours after prophylactic-dose LMWH or 24 hours after therapeutic-dose
LMWH can be considered. As these patients are at high risk of hemorrhage, they will be
managed with intravenous unfractionated heparin throughout this time. Regional anaesthetic
or analgesic techniques should not be undertaken until at least 24 hours after the last dose of
therapeutic LMWH.
Postpartum
Depending on the patient's individual circumstances, she may be managed with ongoing
heparin treatment or warfarin postpartum. If she opts for warfarin, this needs to be avoided
until at least day three postpartum with an INR check at day two of warfarin treatment: aim
for an INR between 2 and 3. Continue heparin treatment until there have been two successive
readings of an INR >2. Although these drugs are detectable in breast milk, all are safe for use
during breast-feeding because warfarin metabolites are inactive and heparin is not absorbed
through the gastrointestinal tract.
7. Postnatal review for women who develop VTE during pregnancy or the puerperium should,
whenever possible, be at an obstetric medicine clinic or a joint obstetric hematology clinic.
Stopping treatment
In theory, therapy should be continued for six months as would be the case for non-pregnant
patients. However, the postpartum state is a period of physiological fluctuation of coagulation
factors. Therefore, current advice is to continue therapy for at least 6-12 weeks postpartum or
until at least three months of therapy have been completed. At that point, the patient should be
assessed for the presence of ongoing risk factors for a VTE prior to making the decision to
stop anticoagulation therapy.
Complications
Thrombophilia and placental vascular complications
Fetal loss: although the figures are likely to be small (there are not many studies),
there is thought to be a doubling of risk of fetal loss in women with genetic
thrombophilia.
Intrauterine growth restriction: a specific association between this and
thrombophilia has not been identified but chronic abruption and extensive placental
infraction have been noted to occur more frequently in these patients.
HELLP syndrome: Hemolysis, Elevated Liver enzymes, Low Platelet count - this
may be associated with certain forms of thrombophilia.
Post-thrombotic syndrome
Up to 60% of patients who have experienced a DVT go on to have post-thrombotic syndrome
up to 12 months following the acute event. This arises from damage to the lumen of the vein
following the presence of a thrombus. Subsequently, patients manifest symptoms and signs
akin to those of varicose veins: aching, swollen legs, pruritus, dermatitis and
hyperpigmentation of the affected area. Ulceration and cellulitis may complicate the picture.
Compression stockings worn on the affected leg for at least two years have been
recommended after the acute event to reduce the risk of developing post-thrombotic
syndrome. However, a recent large randomized trial found no evidence to support this. PE is
the other complication of DVTs and is discussed above.
Other complications
Prolonged unfractionated heparin use during pregnancy may result in osteoporosis and
fractures.
Prevention: prophylaxis
Guidance from the Royal College of Obstetricians and Gynecologists’ suggests:
Antenatally
Regardless of their VTE risk, dehydration and immobilization of the patient should
be avoided throughout pregnancy.
Women at high risk of VTE in pregnancy should be offered pre-pregnancy
counseling and a prospective management plan for thromboprophylaxis in pregnancy.
8. Those who become pregnant before receiving such counseling should be referred to a
nominated expert early in pregnancy.
All women with previous VTE should receive postpartum prophylaxis, as this is the
time of highest risk.
In addition, women whose original VTE was unprovoked, idiopathic or related to
estrogen, or who have other risk factors, a family history of VTE in a first-
degree relative or a documented thrombophilia require LMWH antenatally and for
six weeks postpartum.
Women with recurrent VTE may already be on warfarin. They should be advised to
stop warfarin and change to LMWH as soon as pregnancy is confirmed, ideally
within two weeks of the missed period and before the sixth week of pregnancy.
Women not on warfarin should be advised to start LMWH as soon as they have a
positive pregnancy test.
Women with asymptomatic inherited or acquired thrombophilia only, may be
managed with close surveillance antenatally and be considered for LMWH for at least
seven days postpartum. Exceptions are women with antithrombin deficiency, those
with more than one thrombophilic defect (including homozygosity for factor V
Leiden) or those with additional risk factors where antenatal prophylaxis should be
considered.
Intrapartum
Women taking LMWH should be advised that, if they bleed vaginally or contractions begin,
they should not inject any further doses. They should be assessed in hospital and further doses
be prescribed by medical staff.
Postpartum
All women with obesity (BMI greater than 40 kg/m2
) should be considered for
prophylactic LMWH for seven days after delivery. Other postnatal risks include
prolonged labour, immobility, infection, hemorrhage and blood transfusion.
All women who have had an emergency Caesarean section should be considered for
LMWH for seven days after delivery. All women who have had an elective caesarean
section who have one or more additional risk factors should be considered for
LMWH for seven days after delivery.
In addition, properly applied graduated compression stockings are recommended for women
travelling long-distance for more than four hours, women who are still outpatients but have
prior VTE (usually combined with LMWH), women who are hospitalized and have a contra-
indication to LMWH and those who are hospitalized post-caesarean section (combined with
LMWH) and considered to be at particularly high risk of VTE.
References:
1. http://www.aafp.org/afp/2008/0615/p1709.html
2. http://atvb.ahajournals.org/content/29/3/326.full
3. http://patient.info/doctor/venous-thromboembolism-in-pregnancy#ref-3