Venous Thromboembolism in Pregnancy

Venous thromboembolism (VTE) refers to the formation of a thrombus within veins. This can occur anywhere in the venous system but the clinically predominant sites are in the vessels of the leg (giving rise to deep vein thrombosis, DVT) and in the lungs (resulting in a pulmonary embolus, PE).¹ The pathophysiology of VTE in pregnancy appears to relate to the increased venous stasis noted during this period but other factors such as alterations in the balance of proteins of the coagulation and fibrinolytic systems have also been implicated.² Its importance in obstetrics is highlighted by the statistic that PE is the most common cause of maternal death in the UK.³

• It is about 5 times more common in pregnant than in non-pregnant women of a similar age.²
• Occurs in about 1/1000 pregnancies in women under the age of 35.
• Occurs in 2.4/1000 pregnancies in women over the age of 35.
• 10-20% of VTEs are PEs which are the main contributors to VTE mortality.

Mortality Rate³

• The mortality rate is low but exact figures are not widely published. A recent study suggested a rate of 8.9 per million pregnancy years but this was in young women (the risk is highest in the over 35 age group).⁴
• 62% of women with fatal VTEs die in the first trimester although the risk per day is actually greatest in the weeks following delivery.
• 71% of postpartum deaths from VTE occur following vaginal delivery.
• 10% of postpartum deaths from VTE occur following operative (interventional) vaginal delivery.

Presentation is similar to non-pregnant patients with DVT or PE⁵:

• DVT: leg pain and discomfort (the left is more commonly affected), swelling, tenderness, oedema, 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: dyspnoea, pleuritic chest pain, haemoptysis, faintness, collapse. The patient may have focal signs in the chest, tachypnoea, a raised JVP and there may be ECG changes (S1Q3T3). Arterial blood gases taken with patient sitting down may show respiratory alkalosis and hypoxaemia. There may also be symptoms or signs of a DVT.

• 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 jugular venous pressure).

DVT

1 - Assess likelihood of DVT.

Score 1 point for each of the following: tenderness along entire deep vein system, swelling of entire leg, > 3cm difference in calf circumference, pitting oedema, collateral superficial veins, presence of risk factors (by the nature of the fact that the patient is pregnant, a point is already notched). Subtract 2 points if you think that an alternative diagnosis is likely. Categorize patient's likelihood of having a DVT (> 3 points: highly likely, 1-2 points: moderate risk, 0 points: low risk).

2 - In the low risk patient: perform a D-dimer blood test: if it is negative, there is no DVT. If it is positive, organise an ultrasound scan. If this is negative there is no DVT. If it is positive, treat for DVT.
3 - In the moderate to high risk patient: organise an ultrasound scan. If this is positive, treat for DVT. If this is negative, perform a D-dimer blood test. If this is positive, anticoagulate and repeat ultrasonography in 1 week. If it is negative, there is no DVT.

PE

1 - Assess likelihood of PE.

Score 3 points for each of the following: DVT, no explanation of acute breathlessness or pleuritic chest pain. Score 1.5 points for each of: prolonged immobility or surgery in past 4 weeks, history of DVT/PE, resting heart rate of >100bpm. Score 1 point for each of active cancer or haemoptysis. Categorize patient's likelihood of having a PE: > 6 points - highly likely (60%), 4-6 points - moderate risk (20%), 1.5 or less points - low risk(3-4%).

2 - In the low risk patient: perform a D-dimer blood test: if it is negative, there is no PE. If it is positive, organise ventilation perfusion scan or CT pulmonary angiography... (see next step below:)
3 - In the moderate to high risk patient: organise a ventilation perfusion scan or CT angiography. If this is positive, treat for PE. If this is negative, perform a D-dimer blood test. If this is normal, there is no PE. If this shows high probability, treat for PE. If it is non-diagnostic, organise ultrasonography of leg veins. If this is positive, treat for PE, further scans should be carried out at weekly intervals. Two more negative scans suggest no PE. A positive scan should prompt treatment for PE.

Clearly when investigating for the possible presence of a PE, the mother (and hence foetus) will inevitably be exposed to radiation which itself is potentially harmful. This has to be balanced against the fact that significant morbidity - or even mortality - from an untreated PE (or from misguided prolonged anticoagulation) is the other option. In some centres, a spiral CT scan is replacing the ventilation / perfusion scan. The former emits less radiation and hence less exposure to the foetus.⁶

General points

• 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 contraindication 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 foetus (it does not cross the placental barrier). However, its main disadvantages are that it has to be parentally administered and on the long-term, may give rise to heparin-induced osteoporosis and thrombocytopaenia. In some patients, it can also provoke a painful, localised allergic reaction on administration.⁷ Warfarin is the other treatment option in the postnatal patient but it must be avoided ante-natally as it teratogenic and can also cause placental abruption and foetal / neonatal haemorrhage.
• In clinically suspected DVT or PE, treatment with unfractionated heparin or low molecular weight heparin (LMWH) should be given until the diagnosis is excluded by objective testing, unless treatment is strongly contraindicated.⁵

Initiating treatment

Baseline assessment:

• Carry out a full thrombophilia screen - this will not influence initial management but will provide information guiding the duration and intensity of long-term management. These results should be interpreted in the light of normal physiological changes during pregnancy: coagulation factors II, VII, & X increase by mid pregnancy, fibrin generation increases as protein S levels decrease, fibrinolytic system inhibited particularly by 3rd trimester.
• Check full blood count, coagulation screen, urea and electrolytes and liver function tests (renal and hepatic dysfunction will influence intensity of treatment).

• Intravenous unfractionated heparin: this is an extensively used drug in the acute management of VTE, particularly massive PE. It is initiated with a loading dose of 5000 iu followed by a continuous infusion of 1000-2000 iu / hour depending on (daily - at least) APTT measurements, the first of which is taken 6 hours post loading dose. Thus, there is the benefit of accurate drug 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 lab), 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 5000 iu bolus and subsequent 15,000 - 20,000 iu doses at 12 hourly intervals. The APTT needs to be checked and is best done mid-way between the 12 hourly doses, once every 24 hours. A target of 1.5-2.5 times the control should be aimed for.
• Low molecular weight heparin: this has been shown to be more effective than unfractionated heparin with lower mortality and fewer haemorrhagic complications in the initial treatment of DVT in nonpregnant 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 tends to be administered twice daily.

Maintenance therapy

1. During 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 (although platelet counts and levels of anti-Xa will need to be monitored on a monthly basis) and allowing out-patient treatment. Women should be taught to self-inject and can then be managed as out-patients until delivery.
2. Labour When the patient thinks she is going into labour, she should stop injecting and get in touch with the delivery ward who will manage the anticoagulation throughout labour and immediately post delivery. As these patients are at high risk of haemorrhage, they will be managed with intravenous unfractionated heparin throughout this time.
3. Postpartum period Depending on the patient's individual circumstances, she may be managed with ongoing heparin treatment or warfarin postpartum. If she opts for warfarin, this can be initiated day 2 or 3 post partum with an INR check at day 2. Continue heparin treatment until there have been two successive readings of an INR > 2. It is not thought to pass into breast milk.

Stopping treatment

Therapy is continued for six months in the first instance, as would be the case for non-pregnant patients. However, owing to the physiological fluctuation of coagulation factors, current advice is to continue therapy for at least 6-12 weeks post partum or until 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.

Up to 60% of patients who have suffered from 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, pruritis, dermatitis and hyperpigmentation of the affected area. Ulceration and cellulitis may complicate the picture. There is emerging evidence to suggest that compression stockings worn on the affected leg reduces the risk of developing post thrombotic syndrome.⁸ PE is the other complication of DVTs and is discussed above.

There are obvious risks associated with ante-natal anticoagulation and the decision to go ahead with prophylactic thrombolysis is one made jointly by the obstetricians and haematologists. Guidance suggested by the Royal College of Obstetricians and Gynaecologists suggests:

• Regardless of their VTE risk, dehydration and immobilisation of the patient ante-natally, during labour and post-partum should be avoided
• If a decision is made to go ahead with prophylaxis, this should be initiated as early in the pregnancy as possible (post-partum prophylaxis should commence as soon after the delivery as is practically possible)
• Women with a history of a VTE but no thrombophilia should be offered LMWH for 6 weeks post partum (there is some debate about the ante-natal period owing to conflicting evidence) unless the she the VTE was clearly associated with a (now fully resolved) risk factor. If she has had multiple VTEs or if there is a strong family history of VTEs in a first degree relative, ante-natal prophylaxis should also be offered.
• Women with a history of VTE and known thrombophilia should be offered LMWH prophylaxis ante-natally and for at least 6 weeks post partum
• Women with inherited thrombophilia but no previous VTE may or may not qualify for ante / post natal prophylaxis depending on the nature of the thrombophilia and the whether there are associated risk factors
• Patients with acquired thrombophilia (antiphospholipid syndrome) generally should receive prophylaxis throughout and after pregnancy in most but a handful of cases
• Women without previous VTE or thrombophilia: if there are three or more persisting risk factors, antenatal thromboprophylaxis should be considered through to 3-5 days post-partum. Notably, if the patient is over 35, has a BMI of over 30 or a body weight of over 90kg, prophylaxis is almost mandatory, especially in the immediate post partum period.
• High risk women may need to have ongoing prophylaxis for several weeks but it should also be noted that the prothrombotic changes of pregnancy do not revert to normal until several weeks post partum. The risk does diminish if the patient is mobile but does not disappear. This should be borne in mind if there is exposure to risk factors (surgery, long-haul flights), even several weeks after an uneventful vaginal delivery.