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

Epidemiology

• VTE affects about 1 in 100,000 women of childbearing age.³
• It is up to 10 times more common in pregnant than in nonpregnant women of a similar age.⁴
• It occurs in about 1/1,000 pregnancies in women under the age of 35.
• It occurs in 2.4/1,000 pregnancies in women over the age of 35.
• Inherited thrombophilia is present in 30%-50% of women with pregnancy-associated VTE.³
• 10-20% of VTEs are PEs which are the main contributors to VTE mortality. They are the leading direct cause of maternal mortality in the UK, being responsible for a third of maternal deaths.⁵

Mortality rate

PE is the most common cause of maternal death in the UK - 1.56/100,000 maternities.⁶

• 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).⁷
• 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.

Risk factors

There are a number of known risk factors, some hereditary and others acquired and, in 80% of patients, at least one risk factor can be identified. Notably, the antenatal period 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:⁸

• 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.
  • Immobilisation (>4 days of bedrest).
  • Previous thrombotic event.
  • Trauma.
  • Inflammatory disorders such as inflammatory bowel disease.
  • Cancer.
  • Oestrogen 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.
  • Long-haul travel ≥4 hours.
• Factors specific to pregnancy:³
  • Venous stasis.
  • Maternal age of ≥35 years.
  • Multiparity.
  • Gestation <36 weeks.
  • Instrument-assisted or Caesarean delivery.
  • Haemorrhage.
  • Pre-eclampsia.
  • Prolonged labour.

Presentation

Presentation is similar to nonpregnant patients with DVT or PE:⁹

• 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 jugular venous pressure (JVP) and there may be ECG changes (S1Q3T3). Arterial blood gases taken with the patient sitting down may show respiratory alkalosis and hypoxaemia. 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).

Investigations and diagnosis

Any woman with symptoms and signs suggestive of VTE should have objective testing performed promptly. Treatment with low molecular weight heparin (LMWH) - see below under 'Initiating treatment' - should be started immediately (before diagnosis), unless treatment is strongly contra-indicated. Many hospitals have local policies regarding the management of these patients. This may involve the obstetricians, haematologists, physicians and radiologists.

DVT

If there is a clinical suspicion of a DVT, arrange an urgent compression duplex ultrasound scan. If this is negative and your suspicion is low, discontinue treatment. If it is negative but your suspicion is high, repeat the scan (or order an alternative imaging modality) one week later, whilst keeping the patient anticoagulated. If this is negative, discontinue anticoagulation.

NB: if you suspect an iliac vein thrombosis (back pain and swelling of the entire limb), magnetic resonance venography or conventional contrast venography may be considered.

PE

If there is a clinical suspicion of a PE, organise a CXR and, if this normal, arrange compression duplex Doppler. The CXR may identify other pulmonary disease, such as pneumonia, pneumothorax or lobar collapse. If these are negative, the patient needs to have a ventilation-perfusion (V/Q) lung scan or a computed tomography pulmonary angiogram (CTPA) - discuss with the radiologist. If these are normal but the clinical suspicion remains high, continue anticoagulation and repeat the tests a week later.

NB: ideally, informed consent should be obtained before these tests are undertaken as there are risks associated with these investigations (V/Q scanning carries a slightly increased risk of childhood cancer compared with CTPA - 1/280,000 versus less than 1/1,000,000 - but carries a lower risk of maternal breast cancer).

Blood tests

D-dimer is an unreliable test to carry out in these patients. In pregnancy, it can be elevated because of the physiological changes in the coagulation system and levels become 'abnormal' at term and in the postnatal period in most healthy pregnant women. However, do take blood to check the FBC, coagulation screen, U&Es and LFTs before anticoagulant therapy is commenced. There is controversy surrounding the performance of a thrombophilia screen: it will not affect the immediate management of the patient and results are distorted by the pregnant state and by the presence of a thrombus. However, it can provide information that can influence the duration and intensity of anticoagulation. This is therefore best left to be discussed with everybody involved once the acute situation has been dealt with.

Management

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.³ Refer all women who are on warfarin as this will have to be stopped or replaced by heparin before the 7th week of conception, depending on her risk of VTE.⁵
• 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, localised 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 haemorrhage.
• In clinically suspected DVT or PE, treatment with unfractionated heparin or low molecular weight heparin should be given until the diagnosis is excluded by objective testing, unless treatment is strongly contraindicated.⁹

Initiating treatment

There are several different types of heparin to choose from:

• Low molecular weight heparin (LMWH): this is the drug of choice. It 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 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 6 hours after the 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 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

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 (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.
2. Labour: when the patient thinks she is going into labour, she should stop injecting and get in touch with the delivery ward staff who 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 low LMWH can be considered.³ As these patients are at high risk of haemorrhage, 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.
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 needs to be avoided until at least day 3 postpartum with an INR check at day 2 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.³

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 haematology clinic.

Stopping treatment

In theory, therapy should be continued for six months as would be the case for nonpregnant 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: Haemolysis, EL (elevated liver) enzymes , LP (low platelet) count - this may be associated with certain forms of thrombophilia.

Post-thrombotic syndrome

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, pruritus, 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 for at least 2 years after the acute event reduces the risk of developing post-thrombotic syndrome.⁹ 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

See also the separate article on the prevention of deep vein thrombosis.
Guidance suggested by the Royal College of Obstetricians and Gynaecologists suggests:⁴

Antenatally

• Regardless of their VTE risk, dehydration and immobilisation of the patient should be avoided throughout pregnancy.
• Women at high risk of VTE in pregnancy should be offered pre-pregnancy counselling and a prospective management plan for thromboprophylaxis in pregnancy. Those who become pregnant before receiving such counselling 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 oestrogen, 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 6 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 7 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 7 days after delivery. Other postnatal risks include prolonged labour, immobility, infection, haemorrhage and blood transfusion.
• All women who have had an emergency Caesarean section should be considered for LMWH for 7 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 7 days after delivery.

In addition, properly applied graduated compression stockings are recommended for women travelling long distance for more than 4 hours, women who are still outpatients but have prior VTE (usually combined with LMWH), women who are hospitalised and have a contra-indication to LMWH and those who are hospitalised post-Caesarean section (combined with LMWH) and considered to be at particularly high risk of VTE.

Document references

1. Blann AD, Lip GY; Venous thromboembolism. BMJ. 2006 Jan 28;332(7535):215-9.
2. Lockshin MD, Venous thromboembolism during pregnancy. N Engl J Med. 1996 Dec 12;335(24):1847.
3. Lim W, Eikelboom JW, Ginsberg JS; Inherited thrombophilia and pregnancy associated venous thromboembolism. BMJ. 2007 Jun 23;334(7607):1318-21.
4. Reducing the Risk of Thrombosis and Embolism during Pregnancy and the Puerperium, Royal College of Obstetricians and Gynaecologists (November 2009)
5. Pre-conception - advice and management, Clinical Knowledge Summaries (2007)
6. CEMACH - Saving Mothers' Lives; Confidential Enquiry into Maternal and Child Health (CEMACH) - Reviewing maternal deaths to make motherhood safer 2003-2005 Executive Summary; (2003-2005), December 2007
7. Samuelsson E, Hedenmalm K, Persson I; Mortality from venous thromboembolism in young Swedish women and its relation to pregnancy and use of oral contraceptives--an approach to specifying rates. Eur J Epidemiol. 2005;20(6):509-16. [abstract]
8. Sellman JS, Holman RL; Synopsium: thromboembolism during pregnancy - risks, challenges and recommendations. J Postgrad Med (online), 2000; 108 (4).
9. Thromboembolic Disease in Pregnancy and the Puerperium: Acute Management, Royal College of Obstetricians and Gynaecologists (2007)

Acknowledgements