Venous thromboembolism in pregnancy

What is venous thromboembolism?¹

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).

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.

How common is venous thromboembolism in pregnancy? (Epidemiology)

• VTE affects about 1 in 100,000 women of childbearing age.²

• Although the relative risk of VTE in pregnancy is increased 4- to 6-fold and this is increased further postpartum, the absolute risk is low with an overall incidence of VTE in pregnancy and the puerperium of 1-2 per 1,000.³

• It occurs in about 1/1,000 pregnancies in women under the age of 35.¹

• It occurs in 2.4/1,000 pregnancies in women over the age of 35.⁴

• Inherited thrombophilia is present in 30-50% of women with pregnancy-associated VTE.²

• 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 rate⁶

Thrombosis and thromboembolism were the leading causes of maternal deaths between 2017-2019 in the UK and Ireland, occurring in 0.89 in 100,000 maternities (a maternity is defined as a pregnancy resulting in the birth of 1 or more children, including stillbirths):

• 32 women died in the UK and Ireland from venous thromboembolism during or up to a year after the end of pregnancy:

  • 31 died from pulmonary embolism and one from a cerebral venous sinus thrombosis.

  • 21 women died during or up to six weeks after the end of pregnancy.

  • Seven women were undelivered at the time of their death, three of whom were in the first trimester and four in the second trimester.

  • Among the women who died from venous thromboembolism, there was the relatively high proportion of young, obese women. Eight of the women who died (25%) were aged under 25 years, and five of these women (63%) had a BMI of 40 kg/m² or greater.

  • Overall, 23 of the women who died (72%) were overweight or obese on the basis of their first recorded weight in pregnancy, 19 (59%) had a BMI of 30 kg/m² or greater, 15 (47%) had a BMI of 35 kg/m² or greater, 12 (38%) had a BMI of 40 kg/m² or greater and (16%) had a BMI of 45 kg/m² or greater.

Risk factors³

Pre-existing:

• Previous VTE.

• Thrombophilia:

  • Heritable: antithrombin deficiency, protein C deficiency, protein S deficiency, factor V Leiden, prothrombin gene mutation.

  • Acquired: antiphospholipid antibodies, persistent lupus anticoagulant and/or persistent moderate/high titre anticardiolipin antibodies and/or β2-glycoprotein 1 antibodies.

• Medical comorbidities - eg, cancer; heart failure; active SLE, inflammatory polyarthropathy or IBD; nephrotic syndrome; type I diabetes mellitus with
  nephropathy; sickle cell disease; current intravenous drug user.

• Age >35 years.

• Obesity (BMI ≥ 30 kg/m²) either pre-pregnancy or in early pregnancy.

• Parity ≥3 (a woman becomes para 3 after her third delivery).

• Smoking.

• Gross varicose veins (symptomatic or above knee or with associated phlebitis, oedema/skin changes).

• Paraplegia.

Obstetric risk factors:

• Multiple pregnancy.

• Current pre-eclampsia.

• Caesarean section.

• Prolonged labour (>24 hours).

• Mid-cavity or rotational operative delivery.

• Stillbirth.

• Preterm birth.

• Postpartum haemorrhage (>1 litre/requiring transfusion).

New onset/transient:

• Any surgical procedure in pregnancy or puerperium except immediate repair of the perineum - eg, appendicectomy, postpartum sterilisation.

• Bone fracture.

• Hyperemesis, dehydration.

• Ovarian hyperstimulation syndrome (first trimester only): assisted reproductive technology (ART), in vitro fertilisation (IVF).

• Admission or immobility (≥3 days’ bed rest) - eg, pelvic girdle pain restricting mobility.

• Current systemic infection (requiring intravenous antibiotics or admission to hospital) - eg, pneumonia, pyelonephritis, postpartum wound infection.

• Long-distance travel (>4 hours).

Assessment^{5 7 8}

The National Institute for Health and Care Excellence (NICE) recommends:

Preconception:

For any woman with a history of venous thromboembolism who wishes to become pregnant:

• Seek specialist advice from a clinician with expertise in thrombosis in pregnancy for women who have a past history of deep vein thrombosis or pulmonary embolism, and for those with an abnormal thrombophilia screen.

Refer all women receiving warfarin therapy who are planning a pregnancy to a specialist for advice, as warfarin will need to be stopped or replaced by heparin, depending on the woman's degree of risk of VTE.

Assess the woman's risk factors for venous thromboembolism at the first antenatal (booking) appointment, and after any hospital admission or significant health event during pregnancy. Consider using guidance by an appropriate professional body - eg, the Royal College of Obstetricians and Gynaecologists' guideline on reducing the risk of venous thromboembolism during pregnancy. (See reference links for the RCOG guideline.)

For pregnant women who are admitted to a hospital or a midwife-led unit, see the section on interventions for pregnant women and women who gave birth or had a miscarriage or termination of pregnancy in the past six weeks in the NICE guideline on venous thromboembolism in over 16s.

For women at risk of venous thromboembolism, offer referral to an obstetrician for further management.

Consider low-molecular-weight heparin (LMWH) for all women who are admitted to hospital or a midwife-led unit if they are pregnant or gave birth, had a miscarriage or had a termination of pregnancy in the past six weeks, and whose risk of VTE outweighs their risk of bleeding.

Consider combined prophylaxis with LMWH plus mechanical prophylaxis for pregnant women or women who gave birth or had a miscarriage or termination of pregnancy in the past six weeks and who are likely to be immobilised, or have significantly reduced mobility relative to their normal or anticipated mobility for three or more days after surgery, including caesarean section:

• Use intermittent pneumatic compression as first-line treatment.

• If intermittent pneumatic compression is contra-indicated, use anti-embolism stockings.

• Continue until the woman no longer has significantly reduced mobility relative to her normal or anticipated mobility or until discharge from hospital.

Venous thromboembolism in pregnancy symptoms (presentation)

See also the articles on Deep Vein Thrombosis and Pulmonary Embolism.

Presentation is similar to non-pregnant 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. 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 diagnosis⁹

Many hospitals have local policies regarding the management of these patients. This may involve the obstetricians, haematologists, physicians and radiologists.

DVT

Compression duplex ultrasound should be undertaken where there is clinical suspicion of DVT. If ultrasound is negative and there is a low level of clinical suspicion, anticoagulant treatment can be discontinued. If ultrasound is negative and a high level of clinical suspicion exists, anticoagulant treatment should be discontinued but the ultrasound should be repeated on days 3 and 7.

PE

Women presenting with symptoms and signs of an acute PE should have an electrocardiogram (ECG) and a chest X-ray (CXR) performed. In women with suspected PE who also have symptoms and signs of DVT, compression duplex ultrasound should be performed.

If compression ultrasonography confirms the presence of DVT, no further investigation is necessary and treatment for VTE should continue. In women with suspected PE without symptoms and signs of DVT, a ventilation/perfusion (V/Q) lung scan or a computerised tomography pulmonary angiogram (CTPA) should be performed.

When the chest X-ray is abnormal and there is a clinical suspicion of PE, CTPA should be performed in preference to a V/Q scan. Alternative or repeat testing should be carried out where V/Q scan or CTPA is normal but the clinical suspicion of PE remains. Anticoagulant treatment should be continued until PE is definitively excluded.

Compared with CTPA, V/Q scanning may carry a slightly increased risk of childhood cancer but is associated with a lower risk of maternal breast cancer. In both situations, the absolute risk is very small.

Blood tests

D-dimer testing should not be performed in the investigation of acute VTE in pregnancy. The use of D-dimers to guide diagnostic decisions in pregnancy is limited due to their physiological increase during pregnancy, especially during the second and third trimesters.¹⁰

Before anticoagulant therapy is commenced, blood should be taken for a full blood count, coagulation screen, urea and electrolytes, and liver function tests. Performing a thrombophilia screen prior to therapy is not recommended.

Obstetric patients who are postoperative and receiving unfractionated heparin should have platelet count monitoring performed every 2-3 days from days 4 to 14 or until heparin is stopped.

Venous thromboembolism in pregnancy treatment and management⁹

Initial anticoagulant treatment

In clinically suspected DVT or PE, treatment with low-molecular-weight heparin (LMWH) should be commenced immediately until the diagnosis is excluded by objective testing, unless treatment is strongly contra-indicated.

LMWH is generally the heparin of choice, rather than intravenous or subcutaneous unfractionated heparin. Prolonged unfractionated heparin use during pregnancy may result in osteoporosis and fractures. However:

• Intravenous unfractionated heparin is the preferred, initial treatment in massive PE with cardiovascular compromise.

• Any woman who is considered to be at high risk of haemorrhage, and in whom continued heparin treatment is considered essential, should be managed with intravenous unfractionated heparin until the risk factors for haemorrhage have resolved.

• When VTE occurs at term, consideration should be given to the use of intravenous unfractionated heparin which is more easily manipulated.

Consideration should be given to the use of newer anticoagulants (fondaparinux, argatroban or r-hirudin) in pregnant women who are unable to tolerate heparin (LMWH or unfractionated heparin) or danaparoid and who require continuing anticoagulant therapy.

Routine measurement of peak anti-Xa activity (used to measure absolute levels of heparin in patient plasma) for patients on LMWH for treatment of acute VTE in pregnancy or postpartum is not recommended except in women at extremes of body weight (less than 50 kg and 90 kg or more) or with other complicating factors (eg, renal impairment or recurrent VTE).

Routine platelet count monitoring should not be carried out. Obstetric patients who are postoperative and receiving unfractionated heparin should have platelet count monitoring performed every 2-3 days from days 4 to 14 or until heparin is stopped.

Additional therapies

In the initial management of DVT, the leg should be elevated and a graduated elastic compression stocking applied to reduce oedema. Mobilisation with graduated elastic compression stockings should be encouraged.

Consideration should be given to the use of a temporary inferior vena cava filter in the peripartum period for patients with iliac vein VTE to reduce the risk of PE or in patients with proven DVT and who have recurrent PE despite adequate anticoagulation.

Maintenance treatment

Treatment with therapeutic doses of subcutaneous LMWH should be employed during the remainder of the pregnancy and for at least six weeks postnatally and until at least three months of treatment have been given in total.

Women should be taught to self-inject LMWH and arrangements made to allow safe disposal of needles and syringes. Outpatient follow-up should include clinical assessment and advice with monitoring of blood platelets and peak anti-Xa levels if appropriate.

Pregnant women who develop heparin-induced thrombocytopenia or have heparin allergy and require continuing anticoagulant therapy should be managed with an alternative anticoagulant under specialist advice.

Because of their adverse effects on the fetus, vitamin K antagonists, such as warfarin, should not be used for antenatal VTE treatment.

Consideration should be given to the use of newer anticoagulants (fondaparinux, argatroban or r-hirudin) in pregnant women who are unable to tolerate heparin (LMWH or unfractionated heparin) or danaparoid and who require continuing anticoagulant therapy.

Anticoagulant therapy during labour and delivery

When VTE occurs at term, consideration should be given to the use of intravenous unfractionated heparin which is more easily manipulated.

Once in established or suspected labour, the pregnant woman should not inject any further heparin.

Where delivery is planned, either by elective caesarean section or induction of labour, LMWH maintenance therapy should be discontinued 24 hours prior to planned delivery. Regional anaesthetic or analgesic techniques should not be undertaken until at least 24 hours after the last dose of therapeutic LMWH.

LMWH should not be given for four hours after the use of spinal anaesthesia or after the epidural catheter has been removed, and the epidural catheter should not be removed within 12 hours of the most recent injection.

In patients receiving therapeutic doses of LMWH, wound drains (abdominal and rectus sheath) should be considered at caesarean section and the skin incision should be closed with interrupted sutures to allow drainage of any haematoma.

Any woman who is considered to be at high risk of haemorrhage, and in whom continued heparin treatment is considered essential, should be managed with intravenous unfractionated heparin until the risk factors for haemorrhage have resolved.

Postnatal anticoagulation

Therapeutic anticoagulant therapy should be continued for the duration of the pregnancy and for at least six weeks postnatally and until at least three months of treatment has been given in total. Before discontinuing treatment the continuing risk of thrombosis should be assessed.

Women should be offered a choice of LMWH or oral anticoagulant for postnatal therapy after discussion about the need for regular blood tests for monitoring of warfarin, particularly during
the first 10 days of treatment. Postpartum warfarin should be avoided until at least the fifth day and for longer in women at increased risk of postpartum haemorrhage.

Neither heparin (unfractionated or LMWH) nor warfarin is contra-indicated in breastfeeding.

Prevention of post-thrombotic syndrome

Women should be advised that prolonged use of LMWH (more than 12 weeks) is associated with a significantly lower chance of developing post-thrombotic syndrome.

Following a DVT, graduated elastic compression stockings should be worn on the affected leg to reduce pain and swelling. The role of compression stockings in the prevention of post-thrombotic syndrome is unclear.

Postnatal clinic review

Postnatal review for patients who develop VTE during pregnancy or the puerperium should, whenever possible, be at an obstetric medicine clinic or a joint obstetric haematology clinic.

Thrombophilia testing should be performed once anticoagulant therapy has been discontinued only if it is considered that the results would influence the woman’s future management.

Complications

• Thrombosis and thromboembolism remain the leading cause of direct maternal death during or up to six weeks after the end of pregnancy. In 2017-19, 191 women died during or up to six weeks after the end of pregnancy, from causes associated with their pregnancy, among 2,173,810 women giving birth in the UK. 20 of these deaths were attributable to thrombosis and thromboembolism.⁶

• Recurrence. The risk of recurrence will depend on the presence and nature of any underlying cause for VTE.

• Thrombophilia, the hereditary or acquired tendency to develop VTE, is also thought to be associated with complications in pregnancy, such as recurrent miscarriage and pre-eclampsia.¹²

Post-thrombotic syndrome

Post-thrombotic syndrome is a form of chronic venous insufficiency secondary to prior deep vein thrombosis. It affects up to 50% of patients after proximal DVT.¹³

Symptoms and signs may include 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.⁹ However, a large randomised trial found no evidence to support this.¹⁴

Prevention: prophylaxis

See also the separate article on the Prevention of Venous Thromboembolism.

Guidance from the Royal College of Obstetricians and Gynaecologists advises:³

• Any woman with four or more current risk factors (see above), other than previous VTE or thrombophilia, should be considered for prophylactic low-molecular-weight heparin (LMWH) throughout the antenatal period and will usually require prophylactic LMWH for six weeks postnatally but a postnatal risk reassessment should be made.

• Any woman with three current risk factors (other than previous VTE or thrombophilia) should be considered for prophylactic LMWH from 28 weeks and will usually require prophylactic LMWH for six weeks postnatally but a postnatal risk reassessment should be made.

• Any woman with two current risk factors (other than previous VTE or thrombophilia) should be considered for prophylactic LMWH for at least 10 days postpartum.

• Women admitted to hospital when pregnant (including to the gynaecology ward with hyperemesis gravidarum or ovarian hyperstimulation syndrome) should usually be offered thromboprophylaxis with LMWH unless there is a specific contra-indication such as risk of labour or active bleeding.

The use of properly applied anti-embolism stockings of appropriate size and providing graduated compression with a calf pressure of 14-15 mm Hg is recommended in pregnancy and the puerperium for women who are hospitalised and have a contra-indication to LMWH. These include women who are hospitalised post-caesarean section (combined with LMWH) and considered to be at particularly high risk of VTE (eg, previous VTE, more than four risk factors antenatally or more than two risk factors postnatally) and women travelling long-distance for more than four hours.

See the reference link for the RCOG guideline for further specific guidance, including if previous VTE, thrombophilia.