Venous Thromboembolism (VTE) in Pregnancy

Venous Thromboembolism (VTE) in pregnancy

Venous thromboembolism (VTE) is a collective term that describes deep vein thrombosis (DVT) and pulmonary embolism (PE). Venous thromboembolism is a leading cause of maternal mortality responsible for approximately 1/3 of maternal deaths. VTE affects about 1 in 100,000 women of childbearing age. 1-It is up to 10 times more common in pregnant than in non- pregnant women of a similar age. 2-It occurs in about 1/1,000 pregnancies in women under the age of 35. 3-It occurs in 2.4/1,000 pregnancies in women over the age of 35. 4-10-20% of VTEs are PEs which are the main contributors to VTE mortality.

Pregnancy is a major risk factor for VTE, resulting in a 4-5x increased risk. This is thought to be due to changes in the levels of some of the proteins of the clotting cascade (such as increased fibrinogen, and decreased protein S). These changes become more pronounced as the pregnancy progresses, and thus the period of highest risk is postpartum. Pathological requirement for DVT Virchow's triad of hypercoagulation, vascular damage, and venous stasis all occur in pregnancy, resulting in a relative risk of 4.3 (95% confidence interval [CI], 3.5 to 5.2) for VTE in pregnant or postpartum women compared with nonpregnant women

Introduction One of the many early physiological adaptations of pregnancy involves changes in the coagulation system, which promote coagulation and impair fibrinolysis. The physiological goal is to prepare for the haemostatic challenge of delivery. A side effect of this change is an increased risk of thrombosis. All pregnant women are therefore at risk of thrombosis, compared with non- pregnant women. This risk is manifest from early in the first trimester until 4 6 weeks post partum

Whilst pregnancy itself is a major risk factor for developing a VTE, there are additional factors that can further increase risk. They can be divided into pre-existing factors, obstetric factors and transient factors Obstetric Factors Multiple pregnancy Pre-eclampsia Caesarean section Prolonged labour Stillbirth Preterm birth PPH immobility (4 days) Transient Factors Any surgical procedure in pregnancy or puerperium Dehydration (e.g hyperemesis) Ovarian hyperstimulation syndrome Admission or immobility Systemic infection Long distance travel 4 hours Pre-existing Factors Thrombophilia (e.g. Antiphospholipid syndrome) Medical co-morbidities (e.g. cancer) Age >35 years BMI >30 kg/m2 Parity >3 Smoking Varicous vein paraplegia

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.

Obesity - body mass index (BMI) 30 kg/m2. Immobilisation (>4 days of bed rest). Previous thrombotic event. 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. Long-haul travel of 4 hours.

Presentation is similar to non-pregnant patients with DVT or PE: DVT: leg pain and discomfort (the left is more commonly affected 80%), 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.

DVT in pregnancy usually proximal Unilateral leg pain/tenderness Swelling in an extremity Increase calf/thigh circumference Increased temperature Prominent superficial veins and Pitting edema symptoms or signs of DVT Dyspnea Palpitations Pleuritic chest pain Hemoptysis Cyanosis/hypoxia in massive PE Tachycardia Tachypnea Hypotension Collapse Signs and Symptoms of Pulmonary embolism

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).

Any woman with symptoms and signs suggestive of VTE should have objective testing performed promptly. Treatment with low molecular weight heparin (LMWH) - 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.

If there is a clinical suspicion of a DVT, arrange an urgent compression duplex ultrasound scan. If this is negative and 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.

If there is a clinical suspicion of a PE, organize a CXR and if this is 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). 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).

1-Take blood to check the FBC, coagulation screen, U&Es and LFTs before anticoagulant therapy is commenced. 2-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 sys tem and levels become 'abnormal' at term and in the postnatal period in most healthy pregnant women. Although a low D-dimer may be helpful in ruling out DVT, a positive (high) D-dimer result will be common during pregnancy and always requires confirmatory testing. 3-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.

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 PTE is confirmed or, in extreme circumstances prior to confirmation, immediate thrombolysis should be considered. Intravenous unfractionated heparin is the preferred treatment.

All women with symptoms of VTE should have low-molecular weight heparin (LMWH) started immediately until the diagnosis is excluded by definitive testing. The dose should be titrated against the woman s booking weight. In confirmed venous thromboembolism, anticoagulation should be maintained throughout the pregnancy, until 6-12 weeks post- partum. Women should be advised to omit their dose 24 hours before any planned induction of labour or caesarean section. Furthermore, they should not take their dose if they think they are going into labour. LMWH is the anticoagulant of choice. Alternatives include unfractionated heparin and new oral anticoagulants (e.g rivaroxaban). Warfarin should never be used in the treatment of VTE during pregnancy as it is teratogenic, and can lead to foetal loss through haemorrhage.

1-Medical anticoagulation 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. There are several different types of heparin to choose from: LMWH: this is the drug of choice. It more effective than unfractionated heparin with lower mortality and fewer hemorrhagic complications in the initial treatment of DVT unfractionated heparin: this is an extensively used drug in the acute management of VTE, particularly massive PE with cardiovascular compromise .

2- Additionally, the leg should be elevated and a graduated elastic compression stocking applied to reduce edema. Mobilization with graduated elastic compression stockings should be encouraged.

] There are several different 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 haemorrhagic 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

Therapeutic Dosing of Heparin in Pregnancy LMWH (enoxaparin) 1 mg per kg subcutaneously every12 hours UFH IV loading dose of 5,000 IU followed by Continuous IV infusion for a total of at least 30,000 IU over 24 hours Or 10,000 IU subcutaneously every 8 hours or20,000 IU subcutaneously every 12 hours Monitor aPTT and adjust dose to maintain aPTT 1.5 to 2 times control value . .

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. 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 under specialist supervision.

Heparins are the maintenance treatment of choice. Subcutaneous LMWH appears to have advantages over unfractionated heparin (aPTT- monitored )in the maintenance treatment of VTE in pregnancy. 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.

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. Regional anaesthetic or analgesic techniques should not be undertaken until at least 24 hours after the last dose of therapeutic LMWH.

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. 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

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.

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. Those who become pregnant before receiving such counseling should be referred to a nominated expert early in pregnancy. All women should be assessed for their risk of VTE early in the pregnancy. This assessment should be repeated in the intrapartum and postnatal periods. The general principles of VTE prophylaxis in pregnancy are: , pregnant women are offered thromboprophylaxis if they have 4 risk factors in the first 2 trimesters, 3 in the 3rdtrimester, and 2 in the post-partum period. Any woman receiving thromboprophylaxis antenatally should continue anticoagulation until at least 6 weeks postpartum (as the immediate postnatal period carries the highest risk).

Previous VTE (provoked from major surgery) Thromboprophylaxis with LMWH from 28 weeks onward Other previous VTE Thromboprophylaxis with LMWH throughout antenatal period Known antithrombin deficiency Thromboprophylaxis with high dose LMWH (usually 50%, 75% or full treatment dose) Known antiphospholipid syndrome Thromboprophylaxis with high dose LMWH (usually 50%, 75% or full treatment dose Women with asymptomatic inherited or acquired thrombophilia only, may be managed with close surveillance antenatally and be considered for LMWH for at least ten 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 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.

for 10days after delivery All women with obesity (BMI greater than 40 kg/m2) should be considered for prophylactic LMWH. 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. All women who have had an elective caesarean section who have one or more additional risk factors should be considered for LMWH. 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.

Prophylactic Dosing of Heparin in Pregnancy (Enoxaparin ) 110 to 199 lb (50 to 90 kg)40 mg SC daily < 110 lb 20 mg SC daily > 199 lb 40 mg SC every 12 hours UFH First trimester 5,000 IU SC twice daily Second trimester 7,500 IU SC twice daily Third trimester 10,000 IU SC twice daily

Acute complication is PE Chronic complications 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 Complications of drugs :Prolonged unfractionated heparin use during pregnancy may result in osteoporosis and fractures 3 Recurrence of DVT: in subsequent pregnancies 12% .

Approximately 50 percent of pregnant women with VTE have a thrombophilia, compared with 10 percent of the general population. Current evidence does not support universal thrombophilia screening. However, expert opinion suggests testing women with a personal or strong family history of thrombosis or thrombophilia. During pregnancy, results must be interpreted with caution, because protein S levels normally fall in the second trimester. Massive thrombus and nephrotic syndrome can decrease antithrombin levels, and liver disease decreases protein C and S levels.

Inherited thrombophilia is present in 30-50% of women with pregnancy-associated VTE .Thrombophilic disorders may be inherited or acquired. Factor V Leiden and prothrombin G20210A mutations are the most common. Antiphospholipid antibody syndrome, the most important acquired thrombophilia in pregnancy, is defined by the presence of antiphospholipid antibodies and one or more clinical manifestations, most commonly thrombosis or recurrent miscarriage. A positive test for lupus anticoagulant, or medium-to-high titers of anticardiolipin immunoglobulin G or M antibodies, provides adequate laboratory confirmation of antiphospholipid antibody syndrome if found twice at least six weeks apart.

Fetal loss: 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, Elevated Liver enzymes, Low Platelet count - this may be associated with certain forms of thrombophilia.

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