THROMBOPROPHYLAXIS

Thromboembolism Defined

In deep vein thrombosis a blood clot forms in one of the veins deep inside the leg. It can occur at any age but is much more common in pregnant and older people. It can be caused by a wide variety of factors other than air travel. The clot may break away from its position and travel through the heart to the lung - pulmonary thrombosis, where it may cause severe symptoms which can result in death.

Maternal Mortality Rates

Figure 1. Pulmonary thromboembolism (PTE) is the most common direct cause of maternal death in the UK.

(From Why Mothers Die 2000 - 2002: CEMACH)

Figure 2. Maternal Mortality from Pulmonary Embolism occurred until 1980 but has remained static subsequently.

(From Why Mothers Die 2000 - 2002: CEMACH)

Figure 3. Pulmonary thromboembolism (PTE) - the incidence has been fairly constant over recent years.

(From Why Mothers Die 2000 - 2002: CEMACH)

Pulmonary thromboembolism (PTE) is the most common direct cause of maternal death in the UK (Figure 1). Successive reports on Confidential Enquiries into Maternal Deaths have highlighted failures in recognising risk factors for VTE and employing adequate prophylaxis. Although PTE remains the leading cause of maternal death, in the latest Confidential Enquiry, the proportion of postpartum deaths following caesarean section had fallen, suggesting that adoption of published recommendations1 may have had a beneficial effect. However, no impact has been made over the last decade on reducing the four to five deaths annually from antenatal PTE or the three deaths annually from PTE following vaginal delivery (Figure 2). In the most recent Confidential Enquiries into Maternal Deaths, the majority of the women with fatal antenatal PTE died in the first trimester and most postpartum deaths followed vaginal delivery.  Although most VTE occurs antenatally, the risk per day is greatest in the weeks immediately after delivery.9901

Risk Factors

Pregnancy is a risk factor for VTE and is associated with a ten-fold increase compared with the risk for nonpregnant women.SIGN Some women are at even higher risk during pregnancy because they have one or more additional risk factors:

Pre-existing:

Thrombophilia

  • Congenital
    • antithrombin deficiency
    • protein C deficiency
    • Factor V Leiden
    • prothrombin gene variant
  • Aquired (antiphospholipid syndrome)
    • lupus anticoagulant
    • anticardiolipin antibodies

Age > 35 years

Obesity (BMI > 30 kg/m2

Parity > 4

Severe varicose veins

Sickle cell disease

Essential Thrombocytopenia

Polycythaemia vera

Medical Disorders e.g. inflammatory bowel disorders, cardiac disease nephrotic syndrome

New Onset or Transient

Dehydration

Hyperemesis

Ovarian Hyperstimulation Syndrome

Severe infections e.g. pyelonephritis

Immobilisation (> 4 days)

Pre-eclampsia

Excessive blood loss

Long-haul travel

Prolonged labour

Surgery e.g. ERPC, postpartum sterilisation, mid-cavity instrumental delivery, caesarean section

A study in Norway confirmed that assisted reproduction and gestational diabetes were significant antenatal risk factors; whereas cesarean section and preeclampsia were strong postnatal risk factors.2008-01

Prevalence

In a study of nearly 400,000 pregnancies0101

In a study of women in Minnesota with deep venous thrombosis or pulmonary embolism first diagnosed between 1966 and 1995,0501 including women with venous thromboembolism during pregnancy or the postpartum period, the overall incidence of venous thromboembolism was 199.7 per 100,000 woman-years. The annual incidence was 5 times higher among postpartum women than pregnant women and the incidence of deep venous thrombosis was 3 times higher than that of pulmonary embolism . Pulmonary embolism was relatively uncommon during pregnancy versus the postpartum period (10.6 vs. 159.7 per 100,000). Over the 30-year study period, the incidence of venous thromboembolism during pregnancy remained relatively constant whereas the postpartum incidence of pulmonary embolism decreased more than 2-fold.

Screening For Risk Factors

An individual assessment of thrombotic risk should be undertaken, ideally before pregnancy or in early pregnancy. This assessment should be repeated if the woman is admitted to hospital or develops other intercurrent problems.

Women at high risk of VTE, including those with previous confirmed VTE, should be offered prepregnancy counselling with a prospective management plan. Haematological screening for congenital thrombophilia is not indicated.9701

Previous VTE - Investigation

Women with previous VTE have an increased risk of recurrence in pregnancy.0502  The probability of VTE during pregnancy without thrombosis prophylaxis was 6.2%. There were no recurrences in the 44 women who had no evidence of thrombophilia and who also had a previous episode of thrombosis that was associated with a temporary risk factor. Among the 51 women with abnormal laboratory results or a previous episode of idiopathic thrombosis, or both, 3 (5.9 percent) had an antepartum recurrence of venous thromboembolism (95 percent confidence interval, 1.2 to 16.2 percent).

Women with a previous VTE should have a careful history documented and undergo screening for both inherited and acquired thrombophilia, ideally before pregnancy. Women with previous VTE should be screened for inherited and acquired thrombophilia ideally before pregnancy.

Thromboprophylaxis during pregnancy and the puerperium

Expert haematological advice or referral to a joint obstetric and haematology clinic should be sought in cases when the antenatal team are uncertain about thromboprophylaxis. Immobilisation of women during pregnancy, labour and the puerperium should be minimised and dehydration should be avoided, regardless of their risk of VTE.

Previous VTE and no thrombophilia

Women with previous VTE and no thrombophilia should be offered prophylaxis with low molecular weight heparin (LMWH) for six weeks after delivery. There is some evidence that if the previous VTE was associated with a temporary risk factor, such as trauma, antenatal anticoagulation is not required.0001 In the study by Brill-Edwards et al0001125 pregnant women with a single previous episode of venous thromboembolism were prospectively studied. Antepartum heparin was withheld, but anticoagulant therapy was given for four to six weeks post partum. There were no recurrences in the 44 women who had no evidence of thrombophilia and who also had a previous episode of thrombosis that was associated with a temporary risk factor. Among the 51 women with abnormal laboratory results or a previous episode of idiopathic thrombosis, or both, 3 had an antepartum recurrence of venous thromboembolism. If the previous VTE was oestrogen-related (pregnancy or the combined oral contraceptive pill) or if there are additional risk factors such as obesity, thromboprophylaxis with LMWH has been advocated. Women with previous VTE should be offered postpartum thromboprophylaxis with LMWH. It may be reasonable not to use antenatal thromboprophylaxis with heparin in women with a single previous VTE associated with a temporary risk factor that has now resolved.  Women who have had more than one previous episodes of VTE, who have had one episode and in addition have a family history of VTE in a first degree relative or whose episode of VTE was in an unusual site (such as the axillary vein), all of which are markers for a thrombophilic state, should be considered for antenatal thromboprophylaxis with LMWH.0401

Women with previous recurrent VTE or a previous VTE and a family history of VTE in a first-degree relative should be offered thromboprophylaxis with LMWH antenatally and for at least six weeks postpartum.

Previous VTE and inherited thrombophilia

Women with thrombophilias have an increased risk of VTE in pregnancy0001, 0301 but this risk varies according to the specific thrombophilia.0002

The risk also depends on whether the woman or her close family have had a previous VTE.0003

Current evidence supports, and existing guidelines recommend, that women with previous VTE and an identifiable thrombophilia should receive antenatal thromboprophylaxis with LMWH; prophylaxis should continue for six weeks postpartum.

Expert haematological advice should be sought for women with symptomatic thrombophilia, as specific thrombophilias, particularly AT deficiency, merit higher doses of LMWH for thromboprophylaxis.

Prophylaxis Enoxaprin
Normal body weight (50-90 kg) 40 mg daily
Body weight < 50 kg 20 mg daily
Body weight > 90kg 40 mg 12 hourly
Higher prophylactic dose 40 mg 12 hourly
Therapeutic dose 1 mg/kg 12 hourly
Table 1. Antenatal prophylactic and therapeutic doses of enoxaprin.

Inherited thrombophilia without previous VTE

The risk of VTE associated with thrombophilia varies considerably. Antithrombin deficiency is associated with a high risk (30%) of VTE in pregnancy. Asymptomatic women with protein C or protein S deficiencies have an eight-fold increased risk of VTE associated with pregnancy but most events occur postpartum.9601

Data from retrospective family studies confirm a high risk of VTE for women with homozygous factor V Leiden0102 and combined defects of factor V Leiden and prothrombin gene mutation.0103 Women heterozygous for the factor V Leiden mutation or the prothrombin gene variant are at considerably lower risk.0002

Women should be treated according to the level of risk associated with their thrombophilia. Since the risk of VTE is lower in women with no history of VTE, antenatal thromboprophylaxis is not always necessary, except in those with combined defects, those homozygous for defects or those with antithrombin deficiency.9701, 0002, 0102, 0103 Women with antithrombin deficiency should always receive thromboprophylaxis in pregnancy and the puerperium.

Women with known inherited or acquired thrombophilia may qualify for LMWH or warfarin for six weeks following delivery, even if they were not receiving antenatal thromboprophylaxis if they have other risk factors.

Women with asymptomatic inherited or acquired thrombophilia may qualify for antenatal or postnatal thromboprophylaxis, depending on the specific thrombophilia and the presence of other risk factors.

Acquired thrombophilia (antiphospholipid syndrome)

Antiphospholipid syndrome (APS) is defined as the presence of lupus anticoagulant or anticardiolipin antibodies of medium?high titre on two occasions eight weeks apart, found in association with a history of thrombosis (arterial or venous) or adverse pregnancy outcome (three or more unexplained miscarriages before ten weeks of gestation, a fetal death after ten weeks of gestation or a premature {less than 35 weeks} birth due to severe pre-eclampsia or intrauterine growth restriction). The risk of recurrent thromboses in women with APS is up to 70% and may be even higher in pregnancy. Therefore, pregnant women with APS and previous thromboses should receive antenatal and postnatal thromboprophylaxis with LMWH.

The management of women with obstetric manifestations of APS is controversial. Low-dose aspirin has been shown to improve pregnancy outcome in APS and is recommended for all women with APS. However, the presence of antiphospholipid antibodies with no previous ?APS classifiable? pregnancy loss or thrombosis does not equate to APS and such women do not require LMWH (or low-dose aspirin).9702, 0004

Women with antiphospholipid syndrome identified because of recurrent miscarriage may not require LMWH for six weeks postpartum but should receive LMWH for at least three to five days, especially if they have other risk factors.

No previous VTE or thrombophilia 

Data to support recommendations for many of the individual risk factors listed in Table 1 is lacking.

Women should be reassessed before or during labour for risk factors for VTE. Age over 35 years and BMI greater than 30/body weight greater than 90 kg are important independent risk factors for postpartum VTE even after vaginal delivery. The combination of either of these risk factors with any other risk factor for VTE (such as pre-eclampsia or immobility) or the presence of two other persisting risk factors should lead the clinician to consider the use of LMWH for three to five days postpartum.

Clinical judgement is required with regard to the weighting of the above risk factors. There are circumstances where one or two risk factors alone may be sufficient to justify antenatal thromboprophylaxis with LMWH, for example an extremely obese woman admitted to the antenatal ward.

A woman with two current or persisting risk factors should be considered for prophylactic LMWH for three to five days after vaginal delivery.

In general, women with three or more current or persisting risk factors (other than those with a previous VTE or a thrombophilia should be considered for prophylactic LMWH antenatally and for at least three to five days postpartum.

Timing and duration of treatment

Pregnancy

As VTE during pregnancy has an equal distribution throughout gestation,9901 if a decision is made to initiate thromboprophylaxis antenatally, this should begin as early in pregnancy as practical.SIGN Once antenatal treatment is initiated it should continue until delivery unless a specific risk factor is removed or disappears.

Women with ovarian hyperstimulation syndrome (OHSS) require thromboprophylaxis for at least the period of inpatient stay.

Women with multiple risk factors for VTE and at risk of OHSS undergoing ovulation induction may also be considered for thromboprophylaxis.

There is no direct evidence-based data to guide thromboprophylactic advice for pregnant travellers. However, it seems prudent that precautionary conservative measures advised for all travellers should also be recommended in pregnancy. These include isometric calf exercises (as increasingly advised on in-flight media by major airlines), walking around the aircraft cabin when possible, avoiding dehydration by drinking plenty of water/juices/soft drinks and by minimising alcohol and caffeine intake. The case for aspirin would be empirical at this time.

Antenatal thromboprophylaxis should begin as early in pregnancy as practical.

Puerperium

  • Postpartum thromboprophylaxis should be given as soon as possible after delivery, provided that there is no postpartum haemorrhage.
  • Those with postpartum haemorrhage should be fitted with thromboembolic deterrent stockings.
  • If the woman has been given regional analgesia, LMWH should be withheld until four hours after insertion or removal of the epidural catheter (or six hours if either insertion or removal were traumatic). The first postpartum dose can be given after insertion but before removal of the epidural catheter.

Postpartum thromboprophylaxis is normally continued for six weeks in high-risk women as the prothrombotic changes of pregnancy do not revert completely to normal until several weeks after delivery. Women need to learn how to inject themselves. However, for women at lower risk prophylaxis for three to five days is usually recommended, despite the lack of evidence in this area. Low risk includes those with two current or persisting risk factors as discussed above (Table 1) and asymptomatic thrombophilias with low thrombotic risk (heterozygous factor V Leiden and prothrombin gene variant). The risk of VTE reduces when women are mobile postpartum but does not disappear. If the woman is discharged home early, her thromboprophylaxis should be continued at home, to complete the course of three to five days.

The combined oral contraceptive pill should not be prescribed during the first three months postpartum for women with other risk factors for VTE.

Risk factors may change. Therefore, puerperal women undergoing surgery for any reason or those who develop severe infection or who choose to travel long-haul are at increased risk of VTE even  though they may have been discharged from hospital following vaginal delivery several weeks before.

Postpartum prophylaxis should begin as soon as possible after delivery.

Agents for Thromboprophylaxis

Low molecular weight heparin

Low molecular weight heparins are the agents of choice for antenatal thromboprophylaxis. They are as effective as and safer than unfractionated heparin in pregnancy.9201, 9703

Systematic reviews and retrospective studies have concluded that LMWH is a safe alternative to unfractionated heparin as an anticoagulant during pregnancy9902, 0104  and from a safety perspective LMWH is to be preferred.

The risk of heparin-induced thrombocytopenia is reduced with LMWH.9503, 9703 The risk of heparin-induced thrombocytopenia is extremely low with LMWH and has never been reported in pregnancy, current guidelinessign still recommend checking the platelet count one week after starting LMWH.

Prolonged unfractionated heparin use during pregnancy may result in osteoporosis and fractures 9703 but this risk is low with LMWH.9902, 0005, 0104, 0201

For postpartum thromboprophylaxis, LMWH is probably the agent of choice for women who had LMWH antenatally or for those requiring only three to five days of postpartum treatment. Experience of enoxaparin in the puerperium reports no adverse effects on the baby resulting from breastfeeding.9703

Low dose aspirin

Low-Low dose aspirin is safe in pregnancy,9401 although its use for thromboprophylaxis in this setting has never been assessed by a controlled trial. One trial suggested that low-dose aspirin, compared with placebo, reduces by 36% the risk of VTE after orthopaedic surgery, even in some women taking concomitant heparin therapy.0006 Meta-analysis of trials in surgical and medical patients also shows a significant reduction in deep vein thrombosis and pulmonary embolism with antiplatelet prophylaxis.9402 The use of low-dose aspirin (75 mg daily) may, therefore, be appropriate in situations where the risk of VTE is increased but is not deemed high enough to warrant the use of antenatal LMWH; for example, in women with previous provoked VTE without thrombophilia. Women should be advised of the lack of evidence for benefit of aspirin use for thromboprophylaxis in pregnancy.

Warfarin

Warfarin should be Warfarin should be avoided if possible during pregnancy,SIGN particularly between 6 and 12 weeks of gestation, because it is associated with an up to 6.4% risk of teratogenesis and increases the risk of miscarriage, fetal and maternal haemorrhage, neurological problems in the baby and stillbirth.0007

Warfarin is safe after delivery and for breastfeeding, although it requires close monitoring, frequent visits to an anticoagulant clinic and carries an increased risk of postpartum haemorrhage and perineal haematoma compared with LMWH. It is inappropriate for women requiring only three to five days of postpartum prophylaxis.

If the woman chooses to commence warfarin postpartum, this can usually be initiated on the second or third postnatal day. LMWH should be continued until the international normalised ratio is greater than 2.0.

Warfarin should usually be avoided during pregnancy. It is safe after delivery and during breastfeeding.

Dextran

Warfarin should

Dextran should not be used primarily because of the risk of anaphylaxis, which has killed fetuses by causing massive histamine release and uterine hypertonus.

Graduated elastic stockings

Graduated elastic compression stockings may be used antenatally. There are no trials to support such practice but the British Society for Haematology guidelines give a grade C recommendation that all women with previous VTE or a thrombophilia should be encouraged to wear class-II graduated elastic compression below knee stockings throughout their pregnancy and for 6?12 weeks after delivery. Class-I thromboelastic stockings are appropriate for hospital inpatients at increased risk of VTE and may be combined with LMWH. Their use is also recommended for pregnant women travelling by air.

Labour and Delivery

Once the woman is in labour or thinks she is in labour, she should be advised not to inject any further heparin. She should be reassessed on admission to hospital and further doses should be prescribed by medical staff.

The pregnancy-associated prothrombotic changes in the coagulation system are maximal immediately following delivery. It is, therefore, desirable to continue LMWH during labour or delivery in women receiving antenatal thromboprophylaxis with LMWH. For women receiving high prophylactic or therapeutic doses of LMWH, the dose of heparin should be withheld if the woman goes into labour or reduced to its thromboprophylactic dose on the day before induction of labour or elective caesarean section and continued in this dose during labour. If the woman is of normal weight, the dose for unfractionated heparin should be 5000 units 12 hourly. For LMWH preparations, a once-daily regimen should be adopted using the following doses: enoxaparin 40 mg, dalteparin 5000 iu, tinzaparin 50 units/kg.

Epidural anaesthesia can be sited only after discussion with a senior anaesthetist, in keeping with local anaesthetic protocols. It is important to discuss the implication of treatment with heparin or LMWH for epidural or spinal anaesthesia with the woman before labour or caesarean section. To minimise the risk of epidural haematoma, regional techniques should not be used until at least 12 hours after the previous prophylactic dose of LMWH. When a woman presents while on a therapeutic regimen of LMWH, regional techniques should not be employed for at least 24 hours after the last dose of LMWH. LMWH should not be given for at least four hours after the epidural catheter has been inserted or removed and the cannula should not be removed within 10?12 hours of the most recent injection.

The woman should receive a thromboprophylactic dose of LMWH on the day before delivery by elective caesarean section,. On the day of delivery, the morning dose should be omitted and the operation performed that morning. The thromboprophylactic dose of LMWH should be given by three hours postoperatively (or four hours after insertion or removal of the epidural catheter, if appropriate). There is an increased risk of around 2% of wound haematoma following caesarean section with both unfractionated heparin and LMWH.

Women At Risk Of Haemorrhage

Women Those at high risk of haemorrhage with risk factors including major antepartum haemorrhage, coagulopathy, progressive wound haematoma, suspected intraabdominal bleeding and postpartum haemorrhage may be more conveniently managed with unfractionated heparin. Unfractionated heparin has a shorter half-life than LMWH and there is more experience in the use of protamine sulphate to reverse its activity. If a woman develops a haemorrhagic condition while taking LMWH, the treatment should be stopped and expert haematological advice sought. It should be remembered that excess blood loss and blood transfusion are risk factors for VTE, so thromboprophylaxis should be commenced or reinstituted as soon as the immediate risk of haemorrhage is reduced.

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