Show Summary Details
Page of

Thrombosis in pregnancy 

Thrombosis in pregnancy
Chapter:
Thrombosis in pregnancy
Author(s):

I.A. Greer

DOI:
10.1093/med/9780199204854.003.1407

November 30, 2011: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.

Page of

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford University Press, 2016. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy and Legal Notice).

Subscriber: null; date: 20 June 2018

Essentials

Aetiology—features that predispose to venous thromboembolism include (1) pregnancy is a thrombophilic state; (2) there is relative venous stasis during pregnancy; and (3) some endothelial damage to the pelvic vessels occurs during delivery.

Epidemiology— venous thromboembolism complicates around 1 in 1000 pregnancies, with highest risk just after delivery. Deep venous thromboses usually occur on the left side, and a much higher proportion are ileofemoral than in patients who are not pregnant.

Screening—there is no evidence to support universal screening for thrombophilia in pregnancy, but such screening is appropriate for women with a personal or well-proven family history of venous thromboembolism, also in patients who might reasonably be suspected of having antiphospholipid antibody syndrome.

Diagnosis—ultrasound venography is the first line diagnostic test for deep venous thrombosis in pregnancy. If pulmonary thromboembolism is suspected, ultrasound venography of the leg veins can also be performed: if positive anticoagulation can be given; if negative a chest radiograph and ventilation–perfusion scan or CT pulmonary angiogram are required.

Management—low molecular weight heparin (LMWH) is the anticoagulant of choice in pregnancy because of a better side-effect profile than warfarin or unfractionated heparin, good safety record for mother and fetus, and convenient once-daily dosing for prophylaxis. Typical recommendations are as follows: (1) prophylaxis for women at low but still probably increased risk, e.g. history of previous venous thromboembolism that was not pregnancy-related, associated with a risk factor that is no longer present, and with no additional risk factor or underlying thrombophilia can be offered surveillance antenatally, with postpartum anticoagulation therapy (usually with LMWH) for at least 6 weeks; antenatal LMWH would not be routinely given. (2) Prophylaxis for women at higher risk of recurrent venous thromboembolism in pregnancy—these should usually be prescribed prophylactic LMWH, which should be started as soon as possible following the diagnosis of pregnancy and continued for at least 6 weeks after delivery. (3) Treatment of proven venous thromboembolism in pregnancy—in most cases a twice-daily regimen (because of increased renal excretion) of LMWH is the treatment of choice, but intravenous unfractionated heparin remains the preferred treatment in massive pulmonary thromboembolism.

Introduction

Pulmonary thromboembolism remains a major direct cause of maternal mortality. Venous thromboembolism complicates around 1/1000 pregnancies, with the greatest risk after delivery. Almost half antenatal venous thromboembolism occurs before 15 weeks gestation, emphasizing the need for risk assessment before pregnancy and prophylaxis in early pregnancy. Almost 90% of pregnancy-associated deep venous thomboses occur on the left side, compared with 55% in nonpregnant women, possibly reflecting some compression of the left common iliac vein by the right iliac artery. Over 70% of gestational deep venous thromboses are ileofemoral, compared with around 9% in nonpregnant women, where calf vein thromboses predominate. This is important because ileofemoral thromboses are more likely to embolize than calf vein thromboses.

Venous thromboembolism causes long-term problems as well as acute problems. Deep venous thrombosis is associated with a significant risk of recurrent venous thromboembolism and deep venous insufficiency. Mild to moderate post-thrombotic syndrome can be found in over 60% of cases within 5 years, and about 5% of patients with deep venous thromboses develop venous ulcers within 10 to 20 years of the primary event. The risk of pulmonary hypertension after pulmonary thromboembolism is probably 3 to 4%.

The physiological changes in the haemostatic system in pregnancy (see Chapter 14.16) result in an acquired thrombophilic state due to increased concentrations of coagulation factors such as factor VIII and fibrinogen, reduced endogenous anticoagulants, and suppression of fibrinolysis. Relative venous stasis also occurs, with a 50% reduction in venous flow velocity by 25 to 29 weeks gestation, reaching a nadir at 36 weeks. In addition, some degree of endothelial damage to pelvic vessels is inevitable during vaginal or abdominal delivery. Thus the components of Virchow’s triad are all present in the course of normal pregnancy and delivery.

Risk factors for gestational venous thromboembolism and thrombophilia screening

Thromboprophylaxis in pregnancy depends on identifying the level of risk for individual women. The common risk factors for venous thromboembolism are set out in Box 14.7.1.

With regard to thrombophilia, the likelihood of thrombosis depends on the thrombophilia (Table 14.7.1), whether more than one thrombophilia is present or the woman is homozygous for factor V Leiden or prothrombin G20210A, whether previous venous thromboembolism have occurred, and additional risk factors, such as obesity. At present there is no evidence to support universal screening for thrombophilia in pregnancy. The natural history of many of these thrombophilias—particularly in asymptomatic kindred—is not yet established, appropriate intervention is unclear, and screening is not cost effective. Selective screening (after appropriate counselling) of women with venous thromboembolism in pregnancy or who have a personal or family history of venous thromboembolism (preferably objectively confirmed) may be of value, with around 50% of such women having a heritable thrombophilia. Screening for thrombophilia in patients with problems such as recurrent miscarriage or severe pre-eclampsia, which may be associated with an underlying thrombophilia and therefore risk of venous thromboembolism, should also be considered. However, apart from recurrent miscarriage associated with antiphosphlipid antibody syndrome (see Chapter 14.14), effective intervention for these pregnancy complications is not established.

Table 14.7.1 Typical prevalence of particular causes of thrombophilia and association with gestational venous thromboembolism in European populations

Thrombophilia

Population prevalence (%)

Approximate prevalence in women with gestational venous thromboembolism (%)

Typical estimate of odds ratio of venous thromboembolism in woman with specific thrombophilias

Factor V Leiden heterozygous

2–7

20–40

8 (homozygote OR 34)

Prothrombin G20210A heterozygous

2

6 (increasing to 20% with strong family history)

2–7 (homozygote OR 26)

Antithrombin deficiency

0.25–0.55

<10

  • Type 1 280

  • Type 2 28

Protein C deficiency

0.20–0.33

4–5

Protein S deficiency

0.03–0.13

3

NB: combined defects substantially increase risk, with an odds ratio estimated at 107 for factor V Leiden and prothrombin G20210A compound heterozygotes.

Antithrombotic therapy in pregnancy

Antithrombotic therapy in pregnancy is limited essentially to warfarin and heparin. There are insufficient data on newer antiocoagulants such as recombinant hirudin and fondaparinux to allow recommendations in pregnancy. Low dose aspirin is not associated with adverse pregnancy outcome in the second and third trimesters and may be useful in some situations, either alone or combined with low molecular weight heparin (LMWH) such as in antiphospholipid syndrome.

Warfarin

The use of warfarin in pregnancy is restricted to only a few situations where heparin is considered unsuitable. Although warfarin is not secreted in breast milk in significant amounts and is safe to use during lactation, it crosses the placenta and is teratogenic with around 6% of pregnancies exposed being associated with congenital abnormalities. With exposure between 6 and 9 weeks’ gestation warfarin embryopathy (midface hypoplasia, stippled chondral calcification, scoliosis, short proximal limbs, and short phalanges) may occurs with estimates varying from 0.6 to 5%. This problem is potentially preventable by substitution of heparin for warfarin during the first trimester. Prenatal exposure to coumarins is also associated with an increased risk of neurodevelopmental problems. Warfarin should be avoided around the time of delivery because of maternal and fetal bleeding risk, and hence if used in pregnancy is usually stopped at around 36 weeks gestation (see Chapter 14.6).

Heparin

Neither unfractionated heparin (UFH) nor LMWH appears to cross the placenta and there is no evidence of teratogenesis or risk of fetal haemorrhage. Heparins are not secreted in breast milk and can be used during breastfeeding.

Prolonged use of UFH is associated with symptomatic osteoporosis, with a 2% incidence of osteoporotic fractures. Allergy and heparin-induced thrombocytopenia, an antibody-mediated effect that leads to arterial and venous thrombosis due to platelet activation, may occur.

LMWHs appear safe for the mother and fetus, with a substantially lower risk of osteoporosis and a negligible risk of heparin-induced thrombocytopenia compared to UFH, but local allergic reactions (itchy, erythematous lesions at the injection sites) can occur as with UFH. Changing the heparin preparation may be helpful, but cross-reactivity is common. Skin reactions can be associated with heparin-induced thrombocytopenia, hence the platelet count should be checked if these develop. The risk of recurrent venous thrombosis with LMWH used for thromboprophylaxis in pregnancy is less than 1%. LMWHs are not associated with an increased risk of severe peripartum bleeding, hence LMWH is now the anticoagulant of choice in pregnancy because of a better side effect profile, good safety record for mother and fetus, and convenient once-daily dosing for prophylaxis.

Graduated elastic compression stockings

In view of the pregnancy-related changes in the venous system, graduated elastic compression stockings should be of value in pregnancy and postpartum. Full-length stockings are usually used in pregnancy where ileofemoral thrombosis is more common, and indeed they are recommended in high-risk situations for prophylaxis, but most data on efficacy in nonpregnant women come from below-knee stockings, which patients may be more likely to wear. Antiembolism stockings for prophylaxis have a pressure of around 20 mmHg at the ankle, but graduated elastic compression stocking with an ankle pressure of 30 to 40 mmHg should be used after a deep venous thromboses. Long-term use after deep venous thromboses may reduce the risk of post-thrombotic syndrome.

Thromboprophylaxis in pregnancy

The woman with a previous venous thromboembolism that was not pregnancy-related, associated with a risk factor that is no longer present, and with no additional risk factor or underlying thrombophilia, should not routinely receive antenatal LMWH as her risk of recurrence is considered relatively low, but this strategy must be discussed with the woman and her views taken into account because of the relatively limited data available. Surveillance can be offered antenatally to such women, with postpartum anticoagulant therapy, usually with LMWH, for at least 6 weeks (Table 14.7.2).

Table 14.7.2 Suggested management strategies for various clinical situations (NB: specialist advice for individualized management of patients is advisable in many of these situations)

Clinical situation

Suggested management

Single previous venous thromboembolism (not related to pregnancy or oral contraceptive) associated with a transient risk factor and no additional current risk factors, such as obesity.

  • Antenatal—surveillance or prophylactic doses of LMWH (e.g. 40 mg enoxaparin or 5000 IU dalteparin daily). Discuss decision regarding antenatal LMWH with the woman

  • Postpartum—anticoagulant therapy for at least 6 weeks (e.g. 40 mg enoxaparin or 5000 IU dalteparin daily or warfarin (target INR 2–3) with LMWH overlap until the INR is ≥2.0) ± graduated elastic compression stockings

Single previous idiopathic venous thromboembolism or single previous venous thromboembolism with underlying thrombophilia or positive family history and not on long-term anticoagulant therapy, or single previous venous thromboembolism and additional current risk factor(s) (e.g. morbid obesity, nephrotic syndrome)

  • Antenatal—prophylactic doses of LMWH (e.g. 40 mg enoxaparin or 5000 IU dalteparin daily) ± graduated elastic compression stockings. NB: there is a strong case for more intense LMWH therapy in antithrombin deficiency, homozygotes or compound heterozygotes for FV Leiden and prothrombin 20210A (e.g. enoxaparin 0.5–1 mg/kg 12 hourly or dalteparin 50–100 IU/kg 12 hourly)

  • Postpartum—anticoagulant therapy for at least 6 weeks (e.g. 40 mg enoxaparin or 5000 IU dalteparin daily or warfarin (target INR 2–3) with LMWH overlap until the INR is > 2.0.) ± graduated elastic compression stockings

More than one previous episode of venous thromboembolism, with no thrombophilia and not on long-term anticoagulant therapy

  • Antenatal—prophylactic doses of LMWH (eg 40 mg enoxaparin or 5000 IU dalteparin daily) + graduated elastic compression stockings.

  • Postpartum—anticoagulant therapy for at least 6 weeks (e.g. 40 mg enoxaparin or 5000 IU dalteparin daily or warfarin (target INR 2–3) with LMWH overlap until the INR is ≥2.0.) + graduated elastic compression stockings

Previous episode(s) of venous thromboembolism in women receiving long-term anticoagulants (e.g. with underlying thrombophilia)

  • Antenatal—switch from oral anticoagulants to LMWH therapy (e.g. enoxaparin 0.5–1 mg/kg 12 hourly or dalteparin 50–100 IU/kg 12 hourly) by 6 weeks gestation + graduated elastic compression stockings

  • Postpartum—resume long-term anticoagulants with LMWH overlap until INR in prepregnancy therapeutic range + graduated elastic compression stockings

Thrombophilia (confirmed laboratory abnormality) but no prior venous thromboembolism

  • Antenatal—surveillance or prophylactic LMWH ± graduated elastic compression stockings. An individual risk assessment is required. The indication for pharmacological prophylaxis in the antenatal period is stronger in AT-deficient women, homozygotes, or compound heterozygotes for FV Leiden and prothrombin 20210A than the other thrombophilias, in symptomatic kindred compared to asymptomatic kindred, and also where additional risk factors are present

  • Postpartum—anticoagulant therapy for at least 6 weeks (e.g. 40 mg enoxaparin or 5000 IU dalteparin daily or warfarin (target INR 2–3) with LMWH overlap until the INR is ≥2.0) ± graduated elastic compression stockings

Following caesarean section or vaginal delivery

Carry out risk assessment for venous thromboembolism. If additional risk factors such as emergency caesarean section in labour, age >35 years, high BMI, etc. present, then consider LMWH thromboprophylaxis (e.g. 40 mg enoxaparin or 5000 IU dalteparin) ± graduated elastic compression stockings

In women with a single previous venous thromboembolism and an underlying thrombophilia, or where the venous thromboembolism was idiopathic or pregnancy-related (or related to the oral contraceptive ‘pill’), or where there are additional risk factors such as obesity or nephrotic syndrome, there is a stronger case for LMWH prophylaxis. Antenatally, these women should usually be prescribed prophylactic LMWH, which should be started as soon as possible following the diagnosis of pregnancy. More intense LMWH therapy may be indicated in the presence of antithrombin deficiency. Postpartum anticoagulant therapy for at least 6 weeks is recommended (Table 14.7.2).

Women with more than one previous venous thromboembolism or on long-term anticoagulant therapy usually require LMWH prophylaxis. Following delivery, particularly if by caesarean section, a risk assessment should be made and those at increased risk prescribed thromboprophylaxis.

Use of LMWH in pregnancy

The prophylactic dose of LMWH may need adjustment in women with very low or very high body weight, with lower doses (e.g. 20 mg enoxaparin daily or 2500 IU dalteparin daily) at low body weight (<50 kg or BMI less than 20 kg/m2), and higher doses in obese women. There are no data to guide practice on this issue: clinical judgement of risk is required after individual assessment. In women with morbid obesity the author uses 40 mg enoxaparin or 5000 IU dalteparin twice daily; or for those considered at greater risk but with a lower level of obesity 60 mg enoxaparin or 7500 IU daltaparin once daily.

Traditionally the platelet count was checked before and 1 week after the introduction of LMWH, then on around a monthly basis to detect heparin-induced thrombocytopenia. However, where a woman has not previously received UFH the risk of heparin-induced thrombocytopenia with exclusive use of LMWH is so low that current guidelines do not recommend routine monitoring of the platelet count in this situation.

There has been concern with regard to LMWH and epidural haematoma. As a general rule, neuraxial anaesthesia is not used until at least 12 h after the previous prophylactic dose of LMWH, and regional techniques should not be employed for at least 24 h after the last dose when a woman presents while on a therapeutic regimen of LMWH. LMWH should not be given for at least 3 h after an epidural catheter has been removed, and the cannula should not be removed within 10 to 12 h of the most recent injection. Planning management of anticoagulation around delivery requires prior involvement and discussion with obstetric anaesthetists. LMWH may preclude urgent regional analgesia and anaesthesia and assessment of general anaesthetic risk may influence timing and route of delivery.

Diagnosis of venous thromboembolism in pregnancy

The clinical diagnosis of deep venous thromboses and pulmonary thromboembolism is unreliable and objective testing is required if there is substantial clinical suspicion. Anticoagulant treatment should be employed in women with clinical features consistent with venous thromboembolism until an objective diagnosis is made.

Ultrasound venography is the first line diagnostic test for deep venous thromboses in pregnancy. If ultrasonography is negative but there is a high level of clinical suspicion, then the patient should be anticoagulated and ultrasonography repeated in one week, or an alternative test such as radiological venography should be considered. If repeat testing is negative, anticoagulant treatment should be discontinued.

If pulmonary thromboembolism is suspected, ultrasound venography of the leg veins can also be performed: if positive anticoagulation can be given; if negative a chest radiograph and ventilation–perfusion scan or CT pulmonary angiogram should be performed. None of these investigations is considered to pose a significant radiation risk to the fetus in the context of the diagnosis of pulmonary thromboembolism, and they should not be withheld in pregnancy because of fetal considerations when pulmonary thromboembolism is suspected. The average fetal radiation dose with CT pulmonary angiogram is less than that with ventilation–perfusion lung scanning during all trimesters of pregnancy. However, this is offset by the relatively high radiation dose (≥0.02 Gy) to the mother’s thorax and in particular breast tissue, which may be especially sensitive to radiation exposure during pregnancy. The delivery of 0.01 Gy to a woman’s breast has been calculated to increase her lifetime risk of developing breast cancer by up to 14%. This emphasizes the continued role for ventilation–perfusion scans in pregnancy.

In an appropriate clinical context outside pregnancy an increased level of D-dimer suggests that thrombosis may be present and an objective diagnostic test for deep venous thromboses and/or pulmonary thromboembolism should be performed. In pregnancy, D-dimer can be elevated due to the physiological changes in the coagulation system, and levels become ‘abnormal’ at term and in the post-natal period in most healthy pregnant women. Furthermore, D-dimer levels are increased if there is a concomitant problem such as pre-eclampsia. Thus a ‘positive’ D-dimer test in pregnancy does not indicate the presence of venous thromboembolism and objective testing is required, but a low level of D-dimer in pregnancy is likely—as in the nonpregnant—to suggest that there is no venous thromboembolism. However, it is important to note that in the nonpregnant, even with a high pretest probability and a highly sensitive D-dimer assay, around 4% of DVTs will not be identified by a D-dimer test. Hence in patients with a moderate or high pretest probability—which accounts for most pregnant patients—it would be inappropriate to rely on D-dimer to exclude venous thromboembolism in pregnancy.

Treatment of venous thromboembolism in pregnancy

LMWH is the treatment of choice for venous thromboembolism in pregnancy in most cases. With massive pulmonary thromboembolism causing haemodynamic compromise there may be a place for management with intravenous UFH and thrombolysis. In women at risk of thrombosis and with concurrent high risk of haemorrhage, such as those with major antepartum haemorrhage, coagulopathy, progressive wound haematoma, suspected intra-abdominal bleeding, or postpartum haemorrhage, UFH is often preferred as it has a shorter half-life than LMWH and its activity is more completely reversed with protamine sulphate.

A large systematic review demonstrated a risk of recurrent venous thromboembolism of 1.15% when treatment doses of LMWH were used to manage venous thromboembolism in pregnancy, which compares favourably with recurrence rates of 5 to 8% reported in trials carried out in nonpregnant patients treated with LMWH or UFH followed by coumarin therapy who were followed up for 3 to 6 months.

In view of the increased renal excretion of dalteparin and enoxaparin during pregnancy, a twice daily dosage regimen for these LMWHs in the treatment of venous thromboembolism in pregnancy is currently recommended (enoxaparin 1 mg/kg twice daily; dalteparin 100 units/kg twice daily) for initial treatment (Table 14.7.3). Experience indicates that satisfactory anticoagulant effects are obtained using this weight-based regimen. Monitoring of anti-Xa to assess the effect of LMWH is not routinely required, particularly as there are concerns over the accuracy of such monitoring, but there is a case doing so at extremes of body weight or in the presence of renal impairment: the target therapeutic range is 0.5 to 1.2 units/ml for peak levels (around 3 h post injection).

Table 14.7.3 Typical initial doses of LMWH used for treatment of acute venous thromboembolism in pregnancy.

Early pregnancy weight (kg)

Initial dose of enoxaparin (mg, twice daily)

<50

40

50–69 kg

60

70–89 kg

80

≥90 kga

100

a In obese patients it is recommended that dose capping is not used.

As warfarin is generally avoided for maintenance therapy in pregnancy, women with antenatal venous thromboembolism are usually managed with therapeutic subcutaneous LMWH for the remainder of the pregnancy. They should be taught to self-inject, appropriate arrangements should be made to allow safe disposal of needles and syringes, and they can then be managed as outpatients until delivery.

In order to avoid an unwanted anticoagulant effect during delivery, it is suggested that heparin be discontinued 24 h before elective induction of labour or caesarean section.

Anticoagulant therapy should be continued for at least 6 weeks postpartum, and longer if required to allow a total duration of treatment of 6 months. If the woman chooses to commence warfarin postpartum, this can usually be initiated on the third postnatal day. Switching from LMWH to warfarin can be associated with secondary postpartum haemmorrhage, hence warfarin administration should be delayed further in women with risk of postpartum haemmorrhage.

Massive pulmonary thromboembolism

Intravenous UFH remains the preferred treatment in massive pulmonary thromboembolism because of its rapid effect and extensive experience of its use in this situation. A loading dose of 5000 IU followed by continuous intravenous infusion of 1000 to 2000 IU/h adjusted by the activated partial thromboplastin time (APTT) (target APTT ratio usually 1.5–2.5) monitoring 6 h after the loading dose and then at least daily. However, the APTT is unreliable in pregnancy and an apparent heparin resistance occurs due to the coagulation changes in pregnancy. Anti-Xa monitoring can be used in this situation (target 0.35–0.70 IU/ml—note that this is different for the target used with LMWH due to differences in action of UFH). Thrombolysis can be considered in severe cases.

Women receiving therapeutic-dose UFH should have their platelet count monitored (see above). Pregnant women who develop HIT and require ongoing anticoagulant therapy should be managed with the heparinoid danaparoid sodium, or possibly fondaparinux. Warfarin may also be justified in this situation.

Further reading

Bates SM, et al. (2008). Thromboembolism, thrombophilia, antithrombotic therapy, and Pregnancy, Chest, 133, 844S–886S.Find this resource:

Confidential Enquiry into Maternal and Child Health. Saving Mothers’ Lives: Reviewing Maternal Deaths to Make Motherhood Safer, 2003–2005. The Seventh Report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. London: CEMACH; 2007 [www.cmace.org.uk/Publications/CEMACHPublications/Maternal-and-Perinatal-Health.aspx].Find this resource:

    Gherman RB, et al. (1999). Incidence, clinical characteristics, and timing of objectively diagnosed venous thromboembolism during pregnancy. Obstet Gynecol, 94, 730–4.Find this resource:

    Greer IA, Nelson-Piercy C (2005). Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood, 106, 401–7.Find this resource:

    Greer IA, Thomson AJ (2001). Management of venous thromboembolism in pregnancy. Best Pract Res Clin Obstet Gynaecol, 15, 583–603.Find this resource:

    Robertson L, et al. (2006). Thrombophilia in pregnancy: a systematic review. Br J Haematol, 132, 171–96.Find this resource:

    Scarsbrook AF, et al. (2006). Diagnosis of suspected venous thromboembolic disease in pregnancy. Clin Radiol, 61, 1–12.Find this resource: