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Position statement

Anticoagulation in pregnancy and the puerperium

Med J Aust 2001; 175 (5): 258-263.

Position Statement

Anticoagulation in pregnancy and the puerperium

A Working Group on behalf of the Obstetric Medicine Group of Australasia

MJA 2001; 175: 258-263
 

Abstract - Management and prophylaxis of venous thromboembolism in pregnancy and the puerperium - Acute venous thromboembolism - Prophylaxis of venous thromboembolism - General - Previous thromboembolism - Previous single VTE and no recognised thrombophilia - Previous recurrent VTE or idiopathic VTE - Familial thrombophilia - Hyperhomocysteinaemia - Antiphospholipid syndrome and VTE - Management and prophylaxis of obstetric problems associated with uteroplacental thrombosis - References - Authors' details
- - More articles on Obstetrics & gynaecology and women's health


Abstract

  • For the management of acute thrombotic events in pregnancy therapeutic doses of low molecular weight heparins (LMWH) may be used, unless the shorter half-life of intravenous unfractionated heparin (UH) and predictable reversibility by protamine are important. Treatment should be continued up until delivery and into the puerperium.

  • Pregnant women who have had an acute thrombotic event should be delivered by a specialist team.

  • In the case of recent thrombosis, delivery should be planned and the time during which anticoagulation therapy is ceased around the time of delivery should be minimised.

  • Therapeutic doses of LMWH contraindicate the use of regional anaesthesia, and a switch to intravenous UH before delivery may allow greater flexibility in this regard.

  • Prophylactic doses of LMWH can be used to reduce the risk of recurrent thromboembolic events in pregnancy. The regimen used will depend on the previous history, the family history and the presence of risk factors, including the genetic and acquired causes of thrombophilia.

  • Women with mechanical heart valves are at high risk during pregnancy and require therapeutic anticoagulation throughout pregnancy under the direction of experienced specialists.

  • Low-dose aspirin can reduce the risk of recurrent pre-eclampsia by about 15%, but the role of UH and LMWH in the prevention of recurrent miscarriage or obstetric complications associated with uteroplacental insufficiency is still uncertain.

Low molecular weight heparins (LMWH) are being used increasingly as standard treatment for venous thrombosis, replacing unfractionated heparin (UH) for both therapeutic and prophylactic anticoagulation. Compared with UH, LMWH have increased bioavailability and a longer half-life. They also have the benefits of ease of administration, often as a single daily dose, have reduced requirements for monitoring, and are associated with less heparin-induced thrombocytopenia, reduced bleeding complications and improved patient acceptability.1

Heparins do not cross the placenta, whereas warfarin does.2,3 By contrast, warfarin is teratogenic between six and 12 weeks' gestation, and may cause fetal and neonatal bleeding if used during the second or third trimester. Except perhaps in women with mechanical heart valves, there is general agreement that UH or LMWH should be substituted for warfarin as soon as pregnancy is diagnosed.

Long-term treatment with UH carries risks of maternal osteoporosis4-6 and heparin-induced thrombocytopenia. Consistent, long term therapeutic anticoagulation can be hard to achieve with subcutaneous UH, because of low bioavailability and the changing anticoagulant response to UH as pregnancy progresses, often requiring close laboratory monitoring. LMWH require much less monitoring and appear to carry a smaller risk of heparin-induced thrombocytopenia, bleeding, and probably osteoporosis.7-9

Data on the effectiveness and safety of LMWH in pregnancy are limited but systematic reviews are becoming available.10 Given the convenience of LMWH and doctors' increasing familiarity with their use, there is growing opinion that LMWH have a role in pregnancy in preference to UH. In this position paper we summarise current views and make consensus recommendations for anticoagulation in pregnancy and the puerperium. The consensus process followed for this article is summarised in Box 1.


Management and prophylaxis of venous thromboembolism in pregnancy and the puerperium

Acute venous thromboembolism

Antenatal management: Clinical trials in non-pregnant patients show that LMWH are at least as effective and safe as UH in the initial management of acute proximal or calf deep venous thrombosis (DVT).1 Recurrence of thromboembolism is reduced by ongoing warfarin therapy and, in the case of proximal DVT, treatment should be continued for at least six months (C1). The standard initial treatment for pulmonary embolism, whether during pregnancy or not, remains intravenous UH (C2).

For an antenatal DVT, treatment should start with a LMWH at the therapeutic dose recommended by the manufacturers9(Box 2) (C1). Intravenous UH may be preferred in situations where its short half-life and predictable reversibility by protamine sulfate are important (eg, when delivery or surgery may be imminent). Calf DVT should be treated in the same way as proximal DVT in pregnancy because of ongoing hypercoagulability during pregnancy (C2). If intravenous UH is used for the initial treatment of pulmonary embolism, therapeutic doses of LMWH may be commenced once the patient is haemodynamically stable (C1).

Anticoagulation therapy should then be maintained until delivery (C1). It is generally recommended that therapeutic doses of UH or LMWH be continued throughout pregnancy.9,11,12 In practice, some clinicians change to a prophylactic dose of LMWH after 12 weeks of therapy if the woman is still pregnant, and continue with this dose until labour (Box 2) (C3). The rationale for this approach includes a declining risk of recurrence with time after acute venous thromboembolism (VTE),13 a desire to reduce osteoporosis associated with LMWH, and the suggestion from small trials in non-pregnant patients that lower prophylactic or intermediate doses of LMWH may be as effective as warfarin in preventing secondary recurrence of VTE.14-16 The safety of such a reduction of LMWH dose before 12 weeks after acute VTE in pregnancy needs to be established in clinical trials.

Monitoring: There is no need to use an anti-factor Xa assay to monitor either therapeutic or prophylactic doses of LMWH (C2). Therapy with UH can be monitored and managed according to the activated partial thromboplastin time (APTT).

Management of labour and delivery: Women requiring therapeutic anticoagulation should be counselled before delivery, which should be planned under the care of a specialist team (C1). Elective delivery allows for dose adjustment to minimise the opposing risks of bleeding at delivery and of further thrombosis.13 Vaginal delivery is preferable, as there is less risk of haemorrhage than with caesarean section. Delivery by caesarean section should be determined on the basis of obstetric indications (C1). The use of regional anaesthesia requires special consideration, and is outlined in Box 3.

The intensity of anticoagulation therapy required during delivery depends on how recently the VTE occurred. If within the last month, each day without anticoagulation therapy is associated with a 1% absolute increase in the risk of recurrence.13 It is therefore important to minimise the time off anticoagulation. Intravenous UH should be substituted for LMWH 24-36 hours before obstetric intervention, aiming to maintain the APTT at 1.5-2 times baseline. After induction, UH therapy is ceased once labour is established, allowing the APTT to return to normal, usually within 4-6 hours. Women requiring elective caesarean section should cease UH therapy six hours before surgery to allow for the full range of obstetric and anaesthetic options (C1).

If the VTE occurred between one and three months previously, therapeutic LMWH can be reduced to a prophylactic dose for 24-48 hours and labour can then be induced. The last dose of LMWH is given the night before induction. In women whose cervical assessment suggests that labour is likely to be established within a few hours of induction, the last dose of LMWH before induction may be withheld (C2).

Women who have had a VTE more than three months previously and who are still receiving a therapeutic dose of LMWH can be switched to a prophylactic dose at 38 weeks' gestation, allowing spontaneous labour to occur. Again, LMWH are withheld at the onset of labour (C2). Alternatively, if a woman wishes to be assured of access to epidural anaesthesia, induction of labour can be offered, with the last dose of LMWH on the day before the day of induction (C2).

Anti-embolism stockings, compression devices and electrical calf stimulators may be used and continued postpartum, especially if caesarean delivery is undertaken (C1).

In all women in whom anticoagulants have been used, the third stage of labour should be managed actively with oxytocic therapy and controlled cord traction to minimise the risk of postpartum haemorrhage (C1).

Postpartum management: Postpartum, anticoagulation therapy is usually recommenced at the same intensity as that used antenatally. Prophylactic doses can be recommenced within 2-6 hours of both vaginal and caesarean deliveries (C1). This may be prophylactic doses of LMWH or low-dose (12 000 U/24 h) UH infusion, if rapid reversal of anticoagulation may be required.

Therapeutic doses of UH or LMWH may be reintroduced 24 hours after vaginal delivery (C2). Caution should be exercised in recommencing therapeutic doses of LMWH earlier than 24 hours after operative delivery because of the risk of surgical bleeding, but most women can be receiving therapeutic doses by 36-48 hours after caesarean section (C1). Warfarin therapy can then be initiated and, once therapeutic levels have been achieved, continued in place of LMWH to complete the six months of therapy and for at least six weeks postpartum. Neither medication contraindicates breastfeeding (C1).


Prophylaxis of venous thromboembolism

General

VTE remains a major cause of maternal mortality in Australia, the United Kingdom and in the United States, occurring at a rate of approximately one death per 100 000 maternities.11,12,18 The rate is much higher in older women; in the UK, women aged over 39 years had a mortality rate of 1 per 3300 pregnancies.19 VTE can occur at any time during pregnancy; its prevalence is approximately equally distributed between the three trimesters.20 Although two-thirds of events occur antenatally, the day-by-day risk is greatest in the first weeks after delivery.20

Major known risk factors for VTE in pregnancy and postpartum include caesarean section (particularly in labour), obesity, prolonged bed rest and immobility, pre-eclampsia, nephrotic syndrome, current infection and other recent surgery, in addition to previous VTE and thrombophilia. These risk factors often coexist and reinforce each other. A risk-assessment profile may be constructed, as suggested in the consensus report from the Royal College of Obstetricians and Gynaecologists,21 which recommends that:

  • all "at risk" women should be monitored for symptoms and signs of VTE during the first week postpartum;

  • hydration should be maintained and early mobilisation encouraged;

  • graduated compression stockings with or without calf stimulation should be used during and after caesarean section in women at moderate risk (one or two risk factors);

  • in women at high risk (three or more risk factors), LMWH or UH prophylaxis should be used and continued for at least five days.

The efficacy or benefit of these interventions is unknown, as no high grade evidence is available.

Previous thromboembolism

In women who have had previous VTE, the risk of recurrence will be influenced by a number of factors, including whether the index event was spontaneous or provoked, the presence or absence of a family history of VTE, the presence of a known thrombophilia, or whether there has been more than one episode of VTE. The decision as to whether VTE prophylaxis is required throughout pregnancy or only postpartum may be based on this information (Box 4).22

Women requiring prophylaxis during pregnancy can be managed with low-dose LMWH (Box 2). They can then be allowed to come into spontaneous labour (C2). LMWH are withheld at the onset of labour (C2). Alternatively, if such a woman wishes to be assured of access to regional anaesthesia, induction of labour can be offered, with the last dose of LMWH on the day before the day of induction (Box 3) (C2).

Previous single VTE and no recognised thrombophilia

Both earlier and more recent cohort data suggest that most pregnant women with a past history of a single precipitated thrombotic event in or out of pregnancy, or associated with the combined oral contraceptive pill, and who have no underlying thrombophilia, can be safely managed by careful observation before delivery and postpartum thromboprophylaxis for six weeks23 (C2).

Previous recurrent VTE or idiopathic VTE

Women who have either recurrent VTE, previous idiopathic VTE, or a previous VTE and a strong family history of VTE but with no demonstrated cause for thrombophilia, may be given thromboprophylaxis throughout pregnancy and for six weeks postpartum23,24 (C1).


Familial thrombophilia

Thromboembolism is a multifactorial disease, in many cases developing as a result of a thrombotic tendency (a thrombophilia) interacting with other factors, such as pregnancy.25,26 Situations in which such a thrombophilia may require consideration during pregnancy are:

  • previous personal thromboembolic disease and known thrombophilia;

  • no previous VTE, but a strong family history (ie, one or more first-degree relatives affected) and known thrombophilia;

  • no previous VTE, strong family history, no previous investigations;

  • no previous VTE, weak family history (ie, incidental finding of thrombophilia in a family member); and

  • no personal or family history of VTE, but known thrombophilia detected after screening (eg, after obstetric complications or before starting to take the combined oral contraceptive pill).

The known causes of familial thromboembolism differ in their risk of associated thrombosis.27 The prevalence of such thrombophilic disorders varies between populations.28 A combination of any two or more inherited factors substantially increases the risk of thromboembolism. Box 4 summarises the risk profiles of the various genetic thrombophilias and offers guidelines for therapy. Box 5 describes management during pregnancy of medical problems requiring anticoagulation outside pregnancy.


Hyperhomocysteinaemia

In women with a previous history of VTE and hyperhomocysteinaemia, it may be prudent to reduce plasma homocysteine concentrations by folate supplementation throughout pregnancy, in addition to other thromboprophylaxis (C2).


Antiphospholipid syndrome and VTE

The presence of a lupus anticoagulant or of moderately to strongly positive titres of anticardiolipin antibody (ACA) is a strong risk factor for recurrent VTE, especially in pregnancy. Suggestions for treatment are shown in Box 4. Unless there is an associated history of poor obstetric outcome (see below), low-dose aspirin therapy need not be added (C2). On the other hand, it is contentious whether women with a positive lupus anticoagulant with or without ACA with no previous history of VTE (eg, women with systemic lupus erythematosus) require any prophylactic treatment at all during pregnancy. Low-dose aspirin may be a reasonable option for such women (C1).


Management and prophylaxis of obstetric problems associated with uteroplacental thrombosis

A common pathophysiological link between various poor pregnancy outcomes, including recurrent miscarriage, stillbirth, placental abruption, fetal growth restriction and pre-eclampsia, is thrombosis in the uteroplacental circulation. Antiplatelet agents (especially low-dose aspirin) have been trialled, particularly for preventing pre-eclampsia. A recent systematic review has shown a 15% reduction in the incidence of recurrent pre-eclampsia when low-dose aspirin is used, less benefit for the prevention of preterm birth and no benefit for the prevention of fetal growth restriction.35 Whether LMWH or UH can be used safely and more effectively than just aspirin in placental vasculopathy, with or without thrombophilia, is currently under investigation. Only in the case of recurrent miscarriage associated with the antiphospholipid syndrome has the addition of UH to aspirin been shown to be beneficial.36 A number of small cohort studies in women with previous obstetric complications who were treated with LMWH showed a good outcome, but whether the outcome was related to the use of LMWH is uncertain.37,38

While awaiting the results of further studies, and given the small numbers of affected women, no specific treatment recommendations can be made. We encourage clinicians to refer such patients to centres where randomised controlled trials are being carried out or where cohort studies are under way.

Competing interests: The authors are grateful to Pharmacia Upjohn for an unrestricted financial grant towards the costs involved in the preparation of this article, although the company did not contribute in any way either to the analysis or to the recommendations. There are no other known conflicts of interest.

Future research questions

The working party identified further areas for research. These include:

  • Comparison of LMWH versus intravenous UH in acute DVT and pulmonary embolism in pregnancy.
  • High-dose versus low-dose LMWH therapy for secondary prophylaxis after acute DVT in pregnancy.
  • The value of prospective blinded anti-Xa levels in the use of therapeutic LMWH in pregnancy.
  • The timing, benefits and risks of any dose adjustment of LMWH/UH, particularly peripartum.
  • Controlled longitudinal studies of bone density and fracture rates in women using long-term LMWH.
  • Prevention of pregnancy-associated VTE: the risks and benefits of LMWH thromboprophylaxis during pregnancy and postpartum for specific groups.
  • Prevention of adverse pregnancy complications related to placental insufficiency.
  • Randomised studies to determine the efficacy of LMWH in improving subsequent pregnancy outcome in women with specific pregnancy complications and an underlying thrombophilia.
  • A register of women being treated with anticoagulants during pregnancy.
  • A register to determine the clinical significance of thrombophilias in particular patient groups.


References

  1. Weitz J. Drug therapy: low molecular weight heparins. N Engl J Med 1997; 337: 688-698.
  2. Flessa H, Kapstrom AB, Glueck HI, Will JJ. Placental transport of heparin. Am J Obstet Gynecol 1965; 934: 570-573.
  3. Forestier F, Sole Y, Aiach M, et al. Absence of transplacental passage of fragmin (Kabi) during the second and the third trimesters of pregnancy. Thromb Haemostas 1992; 67: 180-181.
  4. Dahlman TC, Sjoberg HE, Ringertz H. Bone mineral density during long-term prophylaxis with heparin in pregnancy. Am J Obstet Gynecol 1994; 170: 1315-1320.
  5. Douketis JD, Ginsberg JS, Burrows RF, et al. The effects of long-term heparin therapy during pregnancy on bone density — a prospective matched cohort study. Thromb Haemost 1996; 75: 254-257.
  6. Barbour LA, Kick SD, Steiner JF, et al. A prospective study of heparin-induced osteoporosis in pregnancy using bone densitometry. Am J Obstet Gynecol 1994; 170: 862-869.
  7. Nelson-Piercy C. Heparin-induced osteoporosis in pregnancy. Lupus 1997; 6: 500-504.
  8. Farquharson RG. Heparin, osteoporosis and pregnancy. Br J Hosp Med 1997; 58: 205-207.
  9. Ginsberg J, Greer I, Hirsh J. Use of antithrombotic agents during pregnancy. Chest 2001; 199: 122S-131S.
  10. Sanson BJ, Lensing AW, Prins MH, et al. Safety of low molecular weight heparin in pregnancy: a systematic review. Thromb Haemost 1999; 81: 668-672.
  11. Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet 1999; 353: 1258-1265.
  12. Toglia M, Weg J. Current concepts: venous thromboembolism during pregnancy. N Engl J Med 1996; 335: 108-114.
  13. Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Engl J Med 1997; 336: 1506-1511.
  14. Pini M, Aiello S, Manotti C, et al. Low molecular weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis. Thromb Haemost 1994; 72: 191-197.
  15. Gonzalez-Fajardo J, Arreba E, Castrodeza J, Perez J, et al. Venographic comparison of subcutaneous low-molecular weight heparin with oral anticoagulant therapy in the long-term treatment of deep venous thrombosis. J Vasc Surg 1999; 30: 283-292.
  16. Das S, Cohen A, Edmonson R, et al. Low molecular weight heparin versus warfarin for prevention of recurrent venous thromboembolism: a randomized trial. World J Surg 1996; 20: 521-527.
  17. Tryba M. European practice guidelines: thromboembolism prophylaxis and regional anesthesia. Regional Anesthes Pain Med 1998; 23 (6 Suppl 2): 178-182.
  18. Maternal mortality committee. Maternal deaths in Australia 1991-1993. Canberra: NHMRC, 1998.
  19. Department of Health. Why mothers die. Report on confidential enquiries into maternal deaths in the United Kingdom 1994-1996. London: The Stationery Office; 1998.
  20. Ray JG, Chan WS. Deep vein thrombosis during pregnancy and the puerperium: a meta-analysis of the period of risk and the leg of presentation. Obstet Gynecol Surv 1999; 54: 265-271.
  21. Royal College of Obstetricians and Gynaecologists. Report of the RCOG Working Party on prophylaxis against thromboembolism in gynaecology and obstetrics. London: RCOG, 1995.
  22. McColl MD, Walker ID, Greer IA. The role of inherited thrombophilia in venous thromboembolism associated with pregnancy. Br J Obstet Gynaecol 1999; 106: 756-766.
  23. Brill-Edwards P, Ginsberg J, Gent M, et al. Safety of withholding antepartum heparin in women with a previous episode of venous thromboembolism. N Engl J Med 2000; 343: 1439-1444.
  24. Letsky EA. Peripartum prophylaxis of thrombo-embolism. Baillieres Clin Obstet Gynaecol 1997; 11: 523-543.
  25. Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167-1173.
  26. Preston FE, Rosendaal FR, Walker ID, et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348: 913-916.
  27. Gerhardt A, Scharf RE, Beckmann MW, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000; 342: 374-380.
  28. Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001; 344: 1222-1231.
  29. Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves — a systematic review of the literature. Arch Intern Med 2000; 160: 191-196.
  30. Arnaout M, Kazma H, Khalil A, et al. Is there a safe anticoagulation protocol for pregnant women with prosthetic valves? Clin Exp Obstet Gynecol 1998; 25: 101-104.
  31. Elkayam U. Pregnancy through a prosthetic heart valve. J Am Coll Cardiol 1999; 33: 1642-1645.
  32. Lee LH, Liauw PCY, Ng ASH. Low molecular weight heparin for thromboprophylaxis during pregnancy in 2 patients with mechanical mitral valve replacement. Thromb Haemost 1996; 76: 628-630.
  33. Sadler L, McCowan L, White H, et al. Pregnancy outcomes and cardiac complications in women with mechanical, bioprosthetic and homograft valves. Br J Obstet Gynaecol 2000; 107: 245-253.
  34. Rowan J, McCowan L, Raudkivi P, North R. Enoxaparin treatment in women with mechanical heart valves during pregnancy. Am J Obstet Gynecol. In press.
  35. Knight M, Duley L, Henderson Smart DJ, King JF. Antiplatelet agents for preventing and treating pre-eclampsia. Cochrane Database Syst Rev 2000; 2.
  36. Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997; 314: 253-257.
  37. Brenner B, Hoffman R, Blumenfeld Z, et al. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin. Thromb Haemost 2000; 83: 693-697.
  38. Riyazi N, Leeda M, de Vries J, et al . Low-molecular-weight heparin combined with aspirin in pregnant women with thrombophilia and a history of preeclampsia or fetal growth restriction: a preliminary study. Eur J Obstet Gynecol Reprod Biol 1998; 80: 49-54.

The authors of the Position Statement are listed below


Authors' details

Department of Obstetrics, University of Adelaide, Women's and Children's Hospital, North Adelaide, SA.
William M Hague, FRCP, FRCOG, Senior Physician in Obstetric Medicine and Clinical Senior Lecturer.

National Women's Hospital, Auckland, New Zealand
Robyn A North, PhD, FRACP, Associate Professor in Obstetric Medicine.

Flinders Medical Centre, Bedford Park, SA.
Alexander S Gallus, FRCPA, FRACP, Haematologist and Professor.

King Edward Memorial Hospital, Subiaco, WA.
Barry N J Walters, MB BS, FRACP, Physician in Obstetric Medicine and Clinical Associate Professor, Department of Obstetrics and Gynaecology, University of Western Australia.
Christopher Orlikowski, MB BS, FANZCA, Anaesthetist.

Monash University, Monash Medical Centre, Melbourne, VIC.
Robert F Burrows, FACOG, FRANZCOG, Professor of Maternal-Fetal Medicine.

Mater Mothers' Hospital, South Brisbane, QLD
Robert B Cincotta, FRANZCOG, CMFM, Specialist in Maternal-Fetal Medicine.

North Western Adelaide Health Service, Adelaide, SA.
Gustaaf A Dekker, PhD, FRANZCOG, Professor of Obstetrics and Gynaecology.

Mercy Hospital for Women, East Melbourne, VIC.
John R Higgins, MD, FRANZCOG, Senior Lecturer in Obstetrics and Gynaecology (currently, Professor of Obstetrics and Gynaecology, University College, Cork, Ireland).

Royal Hospital for Women, Sydney, NSW.
Sandra A Lowe, MD, FRACP, Physician in Obstetric Medicine.

Royal North Shore Hospital, Sydney, NSW.
Jonathan M Morris, MD, FRANZCOG, Senior Lecturer in Obstetrics and Gynaecology.

Nepean Hospital, Sydney, NSW.
Michael J Peek, PhD, FRANZCOG, Professor of Obstetrics and Gynaecology.

Reprints will not be available from the authors.
Correspondence: Dr W M Hague, Department of Obstetrics, Women's and Children's Hospital, North Adelaide, SA 5006.
bill.hagueATadelaide.edu.au


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1: Consensus process

The authors of this position statement are members of the Obstetric Medicine Group of Australasia (OMGA), with a particular clinical and research interest in managing pregnant women with thromboembolic problems. The authors were all members of the working party, and include six obstetricians, four obstetric physicians, an obstetric anaesthetist and a clinical haematologist. We met collectively in October 1999 to discuss the broad issues of the use of low molecular weight heparins in pregnancy before producing a draft document; this was subsequently modified by written comments and refined at teleconferences in May, June and September 2000. The position statement is a consensus statement inasmuch as there is little high-grade evidence from either randomised trials or other cohort studies on which to make recommendations, especially for management. Our recommendations have been annotated to reflect the degree of agreement among us as follows:

    C1 Complete consensus;

    C2 Near-complete consensus (nine or more of the 12 authors); and

    C3 No consensus.

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2: Doses of low molecular weight heparins
     
Low molecular    
weight heparin Therapeutic dose Prophylactic dose

Dalteparin (Fragmin) 100U/kg twice daily 5000U daily
Enoxaparin (Clexane) 1 mg/kg twice daily 40mg daily
  or 1.5mg/kg daily  
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3: Suggested guidelines for regional anaesthesia and levels of consensus (Box 1)

  • Regional anaesthesia (epidural or spinal block) is contraindicated during anticoagulation therapy because of the increased (although unquantified) risks of spinal haematoma17 (C1).
  • If a regional anaesthetic is desired in women who require anticoagulation therapy, an elective delivery will allow for a planned reduction in dose or a change to intravenous unfractionated heparin (UH) (C1).
  • Therapeutic subcutaneous injections of low molecular weight heparins (LMWH) or UH should be ceased at least 24 hours, and preferably 36 hours, before regional anaesthesia (epidural or spinal block) (C1).
  • Intravenous UH (used to permit a rapid return of the APTT to normal after cessation of the infusion) should be discontinued at least six hours, and preferably 12 hours, before regional anaesthesia (C1).
  • In women receiving prophylactic LMWH, an interval of more than 20 hours from the last dose should allow the placement of a regional block with minimal risk of complications (C2).
  • A normal activated partial thromboplastin time (APTT) does not ensure minimal anticoagulant effect of LMWH, and the platelet count should be determined to exclude heparin-induced thrombocytopenia (C2).
  • If caesarean section is being undertaken, further doses of LMWH should be delayed for at least four hours after placement of an uncomplicated regional block, and longer if the regional block has been complicated (C1).
  • Low-dose LMWH therapy can be continued after delivery if there have been no complications in the siting of the regional block.17
  • An epidural catheter can be removed 12-20 hours after a prophylactic dose of LMWH, and the next injection should be delayed by at least four hours after removal (C1).
  • Women should be closely monitored postpartum for any symptoms or signs of spinal haematoma, in particular for numbness and weakness in the lower limbs, severe back pain, and bladder or bowel incontinence (C1).
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Box 4 consists of 4a, 4b, 4c, 4d.  
4a: Suggested management guidelines and levels of consensus (see Box 1)
Thromboprophylaxis against recurrent venous thromboembolism (VTE) in pregnant women with previous VTE and no identified thrombophilia, according to estimated pregnancy-related risk of thrombosis
Single episode of VTE

Thrombosis history Recurrent VTE Spontaneous Probable cause*

Family history of VTE in one or more 1st degree relatives PrA (option ThA) (C2) PrA (C2) Negot (C2)
No family history of VTE PrA (C1) Negot (C2) Nil (C2)

*Risk factors present such as surgery, combined oral contraceptive pill.
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4b: Anticoagulation to prevent venous thromboembolism (VTE) in pregnant women testing positive for lupus anticoagulant or anticardiolipin antibodies (ACA), according to estimated pregnancy-related risk of thrombosis
Lupus anticoagulant  
and/or ACA IgG ACA IgG weak
moderate-strong positive,* ACA
Thrombosis history positive* IgM positive

Recurrent VTE in pregnancy despite prophylaxis ThA (C1) ThA (C1)
Recurrent VTE outside pregnancy ThA (C2) ThA (C2)
Previous VTE PrA (C1) Negot (C1)
No previous VTE Nil (C1) Nil (C1)

*Based on the highest-ever titre measured in the individual patient.
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4c: Preventing venous thromboembolism (VTE) in pregnant women with established thrombophilias, according to estimated pregnancy-related risk of thrombosis
   
 
Thrombosis history Antithrombin deficiency
(Very rare)
Protein C deficiency
(Rare)
Protein S deficiency
(Rare)
FVL* or PGM†
homozygous
(Uncommon)
FVL* or PGM†
heterozygous
(Common)

Personal history of VTE independent of family history ThA (C2) PrA (C1) PrA (C1) PrA (C1) Negot (C1)
 
Family history of VTE in one or more 1st degree relatives ThA/PrA (C3) PrA (C1) PrA (C1) PrA (C1) Negot (C1)
 
Family history of VTE in a distant relative ThA/PrA (C3) PrA (C1) Negot (C1) Negot (C1) Nil (C1)
 
No personal or family history of VTE ThA/PrA (C3) PrA (C1) Nil (C1) Nil (C1) Nil (C1)

*G1691A mutation in the factor V gene [Factor V Leiden] causing activated protein C resistance; †G20210A mutation in the prothrombin (factor II) gene.
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4d: Key to management recommendations
ThA Therapeutic anticoagulation necessary throughout pregnancy and postpartum - very high risk (>20%).
   
PrA Prophylaxis necessary throughout pregnancy and puerperium - high risk (10%-20%).
   
Negot Need for prophylaxis negotiable on a case-by-case basis until further data become available - moderate risk (3%-10%).
   
Nil Postpartum prophylaxis or no prophylaxis - low risk (3%).
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5: Management during pregnancy of medical problems requiring anticoagulation therapy outside pregnancy (consensus levels are described in Box 1)

  • Women with mechanical heart valves require therapeutic doses of anticoagulant medication throughout pregnancy to prevent valve thrombosis or maternal thromboembolic events9 (C1).
  • Women with mechanical heart valves should be managed under joint subspecialty care (C1).
  • The maternal benefits of warfarin (prevention of valve occlusion and systemic embolism) must be balanced against hazards to the fetus (congenital anomalies, intracranial haemorrhage and fetal loss).29
  • Unfractionated heparin (UH) and low molecular weight heparins (LMWH) are safe for the fetus, but there is still debate as to their therapeutic efficacy in the mother compared with that of warfarin.29-33
  • UH is associated with higher rates of maternal thromboembolic complications, including fatal events.29,33
  • There are limited data on the efficacy of LMWH in mechanical valves during pregnancy, but valve thrombosis may occur.34
  • High rates of maternal valve thrombosis occur if subtherapeutic doses of UH or LMWH are used.9,30
  • Women should participate in the choice of anticoagulation therapy (C2).
  • In women with other diseases (eg, dilated cardiomyopathy) who require anticoagulation therapy to prevent thromboembolic complications, the use of therapeutic or prophylactic doses of LMWH will depend on the perceived risk of thromboembolism (C1).
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