---

Deep vein thrombosis and pregnancy: etiopathogenic and therapeutic aspects
(Portuguese PDF version)

Paulo Roberto Mattos da Silveira¹

1. Associate professor, Department of Internal Medicine, School of Medicine of Universidade do Estado do Rio de Janeiro. Head of the Department of Angiology, CENTERVASC-Rio.

Correspondence:
Paulo Roberto Mattos da Silveira
Av. Senador Danton Jobim, 301/21
CEP: 22.631-060 - Rio de Janeiro - RJ
E-mail: mattos13@terra.com.br

---

ABSTRACT

Despite the low incidence rate, deep vein thrombosis during pregnancy is a dramatic situation to the physician, since both the life of the fetus and mother are at risk. The author reviews the topic thoroughly but not definitively, taking the experience of several specialists into consideration. The aim is to try to solve many questions of those who may get involved with this type of morbidity.

Key words: venous thrombosis, pregnancy, coagulation inhibitor, heparin
Palavras-chave: trombose venosa, gravidez, anticoagulantes, heparina.

J Vasc Br 2002;1(1):65-70.

---

EPIDEMIOLOGY

Venous thromboembolic disease (VTD) is an important cause of obstetric morbidity and mortality, but the actual incidence of deep vein thrombosis (DVT) during pregnancy and in the postpartum period has not been totally established.¹ In general, we can affirm that pregnant women are six times more likely to have venous thromboembolism² and that DVT is present in one to two cases per every 1,000 pregnancies.³ After toxemia of pregnancy, pulmonary embolism is the leading cause of maternal mortality, affecting between 15 and 25% of untreated cases, resulting in a mortality rate of 12 to 15%. An appropriate treatment can reduce the incidence of pulmonary embolism to 4.5%, with a 0.7% reduction in the average mortality rate.¹

Usually, the risk of thrombosis during pregnancy is higher in the third quarter of gestation and, especially, in the puerperium, that is, from the sixth week to delivery. However, prospective studies made with objective diagnostic tests did not show a higher prevalence of venous thromboembolism in the third quarter in comparison with the two first quarters.⁴ Recent studies,⁴,⁶ which also applied objective diagnostic tools, show that DVT during pregnancy is as common as DVT in the postpartum period.

ETIOPATHOGENY

Specific studies^4-6 have shown that DVT during pregnancy often affects the left lower extremity, which hypothetically occurs due to venous stasis in the left iliac vein caused by abnormal compression of this vein by the right common iliac artery (Cockett's Syndrome).

Several factors can be associated with and contribute towards the development of venous thromboembolism during pregnancy. Venous stasis, of multiple causes, is probably the physiopathological substrate for venous thromboembolism, since it increases distensibility and venous capacitance, which can be observed in the first quarter of the gestation period with subsequent reduction in the speed of venous blood flow in the lower limb, and also due to the compression of the inferior vena cava and left iliac vein by the pregnant uterus, which could cause delayed venous flow.⁷ Increased levels of fibrinogen and of other coagulation factors, especially II,VII and X,⁸ and low levels of natural inhibitors, such as antithrombin and protein S,⁹ as well as the gradual reduction of fibrinolytic activity¹⁰ during pregnancy produce a relative hypercoagulable state. These thrombogenic changes are believed to be involved in the preparation of delivery, minimizing the chances of remarkable hemorrhage in the mother.¹¹ DVT can also be the first sign of thrombophilia due to the presence of factor V Leiden or antiphospholipid antibodies in pregnant women.¹²

Previous history of VTD or superficial phlebitis is a significant risk factor for the onset of this disease in pregnant women. Aaro and Jurgens¹³ found a 35% incidence of this factor in pregnant women with DVT. Other risk factors associated with the development of DVT in pregnant women are similar to those presented by the population at large, including age greater than 30 years, obesity, long time spent in bed, hereditary thrombophilia, multiparity, and C-section delivery. C-section is associated with the highest incidence of DVT in child-bearing patients than vaginal delivery. Pelvic vein thrombosis during vaginal delivery and tissue injury during a C-section can contribute to venous thrombosis in the immediate puerperium.²

DIAGNOSIS

The clinical diagnosis of DVT during pregnancy is sometimes difficult to make, since pain and swelling in lower extremities are quite common in pregnant women. Therefore, although the diagnosis based only on signs and symptoms is not reliable, some studies, such as that conducted by Barnes, Wu and Hoak,¹⁴ showed that DVT was objectively confirmed in suspected cases in less than 50% of investigated cases. Approximately half of the pregnant women with DVT do not show characteristic clinical signs and symptoms, whereas 30 to 50% of symptomatic patients do not show pathological changes.¹⁵ Certainly, Doppler ultrasonography can minimize this problem; however, as it is a sensitive and specific exam for the diagnosis of symptomatic proximal thrombosis in pregnant women, it does not safely detect an isolated thrombus in the iliac vein, which seems to be highly frequent during pregnancy, or a thrombus in sural veins.¹

TREATMENT OF THE ACUTE PHASE

Anticoagulation

AThe conventional treatment of acute DVT in pregnant women initially consists of intravenous bolus administration of unfractionated heparin at 5,000 to 10,000 units or 80 IU/kg, followed by a daily continuous infusion of 200 to 500 IU/kg/day (on average 25,000 IU/day) or 10,000 to 15,000 IU every eight hours in 250 to 500 ml of glucose saline at 5% every eight hours, or 22 IU/kg/hour, at the speed of 1,000-2,000 IU/hour, with an attempt to keep the activated partial thromboplastin time (APTT) between 1.5 and 2.5 times the normal value.¹⁶,¹⁷ After five to 10 days, the treatment with subcutaneous administration of unfractionated heparin every 12 hours in adjusted doses can be maintained throughout the gestational period in order to keep the APTT (six hours after administration) within therapeutic range. In this case, an initial daily dose of 250 IU/kg (for patients with less than 70 kg), 225 IU/kg (patients between 71 and 84 kg) and 200 IU/kg (patients weighing more than 85 kg) can be used. The medication should be administered twice a day and should not exceed the dose of 20,000 IU/day. After the ideal dosage is reached, the APTT can be monitored every week or every two weeks. Although there is too little information about the use of this substance in pregnant women,^18-20 the long-term treatment can optionally include unfractionated heparin or low-molecular-weight heparin (LMWH); in these cases, the recommended doses to extend APTT at therapeutic anticoagulation levels are 171 IU AXa/kg of nadroparin, 200 IU AXa/kg (or 2 mg/kg) of enoxaparin and 200 IU AXa/kg of dalteparin, also administered twice a day (12/12 hrs).

The anticoagulant response to subcutaneous unfractionated heparin can be extended, thus causing a persistent anticoagulant effect for over 28 hours, when given in high doses immediately before delivery. This persistent anticoagulation state can be dangerous to epidural anesthesia and offers the risk of excessive bleeding. The mechanism of such anticoagulant effect is yet unknown. This potential problem can be avoided by electively induced term labor (for example, after the 37th week), and by discontinuing heparin administration 24 hours before labor induction.²¹ APTT should be checked before delivery to make sure it has normalized after heparin discontinuation. If APTT is 1.5 times greater than the control, heparin effect can be reversed with protamine sulfate. Unfractionated heparin can be infused intravenously after the discontinuation of subcutaneous heparin in patients who are at greater risk for thrombotic complications. This infusion should be interrupted four to six hours before delivery, thus allowing APTT to reach normal levels by the time of delivery.¹ If the patient being treated with adjusted doses of subcutaneous heparin goes into spontaneous labor, heparin injections must be immediately discontinued. Protamine sulfate may be necessary if APTT is overly extended before delivery.

Since there is significant risk of VTD in the postpartum period, the treatment with subcutaneous or intravenous doses of heparin should be re-established as soon as adequate hemostasis is reached. The administration of oral anticoagulants (OAC) can be initiated on the same day. Heparin administration is maintained until warfarin or phenprocoumon have reached a therapeutic level (INR of 2.0 to 3.0) for two consecutive days. Oral anticoagulants should be maintained for four to six weeks after delivery or for at least three months when the venous thromboembolic event occurs at a later time during pregnancy (that is, in the third quarter).

Unfractionated heparin. Hall et al.,²² in a study published in 1980 in the American Journal of Medicine, concluded that unfractionated heparin administered during the gestational period was associated with fetal complications in approximately one third of the cases. However, studies published later,²³,²⁴ in a meticulous critical review, showed that unfractionated heparin is safe for the fetus. The reported frequency of maternal bleeding in a study of 100 consecutive gestations was only 2%. Since conventional heparin does not cross the placental barrier, there is no risk of bleeding for the fetus. Heparin-induced thrombocytopenia is an immunological phenomenon associated with a reduced platelet count seven to 10 days after the beginning of therapy. In nonpregnant patients, the prevalence of thrombocytopenia is around 4%.¹ Paradoxal embolism associated with heparin-induced thrombocytopenia results in DVT, pulmonary embolism, arterial thrombosis, gangrene and limb loss. Some reports also show that long-term heparin therapy provokes osteoporosis,²¹ as a consequence of the formation of a heparin complex with calcium ions that acts as a cofactor, enhancing the effect of the parathyroid hormone on bone reabsorption.¹⁵ The incidence of pathological fracture is less than 5%, whereas the subclinical reduction of bone density has been reported in approximately one third of the patients that received doses of unfractionated heparin for over 30 days.¹ Heparin seems to be safe for infants during the breastfeeding period.

Fractionated heparin. Low-molecular-weight heparins are fragments produced by chemical or enzyme depolymerization of conventional heparin or heparin fractions that are separated by gel filtration based on molecular weight. The use of LMWH during pregnancy can be more advantageous because it has a longer half-life than conventional heparin, which allows for a single daily dose, minimizes the need to monitor the anticoagulant effect, and reduces heparin-induced thrombocytopenia. Its use seems to be associated with reduced risk for osteoporosis provoked by long-term heparin therapy.²¹ In nonpregnant patients, LMWH has been as effective and safe as unfractionated heparin in the treatment of proximal venous thrombosis²⁵,²⁶ and in the prevention of DVT in patients submitted either to general surgery or orthopedic surgery.²⁷ Several studies have shown that these agents do not cause placental detachment.²¹ Although there has been wider experience with the use of LMWH in pregnant patients, the costs are higher than those of conventional heparin and, in addition, we do not have clinical assays that compare its efficiency and safety with unfractionated heparin in this population.

Additional measures. As soon as possible, patients should be encouraged to walk and wear elastic stockings.

Oral anticoagulants. They can cause early detachment of the placenta, characteristic embryopathy, central nervous system disorders, and fetal bleeding. Warfarin embryopathy is characterized by nasal hypoplasia and/or nonconsolidated epiphysis and is associated with exposure to warfarin between the sixth and twelfth weeks of gestation.¹ Even though the actual incidence rate of warfarin embryopathy is unknown, according to some studies, approximately 30% of all fetuses exposed to warfarin between the sixth and twelfth weeks of gestation have been affected. Central nervous system disorders associated with the administration of oral anticoagulants to the mother include dorsal midline dysplasia with agenesis of the corpus callosum, midline cerebellar atrophy, ventral midline dysplasia with optical atrophy and amaurosis, and hemorrhage. Differently from warfarin embryopathy, which has been only reported after exposure to warfarin in the first quarter of gestation, central nervous system disorders can occur after exposure to warfarin at any time during the gestational period. While the incidence rates of CNS disorders seems to be low (less than 5%), its long-term sequelae pose the risk of being more devastating than the sequelae caused by warfarin embryopathy.²⁸ When warfarin is continually used until the end of gestation, birth trauma can produce significant fetal hemorrhage.²¹ Therefore, if it is necessary to use warfarin during pregnancy (as in valvar diseases or in thrombophilia), which is advocated by some authors, it should be administered only during the second and third quarters, avoiding its use close to delivery time in order to prevent the birth of an anticoagulated fetus. Warfarin seems to be safe for breastfeeding infants of women who received oral anticoagulants. Some studies did not find any warfarin activity in the breastmilk of treated patients or in the bloodstream of their babies.²⁹

Two approaches can be used to minimize the risk of thrombotic complications and of warfarin embryopathy in women who require prolonged anticoagulation therapy and who intend to get pregnant again. An alternative is to maintain warfarin therapy and perform pregnancy tests on a regular basis. As soon as pregnancy is detected and before the sixth week of gestation, heparin treatment should be substituted for warfarin therapy. This shows that warfarin therapy is safe during the first four or six weeks of gestation.²¹ Another option is to discontinue the administration of warfarin and implement heparin therapy as soon as the decision to get pregnant again is taken. This could expose the patient to several months of heparin therapy, thus increasing the risk of heparin-induced osteoporosis.

PROPHYLAXIS

Thromboembolism prophylaxis during pregnancy

In general, patients with previous thromboembolism have a greater risk of recurrence. of the event. There is a consensus that women with previous history of DVT or pulmonary embolism have a higher risk of recurrence during pregnancy and in the postpartum period, although the estimates for the recurrence rates of venous thromboembolism are not very safe. Women who developed initial thrombosis in the presence of a transient predisposing factor (after surgery or trauma or due to hormone therapy, etc.) are expected to be at a lower risk of recurrence during pregnancy than those whose event did not have any predisposing causes or than those with a continuous risk factor (thrombophilia, for example).

Natural deficiency of antithrombin (AT), protein C (PC) and protein S (PS) or, as observed by Kupferminc et al.¹² as the most common thrombophilic disorders in pregnant women, the presence of factor V Leiden and hyperhomocysteinemia caused by genetic mutation, are disorders that can produce thrombogenic complications, including DVT. In addition, for each of these disorders, the risk seems to be greater in the postpartum period than in the period that precedes it.³⁰

Prophylaxis in women with history of venous thromboembolism

The ideal treatment of a pregnant patient with previous history of venous thromboembolism is yet to be known. The standard practice ranges from exclusive clinical follow-up to heparin therapy before delivery and treatment with oral anticoagulants in the postpartum period. There is no common ground as to the ideal prophylaxis. The American College of Chest Physicians (1995) recommends three options: (1) 5,000 units of subcutaneous unfractionated heparin every 12 hours during pregnancy, (2) adjusted doses of unfractionated heparin to produce a heparinemia level of 0.1 to 0.2 IU/ml for Xa antifactor activity throughout pregnancy, or (3) clinical follow-up combined with regular impedance or duplex plethysmography for those women who cannot or do not want to use heparin or for those who developed previous thrombosis in association with a transient risk factor (after surgery, fracture, etc.). In each of these situations, the use of oral anticoagulants is also recommended four or six weeks after delivery.²¹ The British Society for Haematology Guidelines recommends treatment with 5,000 units of unfractionated heparin every 12 hours during the first and second quarters of gestation, with an increase that allows extending APTT 1.5 times the control in the third quarter, or treatment with 10,000 units of unfractionated heparin every 12 hours throughout the gestational period (with a reduction of the dose only if the level of heparinemia is greater than 0.3 IU/ml).³¹ The Maternal and Neonatal Haemostasis Working Party of the Haemostasis and Thrombosis Task³² suggests postponing anticoagulation until puerperium in women whose episode occurred after delivery and implementing heparin treatment four to six weeks before the period in which thrombosis occurred for those women with history of thrombosis during pregnancy. In women in whom thrombosis was not associated with pregnancy, prophylaxis can be maintained throughout the gestational period, if the previous episode was serious or during the third quarter, or in the puerperium, if the previous episode was less serious. The recommended doses consist of 7,500 units of unfractionated heparin every 12 hours when used before the 36th week of gestation or in the postpartum period and 10,000 units every 12 hours when used between the 36th week and delivery. The treatment with warfarin or phenprocoumon is recommended for at least six weeks after delivery.

Prophylaxis in women with hereditary thrombotic disorders

The treatment of women with hereditary disorders of AT, PC or PS or PCR is controversial. Patients with hereditary hypercoagulable states and history of DVT or pulmonary embolism always receive prolonged anticoagulation. In these individuals, warfarin should be replaced with therapeutic doses of heparin, especially during the first quarter of gestation. The ideal prophylaxis for asymptomatic patients that do not receive prolonged anticoagulation is still unknown. Some studies suggest that anticoagulant prophylaxis is more advantageous during the postpartum period. It is unclear whether prophylaxis is needed during pregnancy, especially for patients with PS deficiency. Evidently, each case should be separately analyzed. Women with relevant family history of thrombosis should receive prophylactic anticoagulation. Other cases can be treated with heparin at low doses throughout the gestational period or can be regularly followed up clinically and by means of impedance and/or duplex plethysmography.²¹ Those patients who have hyperhomocysteinemia, supplementation with folic acid is recommended.

Prophylaxis in women with antiphospholipid antibodies

Antiphospholipid antibodies include anticardiolipin (detected by immunoassay) and lupus anticoagulant (detected by coagulation tests). The presence of persistent antiphospholipid antibodies can be associated with recurrent venous thrombosis, arterial thrombosis, thrombocytopenia and fetal loss. It is not clear whether women with antiphospholipid antibodies but with no previous history of thrombosis should receive anticoagulant prophylaxis. The clinical practice normally consists of regular follow-up or heparin therapy at low doses throughout the gestational period. Subcutaneous unfractionated heparin in adjusted doses is an acceptable approach for pregnant women with antiphospholipid antibodies and history of venous thrombosis. Patients on long-term oral anticoagulation should have this therapy replaced with full subcutaneous heparin administration before the sixth week of gestation. The ideal treatment for women with antiphospholipid antibodies and recurrent fetal loss is not known yet. For these cases, the best results have been obtained from the use of aspirin (75 to 80 mg of aspirin a day) throughout pregnancy and unfractionated heparin at low doses as soon as pregnancy is confirmed.¹

REFERENCES

1. Bates SM, Ginsberg JS. Diagnosis of Deep Vein Thrombosis during Pregnancy. In: Ginsberg J, Kearon C, Hirsh J. Critical Decisions in Thrombosis and Hemostasis. Ontario: BC Decker Inc; 1998. p.32-86.

2. Garcia AA, Franco RF. Trombofilias Adquiridas. In: Maffei FHA, Lastória S, Yoshida WB, Rollo HA, editores. Doenças Vasculares Periféricas. 3ª ed. Rio de Janeiro: Medsi; 2002. p.1397-1405.

3. Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet 1999;345:1258-65.

4. Ginsberg JS, Brill-Edwards P, Burrows RF, et al. Venous thrombosis during pregnancy: leg and trimester of presentation. Thromb Haemost 1992;67(5):519-20.

5. Rutherford SE, Phelan JP. Thromboembolic disease in pregnancy. Clin Perinatol 1988;13(4):719-39.

6. Rutherford S, Montoro M, McGehee W, Strong T. Thromboembolic disease associated with pregnancy; an 11-year review (abstract). Am J Obstet Gynecol 1991;164 Suppl :286.

7. Ikaard RW, Ueland K, Folse R. Lower limb venous dynamics in pregnant women. Surg Gynecol Obstet 1971;132(3):483-8.

8. Woodhans BJ, Candotti G, Shaw R, Kernoff PB. Changes in coagulation and fibrinolysis during pregnancy: evidence of activation of coagulation preceding spontaneous abortion. Thromb Res 1989;55:99-107.

9. Faught W, Garne P, Jones G, Ivey B. Changes in protein C and S levels in normal pregnancy. Am J Obstet Gynecol 1995;172:147-50.

10. Bremme K; Ostlund E; Almqvist I; Heinonen K; Blomback M. Enhanced thrombin generation and fibrinolitic activity in normal pregnancy and the puerperium. Obstet Gynecol 1992;80:132-7.

11. Salles LRA, Kuzniec S, Kauffman P. Trombose venosa profunda no ciclo gravídico-puerperal. In: Puech-Leão P, Kauffman P. Interfaces da Angiologia e Cirurgia Vascular. São Paulo: Roca; 2002. p.159-65.

12. Kupferminc MJ, Eldor A, Steinman N, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999;340:9-13.

13. Aaro LA, Juergens JL. Thrombophlebitis associated with pregnancy. Am J Obstet Gynecol 1971;109:1128-33.

14. Barnes RW, Wu KK, Hoak JC. Fallibility of clinical diagnosis of venous thrombosis. JAMA 1975;234:605-7.

15. Rosenfeld JC, Estrada FP, Orr RM. Management of deep venous thrombosis in the pregnant female. J Cardiovasc Surg 1990;31:678-82.

16. Hirsh J, Warkentin TE, Raschke R, Granger C; Ohman EM; Dalen JE. Heparin and low molecular weight heparin. Mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1998; 114 Suppl 5:489-510.

17. Ageno W. Treatment of venous thromboembolism. Thromb Res 2000;97:63-72.

18. Gillis S, Shushan A, Eldor A. Use of low weight heparin for prophylaxis and treatment of thromboembolism in pregnancy. Int J Gynecol Obstet 1992;39:297-301.

19. Fejgin MD, Lourwood DL. Low Molecular Weight Heparins and their use in Obstetrics and Gynecology. Obstet Gynecol Surv 1994;49:424-31.

20. Sanson BJ, Lensing AWA, Prins MH, et al. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost 1999;81(5):668-72.

21. Ginsberg JS, Hirsh J. Use of antithrombotic agents during pregnancy. Chest 1995; 108 Suppl 4:305-11.

22. Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulants during pregnancy. Am J Med 1980;68:122-40.

23. Ginsberg JS, Hirsh J, Turner DC, Levine MN, Burrows R. Risks to the fetus of anticoagulant therapy during pregnancy. Thromb Haemost 1989;61:197-203.

24. Ginsberg JS, Kowalchuk G, Hirsh J, Brill-Edwards, Burrows R. Heparin therapy during pregnancy: risks to the fetus and mother. Arch Intern Med 1989;149:2233-6.

25. Koopman MMW, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996;334(11):682-7.

26. Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996;334(11):677-81.

27. Nurmohamed MT, Rosendaal FR, Buller HR, et al. Low-molecular-weight heparin in general and orthopaedic surgery: a meta-analysis. Lancet 1992;340:152-6.

28. Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulants during pregnancy. Am J Med 1980;68:122-40.

29. Bates SM, Ginsberg JS. Anticoagulants in pregnancy: fetal effects. Baillieres Clin Obstet Gynaecol 1997;11:479-88.

30. Demers C, Ginsberg JS. Deep vein thrombosis and pulmonary embolism in pregnancy. Clin Chest Med 1992;13:645-56.

31. Colvin BT, Barrowcliff TW. The British Society for Haematology guidelines on the use and monitoring of heparin 1992: second revision. J Clin Pathol 1993;45:97-103.

32. Maternal and Neonatal Haemostasis Working Party of the Haemostasis and Thrombosis Task. Guidelines on the presentation, investigation, and management of thrombosis associated with pregnancy. J Clin Pathol 1993;47:489-96.