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Anticoagulation in Patients with Mechanical Valves During Pregnancy

Department of Cardiothoracic and Vascular Surgery, GB Pant Hospital, New Delhi, India

For reprint information contact: Muhammad A Geelani, MCh Tel: 91 11 2205 9248 Fax: 91 11 2323 9442 Email: mageelani{at}hotmail.com, Department of Cardiothoracic and Vascular Surgery, GB Pant Hospital, New Delhi 110002, India.

	ABSTRACT

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Mechanical valve thrombosis is a life-threatening event, while pregnancy is associated with a hypercoagulable state. Thus, in pregnant women with mechanical valves, adequate anticoagulation becomes even more critical. This prospective study was conducted to establish a uniform anticoagulation regimen for these women. A total of 250 pregnancies in 245 women with mechanical heart valves were evaluated. The patients were divided into 2 groups: group 1 (n = 150) took oral warfarin throughout pregnancy and group 2 (n = 100) received subcutaneous heparin in the 1^st trimester and oral warfarin for the other trimesters. Both groups received heparin at the time of delivery. There were no coumarin-induced fetal malformations. Minor thromboembolic episodes took place in 5 women in group 1 and 3 in group 2. Valve thrombosis occurred in 1 woman in group 2 and led to 1 maternal death in this series. The incidence of spontaneous abortion was similar between the groups. We conclude that warfarin is safe and convenient to use during pregnancy. The teratogenic effects of warfarin during the 1^st trimester are overstated, and switching to heparin is not mandatory.

	INTRODUCTION

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Rheumatic heart disease is more common in developing countries like India, where it is estimated to occur at a rate of 1.62 per 1,000 in the general population¹ and constitutes 40% to 50% of all cardiac diseases.² As a result, a large number of young women have undergone valve replacement before they conceive.

Pregnancy is associated with a hypercoagulable state as a result of various physiologic and biochemical changes that take place during this period.³ For women with mechanical valve prostheses, there is a general acceptance worldwide that subcutaneous heparin be used during the 1^st trimester of pregnancy and oral anticoagulants for the remaining period until about 2 to 3 weeks before the expected delivery date, when the patient is switched back to heparin. Various studies have demonstrated that such a regimen is not entirely safe owing to lack of compliance, which may in fact pose a considerable risk to the mother’s life.⁴ Some studies have also suggested that the risk of fetopathy associated with warfarin use in the 1^st trimester is overstated.^5,6

In this study we evaluated our experience with the use of oral warfarin and subcutaneous heparin in the 1^st trimester of pregnancy in women with mechanical valves.

	PATIENTS AND METHODS

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A prospective study of 250 pregnancies in 245 women who had mechanical valve replacement at our hospital and who were on regular follow-up was carried out between July 1992 and September 2002. The ages of these women ranged from 20 to 39 years (mean, 26 years). Five of the patients had two pregnancies. A total of 150 patients had isolated mitral valve replacement, 50 had isolated aortic valve replacement, and 45 had both the mitral and aortic valves replaced. The type of prosthesis used is listed in Table 1. The choice of prosthesis was a matter of the surgeon’s preference. Patients with bioprosthetic valves and patients who were lost during follow-up were excluded from the study.

	RESULTS

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There were 225 live births overall, 138 (92%) in group 1 and 87 (87%) in group 2. Only 1 baby was stillborn and it occurred in group 2. There was 1 maternal mortality. There were a total of 18 spontaneous and 6 medically induced abortions. The breakdown of the results, including complications, for the groups is presented in Table 1.

Postpartum hemorrhage occurred in 7 patients, all of whom responded well to conservative management. Minor thromboembolic complications occurred in 8 patients, while 1 patient had valve thrombosis. This 25-year-old patient from group 2 presented with a blocked bileaflet prosthesis at the mitral position at 29 weeks of gestation and was poorly compliant with heparin therapy. She underwent prosthesis replacement without cooling and died of low cardiac output on the 2^nd postoperative day.

No coumarin embryopathy was seen. Among the live births, 21 babies had a low birth weight ranging between 1.9 and 2.5 kg but were otherwise healthy.

	DISCUSSION

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After mechanical valve replacement, sufficient anticoagulation is required to prevent thromboembolic complications. Pregnant women with mechanical valves represent a special problem because of the hypercoagulable state during pregnancy and the concern with the fetopathic effects of warfarin. Different regimens have been recommended, including the administration of coumarin derivatives throughout pregnancy and subcutaneous heparin near term; substitution of coumarin derivatives with subcutaneous heparin in the 1^st trimester and near term; and the use of subcutaneous heparin throughout pregnancy.^4,7,8 Each of these 3 "standard" approaches renders mother and fetus susceptible to different anticoagulant-related complications. Chan and coworkers⁹ conducted the most detailed review of the literature on this subject from 1966 to 1997. The results clearly demonstrate that the maternal risk of thromboembolic events and death is increased when coumarin derivatives are replaced with heparin. The majority of maternal deaths were caused by valve thrombosis, and most of the complications took place in patients receiving heparin.

There is general acceptance that warfarin is contraindicated in the 1^st trimester of pregnancy because of its teratogenic effects and its association with a high rate of abortion. It is suggested that warfarin should be replaced with heparin during this period. However, heparin has its own drawbacks. Its narrow therapeutic margin makes it difficult to achieve an adequate and consistent level of anticoagulation. Thus, its efficacy is difficult to control, and its short duration of action leaves the patient without proper protection for a few hours every day.¹⁰ There has been no consensus on its therapeutic target, and therefore neither the dose nor the frequency of administration has been agreed on. A target APTT of 1.5 times normal was initially thought to be adequate.¹¹ This was subsequently revised to a minimum of 2 times normal to maintain adequate anticoagulation.¹² Yet, major thromboembolic episodes leading to maternal death have been reported with an APTT of up to 2.5 times normal.⁴ In India and other countries with poor socioeconomic conditions, compliance is hampered by the fact that heparin requires 2 to 3 injections every day. It is difficult, if not impossible, for a villager to travel a long distance to receive the injection. It would be more practical for her to use tablets.

Studies have found similar rates of fetal loss from spontaneous abortion in women who took warfarin throughout pregnancy and in women who were given heparin in the 1^st trimester. Salazar and associates⁴ reported a high incidence of spontaneous abortion of 37.5%, which they partly attributed to warfarin, as their patients became pregnant while on warfarin and did not switch to heparin until the 6^th week. However, Pavankumar and colleagues,⁶ who put all their patients solely on warfarin throughout pregnancy, reported that the rates of spontaneous abortion (4.2%), prematurity (6.4%), and stillbirth (2.1%) in their series were comparable to or lower than those in the general population. Al-Lawati and coworkers¹⁰ observed no significant difference in fetal loss between women on warfarin and those who used heparin during the 1^st trimester. This was similarly found in our series, in which the rate of spontaneous abortion was 6.7% in the warfarin group and 8.0% in the heparin group.

The fact that warfarin is associated with teratogenicity is of major concern. Heparin is thus advocated in the early weeks of pregnancy to avoid fetal malformation, since the large heparin molecule cannot cross the placental barrier.¹² Various fetal abnormalities were reported in the USA, where a large dose of warfarin was used to prolong the prothrombin time to the therapeutic range.¹³ In Europe and other parts of the world, such a large dose of warfarin was found to be unnecessary.^14,15 It was also noted that keeping the dose of warfarin at 5 mg·day^–1 or less reduced coumarin embryopathy to an acceptable rate or perhaps even eliminated it.^16–18 Studies in Tunisia, India, and Oman reported no fetal abnormality in patients on oral coagulation.^5,6,10 Neither did we, even in patients taking warfarin in the 1^st trimester.

The amount of bleeding during delivery is not alarming with these anticoagulants, as the need for massive transfusion has not been reported. There was no excessive bleeding requiring more than the usual amount of blood transfusion in either group when our patients were put on heparin near term. Hence, it appears that if anticoagulation is maintained within the therapeutic range, the risk of massive uncontrollable bleeding is diminished.

In conclusion, no drug is totally safe when used during pregnancy; but in countries with poor socioeconomic conditions as in India, it is probably safer to use warfarin throughout pregnancy. The teratogenic effects of warfarin during the 1^st trimester are overemphasized, and switching to heparin is not mandatory. However, patients who can comply with the heparin regimen should continue using it.

	REFERENCES

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1. Berry JN. Prevalence survey for chronic rheumatic heart disease and rheumatic fever in northern india. Br Heart J 1972;34:143–9.[Free Full Text]

2. Sapru RP. A lowest estimate and the prevalence of cardiovascular disease in India. J Assoc Phys India 1984;32:251–5.

3. Schafer AI. The hypercoagulable states. Ann Intern Med 1985;102:814–28.

4. Salazar E, Izaguirre R, Verdejo J, Mutchinick O. Failure of adjusted doses of subcutaneous heparin to prevent thromboembolic phenomena in pregnant patients with mechanical cardiac valve prostheses. J Am Coll Cardiol 1996;27:1698–703.[Abstract]

5. Ben Ismail M, Abid F, Trabelsi S, Taktak M, Fekih M. Cardiac valve prostheses, anticoagulation, and pregnancy. Br Heart J 1986;55:101–5.[Abstract/Free Full Text]

6. Pavankumar P, Venugopal P, Kaul U, Iyer KS, Das B, Sampathkumar A, et al. Pregnancy in patients with prosthetic cardiac valve. A 10-year experience. Scand J Thorac Cardiovasc Surg 1988;22:19–22.[Medline]

7. Leyh RG, Fischer S, Ruhparwar A, Haverich A. Anticoagulation for prosthetic heart valves during pregnancy: is low-molecular-weight heparin an alternative? Eur J Cardiothorac Surg 2002;21:577–9.[Abstract/Free Full Text]

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11. Ginsberg JS, Hirsh J. Use of antithrombotic agents during pregnancy. Chest 1992;102:385S–90S.

12. Noller KL. Pregnancy after cardiac surgery. In: Elkayam U, Gleicher N, editors. Cardiac problems in pregnancy. 2^nd ed. New York: Liss 1982;207–18.

13. Fillmore SJ, McDevitt E. Effects of coumarin compounds on the fetus. Ann Intern Med 1970;73:731–5.

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15. Butchart EG, Lewis PA, Kulatilake EN, Breckenridge IM. Anticoagulation variability between centres: implications for comparative prosthetic valve assessment. Eur J Cardiothorac Surg 1988;2:72–81.[Abstract]

16. Cotrufo M, de Luca TS, Calabro R, Mastrogiovanni G, Lama D. Coumarin anticoagulation during pregnancy in patients with mechanical valve prostheses. Eur J Cardiothorac Surg 1991;5:300–5.[Abstract]

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18. Cotrufo M, De Feo M, De Santo LS, Romano G, Della Corte A, Renzulli A, et al. Risk of warfarin during pregnancy with mechanical valve prostheses. Obstet Gynecol 2002;99:35–40.[Medline]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Muhammad A Geelani Sandeep Singh Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Geelani, M. A Articles by Nigam, M. Search for Related Content PubMed PubMed Citation Articles by Geelani, M. A Articles by Nigam, M. Related Collections Diaphragm