Asian Cardiovasc Thorac Ann 2007;15:493-496
© 2007 Asia Publishing EXchange Ltd
Anticoagulation for Prosthetic Heart Valves in Pregnancy. Is There an Answer?
Amir J Khamooshi, MD,
Fahimeh Kashfi, MScMW,
Saeed Hoseini, MD,
Mohammad B Tabatabaei, MD,
Hossein Javadpour, FETCS,
Fereydoon Noohi, MD
Department of Cardiac Surgery & Cardiology, Shahid Rajaee Heart Centre, Tehran, Iran
For reprint information contact: Hossein Javadpour, FETCS, Tel: 98 912 348 4368, Fax: 98 21 8809 5481, Email: javadpoursh{at}hotmail.com, Laleh General Hospital, Simay e Iran Avenue, Shahrak e Ghods, Tehran, Iran.
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ABSTRACT
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The aim of this retrospective study was to compare the different anticoagulation regimens used in pregnant women with prosthetic heart valves. We reviewed 196 pregnancies in 110 women from 1974 to 2000. The patients were divided into two groups: group 1 (142 pregnancies) had warfarin throughout pregnancy; and in group 2 (54 pregnancies), warfarin was replaced by subcutaneous heparin during the first trimester and last two weeks of pregnancy. There were no maternal complications in 129 pregnancies in group 1 and 44 in group 2. There were significantly fewer normal births in group 1 (56; 39.4%) compared to group 2 (39; 72.2%). Group 1 had a significantly higher rate of spontaneous abortion (46.5% vs 14.8%), but group 2 had a higher rate of valve thrombosis. In group 1, women with a warfarin requirement < 5 mg had a lower rate of spontaneous abortion. Warfarin is an effective anticoagulant in pregnant women with mechanical valves but it results in significant fetal loss when the dose is > 5 mg. Heparin is a less effective anticoagulant resulting in more maternal complications, but it is more protective of the fetus.
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INTRODUCTION
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The controversy regarding the safest anticoagulant regimen during pregnancy has not been resolved. Pregnant women are in a hypercoagulable state due to increased clotting factors, platelet adhesiveness, and viscosity, as well as diminished fibrinolysis.1 These physiological changes favor thromboembolism, and the risk is greatest in women with prosthetic heart valves. Coumarin derivatives have been shown to be effective in providing adequate anticoagulation in patients with mechanical heart valves; however, warfarin can cross the placental barrier and carries a teratogenic risk, especially when administered between the 6th and 9th week of gestation.2–5 In addition, as vitamin K-dependent coagulation factors do not cross the placenta, the fetus is over-anticoagulated and there is a risk of neurological complications later in pregnancy because of hemorrhage. Several investigators have advocated substituting subcutaneous heparin for warfarin during the first trimester and the last week of pregnancy.2,3,6–8 However, heparin, both unfractionated and low molecular weight, has been shown to be much less effective in protecting the mother from prosthetic valve thrombosis during pregnancy.9–11 Moreover, there have been reports of high fetal wastage with this anticoagulant, attributable to retroplacental hemorrhage.12 More recent reports point to the dose-dependent effect of warfarin, indicating that if adequate anticoagulation can be achieved with a dose of 5 mg or less, it can be safely given throughout pregnancy.13 To answer these questions, we reviewed retrospectively the results of different anticoagulant regimens used at our institution in pregnant women with mechanical heart valves.
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PATIENTS AND METHODS
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All women of childbearing age who had prosthetic heart valve replacement at our institution were identified through the surgical database. It is our policy to bring those women who become pregnant to a special clinic to be examined regarding their cardiac status and given advice on management of their anticoagulation regimen. From 21st March 1974 to 20th March 2000, 196 pregnancies occurred in 110 women, the mean age at pregnancy was 26.7 ± 5.3 years. There were 128 pregnancies in women with mitral valve replacement, 26 in women with aortic valve replacement, and 42 in those with both aortic and mitral valve replacement. The type of valve implanted was at the discretion of the surgeon; however, almost equal numbers of tilting and bileaflet prosthetic valves were used. The patients were divided into 2 groups according to anticoagulation regimen: group 1 had warfarin throughout their pregnancy; in group 2, warfarin was replaced with subcutaneous heparin during the first trimester, subsequently the patient received warfarin until the 36th week of gestation when it was again replaced by heparin for the last 2 to 4 weeks of the pregnancy. During warfarin treatment, the international normalized ratio was checked monthly and earlier if necessary, and kept at 2.5 to 3.5. During heparin treatment, the activated partial thromboplastin time was maintained at twice the control level. The dose of warfarin at the time of pregnancy was obtained from the medical records to see if dosage had any effect on outcome. The dose of warfarin could be ascertained in 90 pregnancies (63.4%) because it was usually recorded in a warfarin booklet that was kept by the patient. The 2 groups had similar characteristics regarding age, type of operation, and type of valve (bileaflet or tilting valve). The only difference was in the percentage of combined valve replacements (Table 1
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Neonatal death was defined as death of a live-born neonate before 29 days. Spontaneous abortion was defined as fetal loss before 20 weeks of gestation. Statistical analysis was performed using SPSS version 1 software (SPSS, Inc., Chicago, IL, USA). Continuous variables were described using mean ± standard deviation. Student’s t test was used to compare continuous variables. The Mann-Whitney rank-sum test was used to compare medians where the normality test failed. Noncontinuous variables were compared using the chi-squared test or Fisher’s exact test, as appropriate. A p value of less than 0.05 was considered to be statistically significant.
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RESULTS
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There were 88 normal vaginal deliveries and 28 Cesarean Sections. Table 2 compares fetal outcome between the 2 groups. The heparin group had a significantly higher number of normal births (72.2% vs 39.4%, p < 0.001). There were more embryopathies in the warfarin group, but not all were attributable to the effect of warfarin; these included hydrocephalus in 2, strabismus in 3, telebrachydactyly in 1, and hypoplasia of the nasal bridge in 2 live births. The warfarin group had significantly more spontaneous abortions. In the 90 pregnancies where the warfarin dosage could be ascertained, patients consuming 5 mg or less had significantly fewer spontaneous abortions (Table 3). Furthermore, these women had a similar rate of spontaneous abortion to the heparin group (18.5% vs 14.8%; Tables 2 and 3). There were fewer complications in the warfarin group (Table 4). Women in the heparin group had a significantly higher incidence of valve thrombosis and re-operation. The mortality rates were similar in both groups. Four women died because of valve thrombosis (3 were operated on), one died of renal failure and cerebrovascular accident, and the cause of death was unknown in 2. The 2 incidences of bleeding in the heparin group were vaginal and resolved with conservative management. Seven patients in the heparin group had valve thrombosis and underwent re-operation, 6 of them had undergone previous mitral valve replacement; only 2 of these pregnancies resulted in live births.
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DISCUSSION
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The ideal anticoagulant in pregnant women, in addition to providing adequate anticoagulation, should have minimal or no effect on the developing fetus. In our experience, the use of warfarin in pregnant women during the first trimester resulted in a high rate of spontaneous abortion (46.5%). The rate of spontaneous abortion in this group of patients prior to valve replacement and consumption of warfarin was only 6.7%. Other studies have reported spontaneous abortion rates of between 16.2% and 44.0%.2–4,14–18 Heparin is a large molecule that does not cross the placenta, thus it cannot have any teratogenic or anticoagulant effects on the fetus.
Ginsberg and colleagues19 reported a low incidence of spontaneous abortion (8.8%) in pregnant women using subcutaneous heparin for treatment of deep venous thrombosis in the first 20 weeks of pregnancy. Some authors have suggested replacing warfarin with heparin in the first trimester to decrease the incidence of fetal loss due to warfarin. The incidence of spontaneous abortion in our patients using heparin in the first trimester was 14.8% which was significantly lower than that in patients using warfarin during the same period. However, Salazar and colleagues11 found a high rate of spontaneous abortion (37.5%) in women using heparin in the first trimester, which was the same as those using warfarin. They attributed this to the fact that all women received warfarin for 4 to 6 weeks prior to the initiation of heparin therapy. Another explanation for the high fetal loss with heparin is an increased incidence of retroplacental hemorrhage.
Vitale and colleagues13 have shown a close relationship between fetal complications and warfarin dosage. Among our patients, those who were taking warfarin at a dose of less than 5 mg had a significantly lower rate of spontaneous abortion (18.5% vs 43.3% for higher doses). In fact, the rate of spontaneous abortion in these women was similar to that in the heparin group (14.8%). However, we should mention that the warfarin dosage could only be determined in 63.4% of our patients. Although use of heparin resulted in less fetal morbidity and better pregnancy outcomes, it led to significantly more valve thromboses and re-operations. Our results support the view that subcutaneous heparin is not effective in providing anticoagulation in pregnant women with prosthetic heart valves.11 Sbarouni and Oakely10 performed a retrospective study on the outcome of pregnancy in women with artificial heart valves treated in major European centers; 13 valve thromboses occurred in 151 pregnancies, all of the women were on heparin, and the outcome was fatal in 4.
It was concluded that the question of anticoagulation in pregnant women with mechanical heart valves remains unanswered. In our experience, heparin was not an effective anticoagulant in this group of patients. When adequate anticoagulation is achieved with a warfarin dose of 5 mg or less, taking warfarin throughout pregnancy may be justified. In those who require more than 5 mg of warfarin, the decision should be taken after discussion of the risks and benefits with the mother.
Presented at the 4th International Congress of the Iranian Society of Cardiac Surgeons, Tehran, Iran, November 16–19, 2005.
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ABSTRACT
INTRODUCTION
