Asian Cardiovasc Thorac Ann 2007;15:497-501
© 2007 Asia Publishing EXchange Ltd
Anticoagulation in Pregnancy with Mechanical Heart Valves: 10-Year Experience
Raja P Akhtar, FRCS,
Abdul R Abid, MBBS1,
Hasnain Zafar, MBBS,
Masud A Cheema, FRCS,
Jawad S Khan, FRCS
Department of Cardiac Surgery
1 Department of Cardiology, Punjab Institute of Cardiology, Lahore, Pakistan
For reprint information contact: Raja P Akhtar, FRCS, Tel: 92 300 846 5515, Fax: 92 42 920 0028, Email: rajapakhtar{at}gmail.com, Punjab Institute of Cardiology, Ghaus-ul-Azam Road, Lahore, Pakistan.
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ABSTRACT
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Anticoagulation in pregnancy was evaluated in 33 women with a mechanical heart valve prosthesis who had 53 pregnancies between 1994 and 2006. Their mean age at valve operation was 24.4 ± 5.4 years, and 22 (67%) had isolated mitral valve disease. Of these patients, 22 had a single pregnancy, 5 had 2 pregnancies, 3 had 3, and 3 had 4. In 43 pregnancies, the patients took warfarin throughout; in the other 10, heparin was used in the first trimester followed by warfarin until the last 15 days. Mean international normalized ratio and warfarin levels before, during, and after pregnancy were similar. Complications occurred in 3 (6%) women who had thrombosed valves: 2 (20%) in the heparin group and 1 (2%) who had warfarin only. Live births resulted from 37 (70%) pregnancies. There were significantly more abortions in the heparin group (6; 60%) than the warfarin group (8; 19%). Hemorrhage requiring transfusion occurred in 2 (5%) patients in the warfarin group. All live births resulted in healthy babies. It was concluded that anticoagulation with warfarin is safe during pregnancy in women with mechanical heart valves.
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INTRODUCTION
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Rheumatic heart disease, a leading cause of morbidity and premature mortality, is endemic in Pakistan, with a prevalence of 5.7 per 1,000, and females are significantly more likely to be affected.1 Studies from South Asia, the Middle East, and North Africa have also shown that females are more likely to develop rheumatic heart disease, and a high proportion are 20 years old or less.1–4 The ideal valve prosthesis for young women is unresolved as each type of valve is associated with particular problems.5 Structural valve deterioration was reported in 47% of patients with a history of pregnancy compared with only 14% in nonpregnant patients.6 Reoperation rates in mothers with a bioprosthesis range from 13% to 59% at 7–12 months after delivery.6 Women with mechanical valves are at a high risk of thromboembolism.5,7 Warfarin use in pregnancy is associated with a low risk of maternal thromboembolic complications but a high rate of fetal loss.5 It has been suggested that warfarin should be avoided in the first trimester of pregnancy as it is teratogenic and causes coumadin embryopathy (0%–3.4%).8–10 Heparin therapy significantly improves fetal outcome, but up to a third of pregnant women with mechanical valves have thromboembolic complications, including fatal events.9 The European Society of Cardiology and the American College of Cardiology have recommended 2 strategies for anticoagulation during pregnancy in patients with prosthetic valves.11,12 Strategy 1: heparin during the first trimester (to avoid warfarin embryopathy), followed by oral anticoagulation up to the 36th week, with subsequent replacement by heparin until delivery. Strategy 2: oral anticoagulation until the 36th week, followed by heparin until delivery. The second strategy was more highly recommended as it has a lower rate of maternal complications.11,12 This study evaluated the complications with each strategy to provide recommendations for a protocol for Pakistan, keeping in view the socioeconomic background of the patients.
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PATIENTS AND METHODS
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This prospective observational study was conducted at the Punjab Institute of Cardiology Lahore, Pakistan, from September 1994 to June 2006. A single surgeon carried out 512 valve replacements in 296 (58%) males and 216 (42%) females of whom 185 were of child-bearing age. Detailed interviews were conducted to record marital as well as previous obstetric history. In the postoperative period, 33 women conceived and were followed up to the end of the pregnancy. Their mean age at valve operation was 24.4 ± 5.4 years. Demographic data are listed in Table 1
. Of the 12 who had children prior to valve surgery, 10 had one or more female offspring. Social and family pressures to have a male child lead them to conceive after the operation. Mechanical valves were used in all cases (Starr-Edwards, St Jude Medical, Carbomedics, or Sorin). Despite their high thrombogenicity, a ball and cage was used until 2004 for economic reasons.13,14 All patients were followed up fortnightly for 2 months after the operation, and monthly thereafter. At each follow-up, anticoagulation was monitored by checking the prothrombin time and international normalized ratio (INR). All patients were given 5 mg oral warfarin sodium (DuPont Ethical Pharmaceuticals, Massachusetts, USA), adjusted to give an INR of 2.5–3.5. If a patient was found to have an INR outside the target range, she was admitted until the optimal INR was achieved, and followed up weekly until control of the INR was ensured. The hazards of anticoagulation in pregnancy and possible embryopathy as a result of warfarin therapy were explained before pregnancy. In 10 pregnancies (group 1), 5,000 IU of subcutaneous heparin was administered every 6–8 hours for the first 12 weeks. The activated partial thromboplastin time (aPTT) was monitored fortnightly at the follow-up visit; more frequent visits were not possible due to distance and cost. The aPTT was measured at each follow-up visit, with a target of twice the control value. The aPTT of our patients during follow-up ranged from 1.5 to 2 times the control level. After 12 weeks, oral warfarin therapy was initiated until the last 15 days of pregnancy when the patient was admitted and switched to intravenous heparin until delivery. Warfarin was restarted 24 hours after delivery at the pre-delivery dosage, along with intravenous heparin until the INR was > 2. We did not use low-molecular-weight heparin due to cost. Because of the complications resulting from this mode of anticoagulation, poor compliance, and lack of monitoring of aPTT, it was discontinued. In the next 43 pregnancies, oral warfarin was continued up to the last 2 weeks before delivery when the patient was admitted and put on intravenous heparin with a target aPTT of twice the control value.
There were 53 pregnancies in 33 women during the study period. A fetal anomaly scan was carried out at 12 and 32 weeks of gestation. Cesarean section for safety reasons was decided on by the obstetrician at the time of delivery. All neonates were examined for any fetal embryopathy by a neonatologist. Coumadin embryopathy was defined as facial abnormalities, optic atrophy, digital abnormalities, epithelial changes, or mental impairment.9 Spontaneous abortion was defined as any spontaneous fetal loss before 28 weeks of gestation.8 Therapeutic abortions included all medically indicated terminations before 28 weeks of gestation.8 Still birth referred to fetal loss after 28 weeks of gestation.8
The data were analyzed using SPSS 12.0 version 12.0 for Windows (SPSS, Inc., Chicago, IL, USA). Categorical variables were expressed as percentages, continuous variables were expressed as mean ± standard deviation. Incidences of abortion, still birth, forceps delivery, spontaneous vaginal delivery, caesarian section, thrombosed valves, and bleeding were compared in both groups by applying the chi-squared test. A p value 
0.05 was considered significant.
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RESULTS
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The majority of patients had undergone isolated mitral valve replacement (Table 1
). Atrial fibrillation was more common than sinus rhythm; postoperatively, none of these patients reverted to sinus rhythm. The patients with multiple live births were all in the warfarin group and followed the same regimen each time. The characteristics of the 53 pregnancies are listed in Table 2. The mean INR and warfarin dosage before, during, and after pregnancy were similar. Most pregnancies were free of maternal complications (Table 3). Two patients had thrombosed valves in the heparin group: 1 at 10 weeks, 1 at 12 weeks.
One of them died in the emergency room, and the other underwent emergency surgery to explant the valve; she recovered with no complications. The 3rd patient with a thrombosed valve was in the warfarin group. She switched from warfarin to heparin at 32 weeks, and also underwent successful valve explantation. Another patient died 2 months after delivery due to arrhythmia. One patient had multiple pregnancies in her village, and continued warfarin throughout pregnancy and delivery, with no ill effect on her or the baby. Both patients who suffered per vaginal hemorrhage requiring transfusion aborted at 10 weeks. Cerebrovascular accident occurred in the 30th week in one patient with an INR of 2.0 taking warfarin; she made a complete recovery.
Various characteristics were compared between the two groups (Figure 1). There were more live births in the warfarin group, and more spontaneous abortions in the heparin group. Spontaneous vaginal delivery occurred more frequently in the warfarin group. Thrombosed valves were encountered more often in the heparin group. Hemorrhage requiring transfusion occurred in the warfarin group only. All the newborn babies were healthy with no signs of warfarin embryopathy. Apart from the 2 patients who died, all others were well at the end of the study.
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Figure 1. Comparison of heparin and warfarin anticoagulation during pregnancy. SVD = spontaneous vaginal delivery.
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DISCUSSION
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Pregnancy is a hypercoagulable state, characterized by increases in clotting factors, fibrinogen, and platelet adhesiveness.8 Even with anticoagulation, 7.5%–23% of pregnant patients with a mechanical prosthesis have a thromboembolic event, mostly valve thrombosis, with a resultant mortality rate of 40%.9,10,15 Older mechanical valves and the mitral position have the highest risks of thromboembolism.13 If warfarin dosage does not exceed 5 mg daily, the risk of fetal warfarin embryopathy is extremely small.8 Our results indicate that warfarin can be safely used as an anticoagulant during pregnancy, in agreement with previous studies.8,10,16–18
Geelani and colleagues16 from India reported 250 pregnancies in 245 women. One group took oral warfarin throughout pregnancy and another switched to subcutaneous heparin in the first trimester. Similar incidences of spontaneous abortion were found in both groups; whereas in our study, spontaneous abortion occurred more frequently in the heparin group. There was no fetal embryopathy in either study, but both had incidences of maternal death due to valve thrombosis in the heparin group. We think the reason for valve thrombosis in the heparin group is poor compliance, irregular dosing, and inadequate monitoring of aPTT. Nassar and colleagues17 retrospectively reviewed 82 pregnancies: there were 54 live births, 9 stillbirths, 12 spontaneous and 7 therapeutic abortions. The rate of spontaneous abortion was higher in women on warfarin throughout pregnancy, but the live birth rate was higher in women on heparin. Their rates of valve thrombosis and hemorrhagic complications are comparable with those in our series. In another retrospective study, Al-Lawati and colleagues18 found similar rates of thrombosis of mitral valve prostheses in patients on warfarin to those on initial heparin followed by warfarin. They found no cases of coumadin embryopathy but more spontaneous abortions in patients on warfarin only; whereas we noticed more spontaneous abortions in the heparin group.
Vitale and colleagues8 studied 58 pregnancies in 43 women with prosthetic heart valves who took warfarin 5 mg or > 5 mg (target INR, 2.5–3.5) until elective caesarian section at 38 weeks. There were significantly fewer fetal complications in women taking 5 mg warfarin. It was suggested that warfarin at doses 5 mg to achieve a therapeutic INR may be safe during the first trimester. In our study, the dose of warfarin before, during, and after pregnancy was approximately 5 mg, similar to that in reports from Lebanon, India, and Oman.16–18 Salazar and colleagues10 used subcutaneous low-molecular-weight heparin from weeks 6 to 12 weeks and again in the last 2 weeks of pregnancy in 37 women with prosthetic heart valves; 2 died of fatal massive thrombosis of the mitral tilting disc prosthesis during heparin therapy, and one died of anticoagulant-related gastrointestinal bleeding. Fetal complications included 15 spontaneous abortions in the first trimester, with no incidence of coumadin-induced embryopathy, which is similar to our findings. It was recommended that because there were no advantages to the fetus in substituting heparin for warfarin, warfarin should be used until the 38th week of gestation, with substitution of heparin at this time to avoid oral anticoagulant during the last 2 weeks.
We found that anticoagulation with warfarin was effective during pregnancy in patients with mechanical heart valves. Neither regimen is entirely safe for mother and fetus, but anticoagulation with warfarin is easier to manage than subcutaneous heparin, and it is effective with a lower incidence of valve thrombosis. We saw no fetal warfarin embryopathy in this series. We recommend the use of warfarin throughout pregnancy, with admission to hospital in the last 2 weeks for a switch to intravenous heparin until delivery.
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ABSTRACT
INTRODUCTION
