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Management of prosthetic heart valve anticoagulation in pregnancy
General Cardiology
Management of Prosthetic Heart Valve Anticoagulation in Pregnancy
Focused Review growing fetus. Peripheral resistance, reflected in systemic blood pressure, decreases. Fibrinogen levels are elevated, there is a decrease in protein S activity, and both venous hypertension and stasis are common. Indeed the mechanisms of normal hemostasis are perturbed such that pregnancy is generally considered to be a hypercoagulable state. The degree of alterations in the coagulation system during pregnancy varies greatly. Factors that influence the coagulation system include duration of pregnancy, body composition and rapid fluid shifts. In addition, there is significant inter-individual variability, and in general the degree to which any individual is hypercoagulable is unpredictable. Antithrombotic regimens commonly proposed for mechanical valve anticoagulation during pregnancy include warfarin-based, heparin-based and mixed regimens. Warfarin-based regimens usually utilize warfarin throughout the first, second and most of the third trimesters until the last few weeks of pregnancy, at which point continuous intravenous or adjusted dose subcutaneous unfractionated heparin is substituted in order to prevent fetal hemorrhage associated with labor and delivery. This option likely represents the safest method for the mother; however, fetal risk is elevated. Heparin-based regimens utilize continuous intravenous, subcutaneous unfractionated or subcutaneous low–molecular-weight heparin. This option avoids exposure of the fetus to warfarin; however, there is a higher risk of maternal thromboembolic events. Mixed regimens utilize warfarin with the exception of during weeks 6 –12 and the last few weeks of pregnancy, during which time heparin is substituted. This option attempts to balance the abovestated risks by avoiding warfarin during the period of highest teratogenicity, while providing for superior anticoagulation during the remaining weeks of pregnancy. Unfortunately, all options have a high potential for unacceptable consequences for patients. In addition, there are medicolegal roadblocks that may prevent physicians from recommending the best therapeutic option for an individual patient. Alternative regimens using newer antithrombotic agents have been proposed; however, there are little data upon which to assess risk.
David B. S. Dyke, MD, Petar G. Igic, MD, Division of Cardiovascular Medicine, University of Michigan Health System Ann Arbor, Michigan Case Report A 23-year-old Gravida 4 Para 1 with a history of congenital bicuspid aortic valve, endocarditis, implantation of an aortic homograft valve, subsequent mechanical aortic and mitral valve replacements after deterioration of the original homograft and severe native-valve mitral regurgitation presented in the 11th week of pregnancy with a chief complaint of palpitations, lightheadedness and shortness of breath that had worsened over the prior 3 weeks. She also carried the diagnosis of paroxysmal atrial flutter that predated the mechanical valve implantation and unexplained flank pain 2 weeks prior to admission. Her past obstetrical history included both elective and spontaneous abortions prior to aortic homograft implantation, a term normal spontaneous vaginal delivery during the homograft period (no complications during pregnancy, labor or postpartum), and the current pregnancy. The patient was on warfarin alone at the time of conception with an average dose of 10 mg/day and an adequate international normalized ratio (INR). She was switched to subcutaneous unfractionated heparin (18,000 units BID) alone at the seventh week of the pregnancy. Initial mid-interval aPTT was ⬎100 seconds, however in the weeks preceding admission, levels in the mid 50 – 60s had been noted, with subsequent dose adjustment. The aPTT was 40.6 seconds on admission. Initial physical exam was unremarkable other than a rapid, regular pulse. ECG demonstrated paroxysms of supraventricular tachycardia. Echocardiography demonstrated a normal right ventricular systolic pressure and a mean gradient of 15 across her mitral prosthesis. Prosthetic valve dysfunction was presumed and intravenous heparin was initiated pending further study of her valve. Despite this, the patient developed acute pulmonary edema and cardiogenic shock. Systemic thrombolytics were administered with resolution to normal hemodynamics. Unfortunately, the patient suffered from a large cerebrovascular accident and ultimately progressed to clinical brain death. The family consented to organ donation.
Issues Related to Warfarin Use During Pregnancy Warfarin is known to cross the placenta, and is associated with early and late teratogenic effects. The majority of these effects are the result of fetal exposure between the 6th and 12th weeks of pregnancy. The classically described warfarin embryopathy is characterized by fetal anomalies ranging from nasal hypoplasia, stippled epiphyses (chondrodysplasia punctata), central nervous system abnormalities as well as other malformations. Outside of the classically described warfarin embryopathy, other difficulties are common. Second and third trimester anomalies can include fetal wast-
Introduction The above case report highlights the difficulty and controversy involved in the management of patients with prosthetic heart valves during pregnancy. Pregnancy and the peripartum period are rife with changes in cardiovascular physiology. Cardiac output, total blood volume, and total hemoglobin content increase to meet the needs of the
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age, scarring as a result of fetal hemorrhage, mental retardation, blindness, other central nervous system abnormalities, congenital heart disease, polydactyly, as well as a long list of other malformations. These can all be grouped into what is called the warfarin syndrome. The exact incidence of this syndrome is not known. It has been described in the literature as occurring in 4 – 67% of exposed fetuses. However, larger series reports support a true rate of approximately 4 –10%. After the 12th week, the risk of anomalies with exposure is generally felt to be less than 5%. The product monograph for the most commonly used form of warfarin in the United States contains the following warning: “Warfarin is contraindicated in women who are or may become pregnant.” This obviously makes most health care providers uncomfortable with this option, at least in North America where the risk of litigation is higher than for the rest of the world. However, the risk of warfarin-related fetal complications appears to vary depending on the dose of warfarin given to the mother. In a recent retrospective study, 58 pregnancies were evaluated in the presence of warfarin. In the group of mothers who used ⬎ 5 mg of warfarin per day to obtain a therapeutic international normalized ratio (INR), 22 fetal complications (19 spontaneous abortions and stillbirths, two warfarin embryopathies, one VSD) occurred. In the group that required ⱕ 5 mg per day of warfarin to achieve a therapeutic INR, only five fetal complications (four spontaneous abortions and one growth retardation) occurred. Of note, in this study, two cases of mechanical valve thromboses were seen despite adequate INR. If labor and delivery occurs while the mother is on warfarin, cesarean section is indicated; this minimizes the risk of fetal hemorrhage associated with spontaneous vaginal delivery. Maternal bleeding can usually be managed by giving fresh-frozen plasma.
has been seen in as many as 12–24% of patients, once again depending on the series reviewed. Careful note should be made of the fact that the data that exist in the literature are largely driven by case reports and small series. To date no data from randomized trials exist to guide our therapy. However, from a strictly medico-legal standpoint, there are no product monograph–listed contraindications to the use of unfractionated heparin during pregnancy. Given the issues of ensuring adequate anticoagulation with subcutaneous unfractionated heparin, many physicians have advocated using low–molecular-weight heparin (with adequate monitoring of anti-Factor Xa levels) as an alternative. Advantages include greater bioavailability, less need for laboratory monitoring, and a lower incidence of thrombocytopenia and osteoporosis. Unfortunately, cases of prosthetic heart valve thrombosis have been reported in patients with prosthetic valves who have received low– molecular-weight heparin for thromboprophylaxis. Two of the cases involved pregnant women in whom valve thrombosis led to maternal and fetal deaths. Detailed evaluation of these cases and the clinical trial protocol indicate that the enoxaparin was likely under dosed. The clinical trial protocol specified for 1 mg/kg of SQ enoxaparin (rounded to the nearest 20 mg) early in pregnancy without dosage adjustments for weight gain as pregnancy progressed. Monitoring was performed monthly, and dosage adjustments only occurred for peak anti-Factor Xa levels of greater than 1.2 IU/mL. Patient 1 was noted to have a level of only 0.33 IU/mL two days prior to her death, and Patient 2 had a level of 0.43 IU/mL 20 days prior to death with no subsequent level obtained. As experience with this drug has increased, most experts agree that a full mg/kg SQ should be given BID, that appropriate 4-hour troughs should fall between 0.5–1.1 IU/mL (some feel a lower level of 0.6 IU/mL may be more appropriate in high-risk cases) and that monitoring should occur at a very minimum of weekly. Despite this, the product monograph for enoxaparin has been updated to include the following statement: “. . .the use of Enoxaparin injection is not recommended for thromboprophylaxis in patients with (any) prosthetic heart valves. Pregnant women with prosthetic heart valves may be at higher risk for thromboembolism. . .” These recommendations have not been well accepted by the medical community. One reason is that low–molecularweight heparins have been increasingly used to minimize the need for protracted hospital stays for patient with mechanical valves who undergo invasive procedures. Despite the previously described index cases of valve thrombosis involving two pregnant patients with mechanical valves, clinical data supporting safety in non-pregnant patients with mechanical valves are actually reassuring. Although reports of valve thrombosis with low–molecular-weight heparins are slowly accumulating (mostly in the form of single-case reports), thrombosis with unfractionated heparin is problematic as well (largely reported in retrospective/ cohort studies). Thus far, there is no evidence that low–
Issues Related to Heparin Use During Pregnancy Complications related to the long-term use of heparin include not only the obvious risk for maternal hemorrhage, but also osteopenia, heparin-induced thrombocytopenia and fetal loss secondary to retroplacental hemorrhage. Unlike warfarin, unfractionated heparin does not cross the placenta. Direct teratogenic effects have not been documented. However, the thromboembolic rate for mechanical valve patients receiving intravenous heparin during pregnancy has been estimated to be 8 –29%, depending on the series reviewed. In addition, there are obvious logistical difficulties associated with long-term intravenous heparin, particularly related to the mode of delivery. In an effort to minimize this issue, some physicians recommend subcutaneously administered unfractionated heparin. The risks associated with subcutaneously administered unfractionated heparin appear to be similar to intravenous heparin. Thromboembolism, including valve thrombosis,
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Table 1. Recommendations for Anticoagulation During Pregnancy in Patients With Mechanical Prosthetic Valves: Weeks 1–35
molecular-weight heparins are any worse than IV or SQ unfractionated heparin, particularly during pregnancy. A recent consensus statement sums the issue up quite well with the following statement: “. . .although concerns about efficacy and safety was justified for all agents, the available literature and index cases did not support selective, asymmetrical warning language in the case of enoxaparin.” Nevertheless, many physicians are wary of using low–molecular-weight heparins in patients with mechanical valves during pregnancy.
Indication 1. The decision whether to use heparin during the first trimester or to continue oral anticoagulation throughout pregnancy should be made after full discussion with the patient and her partner; if she chooses to change to heparin for the first trimester, she should be made aware that heparin is less safe for her, with a higher risk of both thrombosis and bleeding and that any risk to the mother also jeopardizes the baby. 2. High-risk women (a history of thromboembolism or an oldergeneration mechanical prosthesis in the mitral position) who choose not to take warfarin during the first trimester should receive continuous unfractionated heparin intravenously in a dose to prolong the midinterval (6 hours after dosing) aPTT to 2–3 times control. Transition to warfarin can occur thereafter. 3. In patients receiving warfarin, INR should be maintained between 2.0–3.0 with the lowest possible dose of warfarin, and low-dose aspirin should be added. 4. Women at low risk (no history of thromboembolism, newer lowprofile prosthesis) may be managed with adjusted-dose subcutaneous heparin (17,500–20,000 U BID) to prolong the midinterval (6 hours after dosing) aPTT to 2–3 times control.
Appropriate Monitoring of Anticoagulation for Mechanical Valves During Pregnancy If low–molecular-weight heparin is used during pregnancy, it is advisable to monitor peak and 4-hour trough antiFactor Xa levels at least every few days on initiation of the drug and a minimum of weekly thereafter in anticipation of weight gain and alterations in body fluid composition. If unfractionated heparin (either intravenous or subcutaneous) is utilized, it is advisable to monitor 6-hour troughs daily during initiation of treatment and a minimum of twice weekly thereafter (the bioavailability of unfractionated heparin is somewhat less consistent than that of LMWHs). The goal aPTT should be at least 2.0 times control. If the subcutaneous route is chosen for unfractionated heparin, starting doses should be high (17,500 –20,000 U every 12 hours). In patients who undergo transition from warfarin to heparin or heparin to warfarin, the highest likelihood of anticoagulation failure is during the transition period, and monitoring should be appropriately intense during these time periods. When switching from heparin to warfarin, monitoring should occur daily until an adequate INR is achieved. Given the rapid changes in body composition during pregnancy, warfarin should be monitored weekly during non-transition times. The degree of anticoagulation with warfarin depends on the type and position of the mechanical valve(s).
Class I
I
IIa
IIb
heparin is less safe for her with a higher risk of both thrombosis and bleeding and that any risk to the mother also jeopardizes the baby.” The more recent consensus-driven ACC/AHA Guidelines for the Management of Patients With Valvular Heart Disease are slightly more comprehensive but perhaps are more influenced by product monograph and packaging information (Table 1). These guidelines do not recommend the use of low–molecular-weight heparins, primarily because of a lack of clinical data. Of note, this document was published prior to the widespread use of low–molecularweight heparin and the case reports of prosthetic valve thrombosis. Given these issues, it seems unlikely that low– molecular-weight heparins will be given an indication for use in pregnancy in the next iteration of these guidelines. Aspirin is frequently used as an adjuvant method of thromboprophylaxis in patients with mechanical valves. Given that low-dose aspirin is felt to be reasonably safe in pregnancy, it is recommended for patients with mechanical valves receiving warfarin during pregnancy. Although not listed in the Guideline’s indication tables, low-dose aspirin is also recommended (in the body of the text) for patients receiving heparin as well. To make clinical decision making more confusing, the likelihood of thromboembolism likely depends on the type and position of the valve as well as other co-morbidities. Low-risk valves are defined by the AHA/ACC to be newer, low-profile valves and any valve in the aortic position. High-risk valves include old generation mitral valves. However, undefined risk groups exist, as exemplified by the above case presentation. What is the risk associated with two low-risk valves? Although intuitively it seems reasonable to expect the risk to be higher with two valves, to what extent is not clear. I would recommend that patients with
Specific Guidelines Given the described problems with all forms of thromboprophylaxis and the lack of well-controlled data, clinical decision making is difficult. However, guidelines derived from expert consensus do exist. The first set of guidelines comes from the European Society of Cardiology Guidelines for Prevention of Thromboembolic Events in Valvular Heart Disease. The following general statement sets the general tone of the document: “The use of heparin . . . this strategy exposes the mother to a period of greater risk, and thus the use of an oral anticoagulation throughout pregnancy is to be preferred.” The committee thereafter recommends the following: “The decision whether to use heparin during the first trimester or to continue oral anticoagulant treatment throughout should be made after full discussion with the patient and her partner. If she chooses to change to heparin for the first trimester, she should be made aware that
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multiple mechanical valves or other co-morbidities such as prior cerebrovascular accident, thromboembolic event, atrial fibrillation or depressed right or left ventricular function be considered high-risk regardless of the valve type.
term IV heparin should be utilized, and if no improvement is seen, either thrombolytics or subcutaneous heparin plus warfarin for 1–3 months can be utilized in order to allow for endogenous thrombolysis to occur. There is, however, no data for this in the setting of pregnancy.
Diagnosis of Prosthetic Valve Dysfunction Counseling Prior to Pregnancy
Diagnosis of prosthetic valve dysfunction thrombosis is usually made by a combination of clinical exam, transesophageal echocardiography and/or fluoroscopy. Transesophageal echocardiography is limited by acoustic shadowing (although less so than transthoracic echocardiography) and an inability to clearly delineate all mechanical valve elements. However, it is superior for assessing clot burden. Fluoroscopy gives the best visualization of valve elements, however, it can be difficult to differentiate chronic panus from acute thrombosis. It should be noted that adequate fetal shielding should be employed during fluoroscopy. Because prosthetic valve thrombosis and/or thromboembolism can occur rapidly despite apparently adequate anticoagulation, a high index of suspicion and a rapid move to make a definitive diagnosis should be considered the standard of care in these patients.
The medical issues related to the management of the patients with mechanical prosthetic valves during pregnancy have now been defined for the reader. Personal choice, religious and cultural issues obviously play a major role in the decision process. While one patient may wish to avoid the perils of anticoagulation during pregnancy by opting for elective termination, another patient may hold the life of the fetus as the highest priority and choose term-long heparin despite elevated risks to herself. Obviously this presents a complex scenario for both the patient and physician, and no particular strategy appears to be obviously superior. With this defined, it should be obvious that adequate preparation is essential in order to optimize the likelihood for success (however this may be defined). Full disclosure of the risks involved with regards to pregnancy occurring in a patient with prosthetic valves should be given to the involved parties. The therapeutic options should be presented in a logical way (see Figure 1 as an example of a possible template) so that the involved individuals have a reasonable expectation of possible outcomes. Pitfalls of therapeutic options, including risks, and even labeling information, should be presented. This should be discussed well in advance of conception, whenever possible. Because of the obvious medico-legal issues, all information presented and therapeutic plans should be thoroughly documented in the medical record. In addition, early involvement of both obstetricians and cardiovascular specialists who are experienced in (or at least knowledgeable about) these high-risk patients is essential. This cannot, in the author’s opinion, occur within the confines of a routine 15-minute office visit.
Treatment of Prosthetic Valve Thrombosis Treatment of prosthetic valve thrombosis is problematic. Indications for surgical therapy are not steadfast; however, a large clot burden, functional class III/IV or evidence of severe valve obstruction are generally accepted. However, surgical therapy is associated with poor maternal and fetal outcomes. Fetal mortality is approximately 30%, with substantial additional morbidity. Maternal mortality and morbidity is approximately 6% and 24%, respectively. Data for thrombolysis of acutely thrombosed valves are somewhat discouraging. Ineffective or incomplete thrombolysis is seen in 16 –29% of cases, and recurrent thrombosis occurs in 11% of cases. A thromboembolic rate of 12–15% has been seen, specifically with a cerebrovascular accident rate of 3–10%. Major bleeding can be seen in up to 5% of all cases. Overall, thrombolysis is associated with a mortality rate of 6 –12%. The literature supporting use of thrombolytics for mechanical valve thrombosis in pregnancy is somewhat more reassuring. There are 36 reports of thrombolytic use for mechanical valves in a total of 172 pregnancies. Maternal mortality was only seen in 1.2% of these cases, with a pregnancy loss rate of only 5.8%. These data make surgical options appear less attractive, however, larger clot burdens may still do better with surgical therapy. This is speculative, however. Once again, there are inadequate data to provide us with information as to which patients do better with surgery vs. with thrombolytic therapy. Augmented anticoagulation has been advocated in certain cases. Indications include a small clot burden in the setting of an acceptable functional class. In-hospital, short-
Which Valves Should Be Used in Women of Reproductive Age Due to a lack of need for systemic anticoagulation, it is clear that bioprosthetic valves engender less immediate maternal and fetal morbidity and mortality; however, there is a high rate of early structural valve deterioration in young patients. This process appears to be accelerated in pregnancy (4 – 35% deterioration during pregnancy). Thus, some of the risks are not avoided, but simply postponed secondary to the possible need for a re-operation. There are no clear-cut best valve options for women in their reproductive years. Mechanical valves are clearly more durable but are associated with an increased risk during pregnancy over bioprosthetic valves. Less is known about stentless valves, homografts and the Ross procedure as they pertain to pregnancy; however, they may be more durable than traditional bioprosthetic valves in this situation.
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Figure 1. An example of a possible template for a logical discussion with the patient and a guide to clinical approach.
Conclusion
agencies, and treating physicians and their patients. Existing packaging warnings create a medico-legal environment that offers suboptimal choices for patients, families and their health care team. There is a critical need for the pharmaceutical industry and regulatory agencies to re-examine the packaging information so that they are consistent with the known literature.
In summary, pregnancy is associated with an increased risk of prosthetic valve-related morbidity and mortality. Fetal loss is higher with warfarin-based therapies, particularly if higher (⬎5 mg) doses are used. On the other hand, maternal loss is higher with heparin-based strategies. Medical, cultural, religious and legal issues all should be carefully explored prior to pregnancy if at all possible. Despite this, even the best-intended decisions can lead to a less than optimal outcome. This being the case, pregnant patients with suspected prosthetic valve thrombosis should be urgently evaluated and rapidly treated. Hemodynamic stability on presentation can lower your guard. Full systemic anticoagulation using any mode anticoagulation does not necessarily offer acceptable levels of protection. The treating physician is advised to be wary! I believe that is it time for a national registry in order to collect data from this high-risk group of patients. This should be as a prelude to well-designed randomized clinical trials. In addition, I believe that there exists an unacceptable conflict between the pharmaceutical industry, regulatory
Questions and Answers 1. Which of the following statements is true? A) Warfarin crosses the placenta B) Heparin crosses the placenta C) Maternal warfarin doses of ⬍10 mg a day are likely safe for the fetus D) The greatest risk for warfarin embryopathy is during the second trimester The answer is A. 2. Strictly by product monographs, which of the following are contra-indicated in pregnancy? A) Low-molecular-weight heparin (enoxaparin)
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B) Warfarin C) Unfractionated heparin D) Aspirin
C) Present all data in an easily understandable way D) Document what you do and why The answers are all of the above.
The answers are A and B.
The authors wish to thank Julie Kovach, MD for her review of this manuscript, and Kimberly Keifer for her assistance in preparation of the table and figure.
3. Which of the following statements are true to the ACC/ AHA guidelines? A) Patients with high-risk valves who choose not to take warfarin should be treated with intravenous unfractionated heparin to prolong the midinterval aPTT to 2 to 3 times control B) Patients with low-risk valves may be managed with adjusted-dose SQ heparin to prolong the midinterval aPTT to 2 to 3 times control C) Low–molecular-weight heparin can be used for low-risk patients D) Low-dose aspirin should be added in patients receiving warfarin
Suggested Reading Physicians Desk Reference. Murray L, Kelly GL, eds. 56th ed. Montvale, NJ: Medical Economics Co., Inc., 2002. Vitale N, De Feo M, De Santo LS, et al. Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves. J Am Coll Cardiol 1999;33:1637– 41. ACC/AHA Guidelines for the Management of Patients With Valvular Heart Disease. J Am Coll Cardiol 1998;32:1486 –588. Guidelines for prevention of thromboembolic events in valvular heart disease—Study Group of the Working Group on Valvular Heart Disease of the European Society of Cardiology. Eur Heart J 1995;16:1320 –30. Topol EJ, Casele H, Elkayam U, et al. Report and recommendations of the Anticoagulation in prosthetic valves and pregnancy consensus report (APPCR). Anticoagulation and enoxaparin use in patients with prosthetic heart valves and/or pregnancy. Clinical Cardiology Consensus Reports. Oct 1, 2002. Elkayam U. Pregnancy through a prosthetic heart valve. J Am Coll Cardiol 1999;33:1642–5. Wiess BM, von Segesser LK, Alou E, et al. Outcome of cardiovascular surgery and pregnancy: a systematic review of the period 1984 –1996. Am J Obstet Gynecol 1998;179:1643–53. Turrentine MA, Braems G, Ramirez MM. Use of thrombolytics for the treatment of thromboembolic disease during pregnancy. Obstet Gynecol Surv 1995;7:534 – 41.
The answers are A, B and D. 4. A 25-year-old with a Starr-Edward valve in the mitral position presents anticipating a future pregnancy. You should do which of the following? A) Consider this to be a low-risk valve B) Consider this to be a high-risk valve C) Consider low-dose aspirin added to the warfarin D) Plan on switching to heparin (high-dose guided by mid-interval aPTT to at least 2 to 3 times control for the last 3– 4 weeks of pregnancy The answers are B, C and D. 5. A 32-year-old patient with dual mechanical mitral and tricuspid valves presents in her 8th week of pregnancy. She is presently on warfarin. She is unwilling to accept either high fetal or maternal risk. What is the best option for anticoagulation? A) Data are insufficient to be certain B) Involve other family members, social support and clergy if possible
Address correspondence and reprint requests to David B. Dyke, MD, Clinical Assistant Professor of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Health System, 1500 E. Medical Center Drive, Room L3623, Ann Arbor, MI 48109-0271.
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Management of Prosthetic Heart Valve Anticoagulation in Pregnancy
Focused Review growing fetus. Peripheral resistance, reflected in systemic blood pressure, decreases. Fibrinogen levels are elevated, there is a decrease in protein S activity, and both venous hypertension and stasis are common. Indeed the mechanisms of normal hemostasis are perturbed such that pregnancy is generally considered to be a hypercoagulable state. The degree of alterations in the coagulation system during pregnancy varies greatly. Factors that influence the coagulation system include duration of pregnancy, body composition and rapid fluid shifts. In addition, there is significant inter-individual variability, and in general the degree to which any individual is hypercoagulable is unpredictable. Antithrombotic regimens commonly proposed for mechanical valve anticoagulation during pregnancy include warfarin-based, heparin-based and mixed regimens. Warfarin-based regimens usually utilize warfarin throughout the first, second and most of the third trimesters until the last few weeks of pregnancy, at which point continuous intravenous or adjusted dose subcutaneous unfractionated heparin is substituted in order to prevent fetal hemorrhage associated with labor and delivery. This option likely represents the safest method for the mother; however, fetal risk is elevated. Heparin-based regimens utilize continuous intravenous, subcutaneous unfractionated or subcutaneous low–molecular-weight heparin. This option avoids exposure of the fetus to warfarin; however, there is a higher risk of maternal thromboembolic events. Mixed regimens utilize warfarin with the exception of during weeks 6 –12 and the last few weeks of pregnancy, during which time heparin is substituted. This option attempts to balance the abovestated risks by avoiding warfarin during the period of highest teratogenicity, while providing for superior anticoagulation during the remaining weeks of pregnancy. Unfortunately, all options have a high potential for unacceptable consequences for patients. In addition, there are medicolegal roadblocks that may prevent physicians from recommending the best therapeutic option for an individual patient. Alternative regimens using newer antithrombotic agents have been proposed; however, there are little data upon which to assess risk.
David B. S. Dyke, MD, Petar G. Igic, MD, Division of Cardiovascular Medicine, University of Michigan Health System Ann Arbor, Michigan Case Report A 23-year-old Gravida 4 Para 1 with a history of congenital bicuspid aortic valve, endocarditis, implantation of an aortic homograft valve, subsequent mechanical aortic and mitral valve replacements after deterioration of the original homograft and severe native-valve mitral regurgitation presented in the 11th week of pregnancy with a chief complaint of palpitations, lightheadedness and shortness of breath that had worsened over the prior 3 weeks. She also carried the diagnosis of paroxysmal atrial flutter that predated the mechanical valve implantation and unexplained flank pain 2 weeks prior to admission. Her past obstetrical history included both elective and spontaneous abortions prior to aortic homograft implantation, a term normal spontaneous vaginal delivery during the homograft period (no complications during pregnancy, labor or postpartum), and the current pregnancy. The patient was on warfarin alone at the time of conception with an average dose of 10 mg/day and an adequate international normalized ratio (INR). She was switched to subcutaneous unfractionated heparin (18,000 units BID) alone at the seventh week of the pregnancy. Initial mid-interval aPTT was ⬎100 seconds, however in the weeks preceding admission, levels in the mid 50 – 60s had been noted, with subsequent dose adjustment. The aPTT was 40.6 seconds on admission. Initial physical exam was unremarkable other than a rapid, regular pulse. ECG demonstrated paroxysms of supraventricular tachycardia. Echocardiography demonstrated a normal right ventricular systolic pressure and a mean gradient of 15 across her mitral prosthesis. Prosthetic valve dysfunction was presumed and intravenous heparin was initiated pending further study of her valve. Despite this, the patient developed acute pulmonary edema and cardiogenic shock. Systemic thrombolytics were administered with resolution to normal hemodynamics. Unfortunately, the patient suffered from a large cerebrovascular accident and ultimately progressed to clinical brain death. The family consented to organ donation.
Issues Related to Warfarin Use During Pregnancy Warfarin is known to cross the placenta, and is associated with early and late teratogenic effects. The majority of these effects are the result of fetal exposure between the 6th and 12th weeks of pregnancy. The classically described warfarin embryopathy is characterized by fetal anomalies ranging from nasal hypoplasia, stippled epiphyses (chondrodysplasia punctata), central nervous system abnormalities as well as other malformations. Outside of the classically described warfarin embryopathy, other difficulties are common. Second and third trimester anomalies can include fetal wast-
Introduction The above case report highlights the difficulty and controversy involved in the management of patients with prosthetic heart valves during pregnancy. Pregnancy and the peripartum period are rife with changes in cardiovascular physiology. Cardiac output, total blood volume, and total hemoglobin content increase to meet the needs of the
ACC CURRENT JOURNAL REVIEW Jul/Aug 2003 © 2003 by the American College of Cardiology Foundation Published by Elsevier Inc.
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1062-1458/03/$30.00 doi:10.1016/S1062-1458(03)00336-2
age, scarring as a result of fetal hemorrhage, mental retardation, blindness, other central nervous system abnormalities, congenital heart disease, polydactyly, as well as a long list of other malformations. These can all be grouped into what is called the warfarin syndrome. The exact incidence of this syndrome is not known. It has been described in the literature as occurring in 4 – 67% of exposed fetuses. However, larger series reports support a true rate of approximately 4 –10%. After the 12th week, the risk of anomalies with exposure is generally felt to be less than 5%. The product monograph for the most commonly used form of warfarin in the United States contains the following warning: “Warfarin is contraindicated in women who are or may become pregnant.” This obviously makes most health care providers uncomfortable with this option, at least in North America where the risk of litigation is higher than for the rest of the world. However, the risk of warfarin-related fetal complications appears to vary depending on the dose of warfarin given to the mother. In a recent retrospective study, 58 pregnancies were evaluated in the presence of warfarin. In the group of mothers who used ⬎ 5 mg of warfarin per day to obtain a therapeutic international normalized ratio (INR), 22 fetal complications (19 spontaneous abortions and stillbirths, two warfarin embryopathies, one VSD) occurred. In the group that required ⱕ 5 mg per day of warfarin to achieve a therapeutic INR, only five fetal complications (four spontaneous abortions and one growth retardation) occurred. Of note, in this study, two cases of mechanical valve thromboses were seen despite adequate INR. If labor and delivery occurs while the mother is on warfarin, cesarean section is indicated; this minimizes the risk of fetal hemorrhage associated with spontaneous vaginal delivery. Maternal bleeding can usually be managed by giving fresh-frozen plasma.
has been seen in as many as 12–24% of patients, once again depending on the series reviewed. Careful note should be made of the fact that the data that exist in the literature are largely driven by case reports and small series. To date no data from randomized trials exist to guide our therapy. However, from a strictly medico-legal standpoint, there are no product monograph–listed contraindications to the use of unfractionated heparin during pregnancy. Given the issues of ensuring adequate anticoagulation with subcutaneous unfractionated heparin, many physicians have advocated using low–molecular-weight heparin (with adequate monitoring of anti-Factor Xa levels) as an alternative. Advantages include greater bioavailability, less need for laboratory monitoring, and a lower incidence of thrombocytopenia and osteoporosis. Unfortunately, cases of prosthetic heart valve thrombosis have been reported in patients with prosthetic valves who have received low– molecular-weight heparin for thromboprophylaxis. Two of the cases involved pregnant women in whom valve thrombosis led to maternal and fetal deaths. Detailed evaluation of these cases and the clinical trial protocol indicate that the enoxaparin was likely under dosed. The clinical trial protocol specified for 1 mg/kg of SQ enoxaparin (rounded to the nearest 20 mg) early in pregnancy without dosage adjustments for weight gain as pregnancy progressed. Monitoring was performed monthly, and dosage adjustments only occurred for peak anti-Factor Xa levels of greater than 1.2 IU/mL. Patient 1 was noted to have a level of only 0.33 IU/mL two days prior to her death, and Patient 2 had a level of 0.43 IU/mL 20 days prior to death with no subsequent level obtained. As experience with this drug has increased, most experts agree that a full mg/kg SQ should be given BID, that appropriate 4-hour troughs should fall between 0.5–1.1 IU/mL (some feel a lower level of 0.6 IU/mL may be more appropriate in high-risk cases) and that monitoring should occur at a very minimum of weekly. Despite this, the product monograph for enoxaparin has been updated to include the following statement: “. . .the use of Enoxaparin injection is not recommended for thromboprophylaxis in patients with (any) prosthetic heart valves. Pregnant women with prosthetic heart valves may be at higher risk for thromboembolism. . .” These recommendations have not been well accepted by the medical community. One reason is that low–molecularweight heparins have been increasingly used to minimize the need for protracted hospital stays for patient with mechanical valves who undergo invasive procedures. Despite the previously described index cases of valve thrombosis involving two pregnant patients with mechanical valves, clinical data supporting safety in non-pregnant patients with mechanical valves are actually reassuring. Although reports of valve thrombosis with low–molecular-weight heparins are slowly accumulating (mostly in the form of single-case reports), thrombosis with unfractionated heparin is problematic as well (largely reported in retrospective/ cohort studies). Thus far, there is no evidence that low–
Issues Related to Heparin Use During Pregnancy Complications related to the long-term use of heparin include not only the obvious risk for maternal hemorrhage, but also osteopenia, heparin-induced thrombocytopenia and fetal loss secondary to retroplacental hemorrhage. Unlike warfarin, unfractionated heparin does not cross the placenta. Direct teratogenic effects have not been documented. However, the thromboembolic rate for mechanical valve patients receiving intravenous heparin during pregnancy has been estimated to be 8 –29%, depending on the series reviewed. In addition, there are obvious logistical difficulties associated with long-term intravenous heparin, particularly related to the mode of delivery. In an effort to minimize this issue, some physicians recommend subcutaneously administered unfractionated heparin. The risks associated with subcutaneously administered unfractionated heparin appear to be similar to intravenous heparin. Thromboembolism, including valve thrombosis,
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Table 1. Recommendations for Anticoagulation During Pregnancy in Patients With Mechanical Prosthetic Valves: Weeks 1–35
molecular-weight heparins are any worse than IV or SQ unfractionated heparin, particularly during pregnancy. A recent consensus statement sums the issue up quite well with the following statement: “. . .although concerns about efficacy and safety was justified for all agents, the available literature and index cases did not support selective, asymmetrical warning language in the case of enoxaparin.” Nevertheless, many physicians are wary of using low–molecular-weight heparins in patients with mechanical valves during pregnancy.
Indication 1. The decision whether to use heparin during the first trimester or to continue oral anticoagulation throughout pregnancy should be made after full discussion with the patient and her partner; if she chooses to change to heparin for the first trimester, she should be made aware that heparin is less safe for her, with a higher risk of both thrombosis and bleeding and that any risk to the mother also jeopardizes the baby. 2. High-risk women (a history of thromboembolism or an oldergeneration mechanical prosthesis in the mitral position) who choose not to take warfarin during the first trimester should receive continuous unfractionated heparin intravenously in a dose to prolong the midinterval (6 hours after dosing) aPTT to 2–3 times control. Transition to warfarin can occur thereafter. 3. In patients receiving warfarin, INR should be maintained between 2.0–3.0 with the lowest possible dose of warfarin, and low-dose aspirin should be added. 4. Women at low risk (no history of thromboembolism, newer lowprofile prosthesis) may be managed with adjusted-dose subcutaneous heparin (17,500–20,000 U BID) to prolong the midinterval (6 hours after dosing) aPTT to 2–3 times control.
Appropriate Monitoring of Anticoagulation for Mechanical Valves During Pregnancy If low–molecular-weight heparin is used during pregnancy, it is advisable to monitor peak and 4-hour trough antiFactor Xa levels at least every few days on initiation of the drug and a minimum of weekly thereafter in anticipation of weight gain and alterations in body fluid composition. If unfractionated heparin (either intravenous or subcutaneous) is utilized, it is advisable to monitor 6-hour troughs daily during initiation of treatment and a minimum of twice weekly thereafter (the bioavailability of unfractionated heparin is somewhat less consistent than that of LMWHs). The goal aPTT should be at least 2.0 times control. If the subcutaneous route is chosen for unfractionated heparin, starting doses should be high (17,500 –20,000 U every 12 hours). In patients who undergo transition from warfarin to heparin or heparin to warfarin, the highest likelihood of anticoagulation failure is during the transition period, and monitoring should be appropriately intense during these time periods. When switching from heparin to warfarin, monitoring should occur daily until an adequate INR is achieved. Given the rapid changes in body composition during pregnancy, warfarin should be monitored weekly during non-transition times. The degree of anticoagulation with warfarin depends on the type and position of the mechanical valve(s).
Class I
I
IIa
IIb
heparin is less safe for her with a higher risk of both thrombosis and bleeding and that any risk to the mother also jeopardizes the baby.” The more recent consensus-driven ACC/AHA Guidelines for the Management of Patients With Valvular Heart Disease are slightly more comprehensive but perhaps are more influenced by product monograph and packaging information (Table 1). These guidelines do not recommend the use of low–molecular-weight heparins, primarily because of a lack of clinical data. Of note, this document was published prior to the widespread use of low–molecularweight heparin and the case reports of prosthetic valve thrombosis. Given these issues, it seems unlikely that low– molecular-weight heparins will be given an indication for use in pregnancy in the next iteration of these guidelines. Aspirin is frequently used as an adjuvant method of thromboprophylaxis in patients with mechanical valves. Given that low-dose aspirin is felt to be reasonably safe in pregnancy, it is recommended for patients with mechanical valves receiving warfarin during pregnancy. Although not listed in the Guideline’s indication tables, low-dose aspirin is also recommended (in the body of the text) for patients receiving heparin as well. To make clinical decision making more confusing, the likelihood of thromboembolism likely depends on the type and position of the valve as well as other co-morbidities. Low-risk valves are defined by the AHA/ACC to be newer, low-profile valves and any valve in the aortic position. High-risk valves include old generation mitral valves. However, undefined risk groups exist, as exemplified by the above case presentation. What is the risk associated with two low-risk valves? Although intuitively it seems reasonable to expect the risk to be higher with two valves, to what extent is not clear. I would recommend that patients with
Specific Guidelines Given the described problems with all forms of thromboprophylaxis and the lack of well-controlled data, clinical decision making is difficult. However, guidelines derived from expert consensus do exist. The first set of guidelines comes from the European Society of Cardiology Guidelines for Prevention of Thromboembolic Events in Valvular Heart Disease. The following general statement sets the general tone of the document: “The use of heparin . . . this strategy exposes the mother to a period of greater risk, and thus the use of an oral anticoagulation throughout pregnancy is to be preferred.” The committee thereafter recommends the following: “The decision whether to use heparin during the first trimester or to continue oral anticoagulant treatment throughout should be made after full discussion with the patient and her partner. If she chooses to change to heparin for the first trimester, she should be made aware that
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multiple mechanical valves or other co-morbidities such as prior cerebrovascular accident, thromboembolic event, atrial fibrillation or depressed right or left ventricular function be considered high-risk regardless of the valve type.
term IV heparin should be utilized, and if no improvement is seen, either thrombolytics or subcutaneous heparin plus warfarin for 1–3 months can be utilized in order to allow for endogenous thrombolysis to occur. There is, however, no data for this in the setting of pregnancy.
Diagnosis of Prosthetic Valve Dysfunction Counseling Prior to Pregnancy
Diagnosis of prosthetic valve dysfunction thrombosis is usually made by a combination of clinical exam, transesophageal echocardiography and/or fluoroscopy. Transesophageal echocardiography is limited by acoustic shadowing (although less so than transthoracic echocardiography) and an inability to clearly delineate all mechanical valve elements. However, it is superior for assessing clot burden. Fluoroscopy gives the best visualization of valve elements, however, it can be difficult to differentiate chronic panus from acute thrombosis. It should be noted that adequate fetal shielding should be employed during fluoroscopy. Because prosthetic valve thrombosis and/or thromboembolism can occur rapidly despite apparently adequate anticoagulation, a high index of suspicion and a rapid move to make a definitive diagnosis should be considered the standard of care in these patients.
The medical issues related to the management of the patients with mechanical prosthetic valves during pregnancy have now been defined for the reader. Personal choice, religious and cultural issues obviously play a major role in the decision process. While one patient may wish to avoid the perils of anticoagulation during pregnancy by opting for elective termination, another patient may hold the life of the fetus as the highest priority and choose term-long heparin despite elevated risks to herself. Obviously this presents a complex scenario for both the patient and physician, and no particular strategy appears to be obviously superior. With this defined, it should be obvious that adequate preparation is essential in order to optimize the likelihood for success (however this may be defined). Full disclosure of the risks involved with regards to pregnancy occurring in a patient with prosthetic valves should be given to the involved parties. The therapeutic options should be presented in a logical way (see Figure 1 as an example of a possible template) so that the involved individuals have a reasonable expectation of possible outcomes. Pitfalls of therapeutic options, including risks, and even labeling information, should be presented. This should be discussed well in advance of conception, whenever possible. Because of the obvious medico-legal issues, all information presented and therapeutic plans should be thoroughly documented in the medical record. In addition, early involvement of both obstetricians and cardiovascular specialists who are experienced in (or at least knowledgeable about) these high-risk patients is essential. This cannot, in the author’s opinion, occur within the confines of a routine 15-minute office visit.
Treatment of Prosthetic Valve Thrombosis Treatment of prosthetic valve thrombosis is problematic. Indications for surgical therapy are not steadfast; however, a large clot burden, functional class III/IV or evidence of severe valve obstruction are generally accepted. However, surgical therapy is associated with poor maternal and fetal outcomes. Fetal mortality is approximately 30%, with substantial additional morbidity. Maternal mortality and morbidity is approximately 6% and 24%, respectively. Data for thrombolysis of acutely thrombosed valves are somewhat discouraging. Ineffective or incomplete thrombolysis is seen in 16 –29% of cases, and recurrent thrombosis occurs in 11% of cases. A thromboembolic rate of 12–15% has been seen, specifically with a cerebrovascular accident rate of 3–10%. Major bleeding can be seen in up to 5% of all cases. Overall, thrombolysis is associated with a mortality rate of 6 –12%. The literature supporting use of thrombolytics for mechanical valve thrombosis in pregnancy is somewhat more reassuring. There are 36 reports of thrombolytic use for mechanical valves in a total of 172 pregnancies. Maternal mortality was only seen in 1.2% of these cases, with a pregnancy loss rate of only 5.8%. These data make surgical options appear less attractive, however, larger clot burdens may still do better with surgical therapy. This is speculative, however. Once again, there are inadequate data to provide us with information as to which patients do better with surgery vs. with thrombolytic therapy. Augmented anticoagulation has been advocated in certain cases. Indications include a small clot burden in the setting of an acceptable functional class. In-hospital, short-
Which Valves Should Be Used in Women of Reproductive Age Due to a lack of need for systemic anticoagulation, it is clear that bioprosthetic valves engender less immediate maternal and fetal morbidity and mortality; however, there is a high rate of early structural valve deterioration in young patients. This process appears to be accelerated in pregnancy (4 – 35% deterioration during pregnancy). Thus, some of the risks are not avoided, but simply postponed secondary to the possible need for a re-operation. There are no clear-cut best valve options for women in their reproductive years. Mechanical valves are clearly more durable but are associated with an increased risk during pregnancy over bioprosthetic valves. Less is known about stentless valves, homografts and the Ross procedure as they pertain to pregnancy; however, they may be more durable than traditional bioprosthetic valves in this situation.
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Figure 1. An example of a possible template for a logical discussion with the patient and a guide to clinical approach.
Conclusion
agencies, and treating physicians and their patients. Existing packaging warnings create a medico-legal environment that offers suboptimal choices for patients, families and their health care team. There is a critical need for the pharmaceutical industry and regulatory agencies to re-examine the packaging information so that they are consistent with the known literature.
In summary, pregnancy is associated with an increased risk of prosthetic valve-related morbidity and mortality. Fetal loss is higher with warfarin-based therapies, particularly if higher (⬎5 mg) doses are used. On the other hand, maternal loss is higher with heparin-based strategies. Medical, cultural, religious and legal issues all should be carefully explored prior to pregnancy if at all possible. Despite this, even the best-intended decisions can lead to a less than optimal outcome. This being the case, pregnant patients with suspected prosthetic valve thrombosis should be urgently evaluated and rapidly treated. Hemodynamic stability on presentation can lower your guard. Full systemic anticoagulation using any mode anticoagulation does not necessarily offer acceptable levels of protection. The treating physician is advised to be wary! I believe that is it time for a national registry in order to collect data from this high-risk group of patients. This should be as a prelude to well-designed randomized clinical trials. In addition, I believe that there exists an unacceptable conflict between the pharmaceutical industry, regulatory
Questions and Answers 1. Which of the following statements is true? A) Warfarin crosses the placenta B) Heparin crosses the placenta C) Maternal warfarin doses of ⬍10 mg a day are likely safe for the fetus D) The greatest risk for warfarin embryopathy is during the second trimester The answer is A. 2. Strictly by product monographs, which of the following are contra-indicated in pregnancy? A) Low-molecular-weight heparin (enoxaparin)
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B) Warfarin C) Unfractionated heparin D) Aspirin
C) Present all data in an easily understandable way D) Document what you do and why The answers are all of the above.
The answers are A and B.
The authors wish to thank Julie Kovach, MD for her review of this manuscript, and Kimberly Keifer for her assistance in preparation of the table and figure.
3. Which of the following statements are true to the ACC/ AHA guidelines? A) Patients with high-risk valves who choose not to take warfarin should be treated with intravenous unfractionated heparin to prolong the midinterval aPTT to 2 to 3 times control B) Patients with low-risk valves may be managed with adjusted-dose SQ heparin to prolong the midinterval aPTT to 2 to 3 times control C) Low–molecular-weight heparin can be used for low-risk patients D) Low-dose aspirin should be added in patients receiving warfarin
Suggested Reading Physicians Desk Reference. Murray L, Kelly GL, eds. 56th ed. Montvale, NJ: Medical Economics Co., Inc., 2002. Vitale N, De Feo M, De Santo LS, et al. Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves. J Am Coll Cardiol 1999;33:1637– 41. ACC/AHA Guidelines for the Management of Patients With Valvular Heart Disease. J Am Coll Cardiol 1998;32:1486 –588. Guidelines for prevention of thromboembolic events in valvular heart disease—Study Group of the Working Group on Valvular Heart Disease of the European Society of Cardiology. Eur Heart J 1995;16:1320 –30. Topol EJ, Casele H, Elkayam U, et al. Report and recommendations of the Anticoagulation in prosthetic valves and pregnancy consensus report (APPCR). Anticoagulation and enoxaparin use in patients with prosthetic heart valves and/or pregnancy. Clinical Cardiology Consensus Reports. Oct 1, 2002. Elkayam U. Pregnancy through a prosthetic heart valve. J Am Coll Cardiol 1999;33:1642–5. Wiess BM, von Segesser LK, Alou E, et al. Outcome of cardiovascular surgery and pregnancy: a systematic review of the period 1984 –1996. Am J Obstet Gynecol 1998;179:1643–53. Turrentine MA, Braems G, Ramirez MM. Use of thrombolytics for the treatment of thromboembolic disease during pregnancy. Obstet Gynecol Surv 1995;7:534 – 41.
The answers are A, B and D. 4. A 25-year-old with a Starr-Edward valve in the mitral position presents anticipating a future pregnancy. You should do which of the following? A) Consider this to be a low-risk valve B) Consider this to be a high-risk valve C) Consider low-dose aspirin added to the warfarin D) Plan on switching to heparin (high-dose guided by mid-interval aPTT to at least 2 to 3 times control for the last 3– 4 weeks of pregnancy The answers are B, C and D. 5. A 32-year-old patient with dual mechanical mitral and tricuspid valves presents in her 8th week of pregnancy. She is presently on warfarin. She is unwilling to accept either high fetal or maternal risk. What is the best option for anticoagulation? A) Data are insufficient to be certain B) Involve other family members, social support and clergy if possible
Address correspondence and reprint requests to David B. Dyke, MD, Clinical Assistant Professor of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Health System, 1500 E. Medical Center Drive, Room L3623, Ann Arbor, MI 48109-0271.
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