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Keywords:

  • anticoagulation;
  • pregnancy;
  • cardiovascular diseases

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. Changes in Homeostasis and Coagulability During Pregnancy
  4. Anticoagulation Therapies
  5. Anticoagulation Regimens in Pregnant Patients with Prosthetic MHVs
  6. Anticoagulation in Other Cardiac Disorders During Pregnancy
  7. VTE Associated with Pregnancy
  8. References
Clinical Development Phases I-III Regulatory, Quality, Manufacturing

Pregnancy-associated thrombosis is an important cause of morbidity and mortality during pregnancy. All anticoagulation options are associated with risks and benefits. Thus, although anticoagulation therapy is an important component of the management of thrombotic complications in pregnancy, it is associated with fetal and maternal complications. Therefore, pregnancy poses a serious therapeutic dilemma for both physicians and their patients. This review summarizes the available data on anticoagulation therapy for thromboembolic prophylaxis in pregnant women focusing on cardiovascular disorders, especially on treatment strategy in pregnant women with mechanical heart valves.


Changes in Homeostasis and Coagulability During Pregnancy

  1. Top of page
  2. ABSTRACT
  3. Changes in Homeostasis and Coagulability During Pregnancy
  4. Anticoagulation Therapies
  5. Anticoagulation Regimens in Pregnant Patients with Prosthetic MHVs
  6. Anticoagulation in Other Cardiac Disorders During Pregnancy
  7. VTE Associated with Pregnancy
  8. References

Normal pregnancy is accompanied by changes in homeostasis that result in a hypercoagulable state helping to prevent possible hemorrhage at the time of delivery or miscarriage. Most clotting factors usually increase in pregnancy together with a decrease in several anticoagulants and fibrinolytic activity. Specifically, there is an increased concentration of factors VII, VIII, X, and von Willebrand's factor [Bremme, 2003] with a concomitant decrease in anticoagulant factors including free and total protein S, as well as a decreased activity during early pregnancy. Although protein C levels remain unchanged [Franchini, 2006; Rosenkranz et al., 2008], there is an increase in activated protein C resistance, partly due to a number of modifiers such as the presence of factor V Leiden mutation, thrombin generation, and the presence of antiphospholipid antibodies [Clark and Walker, 2001]. Fibrinolysis is decreased, predominantly due to diminished tissue plasminogen activator (tPA) activity. Plasminogen activator inhibitor type 1 levels are increased as well as levels of plasminogen activator inhibitor type 2, produced by the placenta. Other markers of thrombin generation include increased thrombin–antithrombin complexes, prothrombin fragments 1 and 2, peak thrombin generation, and increased d-dimer levels [Kjellberg et al., 1999; Franchini, 2006; Rosenkranz et al., 2008]. All these changes result in a hypercoagulable state of pregnancy and may not return to normal ranges for at least 8 weeks after delivery [James, 2009] and lead to three- to fourfold and four- to fivefold increase in arterial thromboembolism (strokes and myocardial infarction) and venous thromboembolism (VTE), respectively, during gestation and a further increased in risk (20-fold) post partum [Heit et al., 2005] compared with that of nonpregnant women [Heit et al., 2005; James et al., 2005a; James et al., 2006b; James, 2012]. Due to alterations in homeostasis and coagulability [McGehee, 1998; Brenner, 2004], pregnancy in women with mechanical heart valves (MHVs) carries a high rate of thromboembolic complications. Earlier published studies reported thromboembolic events in 7–23% of such cases [Born et al., 1992; Sbarouni and Oakley, 1994; McGehee, 1998]; half of them with valve thrombosis leading to high mortality rate of up to 40%. More recent reports including mostly women with new generation, less thrombogenic MHVs have described maternal mortality between 1% and 4%, with most deaths attributable to thrombotic complications [Chan et al., 2000; Elkayam and Bitar, 2005]. Because of the increased risk of severe thromboembolic complications in pregnancy, effective anticoagulation is critical in such patients but remains problematic as both vitamin K antagonists (VKAs) and heparins (unfractionated heparin [UFH]) can be associated with important fetal and maternal complications.

Anticoagulation Therapies

  1. Top of page
  2. ABSTRACT
  3. Changes in Homeostasis and Coagulability During Pregnancy
  4. Anticoagulation Therapies
  5. Anticoagulation Regimens in Pregnant Patients with Prosthetic MHVs
  6. Anticoagulation in Other Cardiac Disorders During Pregnancy
  7. VTE Associated with Pregnancy
  8. References

VKAs

VKAs are the preferred agents for long-term anticoagulation in nonpregnant women with MHV but can have harmful fetal effects. When used during the critical period for organogenesis, the 4th–8th week after conception, there is a 15–56% reported risk of miscarriage [Chen et al., 1982; Meschengieser et al., 1999; Wesseling et al., 2001; Blickstein and Blickstein, 2002; Cotrufo et al., 2002; Srivastava et al., 2002; Bates et al., 2012] and, depending on the case series, a 5–30% risk of congenital anomalies [Meschengieser et al., 1999; Blickstein and Blickstein, 2002; Srivastava et al., 2002]. Placental transfer of warfarin later in pregnancy can result in fetal bleeding or stillbirth [Chen et al., 1982; Wesseling et al., 2001; Cotrufo et al., 2002] and long-term sequelae including an increased risk of adverse neurologic outcome [Chan et al., 2000]. Vitale et al. [1999] reported a high frequency of fetal complications (88%), including spontaneous abortions, congenital heart disease, growth retardation, and warfarin embryopathy in women with MHVs when treated with warfarin at a dose exceeding 5 mg/day throughout the pregnancy with Sadler et al. [2000] describing similar results, regardless of the warfarin dose. Long-term effects included an adverse neurologic outcome in 14% of cases and low IQ in 4% [Wesseling et al., 2001].

UFH

UFH has been traditionally considered the drug of choice for the prevention and treatment of thrombotic disorders during pregnancy [Bates et al., 2012]. This drug does not cross the placenta and therefore offers little direct risk to the fetus [Flessa et al., 1965; Schneider et al., 1995]. However, UFH has several disadvantages including heparin-induced thrombocytopenia (HIT) and osteopenia; the latter may lead to symptomatic vertebral fracture in approximately 2% of women [Barbour and Pickard, 1995; Dahlman, 1999]. In addition, an increase in the volume of distribution due to 40–50% increase in maternal blood volume, as well as an increase in glomerular filtration [McGehee, 1998; Gordon et al., 2002] lead to enhanced renal excretion of heparin compounds. Therefore, higher doses and more frequent administration of heparin have to be used to achieve adequate anticoagulation during pregnancy [Brancazio et al., 1995]. The incidence of HIT is low in pregnancy, but the actual risk is unknown [Bates et al., 2012]. In case of HIT, fondaparinux, a new selective factor Xa inhibitor, is the anticoagulant of choice, although data on its use in pregnancy are limited [Mazzolai et al., 2006].

Low-Molecular-Weight Heparin (LMWH)

Therapy with LMWH in pregnancy is an attractive alternative to VKAs and UFH. LMWH has superior subcutaneous absorption and bioavailability [90% versus 10%; Weitz, 1997] and a two- to fourfold longer half-life. Because LMWH does not bind to plasma proteins, it may be associated with a more predictable dose response compared with UFH [Evans et al., 1997]. Similar to UFH and because of accelerated clearance, LMWH has shorter half-life and lower peak plasma concentration during pregnancy than in nonpregnant women and therefore requires higher doses and sometimes more frequent administration [Casele et al., 1999]. In nonpregnant patients, LMWH has been associated with fewer side effects than UFH [Bates et al., 2012]. Potential advantages of LMWH include less bleeding, a more predictable and stable response, and a lower risk of HIT [Sanson et al., 1999; Greer and Nelson-Piercy, 2005]. However, in a randomized trial of low-dose UFH versus LMWH for thromboprophylaxis in pregnancy, there was no difference in the incidence of clinically significant bone loss (2.0–2.5%) between women on UFH compared with those on enoxaparin [Casele et al., 2006]. Disadvantages of LMWH are its longer half-life and the inability to fully reverse its effect, issues that may increase the risk of bleeding at the time of delivery [James, 2009].

Anticoagulation Regimens in Pregnant Patients with Prosthetic MHVs

  1. Top of page
  2. ABSTRACT
  3. Changes in Homeostasis and Coagulability During Pregnancy
  4. Anticoagulation Therapies
  5. Anticoagulation Regimens in Pregnant Patients with Prosthetic MHVs
  6. Anticoagulation in Other Cardiac Disorders During Pregnancy
  7. VTE Associated with Pregnancy
  8. References

Prepregnancy counseling and education of the patient and her family regarding appropriate anticoagulation strategy plan are of paramount importance. Unfortunately, however, women often come to medical attention already pregnant posing serious therapeutic dilemmas for their physicians.

Current Guidelines for Anticoagulation in Pregnant Women with MHVs

The 2008 American College of Cardiology/American Heart Association (ACC/AHA) guidelines state that there are insufficient grounds to make definitive recommendations about optimal antithrombotic therapy in pregnant patients with MHVs, because properly designed studies have not been performed [Bonow et al., 2008]. Generally, both the ACC/AHA and the European Society of Cardiology (ESC) [Regitz-Zagrosek et al., 2011] guidelines recommend discussing the risks of available anticoagulation regimens with the pregnant patient. Antithrombotic preventive therapy options during pregnancy include continuation of VKAs throughout the second trimester of pregnancy as well as dose-adjusted sc or iv UFH between the 6th and the 12th week or throughout pregnancy with an activated partial thromboplastin time (aPTT) at least twice the control level. The ACC/AHA guidelines include the option of LMWH instead of UFH with peak anti-Xa factor levels between 0.7 and 1.2 U/ml 4 h after administration. The American College of Chest Physicians Conference (ACCP) on antithrombotic and thrombolytic therapy concluded that it is reasonable to use one of the following three regimens: (i) either LMWH or UFH between 6 and 12 weeks and close to term only, with warfarin used at other times; (ii) aggressive dose-adjusted UFH throughout pregnancy; or (iii) aggressive adjusted-dose LMWH throughout pregnancy aiming to attain a peak anti-Xa levels of 0.7–1.2 U/ml at 4–6 h after administration [Bates et al., 2012]. The authors recommend that the decision has to be completely individualized. Women of childbearing age and pregnant women MHVs should be counseled about potential maternal and fetal risks associated with various anticoagulant regimens. In women at very high risk of thromboembolism in whom concerns exist about the efficacy and safety of UFH or LMWH, the guidelines suggest VKAs throughout pregnancy with replacement by UFH or LMWH close to delivery rather than one of the regimens above (Grade 2C). However, those women who place a higher value on avoiding fetal risk than on avoiding maternal complications are likely to choose LMWH or UFH over VKAs. In addition to VKAs or heparins, low dose aspirin is recommended for high-risk group of pregnant women with MHVs.

UFH or LMWH throughout pregnancy is not recommended by the recent ESC guidelines, considering continuation of VKAs throughout pregnancy when the warfarin dose is <5 mg daily [Regitz-Zagrosek et al., 2011]. Discontinuation of VKAs and a switch to UFH or LMWH is recommended between weeks 6 and 12 under strict dose control and supervision. When a higher dose of VKAs is required, discontinuation of VKAs between weeks 6 and 12 and replacement by adjusted-dose UFH (aPTT ≥ 2 times the control, in high-risk patients applied as an intravenous fusion) or LMWH twice daily (dose adjusted according to weight) is recommended (the anti-Xa level should be maintained between 0.8 and 1.2 U/ml 4–6 h after application).

Published Data and Recommendations on Anticoagulation Regimens in Pregnant Patients with Prosthetic MHVs

In the absence of controlled clinical trials, current recommendations are based on limited, observational data. Unfortunately, only a few, mostly small, series [Iturbe-Alessio et al., 1986; Sbarouni and Oakley, 1994; Vitale et al., 1999; Al-Lawati et al., 2002; Geelani et al., 2005] comprise the basis from which current guidelines and recommendations are derived [Bonow et al., 2008; Regitz-Zagrosek et al., 2011]. Maternal mortality in patients with MHVs remains the most devastating complication and even contemporary series confirm that mortality and complications may not necessarily be avoided [Born et al., 1992; Sbarouni and Oakley, 1994; McGehee, 1998]. Chan et al. [2000] evaluated maternal and fetal outcomes according to the type of anticoagulation used during pregnancy: VKAs alone, VKAs with UFH during the first trimester, UFH throughout pregnancy, and antiplatelet agents alone. Rates of maternal thromboembolic complications in women who received UFH alone, VKAs with heparin substitution during the first trimester, and warfarin alone were 33.3%, 9.2%, and 3.9%, respectively. However, the rates of congenital fetal anomalies were 0%, 3.4%, and 6.4%, respectively. These results suggest that heparin alone is insufficient to prevent thromboembolism among pregnant women with MHV compared with VKAs regimens. Compared with regimens using warfarin alone, substitution with UFH during the first trimester was associated with a reduction in embryopathy from 6.4% to 3.4% but at the same time with an increase in maternal thromboembolic risk from 3.9% to 9.2%. Vitale et al. [1999] suggested that the risk of fetal damage was reduced although not eliminated, if the daily warfarin dose was below 5 mg. Several reports however described the development of warfarin embryopathy and fetal loss even with low dose warfarin [Meschengieser et al., 1999; Sadler et al., 2000; Finkelstein et al., 2005; Khan, 2007]. For this reason, one cannot guarantee any fetal complications even to women who are well anticoagulated on a <5 mg/day of warfarin during pregnancy. The risk of fetal malformation and other effects associated with use of VKAs throughout pregnancy suggests that these drugs should only be considered in women with a very high risk of thrombosis, such as highly thrombogenic MHVs or a history of thromboembolic complications on a therapeutic dose of heparin [Elkayam and Bitar, 2005; Bates et al., 2012]. Supporting the published review by Chan et al. [2000], Sillesen et al. [2011] more recently described 79 women who had 155 pregnancies after valve replacement. Two women died during pregnancy, one from heart failure and one from postpartum bleeding. There were four thromboembolic episodes in the early study period in women with a mitral prosthesis on UFH. Detailed information on the UFH regimen and monitoring results at the time of the episodes were not available. Owing to lack of information related to the level of anticoagulation and its monitoring, these reports might suggest resistance to moderate doses of UFH in high-risk women with old-generation MHVs. For this reason, UFH should be avoided if all possible. If no other choice is available in a woman who prefers not to use warfarin, a high dose UFH should be preferably administered as an intravenous continuous infusion and at high dose [Elkayam and Bitar, 2005; Bonow et al., 2008] and adjusted to achieve an aPTT ratio of >2.5 control value with very careful maintenance of the central line to prevent infection and a risk of endocarditis. If continuous iv infusion is not feasible, a high dose sc UFH (7500 to 20 000 U every 12 h) should be used aiming to achieve a mid level (6 h) of aPTT ratio of >2.5 control value.

Therapy with LMWH in pregnancy is an attractive and convenient alternative to VKAs and UFH. Substantial evidence shows the efficacy and safety of LMWH in prevention and treatment of thromboembolism during pregnancy in patients with evidence of deep vein thrombosis (DVT) and thrombophilia [James, 2009], and there has been an increasing experience with the use of this therapy in women with MHVs. Earlier published data on the use of LMWH in women with MHVs during pregnancy was described by Elkayam et al. [2004] and was limited to small groups of patients or to isolated reports with several of these cases complicated by valve thrombosis and even death. A careful review of the reported cases, however, indicated that most, if not all, of these cases were associated with an inadequate dose, lack of monitoring, or subtherapeutic anti-Xa levels [Arnaout et al., 1998; Berndt et al., 2000; Lev-Ran et al., 2000; Rowan et al., 2001; Consensus Reports, 2002; Aventis Pharmaceuticals, 2004; Oran et al., 2004; Bates et al., 2012]. A more recent review by Oran et al. [2004] comprised of 81 pregnancies with MHVs in whom LMWH was used reported 10 thromboembolic events in women with mechanical mitral valves, of which nine occurred in the 30 pregnancies with a fixed LMWH dose and only one in the 51 pregnancies with adjusted LMWH dose. Rowan et al. [2001] reported on their experience in 14 pregnancies in women with MHVs who were treated with LMWH [Rowan et al., 2001], valve thrombosis was described in one patient who had a St Jude mitral valve and had stopped warfarin 3 months before conception. She presented at 8 weeks' gestation, on no anticoagulation treatment, with transient ischemic attacks and suspected thrombus on transesophageal echocardiography (TEE). The patient was started on enoxaparin, with apparent resolution of the thrombus on TEE but re-presented at 20 weeks' gestation after further transient ischemic attack due to subtherapeutic level of anticoagulation (peak anti-Xa level was 0.62 U/ml). Abildgaard et al. [2009] reported on 12 pregnancies with MHVs treated with LMWH, in which thromboembolism occurred in two women with aortic MHVs. Both events were attributed to subtherapeutic doses of LMWH during the initial 3 weeks of pregnancy. Quinn et al. [2009] conducted a prospective audit of the use of adjusted dose LMWH in 12 pregnancies with MHV. LMWH +/− low-dose aspirin was started at therapeutic-dose with monitoring of anti-Xa levels to achieve a target level of 1.0–1.2 U/ml. This necessitated a mean increase in the dose of LMWH of 54.4% over initial dose. One nonfatal valve thrombosis occurred at 26 weeks gestation associated with subtherapeutic anti-Xa levels, and three patients experienced major bleeding. McLintock et al. [2009] reported thromboembolic complications in seven out of 47 pregnancies, of which five were thought to be associated with the use of enoxaparin therapy. Similar to reports by other investigators described above, poor compliance with therapy and subtherapeutic peak anti-Xa levels was an issue in all cases. No thromboembolic complications occurred in the 20 pregnancies when enoxaparin was commenced before 6 weeks' gestation, a group that was compliant with medication and monitoring of peak anti-Xa levels. Based on the published data, there is increasing experience with the use of LMWH for anticoagulation in pregnant women with MHVs, most, if not all, the cases reported to develop thromboembolic complications were related to poor compliance with therapy, inadequate monitoring and subtherapeutic levels of anticoagulation. The pharmacokinetics of LMWH are altered during pregnancy with lower plasma concentrations, probably related to higher clearance and volume of distribution [Casele et al., 1999]. A recent review by McLintock [2011] has summarized the maternal and fetal complications in 92 women from five prospective cohort studies treated with dose-adjusted LMWH throughout pregnancy. Nine episodes of valve thrombosis were reported and were attributed to poor compliance or suboptimal LMWH doses in the majority of the cases. However, Yinon et al. [2009] reported a case of valve thrombosis in a woman with a Medtronic Hall aortic valve replacement who presented with a transient ischemic attack at 24 weeks' gestation in spite of guideline recommended levels of peak anti-Xa levels and a history of compliance with therapy. Trough levels of anti-Xa however, were not measured. This woman had a new generation mechanical aortic prosthesis and achieved therapeutic peak anti-Xa levels (1.0–1.4 U/ml) and was treated with warfarin until 5 weeks of gestation and then was switched to LMWH and aspirin. At 24 weeks of gestation she presented with a transient ischemic event (peak anti-Xa level was 0.99 U/ml). Echocardiography demonstrated an elevated mean gradient across her aortic valve and on TEE no thrombus was seen, but the aortic valve leaflets were not optimally visualized. The LMWH dose was increased, but at 26 weeks of gestation, the patient was admitted with cardiac arrest and died. The autopsy demonstrated aortic valve thrombosis. This case demonstrates the potential limitations of reliance on guidelines recommended peak anti-Xa levels and the need to also assure a therapeutic trough level as well. This suggestion was initially made by Barbour et al. [2004], who evaluated 138 peak and 112 troughs anti-Xa levels in 13 pregnancies in 12 patients. With peak levels of 0.63, 0.70, and 0.69 U/ml, at the 1st, 2nd and 3rd trimesters, respectively, mean trough level were 0.21, 0.30, and 0.40 U/ml with only 9% of the measurements >0.5 U/ml. Even when peak levels were between 0.75 and 1.0 U/ml, only 15% of trough levels were >0.5 U/ml. [Barbour et al., 2004]. Similarly, in a recent series of 15 pregnant women at different gestational ages, a subtherapeutic anti-Xa level was demonstrated in 20% of the peak levels and 73% of the trough levels despite “therapeutic” enoxaparin administration [1 mg/kg bid; Friedrich and Hameed, 2010]. In an unpublished study on 26 pregnant women who received anticoagulation with LMWH for various indication including nine patients with MHV s/c q12 h, we analyzed both through and peak anti-Xa levels throughout pregnancy for a total of 177 determinations [Fan et al., 2011]. Adjusted dose LMWH achieving guidelines recommended peak anti-Xa between 0.7 U/ml and 1.2 U/ml were associated with subtherapeutic trough anti-Xa levels in about 50% of cases. On the other hand, therapeutic trough anti-Xa levels 0.6 U/ml–0.8 U/ml were rarely associated with excessive peak anti-Xa levels.

Supporting the use of both peak and trough for adequate anti-Xa level monitoring, Vijayan and Rachel [2012] recently published a longitudinal observational study of 13 pregnancies in a cohort of five women with MHVs (four mitral and one aortic, Sorin, St Jude and Caromedics) from 2006 to 2010 comparing outcomes of pregnancies on warfarin and LMWH managements [Vijayan and Rachel, 2012]. Eight pregnancies prior to 2007 were anticoagulated with warfarin that was given at 14 through 36 weeks gestation followed by heparin. Dose of warfarin had to be increased in pregnancy and apart of one woman who perpetually required high prepregnancy doses of 7 mg, all others required dose increments of 40–50% in pregnancy, and all case treated with warfarin ended with fetal loss. The five pregnancies since 2007 anticoagulated with the LMWH (enoxaparin) using peak and trough anti-Xa level monitoring resulted in livebirths after normal vaginal deliveries. Coagulation profiles were monitored on a weekly basis until therapeutic targets were achieved. A trough anti-Xa level of 0.7/ml and a peak level of 1.0–1.2/ml were targeted for enoxaparin and monitoring was continued 2–3 weekly once targets were achieved. All women were also prescribed low dose aspirin of 75 mg daily as an adjunct. In addition to this series, Schwartzenberg et al. [2013] described a case of a 33-year-old high-risk pregnant woman with MHV and four previous miscarriages and endocarditis on previous warfarin and heparin treatments who presented with mitral valve thrombosis during early pregnancy. Resolution of the thrombus and eventually resumption of normal prosthetic mitral valve function and normal delivery was obtained through LMWH treatment with close peak and trough anti-Xa level monitoring. The available data [Fan et al., 2011; McLintock, 2011; Goland and Elkayam, 2012; Vijayan and Rachel, 2012; Schwartzenberg et al., 2013] in addition to the documented risk of valve thrombosis with subtherapeutic predose anti-Xa levels suggest the importance of routine measurement and maintenance of trough levels at therapeutic range of anti-Xa ≥0.6 in low risk and ≥0.7 U/ml in high-risk patients (Table 1) [Elkayam and Goland, 2012]. Because of possible bleeding complications [Quinn et al., 2009], peak levels should also be monitored to prevent excessive anticoagulation (anti-Xa levels >1.5 U/ml), in which case, an 8-hourly rather than a12-hourly dosing should be used. To ensure patient compliance and adequate prophylaxis, anti-Xa activity should be measured once weekly for the first 4 weeks and at least once every 2 weeks for the duration of treatment. Catheter placement for epidural anesthesia is not advisable within 10–12 h of the last dose, because of longer half-life of LMWH [Elkayam et al., 2004]. For this reason, and to prevent spinal or epidural hematoma, LMWH should be withdrawn 18–24 h before an elective delivery and substituted with intravenous UFH. Because of the potential added benefit, a small dose of aspirin (75–100 mg/day), which is safe during pregnancy [Elkayam et al., 2004; Bonow et al., 2008], might be added in high-risk patients to further reduce the incidence of thromboembolism.

Table 1. Recommended Approach to Anticoagulation Therapy for Women with Mechanical Prosthetic Heart Valve
Higher riskLower risk
  1. Adapted from Elkayam U and Goland S, JACC 2012 [Elkayam and Goland, 2012].

  2. a

    IV preferred.

  3. aPTT, activated partial thromboplastin time; ASA, acetylsalicylic acid; INR, international normalized ratio; IV, intravenous; LMWH, low-molecular-weight heparin; MPHV, mechanical prosthetic heart valve; Q, every; SQ, subcutaneous; TE, thromboembolism; UFH, unfractionated heparin.

Old-generation MPHV in mitral position, MPHV in tricuspid position, atrial fibrillation, history of TE on heparinNew-generation MPHV in mitral position and MPHV in aortic position
Warfarin (INR 2.5–3.5) for 35–36 weeks followed by IV UFH (aPTT > 2.5) to parturition + ASA 81–100 mg/dayLMWH SQ Q12 h (trough anti-Xa ≥0.6 IU/ml, peak anti-Xa <1.5 IU/ml) to 35–36 weeks, then UFH IV (aPTT >2.0) to parturition
OROR
LMWH SQ Q12 h (trough anti-Xa ≥0.7 IU/ml, peak anti-Xa <1.5 IU/ml) or UFH SQ Q12 h or IVa(mid interval aPTT >2.5) for 12 weeks, followed by warfarin (INR: 2.5–3.5) to 35–36 weeks, then UFH IV (aPTT >2.5) to parturition + ASA 81–100 mg/day.LMWH SQ Q12 h (trough anti-Xa ≥0.6 IU/ml, peak anti-Xa <1.5 IU/ml) or UFH SQ Q12 h or IVa(midinterval aPTT >2.0) for 12 weeks followed by warfarin (INR: 2.5–3.0) until 35–36 weeks, then UFH IV (aPTT >2.0) to parturition

Anticoagulation in Other Cardiac Disorders During Pregnancy

  1. Top of page
  2. ABSTRACT
  3. Changes in Homeostasis and Coagulability During Pregnancy
  4. Anticoagulation Therapies
  5. Anticoagulation Regimens in Pregnant Patients with Prosthetic MHVs
  6. Anticoagulation in Other Cardiac Disorders During Pregnancy
  7. VTE Associated with Pregnancy
  8. References

Mitral stenosis (MS), atrial fibrillation (AF), and dilated cardiomyopathy are the most common cardiac conditions where anticoagulation may be important to prevent thromboembolic events during pregnancy.

MS is the most common valvular heart disease in pregnancy and carries a significant risk of thromboembolism [Reimold and Rutherford, 2003; Bonow et al., 2008; Fan et al., 2011; Elkayam and Goland, 2012; Goland and Elkayam, 2012; Vijayan and Rachel, 2012; Schwartzenberg et al., 2013]. Currently oral anticoagulation is indicated in MS patients who have the highest risk for thromboembolic events: patients with AF or a prior history of an embolic event [Bonow et al., 2008]. The ACC/AHA guidelines recommend considering anticoagulation also for asymptomatic patients with severe MS and enlarged left atrial size (dimension ≥55 mm by echocardiography) even in the absence of AF. These recommendations are supported by a published case series that reported left atrial thrombus formation and following clinical events in three pregnant patients with MS in the absence of AF [Hameed et al., 2001].

Peripartum cardiomyopathy (PPCM) is a cardiomyopathy of unknown cause presenting with heart failure secondary to left ventricle (LV) systolic dysfunction toward the end of pregnancy or in the months following delivery [Hameed et al., 2005]. This condition is associated with important and lasting complications, including thromboembolic events. LV thrombus has been found on initial echocardiography in 10–17% of patients [Amos et al., 2006; Sliwa et al., 2010] and several reports have described severe thromboembolic events as a result of embolization to the coronary, pulmonary, peripheral, and cerebral arteries [Napporn et al., 2000; Box et al., 2004; Quinn et al., 2004; Jha et al., 2005; Amos et al., 2006; Ibebuogu et al., 2007; Agunanne, 2008; Shimamoto et al., 2008; Goland et al., 2009; Sliwa et al., 2010]. Goland et al. [2009] described four patients with severe embolic complications, all with left ventricular thrombus, three presented as cerebrovascular accident with residual brain damage (plus pulmonary embolism [PE] in one), and two patients with leg ischemia requiring amputation in one. The increased incidence of thromboembolism in women with PPCM is related to the hypercoagulable state of pregnancy [Heit et al., 2005; James et al., 2006a,b], cardiac dilatation and dysfunction, endothelial injury, venous stasis, and prolonged bed rest. Embolic events usually occur during the period of LV dysfunction until LV function recovers and anticoagulation is therefore strongly advisable [Elkayam, 2011]. Anticoagulation seems particularly important during pregnancy and the first 6–8 weeks postpartum because of the persistent hypercoagulable state [James, 2009]. The risk of thromboembolism in nonpregnant patients with idiopathic dilated cardiomyopathy (IDC) may be particularly high in cases with concomitant AF, a history of VTE, and LV thrombus that require chronic anticoagulation. Because of the increased risk of thromboembolic events during pregnancy [Chan and Ngan Kee, 1999], all patients with IDC and left ventricular ejection fraction (LVEF) ≤40% should be anticoagulated even in the absence of above-mentioned other risk factors for thromboembolic events [Siu et al., 1997, 2001; Chan and Ngan Kee, 1999; Grewal et al., 2009; Stergiopoulos et al., 2011].

Increased frequency of arrhythmia has been reported during pregnancy in healthy women or in women with structural heart disease, especially when cardiac output raises 30–50% [Shotan et al., 1997; Gowda et al., 2003; Yarnoz and Curtis, 2008]. The incidence of AF during pregnancy, however, is low and is usually secondary to congenital or rheumatic valvular disease, hypertrophic cardiomyopathy, thyroid disease, or a preexcitation syndrome [Forfar et al., 1979; Whittemore et al., 1982; Bryg et al., 1989]. Patients with chronic AF, who are considered to be at increased risk for embolic stroke, should be anticoagulated during pregnancy. However, it can represent a benign episode of lone AF in a pregnant woman with a normal heart [DiCarlo-Meacham and Dahlke, 2011]. In a pregnant woman who develops lone AF, the role of anticoagulation to prevent systemic arterial embolism has not been systematically studied; anticoagulation therapy is probably not required in pregnant women with a short episode of lone AF. If spontaneous conversion to normal sinus rhythm does not occur, cardioversion should be considered within 48 h of the onset of AF to avoid the need for anticoagulation. In cases of persistent lone AF because of the hypercoagulable state during pregnancy, it may be reasonable to consider anticoagulation.

As mentioned earlier, because of warfarin-related risk to the fetus, either UFH or LMWH is favored in pregnancy because (unlike warfarin) they do not cross the placenta [Quinn et al., 2004]. Neither warfarin nor heparin is secreted into breast milk, and both drugs are therefore compatible with breastfeeding [Briggs et al., 2008]. LMWHs are the preferred drugs for this population and dose has to be adjusted to achieve therapeutic trough anti-Xa levels (≥0.6 U/ml).

VTE Associated with Pregnancy

  1. Top of page
  2. ABSTRACT
  3. Changes in Homeostasis and Coagulability During Pregnancy
  4. Anticoagulation Therapies
  5. Anticoagulation Regimens in Pregnant Patients with Prosthetic MHVs
  6. Anticoagulation in Other Cardiac Disorders During Pregnancy
  7. VTE Associated with Pregnancy
  8. References

Pregnant women are at an increased risk of both venous and arterial thromboembolism. During pregnancy the risk of VTE is increased four- to fivefold, and the risk of arterial thromboembolism (stroke and myocardial infarction) is increased three- to fourfold compared with nonpregnant women and even higher in postpartum (20-fold) [Heit et al., 2005; James et al., 2005a,b, 2006a,b; James, 2012]. Most events during pregnancy are venous (80%), and the overall prevalence of thromboembolic events during pregnancy is approximately 2 per 1000 deliveries; 75–80% of VTE in pregnancy is DVT and 20–25% is PE [Blanco-Molina et al., 2010; James, 2012].

VTE in pregnancy is the major cause for morbidity and mortality and accounts for 20–30% of all maternal deaths [James et al., 2005a, 2006b]. In addition to hypercoagulability, physiologic changes through pregnancy play an important role in occurrence of VTE including increased venous capacitance, mechanical obstruction by the enlarged uterus, bed rest, and vascular injury [James et al., 2005a, 2006b]. The history of thrombosis and thrombophilia are important individual risk factors with approximately 25% of VTEs being recurrent events. Among pregnant women who did not receive anticoagulation, the rate of recurrent VTE may reach 12.2%. In contrast, in those who received anticoagulation therapy, the rates are much lower (0–2.4%). The overall VTE risk associated with specific acquired or inherited thrombophilia is well described by Robertson et al. [2006] and by the ACCP guidelines [Bates et al., 2012, Table 2]. Overall, thrombophilia is present in 20–50% of women through ante- and postpartum period. Women homozygous for factor V Leiden and for the prothrombin G20210A mutation have the highest relative risk for VTE occurrence (odds ratio 34.4 and 26.36, respectively).

Table 2. Risk of VTE Conferred by Type of Thrombophilia
ThrombophiliaOR (CI)
  1. Adapted from Robertson L et al. Br J Haematol 2006 [Robertson et al., 2006] and ACCP guidelines 2012 [Bates et al., 2012].

  2. VTE, venous thromboembolism; OR, odds ratio; CI, confidence interval.

Factor V Leiden, homozygosity34.40 (9.86, 120.05)
Factor V Leiden, heterozygosity8.32 (5.44, 12.70))
Prothrombin G20210A mutation (homozygosity)26.36 (1.24, 559.29)
Prothrombin G20210A mutation (heterozygosity)6.80 (2.46, 18.77)
Protein C deficiency4.76 (2.15, 10.57)
Protein S deficiency2.19 (1.48, 6.00)
Antithrombin deficiency4.76 (2.15, 10.57)
MTHFR C677T homozygosity0.74 (0.22, 2.48)
Lupus anticoagulants (persistent)2–10 (wide CIs)

Anticoagulation for VTE Prevention

Despite higher risk of VTE in pregnancy and postpartum, most women do not need anticoagulation [James, 2007]. Anticoagulation for thrombosis prevention is indicated for those whose risk of VTE (∼2%) outweighs the risk of bleeding from UFH/LMWH [Ginsberg et al., 1989; Sanson et al., 1999; Lepercq et al., 2001; Greer and Nelson-Piercy, 2005; Barco et al., 2013]. Therefore, pregnant women with current thrombosis, a history of VTE, or those with any risk factor for postpartum VTE may benefit from anticoagulation. In addition, some women without a history of VTE but with thrombophilia may also benefit. The optimal period for counseling and evaluating the need for anticoagulation is before conception or very early in pregnancy mainly in women with very high risk [Bates et al., 2012; James, 2012].

The recommendations for anticoagulants use in pregnancy are based on case series and expert opinion. The most recent recommendations have been published by the ACCP [Bates et al., 2012]. Protocols for thrombophylaxis in pregnant women were presented by James [2012] [see also: James et al., 2005a; Casele et al., 2006; James, 2011].

Anticoagulation is not necessary in cases of inherited thrombophilia if there is no history of VTE or poor pregnancy outcome except in homozygosity for factor V Leiden mutation, prothrombin gene G20210A mutation, or heterozygosity for both mutations (regardless of family history). Women with other inherited thrombophilias but with a family history of VTE should also have thrombophylaxis. For women with thrombophilia other than homozygous factor V Leiden or prothrombin gene mutations with no family history of VTE, the ACCP guidelines recommend only clinical surveillance in antepartum and postpartum [Bates et al., 2012]. In antiphospholipid syndrome, several studies have demonstrated that anticoagulation improves the outcome in pregnancy. For women with acceptable criteria for antiphospholipid syndrome, prophylactic intermediate dose UFH or LMWH combined with low dose aspirin (75–100 mg/d) is recommended. Full-dose (adjusted dose) anticoagulation is recommended for women with either a need for life-long anticoagulation or with antiphospholipid syndrome with a history of thrombosis. For women with a history of unprovoked thrombosis not on life-long anticoagulation, either low-dose anticoagulation or close observation with postpartum prophylaxis is recommended. Treatment begins at conception and continues for 6–12 weeks postpartum regardless of history of thrombosis [James et al., 2006b; Lockshin, 2013]. Elastic stockings are safe and should be used during thrombophylaxis in women with a high-risk profile and multiple risk factors for VTE [Bates et al., 2012].

Anticoagulation for VTE Treatment

The strategy of acute DVT treatment in pregnancy is usually the same as in nonpregnant patients, besides hospital admission due to a tendency for larger clots [James, 2007, 2012]. As was mentioned above, LMWH is the preferred treatment due to its bioavailability, longer plasma half-life, dose-related response, and improved maternal and fetal safety [Greer and Nelson-Piercy, 2005]. In pregnancy and breastfeeding, oral direct thrombin (dabigatran) and anti-Xa (rivaroxaban or apixaban) inhibitors should be avoided [Bates et al., 2012; Barco et al., 2013]. These medications have been not used in pregnant women excluded from all clinical trials evaluating those new drugs. In animals, dabigatran and rivaroxaban caused reproductive toxicity and was secreted into breastmilk. In humans, the risks are still unknown [Bayer Schering Pharma AG, 2009; Boehringer Ingelheim Canada Ltd, 2012]. Even when the pregnancy is not continued the use of these anticoagulants should be avoided due to the lack of reversing agent [James, 2012]. Pregnant patients should be fully anticoagulated with LMWH regimen for at least 6 months from the initial presentation with VTE. It is still unknown whether LMWH (or UFH) dose can be reduced after the initial period of full LMWH regimen. Some recommend that full dose of anticoagulation should be continued all over pregnancy and postpartum period, but others suggest to reduce the degree of anticoagulation using intermediate dose regimen of LMWH 40 mg subcutaneously every 12 h or 75% of a full treatment dose [Monreal et al., 1994; Bates et al., 2012]. The latter strategy is reasonable, especially in preparation for epidural anesthesia in order to decrease the risk of anticoagulant associated bleeding. There is no general agreement regarding the optimal duration of the anticoagulant treatment. It is recommended that following delivery, the UFH or LMWH should be restarted and bridged to warfarin and remained for at least 3–6 month after delivery [Bates et al., 2012].

The treatment of nonmassive PE is based mostly on LMWH [Conti et al., 2013]. As an initial treatment of PE in pregnant women, IV UFH is usually used. This allows turning off the heparin promptly in situations of urgent surgery, delivery, or initiation of thrombolysis. UFH can be switched to LMWH if a patient becomes stable [Greer, 2012]. In massive PE, the treatment with LMWH or IV UFH is not efficient enough. Thrombolytic therapy has been used in pregnancy with a risk of bleeding that is similar to the risk observed outside of pregnancy [Conti et al., 2013]. The incidence of bleeding with thrombolysis in pregnancy is about 8%, mainly in the genital tract. Streptokinase or tPAs have minimal transplacental passage. There may be a risk of obstetric and neonatal complications, e.g., pregnancy loss, abruption, and preterm labor. However, it is difficult to ascertain whether these complications are a result of the underlying disease, the therapy, or neither. With such limited data regarding the safety of thrombolysis in pregnancy, the use of thrombolysis in pregnancy should be reserved for women with PE who are hemodynamically unstable with refractory hypoxemia, or right ventricular dysfunction on echocardiogram [Fasullo et al., 2011]. Although the experience of thrombolytic therapy in pregnancy is small (18 cases were reported using different kinds of thrombolytic drugs), the use of thrombolysis in unstable pregnant women with massive PE may be life-saving [Huang et al., 2000; Ahearn et al., 2002; Trukhacheva et al., 2005; Leonhardt et al., 2006; te Raa et al., 2009; Holden et al., 2011]. The treatment approach to massive PE should be individualized and be changed according to the circumstances. During delivery, thrombolytic agents are contraindicated unless there is life-threatening danger and in cases which surgical embolectomy is not feasible [Jacobson et al., 2003; Bourjeily et al., 2010; Miller et al., 2011; Conti et al., 2013]. After delivery, the timing and the reinitiation of the anticoagulation should be individualized according to bleeding and recurrent VTE patient risk. In recent PE (2–4 weeks old), the IV heparin should be reinitiated soon after delivery with overlap with warfarin as hemostasis is achieved. In remote PE (more than 3 months old), it is safe to restart anticoagulation more than 12 h after delivery [Bourjeily et al., 2010].

There is no general agreement whether the dose of LMWH must be adjusted when using full dose for treatment or prevention of VTE. Some of the experts do recommend 4 h peak anti-Xa level monitoring at weekly and then monthly visits to maintain ranges of 0.6–1.0 U/ml [Rodie et al., 2002; Barbour et al., 2004]. Others feel that routine monitoring with anti-Xa levels is difficult to justify based on the lack of correlation of the dose adjustment with risk of bleeding and recurrence [Horlocker et al., 2003].

Women on either low or full LMWH management need to be converted to UFH in the last month of pregnancy to lower the bleeding risk at the time of delivery, but more importantly to prevent epidural or spinal hematoma with anesthesia. Catheter placement for epidural anesthesia is not advisable within 10–12 h of the last dose, because of longer half-life of LMWH. For this reason, and to prevent spinal or epidural hematoma, LMWH should be withdrawn 18–24 h before an elective delivery and substituted with intravenous UFH [Horlocker et al., 2003; Elkayam et al., 2004]. Women with DVT in the last month of pregnancy are at high risk at the time of delivery and a vena cava filter placement may be considered with removal postpartum [Greer, 2012].

References

  1. Top of page
  2. ABSTRACT
  3. Changes in Homeostasis and Coagulability During Pregnancy
  4. Anticoagulation Therapies
  5. Anticoagulation Regimens in Pregnant Patients with Prosthetic MHVs
  6. Anticoagulation in Other Cardiac Disorders During Pregnancy
  7. VTE Associated with Pregnancy
  8. References
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