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INTRODUCTION — Pregnancy presents a unique set of problems for women with prosthetic heart valves. Prosthetic heart valves may be mechanical or bioprosthetic (the latter including heterografts and homografts).
Mechanical heart valves are associated with an increased incidence of thromboembolic events during pregnancy. Therapeutic anticoagulation throughout pregnancy is essential to reduce the risk of thromboembolic complications , but given the absence of adequate prospective controlled trials, the optimum anticoagulant regimen is uncertain [2-4]. Maternal and fetal complications associated with the different anticoagulant regimens in women with mechanical and prosthetic valves and management guidelines are reviewed here [1,5]. (See 'Anticoagulation during pregnancy for mechanical heart valves' below.)
Bioprosthetic valves typically do not require anticoagulation (unless there are other thromboembolic risk factors), but bioprostheses have a significantly higher incidence of valve failure than mechanical valves. This may be of particular concern for young women, who must consider the potential for future valve surgery if they have a bioprosthesis. (See "Overview of the management of patients with prosthetic heart valves".)
Management of pregnant women with prosthetic heart valves, including anticoagulant therapy, is discussed here. Antimicrobial prophylaxis in patients with prosthetic heart valves and issues regarding pregnancy and native valve disease (including valve surgery prior to pregnancy) are discussed separately. (See "Pregnancy and valve disease" and "Antimicrobial prophylaxis for bacterial endocarditis".)
RISKS ASSOCIATED WITH PROSTHETIC VALVES
Overview — Patients with prosthetic heart valves are at risk for complications including thromboembolism, valve thrombosis, and bleeding due to anticoagulation (with mechanical valves); structural valve failure (with bioprosthetic valves); and endocarditis. In addition, patients with ventricular or valve dysfunction are at risk for heart failure or arrhythmias. The risks of thromboembolism, valve thrombosis and anticoagulation are major issues in pregnant women with prosthetic (particularly mechanical) valves. (See "Complications of prosthetic heart valves".)
Valve thrombosis and thromboembolism — Valve thrombosis and thromboembolism are potentially life-threatening complications. The hypercoagulable state of pregnancy increases the risk of valve thrombus formation among women with mechanical valves. The risk of valve thrombosis and thromboembolic events depends upon the type and location of the prosthetic valve, as well as a number of other clinical features . Mechanical prosthetic heart valves have a higher thromboembolic risk than bioprosthetic valves or homografts . Women of childbearing age are likely to have newer generation mechanical valves, with a lower thromboembolic risk than older mechanical valves. Other factors that increase the risk of valve thrombosis and thromboembolism include:
●History of a prior thromboembolic event
●Prosthesis in the mitral position
●Multiple prosthetic valves
All women with mechanical heart valves (regardless of valve type or site) should be treated with therapeutic anticoagulation throughout pregnancy . The risk of thromboembolism in pregnant women with mechanical valves is increased with unfractionated heparin and, to a lesser degree, with low molecular weight heparin compared with warfarin [8,9]. (See 'Anticoagulation during pregnancy for mechanical heart valves' below and "Complications of prosthetic heart valves", section on 'Valve thrombosis and thromboembolism'.)
Bioprosthetic valves, independent of position, do not usually require chronic anticoagulation unless other thromboembolic risk factors are present. Aspirin therapy is recommended for the patient with a bioprosthetic valve , and this therapy is continued during pregnancy. (See 'Anticoagulation during pregnancy for mechanical heart valves' below and "Antithrombotic therapy for prosthetic heart valves: Indications".)
Complications of anticoagulation — When therapeutic anticoagulation is required during pregnancy and postpartum, there is the risk of pregnancy-specific bleeding related to the placenta or to delivery. Antepartum hemorrhage (unexplained or due to placenta previa or abruption) appears to be increased in women with mechanical valves on therapeutic anticoagulation [10,11]. Post-delivery, bleeding related to cesarean delivery, as well as vaginal and perineal trauma, may be increased. As such, detailed planning of anticoagulation management before, during, and after delivery is critical. (See "Use of anticoagulants during pregnancy and postpartum" and 'Delivery' below.)
While warfarin is the most effective therapy to prevent valve thrombosis and thromboembolism, warfarin use is associated with an increased risk of fetal anomalies and a high risk of late fetal loss, as discussed below. (See 'Warfarin' below.)
Heart failure — The increased physiologic demands of pregnancy (increased blood volume and cardiac output) may result in the development or exacerbation of heart failure in patients with ventricular dysfunction or dysfunction of native or prosthetic valves. (See "Maternal cardiovascular and hemodynamic adaptations to pregnancy".)
Endocarditis — Antimicrobial prophylaxis in patients with prosthetic heart valves is discussed separately. (See "Pregnancy and valve disease", section on 'Endocarditis prophylaxis' and "Antimicrobial prophylaxis for bacterial endocarditis".)
PRECONCEPTION EVALUATION AND COUNSELING
Overview — Women of childbearing age who have prosthetic heart valves should receive preconception (or initial if the patient presents during pregnancy) assessment including clinical evaluation, 12 lead electrocardiogram, transthoracic echocardiogram, and counseling by a cardiologist with expertise in managing patients with valvular heart disease during pregnancy . The baseline transthoracic echocardiogram enables assessment of valve function and hemodynamics, identification of valve dysfunction that may require treatment prior to pregnancy, and comparison if valve thrombosis is suspected during pregnancy. In some cases, the consequences of longstanding valve disease or comorbid conditions (eg, left ventricular dysfunction or pulmonary hypertension) result in prohibitive risks and pregnancy should be avoided. However, many women with prosthetic heart valves can safely complete a pregnancy with careful management. (See "Pregnancy and valve disease", section on 'Preconception or initial evaluation'.)
For women with native valve disease with an indication for valve intervention prior to conception, counseling should include a detailed discussion of the risks and benefits of various options including percutaneous intervention, surgical valve repair, and valve replacement with a mechanical prosthesis or bioprosthesis. For patients requiring a valve replacement, discussion should include the trade-off between risk of thrombus and thromboembolism with mechanical valves (with associated need for therapeutic anticoagulation and related risks, particularly during pregnancy) compared with the longer term risk of limited durability of valve repair or bioprosthetic valves . (See "Pregnancy and valve disease", section on 'Interventions prior to pregnancy'.)
Anticoagulation for mechanical valves — For women with mechanical valves, counseling should include an informed discussion about the requirement for continuation of therapeutic anticoagulation throughout pregnancy and the maternal and fetal risks associated with available anticoagulation options. The patient should also be informed that the risk of life-threatening thromboembolic events such as stroke exists regardless of the anticoagulant regimen utilized. Discussion of these risks should be included in counseling patients about future plans, including whether to forgo pregnancy. (See 'Risks associated with prosthetic valves' above and "Contraceptive counseling and selection".)
Women with regular menstrual periods receiving anticoagulation and attempting to conceive should be advised to continue vitamin K antagonist (eg, warfarin) until they are pregnant because the risk of warfarin embryopathy (defects in cartilage and bone) is low in the first six weeks of gestation. They should closely monitor their menses and, if delayed, promptly undergo a pregnancy test. Women with irregular menstrual periods receiving anticoagulation and attempting to conceive should undergo periodic pregnancy testing. If the plan is to use therapeutic low molecular weight heparin (LMWH) for at least the first trimester, a plan should be made as to how this will be arranged once pregnancy is confirmed. (See "Use of anticoagulants during pregnancy and postpartum", section on 'Women on warfarin'.)
RISK ASSESSMENT AND FOLLOW-UP
The frequency of follow-up during pregnancy in women with cardiovascular disease is adjusted according to risk. We agree with the following recommendations based upon the modified World Health Organization (WHO) classification as described in the 2011 European Society of Cardiology guidelines for management of cardiovascular disease during pregnancy  (See "Pregnancy and valve disease", section on 'Modified WHO classification'.):
●Patients with mechanical valves are included in modified WHO class III, which indicates significantly increased risk of maternal mortality or severe morbidity. These patients require expert counseling and intensive cardiac and obstetric monitoring throughout pregnancy. Monthly or bimonthly cardiology and obstetric review is recommended during pregnancy.
●Patients with bioprosthetic valves are included in modified WHO class II, which indicates small increased risk of maternal mortality or moderate increase in morbidity. Cardiology follow-up at least every trimester is recommended, though more frequent visits may be required on an individual basis.
Of note, patients with prosthetic heart valves with high-risk conditions such as severe pulmonary arterial hypertension of any cause or severe systemic ventricular dysfunction (left ventricular ejection fraction <30 percent, New York Heart Association functional class III or IV) are included in modified WHO class IV (instead of the above classes), which indicates extremely high risk of maternal mortality or severe morbidity with pregnancy contraindicated. If pregnancy occurs, termination should be discussed as it may be life-saving for the mother. If pregnancy continues, the frequency of follow-up is as for class III.
In addition to the above scheduled follow-up, a follow-up echocardiogram is indicated to evaluate the hemodynamics of the prosthetic valve and ventricular function in a pregnant patient with a prosthetic valve who develops symptoms (eg, dyspnea) or change in physical examination . Elevated transvalvular gradients are expected during pregnancy due to increased cardiac stroke volume. A transthoracic echocardiogram is generally the initial test to evaluate aortic and mitral prosthetic valves, though a transesophageal echocardiogram (TEE) may be needed if prosthetic mitral regurgitation is suspected . A TEE is also recommended in pregnant patients with a mechanical valve with prosthetic valve obstruction or an embolic event . (See "Complications of prosthetic heart valves" and "Echocardiographic evaluation of prosthetic heart valves" and "Pregnancy and valve disease" and "Maternal cardiovascular and hemodynamic adaptations to pregnancy".)
ANTICOAGULATION DURING PREGNANCY FOR MECHANICAL HEART VALVES
Our approach — Therapeutic anticoagulation with frequent monitoring is essential in all pregnant women with mechanical prosthetic heart valves to prevent valve thrombosis and thromboembolic events [1,4,12]. The absence of any adequate randomized trials and the paucity of prospective cohort data make it difficult to offer definitive recommendations on the anticoagulant regimen during pregnancy . (See "Use of anticoagulants during pregnancy and postpartum".)
Patients should be informed fully about the importance of therapeutic anticoagulation throughout pregnancy and the maternal and fetal risks associated with each anticoagulant regimen. The patient should participate in and agree with the decision about the treatment regimen.
The following are key issues that should inform choice of an anticoagulant regimen in pregnant women with mechanical valves:
●The woman's individual risk of developing thromboembolic complications should be considered based upon the type and site of mechanical valve and other factors such as previous thromboembolic complications. (See 'Valve thrombosis and thromboembolism' above.)
●Warfarin is the safest anticoagulant option for the mother since it is the most effective therapy to prevent valve thrombosis and thromboembolism, with a rate of pregnancy-related valve thromboembolic complications in the order of 2 to 4 percent with currently used valves . However, warfarin use is associated with an increased risk of fetal anomalies (estimated at 5 to 10 percent [8,13-15]) and a high risk of late fetal loss (approximately 10 percent [8,10,16]). The risk of fetal anomalies and fetal loss is probably lower with a warfarin dose ≤5 mg than with higher doses [14,17], though the clinical relevance of this finding for the individual patient is limited since some risk remains with a warfarin dose ≤5 mg and dosing for each patient is adjusted to achieve a therapeutic international normalized ratio (INR) . (See 'Warfarin' below and "Antithrombotic therapy for prosthetic heart valves: Indications" and "Warfarin and other VKAs: Dosing and adverse effects".)
●Unfractionated heparin (UFH) does not cross the placenta and does not have direct harmful effects on the fetus. The risk of thromboembolic complications is high in pregnant women with mechanical valves when subcutaneous (SC) UFH is used throughout pregnancy (eg, 25 percent) or during the first trimester (eg, 9.2 percent) . Poor compliance and sub-therapeutic regimens contribute to this high rate of valve thrombosis, but thromboembolic complications can occur with therapeutic SC heparin . Maternal thromboembolic complications requiring valve replacement or resulting in maternal death may contribute to fetal losses associated with UFH reported in some studies . The 2014 American Heart Association/American College of Cardiology (AHA/ACC) guideline for the management of patients with valvular heart disease does not recommend using subcutaneous UFH during pregnancy . Intravenous (IV) UFH (with targeted activated partial thromboplastin time [aPTT] 2 to 2.5 times control) may provide better protection against thromboembolism than SC UFH, but its efficacy and safety over weeks is uncertain. Long-term UFH may also reduce bone mineral density. (See 'Unfractionated heparin' below.)
●Low molecular weight heparin (LMWH) does not cross the placenta and does not have known harmful effects on the fetus. LMWH has several advantages over UFH, including more predictable attainment of therapeutic levels of anticoagulation, less effect on bone, and less bleeding and thrombocytopenia. The risk of thromboembolic complications with LMWH has been reported as 12 percent , though it may be lower with careful anti-Xa monitoring to target level of 1.0 to 1.2 U/mL and adequate trough levels. Use of LMWH at sub-therapeutic dose regimens or poor compliance accounts for some, but not all, reported cases of valve thromboses or thromboembolism [8,9,20,21]. (See 'Low molecular weight heparin' below.)
The following is a summary of our approach to anticoagulant therapy in pregnant women with mechanical valves:
●During the first trimester:
•For patients with baseline warfarin dose ≤5 mg/d, we suggest continuing warfarin with close INR monitoring throughout the first trimester.
-Dose-adjusted SC LMWH from 6 to 12 weeks is an alternative for patients who wish to avoid the risk of low-dose warfarin during the first trimester.
-If LMWH is unavailable due to resource limitations, dose-adjusted continuous IV infusion of UFH (with targeted aPTT 2 to 2.5 times control) is an option, though the efficacy and safety of this treatment over weeks is uncertain.
•For patients whose baseline warfarin dose is greater than 5 mg/day, we suggest switching to dose-adjusted SC LMWH throughout the first trimester. Once pregnancy is confirmed, LMWH should be dosed at least twice per day (target anti-Xa level 1.0 U/mL to 1.2 U/mL at four to six hours post-dose, and we recommend checking trough levels as well). A plan should be made prior to conception as to how this change in therapy will be arranged.
If LMWH is unavailable due to resource limitations, dose-adjusted continuous IV infusion of UFH (with an aPTT 2 to 2.5 times control) is a potential option, although the efficacy and safety of this treatment over weeks is uncertain.
●During the second and third trimester:
•We recommend warfarin (adjusted to INR goal) plus aspirin 75 to 100 mg daily until 36 weeks as the safest option for the mother. Timing of the transition of warfarin to LMWH may need to be individualized for women at high risk for preterm delivery (eg, women with Fontan operations).
•If the mother chooses to avoid the fetal risk associated with warfarin therapy, we suggest therapeutic SC LMWH twice per day with the dose adjusted to achieve target anti-Xa levels of 1.0 U/mL to 1.2 U/mL at four to six hours post-dose and ensuring adequate trough levels as well.
•If LMWH is unavailable in low resource settings, warfarin should be strongly advised as the preferred anticoagulant and dose-adjusted SC UFH (with regular monitoring to ensure the six-hour post-dose aPTT is at least twice baseline) only offered if the mother declines to take warfarin.
●From 36 weeks to delivery: Management of antithrombotic therapy from 36 weeks to delivery is discussed below. (See 'Change in antithrombotic therapy' below.)
When warfarin is used during pregnancy, meticulous control is required including close monitoring of the INR (eg, twice weekly), patient education regarding dietary intake of vitamin K, and a dedicated prescriber adjusting the dose as needed.
Considerations — Additional efficacy and safety data reported on anticoagulants in pregnant women with mechanical heart valves are provided below.
Warfarin — While warfarin appears to offer the best protection against thromboembolic complications in women with mechanical heart valves including maternal death, it freely crosses the placenta and is associated with both a characteristic embryopathy and an increase in late fetal deaths and fetal hemorrhagic sequelae [1,8,10]. The safety and efficacy of various anticoagulant regimens in pregnant women with mechanical prosthetic heart valves was illustrated in a systematic review of 28 studies that included 976 women with 1234 pregnancies from 1966 to 1997 . In pregnant women with mechanical heart valves, warfarin was associated with the lowest rates of maternal thromboembolic complications, including valve thrombosis (3.9 percent for warfarin alone, 9.2 percent for UFH in the first trimester followed by warfarin, and 25 percent when therapeutic dose UFH was used throughout pregnancy) [8,19]. The applicability of these findings to contemporary practice is uncertain. None of the studies were randomized, approximately 50 percent of the women had older cage and ball valves that are more thrombogenic, and only 7 percent had newer bileaflet valves. Overall, the data indicate that warfarin use is associated with a low risk of maternal thromboembolic complications, in the order of 2 to 4 percent.
In contrast to the potential maternal benefit, there is a substantial increase in congenital fetal anomalies with warfarin therapy, primarily when used in the first trimester of pregnancy. Warfarin exposure early in pregnancy can cause a specific embryopathy affecting cartilage and bone (chondromalacia punctata, with stippled epiphyses and nasal and limb hypoplasia). The estimated incidence is 5 to 10 percent, although reported ranges vary [8,13-15]. It is thought that the greatest risk of warfarin embryopathy is after six weeks. In one review, the risk of major anomalies was 4.8 percent when vitamin K antagonist (VKA) therapy was discontinued by eight weeks gestation as compared with 1.4 percent in the general population . The major anomaly rate appeared to be higher among those receiving warfarin as compared with those taking other anticoagulants such as acenocoumarol.
Fetal warfarin exposure after the first trimester appears to increase the risk of central nervous system defects, presumably from microhemorrhages in neuronal tissues; five case reports have described massive fetal intracranial hemorrhage associated with maternal warfarin use [23,24]. The fetal INR runs at a higher level than the maternal INR due to fetal hepatic immaturity, which contributes to the risk of hemorrhagic complications. (See "Use of anticoagulants during pregnancy and postpartum", section on 'Warfarin teratogenicity'.)
Warfarin is associated with a high rate of late fetal loss. In one review, after exclusion of spontaneous abortions, 12 percent of the 596 pregnancies in a women taking warfarin throughout pregnancy ended in a fetal death . More data report a similar high perinatal death rate associated with warfarin .
A dose-dependent effect of warfarin on fetal embryopathy and fetal loss has been reported, with warfarin ≤5 mg per day having lower rates of fetal complications than warfarin >5 mg per day [13,14,17], although fetal warfarin syndrome has been reported with warfarin ≤5 mg per day . The clinical relevance of these findings is limited since the dosing is adjusted to achieve adequate anticoagulation (as measured by the INR) for each patient with a mechanical valve .
Low molecular weight heparin — When heparin is used, LMWHs are the preferred treatment modality over UFH given their improved pharmacokinetics and bioavailability, their reduced side effect profile, and apparent lower rates of associated valve thrombosis [10,20,26]. LMWH does not cross the placenta and has several advantages over UFH: It has a more predictable attainment of therapeutic levels of anticoagulation, appears to have less effect on bone, and is associated with less bleeding and thrombocytopenia. (See "Heparin and LMW heparin: Dosing and adverse effects".) At maternal request, therapeutic dose LMWH is increasingly used in clinical practice as an alternative to oral anticoagulants in pregnant women with mechanical heart valves [2,9-11,20,21,26]. Increasing evidence suggests therapeutic LMWH may be an acceptable alternative to warfarin for many women as they balance the slightly higher level of thrombotic risk against improved fetal outcomes [10,20,26].
When therapeutic LMWH is used, it is recommended that peak anti-factor Xa (four to six hours after subcutaneous injection) be measured at regular intervals and the LMWH dose adjusted accordingly [11,20]. The 2004 American College of Chest Physicians (ACCP) guidelines recommended a peak anti-Xa target of 1.0 to 1.2 U/mL, and the 2012 ACCP guidelines similarly recommended adjusting the LMWH dose to achieve the manufacturer's peak anti-Xa levels (approximately 1 U/mL). The 2014 AHA/ACC valve guidelines recommend maintaining anti-Xa levels between 0.8 and 1.2 U per mL .
In July 2002, the United States Food and Drug Administration issued a warning to the product labeling for enoxaparin, indicating that this product is not recommended for thromboprophylaxis in pregnant women with prosthetic heart valves . This warning was subsequently endorsed by the Committee on Obstetric Practice of the American College of Obstetricians and Gynecologists . However, some experts, including a 2002 Consensus Report Panel and Scientific Roundtable in fetal-maternal medicine, the 2012 ACCP guidelines, and the 2014 ACC/AHA valve guidelines, support maintaining LMWH as a treatment option in pregnant women with prosthetic heart valves [2,4,29]. The consensus panel concluded that prosthetic valve thrombosis in the above reports was related to underdosing or inadequate monitoring of LMWH .
There are no randomized trials of LMWH use versus warfarin or UFH in pregnant women with mechanical heart valves. A review of early publications reporting LMWH use in pregnant women with mechanical heart valves (16 studies, 1996 to 2003) found thromboembolic complications occurred in 12.3 percent of 81 pregnancies . When only women who received therapeutic LMWH were included, thromboembolism occurred in one of 37 pregnancies (2.7 percent) . A second review raised concerns with a 22 percent  rate of thrombotic events in 76 pregnancies reported in 23 papers (1996 to 2005) . Publication bias in part contributes to these rates, with the higher rate of thromboembolic events in the second review due to inclusion of a greater number of single case reports [9,30]. In several cases, thrombotic events were related to use of subtherapeutic doses of LMWH, suboptimal anti-Xa levels, and poor patient compliance [9,10,20].
Studies suggest the rate of thromboembolic events in pregnant women with mechanical valves may be lower when therapeutic LMWH is managed with intensive anti-Xa monitoring, followed by dose adjustment [10,11,20,21,26]. In these small cohorts, a total of 109 pregnancies treated with twice-daily, dose-adjusted therapeutic LMWH have been reported. These include 14 pregnancies (13 pregnancies in one series  plus one pregnancy in another report ) in which warfarin was the predominant therapy. In the remaining 95 pregnancies, thromboembolic complications occurred in 9.5 percent of women with mechanical valves treated with therapeutic range LMWH. In eight of the nine pregnancies with thromboembolic complications, there was subtherapeutic dosing, poor compliance, or low anti-Xa levels. There was one maternal death related to valve thrombosis . These data suggest that if therapeutic LMWH with dose adjustment to maintain anti-Xa levels of 1.0 to 1.2 U/mL is achieved, the risk of thromboembolic complications is low, probably less than 5 percent. When translated into clinical practice, however, the failure rate is likely to be in the order of 5 to 10 percent due to issues such as patient compliance.
In later reports of therapeutic LMWH in women with mechanical heart valves, there appears to be an increased rate of antepartum and postpartum bleeding complications. Of the 95 pregnancies summarized above, there were seven antepartum hemorrhages (secondary to placental abruption, placental previa, or unexplained), nine postpartum hemorrhages, four bleeds related to cesarean delivery, and four other hemorrhagic complications such as epistaxis [10,11,20,21,26].
Unfractionated heparin — UFH is a large molecule that does not cross the placenta and therefore does not have any known harmful effects on the fetus. Published data on the use of UFH throughout pregnancy in women with mechanical valves are limited [8,19]. There are more data regarding staged therapy, with the use of UFH in the first trimester, followed by VKAs [8,31-34]. (See "Use of anticoagulants during pregnancy and postpartum", section on 'Unfractionated heparin'.)
In the systematic review described above, thromboembolic complications were more common in women treated with UFH throughout pregnancy than when UFH was used during the first trimester than in women who took warfarin throughout pregnancy (25 percent of 16, 9.2 percent of 229, and 3.9 percent of 792 pregnancies, respectively) . Further comparisons with UFH are limited by the use of prophylactic rather than therapeutic dose UFH in some cases and uncertainty about the intensity of monitoring aPTT [8,19,32].
High-dose SC or IV UFH (eg, mid-dose target aPTT at least two times control) may provide better protection against thromboembolism, but even with this approach, concerning rates of thromboembolic complications have been reported [19,34]. In addition, with the advent of LMWH treatment for thromboembolism, there is declining clinician familiarity with IV UFH, and IV UFH is associated with risk of infection from the prolonged use of IV catheters .
Months of UFH may cause bone loss with reduced bone mineral density (BMD) in many pregnant women and osteoporotic fractures in a significant minority of these patients (2.2 percent in one series) . Although recovery of BMD occurs postpartum after heparin is discontinued, it is unclear if recovery is complete. Given the adverse effect of heparin on BMD, we suggest calcium supplementation (1.2 g/day) during pregnancy and postpartum for women taking heparin to ensure that the recommended daily allowance is achieved. (See "Drugs that affect bone metabolism", section on 'Heparin'.)
In practice, UFH is generally confined to IV administration at times when rapid reversal of the anticoagulant effect may be required (eg, intrapartum).
Aspirin — Data on the safety and efficacy of aspirin in pregnant women with prosthetic heart valves are limited. However, aspirin has been studied in pregnant women with other indications, and its use appears safe . In selected nonpregnant patients with prosthetic heart valves, the addition of low-dose aspirin to warfarin reduced thromboembolic complication rates . (See "Antithrombotic therapy for prosthetic heart valves: Indications", section on 'VKA plus aspirin better than VKA alone'.)
Direct thrombin inhibitors and direct factor Xa inhibitors — Direct thrombin inhibitors (eg, dabigatran) and direct factor Xa inhibitors (eg, rivaroxaban, apixaban, and edoxaban) should not be considered alternatives to therapy with warfarin or heparin in patients with prosthetic valves (during or outside of pregnancy). Adverse events have been observed in some animal studies, and safety data in pregnant women are lacking. A United States Food and Drug Administration safety communication specifically notes that dabigatran is contraindicated in patients with mechanical heart valves based upon the results of the RE-ALIGN trial. (See "Antithrombotic therapy for prosthetic heart valves: Indications", section on 'Oral direct thrombin inhibitors and factor Xa inhibitors'.)
Major society guidelines — The 2014 AHA/ACC valvular heart disease guideline, the 2012 ACCP Consensus Conference on Antithrombotic Therapy, and the 2011 European Society of Cardiology (ESC) guidelines on the management of cardiovascular disease during pregnancy included recommendations concerning anticoagulation in women with mechanical prosthetic valves who become pregnant [1,4,5].
Our approach is similar to, but differs somewhat from, that recommended in the 2014 AHA/ACC guidelines (algorithm 1) . The preferred anticoagulant regimen in the first trimester varies depending upon the baseline dose of warfarin in both our recommendations and the 2014 AHA/ACC guidelines. In the first trimester, LMWH is an alternative when the woman is taking higher dose warfarin or because of maternal choice. This aligns with the 2011 ESC guidelines. In contrast to the 2014 AHA/ACC guidelines, we include dose-adjusted therapeutic LMWH as an alternative in the second and third trimester. Incorporation of therapeutic LMWH as an alternative to warfarin in later pregnancy was recommended in the 2012 Ninth ACCP guidelines.
●The 2012 Ninth ACCP guidelines recommended that the decision about anticoagulation management during pregnancy include an assessment of additional thromboembolic risk factors (such as valve type, position, and history of thromboembolism) and that the decision be strongly influenced by patient preferences .
The following four treatment options are recommended for anticoagulation in women who have a mechanical prosthetic valve. The first three recommendations place a higher value on avoiding fetal risk than on avoiding maternal complications, while the fourth recommendation places equal value on avoiding maternal complications.
•Adjusted-dose every 12 hours LMWH therapy throughout pregnancy (eg, enoxaparin initiated at a dose of 1 mg/kg subcutaneously every 12 hours). It is suggested that the dose be adjusted to achieve a four-hour post-injection anti-Xa heparin level at the manufacturer's peak anti-Xa level (approximately 1.0 U/mL). (The prior 2004 ACCP guidelines had similarly recommended a peak anti-Xa level of 1.0 to 1.2 U/mL .)
•Adjusted-dose UFH every 12 hours throughout pregnancy. Heparin is administered subcutaneously every 12 hours in doses adjusted to keep the mid-interval aPTT at 2 to 2.5 times control, or an anti-Xa heparin level of 0.35 to 0.70 U/mL.
•LMWH or UFH therapy (using the above regimens) until the 13th week, a change to warfarin until close to delivery (eg, 36th week), and then restart LMWH or UFH therapy until delivery. Warfarin should not be given close to term in order to minimize the possibility of serious bleeding caused by the trauma of delivery to the anticoagulated fetus.
•In women judged to be at very high risk of thromboembolism in whom concerns exist about the efficacy and safety of UFH or LMWH as dosed above (eg, older generation prosthesis in the mitral position or history of thromboembolism), warfarin is suggested throughout pregnancy with replacement by UFH or LMWH (as above) close to delivery, after a thorough discussion with the patient of the potential risks and benefits of this approach.
In addition, for pregnant women with prosthetic valves at high risk of thromboembolism, the addition of low-dose aspirin (75 to 100 mg/day) is suggested.
●The 2011 ESC guidelines on management of cardiovascular diseases during pregnancy include the following recommendations  (which were cited in the 2012 ESC guidelines on the management of valvular heart disease ):
•The advantages and disadvantages of the various anticoagulation options should be discussed in detail with the patient. While evidence indicates that warfarin is the most effective regimen to prevent valve thrombosis and reduce maternal risk, its use is also associated with embryopathy, primarily when used during the first trimester. (See 'Warfarin' above and "Use of anticoagulants during pregnancy and postpartum".)
•Anticoagulation during the first trimester:
-Warfarin during the first trimester is suggested as an option with the patient's consent after discussion of the potential risks and benefits if the warfarin dose required for therapeutic anticoagulation is <5 mg/day (or phenoprocumon <3 mg/day or acenocoumarol <2 mg/day).
-If a warfarin dose ≥5 mg/day (or phenprocoumon ≥3 mg/day or acenocoumarol ≥2 mg/day) is required for therapeutic anticoagulation, discontinuation of VKA therapy between 6 to 12 weeks and replacement by adjusted dose LMWH twice daily with dose adjusted according to weight and anti-Xa levels or adjusted dose continuous intravenous infusion UFH with aPTT 2 to 2.5 times control is suggested.
•Warfarin is recommended during the second and third trimesters until the 36th week, at which time it should be replaced with either adjusted-dose LMWH (target anti-Xa level four to six hours post-dose 0.8 to 1.2 U/mL) or adjusted-dose UFH (aPTT at 2 to 2.5 times control) until delivery. Change of anticoagulation regimen during pregnancy should be implemented in hospital.
•Pregnant women treated with LMWH should have post-dose anti-Xa levels assessed weekly.
MANAGEMENT OF VALVE THROMBOSIS DURING PREGNANCY — When valve thrombosis occurs during pregnancy, we favor management as for valve thrombosis generally. (See "Complications of prosthetic heart valves".)
Experience with the management of valve thrombosis in pregnant women is limited. Controlled data do not exist, and published reports are mostly from case series. Heparin may be considered for small, nonobstructive thrombi. However, for obstructive valve thrombosis, the treatment options are surgical intervention and thrombolysis, both of which carry substantial fetal and maternal risks.
●In the largest reported series of thrombolysis as the initial therapy for valve thrombosis during pregnancy, 24 women with 28 episodes of valve thrombosis were treated with tPA using a low-dose, slow-infusion protocol (25 mg delivered intravenously over six hours without a bolus, with repeated doses as needed if prosthetic valve dysfunction persisted, mean dose 49 mg) . All patients had successful thrombolysis, with no maternal mortality and five fetal deaths (20 percent).
●In a series of 10 women treated for 12 episodes of valve thrombosis with surgery (four cases), thrombolysis (seven cases), and heparin (one case), there was one maternal death and one additional fetal death in the surgical group, while there were two maternal deaths and one bleeding event requiring surgical drainage but no additional fetal mortality in the thrombolysis group .
There are reports of both cardiac surgery and thrombolysis in pregnant women involving larger numbers of patients with a variety of conditions. Even in these diverse case series, patient numbers are still small and no direct comparisons exist.
●A review of published reports of cardiac surgery during pregnancy included a total of 70 patients . Perioperative maternal and fetal mortality were 6 and 30 percent, respectively.
●A review of thrombolysis during pregnancy included 172 patients . Maternal mortality, hemorrhagic complications, and fetal mortality rates were 1.2, 8, and 5.8 percent, respectively.
These data should be interpreted with caution since both of these series included patients treated for a variety of conditions at a number of centers over an extended period of time (12 years for the surgical series and 34 years for thrombolysis).
DELIVERY — Whenever possible, delivery should be planned and its modality discussed in close collaboration with the obstetricians, cardiologists, hematologists, and anesthesiologists . Planned inductions or cesarean deliveries are necessary to safely transition and manage anticoagulants. Vaginal delivery is preferred in most cases, and cesarean delivery should be reserved for specific obstetrical indications. However, urgent cesarean delivery is suggested for women who present in labor on vitamin K antagonist (VKA) or those with advanced heart failure and hemodynamic instability despite treatment . (See "Pregnancy in women with congenital heart disease: General principles", section on 'Role of cesarean delivery' and "Acquired heart disease and pregnancy".)
Delivery involves additional hemodynamic and hemorrhagic risks in a woman with a prosthetic heart valve. Due to a lack of relevant data and the impact of patient-specific variables, standard guidelines do not exist, and management in each case should be individualized with input from the patient, her obstetrician, cardiologist, thrombosis expert, and an anesthesiologist.
Vaginal or cesarean delivery is not an indication for routine antibiotic prophylaxis for endocarditis as discussed separately. (See "Antimicrobial prophylaxis for bacterial endocarditis", section on 'Vaginal or cesarean delivery'.)
Change in antithrombotic therapy — To minimize the risks of maternal and fetal hemorrhage, the following changes in antithrombotic therapy for women with mechanical valves should be made as the time for delivery approaches:
●At approximately 36 weeks, VKA (eg, warfarin) should be switched to dose-adjusted subcutaneous (SC) low molecular weight heparin (LMWH) administered at least twice per day (target anti-Xa level 1.0 units/mL to 1.2 units/mL at four to six hours post-dose with consideration of checking trough levels as well). Dose-adjusted continuous infusion of unfractionated heparin (UFH; maintaining the activated partial thromboplastin time [aPTT] at 2.0 to 2.5 times control) should only be offered if LMWH is unavailable.
●Cessation of low-dose aspirin is suggested in the week prior to planned delivery.
●Women treated with LMWH should be switched to dose-adjusted intravenous (IV) UFH (target aPTT at least twice control) prior to the induction of labor or cesarean delivery, in order to provide tighter control of anticoagulation throughout the peri-partum period. The last dose of SC LMWH is administered 24 hours before planned induction of labor or cesarean delivery if the mother has normal renal function. Twelve hours later, IV UFH is commenced at 1000 to 1250 units/hour (with no loading dose) and the infusion rate adjusted at six hourly intervals to achieve an aPTT that is twice control.
●The timing of the cessation of IV UFH can be difficult when the woman is induced. The aim is to cease the infusion four to six hours pre-delivery, but in practice, the IV UFH is usually ceased once the woman is in established labor.
●IV UFH should be discontinued four to six hours prior to cesarean delivery.
Delivery — On rare occasions, urgent delivery is indicated when a woman with a mechanical valve is still receiving therapeutic anticoagulation. Management involves balancing the risk of life-threatening maternal hemorrhage against the potentially catastrophic risk of thromboembolism or valve thrombosis if anticoagulation is reversed and the fetal consequences of not performing urgent delivery. (See 'Valve thrombosis and thromboembolism' above.)
Because the likelihood of serious hemorrhagic and thromboembolic complications cannot be accurately quantified, there are differing opinions regarding when and how aggressively to reverse anticoagulation. Full reversal of anticoagulation is not necessary for either vaginal or cesarean delivery. However, if the woman is on warfarin, reversal with vitamin K is appropriate to try to protect the fetus from hemorrhage. Full reversal is also warranted in patients with life-threatening maternal hemorrhage.
In a patient on VKAs with an elevated international normalized ratio (INR; therapeutic or supratherapeutic) at the time of an urgent delivery, we suggest the following:
●Because the fetus is also therapeutically anticoagulated, we favor cesarean delivery to reduce the risk of fetal trauma and hemorrhage (as suggested in the 2011 European Society of Cardiology guidelines) , though evidence is lacking and the risk of maternal hemorrhage is increased with cesarean delivery.
●When urgent or emergent delivery is necessary, the following steps should be taken:
•Warfarin should be stopped and four-factor prothrombin complex concentrate (PCC) should be administered to a target INR of 2.0. If a four-factor PCC is unavailable, a three-factor PCC can be given. If no PCC product is available, fresh frozen plasma (FFP) can be administered alone (initial dose, 15 to 30 mL/kg). FFP administration is not generally sufficient in an emergent situation, given the time required for administration, and is not recommended. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Serious/life-threatening bleeding'.)
•Small doses (eg, 2 mg) of oral or intravenous vitamin K will reverse the maternal INR in approximately six hours or more, so we recommend giving this as well, but the fetal INR will not fully reverse. Though maternal administration of vitamin K reduces the risk of maternal bleeding, it leaves a high risk of fetal/neonatal hemorrhage.
●If the woman is on LMWH and emergent delivery is necessary, protamine should be considered, bearing in mind that protamine will only partially reverse the anticoagulant effect of LMWH. The dose of protamine should be discussed with the obstetric anesthesiologist. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Reversal (protamine)'.)
●If the woman is on IV UFH, cessation of the infusion will rapidly reverse the anticoagulant effect. Protamine is only required if the woman has major bleeding complications.
Postpartum — In the absence of significant bleeding, anticoagulation should be resumed shortly after delivery.
●IV UFH should be resumed within four to six hours after delivery if there are no bleeding complications . We suggest starting an infusion of UFH at a usual dose with no bolus and gradually increasing the dose to achieve therapeutic anticoagulation over 24 to 48 hours if a vaginal delivery and 48 to 72 hours if a cesarean delivery. Some clinicians have raised concern that overlap of therapeutic dose LMWH with the recommenced warfarin, especially after cesarean delivery, may contribute to postpartum bleeding complications. Use of IV UFH postpartum may allow more rigorous control of anticoagulation.
●After an uncomplicated vaginal delivery, oral anticoagulants can be resumed the same day. If the woman has had a cesarean delivery, this should be delayed for one to two days or longer if there are hemorrhagic complications. Due to concern that postpartum hemorrhagic complications may occur when therapeutic IV UFH is overlapped with warfarin, the heparin infusion is discontinued once the INR is in the therapeutic range, although standard anticoagulation guidelines suggest continuing heparin until the INR has been therapeutic for 24 to 48 hours.
SUMMARY AND RECOMMENDATIONS
●Management of pregnant women with prosthetic valves requires special clinical expertise and collaborative management by the cardiologist, thrombosis expert, obstetrician, and maternal-fetal medicine specialist.
●Patients should be informed fully about the importance of therapeutic anticoagulation throughout pregnancy and the maternal and fetal risks associated with each anticoagulant regimen. The patient should participate in and agree with the decision about the treatment regimen.
●The following is a summary of our approach to anticoagulant therapy in pregnant women with mechanical valves:
•During the first trimester, for patients with baseline warfarin dose ≤5 mg/day, we suggest continuing warfarin with close international normalized ratio (INR) monitoring throughout the first trimester.
Dose-adjusted subcutaneous (SC) low molecular weight heparin (LMWH) from 6 to 12 weeks is an alternative for patients who wish to avoid the risk of low-dose warfarin during the first trimester.
If LMWH is unavailable due to resource limitations, dose-adjusted continuous intravenous (IV) infusion of unfractionated heparin (UFH) is an option, though the efficacy and safety of this treatment over weeks is uncertain.
•During the first trimester, for patients whose baseline warfarin dose is greater than 5 mg/d, we suggest switching to dose-adjusted LMWH dosed at least twice per day (target anti-Xa level 1.0 U/mL to 1.2 U/mL at four to six hours post-dose, with consideration of checking trough levels as well) once pregnancy is confirmed. A plan should be made prior to conception as to how this change in therapy will be arranged.
If LMWH is unavailable due to resource limitations, dose-adjusted continuous IV infusion of UFH (with an activated partial thromboplastin time [aPTT] at least twice control) is a potential option, although the efficacy and safety of this treatment over weeks is uncertain.
If the mother chooses to avoid the fetal risk associated with warfarin therapy, we suggest therapeutic LMWH twice per day with the dose adjusted to achieve target anti-Xa levels of 1.0 U/mL to 1.2 U/mL at four to six hours post-dose, with consideration of checking trough levels as well.
If LMWH is unavailable in low resource settings, warfarin should be strongly advised as the preferred anticoagulant and dose-adjusted SC UFH (with regular monitoring to ensure the six-hour post-dose aPTT is twice baseline) only offered if the mother declines to take warfarin.
●To minimize the risks of maternal and fetal hemorrhage, the following changes in antithrombotic therapy for pregnant women with mechanical valves should be made as the time for delivery approaches (see 'Change in antithrombotic therapy' above):
•At approximately 36 weeks, vitamin K antagonist (eg, warfarin) should be switched to dose-adjusted SC LMWH administered at least twice per day. Dose-adjusted continuous infusion of UFH (maintaining the aPTT at least twice the mean of the control) should only be offered if LMWH is unavailable.
•Cessation of low-dose aspirin in the week prior to planned delivery is suggested.
•Women treated with SC LMWH should be switched to dose-adjusted IV UFH (target aPTT at least twice control) prior to the induction of labor or cesarean delivery, in order to provide tighter control of anticoagulation throughout the peri-partum period as detailed above. (See 'Change in antithrombotic therapy' above.)
•The timing of the cessation of IV UFH can be difficult when the woman is induced. The aim is to cease the infusion four to six hours pre-delivery, but in practice, the IV UFH is usually ceased once the woman is in established labor. IV UFH should be discontinued four to six hours prior to cesarean delivery.
●In the absence of significant bleeding, anticoagulation for women with mechanical valves should be resumed shortly after delivery. (See 'Postpartum' above.)
●Due to the risk of embryopathy with warfarin early in pregnancy, the small risk of central nervous system abnormalities at any stage of pregnancy, and substantial risk of late fetal losses, some clinicians and patients may prefer to avoid warfarin entirely in favor of LMWH or UFH throughout pregnancy. (See 'Warfarin' above.)
●Available data are limited, and overall outcomes are poor in cases of valve thrombosis during pregnancy. Both maternal and fetal mortality rates are high. Management options are surgery and thrombolytic therapy. (See 'Management of valve thrombosis during pregnancy' above.)
●On rare occasions, urgent delivery is necessary for a woman with a mechanical valve while she is still receiving therapeutic anticoagulation. Management involves balancing the risk of life-threatening maternal hemorrhage against the potentially catastrophic risk of thromboembolism or valve thrombosis if anticoagulation is reversed and the fetal consequences of not performing an urgent delivery. (See 'Delivery' above.)
- Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 63:e57.
- Elkayam U, Bitar F. Valvular heart disease and pregnancy: part II: prosthetic valves. J Am Coll Cardiol 2005; 46:403.
- Ginsberg JS, Chan WS, Bates SM, Kaatz S. Anticoagulation of pregnant women with mechanical heart valves. Arch Intern Med 2003; 163:694.
- Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e691S.
- Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC), European Association for Cardio-Thoracic Surgery (EACTS), Vahanian A, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012; 33:2451.
- Vongpatanasin W, Hillis LD, Lange RA. Prosthetic heart valves. N Engl J Med 1996; 335:407.
- North RA, Sadler L, Stewart AW, et al. Long-term survival and valve-related complications in young women with cardiac valve replacements. Circulation 1999; 99:2669.
- Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature. Arch Intern Med 2000; 160:191.
- Oran B, Lee-Parritz A, Ansell J. Low molecular weight heparin for the prophylaxis of thromboembolism in women with prosthetic mechanical heart valves during pregnancy. Thromb Haemost 2004; 92:747.
- McLintock C, McCowan LM, North RA. Maternal complications and pregnancy outcome in women with mechanical prosthetic heart valves treated with enoxaparin. BJOG 2009; 116:1585.
- Quinn J, Von Klemperer K, Brooks R, et al. Use of high intensity adjusted dose low molecular weight heparin in women with mechanical heart valves during pregnancy: a single-center experience. Haematologica 2009; 94:1608.
- European Society of Gynecology (ESG), Association for European Paediatric Cardiology (AEPC), German Society for Gender Medicine (DGesGM), et al. ESC Guidelines on the management of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC). Eur Heart J 2011; 32:3147.
- Cotrufo M, De Feo M, De Santo LS, et al. Risk of warfarin during pregnancy with mechanical valve prostheses. Obstet Gynecol 2002; 99:35.
- 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.
- Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980; 68:122.
- Sillesen M, Hjortdal V, Vejlstrup N, Sørensen K. Pregnancy with prosthetic heart valves - 30 years' nationwide experience in Denmark. Eur J Cardiothorac Surg 2011; 40:448.
- De Santo LS, Romano G, Della Corte A, et al. Mechanical aortic valve replacement in young women planning on pregnancy: maternal and fetal outcomes under low oral anticoagulation, a pilot observational study on a comprehensive pre-operative counseling protocol. J Am Coll Cardiol 2012; 59:1110.
- Elkayam U, Goland S. The search for a safe and effective anticoagulation regimen in pregnant women with mechanical prosthetic heart valves. J Am Coll Cardiol 2012; 59:1116.
- Sadler L, McCowan L, White H, et al. Pregnancy outcomes and cardiac complications in women with mechanical, bioprosthetic and homograft valves. BJOG 2000; 107:245.
- Abildgaard U, Sandset PM, Hammerstrøm J, et al. Management of pregnant women with mechanical heart valve prosthesis: thromboprophylaxis with low molecular weight heparin. Thromb Res 2009; 124:262.
- Yinon Y, Siu SC, Warshafsky C, et al. Use of low molecular weight heparin in pregnant women with mechanical heart valves. Am J Cardiol 2009; 104:1259.
- Schaefer C, Hannemann D, Meister R, et al. Vitamin K antagonists and pregnancy outcome. A multi-centre prospective study. Thromb Haemost 2006; 95:949.
- Coumarin derivatives. www.reprotox.org (Accessed on June 08, 2011).
- Wainwright H, Beighton P. Warfarin embryopathy: fetal manifestations. Virchows Arch 2010; 457:735.
- Basu S, Aggarwal P, Kakani N, Kumar A. Low-dose maternal warfarin intake resulting in fetal warfarin syndrome: In search for a safe anticoagulant regimen during pregnancy. Birth Defects Res A Clin Mol Teratol 2016; 106:142.
- Saeed CR, Frank JB, Pravin M, et al. A prospective trial showing the safety of adjusted-dose enoxaparin for thromboprophylaxis of pregnant women with mechanical prosthetic heart valves. Clin Appl Thromb Hemost 2011; 17:313.
- www.fda.gov/medwatch/SAFETY/2002/lovenox.htm (Accessed on March 07, 2005).
- American College of Obstetricians and Gynecologists. ACOG Committee Opinion: safety of Lovenox in pregnancy. Obstet Gynecol 2002; 100:845.
- The Anticoagulation in Prosthetic Valves and Pregnancy Consensus Report Panel and Scientific Roundtable. Anticoagulation and enoxaparin use in patients with prosthetic heart valves and/or pregnancy. Fetal-Maternal Medicine Consensus Reports 2002; 3:1.
- James AH, Brancazio LR, Gehrig TR, et al. Low-molecular-weight heparin for thromboprophylaxis in pregnant women with mechanical heart valves. J Matern Fetal Neonatal Med 2006; 19:543.
- Sbarouni E, Oakley CM. Outcome of pregnancy in women with valve prostheses. Br Heart J 1994; 71:196.
- Salazar E, Izaguirre R, Verdejo J, Mutchinick O. Failure of adjusted doses of subcutaneous heparin to prevent thromboembolic phenomena in pregnant patients with mechanical cardiac valve prostheses. J Am Coll Cardiol 1996; 27:1698.
- Iturbe-Alessio I, Fonseca MC, Mutchinik O, et al. Risks of anticoagulant therapy in pregnant women with artificial heart valves. N Engl J Med 1986; 315:1390.
- Meschengieser SS, Fondevila CG, Santarelli MT, Lazzari MA. Anticoagulation in pregnant women with mechanical heart valve prostheses. Heart 1999; 82:23.
- Dahlman TC. Osteoporotic fractures and the recurrence of thromboembolism during pregnancy and the puerperium in 184 women undergoing thromboprophylaxis with heparin. Am J Obstet Gynecol 1993; 168:1265.
- Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev 2007; :CD004659.
- Turpie AG, Gent M, Laupacis A, et al. A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement. N Engl J Med 1993; 329:524.
- Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of antithrombotic agents during pregnancy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126:627S.
- Özkan M, Çakal B, Karakoyun S, et al. Thrombolytic therapy for the treatment of prosthetic heart valve thrombosis in pregnancy with low-dose, slow infusion of tissue-type plasminogen activator. Circulation 2013; 128:532.
- Sahnoun-Trabelsi I, Jimenez M, Choussat A, Roudaut R. [Prosthetic valve thrombosis in pregnancy. A single-center study of 12 cases]. Arch Mal Coeur Vaiss 2004; 97:305.
- Weiss BM, von Segesser LK, Alon E, et al. Outcome of cardiovascular surgery and pregnancy: a systematic review of the period 1984-1996. Am J Obstet Gynecol 1998; 179:1643.
- Turrentine MA, Braems G, Ramirez MM. Use of thrombolytics for the treatment of thromboembolic disease during pregnancy. Obstet Gynecol Surv 1995; 50:534.
- Butchart EG, Gohlke-Bärwolf C, Antunes MJ, et al. Recommendations for the management of patients after heart valve surgery. Eur Heart J 2005; 26:2463.