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Management of antithrombotic therapy for a prosthetic heart valve during pregnancy
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Management of antithrombotic therapy for a prosthetic heart valve during pregnancy
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2017. | This topic last updated: Oct 04, 2017.

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 [1], but given the absence of adequate prospective controlled trials and the differing maternal and fetal risks associated with various anticoagulants, the optimum anticoagulant regimen is uncertain [2-4].

Bioprosthetic valves typically do not require anticoagulation (unless there are other thromboembolic risk factors). However, bioprostheses have a significantly higher incidence of valve failure than mechanical valves. This is an important concern for young women, who must consider the potential for future valve surgery if they have a bioprosthesis. (See "Pregnancy and valve disease", section on 'Interventions prior to pregnancy'.)

Anticoagulant therapy for prosthetic heart valves during pregnancy is discussed here. Other prosthetic valve issues and native valve issues during pregnancy are discussed separately. (See "Pregnancy and valve disease".)

KEY CONSIDERATIONS

Antithrombotic therapy concerns — Therapeutic anticoagulation with frequent monitoring (along with aspirin therapy) is essential in all pregnant women with mechanical prosthetic heart valves to prevent valve thrombosis and thromboembolic events [1,4,5]. Anticoagulation is generally not required for bioprosthetic valves, although there are some exceptions (eg, a patient with prior bioprosthetic valve thrombosis). (See "Complications of prosthetic heart valves".)

The following are key considerations in managing antithrombotic therapy in a pregnant woman with a mechanical valve (or a bioprosthetic valve with a clear requirement for anticoagulation):

The risk of developing thromboembolic complications should be balanced against the risk of maternal and fetal complications of anticoagulation during pregnancy and delivery.

A woman’s individual risk of thromboembolic complications is estimated based upon the number, type, size, and site of the mechanical valve and other factors such as previous thromboembolic complications.

Choice of anticoagulant regimen during pregnancy is based upon careful consideration of maternal risks and fetal risks associated with various types of anticoagulants. (See 'Approach during pregnancy' below.)

Anesthesia concerns — Antithrombotic therapy may increase the risk of spinal epidural hematoma (SEH) after neuraxial analgesia/anesthesia. Guidelines have been developed for the timing of neuraxial anesthesia techniques before and after administration of anticoagulant and antiplatelet drugs, with the goal of reducing the risk of SEH, a rare but potentially devastating condition. These guidelines are based on expert opinion and the pharmacokinetics of the individual drugs, and are largely consistent with the approach outlined in this topic. (See "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication", section on 'Problem overview'.)

Patients receiving antithrombotic therapy during the peripartum period should undergo antenatal anesthesia evaluation; a multidisciplinary, individualized plan should be created for management of antithrombotic therapy and anesthesia for planned and/or urgent delivery, considering the following:

The small, unknown risk of SEH with neuraxial anesthesia

The risk of thromboembolic complications

The optimal method for labor analgesia, given the patient’s cardiac physiology, predictors for difficult airway management, and values and preferences (see "Anesthesia for labor and delivery in high-risk heart disease: Specific lesions" and "Neuraxial analgesia for labor and delivery (including instrumented delivery)" and "Pharmacologic management of pain during labor and delivery" and "Airway management of the pregnant patient at delivery")

The risks associated with general anesthesia if cesarean delivery is necessary

PRECONCEPTION EVALUATION AND COUNSELING — Women of childbearing age who have prosthetic heart valves should receive preconception evaluation and counseling regarding risks associated with prosthetic valves and the risks and benefits of antithrombotic therapy, as discussed separately.

APPROACH DURING PREGNANCY — The absence of any adequate randomized trials and the paucity of prospective cohort data make it difficult to offer definitive recommendations on an antithrombotic regimen for prosthetic valves during pregnancy [4]. (See "Use of anticoagulants during pregnancy and postpartum".)

The following is a summary of our approach to anticoagulant therapy in pregnant women with prosthetic valves during pregnancy until the peripartum period.

For bioprosthetic valves — Bioprosthetic valves typically do not require anticoagulation (except anticoagulation for the first three to six months after surgical implantation) unless the patient has other thromboembolic risk factors (such as atrial fibrillation). (See "Antithrombotic therapy for prosthetic heart valves: Indications", section on 'Surgical bioprosthetic valves'.)

For patients with a bioprosthetic valve, we suggest continuing low-dose aspirin (75 to 100 mg/day) during pregnancy. (See 'Aspirin' below and "Antithrombotic therapy for prosthetic heart valves: Indications", section on 'Surgical bioprosthetic valve recommendations'.)

For mechanical valves — Pregnant women with mechanical valves should be fully informed about the importance of therapeutic anticoagulation throughout pregnancy and the maternal risks and fetal risks associated with each anticoagulant regimen. The patient’s values and preferences inform decision making in this setting. The patient should participate in and agree with the decision about the treatment regimen.

For pregnant women with mechanical prosthetic valves, we recommend low-dose aspirin (75 to 100 mg/day) in addition to anticoagulation throughout pregnancy. Peripartum management of aspirin is discussed below. (See "Antithrombotic therapy for prosthetic heart valves: Indications", section on 'VKA plus aspirin better than VKA alone' and 'Aspirin' below.)

With risk factors for prosthetic valve thrombosis

For pregnant women with a mechanical valve with one or more of the following risk factors for prosthetic valve thrombosis/thromboembolism, we suggest continuing vitamin K antagonist (VKA; eg, warfarin) with close international normalized ratio (INR) monitoring throughout pregnancy (along with low-dose aspirin) until 36 weeks. In making this recommendation, we are placing high value on reducing maternal risk. Pregnant women who place a high value on reducing fetal risk may reasonably choose dose-adjusted twice daily subcutaneous (SC) low molecular weight heparin (LMWH) during the first trimester.

Risk factors for prosthetic valve thrombosis/thromboembolism (see "Antithrombotic therapy for prosthetic heart valves: Indications"):

Old or small mechanical mitral valve

Atrial fibrillation or flutter

Previous thromboembolic complications

Multiple mechanical heart valves

Without risk factors for prosthetic valve thrombosis

For pregnant women with a mechanical valve without one or more of the above four risk factors for prosthetic valve thrombosis/thromboembolism, the following approach for antithrombotic therapy during the first trimester is based upon baseline warfarin dose:

For patients with baseline warfarin dose ≤5 mg/day, the following are options for anticoagulation:

-Continuing warfarin with close INR monitoring throughout the first trimester.

OR

-Dose-adjusted SC LMWH from 5 to 12 weeks is an alternative for patients who wish to avoid the risk of low-dose warfarin during the first trimester. Twice a day dosing is necessary to prevent thromboembolic complications.

-If LMWH is unavailable due to resource limitations, dose-adjusted continuous inpatient intravenous (IV) infusion of unfractionated heparin (UFH; with targeted activated partial thromboplastin time [aPTT] 2 to 2.5 times control) is a potential option, though the efficacy and safety of this treatment over weeks are uncertain, given difficulties in monitoring IV UFH, the limited efficacy of UFH in this setting, and the risk of infection.

For patients whose baseline warfarin dose is >5 mg/day, we suggest switching to dose-adjusted SC LMWH throughout the first trimester. Once pregnancy is confirmed and ideally before the fifth week of gestation, LMWH should be dosed at least twice per day (target anti-Xa activity 1.0 to 1.2 units/mL for mitral valve prosthesis and 0.8 to 1.0 units/mL for aortic valve prosthesis at four to six hours post-dose). We recommend checking trough activity as well (proposed minimum trough level of 0.6 units/mL [6]), although the efficacy and safety of this approach have not been established. 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 are uncertain.

During the second trimester and third trimester until 36 weeks:

We suggest VKA (eg, 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 VKA to LMWH at 36 weeks may need to be individualized for women at high risk for preterm delivery (eg, women with multifetal gestation or previous preterm delivery).

If the mother chooses to avoid the fetal risk associated with VKA therapy, we suggest therapeutic SC LMWH. Therapeutic SC LMWH is dosed twice per day with dose adjusted to achieve target anti-Xa activity of 1.0 to 1.2 units/mL for mitral valve prosthesis and 0.8 to 1.0 units/mL for aortic valve prosthesis at four to six hours post-dose and ensuring adequate trough activity as well.

If LMWH is unavailable in low resource settings, VKA is the preferred anticoagulant. Dose-adjusted SC UFH (with regular monitoring to ensure the six-hour post-dose aPTT is at least twice baseline) is offered as an alternative option (last resort) when LMWH is unavailable only if the mother declines to take warfarin. Use of SC UFH in this setting is controversial and not endorsed by some experts [1].

Management of antithrombotic therapy from 36 weeks to delivery is discussed below. (See 'Peripartum management' below.)

PERIPARTUM MANAGEMENT — Whenever possible, delivery should be planned and its modality discussed in close collaboration with the obstetrician/maternal-fetal medicine specialist, cardiologist, thrombosis expert, and anesthesiologist [7]. 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, for women who present in labor on vitamin K antagonist (VKA) or those with advanced heart failure and hemodynamic instability despite treatment, urgent cesarean delivery is suggested [8]. (See "Pregnancy in women with congenital heart disease: General principles", section on 'Role of cesarean delivery' and "Acquired heart disease and pregnancy", section on 'Mode and timing of delivery' and 'Approach for planned delivery' below and 'Approach for urgent delivery' below.)

Labor and delivery involve additional hemodynamic and hemorrhagic risks (including the risk of spinal epidural hematoma [SEH] with neuraxial anesthesia) 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. A plan for anticoagulation in labor/peripartum should be agreed to by obstetricians, anesthesiologists, cardiologists, and hematologists and documented clearly. The risks of valve thrombosis and obstetric hemorrhage as well as the risks and benefits of regional anesthesia need to be balanced and the patient fully informed of the rationale for the individualized plan. (See "Management of normal labor and delivery" and "Cesarean delivery: Postoperative issues", section on 'Complications' and "Operative vaginal delivery", section on 'Complications' and "Neuraxial analgesia for labor and delivery (including instrumented delivery)" and "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication" and 'Anesthesia concerns' above.)

Vaginal or cesarean delivery is not an indication for routine antibiotic prophylaxis for endocarditis, as discussed separately. (See "Antimicrobial prophylaxis for the prevention of bacterial endocarditis", section on 'Vaginal or cesarean delivery'.)

Approach for planned delivery — 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 activity 1.0 to 1.2 units/mL for mitral valve replacement and 0.8 to 1.0 units/mL for aortic valve replacement at four to six hours post-dose with consideration of checking trough activity as well). Dose-adjusted continuous infusion of unfractionated heparin (UFH; maintaining the activated partial thromboplastin time [aPTT] at 2 to 2.5 times control) should only be offered if LMWH is unavailable.

We prefer to continue low-dose aspirin up until planned delivery. This should be discussed with the anesthesiologist, as aspirin with concurrent early postpartum anticoagulation may increase the risk of SEH. (See 'Aspirin' below.)

The last dose of dose-adjusted SC LMWH is administered 24 hours before planned induction of labor or cesarean delivery if the mother has normal renal function. This is to facilitate use of regional anesthesia/analgesia and minimize the risk of bleeding at delivery. Various options then exist:

Use of dose-adjusted intravenous (IV) UFH (target aPTT at least twice control).

-Twelve hours after cessation of LMWH, IV UFH is commenced with no loading dose at 1000 to 1250 units/hour (ie, 18 units/kg/hour) and the infusion rate adjusted at six hourly intervals to achieve an aPTT that is twice control.

-IV UFH is stopped prior to delivery. The timing of the cessation of IV UFH can be difficult when the woman is induced. IV UFH should be discontinued four to six hours prior to initiation of neuraxial anesthesia or analgesia. A neuraxial catheter can be placed once the aPTT has returned to normal. (See "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication", section on 'Preoperative intravenous (IV) UFH'.)

OR

Use of intermittent prophylactic doses of LMWH (eg, enoxaparin 40 mg subcutaneously once daily). Initiation of neuraxial anesthesia or analgesia should be delayed for at least 10 to 12 hours after the last dose of prophylactic LMWH. Cesarean delivery is performed 24 hours after the last dose of LMWH. (See "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication", section on 'Neuraxial placement after prophylactic LMWH'.)

OR

Induction of labor is commenced 24 hours after the last therapeutic dose of LMWH, and an early epidural catheter is sited. At least six to eight hours after nontraumatic (at least 24 hours after traumatic) epidural catheter placement, a prophylactic dose of LMWH is given if the woman is not in active labor and repeated every 24 hours until the woman is in active labor (cervix is dilated to 6 cm or more). (See "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication", section on 'Timing of placement and removal of spinal or epidural'.)

Approach for urgent 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.

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 [5]), though evidence is lacking and the risk of maternal hemorrhage is increased with cesarean delivery.

When urgent or emergency 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 (initial dose, 15 to 30 mL/kg). FFP administration is not generally sufficient in an emergency situation, given the time required for administration, and thus 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 IV 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. Vitamin K is routinely given to newborns shortly after birth to prevent vitamin K deficiency bleeding. (See "Overview of vitamin K", section on 'Vitamin K deficient bleeding in newborns and young infants' and "Overview of the routine management of the healthy newborn infant", section on 'Vitamin K'.)

If the woman is on therapeutic LMWH and emergency 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'.)

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.

Residual anticoagulation at the time of labor or delivery may preclude use of neuraxial analgesia or anesthesia. Parenteral analgesia for labor and anesthesia for cesarean delivery are discussed separately. (See 'Anesthesia concerns' above and "Pharmacologic management of pain during labor and delivery" and "Anesthesia for cesarean delivery" and "Anesthesia for cesarean delivery", section on 'General anesthesia'.)

POSTPARTUM MANAGEMENT — Neuraxial catheters may be removed no sooner than 10 to 12 hours after the last dose of prophylactic low molecular weight heparin (LMWH) and before resumption of anticoagulant therapy. (See "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication", section on 'Therapeutic LMWH after neuraxial catheter removal'.)

In the absence of significant bleeding, anticoagulation should be resumed shortly after delivery. The timing of resumption of anticoagulation is selected by balancing the risk of incisional or uterine bleeding versus the risk of thromboembolic complications including prosthetic valve thrombosis.

Intravenous (IV) unfractionated heparin (UFH) or subcutaneous (SC) LMWH should be resumed within four to six hours after delivery if there are no bleeding complications [5].

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 but may be impractical for service providers who are no longer familiar with the use of IV UFH.

We suggest a prophylactic dose of SC LMWH initially and then half a therapeutic dose (ie, enoxaparin 0.75 mg/kg) based upon the patient’s postpartum weight 12 hours later and continued as twice daily dosing (eg, enoxaparin 0.75 mg/kg every 12 hours).

Due to concern that postpartum hemorrhagic complications may occur when therapeutic IV UFH or LMWH is overlapped with warfarin, warfarin should not be reintroduced until day 5 to 7. Either the heparin infusion or the LMWH is discontinued once the international normalized ratio (INR) is in the therapeutic range, although standard anticoagulation guidelines suggest continuing heparin until the INR has been therapeutic for 24 to 48 hours.

MAJOR SOCIETY GUIDELINES — The 2014 American Heart Association/American College of Cardiology (AHA/ACC) valvular heart disease guidelines, the 2012 American College of Chest Physicians (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 [1,4,9].

Our approach is similar to, but differs somewhat from, that recommended in the 2014 AHA/ACC guidelines [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; however, our approach differs for patients with risk factors for prosthetic valve thrombosis. In the first trimester, low molecular weight heparin (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 trimesters. Incorporation of therapeutic LMWH as an alternative to warfarin in later pregnancy was recommended in the 2012 Ninth ACCP guidelines.

USE AND EFFECTS OF SPECIFIC AGENTS — Our approach is based upon efficacy and safety data on anticoagulants in pregnant women with mechanical heart valves. 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 placental 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 'Peripartum management' above.)

The main options for long-term anticoagulation for a mechanical valve during pregnancy are vitamin K antagonist (VKA; eg, warfarin) and low molecular weight heparin (LMWH). Unfractionated heparin (UFH) is used as a last resort in settings in which LMWH is unavailable and the patient declines use of VKA. While VKA (eg, warfarin) is the most effective therapy to prevent mechanical prosthetic 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. LMWH use is associated with low fetal risk but higher risk of maternal mortality and thromboembolism than with VKA. (See 'Warfarin' below and 'Low molecular weight heparin' below.)

Warfarin

Use — When warfarin is used during pregnancy, meticulous control is required including close monitoring of the international normalized ratio (INR; eg, twice weekly or weekly in some centers), patient education regarding dietary intake of vitamin K, and a dedicated prescriber adjusting the dose as needed.

When using warfarin therapy for a mechanical prosthetic valve, the target INR varies with the type of valve, location of the valve (aortic versus mitral), and the presence of risk factors for thromboembolism, as discussed separately. (See "Antithrombotic therapy for prosthetic heart valves: Indications", section on 'Mechanical valve recommendations'.)

Evidence — Warfarin is the safest anticoagulant option for the mother since it is the most effective therapy to prevent complications of valve thrombosis (including valve obstruction, thromboembolism, and maternal death) with a rate of pregnancy-related valve thromboembolic complications on the order of 2 to 4 percent with currently used valves [12,13].

However, warfarin freely crosses the placenta, and its use is associated with a characteristic embryopathy with risk of fetal anomalies estimated at 5 to 10 percent (associated primarily with warfarin exposure during the first trimester) [12-17], risk of miscarriage (pregnancy loss before the 20th week of gestation; approximately 30 percent) [13,18], a high risk of late fetal loss (pregnancy loss at ≥20th week of gestation; approximately 10 percent), and fetal hemorrhagic sequelae [10,14,18,19]. The risk of both fetal anomalies and spontaneous miscarriage increases after week 5 [13].

A dose-dependent effect of warfarin on fetal embryopathy and fetal loss has been reported, with warfarin ≤5 mg/day having lower rates of fetal complications than warfarin >5 mg/day [15,16,20-22], although fetal warfarin syndrome has been reported with warfarin ≤5 mg/day [22,23]. 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 [24]. (See "Antithrombotic therapy for prosthetic heart valves: Indications" and "Warfarin and other VKAs: Dosing and adverse effects".)

Overall, the data indicate that warfarin use is associated with a low risk of maternal thromboembolic complications, on the order of 2 to 4 percent. The safety and efficacy of various anticoagulant regimens in pregnant women with mechanical prosthetic heart valves were illustrated by a systematic review of the literature up to 2016 of 46 observational studies including 1307 pregnancies; maternal complications including maternal mortality (0.9 percent with VKA, 2 percent with sequential treatment [first trimester heparin followed by VKA], and 2.9 percent with LMWH) and thromboembolic events (2.7 percent with VKA, 5.8 percent with sequential treatment, and 8.7 percent with LMWH) were lowest with VKA [12]. A systematic review up to 2016 of 18 publications including 800 pregnancies reported a higher composite maternal risk (death, prosthetic valve failure, and systemic thromboembolism) of 16 percent with LMWH compared with VKA (5 percent) [21].

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 [13-17]. It is thought that the greatest risk of warfarin embryopathy is after five weeks. In one review, the risk of major anomalies was 4.8 percent when VKA therapy was discontinued by eight weeks gestation as compared with 1.4 percent in the general population [25]. A cohort study of phenprocoumon demonstrated that cessation before five completed weeks of gestation resulted in no increased risk of birth defects, but that if the VKA was continued after seven weeks, the risk of birth defects was 10.8 percent compared with 2.3 percent in unexposed pregnancies. Furthermore, the risk of miscarriage was also increased (38 percent compared with 17.5 percent in the unexposed pregnancies and the hazard ratio of miscarriage was 1.12 for every additional week of exposure) [13]. In the ROPAC study, the rate of miscarriage was 28.6 percent with VKA compared with 9.2 percent with heparin, and the rates for late fetal loss were 7.1 and 0.7 percent, respectively [18]. In the systematic review of Steinberg, the composite fetal risk (miscarriage, death, congenital abnormalities) was 39 percent with VKA compared with 13 percent with LMWH and 23 percent with sequential LMWH and VKA [21].

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 [26,27]. 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 also associated with a high rate of late fetal loss. In one review, after exclusion of spontaneous abortions, 12 percent of the 596 pregnancies in women taking warfarin throughout pregnancy ended in a fetal death [14]. Additional data report a similar high perinatal death rate associated with warfarin [10].

Low molecular weight heparin

Use — When therapeutic weight-adjusted LMWH is used (eg, initial dose of enoxaparin 1 mg/kg every 12 hours), it is recommended that peak anti-factor Xa (four to six hours after subcutaneous [SC] injection) be measured at one to two weekly intervals and the LMWH dose adjusted accordingly [11,28]. We use higher targets (1.0 to 1.2 units/mL) for mechanical valves in the mitral position and lower targets (0.8 to 1.0 units/mL) for mechanical aortic valve replacements. Peak anti-Xa levels should be <1.5 units/mL to avoid excessive anticoagulation and increased risk of bleeding. We also suggest monitoring anti-Xa trough levels (target ≥0.6 units/mL [6]).

The 2004 American College of Chest Physicians (ACCP) guidelines recommended a peak anti-Xa target of 1.0 to 1.2 units/mL, and the 2012 ACCP guidelines similarly recommended adjusting the LMWH dose to achieve the manufacturer's peak anti-Xa activity (approximately 1.0 unit/mL). The 2014 AHA/ACC valve guidelines recommend maintaining anti-Xa activity between 0.8 and 1.2 units/mL [1].

Evidence — LMWH does not cross the placenta and does not have known harmful effects on the fetus. 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 [10,28,29]. LMWH has several advantages over UFH: It has a more predictable attainment of therapeutic level 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".)

Increasingly, pregnant women are choosing to use LMWH during pregnancy after counseling about the maternal and fetal effects of various anticoagulant options [2,10,11,28-31]. 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 compared with warfarin [10,28,29,31]. In a systematic review, live birth rates were 92 percent with LMWH, 80 percent with sequential therapy (first trimester heparin followed by VKA), and 65 percent with VKA [12]. The risk of thromboembolic complications with LMWH use during pregnancy has been reported as 12 percent [12,30], though it may be lower with careful anti-Xa monitoring to target four-hour peak level of 1.0 to 1.2 units/mL and adequate trough activity. Use of LMWH at subtherapeutic dose regimens or poor compliance accounts for many, but not all, reported cases of valve thromboses or thromboembolism [14,28,30,31].

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 [30]. When only women who received therapeutic LMWH were included, thromboembolism occurred in one of 37 pregnancies (2.7 percent) [30]. A second review raised concerns with a 22 percent [32] rate of thrombotic events in 76 pregnancies reported in 23 papers (1996 to 2005) [32]. 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 [30,32]. In several cases, thrombotic events were related to use of subtherapeutic doses of LMWH, suboptimal anti-Xa activity, and poor patient compliance [10,28,30].

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 [10,11,28,29,31]. 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 [10] plus one pregnancy in another report [11]) 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 activity. There was one maternal death related to valve thrombosis [31]. These data suggest that if therapeutic LMWH with dose adjustment to maintain anti-Xa activity of 1.0 to 1.2 units/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 on the order of 5 to 10 percent due to issues such as patient compliance. In a systematic review, studies that used subtherapeutic, unadjusted, or unclear anticoagulation regimens were excluded [12]. In the ROPAC study, there were 10 (4.7 percent) thrombosed mechanical valves, and five of these occurred in the first trimester following a switch to some form of heparin [18].

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, placenta previa, or unexplained), nine postpartum hemorrhages, four bleeds related to cesarean delivery, and four other hemorrhagic complications such as epistaxis [10,11,28,29,31]. In a single-center study of 32 pregnancies from 2003 to 2011, the only maternal death was from an intracerebral hemorrhage in a woman managed with LMWH throughout pregnancy [33]. In the ROPAC study, the rate of hemorrhage in those with mechanical valves was 23.1 percent compared with 5.1 percent in those with bioprosthetic valves [18].

Unfractionated heparin

Use — In practice, UFH use for anticoagulation for a mechanical valve is generally confined to intravenous (IV) administration at times when rapid reversal of the anticoagulant effect may be required (eg, pre- or postpartum).

UFH is a possible option for long-term anticoagulation for a mechanical valve only in clinical settings in which warfarin is not an option (due to risks and/or patient preference) and LMWH is unavailable due to resource limitations:

During the first trimester, dose-adjusted continuous IV infusion of UFH (with targeted activated partial thromboplastin time [aPTT] 2 to 2.5 times control) is a potential option, though the efficacy and safety of this treatment over weeks are uncertain, given limited efficacy, difficult monitoring, and the risk of infection.

During the second and third trimesters, dose-adjusted SC administration (with targeted aPTT 2 to 2.5 times control) is a potential option (last resort) when LMWH is unavailable only if the mother declines to take warfarin. The efficacy and safety of this treatment over weeks are uncertain, and use of SC UFH in this setting is controversial and not endorsed by some experts [1].

Given the adverse effect of UFH on bone mineral density (BMD), we suggest calcium supplementation (1.2 g/day) during pregnancy and postpartum for women taking UFH to ensure that the recommended daily allowance is achieved. (See "Drugs that affect bone metabolism", section on 'Heparin'.)

Evidence — UFH does not cross the placenta and does not have direct harmful effects on the fetus. However, the risk of thromboembolic complications is high in pregnant women with mechanical valves when UFH is used throughout pregnancy (eg, 11.2 percent) or during the first trimester (eg, 5.8 percent) [12,14], and thus use of SC UFH during pregnancy for prosthetic valves is not recommended by some major society guidelines [1]. Poor compliance and subtherapeutic regimens contribute to this high rate of valve thrombosis, but thromboembolic complications can occur with therapeutic SC heparin [34]. Maternal thromboembolic complications requiring valve replacement or resulting in maternal death may contribute to fetal losses associated with UFH reported in some studies, and the magnitude of risk is uncertain given the limited number of cases [12,14]. IV UFH (with targeted aPTT 2 to 2.5 times control) may provide better protection against thromboembolism than SC UFH, but its efficacy and safety over weeks are uncertain. Long-term UFH may also reduce BMD.

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 [14,34]. There are more data regarding staged therapy, with the use of UFH in the first trimester, followed by VKAs [14,35-38]. (See "Use of anticoagulants during pregnancy and postpartum", section on 'Unfractionated heparin'.)

In the systematic review described above, thromboembolic complications were more common when UFH was used throughout pregnancy than when UFH was used only during the first trimester, which in turn was higher than in women who took warfarin throughout pregnancy (8.7, 5.8, and 2.7 percent, respectively) [12,14]. 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 [14,34,36].

High-dose SC or IV UFH (eg, mid-dose target aPTT at least two times control) may provide better protection against thromboembolism than low SC doses, but even with this approach, concerning rates of thromboembolic complications have been reported [34,38]. 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 [1].

Months of UFH may cause bone loss with reduced BMD in many pregnant women and osteoporotic fractures in a significant minority of these patients (2.2 percent in one series) [39]. Although recovery of BMD occurs postpartum after heparin is discontinued, it is unclear if recovery is complete.

Aspirin

Use — As noted above, for women with bioprosthetic valves not requiring anticoagulation, we suggest use of low-dose aspirin during pregnancy. Cessation of aspirin prior to delivery is not required if no other antithrombotic agents will be administered during the peripartum period. (See "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication", section on 'Aspirin and other NSAIDs'.)

For women with mechanical prosthetic valves, we recommend use of low-dose aspirin (in addition to anticoagulation) during pregnancy.

United States anesthesia guidelines recommend generally stopping aspirin 7 to 10 days prior to neuraxial analgesia/anesthesia in patients receiving other antithrombotic medications (before or soon after neuraxial catheter placement or removal) given the potential increased risk of spinal epidural hematoma [40] (see "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication", section on 'Aspirin and other NSAIDs'). However, management of antithrombotic therapy in the parturient with a mechanical prosthetic valve requires risk/benefit analysis. We favor continuing aspirin up to delivery despite early postpartum administration of anticoagulants, in consultation with the anesthesiologist. (See "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication" and 'Approach for planned delivery' above.)

Evidence — Data on the safety and efficacy of low-dose aspirin in pregnant women with prosthetic heart valves are limited. However, low-dose aspirin has been studied in pregnant women with other indications, and its use appears safe [41]. (See "Use of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation", section on 'Aspirin (low-dose)'.)

In nonpregnant patients with bioprosthetic valves, limited observational data are available on the use of aspirin. (See "Antithrombotic therapy for prosthetic heart valves: Indications", section on 'Effect of long-term antithrombotic therapy'.)

In nonpregnant patients with mechanical heart valves, meta-analyses of randomized trials found that the addition of low-dose aspirin to warfarin reduced the risk of mortality as well as the risk of thromboembolism and increased the risk of major hemorrhage compared with anticoagulation alone. (See "Antithrombotic therapy for prosthetic heart valves: Indications", section on 'VKA plus aspirin better than VKA alone'.)

Direct oral anticoagulants — Direct oral anticoagulants (DOACs, also known as non-vitamin K oral anticoagulants [NOACs]) including 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 mechanical heart valves (during or outside of pregnancy). Adverse events have been observed in some animal studies, and safety data in pregnant women are lacking. A US 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 'Direct oral anticoagulants'.)

SUMMARY AND RECOMMENDATIONS

For bioprosthetic valves

For patients with bioprosthetic valves, we suggest continuing low-dose aspirin (75 to 100 mg/day) throughout pregnancy (Grade 2C). (See 'Aspirin' above and "Antithrombotic therapy for prosthetic heart valves: Indications", section on 'Surgical bioprosthetic valve recommendations'.)

For mechanical valves

Pregnant women with mechanical prosthetic valves should be fully informed about the importance of therapeutic anticoagulation throughout pregnancy and the maternal and fetal risks associated with each anticoagulant regimen. The patient’s values and preferences inform decision making in this setting. The patient should participate in and agree with the decision about the treatment regimen. (See 'For mechanical valves' above.)

The main options for long-term anticoagulation for a mechanical valve during pregnancy are vitamin K antagonist (VKA; eg, warfarin) and low molecular weight heparin (LMWH). Unfractionated heparin (UFH) is used as a last resort in settings in which LMWH is unavailable and the patient declines use of VKA. While VKA (eg, warfarin) is the most effective therapy to prevent mechanical prosthetic valve thrombosis and thromboembolism, VKA use is associated with an increased risk of fetal anomalies (particularly with warfarin doses >5 mg/day) and a high risk of late fetal loss. LMWH use is associated with low fetal risk but higher risk of maternal mortality and thromboembolism than with VKA. (See 'Use and effects of specific agents' above.)

For all patients with mechanical prosthetic valves, we recommend low-dose aspirin (75 to 100 mg/day) in addition to anticoagulation throughout pregnancy (Grade 1B). (See 'Aspirin' above and "Antithrombotic therapy for prosthetic heart valves: Indications", section on 'VKA plus aspirin better than VKA alone'.)

With risk factors for prosthetic valve thrombosis

For patients with mechanical prosthetic valves with one or more risk factors for prosthetic valve thrombosis/thromboembolism (old or small mechanical mitral valve, atrial fibrillation or flutter, previous thromboembolic complications, or multiple mechanical heart valves), we suggest continuing VKA (eg, warfarin) with close international normalized ratio (INR) monitoring throughout pregnancy until 36 weeks (Grade 2C). In making this recommendation, we are placing high value on reducing maternal risk. Pregnant women with mechanical valves who place a high value on minimizing fetal risk may reasonably choose dose-adjusted twice daily subcutaneous (SC) LMWH (target anti-Xa level 1.0 to 1.2 units/mL for mitral valve and 0.8 to 1.0 units/mL for aortic valve replacements at four to six hours post-dose, with trough activity checked as well) during the first trimester. (See 'With risk factors for prosthetic valve thrombosis' above.)

Without risk factors for valve thrombosis — For pregnant women with mechanical valves without risk factors for prosthetic valve thrombosis, anticoagulant options during the first trimester differ from those during the later trimesters (see 'Without risk factors for prosthetic valve thrombosis' above):

During the first trimester

Our approach for patients with mechanical valves without one or more of the above four risk factors for prosthetic valve thrombosis or thromboembolism is as follows:

For patients with baseline warfarin dose ≤5 mg/day, the following are options for anticoagulation:

-Continuing warfarin with close INR monitoring throughout the first trimester.

OR

-Dose-adjusted SC LMWH from 5 to 12 weeks is an alternative for patients who wish to avoid the risk of low-dose warfarin during the first trimester.

For patients whose baseline warfarin dose is >5 mg/day, we suggest switching to dose-adjusted twice daily SC LMWH throughout the first trimester (Grade 2C).

When dose-adjusted LMWH is used as an anticoagulant therapy for a mechanical valve, it must be dosed twice per day (target anti-Xa level 1.0 to 1.2 units/mL for mitral valve and 0.8 to 1.0 units/mL for aortic valve replacements at four to six hours post-dose, with trough activity ≥0.6 units/mL) once pregnancy is confirmed. A plan should be made prior to conception as to how this change in therapy will be arranged ideally before five weeks gestation.

During the second and third trimesters

VKA (eg, warfarin) is the anticoagulant option associated with the lowest maternal risk for pregnant women with a mechanical valve. After the first trimester, the risk of warfarin associated fetopathy declines although there remains a risk of fetal loss and fetal hemorrhagic complications. (See 'Evidence' above.)

For most women with mechanical valves, we suggest warfarin (adjusted to INR goal) during the second and third trimesters until 36 weeks (Grade 2C). In making this recommendation, we are placing high value on reducing maternal risk.

Timing of the transition of warfarin to LMWH prior to delivery may need to be individualized for women at high risk for preterm delivery (eg, women post-Fontan operations).

If the mother chooses to avoid the fetal risk associated with warfarin therapy, therapeutic SC LMWH is a reasonable alternative. SC LMWH is dosed twice per day with the dose adjusted to achieve target anti-Xa activity of 1.0 to 1.2 units/mL for mitral valve prosthesis and 0.8 to 1.0 units/mL for aortic valve prosthesis at four to six hours post-dose and ensuring adequate trough activity as well.

Peripartum management for mechanical valves

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. A plan for anticoagulation in labor/peripartum should be agreed to by obstetricians, anesthesiologists, and hematologists and documented clearly. The risks of valve thrombosis and obstetric hemorrhage as well as the desire to use regional anesthesia need to be balanced and the patient fully informed of the rationale for the individualized plan. (See 'Approach for planned delivery' above.)

At approximately 36 weeks, VKA (eg, warfarin) should be switched to dose-adjusted SC LMWH administered at least twice per day.

We prefer to continue low-dose aspirin up until planned delivery. This should be discussed with the anesthesiologist, as aspirin with concurrent early postpartum anticoagulation may increase the risk of spinal epidural hematoma. (See 'Aspirin' above.)

Women treated with SC LMWH can be switched to either 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 peripartum period as detailed above, or receive prophylactic doses of LMWH.

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 'Approach for urgent delivery' above.)

In the absence of significant bleeding, anticoagulation for women with mechanical valves should be resumed shortly after delivery. (See 'Postpartum management' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff would like to thank Drs. Robyn A. North, Beverley Hunt, and William Gaasch for their past contributions as authors and Drs. Catherine Otto and Charles Lockwood for their past contributions as section editors to prior versions of this topic review.

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