Anticoagulation in Pregnancy


9


 


Anticoagulation in Pregnancy


 


Rachel A. Newman, Ather Mehboob, and Judith H. Chung


 



Key Points


Venous thromboembolism occurs in 1–4 per 1000 pregnancies, representing a fivefold increase in the risk of VTE as compared to the nonpregnant state


The highest risk maternal cardiac condition requiring anticoagulation in pregnancy is the presence of a mechanical heart valve


The highest risk thrombophilias include factor V Leiden homozygosity and prothrombin gene G20210A mutation homozygosity


Low molecular weight heparin is the anticoagulant of choice in pregnancy; however, it is primarily excreted by the kidney and therefore is relatively contraindicated in significant renal impairment


The primary advantage for choosing low-dose unfractionated heparin is it the least likely to preclude neuraxial anesthesia


Introduction


Pregnancy is a hypercoagulable state resulting from low-level activation of intravascular coagulation. This physiologic adaptation helps in prevention of hemorrhage at the time of implantation, maintenance of the utero-placental interface, and hemostasis in the third stage of labor. However, hypercoagulability of pregnancy coupled with stasis related to the gravid state leads to an increased risk of venous thromboembolism (VTE) as compared to the nonpregnant state.


 


Physiologic Changes in Pregnancy


VTE occurs in 1–4 per 1000 pregnancies, representing a fivefold increase in the risk of VTE as compared to the nonpregnant state [18]. This increased risk is due to the fact that the three components of Virchow’s triad—hypercoagulability, stasis, and endothelial damage—are effected by the physiologic and hormonal changes of pregnancy. Hormonal factors increase the quantity of coagulation factors while decreasing levels of some natural inhibitors of coagulation [9]. These changes are summarized in Table 9.1.



























Table 9.1


Changes in Coagulation Factors during Pregnancy [9,10]


Coagulation Factors


Effect


Change in Pregnancy


I (fibrinogen), VII, VIII, IX, X


Procoagulant


Increased


II, V, and XII


Procoagulant


Unchanged or mildly increased


Protein S, plasminogen activator


Anticoagulant


Decreased


Protein S, antithrombin III


Anticoagulant


Unchanged


Markers of platelet activation and low levels of fibrin degradation products have been documented in maternal circulation [9], consistent with pregnancy being a state of low level of intravascular coagulation [9,11,12]. These changes occur at the beginning of pregnancy, thus accounting for the increase in VTE occurrence as early as the first trimester [1,13]. Stasis is a result of compression of inferior vena cava and pelvic vessels by the growing uterus and hormone-mediated venous dilation [14]. Furthermore, vascular injury may occur during labor due to fetal descent into the pelvis and possible need for an operative delivery, either vaginal or cesarean, which coincides with the increased risk of VTE in the postpartum period [1517].


 


Maternal Cardiac Lesions That May Require Anticoagulation during Pregnancy


Cardiac lesions in which anticoagulation may be considered are summarized in Table 9.2 [18]. They range from valve prosthesis and structural cardiac defects to arrhythmias. The highest risk maternal cardiac condition requiring anticoagulation in pregnancy is the presence of a mechanical heart valve, as there is elevated risk for valve thrombosis, systemic embolism, and even death [19]. In the nonpregnant state, vitamin K antagonists (VKAs) are the preferred agents for anticoagulation. Use of VKA during pregnancy has also been shown to have the lowest risk of valve thrombosis/systemic embolism at a rate of 3.9% [20,21]; however, due to their teratogenic potential, alternate treatment regimens are utilized in pregnancy [22].





































Table 9.2


Cardiac Lesions in Which Anticoagulation during Pregnancy May Be Considered


Cardiac Lesion


Anticoagulation Indicated


Treatment


Native valve disease


Only in the presence of


Atrial fibrillation or


Atrial flutter or


Left atrial thrombosis or


Prior embolism


Therapeutic anticoagulation in combination or without


VKA


UFH


LMWH


Prosthetic heart valve


Yes


Therapeutic anticoagulation


VKA


UFH


LMWH


Cardiomyopathies—Systolic dysfunction


Only in the presence of Intracardiac thrombus or Atrial fibrillation or Treatment with bromocriptine


Therapeutic anticoagulation in combination or without in Intracardiac thrombus or atrial fibrillation


VKA


UFH


LMWH


Prophylactic anticoagulation in patients on bromocriptine


UFH


LMWH


Implantable cardioverter defibrillator (ICD)


No


N/A


Pulmonary hypertension


Yes, in patients with chronic thromboembolic pulmonary hypertension


Therapeutic anticoagulation with UFH or
LMWH


Congenitally corrected transposition of the great arteries


Yes, anticoagulation should be considered


Therapeutic anticoagulation with UFH or
LMWH


 


Other Considerations for Anticoagulation in Pregnancy


Inherited Thrombophilias


Inherited thrombophilias are a group of genetic disorders that result in an increased risk of venous thromboembolism [23]. The most common and well-studied include factor V Leiden mutation, prothrombin G20210A mutation, protein C deficiency, protein S deficiency, and antithrombin deficiency [23]. Among these, the highest risk thrombophilias include factor V Leiden homozygosity and prothrombin gene G20210A mutation homozygosity. In women with these conditions, the risk of pregnancy-related VTE is approximately 4% [22]. Compound heterozygosity for factor V Leiden and prothrombin gene mutation, in addition to antithrombin deficiency, are also considered to be high risk for VTE [23]. Other less important thrombophilias are methylenetetrahydrofolate reductase (MTHFR) and elevated homocysteine levels. Currently, routine testing is not recommended due to insufficient evidence. In addition, while elevated homocysteine levels, possibly caused by mutations in MTHFR are thought to be a weak risk factor for VTE, MTHFR mutations themselves do not appear to be associated with an increased risk of VTE [23].


Anticoagulation during pregnancy and postpartum women with inherited thrombophilia depends on the underlying diagnosis plus personal or family history of prior thromboembolism. Recommendations vary between the American College of Obstetrics and Gynecology (ACOG) and the American College of Chest Physicians (ACCP) CHEST guidelines summarized in Table 9.3.



























































































Table 9.3


Anticoagulation Guidelines as a Function of Thrombophilia Status, Prior History, and Time during Pregnancy


Thrombophilia Status


Prior History


American College of Obstetrics and Gynecology (ACOG) Guidelines


American College of Chest Physicians (CHEST) Guidelines


Antepartum Anticoagulation


Postpartum Anticoagulationa


Antepartum Anticoagulation


Postpartum Anticoagulation


Negative


1 episode of VTE due to transient risk factor that is no longer present


None


None


Prophylactic dose or


VKA with target INR of 2.0–3.0


None


Prophylactic dose


Intermediate dose


VKA targeted at INR 2.0–3.0


Negative


1 episode of unprovoked, pregnancy- or estrogen-related VTE and not receiving long-term anticoagulation


None


Prophylactic dose


Prophylactic dose or VKA with target INR of 2.0–3.0


Prophylactic dose


Intermediate dose


Prophylactic


Intermediate dose


VKA targeted at INR 2.0–3.0


Low riskb


No VTE


None


None


If other risk factors (first degree relative with history of thrombotic event prior to 50 years old, obesity, prolonged immobility), consider prophylactic anticoagulation or VKA with target INR of 2.0–3.0


None


Prophylactic dose


Intermediate dose


VKA targeted at INR 2.0–3.0 can be considered in women without protein C or S deficiency


Low riskb


1 episode of VTE and not receiving long term anticoagulation


Prophylactic Intermediate dose


No anticoagulation can also be considered


Prophylactic or VKA with target INR of 2.0–3.0


Intermediate dose


No specific recommendations


No specific recommendations


High riskc


No VTE


Prophylactic dose


Prophylactic dose or VKA with target INR of 2.0–3.0


No family history of VTE, no anticoagulation


Positive family history, Prophylactic or Intermediate dose


Prophylactic


Intermediate dose


High riskc


1 episode of VTE and not receiving long term anticoagulation


Prophylactic


Intermediate


Adjusted dose


Prophylactic or VKA with target INR of 2.0–3.0


Intermediate


Adjusted dose


No specific recommendations


No specific recommendations


Thrombophilia or no thrombophilia


Acute VTE during pregnancy


Therapeutic dose


No recommendations given


Adjusted dose for a minimum duration of 3 months followed by Prophylactic or Intermediate dose


Prophylactic


Intermediate dose


Therapeutic dose if minimum duration of treatment was not achieved prior to delivery


Thrombophilia or no thrombophilia


2 episodes of VTE and not receiving long term anticoagulation


Prophylactic


Therapeutic dose


Prophylactic or VKA with target INR of 2.0–3.0


Therapeutic dose


No specific recommendations


No specific recommendations


Thrombophilia or no thrombophilia


2 episodes of VTE and receiving long term anticoagulation


Therapeutic dose


Resumption of long-term anticoagulation regimen


No specific recommendations


No specific recommendations


Thrombophilia or no thrombophilia


Mechanical heart valve


Therapeutic dose


Therapeutic dose


Therapeutic dose plus low-dose aspirin


Options include


Therapeutic LMWH or UFH throughout pregnancy


UFH or LMWH until 13 weeks with transition to VKA until delivery when UFH or LMWH is resumed


VKA through the entirety of the pregnancy with transition to UFH or LMWH at delivery


Therapeutic dose


(Continued)


Antiphospholipid Syndrome


In contrast to inherited thrombophilias, antiphospholipid syndrome (APS) is an acquired thrombophilia with an increased risk of VTE along with pregnancy complications. It is an autoimmune disorder characterized by the presence of at least one circulating antiphospholipid antibody (present on two or more occasions at least 12 weeks apart) in conjunction with at least one clinical criterion [24,78]. The requirements for the diagnosis of APS is summarized in Table 9.4.















Table 9.4


Required Laboratory and Clinical Criteria for the Diagnosis of Antiphospholipid Antibody Syndrome (APS)a


Laboratory Criteriab


Clinical Criteria


1.Circulating lupus anticoagulant


2.Medium to high titers of anticardiolipin antibodies (IgM and/or IgG)


3.Medium to high titers of anti-B2 glycoprotein I antibodies (IgM and/or IgG)


1.Vascular thrombosis


History of one or more episodes of arterial, venous, or small vessel thrombosis


2.Pregnancy morbidity


Prior pregnancy morbidity including three or more unexplained spontaneous pregnancy losses prior to 10 weeks’ gestation with other causes excluded


One or more unexplained fetal death after 10 weeks’ gestation with other causes excluded


One or more preterm births prior to 34 weeks’ gestation due to eclampsia, preeclampsia with severe features, or evidence of placental insufficiency


Due to the elevated risk of vascular thrombosis and pregnancy complications, it is imperative that women meeting the criteria for APS should receive treatment before, during, and after pregnancy. Indications for APS testing include a history of venous or arterial thrombosis or a history of pregnancy loss, either three or more unexplained losses prior to 10 weeks’ gestation, or one unexplained death after 10 weeks’ gestation. While clinical criteria for APS also includes early-onset preeclampsia or growth restriction requiring delivery prior to 34 weeks, expert opinion does not uniformly recommend screening for APS in women with this history as there is not enough evidence to suggest that diagnosis and treatment of APS in these scenarios improves the outcome of subsequent pregnancies [25]. Other conditions often associated with APS include hemolytic anemia, autoimmune thrombocytopenia, amaurosis fugax, livedo reticularis, systemic lupus erythematosus, and false positive rapid plasma regain test [25]. However, as these are not among the clinical criteria for a diagnosis of APS, the ACOG does not recommend APS testing in these patients for the purposes of pregnancy management. Recommendations for anticoagulation in pregnancy with APS are summarized in Table 9.5.



































Table 9.5


Anticoagulation Guidelines in Patients with Antiphospholipid Antibody Syndrome (APS)


Prior History of Thromboembolism


American College of Obstetrics and Gynecology (ACOG) Guidelines


American College of Chest Physicians
CHEST Guidelines


Antepartum


Anticoagulation


Postpartum Anticoagulationa


Antepartum


Anticoagulation


Postpartum
Anticoagulation


None


None or prophylactic dose


Prophylactic dose


No specific recommendations


No specific recommendations


Recurrent pregnancy loss


Prophylactic dose and low-dose aspirin


Prophylactic anticoagulation and low-dose aspirin


Prophylactic and low-dose aspirin


Intermediate dose and low-dose aspirin


No specific recommendations


History of arterial, venous, or small vessel thrombosis


Prophylactic dose ± low-dose aspirin


Prophylactic anticoagulation



What Are the Options for Anticoagulation in Pregnancy?


There is limited high-quality data regarding specific thromboprophylaxis guidelines in pregnancy [26]. However, multiple guidelines prefer low molecular weight heparin (LMWH) over unfractionated heparin (UFH) in the antepartum outpatient setting [22,27,29]. When choosing a treatment plan, maternal and fetal safety must be balanced. Considerations include altered pharmacokinetics of the drug, concern for teratogenicity to the fetus, and management of anticoagulation around the time of delivery.


There are two categories of anticoagulation dosing: prophylactic and therapeutic. Prophylactic dosing reduces the risk of VTE while minimizing bleeding complications [30]. Therapeutic anticoagulation is utilized for treatment of active thromboembolic disease, or when there is a concern that prophylactic dosing will be inadequate for a patient at high risk of developing a thromboembolism. If required, both prophylactic and therapeutic prophylaxis should be initiated as soon as an intrauterine gestation is confirmed [27,31]. Both ACOG and ACCP have published guidelines to assist in determining whether a patient requires prophylactic versus therapeutic prophylaxis [10,27,32].


Patients with a low-risk thrombophilia (factor V Leiden or prothrombin gene mutation heterozygosity, protein C or S deficiency), low-risk thrombophilia with a family history of VTE, or a prior provoked VTE (associated with a temporary risk factor such as surgery, indwelling catheter, prolonged immobilization) are considered low risk and do not require antepartum prophylactic or therapeutic anticoagulation. The medium-risk category includes:


1.Prior idiopathic VTE


2.Prior VTE with pregnancy or estrogen-containing oral contraception


3.Prior VTE with low-risk thrombophilia


4.Family history of VTE with high-risk thrombophilia


5.High-risk thrombophilia or antiphospholipid syndrome


High-risk thrombophilias include antithrombin III deficiency, factor V Leiden or prothrombin gene mutation homozygosity, or compound heterozygosity. Patients who fall into this category should receive prophylactic LMWH or UFH throughout their pregnancies. Those at high risk of developing a VTE in pregnancy include patients with:


1.Current VTE or multiple prior VTEs


2.Prior VTE with a high-risk thrombophilia


3.Prior VTE with antiphospholipid syndrome


These patients should be started on therapeutic dose LMWH or UFH as soon as a pregnancy is confirmed. If a patient has another medical condition requiring anticoagulation (e.g., mechanical heart valve), she should continue on therapeutic thromboprophylaxis throughout her pregnancy. It is recommended that women on therapeutic anticoagulation be co-managed with maternal-fetal medicine and hematology [27].


 


What Are the Different Options for Anticoagulation Therapy?


Low Molecular Weight Heparin


Heparins (LMWH and UFH) are considered safe in pregnancy as they do not cross the placenta and have not been found to be teratogenic [27]. LMWH is more often recommended as it has a more predictable anticoagulant response and does not require as intensive monitoring as in in the case of UFH [33,34].


LMWH is administered subcutaneously, either once or twice daily, depending on whether therapeutic or prophylactic dosing is needed. There are several formulations of LMWH. As enoxaparin is most widely used in the United States, it will be the basis for the following discussion. For prophylactic dosing, typically enoxaparin 40 mg every 24 hours is used. As a patient’s weight increases during pregnancy, dosing can be increased to 1 mg/kg daily [30]. Therapeutic dosing is based on patient’s weight (in kilograms) and anti-factor Xa levels. Therapeutic LMWH is often administered as enoxaparin 1 mg/kg every 12 hours. Therapeutic dosing can also be achieved with enoxaparin 1.5 mg/kg daily. This regimen creates greater fluctuation in heparin levels and is avoided in pregnancy [10].


LMWH is metabolized by the liver and is exclusively excreted by the kidney. A baseline platelet and creatinine are drawn prior to starting prophylactic LMWH. Therapeutic LMWH requires regular monitoring. The mechanism of action for LMWH is inhibition of activated factor X (Xa). To assess anticoagulation, an anti-Xa assay is drawn after the third dose, measuring the inactivation of the coagulation factor. In general, anti-Xa 0.6–1.0 IU/mL 4–6 hours after receiving a dose of enoxaparin is considered therapeutic. Of note, anti-Xa levels have not been validated in pregnancy [22,29]. After a therapeutic dose is achieved, routine anti-Xa monitoring is not recommended due to cost and lack of high-quality evidence [22,29].


In addition, for patients on therapeutic LMWH, obtain a baseline platelet count. It should be drawn at regular intervals to monitor for development of heparin-induced thrombocytopenia (HIT), a rare, potentially life-threatening complication of heparin use [22,35]. As the risk of HIT is 14-fold higher with use of UFH compared to LWMH, it will be discussed further under UFH [27]. In heparin-naïve patients, the onset of HIT is typically 5–10 days after initiation; platelets should be watched most closely the first 2 weeks of starting any heparin therapy [36].


Limitations and Benefits of LMWH


LMWH has a longer half-life than UFH, however it cannot be fully reversed with protamine sulfate.


Regarding delivery planning, the Society for Obstetric Anesthesia and Perinatology and the American Society of Regional Anesthesia and Pain Medicine (ASRA) state that a patient on LMWH cannot receive neuraxial anesthesia if she has received a prophylactic dose within the last 12 hours or a therapeutic dose within the last 24 hours [27,37,38]. To avoid this inconvenience, the provider can schedule an induction, or if indicated for obstetric reasons, a cesarean section, and instruct the patient to take the last dose 12 or 24 hours prior to procedure, depending on the dosing.


LMWH is primarily excreted by the kidney and is relatively contraindicated in significant renal impairment. If a patient shows signs of renal damage, she may need to be switched to UFH, which is cleared by both the kidneys and the liver.


Despite these limitations, LMWH is the preferred anticoagulant for the majority of patients [21,29,41,42]. It is widely available and cost effective. It has greater bioavailability than UFH and does not cross the placenta, minimizing the risk of teratogenicity and fetal anticoagulation. As mentioned, there is a stronger association between dose and anticoagulant response, so it does not have to be monitored too frequently. In addition, HIT is significantly less likely to occur in women using LMWH.


Unfractionated Heparin


UFH has a shorter half-life than LWMH. The majority of women are switched to UFH at 36–37 weeks’ gestation, or earlier if there is a concern for preterm labor, to increase the likelihood that a patient will be able to receive neuraxial anesthesia for delivery [10,27,31]. The general exception to this is women at a very high risk for VTE (e.g., mechanical heart valves, atrial fibrillation with thrombus) and time without anticoagulation should be avoided. Separate guidelines exist for managing anticoagulation and delivery planning in these women.


UFH is available as a subcutaneous injection or an intravenous drip. Prophylactic dosing of UFH is often started at 5000–7500 units twice daily and may be titrated up to 10,000 units subcutaneously twice a day in the third trimester.


Therapeutic dosing is titrated based on activated partial thromboplastin time. Therapeutic range is generally 1.5–2.5 times a patient’s baseline aPTT but can change based on why the anticoagulation is indicated. Blood sample for aPTT is collected 6 hours after an injection. Activated partial thromboplastin time is measured daily until a therapeutic dose is achieved, and every 1–2 weeks subsequently.


Limitations and Benefits of UFH


The incidence of HIT is higher in women on UFH due to an autoantibody to the platelet factor 4 heparin complex, which then paradoxically causes thrombosis [27]. To diagnose HIT, a patient must display at least one of the following: 50% decrease in platelet count after administration of heparin, necrosis at the heparin injection site, general skin necrosis, or heparin-dependent platelet-activating IgG antibodies. Obstetric practitioners must consult hematology if there is a concern for HIT [27]. In patients who have received any type of heparin in the preceding 100 days and are restarting UFH or LMWH, HIT can occur in up to 0.8% of patients [36]. A baseline platelet count is drawn within 24 hours of restarting therapy [27,36,44,45]. If a heparin has been used recently, HIT will manifest within the first 24 hours rather than the typical 5–10 days post-heparin initiation [36].


Studies are inconclusive, though some suggest that prolonged use of UFH can lead to decreased bone mineral density [46,47].


UFH is preferred in the peripartum period as it is less likely to limit a patient’s ability to have neuraxial anesthesia. Variation in expert opinion exists regarding time interval between low-dose UFH and spinal and/or epidural administration; a discussion regarding timing should be held between the anesthesia and obstetric teams and the patient [48]. The effects of UFH can be reversed with protamine sulfate. As UFH is primarily cleared by the reticuloendothelial system, it is a preferred agent in renal failure patients with creatinine clearance <30 mL/min.


Heparin Drip


In patients who have been on therapeutic LMWH during pregnancy and require anticoagulation in labor, on admission to the hospital an intravenous heparin drip is often started. Intravenous drip allows for rapid dose adjustments and quicker initiation/termination of therapy, should emergent circumstances arise.


When a patient requiring therapeutic anticoagulation arrives on Labor and Delivery, at minimum, a baseline CBC, PT with international normalized ratio (INR), and aPTT should be obtained. At many institutions, dosing a heparin drip is done by pharmacy. There is a paucity of conclusive evidence regarding the optimal initial dosing of a heparin drip [49]. The 2012 ACCP recommend either a fixed regimen of an initial 5000 unit bolus followed by 1300 units/hr or a weight based regimen (Raschke regimen) [32,49,50]. One has not been shown to be superior to the other regarding VTE prevention in the nonpregnant population [51]. This can be extrapolated to the obstetric patient.


Once a heparin drip has been started, obtain an anti-factor Xa level 6 hours after initiating the treatment. Target therapeutic heparin level is 0.3–0.7 unit/mL [52]. Continue monitoring anti-factor Xa every 4–8 hours while the infusion is running, even if therapeutic levels have been achieved. The heparin infusion is typically stopped six hours prior to expected delivery [27].


It is also crucial to monitor platelets for signs of HIT (platelet drop >50% or decrease <150,000 k/µL).


Limitations and Benefits of UFH Drip


The primary challenge with unfractionated heparin use is the nonlinear dose-response relationship [49]. Nevertheless, UFH drips are preferred in labor as they allow patients to have the option of neuraxial anesthesia more readily than those on LMWH.


Guidelines recommend that the unfractionated heparin drip should be stopped 4–6 hours prior to placing an epidural [53,54]. A normal aPTT should be verified. After the epidural is placed, only 1 hour needs to elapse prior to restarting therapy [38,50,54].


Should delivery be required emergently, unfractionated heparin can be fully reversed with protamine sulfate.


Thus, a heparin drip allows for greater flexibility in balancing anticoagulation with comfort and control in labor.


Warfarin


Warfarin, an oral vitamin K antagonist, is generally avoided in pregnancy as it can cross the placenta and cause fetal anticoagulation as well as multiple birth defects [55,56]. Exception to this is women with mechanical heart valves and risk factors such as atrial fibrillation, previous thromboembolic complications, or multiple mechanical valves. It is recommended that warfarin be continued through 36 weeks of gestation. This places highest importance on reducing maternal risk of a thrombotic event. If reduction of fetal risk is prioritized, patients should be counseled that warfarin has been associated with poor development of bone and cartilage, leading to nasal and limb bone hypoplasia and epiphyseal stipping [57]. It may also be associated with early miscarriage and late fetal loss [3,56,58,59]. Studies are not conclusive as to whether this is due to the warfarin itself or the underlying conditions for which it is used.


If warfarin is continued, doses <5 mg/day appear to be the safest, though teratogenic effects have been reported [58,60,61]. At any dose, risk of fetal complication is highest between the 6th and 12th weeks of gestation [57]. If a patient’s pre-pregnancy daily dose is >5 mg/day, it is recommended a patient switch to therapeutic LMWH for the first trimester [62].


Warfarin is only used for therapeutic purposes. Prior to initiating treatment, a CBC, basic metabolic panel, and coagulation panel (PT, aPTT, INR) are obtained to assess for baseline abnormalities with platelets, creatinine, liver function, and coagulation. A Cochrane review of randomized trials comparing initial doses of 5 or 10 mg did not demonstrate improved outcomes [63]. In addition, the 10 mg dose was more likely to result in a supra therapeutic INR, increasing the risk of bleeding [64,65]. A starting dose of <5 mg is recommended.


The full anticoagulation effect of warfarin does not occur until 2 or 3 days after first administration. The first lab value to reflect this is PT/INR, as factor VII is quickly depleted [66]. Other vitamin Kdependent factors take longer to deplete, i.e., another 23 days. The goal INR may vary based on the clinical setting, but the recommended range is typically 2.0–3.0 times normal. A patient on warfarin must have her INR monitored 3–4 days after the first dose and then serially through the pregnancy. Intervals may vary depending on the dose and indication as determined by the hematology and/or maternal-fetal medicine specialist. Once therapeutic level is achieved, warfarin should be continued until 36 weeks’ gestation, at which time the patient is transitioned to therapeutic LMWH or UFH. If a patient is at high risk for early delivery, the timing of this transition may vary.


Limitations and Benefits of Warfarin


Warfarin use is less frequent in pregnancy. As mentioned, the primary drawback is its ability to cross the placenta, resulting in known fetal teratogenicity and increased risk of hemorrhage. It is also challenging because of the narrow therapeutic window and frequent monitoring. As it is a vitamin K antagonist, patients need to comply to avoid food rich in vitamin K (leafy green vegetables, broccoli, liver, etc.).


Despite its limitations, warfarin has distinct advantages. Warfarin is inexpensive and widely available. It is possible to reverse its anticoagulant effect with vitamin K, fresh frozen plasma, or prothrombin complex concentrates. More importantly, it is taken by mouth, which may appeal to patients with a fear of needles.


Other Anticoagulants


There are a multitude of new oral anticoagulants. These include direct thrombin inhibitors, such as dabigatran and argatroban, as well as direct factor Xa inhibitors, such as rivaroxaban and apixaban. In general, they should not be used in pregnancy as little is known about efficacy and fetal safety [21]. If a woman is on one of these medications and becomes pregnant, she should switch to LMWH immediately.


Aspirin


Aspirin (acetylsalicylic acid) is not an anticoagulant but is often used in pregnancy as part of a thromboprophylaxis regimen. The mechanism of action is to prevent platelet aggregation through irreversible inhibition of cyclooxygenase-1 and 2 (COX-1 and 2) enzymes [67].


Studies have shown the efficacy of using aspirin in conjunction with thromboprophylaxis in women with mechanical heart valves as well as those with recent strokes or at high risk for developing an ischemic event [21].


Low-dose aspirin has also been used in pregnancy to help prevent preeclampsia [68]. The etiology of preeclampsia is multifactorial. There is some evidence suggesting that an imbalance of prostacyclin and TXA2 may result in preeclampsia [69]. At doses <150 mg/day, aspirin may help by preferentially inhibiting TXA2 [70,71]. Initially, use of low dose aspirin for preeclampsia prevention was based on results of several small trials. More recently, larger randomized controlled trials and multiple meta-analyses have confirmed these findings [70,7276]. Treatment is generally initiated between 12 and 28 weeks of pregnancy, but a recent meta-analysis demonstrated that maximal efficacy only occurs when started prior to 16 weeks [73]. While no consensus exists on timing or dosage of treatment, multiple guidelines, including the World Health Organization (WHO), ACOG, and U.S. Preventative Task Force recommend use of low-dose aspirin for preeclampsia prevention as there is clear benefit and few maternal or fetal adverse effects.


Low-dose aspirin has also been used to treat women with APS. There are three antiphospholipid proteins assessed as part of the diagnosis for APS: lupus anticoagulant, anticardiolipin, and anti-β2 glycoprotein. β2 glycoprotein is primarily clinically relevant as it may have a regulatory role in coagulation and fibrinolysis [77]. In women with APS who have had a thrombotic event, prophylactic anticoagulation is recommended throughout pregnancy and 6 weeks postpartum [22,25]. Low-dose aspirin is also added, though the evidence remains inconclusive about the benefit of this treatment [25].


The optimal treatment for women with APS without a preceding thrombotic event is not well studied. Expert consensus recommends either clinical surveillance or prophylactic heparin in addition to 6 weeks of postpartum anticoagulation [22,25]. A recent meta-analysis found that in women with recurrent pregnancy loss and antiphospholipid antibodies, prophylactic heparin and low-dose aspirin can reduce pregnancy loss by 50% [79]. This combination is superior to low-dose aspirin or prednisone alone [79].


To date, there is insufficient evidence to recommend use of low-dose aspirin for prevention of stillbirth, fetal growth restriction, or preterm birth [69].


 


Preconception Period


The majority of women will not require thromboprophylaxis during the antenatal period. Women who are already on anticoagulation or have a high-risk condition that will necessitate thromboprophylaxis in pregnancy require preconception counseling. Patients at high risk can be identified by existing ACOG and ACCP guidelines. See Chapter 4 on preconception counseling for further information.


 


Delivery Planning


Delivery is a time at which women are at increased risk of hemorrhage. Therefore, careful multidisciplinary planning must be done for patients on thromboprophylaxis. LMWH is the preferred anticoagulant during pregnancy; however, the duration of its half-life can limit a patient’s ability to receive neuraxial anesthesia and theoretically increase her risk of postpartum hemorrhage. For this reason, after 36 weeks’ gestation, or earlier if preterm labor is suspected, alternative anticoagulation plans are made [27,80]. A patient may choose to continue LMWH (either prophylactic or therapeutic), transition to low-dose UFH twice daily (5000 units), or transition to high-dose UFH twice daily (10,000 units, ACOG recommended).


If a patient chooses to continue LWMH, the main advantage is the close correlation between dose and anticoagulant effect. In addition, monitoring requirements are limited. The primary disadvantage is the prolonged length of time between the last dose of LMWH and the possibility of neuraxial anesthesia.


The primary advantage for choosing low-dose UFH is that it the least likely to preclude neuraxial anesthesia. The potential disadvantages include twice-daily dosing, increased dose requirements in the third trimester, and significant variation in guidelines between timing of last dose and neuraxial anesthesia.


High-dose UFH may be advantageous over low-dose UFH for providing more effective thromboprophylaxis, but there is no high-quality research to substantiate this [10]. Similar to low-dose UFH, the primary disadvantages include variable dose-response relationship, frequent lab monitoring, and twice-daily dosing.


There is no established gestational age for delivery; it depends on indication for anticoagulation. Patients are instructed to take the last dose 12–24 hours prior to a planned induction of labor or scheduled cesarean delivery [38,48].


Induction of Labor


For an induction, patients who have been on therapeutic anticoagulation are started on an unfractionated heparin drip. Close monitoring of the therapeutic level is monitored with aPTT. When a patient desires neuraxial anesthesia, preliminary ASRA guidelines recommend 46 hours between administration of a therapeutic dose and neuraxial blockade [27,48]. Prior to placement, aPTT should have normalized. If it has not, aPTT is rechecked in 1 hour, and repeated until the value has normalized before placing the catheter for neuraxial anesthesia.


After the epidural catheter or spinal is placed, the 2018 ASRA guidelines recommend that 4 hours elapse prior to restarting the UFH drip [53]. If the placement of neuraxial anesthesia is complicated, the obstetric and anesthesia teams must work together to balance the need for maternal anticoagulation with the rare but serious risk of a spinal hematoma. If a UFH drip has been restarted and the patient continues to labor, the clinical expertise of the provider is used to determine at what cervical dilation it should be stopped. This is often between 6–8 cm dilation. See the below section for a discussion of when thromboprophylaxis should be restarted in the postpartum period.


Spontaneous Labor


If a patient presents in spontaneous labor, recent anticoagulation use often makes her ineligible for an immediate epidural. LMWH effect cannot be reliably reversed with protamine sulfate and therefore is not used for reversal purposes in these patients. Instead, the patient’s primary pain control in labor will be intravenous medication. If, in the course of her labor, anesthesia determines that it is safe to place an epidural catheter, it is at the discretion of their team. If the patient has been receiving UFH for her anticoagulant, it can be reversed with protamine sulfate and has a shorter half-life. These patients may be candidates for neuraxial anesthesia.


Emergency Cesarean Section


Should a patient who has been fully anticoagulated require an emergency cesarean section, protamine sulfate is given regardless of whether she has been on LWMH or UFH. All members of the team should be aware of the type of anticoagulant the patient has been on and have a contingency plan outlined accordingly in conjunction with anesthesia and hematology. In the event of postpartum- or surgery-related hemorrhage, blood products should be made available immediately.


 


Risk of Postpartum Hemorrhage


Use of anticoagulation in pregnancy increasing the risk of postpartum hemorrhage (PPH) has not been borne out in the literature. A small retrospective cohort study on the effects of LWMH on bleeding at the time of vaginal delivery found that the risk of PPH was significantly higher in the cohort of women on therapeutic LMWH [39]. However, the risk of severe PPH (>1000 cc estimated blood loss) was comparable between the two groups [39]. There was no significant difference in PPH for patients who delivered by cesarean section, including emergent deliveries [39]. Overall, the PPH risk was not increased in women who delivered within 24 hours after the last dose of LMWH versus those who delivered more than 24 hours after the last dose [39].


Another retrospective cohort study (n = 77) found that antepartum anticoagulation had a greater incidence of wound complications, but there were no differences in the mean estimated blood loss or women receiving blood products [81]. Although these studies are small, the findings have been replicated [40].


 


Postpartum


There is an absence of high-quality evidence regarding the best postpartum prophylactic anticoagulation regimen. For patients who have been on UFH prophylaxis, the first dose may be administered 1 hour after the spinal needle was placed or the epidural catheter has been removed [31,82]. If LMWH has been used for prophylaxis, the CMQCC Maternal VTE Task Force and ASRA recommends that a minimum of 12 hours elapse between removal of the epidural catheter or spinal needle placement and administration of LWMH.


For patients who have been on therapeutic anticoagulation during pregnancy, ACOG and ASRA recommend waiting at least 24 hours after delivery (vaginal or cesarean) prior to initiating therapeutic LMWH (e.g., enoxaparin 1 mg/kg every 12 hours) [10,27,48]. The most recent preliminary ASRA guidelines also support waiting an hour after neuraxial block or epidural catheter removal prior to administration of therapeutic UFH (>10,000 units per day) [38,48]. ACOG recommends that the dose of therapeutic anticoagulation be equal or greater to that required in pregnancy [10].


For women at a high risk of postpartum VTE, anticoagulation should continue for 6 weeks postpartum [10,27]. This includes women with a high-risk thrombophilia, personal history of VTE, or a low-risk thrombophilia with a family history of VTE. Women at very high risk of postpartum VTE (antithrombin III deficiency, mechanical heart valves, recent VTE) will also require 6 weeks of postpartum anticoagulation.


If a patient has had a single prior provoked pulmonary embolism or a low-risk thrombophilia, she does not require antepartum coagulation. As the risk for a VTE increases in the postpartum period, the National Partnership for Maternal Safety, ACCP, and Royal College of Obstetricians and Gynecologists recommend postpartum prophylaxis for 6 weeks [15,28,44]. ACOG allows for 4 weeks of postpartum treatment [10].


 


Bridging Anticoagulation


If a patient will not require anticoagulation greater than 6 weeks postpartum, she will often choose to remain on LMWH rather than bridge to warfarin. For patients on warfarin prior to pregnancy or who will require anticoagulation longer than 6 weeks, a bridge to warfarin is recommended [15,27,31]. There are varying opinions on when to (re)start warfarin postpartum. It is not uncommon to see warfarin restarted 24–48 hours after delivery. However, the CMQCC Maternal VTE Task Force does not recommend bridging sooner than 2 weeks postpartum [27]. While bridging, a patient typically requires simultaneous warfarin and heparin. This increases a patient’s bleeding risk. Frequent monitoring is required until the INR is in therapeutic range. The patient should be closely followed by an anticoagulation specialist and/or hematologist during this period of transition.


Breastfeeding


Neither heparin nor warfarin is contraindicated in breastfeeding. Should a patient desire to transition to one of the newer oral anticoagulants, there is insufficient data to support safety of use while breastfeeding.


 


Contraception


Contraception options depend on the indication for thromboprophylaxis in pregnancy. In general, the risk of a VTE is increased during pregnancy and in the postpartum period. The risk is most pronounced in the first 3 weeks after delivery, declining to baseline levels by 42 days postpartum [15,16,28]. Please refer to the chapter on contraception for further information.


 


Conclusion


Pregnancy affords unique challenges in women with an underlying risk of venous and/or arterial thrombosis. Pregnancy itself may increase the inherent risk of thrombosis in such women due to the hypercoagulable changes that occur as the result of the pregnant state. Pregnancy may also require individualization of therapy in women on VKA given the potential fetal risks. The management of labor and delivery can be particularly complex for women requiring anticoagulation given the innate risk of hemorrhage during this process. The role of multidisciplinary planning with the anesthesiologist and hematologist cannot be overemphasized.


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