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Pregnancy-Related Venous Thromboembolism Emily M. Armstrong, Jessica M. Bellone, Lori B. Hornsby, Sarah Treadway and Haley M. Phillippe Journal of Pharmacy Practice published online 17 April 2014 DOI: 10.1177/0897190014530425 The online version of this article can be found at: http://jpp.sagepub.com/content/early/2014/04/16/0897190014530425
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Article Journal of Pharmacy Practice 1-10 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190014530425 jpp.sagepub.com
Pregnancy-Related Venous Thromboembolism Emily M. Armstrong, PharmD, BCACP1,2, Jessica M. Bellone, PharmD, BCACP3, Lori B. Hornsby, PharmD, BCPS1,4, Sarah Treadway, PharmD, BCPS1,5, and Haley M. Phillippe, PharmD, BCPS1,6
Abstract Pregnancy is associated with an increased risk of venous thromboembolism (VTE), with a reported incidence ranging from 0.49 to 2 events per 1000 deliveries. Risk factors include advanced maternal age, obesity, smoking, and cesarian section. Women with a history of previous VTE are at a 4-fold higher risk of recurrent thromboembolic events during subsequent pregnancies. Additionally, the presence of concomitant thrombophilia, particularly factor V Leiden (homozygosity), prothrombin gene mutation (homozygosity), or antiphospholipid syndrome (APS), increases the risk of pregnancy-related VTE. Low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) are the drugs of choice for anticoagulation during pregnancy. LMWH is preferred due to ease of use and lower rates of adverse events. Women with high thromboembolic risk particularly those with a family history of VTE should receive antepartum thromboprophylaxis. Women with low thromboembolic risk or previous VTE caused by a transient risk factor (ie, provoked), who have no family history of VTE, may undergo antepartum surveillance. Postpartum anticoagulation can be considered in women with both high and low thromboembolic risk. Keywords thrombophilia, pregnancy, inherited thrombophilia, acquired thrombophilia, prophylaxis
Introduction Pregnancy increases the risk of venous thromboembolism (VTE) due to various physiological and anatomical changes.1-3 The presence of an underlying thrombophilia, either inherited or acquired, may further increase this risk.4 Studies reporting a higher risk of VTE during the postpartum period as compared to the antepartum period suggest differences in VTE throughout the course of pregnancy.4-7 This review will focus on risk factors associated with VTE in pregnancy as well as considerations for both prophylaxis and treatment of VTE during pregnancy and the postpartum period.
Incidence and Overall Risk VTE remains one of the leading causes of maternal morbidity and mortality in developed countries, accounting for approximately 10% of pregnancy-related deaths.8 During pregnancy, there is a 4- to 5-fold increased risk of VTE, with a reported incidence ranging from 0.49 to 2 events per 1000 deliveries.1,4,9 Approximately 80% of cases with pregnancy-associated VTE are due to deep vein thrombosis (DVT) and 20% due to pulmonary embolism (PE). One meta-analysis found two-thirds of DVT occurred during the antepartum period (period before childbirth), while as many as 60% of pregnancy-related PE
occur up to 6 weeks postpartum.5-7 The risk of VTE begins to increase in the first trimester prior to the anatomic changes associated with pregnancy.4,9 Although a higher risk of VTE during the third trimester has been reported, other studies have suggested there is an equal risk of events throughout each trimester.5,9-13 The postpartum risk of VTE exceeds that of the antepartum period. During the first 6 weeks postpartum, the risk of VTE is up to 80-fold higher, with the highest risk occurring during the first week postpartum.4 Although the rate of
1 Department of Pharmacy Practice, Auburn University Harrison School of Pharmacy, Auburn, AL, USA 2 Department of Internal Medicine, University of South Alabama, Mobile, AL, USA 3 Department of Pharmacy Practice, Concordia University Wisconsin School of Pharmacy, Mequon, WI, USA 4 Midtown Medical Center, Outpatient Clinic, Columbus, GA, USA 5 Department of Family Medicine, University of South Alabama, Mobile, AL, USA 6 Family Medicine-Huntsville Campus, University of Alabama School of Medicine, Huntsville, AL, USA
Corresponding Author: Emily M. Armstrong, Department of Internal Medicine, University of South Alabama, 650 Clinic Drive, Suite 2100, Mobile, AL 36688, USA. Email: [email protected]
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VTE is approximately 100 per 100 000 woman years during pregnancy, the rate during the postpartum period increases to approximately 500 per 100 000 woman years.10 In comparison, studies have estimated that the risk of VTE following cesarean section ranges from 30 kg/m2), smoking, and cesarian section have been reported to increase the risk of VTE.27 When determining an individual’s risk of thrombosis during pregnancy, all potential risk factors (Table 2) should be taken into consideration.1,3,14
Treatment Oral Anticoagulants Women who experience an acute VTE during pregnancy should receive therapeutic doses of anticoagulation throughout pregnancy and up to 6 weeks postpartum, for a total minimum
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Table 2. Additional VTE Risk Factors in Pregnancy.1,4,5,14 Preexisting Personal history VTE Sickle cell disease Smoking—postpartum VTE Obesity—postpartum VTE Smoking—antepartum VTE Age > 35 years Diabetes Obesity—antepartum VTE Hypertension
Odds ratio (95% CI) 24.8 6.7 3.4 2.4 2.1 2.1 2.0 1.8 1.8
(17.1-36.0) (4.4-10.1) (2.0-5.5) (1.7-3.3) (1.3-3.4) (2.0-2.3) (1.4-2.7) (1.3-2.4) (1.4-2.3)
Transient
Odds ratio (95% CI)
Infection—vaginal delivery Postpartum hemorrhage with surgery Immobility—postpartum VTE Immobility—antepartum VTE In vitro fertilization—twins Infection—any cesarian section Preeclampsia with IUGR In vitro fertilization—singleton Postpartum hemorrhage with surgery without surgery Preeclampsia without IUGR Cesarian section Emergency without infection Twin pregnancy Cesarian section Routine without infection
20.2 12 10.8 7.7 6.6 6.2 5.8 4.3 4.1 3.1 2.7
(6.4-63.5) (3.9-36.9) (4.0-28.8) (3.2-19.0) (2.1-21.0) (2.4-16.2) (2.1-16.0) (2.0-9.4) (2.3-7.3) (1.8-5.3) (1.8-4.1)
2.6 (1.1-6.2) 1.3 (0.7-2.2)
Abbreviations: CI, confidence interval; IUGR, intrauterine growth restriction; VTE, venous thromboembolism.
duration of 3 months.2,27 Although warfarin is the drug of choice for long-term management of VTE in most situations, it is considered category X by the Food and Drug Administration due to the teratogenic effects seen in the fetus and infant.27 Warfarin exposure during the 6th to 10th week of gestation has been associated with a coumarin embryopathy, which consists of nasal hypoplasia and stippled epiphyses.27 There is also an increased risk of miscarriage, stillbirth, dorsal midline dysplasia, ventral midline dysplasia, and fetal wastage with warfarin use in pregnancy.3,27 Warfarin may however be used during the breast-feeding period.27 Rivaroxaban, although approved for the treatment of VTE in the nonpregnant population, does not have data for treatment during pregnancy. Preclinical animal studies have shown that rivaroxaban crosses the placenta and causes maternal hemorrhagic complications, increases fetal toxicity, decreases the number of live fetuses, and reduces fetal body weight.30-32 Animal studies have also demonstrated rivaroxaban to be secreted into breast milk and therefore should not be used for VTE treatment in breast-feeding women at this time.30-32
Heparin Compounds Heparin compounds such as unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) do not cross the placenta and have not been associated with fetal bleeding or teratogenicity; therefore, these agents are the preferred anticoagulants during pregnancy.2,4,27 Additionally, as UFH and LMWH do not accumulate in breast milk, they are considered compatible with breast-feeding.2,27 LMWHs have largely replaced UFH for treatment of thromboembolism in pregnancy. In studies of nonpregnant patients, LMWH has been shown to be as safe and efficacious as UFH in the acute treatment of DVT and PE.1,4 Other studies in the nonpregnant population have also demonstrated that LMWH is as effective as warfarin in preventing recurrent VTE.27 LMWH use in 2777 pregnancies was found to be safe and efficacious, with no maternal
deaths and an overall rate of VTE of 0.86% (95% CI 0.55%-1.28%).33 In one Cochran review of pregnancy-related VTE, symptomatic VTE occurred more frequently in women receiving UFH than LMWH; however, the included studies were not powered to detect a statistically significant difference between treatment groups (risk ratio [RR] 0.47, 95% CI 0.092.49).34 The primary concern with anticoagulation use is the risk of major bleeding, which is approximately 2% in nonpregnant patients with acute VTE receiving standard anticoagulation. The risk of major antepartum bleeding may be slightly lower in pregnancy than in the nonpregnant population, and postpartum hemorrhage does not seem appreciably higher in women receiving LMWH compared to women who do not.1,33 The rate of major antepartum bleeding with UFH use in 100 pregnancies was 1% (95% CI 0.2%-5.4%), similar to that seen in nonpregnant patients.33,34,36,37 In contrast, in a systematic review including studies of LMWH use in pregnancy, the rates of antepartum bleeding and postpartum bleeding were found to be 0.43% (95% CI 0.22%-0.75%) and 0.94% (95% CI 0.61%1.37%), respectively.33 Heparin-induced thrombocytopenia (HIT) occurs with both UFH and LMWH. Cross-reactivity can occur and negates the use of LMWH in patients who experienced HIT with UFH.1,27 In nonpregnant patients, the rate of HIT was found to be significantly lower with LMWH compared to UFH (0% vs 2.7%; P ¼ .0018).35 However, the overall rate of documented HIT in pregnancy is low, occurring in less than 1% of patients.33,38 Prolonged treatment with UFH has been associated with osteoporosis. Symptomatic vertebral fractures have been reported in 2% to 3% of patients, and reductions in bone density have been reported in up to 30% of patients receiving UFH.27,39,40 LMWH has been traditionally considered to have less risk of bone loss than UFH. In 1 study of 80 nonpregnant patients, osteoporosis occurred more often with UFH (15%, 95% CI 6%-30%) than with LMWH (3%, 95% CI 0%-11%).41 In pregnant women receiving prophylactic doses
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Table 3. Recommended Anticoagulation Regimens During Pregnancy.2,27,44 Management type
Dosage
Prophylactic LMWH
Enoxaparin 40 mg SC once daily Dalteparin 5000 units SC once daily Tinzaparin 4500 units SC once daily Enoxaparin 40 mg SC every 12 hours Dalteparin 5000 units SC every 12 hours Enoxaparin 1 mg/kg every 12 hours Dalteparin 100 units/kg every 12 hours Dalteparin 200 units/kg once daily Tinzaparin 175 units/kg once dailyc UFH 5000 units SC every 12 hours UFH 5000-10 000 units SC every 12 hours UFH 5000-7500 units SC every 12 hours (first trimester) UFH 7500-10 000 units SC every 12 hours (second trimester) UFH 10 000 units SC every 12 hours (third trimester)d UFH SC every 12 hours adjusted to anti-Xa level of 0.1-0.3 U/mL UFH 10 000 units or more SC every 12 hours Doses adjusted to target aPTT 1.5-2.5, 6 hours after injection Prophylactic LMWH/UFH 4-6 weeks Vitamin K antagonist 4-6 weeks Target INR 2-3 Initial LMWH/UFH overlap until INR 2.0
Intermediate-dose LMWHa Therapeutic LMWHb (adjusted dose, weight-based dose, full dose)
Minidose prophylactic UFH Prophylactic UFH
Intermediate UFHa Therapeutic UFH (adjusted dose, weight-based dose, full dose) Postpartum anticoagulation
Abbreviations: aPTT, activated partial thromboplastin time; INR, international normalized ratio; LMWH, low-molecular-weight heparin; UFH, unfractionated heparin; SC, subcutaneously. a As recommended by the Chest 2012 guidelines only.27 b May target anti-Xa level of 0.6 to 1.0 units/mL for twice daily regimen. c The reader should note that tinzaparin is no longer available on the US market. d Unless aPTT is elevated.
of LMWH, bone mineral density was significantly lower in patients receiving UFH (P ¼ 0.02), and similar as compared to aspirin or placebo.41-43 Alternatively, 1 trial demonstrated that the incidence of clinically significant bone loss was no different in patients receiving UFH compared to patients taking LMWH (2.5% vs 2.0%, respectively; P ¼ 1.0), which suggests that osteoporosis may be due to individual susceptibility.27,44 The anticoagulant dose will depend on the indication, with low, intermediate, and treatment doses available for both UFH and LMWH. There are no large clinical trials evaluating the optimal dosing regimens of anticoagulants during pregnancy. Therefore, recommendations are largely based on expert opinion and case series (Table 3).2 As changes in renal excretion and protein binding occur during pregnancy, the half-lives and peak plasma concentrations of these agents may be altered, requiring a higher dose and/or more frequent administration.2,4 Due to these alterations in the pharmacokinetics of LMWH, twice-daily dosing is often recommended.45 However, data suggest that once-daily dosing of LMWH may be appropriate for VTE treatment.46,47 Because of small studies indicating the need for LMWH dose escalation to maintain the therapeutic anti-Xa levels, some support monitoring anti-Xa levels every 1 to 3 months to maintain an anti-Xa level of 0.6 to 1.0 units/ mL for twice-daily regimens.27,48,49 However, other studies have shown that few women require an adjustment in LMWH dose when therapeutic doses are used.50,51 Additional arguments suggesting routine monitoring of anti-Xa levels that may
not be necessary in pregnancy include concerns with testing reliability and accuracy, insufficient clinical end points demonstrating an optimal therapeutic anti-Xa range, a lack of data correlating monitoring with risk of bleeding and/or VTE recurrence, and the cost of monitoring.27 Due to these arguments, it is difficult to justify routine monitoring of anti-Xa levels for the treatment of VTE in pregnancy at this time. When choosing an anticoagulant in pregnancy, it is important to weigh the advantages and disadvantages of individual agents. Disadvantages of UFH, in addition to the possible need for continuous infusion or intravenous administration with therapeutic doses, include the risk of major bleeding, bone loss, vertebral fracture, and HIT.4 Potential advantages of LMWH over UFH are lower rates of bleeding, decreased risk of HIT, improved bioavailability, longer half-life requiring less frequent administration, and a more predictable dose response.1,4,27 The longer half-life of LMWH may also be considered a disadvantage, as it may become troublesome at the time of delivery when rapid cessation of anticoagulant effect is desired.1,4 However, patients can be transitioned from LMWH to UFH prior to delivery. Another potential disadvantage of LMWH is the higher drug acquisition cost.4
Prophylaxis When determining the appropriateness of prophylaxis during pregnancy for those with a prior VTE, guidelines suggest
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Table 4. Recommended Thromboprophylaxis Management During Pregnancy.2,27 Clinical setting
Antepartum treatment
Postpartum treatmenta
Acute VTE
Therapeutic LMWH/UFH
Low-risk thrombophilia, no previous VTE
Surveillance only Prophylactic LMWH/UFH Intermediate LMWHb Prophylactic LMWH/UFH Intermediate LMWH Surveillance only Prophylactic LMWH/UFH Intermediate LMWHb Surveillance onlyb Prophylactic LMWH/UFH Prophylactic LMWH/UFH Intermediate LMWH Therapeutic LMWH/UFH Surveillance only
Anticoagulation continued for 6 weeks Minimum duration 3 months total treatment Surveillance Postpartum anticoagulation if additional risk factorsc
Low-risk thrombophilia, single previous VTE, not on long-term therapy High-risk thrombophilia, no previous VTE, family history VTE High-risk thrombophilia, no previous VTE, no family history VTE High-risk thrombophilia, single previous VTE, no long-term anticoagulation Previous single VTE, transient risk factor no longer presentd,e Previous single VTE, pregnancy- or estrogen-related risk factor Previous single VTE, idiopathic, not on long-term therapy 2 episodes VTE, not on long-term therapy
2 episodes VTE, on long-term therapy Laboratory and clinical criteria for APSb
Prophylactic LMWH/UFH Intermediate LMWHb Prophylactic LMWH/UFH Intermediate LMWHb Prophylactic LMWH/UFH Intermediate LMWHb Therapeutic LMWH/UFH Therapeutic LMWH/UFH 75% LMWH doseb Intermediate LMWH/UFH Prophylactic LMWH þ ASA
Intermediate-dose LMWH/UFH
Intermediate LMWHb Postpartum anticoagulation Intermediate LMWHb Postpartum anticoagulation Postpartum anticoagulation Intermediate LMWH/UFH (6 weeks) Therapeutic LMWH/UFH (6 weeks) Postpartum anticoagulation Surveillance only Postpartum anticoagulation Prophylactic LMWH/UFH Postpartum anticoagulation Postpartum anticoagulation Therapeutic LMWH/UFH (6 weeks) Resume long-term anticoagulant
Abbreviations: APLA, antiphospholipid antibody; ASA, aspirin; INR, international normalized ratio; LMWH, low-molecular-weight heparin; UFH, unfractionated heparin; VTE, venous thromboembolism. a Postpartum anticoagulation should be greater or equal to antepartum treatment2; includes vitamin K antagonist with a target INR 2 to 3 or prophylactic anticoagulant for 4 to 6 weeks.27 b Recommended by Chest, 201227 only. c Per ACOG2: first degree relative to history of VTE before age 50, obesity, immobility, and other thrombotic risk factors. d Does not include pregnancy- or estrogen-related risk factor. e Per Chest, 201227: low risk of recurrence.
patients at low risk of recurrence undergo clinical vigilance during the antepartum period, while those at moderate to high risk of recurrence receive antepartum prophylaxis with prophylactic or intermediate dosages of LMWH or UFH, with preference given to LMWH.2,27 Low risk includes women with a single episode of VTE associated with a transient risk factor, not including pregnancy, or use of estrogen. Moderate to high risk includes women with a history of an idiopathic VTE, pregnancy- or estrogen-related VTE, or multiple prior VTE not currently receiving anticoagulation therapy.2,27 All women with a prior VTE should receive postpartum anticoagulation for 6 weeks with LMWH or vitamin K antagonists (Table 4).2,27 Although the presence of an underlying thrombophilia may increase the risk of pregnancy-related thrombosis, prophylaxis during pregnancy may not be necessary with all thrombophilia. The need for prophylaxis depends on several factors, such as the risk of thrombosis associated with the thrombophilia, the history of previous VTE, family history of VTE, and if the previous VTE was due to a transient risk factor or an idiopathic event. Patients homozygous for FVL or prothrombin 20210A
mutation with a positive family history but no prior history of VTE should receive antepartum and postpartum prophylaxis with prophylactic- or intermediate-dose LMWH or UFH, again with preference given to LMWH.2,27 Patients homozygous for FVL or prothrombin 20210A mutation without a previous VTE and no family history, antepartum clinical vigilance and postpartum prophylaxis are recommended.27 For pregnant women with other thrombophilia and a positive family history of VTE, postpartum prophylaxis is suggested, while those without a positive family history may simply undergo clinical vigilance.27 Warfarin may be utilized for postpartum prophylaxis in all patients other than those with protein C or S deficiency due to concerns with warfarin-induced skin necrosis27 (see Table 4). Antiphospholipid syndrome (APS) requires a different approach and is discussed subsequently.
APS APS is a thrombophilia that warrants discussion regarding management in pregnancy. Women with APS who become
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pregnant are at a higher risk of both thrombosis52 and pregnancy loss.53 Pregnancy morbidity is a component of the clinical criteria included in the diagnostic criteria for APS. Pregnancy morbidity in APS is described as 1 or more unexplained fetal deaths beyond the 10th week of gestation, 1 or more premature births before the 34th week of gestation, or 3 or more consecutive spontaneous abortions prior to the 10th week of gestation.54 Hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome) coexisting with preeclampsia may also be associated with APS; however, the prevalence is unknown.53 Management of APS in pregnancy aims to prevent pregnancy loss and decrease the risk of thrombosis to the mother.55 Several different scenarios may exist in pregnant patients with APS: pregnancy loss with or without thrombosis, as well as thrombosis with no history of pregnancy loss.
APLAs and Pregnancy Loss Lupus anticoagulant, anticardiolipin antibody, and anti-b2 glycoprotein antibody are antibodies included in the classification criteria for antiphospholipid syndrome.54 Titer and isotype of anticardiolipin antibody and anti-b2 glycoprotein antibody are also important laboratory considerations upon initial diagnosis. Immunoglobulin (Ig) G and IgM isotypes and high titers are more closely associated with thrombosis.54,55 Compared to the general population, the risk of pregnancy loss is higher in women with APLA positivity after the 10th week of gestation.53 Presence of APLAs (lupus anticoagulant or anticardiolipin antibodies 20 IgG phospholipid [GPL] units ) was associated with at least 1 fetal death in more than 80% of women according to a study conducted by Oshiro et al.56 Positivity of APLAs other than those outlined in the diagnostic criteria (ie, phosphatidylserine) and positivity of anticardiolipin or anti-b2 glycoprotein antibodies at lower titers or IgA isotype in women with recurrent pregnancy loss are areas for further investigation.55
APS With Pregnancy Loss Without a History of Thrombosis In patients with APS without a history of thrombosis, combination therapy with UFH and aspirin has been shown to reduce pregnancy loss by 54%.57 Kutteh58 and Rai et al59 demonstrated that treatment with aspirin and heparin provided improvement in pregnancy outcomes compared to aspirin alone in women with APLAs and a history of pregnancy loss.57,59 Consistent with these results, a meta-analysis of randomized controlled trials showed higher birth rates in mothers who received heparin and aspirin compared to aspirin alone (RR 1.301, 95% CI 1.040-1.629).60 Recommendations from the American College of Chest Physicians suggest antepartum use of prophylactic or intermediate-dose UFH, or prophylactic LMWH, combined with low-dose aspirin in patients with APS who have a history of 3 or more pregnancy losses.27 Recommended anticoagulation regimens during pregnancy can be found in Table 3.
Intravenous immunoglobulin has been suggested as a potential add-on therapy in women who experience recurrent pregnancy loss, despite heparin and low-dose aspirin therapy. However, studies have not shown improved neonatal outcomes when compared with UFH and aspirin.55,61,62 Prednisone has also been proposed as a potential treatment modality in combination with aspirin but is associated with more preeclampsia and adverse effects.63
APS With a History of Thrombosis Since patients with APS are at a high risk of recurrent thrombosis, patients are often treated with warfarin indefinitely. Due to teratogenicity associated with warfarin therapy, warfarin should be discontinued and therapeutic anticoagulation with UFH or LMWH is suggested during pregnancy.52,55 In these patients, American College of Chest Physicians recommend adjusted-dose LMWH or 75% of a therapeutic dose of LMWH during pregnancy, followed by reinitiation of long-acting oral anticoagulants postpartum.27 Refer to Table 3 for recommended anticoagulation regimens during pregnancy. For women with APS who have a history of a single episode of thrombosis but are not being treated with anticoagulants indefinitely, antepartum prophylactic or intermediate-dose LMWH or UFH in addition to postpartum prophylaxis is recommended.64
Postpartum Management in APS In patients previously treated with warfarin for a history of thrombosis, postpartum anticoagulation with UFH or LMWH overlapped with warfarin therapy until a target international normalized ratio (INR) of 2.0-3.0 is obtained is recommended. Table 4 includes recommended postpartum treatment options according to clinical setting. Postpartum prophylaxis is recommended in those with a history of a single episode of thrombosis not being treated with anticoagulants indefinitely.27 For women who have not experienced a previous thrombotic episode, the risk of thrombosis is unclear in patients with APS; therefore, guidance for postpartum management is limited. According to Giannakopoulos and Krilis, therapy should be individualized based on patient-specific risk factors (ie, APLA positivity on multiple instances, age > 35, family history, immobility, obesity, and cesarean section).65 Clinical observation is suggested in women with other thrombophilias (w/ exception of Factor V leiden and prothrombin 20210 A mutation) without a family history of VTE and no previous thrombosis27; however, it is unclear whether this recommendation should be extrapolated to patients with obstetric APS.
Emerging Concepts Assisted Reproductive Technology Assisted reproductive technology (ART) may be associated with an increased risk of thrombosis.28 Population prevalence studies have demonstrated an overall thrombosis estimate of
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2.66 per 1000 cycles, compared to 0.97 for natural pregnancy.66,67 Thrombosis occurred in 0.1% (95% CI 0%-0.3%) to 0.3% (95% CI 0%-0.8%) of cycles in large retrospective cohort studies.68,69 Thrombotic risk with ART is significantly higher in the first trimester but does not differ in the second or third trimester.67,70 The overall magnitude of VTE risk in patients undergoing ovarian stimulation is low, but it does represent a 10-fold increase in the baseline relative risk in women of reproductive age.21
Ovarian Hyperstimulation Syndrome The incidence of thrombosis may be higher in women with ovarian hyperstimulation syndrome (OHSS), with a reported incidence of 4.1% (95% CI 1.1%-13.7%) in severe cases.70 OHSS was reported in 90% of arterial events and 78% of venous events; additionally, 98% of reported thrombosis occurred after ovulation induction.71 Arterial events occurred earlier after embryo transfer (10.7 days) than venous events (42.4 days) and were almost always concurrent with the development of OHSS, whereas venous events occurred after the resolution of OHSS.71 During ovarian stimulation, there is an increase in the levels of estradiol, vWF, factors V and VIII, and fibrinogen, as well as an increase in activated protein C resistance in addition to a reduction in antithrombin levels and proteins C and S.71 Both arterial and venous thrombotic events have been reported. Venous thrombosis in relation to ART has been reported in unusual locations, such as the upper extremities, head, and neck, compared to the usual location in the left leg. Ischemic stroke has been reported as the most common arterial event.71 The occurrence of thrombotic events in the neck and upper extremities may be due to estrogen-rich lymphocytic drainage from ascitic fluid into the thoracic duct, which further drains into the left subclavian vein, or obstruction at the base of the subclavian and jugular veins due to brachial cysts that fill with fluid during OHSS.71 Dosage and duration of thromboprophylaxis have not been well studied to date. However, due to the increase in thrombotic events associated with OHSS, prophylaxis with LMWH may be considered. Recent guidelines recommend that patients who develop severe OHSS receive prophylactic doses of LMWH for 3 months after resolution of OHSS.27 Other suggestions include initiating thromboprophylaxis and continuing for a minimum duration of 4 to 8 weeks beyond the resolution of OHSS or until the end of the first trimester in women who conceive.71,72 In women who develop thrombosis, therapeutic doses of LMWH or UFH should be initiated and continued as recommended by practice guidelines.2,27,71
Repeated Implantation Failure Acquired and inherited thrombophilia have been implicated in women with repeated implantation failure after ART.72 Factor V Leiden and prothrombin G20210A heterozygosity, as well as an increase in MTHFR C677TT and combined thrombophilias,
were found to occur more often in women with 3 or more implantation failures.73,74 Additionally, it appears that women who experience 3 or more implantation failures exhibit a higher prevalence of APLAs.72 Therefore, it would be reasonable to screen women with repeated implantation failures for thrombophilia. Studies of LMWH use in women with repeated implantation failures have demonstrated conflicting but encouraging results. Qublan et al found that LMWH use was associated with an increase in implantation rates (20.9% vs 6.1%, P < .001), pregnancy rates (31% vs 9.6%, P < .05), and live birth rate (23.8 vs 2.8, P < .05) compared to placebo.74 In a study of 150 women with 2 or more failed ART cycles, LMWH use was found to correlate with an increase in live births (34.7% vs 26.7%, 95% CI 4.2%-24.9%; P ¼ .29).75 Although not statistically significant, the 30% relative increase in live births calls for additional research on empirical use of LMWH in women with repeated implantation failures.76
Suggested Future Research Currently, there are no human studies available concerning rivaroxaban use in pregnancy and lactation. Due to the oral availability and lack of monitoring requirements, it would be helpful to have more information regarding safety and efficacy in the pregnant population. Until this time, rivaroxaban should not be used for VTE treatment in pregnancy or lactation on the basis of animal studies. Controversy continues regarding the need for anti-Xa monitoring with LMWH use in pregnancy. Future research should attempt to correlate clinical end points, such as VTE occurrence and bleeding risk, with anti-Xa level ranges in order to better understand the usefulness of monitoring in pregnancy. Finally, further research is needed in the area of routine prophylaxis for ART and repeated implantation failure regarding the benefit as well as the appropriate duration of thromboprophylaxis if utilized.
Conclusion Pregnancy increases the risk of VTE due to various physiologic mechanisms, with the highest risk during the postpartum period.4 Women who have a personal history of VTE are at increased risk of developing recurrent events during subsequent pregnancies. Evidence regarding prognostic factors for recurrent thromboembolism during pregnancy is conflicting.25,26 The presence of concomitant thrombophilia may increase the risk of events and is identified in up to 50% of women who experience pregnancy-related VTE. Factor V Leiden homozygosity, prothrombin mutation homozygosity, and APS are thrombophilia associated with the highest risk of VTE in pregnancy, along with pregnant women who have a family history of thromboembolism.4,28,77 Warfarin should be avoided during pregnancy due to the risk of teratogenicity. Treatment with LMWH or UFH is recommended for acute VTE, with preference often given to LMWH due to ease of dosing and other advantages over UFH.4,10,28 Prophylactic or treatment doses of
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LMWH or UFH may be warranted during pregnancy and/or the postpartum period in women with prior VTE and in certain women with underlying thrombophilia.
14.
Authors’ Note All the listed authors had a role in writing the article.
15.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
16.
Funding
17.
The author(s) received no financial support for the research, authorship, and/or publication of this article. 18.
References 1. Chunilal SD, Bates SM. Venous thromboembolism in pregnancy: diagnosis, management and prevention. Thromb Haemost. 2009; 101(3):428-438. 2. The American College of Obstetricians and Gynecologists. Thromboembolism in pregnancy. Obstet Gynecol. 2011;118: 718-729. 3. Calderwood CJ, Thanoon OI. Thromboembolism and thrombophilia in pregnancy. Obstet Gynaecol Reprod Med. 2009;19: 339-343. 4. James AH. Pregnancy-associated thrombosis. Hematology. 2009; 1:277-285. 5. Ray JG, Chan WS. Deep vein thrombosis during pregnancy and the puerperium: a meta-analysis of the period of risk and leg of presentation. Obstet Gynecol Surv. 1999;54(4):254-271. 6. Simpson EA, Lawrenson RA, Nightingale AL, et al. Venous thromboembolism during pregnancy and the peurperium: incidence and additional risk factors from a London perinatal database. Br J Obstet Gynaecol. 2001;108(1):56-60. 7. Gherman RB, Goodwin TM, Leung B, et al. Incidence, clinical characteristics, and timing of objectively diagnosed deep vein thromboembolism during pregnancy. Obstet Gynecol. 1999;94(5 pt 1):730-734. 8. Berg CJ, Callaghan WM, Syverson C, et al. Pregnancy-related mortality in the United States, 1998 to 2005. Obstet Gynecol. 2010;116(6):1302-1309. 9. Pomp ER, Lenselink AM, Rosendaal FR, et al. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost. 2008;6(4): 632-637. 10. James AH, Tapson VF, Goldhaber SZ. Thrombosis during pregnancy and the postpartum period. Am J Obstet Gynecol. 2005; 193(1):216-219. 11. Ginsberg JS, Brill-Edwards P, Burrows RF, et al. Venous thrombosis during pregnancy: leg and trimester of presentation. Thromb Haemost. 1992;67(5):519-520. 12. Blanco-Molina A, Trujillo-Santos J, Criado J, et al. Venous thromboembolism during pregnancy or postpartum: findings from the RIETE Registry. Thromb Haemost. 2007;97(2):186-190. 13. Heit JA, Kobbervig CE, James AH, et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a
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30-year population-based study. Ann Intern Med. 2005;143(10): 697-706. Jacobsen AF, Skjeldestat FE, Sandset PM. Ante- and postnatal risk factors of venous thrombosis: a hospital-based case control study. J Thromb Haemost. 2008;6(6):905-912. Macklon NS, Greer IA. Venous thromboembolic disease in obstetrics and gynaecology: the Scottish experience. Scott Med J. 1996; 41(3):83-86. Blondon MB, Perrier A, Nendaz M, et al. Thomboprophylaxis with low-molecular weight heparin after cesarean delivery. Thromb Haemost. 2010;103(1):129-137. Bergqvist A, Bergqvist D, Hallbook T. Acute deep vein thrombosis (DVT) after cesarean section. Acta Obstet Gynecol Scand. 1979;58(5):473-476. Chan LY, Lam KY, Metreweli C, et al. Duplex ultrasound screening for deep vein thrombosis in Chinese after cesarean section. Acta Obstet Gynecol Scand. 2005;84(4):368-370. Jacobsen AF, Drolsum A, Klow NE, et al. Deep vein thrombosis after elective cesarean section. Thromb Res. 2004;113(5):283-288. Kalro BN, Davidson RA, Owen P. Low incidence of asymptomatic deep vein thrombosis following cesarean section: a colour Doppler study. Health Bull (Edinb). 1999;57(6):418-421. Lindqvist P, Dahlback B, Marsal K. Thrombotic risk during pregnancy: a population study. Obstet Gynecol. 1999;94(4):595-599. Sia WW, Powrie RO, Cooper AB, et al. The incidence of deep vein thrombosis in women undergoing cesarean delivery. Thromb Res. 2009;123(3):550-555. White RH, Brickner LA, Scannel KA. ICD-9-CM codes poorly identified venous thromboembolism during pregnancy. J Clin Epidemiol. 2004;57(9):985-988. Pabinger I, Grafenhofer H, Kaider A, et al. Risk of pregnancyassociated recurrent venous thromboembolism in women with a history of venous thrombosis. J Thromb Haemost. 2005;3(5): 949-954. De Stefano V, Martinelli I, Rossi E, et al. The risk of recurrent venous thromboembolism in pregnancy and puerperium without antithrombotic prophylaxis. Br J Haematol. 2006;135(3):386-391. Brill-Edwards P, Ginsberg JS, Gent M, et al. Recurrence of clot in this pregnancy study group. Safety of withholding heparin in pregnant women with a history of thromboembolism. N Engl J Med. 2000;343(20):1439-1444. Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy. Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e619s-e726s. Pabinger I. Thrombophilia and its impact on pregnancy. Thromb Res. 2009;123(suppl 3):S16-S21. Robertson L, Wu O, Langhorne P, et al. Thrombophilia in pregnancy: a systemic review. Br J Haematol. 2006;132(2):171-196. Janssen Pharmaceuticals, Inc. Xarelto1 [rivaroxaban] Tablets for Oral Use Package Insert. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2011. Cutts BA, Dasgupta D, Hunt BJ. New directions in the diagnosis and treatment of pulmonary embolism during pregnancy. Am J Obstet Gyencol. 2013;208(2):102-108.
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32. Turpie AGG, Kreutz R, Llau J, et al. Management consensus guidance for the use of rivaroxaban—an oral, direct factor Xa inhibitor. Thromb Haemost. 2012;108(5):876-886. 33. Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood. 2005;106(2):401-407. 34. Tooher R, Gates S, Dowswell T, et al. Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period. Cochrane Database Syst Rev. 2010;(5):CD001689. 35. Warkentin TE, Greinacher A, Koster A, et al. Heparin-induced thrombocytopenia in patients treated with low molecular weight heparin or unfractionated heparin. N Engl J Med. 1995;332: 1330-1335. 36. Ginsberg JS, Kowalchuk G, Hirsh J, et al. Heparin therapy during pregnancy. Risks to the fetus and mother. Arch Intern Med. 1989; 149(10):2233-2236. 37. Hull RD, Delmore TJ, Carter CJ, et al. Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis. N Engl J Med. 1982;306(4):189-194. 38. Voke J, Keidan J, Pavord S, et al. The management of antepartum venous thromboembolism in the UK and Ireland: a prospective multicenter observational survey. Br J Haematol. 2007;139(4): 545-558. 39. Dahlman TC. Osteoporotic fractures and the recurrence of thromboembolism during pregnancy and the puerperium in 184 women undergoing thromboprophylaxis with heparin. Am J Obstet Gynecol. 1993;168(4):1265-1270. 40. Petilla V, Leinonen P, Marrkova A, et al. Postpartum bone mineral density in women treated for thromboprophylaxis with unfractionated heparin or low molecular weight heparin. Thromb Haemost. 2002;87:182-183. 41. Monreal M, Lafoz E, Olive A, et al. Comparison of subcutaneous unfractionated heparin with a low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to coumarin. Thromb Haemost. 1994;71(1):7-11. 42. Carlin AG, Farquharson RG, Quenby SM, et al. Prospective and observational study of bone mineral density during pregnancy: low molecular weight heparin versus control. Hum Reprod. 2004;19(5):1211-1214. 43. Rodger MA, Kahn SR, Cranney A, et al. Long-term dalteparin in pregnancy not associated with a decrease in bone mineral density: substudy of a randomized controlled trial. J Thromb Haemost. 2007;5(8):1600-1606. 44. Casele J, Haney EI, James A, et al. Bone density changes in women who receive thromboprophylaxis in pregnancy. Am J Obstet Gynecol. 2006;195(4):1109-1113. 45. Greer IA. Thrombosis in pregnancy: updates in diagnosis and management. Hematol Am Soc Hematol Educ Prog. 2012;2012: 203-207. 46. Nelson-Piercy C, Powrie R, Borg JV, et al. Tinzaparin use in pregnancy: an international, retrospective study of the safety and efficacy profile. Eur J Obstet Gynecol Reprod Biol. 2011;159(2):293-299. 47. Smith MP, Norris LA, Steer PJ, et al. Tinzaparin sodium for thrombosis treatment and prevention during pregnancy. Am J Obstet Gynecol. 2004;190(2):495-501.
48. Barbour LA, Oja JL, Schultz LK. A prospective trial that demonstrates that dalteparin requirements increase in pregnancy to maintain therapeutic levels of anticoagulation. Am J Obstet Gynecol. 2004;191(3):1024-1029. 49. Jacobsen AF, Qvigstad E, Sandset PM. Low molecular weight heparin (dalteparin) for the treatment of thromboembolism in pregnancy. BJOG. 2003;110(2):139-144. 50. Rodie VA, Thomson AJ, Steward FM, et al. Low molecular weight heparin for the treatment of venous thromboembolism in pregnancy: a case series. BJOG. 2002;109(9):1020-1024. 51. Rey E, Rivard GE. Prophylaxis and treatment of thromboembolic diseases during pregnancy with dalteparin. Int J Gynaecol Obstet. 2000;71(1):19-24. 52. Petri M, Qazi U. Management of antiphospholipid sydnrome in pregnancy. Rheum Dis Clin North Am. 2006;32(3):591-607. 53. Tincani A, Bazzani C, Zinarelli S, et al. Lupus and the antiphospholipid syndrome in pregnancy and obstetrics: clinical characteristics, diagnosis, pathogenesis, and treatment. Semin Thromb Hemost. 2008;34(3):267-273. 54. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification of criteria for definite antiphospholipid syndrome. J Thromb Haemost. 2006;4(2): 295-306. 55. Branch DW, Khamashta MA. Antiphospholipid syndrome: obstetric diagnosis, management, and controversies. Obstet Gynecol. 2003;101(6):1333-1344. 56. Oshiro BT, Silver RM, Scott JR, et al. Antiphospholipid antibodies and fetal death. Obstet Gynecol. 1996;87(4):489-493. 57. Empson M, Lassere M, Craig J, et al. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev. 2005;(2): CD002859. doi:10.1002/14651858.CD002859.pub2. 58. Kutteh W. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low dose aspirin alone. Am J Obstet Gynecol. 1996;174(5): 1584-1589. 59. Rai R, Cohen H, Dave M, et al. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ. 1997;314(7076):253-257. 60. Mak A, Cheung MW-L, Cheak AA, et al. Combination of heparin and aspirin is superior to aspirin alone in enhancing live births in patients with recurrent pregnancy loss and positive antiphospholipid antibodies: a meta-analysis of randomized controlled trials and meta-regression. Rheumatology. 2010; 49(2):281-288. 61. Sammaritano L. Antiphospholipid syndrome: review. South Med J. 2005;98(6):617-625. 62. Branch DW, Peaceman AM, Druzin M, et al. A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. Am J Obstet Gynecol. 2000;182(1 pt 1):122-127. 63. Cowcheck FS, Reece EA, Balaban D, et al. Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am J Obstet Gynecol. 1992;166(5):1318-1323.
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64. Bates SM, Greer IA, Pabinger I, et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy. Chest. 2008;133(6 suppl):844s-886s. 65. Giannakopoulos B, Krilis SA. How I treat the antiphospholipid syndrome. Blood. 2009;114:2020-2030. 66. Nelson SM. Venous thrombosis during assisted reproduction: novel risk reduction strategies. Thromb Res. 2013;131(suppl 1):S1-S3. 67. Rova K, Passmark H, Lindqvist PG. Venous thromboembolism in relation to in vitro fertilization: an approach to determining the incidence and increase in risk in successful cycles. Fertil Steril. 2012;97(1):95-100. 68. Mara M, Koryntova D, Rezabek K, et al. Thromboembolic complications in patients undergoing in vitro fertilization: retrospective clinical study [in Czech]. Ceska Gynekol. 2004;69(4):312-316. 69. Aurousseau MH, Samama MM, Belhassen A, et al. Risk of thromboembolism in relation to an in-vitro fertilization programme: three case reports. Hum Reprod. 1995;10(1):94-97. 70. Henriksson P, Westerlund E, Wallen H, et al. Incidence of pulmonary and venous thromboembolism in pregnancies after in vitro fertilization: cross sectional study. BMJ. 2013;346:e8632.
71. Chan WS. The ‘ART’ of thrombosis: a review of arterial and venous thrombosis in assisted reproductive technology. Curr Opin Obstet Gynecol. 2009;21(3):207-218. 72. Nelson SM. Prophylaxis of VTE in women-during assisted reproductive techniques. Thromb Res. 2009;123(suppl 3):S8-S15. 73. Grandone E, Colaizzo D, Lo Bue A, et al. Inherited thrombophilia and in vitro fertilization implantation failure. Fertil Steril. 2001; 76(1):201-202. 74. Qublan HS, Eid SS, Ababneh HA, et al. Acquired and inherited thrombophilia: implication in recurrent IVF and embryo transfer failure. Hum Reprod. 2006;21(10):2694-2698. 75. Urman B, Ata B, Yakin K, et al. Luteal phase empirical low molecular weight heparin administration in patients with failed ICSI embryo transfer cycles: a randomized open-labeled pilot trial. Human Reprod. 2009;24(7)1640-1647. 76. Allahbadia GN. Low-molecular-weight heparin (LMWH) in women with repeated implantation failure. J Obstet Gynaecol India. 2012;62(4):381-383. 77. Buhimschi CS, Weinger CP. Medications in pregnancy and lactation. Obstet Gynecol. 2009;113(6):166-188.
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Pregnancy-Related Venous Thromboembolism Emily M. Armstrong, Jessica M. Bellone, Lori B. Hornsby, Sarah Treadway and Haley M. Phillippe Journal of Pharmacy Practice published online 17 April 2014 DOI: 10.1177/0897190014530425 The online version of this article can be found at: http://jpp.sagepub.com/content/early/2014/04/16/0897190014530425
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New York State Council of Health-system Pharmacists
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Article Journal of Pharmacy Practice 1-10 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190014530425 jpp.sagepub.com
Pregnancy-Related Venous Thromboembolism Emily M. Armstrong, PharmD, BCACP1,2, Jessica M. Bellone, PharmD, BCACP3, Lori B. Hornsby, PharmD, BCPS1,4, Sarah Treadway, PharmD, BCPS1,5, and Haley M. Phillippe, PharmD, BCPS1,6
Abstract Pregnancy is associated with an increased risk of venous thromboembolism (VTE), with a reported incidence ranging from 0.49 to 2 events per 1000 deliveries. Risk factors include advanced maternal age, obesity, smoking, and cesarian section. Women with a history of previous VTE are at a 4-fold higher risk of recurrent thromboembolic events during subsequent pregnancies. Additionally, the presence of concomitant thrombophilia, particularly factor V Leiden (homozygosity), prothrombin gene mutation (homozygosity), or antiphospholipid syndrome (APS), increases the risk of pregnancy-related VTE. Low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) are the drugs of choice for anticoagulation during pregnancy. LMWH is preferred due to ease of use and lower rates of adverse events. Women with high thromboembolic risk particularly those with a family history of VTE should receive antepartum thromboprophylaxis. Women with low thromboembolic risk or previous VTE caused by a transient risk factor (ie, provoked), who have no family history of VTE, may undergo antepartum surveillance. Postpartum anticoagulation can be considered in women with both high and low thromboembolic risk. Keywords thrombophilia, pregnancy, inherited thrombophilia, acquired thrombophilia, prophylaxis
Introduction Pregnancy increases the risk of venous thromboembolism (VTE) due to various physiological and anatomical changes.1-3 The presence of an underlying thrombophilia, either inherited or acquired, may further increase this risk.4 Studies reporting a higher risk of VTE during the postpartum period as compared to the antepartum period suggest differences in VTE throughout the course of pregnancy.4-7 This review will focus on risk factors associated with VTE in pregnancy as well as considerations for both prophylaxis and treatment of VTE during pregnancy and the postpartum period.
Incidence and Overall Risk VTE remains one of the leading causes of maternal morbidity and mortality in developed countries, accounting for approximately 10% of pregnancy-related deaths.8 During pregnancy, there is a 4- to 5-fold increased risk of VTE, with a reported incidence ranging from 0.49 to 2 events per 1000 deliveries.1,4,9 Approximately 80% of cases with pregnancy-associated VTE are due to deep vein thrombosis (DVT) and 20% due to pulmonary embolism (PE). One meta-analysis found two-thirds of DVT occurred during the antepartum period (period before childbirth), while as many as 60% of pregnancy-related PE
occur up to 6 weeks postpartum.5-7 The risk of VTE begins to increase in the first trimester prior to the anatomic changes associated with pregnancy.4,9 Although a higher risk of VTE during the third trimester has been reported, other studies have suggested there is an equal risk of events throughout each trimester.5,9-13 The postpartum risk of VTE exceeds that of the antepartum period. During the first 6 weeks postpartum, the risk of VTE is up to 80-fold higher, with the highest risk occurring during the first week postpartum.4 Although the rate of
1 Department of Pharmacy Practice, Auburn University Harrison School of Pharmacy, Auburn, AL, USA 2 Department of Internal Medicine, University of South Alabama, Mobile, AL, USA 3 Department of Pharmacy Practice, Concordia University Wisconsin School of Pharmacy, Mequon, WI, USA 4 Midtown Medical Center, Outpatient Clinic, Columbus, GA, USA 5 Department of Family Medicine, University of South Alabama, Mobile, AL, USA 6 Family Medicine-Huntsville Campus, University of Alabama School of Medicine, Huntsville, AL, USA
Corresponding Author: Emily M. Armstrong, Department of Internal Medicine, University of South Alabama, 650 Clinic Drive, Suite 2100, Mobile, AL 36688, USA. Email: [email protected]
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VTE is approximately 100 per 100 000 woman years during pregnancy, the rate during the postpartum period increases to approximately 500 per 100 000 woman years.10 In comparison, studies have estimated that the risk of VTE following cesarean section ranges from 30 kg/m2), smoking, and cesarian section have been reported to increase the risk of VTE.27 When determining an individual’s risk of thrombosis during pregnancy, all potential risk factors (Table 2) should be taken into consideration.1,3,14
Treatment Oral Anticoagulants Women who experience an acute VTE during pregnancy should receive therapeutic doses of anticoagulation throughout pregnancy and up to 6 weeks postpartum, for a total minimum
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Table 2. Additional VTE Risk Factors in Pregnancy.1,4,5,14 Preexisting Personal history VTE Sickle cell disease Smoking—postpartum VTE Obesity—postpartum VTE Smoking—antepartum VTE Age > 35 years Diabetes Obesity—antepartum VTE Hypertension
Odds ratio (95% CI) 24.8 6.7 3.4 2.4 2.1 2.1 2.0 1.8 1.8
(17.1-36.0) (4.4-10.1) (2.0-5.5) (1.7-3.3) (1.3-3.4) (2.0-2.3) (1.4-2.7) (1.3-2.4) (1.4-2.3)
Transient
Odds ratio (95% CI)
Infection—vaginal delivery Postpartum hemorrhage with surgery Immobility—postpartum VTE Immobility—antepartum VTE In vitro fertilization—twins Infection—any cesarian section Preeclampsia with IUGR In vitro fertilization—singleton Postpartum hemorrhage with surgery without surgery Preeclampsia without IUGR Cesarian section Emergency without infection Twin pregnancy Cesarian section Routine without infection
20.2 12 10.8 7.7 6.6 6.2 5.8 4.3 4.1 3.1 2.7
(6.4-63.5) (3.9-36.9) (4.0-28.8) (3.2-19.0) (2.1-21.0) (2.4-16.2) (2.1-16.0) (2.0-9.4) (2.3-7.3) (1.8-5.3) (1.8-4.1)
2.6 (1.1-6.2) 1.3 (0.7-2.2)
Abbreviations: CI, confidence interval; IUGR, intrauterine growth restriction; VTE, venous thromboembolism.
duration of 3 months.2,27 Although warfarin is the drug of choice for long-term management of VTE in most situations, it is considered category X by the Food and Drug Administration due to the teratogenic effects seen in the fetus and infant.27 Warfarin exposure during the 6th to 10th week of gestation has been associated with a coumarin embryopathy, which consists of nasal hypoplasia and stippled epiphyses.27 There is also an increased risk of miscarriage, stillbirth, dorsal midline dysplasia, ventral midline dysplasia, and fetal wastage with warfarin use in pregnancy.3,27 Warfarin may however be used during the breast-feeding period.27 Rivaroxaban, although approved for the treatment of VTE in the nonpregnant population, does not have data for treatment during pregnancy. Preclinical animal studies have shown that rivaroxaban crosses the placenta and causes maternal hemorrhagic complications, increases fetal toxicity, decreases the number of live fetuses, and reduces fetal body weight.30-32 Animal studies have also demonstrated rivaroxaban to be secreted into breast milk and therefore should not be used for VTE treatment in breast-feeding women at this time.30-32
Heparin Compounds Heparin compounds such as unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) do not cross the placenta and have not been associated with fetal bleeding or teratogenicity; therefore, these agents are the preferred anticoagulants during pregnancy.2,4,27 Additionally, as UFH and LMWH do not accumulate in breast milk, they are considered compatible with breast-feeding.2,27 LMWHs have largely replaced UFH for treatment of thromboembolism in pregnancy. In studies of nonpregnant patients, LMWH has been shown to be as safe and efficacious as UFH in the acute treatment of DVT and PE.1,4 Other studies in the nonpregnant population have also demonstrated that LMWH is as effective as warfarin in preventing recurrent VTE.27 LMWH use in 2777 pregnancies was found to be safe and efficacious, with no maternal
deaths and an overall rate of VTE of 0.86% (95% CI 0.55%-1.28%).33 In one Cochran review of pregnancy-related VTE, symptomatic VTE occurred more frequently in women receiving UFH than LMWH; however, the included studies were not powered to detect a statistically significant difference between treatment groups (risk ratio [RR] 0.47, 95% CI 0.092.49).34 The primary concern with anticoagulation use is the risk of major bleeding, which is approximately 2% in nonpregnant patients with acute VTE receiving standard anticoagulation. The risk of major antepartum bleeding may be slightly lower in pregnancy than in the nonpregnant population, and postpartum hemorrhage does not seem appreciably higher in women receiving LMWH compared to women who do not.1,33 The rate of major antepartum bleeding with UFH use in 100 pregnancies was 1% (95% CI 0.2%-5.4%), similar to that seen in nonpregnant patients.33,34,36,37 In contrast, in a systematic review including studies of LMWH use in pregnancy, the rates of antepartum bleeding and postpartum bleeding were found to be 0.43% (95% CI 0.22%-0.75%) and 0.94% (95% CI 0.61%1.37%), respectively.33 Heparin-induced thrombocytopenia (HIT) occurs with both UFH and LMWH. Cross-reactivity can occur and negates the use of LMWH in patients who experienced HIT with UFH.1,27 In nonpregnant patients, the rate of HIT was found to be significantly lower with LMWH compared to UFH (0% vs 2.7%; P ¼ .0018).35 However, the overall rate of documented HIT in pregnancy is low, occurring in less than 1% of patients.33,38 Prolonged treatment with UFH has been associated with osteoporosis. Symptomatic vertebral fractures have been reported in 2% to 3% of patients, and reductions in bone density have been reported in up to 30% of patients receiving UFH.27,39,40 LMWH has been traditionally considered to have less risk of bone loss than UFH. In 1 study of 80 nonpregnant patients, osteoporosis occurred more often with UFH (15%, 95% CI 6%-30%) than with LMWH (3%, 95% CI 0%-11%).41 In pregnant women receiving prophylactic doses
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Table 3. Recommended Anticoagulation Regimens During Pregnancy.2,27,44 Management type
Dosage
Prophylactic LMWH
Enoxaparin 40 mg SC once daily Dalteparin 5000 units SC once daily Tinzaparin 4500 units SC once daily Enoxaparin 40 mg SC every 12 hours Dalteparin 5000 units SC every 12 hours Enoxaparin 1 mg/kg every 12 hours Dalteparin 100 units/kg every 12 hours Dalteparin 200 units/kg once daily Tinzaparin 175 units/kg once dailyc UFH 5000 units SC every 12 hours UFH 5000-10 000 units SC every 12 hours UFH 5000-7500 units SC every 12 hours (first trimester) UFH 7500-10 000 units SC every 12 hours (second trimester) UFH 10 000 units SC every 12 hours (third trimester)d UFH SC every 12 hours adjusted to anti-Xa level of 0.1-0.3 U/mL UFH 10 000 units or more SC every 12 hours Doses adjusted to target aPTT 1.5-2.5, 6 hours after injection Prophylactic LMWH/UFH 4-6 weeks Vitamin K antagonist 4-6 weeks Target INR 2-3 Initial LMWH/UFH overlap until INR 2.0
Intermediate-dose LMWHa Therapeutic LMWHb (adjusted dose, weight-based dose, full dose)
Minidose prophylactic UFH Prophylactic UFH
Intermediate UFHa Therapeutic UFH (adjusted dose, weight-based dose, full dose) Postpartum anticoagulation
Abbreviations: aPTT, activated partial thromboplastin time; INR, international normalized ratio; LMWH, low-molecular-weight heparin; UFH, unfractionated heparin; SC, subcutaneously. a As recommended by the Chest 2012 guidelines only.27 b May target anti-Xa level of 0.6 to 1.0 units/mL for twice daily regimen. c The reader should note that tinzaparin is no longer available on the US market. d Unless aPTT is elevated.
of LMWH, bone mineral density was significantly lower in patients receiving UFH (P ¼ 0.02), and similar as compared to aspirin or placebo.41-43 Alternatively, 1 trial demonstrated that the incidence of clinically significant bone loss was no different in patients receiving UFH compared to patients taking LMWH (2.5% vs 2.0%, respectively; P ¼ 1.0), which suggests that osteoporosis may be due to individual susceptibility.27,44 The anticoagulant dose will depend on the indication, with low, intermediate, and treatment doses available for both UFH and LMWH. There are no large clinical trials evaluating the optimal dosing regimens of anticoagulants during pregnancy. Therefore, recommendations are largely based on expert opinion and case series (Table 3).2 As changes in renal excretion and protein binding occur during pregnancy, the half-lives and peak plasma concentrations of these agents may be altered, requiring a higher dose and/or more frequent administration.2,4 Due to these alterations in the pharmacokinetics of LMWH, twice-daily dosing is often recommended.45 However, data suggest that once-daily dosing of LMWH may be appropriate for VTE treatment.46,47 Because of small studies indicating the need for LMWH dose escalation to maintain the therapeutic anti-Xa levels, some support monitoring anti-Xa levels every 1 to 3 months to maintain an anti-Xa level of 0.6 to 1.0 units/ mL for twice-daily regimens.27,48,49 However, other studies have shown that few women require an adjustment in LMWH dose when therapeutic doses are used.50,51 Additional arguments suggesting routine monitoring of anti-Xa levels that may
not be necessary in pregnancy include concerns with testing reliability and accuracy, insufficient clinical end points demonstrating an optimal therapeutic anti-Xa range, a lack of data correlating monitoring with risk of bleeding and/or VTE recurrence, and the cost of monitoring.27 Due to these arguments, it is difficult to justify routine monitoring of anti-Xa levels for the treatment of VTE in pregnancy at this time. When choosing an anticoagulant in pregnancy, it is important to weigh the advantages and disadvantages of individual agents. Disadvantages of UFH, in addition to the possible need for continuous infusion or intravenous administration with therapeutic doses, include the risk of major bleeding, bone loss, vertebral fracture, and HIT.4 Potential advantages of LMWH over UFH are lower rates of bleeding, decreased risk of HIT, improved bioavailability, longer half-life requiring less frequent administration, and a more predictable dose response.1,4,27 The longer half-life of LMWH may also be considered a disadvantage, as it may become troublesome at the time of delivery when rapid cessation of anticoagulant effect is desired.1,4 However, patients can be transitioned from LMWH to UFH prior to delivery. Another potential disadvantage of LMWH is the higher drug acquisition cost.4
Prophylaxis When determining the appropriateness of prophylaxis during pregnancy for those with a prior VTE, guidelines suggest
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Table 4. Recommended Thromboprophylaxis Management During Pregnancy.2,27 Clinical setting
Antepartum treatment
Postpartum treatmenta
Acute VTE
Therapeutic LMWH/UFH
Low-risk thrombophilia, no previous VTE
Surveillance only Prophylactic LMWH/UFH Intermediate LMWHb Prophylactic LMWH/UFH Intermediate LMWH Surveillance only Prophylactic LMWH/UFH Intermediate LMWHb Surveillance onlyb Prophylactic LMWH/UFH Prophylactic LMWH/UFH Intermediate LMWH Therapeutic LMWH/UFH Surveillance only
Anticoagulation continued for 6 weeks Minimum duration 3 months total treatment Surveillance Postpartum anticoagulation if additional risk factorsc
Low-risk thrombophilia, single previous VTE, not on long-term therapy High-risk thrombophilia, no previous VTE, family history VTE High-risk thrombophilia, no previous VTE, no family history VTE High-risk thrombophilia, single previous VTE, no long-term anticoagulation Previous single VTE, transient risk factor no longer presentd,e Previous single VTE, pregnancy- or estrogen-related risk factor Previous single VTE, idiopathic, not on long-term therapy 2 episodes VTE, not on long-term therapy
2 episodes VTE, on long-term therapy Laboratory and clinical criteria for APSb
Prophylactic LMWH/UFH Intermediate LMWHb Prophylactic LMWH/UFH Intermediate LMWHb Prophylactic LMWH/UFH Intermediate LMWHb Therapeutic LMWH/UFH Therapeutic LMWH/UFH 75% LMWH doseb Intermediate LMWH/UFH Prophylactic LMWH þ ASA
Intermediate-dose LMWH/UFH
Intermediate LMWHb Postpartum anticoagulation Intermediate LMWHb Postpartum anticoagulation Postpartum anticoagulation Intermediate LMWH/UFH (6 weeks) Therapeutic LMWH/UFH (6 weeks) Postpartum anticoagulation Surveillance only Postpartum anticoagulation Prophylactic LMWH/UFH Postpartum anticoagulation Postpartum anticoagulation Therapeutic LMWH/UFH (6 weeks) Resume long-term anticoagulant
Abbreviations: APLA, antiphospholipid antibody; ASA, aspirin; INR, international normalized ratio; LMWH, low-molecular-weight heparin; UFH, unfractionated heparin; VTE, venous thromboembolism. a Postpartum anticoagulation should be greater or equal to antepartum treatment2; includes vitamin K antagonist with a target INR 2 to 3 or prophylactic anticoagulant for 4 to 6 weeks.27 b Recommended by Chest, 201227 only. c Per ACOG2: first degree relative to history of VTE before age 50, obesity, immobility, and other thrombotic risk factors. d Does not include pregnancy- or estrogen-related risk factor. e Per Chest, 201227: low risk of recurrence.
patients at low risk of recurrence undergo clinical vigilance during the antepartum period, while those at moderate to high risk of recurrence receive antepartum prophylaxis with prophylactic or intermediate dosages of LMWH or UFH, with preference given to LMWH.2,27 Low risk includes women with a single episode of VTE associated with a transient risk factor, not including pregnancy, or use of estrogen. Moderate to high risk includes women with a history of an idiopathic VTE, pregnancy- or estrogen-related VTE, or multiple prior VTE not currently receiving anticoagulation therapy.2,27 All women with a prior VTE should receive postpartum anticoagulation for 6 weeks with LMWH or vitamin K antagonists (Table 4).2,27 Although the presence of an underlying thrombophilia may increase the risk of pregnancy-related thrombosis, prophylaxis during pregnancy may not be necessary with all thrombophilia. The need for prophylaxis depends on several factors, such as the risk of thrombosis associated with the thrombophilia, the history of previous VTE, family history of VTE, and if the previous VTE was due to a transient risk factor or an idiopathic event. Patients homozygous for FVL or prothrombin 20210A
mutation with a positive family history but no prior history of VTE should receive antepartum and postpartum prophylaxis with prophylactic- or intermediate-dose LMWH or UFH, again with preference given to LMWH.2,27 Patients homozygous for FVL or prothrombin 20210A mutation without a previous VTE and no family history, antepartum clinical vigilance and postpartum prophylaxis are recommended.27 For pregnant women with other thrombophilia and a positive family history of VTE, postpartum prophylaxis is suggested, while those without a positive family history may simply undergo clinical vigilance.27 Warfarin may be utilized for postpartum prophylaxis in all patients other than those with protein C or S deficiency due to concerns with warfarin-induced skin necrosis27 (see Table 4). Antiphospholipid syndrome (APS) requires a different approach and is discussed subsequently.
APS APS is a thrombophilia that warrants discussion regarding management in pregnancy. Women with APS who become
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pregnant are at a higher risk of both thrombosis52 and pregnancy loss.53 Pregnancy morbidity is a component of the clinical criteria included in the diagnostic criteria for APS. Pregnancy morbidity in APS is described as 1 or more unexplained fetal deaths beyond the 10th week of gestation, 1 or more premature births before the 34th week of gestation, or 3 or more consecutive spontaneous abortions prior to the 10th week of gestation.54 Hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome) coexisting with preeclampsia may also be associated with APS; however, the prevalence is unknown.53 Management of APS in pregnancy aims to prevent pregnancy loss and decrease the risk of thrombosis to the mother.55 Several different scenarios may exist in pregnant patients with APS: pregnancy loss with or without thrombosis, as well as thrombosis with no history of pregnancy loss.
APLAs and Pregnancy Loss Lupus anticoagulant, anticardiolipin antibody, and anti-b2 glycoprotein antibody are antibodies included in the classification criteria for antiphospholipid syndrome.54 Titer and isotype of anticardiolipin antibody and anti-b2 glycoprotein antibody are also important laboratory considerations upon initial diagnosis. Immunoglobulin (Ig) G and IgM isotypes and high titers are more closely associated with thrombosis.54,55 Compared to the general population, the risk of pregnancy loss is higher in women with APLA positivity after the 10th week of gestation.53 Presence of APLAs (lupus anticoagulant or anticardiolipin antibodies 20 IgG phospholipid [GPL] units ) was associated with at least 1 fetal death in more than 80% of women according to a study conducted by Oshiro et al.56 Positivity of APLAs other than those outlined in the diagnostic criteria (ie, phosphatidylserine) and positivity of anticardiolipin or anti-b2 glycoprotein antibodies at lower titers or IgA isotype in women with recurrent pregnancy loss are areas for further investigation.55
APS With Pregnancy Loss Without a History of Thrombosis In patients with APS without a history of thrombosis, combination therapy with UFH and aspirin has been shown to reduce pregnancy loss by 54%.57 Kutteh58 and Rai et al59 demonstrated that treatment with aspirin and heparin provided improvement in pregnancy outcomes compared to aspirin alone in women with APLAs and a history of pregnancy loss.57,59 Consistent with these results, a meta-analysis of randomized controlled trials showed higher birth rates in mothers who received heparin and aspirin compared to aspirin alone (RR 1.301, 95% CI 1.040-1.629).60 Recommendations from the American College of Chest Physicians suggest antepartum use of prophylactic or intermediate-dose UFH, or prophylactic LMWH, combined with low-dose aspirin in patients with APS who have a history of 3 or more pregnancy losses.27 Recommended anticoagulation regimens during pregnancy can be found in Table 3.
Intravenous immunoglobulin has been suggested as a potential add-on therapy in women who experience recurrent pregnancy loss, despite heparin and low-dose aspirin therapy. However, studies have not shown improved neonatal outcomes when compared with UFH and aspirin.55,61,62 Prednisone has also been proposed as a potential treatment modality in combination with aspirin but is associated with more preeclampsia and adverse effects.63
APS With a History of Thrombosis Since patients with APS are at a high risk of recurrent thrombosis, patients are often treated with warfarin indefinitely. Due to teratogenicity associated with warfarin therapy, warfarin should be discontinued and therapeutic anticoagulation with UFH or LMWH is suggested during pregnancy.52,55 In these patients, American College of Chest Physicians recommend adjusted-dose LMWH or 75% of a therapeutic dose of LMWH during pregnancy, followed by reinitiation of long-acting oral anticoagulants postpartum.27 Refer to Table 3 for recommended anticoagulation regimens during pregnancy. For women with APS who have a history of a single episode of thrombosis but are not being treated with anticoagulants indefinitely, antepartum prophylactic or intermediate-dose LMWH or UFH in addition to postpartum prophylaxis is recommended.64
Postpartum Management in APS In patients previously treated with warfarin for a history of thrombosis, postpartum anticoagulation with UFH or LMWH overlapped with warfarin therapy until a target international normalized ratio (INR) of 2.0-3.0 is obtained is recommended. Table 4 includes recommended postpartum treatment options according to clinical setting. Postpartum prophylaxis is recommended in those with a history of a single episode of thrombosis not being treated with anticoagulants indefinitely.27 For women who have not experienced a previous thrombotic episode, the risk of thrombosis is unclear in patients with APS; therefore, guidance for postpartum management is limited. According to Giannakopoulos and Krilis, therapy should be individualized based on patient-specific risk factors (ie, APLA positivity on multiple instances, age > 35, family history, immobility, obesity, and cesarean section).65 Clinical observation is suggested in women with other thrombophilias (w/ exception of Factor V leiden and prothrombin 20210 A mutation) without a family history of VTE and no previous thrombosis27; however, it is unclear whether this recommendation should be extrapolated to patients with obstetric APS.
Emerging Concepts Assisted Reproductive Technology Assisted reproductive technology (ART) may be associated with an increased risk of thrombosis.28 Population prevalence studies have demonstrated an overall thrombosis estimate of
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2.66 per 1000 cycles, compared to 0.97 for natural pregnancy.66,67 Thrombosis occurred in 0.1% (95% CI 0%-0.3%) to 0.3% (95% CI 0%-0.8%) of cycles in large retrospective cohort studies.68,69 Thrombotic risk with ART is significantly higher in the first trimester but does not differ in the second or third trimester.67,70 The overall magnitude of VTE risk in patients undergoing ovarian stimulation is low, but it does represent a 10-fold increase in the baseline relative risk in women of reproductive age.21
Ovarian Hyperstimulation Syndrome The incidence of thrombosis may be higher in women with ovarian hyperstimulation syndrome (OHSS), with a reported incidence of 4.1% (95% CI 1.1%-13.7%) in severe cases.70 OHSS was reported in 90% of arterial events and 78% of venous events; additionally, 98% of reported thrombosis occurred after ovulation induction.71 Arterial events occurred earlier after embryo transfer (10.7 days) than venous events (42.4 days) and were almost always concurrent with the development of OHSS, whereas venous events occurred after the resolution of OHSS.71 During ovarian stimulation, there is an increase in the levels of estradiol, vWF, factors V and VIII, and fibrinogen, as well as an increase in activated protein C resistance in addition to a reduction in antithrombin levels and proteins C and S.71 Both arterial and venous thrombotic events have been reported. Venous thrombosis in relation to ART has been reported in unusual locations, such as the upper extremities, head, and neck, compared to the usual location in the left leg. Ischemic stroke has been reported as the most common arterial event.71 The occurrence of thrombotic events in the neck and upper extremities may be due to estrogen-rich lymphocytic drainage from ascitic fluid into the thoracic duct, which further drains into the left subclavian vein, or obstruction at the base of the subclavian and jugular veins due to brachial cysts that fill with fluid during OHSS.71 Dosage and duration of thromboprophylaxis have not been well studied to date. However, due to the increase in thrombotic events associated with OHSS, prophylaxis with LMWH may be considered. Recent guidelines recommend that patients who develop severe OHSS receive prophylactic doses of LMWH for 3 months after resolution of OHSS.27 Other suggestions include initiating thromboprophylaxis and continuing for a minimum duration of 4 to 8 weeks beyond the resolution of OHSS or until the end of the first trimester in women who conceive.71,72 In women who develop thrombosis, therapeutic doses of LMWH or UFH should be initiated and continued as recommended by practice guidelines.2,27,71
Repeated Implantation Failure Acquired and inherited thrombophilia have been implicated in women with repeated implantation failure after ART.72 Factor V Leiden and prothrombin G20210A heterozygosity, as well as an increase in MTHFR C677TT and combined thrombophilias,
were found to occur more often in women with 3 or more implantation failures.73,74 Additionally, it appears that women who experience 3 or more implantation failures exhibit a higher prevalence of APLAs.72 Therefore, it would be reasonable to screen women with repeated implantation failures for thrombophilia. Studies of LMWH use in women with repeated implantation failures have demonstrated conflicting but encouraging results. Qublan et al found that LMWH use was associated with an increase in implantation rates (20.9% vs 6.1%, P < .001), pregnancy rates (31% vs 9.6%, P < .05), and live birth rate (23.8 vs 2.8, P < .05) compared to placebo.74 In a study of 150 women with 2 or more failed ART cycles, LMWH use was found to correlate with an increase in live births (34.7% vs 26.7%, 95% CI 4.2%-24.9%; P ¼ .29).75 Although not statistically significant, the 30% relative increase in live births calls for additional research on empirical use of LMWH in women with repeated implantation failures.76
Suggested Future Research Currently, there are no human studies available concerning rivaroxaban use in pregnancy and lactation. Due to the oral availability and lack of monitoring requirements, it would be helpful to have more information regarding safety and efficacy in the pregnant population. Until this time, rivaroxaban should not be used for VTE treatment in pregnancy or lactation on the basis of animal studies. Controversy continues regarding the need for anti-Xa monitoring with LMWH use in pregnancy. Future research should attempt to correlate clinical end points, such as VTE occurrence and bleeding risk, with anti-Xa level ranges in order to better understand the usefulness of monitoring in pregnancy. Finally, further research is needed in the area of routine prophylaxis for ART and repeated implantation failure regarding the benefit as well as the appropriate duration of thromboprophylaxis if utilized.
Conclusion Pregnancy increases the risk of VTE due to various physiologic mechanisms, with the highest risk during the postpartum period.4 Women who have a personal history of VTE are at increased risk of developing recurrent events during subsequent pregnancies. Evidence regarding prognostic factors for recurrent thromboembolism during pregnancy is conflicting.25,26 The presence of concomitant thrombophilia may increase the risk of events and is identified in up to 50% of women who experience pregnancy-related VTE. Factor V Leiden homozygosity, prothrombin mutation homozygosity, and APS are thrombophilia associated with the highest risk of VTE in pregnancy, along with pregnant women who have a family history of thromboembolism.4,28,77 Warfarin should be avoided during pregnancy due to the risk of teratogenicity. Treatment with LMWH or UFH is recommended for acute VTE, with preference often given to LMWH due to ease of dosing and other advantages over UFH.4,10,28 Prophylactic or treatment doses of
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LMWH or UFH may be warranted during pregnancy and/or the postpartum period in women with prior VTE and in certain women with underlying thrombophilia.
14.
Authors’ Note All the listed authors had a role in writing the article.
15.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
16.
Funding
17.
The author(s) received no financial support for the research, authorship, and/or publication of this article. 18.
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